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While President Donald Trump and first lady Melania Trump won't be attending Saturday’s highly-anticipated royal wedding in the United Kingdom, the White House confirms they will be sending a wedding gift instead.
Interested in Royal Family?
Add Royal Family as an interest to stay up to date on the latest Royal Family news, video, and analysis from ABC News.
“President Donald Trump and First Lady Melania Trump will be making a contribution to one of the seven charities the royal couple has designated in lieu of gifts,” White House deputy press secretary Lindsay Walters said in a statement.
The White House did not disclose the amount of the donation.
American actress Meghan Markle and Prince Harry requested wedding guests and well-wishers make donations to charities they care about including the Children’s HIV Association, Crisis – a charity for homeless people, Scotty’s Little Soldiers – a charity for bereaved Armed Forces children, Street Games, the Myna Mahila Foundation, which works to empower women in Mumbai’s urban slums, and the Wilderness Foundation UK, which introduces vulnerable youth to the outdoors.
REX/Shutterstock
Meghan Markle and Prince Harry arrive for the ANZAC Day service at Westminster Abbey, London, UK, April 25, 2018.
The Trump’s donation will follow in the tradition of American presidents who have sent gifts to Royal couples – in 1947, President Harry Truman sent Prince Philip and Princess Elizabeth a glass bowl and President Ronald Reagan and First Lady Nancy Reagan also sent a glass bowl to Prince Charles and Diana for their wedding in 1981.
Wallace McNamee/Corbis via Getty Images
Prince Charles escorts Princess Diana to the balcony at Buckingham Palace just after their wedding.
The Trumps won’t be alone in their exclusion from one of the most exclusive events in the world this Saturday – Prince Harry requested that no political officials be invited to the wedding.
“It has been decided that an official list of political leaders - both UK and international - is not required for Prince Harry’s and Ms. Markle’s wedding. Her Majesty's Government was consulted on this decision which was taken by the Royal Household,” said Kensington Palace in a statement.
Even the Obamas – who have had a friendly relationship with Prince Harry – will not be attending the wedding, although a spokesman noted: “The couples look forward to seeing each other soon.”
Chris Jackson/Getty Images for the Invictus Games Foundation
Former President Barack Obama and Prince Harry share a joke as they watch wheelchair basketball on day 7 of the Invictus Games 2017 on September 29, 2017 in Toronto, Canada.
Trump told Piers Morgan he wasn’t aware of any invitation to the Royal Wedding but said of the couple in an interview, “I want them to be happy. I really want them to be happy.”
The White House has not said whether or not the president and first lady plan to watch the wedding ceremony, which will be broadcast live in the early morning hours Saturday. |
On #WorldWaterDay, check out our deep dive article on options for treating and re-using wastewater:
Our wastewater infrastructure is largely invisible and little understood. Most of us never question the wisdom of polluting pristine drinking water, losing valuable nitrogen and irreplaceable phosphorus in the process, just so we can make our poop disappear. Our own waste is a classic SEP—Somebody Else’s Problem. The result? “Aging pipes and inadequate capacity lead .... to the discharge of an estimated 900 billion gallons of untreated sewage each year,” warns the American Society of Civil Engineers in its report Failure to Act . “Water infrastructure in the United States is clearly aging, and investment is not able to keep up with the need.” (For more, see “Failing Water Infrastructure Drains Economy, Report Warns,” EBN Feb. 2012.) Though most rest areas still use one-way water cycling (onsite septic fields or long-distance connections with centralized systems), a few thr... |
Combined presence of multiple gastrointestinal stromal tumors along with duodenal submucosal somatostatinoma in a patient with neurofibromatosis type 1.
Neurofibromatosis type-1 (NF-1) is an autosomal dominant disorder, with increased risk of developing benign and malignant tumors of the gastrointestinal tract (GIT). However, the synchronous presence of multiple GIT stromal tumors and duodenal submucosal somatostatinoma, like in this 50-year-old female NF-1 patient, is very rare. She presented with hematemesis, malena, along with multiple neurofibromas all over the body. Thorough radiological and peroperative work-up revealed multiple ulcerated submucosal and serosal nodules in the proximal small intestine. Histological work-up revealed diagnosis of a duodenal submucosal somatostatinoma with multifocal serosal gastrointestinal stromal tumors. This case is being reported to highlight the rare coincidence of multiple GIT tumors in an NF-1 patient. |
var bar = require('./event-bar.js');
bar();
|
Rotation-invariant and controllable space-variant optical correlation.
