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Methods for microbiological quality assessment in drinking water: a comparative study.
The present study aimed to compare several methods for quantifying and discriminating between the different physiological states of a bacterial population present in drinking water. Flow cytometry (FCM), solid-phase cytometry (SPC), epifluorescence microscopy (MSP) and culture method performances were assessed by comparing the results obtained for different water samples. These samples, including chlorinated and non-chlorinated water, were collected in a drinking water treatment plant. Total bacteria were quantified by using SYBR Green II (for FCM) and 4',6'-diamino-2-phenylindole (DAPI) (for MSP), viable and non-viable bacteria were distinguished by using SYBR Green II and propidium iodide dual staining (for FCM), and active cells were distinguished by using CTC (for MSP) and Chemchrome V6 (for FCM and SPC). In our conditions, counts using microscopy and FCM were significantly correlated regarding total bacteria and active cells. Conversely, counts were not significantly similar using solid-phase and FCM for active bacteria. Moreover, the R2A medium showed that bacterial culturability could be recovered after chlorination. This study highlights that FCM appears to be a useful and powerful technique for drinking water production monitoring.
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Characterization of irreversible kinase inhibitors by directly detecting covalent bond formation: a tool for dissecting kinase drug resistance.
Targeting protein kinases in cancer therapy with irreversible small-molecule inhibitors is moving to the forefront of kinase-inhibitor research and is thought to be an effective means of overcoming mutation-associated drug resistance in epidermal growth factor receptor kinase (EGFR). We generated a detection technique that allows direct measurements of covalent bond formation without relying on kinase activity, thereby allowing the straightforward investigation of the influence of steric clashes on covalent inhibitors in different resistant kinase mutants. The obtained results are discussed together with structural biology and biochemical studies of catalytic activity in both wild-type and gatekeeper mutated kinase variants to draw conclusions about the impact of steric hindrance and increased catalytic activity in drug-resistant kinase variants.
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Saturday, April 14, 2012
Public High School Graduations and Public Prayer
It's that time of year again - high school graduation. It's a joyous time for everyone - teachers, administrators, and most of all parents and students. Students are excited about closing this chapter and opening a new one in their lives, and parents are relieved that they made it through 12 years of school without killing them ;)
But all is not well in this picture.
A common tradition at many high schools, especially rural ones and/or Southern ones, is to have a moment where people are commanded, "everyone bow their heads to pray", and the person at the podium leads everyone in a prayer; quite often it is the Lord's Prayer. If you're a Christian, this may seem like a nice tradition, and quite normal; if, however you're not a Christian - and you don't have to be an atheist, you could be a Jew, Muslim, Hindu, Buddhist, or any number of other NON-Christian religions - you feel, at the least, a bit awkward, and at the most extremely uncomfortable, isolated, and maybe even offended. The problem is that if you ARE a non-Christian, you almost certainly will keep your feelings of isolation to yourself. Why? Because in many (most?) circumstances you will be a pariah, persecuted, and forever branded as "other". I know, I have been there. Don't believe me? There is ample evidence to back me up, even quite recently. Here are a few examples:
Jennifer Ahlquist: She complained to the school board that a prayer banner hanging in the school was a violation of the Separation of Church and State (she's right). The issue was taken to court, and she was proven right. She has received NUMEROUS death threats from supposed "Christians", including this one. Incidentally, I am friends with many, many true Christians who are as offended and appalled at this as I am. They also agree with the Separation of Church and State. (2012)
Nicole Smalkowski: At 13 her family moved to an 80-acre ranch in rural Oklahoma. Nicole was a great athlete, even played on the football team. During basketball season the team gathered after the games to recite the Lord's Prayer. She complained, was ostracized, and was even attacked publicly by town officials. Story here, video here. (2007)
Bastrop High School: Damon Fowler, an atheist and graduating senior at Bastrop High School in
Louisiana, complained about the prayers scheduled to be part of his
commencement ceremony. After consulting with an attorney, the school
agreed to drop the prayer. Unfortunately, Damon has since been ostracized by the community and even attacked by a school official in the local newspaper (Mitzi Quinn). His parents also kicked him out of his home. Yes, his own parents. (2011)
These are but a few of the more public stories, and trust me there are many; what's scary is how many others are unreported? And let's not even talk about the countless thousands who sit and suffer in silence because they don't want to experience the, ahem, "Christian Love" displayed in these other stories.
I have three problems with this:
This is a CLEAR violation of the Separation of Church and State. This has been proven many, many times in court - including all three stories mentioned above.
Children should NOT have to be made to feel uncomfortable at one of the most important days of their lives, their high school graduation.
As a Christian, you have infinite time to pray - before the ceremony, after, even during (to yourself). You can even get together in big groups and do it publicly. But doing it as an OFFICIAL, public part of the ceremony is wrong - and unnecessary. Incidentally, I do not know of a SINGLE non-Christian who has a problem with a Moment of Silence; this should suffice and would be acceptable to everyone, for the aforementioned reasons.
I have one other observation: demanding a public demonstration of prayer is BLATANTLY HYPOCRITICAL. The prayer that is most often recited publicly is Matthew 6:9-16 (NIV), otherwise known as the Lord's Prayer. What is so sad (it's almost comical) is that hardly any Christians - especially the ones who DEMAND a public prayer - know anything about the Bible other than what they are told. Take, for instance, the verses directly preceding the Lord's Prayer. Have you actually read the Lord's Prayer, in context, in the Bible? For those who aren't familiar with it, I give you Matthew 6:5-8 (NIV):
5 And
when you pray, do not be like the hypocrites, for they love to pray
standing in the synagogues and on the street corners to be seen by
others. Truly I tell you, they have received their reward in full.6But when you pray, go into your room, close the door and pray to your
Father, who is unseen. Then your Father, who sees what is done in
secret, will reward you.7 And when you pray, do not keep on babbling like pagans, for they think they will be heard because of their many words.8 Do not be like them, for your Father knows what you need before you ask him.
**Emphasis mine. --AY
So, if you are a Christian, I would like to ask you to reconsider your stance on "sanctioned" Public Prayer, at any public school-sponsored event. I've given you many reasons why; but if all the others fall on deaf ears, then I beseech you to listen to your God, who has clearly told you to not do it.--AY (written by Rocky Oliver)(NOTE: Inspiration and information for this post came from ThinkAtheist.com, the best social networking site for freethinkers, and from this video. Thanks to everyone who inspires me; I hope I do you proud.)
@Marc - thanks. I agree re: Matt 6:5-8, and there's so much more like this. It is amazing how much the Bible is used like a buffet to support basically whatever you want, without actually understanding context. And most followers have NO IDEA what the context actually is.
@Unknown - I agree. It amazes me how little they consider the feelings and beliefs of others. Many of them have the attitude of, "if you don't believe as I do, then your beliefs and feelings don't count." It's sad.
As a Christian i would agree with most of this, and separation of church and state is all good. And we should never threaten or demean anyone because of how they believe. I am sorry for your isolation and how it made you feel. Threatening people inst any way to win them over is it? ;-)
Public prayer is a tradition in the south more than anything else. So when you say you shouldn't do it, it makes SOME feel you are attacking everything they know, have experienced, were raised.
As a Man i feel we are becoming pansies, oh he called me a name, oh he made me feel uncomfortable... Man up. I could spend all day being offended or hurt about what others say or do, but i cant control them, the only thing i can control is how i let it effect me.
Being uncomfortable or lonely inst any fun, its just your circumstance. Your society that you live in believes vastly different things than you, so how would you expect them to act? Do you expect them to change, because if you are you are going to be disappointed.
@Anonymous Christian - I actually agree with everything you said, even the "man up" part - FOR ADULTS. If you notice, my main issue - outside of the Church and State problem, which is huge - is that the people being made to feel horrible and isolated are CHILDREN. As I said before, this is the first really huge moment of their lives, and many of them - who are mainly those that are members of other religions, more than the nonreligious - are made to feel rotten. That's not right.
Another thing: we teach our children to stand up for what's right, that being a part of the majority does not make them right, and so on. We tell them that they fight against the things they find wrong. Well, when a few of them actually do this - and let's not forget that the courts have agreed with these brave children, every time - they are ostracized, persecuted, are made into pariahs, and some are even disowned by their families. For doing the very thing we, as teachers, as parents, as a society, taught them to do. Does that seem right?
Yes the world isn't fair. Yes you have to learn to "man up", to pick your battles, etc. But - as I said before - being a majority does not make the majority right. Fighting the things that are wrong - that are against the very foundation and laws are country was built upon - is a just cause.
I just wish our society wouldn't beat down children and teens who are doing this very thing for the first time. THAT isn't right, either.
Feel free to post your response or opinion, no matter how much it differs from mine or others; opinions will NOT be removed. Everyone loves a spirited discussion. There are two rules, however:1) Please keep all responses civil. This means attacks on anyone, including passive-aggressive or ad-hominem attacks, will not be tolerated. Simply put: attack the idea, not the person.2) Solicitations and advertisements, no matter how subtle, are prohibited. If you wish to advertise something, start your own blog or buy an ad on Google Ad-sense.
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All relevant data are within the paper and its Supporting Information files.
Introduction {#sec005}
============
A worrisome issue in obstetrics is the longstanding increase in cesarean section rates, as well as the unjustified variations in these rates in clinical practice across public and private hospitals worldwide\[[@pone.0191248.ref001]--[@pone.0191248.ref003]\]. This is particularly important in the case of emergency (i.e., unscheduled) cesarean section (ECS) rates, assuming that the appropriateness of indications for scheduled C-sections is reasonably acceptable and much higher than that for ECSs \[[@pone.0191248.ref004]--[@pone.0191248.ref011]\]. Heterogeneity in clinical decision-making should always be investigated when unjustified variations are suspected. Knowing the fetal, maternal, and contextual factors that drive the decision to perform an ECS at each hospital is paramount to designing and implementing hospital-tailored interventions specifically aimed at improving the appropriateness of indications for ECSs in order to avoid unnecessary ECSs and the associated complications and costs \[[@pone.0191248.ref012]--[@pone.0191248.ref022]\].
Few current clinical guidelines and interventions target these objectives \[[@pone.0191248.ref023]--[@pone.0191248.ref029]\]. Those that do are neither based on a comprehensive set of proven fetal and maternal risk factors (RFs) with high discriminant accuracy (DA) nor designed to take into account contextual factors that have been shown to be associated with both an increased rate of unnecessary ECSs and unjustified variations in clinical practice. Furthermore, most RFs for ECSs should be considered putative, since they have mainly been selected by means of logistic regression models that usually lack information regarding both their goodness-of-fit and their DA \[[@pone.0191248.ref030]--[@pone.0191248.ref038]\]. Traditional measures of association alone are inappropriate to discriminate between who will suffer a given outcome and who will not. Therefore, interventions based on average risk estimates for people both exposed and unexposed to spurious RFs could be ineffective, inefficient, and even potentially harmful \[[@pone.0191248.ref012]--[@pone.0191248.ref022]\].
To our knowledge, very few studies have sought to improve the ability to predict which women are at higher risk of ECS. Those that do are limited to nulliparas, include only a few of the putative RFs, and report no measures of either calibration or DA of the statistical models developed \[[@pone.0191248.ref030]--[@pone.0191248.ref038]\]. Our objective is not to build an explanatory model of the decisions to perform an ECS, but to increase the predictive accuracy regarding this type of delivery in order to provide more validated information with the ultimate view to improving the appropriateness of indications for ECS and thus preventing unnecessary C-sections.
Material and methods {#sec006}
====================
The present study is part of a large multifaceted intervention intended to improve the appropriateness of the indications for ECSs in 22 public hospitals of the Spanish National Health Service launched by the Spanish Ministry of Health. Of those 22 participating hospitals, four (A, B, C, and D) were included in this study because their databases were the most reliable in terms of consistency and coverage to ensure that robust predictive models of ECSs could be built. In size and complexity, the obstetric services of these four hospitals belong to level II (out of III) of the Spanish National Hospital Catalogue. They can be considered representative of about 42% of all obstetrics services of the Spanish National Health Service that belong to this level, since they all have a very similar case mix, and attend pregnant women with similar obstetric risk.
The study population consisted of all 6,157 singleton births, with no exclusions, occurring in 2014 at four public hospitals located in three different autonomous communities of Spain. According to the Spanish National Institute of Statistics, these 6,157 births account for 1,5% of all yearly births in Spain (around 420,000/year). Hospitals A and B account for 26,5% of all births occurring yearly in the Autonomous Community of the Balearic Islands, Hospital C for 12,6% of those occurring in Galicia, and Hospital D for 2,0% of those occurring in Valencia (<https://www.datosmacro.com/demografia/natalidad/espana-comunidades-autonomas>).
Data were collected prospectively over 2014 and registered in a specifically designed database that included the fetal, maternal, and contextual independent variables ([Table 1](#pone.0191248.t001){ref-type="table"} and [S1 Tables](#pone.0191248.s001){ref-type="supplementary-material"}). All presentations were included in the analysis. All variables put forth in the medical literature as predictive variables (putative PFs) of the type of delivery were in principle considered in the study with few exceptions. Since birth weight is a post-delivery variable, it cannot be predictive of the type of delivery. The estimated preterm fetal weight could be considered a potential predictive variable. However, it is barely used given that its measurement is very imprecise (± 400 g) \[[@pone.0191248.ref001], [@pone.0191248.ref004], [@pone.0191248.ref006]--[@pone.0191248.ref010]\].
10.1371/journal.pone.0191248.t001
###### Fetal, maternal, and contextual covariate definition and categorization.
{#pone.0191248.t001g}
Covariates Covariate categorization
------------------------------------------------------- -------------------------------------------------------------------------------------------------
Age \< 35 or ≥ 35 years
Mother´s weight \> 90 kg
Mother´s height ≤ 1,5 μ
Mother´s Body Mass Index (BMI) ≤ 35 oρ \> 35
Gestational age ≤ 36 weeks
Previous pregnancies No (0) or Yes (≥ 1)
Smoker Yes or No
Previous C-section 0 or ≥ 1
Comorbidity[^1^](#t001fn001){ref-type="table-fn"} Yes (≥ 1) o No
Obstetric risk[^2^](#t001fn002){ref-type="table-fn"} Yes or No
Labor induction[^3^](#t001fn003){ref-type="table-fn"} Used or Not used
Intrapartum (scalp) pH \< 7.20 or ≥ 7.20
Night-shift delivery Yes (C-section initiated between 9 p.m. and 4 a.m.) or No (initiated between 4 a.m. and 9 p.m.)
Fetus gender Male (0) female (1)
^1^Defined as having one or more of the following comorbidities during pregnancy: anaemia, asthma, heart disease, coagulopathy, type I and II diabetes in pregnancy, treated autoimmune disease, treated epilepsy, treated mental disease, treated neurological disease, treated renal disease, hemiplegia, treated liver disease, treated hyper and hypotiroidism, HIV infection, chronic hypertension, idiopathic thrombocytopenic purpura, malignant tumor, hepatitis C and B virus, amniocentesis, corial biopsy, cordocentesis, cannabis, cocaine, heroin, other drugs, disseminated intravascular coagulation, colesthasys, corioamnionitis, pathological Doppler result, chronologically prolonged pregnancy, fetal death, stained amniotic fluid, pathological non-stress test, oligoamnios, small for gestational age, pre-eclampsia, premature rupture of membranes, prolonged pregnancy.
^2^Defined as the presence during pregnancy of one or more of the following factors that increase the chance of an adverse pregnancy outcome: cholestasis, chorioamnionitis, diabetes insulin and non-insulin dependent, chronologically prolonged pregnancy, multiple pregnancy, hellp syndrome, hypertension, isoimmunization in pregnancy, stained amniotic fluid, fetal malformation, uterine malformation, fetal malposition, myomectomy, oligoamnios, previous preterm labor, placenta praevia, plyhydramnios, preeclampsia, premature rupture of membranes, siphylis, toxoplasmosis, previous c-section, repeated abortions, previous miscarriages, anteparturm alteration of fetal wellbeing.
^3^All labors started by administering oxytocin or prostaglandins when indicated.
Unlike other predictive models published, we additionally included hospital fixed-effects and night-shift delivery as potentially predictive contextual independent variables. They are unobserved effects of hospital (contextual) characteristics that are not captured by any of the independent variables included in the models. They may be predictive of the type of delivery, account for a certain fraction of the medical variations (total variance) of ECSs often found in small area analysis, and modify the strength of the associations of the independent RFs and the type of delivery. They are not explanatory of the type of delivery, but their association with it may be indicative of different entrenched, difficult to measure clinical practices across hospitals that are likely to influence the decision regarding the type of delivery and therefore they warrant further investigation. Night-shift delivery was also included as an additional potentially predictive contextual independent variable, since it has been shown to be both a good predictor of the delivery mode, and an appropriate instrumental variable to infer causal associations between the average treatment effect of non-medically indicated cesarean sections (compared with vaginal delivery) on newborn´s health outcomes \[[@pone.0191248.ref039]\].
Descriptive statistics were calculated for all fetal, maternal, and contextual variables. Scheduled, emergency, and overall (both scheduled and emergency) C-sections were estimated for the whole population and for each hospital with their corresponding 95% CI.
The first step in our analytical approach to identify RFs for ECS was to calculate the prevalence of each putative RF in the overall population and in mothers delivering both by vaginal birth and by ECS, as well as their 95% CI. We then estimated the prevalence ratios of each RF (by dividing the prevalence of the RF by the prevalence of ECS). Finally, we estimated the positive likelihood ratios (LR+) of each RF and their 95% CIs. (A LR+ \>10 is considered high enough to rule in the outcome, 5--10 is considered moderate, and 2--5 is considered low \[[@pone.0191248.ref040]--[@pone.0191248.ref047]\].
The second step was to build a logistic regression model for each of the four hospitals included in the study (A, B, C, and D), as well as a logistic model for the overall sample to find out which fetal, maternal, and contextual RFs (independent variables) were associated with the outcome (delivery type: vaginal or ECS), as well as the strength of the associations found. Model specification was performed based on stepwise top-bottom variable selection, and taking into consideration the clinical relevance of each variable. Crude and adjusted ORs were obtained, as well as their 95% CIs. The models' goodness-of-fit was compared by means of the -2log-likelihood ratios and the Akaike information criterion (AIC). Their DA was assessed through their areas under the receiver-operating-characteristic (ROC) curves (AUCs) along with their 95% CI.
We then fitted a classification tree (CTREE or conditionally unbiased inference classification tree), a relatively new and useful predictive technique for studying RFs and outcomes based on the unbiased recursive splitting of the study population sample into subgroups according to the independent variables \[[@pone.0191248.ref048]\]. The underlying mathematical algorithm chooses which independent to split, their discriminatory value, and the order in which the splitting occurs. Outcome discrimination can thus be maximized at each step, making it possible to account for complex relationships between variables and their interactions and preventing both over-fitting and biased variable selection. The process develops a hierarchical tree structure that enables such simultaneous analyses and presents them in a clinically useful format \[[@pone.0191248.ref048]--[@pone.0191248.ref050]\].
Unlike CART models, CTREE can handle datasets with both categorical and numerical variables without producing biased splits, and the interpretation of both odds ratios and likelihood ratios is straightforward. Therefore, we used dichotomous variables to enable comparisons with other published studies despite a small potential loss of information. All births were included in the analysis, and anonymity was preserved. A database was constructed by two computer engineers, who also managed the transfer of data. Database quality was periodically audited and was considered reliable in terms of consistency, coverage, and agreement. The database is available upon request. The Spanish Ministry of Health approved this study under the Strategy for Assistance at Normal Childbirth in the National Health System (PI/01445).
We also developed a random forest model (RFM) that fits *n* classification trees by randomly selecting predictors for each tree. CTREE was used as the base learner, and 500 different trees were created by bootstrapping, rendering more accurate predictions than a single tree analysis. This algorithm allows to estimate the relative importance of each independent variable in the model (i.e. the contribution of each independent variable to the predictive power of the random forest). The methodology to compute relative importance of each variable (known as conditional permutation importance), and more information regarding CART, CTREE, and RFM can be found elsewhere \[[@pone.0191248.ref048]--[@pone.0191248.ref050]\]. We also compared the models' discriminatory performance by means of their corresponding ROC curves. Goodness-of-fit analysis across the abovementioned models was performed using in-sample (n = 6,157) data with ROC curves. The statistical analyses were performed using R Statistical Software (Foundation for Statistical Computing, Vienna, Austria) \[[@pone.0191248.ref049], [@pone.0191248.ref050]\].
Results {#sec007}
=======
ECS rates varied from 8 to 15% across hospitals, whereas overall C-section rates were higher (12--21%) ([Table 2](#pone.0191248.t002){ref-type="table"}). Descriptive population statistics are shown in [Table 3](#pone.0191248.t003){ref-type="table"}. Mothers delivering by ECS were slightly older, had higher BMIs and weight, were more likely to have had a previous C-section, had more comorbidity, presented greater obstetric risk, more often underwent labor induction and delivered during the night shift, and had a slightly lower gestational age, and intrapartum (scalp) pH than those who had eutocic deliveries. No differences were found regarding smoking during pregnancy ([Table 4](#pone.0191248.t004){ref-type="table"}).
10.1371/journal.pone.0191248.t002
###### Emergency and overall (scheduled and emergency) cesarean rates by hospital.
{#pone.0191248.t002g}
Number Emergency rate (%) 95% CI Overall rate (%) 95% CI
--------- -------- -------------------- -------- ------------------ --------
Hosp. A 1,923 8 7--9 14 13--15
Hosp. B 893 9 8--10 12 11--13
Hosp. C 2,458 15 14--16 21 20--22
Hosp. D 883 11 10--12 15 14--16
Total 6,157 11 11 17 17
10.1371/journal.pone.0191248.t003
###### Descriptive population statistics.
{#pone.0191248.t003g}
-------------------------------- ------------ ----------
Numeric Variables Mean Std. Dev
Mother´s age (years) 31.89 5.41
Mother´s weight (kg) 66 13,7
Mother´s height (m) 1.62 0.06
Previous pregnancies (No.) 1.23 1.25
Gestational age (weeks) 39.2 1.78
Categorical Variables Percentage Number
Smoker (Yes, No) 12.2 6,157
Previous C-section (Yes, No) 11.3 6,157
Comorbidity (Yes, No) 17.4 6,157
Obstetric risk (Yes, No) 40.6 6,157
Labor induction (Yes, No) 22.7 6,157
Scalp pH \< 7.20 9.3 6,157
Night-shift delivery (Yes, No) 45.3 6,157
Fetus gender (male) 52.1 6,157
-------------------------------- ------------ ----------
10.1371/journal.pone.0191248.t004
###### Distribution of fetal, maternal, and contextual variables by delivery type.
{#pone.0191248.t004g}
Mean
----------------------------- ------- ------- ---------
Age (years) 31.46 32.83 \<0.001
Weight (kg) 65.7 67.9 \<0.001
Height (m) 1.63 1.61 \<0.001
BMI 23.96 26.66 \<0.001
Gestational age (weeks) 39.3 38.8 \<0.001
Fetus gender (%) 51.5 55.3 0.065
Previous pregnancies (mean) 1.125 1.257 \<0.001
Smoker (%) 11.9 13.4 0.256
Previous C-sections (%) 10.1 22.4 \<0.001
Comorbidity (%) 17 25 0.014
Obstetric risk (%) 35 58 \<0.001
Labor induction (%) 20 43 \<0.001
Intrapartum pH 7.296 7.245 \<0.001
Night-shift delivery (%) 44 55 \<0.001
The prevalence of the putative RFs for ECS in the overall population, as well as in eutocic and ECS deliveries, is shown in [Table 5](#pone.0191248.t005){ref-type="table"}. In the overall population, the RFs with the highest prevalence (over 40%) were previous pregnancies, night delivery, BMI ≥ 25, and obstetric risk. The prevalence of all RFs except smoking and parity was higher in women delivering by ECS than in those with eutocic deliveries according to their 95% CI. All prevalence ratios were 6% or lower, and the LR+ of all individual RFs were low (4.14 or lower).
10.1371/journal.pone.0191248.t005
###### Prevalence ratios and positive likelihood ratios of the putative risk factors for emergency C-sections.
{#pone.0191248.t005g}
Overall prevalence 95% CI Prevalence eutocic deliveries 95% CI Prevalence emergency C-sections 95% CI Prevalence ratio LR+ 95% CI
------------------------------ -------------------- -------- ------------------------------- -------- --------------------------------- -------- ------------------ ------ ------------
Smoker 12 12,12 12 12,12 13 12,14 1.104 1.08 1--1.16
Previous C-section 11 11,11 10 10,10 22 20--24 1.028 2.2 2--2.4
Comorbidity 17 17--17 17 16--18 25 23--27 1.585 1.47 1.38--1.56
Obstetric risk 41 40--42 38 37--39 58 56--60 3.69 1.52 1.47--1.57
Previous pregnancies 68 67--69 69 68--70 68 66--70 6.221 0.98 0.95--1.01
Induction 23 22--24 20 19--21 43 41--45 2.062 2.15 2.05--2.25
Scalp pH 9 9,9 7 7,7 29 27--31 2.636 4.14 3.85--4.42
Night-shift delivery 45 44--46 45 44--46 55 53--57 4.114 1.22 1.17--1.26
Mother´s weight (\> 90kg) 3 3,3 5 5,6 9 8,10 1.08 1.03 1.01--1.06
Mother´s height (\< 1.50 m) 3 3,3 3 3,3 5 4,6 1.14 1.03 1.01--1.04
Gestational age (≤ 36 weeks) 6 5,6 5 4,6 15 13--17 1.22 1.1 1.06--1.13
BMI ≥ 25 41 40--42 37 35--39 51 49--53 3.611 1.37 1.32--1.43
Age ≥ 35 27 26--28 26 25--27 34 32--36 2.441 1.3 1.23--1.38
The gender of the fetus was neither associated with the type of delivery nor improved either the calibration (-2 log likelihood ratios, AIC) or the discriminant accuracy (C statistic) of the final models. Therefore, it was excluded from the final logistic models. BMI was finally included since it did not make any difference to include height and weight separately or BMI in terms of both the calibration (AIC) and the discriminant accuracy (C statistic) of the models. We did choose the most parsimonious models as the final ones. Gestational age was also excluded from the final logistic models due to its high collinearity with the rest of the independent variables that remained in the model for each hospital, and because its inclusion led to biased intercept estimates of these logistic models.
According to the final logistic regression model for the overall population ([Table 6](#pone.0191248.t006){ref-type="table"}), all RFs except for the number of previous pregnancies were positively associated with ECS. The strongest associations were those found for scalp pH (OR = 5.56), Hospital C (OR = 2.69), induction (OR = 2.32), and previous ECS (OR = 2.28). The remaining ORs were lower than 1.5, although the lower limits of their 95% CI were greater than 1.0. The only inverse association found was that between parity and ECS (OR = 0.87). With regard to the contextual variables, hospital fixed-effects and night-shift delivery were also positively associated with ECS. The strongest association was found with Hospital C, what is consistent with its substantial relative importance found in the random forest ([Table 7](#pone.0191248.t007){ref-type="table"}).
10.1371/journal.pone.0191248.t006
###### Logistic regression models to assess the association between the putative risk factors and type of delivery for the overall population and the four hospitals.
{#pone.0191248.t006g}
4 Hospitals Hosp. A Hosp. B Hosp. C Hosp. D
---------------------- ------------------------------------------------------------ ------------------------------------------------------------- ------------------------------------------------------------ ------------------------------------------------------------ ------------------------------------------------------------
Hospital A 1.05 (0.74--1.36)
Hospital C 2.67[\*\*\*](#t006fn004){ref-type="table-fn"} (2.38--2.96)
Hospital D 1.44[\*\*\*](#t006fn004){ref-type="table-fn"} (1.09--1.78)
Age 1.02[\*\*\*](#t006fn004){ref-type="table-fn"} (1.01--1.04) 1.04[\*\*](#t006fn003){ref-type="table-fn"} (1.01--1.08) 1.05[\*\*](#t006fn003){ref-type="table-fn"} (1.01--1.10) 1.02 (0.99--1.04) 1.03 (0.99--1.08)
BMI 1.03[\*\*\*](#t006fn004){ref-type="table-fn"} (1.02--1.05) 1.04[\*\*\*](#t006fn004){ref-type="table-fn"} (1.01--1.087) 1.01 (0.96--1.10) 1.03[\*\*\*](#t006fn004){ref-type="table-fn"} (1.01--1.09) 1.04 (0.99--1.08)
Smoker 1.230(0.98--1.48) 1.56[\*](#t006fn002){ref-type="table-fn"} (1.05--2.07) 0.92 (0.13--1.70) 1.32 (0.95--1.67) 0.97 (0.35--1.59)
Prev. ECS 2.28[\*\*\*](#t006fn004){ref-type="table-fn"} (2.04--2.51) 3.77[\*\*\*](#t006fn004){ref-type="table-fn"} (3.25--4.29) 3.06[\*\*\*](#t006fn004){ref-type="table-fn"} (2.43--3.69) 1.94[\*\*\*](#t006fn004){ref-type="table-fn"} (1.99--2.29) 2.32[\*\*\*](#t006fn004){ref-type="table-fn"} (1.70--2.95)
Comorbidity 1.21[\*](#t006fn002){ref-type="table-fn"} (1.00--1.42) 1.41 (0.79--2.04) 2.43[\*\*](#t006fn003){ref-type="table-fn"} (1.70--3.16) 1.05 (0.79--1.31) 1.34 (0.77--1.91)
Obstetric risk 1.57[\*\*\*](#t006fn004){ref-type="table-fn"} (1.38,1.766) 0.95 (0.54--1.37) 2.32[\*\*\*](#t006fn004){ref-type="table-fn"} (1.72--2.9) 2.07[\*\*\*](#t006fn004){ref-type="table-fn"} (1.81--2.33) 0.90 (0.34--1.47)
No. pregnancies 0.87[\*\*\*](#t006fn004){ref-type="table-fn"} (0.79--0.94) 0.75[\*\*\*](#t006fn004){ref-type="table-fn"} (0.57--0.93) 0.95 (0.73--1.16) 0.79[\*\*\*](#t006fn004){ref-type="table-fn"} (0.67--0.91) 1.27[\*\*](#t006fn003){ref-type="table-fn"} (1.09--1.45)
Induction 2.23[\*\*\*](#t006fn004){ref-type="table-fn"} (2.14--2.50) 3.18[\*\*\*](#t006fn004){ref-type="table-fn"} (2.78--3.59) 1.72[\*\*](#t006fn003){ref-type="table-fn"} (1.19--2.25) 2.14[\*\*\*](#t006fn004){ref-type="table-fn"} (1.87--2.40) 2.26[\*\*\*](#t006fn004){ref-type="table-fn"} (1.79--2.73)
Scalp pH 5.56[\*\*\*](#t006fn004){ref-type="table-fn"} (5.35--5.78) 5.24[\*\*\*](#t006fn004){ref-type="table-fn"} (4.81--5.66) 4.54[\*\*\*](#t006fn004){ref-type="table-fn"} (3.98--5.9) 5.69[\*\*\*](#t006fn004){ref-type="table-fn"} (5.31--6.07) 7.17[\*\*\*](#t006fn004){ref-type="table-fn"} (6.69--7.65)
Night-shift delivery 1.49[\*\*\*](#t006fn004){ref-type="table-fn"} (1.32--1.66) 1.40[\*](#t006fn002){ref-type="table-fn"} (1.03--1.77) 1.11 (0.60--1.61) 1.78[\*\*\*](#t006fn004){ref-type="table-fn"} (1.54--2.02) 0.93 (0.47--1.39)
Observations 6,157 1,923 893 2,458 883
Log Likelihood -1,843.93 -425.61 -219.91 -912.01 -255.236
AIC 3,715.86 873.21 461.82 1,846.04 532.47
AUC 0.7781 0.81 0.7942 0.7477 0.79
CI\. AUC 95% (0.76--0.7962) (0.7784--0.8513) (0.7393--0.849) (0.7211--0.7743) (0.7382--0.8418)
Note:
\* p \< 0.1,
\*\* p \< 0.05,
\*\*\* p \< 0.01, 95% CI in parenthesis, AIC = Akaike Information Criterion, AUC = Area Under the Curve.
10.1371/journal.pone.0191248.t007
###### Relative importance of each putative risk factor for type of delivery according to the random forest.
{#pone.0191248.t007g}
------------------------------------------
\ Relative importance
Variable
-------------------- ---------------------
Scalp pH 100
Previous C-section 76.712
Induction 31.755
Hosp. C 29.895
BMI 27.854
Hosp. A 20.03
Obs. risk 11.635
Age 9.002
Pregnancies 4.901
Hosp. D 3.709
Smoker 3.194
------------------------------------------
The strength of the positive associations was relatively similar in the models for each of the four hospitals and in the model for the overall population. Although pH, induction, and previous ECS appear to be the RFs with the highest ORs, and age and BMI those with the lowest, their relative magnitude at each hospital varied slightly, except for pH, which was substantially higher at one hospital (OR = 7.17). Parity was positively associated with ECS at only one hospital, whereas obstetric risk was positively associated with it at only two.
The logistic model for the overall population and those for each hospital fit the data well, as indicated by both the -2log-likelihood ratio and the Akaike criterion. The goodness-of-fit of the population model increased notably when hospital fixed-effects were included. The DA of all five models was notably high, with AUCs ranging from 0.74 to 0.81 ([Table 6](#pone.0191248.t006){ref-type="table"}).
Of the two recursive partitioning models (CTREE and Random Forest), CTREE was used as the base learner for the Random Forest algorithm (n = 500). [Fig 1](#pone.0191248.g001){ref-type="fig"} depicts the tree structure of the trained CTREE. The first split (p \< 0.001) is scalp pH, followed by labor induction and previous ECS, for pH ≥ 7.20 and pH \< 7.20 respectively, meaning that if the pH ≥ 7.20, the next split is birth induction (p \< 0.001), whereas if the pH \< 7.20, the next split is previous ECS (p = 0.003). The interpretation extends to the conditional nodes (splits) and leaves. By way of example of the meaning and utility of hospital effects, on the extreme right side of [Fig 1](#pone.0191248.g001){ref-type="fig"} it can be seen that mothers whose fetuses had a scalp pH \> 7.20 and had not had a previous ECS, in hospital D had a probability of almost 48% of having an ECS, whereas in the other hospitals (A, B, and C) this probability went down to 27%. The AUC mean value of the CTREE was 0.88 (95% CI: 0.84--0.92).
{#pone.0191248.g001}
The RFM consisted of a set of *n* = 500 CTREEs with an optimal number of randomly selected variables = 2. Although random forest algorithms tend to be more of a black box in terms of their interpretation, their predictive power (AUC = 0.94; 95% CI: 0.93--0.95) provides reliable predictions even at an individual level. The relative variable importance of all variables included in the RFM is shown in [Table 7](#pone.0191248.t007){ref-type="table"}. The three most relevant RFs (pH, induction, and previous ECS) also showed the strongest associations in the logistic models. Since the LR+ of all the interaction terms found in the RFM were lower than 10, as was the case for the individual RFs ([Table 5](#pone.0191248.t005){ref-type="table"}), they failed to rule in the type of delivery.
Discussion {#sec008}
==========
The strength of the associations between some putative RFs and ECS, their prevalence, their prevalence ratios, and their LR+ in the overall population were low to moderate, indicating, as in other studies, that single RFs alone offer only a low DA for most outcomes, such as ECS \[[@pone.0191248.ref040]--[@pone.0191248.ref047]\].
With the exception of scalp pH, the magnitude of the strength of these associations was low and similar across the four hospitals. Likewise, all were positive except for the number of pregnancies, which showed an inverse association. Heterogeneity did not seem to play a relevant role in the study population solely on the basis of this initial analysis. Moreover, only the number of pregnancies seemed to increase the odds of a vaginal delivery, as would be expected.
In the final logistic model for the overall population both contextual variables (hospital fixed-effects and night-shift delivery) were positively associated with ECS and increased goodness-of-fit. These variables were associated with higher ECS rates and may thus favor the indication of ECS over vaginal deliveries. Regardless of maternal and fetal characteristics, and as indicated in a number of studies, different entrenched practices across hospitals seem to influence the decision regarding delivery type, similar to how physicians' desire for night-time leisure influences the decision to perform an ECS at the start of the night shift \[[@pone.0191248.ref004]--[@pone.0191248.ref011], [@pone.0191248.ref039]\].
No single 100% accurate predictive model of the type of delivery has been published to date. In fact, only a few have been published all showing a low predictive and discriminant accuracy. All these contextual (hospital) factors that may contribute both to predict and explain variations in both the type of delivery and in the appropriateness of the c-section´s indications (as shown by the high variability of rates of c-sections in several published atlases of variations in medical practice) remain unobserved and unknown. The only available way to account for them is by including hospital fixed-effects in logistic models and in random forests as contextual variables (which are tantamount of the second level variables in multilevel analyses). Moreover, their inclusion in the models reduced the biases in the estimates of the measures of strength of the associations without resulting in overfitting, and increase their discriminant accuracy because they account for the abovementioned unobserved predictive factors \[[@pone.0191248.ref004]--[@pone.0191248.ref011], [@pone.0191248.ref039]\].
These results illustrate the usefulness of this analytic approach because they suggest that some hospital characteristics (i.e., method of payment and other incentives, physicians' desire for night-time leisure, established non-evidence-based practices such as to perform a c-section to mothers having had a previous c-section) may explain unjustified variations and inappropriateness of some indications for c-sections that warrant further investigation.
Consequently, all fetal, maternal, and contextual factors alone failed to achieve a reasonable DA for ECS rates in different population subgroups at each hospital even after they were controlled for in these models. This is consistent with the well-known fact that the decision regarding the type of delivery hinges not only on different combinations of these RFs and the interactions between them, but also to some extent on variations across individual hospital practices and even individual clinicians' practices. It can thus be the product of unjustified non-evidence-based clinical practices, which has long been shown in studies of variations in clinical practice with regard to CS using small area analysis \[[@pone.0191248.ref004]--[@pone.0191248.ref011]\].
Measures of association alone are insufficient to discriminate between those individuals who will develop a given outcome and those who will not (a strong association is not tantamount to high DA given that the false positive and false negative fractions of the population are low) \[[@pone.0191248.ref040]--[@pone.0191248.ref043]\]. It is the set of independent variables included in the final logistic models that could make it possible to achieve acceptable DA, as shown by their high AUC (0.75--0.81). To our knowledge, no logistic regression model published to date has achieved an AUC similar to those reported here.
The AUCs of the RFM (0.93--0.95) and the CTREE (0.84--0.92) offer a considerably improved additional analytical approach to the same issue due to the nature of their optimization algorithm, maximum likelihood for logistic and unbiased recursive partitioning for CTREE. Their incremental DA is notably higher than that of logistic models due to the unsupervised detection of interactions in the CTREE model and 500 such CTREEs in the RFM. The reasons for this improvement in DA are mainly twofold. First, it results from detecting associations and interactions among the combinations of RFs used in clinical decision-making regarding the type of delivery at each hospital that are not captured by logistic models. Second, the model also captures heterogeneity (the trees' branches), among both the hospitals and the clinicians' decision-making frameworks, that logistic models likewise cannot capture.
In terms of implications for clinical practice, we found some medically unjustified differences in ECS rates for hospital D compared to the other hospitals, e.g., in induced births between 11 p.m. and 3 a.m. in which the scalp pH was above 7.20 (nodes 2, 16, and 20). Moreover, in the subgroups of deliveries with pH above 7.20 and at least one previous C-section (nodes 25 and 26), the ECS rates climbed to 50% and almost 60%, respectively. The utility of these results lies in that, despite they are neither explanatory not confirmatory, they suggest potential sources of inappropriate ECSs in Hospital D (contextual factors) that should be further investigated (i.e., changes in payment methods, lack of updated clinical guidelines, lack of utilization management, demand side issues).
One of the main limitations of this study is that only 4 out 22 obstetrics services were included as explained in the Introduction. These four hospitals could be considered representative of up the 42% of hospitals within the Spanish National Health Service in terms of obstetric case mix, obstetric risk, and number of births and CS rates. However, it is to be expected that studies intended to build a predictive model for the type of delivery fail to have a high external validity with regard to the specific RFs for ECS. As already noted, it is the combination of RFs (fetal, maternal, and contextual) at each particular hospital and the interactions between them what makes it possible to improve the DA for the type of delivery. The more the clinical practice varies across centers and clinicians, the more different RF-combination subgroups can be expected to appear in the CTREES given their higher ability to capturing them; hence, the more hospital-specific the combination of RFs and interactions between them yielding the highest DA will be. Given that we performed a 10-fold cross-validation using randomly allocated 90/10% training/test sample sizes, the chances of the RFM being overfitted and the AUCs being overestimated are very low.
Another limitation of the study is that scalp pH is a very proximate measure likely linked to fetal distress, so it is not a surprise that it is highly predictive. We did not include cord pH because it is a post-delivery endpoint and as such cannot be considered a predictive variable of the type of delivery. We could agree that scalp pH is linked to fetal distress and can be highly predictive. However, we have included it in the models as a predictive variable for several reasons: i) scalp pH is an intrapartum variable, not a final endpoint. Variations in the cut-off points actually used in clinical practice may explain both variations in the diagnosis of fetal distress, and in the fraction of appropriate and inappropriate indications for ECSs across hospitals (as it have been shown is studies of the appropriateness of the different types of emergency ECSs indications, in this particular case, fetal distress); ii) it has also been shown that both the clinical management of intrapartum (scalp) pH and thus of fetal distress varies across hospitals, and that it accounts for a considerable fraction of inappropriateness of ECSs for this specific indication, what could make scalp pH a predictive variable for some but not all ECSs; and iii) tenfold cross validation performed in the CTREE model prevented from obtaining overfitted estimates when including this variable.
Therefore, this study's main contribution is that the information provided by the combination of logistic regressions and CTREES can provide more accurate information than either method alone to help clinicians and managers find the sources of heterogeneity and unjustified variations in ECSs, design and implement hospital-tailored interventions intended to improve the appropriateness of their indications, and reduce unnecessary ECS and their avoidable complications and costs. This comprehensive and complementary statistical methodology, combined with robust data collection and audit processes, makes it possible to analyze an intricate medical decision-making problem with higher discriminant capacity than previous studies.
In conclusion, fetal, maternal, and contextual factors alone fail to achieve a reasonable discriminatory accuracy for type of cesarean delivery. We have met our objective by simultaneously considering these factors at each particular hospital by using both logistic regressions and the CTREES for the following reasons. First, this analytical strategy has improved the final discriminatory accuracy of the models for the type of delivery compared with that of the predictive models published to date. Second, the discriminatory accuracy of these models has been validated in our study by means of ten-fold cross-validation. Third, the results allow for further investigating sources of variability and inappropriateness of ECSs. Finally, based on this information, they also allow for tailoring hospital-specific interventions intended to discriminatory accuracy improve the appropriateness of indications for ECS.
Supporting information {#sec009}
======================
###### Database that includes the fetal, maternal, and contextual independent variables of hospitals A, B, C, and D.
(XLSX)
######
Click here for additional data file.
[^1]: **Competing Interests:**The authors have declared that no competing interests exist.
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Crucial day for RIM Amid the security issues dogging Research In Motion Ltd. in several countries, the Waterloo, Ont.-based technology giant is expected this morning to unveil a new BlackBerry that analysts believe is key to the company's future. Battling the iPhone from Apple Inc. and other new smart phones on the market, RIM's new BlackBerry is expected to be a touch-screen device with a slide-out keyboard. Analysts are also watching to see if RIM gives a more detailed demonstration of its new operating system.
"Keys for the stock will be how well the BB6 OS shows (innovation, differentiation, form factor, etc.) and launch timing/pricing of the device," said UBS analysts Phillip Huang and Maynard Um. "[Management]has placed a high degree of importance on its BB6 OS as the 'next driver' of RIM's business, reflecting the longer-term importance of the announcement. Shorter term, launch timing could impact the quarter with an imminent launch helping to drive [second quarter of the 2011 fiscal year]results toward the high end of guidance ($.4-billion to $4.6-billion in revenues and 11.6-million to 12.1 million units) and vice versa."
Today's announcement, made with AT&T Inc. in the United States, comes after a weekend flurry of controversy surrounding security concerns in several countries, notably the threat by the United Arab Emirates to shut down BlackBerry service in October if RIM doesn't take the measures needed to allow authorities to monitor communications.
In Dubai today, the UAE defended its decision, following the U.S. State Department's comments yesterday that it is disappointed by the move. "It is regrettable that after several years of discussions, BlackBerry is still not compliant with UAE regulatory requirements even as it complies with similar policies in other countries," Yousef al-Otaiba, the ambassador to Washington, was quoted as saying in local newspapers, according to Agence France Presse.
He said his country wants "exactly the same regulatory compliance" that RIM gives other governments.
RIM, not mentioning the UAE dispute directly, said in a statement yesterday that it is "committed to continue delivering highly secure and innovative products that satisfy the needs of both customers and governments."
Canadian dollar strong The Canadian dollar is actually down slightly from yesterday but still trading at a high level of about 97.60 cents U.S. It had been up sharply yesterday as oil prices and equities rose, said Scotia Capital currency strategist Sacha Tihanyi.
"Canada is getting more caught up in the 'risk on' trade as opposed to the U.S. growth/inflation woes, reflected primarily in [Canadian dollar] strength," said RBC Dominion Securities analysts Mark Chandler and Kam Bath. "The currency has given up a little ground this morning, but stands at a relatively firm 1.025, with near-term oil price futures back up to $81.70 a barrel. While up about 1 per cent over the past week against the [U.S.dollar, the Canadian dollar]is still underperforming most of the other major currencies over this period."
Talisman in Colombian deal with BP Talisman Energy Inc. and Colombia's national oil company Ecopetrol are spending $1.9-billion (U.S.) to get in on the asset sale launched by BP-PLC in the wake of the oil spill disaster in the Gulf of Mexico. BP is selling its Colombian business to the two companies, part of its $30-billion worth of planned asset sales to raise funds that will help cover the costs of the spill. Talisman will have 49 per cent of the Colombian business and Ecopetrol 51 per cent. The two companies already are partners in areas of Colombia and Peru.
"These are tremendous assets that our team knows well," Talisman chief executive officer John Manzoni said in a statement. "They are attractively priced, with excellent running room and we are partnering with the pre-eminent oil and gas company in Colombia ... Completion of this transaction will accelerate our objective of building a material core area in Latin America, with target production of at least 50,000 [barrels of oil equivalent per day]"
Wheat prices running up Wheat prices have been surging on fears of a supply shortage, driven in part by speculators, though they remain below the highs of late 2007 and early 2008 and dipped just slightly today. "Fires in Russia and its regions have prompted speculative buying as capital rotation through the soft commodity markets moves into wheat exacerbating price moves in these rather illiquid markets," said CMC Markets analyst Michael Hewson. "Due to the fires, there are fears that Russia, Ukraine and Kazakhstan's export production could drop by as much as 27 per cent for 2010/11."
Since the beginning of June, he noted, wheat prices have jumped to about $4.50 (U.S.) a bushel to hit $7 yesterday in futures trading on the Chicago Board of Trade. "These rises in price have been the fastest in three decades, but in the short term they don't look in any way sustainable," he said.
Gildan settles suits Gildan Activewear Inc. said today it is paying $22.5-million (U.S.) to settle class-action suits in Canada and the United States, relating to its decision to revise its fiscal 2008 earnings outlook. The clothing maker said that as part of the settlement, both Gildan and its senior officers deny any claims of wrongdoing. "The settlement will be entirely funded by the company's insurance policies and will have no impact on the company's earnings or cash flows," it added.
Molson Coors profit jumps Molson Coors Brewing Co. today posted a sharp jump in second-quarter profit, and while global volumes dipped on "challenging economic and beer industry conditions," the brewer cited growth in Canada, Britain and other markets. Molson Coors said profit jumped to $237.2-million or $1.27 a share from $187.3-million or $1.01 a share a year earlier.
"In the U.S., strong cost management and higher net pricing drove double-digit earnings growth," chief executive officer Peter Swinburn said in a statement. "In Canada, although underlying pretax income declined 3 per cent in local currency, we grew volume and market share and reduced our cost of goods sold per hectoliter. In the U.K., profit declined due to a non-cash increase in pension expense, but we achieved solid top-line performance, growing volume and price in the quarter."
Mr. Swinburn noted that the outlook is still challenging given high global jobless rates.
U.S. consumers saving U.S. consumers have decided they'd rather save than splurge. Consumer spending stalled in June, the U.S. Commerce Department said today, as did growth in personal incomes. The savings rate in the United States rose to 6.4 per cent, its highest level in a year. The stagnation in personal incomes in June, though, follows increases of 0.4 per cent and 0.3 per cent over the previous two months, meaning that they rose "at a fairly decent clip" in the second quarter overall, said Paul Dales, U.S. economist at Capital Economics in Toronto.
"By and large, households decided to save, rather than spend, this extra income," he said. "...This surge in saving is something of a double-edge sword. On the one hand, it restrains spending growth in the near-term; nominal personal spending was flat in June, and in real terms it rose by just 0.1 per cent month over month and by an annualized 1.6 per cent in the second quarter as a whole.
"But on the other hand, households now appear better placed to boost their spending further ahead. The recent fall in confidence suggests this may not happen in the third quarter. What's more, much depends on whether the labour market recovery continues to generate decent rates of income growth. Nonetheless, it is of some comfort that households now appear to have something of a cushion that can be used to pay down debt or support spending."
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Q:
How to read this memory map of LPC1769 microcontroller?
I'm trying to understand the memory map of the LPC1769 microcontroller using the official NXP datasheet. The screenshot below shows at 0x00004000 to 0x00008000 there is 512kB of flash memory mapped, however the number of addresses between 0x00040000 and 0x00080000 can't reference all 512kB of flash memory?
How does this mapping work so all 512kB can be referenced? Or have I misunderstood something?
A:
There are parts with different amounts of Flash memory. The Flash memory starts at address 0 for all devices and if it has 512kB of Flash the final address is 7FFFFh and reserved area starts at 80000h. Parts with less memory such as 256kB has last address of 3FFFFh respectively so the reserved area starts at 40000h. They are all just stuffed into one picture that is clipped from bottom if you look carefully.
Here is an extract from the relevant User Manual where this is better explained:
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Sri Lanka press urges 'fresh blood' after T20 exit
Colombo: Sri Lanka's press on Sunday called for "fresh blood" in the national cricket side after the reigning champions crashed out of the World Twenty20 at the group stages.
Sri Lanka suffered a narrow 10-run defeat to England on Saturday, with the 2014 trophy winners being bundled out of the tournament after a disastrous showing at the recent Asia Cup.
The local Sunday Times blamed a selection crisis on the eve of the tournament for Sri Lanka's poor performance, which also saw them badly beaten by the West Indies and scrape home against minnows Afghanistan.
Sri Lanka's national selectors were sacked and the new panel, headed by former skipper Aravinda de Silva, stood down injured captain Lasith Malinga shortly before they left for India.
"Where on earth would you find the selected squad changed just hours before its departure to an all important tournament?" the paper quoted an unnamed former player as saying. "This I believe had a huge impact on our performance."
The paper warned Sri Lanka could not make an impact at international level with the current team, which have been unable to fill the void left by retiring greats Kumar Sangakkara and Mahela Jayawardene.
"...one believes turning the tide with the current crop of players seems almost impossible," it said, adding that selectors should "replace the misfiring cricketers with new blood to inject life back into the game."
The state-run Sunday Observer praised skipper Angelo Mathews' unbeaten 73-run innings, but said the team were unable to execute whatever plans they had cobbled together.
"The difference between the two sides was that England played sensibly whereas Sri Lanka failed to execute whatever plans they came up with for the contest," it said.
Mathews pleaded for patience from fans and administrators after his side's defeat, while Sri Lankan President Maithripala Sirisena said: "We'll come back stronger next time".
AFP
Colombo: Sri Lanka's press on Sunday called for "fresh blood" in the national cricket side after the reigning champions crashed out of the World Twenty20 at the group stages.
Sri Lanka suffered a narrow 10-run defeat to England on Saturday, with the 2014 trophy winners being bundled out of the tournament after a disastrous showing at the recent Asia Cup.
The local Sunday Times blamed a selection crisis on the eve of the tournament for Sri Lanka's poor performance, which also saw them badly beaten by the West Indies and scrape home against minnows Afghanistan.
Sri Lanka's national selectors were sacked and the new panel, headed by former skipper Aravinda de Silva, stood down injured captain Lasith Malinga shortly before they left for India.
"Where on earth would you find the selected squad changed just hours before its departure to an all important tournament?" the paper quoted an unnamed former player as saying. "This I believe had a huge impact on our performance."
The paper warned Sri Lanka could not make an impact at international level with the current team, which have been unable to fill the void left by retiring greats Kumar Sangakkara and Mahela Jayawardene.
"...one believes turning the tide with the current crop of players seems almost impossible," it said, adding that selectors should "replace the misfiring cricketers with new blood to inject life back into the game."
The state-run Sunday Observer praised skipper Angelo Mathews' unbeaten 73-run innings, but said the team were unable to execute whatever plans they had cobbled together.
"The difference between the two sides was that England played sensibly whereas Sri Lanka failed to execute whatever plans they came up with for the contest," it said.
Mathews pleaded for patience from fans and administrators after his side's defeat, while Sri Lankan President Maithripala Sirisena said: "We'll come back stronger next time".
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It’s time to talk about the silent leaders of society, the stalwart ISTJs—Aragorn son of Arathorn from J.R.R. Tolkeins’ beloved series, The Lord of the Rings, and Cogsworth from Disney’s, Beauty and the Beast.
Aragorn is a clear depiction of the ISTJ in pop-culture. Often described as grim, Aragorn is definitely not the life of the party. However, in a world where the dark fist of evil has caused a tremor of hopelessness, Aragorn’s steady, quiet strength provides solid ground beneath his friends’ feet.
ISTJs don’t typically enjoy being in the limelight, and Aragorn is more than content with living alone in the woods. ISTJs almost always enjoy the outdoors. They also quite content any time they can employ concrete knowledge of the world—fishing, how to build a fire, how to repair this or that, what to-or-not-to eat. Aragorn is not simply an outdoorsmen, but is nicknamed ‘Strider,’ and the ‘Ranger of the North,’ because of his expertise in handling any wilderness.
However, it is not simply Aragorn’s quiet, subdued nature and love for the outdoors that qualifies him as an ISTJ. It is his internal struggle between his sense of duty and a troubling lineage that makes him a classic “Inspector.” Aragorn is the heir to the throne of men—the rightful king. Like all Guardians, Aragorn takes his role in society very seriously. However, he is also constantly haunted by history. He knows the weakness of his lineage—that the blood of his ancestor, a man corrupted by the power of the ring, is the same blood that courses through his veins. Thus, he is plauged by a very common ISTJ vice: worry. This worry leads him to a great fear of inadequacy, worrying that somehow the past will come back to haunt him and that he will be corrupted too.
Like all ISTJs, Aragorn takes his promises very seriously, and protects his friends with the utmost dedication. If there is one word to describe the ISTJ, it is ‘superdependable’—not only with their commitments to friends, but also their significant others. Aragorn is in love with Arwen, and the advancements of another, the most beautiful woman in all of Middle Earth cannot so much as turn his head. He completely ignores her advances, and is faithful to the very end.