We propose a method for designing a correlator for achieving rotation-invariant and controllable space-variant optical correlation. The design concept is based on a combination of fractional correlation and circular-harmonic decomposition of the reference object. The suggested method is described and analyzed in detail. Numerical simulations show that this new correlator might provide potential applications in practice. |
Ruptured popliteal artery aneurysm. An insidious complication.
To evaluate the incidence and clinical presentation of ruptured popliteal aneurysms. The records of 89 consecutive patients, all males, seen between 1958 and 1995 with 124 arteriosclerotic popliteal aneurysms were reviewed retrospectively. Most aneurysms were symptomatic (69/124; 55.6%). In six cases (6/124; 4.8%) a rupture was present. There was a wide range in primary diagnosis varying from deep venous thrombosis to peroneal nerve palsy. In all cases primary reconstructive surgery was performed. No primary or secondary amputations were necessary. Surgical outcome was good in four cases. In the remaining cases one patient suffered from a permanent peroneal nerve palsy and one from non-disabling claudication. Review of the literature showed a rupture incidence of 2.5% (range 0-16%) and amputation rates as high as 100%. An acute rupture of a popliteal aneurysm is rare. Although the clinical presentation can be non-specific, this possibility must be especially taken into account when dealing with older male patients presenting with signs and symptoms of generalised atherosclerosis and non-specific pain in the popliteal region. |
[Eurhytmy by Steiner].
According to Rudolph Steiner the aim of medical anthroposophy must be to revalue the soul-body intercourse as a function of recovery. To this purpose, along with mineral, organic and vegetable medicinal principles, of a particular importance is eurhythmy: a series of static postures and dancing shapes which encourage the course of selfeuring innate with man. |
The full weight of the law must be brought against the ‘antifascists’ who brutally beat a woman, reportedly for wearing a bracelet bearing the national flag, Spain’s interior minister said on Tuesday.
The attack, which left the 20-year-old woman with head injuries and a broken tooth, has been celebrated by the far left on social media. Among the seven so-called anti-fascists who have so far been arrested for the vicious assault is Alejandro Espín Sogo, who stood in local elections as a candidate for the United Left party in 2015.
The young woman was beaten by a group of as many as 20 hooded youths on Sunday morning in the city of Murcia, La Gaceta reported.
Speaking to the national newspaper, the 20-year-old recalled receiving a shower of insults from the far left mob when she exited the cocktail bar she was visiting with friends to have a smoke. Once outside, a woman chanted “Pig, pig, we’re going to kill you”, and shoved her.
The female aggressor then fled the scene while the men from the group moved in to beat their victim. After being knocked to the ground by the left wing extremists, the 20-year-old said she tried to protect herself, but that the mob then “started kicking [her] in the head”.
Aquí unos machotes antifascista dándole una paliza a una chica de 20 años…Donde estan las feministas??? https://t.co/2te67I6oNr — walewska (@waleska0328) January 23, 2017
The woman denied being a member of any political groups and said she was targeted for wearing jewellery which featured “no political symbols, it was just a bracelet of the flag of Spain”.
“They beat me for that, they want to ban us from carrying our flag”, she said on Monday.
Murcia’s police force said the attack was typical of far left gangs, telling La Gazeta: “Attacking as a group and in greater numbers [than their victims] is characteristic of how self-proclaimed antifascists behave.”
Police don’t have a definitive motive for the attack so far, but said it’s feasible that the sight of a Spanish flag caused the leftist mob to launch the brutal attack. If confirmed to have been the reason for the assault, the source noted it would constitute a hate crime.
In a press conference on Tuesday, Spain’s interior minister Juan Ignacio Zoido described the attack in Murcia as “evil”, and called for the “full weight of the law” to be brought against the perpetrators of the “horrible act”.
The attack on Sunday comes amidst a rise in violence and extremism from the radical left in recent years, and Spain’s Interior Ministry has warned for some time that left wing extremism poses a threat to the nation. |
During a discussion with the Rotary Club of Flint, Mich. on Friday, University president Mary Sue Coleman verbalized the obvious — bringing Rich Rodriguez to Michigan was a mistake.
In three seasons as the head coach of the Michigan football team, Rodriguez's program was marred with a series of NCAA violations and a dismal 15-22 record.
But when Coleman and then-Athletic Director Bill Martin conducted a national search to replace Lloyd Carr in late 2007, they were intrigued by Rodriguez, then at West Virginia. He was gaining rapid popularity as the pioneer of the spread offense.
“He was a hot, young coach with a different approach,” Coleman said in Flint, according to MLive.com.
Rodriguez’s offense was a big factor in Michigan’s decision to hire him, Coleman said, since Carr’s pro-style, old-fashioned offense had been widely criticized as his tenure came to a close.
“We thought, ‘OK, well let's go hire the guy who invented the spread offense,’ ” Coleman said.
So they did. And three years later he was out the door.
He was replaced by Brady Hoke, who was an assistant coach at Michigan under Carr. In 2011, Hoke's first season as head coach, he took the Wolverines to a 10-2 regular-season record and a Sugar Bowl victory.
"(Hoke) has more of the kind of Midwestern ethos," Coleman said.
After working as a college football analyst for CBS Sports during the 2011 season, Rodriguez accepted the head coaching position at Arizona, where he will begin his first season this fall. According to MLive.com, Coleman said she was “very happy” to hear of Rodriguez’s new job and she wishes him luck.
Rodriguez himself admitted a year ago that leaving West Virginia for Michigan was a mistake.
“I think it's easy to go back now and say, ‘Gee, made a mistake,’ ” Rodriguez told CBSSports.com last April. “And you can say that now because of hindsight.
“But at the time, some of the things I was looking to do and the opportunity that was there, you kind of make the move.”
In seven years at West Virginia, Rodriguez compiled a 60-26 record and made two BCS bowl appearances. But in three seasons at Michigan, Rodriguez never beat rivals Michigan State and Ohio State and compiled a 6-18 Big Ten record.
“Hindsight is always easier to look back and say, ‘It was a mistake,’ ” Rodriguez said. “Because we did have a good thing going at West Virginia, and we really enjoyed it. As you look back at it, wasn't the best move. Easy to say now.”
CLARIFICATION: A previous version of this article included a quote from former Michigan center David Molk that was deleted as it was deemed as misleading. |
Ein Fehler in der Programmierschnittstelle von Instagram hat Ende der Woche zur Veröffentlichung der Kontaktdaten von Millionen Nutzern der Bilderplattform geführt, berichten US-Medien. Betroffen sind laut Instagram nicht nur Prominente.
Entdeckt wurde der Bug, als das Profil von Selena Gomez gehackt wurde. Laut Instagram könnten Hacker auf die persönlichen Daten wie Telefonnummern und E-Mail-Adressen zugreifen.
Etliche solcher Daten kursierten bereits im Internet, berichtet The Verge. So hätten Hacker eine Datenbank eingerichtet, die man für 10 US-Dollar nach Kontaktinformationen von 1000 betroffenen User durchsuchen könne. Die Liste beinhalte die 50 meist-gefolgten Instagram-Nutzer. Die müssen nun wohl ihre Handynummern und Email-Adressen wechseln.
Möglicherweise 6 Millionen Instagrammer betroffen
Zunächst hatte Instagram berichtet, dass nur sogenannte High-Profile-Nutzer betroffen seien; dabei handelt es sich um Prominente, deren Daten besonders geschützt sind. Wenig später räumte die Facebook-Tochter ein, dass auch gewöhnliche Profile betroffen sind.
Über die genaue Anzahl der Hacks konnte Instagram laut The Verge noch nichts sagen: Man glaube, dass wenige Prozent aller Accounts betroffen seien. Angesichts von 700 Millionen Accounts, allein 15 Millionen Instagrammer in Deutschland, sind "wenige Prozent" allerdings gar nicht mal so wenig. Hacker gaben laut The Verge an, Informationen zu 6 Millionen Nutzern gesammelt zu haben.