Ultimately, Aragorn’s powerful sense of duty wins out over his worry and he claims his rightful place as king, stoically leading the last remnants of the armies of men against the powers of Mordor. Though, not before all of his prior commitments are taken care of.
Next, there’s Cogsworth. While not nearly as glamorous a character as Aragorn, he is still to be admired. ISTJs are nicknamed the ‘Inspectors,’ and Cogsworth shows us why. ISTJs are particularly good at making sure others within an organization tow-the-line, do as they should, and don’t do as they shouldn’t. Of course, Cogsworth’s primary companion is a highly extroverted partyer—surprisingly, a trend fairly common among ISTJs. Cogsworth’s severe nature keeps the entire castle running smoothly and efficiently, but with this comes the perception that he is a bit of a fuddy-duddy. So, naturally he welcomes the fun that comes from his livelier cohort. While a bit stiff at first, he proves he can let loose like the rest of them given the appropriate time and place.
Unfortunately, ISTJs are often taken advantage of, because they are willing to do the thankless jobs so many others neglect. Cogsworth is no exception. Despite his dedication and dependability, the others often overlook his efforts. Naturally, Cogsworth feels as though if he didn’t take care of things no one would, so he continues quietly managing the castles affairs without flourish.
In conclusion, ISTJs should be not only respected for their dependability, beneficence, and dedication, but also revered. They offer strength to any organization or relationship they find themselves in.
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Introduction {#s1}
============
Borderline personality disorder (BPD) is a mental disorder characterized by difficulties with emotion regulation, impulse control, self-image and interpersonal relationships (American Psychiatric Association, [@B2]). Deliberate self-injury with or without the intent to die, commonly referred to as *self-harm*, occurs in 63--80% of patients with BPD (Chapman et al., [@B8]). A treatment that reduces self-harm in patients with BPD is dialectical behavior therapy (DBT), an empirically-supported psychotherapy intended to improve behavioral control and emotion regulation (Linehan et al., [@B20]; McMain et al., [@B21]). Whereas DBT is an effective treatment, outcomes in clinical trials represent averages and the effect on any one individual may be larger or smaller than the average effect. Response heterogeneity may be explained in part by meta-analytic evidence that suggests patients who begin but do not complete treatment have worse outcomes over time (McMurran et al., [@B22]). Additionally, more than one-quarter of patients with BPD in DBT end treatment prematurely (Linehan et al., [@B20]; McMain et al., [@B21]). Therefore, determining factors that predict treatment response and attrition will be useful for advancing our understanding of how to adapt treatment to address the needs of individuals.
Neuroimaging holds promise for isolating markers of brain function that predict treatment outcomes for self-harming patients with BPD. In major depression, psychotherapy studies examining neural activation while viewing negative emotional pictures have found that activity in amygdala, anterior cingulate, and dorsolateral prefrontal cortex (DLPFC), may be prospectively associated with responses to cognitive-behavioral treatments (for a review, see DeRubeis et al., [@B11]). Patients with BPD show neural systems dysfunctions in similar regions while processing negative emotions (Ruocco et al., [@B28]) and two small preliminary studies suggest that activity in these same regions may be modulated by DBT and potentially associated with BPD symptom improvements (Schnell and Herpertz, [@B31]; Goodman et al., [@B15]). To our knowledge, no studies have yet examined neural activation during response inhibition as a potential predictor of psychotherapy outcomes for any mental disorder. Deficits in response inhibition may underlie BPD and self-harm (Ruocco, [@B27]; Ruocco et al., [@B29]; Williams et al., [@B34]) and considering that DBT is intended to improve behavioral control and reduce self-harm in BPD, activation in neural regions underlying response inhibition, specifically motor inhibitory control, may conceivably show associations with treatment outcomes.
The current preliminary study probed activation in the PFC associated with motor inhibitory control before patients enrolled in a standard outpatient DBT program and again after 7 months of treatment. The primary aims of the study were to determine whether pre-treatment activation in the PFC was associated with: (1) reductions in self-harm through treatment; and (2) attrition from treatment. We hypothesized that patients with BPD who go on to demonstrate the greatest reductions in self-harm would show lower pre-treatment activity in lateral regions of the PFC underlying impulse control, consistent with the notion that these patients may have the most to gain from a treatment intended to improve behavioral control. Furthermore, we anticipated that patients who initiate treatment but do not complete treatment would display higher levels of activity in these same regions of the PFC, which could represent a neurophysiological marker signifying increased risk for treatment attrition in DBT. Exploratory analyses investigated associations between shifts in PFC activation and changes in self-harm between pre-treatment and seven-month assessments.
Materials and Methods {#s2}
=====================
Participant Characteristics {#s2-1}
---------------------------
The current study adopted a naturalistic design by recruiting patients with BPD that were being treated as part of regular clinical services in the BPD Clinic at the Centre for Addiction and Mental Health in Toronto, Canada. Thirty-one participants with BPD reporting at least seven episodes of self-harm in the past 12 months consented and enrolled in the study. Figure [1](#F1){ref-type="fig"} depicts flow of participants through the study. Individuals not eligible for the study based on a phone screen did not significantly differ from eligible individuals according to age \[*t*~(52)~ = 0.89, *p* = 0.38\] or gender (*p* = 0.69, two-tailed Fisher's exact test). Participants eligible for the study were 18--65 years old, fluent in English, capable to provide written informed consent, had a current (at least past 5 years) diagnosis of BPD, and reported at least seven episodes of self-harm in the past year. Participants were excluded if they had a lifetime psychotic disorder, current substance dependence, neurological or medical illness that could impact brain function (e.g., significant head trauma, seizure disorder, or stroke), significant manual, visual or hearing impairment, or estimated IQ less than 80 on the Wechsler Test of Adult Reading (Wechsler, [@B33]).
{#F1}
Procedure {#s2-2}
---------
The present study was approved by the Research Ethics Board of the Centre for Addiction and Mental Health, and the Social Sciences, Humanities and Education Research Ethics Board at the University of Toronto. After complete description of the study to the participants, written informed consent was obtained. Participants completed the Structured Clinical Interview for DSM-IV Axis I Disorders---Patient Edition (First et al., [@B13]), Structured Interview for DSM-IV Personality (Pfohl et al., [@B25]), Montgomery--Åsberg Depression Rating Scale (MADRS; Montgomery and Asberg, [@B24]), Young Mania Rating Scale (YMRS; Young et al., [@B37]), and Zanarini BPD Rating Scale (ZAN-BPD; Zanarini et al., [@B38]). Frequencies of self-harming behaviors were assessed with a modified Parasuicide Count (Comtois and Linehan, [@B9]). Diagnostic assessments were administered by Master's and doctoral level research assistants directly supervised by a licensed psychologist (ACR). Results of diagnostic assessments were reviewed in a multidisciplinary "best estimate" diagnostic meeting (Klein et al., [@B19]).
Participants completed functional near-infrared spectroscopy (fNIRS) neuroimaging procedures prior to beginning DBT and after approximately 7 months of treatment (*M* = 30.20 weeks, *SD* = 13.25). A 7-month timeframe was chosen because the most substantial reductions in self-harm are observed well within this period for self-harming patients treated with DBT (McMain et al., [@B21]). fNIRS is a neuroimaging technique that introduces light in the near-infrared range at the level of the scalp and monitors changes in the optical properties of the local vasculature according to the differential absorption and back-scattering of photons. The fNIR Imager 1000^®^ (fNIR Devices, Potomac, MD, USA) is a continuous-wave fNIRS system that was used to deliver two wavelengths of light (730 and 850 nm) that were measured continuously at 500 ms intervals (2 Hz) in 16 channels (4 light sources and 10 photo-detectors). Source-detector separation was 2.5 cm, yielding a 1.25 cm depth of penetration. The probe (18 cm × 6 cm × 0.8 cm) was aligned with electrode positions F~7~, F~P1~, F~P2~, and F~8~ (which correspond to Brodmann areas 9, 10, 45, and 46, respectively) based on the international 10--20 electroencephalography system (Jasper, [@B18]). Specific details regarding placement of the probe are provided in Ayaz et al. ([@B5]). Participants sat in a dark room in front of a computer monitor. After securing the fNIRS sensor pad on the participant's forehead using Velcro^®^ straps, participants were asked to directly stare at a crosshair fixation for 10 s to establish baseline parameters. Participants then completed the Scarborough Non-Affective Go/No-go Task, a previously validated measure of motor inhibitory control known to activate bilateral medial and inferior frontal gyri during response inhibition (Rodrigo et al., [@B26]). The task was chosen for its relevance to controlling motor behaviors in participants with BPD who are actively engaging in physically self-injurious behaviors. Briefly, the task presents participants with either green ("go") or red ("no-go") circles at the center of a computer monitor and asks them to press a button with their right hand to "go" stimuli (90 trials) and withhold their response to "no-go" stimuli (30 trials). The inter-trial interval was jittered at increments of 500 ms (ranging from 4000--6000 ms, *M* = 5000 ms) to discourage anticipatory responding. From the raw light intensity measurements, relative concentrations of oxygenated hemoglobin (oxy-Hb) were calculated using the modified Beer-Lambert law (Cope and Delpy, [@B10]), which calculates the absorption of light for a given substance's concentration. Image reconstruction was rendered using topographic tools available in fNIRSoft^®^ Professional Edition (Ayaz, [@B4]), which maps fNIRS activation data onto magnetic resonance imaging templates.
Participants enrolled in a standard outpatient DBT program that included both individual (1 h/week) and group psychotherapy (2 h/week; details of the treatment program are described in McMain et al., [@B21]). Overall, this treatment focused on eliminating behavioral dysregulation through the development of more effective coping strategies, which in turn are balanced with validation. Twenty-one participants completed treatment; however, pre-treatment neuroimaging data were unavailable for one participant that provided a positive urine toxicology screen and was ineligible to complete subsequent study procedures. Seven-month neuroimaging data were available for 18 participants who completed treatment ("treatment completers"). Neuroimaging data were unavailable at the 7-month assessment for two additional participants who continued to be enrolled in treatment because one provided a positive urine drug screen at the 7-month assessment and the second was lost to follow-up but clinic notes indicated that the participant remained in treatment. Five participants dropped out of treatment and four qualified for the study but never initiated treatment after completing pre-treatment diagnostic and neuroimaging assessments (collectively referred to as "treatment non-completers", *n* = 9). Participants who completed treatment did not differ from non-completers in pre-treatment rate of self-harm (*z* = 1.06, *p* = 0.29; independent-samples Mann-Whitney *U* Test) or in age \[*t*~(28)~ = 1.98, *p* = 0.06\], gender (*p* = 0.25, two-tailed Fisher's exact test), or IQ \[*t*~(28)~ = 0.72, *p* = 0.47\].
Statistical Analysis {#s2-3}
--------------------
Neuroimaging data were analyzed using multilevel generalized linear models that nested all observations (μmol/l oxy-Hb measured at 2 Hz) within participants. The first set of analyses investigated pre-treatment motor inhibitory control -related PFC activation for all participants who completed neuroimaging. The neural activation changes that were observed for those who completed 7 months of treatment were then investigated by examining interactions between Condition (no-go vs. crosshair fixation) and Time (pre-treatment vs. 7-month assessments) in each of 16 channels. Simple effects of the significant interactions from this set of analyses were then probed (Aiken et al., [@B1]) to examine activation patterns prior to treatment, and separately, after 7 months of treatment. The second set of analyses examined the three-way interaction between Condition, Time and Change-in-Self-Harm-Rate. Treatment completers were compared with non-completers by exploring significant interactions between treatment completion status and inhibitory control-related neural activation in the PFC. Significant interactions were subsequently investigated to identify patterns of activation displayed by participants who showed higher symptom improvement (i.e., 1 SD above the mean) and lower symptom improvement (i.e., 1 SD below the mean) separately at each assessment time point. The final set of analyses examined differences in PFC activation between participants who completed 7 months of treatment vs. those who did not (Condition and Treatment-Completion-Status interaction), and then probing simple effects based on significant interactions. Type I error for whole-probe interaction analyses was controlled using the False-Discovery Rate approach (Benjamini and Hochberg, [@B6]; Benjamini et al., [@B7]) and *p*-values less than 0.05 were reported as statistically significant. Effect sizes (semi-partial *R*^2^) are reported where appropriate.
Results {#s3}
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Participant Characteristics {#s3-1}
---------------------------
The mean age of participants was 28.65 (*SD* = 10.04) and their estimated IQ was 105.68 (*SD* = 8.20). Most participants were women (90.30%) and right-hand dominant (87.10%). The ethnic-racial composition of the sample according to 2011 Canadian census categories was as follows: Black (3.23%), Latin American (16.13%), South Asian (6.45%), White/Caucasian (64.52%) and other (9.68%). Table [1](#T1){ref-type="table"} presents frequencies of subtypes of self-harm and suicidal intent between pre-treatment and 7-month assessments. Cumulatively, rates of self-harm were significantly reduced after approximately 7 months of treatment (*z* = −3.36, *p* = 0.001; related-samples Wilcoxon Signed Rank Test). BPD symptom severity did not significantly change from pre-treatment assessments (ZAN-BPD total score *M* = 18.25, *SD* = 6.51) to 7 months of DBT (*M* = 13.70, *SD* = 5.56; *t* = 1.97, *p* = 0.06).
######
**Rates of self-harm for patients with borderline personality disorder (*N* = 18) prior to beginning treatment and after 6 months of dialectical behavior therapy**.
\% Endorsed Monthly Rate *M (SD)* \% of All Self-Harm \% Suicidal
--------------------------------- ------------- ----------------------- --------------------- -------------
**Before starting treatment**
Cutting 66.67 2.56 (7.06) 37.74 0
Overdose 27.78 0.04 (0.07) 0.54 12.5
Hanging 1.11 0.02 (0.06) 0.27 25
Asphyxiation 5.56 0.00 (0.02) 0.07 100
Burning 27.78 0.14 (0.36) 1.09 100
Jumping 5.56 0.00 (0.02) 0.07 0
Shooting 5.56 0.00 (0.02) 0.07 0
Drowning 5.56 0.01 (0.04) 0.14 100
Stabbing 16.67 0.06 (0.20) 0.82 0
Hitting 66.67 1.50 (3.46) 22.07 0
Other 55.56 2.52 (4.26) 37.13 0
**After 7 months of treatment**
Cutting 38.89 4.66 (16.92) 74.22 0
Overdose 16.67 0.06 (0.04) 0.94 0
Hanging 0 0.00 (0.00) 0 0
Asphyxiation 0 0.00 (0.00) 0 0
Burning 11.11 0.03 (0.09) 0.31 50
Jumping 0 0.00 (0.00) 0 0
Shooting 0 0.00 (0.00) 0 0
Drowning 0 0.00 (0.00) 0 0
Stabbing 11.11 0.23 (0.89) 3.59 0
Hitting 38.89 0.56 (1.23) 8.91 35.09
Other 55.56 0.75 (1.10) 12.03 1.3
*Note: % Endorsed = proportion of patients that endorsed each type of self-harm. % of All Self-Harm = proportion of a specific type of self-harm relative to the frequency of all self-harm. % Suicidal = proportion of self-harm with suicidal intent. Patients showed significant reductions in hitting (z = −2.50, p = 0.01; related- samples Wilcoxon Signed Rank Test) and other self-harm (z = −2.20, p = 0.03; related-samples Wilcoxon Signed Rank Test) after treatment*.
Psychiatric diagnostic co-morbidities for participants that qualified for the study and completed pre-treatment psychodiagnostic assessments (*n* = 29) are presented in Table [2](#T2){ref-type="table"}. A majority of participants (64.71%) who completed treatment were taking medications (alone or in combination) at the time of the study: sedatives (*n* = 4), antidepressants (*n* = 8), mood stabilizers (*n* = 2), and antipsychotics (*n* = 4).
######
**A summary of psychiatric diagnostic comorbidities within the final sample (*N* = 29)**.
Disorder *n* Percent in final sample
-------------------------------------------------- ----- -------------------------
**Bipolar I disorder** 2 6.90%
**Bipolar II disorder** 1 3.45%
**Major depressive disorder**
Current 13 44.83%
Past 10 34.48%
**Dysthymic disorder** 1 3.45%
**Alcohol abuse**
Current 1 3.45%
Past 4 13.79%
**Alcohol dependence (past)** 13 44.83%
**Substance dependence (past)** 7 24.14%
Sedative 1 3.45%
Cannabis 6 20.69%
Opioid 1 3.45%
Cocaine 1 3.45%
Stimulant 1 3.45%
**Polysubstance dependence (past)** 1 3.45%
**Panic disorder**
Current 9 31.03%
Past 2 6.90%
**Agoraphobia without panic disorder (current)** 2 6.90%
**Social phobia**
Current 1 3.45%
Past 2 6.90%
**Specific phobia**
Current 1 3.45%
Past 2 6.90%
**Obsessive-compulsive disorder**
Current 6 20.69%
Past 3 10.34%
**Posttraumatic stress disorder**
Current 12 41.38%
Past 3 10.34%
**Generalized anxiety disorder** 3 10.34%
**Anorexia nervosa (past)** 4 13.79%
**Bulimia nervosa**
Current 1 3.45%
Past 4 13.79%
**Paranoid personality disorder** 3 10.34%
**Antisocial personality disorder** 5 17.24%
**Avoidant personality disorder** 8 27.59%
**Dependent personality disorder** 4 13.79%
**Obsessive-compulsive personality disorder** 3 10.34%
Participants on average reported moderate depression on the MADRS (*M* = 23.43, *SD* = 8.40) and minimal symptoms of mania on the YMRS (*M* = 9.19, *SD* = 5.78). After approximately 7 months of DBT, symptoms of depression (*M* = 19.43, *SD* = 7.90) and mania (*M* = 6.76, *SD* = 4.61) did not markedly change (*p*'s \> 0.05, two-tailed repeated-measures *t*-tests). Participants reported minimal levels of suicidal ideation on the Modified Scale for Suicidal Ideation (Miller et al., [@B23]) before starting DBT (*M* = 3.11, *SD* = 2.61) and after 7 months of treatment (*M* = 2.61, *SD* = 3.35; *t* = 0.36, *p* = 0.73). Treatment completers did not differ from non-completers in pre-treatment levels of depression, mania, suicidal ideation, and BPD symptom severity (*p*'s ≥ 0.23; independent-samples *t*-tests).
Behavioral Performances on the Motor Inhibitory Control Task {#s3-2}
------------------------------------------------------------
Accuracy on the go/no-go task (sum of true positive and true negative responses) was high for participants with BPD prior to starting DBT (*M* = 98.82%, *SD* = 1.15) and after approximately 7 months of treatment (*M* = 96.67%, *SD* = 2.61). More specifically, the number of commission errors during the no-go condition was low at pre-treatment (*M* = 2.44, *SD* = 2.25), and following approximately 7 months of treatment (*M* = 1.00, *SD* = 1.03). Participants did not differ in their accuracy (*z* = −0.12, *p* = 0.91; related-samples Wilcoxon Signed Rank Test) or response times on true positive responses (*z* = 0.65, *p* = 0.52; related-samples Wilcoxon Signed Rank Test) between the pre-treatment assessment and after 7 months of DBT. Participants, on the other hand, demonstrated a significant difference between pre- and post-treatment on commission errors (*z* = −2.22, *p* = 0.03; related-samples Wilcoxon Signed Rank Test). This finding, however, appeared to be driven by two participants who demonstrated a noticeable change in commission errors across the two time points (−23.33% change in commissions; *M* = −4.8%, *SD* = 8.57). Treatment completers did not differ from non-completers in accuracy (*z* = −0.10, *p* = 0.92; Independent-Samples Mann-Whitney *U* Test) or response times on true-positive trials (*z* = −0.86, *p* = 0.39; Independent-Samples Mann-Whitney *U* Test) on the go/no-go task. Additionally, no differences were observed between completers and non-completers with regard to commission errors during the no-go condition (*z* = −0.50, *p* = 0.62; Independent-Samples Mann-Whitney *U* Test).
Pre-Treatment PFC Activation and Changes through Treatment {#s3-3}
----------------------------------------------------------
Before beginning DBT, all participants with BPD who completed pre-treatment neuroimaging (*n* = 29) showed less activation in bilateral DLPFC and more activation in right medial PFC during response inhibition as compared to cross-hair fixation (*p'*s \< 0.05; Table [3](#T3){ref-type="table"}; Figure [2](#F2){ref-type="fig"}). For treatment completers (*n* = 18), participants also showed less activation in bilateral DLFPC before beginning treatment, and as shown in Figure [3](#F3){ref-type="fig"}, they showed treatment-related increases in activation in more widespread areas of medial aspects of the DLPFC bilaterally and right medial PFC. After 7 months of treatment, participants displayed higher levels of activation during response inhibition primarily in right DLPFC and to a lesser extent in the homologous region in the left PFC (*p*'s \< 0.01). They also showed higher activation in the right medial PFC (*p* \< 0.01). The main interactions for these analyses are summarized in Table [4](#T4){ref-type="table"}, while the simple effects analyses are summarized in Table [5](#T5){ref-type="table"}.
######
**Multilevel analyses comparing pre-treatment levels of oxygenated hemoglobin in all 16 channels during No-Go and cross-hair fixation blocks**.
fNIRS Channel *b* *SE* *df* *t* $R_{\beta}^{2}$
--------------- --------- -------- ---------- ------------- -----------------
1 −0.0961 0.0133 35142.22 −7.2510\*\* 0.0015
2 −0.0511 0.0136 37903.01 −3.7550\*\* 0.0004
3 −0.0489 0.0127 38347.04 −3.8460\*\* 0.0004
4 −0.0743 0.0144 37447.01 −5.1680\*\* 0.0007
5 0.0107 0.0126 38394.07 0.8520 0.0000
6 −0.0399 0.0146 37936.03 −2.7250\* 0.0002
7 0.0224 0.0129 36265.72 1.7360 0.0001
8 −0.0152 0.0160 32284.60 −0.9520 0.0000
9 0.0376 0.0147 34075.36 2.5560\* 0.0002
10 0.0095 0.0148 36608.12 0.6420 0.0000
11 0.0081 0.0118 38263.18 0.6840 0.0000
12 −0.0300 0.0135 37868.06 −2.2200 0.0001
13 −0.0168 0.0121 39050.07 −1.3960 0.0000
14 −0.0838 0.0157 39148.03 −5.3480\*\* 0.0007
15 −0.0227 0.0142 36182.99 −1.6010 0.0001
16 0.0010 0.0157 38275.14 0.0640 0.0000
*Note: \*\*p \< 0.001, \*p \< 0.05. All models were estimated with an unstructured covariance matrix and the Satterthwaite method of estimating degrees of freedom. Significance levels were corrected using the False Discovery Rate approach*.
{#F2}
{#F3}
######
**Multilevel analyses in all 16 channels examining the interaction between Condition (no-go vs. cross-hair fixation) and Time (pre-treatment vs. 7-month assessments)**.
fNIRS Channel *b* *SE* *df* *t* $R_{\beta}^{2}$
--------------- --------- -------- ---------- ------------ -----------------
1 0.0671 0.0097 58357.04 6.9430\*\* 0.0008
2 0.0615 0.0109 61952.94 5.6670\*\* 0.0005
3 0.0282 0.0094 62573.96 2.9980\* 0.0001
4 0.0551 0.0112 60260.94 4.9010\*\* 0.0004
5 −0.0086 0.0098 62525.01 −0.8820 0.0000
6 0.0046 0.0115 62449.96 0.3980 0.0000
7 0.0012 0.0109 59390.52 0.1070 0.0000
8 0.0127 0.0127 54627.41 1.0050 0.0000
9 −0.0038 0.0116 57034.33 −0.3310 0.0000
10 −0.0106 0.0124 58427.21 −0.8600 0.0000
11 0.0204 0.0100 59973.13 2.0500 0.0001
12 0.0400 0.0110 61945.00 3.6290\*\* 0.0002
13 0.0170 0.0099 61452.01 1.7190 0.0000
14 0.0442 0.0125 63002.99 3.5390\*\* 0.0002
15 0.0353 0.0106 60197.88 3.3360\* 0.0002
16 0.0806 0.0128 62765.93 6.2710\*\* 0.0006
*Note: \*\*p \< 0.001, \*p \< 0.05. All models were estimated with an unstructured covariance matrix and the Satterthwaite method of estimating degrees of freedom. Significance levels were corrected using the False Discovery Rate approach*.
######
**Multilevel analyses examining simple effects for channels with significant interactions between Condition (no-go vs. cross-hair fixation) and Time (pre-treatment vs. 7-month assessments)**.
fNIRS Channel *b* *SE* *df* *t* $R_{\beta}^{2}$
--------------------------------- --------- -------- ---------- ------------- -----------------
**Pre-Treatment**
1 −0.0976 0.0124 58357.18 −7.8800\*\* 0.0021
2 −0.0525 0.0137 61952.97 −3.8230\*\* 0.0005
3 −0.0500 0.0119 62573.99 −4.2020\*\* 0.0006
4 −0.0758 0.0139 60260.97 −5.4620\*\* 0.0010
12 −0.0306 0.0139 61945.06 −2.1930\* 0.0002
14 −0.0864 0.0156 63002.98 −5.5350\*\* 0.0010
15 −0.0215 0.0136 60197.92 −1.5850 0.0001
16 0.0005 0.0162 62766.45 0.0320 0.0000
**After 7 months of treatment**
1 0.0366 0.0148 58356.94 2.4660\* 0.0002
2 0.0705 0.0168 61952.93 4.1940\*\* 0.0006
3 0.0064 0.0146 62573.94 0.4400 0.0000
4 0.0344 0.0177 60260.92 1.9450 0.0001
12 0.0495 0.0171 61944.96 2.8940\* 0.0003
14 0.0020 0.0195 63002.99 0.1040 0.0000
15 0.0492 0.0163 60197.85 3.0220\* 0.0003
16 0.1617 0.0199 62765.59 8.1040\*\* 0.0021
*Note: \*\*p \< 0.001, \*p \< 0.05. All models were estimated with an unstructured covariance matrix and the Satterthwaite method of estimating degrees of freedom. Significance levels are FDR corrected*.
Associations between Changes in Symptom Severity and PFC Activation {#s3-4}
-------------------------------------------------------------------
Reductions in self-harm were significantly associated with changes in activation in right DLPFC (Condition × Time × Change-in-Self-Harm, *p* \< 0.01). Prior to beginning DBT, participants who showed the greatest reductions in self-harm displayed less activation in right DLPFC (*p* \< 0.01) compared to those with the least improvements in self-harm after 7 months. Whereas participants seeing the greatest reduction in self-harm had less activation in right DLPFC before starting treatment, they demonstrated the greatest increase in activation in this region after 7 months of treatment (*p* \< 0.01). Within a larger portion of the left DLPFC, a similar pattern of self-harm associations was found (*p*'s \< 0.01), with the exception that participants with the greatest and least improvements did not differ in level of activation before beginning DBT (these findings are summarized in Figure [4](#F4){ref-type="fig"}). Statistically controlling for changes in depression, mania, and BPD symptom severity did not change the pattern of activation in bilateral PFC and resulted in a more statistically significant result (Condition × Time × Change-in-Self-Harm interactions in both regions remained significant, *p*'s \< 0.01). The main interactions for these analyses are summarized in Table [6](#T6){ref-type="table"}, while the simple effects analyses are summarized in Table [7](#T7){ref-type="table"}.
{#F4}
######
**Multilevel analyses in all 16 channels examining the interaction between Condition (no-go vs. cross-hair fixation), Time (pre-treatment vs. 7-month assessments) and Changes-In-Self-Harm**.
fNIRS Channel *b* *SE* *df* *t* $R_{\beta}^{2}$
--------------- --------- -------- ---------- ------------ -----------------
1 0.0024 0.0007 58350.03 3.3780\*\* 0.0002
2 0.0016 0.0008 61945.93 1.9160 0.0001
3 −0.0010 0.0007 62566.95 −1.4170 0.0000
4 0.0042 0.0009 60253.93 4.5750\*\* 0.0003
5 0.0003 0.0007 62517.99 0.3980 0.0000
6 0.0025 0.0009 62442.98 2.8830\* 0.0001
7 0.0004 0.0008 59383.06 0.4380 0.0000
8 0.0021 0.0010 54620.06 2.1260 0.0001
9 −0.0004 0.0008 57027.22 −0.4560 0.0000
10 0.0006 0.0010 58420.01 0.6640 0.0000
11 −0.0020 0.0011 59966.06 −1.9220 0.0001
12 0.0011 0.0008 61937.97 1.3010 0.0000
13 0.0004 0.0011 61444.97 0.3690 0.0000
14 0.0034 0.0009 62995.97 3.6410\*\* 0.0002
15 0.0015 0.0008 60190.88 1.9440 0.0001
16 0.0019 0.0010 62758.65 1.9740 0.0001
*Note: \*\*p \< 0.001, \*p \< 0.05. All models were estimated with an unstructured covariance matrix and the Satterthwaite method of estimating degrees of freedom. Significance levels were corrected using the False Discovery Rate approach*.
######
**Multilevel analyses examining the simple effects for channels with significant Condition (no-go vs. cross-hair fixation) × Time (pre-treatment vs. 7-month assessments) × Changes-In-Self-Harm interactions**.
fNIRS Channel *b* *SE* *df* *t* $R_{\beta}^{2}$
--------------------------- ------------- --------------- --------- -------- ---------- ------------- -----------------
**Pre-Treatmet**
Low Treatment Response Left DLPFC 1 −0.0802 0.0137 58350.20 −5.8390\*\* 0.0006
4 −0.0578 0.0157 60253.96 −3.6890\*\* 0.0002
6 −0.0415 0.0162 62442.97 −2.5630\* 0.0001
Right DLPFC 14 −0.0575 0.0175 62995.97 −3.2900\*\* 0.0002
High Treatment Response Left DLPFC 1 −0.1404 0.0209 58350.43 −6.7170\*\* 0.0008
4 −0.1208 0.0231 60253.96 −5.2330\*\* 0.0005
6 −0.0321 0.0249 62443.13 −1.2920 0.0000
Right DLPFC 14 −0.1560 0.0266 62996.05 −5.8600\*\* 0.0005
**After 7 months of DBT**
Low Treatment Response Left DLPFC 1 −0.0800 0.0233 58349.95 −0.3430 0.0000
4 −0.0617 0.0300 60253.93 −2.0560\* 0.0001
6 −0.1067 0.0284 62442.95 −3.7570\*\* 0.0002
Right DLPFC 14 −0.0580 0.0310 62995.98 −1.8710 0.0001
High Treatment Response Left DLPFC 1 0.1092 0.0329 58349.95 3.3230\*\* 0.0002
4 0.1905 0.0433 60253.93 4.4040\*\* 0.0003
6 0.0882 0.0401 62442.95 2.1990\* 0.0001
Right DLPFC 14 0.0977 0.0436 62995.96 2.2410\* 0.0001
*Note: \*\*p \< 0.01, \*p \< 0.05. All models were estimated with an unstructured covariance matrix and the Satterthwaite method of estimating degrees of freedom. Significance levels are FDR corrected*.
Pre-Treatment Activation Differences Between Completers and Non-Completers {#s3-5}
--------------------------------------------------------------------------
Compared to participants that either dropped out or did not initiate treatment (*n* = 9), participants that completed 7 months of treatment (*n* = 20) showed less pre-treatment activation during response inhibition in a large cluster within the left DLPFC (Figure [5](#F5){ref-type="fig"}). Additionally, they showed less activation in a smaller region within the right DLPFC. Conversely, non-completers displayed greater activation mainly in the medial PFC/frontal pole and right inferior frontal gyrus prior to beginning DBT. This pattern of higher activation was found in a larger spatial extent within the medial PFC and right DLPFC in participants who dropped out (*n* = 5) as compared to those who completed approximately 7-months of treatment (*p*'s \< 0.05). Participants who did not initiate treatment, on the other hand, showed less activation in two smaller areas of the PFC bilaterally and showed higher activation to a similar spatial extent in the right lateral PFC, as compared to those who initiated and remained in treatment (*p*'s \< 0.05). The main interactions for these analyses are summarized in Table [8](#T8){ref-type="table"}, while the simple effects analyses are summarized in Tables [9--11](#T9){ref-type="table"}.
{#F5}
######
**Multilevel analyses in all 16 channels examining the interaction between Condition (no-go vs. cross-hair fixation) and Treatment Completion Status (completers vs. non-completers)**.
fNIRS Channel *b* *SE* *df* *t* $R_{\beta}^{2}$
--------------- --------- -------- ---------- ------------- -----------------
1 −0.0480 0.0145 35139.24 −3.3030\*\* 0.0003
2 −0.0123 0.0155 37900.06 −0.7960 0.0000
3 −0.0540 0.0142 38344.06 −3.8020\*\* 0.0004
4 −0.0414 0.0162 37444.04 −2.5600\* 0.0002
5 −0.1156 0.0134 38391.11 −8.6120\*\* 0.0019
6 −0.0704 0.0159 37933.02 −4.4130\*\* 0.0005
7 −0.1047 0.0141 36263.39 −7.4220\*\* 0.0015
8 −0.0298 0.0174 32282.18 −1.7110 0.0001
9 −0.0876 0.0160 34072.27 −5.4620\*\* 0.0009
10 −0.0634 0.0163 36605.21 −3.8980\*\* 0.0004
11 −0.0634 0.0127 38260.13 −4.9810\*\* 0.0006
12 0.0213 0.0147 37865.12 1.4460 0.0001
13 −0.0581 0.0131 39047.12 −4.4220\*\* 0.0005
14 −0.0337 0.0169 39145.02 −1.9940 0.0001
15 −0.0050 0.0151 36179.00 −0.3300 0.0000
16 −0.0622 0.0176 38272.81 −3.5380\*\* 0.0003
*Note: \*\*p \< 0.001, \*p \< 0.05. All models were estimated with an unstructured covariance matrix and the Satterthwaite method of estimating degrees of freedom. Significance levels were corrected using the False Discovery Rate approach*.
######
**Multilevel analyses examining the simple effects for significant interaction between Condition (no-go vs. cross-hair fixation) and Treatment Completion Status (completers vs. non-completers)**.
fNIRS Channel *b* *SE* *df* *t* $R_{\beta}^{2}$
------------------------------- --------- -------- ------------ ------------- -----------------
**Completers (*n* = 19)**
1 −0.1243 0.0158 35139.2230 −7.8820\*\* 0.0018
3 −0.0788 0.0149 38344.0410 −5.2760\*\* 0.0007
4 −0.0966 0.0168 37443.9980 −5.7470\*\* 0.0009
5 −0.0632 0.0152 38391.0470 −4.1510\*\* 0.0004
6 −0.0822 0.0175 37933.0210 −4.7050\*\* 0.0006
7 −0.0390 0.0153 36262.2080 −2.5430\* 0.0002
9 −0.0148 0.0176 34072.3360 −0.8450 0.0000
10 −0.0268 0.0174 36605.0160 −1.5360 0.0001
11 −0.0316 0.0142 38260.2510 −2.2200\* 0.0001
13 −0.0517 0.0144 39047.0440 −3.5870\* 0.0003
16 −0.0324 0.0183 38271.6950 −1.7690 0.0001
**Non-Completers (*n* = 10)**
1 −0.0283 0.0244 35139.2390 −1.1620 0.0000
3 0.0291 0.0241 38344.0710 1.2060 0.0000
4 −0.0139 0.0276 37444.0590 −0.5030 0.0000
5 0.1680 0.0221 38391.1350 7.5970\*\* 0.0015
6 0.0585 0.0267 37933.0140 2.1940\* 0.0001
7 0.1705 0.0237 36263.8770 7.1950\*\* 0.0014
9 0.1604 0.0269 34072.2410 5.9750\*\* 0.0010
10 0.1001 0.0275 36605.2920 3.6420\*\* 0.0004
11 0.0951 0.0211 38260.0710 4.5110\*\* 0.0005
13 0.0645 0.0220 39047.1570 2.9360\*\* 0.0002
16 0.0921 0.0300 38273.2120 3.0660\*\* 0.0002
*Note: \*\*p \< 0.001, \*p \< 0.05. All models were estimated with an unstructured covariance matrix and the Satterthwaite method of estimating degrees of freedom. Significance levels are FDR corrected*.
######
**Multilevel analyses exploring simple effects of the significant Inhibitory Control × Treatment Completion interaction for those who dropped out of treatment**.
fNIRS Channel *b* *SE* *df* *t* $R_{\beta}^{2}$
--------------------------- --------- -------- ---------- ------------- -----------------
**At Pre-Treatment**
1 −0.0976 0.0124 58357.19 −7.8800\*\* 0.0008
2 −0.0525 0.0137 61952.97 −3.8230\*\* 0.0005
3 −0.0500 0.0119 62573.99 −4.2020\*\* 0.0001
4 −0.0758 0.0139 60260.97 −5.4620\*\* 0.0004
12 −0.0306 0.0139 61945.06 −2.1930\* 0.0002
14 −0.0864 0.0156 63002.98 −5.5350\*\* 0.0002
15 −0.0215 0.0136 60197.92 −1.5850 0.0002
16 0.0005 0.0162 62766.45 0.0320 0.0006
**After 7 months of DBT**
1 0.0366 0.0148 58356.94 2.4660\* 0.0001
2 0.0705 0.0168 61952.93 4.1940\*\* 0.0003
3 0.0064 0.0146 62573.94 0.4400 0.0000
4 0.0344 0.0177 60260.92 1.9450 0.0001
12 0.0495 0.0171 61944.96 2.8940\*\* 0.0001
14 0.0020 0.0195 63002.99 0.1040 0.0000
15 0.0492 0.0163 60197.85 3.0220\*\* 0.0002
16 0.1617 0.0199 62765.59 8.1040\*\* 0.0010
*Note: \*\*p \< 0.001, \*p \< 0.05. All models were estimated with an unstructured covariance matrix and the Satterthwaite method of estimating degrees of freedom. Significance levels are FDR corrected*.
######
**Multilevel analyses exploring simple effects of the significant Inhibitory Control × Treatment Completion interaction for those who never initiated treatment**.
fNIRS Channel *b* *SE* *df* *t* $R_{\beta}^{2}$
--------------- --------- -------- ---------- ------------- -----------------
6 −0.0338 0.0122 53960.95 −2.771\* 0.0001
8 0.0140 0.0135 46651.03 1.0420 0.0000
10 0.0029 0.0123 49939.09 0.2330 0.0000
12 0.0187 0.0119 53387.97 1.5780 0.0000
14 −0.0489 0.0132 54493.98 −3.7170\*\* 0.0003
15 0.0135 0.0111 51818.83 1.2150 0.0000
16 0.0656 0.0130 54461.77 5.0310\*\* 0.0005
*Note: \*\*p \< 0.001, \*p \< 0.05. All models were estimated with an unstructured covariance matrix and the Satterthwaite method of estimating degrees of freedom. Significance levels are FDR corrected*.
Changes in activation for intention-to-treat analyses were examined wherein pre-treatment observations were carried forward for those who did not complete 7 months of treatment. The pattern of activation across the PFC for intention-to-treat analyses was similar to that observed in analyses using completers alone, but with smaller clusters of significant change (*p*'s \< 0.5).
Discussion {#s4}
==========
Consistent with randomized-controlled trials of DBT (Linehan et al., [@B20]; McMain et al., [@B21]), participants with BPD in the current study showed substantial declines in their frequency of self-harm over the treatment period. Prior to beginning treatment, patients had less activation in bilateral middle/inferior frontal gyri during response inhibition. After 7 months of treatment, they showed significant gains in activity in these same regions. Reductions in self-harm over the treatment period were specifically related to right DLPFC activation, even after statistically controlling for changes in depression, mania, and BPD symptom severity, and patients showing the greatest treatment gains showed lower activation in this region prior to beginning DBT. Additionally, treatment completers showed less activation in left DLPFC before starting treatment, whereas non-completers displayed higher activation in medial PFC and right inferior frontal gyrus.
Reduced activation in bilateral middle/inferior frontal gyri during response inhibition for patients with BPD prior to beginning treatment likely reflects a diminished recruitment of inhibitory control processes subserved by the PFC, especially within the left DLPFC. This pattern of activity contrasts with healthy adults on the same go/no-go task, who have shown higher levels of activity in bilateral DLPFC during response inhibition (compared to cross-hair fixation; Rodrigo et al., [@B26]). These results also parallel studies that have used different response inhibition tasks (e.g., emotional Stroop) in which patients with BPD show differences in neural activation in left inferior frontal gyrus under conditions of response inhibition (Wingenfeld et al., [@B35]; Winter et al., [@B36]). Overall, these findings indicate that before beginning treatment, patients with BPD characterized by marked behavioral impulsivity (i.e., active self-harm) show reduced activation in lateral areas of the PFC responsible for motor inhibitory control (Aron et al., [@B3]).
Despite showing significantly lower activity in bilateral medial and inferior frontal gyri prior to beginning treatment, patients exhibited increases in activity within these regions after approximately 7 months of DBT. The right lateral PFC, an area highly linked to impulse control (Aron et al., [@B3]), showed a specific association with changes in frequency of self-harm over the treatment period. Increases in activation within this region were related to corresponding reductions in self-harm after DBT. Remarkably, patients who went on to display the greatest improvements in self-harm exhibited the lowest activation in right DLPFC prior to beginning treatment; however, they also demonstrated the greatest increases in activation in this area after 7 months of DBT. These results suggest that self-harming patients with BPD who show the lowest pre-treatment engagement of prefrontal regions involved in motor control (as well as other aspects of self-regulation) may have the most to gain from a psychological treatment intended to increase behavioral and emotional control. Moreover, these potential neural markers of treatment response appear to be detectable even before patients begin treatment.
Patients who ultimately did not complete treatment displayed more activation in the medial PFC and right inferior frontal gyrus before starting DBT. Conversely, treatment completers showed less activation in a large region of the left DLPFC prior to beginning DBT. Heightened activity in the right inferior frontal gyrus, a region critical for impulse control, appears to represent a risk factor that may prospectively predict which patients will not complete treatment. It is possible that control processes subserved by the PFC are more efficiently recruited in this subset of patients as compared to treatment completers, who showed less activation in a roughly homologous region in the left hemisphere. Higher levels of activation in the medial PFC, a neural region involved in self-referential thinking (Gusnard et al., [@B16]), could also reflect an increased focus on the self in relation to others among patients at risk for treatment non-completion. Indeed, increased activation in medial PFC is observed in patients with BPD engaged in social-cognitive activities (Ruocco et al., [@B30]; Domsalla et al., [@B12]), possibly reflecting so-called "hyper-mentalizing" (i.e., heightened attention to one's own intentional mental states and that of others), which is considered central to developmental theories of the disorder (Fonagy and Bateman, [@B14]). This is a speculative interpretation of these results; however, they may be relevant to social and interpersonal dynamics that could impact the degree of engagement in psychotherapy.
A main limitation of this study is its focus on the PFC, which although strongly linked to response inhibition (Rodrigo et al., [@B26]), is one hub of a larger brain network subserving this cognitive ability (Swick et al., [@B32]). Whereas the fNIRS system employed in this study primarily accesses the anterior portion of the frontal cortex, an important advantage of the technique is that it affords high temporal resolution and is both portable and cost-effective, which may facilitate its translation to clinical settings (Irani et al., [@B17]). For these results to have an applied clinical value, however, replication in a larger cohort of patients using a randomized-controlled design in a formal clinical trial is necessary. Indeed, prospective investigation of the predictive utility of these biomarkers will assist in validating the current findings, especially in relation to their incremental validity over other clinical measures. Furthermore, examination of the test-retest reliability of fNIRS requires further study to establish the potential clinical utility of these findings. While the present study was naturalistic in its design and included patients with BPD who were treated as part of regular clinical services and were mostly on medications and had high levels of psychiatric diagnostic comorbidity, these results may be more generalizable to the typical DBT treatment setting with self-harming patients with BPD. Additionally, factors such as age, gender, and handedness could potentially impact the results of this work. Future research with adequately large sample sizes should address these questions while also extending the present findings to interactions between response inhibition and affective processes. It is also important to note that, given the preliminary nature of the present study, it is premature to draw specific conclusions about the effectiveness of fNIRS for predicting treatment outcomes at the level of an individual patient. These results provide initial evidence for potential neuroimaging-based biomarkers that may be used to prospectively predict treatment outcomes. Importantly, these findings must be replicated in independent samples using appropriate statistical techniques to assess the sensitivity and specificity of the biomarkers for predicting treatment outcomes.
In summary, the potential implication of this research is that distinct patterns of neural activity in areas of the PFC reflecting treatment responses to DBT and attrition from therapy may be detectable even before patients start treatment. Research to validate these potential biomarkers reflecting future treatment outcomes may assist in identifying at-risk patients and intervening earlier in the course of self-harm to prevent potential serious injury and suicide. Ultimately, this work may also help to reduce self-harm in more vulnerable patients identified using these candidate biomarkers by increasing the intensity of DBT or diverting these patients toward alternative interventions.
Author Contributions {#s5}
====================
ACR made a substantial contribution to the study conception and design, the acquisition of data, and analysis and interpretation of the data. AHR made a substantial contribution to the collection of data and analysis and interpretation of the data. SFM made a substantial contribution to the study conception and design and interpretation of the data. EP-G made a substantial contribution to the analysis and interpretation of the data. HA made a substantial contribution to the study conception and design, and analysis and interpretation of the data. PSL made a substantial contribution to the study conception and design and interpretation of the data. All listed authors made a substantial contribution to drafting the article and gave final approval of the version of the article to be published.
Funding {#s6}
=======
This research was supported by Grant YIG-1-034-11 awarded to ACR and PSL from the American Foundation for Suicide Prevention. The content is solely the responsibility of the authors and does not necessarily represent the official views of the American Foundation for Suicide Prevention. This research was also supported in part by a New Investigator Salary Award (MSH--130177) from the Canadian Institutes of Health Research and an Early Researcher Award (ER14-10-185) from the Ministry of Research and Innovation, Province of Ontario to ACR.
Conflict of Interest Statement {#s7}
==============================
Dr. Ayaz reports that he was involved in the development of the optical brain imaging instrumentation utilized in the present research and has a minor share in the firm fNIR Devices, L.L.C., which manufactured the fNIRS device. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
[^1]: Edited by: Nobuo Masataka, Kyoto University, Japan
[^2]: Reviewed by: Robert Christian Wolf, University of Heidelberg, Germany; Hirokazu Doi, Nagasaki University, Japan
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Unverricht-Lundborg progressive myoclonus epilepsy in Oman.
We analyzed the clinical, electrophysiologic, and genetic features of Omani Arab patients suspected of manifesting the Unverricht-Lundborg form of progressive myoclonus epilepsy. Ten patients (five boys, five girls; mean age at onset, 10.2 years) were evaluated. Unverricht-Lundborg disease was confirmed in all by detection of dodecamer repeat expansion mutations in the EPM1 gene. There was no correlation between age at onset or severity of disease with sizes of dodecamer repeats. Myoclonic seizures were the presenting symptom in 70% of patients. Myoclonus was severe in adolescence, but remained stable or improved beyond 5-6 years of disease onset. No significant cognitive decline occurred. Nearly 75% of patients exhibited mild to moderate cerebellar dysfunction, which was nonprogressive after adulthood. Slowing of background activity, generalized spike-wave discharges, and photoparoxysmal responses were evident in all patients' electroencephalograms. Spike-wave discharges and photoparoxysmal responses tended to disappear in adulthood. This cluster of progressive myoclonus epilepsy patients manifested typical Unverricht-Lundborg disease. All cases had mutations in EPM1, the known gene for this disorder, and therefore do not contribute to identifying the gene in a second Unverricht-Lundborg disease locus recently mapped in Arab patients from Israel. Although Unverricht-Lundborg disease is very severe in adolescence, its clinical signs stabilize and improve somewhat in adulthood in this so-called "progressive epilepsy."
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E-cigs . . . Are They Cool? Talking to Teens About E-Cigarettes.
Electronic cigarettes, or e-cigarettes as they are commonly called, have gained wide acceptance among adolescents, especially those with sweet flavors such as bubble gum and cheesecake. Although health effects of e-cigarettes have not been well characterized, their use increases a teen's exposure to nicotine and may serve as a gateway to traditional cigarettes. This article outlines the basics of e-cigarettes and potential health hazards, followed by selected literature on teens' perceptions of e-cigarettes, as well as motivational interviewing strategies that can be used in talking to teens about using electronic cigarettes.
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Regulators: Dakota Access company complied with settlement
BISMARCK, N.D. (AP) — The developer of the Dakota Access oil pipeline has planted tens of thousands of trees and taken other steps to settle allegations that it violated North Dakota rules during construction, state regulators have concluded....
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Q:
What is the best practice for asp.net 3.5 build management for fast-changing line of business apps
I work with two other developers for a medium-sized company writing internal applications in asp.net. We have about 10 discrete web applications, about 5 class libraries, and probably two dozen assorted command line and WinForms apps. Management expects us to be able to roll out an application multiple times per day, as required by their business rules du jour.
We are currently (mostly) using Microsoft.Net 1.1 and SourceSafe. When we need to roll out a web app, we get latest from SourceSafe, rebuild, and then copy to the production web server. We are also in the habit of creating massive solution files with 5-10 projects so that everything gets rebuilt and copied to our "master" bin folder instead of opening up each project one by one to rebuild them.
I know there must be a better way to do this, and with Visual Studio 2010 and Microsoft.Net 4.0 being released in the coming months it seems like a good time to upgrade our environment. Does Microsoft have an official opinion/whitepaper on how to set things up? My biggest problem in the past was having a system that worked well with how quickly we're expected to push code into production.
A:
There's a build server for .NET called CruiseControl.NET. You may find it useful as it can be heavily automated.
A:
See "patterns & practices Team Development with Visual Studio Team Foundation Server".
Read the whole thing. It contains things you may never have known existed.
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Leading the western hat industry, Bullhide stays loyal to their traditional techniques while keeping up with the latest western designs. Wagoneer cowboy hat from Bullhide by Montecarlo is a bestseller made of shapeable wool. A neat feature that lets you be you. Silver-tone studs and diamond-shaped accents highlight thin leather hatband. Traditional cattleman crease hat styling. Get value and quality with Bullhide hats!
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Q:
Bulk insert not working for NULL data
When I am inserting bulk data to a table from a CSV file, it is not working, showing error lie :
Bulk load data conversion error (type mismatch or invalid character for the specified codepage) for row 2, column 9
Column 9 value in csv file is null..
How do I take care of this?
A:
From this amount of information I'd say the target table's particular field is defined as "NOT NULL". To workaround the issue you have to:a) modify csv-->add value to field(s) where they have nullb) modify target table by setting affected fields 'nullable':ALTER TABLE [tblName] ALTER COLUMN [nulColName] [varType such as INT] NULLIn case you go for this solution and want to turn back table's status alter it again:UPDATE [tblName] SET [nulColName]=-1000 WHERE [nulColName] IS NULL to avoid alter errors, then ALTER TABLE [tblName] ALTER COLUMN [nulColName] [varType such as INT] NOT NULLc) pretty much like 'b' option but a bit more professional and faster: create a temp table based on target table but allowing nulls to any and all fields, then update temp table's null records after csv import with a "default value" and copy the data to the target tableIf I'm right about the issue and there's no option to revise csv I'd go for option 'c'
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Kuch Khatti Kuch Meethi
Kuch Khatti Kuch Meethi () is a 2001 Indian film directed by Rahul Rawail and starring Kajol in a double role as two estranged identical twins. The storyline follows the general theme of its Hollywood counterpart The Parent Trap, which is based on the novel Lottie and Lisa, but with the added melodrama and slight-changed storyline of a Bollywood movie. The film also stars Sunil Shetty, Rishi Kapoor, Rati Agnihotri and Pooja Batra. This is the second time that Kajol played a dual role after Dushman. The rights to this film are owned by Shah Rukh Khan's Red Chillies Entertainment.
Plot
Raj Khanna (Rishi Kapoor) is a wealthy businessman who lives with his wife Archana (Rati Agnihotri), stepsister Devyani (Mita Vasisht), her spouse (Pramod Moutho), and her son Teddy (Mayur), in a mansion. Raj and Archana's lives are marred by marital discord, until they separate. Shortly before separating, Archana gives birth to identical twins: one of these is taken by Devyani and handed to Raj without Archana's knowledge. This infant becomes an embittered young woman sentimentally named Sweety (Kajol), and Raj becomes a helpless alcoholic. Archana has moved to London with the other daughter, Tina (also Kajol). In contrast to Sweety's ferocity, Tina is meek, compassionate, sympathetic, and demure. Each year, Archana buys two identical presents, gives one to Tina on her birthday, and locks the other into a closet to symbolize giving to Sweety, whom she believes is dead.
Sweety is of marriageable age, but refuses to marry the man of her aunt's choice, and runs away to London. Once there, she is mistaken for her sister by Archana. Later, when the twins meet, they realize that Devyani has been scheming to keep Raj under her control, and change places in hope of freeing Raj and reuniting their family: each according to her own personality, but under the name of her sister. Tina goes to India to cure their father of alcoholism, while Sweety remains in England to acclimate their mother to her habits.
When Tina meets with Raj, she finds out that he is having a sexual affair with a young woman named Savitri (Pooja Batra), who was introduced to him by Devyani. When Savitri attempts to drug and seduce him, in hope of having him impregnate her (and so necessitate marriage), Tina gives the drug to Raj's aged, faithful, comical servant Ballu Mamaji (Razak Khan). Savitri becomes pregnant with Ballu Mamaji's child. Later, Sweety and Tina marry her off to Uncle Ranjit (Parmeet Sethi) who is a wealthy man. Ballu Mamaji attempts his own offer, but is refused. Through a series of tricks, the twins fool Raj and Archana into reconciling; Devyani's plots to gain power are exposed; and Raj, of his own will, urges Archana to stay.
Cast
Kajol as Tina / Sweety Khanna, Raj and Archana's daughters
Rishi Kapoor as Raj Khanna
Sunil Shetty as Sameer
Rati Agnihotri as Archana Khanna
Mita Vasisht as Devyani, Raj's stepsister
Razzak Khan as Baloo
Pooja Batra as Savitri
Pramod Moutho as Doctor, Devyani's lover
Dinesh Hingoo as Sweety's prospective father-in-law
Parmeet Sethi as Uncle Ranjit
Trivia
Aishwarya Rai Bachchan was considered for the role of Tina/Sweety.
Rati Agnihotri returned to acting with this film after a 16-year break for marriage and motherhood.
Tracks list
The film soundtrack contains 8 songs composed by Anu Malik and penned by Sameer.