Laut Instagram sind E-Mail-Adressen und Telefonnummern gehackt, aber keine Passwörter. Allerdings ist es mit ein wenig Social Engeneering möglich, anhand dieser Daten sehr viel mehr über die jeweiligen Nutzer herauszufinden und auch den Account selbst zu hacken.
Dass es nicht einmal eines Fehlers im Code braucht, um an persönliche Daten von Instagram-Nutzern zu gelangen, zeigte ein Experiment der Gizmodo-Journalistin Ashley Feinberg: Sie hatte innerhalb von vier Stunden die Inkognito-Profile des Ex-FBI-Chefs James Comey bei Twitter und Instagram enttarnt. (uk) |
Oud-staatssecretaris Fred Teeven heeft zich teruggetrokken voor een benoeming bij de Raad van State. Dat bevestigen Haagse bronnen na berichtgeving door het AD.
In februari ontstond politieke ophef over de mogelijke voordracht van Teeven. Die was omstreden gezien zijn bemoeienis met de 'Teevendeal' en de nasleep ervan. De bonnetjesaffaire leidde uiteindelijk tot zijn aftreden als staatssecretaris. Hij zat daarna nog twee jaar in de Tweede Kamer, maar stond bij de laatste verkiezingen niet op de lijst.
Minister Plasterk van Binnenlandse Zaken zei in februari dat hij niet van plan was om op korte termijn een voordracht aan het kabinet voor te leggen. Twee maanden later zei Teeven tegen RTL Nieuws dat hij nog in beeld was voor de functie.
Groene-interview
Volgens het AD waren de uitspraken die Teeven half mei deed in De Groene Amsterdammer voor zijn partij doorslaggevend om hem aan te raden de eer aan zichzelf te houden. Teeven zei dat hij zich had toegelegd op bezuinigingen op de advocatuur, nadat hij minimumstraffen er niet doorheen had gekregen bij de PvdA.
"Het is een andere manier om hetzelfde effect te bereiken", zei de VVD'er. "Als je aan een advocaat niet al te veel tijd geeft om aan een verdachte te besteden, dan wordt het ook niet zo veel, die verdediging."
Teevens uitspraken veroorzaakten grote verontwaardiging in de juridische wereld. |
Effects of a 10-week functional training programme on pain, mood state, depression, and sleep in healthy older adults.
The purpose of this study was to analyze the effects of a 10-week functional training (FT) programme on pain, mood state, sleep, and depression in healthy older adults. A group of 38 older adults (32 women, 6 men) voluntarily participated in this study. Participants were randomly assigned to either the experimental group (n = 20; age: 75.44 ± 5.31 years) or the control group (n = 18: age: 76.35 ± 6.45 years). Pain, depression, mood state, and sleep were tested before and after FT. After the treatment, the experimental group experienced significant improvements in geriatric depression (P < 0.001), vigour (P = 0.044), fatigue (P = 0.002), depression (P = 0.005), and hypersomnia (P = 0.014), whereas the control group experienced significant deterioration in geriatric depression (P = 0.003), pain (P < 0.001), vigour (P = 0.011), depression (P = 0.009), and hypersomnia (P = 0.018). In addition, the experimental group showed an iceberg profile of mood; the control group did not show this profile. Ten-week FT improved mood state, depression, and sleep in healthy older adults. Therefore, FT exercises may be recommended for the prevention and treatment of insomnia, depression, and alterations in mood state. |
How Sustainable Is PV Solar Power - stonlyb
http://www.lowtechmagazine.com/2015/04/how-sustainable-is-pv-solar-power.html
======
ZeroGravitas
Interesting analysis.
One thing that struck me as odd: why does it matter if the carbon footprint is
front-loaded in the manufacturing? They seem to suggest that you should wait
for the initial installations to get back to 0 net carbon before making more.
Why?