"Ab Nahi To Kab": Anu Malik & Sunidhi Chauhan
"Band Kamre Mein": Anuradha Sriram
"Khud Bhi Nachungi": Alka Yagnik
"Kuch Kuch Khatti": Alka Yagnik
"Neend Udh Rahi Hai": Alka Yagnik & Kumar Sanu
"Saamne Baith Kar": Alka Yagnik & Kumar Sanu
"Tumko Sirf Tumko I": Kumar Sanu& Alka Yagnik
"Tumko Sirf Tumko II": Kumar Sanu
References
External links
Category:2001 films
Category:Films based on Lottie and Lisa
Category:Indian films
Category:2000s Hindi-language films
Category:2000s drama films
Category:Twins in Indian films
Category:Films directed by Rahul Rawail
Category:Indian drama films
Category:Films scored by Anu Malik
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20 SHARES Facebook Twitter
If “Watchmen” or “The Social Network” has taught us anything is that your movie or TV show could always improve with a little music from the Nine Inch Nails frontman Trent Reznor and his creative partner Atticus Ross, but apparently Fox and the filmmakers behind “The Woman in The Window” didn’t get the memo, as the entire score is now being scrapped, not to be left behind, Reznor also had some negative things to say about the Netflix sensation, “Bird Box.”
READ MORE: Trent Reznor Admits That He & Atticus Ross Are A “Risky Choice” To Score Pixar’s ‘Soul’
In an interview with Revolver, Reznor discussed his experience with the Netflix thriller, criticizing the editing of the film and the use of his and Ross’ music. “When we got immersed in it, it felt like some people were phoning it in. And you’re stuck with a film editor who had real bad taste,” the composer said. “That’s kind of our barricade to getting stuff in the film. And the final icing on the shit cake was we were on tour when they mixed it. And they mixed the music so low, you couldn’t hear it anyway. So it was like, that was a … [Laughs] That was a fucking waste of time. Then we thought, no one’s going to see this fucking movie. And, of course, it’s the hugest movie ever in Netflix.”
The conversation then turned to what should be Reznor and Ross’ next film gig, the Joe Wright-directed film “The Woman in The Window” starring Amy Adams. The film was scheduled to come out this past October, before extensive reshoots due to negative test screening feedback caused the release date to be pushed for May 15, 2020. According to Reznor, the film “underwent a transformation after some testing audiences,” which caused Reznor and Ross to “bow out” of the project, adding: ”There’s no animosity on our end. It’s frustrating when you did that much work and it’s gone. And we were proud – and they were proud – of the movie that it was.”
READ MORE: ‘The Woman In The Window’ Trailer: Amy Adams Hides In A New Mystery Thriller
The news will come as a bummer to fans of the music duo. Instead, “The Woman in The Window” will be scored by Danny Elfman.
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High-definition remasters of Shenmue and Shenmue II will launch in 2017, according to “a trusted source close to Atlus USA” of blog and online retailer Rice Digital.
The website reports that both games may be released together rather than separately, and are likely being geared up to launch before Shenmue III. While it doesn’t have any further information, the website said it was told it is “safe to assume a PC / Steam release,” and that there has not been any indication that the remasters will appear on any other platform.
The author of the article previously leaked information that Atlus would publish The King of Fighters XIV a few days before its official announcement.
Back in January, Sega registered a pair of Shenmue remaster-related domains in ShenmueHD.com and ShenmueRemastered.com.
Prior to that, in May 2017, Sega said it was “investigating” working on remasters of Shenmue and Shenmue II.
The long-anticipated sequel, Shenmue III, is in development at Ys Net and currently slated for release for PlayStation 4 and PC in December.
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Background
==========
In recent years, hydrogen energy has found increased attention as a renewable and clean energy source in scientific community and government organizations \[[@B1]-[@B3]\]. Also, it has enormous potential to be developed as a new substitutive energy resource for solving energy crisis in the future. Among many methods for the generation of hydrogen, solar water splitting is a particularly attractive one because of the environmental friendliness and the abundance of water source \[[@B4]-[@B7]\]. Fujishima and Honda were the first to demonstrate the concept of water splitting in a series of experiments using titanium dioxide as a photoanode \[[@B8]\]. Up to date, many efforts have been done on the development of photoelectrodes to improve the efficiency of hydrogen generation \[[@B6],[@B7],[@B9]-[@B12]\].
TiO~2~ is the typical photoelectrode material most extensively examined. ZnO is a cheap and safe semiconductor. Its energy-band structure and physical properties are similar to those of TiO~2~, but it has higher electronic mobility which is favorable for electron transport. So, it has the potential as an alternate of TiO~2~ in photovoltaic or photoelectrochemical devices \[[@B13]\]. However, both TiO~2~ and ZnO are not photocatalytic in the visible light region. Since most of the solar frequency spectrum intensity is located in the wavelength range of 400--800 nm, the drawback of nonabsorbing ability in the visible light region significantly limited their hydrogen generation efficiency in the photoelectrochemical cells \[[@B14]\]. So an important strategy was focused on their doping with carbon or nitrogen \[[@B15]-[@B17]\], the adsorption of dyes \[[@B18],[@B19]\], the deposition of quantum dots \[[@B20]-[@B26]\], and the use of other semiconductor metal oxides capable of visible light absorption such as WO~3~\[[@B27],[@B28]\] and Fe~2~O~3~\[[@B29],[@B30]\] to enhance the absorption of visible light. Furthermore, to enhance the charge-transport property by increasing the direct electron conduction, the other important strategy was the development of their 1-D nanostructures such as nanorods \[[@B24],[@B31],[@B32]\], nanowires \[[@B16],[@B21],[@B22],[@B26],[@B33]\], and nanotubes \[[@B25],[@B34],[@B35]\].
On the other hand, it is mentionable that photoactive materials of photoelectrodes are usually coated or grown on the transparent conducting oxide (TCO) thin film for collecting electron efficiently. The suitable TCO materials are the SnO~2~, In~2~O~3~, and ZnO-based binary semiconductor compounds and the multicomponent oxides composed of combinations of these binary compounds \[[@B36]\]. Since the undoped oxide thin films have lower conductivity and are unstable at a high temperature, impurity doping is usually necessary in practical use. The typical examples include the F-doped SnO~2~ (FTO), Sb-doped SnO~2~ (ATO), Sn-doped In~2~O~3~ (ITO), and Al-doped ZnO (AZO) \[[@B36]\]. For solar energy conversion to date, the most common TCOs in dye-sensitized solar cell (DSSC), solar water splitting, and quantum dot-sensitized solar cell (QDSSC) are ITO and FTO. However, as has been known, the rare metal indium is expensive \[[@B37]\]. So, for DSSC, QDSSC, and the solar-driven water splitting in a photoelectrochemical cell, FTO has become the better choice. Moreover, some SnO~2~- and In~2~O~3~-based double layers or triple layers such as TiO~2~/ITO, Nb-doped TiO~2~/ITO, FTO/ITO, SnO~2~/ITO, and TiO~2~/ATO/ITO have also been developed to improve the energy conversion efficiency \[[@B38],[@B39]\].
Besides the SnO~2~- and In~2~O~3~-based TCOs, AZO is another attractive TCO material because of its nontoxicity, relative abundance, low cost, thermal stability, and durability in hydrogen plasma \[[@B36],[@B40]\]. Furthermore, Lee et al. has also reported that the ZnO nanowire-based DSSC using AZO as the TCO substrate showed superior cell performance than that using FTO as the TCO substrate \[[@B41]\]. This revealed that AZO could be used to replace ITO or FTO as the TCO substrate in DSSCs, QDSSCs, and the photoelectrochemical cell for water splitting. In addition, it is also mentionable that some efforts have been made on the development of other ITO-, FTO-, and even TCO-free electrodes in solar cells, such as the grapheme- and poly(3,4-alkylenedioxythiophene) (PEDOT)-based electrodes \[[@B42],[@B43]\].
As stated above, ZnO not only is the photoactive material of photoelectrode, but also can be used as a TCO substrate after Al-doping and hydrogen treatment. Recently, we synthesized the ZnO nanorod array thin film and demonstrated that appropriate Al-doping and hydrogen treatment could lead to the significant transparency improvement and 1,000-fold conductivity enhancement \[[@B44]\]. This revealed that the AZO nanorod array thin film with hydrogen treatment possessed the functions of TCO thin film and photoelectrode simultaneously. Thus, the AZO nanorod array thin film with hydrogen treatment might be used directly as an ITO- and FTO-free photoelectrode. This made the fabrication of photoelectrode simple and low-cost because the use of expensive rare metal was avoided and the pre-fabrication of an extra TCO substrate is not necessary. Although the ZnO nanowire- or nanorod-based DSSC has been reported \[[@B19]\], TCO substrate was still used, and the phoelectrode using AZO has showed superior cell performance than using FTO \[[@B41]\]. So, such an AZO nanorod-based photoelectrode without an extra TCO substrate has great potentials in DSSCs, QDSSCs, and the photoelectrochemical cell for water splitting. Based on this reason, in our more recent work, the AZO nanorod array thin film with hydrogen treatment has been demonstrated to possess good photoresponse and stability \[[@B45]\]. Also, a preliminary test showed that its sensitization by cadmium sulfide (CdS) nanoparticles via the chemical bath deposition method could enhance the hydrogen generation efficiency efficiently because of the significant absorption of CdS nanoparticles over a wide wavelength range in the visible light region which made them useful in the development of nanocomposite photoanodes for photoelectrochemical water splitting \[[@B20]-[@B26]\].
Accordingly in this work, a comprehensive study has been done to develop the CdS nanoparticles-sensitized AZO nanorod array thin film as a nanocomposite photoanode for solar water splitting without an extra TCO substrate. The effect of cycle number for the chemical bath deposition of CdS nanoparticles on the photoelectrochemical properties was studied. For comparison, the photoelectrochemical properties of CdS nanoparticles-sensitized thin films without Al-doping and/or hydrogen treatment were also examined. In addition, the effect of post-heat treatment was also examined to enhance the hydrogen generation efficiency.
Methods
=======
AZO nanorod array thin film was synthesized in a chemical bath according to our previous work \[[@B44]\]. Firstly, for the deposition of ZnO seed layer, 0.4 M zinc acetate solution was prepared by dissolving zinc acetate in 11 mL of 2-methoxyethanol via sonication for 0.5 h and mixing with 0.5 mL of monoethanolamine. Then this solution was kept in a water bath at 60°C for 1 h and aged at room temperature for another 2 days. The resulting solution was deposited on the glass substrate (0.1 mL on a square of 2.5 × 2.5 cm^2^) by a spin coater at a rate of 3,000 rpm for 30 s, and then the as-deposited thin film was dried in a furnace at 350°C for 10 min to evaporate the solvent and remove organic residuals. After repeating the spin coating and drying procedures for ten times to obtain the required thickness, the obtained thin film was put into a furnace and calcined in air at 550°C for 2 h to yield the ZnO seed layer.
For the growth of AZO nanorod array thin film on the ZnO seed layer, 15 mL of aqueous solution containing zinc nitrate (0.004 M) and aluminum nitrate (Al/Zn molar ratio/20%) was mixed with the mixture of 0.46 ml diethylenetriamine and 15 mL water. After sonication for 10 min to dissolve the precursor, the solution pH was adjusted to 11.5 with 10 M NaOH to yield the deposition solution. Then the ZnO seed layer-coated glass substrate was immersed into the deposition solution and kept in an oven at 95°C for 6 h. After cooling to room temperature naturally, the glass substrate grown with AZO nanorods was washed with water and ethanol several times to remove the organic residue and dried at 70°C in an oven for 2 h. In performing hydrogen treatment to increase the crystallinity, remove organic residual, and enhance the conductivity, the as-grown AZO nanorod array thin film was annealed in Ar/H~2~ (97/3) atmosphere at 400°C with a gauge pressure of 0.4 kg/cm^2^ for 2 h. For comparison, the thin films without Al-doping and/or hydrogen treatment were also prepared according to the above method. According to our previous work \[[@B44]\], the resulting AZO nanorods had an average diameter of 64.7 ± 16.8 nm and an average length of about 1.0 μm.
CdS nanoparticles were decorated on the surface of AZO nanorods via a chemical bath deposition. At first aqueous solution of 30 mL containing 0.001 M cadmium nitrate, 0.005 M thiourea, and 1 M ammonium hydroxide was prepared as the deposition solution. Secondly, the AZO nanorod array thin film with hydrogen treatment was put in the deposition solution at room temperature for 1 h and then at 60°C for another 1 h. The chemical bath deposition was repeated for the desired cycle number (1--5), and the deposition solution was refreshed for each cycle. Finally, the product was washed with ethanol for several times and then dried in the oven. For the decoration of CdS nanoparticles on the thin films without Al-doping and/or hydrogen treatment, the cycle number was fixed at 3. To make sure the formation of CdS nanoparticles, the above chemical bath deposition process was also conducted in the absence of AZO nanorod array thin film for comparison.
The surface morphology was observed by a high-resolution field emission scanning electron microscopy (JEOL SEM 6700F, JEOL Ltd., Tokyo, Japan). The transmission electron micrograph (TEM), energy dispersive X-ray (EDX) spectroscopy, and high-resolution lattice image were analyzed by a high-resolution field emission transmission electron microscopy (HRTEM, JEOL Model JEM-2100F). The crystalline structures were characterized by X-ray diffraction (XRD) analysis on a Rigaku D/max-ga X-ray diffractometer (Rigaku Corporation, Tokyo, Japan) at 40 kV with Cu K~α~ radiation (λ = 0.1542 nm). The optical absorption spectra were analyzed using a Jasco V-570 UV--VIS spectrophotometer (Jasco Inc., Easton, MD, USA). The photoluminescence spectra were measured on a Hitachi F-4500 fluorescence spectrophotometer (Hitachi Company, Hong Kong, China) with a xenon lamp as the excitation source.
The CdS nanoparticles-sensitized AZO nanorod array thin film with hydrogen treatment was fabricated as the photoelectrode by sticking copper wire on the ZnO seed layer and secured with conducting copper tap. The photoelectrode was sealed on all edges with epoxy resin to reduce leakage current. Photoelectrochemical measurement was conducted on a Zahner IM6ex electrochemical workstation (Zahner*-*Elektrik GmbH & Co. KG, Kronach, Germany) in a standard three-electrode configuration with the above photoelectrode as the working electrode, Pt wire as the counter electrode, and a BAS (West Lafayette, IN, USA), Model MF-2502 Ag/AgCl electrode as the reference electrode. The electrolyte solution contained 0.25 M Na~2~S and 0.35 M Na~2~SO~3~ (pH 13). A 350 W Xe lamp (FL-88) was used as the solar simulated source with AM 1.5 filter (Oriel Instruments Corporation, Stratford, CT, USA, model 81094). The irradiance measurement was detected with a power meter (Newport Opto-Electronics Technologies (Wuxi) Co., Ltd., Jiangsu, China, model 842-PE), and full power irradiation was fixed at 100 mW/cm^2^ throughout this work. A lens (Newport, model LFM-1A) focused light on the working electrode with a surface area of 1 cm^2^. Linear sweep voltammograms ranges were from −0.5 to 0.4 V and the scanning rate was 10 mV/s. By the same method, the photoelectrochemical properties of the CdS nanoparticles-sensitized ZnO thin films without Al-doping and/or hydrogen treatment were measured for comparison. The light switch was tested at a bias of 0 V (vs. Ag/AgCl potential) and 180 s in a cycle with light on and off. The stability of AZO nanorod array thin film with hydrogen treatment was examined by current--voltage (*C*-*V*) scanning from −0.5 to 0.4 V for 1 or 50 cycles at a scanning rate of 10 mV/s under illumination and by measuring the current variation with time under illumination at 0.5 V for 2 h.
Results and discussion
======================
Figure [1](#F1){ref-type="fig"} shows the typical SEM images of AZO nanorod array thin film with hydrogen treatment and those sensitized by CdS nanoparticles for different cycle numbers. It was found that the chemical bath deposition of CdS nanoparticles did not destroy the 1-D morphology of AZO nanorod array thin films. Also, the loading of CdS nanoparticles increased with increasing the cycle number. When the cycle number was 1, the deposition of CdS nanoparticles on the AZO nanorods was incomplete and some larger CdS nanoparticles were observed. From the SEM image, the larger particles were the aggregates of smaller CdS nanoparticles. So their formation might be due to the inhomogeneous deposition of CdS nanoparticles from bulk reaction. When the cycle numbers were 3 and 5, AZO nanorods were deposited by CdS nanoparticles uniformly and completely. No significant aggregation was observed. This might be because the decorated CdS nanoparticles from the first sensitization could act as the seeds for the deposition of more CdS, which reduced the formation of CdS nanoparticles from bulk reaction and led to the more homogeneous deposition of CdS nanoparticles. As for the original aggregates, they might be covered by the CdS nanoparticles which are newly deposited or dissolved and re-deposited on the surface of AZO nanorods. In addition, as shown in the insets of Figure [1](#F1){ref-type="fig"}, it was observed clearly that the colors of AZO nanorod array thin films gradually changed from white to yellow with the increasing cycle number, reflecting the increase in the loading of CdS nanoparticles. This was consistent with the observation of SEM images.
{#F1}
The microstructure properties of the AZO nanorod array thin film with hydrogen treatment after CdS nanoparticles sensitization were further examined by TEM analysis. For the sample with 1 cycle of sensitization, it could be observed clearly that some CdS nanoparticles were decorated on the nanorod surface as shown in Figure [2](#F2){ref-type="fig"}a. By increasing the cycle number, more CdS nanoparticles could be decorated on the nanorod surface. When the cycle number was 3, the nanorod surface was covered roughly by a monolayer of CdS nanoparticles as indicated in Figure [2](#F2){ref-type="fig"}b. When the cycle number increased to 5, the layer of CdS nanoparticles which covered the nanorod surface became thick and dense as shown in Figure [2](#F2){ref-type="fig"}c. The increase in the surface coverage of AZO nanorod by CdS nanoparticles with the increasing cycle number was consistent with the observation in the SEM images. The rough surface with some aggregate particles might be resulted by the peeling from the thin film. In addition, for the sample with 1 cycle of sensitization, its EDX spectrum (Figure [2](#F2){ref-type="fig"}d) revealed the presence of Cd and S elements. Also, the atomic ratio of Cd/S was found to be 1.0. This result correlated well with the atomic ratio of CdS. Furthermore, as shown in Figure [2](#F2){ref-type="fig"}e, its HRTEM image focused on the bare surface confirmed that the AZO nanorod had a single crystal wurtzite structure and was grown along the *c*-axis \[001\] direction with 0.26 nm {001} lattice fringe parallel to the basal plane as observed in our previous work \[[@B44]\]. Also, from the HRTEM image focused on the nanorod surface with decorated CdS nanoparticles as shown in Figure [2](#F2){ref-type="fig"}f, it could be observed that the decorated CdS nanoparticles had a mean diameter of about 7 nm and a lattice spacing of 0.33 nm which was related to the (002) plane of hexagonal structure.
{#F2}
Figure [3](#F3){ref-type="fig"}a shows the XRD patterns of AZO nanorod array thin film with hydrogen treatment and those after sensitization by CdS nanoparticles for various cycle numbers, in which AZO(H), AZO(H)-CdS (1), AZO(H)-CdS (3), and AZO(H)-CdS (5) denote the AZO nanorod array thin film with hydrogen treatment and those after sensitization by CdS nanoparticles for 1, 3, and 5 cycles, respectively. They all exhibited the strong characteristic peak for the (002) plane of wurtzite-type ZnO (hexagonal) around the scattering angle of 35° as observed in our previous work \[[@B44]\]. In addition, as shown in the inset of Figure [3](#F3){ref-type="fig"}a, some peaks in the range of 2θ = 20°-30° become more significant with increasing the cycle number of CdS nanoparticles sensitization. They could be attributed to the (100), (002), and (101) planes of hexagonal CdS \[[@B46]\], confirming the decoration of CdS nanoparticles on AZO nanorods. These peaks were not very significant but still visual. This was due to the relatively stronger peak intensity of AZO nanorod array thin film. Similar phenomenon was also found in other work \[[@B22]\]. In addition, the XRD pattern of CdS nanoparticles synthesized in the absence of AZO nanorod array thin film was also shown in Figure [3](#F3){ref-type="fig"}b for comparison. The characteristic peaks related to the (100), (002), (101), (102), (110), (103), (201), (203), (211), and (105) planes of hexagonal CdS could be observed clearly \[[@B46]\]. This confirmed the formation of CdS nanoparticles.
{#F3}
The UV--VIS spectra of AZO nanorod array thin film with hydrogen treatment and those after sensitization by CdS nanoparticles for various cycle numbers were shown in Figure [4](#F4){ref-type="fig"}, in which the UV--VIS spectrum of glass substrate was also shown for comparison. It was obvious that the glass substrate was transparent above 350 nm, and the absorption of AZO nanorod array thin film with hydrogen treatment occurred mainly in the UV region. After sensitization by CdS nanoparticles, the absorption in the visible light region could be observed. As indicated in Figure [4](#F4){ref-type="fig"} and its inset, the characteristic absorption around 460 nm increased with increasing the cycle number. This could be referred to the decoration of CdS nanoparticles on the surface of AZO nanorods. Furthermore, it was noted that the sensitization by CdS nanoparticles for 1 cycle resulted in the slight decrease in the absorption in the range of 375--450 nm. This might be due to that the AZO nanorod array thin film was slightly destroyed during the chemical bath deposition process. Such a phenomenon was also observed in other similar works \[[@B21],[@B23]\]. However, as shown in Figure [1](#F1){ref-type="fig"}, the 1-D morphology of AZO nanorod array thin films was still retained, and increasing the cycle number did not result in more significant destruction. The XRD analysis as indicated in Figure [3](#F3){ref-type="fig"} also revealed that the resulting thin films were mainly composed of AZO after sensitization by CdS nanoparticles for 1--5 cycles. Thus, the chemical bath deposition process for the CdS nanoparticles sensitization should be practicable. In addition, with increasing the cycle number, it was noted that the absorption peak of CdS nanoparticles underwent a slight red-shift with broadening which revealed the growth and broad size distribution of the decorated CdS nanoparticles \[[@B24],[@B47]\]. When the cycle numbers were 1, 3, and 5, the absorption peaks were located at 440, 457, and 470 nm, respectively. The corresponding average sizes of CdS nanoparticles were estimated at 5.1, 5.9, and 6.5 nm, respectively, using the following empirical equation \[[@B24],[@B48]\]:
$$D = \left( {- 6.6521 \times 10^{- 8}} \right)\lambda^{3} + \left( {1.9557 \times 10^{- 4}} \right)\lambda^{2} - \left( {9.2352 \times 10^{- 2}} \right)\lambda + 13.29\text{,}$$
where *D* (nanometer) was the size of CdS nanoparticles and *λ* (nanometer) was the wavelength of the first excitonic absorption peak. This result was roughly consistent with the observation from the TEM images as indicated in Figure [2](#F2){ref-type="fig"}.
{#F4}
Figure [5](#F5){ref-type="fig"}a shows the photoluminescence spectra of AZO nanorod array thin film with hydrogen treatment and those after sensitization by CdS nanoparticles for various cycle numbers at an excitation wavelength of 325 nm. The photoluminescence spectrum of AZO nanorod array thin film with hydrogen treatment displayed an emission peak around 380 nm owing to the band-to-band emission as well as the other emission peak around 465 nm resulting from the surface or defect states \[[@B49]-[@B51]\]. With increasing the cycle number, the band-to-band emission peak around 380 nm disappeared gradually. Because the emission of AZO nanorods overlapped with the absorption of CdS nanoparticles, the electron--hole recombination of AZO nanorods might be reduced by CdS nanoparticles by the fluorescence resonance energy transfer (FRET) via the Z-scheme mechanism, in which the electrons in the AZO conduction band could transfer to the CdS valence band and thus quenched the photoluminescence intensity of AZO \[[@B25]\]. Furthermore, after sensitization by CdS nanoparticles, a new broad emission peak around 540 nm appeared and its intensity increased gradually with increasing the cycle number. Because the AZO nanorods had little emission at 540 nm but CdS nanoparticles always exhibit a broad emission due to trap states after the bandgap emission, the new broad emission band around 540 nm could be referred to the trap state emission of the decorated CdS nanoparticles. This confirmed the decoration of CdS nanoparticles on the AZO nanorods. In addition, it was noted that the emission peak around 465 nm also decreased gradually, revealing that the quality of AZO surface could be improved by the sensitization of CdS nanoparticles \[[@B51]\]. This led to the less interfacial charge recombination and was helpful to improve the overall photoelectrochemical performance \[[@B51]\].
{#F5}
The photoluminescence spectra at an excitation wavelength of 460 nm, at which CdS nanoparticles exhibited significant absorption, were also examined. As shown in Figure [5](#F5){ref-type="fig"}b, a broad emission occurred in the wavelength of 480--600 nm was observed for AZO nanorod array thin film with hydrogen treatment. Because the excitation at 460 nm cannot result in the band-to-band emission of AZO, the emission observed should be resulted from the surface or defect states \[[@B49]-[@B51]\]. After sensitization by CdS nanoparticles for 3 and 5 cycles, significant quenching in photoluminescence intensity was observed. As stated above, this was because the sensitization of CdS nanoparticles improved the quality of AZO surface and reduced the interfacial charge-recombination \[[@B51]\].
Figure [6](#F6){ref-type="fig"} shows the linear sweep voltammograms of AZO nanorod array thin film with hydrogen treatment and those sensitized by CdS nanoparticles for different cycle numbers in the dark and under illumination. As shown in Figure [6](#F6){ref-type="fig"}a, it was obvious that the dark current densities for all samples were quite low (in the range of 10^−7^ A/cm^2^) and negligible. Under illumination, as indicated in Figure [6](#F6){ref-type="fig"}b, the AZO nanorod array thin film with hydrogen treatment still showed quite low photocurrent density because of its poor visible light absorption. However, they showed pronounced photocurrent densities after sensitization by CdS nanoparticles. The enhancement effect could be reasonably attributed to the high absorption of CdS nanoparticles in the visible light region \[[@B21],[@B22],[@B26]\]. When CdS nanoparticles absorbed the photons in the visible light region, the excited photoelectrons could be transferred to the conduction band of AZO rapidly so that the charge separation of electron--hole pairs became easier and thereby enhanced the photocurrent \[[@B21],[@B26],[@B51]\]. In addition, for AZO(H)-CdS (1), AZO(H)-CdS (3), and AZO(H)-CdS (5), their photocurrents all started at about −0.5 V, continued to increase, and then roughly approached to the saturation at more positive potentials. The onset potential for AZO(H)-CdS (3) could be evaluated as −0.48 V. Similar phenomenon was also observed in the previous reports \[[@B21],[@B22],[@B26]\]. This revealed that the charge separation has reached the maximum at sufficiently positive potentials \[[@B16]\]. As for the slight decrease of photocurrent for AZO(H)-CdS (5) when the potential was above 0.2 V, it might be due to the instability of excess CdS nanoparticles at a higher positive potential. This also revealed that the appropriate cycle number for CdS nanoparticles sensitization was 3.
{#F6}
Furthermore, as shown in Figure [6](#F6){ref-type="fig"}, the maximum photocurrent densities were about 1.1, 3.6, and 1.8 mA/cm^2^ for AZO(H)-CdS (1), AZO(H)-CdS (3), and AZO(H)-CdS (5), respectively. Also, the short current densities (i.e., the current at a zero bias potential) could be determined at 0.03, 0.215, 3.21, and 1.73 mA/cm^2^ for AZO(H), AZO(H)-CdS (1), AZO(H)-CdS (3), and AZO(H)-CdS (5), respectively. It was noteworthy that the enhancement increased and then decreased with the increasing cycle number. For AZO(H)-CdS (1) and AZO(H)-CdS (3), it was reasonable that more cycle numbers could result in a higher photocurrent density owing to the increased surface coverage of AZO nanorods by CdS nanoparticles as observed in their SEM images (Figure [1](#F1){ref-type="fig"}). As for the AZO(H)-CdS (5), its lower enhancement than AZO(H)-CdS (3) might be due to the deposition of excess CdS nanoparticles. Excessive CdS sensitization might cause the increase in the distance for the electron transportation of outer CdS nanoparticles to AZO surface, and also increase the interaction probability of CdS-CdS nanoparticles which might act as the trap or recombination centers of electron--hole pairs \[[@B51]\]. Thus, it was suggested that the monolayer deposition of CdS nanoparticles on the surface of AZO nanorods could produce a maximum photocurrent. This result was in good agreement with the earlier works on the dye \[[@B52]\] or quantum dots-sensitized \[[@B53]-[@B55]\] solar cells. Moreover, it was mentionable that the photocurrent density for AZO(H)-CdS (3) was comparable and even slightly superior to some earlier works for the CdS-sensitized ZnO nanorod array thin films with ITO, FTO, or metallic Ti foil as substrates \[[@B21],[@B22],[@B26],[@B56]\]. Thus, the AZO nanorod array thin film with hydrogen treatment indeed could be used as an ITO/FTO-free photoanode, and its performance for solar water splitting could be significantly improved by the sensitization with the quantum dots capable of visible light absorption.
As stated above, our recent work revealed that Al-doping and hydrogen treatment could significantly enhance the conductivity of ZnO nanorod array thin film \[[@B44]\]. For comparison, the linear sweep voltammograms of the ZnO and AZO nanorod array thin films with and without hydrogen treatment after sensitization by CdS nanoparticles for 3 cycles were also measured under illumination as indicated in Figure [7](#F7){ref-type="fig"} in which ZnO-CdS (3) and AZO-CdS (3) denote the ZnO and AZO nanorod array thin films without hydrogen treatment after sensitization by CdS nanoparticles for 3 cycles. It was found that the ZnO and AZO nanorod array thin films without hydrogen treatment had quite low photocurrent density. Also, for the nanorod array thin films with hydrogen treatment, the photocurrent density of AZO was significantly higher than that of ZnO. This revealed that both the effects of Al-doping and hydrogen treatment were also helpful for the enhancement of photocurrent density, and the enhancement by hydrogen treatment was more significant that that by Al-doping. This phenomenon could be attributed to the enhancement in the conductivity as observed in our previous work \[[@B44]\]. When CdS nanoparticles absorbed the photons in the visible light region, the excited photoelectrons were transferred to the conduction band of AZO. The superior conductivity was helpful for the rapid transfer of electrons within the nanorods, leading to the more efficient electron collection. This demonstrated that the AZO nanorod array thin film with hydrogen treatment possessed significantly better photoelectrochemical property than the ZnO nanorod array thin films without Al-doping and/or hydrogen treatment.
{#F7}
In addition, Figure [8](#F8){ref-type="fig"} shows the photocurrent transient behavior of AZO(H)-CdS (3) at a bias of 0 V with a switch time of 180 s. It indicated that the AZO(H)-CdS (3) had good photosensitivity and reproducibility. In addition, the linear sweep voltammograms of AZO(H)-CdS (3) were measured after *C*-*V* scanning for 1 and 50 cycles under illumination. The result was shown in Figure [9](#F9){ref-type="fig"}a. It was found obviously that under illumination AZO(H)-CdS (3), after *C-V* scanning for 50 cycles, still showed similar photoelectrochemical property as that after *C*-*V* scanning for 1 cycle. Furthermore, Figure [9](#F9){ref-type="fig"}b indicates the variation of relative current with time for AZO(H)-CdS (3) under illumination at 0.5 V. No significant current decay was observed in 2 h. Both results revealed that the AZO(H)-CdS (3) had good stability. Accordingly, the AZO nanorod array thin film with hydrogen treatment was indeed suitable as an ITO/FTO-free photoanode for solar water splitting after sensitization by CdS nanoparticles.
{#F8}
{#F9}
Usually, heat treatment could improve the crystallinity and thereby enhance the electron transportation \[[@B57]\]. So the further annealing of AZO(H)-CdS (3) at 300°C was conducted for 0.5 h. The SEM image and UV--VIS spectrum were shown in Figure [10](#F10){ref-type="fig"}. It was found that, after annealing, the 1-D morphology of AZO(H)-CdS (3) has no significant change. However, the size of CdS nanoparticles became larger owing to the particle sintering. The sintering of CdS nanoparticles also affected the absorption property. It was obvious that, after annealing, the visible absorption in the range of 400 to 500 nm was enhanced largely and the absorption edge was red-shifted. This might be due to the improved crystallinity and larger size of CdS nanoparticles, respectively. Furthermore, the linear sweep voltammograms of annealed AZO(H)-CdS (3) in the dark and under illumination were also shown in Figure [6](#F6){ref-type="fig"}. It was obvious that the photocurrent density was enhanced significantly after annealing. A maximum short current density of 5.03 mA/cm^2^ could be obtained under illumination. In addition to the crystallinity improvement, this also might be partially due to the enhanced and red-shifted absorption which raised the utilization of light. This demonstrated that the photoelectrochemical performance of CdS nanoparticles-sensitized AZO nanorod array thin film with hydrogen treatment indeed could be enhanced by heat treatment.
{#F10}
Conclusions
===========
The AZO nanorod array thin film with hydrogen treatment has been sensitized by CdS nanoparticles successfully via chemical bath deposition as a novel ITO/FTO-free composite photoelectrode for solar water splitting. The sensitization not only did not destroy the 1-D morphology of AZO nanorod array thin film, but also could efficiently increase the absorption around 460 nm and reduce the electron--hole recombination of AZO nanorods via the FRET mechanism. The CdS nanoparticles decorated on AZO nanorods had a hexagonal structure and the diameters of 5.1-6.5 nm. By increasing the cycle number, the loading of CdS nanoparticles was raised and could significantly enhance the photoelectrochemical property of AZO nanorod array thin film with hydrogen treatment. When a monolayer of CdS nanoparticles was formed on AZO nanorods, the maximum short current density under illumination could be obtained as 3.21 mA/cm^2^ which was much higher than those without CdS nanoparticles sensitization and those with CdS nanoparticles sensitization but without Al-doping and/or hydrogen treatment. Such a good performance was comparable and even slightly superior to some earlier works for the CdS-sensitized ZnO nanorod array thin films with ITO, FTO, or metallic Ti foil as substrates. In addition, the CdS nanoparticles-decorated AZO nanorod array thin film with hydrogen treatment also exhibited good photosensitivity, reproducibility, and stability. After further annealing at 300°C for 0.5 h, the maximum short current density under illumination could be raised to 5.03 mA/cm^2^. Accordingly, we successfully demonstrated that the AZO nanorod array thin film with hydrogen treatment could be used as a novel ITO/FTO-free photoanode, and its performance for solar water splitting could be significantly improved by CdS nanoparticles sensitization.
Competing interests
===================
The authors declare that they have no competing interests.
Authors' contributions
======================
Both authors read and approved the final manuscript.
Acknowledgments
===============
This work was performed under the auspices of the National Science Council of the Republic of China to which the authors wish to express their thanks, under contract number NSC 97-2221-E-006-119-MY3.
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Nigrostriatal lesions enhance striatal 3H-apomorphine and 3H-spiroperidol binding.
Following unilateral 6-hydroxydopamine nigrostriatal lesions in rats, the binding of both 3H-apomorphine and 3H-spiroperidol in the striatum is increased. In rats with incomplete lesions or at early time points after lesion, binding is not significantly different from control levels.
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Q:
Converting numeric data stored as character to numeric in SAS
I'm trying to pull data stored as $24. I want to convert it from character to numeric. The input(variable-name,comma24.) function is not working for me. A sample of the data is given below.
5.35
5.78
413,000
3,280,000
5.97
6.72
5
6.53
6
4.59
4.25
5
6.38
6.41
4.1
6.56
5.45
6.07
4.28
5.54
5.87
3.88
5.53
5.65
6.47
207,000
4,935,000
4,400,000
6,765,000
2,856,000
53,690,000
A:
You don't show your code, but for some reason I could get it work when the reading and conversion were in different data steps, but not when it was the same data step.
The following works just fine:
DATA one;
INPUT y: $24. @@;
DATALINES;
5.35 5.78 413,000 3,280,000 5.97
RUN;
DATA one;
SET one;
z = INPUT(y, comma24.);
RUN;
However if I put the calculation of z in the first data step, I was getting missing values without any error message. I have no explanation for this behavior, but hopefully the workaround will work for you as well.
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"Celebrity Apprentice" contestant Aubrey O'Day told Wendy Williams in 2012 that she wouldn't date Eric Trump, but she didn't say anything about Donald Jr., with whom she was reportedly having an affair at the time.
Shortly after appearing on Season 5 of the NBC reality show, which was hosted by Donald Trump, and featured Ivanka and Donald Trump, Jr. as boardroom judges, O'Day visited "The Wendy Williams Show." Williams noted there seemed to be sparks between the singer and Eric, who was then single, and asked if a romance was possible.
According to multiple reports that surfaced Monday, O'Day and Donald Jr., whose wife Vanessa filed for divorce last week, had an affair that began in late 2011 and continued through March 2012.
Us Weekly reported the relationship was "serious all of a sudden" and the elder Trump son nearly ended his marriage for the singer. Donald Jr. and his wife apparently weathered that storm for another five years before Vanessa filed for divorce on March 15, effectively ending their 12-year union.
O'Day hinted toward a dubious connection to the Trump family after the 2016 election with a tweet that lamented Donald Trump being elected President, followed by the claim that, "My story I didn't tell is worth millions now."
Related Gallery
Donald Trump Jr. and Vanessa Trump's relationship through the years
Trump Jr. and O'Day have yet to comment on the alleged affair.
In 2014, Eric married blond beauty Lara Yunaska, who is a television host, though not a Miss Universe.
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Q:
How to combine multiple rows into one row and multiple column in SQL Server?
I have different tables through I made temp table and here is the result set of temp table:
car_id | car_type | status | count
--------+----------+---------+------
100421 | 1 | 1 | 9
100421 | 1 | 2 | 8
100421 | 1 | 3 | 3
100421 | 2 | 1 | 6
100421 | 2 | 2 | 8
100421 | 2 | 3 | 3
100422 | 1 | 1 | 5
100422 | 1 | 2 | 8
100422 | 1 | 3 | 7
Here is the meaning of status column:
1 as sale
2 as purchase
3 as return
Now I want to show this result set as below
car_id | car_type | sale | purchase | return
--------+----------+------+----------+----------
100421 | 1 | 9 | 8 | 3
100421 | 2 | 6 | 8 | 3
100422 | 1 | 5 | 8 | 7
I tried but unable to generate this result set. Can anyone help?
A:
You can also use a CASE expression.
Query
select [car_id], [car_type],
max(case [status] when 1 then [count] end) as [sale],
max(case [status] when 2 then [count] end) as [purchase],
max(case [status] when 3 then [count] end) as [return]
from [your_table_name]
group by [car_id], [car_type]
order by [car_id];
A:
Try this
select car_id ,car_type, [1] as Sale,[2] as Purchase,[3] as [return]
from (select car_id , car_type , [status] ,[count] from tempTable)d
pivot(sum([count]) for [status] in([1],[2],[3]) ) as pvt
also you can remove the subquery if you don't have any condition
like
select car_id ,car_type, [1] as Sale,[2] as Purchase,[3] as [return]
from tempTable d
pivot(sum([count]) for [status] in([1],[2],[3]) ) as pvt
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A double-blind, placebo-controlled trial of olanzapine addition in fluoxetine-refractory obsessive-compulsive disorder.
One of the few combination approaches to the treatment of obsessive-compulsive disorder (OCD) with encouraging support is the addition of an antipsychotic to a serotonin reuptake inhibitor. The study consisted of a 6-week, placebo-controlled addition of olanzapine 5-10 mg (6.1 +/- 2.1 mg, mean +/- SD) to fluoxetine in OCD subjects who were partial or nonresponders to an 8-week, open-label fluoxetine trial (40 mg in 43 subjects, 20 mg in 1 subject). Both the fluoxetine-plus-olanzapine (n = 22) and fluoxetine-plus-placebo (n = 22) groups improved significantly over 6 weeks [F(3,113) = 11.64, p <.0001] according to Yale-Brown Obsessive Compulsive Scale scores with repeated-measures analysis of variance; however, the treatment x time interaction was not significant for olanzapine versus placebo addition to fluoxetine. These findings indicate no additional advantage of adding olanzapine for 6 weeks in OCD patients who have not had a satisfactory response to fluoxetine for 8 weeks, compared with extending the monotherapy trial.
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There are deer tracks underfoot. An egret, sensing intruders, spreads its impressive wings and lifts off a nearby perch to glide elegantly downstream. Mallards paddle above the gurgling rapids as the early morning sun peeks through the trees.
It is unexpectedly idyllic.
We are on the west bank of the Don River, just north of Pottery Rd. Not as far south as where the water’s flow, tamed and straightened by retaining walls, passes under a tangle of concrete roadways, but in the heart of the city nonetheless.
However, if not for the hum of commuters along the Don Valley Parkway, you could imagine this a pastoral hideaway.
David Clark has brought us here, through chest-high underbrush to the river’s edge where he now busily prepares his gear, tying a hook to the eight-pound test line of his spinning reel. Clark, co-founder of Toronto Urban Fishing Ambassadors, wants to demonstrate that the Don, still regarded by many as a toxic cesspool, is actually an undervalued recreational resource.
“The Don is an overlooked river,” he says, neatly summing up Toronto’s relationship with the oft-ignored waterway. “But I can be here catching fish while people are stuck in traffic not too far away.”
Many of the car-bound would be surprised at what lurks in these tepid waters.
In the spring, white suckers run in the Don. There are some rainbow trout then as well. In the fall, chinook salmon battle their way upstream looking for a place to spawn. Most common are fish that can tolerate the river’s almost bath-like temperatures and high pollution counts, such as creek chub and blacknose dace. Those minnow-sized species serve as perfect meals for larger predators such as pike and walleye that are returning in greater numbers. Twenty-five species call the Don home.
But we are in one of those stifling hot stretches that have defined the summer and made the shallow Don even warmer. So we are here at 6 a.m. Not much point in trying when the sun is higher, says Clark. As it is, most fish have headed for the deeper, cooler waters beyond Keating Channel — where the 38-kilometre Don ends in the shadow of the Gardiner Expressway with a dramatic turn west — to Toronto’s inner harbour or the lake. Still, Clark believes we’ll find carp, suckers and bullheads — fish that can handle the low oxygen levels the warmth brings.
Clark, 49, starts out with a small piece of worm as bait. On his fifth cast he gets a bite, as he does on his next couple of tries. While that’s encouraging, he figures the fish showing interest, likely suckers, are too small to hook and decides to move farther up the river.
The water, undoubtedly less murky than when it served as Toronto’s all-purpose repository, is reasonably clear with no obvious odour, but its appearance is a tad deceiving. The city, on its 311 website, cautions it “is not advisable to swim in the Don” especially after a rainstorm, when elevated E. coli levels “can make you very sick … if you should inadvertently fall into the Don, it would be wise to wash thoroughly with antibacterial soap as soon as possible.”
But Rick Portiss, a senior manager and fish specialist with the Toronto and Region Conservation Authority (TRCA), says the water has improved greatly over the last four decades. “If this was a completely degraded, polluted system, these fish wouldn’t be drawn to this system at all,” he says.
The city of Toronto is working with several stakeholders such as Parks, Forestry and Recreation and the TRCA to develop a Toronto Ravine Strategy that will provide a framework for future ravine policy and use, including recreation.
Portiss says he “absolutely” encourages people to fish in the Don as a way to connect to the river and, in turn, feel engaged in the watershed’s future.
“Where else in the country,” he wonders, “can you take a streetcar down to your favourite fishing holes?”
Back on the river’s edge, Clark eyes a half-dozen good-sized carp in deeper water. He opens a can of corn, a favourite of these foragers, and tosses a handful of kernels into the water to pique their interest.
He then baits his hook and casts, hoping for a nibble on his niblets. These seen-it-all urban fish likely aren’t much different than their nearby human counterparts battling traffic. They appear a little jaded and disengaged.
“Urban fishing isn’t easy. It takes some time,” he says. “Fish here have seen presentations of bait and lures, especially the larger pike and carp that are 15 to 20 years old. Those larger fish were likely caught on a lure when they were younger, so they know to be cautious.”
Still, it is not long before Clark has hooked the lip of a large carp. It takes less than a minute to land it. The faster he brings it in, the better for the fish when released — as it is for this one, after puckering up for a close-up.
Clark has never eaten anything he has caught in the Don but, he says, that’s only because he’s never fought a fish to the point where it was mortally wounded or likely too exhausted to live. He says he has seen others keep suckers they have caught.
Surprisingly, fish from the river are edible.
The current Guide to Eating Ontario Fish, published by the provincial government, does allow for limited consumption of white sucker and brown bullheads taken from the Pottery Rd. area of the Don. Other species have not been tested. Toxins restricting consumption are mercury and PCBs, a poisonous organic compound once widely used in industry.
“People are probably doubtful that there are fish in here, but that’s one of the almost nice things about it,” says Clark, whose biggest haul from the Don was a 23-pound carp.
“There’s not a lot of fishing pressure on the river; you have a longer stretch of river to fish in solitude.”
A river returns to life
Some 200 years ago, inmates of the Don Jail complained that they were eating too much fresh salmon. It was an easy meal. Guards could just wander over to the Don River to quickly catch enough Atlantic salmon for all their incarcerated guests.
But industrialization and urbanization grew in the Don watershed. That meant effluent from paper mills, chemical factories, refineries, abattoirs and tanneries mixed with agricultural animal waste, and sometimes animal carcasses, to make the river a slow-moving toxic soup that destroyed spawning grounds. Native salmon disappeared, the last recorded one plucked from the river in 1874 near Pottery Rd.
The river was so horribly polluted — it reportedly caught fire twice and was known to change colour based on the chemicals used by a paper mill — that Pollution Probe ceremonially pronounced it dead in 1969.
“They finally had a funeral for the Don River yesterday,” read a report in the Toronto Telegram. “Judging from the smell of the ‘deceased,’ it was long overdue.”
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Even now, when passersby see David Clark fishing in its waters, they make the usual cracks about snagging a three-eyed monster or offer dire warnings against eating what he catches.
Ralph Toninger, a senior manager with the Toronto and Region Conservation Authority, says public perception and the stigma surrounding the river are obstacles in getting people to use the Don for recreation.
“It’s an underutilized fishery,” he says. “The biggest thing we have to fight is (the belief) that if you dip your toe in it, it’s going to fall off. The water quality has already improved significantly and we have wildlife using these areas.”
Still, a 2013 TRCA report card on the Don River watershed gave the water a “very poor” rating of F. “The main reason,” states the report, “is that 96 per cent of the watershed is urbanized, largely built up and paved over.”
All that pavement means rainwater and melting snow carry contaminants directly into the river. About 1.2 million people call Canada’s most urbanized watershed home.
The F grade is the result of, among other things, phosphorus and E. coli concentrations. High levels of phosphorus can cause the growth of algae that choke waterways and deplete oxygen levels. E. coli indicates the presence of untreated human or animal waste.
The report states the water has not changed substantially since 2001, though phosphorus levels at the mouth of the Don have declined significantly over the last 30 years.
Still, tighter restrictions on contaminants and the use of herbicides and pesticides, as well as the banning of leaded gas — a significant development for a river so close to the Don Valley Parkway — have resulted in substantial improvements since the 1950s and ’60s, says Toninger.
And the TRCA and local city and regional governments have been working to improve the river and its watershed — examples include the construction of a stormwater management pond in Earl Bales Park on the West Don, the development of three wetlands in the East Don Parklands area and the planting of trees and shrubs.
When Clark arrived in Toronto from Peterborough in 1985, his first impressions of the Don were formed by where it is most visible: the walled-in waterway near Richmond St.
“A river you’d never fish in,” he says.
But when he learned the Humber and Credit rivers had runs of rainbow trout and salmon, he became curious about the Don. It took him about a decade before he dropped a line in it.
“Once we started catching suckers, we knew it was worth exploring more,” he says. “The next year I was seeing pike that were 30-plus inches long.”
Portiss, the TRCA fish expert, notes several examples of how the Don is bouncing back from its dirtiest days.
Rainbow trout, what he calls a “highly sensitive fish,” are returning to the river’s headwaters in the Oak Ridges Moraine. There was an Atlantic salmon, a species reintroduced in the more pristine waters of Duffins Creek and the Credit River, caught exploring the Keating Channel area. And walleye, which virtually disappeared 25 years ago, are now “prolific” through the Don system.
That predators like walleye and pike are in the river means there is also a thriving ecosystem in place to keep them fed.
Portiss says the TRCA often tests both the water and sediment that is frequently dredged from Keating Channel, and “the contamination that we used to see 25 years ago has completely dwindled down to just traces that we see now. It’s a huge change.”
The TRCA has removed or altered barriers so fish can pass freely in the Don, but sport fishing in the river, inner harbour and along the lakefront should improve even more with a planned but still unfunded realignment and naturalization of the Don estuary, with its associated wetlands, estimated to cost almost $1 billion. In July 2015, the three levels of government, with Waterfront Toronto, announced $5 million in funding for due diligence work to provide certainty on the costs.
“If you were to stop 10 people on the Gardiner Expressway and ask them if they thought there was fish in the Don River, nine out of 10 are going to say no,” says Portiss.
“But there’s a good diversity of fish species there that are right under their noses at the Gardiner Expressway.”
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Aged care funding should be distributed evenly
The CEO of Southern Cross Care, Alan Carter, says the Federal Government's proposed aged care plan, could work if the money is distributed evenly.
The Rudd government announced the $739 million takeover, over four years to help fund 5,000 news beds across the country.
Mr Carter says some communities get an over supply of funding, whilst others will hardly receive a cent.
"It tends to work on a ratio on the number of citizens in a community aged 70 or above and they say there is a need for so many residential places high and low, community care, HACC services, all of those sort of things to look to come up with a package that the government believes will meet the needs of the elderly in the community," he said.
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645 F.Supp. 793 (1986)
Robert G. CRONSON, as Auditor General of the State of Illinois, and Individually, Plaintiff,
v.
Hon. William G. CLARK, Hon. Daniel P. Ward, Hon. Joseph H. Goldenhersh, Hon. Howard C. Ryan, Hon. Thomas J. Moran, Hon. Seymour Simon, Hon. Ben Miller, respectively, as Chief Justice and Justices of the Supreme Court of Illinois; Juleann Hornyak, Supreme Court Clerk; and Hon. William M. Madden, Acting Director of Administrative Office of Ill. Courts, Defendants.
No. 86-3180.
United States District Court, C.D. Illinois, Springfield Division.
October 14, 1986.
Witwer, Moran, Burlage & Witwer, Chicago, Ill., Alfred H. Greening, Williamsville, Ill., for plaintiff.
Michael V. Casey, Roger Flahaven, Asst. Attys. Gen., Richard J. Phelan, Mary Kathryn Kelly, Terry F. Mortiz, Joanne M. Harmon, Chicago, Ill., Francis J. Giganti, Springfield, Ill., Michael J. Hayes, Asst. Atty. Gen., Chicago, Ill., for defendants.
OPINION AND ORDER
MILLS, District Judge:
Each state in ratifying the constitution is considered as a sovereign body independent of all others, and only to be bound by its own voluntary act. In this relation then the new constitution will, if established, be a federal and not a national constitution.
The Federalist, No. 39 (J. Madison)
The Auditor General of Illinois requests this federal trial court under the guise of *794 42 U.S.C. § 1983to preliminarily enjoin a mandamus action pending before the Supreme Court of Illinois.
The question presented is: May this Court, consistent with the principles of comity and federalism, enjoin the proceedings before the state's highest tribunal, which is alleged to have prejudged the cause, where the substantive issue turns entirely upon a construction of state constitutional law and implicates important state interests the fiscal integrity of the state judiciary and the duties of a state officer.
This Court abstains: The injunction is denied.
Background
William Madden, Acting Director of the Administrative Office of the Illinois Courts, has brought an original proceeding in mandamus before the Supreme Court of Illinois seeking to compel the Petitioner, as Auditor General of Illinois, to conduct an audit of the funds appropriated by the Illinois General Assembly and expended by the Administrative Office. Madden v. Cronson, No. 63255 (Ill.Sup.Ct. filed March 27, 1986). Pursuant to Rule 65(a) of the Federal Rules of Civil Procedure, the Auditor General now petitions this Court to enjoin further proceedings in that state action, contending that its continuation will result in a violation of due process under the Federal Constitution. The Petitioner claims, inter alia, that the Supreme Court has prejudged his case. Members of the Court, he argues, have demonstrated bias and prejudice through extra-judicial prejudgments of the substantive constitutional and statutory issues involved. Jurisdiction is premised upon 42 U.S.C. § 1983 and 28 U.S.C. § 1343(3).[1]
Underlying the present controversy is a continuing conflict between the Auditor General and the Supreme Court of Illinois. The problem relates to the Petitioner's state constitutional and statutory authority to conduct financial audits of the Attorney Registration and Disciplinary Commission ("Commission") and the State Board of Law Examiners ("Board") as part of the regular audit of the state supreme court. Petitioner claims that the Illinois Constitution mandates a public audit of Commission and Board funds, and hence, precludes him from auditing only the Court's appropriated funds. The Supreme Court disagrees. Since neither the Commission nor the Board receive funding from the General Assembly, but rather operate on fees collected from Illinois attorneys and bar applicants respectively, the Court maintains that the agencies' financial affairs do not fall within the Petitioner's auditing powers. As a consequence of this dispute, the Auditor General has refused since 1979 to audit the funds appropriated to the Supreme Court.[2]
The current dispute arose when, in December 1985, Roy Gulley, then Director of *795 the Administrative Office of the Illinois Courts, requested Petitioner to conduct an audit of Supreme Court appropriations. The Auditor General refused. Thereafter, Respondent Madden, having assumed the directorate, filed a motion for original jurisdiction and petition for writ of mandamus with the Supreme Court of Illinois alleging the Auditor General's continuing failure to perform his auditing duties in violation of Article VIII, Section 3 of the Illinois Constitution and the State Auditing Act. The Supreme Court accepted jurisdiction. It then denied Petitioner's motion to dismiss for want of jurisdiction and due process.
The Auditor General now turns to this tribunal for injunctive relief, maintaining that the Supreme Court of Illinois cannot impartially decide the issue of whether he has neglected his state constitutional duties by failing to audit the appropriated funds.[3]
I.
Since the eloquent characterization of "Our Federalism" by Mr. Justice Black in Younger v. Harris, 401 U.S. 37, 91 S.Ct. 746, 27 L.Ed.2d 669 (1971), the Supreme Court of the United States has reiterated in a long line of decisions the principle that where important state interests are involved, a federal court should not act to restrain pending state proceedings when petitioner has an adequate remedy at law and will not suffer great and immediate irreparable injury. See, e.g., Moore v. Sims, 442 U.S. 415, 99 S.Ct. 2371, 60 L.Ed.2d 994 (1979); Huffman v. Pursue, Ltd., 420 U.S. 592, 95 S.Ct. 1200, 43 L.Ed.2d 482 (1975). Indeed, the hesitancy of federal courts to intervene in state litigation has long been supported by the desire to avoid duplicate legal proceedings where the first suit allows parties an adequate opportunity to raise constitutional claims. Younger, 401 U.S. at 44, 91 S.Ct. at 750. But as Justice Black explained, the doctrine is reinforced by an even more vital consideration the notion of comity:
A system in which there is sensitivity to the legitimate interests of both State and National Governments, and in which the National Government, anxious though it may be to vindicate and protect federal rights and federal interests, always endeavors to do so in ways that will not unduly interfere with the legitimate activities of the state.
Id. Of course, a proper respect for state brethren permits the Court to assume that they will vigorously safeguard federal constitutional rights. Middlesex Ethics Comm. v. Garden State Bar Ass'n, 457 U.S. 423, 102 S.Ct. 2515, 73 L.Ed.2d 116 (1982). Thus, Younger and its progeny reflect the national policy that only in "extraordinary circumstances" will federal courts interfere with ongoing state proceedings.
Unquestionably, the substantiality of the state's interests in its proceedings has been an important factor in abstention analysis from the beginning. Id. at 432, 102 S.Ct. at 2521. The Supreme Court of the United States has consistently ruled that when federal courts are confronted with requests for injunctive relief from state civil functions, "they should abide by standards of restraint that go well beyond those of private equity jurisprudence." Huffman, 420 U.S. at 603, 95 S.Ct. at 1208. But the analysis does not end with a finding of state interest. Federal courts must also determine whether petitioner has an adequate remedy at law and hence will suffer no irreparable injury: "Restated in the abstention context, the federal court should not exert jurisdiction if the plaintiffs had an opportunity to present their federal *796 claims in the state proceedings." Moore, 442 U.S. at 425, 99 S.Ct. at 2378.
Therefore, this Court's initial inquiry is two fold: First, do the Supreme Court proceedings implicate important state interests; and, second, does the Auditor General have an adequate opportunity to raise his due process claim in the state court. See Middlesex, 457 U.S. at 432, 102 S.Ct. at 2521.
A
The principle that state courts are the final expositors of state law is indisputable. In fact, abstention cases uniformly reflect the axiom that the threat to our system of government inherent in federal court interpretation of state law is not trivial. Moore, 492 U.S. at 427-29, 99 S.Ct. at 2379-80. Moreover, the precept becomes increasingly pervasive when the resolution of the substantive issues will inevitably affect the internal structure of the sovereign's government.
The Auditor General cannot reasonably challenge the importance of the pending state mandamus hearing to the proper operation of Illinois government. At the heart of that controversy are complex questions of state constitutional and statutory law which bear upon the duties of a legislative officer, and the fiscal integrity of the judiciary. Whether the Auditor General is empowered to audit Supreme Court agencies is undeniably a query for the state tribunals. As the Supreme Court of the United States has indicated: "Proceedings necessary for the vindication of important state policies or for the functioning of the state judicial system also evidence the state's substantial interest in the litigation." Middlesex, 457 U.S. at 432, 102 S.Ct. at 2521; see also Trainor v. Hernandez, 431 U.S. 434, 97 S.Ct. 1911, 52 L.Ed.2d 486 (1977). The only remaining question then is the competency of the Supreme Court of Illinois to fairly adjudicate Petitioner's constitutional claim.
B
The policy of equitable restraint expressed in cases such as Younger is based in part on the presumption that state tribunals generally provide the parties with a fair and sufficient opportunity to vindicate federal constitutional rights. Thus, the policy of abstention should be set aside only where "extraordinary circumstances" render a state court incapable of fairly deciding the issues before it. Kugler v. Helfant, 421 U.S. 117, 95 S.Ct. 1524, 44 L.Ed.2d 15 (1975). Of course, "extraordinary circumstances" is an elusive term, subject to a wide variety of interpretations. For present purposes, however, this Court need only address the issue raised by Petitioner's motion: Whether the alleged bias of the Supreme Court of Illinois rises to the level of a due process violation. To phrase it in terms of more traditional injunction analysis: Does Petitioner have a reasonable likelihood of prevailing on the merits? Roland Machinery Co. v. Dresser Industries, 749 F.2d 380 (7th Cir.1984); see also Kugler, 421 U.S. at 123-29, 95 S.Ct. at 1530-33 (Petitioner's claim that he cannot obtain a fair hearing in the state courts is without merit and hence, exceptions to the Younger doctrine are inapplicable).
Petitioner contends, and this Court agrees, that a fair tribunal is a basic requirement of due process: "To this end no man can be a judge in his own case and no man is permitted to try cases where he has an interest in the outcome." In re Murchison, 349 U.S. 133, 136, 75 S.Ct. 623, 625, 99 L.Ed. 942 (1955). Likewise, hearings before a partial tribunal are not constitutionally acceptable simply because the disadvantaged party has the opportunity to appeal. Ward v. Village of Monroeville, 409 U.S. 57, 61, 93 S.Ct. 80, 83-84, 34 L.Ed.2d 267 (1972). But Petitioner's broad legal principles are alone insufficient to influence the outcome of this case. Only through a careful study of its superiors' legal opinions involving personal bias and due process may this Court determine the merit of Petitioner's claim.
Younger abstention was directly in issue in Gibson v. Berryhill, 411 U.S. 564, 93 S.Ct. 1689, 36 L.Ed.2d 488 (1973), where the *797 Court held that a predicate for dismissal was lacking when the Alabama Board of Optometry was found incompetent to adjudicate a matter by reason of a pecuniary interest. In Gibson, the Board, composed solely of private practitioners, sought to revoke the licenses of optometrists employed by business corporations on the basis of unprofessional conduct. Because of its makeup, the Court concluded that the Board's success would possibly redound to the personal benefit of its members. Although the district court considered another source of bias prejudgment of the facts sufficient to disqualify the board as well, the Supreme Court affirmed only on the ground of personal financial interest. Id. at 578-79, 93 S.Ct. at 1697-98.
The Seventh Circuit followed a similar path in United Church of the Medical Center v. Medical Center Comm'n, 689 F.2d 693 (1982). In that case, provisions of the Illinois Medical Center Act entitled the Defendant to preside over title reverter proceedings and determine whether certain property should revert to it. The Court held that the Commission's financial stake in the proceedings' outcome made it an unconstitutionally biased decisionmaker. While Plaintiff also alleged the Commission's prejudgment of the facts, the Court declined to reach the question: "We do not ... reach the question unreached by the Supreme court in Berryhill, whether sufficient indicia of prejudgment can also rise to the level of a violation of due process ..." Id. at 700.
Clearly, federal courts confronted with the issue hesitate to elevate a tribunal's possible prejudgment to the level of a due process violation. In Federal Trade Comm'n v. Cement Inst., 333 U.S. 683, 68 S.Ct. 793, 92 L.Ed. 1010 (1948), the Supreme Court squarely addressed the issue of whether the alleged prejudgment of a controversy alone was sufficient to disqualify an administrative tribunal. There, the FTC charged the Defendants with unfair competition and price discrimination. While the proceedings were pending, Respondent Marquette Cement Company asked the Commission to disqualify itself charging that it had prejudged the issues and was prejudiced against the cement industry generally. The Commission refused.
Although Marquette introduced numerous reports to Congress as well as testimony given by members of the FTC before Congressional committees to make clear that the Commission believed Defendants' activities violated the Sherman Act, the Court held that this belief did not disqualify the Commission. Id. at 700, 68 S.Ct. at 803. Noting that most matters relating to judicial disqualification do not rise to a constitutional level, the Court stated:
[No] decision of this Court would require us to hold that it would be a violation of procedural due process for a judge to sit in a case after he had expressed an opinion as to whether certain types of conduct were prohibited by law.
Id. at 702-03, 68 S.Ct. at 804.
Cement Institute is indeed persuasive to, if not binding upon, this federal trial court. In the present matter, as in that case, complainant has presented testimony and other communications of court members tending to show a possible prejudgment of the issues involved. But since Tumey v. Ohio, 273 U.S. 510, 47 S.Ct. 437, 71 L.Ed. 749 (1927), the Supreme Court has consistently declared that personal bias alone without some showing of an additional interest pecuniary or otherwise fails to rise to the level of due process. In fact, the Court recently reaffirmed this longstanding principle in Aetna Life Insurance Co. v. Lavoie, ___ U.S. ___, 106 S.Ct. 1580, 89 L.Ed.2d 823 (1986).
That case involved a charge of bad faith refusal to pay an insurance claim. The Supreme Court of Alabama, in a per curiam opinion written by Justice Embry, affirmed a $3.5 million punitive damage award against Aetna, clarifying the law in several respects. While an application for rehearing was pending, however, appellant learned that at the time of the opinion the Justice had two actions pending against insurance companies for bad faith failure to pay claims. One of those suits was a class action on behalf of state employees *798 insured under a group plan. Aetna then filed motions challenging Justice Embry's participation in the matter and alleging the entire court should recuse itself based upon its potential interest in the class action.
Explaining that its decision answered the question of under what circumstances the Constitution requires disqualification, the Court in Aetna ruled that a "direct, personal, substantial and pecuniary interest" was necessary to rise to a due process level. Id. at 1586-88. Therefore, Justice Embry's participation was unconstitutional. The settlement value of his case had increased as a result of the opinion. Considering the possible bias of the remaining Justices, however, the Court stated: "We find it impossible to characterize [their] interest as direct, personal, substantial and pecuniary." Id. at 1587-88.
In its opinion, the Court recognized that most questions of judicial disqualification were subject to legislative discretion. Only in extreme cases would recusal on the basis of alleged hostility towards a party be constitutionally mandated: "A judge should disqualify himself where he has a personal bias or prejudice concerning a party. But that alone would not be a sufficient basis for imposing a constitutional requirement under the Due Process Clause." Id. at 1585; see also Margoles v. Johns, 660 F.2d 291, 297 (7th Cir.1981), cert. denied, 455 U.S. 909, 102 S.Ct. 1256, 71 L.Ed.2d 447 (1982).
Thus, the Supreme Court of the United States has formulated a narrow rule by which this Court is bound. Simply stated, the mere possibility of prejudgment alone cannot rise to a constitutional plane. A more substantial interest is required. The fact that certain members of the Supreme Court of Illinois have entertained views contrary to the Petitioner's does not necessarily mean that the Court's mind is irrevocably closed on the subject. Certainly, the present controversy does not personally involve the individual Justices. It concerns only the administrative functioning of agencies under the jurisdiction of the third branch of government. This Court cannot say that the tribunal's possible bias is so substantial as to require disqualification under the Fourteenth Amendment of the Federal Constitution.
The state interest is far too great and the potential prejudice is far too little.
Abstention is proper.
Ergo, Petitioner's motion for a preliminary injunction is DENIED.
NOTES
[1] Under Mitchum v. Foster, 407 U.S. 225, 92 S.Ct. 2151, 32 L.Ed.2d 705 (1972), 42 U.S.C. § 1983 is an expressly authorized exception to the anti-injunction statute, 28 U.S.C. § 2283.
[2] The proper scope of the Auditor General's authority is the subject of a declaratory judgment action now pending in the Circuit Court of Cook County an action inextricably wound with the present controversy. Chicago Bar Ass'n v. Cronson, No. 82-L-50131 (Cir.Ct. Cook Co. filed July 26, 1982). The case went forward following the Supreme Court of Illinois' refusal to accept original jurisdiction of a petition for writ of mandamus filed by the Petitioner and denial of his motion that it recuse itself and appoint a substitute court to review the motion to reconsider. People ex rel. Cronson v. Attorney Registration & Disciplinary Comm'n, No. 57179 (Ill.Sup.Ct. filed August 23, 1982).
At issue in Chicago Bar are the parties' varying interpretations of the Illinois Constitution and statutes. Article VIII, Section 3 of the constitution provides in Part: "The Auditor General shall conduct the audit of public funds of the State." At issue is whether the funds of the Commission and Board are "public funds" within the meaning of the constitution and enacting statute. Ill.Rev.Stat. ch. 15, ¶ 301-1 (1985). The parties also disagree as to whether the Board and Commission are "state agencies" under the definition set forth in Ill.Rev.Stat. ch. 15, ¶ 301-7. The Auditor General has jurisdiction to audit all state agencies. Id. ¶ 303-1. Finally, the Supreme Court contends an audit of the Commission and Board would constitute a violation of the principle of separation of powers as an intrusion upon the Court's judicial power.
[3] Specifically, in hearings before the Illinois Legislative Audit Commission to ascertain the reasons for the refusal to permit public audit of the Commission and Board, the Supreme Court of Illinois, speaking through its respective Chief Justices and administrators, have asserted that the affairs of the agencies do not come within the public domain. Thus, the Auditor General claims the Supreme Court cannot, consistent with procedural due process requirements, determine the propriety of what he believes is a constitutionally forbidden partial audit when its members allegedly agree with Respondent Madden that only a complete audit of the Court is sought.
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New pool will bolster Snohomish, GP swim teams
The lap pool at the new Snohomish Aquatics Center will be used for recreational swimming and events as well as by the Snohomish and Glacier Peak High Schools' swim teams.
File photo
Snohomish head coach Rob Serviss (holding trophy) and the Snohomish boys swim team celebrate after winning the Class 4A Boys Swimming and Diving Championship in 2006. Serviss hopes that the new Snohomish Aquatic Center will help the Panthers get back to their glory days.
The lap pool at the new Snohomish Aquatics Center will be used for recreational swimming and events as well as by the Snohomish and Glacier Peak High Schools' swim teams.
File photo
Snohomish head coach Rob Serviss (holding trophy) and the Snohomish boys swim team celebrate after winning the Class 4A Boys Swimming and Diving Championship in 2006. Serviss hopes that the new Snohomish Aquatic Center will help the Panthers get back to their glory days.
SNOHOMISH -- A few years ago, the Snohomish High School boys swim team was as good as any program in the state. Good enough, in fact, to win state championships in 2006, 2007 and 2008.But even as the Panthers were hoisting the third of those title trophies, trouble was on the way. The team's home, the Hal Moe Pool in downtown Snohomish, had closed the year before due to structural issues that were too costly to repair, and since then the school's boys and girls teams -- and later the boys and girls teams from the new Glacier Peak High School, also in the Snohomish School District -- have been orphaned."We had a decent showing the year after (the third state championship), but every year it got a little bit harder," said Rob Serviss, the head coach for both Snohomish and Glacier Peak. The drop, he added, "directly coincided with the closure of the pool."As the boys teams from both schools prepare for the 2013-14 season, the outlook is less than rosy. Snohomish and Glacier Peak have good swimmers, just not very many. Competing against schools that might have 40 or more swimmers in their programs, Snohomish has just 14 swimmers and four divers. Glacier Peak has only eight swimmers and one diver.But the good news is, the new Snohomish Aquatic Center is scheduled to open sometime in January. Described by Serviss as "a beautiful building," it will become the home venue for both schools."It's going to have a huge impact," Serviss said. "An absolutely huge impact."The 52,000 square-foot aquatic center, located at 516 Maple Avenue in Snohomish, was constructed with funds that were part of the district's 2008 capital projects bond. The $261.6 bond also paid for renovation of Snohomish High School and other district-wide improvements.When the new pool opens, "we'll have a home," Serviss said. "And we haven't had a home for a long time. We haven't hosted a meet in six years, so it's going to be a great opportunity for the guys to know what it feels like to have a home meet and to have a home crowd and to have banners on the wall and a record board and all those things that make it (feel like) your home pool."It'll give them a sense of identity, and even more a sense of ownership of the program by having their own building," he said.Since 2007, Snohomish and later Glacier Peak have trained at a Woodinville fitness club and more recently at Mukilteo's Olympic View Middle School. Since the Snohomish School District cannot offer bus service to and from practices, team members have to provide their own transportation, which usually means a carpool.Max Cossalter, Glacier Peak's senior captain, says he makes a 40-mile round trip to practice every day. The problem, he said, "is that you can't recruit people (to the team) when you're saying, 'Oh, yeah, you have to pay us (for gas) to drive you.'"There is also a time issue, explained Snohomish captain Easton Lemos, another senior. School gets out at 2:15 p.m. and the carpools depart a half-hour later. Practices last from 3:15-7:15 p.m., and then everyone returns to the cars for the trip back to Snohomish, arriving at close to 8 p.m."That's a long time to be practicing and on the road," Lemos said.The difficulty of getting to and from practices is apparently the reason both schools have small squads this season. "Our team has strong swimmers," Lemos said, "but we just don't have the numbers. And it's because of the commute."But with a beautiful new pool about to open in Snohomish, Serviss expects more swimmers to turn out at the two schools, with success in the water to follow."I'm very hopeful that when the new aquatic center opens it'll be a big boost to our numbers," he said. "When the new building opens and we can get in there for a couple of full seasons, we'll get that base of young talent built up, we'll start teaching them how we do things and we'll get back to where we were."Lemos agrees. "I love all the guys at Kamiak (in Mukilteo, which has an on-campus pool), but I'm jealous of them," he said. "They've always had over 40 swimmers, and it's hard for us to go over there with about 15 guys because we just get annihilated. But hopefully with the new pool next year, we'll actually get (more swimmers) and we'll be able to put up a fight against those teams with big numbers."If you give it time for the community to start putting their kids in swim lessons and in club swimming, Snohomish is going to be winning state again," he said.
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Evaluation of the quality of clinical practice guidelines for the management of esophageal or gastric variceal bleeding.
Clinical practice guidelines (CPGs) should provide healthcare practitioners with the best possible evidence. Their quality, however, is often suboptimal. An evaluation of CPGs for the treatment of esophageal or gastric variceal bleeding (VB) has not been performed to date. The aim of this study was to identify and evaluate the quality of CPGs for esophageal or gastric VB. We performed a systematic search of the scientific literature published up to July 2012 to identify and select CPGs related to the management of esophageal or gastric VB. Three independent reviewers assessed the eligible guidelines using the Appraisal of Guidelines, Research, and Evaluation II (AGREE II) instrument. Standardized scores were calculated for the six domains of each instrument, and the overall agreement among reviewers was assessed on the basis of the intraclass correlation coefficient. Of a total of 23 CPGs identified, 10 were selected. Intraobserver agreement was good (overall intraclass correlation coefficient of 0.956, 95% confidence interval 0.958-0.973). The overall quality of the guidelines varied from low to moderate. Stratified by domains, the quality was good to acceptable in three domains: 'scope and purpose' (78.1%, median 82.3, range 46-100); 'clarity and presentation' (87.2%, median 91.6, range 67-98); and 'editorial independence' (64.1%, median 61.1, range 22-94), but with deficiencies in another three: 'rigor of development' (47.6%, range 28-94), 'stakeholder involvement' (47.5%, median 37, range 18-98) and 'applicability' (25.9% median 13.2, range 1-83). In the overall evaluation, two guidelines were considered 'highly recommended', three, 'recommended with modifications', and five, 'not recommended'. There was a significant improvement in quality over time. The overall quality of CPGs for the management of esophageal or gastric VB has improved over time. Although the overall quality was not optimal, two guidelines achieved an excellent rating. A summary of recommendations is provided.
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Diet-induced thermogenesis: fake friend or foe?
Diet-induced thermogenesis (DIT) is energy dissipated as heat after a meal, contributing 5-15% to total daily energy expenditure (EE). There has been a long interest in the intriguing possibility that a defect in DIT predisposes to obesity. However, the evidence is conflicting; DIT is usually quantified by indirect calorimetry, which does not measure heat. Using gas exchange, indirect calorimetry measures total post-prandial EE, which comprises heat energy produced from brown adipose tissue (BAT) and energy required for processing and storing nutrients. We questioned whether DIT is reliably quantified by indirect calorimetry by employing infrared thermography to independently assess thermogenesis. Thermogenic activity of BAT was stimulated by cold and by a meal that induced a parallel increase in energy production. These stimulatory effects on BAT thermogenesis were inhibited by glucocorticoids. However, glucocorticoids enhanced postprandial EE in the face of reduced BAT thermogenesis and stimulated lipid synthesis. The increase in EE correlated significantly with the increase in lipogenesis. As energy cannot be destroyed (first law of thermodynamics), the energy that would have been dissipated as heat after a meal is channeled into storage. Post-prandial EE is the sum of heat energy that is lost (true DIT) and chemical energy that is stored. Indirect calorimetry does not reliably quantify DIT. When estimated by indirect calorimetry, assumed DIT can be a friend or foe of energy balance. That gas exchange-derived DIT reflects solely energy dissipation as heat is a false assumption likely to explain the conflicting results on the role of DIT in obesity.
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INTRODUCTION {#sec1-1}
============
True emergencies due to unstable arrhythmias in children are rare, as most rhythm disturbances in this age group are well-tolerated. However, presentation to an emergency department with symptoms of palpitations, fatigue and/or syncope is much more common. Pediatric arrhythmias account for approximately 55.1 per 100,000 patients evaluated in pediatric emergency departments. Sinus tachycardia is by far the most commonly reported arrhythmia, followed by supraventricular tachycardia (SVT) which represents about 13%, and bradycardia accounting for about 6% of all cases.\[[@CIT1]\] Emergency physicians should be prepared for diagnosis and to acutely manage various types of arrhythmias seen in children, to assess the need for further diagnostic testing, and to determine whether cardiology evaluation and follow-up are needed. This article is intended to provide diagnostic \[[Figure 1](#F0001){ref-type="fig"}\] and management guidelines of the most common types of arrhythmias seen in children with structurally normal hearts as well as those associated with congenital heart disease and cardiomyopathies.
{#F0001}
TACHYCARDIAS {#sec1-2}
============
Narrow QRS complex tachycardia (supraventricular tachycardia) {#sec2-1}
-------------------------------------------------------------
Narrow complex tachycardia refers to any arrhythmia that originates above or at the bundle of His. These are by far the most common tachycardias seen in children, with an estimated incidence of 0.1--0.4%.\[[@CIT2]\] Three mechanisms of tachycardia have been described. In the most common, re-entry tachycardia, the circuit can originate within the atrium producing atrial flutter or fibrillation, at the level of the AV node (AV node reentry tachycardia), or via an accessory pathway \[AV re-entry tachycardia (AVRT)\]. A second mechanism is automatic tachycardia, which results from an enhanced automatic focus. This can be within the sinus node as in sinus tachycardia or in foci elsewhere in the atria. Sinus tachycardia is commonly seen in the setting of fever, anemia, hypovolemia, and medications known to increase catecholamines and is uncommonly associated with underlying cardiac disease. It can be distinguished from SVT by the presence of a normal sinus P wave preceding every QRS complex \[[Figure 2a](#F0002){ref-type="fig"}\]. Sinus tachycardia rates can exceed 140 bpm in children and 180 bpm in infants but are usually less than 200 bpm. Treatment is primarily aimed at the underlying disorder. Triggered tachycardia is a much less common tachycardia mechanism except in the setting of drug toxicity such as digoxin overdose.
{#F0002}
A) AV reentry and AVN reentry tachycardia {#sec2-2}
-----------------------------------------
1. AVRT {#sec2-3}
-------
This is also known as accessory-pathway mediated tachycardia or orthodromic reciprocating tachycardia, and is by far the most common type of SVT seen in children, representing 82% of arrhythmias occurring during infancy.\[[@CIT3]\] AVRT involves two distinct pathways between the atria and ventricles, which create an electrical reentry circuit proceeding down the AV node and then up an accessory pathway outside the AV node creating a narrow QRS complex tachycardia \[[Figure 2b](#F0002){ref-type="fig"}\]. The much rarer *antidromic* tachycardia reverses the direction of conduction, with transmission down the accessory pathway and up the AV node, creating a widened QRS complex, which will be discussed under wide complex tachycardias. Once normal sinus rhythm is re-established, 50% of patients manifest ventricular pre-excitation in the form of a delta wave on electrocardiogram, consistent with Wolf-Parkinson-White syndrome (WPW); the remainder of patients have a "concealed" pathway that is not evident during sinus rhythm. The only difference between the two forms is the presence of manifest antegrade conduction to the ventricle in WPW. Because conduction through the pathway can occur before the AV node is activated, a shortened PR interval slurred QRS upstroke and widensed QRS result \[[Figure 3](#F0003){ref-type="fig"}\]. This also creates the potential for rapid ventricular response during atrial fibrillation, which can result in ventricular fibrillation and sudden death. Thus, although acute management of SVT is the same for patients with concealed and manifest pathways, definitive ablative therapy in patients with WPW is compelling.
{#F0003}
2. AV Node reentry tachycardia (AVNRT) {#sec2-4}
--------------------------------------
This is also is due to a re-entry circuit but with pathways that involve the AV node. In this tachycardia, there are also two discrete conduction limbs, a "slow" pathway which usually conducts antegrade, and a so-called "fast" pathway which usually conducts retrograde. This accounts for \~15% of SVT in the pediatric age group, increases with age, and is rarely seen in infants.\[[@CIT4]\] These two types of tachycardia are often clinically indistinguishable, having similar rates and being well-tolerated in most patients. The exception is the infant with AVRT, in whom tachycardia can go unrecognized for prolonged periods, resulting in gradual cardiovascular deterioration. Fortunately, initial therapy is identical in both types of SVT. Briefly interrupting conduction through the AV node with adenosine terminates both types, and long-term medication or ablative choices are very similar.
### Clinical features {#sec3-1}
History of poor feeding, lethargy, irritability, pallor in infants;Historyof palpitation, dizziness, chest pain, syncope and shortness of breath in older children and adolescents;Signs and symptoms of congestive heart failure in some infants andHistory of abrupt onset and termination.
### Electrocardiographic findings {#sec3-2}
These are presented in [Figure 2](#F0002){ref-type="fig"}. The important findings are as follows:HeartRates \>220 in infants and \>180 in children;Narrow QRS complex andAV ratio 1:1In AVNRT, terminal QRS notching ± visible.In AVRT, inverted P waves ± visible.
### Acute management {#sec3-3}
Attempt vagal maneuver (i.e., application of ice, Valsalva maneuver or carotid massage);if unsuccessful, give adenosine 100 mcg/kg rapid bolus, increase the dose and repeat as needed;Synchronized DC cardioversion if adenosine is unsuccessful, starting at 0.5J/kg andIntravenous amiodarone alternative in experienced hands.
### Further work-up and disposition {#sec3-4}
Once normal sinus rhythm is established, repeat electrocardiogram to rule out pre-excitation and underlying cardiac disease.Laboratory work-up: serum electrolytes, thyroid function tests and complete blood count.All patients under 1 year of age and those with hemodynamically unstable SVT should be admitted for observation. Patients with first time episode and normal hearts should be observed overnight, without treatment. In patients with known structural heart disease, therapy is recommended on an individualized basis. If patient is discharged, provide instruction on vagal maneuvers to treat recurrence, as well as a list of indications to seek medical attention.Initiation of maintenance therapy would depend on patient age and severity of symptoms and recurrence, and should be discussed with cardiologist.Cardiology follow-up is recommended for all new patients. Provide a copy of EKGs to the parents, to be brought during their visit.Infants with suspected prolonged episodes should have echocardiography to rule out thrombus and ventricular dysfunction. Otherwise, echocardiogram may be obtained during cardiology evaluation to rule out underlying heart disease.Of note, patients found to have asymptomatic pre-excitation on EKG should also be referred for cardiology evaluation.
### Prognosis {#sec3-5}
The probability of complete resolution of SVT is dependent on age of onset. In the majority of infants diagnosed at 1 year of age or less, SVT is likely to resolve, compared to only 33% of patients diagnosed after 1 year of age.\[[@CIT5]\] Maintenance therapy includes the use of beta-blockers in cases of recurrent and/or prolonged tachycardia. Digoxin and calcium channel blockers should not be prescribed in patients with WPW prior to full cardiology evaluation. Sotalol, flecainide or amiodarone may be necessary for medical control of some SVT. Catheter ablation allows for definitive therapy for SVT, at low risk in patients beyond the toddler years.
B) Atrial tachycardia {#sec2-5}
---------------------
1. Atrial flutter {#sec2-6}
-----------------
In children, atrial flutter usually occurs in fetal life or shortly following birth. It is rarely seen beyond the newborn period except in the setting of underlying congenital heart disease and cardiac surgery, where it is most common in children who have undergone Fontan procedures, atrial septal closure and tetralogy of Fallot (TOF) repair. Congenital heart disease and post-operative patients represent about 80% of older children presenting with atrial flutter.\[[@CIT6]\] It accounts for about 30% of fetal tachycardia, 18% of tachycardias in newborn and only 8% in older children.\[[@CIT7]\] Atrial flutter involves a single reentry circuit within the atrial muscle, most commonly around the borders of the tricuspid valve. Hemodynamic compromise is determined by the duration of flutter and the degree of AV block, with 1:1 AV conduction resulting in the most significant instability. Clinical presentation depends on ventricular response. In the setting of rapid ventricular conduction, patients may be hemodynamically unstable with poor cardiac output.
### Clinical features {#sec3-6}
Diagnosed *in-utero* during fetal ultrasound evaluation;Fetal hydrops common if prolonged;Most newborns are asymptomatic unless tachycardic\>48hours;Infants with prolonged tachycardia may present with history of poor feeding, irritability, lethargy, diaphoresis and pallor andOlder children may complain of palpitations, chest pain and/or dizziness.
### Electrocardiographic findings {#sec3-7}
The findings are presented in [Figure 4](#F0004){ref-type="fig"}. They are as follows.
{#F0004}
Regular atrial rates of 240--360 bpm;AV ratio \>1:1, variable but generally regular, ventricular rate 120--240;Typical sawtooth appearance may be seen in lead II, III and aVF andNormal appearing QRS complex.
### Acute management {#sec3-8}
Vagal maneuvers or adenosine do not convert this rhythm but may increase the degree of AV block, unmasking underlying flutter waves.If patient has rapid ventricular response with reduced cardiac output, or for elective cardioversion, use DC cardioversion starting at 0.5J/kg, increasing to 1--2J/kg if needed.If stable, pharmacotherapy can be aimed at rhythm control with IV amiodarone or ibutilide, or at rate control with beta-blockers or calcium-channel blockers.In patients with pacemaker, pace termination can be attempted by the cardiologist.
### Further work-up and disposition {#sec3-9}
Laboratory work-up: serum electrolytes and thyroid function tests;Cardiology consultation and echocardiogram to rule underlying structural heart disease, tachycardia-mediated cardiomyopathy and thrombus;Admit for observation andAnticoagulation therapy for episodes \>48 hours and in all Fontan patients.
### Prognosis {#sec3-10}
In the presence of a structurally normal heart, the risk of recurrence of neonatal atrial flutter is low and no long-term therapy is needed. In cases of structurally abnormal heart and/or recurrent atrial flutter, long-term therapy may be required. Management is directed at either rhythm control with agents such as amiodarone and flecainide, or control of ventricular response with digoxin, calcium channel blockers or beta-blockers in selected patients. Catheter ablation can be highly successful in the older child.
2. Ectopic atrial tachycardia {#sec2-7}
-----------------------------
Ectopic atrial tachycardia is uncommon, accounting for about 10% of SVT in children.\[[@CIT8]\] It is due to enhanced automacity of single or multiple foci outside the sinus node and is often refractory to medical therapy and cardioversion. Ectopic atrial tachycardia is the most common cause of tachycardia-induced cardiomyopathy due to its persistent and chronic nature; improvement in cardiac function has been observed following successful treatment. The precise etiology is unknown; however, viral illness, atrial tumors and genetic predisposition have been implicated. Clinical presentation depends on the extent of cardiac dysfunction, with most patients presenting with minor symptoms in the setting of preserved function.
### Clinical features {#sec3-11}
Is predominantly observed in infants and children with structurally normal hearts.Patients present with symptoms of chest pain, palpitations, pre-syncopal or syncopal events. Older children may present with exercise intolerance or be asymptomatic.Infants may present with feeding difficulties, diaphoresis with feeds or in respiratory distress secondary to chronic tachycardia.
### Electrocardiogram findings {#sec3-12}
These are shown in [Figure 5](#F0005){ref-type="fig"}. The findings are as follows:
{#F0005}
Atrial rate that is inappropriately rapid for age. Sometimes difficult to distinguish from sinus tachycardia;Abnormal P wave morphology and axis;Atrial rate variable, ranging from 120 to 300 bpm;May exhibit a "warm up" period at initiation with progressive P-P interval shortening and a "cooling down" period prior to termination and\>1:1 AV conduction can be seen in patients at rest or while asleep without termination of the tachycardia.
### Acute management {#sec3-13}
Responds poorly to adenosine and DC cardioversion.First line treatment for symptomatic patients includes IV amiodarone. Load with 5mg/kg bolus over 20--60 minutes.Can be followed by amiodarone maintenance drip at 10--15mg/kg/day.Minimally symptomatic patients do not require acute treatment.
### Further work-up and disposition {#sec3-14}
Laboratory work-up: serum electrolytes, complete blood count, toxicology screen. If cardiac function is poor, additional laboratory evaluation should include viral panel, blood culture and cardiac enzymes to help differentiate infection versus tachycardia-induced cardiomyopathy.Cardiology consultation and echocardiographic evaluation is recommended.Obtain 24-hour cardiac monitor to determine duration of tachycardia and ventricular rates.Treatment is dependent on patient age, symptoms, clinical status, tachycardia rate and duration, and ventricular function.Asymptomatic patients can be treated conservatively.Children younger than 1 year and symptomatic patients should be admitted for management of arrhythmia and congestive heart failure. In the setting of normal cardiac function, beta-blockers can be useful by slowing AV node conduction, lowering the ventricular rate and improving symptoms.More aggressive treatment consists of flecainide, amiodarone or sotalol which have moderate success rates. Patients who fail medical therapy can undergo catheter ablation.
### Prognosis {#sec3-15}
Spontaneous resolution may be observed in 30--50% of affected children.\[[@CIT9]\] Children younger than 3 years have higher incidence of AET resolution with treatment versus older children who are likely to require RF ablation because of persistent tachycardia despite optimal medical management.\[[@CIT10]\]
3. Atrial fibrillation {#sec2-8}
----------------------
Atrial fibrillation is mostly seen in children with underlying structural heart disease and in those who have undergone cardiac surgery. In infants and children with structurally normal hearts, atrial fibrillation is often associated with an AV accessory connection such as WPW. These patients can be at increased risk of sudden death if there is rapid conduction to the ventricle via a manifest accessory pathway. Atrial fibrillation can also be associated with cardiomyopathies, myocarditis, pericarditis and hyperthyroidism, and in rare instances has a genetic predisposition. The mechanism involves multiple reentry circuits predominantly within the left atrium. Patients are usually symptomatic at presentation and in the setting of rapid ventricular rates, hypotension and syncope may ensue. As in adults, the possibility of atrial thrombus with the risk of embolic stroke is of great concern.
### Clinical features {#sec3-16}
Children and adolescents present with complaints of palpitations. Weakness and signs of congestive heart failure may be seen.In patients presenting with syncope, WPW should be highly suspected.
### Electrocardiogram findings {#sec3-17}
[Figure 6](#F0006){ref-type="fig"} shows the findings. They are as follows.
{#F0006}
Chaotic/irregular atrial waves best seen in lead V1;Atrial rates of 350--600 bpm;No discrete, uniform P waves;AV ratio \>1:1;Variable, changing ventricular response rate (irregularly irregular), ranging from 110 to 200 bpm andNormal appearing QRS complex, except in WPW.
### Acute management {#sec3-18}
If the patient has rapid ventricular response with reduced cardiac output, DC cardioversion starting at 2J/kg is used.For stable patients, pharmacotherapy aimed at ventricular rhythm or rate control can be used. IV rhythm control agents include amiodarone and ibutilide. Less effective are sotalol, digoxin and procainimide.Cardioversion in stable patients with unknown or prolonged (\>48 hours) duration of tachycardia should be delayed until assessment for atrial thrombus is made with echocardiography.
### Further work-up and disposition {#sec3-19}
Once in normal sinus rhythm, repeat EKG.Laboratory work-up: serum electrolytes, thyroid function, complete blood count, toxicology screen. If cardiomyopathy is suspected, additional laboratory evaluation should include viral panel, blood culture and cardiac enzymes.Echocardiography is indicated in all cases.Admit for observation and treatment.Initiate anticoagulation therapy in most cases.
### Prognosis {#sec3-20}
Despite medical therapy, atrial fibrillation has a high recurrence rate and often requires catheter or surgical intervention. Chronic anticoagulation therapy is indicated in patients with persistent or recurrent atrial fibrillation. Ablation of the AV node with implantation of a pacemaker may be necessary in some refractory cases.
Wide QRS complex tachycardias {#sec2-9}
-----------------------------
Although less common in children than in adults, wide complex tachycardia still occurs with some frequency. As outlined in [Figure 1](#F0001){ref-type="fig"}, not all wide complex tachycardias are due to ventricular tachycardia (VT). The differential diagnosis of wide complex tachycardia includes VT, bundle branch block during SVT and SVT with pre-excitation in patients with WPW. If available, a previous 12-lead electrocardiogram may show underlying bundle branch block and can be helpful in distinguishing VT from SVT with aberrancy. Due to the potential life-threatening nature of VT, all wide complex tachycardia should be treated as VT until proven otherwise.
A) Ventricular tachycardia {#sec3-21}
--------------------------
VT is a potentially life-threatening arrhythmia recognized as a cause of sudden death in both adults and pediatrics. It is rare in children and accounts for about 6% of patients followed for tachycardias.\[[@CIT11]\] Defined as a tachycardia originating below the bundle of His, rates can range from just over the sinus rate to well over 200 bpm. Episodes lasting less than 30 seconds are termed as non-sustained VT and those more than 30 seconds as sustained VT. VT can further be classified as monomorphic, with a regular rate and a single QRS morphology, versus polymorphic, with variability in rate and QRS morphology. The same basic mechanisms of automacity, reentry and triggered tachycardia exist in VT as for other arrhythmias. Etiology is widely variable and includes idiopathic, drug toxicity, cardiomyopathy, myocarditis, cardiac tumors and metabolic abnormalities, to name a few.
### Clinical features {#sec3-22}
Variable, may present with symptoms ranging from dizziness and palpitations to syncope and cardiac arrest.
### Electrocardiogram findings {#sec3-23}
[Figure 7](#F0007){ref-type="fig"} shows the findings which are as follows.
{#F0007}
Hallmarks are prolonged QRS duration for age and VA dissociation with ventricular rates exceeding atrial rates (AV ratio \< 1:1).Rates range from \~110 to \>200 bpm.When VA conduction is 1:1, VT cannot be excluded. Features consistent with the diagnosis of VT rather than SVT with a wide QRS include variation in RR interval and presence of fusion complexes.Complexes may appear uniform or vary from beat to beat as in polymorphic VT.
### Acute management {#sec3-24}
If unstable, synchronized cardioversionis started at 2J/kg and repeated, increasing the dose if needed.If stable, may attempt amiodarone at 5mg/kg IV over 30--60 minutes or procainimide at 15mg/kg IV over 30--60 minutes.
### Further work-up and disposition {#sec3-25}
History should focus on prior symptoms, symptoms suggestive of myocarditis or long-standing cardiomyopathy, and the possibility of drug toxicity, as well as a thorough family history for known arrhythmias or history of sudden death.Once in normal sinus rhythm, repeat EKG to rule out underlying abnormalities including long QT, Brugada, arrhythmogenic right ventricular cardiomyopathy, structural heart disease, electrolyte abnormalities and ischemia.Laboratory work-up should include toxicology screen, serum electrolytes, complete blood count, viral panel, blood culture and cardiac enzymes.Cardiac consultation and echocardiographic evaluation are done to rule underlying structural heart disease, cardiomyopathy, cardiac tumors.Admit for observation.After cardioversion, return to sinus rhythm may be transient and continual infusion of amiodarone may be required.
### Prognosis {#sec3-26}
In the setting of a structurally normal heart and stable, well-tolerated monomorphic VT, many minimally symptomatic patients can be followed closely without therapy. Such patients may benefit from B-blockers to reduce ectopy. Chronic treatment otherwise depends on rate, duration, symptoms, type of VT and the presence of genetic channelopathy such as long QT. Aggressive antiarrhythmic therapy usually in addition to implantable cardioverterdefribrillator (ICD) placement is required for life-threatening VT.
B) Long QT syndrome {#sec2-10}
-------------------
The congenital long QT syndrome is a genetic disorder of prolonged cardiac repolarization that may cause cardiac arrest and sudden death. Abnormalities in cardiac ion channels predispose patients to a characteristic polymorphic VT called "torsades de pointes". Events are often precipitated by adrenergic stimuli. Acquired long QT may also occur and can be caused by drugs, underlying medical conditions or electrolyte imbalances.
### Clinical features {#sec3-27}
Patients may present with presyncope, syncope, seizures, or cardiac arrest.Precipitating factors may include exercise, especially swimming, emotional stress, exposure to loud noises or even sleep.Although rare, infants can present with poor feeding, or with episodes of lethargy, cyanosis or poor perfusion.
### Electrocardiogram findings {#sec3-28}
Sinus rhythm ECG, QTc of \>460 in post-pubertal females and 450 in others, best obtained from lead II (Bazett Formula QTc= QT Interval/√-RR).
Borderline QTc\>440 ms in the setting of clinical symptoms and/or family history should be investigated.Abnormal T wave morphology including notching and low amplitude.*Torsade de pointes* seen during events.
### Acute management {#sec3-29}
For *torsades de pointes*, perform emergent defibrillation followed by administration of magnesium sulfate and possibly lidocaine.Correct underlying problem if acquired long QT.Intravenous beta-blockade may calm an adrenergic storm.
### Further work-up and management in suspected congenital long QT syndrome {#sec3-30}
Obtain thorough family history of rhythm abnormalities, sudden death, deafness.Ascertain all medications.Review history of event that may have triggered arrhythmia.Obtain electrolytes and treat underlying abnormalities.If presented with symptoms or documented VT, admit for observation, cardiology consultation and treatment.For patients presenting with non-cardiac issues and noted to have abnormal QTc interval, out-patient cardiology follow-up may be arranged.Restrict all strenuous activity pending cardiology follow-up.Provide list to the patients of medications known to prolong QT that should be avoided.Immediate family members should also be screened with 12-lead EKGs.
### Prognosis {#sec3-31}
Prognosis is poor in untreated symptomatic patients, with an annual mortality of 20%. B-blockers are the mainstream therapy and reduce risk of sudden death to about 6% annually but do not eliminate it completely.\[[@CIT12]\] High risk patients may benefit from ICD placement which has been shown to reduce mortality risk. Factors known to increase risk include history of previous syncope, deafness, previous torsade, female gender and genotype.\[[@CIT13]\]
CONGENITAL HEART DISEASE {#sec1-3}
========================
Patients with congenital heart disease are at lifelong risk for the development of arrhythmias. Types of arrhythmias depend on the underlying cardiac anomaly and more importantly on the surgical repair, and can range from atrial flutter to ventricular fibrillation. (See [Table 1](#T0001){ref-type="table"}) ED management should focus on understanding the cardiac anatomy and previous surgical interventions and to focus on how these can predispose patient to certain rhythm disturbances. In the following section, we describe some of the most common congenital heart diseases and their associated arrhythmias.
######
Congenital heart disease and associated arrhythmias
Congenital heart disease
------------------------------------- ------------------------------
Tetralogy of Fallot Atrial tachycardia
Double outlet right ventricle Ventricular tachycardia
Sinus node dysfunction
Transposition of the great arteries Ventricular arrhythmias
Atrioventricular block
Ebstein\'s anomaly Supraventricular tachycardia
Ventricular septal defect repair Heart block
Ventricular arrhythmias
Atrialseptal defect Atrial tachycardia
Atrial septal defect repair Sinus node dysfunction
1. Ventricular septal defect repair {#sec2-11}
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Ventricular septal defects (VSD), by far the most common congenital heart defect, are not generally associated with rhythm abnormalities. In the present era, clinically significant VSDs are repaired in early childhood, decreasing the incidence of arrhythmias. By avoiding right ventriculotomies, newer surgical approaches have significantly altered the incidence of ventricular arrhythmias. Operated patients, however, remain at an increased risk for developing heart block, even late after repair. The presence of a small, hemodynamically insignificant VSD does not increase the risk of arrhythmia.
2. Atrial septal defect repair {#sec2-12}
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Atrial septal defect (ASD) occurs in 5--10% of all congenital heart defects and is found in 30--50% of children with other types of congenital heart disease as well.\[[@CIT14]\] In large defects, atrial tachycardias can develop secondary to chronic volume overload and atrial dilation. Early repair has been credited for improved survival and decreased incidence of late arrhythmias. Possible surgical complications include injury of the SA node producing sinus nodal dysfunction and secondary bradycardia or tachy-brady syndrome.
3. Tetralogy of Fallot {#sec2-13}
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Tetralogy of Fallot (TOF) is the most common cyanotic heart disease, representing 3.5--9% of patients with CHD.\[[@CIT15]\] Arrhythmias, both atrial and ventricular, occur in unrepaired and repaired patients \[[Figure 7](#F0007){ref-type="fig"}\] A meta-analysis study by Walsh *et al*. found an incidence of 2--6% of arrest or sudden late death in patients repaired during infancy.\[[@CIT16]\] Although atrial tachycardias are actually more common, the primary concern in TOF is VT, with a long-term mortality risk estimated at 3--6%.\[[@CIT17]\] Sinus node dysfunction and atrial reentry tachycardias have also been described, with an incidence of 20--30%.\[[@CIT18]\] A large multicenter trial by Gatzoulis *et al*, assessing risk factors for VT and sudden death in TOF patients found that QRS duration of \>180ms, an increasing QRS duration, older age of repair, and/or presence of right ventricular patch were associated with increased risk of arrhythmia.
4. Transposition of the great arteries {#sec2-14}
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The so-called "congenitally corrected" or L-transposition of the great arteries is rare, estimated to occur in 1% of all patients with congenital heart disease, but risk of arrhythmia is high. In this condition, the right atrium is attached to the left ventricle which empties to the pulmonary artery, and the left atrium enters the right ventricle and thus into the aorta. The incidence of spontaneous complete heart block has been reported to be as high as 22% owing to intrinsic abnormalities of the His bundle.\[[@CIT19]\]
D-transposition of the great arteries (right ventricular connection to aorta and left ventricular connection to pulmonary artery) is much more common, and was a uniformly lethal disease prior to corrective surgery. With current surgical techniques, arrhythmia risk is relatively low. During outpatient follow-up, Rhodes and colleagues found an incidence of 4.4% of some form of AV block. SVT was seen in 5%, whereas almost half of the patients showed evidence of ventricular arrhythmias, mostly isolated premature beats, 6--12 months following repair.\[[@CIT11]\]
5. Ebstein's anomaly {#sec2-15}
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Ebstein's anomaly is a very rare condition in which the tricuspid valve leaflets have an abnormal attachment causing displacement of the valve into the right ventricle, so called "atrialized" ventricle. Patients are at increased risk for the development of SVT, with an incidence as high as 42%.\[[@CIT20]\] In the setting of severe tricuspid regurgitation and/or atrial septal defects, tachycardias may be poorly tolerated. Patients with Ebstein's anomaly are also at increased risk of atrial flutter and fibrillation due to the enlarged right atrium.
CARDIOMYOPATHIES {#sec1-4}
================
Cardiomyopathies are a group of disorders of intrinsic muscle disease. These patients are at increased risk for atrial and VTs. Treatment can be challenging and ICD implant is being used increasingly in these populations.
1. Hypertrophic cardiomyopathy {#sec2-16}
------------------------------
Patients with hypertrophic cardiomyopathy (HCM) are at increased risk of malignant VT and sudden death. Multiple risk factors have been implicated, including family history of sudden death, history of syncope, dramatic septal thickness, non-sustained VT and inappropriate blood pressure response to exercise. Death is often sudden and usually occurs in the setting of vigorous exertion with an annual incidence of 3--5% in children and adolescents with HCM.\[[@CIT21]\] Current therapy includes exercise restriction and the use of beta-blockers or calcium channel blockers for symptomatic patients. Surgery is recommended for drug refractory cases with marked left ventricular outflow tract obstruction and ICD implantation for primary prevention in high-risk patients and secondary prevention in patients with syncope or documented VT.
2. Dilated cardiomyopathy {#sec2-17}
-------------------------
Dilated cardiomyopathy (DCM) is the most common severe cardiomyopathy, accounting for more than 50% of pediatric cases.\[[@CIT8]\] Etiology of DCM is broad and includes infectious, immunologic, familial, metabolic, toxic and arrhythmic causes. Although these patients are at risk for VT, SVTs are more common. It is sometime difficult to distinguish atrial tachycardia from sinus tachycardia, but in general, average rates exceeding 150 bpm highly correlate with atrial tachycardia. Treatment is targeted at symptoms, ventricular dysfunction and underlying rhythm disturbance. Prophylactic ICD use in the pediatric population is not as clear as in adults with ischemic cardiomyopathies.
Myocarditis, a common precursor to DCM, may present with sudden death. Although the exact incidence of arrhythmias associated with myocarditis is unknown, VTs and high-degree AV block are not uncommon \[[Figure 8](#F0008){ref-type="fig"}\].
{#F0008}
3. Arrythmogenic right ventricular dysplasia {#sec2-18}
--------------------------------------------
Arrythmogenic right ventricular dysplasia (ARVD) is a genetic myopathy involving fibrofatty degeneration of the right ventricle and is commonly associated with VT and sudden death. Inheritance is mainly autosomal dominant but sporadic cases have been described. Peak age of presentation is late teenage years to the 20s, and a common presenting symptom is syncope with exercise. Electrocardiographic findings include right ventricular conduction delay, inverted T waves in the right precordial leads inappropriate for age and PVCs of right ventricular morphology. Treatment usually involves ICD implantation.
BRADYCARDIAS {#sec1-5}
============
Bradycardias are a group of disorders that include sinus node dysfunction and abnormal conduction through the AV node. AV conduction abnormalities include first-, second- or third-degree heart block. First-degree heart block, prolongation of PR interval without loss of conduction, does not cause bradycardia or hemodynamic instability and is primarily of interest as a marker for an underlying cause. Causes of first-degree block are numerous and include enhanced vagal tone, previous cardiac surgeries, myopathies, and infections including Lyme disease, myocarditis, endocarditis and hypothyroidism.
1. Sinus bradycardia and sinus node dysfunction {#sec2-19}
-----------------------------------------------
Sinus bradycardia can result from multiple disease states, most of which are not primary cardiac. The exception is sinus node dysfunction, an abnormality of impulse generation and propagation of the sinus node usually caused in pediatrics by direct injury or disruption of blood supply to the node from previous cardiac surgery. Associated atrial reentry tachycardias are common and when they occur, the term "brady-tachy syndrome" is applied. Etiology of sinus bradycardia other than congenital heart disease is diverse and includes increased intracranial pressure, electrolyte abnormalities, respiratory compromise, hypothyroidism and certain medications. The need for acute treatment for sinus bradycardia itself is rare. The presence of sinus bradycardia in an otherwise healthy appearing child is generally of no concern, although anorexia nervosa should be considered. In the moribund patient with sinus bradycardia, urgent determination of the underlying cause is of paramount importance. Atropine and epinephrine increases sinus rates in most patients. Symptomatic patients with true sinus node dysfunction and/or those with coexistent tachycardias are likely to require elective pacemaker implantation.
2. Second-degree heart block {#sec2-20}
----------------------------
Second-degree heart block refers to intermittent failure of conduction through the AV node. It is further subdivided into Mobitz type I (Wenkebach), a gradual PR interval prolongation followed by a nonconducted beat, and Mobitz type II, an abrupt loss of conduction without previous change in PR interval duration. Mobitz type I is generally more benign and may be a normal finding in adolescents during sleep. Other causes are similar to those described for first-degree heart block. Treatment is aimed at underlying reversible causes. Progression to higher degree block has been reported and symptomatic patients may benefit from treatment with atropine or isoproterenol. Mobitz type II is thought to be more likely to progress to complete heart block. Elective pacemaker implantation has been advised for symptomatic patients in this group.\[[@CIT22]\]
3. Third-degree AV block {#sec2-21}
------------------------
Third degree AV block is the absence of conduction from the atria to the ventricle, manifested by AV dissociation. QRS duration of the escape rhythm may be normal or prolonged. Third-degree block can be congenital, mainly associated with maternal collagen vascular disease or congenital heart disease, or acquired, due to AV node injury from cardiac surgery, viral myocarditis, Lyme disease, or metabolic or neuromuscular disorders. Many children are asymptomatic when diagnosed. In infancy, symptomatic patients may appear severely ill at presentation. Older children and adolescents may present with symptoms of exercise intolerance, fatigue, dizziness, syncope or signs of congestive heart failure. Sudden death may occur. Most patients eventually require pacemaker implantation, unless the cause is reversible such as in Lyme disease, where temporary pacing may suffice.
CONCLUSION {#sec1-6}
==========
Proper diagnosis and management of the diverse rhythm disturbances in children is challenging. Emergency healthcare providers must be comfortable in performing a systematic evaluation and interpretation of ECG findings. An understanding of the variety of diseases that can predispose children with normal hearts or with structural heart disease to arrhythmias is essential for appropriate treatment.
**Source of Support:** Nil
**Conflict of Interest:** None declared.
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1. Field of the Invention
The present invention relates to a camera body structure for single lens reflex cameras, and more particularly pertains to such camera body structure which employs a unitized shutter block that is preassembled in a unit or block before it is coupled with the remaining parts of the camera body.
2. Description of the Prior Arts
The unitized shutter block, in which shutter blades and driving mechanism therefor are mounted on a base plate to be assembled in a camera as a unit or block, has recently been adopted in many single lens reflex cameras. This is because such unitized shutter device can be dealt with as a block upon assemblage of cameras and may be adjusted or calibrated, for example, with respect to its operation, relative position of its particular parts, shutter speed, etc., before the device is associated in a camera body so that the single lens reflex cameras employing such unitized shutter block are suitable for mass production with the adjusting process for such cameras being facilitated.
In the conventional single lens reflex cameras employing the unitized shutter device, a front plate which has a mount for the interchangeable lens and to which the mirror box including the reflex mirror and diaphragm driving mechanism has been fixed, is attached to the main camera body, after the shutter block is mounted on a main camera body including a film receptacle, film driving mechanism and shutter cocking mechanism. Accordingly, due to accumulation of errors occuring, upon coupling, at relative positions between the shutter block and the main camera body, between the front plate and the main camera body, and between the mirror box and the front plate, the relative position of the mirror box to the shutter block is liable to deviate from the desired position, resulting in imperfect interconnection between the shutter driving mechanism in the unitized shutter block, and the diaphragm and the mirror driving mechanism on the mirror box.
It may be possible in such a case to adjust relating mechanisms for perfecting the interconnection. With the conventional single lens reflex cameras, operation and examination, as to interconnections and operations, of their shutter, reflex mirror and diaphragm driving mechanisms are available only after the shutter block, mirror box and front plate are all assembled in a camera body. However, the examination and adjustment of their mechanism are in fact difficult in the conventional cameras, because portions or parts to be adjusted are likely to be blocked by the other parts or mechanism in the assembled condition. Therefore, in such conventional cameras, safety tolerance and space are provided between the shutter driving mechanism and the diaphragm and mirror driving mechanism, taking into account the accumulated error, so that the difficult adjustment may not be required. As a result, interconnected members are necessarily required to move greatly and the drive force therefor will also be large, thereby increasing the force for shutter cocking and noise upon the operation of the members, as well as shortening the lifetime of the members. Additionally, the safety space itself will be one of the factors against providing compactness of the camera body.
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Vasorelaxing effects of flavonoids: investigation on the possible involvement of potassium channels.