I would have thought the medium term comparison to other power sources that it
is displacing would be the relevant benchmark.
|
Taekwondo at the Summer Universiade
Taekwondo events have been contested at Universiade since 2003 Games in Daegu, South Korea,with one exception in 2013 in Kazan, Russia
Editions
Editions
Events
Medals are awarded in ten different weight classes for both men and women.
Medal table
Last updated after the 2019 Summer Universiade
References
Sports123
Category:Sports at the Summer Universiade
Universiade |
Q:
Can't save or load objects
I am new to Realm and its the first time I am using it. I followed every step from the guide and its inserted in my project just fine. I created a model and a function to insert the object into the realm database.
Somehow I keep getting errors. Here is what I do.
my function
do {
let realm = try Realm()
let proposition = Proposition()
proposition.name = (currentProposition.name)
proposition.energyType = (currentProposition.energyType)
proposition.lifetime = (currentProposition.lifetime)
proposition.saving = (currentProposition.saving)
proposition.investing = (currentProposition.investing)
if let _ = propositionsArray.indexOf(proposition) {
try! realm.write {
realm.delete(proposition)
loadPropositions()
}
} else {
try! realm.write {
realm.add(proposition)
loadPropositions()
}
}
} catch let error as NSError {
print("Add proposition error \(error)")
}
Here is my model
import RealmSwift
import Foundation
class Proposition : Object {
dynamic var name: String = ""
dynamic var energyType: String = ""
dynamic var lifetime = 0
dynamic var saving = 0
dynamic var investing = 0
}
Somehow I keep getting the following error
Can someone tell me what I am doing wrong?
A:
The errors you're seeing indicate that the data model defined by your application does not match the data model of the Realm you're opening. This is usually due to changing your data model. In this case, the errors mention that you've added the lifetime, saving, and investing properties, and changed name and energyType to be non-nullable.
There are two ways to accommodate changes to your data model:
If you're in early development and don't need to support your old data model, you can simply remove the Realm files and start over with empty data.
You can perform a migration to have Realm update the data model of the Realm file. See the Migrations section of the Realm documentation for information about how to perform a migration.
|
Q:
Grep for word and line before match
I have a text log file which contains multiple entries like this:
Processing input.jpg (323 of 500)...
Detecting matches in region 1...
Detecting matches in region 2...
Detecting matches in region 3...
Detecting matches in region 4...
Detecting matches in region (n)...
...
NOT ENOUGH MATCHES - FULL FILE OUTPUT
Processing input1.jpg (324 of 500)...
I want to grep the file to match each instance where the sequence FULL FILE appears and then get the name of the file that generated that result - i.e. find the line starting Processing before each FULL FILE match.
How can I do this with grep or another tool like sed or awk?
So far I am able to match each instance where FULL FILE is found in the log and count them:
cat output.txt | grep "FULL FILE" | wc -l
but I need to get the preceding file name from the log file now for each match.
Any help much appreciated.
A:
Assuming no spaces in file names, awk would be up to it
awk '/^Processing/{file=$2};/FULL FILE OUTPUT$/{print file}' output.txt
|
Q:
Пояснение нюансов работы Yii2
Использую для API HttpBasicAuth.
В yii\filters\auth\HttpBasicAuth есть функция
public function challenge($response)
{
$response->getHeaders()->set('WWW-Authenticate', "Basic realm=\"{$this->realm}\"");
}
По дебагеру отследил, что переменная $response экземпляр класса yii\web\Response.
Т.е. идет вызов функции getHeaders(), но после чего идет новый вызов функции, set() которая относится к классу yii\web\HeaderCollection.
Как это возможно? Ведь по идее, чтобы функция set() должна находится в классе yii\web\Response.
Версии:
Yii: 2.0.14
PHP: 7.2.0
A:
В чем вопрос?
У объекта $response есть приватное свойство $_headers типа HeaderCollection. При вызове getHeaders() возвращается ссылка на это свойство (т.к. объекты всегда передаются в функцию и возвращаются по ссылке, это нюансы работы PHP). Затем у этого объекта вызывается метод set(), который добавляет еще один заголовок в коллекцию. По сути заголовок добавляется в свойство $_headers объекта $response.