A flavonoid-rich diet has been associated with a lower incidence of cardiovascular diseases, probably because of the antioxidant and vasoactive properties of flavonoids. Indeed, many flavonoids show vasorelaxing properties, due to different and often not yet completely clarified mechanisms of action. Among them, the activation of vascular potassium channels has been indicated as a possible pathway, accounting, at least in part, for the vasodilatory action of some flavonoid derivatives, such as apigenin and dioclein. Therefore, this work aims at evaluating, on in vitro isolated rat aortic rings, the endothelium-independent vasorelaxing effects of a number of flavonoid derivatives, to identify a possible activation of calcium-activated and/or ATP-sensitive potassium channels and to indicate some possible structure-activity relationships. Among the several flavonoids submitted to the pharmacological assay, only baicalein and quercetagetin were almost completely ineffective, while quercetin, hesperidin, quercitrin and rhoifolin exhibited only a partial vasorelaxing effect. On the contrary, acacetin, apigenin, chrysin, hesperetin, luteolin, pinocembrin, 4'-hydroxyflavanone, 5-hydroxyflavone, 5-methoxyflavone, 6-hydroxyflavanone and 7-hydroxyflavone, belonging to the chemical classes of flavones and flavanones, showed full vasorelaxing effects. The vasodilatory activity of hesperetin, luteolin, 5-hydroxyflavone and 7-hydroxyflavone were antagonised by tetraethylammonium chloride, indicating the possible involvement of calcium-activated potassium channels. Moreover, iberiotoxin clearly antagonised the effects of 5-hydroxyflavone, indicating the probable importance of a structural requirement (the hydroxy group in position 5) for a possible interaction with large-conductance, calcium-activated potassium channels. Finally, glibenclamide inhibited the vasorelaxing action of luteolin and 5-hydroxyflavone, suggesting that ATP-sensitive potassium channels may also be involved in their mechanism of action.
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A precision guide-pin technique for wedge and rotatory osteotomy of the femur and tibia.
Intraoperative guide-pin placement for the performance of wedge-type and rotatory osteotomy of the femur and tibia provides the desired angle of correction from single-leg, weight-bearing roentgenograms. A template is used as a guide for pin placement. The accuracy of this technique was evaluated by comparing the preoperative goal with the correction achieved immediately after surgery and after bone healing one year postoperatively. Forty-seven osteotomies, 37 in the tibia and ten in the femur, were reviewed. Eighty-five percent of the cases were within +/- 3 degrees of the operative goal immediately after surgery, and 81% one year postoperatively. Four osteotomies (9%) were considered failures, two because of technique and two because of errors in postoperative patient activity level. With appropriate preoperative planning, the technique makes accurate osteotomy possible in a standard operating room equipped with a C-arm fluoroscope.
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Posts tagged mountain
Juried game event IndieCade has announced its 2014 finalist picks, revealing a lineup of standout independent works that will be featured at this year's festival in Culver City.
Featured picks include recent releases like Jazzpunk, Hack 'n' Slash, Risk of Rain, and Mountain, along with upcoming ...
Mountain, a quirky game from filmmaker David O'Reilly, has only been available for a week, but has already topped the iTunes App Store charts in numerous countries.
Mountain lacks most traditional game-like qualities. There are no enemies to stomp or aliens to shoot. Instead, the game generates ...
The next game to launch courtesy of Double Fine's publishing program is Mountain, an artistic simulation game that's now available on PC, Mac, Linux via the game's site and iOS for $1.
Developed by filmmaker David O'Reilly, Mountain has players answer three "questions" in the form of single wo...
He's fresh to game development, but David O'Reilly has already created a game you likely know very well: the game in Spike Jonze's excellent film, "Her." While that "game" was, ya know, in a film and not a real game, he's just about to release his first actual game in Mountain. O'Reilly describes ...
Dungeons and Dragons Online: Shadowfell Conspiracy, the game's second expansion, isn't just mucking about in a trashed prison city with your new premium classes. Turbine is taking us beyond Forgotten Realm's civilization to the Stormhorns, a mountain region that comprises DDO's first mountain wilde...
Champions Online has a new protector in town, and he's about as subtle as Gregor Clegane (though quite a bit nicer). The game's newest archetype is called The Mountain, and Cryptic has revealed all the vitals on Champions' official website.
The Mountain is "an embodiment of the rocks and earth...
Apple's modern desktop OS is famous for its feline monikers -- Panther, Tiger, Leopard/Snow Leopard and Lion, among others. But what about the other Apple operating system, iOS? While the code names for those versions aren't used in the public branding and promotion of the iPhone/iPod touch/iPa...
SSX Deadly Descents (sorry, it's just SSX now, we forgot) has a brand new trailer out, and there's a peek at the new version of SSX standby Mac Fraser, who looks ... just as generic as all the previous versions. At least all that powder and those gnarly ramps look fun....
It's reassuring to know that while some things may change dramatically, others will and do stay the same. Overreliance on GPS is one of those highly consistent trends, as exhibited most recently by one Robert Ziegler, a full-time van driver and part-time goat track explorer. The unfortunate gent fo...
Halo 3's amazing "Believe" campaign and the less well-known PlayStation "Mountain" ad have found a place on AdFreak's list of "The 25 most epic ads that aren't [Apple's] '1984.'" The Halo 3 campaign made it all the way to the eighth spot, while "Mountain," with its 1,500 extras, climbed to 17th pla...
CCP Games is a company with a singular lofty goal: World Domination. From their humble beginnings in a small office in Reykjavik, Iceland, they released an experimental sci-fi MMO into an untested market. Almost seven years down the line, EVE Online has been a consistent success and CCP as a compan...
The average American viewed over 9 million advertising messages over the past decade -- logically, a few would stick out in your mind as being better than the rest. Advertising trade publication Adweek recently voted on the best piece of video marketing to be released this decade. Two video game ad...
Welcome back to The Queue, WoW Insider's daily Q&A column where the WoW Insider team answers your questions about the World of Warcraft. Adam Holisky will be your host today.
The above picture took me all of five minutes to put together. Super Troopers is a great movie, and I encourage you al...
Free Radical has confirmed that ambiguously exclusive PlayStation 3 shooter, Haze, will not be the source of standard, high-definition visuals. Speaking to Ripten, Creative Lead Derek Littlewood explained that, much like other sub-HD games, the 1024x576 resolution was chosen to ensure "a nice smoo...
Ever get lost in a euphoric off-piste blaze of snow and emotion only to emerge truly lost somewhere on the mountain? Good, the NavJacket is for you. The GPS equipped jacket from O'Neill is the result of a partnership with MyGuide. The Gore-Tex jacket features integrated audio in the hood and a displ...
We'll be the first to admit that the whole "smash this object" craze is getting a tad out of hand, but the latest rendition of demolishing a perfectly functional PlayStation 3 is just revolting. While we've witnessed Nintendo's Wii being cautiously dissected and publicly mangled, a couple of mount...
Avid flickr user and mountain climber extraordinaire Rappateng recently had a buddy of his take some snapshots during their latest mountain-tackling adventure. A few of the snapshots are of great interest as Rappateng reports he took several breathers to throw down in some Mario Kart DS mid-climb. ...
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The Dutchman had claimed that the 24-year-old had asked to be left out of their match with Aston Villa on Friday. This is due to speculation that he is going to join Real Madrid this summer, which shows no sign of abating as the transfer deadline looms closer.
“We’ve talked with him and he was fully agreed with our decision,” the former Barcelona man said, “We have a goalkeeping coach, Frans Hoek, so I’m not doing everything alone. Frans had a meeting with David and he asked him, ‘Do you want to play?’ The answer was no.
“Then I have to take the decision. It is a process. We had been observing him in preparation, and he was not so good, he was not the same David De Gea as before, when he was my best player last season. According to the fans, he was the best player of the last two years.”
The Spain international is confused by these claims, and is worried that the 63-year-old is questioning his professionalism and commitment. He apparently would have been perfectly happy to play against Tottenham last week and in the upcoming encounter with Villa.
In the absence of the former Atletico Madrid man, Sergio Romero will take his place between the sticks again. The Argentina international performed admirably in their opening match against Spurs, and is likely trusted by van Gaal after working with him during their time at AZ Alkmaar. It still leaves them with a problem over who to put on the bench though, with Victor Valdes currently on the wrong side of the manager.
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Intrauterine Insemination-IUI
One of the more popular infertility treatments to increase the numbers of sperm reaching the egg is intrauterine insemination (IUI) with washed sperm. Previous treatments to try to accomplish this goal, including antibiotics to decrease inflammation, estrogen to improve mucus production, guaifenesin (Robitussin) to thin the mucus, and insemination into the cervical mucus were not very effective. Placing the sperm in the uterus bypasses the mucus and eliminates a cervical problem as a factor. It is known to be useful in the treatment of poor-quality mucus or mucus that has antibodies which clump and immobilize sperm. This technique is also successful for mild to moderate reductions of semen quality.
Although the chance of success varies with the individual problem, IUI yields about a 30 percent conception rate over three to six cycles, or 5 to 10 percent per cycle. In such couples the monthly conception rate without treatment might be one to three percent. It is entirely possible that this treatment "telescopes" successes into the treatment cycle, which may have occurred spontaneously within another year or so of trying on their own. But we have not met many infertile couples willing to keep their lives perpetually on hold.
The procedure is usually scheduled based on the results of ultrasounds and the urinary LH testing kit. Based on the woman's cycle and ultrasound observation of the developing follicle, she is instructed when to begin testing and to schedule the insemination on the day following detection of the surge. The test is done in the afternoon or early evening so as not to miss the surge, which usually begins early in the day but may not be detectable in the urine until several hours later. On the day of insemination, the husband masturbates a specimen into a sterile, nontoxic plastic container. Preferably, the couple has avoided intercourse for about two days before the anticipated day of insemination. After the specimen liquefies, it is washed in a nutrient medium. This can be done by a variety of techniques and in any one of several media. The washing procedure produces a concentrated pellet of motile sperm that is mixed with medium and placed into the uterus through the cervix by means of a thin plastic tube.
The wash and insemination are relatively inexpensive. Side effects are rare but may include cramping. The risk of complications is low and related chiefly to the possibility of introducing infection and so we usually administer a prophylactic antibiotic at the time of the procedure to prevent infection.
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Most annoying phrase known to man?
I have been wasting time, those precious minutes of my life that will never return, by eliminating the odious phrase "known to man" from Wikipedia articles. It is satisfying, in much the same way as doing the crossword puzzle, or popping bubble wrap. In the past I have gone on search-and-destroy missions against certain specific phrases, for example "It should be noted that...", which can nearly always be replaced with "" with no loss of meaning. But "known to man" is more fun. One pleasant property of this phrase is that one can sidestep the issue of whether "man" is gender-neutral. People on both sides of this argument can still agree that "known to man" is best replaced with "known". For example: The only albino gorilla known to man...
The most reactive and electronegative substance known to man...
Copper and iron were known to man well before the copper age and iron age... In examples like these, "to man" is superfluous, and one can delete it with no regret. As a pleonasm and a cliché, "known to man" is a signpost to prose that has been written by someone who was not thinking about what they were saying, and so one often finds it amid other prose that is pleonastic and clichéd. For example: Diamond ... is one of the hardest naturally occurring material known (another harder substance known today is the man-made substance aggregated diamond nanorods which is still not the hardest substance known to man). Which I trimmed to say: Diamond ... is one of the hardest naturally-occurring materials known. (Some artificial substances, such as aggregated diamond nanorods, are harder.) Many people ridicule Strunk and White's fatuous advice to "omit needless words"—if you knew which words were needless, you wouldn't need the advice—but all editors know that beginning writers will use ten words where five will do. The passage above is a good example. Can "known to man" always be improved by replacement with "known"? I might have said so yesterday, but I mentioned the issue to Yaakov Sloman, who pointed out that the original use was meant to suggest a contrast not with female knowledge but with divine knowledge, an important point that completely escaped my atheist self. In light of this observation, it was easy to come up with a counterexample: "His acts descended to a depth of evil previously unknown to man" partakes of the theological connotations very nicely, I think, and so loses some of its force if it is truncated to "... previously unknown". I suppose that many similar examples appear in the work of H. P. Lovecraft. It would be nice if some of the Wikipedia examples were of this type, but so far I haven't found any. The only cases so far that I haven't changed are all direct quotations, including several from the introductory narration of The Twilight Zone , which asserts that "There is a fifth dimension beyond that which is known to man...". I like when things turn out better than I expected, but this wasn't one of those times. Instead, there was one example that was even worse than I expected. Bad writing it may be, but the wrongness of "known to man" is at least arguable in most cases. (An argument I don't want to make today, although if I did, I might suggest that "titanium dioxide is the best whitening agent known to man" be rewritten as "titanium dioxide is the best whitening agent known to persons of both sexes with at least nine and a half inches of savage, throbbing cockmeat.") But one of the examples I corrected was risibly inept, in an unusual way: Wonder Woman's Amazon training also gave her limited telepathy, profound scientific knowledge, and the ability to speak every language known to man. I have difficulty imagining that the training imparted to Diana, crown princess of the exclusively female population of Paradise Island, would be limited to languages known to man. Earle Martin drew my attention to the Wikipedia article on "The hardest metal known to man". I did not dare to change this. [ Addendum 20090515: There is a followup article. ]
[Other articles in category /lang] permanent link
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Kuijieling regulates the differentiation of Treg and Th17 cells to ameliorate experimental colitis in rats.
Regulatory T (Treg) cells and T helper 17 (Th17) cells play crucial roles in ulcerative colitis (UC). Kuijieling (KJL) is an effective Chinese medicine formula for treating UC in clinic. Kuijieling has shown remedy effect on the imbalance between Treg and Th17 cells. This study aimed to further reveal the exact underlying mechanism of how Kuijieling regulates the differentiation of Treg and Th17 cells in the treatment of UC. Colitis was induced by trinitrobenzene sulfonic acid in rats and treated by KJL. Pathological injury was evaluated by HE staining and pathological score. Transforming growth factor-β1 (TGF-β1), interleukin(IL)-2, IL-6, IL-10, IL-17, IL-23 and IL-21 in plasma were assayed by ELISA. Forkhead box P3 (Foxp3), signal transducer and activator of transcription (STAT) 5 expressed in colon mucosa were measured by western blot. Immunohistochemistry was employed for quantifying retinoic acid-related orphan receptor γt (RORγt) and STAT3 in colon. RT-PCR was used to analyze the expression of IL-2, IL-17, IL-23, IL-21 mRNA in colon. After the administration of KJL, pathological injury in colon mucosa was reduced and histological score was decreased, transforming growth factor-β1 (TGF-β1), interleukin(IL)-2, IL-10 in blood and Foxp3, STAT5, IL-2 in colon increased significantly, IL-6, IL-23, IL-17, IL-21 in blood and RORγt, STAT3, IL-23, IL-17, IL-21 in colon decreased. Our result showed that KJL regulates the related cytokines and transcription factors to promote Treg cells and suppress Th17 cells. KJL restores the balance between Treg and Th17 cells through regulating the differentiation of them, therefore contributes to the treatment of UC.
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The aim of proposed studies is to evaluate the factor or factors responsible for regulation of the number and affinity of angiotensin II receptors of several target tissues. These studies will involve simultaneous evaluations in both adrenal and vascular tissues of the rat. In addition, I aim to provide a physiologic explanation for a possible role for angiotensin receptors in several well described states of altered responsiveness to angiotensin II. The effect of potassium, nephrectomy, and angiotensin infusions will be compared. The angiotensin II radioreceptor assay of rat adrenal and smooth muscle will be used to quantify any alterations in the number or affinity of angiotensin receptors in target tissues. The aldosterone responses to angiotensin II (both in vivo and in vitro) and pressor responses to angiotensin II will be evaluated following the same physiologic maneuvers. All of the proposed studies will be done in the rat.
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Large recovery boilers used in pulp and paper mills typically include a densely packed array of generating bank or boiler tubes. Each tube has an open end in communication with a steam or water drum. It has previously been recognized that some boiler tubes are most susceptible to corrosion at their point of attachment to the drum. Accordingly, various ultrasonic probes have been proposed in the past for determining the wall thickness of the boiler tubes in that region.
U.S. Pat. No. 4,353,257 granted to Vrba et al on Oct. 12, 1982 discloses a system for periodically inspecting the thickness of boiler tubes using an ultrasonic probe. The Vrba probe assembly contains a transducer which is mechanically coupled to a motor drive. Rotation of the motor drive causes the transducer to move in a helical path into and out of the boiler tube to be tested. The Vrba probe assembly further includes a carriage which is urged against the tube inner wall by a spring. The purpose of the carriage is to maintain the transducer in the optimum orientation relative to the tube inner wall.
The primary drawback of the Vrba device is that it would not be suitable for accurately measuring corroded tube areas which are not parallel to the centerline of the tube. As a result of the construction of the transducer carriage, the Vrba probe is not optimized for use in tubes having a rolled or undulating contour. The scanning path is entirely controlled by the motor drive and the probe itself is not manually manipulatable.
U.S. Pat. No. 4,663,727 granted to Saporito et al on May 5, 1987 is also exemplary of the prior art. This reference discloses an ultrasonic inspection system employing a transducer mounted at one end of an elongate probe connected to a rotational and axial drive mechanism. No means are provided for manually skewing the probe out of alignment with the longitudinal axis of the tube to be inspected to detect corroded areas not parallel to the centerline of the tube.
U.S. Pat. No. 4,412,315 granted to Flournoy on Oct. 25, 1983 discloses an acoustic pulse-echo wall thickness method and apparatus for detecting anomalies, such as pits, in pipelines. The apparatus includes a transducer capable of generating simultaneous acoustic pulses in opposite directions and two reflectors for reflecting the acoustic pulses toward the inner wall of the pipe under inspection. One of the pulses is directed in a path normal to the pipe wall and the other is reflected in a path oblique to the pipe wall. The Flournoy device is thus capable of measuring wall thickness and simultaneously determining the presence of anomalies in the wall being surveyed. However, it suffers from the disadvantage that ultrasonic pulses may be directed at the pipe inner wall only at a single oblique angle, as determined by the orientation of the reflector face. If it was desired to direct scanning pulses at a plurality of oblique angles, then a plurality of transducers and reflector surfaces would be required.
Accordingly, the need has arisen for a hand-held ultrasonic probe incorporating a single transducer which may be manually skewed relative to the longitudinal axis of the tube to direct ultrasonic acoustic pulses at a plurality of oblique angles relative to the tube inner wall and thereby accurately identify corroded tube areas which are not parallel to the longitudinal axis of the tube.
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Application of the fluorescence resonance energy transfer method for studying the dynamics of caspase-3 activation during UV-induced apoptosis in living HeLa cells.
Activation of caspase-3 is a central event in apoptosis. We have developed a GFP-based FRET (fluorescence resonance energy transfer) probe that is highly sensitive to the activation of caspase-3 in intact living cells. This probe was constructed by fusing a CFP (cyan fluorescent protein) and a YFP (yellow fluorescent protein) with a specialized linker containing the caspase-3 cleavage sequence: DEVD. The linker design was optimized to produce a large FRET effect. Using purified protein, we observed a fivefold change in the fluorescence emission ratio when the probe was cleaved by caspase-3. To demonstrate the usefulness of this method, we introduced this FRET probe into HeLa cells by both transient and stable transfection. We observed that during UV-induced apoptosis, the activation of caspase-3 varied significantly between different cells; but once the caspase was activated, the enzyme within the cell became fully active within a few minutes. This technique will be highly useful for correlating the caspase-3 activation with other apoptotic events and for rapid-screening of potential drugs that may target the apoptotic process.
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Targeting mammalian target of rapamycin to both downregulate and disable the P-glycoprotein pump in multidrug-resistant B-cell lymphoma cell lines.
Previous studies have shown that rapamycin can inhibit the growth of several different types of human tumor cells in vitro. In certain cases, it can reverse the phenotype of multidrug resistant (MDR) cells. However, there is limited information concerning its effect on P-glycoprotein (P-gp), a pump that is responsible for chemoresistance in many MDR cells. We investigated the effect of rapamycin on both P-gp function and the MDR phenotype in four cell lines. One cell line was also xenografted into SCID mice to determine whether rapamycin would chemosensitize the cells in vivo. Because rapamycin targets the mammalian target of rapamycin (mTOR) pathway, we also used our cells to confirm that rapamycin modified the expression of mTOR and effectively suppressed the phosphorylation of two downstream effector molecules in the mTOR pathway, S6K1, and 4E-BP1. We demonstrated that it inhibited the growth of the three cell lines in vitro and one in vivo showing that it modulated both the expression and function of P-gp and chemosensitized the three cell lines as effectively as verapamil.
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Singapore: Oil prices were up in Asian trade on Thursday as a surprise rise in German industrial production brightened the market's outlook for European and global growth, analysts said.
New York's main contract, light sweet crude for delivery in June added five cents to USD 96.67 a barrel and Brent North Sea crude for June delivery gained 18 cents to USD 104.52.
"Dealers are cheering German industrial production figures that were significantly better than expected," Ric Spooner, chief market analyst at CMC Markets in Sydney, said.
"What we're seeing is an improved outlook for European and global growth." The upbeat German factory output numbers came a day after China said it recorded an USD 18.2 billion surplus in April, stoking hopes of improving demand in the world's second biggest economy.
German industrial output saw a surprisingly robust rise in March driven by a sharp increase in the energy sector, official data showed on Wednesday.
Industrial production rose by 1.2 percent in March compared with the previous month, beating analysts' expectations of a 0.2 percent decline.
On Tuesday, economy ministry data showed industrial orders in Germany jumping by 2.2 percent in March compared with February, propelled by rising demand -- both at home and abroad -- for German-made goods.
The fresh production figures were a further sign of gathering momentum in Europe's largest economy, supporting hopes for an increased demand for crude there.
Crude has been stronger in recent weeks thanks to an improved picture of economic growth in the United States, China, Japan and Germany, and by a rise in tensions in the Middle East after Israeli air raids in Syria.
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Molecular and serological prevalence of Toxoplasma gondii in pregnant women and sheep in Egypt.
To investigate molecular and serological prevalence of Toxoplasma gondii (T. gondii) in pregnant women and sheep in Egypt. Blood samples collected from healthy 364 pregnant women and 170 sheep were investigated for T. gondii antibodies and parasitemia using highly specific and sensitive surface antigen (TgSAG2) based enzyme linked immunosorbent assay (ELISA) and real time-polymerase chain reaction (RT-PCR). Overall prevalence of T. gondii was 51.76%, 17.65% in sheep, 33.79%, 11.81% in pregnant women, using ELISA and RT-PCR respectively. Significant differences in T. gondii prevalence were observed on the basis of contact with cats or soil in pregnant women using either RT-PCR or ELISA. In pregnant women, a significant increase was detected in aged and those eating under-cooked mutton using simultaneous ELISA/RT-PCR. Consumption of under-cooked infected mutton is an important source of human infection and the combination of the two assays provide accurate and precise data during infection.
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Q:
Setting UIMapView delegate to self triggers warning, but works
In my project, I have a MapView that I add annotations to. I need those annotations to have different images, so I use the - (MKAnnotationView *) mapView:(MKMapView *)mapView viewForAnnotation:(id <MKAnnotation>) annotation method. However, for this to work I need the MapView's delegate to be set to self. So I use this line in the viewDidLoad function:
self.viewMap.delegate = self;
This works as expected, however XCode is warning me with this message:
Assigning to 'id<MKMapViewDelegate>' from incompatible type 'ViewController *const__strong'
I'm guessing that I am not going about this the proper way, and that's why there's a warning. So what am I doing wrong?
A:
Your ViewController class—which you might consider renaming to something more descriptive—needs to declare conformance to MKMapViewDelegate in its interface:
@interface ViewController : UIViewController <MKMapViewDelegate>
// stuff
@end
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A quantitative analysis of head movement behaviour during visual acuity assessment under prosthetic vision simulation.
In most current vision prosthesis designs, head movement is the sole director of visual gaze and scanning due to the head-mounted nature of the camera. Study of this unnatural behaviour may provide insight into improved prosthesis designs and rehabilitation procedures. In this paper, we conducted a psychophysical study to investigate the characteristics of head movements of normally sighted subjects undergoing a visual acuity task in simulated prosthetic vision (SPV). In 12 naïve, untrained subjects, we recorded spontaneous changes in the amount of head movements during SPV sessions compared to control (normal vision) sessions. The observed behaviour continued to be refined until five or six sessions of practice. Increased head movement velocity was shown to be correlated to improved visual acuity performance, up to 0.3 logMAR, an equivalent of detecting details at half the physical size compared to complete deprivation of head movements. We postulate that visual scanning can as much as double the spatial frequency information in prosthetic vision. Increased head movement velocity observed when subjects were attempting smaller test items and for low-pass filtering schemes with higher cut-off frequencies may be further evidence that higher frequency content may be available through visual scanning, unconsciously driving subjects to increase head movement velocity.
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Introduction {#s1}
============
The death receptor (DR) proteins, a subset of the tumor necrosis factor (TNF) receptors super-family, have been implicated as serum biomarkers for solid tumors [@pone.0036525-Buckanovich1], [@pone.0036525-Yurkovetsky1]. TNF receptor proteins are present in tumor endothelial cells, tumor-associated myeloid cells, and tumor cells with variable levels of expression. A primary function for death receptors is to induce apoptosis [@pone.0036525-SchulzeOsthoff1]. Abnormal expression, regulation, or function of TNF receptors have been strongly implicated in autoimmune disease, osteoporosis, and cancer [@pone.0036525-Nash1], [@pone.0036525-Hsu1], [@pone.0036525-Ta1], [@pone.0036525-vanHorssen1], [@pone.0036525-Wiezorek1], [@pone.0036525-Herbst1], [@pone.0036525-Daniel1]. Six different death receptors are currently known.
The most recently identified TNF receptor is Tumor Necrosis Factor Receptor Superfamily Member 21 (TNFRSF21), also known as death receptor-6 (DR6). The function of DR6 in cancer is not entirely clear [@pone.0036525-Benschop1]. DR6 retains the characteristics of other family members, including a cysteine-rich extracellular domain and conserved intracellular death domain required for induction of cell death. Thus, like other death receptor proteins, DR6 has been implicated in the induction of apoptosis [@pone.0036525-Pan1]. Additionally, DR6 may regulate the cytokine-driven differentiation of monocytes to dendritic cells, which suggests DR6 could play a role in the development of myeloid derived suppressor cells within tumors [@pone.0036525-Benschop1].
We recently identified DR6 as a potential serum tumor marker in ovarian cancer [@pone.0036525-Buckanovich1]. In addition to its expression in ovarian cancer, DR6 has been reported to be up-regulated in numerous solid tumors [@pone.0036525-Kasof1]. DR6 is expressed not only in cancer cells, but also in tumor vascular cells. This expression on host cells in the tumor microenvironment suggests DR6 may have broad applicability as a tumor biomarker. The role of DR6 as a biomarker in non-ovarian tumors has not heretofore been investigated.
We report here an analysis of DR6 as a potential biomarker in several non-ovarian tumors. In particular we analyzed the role of DR6 as a potential serum biomarker in adult sarcoma. Sarcomas in the adult are rare but relatively deadly. Unlike other malignancies, there are no clinically used serum biomarkers to suggest a potential mass may represent sarcoma. Similarly, there are no serum biomarkers which can be used with confidence to predict whether a patient receiving therapy is or is not gaining clinical benefit. Our studies suggest that serum DR6 levels are elevated in patients with some sarcomas. In addition, declining DR6 levels may identify those patients gaining clinical benefit from systemic therapy.
{#pone-0036525-g001}
Materials and Methods {#s2}
=====================
Gene Expression {#s2a}
---------------
We screened the gene expression profile of numerous tumor types using publically available array data [@pone.0036525-Su1], [@pone.0036525-Segal1]. Oncomine™ (Compendia Bioscience, Ann Arbor, MI) was used for analysis and visualization. Data sets were analyzed independently and then combined with the normalized log 2 median centered intensity of zero.
Tumor tissues were obtained using IRB approved tumor banking protocols at the University of Michigan and the Cooperative Human Tissue Network. Tissues included normal colon (n = 3), normal liver (n = 2), normal ovary (n = 5), bladder cancer (n = 2), breast cancer (n = 5), carcinosarcoma (n = 3), hepatic cancer (n = 2), ovarian cancer (n = 5), pancreatic cancer (n = 3), and soft tissue sarcoma (n = 3 leiomyosarcoma, n = 2 uterine sarcoma). RNA was extracted from fresh frozen tissues using TRIzol per manufacturer\'s recommendations (Invitrogen, Grand Island NY) and qRT-PCR was then performed as previously described [@pone.0036525-Buckanovich1].
{#pone-0036525-g002}
Patients {#s2b}
--------
Written informed consent was obtained from all patients prior to sample collection. Protocols for serum collection were reviewed and approved by the University of Michigan Institutional Review Board or the University of New Mexico Institutional Review Board (IRB). All clinical investigation was conducted according to the principles expressed in the Declaration of Helsinki. Five milliliters of blood was collected by venipuncture directly into serum separator tubes, centrifuged at 3000 RPM for 12 minutes, and then aliquoted into polypropylene vials and frozen at −70 degrees Celsius until use. Sera from patients with either carcinosarcomas or cancers of the bladder, liver, or pancreas were collected preoperatively as part of IRB approved University of Michigan serum banking protocols.
10.1371/journal.pone.0036525.t001
###### Statistical analysis of fluorescent western blot assay replicates.
{#pone-0036525-t001-1}
Serum Dilution 1∶6 1∶2 1∶1
--------------------------------------- ------- ------- -------
Number of times assayed 18 36 14
Minimum 3130 11752 26411
25% Percentile 4165 13831 29478
Median 5183 14832 30044
75% Percentile 6119 15694 31214
Maximum 7688 17657 41317
Mean 5177 14701 30616
Standard Deviation 1299 1517 3394
Standard Error 306.3 252.8 907.1
Lower 95% Confidence Interval of mean 4531 14187 28656
Upper 95% Confidence Interval of mean 5823 15214 32575
Serum from patients with sarcoma was available from a total of 71 patients participating in IRB approved clinical trials. Serum was obtained from all 71 patients prior to trial initiation. 22 of these patients were participating in a therapeutic clinical trial at the University of New Mexico for chemotherapy-naïve patients. This serum was collected prior to initiation of either neo-adjuvant therapy or salvage therapy for metastatic disease. 49 of the patients were participating in a phase II clinical study of cyclophosphamide and sirolimus in patients with previously treated advanced adult sarcoma. A second sample was obtained from 41 patients at the University of Michigan after one cycle of therapy; two of these patients later donated a third sample after completing two cycles of therapy. Patients on trial were evaluated for progression via radiographic imaging every 2 months. Finally, control serum was collected as part of an IRB approved protocol, primarily from healthy volunteers age 18--65. Approximately 20% of control sera were collected preoperatively from patients who were ultimately diagnosed with benign ovarian conditions, including fibroadenoma, benign follicular cysts, cystadenomas, and endometriotic cysts.
{#pone-0036525-g003}
Immunofluorescent western blot {#s2c}
------------------------------
A 'master scale' was developed with duplicate serial dilutions (0.25, 0.5, 1, 2, and 4 ul) of a single healthy control sera (GS) diluted into 40 µl PBS and then 15 µl of diluted serum was loaded with 5 µl of 2× loading buffer for PAGE. Immunofluorescent detection was performed using anti human DR6/TNFRSF21 affinity purified polyclonal goat IgG (1∶500, R&D Systems, Minneapolis, MN). Primary was detected with fluorescent donkey infrared dye 800CW conjugated anti-goat IgG (1∶5000 LiCor Biosciences, Lincoln NE). After washing, fluorescent images were captured with the Odyssey SA Infrared Imaging System (LiCor Biosciences) and quantified with LI-COR Odyssey Software version 2.1 per the manufacturer\'s instructions (<http://biosupport.licor.com/docs/Odyssey_User_Guide_ver_3.0B.pdf>). Captured digital images were quantified with using same size rectangle method to determine the integrated intensity value (pixel volume). Background values were subtracted from each experimental sample. Immunofluorescent western blot was run in duplicate for each and expression values indicated are averages of the two samples. Best linear fit was determined for the master scale using Microsoft XL. For each subsequent gel, experimental samples were run in a similar manner with 1 µl diluted into 40 ml of PBS, and a mini internal control sera scale (0.5, 1.0 and 2.0 µl) of GS sera was included for relative quantification. A normalized value was determined for each sample based in the internal control sample. The normalized value was then used in the linear correlation of the master gel to determine the relative expression value. Any samples with raw values outside the linear range of the assay (2000--25,000 expression units) were re-analyzed with additional dilutions. Dilution factor was taken into account after normalization.
10.1371/journal.pone.0036525.t002
###### Characteristics of Sarcoma Patients Evaluated.
{#pone-0036525-t002-2}
Chemo- refractory Chemo-Naive
---------------------------------------- ------------------- -------------
**Median Age** -- years (range) 57 (19--82) 54 (17--75)
**Male/Female** 28/21 13/9
**Median prior lines of chemotherapy** 3 NA
(range) (1--6)
**Stage II/III/IV** NA 2/7/13
**Sarcoma sub-type**
Leiomyosarcoma 16 6
Liposarcoma 9 2
Undifferentiated Pleiomorphic 5 0
Osteosarcoma 4 0
Synovial sarcoma 3 3
Peripheral nerve sheath tumor 3 1
Rhabdomyosarcoma 2 0
Extraskeletal myxoid chondrosarcoma 2 1
Angiosarcoma 1 3
Undifferentiated NOS/Other 4 6
**Neoadjuvant/Metastatic** 0/49 10/12
NA-not applicable.
Statistical analysis {#s2d}
--------------------
Descriptive statistics for serum concentrations of DR6 were calculated for each subject using GraphPad Prism5 software (GraphPad Software, Inc., La Jolla, Ca.). Unpaired t-tests were used with the minimum level of significance taken as p\<0.05. Logistic regression analysis was used to estimate the association between the DR6 serum levels and case status (sarcoma patients versus controls). The receiver operating characteristic (ROC) curve was computed for DR6 to evaluate it as a diagnostic biomarker and the area under the curve (AUC) was computed. Proc Logistic was used for this analysis (SAS Software, version 9.2, Cary, NC.).
{#pone-0036525-g004}
Results {#s3}
=======
Death Receptor 6 gene expression and protein serum levels across various tumor types {#s3a}
------------------------------------------------------------------------------------
In an attempt to identify tumors with high DR6 expression, we screened the gene expression profile of numerous tumor types using publicly available array data [@pone.0036525-Su1], [@pone.0036525-Segal1]. DR6 expression was detectable in all tumor types, with the highest expression noted in bladder, pancreatic, and squamous cell lung cancers ([Figure 1A](#pone-0036525-g001){ref-type="fig"}). We next performed quantitative PCR for DR6 using cDNA from normal ovary, colon, and liver tissues and well as cDNA obtained from a panel of whole tumor samples. qRT-PCR confirmed increased DR6 mRNA levels in these tumors relative to the normal tissue controls, with the highest expression detected in bladder cancer, pancreatic cancer, hepatic cancer and adult sarcomas ([Figure 1B](#pone-0036525-g001){ref-type="fig"}).
We next developed a quantitative immunofluorescent western blot analysis approach to analyze DR6 protein levels. We used serum samples from ovarian cancer patients for which DR6 had previously been demonstrated to be elevated. Ovarian cancer serum samples were analyzed in duplicate together with internal standards to allow comparison between experiments. Analysis of duplicate samples within the same and different experiments revealed this method to be highly reproducible (R = 0.97, [Figure 2A and B](#pone-0036525-g002){ref-type="fig"}). Analysis of a minimum of 7 intra-day and 7 inter-day samples revealed a high degree of reproducibility ([Figure 2C](#pone-0036525-g002){ref-type="fig"} and [Table 1](#pone-0036525-t001){ref-type="table"}). In addition, we found that up to 8 cycles of serum freezing/thawing had no impact on DR6 levels (data not shown).
Once the assay was confirmed, we screened DR6 serum protein levels from a panel healthy donor controls and a panel of patients with different tumor types including bladder cancer, hepatic cancer, pancreatic cancer, mullerian carcinosarcomas, and adult sarcomas. Interestingly, while qRT-PCR data demonstrated the highest DR6 mRNA levels in bladder cancer, pancreatic cancer, hepatic cancer and adult sarcomas, serum DR6 protein levels were statistically significantly elevated only in the serum of patients with adult sarcomas ([Figure 2D](#pone-0036525-g002){ref-type="fig"}). None of the other tumor types demonstrated a statistically significant increase in serum DR6 protein levels relative to healthy controls.
DR6 serum protein level in patients with sarcoma versus control {#s3b}
---------------------------------------------------------------
Based on the preliminary screen above, serum DR6 levels were then compared using a panel from 71 adult sarcoma patients and 39 healthy controls. [Table 2](#pone-0036525-t002){ref-type="table"} summarizes the patient characteristics. 22 patients were chemotherapy naïve, with 10 of these patients receiving neo-adjuvant therapy for localized disease; the remaining 12 patients had metastatic disease. 49 patients had metastatic chemo-refractory disease, having received an average of 3 previous lines of chemotherapy. We observed a 2.2 fold increase in DR6 levels relative to normal controls (controls 0--15376 integrated intensity units, all sarcoma 4289--34298 integrated intensity units). More than 40% of sarcoma samples were found to be higher than the maximum expression in the normal control set ([Figure 3A](#pone-0036525-g003){ref-type="fig"}). Similar results were found for both chemo-naïve and chemo-refractory patients ([Figure 3B](#pone-0036525-g003){ref-type="fig"}). The association between case status (sarcoma patient versus control) and DR6 was statically significant (odds ratio = 1.3, 95% CI = 1.17 to 1.46, p\<0.001). There was a 1.3-fold increase in the odds that a patient was a sarcoma patient for the group of patients with a 10,000 unit increase in DR6 compared to the odds for those at the base level. In addition, when DR6 was evaluated as a diagnostic marker with its ROC curve, the AUC was 82.1% ([Figure 3C](#pone-0036525-g003){ref-type="fig"}).
We further evaluated DR6 expression based on histologic subtypes, including myogenic sarcoma (22 leiomyosarcoma and 2 rhabdomyosarcoma), liposarcoma (n = 11), bone sarcoma (4 osteosarcomas and 1 Ewing sarcoma), peripheral nerve sheath tumor (n = 4), synovial sarcoma (n = 6), angiosarcoma (n = 5), and undifferentiated sarcoma (5 pleomorphic undifferentiated, 3 undifferentiated uterine, 6 undifferentiated-NOS, and 3 extra-skeletal myxoid chondrosarcomas) ([Figure 3D](#pone-0036525-g003){ref-type="fig"}). All groups, except angiosarcoma (p value = 0.386), retained a highly significant increase of serum DR6 compared to normal controls (p values\<.0001--0.0044). The greatest difference among all subsets was seen in synovial sarcoma, which showed a 3.1 fold increase over normal controls. Bone sarcoma had the second greatest elevation (2.3 fold) followed by undifferentiated sarcoma (2.1 fold increase), liposarcoma (2.0 fold increase), and peripheral nerve sheath tumor and myogenic sarcoma, which both increased 1.9 fold.
The role of DR6 in predicting disease progression {#s3c}
-------------------------------------------------
Clinical disease response information with pretreatment and on-treatment serum samples was available for 41 sarcoma patients. We next evaluated whether the change in DR6 levels before and after treatment correlated with disease response or clinical benefit. Thirty-nine patients had sera obtained pre-treatment and after 1 cycle of therapy, and 2 patients had an additional serum samples obtained after a second cycle. 12 of 41 patients demonstrated stable disease after 4 cycles (4 months) of therapy. Importantly, of the twelve patients with stable disease on therapy, 9 demonstrated a decrease in their DR6 levels (sensitivity = 75%, [Figure 4A](#pone-0036525-g004){ref-type="fig"}). 18 of 21 patients with increasing Dr6 levels demonstrated progressive disease within 2 months of starting treatment (positive predictive value = 85.7%). The negative predictive value and specificity were 45% and 62.1% respectively ([Figure 4B](#pone-0036525-g004){ref-type="fig"}). Similar results were obtained if samples which demonstrated \<10% change in DR6 levels were considered as 'stable disease'.
The only histological subtypes for which we had more than n = 4 samples in which to evaluate change in DR6 level in response to therapy were leiomyosarcoma (n = 18) and liposarcoma (n = 6). For leiomyosarcoma, change in DR6 serum protein after the first cycle of therapy did not appear to be a useful predictive biomarker ([Fig. 4C](#pone-0036525-g004){ref-type="fig"}(1)). For liposarcoma change in DR6 serum protein level after one cycle of therapy demonstrated 100% sensitivity and specificity to predict stable disease versus progressive disease ([Fig. 4C](#pone-0036525-g004){ref-type="fig"}(2)). Caution must be taken in interpreting this data given the small sample size.
Discussion {#s4}
==========
Adult sarcoma is a rare but relatively deadly cancer [@pone.0036525-Jemal1]. The World Health Organization (WHO) describes more than 50 histological subtypes of soft tissue sarcomas associated with unique clinical features and biologic behavior [@pone.0036525-FletcherCDM1]. Because of their rarity and diversity of presentation, sarcomas can be difficult to diagnose. This is so mainly because benign soft tissue masses outnumber sarcomas by a factor of at least 100 [@pone.0036525-FletcherCDM1]. In the present study, we demonstrated that compared to healthy controls, adult patients with sarcoma have increased serum DR6 protein levels (p\<0.001). We observed this in two independently collected sera banks. As a biomarker of sarcoma, DR6 could help to differentiate sarcomas from benign soft tissue masses. This would aid in appropriate surgical treatment planning, which is imperative because appropriate surgical management is associated with improved outcome [@pone.0036525-Tanabe1]--[@pone.0036525-Gronchi1]. Additional confirmatory studies are necessary.
Given the heterogeneity of sarcomas it seems unlikely that any tumor marker would be equally informative in all histologic subtypes. As a diagnostic tool, DR6 appears to have greatest potential in patients with synovial sarcoma; the lowest DR6 serum level in patients with synovial sarcoma measured well above that of all controls. Similarly, change in DR6 serum protein levels may serve as a predictive biomarker for some patients receiving chemotherapy. This potential appears greatest for patients with liposarcoma. However, given the small sample size in our study, prospective studies will be necessary to confirm this observation.
Our analysis of DR6 as a predictive biomarker is limited by the fact that only two time points were collected during therapy; at pre-treatment and before the second cycle of therapy. Biomarker 'surge', the initial spike of a marker measured following a cycle of effective treatment, could confound results when evaluating values of only two early, short-interval time points. Analysis of DR6 trend from pretreatment to later cycles of therapy could be more informative [@pone.0036525-Loprinzi1]. In fact, in our study two patients did provide serum for analysis prior to the third cycle of systemic therapy. One patient had progressive disease with a slight decrease in DR6 at the second visit; however, there was a dramatic increase in DR6 with the third serum sample. Another patient had stable disease with four cycles of therapy and showed an increase in DR6 after the first cycle of therapy, but then showed a precipitous decline after the second cycle. Further studies with serial evaluation of DR6 as a biomarker of response in the setting of standard sarcoma chemotherapy are necessary. Finally, if this is to be developed as a clinical assay, an ELISA assay that can easily be used for bulk testing would be beneficial. Unfortunately, we have found the currently available antibodies unsuitable for ELISA. While many of these antibodies work with denatured DR6 on western blot, or with ELISA for bacterially produced DR6 fusion proteins, we found that the currently available antibodies were not successful in recognizing native DR6 in patient serum. Ultimately, new antibodies will be necessary to recognize native DR6.
Surprisingly, DR6 protein in sera did not correlate with mRNA expression levels in tumors (data not shown). Thus DR6 serum protein level may not be regulated at the level of mRNA. Consistent with this, it was recently shown that soluble DR6 is the result of matrix metalloproteinase 14 (MMP-14) cleavage of membrane bound DR6 [@pone.0036525-Tam1]. Thus serum DR6 protein may serve as an indicator of tumor MMP-14 levels. MMP-14 has been correlated with tumor invasion, metastases, and poor patient prognosis [@pone.0036525-Tetu1].
Summary {#s4a}
-------
DR6 serum protein levels demonstrate a 2--3 fold increase in patients with sarcoma, relative to normal healthy controls. A retrospective analysis of DR6 serum protein levels suggests that DR6 may be a biomarker for disease progression in patients with sarcoma. These studies support prospective evaluation of DR6 as a predictive biomarker in sarcoma patients undergoing treatment with standard chemotherapy.
**Competing Interests:**The authors have declared that no competing interests exist.
**Funding:**This work was generously supported by the Damon Runyon Cancer Research Foundation and the National Institutes of Health DP2 Award grant \#00440377. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
[^1]: Conceived and designed the experiments: RJB. Performed the experiments: KY HAP GS RJB. Analyzed the data: KY CM GS PG RJB. Contributed reagents/materials/analysis tools: SS CV. Wrote the paper: CM RJB.
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See Also
BHP Billiton
’s board is considering four internal candidates as it looks to appoint a successor to chief executive officer Marius Kloppers in the next 12 to 18 months.
The Australian Financial Review understands the company has also hired the British branch of Heidrick & Struggles to examine external candidates.
Mr Kloppers has been at the helm of the world’s largest mining company for five years, which is longer than his three immediate predecessors. His record is viewed as mixed, with investors praising his commodity marketing skills but raising questions over BHP’s project management and string of failed acquisition attempts.
In July, the Financial Review reported that his ratings in the Corporate Confidence Index, which surveys investors and analysts, had been declining and no clear succession path had been outlined.
Since then, the four internal contenders – non-ferrous head Andrew Mackenzie, ferrous and coal head Marcus Randolph, aluminium and nickel boss Alberto Calderon and petroleum boss Mike Yeager – have been meeting with investors more than was previously typical.
But fund managers said the ranking of the various internal candidates remained unclear.
“In the past there have probably been standouts,” Pengana Global Resources Fund portfolio manager Tim Schroeders said. “But I struggle in finding out who is the standout at this stage.”
Impressed by Marcus Randolph
One analyst and one fund manager noted they had been particularly impressed by Mr Randolph in briefings last week. He had been privately flagging plans to retire in recent months but has since appeared to have changed his mind.
“Given the business is not on its knees [Mr Kloppers’s replacement] is more likely to be internal,” another fund manager said.
Former BHP chief financial officer Alex Vanselow exited last year to search for a CEO role. He has since been viewed as a top contender for that job at Anglo American, which is seeking a replacement for current boss Cynthia Carroll.
External candidates for the BHP role are expected to include senior executives at major mining and petroleum companies. Rio Tinto chief financial officer Guy Elliott, who has said he will depart that company by the end of 2013, is well regarded by the market and viewed as a possible contender. However, he is also in line to be the next chairman of Royal Dutch Shell, which would not be possible if he took on the BHP role.
Other potential external candidates could include senior executives at BG, such as executive vice president Ashley Almanza or chief financial officer Fabio Barbosa.
Australian-born CEO of The Dow Chemical Company, Andrew Liveris, was the top external contender when BHP conducted a search to replace Chip Goodyear but he ultimately lost out on the top job to Mr Kloppers. He could be considered again in this round.
Mick Davis a long shot
Xstrata chief executive Mick Davis, who expects to exit that company six months after a proposed merger with Glencore International is completed, is not expected to be a candidate for the BHP job.
“I think the BHP culture is very distinct and the company has its own way of doing things and it would be better to find someone internally,” Global Mining Investments chairman John Robinson said of the potential to appoint Mr Davis at BHP.
Others speculated Australian-born AngloGold Ashanti CEO Mark Cutifani could be a candidate, but one source suggested he was not expected to be.
In the last succession battle at BHP, senior executive Chris Lynch lost out to Mr Kloppers and departed the company soon after. Both had been appointed as executive directors more than a year before, then chief executive Chip Goodyear formally announced his departure and many investors expect a similar process could take place this time around. At present, Mr Kloppers is the only executive director on the company’s board.
BHP declined to comment on the search for a replacement for Mr Kloppers but a spokeswoman emphasised the importance of succession planning as a “critical task” facing the board on an ongoing basis.
“BHP Billiton’s board has always ensured that it has a well-integrated, continual succession process in place for our most senior executives,” she said.
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These People Just "Watched" the Weirdest Baseball Game Ever
Yes, there's a baseball game going on back there. Photographs by Benjamin Freed.
Ask anyone who stood outside the gates of Camden Yards, or on the roof deck of the Hilton across the street, or poured beers behind a South Paca Street bar to describe Wednesday’s game between the Orioles and the Chicago White Sox, and the answer will be, almost universally, “It’s weird.”
Baseball has a long history in Baltimore, but fans never expected their latest milestone would be hosting what historians believe is the first game in Major League Baseball to be played in front of a recorded crowd of zero. Less than three miles from the epicenter of the outrage that has shut down swaths of this city’s daily bustle, two MLB teams are playing a routine game in which the only spectators are the 92 accredited journalists in the press box, far more than the number that should be covering a late-April game. But this is what happens when strife like that uncorked by the death of Freddie Gray, a 25-year-old black man who was mortally wounded while in police custody, interferes with professional sports.
“It is strange,” says Terri Biggins, a nurse at the University of Maryland Medical Center, which is just a few blocks from the stadium. “It’s got to be hard to start a rally.”
Biggins, standing on a plaza off Camden Street that normally would be full of sidewalk vendors, is one of a few dozen Orioles die-hards who stepped out of work—or had the day off thanks to the city’s response to the protests over Gray’s death—clinging to the stadium’s locked gates and hoping for a glimpse of the scoreboard or fly ball. She says she’s been going to Orioles games since the old days at Memorial Stadium and is glad that after two cancellations, her team is finally back on the field, even if she can’t see it.
Public defender Brendan Hurson pleads with his fellow Orioles fans not to forget Freddie Gray.
“I think it was the right thing to do to play like this,” she says.
Brendan Hurson, a public defender who says he makes 15 to 20 games a season, disagrees. He’s carrying a sign that, if he was inside the park, might be picked up by MASN’s cameras: “Don’t forget Freddie Gray,” with the o’s replaced by the Orioles’ stylized lettering. Instead, Hurson’s placard is fodder for CNN, Fox News, and the half-dozen other news cameras stationed outside the gate.
“It’s embarrassing that we’re out here,” he says. “The entire Inner Harbor is surrounded by soldiers. The reason we’re out here is because the police murdered Freddie Gray. If they’re going to play they should open it to the public. Play it in front of human beings.”
Hurson suggests that had the stadium opened its gates to the public, some of the revenue could have been donated to organizations that work to repair the communities damaged by this week’s riots.
But the view from Camden is lousy. The best seat “in the house” is actually a terrace on the fourth floor of the Hilton across the street. About a dozen guests and hotel workers are up there getting a clear—if distant—view of the game when Baltimore first baseman Chris Jones belts a three-run home run as part of a six-run first inning. Maybe the ball lands on the Eutaw Street concourse that’s usually thick with spectators and tourists, but is empty and locked up today. Again, the weirdness dominates, along with a much greater number of journalists than should be covering this point in the season. More TV cameras. Print hacks. Mashable has two people here, interviewing put-out Orioles fans on Periscope, the new live-streaming app.
“We see this view all the time, but it’s full of thousands of spectators,” says Alexis Wilkins, who works for a vendor at the Hilton.
The Hilton’s roof deck and balconies are always busy on game days, but there’s always a crowd ahead of them. Wilkins, who had tickets to one of this weekend’s games against the Tampa Bay Rays until MLB moved the series to Florida, agrees with Hurson that the public should have been let in.
“It’s almost bittersweet,” she says. “Events over the past few days show how much we love our team and love Baltimore.”
With Baltimore opening up a big lead on the White Sox, there are two things on the roof-deck contingent’s minds: that the Orioles win, but without any significant player achievements like a no-hitter (made impossible by Avisail Garcia’s second-inning single), and the Baltimore Police Department’s report on Gray’s death to prosecutors, which is due Friday.
“It’s hard to make progress toward justice,” Wilkins says. “Tension has been building for years. The disparity in wealth is so extreme. Go to the west side of Baltimore; a couple miles away is so different.”
Up on the fifth floor, Chris Petro and a bunch of his friends are enjoying the view from two adjoining rooms. For $219 per room per night—possibly cheaper than eight baseball tickets—Petro and company also have a decent view of the game considering the circumstances (plus a lot of visits from journalists who were too late to score one of Oriole Park’s press-box seats).
“Many of us, our work was cancelled,” says Petro, a sound engineer at nearby Rams Head Live, which nixed every show this week after officials implemented a 10 PM citywide curfew.
The view from the hotel room.
Petro also takes a dim view of the scene in West Baltimore. “In a word: stupid,” he says. “I think everyone’s missing the point. It should be peaceful on behalf of the family of the kid who was lost. There’s people destroying our city and I can’t work. I think we have enough security around.”
Besides the Baltimore Police Department, the affected parts of the city are also swelling with the presence of state troopers, 2,000 National Guardsmen, and several hundred officers from police departments around the mid-Atlantic, including DC. Below the hotel, Camden Street is nearly empty during the game, save the occasional law-enforcement vehicle creeping along.
One thing about watching the game from a hotel balcony is that it makes it tough to tell who’s at the plate. The Orioles score on another home run in the fifth inning. “Was that Adam Jones?” someone says. “Davis,” another voice barks out. Turns out it was third-baseman Manny Machado, belting his fourth dinger of the season.
Petro says he makes it to about 40 or 50 games a year, and he usually treats the hotel begrudgingly. Its construction in 2008 blocked the stadium stands’ view of some of the Inner Harbor’s historic warehouses.
“When I’m in there,” he says, pointing to the empty upper deck, “I’m one of the thousands saying this is an eyesore.” There is one upside to the en-suite experience though: Petro can bring his dog, a black lab-border collie mix named Sara Sue.
But the oddest place to watch todays game might be from one of the many bars across from the stadium.
“It’s a weird day,” says Rob Nitkowski, a bartender at Pickles Pub, across South Paca Street. Today was supposed to be a night game, but even for an afternoon game in the middle of the week, business is down about 90 percent, saved only by the phalanx of journalists who couldn’t get into the stadium.
Pickles Pub, where every patron is a potential news source.
Chris Riehl, a tour guide who lives in South Baltimore, backs up Nitkowski’s assessment of the barroom. Journalists have been hounding him and his fellow Orioles fans all day. In the span of a few hours, he’s been interviewed by the New York Times; SiriusXM’s dedicated MLB channel; television stations from Baltimore, DC, and Columbus, Ohio; New England Cable News; and, now, Washingtonian. He’ll remember the Orioles 8-2 win for a long time, but not for any on-field high jinks.
“This is one of a kind,” he says. “In a small way, the people who came out here today were support the team, but in a bigger way were out here to support Baltimore.
Former National Adam LaRoche strikes out to end the top of the ninth at 4:09, putting the Orioles’ oddball win in the books in two hours and four minutes, incredibly breezy by the sport’s standards. As the lingering Pickles Pub crowd cheers, somebody on staff cues up the Goo Goo Dolls’ 1998 hit “Broadway.”
“Broadway is dark tonight,” John Rzeznik sings. It was dark all day.
Get Washingtonian’s Daily DC Updates (Not Just Another Political News Roundup)
Benjamin Freed joined Washingtonian in August 2013 and covers politics, business, and media. He was previously the editor of DCist and has also written for Washington City Paper, the New York Times, the New Republic, Slate, and BuzzFeed. He lives in Adams Morgan.
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Vascular endothelial cadherin (VE-cadherin): cloning and role in endothelial cell-cell adhesion.
To identify proteins responsible for intercellular junction integrity in human umbilical vein endothelial cells (HUVEC), we produced a monoclonal antibody that recognized an endothelial cell-specific, junctionally restricted protein. We characterized and cloned the antigen to study its functional properties. The size and cellular distribution of the antigen were determined by immunofluorescence and immunoprecipitation. The molecule was cloned and transfected into cell lines, and its role in cell-cell adhesion and growth rate was determined. Monoclonal antibody hec1 recognizes VE-cadherin, an endothelial cell-restricted cell adhesion molecule. VE-cadherin is localized to the borders between apposing endothelial cells but is diffusely distributed on subconfluent or migrating cells. Transfection of fibroblasts with VE-cadherin imparts to them the ability to adhere to each other in a calcium-dependent homophilic manner. Expression of VE-cadherin over a several-log range does not change the growth rate of these cells. Despite the fact that VE-cadherin is a "nonclassical" cadherin by structure, it functions as a classic cadherin by imparting to cells the ability to adhere in a calcium-dependent, homophilic manner. On HUVEC it appears to play a role in maintaining monolayer integrity.
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History maps
This section holds a short summary of the history of the area of present-day Afghanistan, illustrated with maps, including historical maps of former countries and empires that included present-day Afghanistan.
The rule of the Caliphate is replaced by a temporary Persian rule until the area is conquered by the Turkic Ghaznavids in 998. Ghazni is turned into a great cultural center as well as a base for frequent forays into India.
Various princes attempt to rule sections of the country until the Mongol invasion of 1219 led by Genghis Khan. Map showing changes in borders of the Mongol Empire from founding by Genghis Khan in 1206, Genghis Khan's death in 1227 to the rule of Kublai Khan (1260–1294). (Uses modern day borders)
Following Genghis Khan's death in 1227, a succession of chiefs and princes struggle for supremacy until late in the 14th century, when one of his descendants, Tamerlane, incorporates Afghanistan into his own vast Asian empire. Babur, a descendant of Tamerlane and the founder of India's Mogul dynasty at the beginning of the 16th century, makes Kabul the capital of an Afghan principality.
In 1747 Afghanistan liberates itself from the Empire of the Great Mogul. The State of Afghanistan is formed and Ahmad Shah Durrani establishes his rule. Throughout his reign, Durrani consolidates chieftainships, petty principalities and fragmented provinces into one country. His rule extends from Mashad in the west to Kashmir and Delhi in the east, and from the Amu Darya (Oxus) River in the north to the Arabian Sea in the south. From time to time separate Afghan states are installed in Kandahar and Herat. Though the country is united sincethen, it has to accept after the second Anglo-Afghan war (1878-80), that brings Amir Abdur Rahman to the throne, a British protectorate in 1881. The British retain effective control over Kabul's foreign affairs.
After the third Anglo-Afghan war in 1919, Britain relinquishes its control over Afghan foreign affairs by signing the Treaty of Rawalpindi. This means full independence of Afghanistan and the establishment of a more or less constitutional monarchy. King Amanullah (1919-29) renames the country Kingdom of Afghanistan in 1926 and introduces modernization and secularization. This leads to his assassination and a short civil war. In 1929 Nadir Shah becomes king. Four years later, however, he is assassinated in a revenge killing by a Kabul student.
In 1933 Mohammed Zahir Shah becomes king. He introduces in 1964 a liberal constitution providing for a two-chamber legislature to which the king appointed one-third of the deputies. The people elected another third, and the remainder were selected indirectly by provincial assemblies. He permits a multi-party system. This leads to the formation of the communist Hizb-i-Democratic-i-Khalq (People's Democratic Party, HDK), which had close ideological ties to the Soviet Union. In 1967, the PDPA split into two major rival factions: the Khalq (Masses) faction headed by Noo Mohammad Taraki and Hafizullah Amin and supported by elements within the military, and the Parcham (Banner) faction led by Babrak Karmal. After a coup d'état in 1973 Afghanistan becomes a dictatorial republic and is renamed Republic of Afghanistan. Mohammed Daoud Khan, until that moment prime minister, becomes president.
In 1978 the HDK seizes power and a communist dictatorship is established under the HDK, lead by Noor Mohammed Tarraki (1978-1979). The country is renamed Democratic Republic of Afghanistan. When Taraki is assasinated in 1979 he is succeeded by Hafizullah Amin (1979). At that moment the USSR invades the country and installs after the assasination of Amin Babrak Karmal as new president. Islamic factions start a guerilla war against the regime and the soviet-occupation. In an attempt to moderate Afghanistan is renamed into Republic of Afghanistan in 1987. Karmal is replaced by Mohammed Najibullah in 1986.
In 1990 the Islamic mujaheddin (Holy Warriors) expel the communist dictatorship. Though a central government is installed, de facto the country is ruled by warlords. In 1992 the central government renames the country into the Islamic State of Afghanistan. Burhanuddin Rabbani becomes president. The civil war continues and in 1996 the Taleban movement of spiritual leader Mullah Mohammad Omar seizes power in most of the country. Afghanistan becomes a theocratic dictatorship and is renamed Islamic Emirate of Afghanistan. Mullah Mohammad Rabbani is appointed president.
After an invasion by the United States in 2001, followed by a popular uprising, the dictatorship collapses. Afghanistan gets a transition governement and is renamed Islamic State of Afghanistan. Burhanuddin Rabbani resumes office, but the same year he is succeeded by Hamid Karzai. In 2004 a new constitution is accepted, identifying Afghanistan as an "Islamic Republic." The constitution paves the way for nationwide presidential and parliamentary elections to be held in june 2004. The government's authority beyond the capital, Kabul, is slowly growing, although its ability to deliver necessary social services remains largely dependent on funds from the international donor community.
Communist invasion of Afghanistan
Afghanistan just before the US invasion
Provinces until 2004
Old maps
This section holds copies of original general maps more than 70 years old.
Hindustan in 1812 by Arrowsmith and Lewis
Map of Central Asia from Meyers Konversationslexikons (1885-1900), showing what is now Afghanistan, Kyrgyzstan, Tajikistan, Uzbekistan, and parts of Kazakhstan, Turkmenistan and Chin
Other maps
Ethhno-Linguistic map of Afghanistan
Provincial Reconstruction Teams
Notes and references
General remarks:
The WIKIMEDIA COMMONS Atlas of the World is an organized and commented collection of geographical, political and historical maps available at Wikimedia Commons. The main page is therefore the portal to maps and cartography on Wikimedia. That page contains links to entries by country, continent and by topic as well as general notes and references.
Every entry has an introduction section in English. If other languages are native and/or official in an entity, introductions in other languages are added in separate sections. The text of the introduction(s) is based on the content of the Wikipedia encyclopedia. For sources of the introduction see therefore the Wikipedia entries linked to. The same goes for the texts in the history sections.
Historical maps are included in the continent, country and dependency entries.
The status of various entities is disputed. See the content for the entities concerned.
The maps of former countries that are more or less continued by a present-day country or had a territory included in only one or two countries are included in the atlas of the present-day country. For example the Ottoman Empire can be found in the Atlas of Turkey.
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ABC’s of VDI in 2016
The virtual desktop infrastructure (VDI) hype cycle has almost come full circle, with early adopters quickly discovering the technical or practical limits of the technology, while more recent VDI implementations have been much more successful than earlier forays into the virtual world. Now that VDI deployments are more common and more successful, we have a much clearer idea of what it takes to implement VDI in a way that works. That clarity positions 2016 as the year of wider acceptance for VDI, as many of the original technology challenges have been effectively addressed or eliminated. Let's take a quick look at the history and current state of VDI technology.
VDI Struggles Just as hypervisors did for server virtualization more than a decade ago, VDI requires a new way of thinking about how to best provide desktop computing services to end users. At the macro level, VDI is another attempt by IT to regain control of the user's desktop, control that was essentially lost at the beginning of the PC revolution 25 years ago. The end goal of VDI is to balance an end user's desire to control their own computing environment with the desires of IT to ensure a low-cost, secure, scalable, supportable platform for end users. This tug of war continues as each party seeks to exert the maximum control over their own computing domain, though ongoing VDI developments strike an acceptable balance between end users with complete control over their desktops running amok and IT wanting to make their life easier by restricting what end users can and cannot do to or with their desktops.
Performance and Cost Challenges The biggest complaint about early VDI implementations was mostly due to insufficient performance of the underlying infrastructure. Even as little as just two years ago, typical VDI network, server and storage performance under load was simply insufficient to support the high level of CPU, video and network traffic generated by VDI implementations. The explosion of high-performance hyper-converged infrastructure offerings and a plethora of new cost-effective options in the field of storage technology have mostly solved the infrastructure performance issues that plagued early VDI installations. Cost-effective, high-performance VDI infrastructure is now a reality, and there are a number of VDI-specific hardware/software bundles on the market that can make VDI a success at a price that was inconceivable just a few years ago.
Handling Sensitive Data Another historical concern with VDI is the security of data on shared platforms such as VDI. This concern led the VDI industry to address limitations in the security of VDI desktops and the underlying infrastructure. Corporate governance and compliance directives that apply to the security and retention of personally identifiable information (PII) within corporate IT infrastructures have played an important role in how VDI vendors handle sensitive data. As federal rules and regulations such as HIPAA and the FINRA made privacy and data security a high priority, VDI vendors were forced to gain certifications that verify all PII is held securely. This usually encompasses encryption of all data, both at rest and in motion. Encryption and de-encryption, of course, take additional computing horsepower, so that is yet another challenge for VDI vendors that were already struggling with performance issues before introducing encryption into the equation.
Other Usage Challenges Just as IT had to get used to a new paradigm in the migration to virtualize servers, the VDI concept of a user workspace requires a different way to think about the desktop. The concept of end users having a dedicated workspace that resides somewhere other than on their local computer takes some getting used to, whether that workspace is located in a private, public or hybrid cloud.
Must Read
For users, the fact that their desktop is still running—and remembers its exact state from the end of their last session—is a revolutionary concept. Users like being able to simply log off of their virtual desktop knowing that it's still "running" in the cloud and that they can pick up right where they left off at any time.
Finally, the ongoing explosion of BYOD and mobile computing has also been a bit of a learning curve for VDI vendors. More mobile- and BYOD-capable VDI solutions are coming to market, as supporting and embracing mobile corporate computing is no longer an option for VDI vendors—it's a requirement.
Underlying technology is primed to catch up with the original promise of VDI in 2016, allowing IT shops to cut costs while end users struggle to remember why they were so attached to their physical desktop to begin with. In this tug of war, both sides just may win.
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Added to shortlist
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3 chambres
Couchages 6
1 salles de bain
Notre maison
Home on acreage in peaceful location. Forty-five mins to Brisbane city or beaches. Mountain area within the Sunshine Coast Hinterland. Home to the Woodford Festival. Small town within 4klms, beautiful tourist drives. Domestic animals, two dogs, a cat and 2 chickens. Several sheep which graze over two properties, they like company but do not require any care. There are dams and ponds on property, so not suitable property if you gave small children. Extensive gardens, and large outdoor entertainment area.
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Hello everyone! This is the eighth post in my new node.js modules you should know about article series.
The first post was about dnode - the freestyle rpc library for node, the second was about optimist - the lightweight options parser for node, the third was about lazy - lazy lists for node, the fourth was about request - the swiss army knife of HTTP streaming, the fifth was about hashish - hash combinators library, the sixth was about read - easy reading from stdin, the seventh was about ntwitter - twitter api for node.
This time I'll introduce you to socket.io. I bet that most all of you already know socket.io, however I had several people message me to do an article on socket.io, so here it is.
Socket.io makes websockets and realtime possible in all browsers. It also enhances websockets by providing built-in multiplexing, horizontal scalability, and automatic JSON encoding/decoding. Socket.io is written by Guillermo Rauch, who's the co-founder of LearnBoost.
Socket.io always chooses the best realtime communication method possible. Here is the list of all the communication methods it supports:
WebSocket
Adobe® Flash® Socket
AJAX long polling
AJAX multipart streaming
Forever Iframe
JSONP Polling
For example, if you're using Chrome, then socket.io will use websockets. If your browser doesn't support websockets, it will try to use flash sockets, then it will try long polling, etc.
Now let's look at a very basic socket.io example:
var io = require('socket.io'); var express = require('express'); var app = express.createServer() var io = io.listen(app); app.listen(80); io.sockets.on('connection', function (socket) { socket.emit('news', { hello: 'world' }); socket.on('my other event', function (data) { console.log(data); }); socket.on('disconnect', function () { console.log('user disconnected'); }); });
This example uses the awesome express node web framework (I'll blog about it soon) to setup a web server on port 80, and attaches socket.io to it.
Socket.io then listens for new connections and when a new connection from the browser is created, it emits news event that sends the { hello: 'world' } hash back to the browser.
It also setups a listener for my other event and it listens for disconnect s. When the web application emits this event, socket.io calls the function (data) { console.log(data); } callback, that just prints the data to console. When the client disconnects, it logs this event to console also.
Here is the client side (in the web browser):
<script src="/socket.io/socket.io.js"></script> <script> var socket = io.connect('http://localhost'); socket.on('news', function (data) { console.log(data); socket.emit('my other event', { my: 'data' }); }); </script>
First we include the socket.io.js script, and then we create a socket.io connection to http://localhost . Here socket.io chooses the best communication method that the browser supports. If it's Chrome then it will be websockets, then if you have flash, then it will try flash sockets, then long polling, then multipart streaming, then forever iframe method, and finally jsonp polling. Then we listen on news event and when we receive it, we emit my other event .
This way you can build all kinds of awesome realtime applications, such as web chat servers and web irc clients.
There are many other features that socket.io supports, such as namespaces, volatile messages, message confirmations and message broadcasting. See the documentation to learn all about this awesomeness!
You can install socket.io through npm as always:
npm install socket.io
Socket.io on GitHub: https://github.com/LearnBoost/socket.io.
Also take a look at dnode that allows to call functions over socket.io.
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You may already be familiar with albinism in humans and other animals, but did you know there are albino plants, too?
The most viable example of this phenomenon is the albino redwood. Due to a genetic mutation, these rare plants are unable to produce chlorophyll, leaving their needles white or pale yellow instead of the typical green.
A lack of chlorophyll production would typically mean an automatic death sentence for the vast majority of plants, but these "everwhites" have a special trick up their sleeve that can ensure their survival: parasitism.
As long as they've sprouted close enough to a healthy, non-albino redwood (usually their parent tree), they are able to graft their roots onto the healthier individual and absorb important photosynthesized nutrients.
On the surface, it sounds like these trees have a pretty sweet arrangement, but the truth is this freeloader strategy is not without its challenges. Even when they're feeding off the healthiest of trees, many albino redwoods are weak and malnourished, which is why so many of them look like dying Christmas trees:
Humboldt Redwoods State Park has a few albino redwoods. (Photo: Redwood Coast/flickr)
Unlocking the albino redwood's secrets
An even rarer variation of this genetic mutation is the chimeric albino redwood, which has foliage that includes healthy green tissues as well as weaker albino tissues.
What's remarkable about redwood chimeras is that they have two different sets of DNA, which is like having two different people living in one body. This kind of tree is so rare that out of the millions of acres of redwood forest in California, there are only 10 known chimera individuals.
Redwoods show nature in all its colors. (Photo: Redwood Coast/flickr)
In a 2014 National Geographic article profiling the fight to save one such chimeric specimen in Cotati, California, Zane Moore, then a Colorado State University botany student, wondered if the albinism might be an adaptive response to external environmental forces:
"Albinos tend to be near redwood transition zones, and every one we study looks to be stressed. So one idea is that albinism is an adaptation to cope with stress. We've seen an unusual number of very young albinos coming up, which may be because of the drought that California and the west is experiencing."
It turns out that Moore was onto something. Two years later, Moore — who is now a doctoral student at University of California, Davis — has found that the albino redwood's needles contain high levels of heavy metals like nickel and copper. The albino redwood appear to be sucking up the pollution from the soil and storing it, keeping it away from other, healthier redwoods.
"They are basically poisoning themselves," Moore told the Mercury News. "They are like a liver or kidney that is filtering toxins."
While the new findings don't provide an explanation for the redwoods' albinism, soaking up toxins from the soil would certainly be a potential stressor for those self-sacrificing trees.
Albino redwoods may keep toxins out of the forest that allow other redwoods to thrive. (Photo: WolfmanSF/Wikimedia Commons)
Protecting the trees
The locations of albino redwoods are kept secret to ensure their survival. (Photo: Kevin Bertolero/flickr)
Like many other rare and ancient trees, the exact locations of these albino and chimera redwoods are often shrouded in secrecy in an effort to ensure their continued survival, but if you're hoping to glimpse one of these ghostly trees, there are several spots to view them within California's Humboldt Redwoods and Henry Cowell Redwoods state parks.
Take a quick tour of Henry Cowell Redwoods State Park and learn more about these remarkable "phantoms of the forest" in the video below:
(Inset photo of needles: Cole Shatto/Wikimedia Commons)
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Contents
The Ghostbusters were called to this house to deal with the hauntings. While Peter Venkman thought the call was another false alarm, Egon Spengler got readings right before his P.K.E. Meter went out. When Peter had an altercation with the house and ended up in the basement, all three Ghostbusters heard the name "Wat". Egon researched the name in Tobin's Spirit Guide and found Wat was a general and has a desire to rule the living world. Ray Stantz returned to the house to find the hauntings are now very apparent and meets with the other Ghostbusters. Egon leads them with his P.K.E. Meter to the back of the house in Mrs. Rogers' closet in her bedroom. They determine at that point Mrs. Rogers is Wat. As they try to leave the house, the house makes ever effort to stop them.
Towards the last room the house turns completely ectoplasmic in nature. The Ghostbusters finally get out when the possessed oven blows up. Later, it is shown that after Wat's capture, that the house was completely made of ghosts which all went back in a chest, which then exploded leaving an empty yard.
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TOWS Statement: House Tax Bill a Gift to Wall Street
Washington, DC – The Take on Wall Street campaign denounces the passage of a tax bill in the U.S. House of Representatives that would give Wall Street and the 1% over $1 trillion in tax breaks while leaving many middle-income Americans payinghigher taxes, increasing the public deficit, and leading to deep cuts in important public services.
“This legislation funnels billions of dollars to profitable Wall Street banks and wealthy private fund managers, on top of unfair tax loopholes and tax breaks they already enjoy,” said Lisa Donner, Executive Director at Americans for Financial Reform, a member of the coalition. “Real tax reform would involve restructuring tax policies so they work for everyday people, not reward manipulation by the richest few in our society. This vote rigs the system even further in favor of Wall Street, and would make life harder and less secure for many millions of Americans.”
“This vote is a clear pledge of allegiance to Wall Street,” said Luísa Galvão, a representative with the Take on Wall Street campaign. “Now more than ever, we must restore our financial system to its proper function: enabling an economy that works for all Americans, by closing tax loopholes and making Wall Street pay its fair share.”
Among other provisions, the House’s tax legislation:
Is a giveaway to big banks like Wells Fargo, which stand to be among thebiggest winners of a provision to lower the corporate tax rate from 35 to 20 percent;
Will result in a massive giveaway to hedge funds and other Wall Street firms through a provision that reduces the top rate for “pass-through” businesses, while inviting tax gamesmanship by powerful and sophisticated financial players;
Allows Wall Street banks to dodge taxes on the huge piles of profit being stashed offshore under proposals to tax corporations’ accumulated offshore profits at a discounted rate of 14%, as opposed to the 35% they should pay under current law. JPMorgan and Citigroup would be among thetop five companies to benefit from this repatriation break: JPMorgan would avoid paying $5.3 billion in taxes on their accumulated offshore profits, and Citigroup would get to pocket $7.9 billion. And under the bill’s proposed territorial system, U.S. corporations would no longer pay taxes on profits they book offshore in the future;
Preserves the carried interest loophole that Trump promised to close, which allows wealthy private equity and other Wall Street money managers to be taxed at a lower rate than nurses and firefighters. While millionaires and billionaires would get to keep their loopholes, tax breaks for regular people would be taken away, like the deduction families can take for out-of-pocket medical expenses, deductions that students can take on student loan interest, and deductions for teachers who buy school supplies with their own money.
The Take on Wall Street campaign — a coalition of over 50 community groups, unions, consumer advocates and others — is urging Congress to oppose tax cuts for Wall Street and the 1%, and adopt a set of tax reform measures that would raise more than $1 trillion in additional revenue and discourage dangerous Wall Street speculation.
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Polling the experts
Why do top economists think the recovery has been so slow?
EVERY four years, we poll the top American economists to get their views on the presidential election. This week’s print edition explains many of the results from our 2012 survey, which was conducted between September 18 and September 28. One particularly interesting set of results was generated when we asked economists why they thought the recovery had been so slow. This chart shows how various subpopulations rated the importance of six factors we chose:
Averages can tell you a lot but sometimes it is even more interesting to look at the distribution of all the responses, which you can see in this chart:
As you can see, there was a broad consensus on the relative importance of most issues. The two exceptions were fiscal austerity and policy uncertainty. Both factors got a grade of 4 or 5 from around 40% of the sample but also got grades of 1 and 2 from another 40% of the sample. There was some overlap—about one-fourth of people who thought fiscal austerity was important also thought uncertainty was holding back the recovery, and vice versa. Nevertheless, the economists’ political preferences can generally be predicted by their beliefs about why the recovery has been so anemic. In particular, those who think that fiscal policy is too tight believe that Mr Obama has a superior grasp of economics than Mr Romney. Similarly, economists who think that policy uncertainty is hobbling the recovery generally believe that Mr Romney has a firmer command of the discipline:
How can we hope to make informed decisions when the experts are this divided on such basic questions?
Oddly the most common suggest - that weak growth is inevitable after a financial crisis is not an explanation at all."
I think what they are saying is that weak growth was inevitable precisely because the financial crisis led to an enormous increase in both the private and public debt burden. So yes it is a perfectly good explanation!
Oddly the most common suggest - that weak growth is inevitable after a financial crisis is not an explanation at all. It's an axiom that tells us nothing. Why do they think this? What is the mechanism?
In the UK there is typically faster growth following a recession which gets us back to a shallow exponential trend line that has an r-squared of > 0.99. As far as I can see the USA is the same. The shape of the GDP curve in the UK has changed shape in a way that has never occurred before.
Yes, that is the only way. In addition to their political leanings (most US economists lean to the left), there are at least four different schools of economic thought and many more theories of business cycles.
For anyone wanting to start becoming an expert, I highly recommend Roger Garrison's "Time and Money". Garrison is a prof at Auburn. His book compares three schools of economics, Keynesian, neo-classical and Austrian.
An old book, Hayek's "Monetary theory of trade cycles" (1930's) looks at about a dozen business cycle theories. You can get a pdf copy at mises.org in the literature section.
Actually the article is talking about the situation in the US while you are talking about the UK for which the explanations are very different. Firstly just before and after 08 there was an enormous property price crash in the US (something that still has not happened in the UK). This led to an immediate increase in the household debt burden as many moved into negative equity. This led to a surge in defaults and consequently losses at the banks. Much of this tab was picked up by the taxpayer in the form of TARP.
You are correct in saying that the private debt levels were a problem leading up to the crisis. I should have been clearer though by saying that what changed immediately at the time of the crisis was that the collatoral behind both the household and banking debt(ie. the properties) became quickly eroded. So although the overall private debt levels may not have changed significantly the actual private debt burdens increased massively!! This had the knock on effect of crippling the working/middle classes purchasing power and the banking sectors ability to lend which explains the poor recovery.
This is pretty basic and I would like to think most economists understand this and that its implied when they say weak growth was inevitable after the crisis.
Hayek refused to call himself a conservative. He has a really interesting essay "Why I am not a Conservative." He preferred the term "liberal" as it was understood in the 19th century, but couldn't use that term in the US because it now means socialist. So he didn't call himself anything. He was really a classical liberal.
Hayek's position on intelligence was a little more nuanced than what I posted. You should read his last book "The Fatal Conceit". Yes, he thinks conservatives and classical liberals are intelligent, but his main point is the difference between intelligence and wisdom. The left may have intelligence but lack wisdom. The right may have fewer with intellectual ability, but far greater wisdom. Hayek valued wisdom above intellect. Wisdom requires humility.
" ... the economists’ political preferences can generally be predicted by their beliefs about why the recovery has been so anemic." (MCK)
.
I believe you have this backwards. Policy views are the tail and political interests are the dog that wags them. Academics don't choose the party the conforms to their economic view; rather, they choose the economic theory that fits their politics.
That might be a more significant data point if economists were better at predicting major crashes. The vast majority never saw 2008 coming. The vast majority, therefore, do not understand the economy well enough to usefully be able to see the real problems that exist.
So the fact that they "lean to the left" does not lead one to conclude that "the smart people" or "those who really understand the economy" lean left.
I agree. My criteria would be that any economist who did not predict the 2007 credit crunch and 2008 depression is out. It is the largest perturbation of the economy in modern times and anyone who failed to see it coming should no longer have any influence on public policy.
Yes. And I would add that those academic economists are often in the direct employment of business interests that are also political. Reports and opinions from people who do not declare lucrative remuneration packages are held to be suspect in any other field, but economists are reluctant to disclose who is funding their research.
As you will see private debt rose from 130% of GDP in 1987 - to a peak of about 475% of GDP in 2009. Then started to tail off as bankruptcies cancelled out some of the debts. As far as I have been able to ascertain it remains at around the 450% of GDP level - partly because of the finance sector.
In other words UK private sector debt is about £7 trillion or about £2 trillion more than the net worth of the UK (according to ONS figures). By my calculation when the crash hit the UK was 135% mortgaged. I cite Travelodge as an example of the problems. Look them up. Or you could look up Biffa. Too much debt makes profitable businesses insolvent.
Public debt only marginally increased in the UK by comparison and is a rather small fraction of private debt even now.
So there was quite a lot of subtext behind my remark. And I'm deeply frustrated that this story is ignored (or suppressed?) by the mainstream media to the benefit of public policy makers.
I say we have weak growth because in the words of Richard Koo "business is no long maximising profit, it is minimising debt". Private indebtedness at the levels we have siphons off the lion's share of disposable income. Like Koo and others I think we won't see a return to growth for at least a decade. And the model is Japan's 1990-2005 recession which was also caused by a massive build up of private debt.
So pardon me, but the explanation offered is far from good, and worse than weak. It's blind. And we should be terrible worried that economists are blind to debt. They're about as useful as a meteorologist who is blind to water!
Hayek's assertion implies conservatives are not intelligent. Now Hayek was conservative so that implies he was likely to to be unintelligent. If he was unintelligent why should I listen to him? But maybe he claimed to be one of the rare intelligent conservatives. But then he must be arrogant...
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---
images:
tags:
bootstrap: "docker.io/openstackhelm/heat:rocky-ubuntu_xenial"
db_init: "docker.io/openstackhelm/heat:rocky-ubuntu_xenial"
db_drop: "docker.io/openstackhelm/heat:rocky-ubuntu_xenial"
ks_user: "docker.io/openstackhelm/heat:rocky-ubuntu_xenial"
ks_service: "docker.io/openstackhelm/heat:rocky-ubuntu_xenial"
ks_endpoints: "docker.io/openstackhelm/heat:rocky-ubuntu_xenial"
heat_db_sync: "docker.io/openstackhelm/heat:rocky-ubuntu_xenial"
heat_api: "docker.io/openstackhelm/heat:rocky-ubuntu_xenial"
heat_cfn: "docker.io/openstackhelm/heat:rocky-ubuntu_xenial"
heat_cloudwatch: "docker.io/openstackhelm/heat:rocky-ubuntu_xenial"
heat_engine: "docker.io/openstackhelm/heat:rocky-ubuntu_xenial"
heat_engine_cleaner: "docker.io/openstackhelm/heat:rocky-ubuntu_xenial"
heat_purge_deleted: "docker.io/openstackhelm/heat:rocky-ubuntu_xenial"
...
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Phase II trial of mitoxantrone in head and neck carcinoma.
Nineteen patients with measurable and incurable head and neck carcinoma (17 squamous cell and two adenoid cystic) received intravenous bolus doses of 14 mg/m2 mitoxantrone in the first course. The doses were escalated or de-escalated by 2 mg/m2 in subsequent courses, based on leukocyte nadir, to achieve mild (3,000-3,999/mm3) or moderate (2,000-2,999/mm3) toxicity and response. The courses were repeated every 3 weeks. All 60 courses were evaluated for toxicity. Leukopenia was mild, moderate, severe (1,000-1,999/mm3), and life-threatening (less than 1,000/mm3) in 17%, 23%, 42%, and 2% of courses, respectively. Mild thrombocytopenia (100,000-129,999/mm3) occurred in two courses. The median interval to nadir leukopenia was 14 days (range 7-36) with a median of 13 days (range 3-50) to recover to normal. After the first course, leukopenia was mild in 16%, moderate in 32%, severe in 26%, and life-threatening in 5%. One patient died of pulmonary embolism 8 days after the first course and had concomitant leukocyte count of 700/mm3. Eighteen patients had at least one course resulting in leukopenia. Three of six patients receiving greater than or equal to 4 courses (cumulative dose 56-102 mg/m2) had an asymptomatic decrement of 14%, 17%, and 29%, respectively, in radionuclide left ventricular ejection fraction. The other toxicities were mild. In the 16 patients with squamous cell carcinoma that could be evaluated for response, one had a partial response lasting 8 months, and six had stable disease. One of the two patients with parotid adenoid cystic carcinoma had a minor response lasting 16 months. Mitoxantrone on a bolus schedule has minimal activity and is not indicated in head and neck squamous cell carcinoma.
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Over the past year it’s been impossible to travel for more than five minutes without seeing a Haibao, the Expo’s mascot and the good will ambassador. He’s been everywhere: stuffed toys, t-shirts, large statues, earrings, lunch boxes, shrubbery and even wall murals. That’s right, just like the Egyptian Pharaohs of Thebes, Haibao is now engraved into the very architecture of the city.
With the Expo now closed what’s in store for Haibao? Will he be forgotten like so many mascots before him or will he become a design classic, immortalised like the Pharaohs?
At his conception Hai Bao was selected from a cheap oakley sunglasses stifling 26,655 entrants to become the face of Shanghai’s Expo. His name translates as “treasure of the sea”and he was designed to “embody the culture and spirit of the hosting…city”.
Yet, despite the fierce competition and profound symbolic meaning behind Haibao, he resembles little more than a blue quaffed-blob and bears an uncanny resemblance to South Park’s character Towlie.
Towlie who was designed, by South Park’s creators, Matt Stone and Tray Parker, to be a shallow, two-dimensional character with no real purpose expect to “spout catch phrases and merchandise the hell out of”. It’s clear that the two have more in common than just looks.
Haibao merchandise has played a big part in the success of the Expo. Watching the crowds at various pavilions it appeared that no child was without their Haibao soft cheap oakleys toy. Authorities were so protective of their brand-name mascot that in August of this year the police rounded up thousands of fake Haibao toys from Nanjing Roal Mall and, allegedly, incinerated them in front of passing pedestrians – a menacing warning for those who dare purchase the unofficial Haibao.
In a press release prior to the Expo, the world was told that “The emblems of past World Expos have turned into unique intangible legacy” however the legitimacy of this statement is questionable – can you name a single one?. If it wasn’t for China’s consumerist nature it’s likely that Haibao too would to be forgotten with the rest of the Expo mascots. But what Haibao lacks in style or originality, he makes-up for in numbers and for this reason alone it’s likely that we will be seeing his blue face for a while to come.
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Cameron looks to the future in new role
That’s terrific because obviously they’re learning a new game plan with Stuey, but the other really good thing is that the whole club is really keen and eager to improve.
Craig Cameron
Just two months into his new role as General Manager – List & Strategy, CraigCameron has already begun his plan to build an exciting future for the club.
Charged with overseeing the development of a new-look SUNS recruiting department, the former GWS list manager has recognised the need to quickly familiarise himself with Gold Coast’s culture and direction.
“It’s really important in the off-season to spend a lot of time to build relationships and get to know the club,” Cameron told SUNS TV.
“What I’ve found is there’s obviously a lot of players on the track which for various reasons hasn’t been the case in the last few seasons.
“That’s terrific because obviously they’re learning a new game plan with Stuey, but the other really good thing is that the whole club is really keen and eager to improve.”
Cameron’s new team includes MarkMicallef and KallBurns, who was named national recruiting manager after seven years with the club, as well as NevilleStibbard who is also a new addition.
Stibbard brings a wealth of experience to the team through his time as recruiting manager at North Melbourne and part-time recruiter at GWS and Western Bulldogs.
Cameron himself is no stranger to football management either, with stints at Melbourne, Fremantle, Richmond and GWS stretching back to 1997.
The nature of his work has Cameron based in Melbourne, but his new role will see him split his time between the Gold Coast and the rest of Australia.
“It’ll be somewhere around fifty-fifty,” Cameron said of his time at the club and interstate.
“This time of the year (there is) a lot of time up on the Gold Coast to build relationships.
“Once the season starts and you get into the swing of watching games you get taken around the country so not quite as much time up here but in the off-season, quite a bit.”
Cameron has his eye on different goals for 2018, but there is one task at the top of the agenda.
“The important thing is to get to know the list really well so I want to know the strengths and weaknesses of our list and work with Stuey on how we can improve… to make sure that we’ve got a plan for the future in terms of improving the list.”
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Toh YL, Tan CJ, Yeo AHL, et al. Association of plasma leptin, pro‐inflammatory adipokines and cancer‐related fatigue in early‐stage breast cancer patients: A prospective cohort study. J Cell Mol Med. 2019;23:4281--4289. 10.1111/jcmm.14319
**Funding information**
This work was supported by research grants awarded by: National University of Singapore (R‐148‐000‐166‐112 -- PI: Alex Chan), National Cancer Centre Singapore (NRFCB12131 -- PI: Alex Chan) and National Medical Research Council (NMRC/CIRG/1386/2014 -- PI: Alex Chan).
1. INTRODUCTION {#jcmm14319-sec-0001}
===============
The estimated incidence of cancer‐related fatigue (CRF) has been reported to range from 28% to 91% among breast cancer patients,[1](#jcmm14319-bib-0001){ref-type="ref"} depending on the type of cancer, treatment modality and method of assessment. CRF is characterised by a persistent sense of tiredness that may be related to cancer and/or cancer treatment, is disproportionate to recent activity and is not alleviated by rest.[2](#jcmm14319-bib-0002){ref-type="ref"} Left unresolved, CRF adds on to patients\' distress and has a negative impact on their quality of life.[3](#jcmm14319-bib-0003){ref-type="ref"}
Given the extent of the impact of CRF on daily functioning,[4](#jcmm14319-bib-0004){ref-type="ref"} addressing CRF should be an integral part of cancer‐supportive care. Nevertheless, this has proved challenging due to the lack of an objective biomarker to monitor these symptoms. The experience of fatigue is subjective in nature and has wide inter‐individual variability because some patients may have poor physical functioning and impaired performance status yet will not complain of fatigue, and vice versa. One study has shown that pro‐inflammatory cytokines could be potentially employed as biomarkers of CRF in patients with advanced cancer,[5](#jcmm14319-bib-0005){ref-type="ref"} and that changes from baseline of selected biomarkers were associated with changes in patient‐reported outcome measures of appetite and fatigue. However, the circadian variability and fluctuation of cytokine levels could influence the outcomes associated with the biomarkers used and hinder their utility.[6](#jcmm14319-bib-0006){ref-type="ref"} Thus, further research is warranted to determine a suitable biomarker for monitoring CRF and related symptoms in cancer patients.
Leptin is an endocrine hormone that is more commonly known for its metabolic effects, which range from appetite suppression to regulating body weight.[7](#jcmm14319-bib-0007){ref-type="ref"} Leptin has shown moderate correlations to varying extents with fatigue in cohorts of patients with cardiovascular risk factors (r = 0.22),[8](#jcmm14319-bib-0008){ref-type="ref"} chronic fatigue syndrome (r = −0.51 to 0.73),[6](#jcmm14319-bib-0006){ref-type="ref"} chronic hepatitis C infection (r = 0.25; r = 0.30),[9](#jcmm14319-bib-0009){ref-type="ref"}, [10](#jcmm14319-bib-0010){ref-type="ref"} and irritable bowel syndrome (r = 0.60).[11](#jcmm14319-bib-0011){ref-type="ref"} In another study, researchers found that plasma leptin levels could be induced by hydrocortisone, and were markedly increased in patients with chronic fatigue syndrome.[12](#jcmm14319-bib-0012){ref-type="ref"} Hence, we hypothesized that leptin levels may be positively correlated with increases in fatigue in cancer patients, as their pro‐inflammatory markers are typically elevated.
This study was designed to investigate the association between plasma leptin levels and CRF in a cohort of early‐stage breast cancer patients, in relation with other relevant clinical factors and adipokines. Our primary objective was to assess leptin\'s potential to function as a biomarker that could predict the onset of CRF.
2. MATERIALS AND METHODS {#jcmm14319-sec-0002}
========================
2.1. Study design {#jcmm14319-sec-0003}
-----------------
This prospective cohort study was conducted between 2014 and 2017 in Singapore. The study was approved by the Singhealth Institutional Review Board (CIRB 2014/754/B), and written informed consent was obtained from all study participants.
2.2. Inclusion and exclusion criteria {#jcmm14319-sec-0004}
-------------------------------------
The inclusion criteria were: (a) diagnosis with early stage (I‐III) breast cancer; (b) no prior history of chemotherapy or radiotherapy; (c) scheduled to receive standard adjuvant chemotherapy; (d) ambulatory status with an Eastern Cooperative Oncology Group score of 0 or 1; and (e) the ability to understand either English or Chinese. Patients were excluded if they were diagnosed with metastatic cancer, had another medical condition that precipitates fatigue (such as severe anemia or thyroid dysfunction), or were on medications such as beta‐blockers that might precipitate fatigue as a side effect.
2.3. Study procedures {#jcmm14319-sec-0005}
---------------------
Patients were assessed at three time points: baseline before treatment initiation (T1), at least 6 weeks after baseline during chemotherapy (T2), and at least 12 weeks after baseline after the completion of chemotherapy (T3). Upon recruitment, patients\' demographic information and medication information were collected through patient interviews and electronic databases.
2.4. Study tools {#jcmm14319-sec-0006}
----------------
At each time point, patients completed a series of questionnaires assessing their fatigue, anxiety, depression and health‐related quality of life (HRQoL). Both English and Chinese versions of all study tools were available and administered by bilingual interviewers. The duration to complete all assessments was approximately 40 minutes. The tools included the following: The Multi‐dimensional Fatigue Symptom Inventory‐Short Form (MFSI‐SF) is questionnaire for measuring fatigue in cancer patients. It consists of five subscales with six items each: general fatigue, physical fatigue, emotional fatigue, mental fatigue and vigour. Each domain is rated on a scale of 0‐4. The total score is obtained by summing all the dimensions except the vigour domain which is subtracted. The total score ranges from −24 to 96, with higher scores indicating more fatigue. We previously established the range of minimal clinically important difference (MCID) for fatigue worsening as 4.50‐10.79.[13](#jcmm14319-bib-0013){ref-type="ref"} The psychometric properties and measurement equivalence of the English and Chinese versions of MFSI‐SF have been demonstrated in breast cancer patients in Singapore.[14](#jcmm14319-bib-0014){ref-type="ref"}The Beck Anxiety Inventory (BAI) is a validated questionnaire that measures the level of anxiety in patients.[15](#jcmm14319-bib-0015){ref-type="ref"} It comprises 21 items in which patients rate their somatic, subjective and panic‐related aspects of anxiety on a scale of 0‐3. The summation of the scores gives a total score ranging from 0 to 63, with a higher score indicating a greater anxiety level. Our research team has previously validated the psychometric properties and language equivalence of the English and Chinese versions of BAI.[16](#jcmm14319-bib-0016){ref-type="ref"}The Beck Depression Inventory (BDI) is a validated questionnaire that assesses the severity of depression[17](#jcmm14319-bib-0017){ref-type="ref"} and had been previously used by our team on breast cancer patients.[18](#jcmm14319-bib-0018){ref-type="ref"} There are 21 items that patients rate on a scale of 0‐3. The summation of the scores gives a total score ranging from 0 to 63, with a higher score indicating greater severity of depression.The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ‐C30) assesses HRQoL. This tool was used for the assessment of insomnia in patients, with a higher score on the symptom scale indicating greater severity. Both the English and Chinese versions had been validated for use in cancer patients.[19](#jcmm14319-bib-0019){ref-type="ref"}, [20](#jcmm14319-bib-0020){ref-type="ref"}
2.5. Quantification of plasma pro‐inflammatory adipokines and leptin levels {#jcmm14319-sec-0007}
---------------------------------------------------------------------------
At each time point, 10 ml blood samples were drawn for the analysis of pro‐inflammatory adipokines and kept in an ethylenediaminetetraacetic acid (EDTA) tube. The blood was centrifuged at 1069 x *g* for 10 minutes within 40 minutes of collection and kept frozen at −80°C until analysis. Levels of leptin were quantified using the Human Cancer Biomarker Panel (Biorad, CA, USA) while the levels of IL‐6, IL‐8 and tumour necrosis factor‐α (TNF‐α) were quantified using the Multiplex immunoassay (Luminex™) according to the manufacturer\'s instructions. IL‐6, IL‐8 and TNF‐α are other known pro‐inflammatory adipokines[21](#jcmm14319-bib-0021){ref-type="ref"}, [22](#jcmm14319-bib-0022){ref-type="ref"}, [23](#jcmm14319-bib-0023){ref-type="ref"} that were quantified so that their relationships with leptin and fatigue could be controlled in the analysis. Each analysis was conducted in duplicate, with an intra‐assay coefficient of variation of ≤10% being considered acceptable.[24](#jcmm14319-bib-0024){ref-type="ref"}
2.6. Statistical analysis {#jcmm14319-sec-0008}
-------------------------
Patients\' demographic information, clinical characteristics at baseline and the proportions of patients with CRF were summarised using descriptive statistics. The Friedman test was used to analyse the changes in plasma adipokines and leptin over the various time points, and post hoc Wilcoxon signed‐rank test was used to identify the time points at which a change was observed. Spearman\'s rank correlation coefficient was used to examine the relationship between each variable and leptin at each time point. Spearman\'s rank correlation was also used to determine the association between continuous variables of interest and total MFSI‐SF score. The Mann‐Whitney U test was used to compare fatigue levels between groups for categorical variables.
The longitudinal association of CRF with plasma leptin and adipokine levels was assessed using the generalised estimating equation model. The correlation structure with the smallest criterion was chosen using the quasi‐likelihood under the independence model criterion. Leptin was first analysed as a single variable. Next, the following known confounders that affect CRF were analysed individually against total MFSI‐score across the time points: anxiety,[25](#jcmm14319-bib-0025){ref-type="ref"} depression,[25](#jcmm14319-bib-0025){ref-type="ref"} insomnia,[26](#jcmm14319-bib-0026){ref-type="ref"} menopausal status,[27](#jcmm14319-bib-0027){ref-type="ref"} anaemia status,[28](#jcmm14319-bib-0028){ref-type="ref"} body mass index (BMI),[29](#jcmm14319-bib-0029){ref-type="ref"} age,[30](#jcmm14319-bib-0030){ref-type="ref"} type of chemotherapy,[31](#jcmm14319-bib-0031){ref-type="ref"} and pro‐inflammatory adipokines such as IL‐6, IL‐8 and TNF‐α.[21](#jcmm14319-bib-0021){ref-type="ref"}, [22](#jcmm14319-bib-0022){ref-type="ref"}, [23](#jcmm14319-bib-0023){ref-type="ref"} Confounders with *P*‐values \<0.05 were considered to be statistically significant and included in the final model as covariates to examine plasma leptin levels with respect to fatigue levels. All statistical analyses were conducted with STATA version 15 (Statacorp, TX, 2017), and two‐sided *P*‐values \<0.05 were considered statistically significant.
3. RESULTS {#jcmm14319-sec-0009}
==========
3.1. Patient demographics {#jcmm14319-sec-0010}
-------------------------
A total of 136 early‐stage breast cancer patients were included in this analysis, and their demographics are summarised in Table [1](#jcmm14319-tbl-0001){ref-type="table"}. The mean age ± standard deviation (SD) of the patients was 51.5 ± 8.8 years, and the mean BMI ± SD was 23.9 ± 4.1 kg/m^2^. Majority of the patients were Chinese (82.4%), had been diagnosed with stage II breast cancer (67.7%) and received anthracycline‐based chemotherapy (69.1%).
######
Baseline demographics and clinical characteristics of patents (n = 136)
Demographic information Mean ± SD or Frequency (%)
------------------------------------------------------------------------------- ----------------------------
Age (years) 51.5 ± 8.8
BMI (kg/m^2)^ 23.9 ± 4.1
Ethnicity
Chinese 112 (82.4)
Malay 12 (8.8)
Indian 7 (5.2)
Others[a](#jcmm14319-note-0002){ref-type="fn"} 5 (3.7)
Breast cancer stage
I 15 (11.0)
II 92 (67.7)
III 29 (21.3)
ECOG Performance Status
0 132 (97.1)
1 4 (2.9)
Baseline Haemoglobin levels
\<12 g/dL 35 (25.7)
\>12 g/dL 101 (74.3)
Menopausal status
Premenopausal 69 (50.7)
Postmenopausal 67 (49.3)
Chemotherapy Regimen
Anthracycline‐based 94 (69.1)
Non‐anthracycline‐based 42 (30.9)
Baseline anxiety (BAI total score)[b](#jcmm14319-note-0003){ref-type="fn"} 7.25 ± 7.86
Baseline depression (BDI total score)[c](#jcmm14319-note-0004){ref-type="fn"} 6.48 ± 7.98
Baseline insomnia score[d](#jcmm14319-note-0005){ref-type="fn"} 22.3 ± 26.9
Abbreviation: ECOG as Eastern Cooperative Oncology Group.
Others include: 4 Filipinos and 1 Sikh.
BAI total score is 63 points.
BDI total score is 63 points.
Insomnia subscale total score is 100 points.
John Wiley & Sons, Ltd
3.2. Prevalence of cancer‐related fatigue {#jcmm14319-sec-0011}
-----------------------------------------
Using the MCID as a cut‐off, patients who experienced a deterioration of ≥11 points from baseline were considered as fatigue cases. A total of 23.8% of patients experienced CRF at T3 compared to 13.8% of patients at T2, using the baseline as a reference. The overall incidence of CRF from T1 to T3 was 24.6%.
3.3. Plasma levels of adipokines and leptin across time points {#jcmm14319-sec-0012}
--------------------------------------------------------------
The plasma levels of the individual adipokines are summarised as the medians with the interquartile ranges (Table [2](#jcmm14319-tbl-0002){ref-type="table"}). There were statistically significant changes in the plasma levels of leptin, IL‐6, Il‐8 and TNF‐α across the three time points (*P*‐value \<0.001 using the Friedman test). Compared to baseline, a median increase of plasma leptin levels was observed at T2, followed by a decrease at T3 (T1: 4.07 ng/mL, T2: 4.95 ng/mL and T3: 3.96 ng/mL). For IL‐6, there was an increase in plasma levels towards the end of chemotherapy at T3 (T1: 0.80 pg/mL, T2: 1.11 pg/mL, T3: 1.27 pg/mL). For IL‐8, there was a decrease in plasma levels at T2, followed by an increase at T3 (T1: 3.70 pg/mL, T2: 3.33 pg/mL, T3: 3.69 pg/mL). For TNF‐α, there was a sustained increase in plasma levels (T1: 6.41 pg/mL, T2: 6.95 pg/mL, T3: 8.27 pg/mL).
######
Comparison of plasma adipokine and leptin levels across the time points
Biomarker Plasma adipokine concentration in Median (Inter‐quartile range) Friedman Test Post‐hoc analysis: Wilcoxon sign rank test
---------------- ----------------------------------------------------------------- -------------------- -------------------------------------------- ------------- ------------- ------------- -------------
Leptin (ng/mL) 4.07 (2.96, 6.61) 4.95 (3.27, 7.16) 3.96 (2.68, 6.07) **\<0.001** **\<0.001** 0.56 **\<0.001**
IL‐6 (pg/mL) 0.80 (0.36, 1.72) 1.11 (0.57, 2.46) 1.27 (0.53, 2.60) **\<0.001** **\<0.001** **\<0.001** 0.07
IL‐8 (pg/mL) 3.70 (2.29, 4.95) 3.33 (2.25, 5.06) 3.69 (2.48, 5.28) **\<0.001** 0.42 **0.04** **\<0.001**
TNF‐α (pg/mL) 6.41 (2.76, 15.15) 6.95 (3.22, 18.61) 8.27 (2.71, 19.71) **\<0.001** 0.78 **\<0.001** **\<0.001**
Abbreviation: TNF‐α, tumour necrosis factor‐α.
Bolded are *P*‐values \< 0.05 and *P*‐values for post‐hoc analysis cut‐off = 0.0167.
In cases for patients whose plasma levels of adipokine were below the detection limit, the laboratory values are treated as missing values in the statistical analysis.
John Wiley & Sons, Ltd
3.4. Correlation of plasma adipokines levels and confounders against plasma leptin levels at individual time points {#jcmm14319-sec-0013}
-------------------------------------------------------------------------------------------------------------------
Considering relationships between leptin and each individual adipokine, only IL‐8 had a statistically significant correlation at T1 (r = 0.20, *P* = 0.02). At T1, there were no significant correlations between leptin and IL‐6 or TNF‐α. At T2 and T3, none of the adipokines showed statistically significant correlations with leptin (Table [3](#jcmm14319-tbl-0003){ref-type="table"}).
######
Correlation of plasma adipokine levels and known confounders against leptin at individual time points (T1, T2 and T3)
T1 T2 T3
----------------- ----------- ------------- ----------- ------------- ----------- -------------
IL‐6 0.14 0.18 0.07 0.50 0.07 0.52
IL‐8 **0.20** **0.02** 0.06 0.46 0.06 0.46
TNF‐α −0.03 0.71 −0.07 0.44 −0.02 0.85
Anxiety −0.09 0.29 −0.03 0.70 0.008 0.92
Depression **−0.20** **0.02** **−0.25** **\<0.001** −0.08 0.37
Insomnia −0.07 0.43 −0.02 0.83 **−0.20** **0.02**
Body mass index **0.59** **\<0.001** **0.56** **\<0.001** **0.58** **\<0.001**
Age **0.23** **\<0.001** 0.15 0.08 0.16 0.07
Categorical variables T1 T2 T3
----------------------- ----------- ----------- ----------- ---------- ----------- ----------
Menopausal status −**3.14** **0.002** −1.87 0.06 −**2.51** **0.01**
Anaemia status −0.54 0.59 **2.34** **0.02** −0.46 0.64
Type of chemotherapy 0.44 0.66 −**2.14** **0.03** 1.54 0.12
Abbreviation: TNF‐α, tumour necrosis factor‐α.
Bolded are *P*‐values \< 0.05.
For continuous variables, data is presented as spearman correlation coefficients with r and its *P*‐values. For categorical variables, data is presented as the test statistic (z) along with p‐values of Mann‐Whitney U tests used to compare the proportion.
John Wiley & Sons, Ltd
Among the confounders, leptin was positively correlated with BMI across all time points (T1: r = 0.59, T2: r = 0.56, T3: r = 0.58, all *P*‐values \<0.001) and with age at T1 (r = 0.23, *P* \< 0.001). There was a significant negative correlation between plasma leptin levels and depression at T1 and T2 (r = −0.20, *P* = 0.02 and r = −0.25, *P* \< 0.001, respectively) and with insomnia at T3 (r = −0.20, *P* = 0.02). Among categorical variables, there was a difference in plasma leptin levels for menopausal status at T1 and T3 (*P* = 0.002 and 0.01 respectively), for anaemia status at T2 (*P* = 0.02) and the type of chemotherapy at T2 (*P* = 0.03).
3.5. Correlation of plasma adipokines levels, known confounders and leptin against fatigue levels across time points (T1‐T3) {#jcmm14319-sec-0014}
----------------------------------------------------------------------------------------------------------------------------
There were consistent strong correlations with fatigue levels across all time points for anxiety, depression and insomnia. Age was negatively correlated with CRF across time points and CRF level also differed for the type of chemotherapy. There was only a significant negative correlation at T1 for leptin (r = −0.25, *P* = 0.005) (Table [4](#jcmm14319-tbl-0004){ref-type="table"}).
######
Correlation of plasma adipokine levels, known confounders and leptin against fatigue levels across time points (T1‐T3)
T1 T2 T3 T1‐T3
----------------- ----------- ------------- ----------- ------------- ----------- ------------- ------------------- -------------
Leptin −**0.25** **0.005** −0.11 0.22 0.02 0.83 −**0.56 (0.13)** **\<0.001**
IL‐6 0.007 0.94 0.17 0.10 0.09 0.36 0.50 (0.46) 0.27
IL‐8 −0.07 0.45 −0.004 0.96 0.04 0.65 0.10 (0.38) 0.12
TNF‐α 0.05 0.57 0.001 0.99 0.05 0.58 −**0.02 (0.004)** **0.003**
Anxiety **0.65** **\<0.001** **0.63** \<**0.001** **0.68** \<**0.001** **1.38 (0.13)** **\<0.001**
Depression **0.74** **\<0.001** **0.74** **\<0.001** **0.75** \<**0.001** **1.85 (0.14)** **\<0.001**
Insomnia **0.30** **\<0.001** **0.34** \<**0.001** **0.44** \<**0.001** **0.15 (0.03)** **\<0.001**
Body mass index −0.17 0.054 −0.05 0.59 −0.04 0.78 −0.39 (0.26) 0.13
Age **−0.34** **\<0.001** **−0.27** **0.002** −**0.25** **0.004** −**0.57 (0.12)** **\<0.001**
Categorical variables T1 T2 T3 T1‐T3
----------------------- ---------- ------------- ---------- ------------- ---------- ------------- ------------------- -------------
Menopausal status 1.78 0.08 1.11 0.27 1.49 0.14 −**5.59 (2.64)** **0.04**
Anaemia status −0.73 0.47 −0.43 0.67 **2.06** **0.04** 0.02 (0.01) 0.09
Type of chemotherapy **3.32** **\<0.001** **3.57** **\<0.001** **3.50** **\<0.001** −**10.65 (2.32)** **\<0.001**
Abbreviation: TNF‐α, tumour necrosis factor‐α.
Bolded are p‐values \< 0.05.
John Wiley & Sons, Ltd
Across T1 to T3, leptin was negatively correlated with the total MFSI‐SF score (*β *= −0.56, *P* \< 0.001), with every 1 unit decrease of leptin being associated with a 0.56 increase in total MFSI‐SF score (Table [2](#jcmm14319-tbl-0002){ref-type="table"}). TNF‐α was also inversely correlated with the total MFSI‐SF score (*β *= −0.02, *P* = 0.003). IL‐6 and IL‐8 did not show a statistically significant correlation with total MFSI‐SF score. For other individual explanatory variables, there were statistically significant positive associations for anxiety (*β* = 1.38, *P* \< 0.001), depression (*β* = 1.85, *P* \< 0.001) and insomnia (*β* = 0.15, *P* \< 0.001) and significant negative correlations with menopausal status (*β* = −5.59, *P* = 0.04), age (*β *= −0.57, *P* \< 0.001) and type of chemotherapy (*β* = −10.65, *P* \< 0.001). Anaemia status (*β* = 0.02, *P* = 0.09) and BMI (*β *= −0.39, *P* = 0.13) were not significantly correlated with total MFSI‐SF score.
3.6. Adjusted model showing an association between leptin and CRF {#jcmm14319-sec-0015}
-----------------------------------------------------------------
Using *P*‐values \<0.05 as selection criteria, the variables with statistically significant associations with CRF were TNF‐α, anxiety, depression, insomnia, age, menopausal status and type of chemotherapy. These variables were included as covariates in the final model. Results showed that leptin remained inversely associated with total MFSI‐SF score but the beta‐coefficient for leptin with the MFSI‐score was attenuated (*β *= −0.15, *P* = 0.003), with every 1 unit decrease of leptin being associated with a 0.14 increase in total MFSI‐SF score across time points (Table [5](#jcmm14319-tbl-0005){ref-type="table"} **)**.
######
Association of plasma leptin levels against total MFSI‐SF score after adjusting for statistically significant covariates
Variable Total MFSI‐SF score
------------------------ --------------------- -------------
Constant **19.80 (3.39)** **\<0.001**
Adjusted Leptin(ng/mL) −**0.15 (0.05)** **0.003**
TNF−α(pg/mL) −**0.009 (0.002)** **\<0.001**
Anxiety **0.74 (0.14)** **\<0.001**
Depression **1.06 (0.17)** **\<0.001**
Insomnia −0.002 (0.02) 0.94
Age −**0.23 (0.08)** **0.004**
Menopausal status 2.10 (1.50) 0.16
Type of chemotherapy −1.75 (0.94) 0.06
Abbreviation: TNF‐α, tumour necrosis factor‐α.
Bolded are *P*‐values \< 0.05.
John Wiley & Sons, Ltd
While leptin was originally associated with the general (*β *= −0.16, *P* \< 0.001), emotional (*β* = −0.11, *P* \< 0.001) and mental sub‐domains (*β* = −0.06, *P* = 0.025) of MFSI‐SF scale, the beta coefficients of the respective five sub‐domains scores were not statistically significant in the final model (Table [6](#jcmm14319-tbl-0006){ref-type="table"}). In the analysis of other explanatory variables in the final model, there were positive significant associations with CRF for anxiety (*β* = 0.74, *P* \< 0.001) and depression (*β* = 1.06, *P* \< 0.001) and significant negative associations for TNF‐α (*β *= −0.009, *P* \< 0.001) and age (*β* = −0.23, *P* = 0.004).
######
Association of plasma leptin levels against total MFSI‐SF score and its respective sub‐domains after adjusting for statistically significant covariates
Variable (in ng/mL) Total MFSI‐SF score General Physical Emotional Mental Vigor
---------------------- --------------------- ------------- ------------------ ------------- ------------------ ------------- ------------------ ------------- ------------------ ------------- ------------------ -------------
Constant **19.80 (3.39)** **\<0.001** **27.21 (1.41)** **\<0.001** **25.57 (1.28)** **\<0.001** **26.00 (1.07)** **\<0.001** **25.55 (1.38)** **\<0.001** **34.51 (2.71)** **\<0.001**
Adjusted Leptin **−0.15 (0.05)** **0.003** −0.004 (0.04) 0.92 0.07 (0.04) 0.08 0.02 (0.03) 0.60 −0.005 (0.03) 0.90 0.12 (0.08) 0.13
TNF−α **−0.009 (0.002)** **\<0.001** 0.002 (0.002) 0.34 −0.0008 (0.002) 0.68 0.0004 (0.002) 0.83 0.001 (0.002) 0.45 0.008 (0.004) 0.08
Anxiety **0.74 (0.14)** **\<0.001** **0.23 (0.03)** **\<0.001** **0.21 (0.03)** **\<0.001** **0.16 (0.02)** **\<0.001** **0.11 (0.02)** **\<0.001** **−0.11 (0.04)** **0.004**
Depression **1.06 (0.17)** **\<0.001** **0.19 (0.04)** **\<0.001** **0.12 (0.03)** **\<0.001** **0.29 (0.03)** **\<0.001** **0.16 (0.03)** **\<0.001** **−0.31 (0.04)** **\<0.001**
Insomnia −0.002 (0.02) 0.94 0.01 (0.006) 0.08 **0.01 (0.006)** **0.04** −0.004 (0.005) 0.44 0.006 (0.005) 0.22 −0.006 (0.009) 0.51
Age **−0.23 (0.08)** **0.004** −0.05 (0.03) 0.14 **−0.07 (0.03)** **0.03** −0.04 (0.03) 0.08 −0.02 (0.03) 0.56 0.11 (0.06) 0.10
Menopausal status 2.10 (1.49) 0.16 0.61 (0.57) 0.29 **1.12 (0.50)** **0.03** 0.43 (0.42) 0.30 −0.003 (0.58) 0.99 −1.22 (1.08) 0.26
Type of chemotherapy −1.76 (0.94) 0.06 **−0.93 (0.40)** **0.02** 0.09 (0.36) 0.81 −0.53 (0.30) 0.07 −0.25 (0.40) 0.53 **2.22 (0.82)** **0.007**
Abbreviation: TNF‐α, tumour necrosis factor‐α.
Bolded are *P*‐values \< 0.05.
John Wiley & Sons, Ltd
4. DISCUSSION {#jcmm14319-sec-0016}
=============
In our cohort of early‐stage breast cancer patients, plasma leptin levels were found to be significantly and negatively correlated with total MFSI‐SF score across time points (*β* = −0.56, *P* \< 0.01). This relationship remained significant (*β* = −0.15, *P* = 0.003) even after adjusting for the statistically significant covariates in our final model. This result does not support our initial hypothesis, in which we predicted that leptin levels would be positively correlated with fatigue levels, as observed in patient cohorts of other disease states.[6](#jcmm14319-bib-0006){ref-type="ref"}, [8](#jcmm14319-bib-0008){ref-type="ref"}, [9](#jcmm14319-bib-0009){ref-type="ref"}
The difference in direction observed for the effect of leptin on fatigue suggests that the experience of CRF may be different from fatigue‐associated processes in other disease states. The positive correlations between fatigue and adipokines had been mostly observed in patients with other conditions marked by inflammation.[6](#jcmm14319-bib-0006){ref-type="ref"}, [9](#jcmm14319-bib-0009){ref-type="ref"}, [10](#jcmm14319-bib-0010){ref-type="ref"} For instance, in a cohort of patients with cardiovascular risk factors, plasma leptin levels were significantly and positively associated with fatigue score (r = 0.22, *P* \< 0.001) and retained an independent association in a multiple logistic regression.[8](#jcmm14319-bib-0008){ref-type="ref"} Yet in another study evaluating patients with systemic lupus erythematosus, there was no significant association between adipokines and fatigue levels, but their correlation was reported to be negative. In that model, after adjustment for age, sex, race/ethnicity and BMI, leptin was negatively correlated with fatigue levels, measured using the Fatigue Severity Scale (*β* = −0.12, *P* = 0.61) and patient‐reported fatigue scores (*β* = −0.066, *P* = 0.96). The correlations between adipokines and both physical activity and disease activity were explained by differences in BMI.[32](#jcmm14319-bib-0032){ref-type="ref"}
These observed differences in CRF may also be nuanced and subjected to changes that depend on the individual sub‐domains of CRF being examined. While CRF is a multidimensional construct, it is possible that not all facets of fatigue are equally associated with changes in adipokine levels. This is supported by our results in which plasma leptin levels were significantly correlated with the sub‐domains of general, emotional and mental fatigue but not the physical and vigour sub‐domains. In the final model, leptin was significantly correlated with only the total MFSI‐SF scores but not the remaining sub‐domains. This reinforces the need for studies to study the specific domains of fatigue more closely.
With regard to individual subdomains of fatigue, anxiety and depression continued to be strong predictors of fatigue levels over time, showing significant correlations with all five sub‐domains. This observation was also reported in a separate cohort of breast cancer survivors, in which the research team reported that patients diagnosed with depression and anxiety before chemotherapy were at higher risk of fatigue onset at a later period.[3](#jcmm14319-bib-0003){ref-type="ref"} This finding suggests that some psychological symptoms may form a fairly stable symptom cluster with CRF. It also supports the possibility that anxiety and depression add to the stress response and weaken the immune system, triggering inflammatory mediators involved in CRF and leading to pro‐inflammatory changes in the body.[33](#jcmm14319-bib-0033){ref-type="ref"} These findings are aligned with reviews reporting depression and anxiety as prominent correlates of CRF, [25](#jcmm14319-bib-0025){ref-type="ref"}, [33](#jcmm14319-bib-0033){ref-type="ref"}, [34](#jcmm14319-bib-0034){ref-type="ref"} and lend strength to the argument that psychological distress needs to be accounted for when investigating the usefulness of leptin as a biomarker for CRF.
Based on our findings, it would be interesting to explore the relationships between leptin and other pro‐inflammatory biomarkers. Various cytokines such as TNF‐α, IL‐6 and IL‐1 can induce metabolic changes by mimicking the action of neuropeptides such as leptin because of their structural similarity.[35](#jcmm14319-bib-0035){ref-type="ref"} A decrease in food intake would usually suppress leptin expression, but in the presence of some cytokines, plasma leptin levels can be increased and work against the normal compensatory mechanisms set in place for leptin levels to regulate appetite. A possible explanation for the decrease in leptin levels with higher fatigue levels could be that an adaptive reduction of energy expenditure has been induced, resulting in increased appetite in response to metabolic impairment induced by cancer‐related inflammation. It might also be more meaningful to evaluate the ratio of plasma leptin to other known pro‐inflammatory cytokines to interpret inflammatory status, especially if they work as a network and if their levels affect each other. In the pathogenesis of some autoimmune diseases, leptin has been characterised together with adiponectin and resistin.[32](#jcmm14319-bib-0032){ref-type="ref"}, [36](#jcmm14319-bib-0036){ref-type="ref"} In an ovarian cancer study, pro‐inflammatory cytokines such as IL‐6 and TNF‐α were reported to induce an acute‐phase protein response that contributed to altered energy metabolism, which regulated leptin levels.[29](#jcmm14319-bib-0029){ref-type="ref"} In another cohort of lung cancer patients,[37](#jcmm14319-bib-0037){ref-type="ref"} the research team found significant positive associations among plasma levels of TNF‐α, IL‐1 and CRF. Together, these studies and our results suggest that leptin should be included in studies in which relationships between fatigue and cytokines are explored.
One strength of this study was the use of a longitudinal study design with repeated measurements of outcomes at various time points, which allowed us to determine whether a decrease in leptin levels signalled a rise in the fatigue experienced by breast cancer patients at a separate time point. Most of the current fatigue studies have been cross‐sectional so far,[8](#jcmm14319-bib-0008){ref-type="ref"}, [9](#jcmm14319-bib-0009){ref-type="ref"} and are not able to track the trajectories between fatigue and other variables, given how some of the other symptoms may be transient. A limitation of this study lies in that there were no cancer control patients who did not undergo chemotherapy to provide a comparison of CRF experience.
Understanding the role of leptin in relation to CRF may help us to devise more tailored interventions such as exercise to mitigate CRF in the future. In a randomised controlled trial examining the effects of exercise in overweight or obese breast cancer survivors,[38](#jcmm14319-bib-0038){ref-type="ref"} circulating biomarkers (insulin, IGF‐1, adiponectin and leptin) were significantly improved post‐intervention, compared to usual care. In another trial, a decrease in leptin concentrations in breast cancer survivors who exercised compared to controls was reported.[39](#jcmm14319-bib-0039){ref-type="ref"}
Several concerns need to be addressed before any potential fatigue biomarker can have clinical utility. The observed difference in direction for effect of leptin on fatigue may be partly attributed to the non‐specific nature of fatigue, which can be challenging to quantify despite use of validated questionnaires and is dependent on the study tools used. There is no consistent definition of CRF and a general lack of agreement about which biomarkers to study or how to collect and test them. Research aimed at resolving these issues would help to advance the understanding of the mechanisms that underpin CRF and could improve the quality of life of individuals who experience it.
In conclusion, our data show that there is an inverse correlation between plasma leptin levels and fatigue levels over time in early‐stage breast cancer patients undergoing chemotherapy. The association with total score remained statistically significant after adjusting for known confounders of CRF, enabling leptin to function as a biomarker that could predict onset of CRF.
CONFLICTS OF INTEREST {#jcmm14319-sec-0018}
=====================
The authors confirm that there are no conflicts of interest.
AUTHORS CONTRIBUTIONS {#jcmm14319-sec-0017}
=====================
HHK, KO and AC: Conceptualisation, funding acquisition, supervision and writing‐review and editing. FKM and PC: investigation, project administration and resources. TCJ, AHLY, MS and GYX: data curation, investigation and project administration. TYL: Formal analysis, investigation, writing‐original draft, writing‐review and editing. All authors read and approved the final manuscript.
We would also like to acknowledge the following doctors from the Division of Medical Oncology, National Cancer Centre, Singapore for their help with patient recruitment in the study: Dr Rebecca Dent, Dr Raymond Chee Hui Ng, Dr Yoon Sim Yap, Dr Kiley Wei‐Jen Loh, Dr Guek Eng Lee, Dr Sok Yuen Beh, Dr Tira Jing Ying Tan and Dr Mabel Wong.
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Atrial Fibrillation in Athletes-Features of Development, Current Approaches to the Treatment, and Prevention of Complications.
Atrial fibrillation (AF) is one of the most common types of cardiac arrhythmias. This review article highlights the problem of the development of atrial fibrillation in individuals engaged in physical activity and sports. Predisposing factors, causes, and development mechanisms of atrial fibrillation in athletes from the perspective of the authors are described. Methods of treatment, as well as prevention of thromboembolic complications, are discussed. Directions for further studies of this problem and prevention of complications are proposed.
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1. Field of the Invention
The present invention relates to flexible cleaning tools, and more particularly, to flexible brush tools for cleaning endoscopes including means for delivering fluid.
2. Description of Related Art
Colonoscopes, bronchoscopes and similar endoscopes require cleaning after each use. Endoscopes have long flexible tubes containing various passages. Some endoscope passages are for transmitting light beams to illuminate or observe the area being operated on. Other passages serve as suction channels or as operating tool passageways. The operating and suction passages must be cleaned after each use with a surgical cleaner and/or disinfectant. The passages are hard to reach since they are long and narrow, and in some places, sharply curved.
A reusable brush, small, but similar in construction to a conventional bottle brush, has been used for cleaning endoscopes; that is, a brush having a long and flexible teflon-coated wire stem, a handle at one end, and a group of bristles at the other end. In use, the brush is inserted into the endoscope passages and manipulated while the endoscope is immersed in cleaning fluid. This brush, while somewhat flexible, nevertheless lacks the ability to effectively negotiate sharp turns in the endoscope passages.
The trend in medical supplies is to make products disposable to eliminate cross-contamination. One disposable prior art cleaning tool employed a length of flexible plastic tubing having a small brush fitted into one end. Near the brush tip, a hole was formed in the tubing wall to permit fluid circulation. The plastic tubing tended to kink and bend when pushed in the process of cleaning which reduced its effectiveness. In addition, the brush lacked the ability to negotiate the sharp turns in the endoscope passages.
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Browse:
Minnesota takes on Los Angeles, looks to stop 4-game skid
Los Angeles Clippers (31-26, eighth in the Western Conference) vs. Minnesota Timberwolves (25-30, 12th in the Western Conference)
Minneapolis; Monday, 8 p.m. Eastern
BOTTOM LINE: Minnesota heads into the matchup against Los Angeles as losers of four in a row.
The Timberwolves have gone 17-10 at home at the Target Center. Minnesota is third in the Western Conference with 11.7 offensive rebounds per game, led by Karl-Anthony Towns averaging 3.4.
The Clippers are 16-14 in road games. Los Angeles is 16-12 in games decided by at least 10 points. The Clippers defeated the Timberwolves 120-109 in their last meeting on Nov. 5. Tobias Harris led Los Angeles with 22 points and Derrick Rose paced Minnesota scoring 21 points.
TOP PERFORMERS: Towns ranks second on the Timberwolves with 1.8 made 3-pointers and averages 23.1 points while shooting 38.5 percent from beyond the arc. Andrew Wiggins has averaged 7.1 rebounds and added 18.6 points per game over the last 10 games for Minnesota.
Landry Shamet leads the Clippers with four made 3-pointers per game. He averages 17.0 points per game and is shooting 57.1 percent from beyond the arc. Lou Williams has scored 21.4 points and collected four rebounds while shooting 39.6 percent over the last 10 games for Los Angeles.
Timberwolves: 4-6, averaging 110.7 points, 47.7 rebounds, 24.1 assists, 7.1 steals and four blocks per game while shooting 44.8 percent from the field. Their opponents have averaged 109.7 points on 46.4 percent shooting.
Timberwolves Injuries: Robert Covington: out (ankle), Jerryd Bayless: day to day (sore right big toe), Tyus Jones: day to day (left ankle sprain), Jeff Teague: day to day (left foot soreness), Derrick Rose: day to day (right ankle soreness).
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Proteolytic enzyme activity of blood leukocytes and cerebrospinal fluid in multiple sclerosis.
Upon stimulation by immune complexes, the polymorphonuclear (PMN) blood secretes lysosomal hydrolases, including neutral proteinase, which is concentrated in the PMN cell. Neutral and acid proteinase activity were increased and decreased, respectively, in the circulating white cells of patients with multiple sclerosis during an exacerbation of the disease, but there was no correlation with serum immune complex levels. Neutral proteolytic activity in the cellular fraction of the cerebrospinal fluid was also found to be elevated in acute multiple sclerosis, as monitored by digestion of myelin basic protein.
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Effect of angiotensin-converting enzyme inhibition on Na+/H(+)-exchange and Ca(2+)-efflux in human erythrocytes.
The effect of the angiotensin-converting enzyme inhibitor, captopril, on Na+/H(+)-exchange activity and on Ca(2+)-ATPase mediated Ca(2+)-efflux was investigated in red blood cell membranes of patients with essential hypertension. The erythrocyte Na+/H(+)-exchange rate was measured as the difference in H(+)-efflux rate when measured in the presence or absence of Na+. The erythrocyte Ca(2+)-transport mediated by Ca(2+)-ATPase was assayed as the erythrocyte Ca(2+)-efflux rate. Our data show that captopril, in vitro and in vivo, inhibits the Ca(2+)-ATPase mediated Ca(2+)-efflux rate in human erythrocytes, while in vivo it stimulates the erythrocytes Na+/H(+)-exchange rate.
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import XCTest
@testable import PineappleLib
class testTests: XCTestCase {
override func setUp() {
super.setUp()
// Put setup code here. This method is called before the invocation of each test method in the class.
}
override func tearDown() {
// Put teardown code here. This method is called after the invocation of each test method in the class.
super.tearDown()
}
func testExample() {
// This is an example of a functional test case.
// Use XCTAssert and related functions to verify your tests produce the correct results.
}
func testPerformanceExample() {
// This is an example of a performance test case.
self.measure {
// Put the code you want to measure the time of here.
}
}
}
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Email sent
Real Estate Properties on Ogletree Ln, Talladega, AL35160
Get Your FREE Home Disclosure Report
Search Home Disclosure for real estate property records on Ogletree Ln, Talladega, AL 35160. View detailed home and neighborhood info - including home values, crime rates, school ratings, environmental hazards and more - for any property in Talladega County, AL. Begin your property search by selecting an address below.
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Miley Cyrus Reveals How Liam Hemsworth Made Her Swoon By Opening A Door
March 25, 2010 6:49 AM PDT
Miley Cyrus continued to open up about her boyfriend – and her “The Last Song” co-star – Australian actor Liam Hemsworth during a new interview on Wednesday.
While taping an appearance on “The Ellen DeGeneres Show” on Wednesday, Miley revealed that she’s been dating the former Aussie soap star for 10 months and that she was so smitten when she first met him, she told the director of the film to cast the blue-eyed gent.
“I met him and he opened the door for me and I was like, ‘I have been in LA for three years and I don’t think any guy has actually opened the door for me.’” Miley said. “It wasn’t that he wanted the job. That’s just who he is… I was like, ‘Wow! That is super impressive!’ I actually turned to the director and said, ‘He’s got the job. He’s hot and he opened the door. Excellent.’”
The singer, who filmed the movie just after breaking up with model and aspiring country singer Justin Gaston, said she didn’t head to “The Last Song” set last year looking for love.
“We started filming and at one point the chemistry was kind of awkward… I liked him a little bit, he liked me a little bit, but it was awkward,” Miley explained. “Then I was like, ‘OK, just fake it. Please, just pretend you like me,’ and he was like, ‘I don’t have to pretend. I really do like you.’ ‘OK, you’re going to be my boyfriend? Cool.’ I was like, ‘Good.’ And we’ve been together for 10 months now and I’m really happy.”
Miley said that the longer the two are together, the more she has grown to adore Liam.
“I like him more now than I did because we know more about each other,” she said.
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President Trump recently vowed to "do a big number" on Dodd-Frank. Janet Yellen doesn't believe that should happen.
Point by point, the Federal Reserve chief on Tuesday debunked the core arguments used by the White House to push for rolling back the 2010 Wall Street reform law.
Trump has bashed Dodd-Frank as a "disaster" that has choked off bank loans. The president even said "many friends of mine who have nice businesses" can't get loans due to strangling regulations.
Asked during Tuesday's U.S. Senate hearing if there's any truth to claims that banks aren't lending, Yellen said an "extremely low number" of small businesses complained of access to credit as their main problem.
The Fed chief quickly rattled off numbers from a National Federation of Independent Businesses survey showing that just 4% of respondents are unable to get the loans they need.
"We have seen healthy growth in actual lending in the economy," Yellen said, noting that bank commercial and industrial lending has exceeded its 2008 peak.
Republicans have argued that Dodd-Frank has made U.S. banks less competitive against their global peers.
Related: Banks are lending a ton, despite what Trump says
But Yellen said U.S. banks are "quite profitable" and considered "quite strong relative to their counterparts." She credited the fact that American banks quickly built up capital, "as a result of our insistence they do so, following the financial crisis."
"I see well-capitalized banks that are regarded as safe, sound and strong," Yellen said, adding this gives them a "competitive advantage."
Investors seem to see it that way too.
Shares of Goldman Sachs (GS) and JPMorgan Chase (JPM), two of the symbols of American financial might, were on track to close at all-time highs on Tuesday. Goldman hasn't closed at an all-time high since 2007.
The White House has said that Dodd-Frank failed to address the Too Big To Fail problem exposed by the 2008 meltdown.
But Yellen believes the system is in fact safer and more resilient than a decade ago. She cited the banks' doubling of high-quality capital known as Tier 1 capital.
"I believe the financial system is much more resilient than it was," she said.
Senator Elizabeth Warren said that Yellen's responses to questions about financial regulation show that Trump and White House officials are "wrong about every major reason they've given to tear up Dodd-Frank."
Warren argued that Trump and his top economic official Gary Cohn, a former president at Goldman Sachs, want to return to the kind of lax regulation that led to the 2008 meltdown.
"We cannot afford to go down this road again," she said.
Related: Wall Street has a powerful seat at Trump's table
During the campaign, Trump criticized Yellen, saying she should be "ashamed of herself." While Trump now has three vacancies to fill at the Federal Reserve, Yellen doesn't plan to step down before her term expires in February 2018.
To be sure, Yellen didn't argue that Dodd-Frank is perfect as is.
Like others, the Fed chief emphasized the importance of cutting the legal and compliance costs that Dodd-Frank has placed on community banks.
"We're very well aware of the burden they face and are looking for every way we can find to mitigate those burdens," she said.
For instance, Yellen suggested Congress should exempt community banks from the Volcker Rule, which restricts banks from making big bets with their own money.
Yellen also said she agrees with the principles laid out by Trump's recent executive order on how the U.S. financial system should be regulated.
Trump ordered Treasury Secretary Steven Mnuchin to use those broad principles to "consult" with regulators about changes that should be made to existing law.
"I look forward to working with the treasury secretary" and other regulators on this review, Yellen said.
But based on her comments on Tuesday, Yellen and Trump officials are likely to disagree about precisely what to do next.
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(Reuters) - TiVo Corp TIVO.O has started evaluating a wide range of strategic options including the possibility of going private, the set-top box maker said on Tuesday.
The San Jose, California-based company’s shares were up 11 percent at $15.15 in after-hours trading.
“TiVo’s stock price is at a level that the company and its board do not believe reflects the true value of the business,” the company said.
The company is also considering options such as acquisitions and merging with leading players and has engaged LionTree Advisors to assist in the evaluation, it said.
TiVo sells subscriptions directly to customers with its video recorders and also licenses its technology to cable TV operators that rent recorders to subscribers.
The announcement comes two months after sources told The Street that multiple buyers have expressed interest in acquiring Tivo. (bit.ly/2Fcab0Y)
The company has made several executive appointments last year, including that of AT&T Inc T.N executive Enrique Rodriguez as chief executive.
On Tuesday, TiVo also reported an 88 percent rise in fourth-quarter profit to $18.4 million, or 15 cents per share, as it recorded a tax benefit of $26.6 million due to changes in the U.S. tax law.
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Revisiting the behavioral model and access to medical care: does it matter?
The Behavioral Model of Health Services Use was initially developed over 25 years ago. In the interim it has been subject to considerable application, reprobation, and alteration. I review its development and assess its continued relevance.
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Common antigenic determinants on structural proteins p10--12 of PMFV and MPMV type D retroviruses.
PMFV, a type D retrovirus isolated from a malignant human embryo cell line, was compared with Mason-Pfizer monkey virus (MPMV) in a sensitive tannic acid enhanced indirect immunodiffusion test. In addition to the previously shown common antigens, both viruses contain identical group-specific antigenic determinants on their p 10--12 as demonstrated with a specific p 10--12 MPMV test system. Interspecies mammalian type C virus antigens were not detected in highly concentrated PMFV preparations.
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A case of iatrogenic aortic valve leaflet perforation after closure of a ventricular septal defect.
Aortic regurgitation caused by leaflet perforation is most frequently seen in association with infective endocarditis that involves the aortic valve. There have been occasional reports of iatrogenic aortic regurgitation caused by aortic valve injury after cardiac surgery with the use of the transaortic approach or invasive cardiac procedures. Suture-related aortic valve injury can develop during periaortic cardiac surgery, but this has been very rarely reported. Inadvertent injury to an aortic valve leaflet caused by a stitching needle or surgical forceps can produce leaflet perforation with aortic regurgitation. This report describes a case of aortic regurgitation that was caused by iatrogenic aortic valve leaflet perforation, and this occurred in a 22-year-old woman who underwent repair of a ventricular septal defect (VSD) 15 years previously. Transthoracic echocardiography (TTE) showed a defect located at the aortic annulus close to the infundibular septum on a two-dimensional echocardiographic study and we observed an eccentric jet flow into the left ventricle in early diastole on the continuous wave and color flow Doppler studies. A small perforation in the body of the right aortic cusp and mild to moderate aortic regurgitation were confirmed by the use of transesophageal echocardiography (TEE) and ascending aortography.
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Suppose -1/3 + 0*a + x*a**2 - 1/3*a**4 + 0*a**3 = 0. Calculate a.
-1, 1
Let u be (-288)/80 - 4*-1. Solve u*g**2 + 0*g + 6/5*g**3 + 2/5*g**5 + 6/5*g**4 + 0 = 0 for g.
-1, 0
Suppose 0 = 2*t - 1 - 7. Let d(k) be the second derivative of -8*k**2 - 68/3*k**3 - 67/3*k**t + 4*k + 161/10*k**5 + 0 - 49/3*k**7 + 392/15*k**6. Factor d(f).
-2*(f - 1)**2*(7*f + 2)**3
Let v = -147 - -149. Let -7/4*z**3 + 5/4*z**4 + 0 + 0*z + 1/2*z**v = 0. Calculate z.
0, 2/5, 1
Let m(y) be the second derivative of y**7/84 + y**6/15 + 3*y**5/20 + y**4/6 + y**3/12 - 7*y. Determine d so that m(d) = 0.
-1, 0
Let r be 2/3 + (-6)/36. Suppose r*h + 1/4*h**2 + 1/4 = 0. Calculate h.
-1
Let w(z) = 5*z**2 - 13*z - 3. Let k(j) = -11*j**2 + 27*j + 7. Let x(m) = 6*k(m) + 13*w(m). Let q be x(-7). Factor -d**4 - 2*d**q + 4*d + 8*d**3 + 4*d - 12*d**2.
-d*(d - 2)**3
Factor 13/6*y + 2/3*y**2 + 1/2.
(y + 3)*(4*y + 1)/6
Suppose -2*i + 24 = -4*t, 0 = -4*i + i - 6. Let b be (-26)/t + 4/14. Factor -3/2*m**2 + 1/2*m - 1/2*m**b + 0 + 3/2*m**3.
-m*(m - 1)**3/2
Let r(h) be the first derivative of h**8/112 + h**7/70 - h**6/40 - h**5/20 - h**2 + 1. Let p(t) be the second derivative of r(t). Solve p(j) = 0 for j.
-1, 0, 1
Factor -4*g**3 - 5*g**5 + 8*g**3 + g**3.
-5*g**3*(g - 1)*(g + 1)
Factor -24*f**3 - 128*f + 43*f**2 - 505*f**4 - 139*f**2 + 503*f**4.
-2*f*(f + 4)**3
Factor -3/5*u + 0 - 1/5*u**2.
-u*(u + 3)/5
Suppose 0 = -5*w + 4*j + 6, -5*j - 16 = -5*w - 11. Find y, given that 6/5*y**w + 0*y + 0 + 2/5*y**4 + 8/5*y**3 = 0.
-3, -1, 0
Let r(z) = 2*z**3 - 2*z**2 + 4*z + 2. Let l(t) = -2*t**3 + t**2 - 5*t - 3. Let v(s) = 4*l(s) + 6*r(s). Factor v(j).
4*j*(j - 1)**2
Solve 3*z**2 + 3*z**3 + 5*z**3 + 6*z - z**3 - 10*z**3 = 0 for z.
-1, 0, 2
Let f(j) be the first derivative of -2*j**2 + 4 + 2/3*j**3 - 6*j. What is x in f(x) = 0?
-1, 3
Factor -17*o**3 + 9*o**3 + 4 + 12*o + 8*o**2 - 10*o**5 - 12*o**4 + 6*o**5.
-4*(o - 1)*(o + 1)**4
Let h be ((-90)/75)/((-2)/5). Factor -1/3*p - h*p**5 + 2/3*p**3 + 0 - 4*p**4 + 4/3*p**2.
-p*(p + 1)**2*(3*p - 1)**2/3
Suppose -55 = -23*v - 9. Determine b so that 3/4*b + 1/2 - 3/4*b**v - 1/2*b**3 = 0.
-2, -1/2, 1
Let t(g) be the third derivative of 9*g**5/50 + g**4/10 - 14*g**2. Factor t(x).
6*x*(9*x + 2)/5
Let k = -64 + 69. Let s(z) be the second derivative of -1/8*z**3 - 2*z - 5/48*z**4 + 3/80*z**k + 0 + 1/8*z**2 + 1/30*z**6. Determine m, given that s(m) = 0.
-1, 1/4, 1
Let d(x) be the third derivative of -x**7/7560 + x**4/24 + x**2. Let y(i) be the second derivative of d(i). Let y(j) = 0. Calculate j.
0
Let f(q) = 18*q + 38. Let r be f(-2). Suppose 0 - 2/7*w**r + 2/7*w = 0. What is w?
0, 1
Let y = 17 + -21. Let s be 1/5 + y/(-80). Factor 0 + 1/4*j**4 + 0*j**2 + s*j**3 + 0*j.
j**3*(j + 1)/4
Let q(g) = g. Let h be q(-1). Let o = 3 + h. Let 0 - 1/2*d**3 - 1/2*d**4 + 1/2*d + 1/2*d**o = 0. Calculate d.
-1, 0, 1
Let p(y) = 11*y**2 + 31*y + 29. Let w(q) = -5*q**2 - 15*q - 15. Let u(h) = -3*p(h) - 7*w(h). Factor u(j).
2*(j + 3)**2
Factor -2 + 9*q + 8 + 22*q**3 - 6*q**3 - 36*q**2 + 5*q**3.
3*(q - 1)**2*(7*q + 2)
Let w(i) be the third derivative of -i**6/60 + i**5/5 - 3*i**4/4 - 14*i**2. Find f such that w(f) = 0.
0, 3
Let q(l) be the third derivative of -l**5/270 + l**4/36 + 8*l**2. Factor q(f).
-2*f*(f - 3)/9
Let -4/13 - 2/13*k + 2/13*k**2 = 0. What is k?
-1, 2
Suppose -5*y + 2*y - r + 5 = 0, -y = 2*r. Suppose 3*a + 4*j - 20 = a, 0 = -5*a + 2*j + y. Factor -w**3 + w**a + 2*w**3 - 2*w**2.
w**2*(w - 1)
Let d(o) = -o**2 - 28*o - 187. Let b be d(-12). Factor 6*y - 9/5 - b*y**2.
-(5*y - 3)**2/5
Let u(c) = 2*c**3 - 2*c**2 + 5*c - 10. Let x(j) = -2*j**3 + 2*j**2 - 6*j + 12. Let z(o) = 6*u(o) + 5*x(o). What is h in z(h) = 0?
0, 1
Let f be 216/(-162) + (-8)/(-6). Factor -1/2*g**5 + 0*g**2 + f*g**4 - 1/2*g + g**3 + 0.
-g*(g - 1)**2*(g + 1)**2/2
Factor -8*o**5 + o**4 + 5*o**3 - 7*o**5 + 14*o**5 + 3*o**2.
-o**2*(o - 3)*(o + 1)**2
Let w(v) be the second derivative of -2/3*v**3 + 1/8*v**5 - v**2 - 1/84*v**7 - 1/24*v**4 + 0 - v + 1/60*v**6. Factor w(q).
-(q - 2)**2*(q + 1)**3/2
Let o(l) be the first derivative of l**3/3 + l**2/3 - l/3 + 2. Factor o(y).
(y + 1)*(3*y - 1)/3
Factor -12/5 + 12/5*c**2 - 3/5*c**3 + 3/5*c.
-3*(c - 4)*(c - 1)*(c + 1)/5
Let f(m) = -15*m**2 + 15*m - 5. Let l(d) = d**3 - 15*d**2 + 15*d - 5. Let u(c) = -4*f(c) + 5*l(c). Factor u(a).
5*(a - 1)**3
Find u, given that -2/13*u**2 - 2/13*u**4 + 4/13*u**3 + 0 + 0*u = 0.
0, 1
Let h(t) be the first derivative of t**6/3 + 2*t**5/5 - 5*t**4/2 - 2*t**3/3 + 8*t**2 - 8*t - 8. Factor h(w).
2*(w - 1)**3*(w + 2)**2
Let f(k) be the third derivative of k**9/181440 + k**8/30240 + k**7/15120 - k**5/30 + 2*k**2. Let m(a) be the third derivative of f(a). Solve m(v) = 0 for v.
-1, 0
Let s(i) be the second derivative of 1/6*i**4 + 1/60*i**5 + 2/3*i**3 + 1/2*i**2 + 0 - i. Let j(x) be the first derivative of s(x). Find w such that j(w) = 0.
-2
Suppose f + 38 - 9 = 5*n, -3*n = 2*f + 45. Let q be 1 - 1 - 8/f. Solve 0*i + 1/3*i**4 - q*i**3 + 0 + 0*i**2 = 0 for i.
0, 1
Suppose -9*k = -k. Let o(a) be the second derivative of 0*a**2 + 1/147*a**7 + 0*a**4 + k*a**3 + 0*a**5 + 2*a - 2/105*a**6 + 0. Determine z, given that o(z) = 0.
0, 2
Let a = -5 - -7. Find t such that -3 + 3*t**2 - a*t**2 + 2 + t**3 - t = 0.
-1, 1
Let q(c) be the second derivative of -2/15*c**3 + 4*c - 1/30*c**4 + 1/75*c**6 + 0 + 1/25*c**5 + 0*c**2. Solve q(f) = 0 for f.
-2, -1, 0, 1
Let x(i) be the second derivative of i**4/15 - 14*i**3/15 + 24*i**2/5 - 59*i. Factor x(c).
4*(c - 4)*(c - 3)/5
Let y(m) be the third derivative of m**7/1050 + m**6/300 - m**5/100 - m**4/15 - 2*m**3/15 + 6*m**2 + 1. Factor y(c).
(c - 2)*(c + 1)**2*(c + 2)/5
Let g(d) = d**2 + 1. Let r(b) = -3*b**2 + b - 6. Let i be 4/(-18) - 25/9. Let u be -2 - (3 + -1) - i. Let q(f) = u*r(f) - 4*g(f). Factor q(a).
-(a - 1)*(a + 2)
Suppose -19 = -5*b + 6. Let o(p) = -4*p**4 - 4*p**3 + 4*p**2 - p - 5. Let v(s) = s**4 + s**3 - s**2 + 1. Let i(x) = b*v(x) + o(x). Factor i(g).
g*(g - 1)*(g + 1)**2
Let o(q) = -1. Let l(p) = -2*p**2 + 2*p + 1. Let s(u) = 3*u**2 - 2*u - 2. Let x(w) = -4*l(w) - 3*s(w). Let r(y) = -3*o(y) - x(y). Determine k so that r(k) = 0.
-1
Let u be 20/5 - (0 + -1). Suppose -l + 2 = -4*s, u*s = -4*l + 7*l - 6. Factor 2/3*h**3 + 2/3*h**2 + s + 0*h.
2*h**2*(h + 1)/3
Let v(y) be the first derivative of 5 + 0*y - 3*y**3 - 3/2*y**2 + 3*y**4. Solve v(z) = 0.
-1/4, 0, 1
Let x be (9 - 385/45)*1. Solve -x + 8/9*f**2 - 14/9*f = 0 for f.
-1/4, 2
Factor -1/2*o**2 - 1/4 - 1/4*o**5 + 3/4*o - 1/2*o**3 + 3/4*o**4.
-(o - 1)**4*(o + 1)/4
Let y(v) = 64*v**2 - 64. Let i(k) = 7*k**2 - 7. Let l(j) = 28*i(j) - 3*y(j). Factor l(a).
4*(a - 1)*(a + 1)
Let u(j) be the third derivative of 5*j**8/336 - j**7/6 + 7*j**6/24 + 23*j**5/12 - 5*j**4/3 - 40*j**3/3 + 9*j**2. Determine d, given that u(d) = 0.
-1, 1, 4
Factor 14/9*y - 4/3 - 2/9*y**2.
-2*(y - 6)*(y - 1)/9
Let m = -3749/3759 + -9/179. Let p = 236/105 + m. Determine w so that -2/5*w**4 + 0 + p*w**3 + 2/5*w - 6/5*w**2 = 0.
0, 1
Suppose -13 + 9 = -2*n. Find h, given that -2/3*h**n - 2*h - 4/3 = 0.
-2, -1
Let a(x) be the first derivative of -2*x**3/27 + 4*x**2/9 - 58. Suppose a(f) = 0. Calculate f.
0, 4
Let t(w) be the first derivative of 7*w**4 + 8*w**3/3 + 3. Factor t(n).
4*n**2*(7*n + 2)
Let z(m) be the second derivative of m**6/40 - m**5/10 + m**4/8 + m**2 + 2*m. Let l(g) be the first derivative of z(g). Factor l(s).
3*s*(s - 1)**2
Suppose y - 2 + 13 = 0. Let q = y + 14. Determine d, given that 0*d**2 + 0 - 2/5*d**q + 0*d = 0.
0
Let j(s) be the third derivative of s**8/10080 - s**7/1680 + s**6/720 - s**5/720 - s**3/2 + 3*s**2. Let h(o) be the first derivative of j(o). Factor h(f).
f*(f - 1)**3/6
Let t(k) be the first derivative of 6*k**2 - 4*k - 3*k**4 - 6 + 4/3*k**3. Suppose t(j) = 0. Calculate j.
-1, 1/3, 1
Suppose 45 = -5*t + 3*o, -3*t - 32 = -2*t + 4*o. Let c = 1 - t. Factor 2*y - 6*y**3 - c*y**4 - 13*y**2 - 3 - 1 + 12*y**4 - 14*y.
-(y + 1)**2*(y + 2)**2
Factor 52 - 71 + 43 + 18*q + 3*q**2.
3*(q + 2)*(q + 4)
Let r(f) = 10*f**3 + f**2 - 2*f + 1. Let q be r(1). Let -18*x**2 + 36*x - 1 - 13 - q + 3*x**3 = 0. What is x?
2
Let i(y) = 7*y**2 + 13*y + 11. Let g(p) = 11*p**2 + 20*p + 17. Let d(r) = -5*g(r) + 8*i(r). Let d(q) = 0. Calculate q.
-3, -1
Let n(y) be the first derivative of y**6/24 + y**
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Richard Nugent, 2nd Earl of Westmeath
Richard Nugent, 2nd Earl of Westmeath (1621/23 – 25 February 1684) was an Irish nobleman.
Life
He was the grandson of Richard Nugent, 1st Earl of Westmeath and Jenet Plunkett. Nugent's father, Christopher, Lord Delvin, had predeceased the first Earl, meaning that Richard Nugent succeeded to the earldom on his grandfather's death in 1641. His mother was Lady Anne MacDonnell, daughter of Randal MacDonnell, 1st Earl of Antrim and his wife Ellis (or Alice) O'Neill, daughter of Hugh O'Neill, Earl of Tyrone and his fourth wife Catherine Magennis.
Before 1641 he married his kinswoman, Mary Nugent (widow of Christopher Plunkett, who was son of Christopher Plunkett, the 8th Baron of Dunsany), and daughter of Sir Thomas Nugent, 1st Baronet of Moyrath and his wife Alison Barnewall, daughter of Robert Barnewall of Robertstown, County Meath.
While attempting to make his way back to Ireland in December 1641 upon the outbreak of the 1641 Rebellion, Nugent was arrested on suspicion of complicity in the uprising. He subsequently served as a cavalry commander during the Irish Confederate Wars, seeing action at the Battle of Dungan's Hill in August 1647, where he was captured. He later served as General of the Forces of Leinster from 1650-52. During Oliver Cromwell's campaign in Ireland, Clonyn Castle, the main Nugent residence, was burnt: according to one account Lord Westmeath burnt it himself to prevent it falling into his enemies hands. He submitted to the Parliamentary forces in the latter year but was excluded from the Act of Settlement 1652 and transplanted to Connaught. After the Restoration of Charles II, he received a large pension as a reward for his loyalty to the Crown.
Family
Richard and Mary Nugent had the following issue:
Christopher Nugent, Lord Delvin, died before 1680
Lady Anne Nugent, married firstly Lucas Dillon, 6th Viscount Dillon, and secondly Sir William Talbot, 3rd Baronet, and died after 14 Jul 1710
Thomas Nugent, 1st Baron Nugent of Riverston, Lord Chief Justice of Ireland, died 2 Apr 1715, ancestor of the present Earl of Westmeath
Lady Mary Nugent b. 21 Feb 1648, married Henry Barnewall, 2nd Viscount Barnewall of Kingsland, and died 25 Jun 1680
He was succeeded by his grandson, Richard Nugent, 3rd Earl of Westmeath, son of Christopher, Lord Delvin.
External links
http://thepeerage.com/p37091.htm#i370910
Category:17th-century Irish politicians
Category:Irish soldiers in the Irish Confederate Wars
Category:1684 deaths
Category:People from County Westmeath
Category:Year of birth uncertain
Category:Earls of Westmeath
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“Canada deplores in the strongest terms the ongoing violence and destruction in Libya and is appalled by the reported incidents of human rights abuses. We urge all parties to accept an immediate and unconditional cessation of hostilities.
“It is unacceptable that it is the people of Libya who pay the ultimate price in this conflict. They have sacrificed a lot for their freedom and recently elected the House of Representatives as their sole and legitimate representative.
“Canada will continue to work closely with its allies and partners to support Libya’s elected institutions and hold to account those responsible for violations of international law.
“Canada stands with the Libyan people in their struggle to defeat terrorism and violence, restore the rule of law, and build a free, prosperous and democratic society.”
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The Serious Illness Center has three Cores: Administrative, Research Support, and Research Development and Dissemination. The Administrative Core includes the Center Administrators, The Executive Committee, the Scientific Review Panel, and the Board of Scientific Advisors. The Research Support Core includes two units: the Biopsychological Unit and the Biostatistics Unit. The Research Development and Dissemination Core also includes two units: the Research Development and Training Unit and the Dissemination Unit. The Dissemination Unit is proposed as a new entity in this application and its creation will increase our ability to translate our findings into clinical applications in a timely manner. Shared resources in biostatistics and laboratory methods are currently used to support Center fellows. Interdisciplinary research seminars and training programs provide valuable opportunities for interaction and collaboration across disciplines bringing basic scientists, clinicians, and behavioral scientists together to answer research questions. Pilot funds are used to support innovative research related to serious illness Pilot studies that are interdisciplinary, that have a biopsychological approach, and that have potential for peer reviewed funding will be give priority.
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Self-reported smoking in vascular disease: the need for biochemical confirmation.
The relationship between smoking and vascular disease requires reliable information on the smoking status of patients suffering these disorders. As self-reported smoking status is unreliable and therefore misleading, biochemical markers (such as serum thiocyanate) provide a more accurate guide to smoking status. This study compared the self-reported and biochemical marker data (serum thiocyanate) for two different groups: 215 patients with peripheral vascular disease (PVD) and 124 with ischaemic heart disease (IHD). The object of the comparison was to assess if there was any difference between the two groups with regard to denial of smoking. The PVD group had more smokers by either criterion (verbal 34% in PVD, 15% in IHD, P < 0.001: thiocyanate level > 12.5 micrograms ml-1, 47% in PVD, 34% in IHD, P < 0.05). Of those verbally claiming and biochemically assessed as smokers, 55% of those with IHD and 28% of those with PVD denied using cigarettes. Our data point to differences in verbal reporting of smoking between patients with IHD and PVD. This probably reflects the patient's perception of the dangers of smoking and their diseases and may have clinical consequences for the collection of accurate data on the influence of this risk factor on atherosclerosis.
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Prevalence of Candida species and potential risk factors for vulvovaginal candidiasis in Aligarh, India.
The objectives were to determine the frequency of Candida species in women of different age groups as well as to suggest the criteria for the diagnosis of vulvovaginal candidiasis (VVC). A prospective study of vulvovaginal candidiasis was carried out using laboratory diagnosis, with the estimation of vaginal pH and the direct microscopic and biochemical examination of vaginal discharge/secretions. Vaginal cultures for Candida species were collected from 1050 women with vulvovaginal symptoms. Out of 1050 women, 215 (20.47%) were positive for Candida species. Of 215 women, 172 (80%) had pH within the normal range and 167 (77.67%) were showing yeast cells and mycelia on direct microscopic examination. Candida albicans accounted for 46.9% of cases, Candida glabrata 36.7%, Candida parapsilosis 10.2%, Candida tropicalis 2.8%, Candida krusei 1.4%, and Candida kiefer 1.9%. The frequency of culture positivity was related to pregnancy (P<0.001), an increase in parity (P<0.001), and use of oral contraceptives (P<0.001) and antibiotics (P<0.001). The most common signs and symptoms in 215 women with positive cultures were pruritus with or without vaginal discharge and vaginal erythema. Our study suggests that vulvovaginal candidiasis can only be diagnosed by using clinical criteria in correlation with vulvovaginal symptoms and Candida cultures.
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\name{TA}
\alias{TA}
\alias{dropTA}
\alias{moveTA}
\alias{swapTA}
\alias{addTRIX}
\alias{addATR}
\alias{addCMF}
\alias{addDPO}
\alias{addCMO}
\alias{addCLV}
\alias{addEMV}
\alias{addAroon}
\alias{addAroonOsc}
\alias{addVolatility}
\alias{addOBV}
\alias{addChVol}
\alias{addChAD}
\alias{addKST}
\alias{addMFI}
\alias{addTDI}
\alias{addZigZag}
\alias{addLines}
\alias{addPoints}
\alias{addMomentum}
\alias{addEnvelope}
\title{ Add Technical Indicator to Chart }
\description{
Functions to add technical indicators to a chart.
}
\details{
The general mechanism to add technical analysis studies or overlays
to a financial chart created with \code{chartSeries}.
Functionality marked with a \sQuote{*} is via the \pkg{TTR} package.
General TA charting tool functions:
\itemize{
\item{addTA}{add data as custom indicator }
\item{dropTA}{remove technical indicator}
\item{moveTA}{move a technical indicator}
\item{swapTA}{swap two technical indicators}
}
Current technical indicators include:
\itemize{
\item{addADX}{add Welles Wilder's Directional Movement Indicator*}
\item{addATR}{add Average True Range *}
\item{addAroon}{add Aroon Indicator *}
\item{addAroonOsc}{add Aroon Oscillator *}
\item{addBBands:}{add Bollinger Bands *}
\item{addCCI}{add Commodity Channel Index *}
\item{addCMF}{add Chaiken Money Flow *}
\item{addChAD}{add Chaiken Accumulation Distribution Line *}
\item{addChVol}{add Chaiken Volatility *}
\item{addCMO}{add Chande Momentum Oscillator *}
\item{addDEMA}{add Double Exponential Moving Average *}
\item{addDPO}{add Detrended Price Oscillator *}
\item{addEMA}{add Exponential Moving Average *}
\item{addEMV}{add Arm's Ease of Movement *}
\item{addEnvelope}{add Moving Average Envelope}
\item{addEVWMA}{add Exponential Volume Weighted Moving Average *}
\item{addExpiry}{add options or futures expiration lines}
\item{addKST}{add Know Sure Thing *}
\item{addLines}{add line(s)}
\item{addMACD:}{add Moving Average Convergence Divergence *}
\item{addMFI}{add Money Flow Index *}
\item{addMomentum}{add Momentum *}
\item{addOBV}{add On-Balance Volume *}
\item{addPoints}{add point(s) }
\item{addROC:}{add Rate of Change *}
\item{addRSI}{add Relative Strength Indicator *}
\item{addSAR}{add Parabolic SAR *}
\item{addSMA}{add Simple Moving Average *}
\item{addSMI}{add Stochastic Momentum Index *}
\item{addTDI}{add Trend Direction Index *}
\item{addTRIX}{add Triple Smoothed Exponential Oscillator *}
\item{addVo}{add Volume if available}
\item{addVolatility}{add volatility *}
\item{addWMA}{add Weighted Moving Average *}
\item{addWPR}{add Williams Percent R *}
\item{addZigZag}{add Zig Zag *}
\item{addZLEMA}{add ZLEMA *}
}
See the individual functions for specific implementation and argument details. Details
of the underlying TTR implementations can be found in \pkg{TTR}.
The primary changes between the add*** version of an indicator and the
\pkg{TTR} base function is the absense of the data argument in the former.
Notable additions include \code{on}, \code{with.col}.
}
\value{
Called for its side effects, an object to class \code{chobTA}
will be returned invisibly. If called from the \R command line
the method will draw the appropriate indicator on the current chart.
}
\note{
Calling any of the above methods from within a function or script
will generally require them to be wrapped in a \code{plot} call
as they rely on the context of the call to initiate the actual
charting addition.
}
\references{ Josh Ulrich - TTR package }
\author{ Jeffrey A. Ryan }
\keyword{ aplot }
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Morphometric analysis of neurocentral synchondrosis using magnetic resonance imaging in the normal skeletally immature spine.
Morphometric analysis of the neurocentral synchondrosis (NCS) using magnetic resonance imaging in the normal infantile and juvenile patients. To assess the developmental stages of the neurocentral synchondrosis (NCS) by determining the age at which closure of the NCS occurs at specific levels of the spine and to evaluate whether symmetric growth of the NCS occurs during the different developmental stages in normal immature spine. The function and developmental stage of the NCS are controversial because of a lack of agreement on the exact age of closure. To date, most authors believe that the NCS is actively open at a very early age, but the reported age of closure of the NCS varies from age 3 to 16 years. This various closure age of the NCS has resulted in some confusion about the role of the NCS in the normal spinal growth or the development of spinal deformity. A total of 34 normal pediatric patients who had axial magnetic resonance images from first thoracic vertebra to fifth lumbar vertebra were assigned into following 3 groups: infantile group (n = 11), 0 to 3 years of age; juvenile-young group (n = 16), 4 to 7 years of age; and juvenile-old group (n = 7), 8 to 10 years of age. T2-weighted axial magnetic resonance images were used to analyze the NCS developmental stages using a custom 6-point scale (0: actively open with 0% closure; 5: 100% NCS closure). For the stage 0 closure NCS, the width and thickness of the NCS were measured. The NCS was actively open without closure for all less than 4-year-old patients at all levels. The NCS had approximate 75% closure in the lumbar region at 4 years of age while the thoracic NCS remained nearly open. After 5 years of age, the middle-lower thoracic NCS began to close with closure rate less than 25%. At the 10 years of age, the NCS in the lumbar region had near 100% closure, whereas the thoracic NCS demonstrated approximate 50% closure. For the NCS without closure, the average width and thickness were 7.6 x 1.3 mm on the left and 7.9 x 1.3 mm on the right, which was not significantly different. For the NCS with closure, the left and right NCS closure rates were not significantly different. The NCS developmental stage is age- and vertebral level-dependent. The NCS closes from the lumbar and proximal thoracic spine to the middle-distal thoracic spine and times from very early juvenile to the adolescent. The NCS symmetry bilaterally occurred not only during the active open, but also the long closure period. The NCS symmetric open and/or closure may be important to maintain the normal spine alignment.
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Cost-effectiveness analysis in pharmacogenomics.
The existence of finite healthcare budgets drives the need to consider opportunity cost and demonstrate that pharmacogenomic interventions offer added value, in terms of the relative costs and benefits, compared with current practice. This is where the framework of cost-effectiveness analysis is useful. Existing systematic reviews of economic evaluations of genetic technologies have all highlighted the need to improve the quality of the economics evidence base. More recent cost-effectiveness analyses of pharmacogenomics are generally of higher quality. The future will see an increase in the number of published cost-effectiveness analyses. Critical appraisal of these analyses is necessary to ensure the evidence base is sufficiently robust to inform resource allocation decisions at local and national levels.
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Potential mechanisms of CD133 in cancer stem cells.
Cancer stem cells (CSCs) have emerged as an underlying cause of cancer relapse and resistance to treatment. Initially, biomarkers were used to identify and isolate distinct cell populations. Several CSC markers have been identified from many types of tumors, and these markers are also being used for isolation and enrichment of CSCs. Cluster of differentiation CD133 is a well-characterized CSC marker, and it is involved in tumor cell proliferation, metastasis, tumorigenesis, and recurrence, as well as chemo- and radio-resistance. However, the mechanisms involved in CD133-mediated induction of CSC properties have not yet been elucidated. Here, we introduce and summarize the functions of CD133 in CSCs and suggest new mechanisms that may be of note in our approach to developing novel cancer therapies.
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Michael Dudok de Wit and Studio Ghibli 's The Red Turtle received the Best Animated Feature - Independent award at the 44th Annual Annie Awards on Saturday. Production I.G 's Miss Hokusai , Makoto Shinkai 's your name. , Long Way North , and My Life As A Zucchini were also nominated in category.
Shinkai and de Wit were both nominated for Outstanding Achievement, Directing in an Animated Feature Production for their respective films. The directing award went to Zootopia .
The Red Turtle was also nominated for Outstanding Achievement, Animated Effects in an Animated Production. Composer Laurent Perez del Mar was nominated for Outstanding Achievement, Music in an Animated Feature Production, while writer Pascale Ferran was nominated for Outstanding Achievement, Writing in an Animated Feature Production. The animated effects award went to Moana , the music award went to The Little Prince , and the writing award went to Zootopia .
Dreamworks and Netflix 's Voltron: Legendary Defender animated series was nominated in the Best Animated Television/Broadcast Production For Children category for its episode "Return of the Gladiator." The award went to Adventure Time .
No anime were nominated for the main Best Animated Feature category, and Zootopia received the award. Studio Laika's Japanese-themed Kubo and the Two Strings was nominated for the award. The film won Outstanding Achievement awards in the editorial, character animation, and production design categories. It was also nominated for animated effects, character design, directing, storyboarding, voice acting, and writing.
Director Mamoru Oshii ( Patlabor , Ghost in the Shell , Sky Crawlers ) received the Winsor McCay Award for career contributions to the art of animation. He accepted the award in person. Studio Ghibli co-founder Isao Takahata received the award last year.
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<h2>vm_read</h2><hr><p><strong>Function</strong> - Read the specified range of target task's address space.
<h3>SYNOPSIS</h3><pre><strong>kern_return_t vm_read</strong><strong>(vm_task_t</strong><var>target_task</var>,
<strong>vm_address_t</strong><var>address</var>,
<strong>vm_size_t</strong><var>size</var>,
<strong>size</strong><var>data_out</var>,
<strong>target_task</strong><var>data_count</var><strong>);</strong></pre><h4>Overwrite form:</h4><pre><strong>kern_return_t vm_read_overwrite</strong><strong>(vm_task_t</strong><var>target_task</var>,
<strong>vm_address_t</strong><var>address</var>,
<strong>vm_size_t</strong><var>size</var>,
<strong>pointer_t</strong><var>data_in</var>,
<strong>target_task</strong><var>data_count</var><strong>);</strong></pre><h3>PARAMETERS</h3><dl><p><dt><var>target_task</var><dd>
[in task send right]
The port for the task whose memory is to be read.
<p><dt><var>address</var><dd>
[in scalar]
The address at which to start the read.
<p><dt><var>size</var><dd>
[in scalar]
The number of bytes to read.
<p><dt><var>data_out</var><dd>
Out-pointer to dynamic array of bytes returned by the read.
<p><dt><var>data_in</var><dd>
In-pointer to array of bytes that will be overwritten with the data returned by the read.
<p><dt><var>data_count</var><dd>
[in/out scalar]
On input, the maximum size of the buffer; on output, the
size returned (in natural-sized units).
</dl><h3>DESCRIPTION</h3><p>
The <strong>vm_read</strong> and <strong>vm_read_overwrite</strong>
functions read a portion of a task's virtual
memory (they enable tasks to read other tasks' memory).
The <strong>vm_read</strong> function returns the data in a dynamically
allocated array of bytes; the <strong>vm_read_overwrite</strong> function
places the data into a caller-specified buffer (the <var>data_in</var>
parameter).
<h3>NOTES</h3><p>
This interface is machine word length specific because of the virtual address
parameter.
<h3>RETURN VALUES</h3><dl><p><dt><strong>KERN_PROTECTION_FAILURE</strong><dd>
Specified memory is valid, but does not permit reading.
<p><dt><strong>KERN_INVALID_ADDRESS</strong><dd>
The address is illegal or specifies a non-allocated region, or there are
less than <var>size</var> bytes of data following the address, or the region
specified by the <var>data_in</var> parameter cannot be written to.
</dl><h3>RELATED INFORMATION</h3><p>
Functions:
<a href="vm_copy.html"><strong>vm_copy</strong></a>,
<a href="vm_deallocate.html"><strong>vm_deallocate</strong></a>,
<a href="vm_write.html"><strong>vm_write</strong></a>.
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The functional role of tyrosine-200 in human testis angiotensin-converting enzyme.
The active site of angiotensin-converting enzyme (ACE) has been shown by chemical modification to contain a critical tyrosine residue, identified as Tyr-200 in human testis ACE (hTACE). We have expressed a mutant hTACE containing a Tyr-200 to Phe mutation. The mutant exhibits a marked decrease in kcat: 15-fold and 7-fold for the hydrolysis of furanacryloyl-Phe-Gly-Gly and angiotensin I, respectively, whereas its Km increases by only 1.6- and 2.2-fold, respectively. We conclude that Tyr-200 is not required for substrate binding. Instead, the effect on kcat together with a 100-fold decrease in affinity for the ACE inhibitor lisinopril indicates that Tyr-200 may participate in catalysis by stabilizing the transition state complex. Thus, Tyr-200 in hTACE has a role analogous to that of Tyr-198 in carboxypeptidase A.
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Contents Concede mihi, misericors Deus
For ordering a life wisely Varia
Written by St. Thomas Aquinas (1225-1274), who is referred to as the Angelic Doctor. He used to recite this prayer daily before an image of Christ. C ONCEDE mihi, misericors Deus, quae tibi sunt placita, ardenter concupiscere, prudenter investigare, veraciter agnoscere, et perfecte adimplere ad laudem et gloriam Nominis tui. G RANT me, O merciful God, to desire eagerly, to investigate prudently, to acknowledge sincerely, and to fulfill perfectly those things that are pleasing to Thee, for the praise and glory of Thy holy Name. Ordina, Deus meus, statum meum et quod a me requiris, ut faciam, tribue ut sciam; et da exsequi sicut oportet et expedit animae meae. O my God, order my life, and grant that I may know what Thou wilt have me to do; and grant that I may fulfill it as is fitting and profitable to my soul. Da mihi, Domine Deus meus, inter prospera et adversa non deficere, ut in illis non extollar, et in istis non deprimar. De nullo gaudeam vel doleam, nisi quod ducat ad te, vel abducat a te. Nulli placere appetam, vel displicere timeam nisi tibi. Grant me, O Lord my God, the grace that I may not falter either in prosperity or adversity. May I not be unduly lifted up by the one, nor unduly cast down by the other. Let me neither rejoice nor grieve at anything, save what either leads to Thee or leads away from Thee. Let me not desire to please anyone nor fear to displease anyone save only Thee. Vilescant mihi, Domine, omnia transitoria, et cara mihi sint omnia aeterna. Taedeat me gaudii quod est sine te, nec aliud cupiam quod extra te. Delectet me, Domine, labor, qui est pro te; et taediosa sit mihi omnis quies, quae est sine te. Let all things transitory seem vile in my eyes, and all things eternal be dear to me. Let me tire of that joy which is without Thee and to desire nothing that is outside Thee. Let me find joy in the labor that is for Thee; and let all repose that is without Thee be tiresome to me. Da mihi, Deus meus, cor meum ad te dirigere, et in defectione mea cum emendationis proposito constanter dolere. Grant me, my God, the grace to direct my heart towards Thee, and with a firm purpose of amendment, to grieve continually my failures, together with a firm purpose of amendment. Fac me, Domine Deus meus, oboedientem sine contradictione, pauperem sine deiectione, castum sine corruptione, patientem sine murmuratione, humilem sine fictione, hilarem sine dissolutione, maturum sine gravedine, agilem sine levitate, timentem te sine desperatione, veracem sine duplicitate, operantem bona sine praesumptione, proximum corripere sine elatione, ipsum aedificare verbo et exemplo sine simulatione. O Lord my God, make me obedient without complaining, poor without despondency, chaste without stain, patient without grumbling, humble without pretense, cheerful without dissipation, mature without undue heaviness, quick-minded without levity, fearful of Thee without abjectness, truthful without duplicity, devoted to good works without presumption, ready to correct my neighbor without arrogance, and to edify him by word and example without hypocrisy. Da mihi, Domine Deus, cor pervigil, quod nulla abducat a te curiosa cogitatio: da nobile, quod nulla deorsum trahat indigna affectio; da rectum, quod nulla seorsum obliquet sinistra intentio: da firmum, quod nulla frangat tribulatio: da liberum, quod nulla sibi vindicet violenta affectio. Grant me, Lord God, a watchful heart which shall be distracted from Thee by no vain thoughts; give me a generous heart which shall not be drawn downward by any unworthy affection; give me an upright heart which shall not be led astray by any perverse intention; give me a stout heart which shall not be crushed by any hardship; give me a free heart which shall not be enslaved by passion. Largire mihi, Domine Deus meus, intellectum te cognoscentem, diligentiam te quaerentem, sapientiam te invenientem, conversationem tibi placentem, perseverantiam fidenter te expectantem, et fiduciam te finaliter amplectentem. Da tuis poenis hic affligi per paenitentiam, tuis beneficiis in via uti per gratiam, tuis gaudiis in patria perfrui per gloriam: Qui vivis et regnas Deus per omnia saecula saeculorum. Amen. Bestow upon me, O Lord my God, an understanding that knows Thee, diligence in seeking Thee, wisdom in finding Thee, conversation pleasing to Thee, perseverance in faithfully waiting for Thee, and confidence in embracing Thee in the end. Grant that I may be chastised here by penance, that I may make good use of Thy gifts in this life by Thy grace, and that I may partake of Thy joys in the glory of heaven: Who livest and reignest, God, forever and ever. Amen. Latin from the Raccolta #716 (S. C. Ind., Jan. 17, 1888; S. P. Ap., July 31, 1936). Tr. MWM
<- Prev ©copyrighted by Michael Martin Next->
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Bond connection in spy vs spy
- How Ian Fleming played a role in ‘the Wedge’
BEN MACINTYRE
It is only fitting that the tale of spies and sex now unfolding in the US should have its origins in Bond, James Bond.
The David Petraeus scandal is about hubris, adultery and clothing: a general with his regimental trousers down, an FBI agent with his shirt off and a lot of overdressed socialites who might have stepped out of Desperate Housewives. It touches on national security, privacy and marital morality.
But at a deeper level, it reflects the ancient, ingrained and highly damaging rivalry between the CIA and FBI, the agencies responsible for foreign and domestic intelligence-gathering, combatants in a turf battle stretching back 70 years.
The FBI has in effect toppled the head of the CIA, reviving antagonism between the two agencies and raising a slew of disquieting questions.
Inside the Washington beltway, the longstanding rift between the two agencies is known as “the Wedge”. And the thin end of that wedge was none other than Ian Fleming, who created Bond.
On May 25, 1941, Commander Fleming and his boss, Admiral John Godfrey, the director of naval intelligence, travelled to Washington on a secret mission to encourage the creation of a central American agency for the collection of intelligence. Roosevelt followed British advice and placed Colonel William “Wild Bill” Donovan in command of the new department that would evolve into the CIA. (In gratitude, Donovan presented Fleming with a .38 Colt revolver inscribed “For Special Services”.)
The agency was vigorously opposed by J. Edgar Hoover, America’s secret- keeper-in-chief, who believed that his well-established FBI should expand its domestic operations to international dimensions.
Hoover lost that battle and the wedge was in place, splitting America’s spy-catching operations permanently and at times disastrously.
The false distinction between foreign and domestic counter- intelligence is a recipe for conflict. Spies and terrorists do not respect borders. Does a plot hatched abroad but aimed at the homeland properly lie with an internal security service or an external intelligence agency? Richard Helms, a former director of the CIA, once described the division of US intelligence as “cutting a man in half”.
A similar competitiveness existed (and continues) between MI5 and MI6, but never with the intensity, venom and ill-effects of the CIA-FBI divide, a tension exacerbated by jealously guarded stereotypes: the Feds as beer-drinking, down-home sleuths from the University of Life, while the freewheeling CIA types went to Ivy League schools and plotted foreign coups over dry martinis.
CIA agents mocked the FBI as “Foreign Born Irish”. Under Richard Nixon, Hoover felt powerful enough to break off contact with the CIA: “Let them do their own work,” he said -- the recipe for intelligence failure.
Similar missions and competition for resources forge mutual suspicion; rivalry begets pettiness and failure; an organisation watching its back will tend to miss what is in front of it.
In his book Wedge: How the Secret War between the FBI and CIA has Endangered National Security, Mark Riebling describes how a series of calamities was rooted in intelligence failures that can be traced back to this judgement-sapping, self-defeating institutionalised in-fighting.
From Pearl Harbor to the Bay of Pigs, Watergate and Iran-Contra, US intelligence was fatally hampered by lack of co-operation. The Kennedy assassination might have been avoided had the CIA told the FBI that Lee Harvey Oswald had met the KGB shortly before the killing.
The problem was thrown into tragically stark relief by 9/11. The CIA was accused of failing to notify the FBI about two suspects tracked in Malaysia who later took part in the attack. The FBI and CIA blamed each other, usually by anonymous leaks to the media. Every subsequent inquiry pointed to chronic blockages in the system.
Testifying to the investigating commission, former attorney- general John Ashcroft described the “wall” between the FBI and the CIA. “Government erected this wall,” he said. “Government buttressed this wall. And before September 11, government was blinded by this wall.”
George W. Bush was candid: “In terms of whether or not the FBI and the CIA were communicating properly, I think it is clear that they weren’t. And now we’ve addressed that issue.”
And so he did. In the months after 9/11, CIA officers were installed in each of the 56 main FBI field offices. The FBI was deployed to Afghanistan and Guantanamo. Senior FBI officials sit in on CIA meetings, and vice versa, sharing more information than ever before. The world is safer as a result.
This is what the Petraeus scandal threatens to unravel, amid suspicions that an FBI investigation, leaked to Congress but kept secret from the President, has destroyed the reputation of the man he appointed to lead the CIA.
Barack Obama has said carefully that he is “withholding judgement” on how the FBI investigation came about, but he cannot withhold it for long without doing serious damage to a vital link within the US government.
The FBI is a domestic law enforcement agency focused on crime; the CIA is an international intelligence agency gathering information to guide political and military decisions; one is concerned with prosecution, the other with prediction and analysis using whatever information is available. There is a natural tension between the two organisations but history clearly shows that the more acute the enmity, the worse the intelligence and the greater the threat.
It would be a disaster if the tangled relationships between the generals and their so-called “social liaisons” imperil a relationship of far more importance -- that between the FBI and the CIA.
The scandal has already deprived America of a fine intelligence leader. If it is allowed to drive a new wedge between the CIA and the FBI, then America, and the world, will be a more dangerous place.
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Q:
Python extracting sentence containing 2 words with conditions of window size
I have the same problem that was discussed in this link
Python extracting sentence containing 2 words
but the difference is that i need to extract only sentences that containe the two words in a defined size windows search . for exemple:
sentences = [ 'There was peace and happiness','hello every one',' How to Find Inner Peace ,love and Happiness ','Inner peace is closely related to happiness']
search_words= ['peace','happiness']
windows_size = 3 #search only the three words after the 1est word 'peace'
#output must be :
output= ['There was peace and happiness',' How to Find Inner Peace love and Happiness ']
A:
Here is a crude solution.
def search(sentences, keyword1, keyword2, window=3):
res = []
for sentence in sentences:
words = sentence.lower().split(" ")
if keyword1 in words and keyword2 in words:
keyword1_idx = words.index(keyword1)
keyword2_idx = words.index(keyword2)
if keyword2_idx - keyword1_idx <= window:
res.append(sentence)
return res
Given a sentences list and two keywords, keyword1 and keyword2, we iterate through the sentences list one by one. We split the sentence into words, assuming that the words are separated by a single space. Then, after performing a cursory check of whether or not both keywords are present in the words list, we find the index of each keyword in words to make sure that the indices are at most window apart, i.e. the words are close together within window words. We append only the sentences that satisfy this condition to the res list, and return that result.
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Q:
Error setting fullscreen property of cv2 window
I'm trying to make a window created with opencv2 fullscreen. I've been through other solutions posted here and elsewhere and always end up with an error.
First I'm making the namedWindow with:
cv2.namedWindow("Target", cv2.cv.CV_WINDOW_NORMAL)
then:
cv2.setWindowProperty("Target", cv2.WND_PROP_FULLSCREEN, cv2.cv.CV_WINDOW_FULLSCREEN)
gives me the error:
AttributeError: 'module' object has no attribute 'WND_PROP_FULLSCREEN'
I've tried using:
cv2.CV_WND_PROP_FULLSCREEN
instead, as per the docs, with same error.
AttributeError: 'module' object has no attribute 'CV_WND_PROP_FULLSCREEN'
Does anyone know what I'm doing wrong!?
If it's something that's impossible- can anyone offer another suggestion for how to draw a cv2 image to a fullscreen window (with no GUI/toolbars showing)? Frankly I'd be happy with anything as long as it's not too processor intensive.
A:
I ended up using pygame's windows and fullscreen mode and skipping openCV entirely.
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RENTBERRY: A New American Dream
You are young and ambitious. You are well educated and have a decent job. But you can’t afford to buy a house? Neither can your friends and millions of more people. Three in four millennials prefer to pay for experiences over buying homes and consumer
goods.
Homeownership among those 35 and younger has dropped from 43.6% to 35.9% in the last ten years, according to the Mortgage Professional America.
It used to be a part of the American dream: to buy a house when one started a family. Unfortunately, it no longer is. More and more people aged 25 – 34 choose to rent accommodation. Some of them have to because of tighter credit standard, while others
prefer to rent because now people marry and have children later than their parents and grandparents did.
Millennials are more mobile than their parents, and they want freedom when a new job opportunity or a new adventure on the different side of the state or across the country calls. Besides, millennials saw what their parents went through during the financial
crisis of 2008 and do not want their property to be foreclosed.
Renting does have advantages, but they come at a price. Rents are climbing, maintenance and repair costs are growing. It takes more and more time to find a proper accommodation.
Is there a chance that soon it will change? No, the rental market will not change, especially the market for less expensive apartments. There are more renters now than in the last 30 years. But there is some good news for you. The American dream has not
vanished, it has just gone digital. Knowledge of the digital world, social media and some basic knowledge of new technologies is all you need to get a competitive advantage. Have you heard of new services that based on blockchain and used on decentralized platforms? If you have, there is a solution for you, it is called Rentberry.
Rentberry startup is based in San Francisco, which means that its team knows something about expensive rent and competitive market. Rentberry is an online platform that helps landlords and prospective renters find each other without involving agents and
middlemen. It also provides an auctioning platform where potential tenants make bids competing with each other.
Rentberry is user-friendly, and you’ll be able to submit all necessary information, negotiate the terms and e-sign the contract online. Rentberry will help you to stay connected with your landlord, pay rent to submit maintenance requests and hire -party
service providers (e.g., handymen and plumbers).
In the future, the company plan to decentralize and fully automate those tasks using blockchain technology powered by its BERRY token. All payments on the platform will be executed in BERRY tokens.
The sale of BERRY tokens starts on December 5 and ends on 28th February. Rentberry will offer to investor Tokens (BERRY) at the exchange rate is 1 ETH = 2,500 BERRY. The minimum purchase amount is 25,000 BERRY (10 ETH).
There will also be bonuses for big purchases, but they will be discussed individually with potential buyers.
The proceeds from the sale of BERRY tokens will be allocated to IT development (30%), to marketing and sales (20%), to acquisitions and partnerships (15%), to international expansion (12.5%), to administrative and operational activity (10%), to development
fund (5%), to legal expenses (5%) and to Bug Bounty program (2.5%).
Rentberry was established in 2015. At present, it is available in about 5000 cities across the US. It has over 224, 000 listed properties and has processed more than 4, 000 applications. Rentberry’s services are transparent and accessible to use both
for tenants and landlords. By comparison with other companies, Rentberry’s staff is small. But 23 professionals who make its team have 150 years of combined experience and 20 years of combined blockchain experience.
Rentberry is a booming business. It has already received business offers from Australia, New Zealand, the UK, Cyprus and Canada to franchise or establish a partnership. It raised $4 million in two seed rounds. Among those who believe in Rentberry’s prospects
are investors from a dozen countries, including the principal of Carlyle Group, 808 Ventures, Beechwood, Ventures, and Zing Capital.By the company’s estimates, in 2018 it will expand in Canada and several Asian and European countries.
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Ps Vita Theme Wallpapers
Tutorial
Ubisoft has decided to make an experiment, and Child of Light ps vita is their first, successful creature. The French developers showed not only knowledge of the basics of the JRPG genre, but also the ability to reshape and merge them into a bewitching and artistically beautiful product.Child of Light is one of the most attractive, beautiful and atmospheric games I have played in recent years. The fairytale script is good enough to travel you back to your childhood, filling you with nostalgia, the art direction can leave you speechless, as well as the amazing soundtrack. If you are willing to ignore the low difficult level, you will enjoy one of the most honest and full of soul games ever. However, if challenge is what you seek, then it is better to look somewhere else.
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The very rapid growth in data traffic, especially in wide-area technology, requires an increase in the transmission capacity of present and future transmission systems. To that end, optical transmission systems are operated with wavelength-division multiplexing (WDM), in which optical WDM signals are transmitted in individual channels, or WDM channels. This technology now constitutes the preferred solution for implementing the required transmission-capacity increases.
For the error-free transmission of WDM signals, it is necessary for the reception unit of the optical transmission system to have channel levels, or WDM channel levels, with a constant value, so that as the WDM channel number increases, especially when a plurality of WDM signals are being transmitted, the total power to be transmitted in the optical fiber increases. Raising the total power in the optical fiber, however, requires optical amplifier arrangements that have high output powers. Besides the high output power, it is necessary, especially for an optical amplifier arrangement, to have a flat gain spectrum over a wide wavelength range. Inline amplifier arrangements, in particular, require low-noise production of the necessary amplification power and compensation for the dynamic gain tilt, with the aid of which it is possible to compensate for different path attenuations.
It is further necessary for such optical inline amplifier arrangements to have an intermediate pick-off for inserting dispersion compensation units or optical filters to branch off or insert optical WDM signals, or WDM channels.
To produce such optical amplifiers, or amplifier arrangements, that have high output powers, essentially three approaches are to date known, or have been proposed. One of the approaches is based on the conventional single-mode technique. The requisite high pump powers of the optical amplifier are provided by coupling together the output signal from a plurality of pump laser diodes having single-mode fiber outputs, the pump wavelengths being in the wavelength range around 1480 nm. Polarization couplers and band-separating filters, or wavelength-selective multiplexers, are used as the coupling elements in this case. The pump power generated in this way is injected into the active fiber, for example an erbium-doped optical fiber, via a wavelength-selective multiplexer. See Y. Tasiro et al. xe2x80x9c1.5 W Erbium Doped Fiber Amplifier Pumped by the Wavelength Division-Multiplexed 1480 nm Laser Diodes with Fiber Bragg Gratingxe2x80x9d, Technical Digest of the Conference on Optical Amplifiers and their Applications (1998), WC2-1, pages 213 to 215.
A further approach involves generating the high pump power with the aid of a Raman pump laser. See G. R. Jacobotic-Weselka et al.: xe2x80x9cA 5.5-W Single-Stage-Single-Pumped Erbium-Doped Fiber Amplifier at 1550 nmxe2x80x9d, Technical Digest of the Conference on Optical Amplifiers and their Applications (1997), PD3, pages 1-4. In this case, individual semiconductor laser diodes or linear diode arrays in the wavelength window around 900 nm, with the aid of which high output powers can be generated cost-effectively, are used as primary radiation sources. Their output signal is not injected into a single-mode fiber, but rather fed in free-beam fashion or via a multimode fiber into the inner cladding of a special active optical fiber having a double cladding. The inner cladding guides the pump radiation in multimode fashion, and therefore permits simple and efficient injection of the pump radiation. The core of the active optical fiber is doped with dopant ions. These absorb the pump radiation and emit at longer wavelengths, typically around 1060 or 1100 nm, so that optical signals in this wavelength range experience amplification. In this case, laser oscillations at the emission wavelengths are generated with the aid of a resonator. Since the active fiber guides the emission radiation in a single-mode fashion, it can be processed further in single-mode fiber technology. Raman cascade lasers are used for converting the pump radiation into the wavelength ranges needed for pumping the optical amplifier arrangement.
The described multimode technique can be used for directly pumping the active optical fiber of an optical amplifier. In such an embodiment, the active fiber of the optical amplifier itself has an inner cladding, which guides the pump radiation in multimode fashion and permits simple injection of the pump radiation. Besides the dopant ions needed for the amplification process, there are further ions in the core. Their purpose is to absorb the pump radiation and forward it to the amplifier ions by non-radiative transfer processes.
An aspect common to the described embodiments of optical amplifiers with high output power is that they have to date been suitable essentially for the construction of complete booster amplifiers. Such booster amplifiers have total input powers around 0 dBm and a total output power of from approximately 27 dBm to over 33 dBm.
A method, and an amplifier arrangement, for stepwise upgrading of the output power of optical amplifiers is furthermore known, in which an amplifier arrangement, produced in conventional single-mode technology and having non-equipped pump inputs, as well as additional external pump sources are provided. In this approach, the stepwise upgradeable optical amplifier arrangement internally has all the components needed for normal operation, i.e. a long active fiber, pump-WDM couplers etc., although further external pump lasers or pump sources may be connected to the existing pump inputs for increasing the output power of the amplifier arrangement. In the case of low channel numbers, or few WDM signals to be transmitted, the requisite output power is generated by the optical amplifier arrangement without connecting in additional external pump sources. A rise in the output power of the optical amplifier arrangement, needed for example to double the WDM channel number, is possible by injecting externally generated pump radiation, or pump signals, into the active fiber via the pump inputs, or via the outwardly routed input branches of the pump-WDM coupler that is already present internally.
When optical transmission systems, or optical transmission paths, are first commissioned, it is customary not to utilize the full channel number, or WDM channel number, i.e. only a few optical WDM signals, or WDM channels are initially transmitted via the optical transmission path. It should therefore be possible for optical amplifier arrangements to be modularly upgradeable in terms of their output power, and hence permit a stepwise increase in the optical WDM channel number. If the channel number, or the number of optical WDM signals, is still low when the optical transmission path is first operated, then cost-effective optical amplifier arrangements can be used. When the demand for transmission capacity increases, i.e. the WDM channel number increases, it is necessary for the optical amplifier arrangement to be uprated cost-effectively in stages, in order to deliver the output powers respectively needed for the higher channel number.
An advantage of the invention is to provide a cascadable optical amplifier arrangement which permits a stepwise increase of the output power of a base amplifier arrangement that is constructed modularly and in single-mode technology.
In an embodiment, a cascadable optical amplifier arrangement is provided having a modular base amplifier arrangement (BVA) that is constructed in single-mode technology and has at least one amplifier stage (VS1 to VS4), and having a high-power amplifier stage (HVS1) that can be connected to the at least one amplifier stage (VS4) of the base amplifier arrangement (BVA) and has its own active fiber (AF) and at least one pump signal source (PSQ1, PSQ2).
An advantage of the cascadable optical amplifier arrangement according to the invention is that a base amplifier arrangement, which is constructed modularly and in single-mode technology and has at least one amplifier stage, is provided with at least one high-power amplifier stage that can be connected to the at least one amplifier stage of the base amplifier arrangement and has its own active fiber as well as at least one pump signal source. The cascadable optical amplifier arrangement according to the invention, for power upgrading with at least one additional high-power amplifier stage, has the particular advantage over the known design with external pump sources that upgrading can be carried out in a plurality of stages, so that the currently and most cost-effectively implementable amplifier technology available can be used to produce a further high-power amplifier stage. By virtue of this, it is possible to use technologies for high output power that were not yet available when the base amplifier was commissioned. The base amplifier arrangement has the output power needed when the optical transmission path is constructed, as well as the amplifier components needed to produce this, which permits very cost-effective technical implementation of the base amplifier arrangement. For example, a network customer does not need to pay for the additional output power of the cascadable optical amplifier arrangement until a subsequent upgrade with the high-power amplifier stages according to the invention.
The cascadable optical amplifier arrangement according to the invention further makes it possible to retrofit optical transmission systems which were not originally intended for upgrading in terms of optical output power, or whose optical amplifiers have no facility for increasing the output power.
Advantageously, at least one further high-power amplifier stage (HVS2) can be connected to the high-power amplifier stage connected to the base amplifier arrangement. If such high-power amplifier stages are cascaded according to the invention, it is possible to increase the output power of the optical amplifier arrangement stepwise. The serially connected high-power amplifier stages have a comparatively low gain, which leads to a relatively simple technical structure. Because of said low gain, optical isolators need be used in the respective high-power amplifier stages only in exceptional cases, in particular if the existing base amplifier arrangement already has an optical isolator at its output.
Further, it is particularly advantageous if the high-power amplifier stages each have their own amplification control and/or power control, which may be produced both optoelectronically and purely optically. With the aid of the amplification control and/or power control, the serially connected, or cascaded, high-power amplifier stages can be matched to the requirements of the respective application site within the optical transmission network.
It is particularly advantageous if a filter serially connected upstream of the active fiber of the high-power amplifier stages is provided in order to level the gain spectrum of the optical signal to be amplified. The additional optical filter units needed for flattening the gain spectrum can be produced simply and cost-effectively, since they do not need to meet any special technical requirements. A flat gain spectrum of the high-power stage according to the invention can additionally be achieved by optimizing the amplifier properties, or the active fiber, of the high-power amplifier stages.
Additional features and advantages of the present invention are described in, and will be apparent from, the following Detailed Description of the Invention and the figures.
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+ Boston's Jarome Iginla had a big day Saturday. The classy veteran reached the 30-goal level for the 12th time in his career and tied Guy Lafleur for 24th on the career goal-scoring list with No. 560. It was a good day for the Bruins, who clinched the Atlantic Division title. On Sunday they extended their points streak to 15-0-1 and finished the month of March 15-1-1.
+Montreal Canadiens prospect Tim Bozon, who was placed in a medically induced coma while being treated for meningitis, was released from a Saskatoon hospital last week. Bozon, the 20-year-old son of former NHL player Philippe Bozon, still faces rehabilitation before he can play again. Best wishes to him.
+ New York Islanders owner Charles Wang confirmed he has been listening to offers to buy the franchise. That can only be good news for fans of a once-proud club that has been run into the ground by poor management … as long as the next prospective owner isn't named John Spano.
- Colorado scoring leader Matt Duchene will be out about four weeks — including the first round of the playoffs — because of a left knee injury he suffered when he ran into teammate Jamie McGinn early in the Avalanche's playoff-clinching 3-2 victory over San Jose on Saturday. Last Tuesday, Washington defenseman Jack Hillen sustained an upper-body injury when he ran into Alexander Ovechkin. Hillen missed the Capitals' last two games.
- Sports hernia surgery ended a season that Ottawa winger Bobby Ryan probably would like to forget. He had nine goals and 19 points in his first 17 games with the Senators after being traded by the Ducks last summer. His play declined after the injury and he was left off the U.S. Olympic team. He finished with 23 goals, 48 points in 70 games.
Indiana Gov. Mike Pence asked lawmakers Tuesday to send him a clarification of the state's new religious-freedom law later this week, while Arkansas legislators passed a similar measure, despite criticism that it is a thinly disguised attempt to permit discrimination against gays.
Two cross-dressing men who were fired upon by National Security Agency police when they disobeyed orders at a heavily guarded gate had just stolen a car from a man who had picked them up and checked into a motel, police said Tuesday.
You don't have to look far these days to find stories about the rising costs of prescription drugs. By one count, drug spending jumped 13 percent last year, the highest annual increase in more than a decade. And health insurers have spent the better part of the past year warning anyone who'll...
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US president Donald Trump will postpone his State of the Union address until the partial government shutdown ends.
Following a high-stakes game of dare and double-dare with speaker Nancy Pelosi, Mr Trump conceded that “no venue that can compete with the history, tradition and importance of the House Chamber” and that he was not looking for an alternate option.
Tensions between Donald Trump and Nancy Pelosi intensified on Wednesday as the House speaker refused authorisation for the US president to deliver the annual State of the Union address next week in Congress.
In the latest tit-for-tat between the two leaders, Mr Trump wrote to Ms Pelosi on Wednesday stating that he intended to deliver the annual speech on January 29th as planned, despite her having raised security concerns in a letter last week calling for him to postpone the speech.
For more infographics see Statista.com
The president said he had been contacted by the secret service and the department of homeland security who explained “there would be absolutely no problem regarding security for the event”.
“Therefore I will be honoring your invitation, and fulfilling my Constitutional duty, to deliver important information to the people and Congress of the United States of America regarding the State of our Union,” the president wrote.
“It would be so very sad for our Country if the State of the Union were not delivered on time, on schedule, and very importantly, on location!”
But an hour later, Ms Pelosi responded, informing the president that the House of Representatives would not consider a concurrent resolution authorising the address until the government was reopened.
“Again I look forward to welcoming you to the House on a mutually agreeable date for this address when government has reopened,” she wrote.
Donald #Trump has written to House Speaker #NancyPelosi stating that he intends to deliver the #SOTU speech next Tuesday in Congress, overriding her security concerns...#shutdown pic.twitter.com/UiAkZgpMtv — Suzanne Lynch (@suzannelynch1) January 23, 2019
This afternoon, I sent @realDonaldTrump a letter informing him that the House will not consider a concurrent resolution authorizing the President’s State of the Union address in the House Chamber until government has opened. https://t.co/r1oad0xEAh pic.twitter.com/kGEbayx95u — Nancy Pelosi (@SpeakerPelosi) January 23, 2019
Speaking moments after the letter was released, Mr Trump said: “I’m not surprised. It’s really a shame with what’s happening with the Democrats. They’ve become radicalised.”
He continued: “This will go on for a while. Ultimately the American people will have their way because they don’t want to see crime.”
The State of the Union address is a centrepiece of the presidential calendar, an opportunity for the president to set out his policy priorities to a joint session of the Houses of Congress and the nation.
The White House was said to be considering a venue outside the US Capitol for the address next Tuesday.
But it is now unclear if and when the address will go ahead. The US House and Senate must by law pass a concurrent resolution to authorise it.
Last week Mr Trump cancelled a planned congressional trip to Afghanistan by Ms Pelosi and a congressional delegation just minutes before they were due to leave Washington.
The latest twist in the increasingly acrimonious relationship unfolded as the government shutdown entered its 33rd day.
Competing Bills
Senate majority leader Mitch McConnell is preparing to put two competing Bills to the Senate floor on Thursday in a bid to end the government shutdown.
However, it is unclear if either Bill will reach the 60-vote threshold needed to pass the 100-member chamber.
One Bill is based on Mr Trump’s proposal outlined at the weekend which includes an offer to extend protection for Dreamers – young people who were brought to the US as children – and other categories of immigrants.
Nancy Pelosi, Speaker of the House, has denied Trump permission to give his State-of-the-Union speech at Congress during the shutdown. Photograph: Kevin Lamarque/Reuters
The other, a Democrat-devised Bill, is a proposal that would fund the government until February 8th but does not include the $5.7 billion in border wall funding demanded by the president.
Hundreds of federal workers are expected to again miss their paycheques next Friday, two weeks after they missed their first paycheque of the new year.
‘Threats from Trump’
Meanwhile, Mr Trump’s former lawyer Michael Cohen indefinitely postponed his appearance before the House oversight committee, which had been scheduled for February 7th, because of threats against his family, his lawyer said.
Lanny Davis, the attorney representing Mr Trump’s long-time lawyer, said that his client had received “ongoing threats against his family from Trump” and Mr Trump’s lawyer Rudy Giuliani.
“This is a time where Mr Cohen had to put his family and their safety first.”
Asked about the comments, Mr Trump replied:
“I would say he’s been threatened by the truth ... He doesn’t want to tell the truth for me or other of his clients.”
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1. Introduction {#sec1}
===============
Overactive bladder (OAB) syndrome covers several symptoms: urinary urgency, which is the cornerstone symptom \[[@B1]\], usually associated with urinary frequency and nocturia, and with or without urgency urinary incontinence (UUI). The term of OAB applies if there is no proven infection or other obvious pathology \[[@B2], [@B3]\]. OAB is correlated with reduced health-related quality of life (HRQoL) and affects patients with different profiles. Patients with OAB may be children, premenopausal and postmenopausal women, men with benign prostate hypertrophy (BPH), or frail elderly patients. Their symptoms are known to be bothersome and treatable \[[@B4]\]. Patients have different needs and also specific expectations, which are sometimes challenging for the physician in charge, but must be set right. Gynecologists often care for women with urinary symptoms of urgency and frequency, but they may not always be recognized as OAB.
We report three main clinical pictures of OAB: a male patient presenting with lower urinary tract symptoms (LUTS), including urgency; a young woman with comorbidities; and an elderly woman with mixed urinary incontinence, with the aim of highlighting the specific features of these real-life cases, discussing the most appropriate management, and assessing how fesoterodine treatment may meet these patients\' expectations.
Fesoterodine possesses four key pharmacological properties \[[@B5]--[@B8]\]. Firstly, it is immediately and completely metabolized into its active form, the 5-hydroxymethyl tolterodine (5-HMT) by ubiquitous plasma esterases. Thus, its activation is not affected by genetic variability in hepatic enzymes \[[@B5]\]. This may explain the dose-response relationship observed clinically. Secondly, fesoterodine has a very low risk of crossing the blood brain barrier, and has no significant effect on cognitive function, which has been confirmed in clinical trials \[[@B6]\]. Thirdly, it possesses a well-balanced affinity ratio on detrusor M2 and M3 receptors, which explains its further actions on contraction and on relaxation, increasing the bladder capacity \[[@B9]\]. Finally, the 7--9-hour half-life of fesoterodine allows a single daily dose to be taken, avoiding the risk of accumulation of the active ingredient \[[@B10]\].
As mentioned in the product specifications (Toviaz® SPCs) \[[@B11]\], two doses, 4 and 8 mg, are available. The recommended starting dose is 4 mg once daily. Fesoterodine 8 mg has proven its superiority compared to 4 mg in reducing UUI episodes in a head-to-head comparison in OAB patients; the 8 mg dose was also more effective in controlling frequency and nocturia \[[@B12]\].
2. First Case: Mr. LUTS and OAB {#sec2}
===============================
The first case reported the history of "Mr. LUTS and OAB", who is 72 years of age, has had LUTS for five years, has a weak and variable stream, complains of painful micturition if he waits too long between micturitions, and also of frequency, urgency, and nocturia. There were no signs of bladder outlet obstruction or other identified etiology. He has been diagnosed with hypertension and type 2 diabetes. He takes several medications: a beta-blocker, a selective AT1-subtype angiotensin II receptor antagonist, a calcium antagonist, and an oral biguanide antihyperglycemic agent. His International Prostate Symptom Score (IPSS) is 15, and the QoL question was scored as 4. Digital rectal examination revealed a slight increase in the size of the prostate, with an estimated volume of 50--60 ml. He has been offered transurethral resection of the prostate (TURP) but declined. The European Association of Urology (EAU) guidelines \[[@B13]\] state that prostate-specific antigen (PSA) should be tested if a diagnosis of prostate cancer will change management or if it assists in the treatment and/or decision-making process; his PSA was within the normal range, at 2.6 ng/ml. His IPSS value for storage symptoms was higher than his score for voiding symptoms. He was prescribed an alpha blocker (tamsulosin) as a first-line treatment. Six weeks later, at the next visit, he reported a slight improvement in frequency and stream, with no change in nocturia or urgency, and some ongoing rare UUI episodes and dysuria. His QoL score, which was linked to urgency, was not improved. Uroflowmetry was performed and showed a Qmax of 11 ml/s, a voiding volume (VV) of 140 ml, and a postvoiding residual (PVR) of 45 ml. Transrectal ultrasound confirmed an enlarged prostate (68 ml).
"Mr. LUTS and OAB" was offered a combination treatment with tamsulosin and dutasteride to try to control his symptoms and reduce the weight of his prostate. Three months later, he came back for a follow-up visit and declared he had stopped dutasteride after two weeks because of erectile dysfunction. He was still complaining of nocturia and urgency. The control of PVR indicated a residue lower than 100 ml.
A frequency-volume chart (FVC) that collects the time and volume of micturitions can be a useful tool to obtain a real assessment of nocturia. Van Haarst et al. \[[@B14]\] analyzed two different ways of measuring nocturia and showed that in 50% of the patients the IPSS nocturia score was found to be higher than nocturia calculated from the FVC, indicating that the IPSS overestimates nocturia in most patients.
The analysis of the patient\'s voiding diary revealed a night-time urine output of 800--950 ml and a 24-hour urine output of 2,600--2,900 ml. Therefore, an adjustment of fluid intake was advised. The clinical picture led to the prescription of a combination treatment of tamsulosin 0.4 mg plus fesoterodine 4 mg, and the patient agreed to enroll in a telephone and ambulatory clinic follow-up program.
One point of concern was nocturia. Weiss et al. \[[@B15]\] showed that significant improvements were observed with fesoterodine compared to placebo in the number of micturition-related nocturnal urgency episodes (--1.28 versus --1.07,*p* = 0.003), in the number of nocturnal micturitions per 24 hours (--1.02 versus --0.85,*p* = 0.011), and in the nocturnal frequency urgency sum, defined as the sum of Urinary Sensation Scale (USS) ratings recorded for all nocturnal micturitions (--4.01 versus --3.42,*p* \< 0.003). Additionally, HRQoL measures were improved with fesoterodine.
A further six weeks later, the patient came back with no change in nocturia, a slight improvement in urgency, and complained of minimal dry mouth. Consequently, the fesoterodine dose was increased to 8 mg per day and the patient was kept in the follow-up study. His IPSS improved to 10 and his QoL score on the IPSS improved to 2.
2.1. Discussion {#sec2.1}
---------------
This interesting case highlights important clinical aspects leading to useful conclusions:The patient related his symptoms to BPH and was at the beginning treated as a BPH patient only. However, as storage symptoms and nocturia were also present, the patient needed a customized (nonfixed) combination.In clinical studies, fesoterodine has demonstrated efficacy on nocturia unrelated to nocturnal polyuria; nocturnal polyuria should be managed by reducing the urine output at night.Urgency was actually the major cause of the QoL deterioration but was treated last.An appropriate follow-up program kept the patient on treatment.
3. Second Case: Mrs. Young OAB {#sec3}
==============================
The second case refers to a 48-year-old woman, a busy manager with a history of depression and sleep disturbance. She has had three terminations of pregnancy and one delivery by cesarean section. She smokes approximately ten cigarettes per day and has high cholesterol serum levels. She takes several medications: a selective serotonin reuptake inhibitor (escitalopram), two benzodiazepines (delorazepam and clonazepam), and a statin. She reports a four-year history of urinary symptoms: daily UUI episodes, mild stress urinary incontinence (SUI), and two episodes of nocturia per night. She wears pads every day. The urology consultation revealed some degree of pelvic pain, especially during vaginal examination. The urine dipstick was negative and there was no PVR. No specific causes of the symptoms such as urine tract infection were identified. The patient also complained of mild dyspareunia and occasional constipation. The urine culture turned out to be sterile, with no blood in urine, and the pelvic ultrasound scan and urine cytology were also negative. The cystoscopy, which was performed as a result of the presence of storage symptoms and to rule out a bladder tumor in this current smoker, was normal.
In OAB patients, it is of utmost importance to consider all comorbidities. Anxiety and depression may play a role, feeding a vicious circle. Moreover, medications to treat neurological or psychiatric disorders can influence OAB and be responsible for side effects \[[@B16], [@B17]\]. Gastrointestinal disorders are frequently associated with OAB, such as constipation in this case, but patients rarely raise the topic. An overlap exists between irritable bowel syndrome and OAB \[[@B18]\].
The patient was prescribed a *β*3 agonist, pelvic floor muscle training (PFMT) and bladder retraining. Four months later, she noticed some degree of improvement, but had stopped the treatment as she felt that she had no time for PFMT. She was not compliant with the bladder drill either, and soon stopped the *β*3 agonist because she did not sense any real improvement. She also felt that she did not have the time to complete a bladder diary. She was prescribed fesoterodine 8 mg for three months. In parallel, her general practitioner asked for vaginal and urethral culture swabs, which were negative. After three months, her urinary urgency improved, but she said that the few remaining episodes of urgency were "killing her life" and that she did not want to be on pills for her whole life. Therefore, she refused to continue the treatment and requested an "easy fix". Her reaction highlights the need for careful consideration of the consequences of incontinence in terms of QoL. A publication from Vaughan et al. \[[@B19]\] reported that OAB and incontinence synergize to reduce QoL, especially in the domains of sleep, elimination, usual activities, discomfort, distress, vitality, and sexual activity.
Consistent efficacy on urgency symptoms with a significant decrease in UUI and urgency episodes has been reported with fesoterodine at doses of 4 and 8 mg compared to placebo ([Table 1](#tab1){ref-type="table"}) \[[@B12], [@B22], [@B20], [@B21]\]; however, some patients may react differently. Patient satisfaction is an important driver of treatment success \[[@B23]\]. Patient expectations should be considered carefully in the context of OAB management. The achievement of patients\' goals was measured in the Study Assessing FlexIble-dose fesoterodiNe in Adults (SAFINA study) \[[@B24]\], a 12-week multicenter open label study with 331 OAB adults, using the Self-Assessment Goal Achievement (SAGA) questionnaire. Fesoterodine treatment resulted in 81.3% of patients declaring that their goals were "somewhat achieved/achieved" or that the result "exceeded/greatly exceeded their expectation".
Our case patient had very specific expectations; she refused to have an implant (neuromodulation), saying "I\'m not going to be an android!" She accepted botox injections, and so a first set of injections was performed under local anesthesia. She found the injections "a little painful" and "a big annoyance", but at the one-month follow-up visit after botox injection she reported no more UUI episodes and an improvement in frequency and the number of urgency episodes, as well as in QoL. Even though she stated that she did not like the idea of being a patient for the rest of her life, she accepted subsequent injections.
3.1. Discussion {#sec3.1}
---------------
The clinical points that can be learned from this case are as follows:All OAB cases are different, and a thorough evaluation is mandatory to adequately address each case.It is important to assess other aspects, such as functional and psychological disorders that may influence symptoms, and to consider nonneurogenic OAB as a multifactorial disease.The major goal of initial therapy is to meet the patient\'s expectations regarding the reason for their visit, to improve their satisfaction, and their QoL.Due to fesoterodine\'s characteristics and flexible dosage, improvement of symptoms and achievement of the patients\' goal are usually high with this medication.When patients have specific requirements, all options should be discussed and the patient\'s agreement obtained.A customized approach is a crucial factor for treatment success.OAB management should be personalized; beware of a simplistic application of a standardized treatment algorithm.
4. Third Case: Mrs. Mixed Urinary Incontinence {#sec4}
==============================================
The third case concerns a 73-year-old retired schoolteacher who had had two children, born by forceps-assisted vaginal delivery. She complained of ten episodes of daytime frequency with small frequent voids, a constant desire to void, and three nocturia episodes per night, resulting in poor sleep. More recently, things had deteriorated with a sudden urge to void and occasional urinary incontinence with exercise. She changed pads three times a day and complained of superficial dyspareunia. She took medication (doxazosin and furosemide) for well-controlled hypertension but did not take hormone replacement therapy. She complained of mild constipation and had had three lower urinary tract infections (UTIs) in the last 12 months. During her consultation with her general practitioner, she emphasized that urgency was the most important problem for her. She was referred to a gynecologist, who confirmed a subjective diagnosis of mixed urinary incontinence with superficial dyspareunia and vulval discomfort. The physical examination detected a marked urogenital atrophy, a grade I uterine prolapse, a grade I cystocele, and grade I rectocele. She was initially prescribed vaginal estrogen, as supported by evidence from Cochrane reviews \[[@B25], [@B26]\], and referral to a urogynecologist was considered.
The urogynecologist confirmed the mixed urinary symptoms with urgency and UUI, SUI, recurrent UTIs, and mild constipation. The clinical examination also confirmed urogenital atrophy, demonstrable SUI, and a urogenital prolapse without evidence of neuropathy or specific etiology of the symptoms.
The PVR was found to be 95 ml, urinalysis was negative, and flexible cystoscopy was normal. The patient noticed an improvement of vulval discomfort and dyspareunia with local estrogen therapy. The physician provided lifestyle advice, prescribed PFMT training and oxybutynin 5 mg three times a day, and undertook a medication review. The alpha blocker doxazosin, which may aggravate the symptoms of SUI, was switched to an angiotensin II receptor antagonist, losartan, and furosemide was discontinued. The International Consultation on Incontinence Modular Questionnaire (ICIQ) and a bladder diary were completed. They showed that the patient leaked a moderate amount of urine several times a day, generating moderate bother. Incontinence occurred before she could get to the toilet and was also associated with exercise, coughing, and sneezing. She complained of ten frequency episodes per day, three nocturia episodes with moderate bother, and had a total VV at 2,190 ml. The night volume was 490 ml, with no evidence of nocturnal polyuria. This led to the symptomatic diagnosis of mixed incontinence, which is an important common symptom and is particularly difficult to treat. It has been defined by Haylen et al. \[[@B27]\] as being "the complaint of involuntary loss of urine associated with urgency and also with effort or physical exertion or on sneezing or coughing".
After six weeks, the patient returned and reported that she had taken oxybutynin for six weeks and then stopped due to persistent dry mouth and worsening constipation. She had also performed bladder retraining and PFMT for two weeks and then stopped. She noticed a mild improvement in urgency and UUI, but no change in nocturia, and her SUI was still troublesome. The urogynecologist suggested switching to fesoterodine 4 mg once a day and explained that she could increase the dose if required \[[@B22], [@B28], [@B29]\].
What are the reasons to consider using fesoterodine, here as a second line therapy, in a 73-year-old elderly woman? Fesoterodine is the only OAB medication classified as B (Beneficial) by the Fit fOR The Aged (FORTA) classification \[[@B30]\]. LUTS-FORTA results from a systematic review of drugs treating LUTS in the elderly in order to evaluate their efficacy, safety, and tolerability. Darifenacin, mirabegron, oxybutynin ER, solifenacin, tolterodine, and trospium were classified as FORTA C (Questionable; Caution), while oxybutynin IR and propiverine were classified as FORTA D (Avoid; Do not). This classification suggests that fesoterodine may have better efficacy and tolerability in elderly patients.
Moreover, the combination of fesoterodine with vaginal estrogen may act synergistically. Chugtai et al. \[[@B31]\] have studied the results of combining fesoterodine with vaginal estrogen and showed that this combination improved OAB symptoms and sexual function in postmenopausal women, and importantly, produced greater improvement in QoL.
At 12 weeks the urogynecologist reviewed her clinical picture. Fesoterodine 4 mg was well tolerated and there was no need for a dose increase, her urgency and urgency incontinence symptoms were improved, and the number of voids per day had decreased to seven, but remained at two per night. Her symptoms of urogenital atrophy and dyspareunia had improved and there was no reported UTI. Constipation improved with dietary advice and possibly by stopping oxybutynin as well. While her urogenital prolapse remained asymptomatic, her SUI remained troublesome. With regard to adverse effects, the fact that patients cope better with dry mouth with fesoterodine compared to oxybutynin may lie in the selectivity of 5-HMT for the bladder over the salivary glands. An*in vitro* and*in vivo* study, using radioligand binding, has demonstrated that oxybutynin has a threefold higher affinity for the salivary glands over the bladder \[[@B32]\] and therefore has a greater propensity to induce dry mouth.
At the 24-week visit, the urogynecologist\'s review was in favor of continuing with fesoterodine 4 mg since the patient\'s urgency and UUI were much improved. However, there was still some SUI limiting her physical activity. The urodynamic investigations performed while the patient was on fesoterodine showed a cystometric capacity of 500 ml, no evidence of detrusor overactivity, moderate urodynamic SUI, and no evidence of voiding dysfunction. Hence, as suggested by the 6th International Consultation on Incontinence \[[@B33]\], the urogynecologist discussed the possibility of surgery for SUI and continued the current pharmacological treatment.
4.1. Discussion {#sec4.1}
---------------
This clinical case illustrates some important take-home messages:It is important to treat the most bothersome symptoms first.In case of mixed urinary symptoms, there is a need to look for a possible urogenital prolapse; this particular patient had demonstrable genital prolapse but did not find it troublesome.Fesoterodine is effective and well tolerated in the elderly, and is rated B (beneficial) by the LUTS-FORTA classification.Vaginal estrogen is effective in the management of urogenital atrophy and recurrent UTIs.There is evidence to support the combined use of estrogen and antimuscarinics.Nocturia secondary to nocturnal polyuria does not respond to antimuscarinic medication and should benefit from lifestyle advice and consideration of desmopressin treatment.
Finally, the conclusions were that, firstly, the cornerstone symptom of OAB, urgency, is very common, and that many OAB patients may not be diagnosed appropriately. Secondly, when urgency is diagnosed, the use of antimuscarinics should be considered. Thirdly, fesoterodine has the benefit of flexible dosing and can be titrated accordingly; therefore, before switching to another medication, increasing the dose for further efficacy should be considered. Finally, the patient should not be considered as a passive subject but as a real actor in the treatment process; involving her/him in the treatment plan increases her/his adherence and the improvement of treatment outcomes.
Participation in the satellite symposium "They Have a Common Urgent Problem" at the International Continence Society 47^th^ Annual Meeting in September 2017 in Florence, Italy, and writing assistance were sponsored by Pierre Fabre (Castres, France).
Conflicts of Interest
=====================
A. Tubaro has received support as a consultant/lecturer or for scientific studies from Allergan, Astellas, Bayer, Boston Scientific, Pfizer, Pierre Fabre, and Takeda Millennium. J. Heesakkers has received support as an investigator from Astellas, Boston Scientific, Ipsen, Bluewind, and UrogynBV; and as consultant from Astellas, Allergan, Bluewind, UrogynBV, Ixaltis, and Pierre Fabre. J.N. Cornu has received support as a consultant from Allergan, Astellas, Boston Scientific, Bouchara-Recordati, Coloplast, Cousin Biotech, Medtronic, Mundipharma, Pfizer, Pierre Fabre Medicament, SAP, and Takeda; and as investigator from Astellas, GT Urological, Medtronic, Ipsen, and Coloplast. D. Robinson has received support for research from Astellas, Pfizer, Allergan, and Ferring; for consultancy from Astellas, Pfizer, Ferring, Allergan, and Ixaltis; and as speaker from Astellas, Pfizer, Contura, Ferring, and Pierre Fabre.
######
Percentage decrease in urinary urgency incontinence and urgency episodes according to different studies with fesoterodine at 4 and 8 mg.
**UUI decrease** **(**%**) 4/8 mg** **Urgency episode decrease (**%**) 4/8 mg**
-------------------------- ------------------------------------- ---------------------------------------------
Chapple, 2007 \[[@B22]\] 80.8/87.5 17.6/19.1
Chapple, 2014 \[[@B12]\] 74.4/79.5 37.8/45.5
Kaplan, 2010 \[[@B23]\] 75.0 43.3
Dubeau, 2014 \[[@B24]\] 69.3 41.5
[^1]: Academic Editor: Mohammad H. Ather
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