Если бы свойство $_headers было публичным, мы бы написали так:
$response->_headers->set('WWW-Authenticate', "Basic realm=\"{$this->realm}\"");
|
UNIX / Linux List Current Logged In Users
ADVERTISEMENTS
w
Tutorial details Difficulty Easy (rss) Root privileges No Requirements w or who command Time N/A
who
users
Examples
How do I print the user names of users currently logged in to the current UNIX / Linux host / server from a command prompt?You need to use any one of the following tool.[a]command – Shows information about the users currently on the machine, and their processes.[b]command – Shows information about users who are currently logged in. [c]command – Shows the login names of the users currently on the system, in sorted order, space separated, on a single line. It reads all information from /var/run/utmp file.
Open a terminal (or login into remote server using ssh command) and type the following commands.
w command
Type the w command:
$ w
Sample outputs:
# w tom
who command
To see info about a user named tom, enter:
who command works on all Unix like operating systems:
# who
Sample outputs:
root pts/0 2013-03-12 15:10 (10.1.3.177)
Pass the -a option to who command:
# who -a
Sample outputs:
system boot 2013-03-02 04:10 run-level 3 2013-03-02 04:10 LOGIN /dev/ttyS1 2013-03-02 04:11 7951 id=v/tt LOGIN tty2 2013-03-02 04:11 7953 id=2 LOGIN tty1 2013-03-02 04:11 7950 id=1 LOGIN tty3 2013-03-02 04:11 7955 id=3 LOGIN tty4 2013-03-02 04:11 7957 id=4 LOGIN tty5 2013-03-02 04:11 7959 id=5 LOGIN tty6 2013-03-02 04:11 7961 id=6 root + pts/0 2013-03-12 15:10 . 7451 (10.1.3.177) pts/1 2013-03-08 12:29 23510 id=ts/1 term=0 exit=0
Other options
You can pass the following options to the who command (taken from the who command man page):
Just open a -a, --all same as -b -d --login -p -r -t -T -u -b, --boot time of last system boot -d, --dead print dead processes -H, --heading print line of column headings -l, --login print system login processes --lookup attempt to canonicalize hostnames via DNS -m only hostname and user associated with stdin -p, --process print active processes spawned by init -q, --count all login names and number of users logged on -r, --runlevel print current runlevel -s, --short print only name, line, and time (default) -t, --time print last system clock change -T, -w, --mesg add user's message status as +, - or ? -u, --users list users logged in --message same as -T --writable same as -T --help display this help and exit --version output version information and exit
users command
Open a terminal or login over the ssh session and enter the following command:
$ users
Sample outputs:
abhi charvi vivek vivek zcafe |
Tokyo’s train perverts shift strategy as Saikyo sinks in significance
On Saturday at around 11:30 a.m., officers arrested Hideaki Shoji, a resident of Yokohama, after he allegedly came up from behind a 21-year-old female college student and shot digital images up her skirt as she stood on a platform at Kuhonbutsu Station in Setagaya Ward.
Located on the relatively small Tokyu Oimachi Line, the station in question is not a major destination within Tokyo’s vast rail network — an indication, according to Nikkan Gendai (Dec. 11), that such purveyors of perversion are changing tactics.
According to police, Shoji, who was charged with violating the Tokyo government’s public nuisance ordinance, had uploaded a total of 1,000 illicit photos of 500 women to Internet voyeur sites since 2011. In March, the suspect submitted images to the site Nozokix.
Prior to the arrest, law enforcement had been monitoring voyeur sites, and confirmed platform locations from the images and victims. On Saturday, investigators had received a tip about a man behaving strangely for several hours on a station platform.
Shoji reportedly admitted to the allegations, saying that he spends between five and six hours on train platforms each Saturday. “In June of 2011, he started shooting peeping photos on escalators and inside book shops,” an investigator is quoted by Nikkan Gendai. “The suspect said that he really got a charge out of reading the comments that followed his posting of the images on the sites.”
Atsushi Tashiro, a journalist specializing in crime, says that the lack of large numbers of commuters makes Kuhonbutsu Station a perfect hunting ground. “Private railways like these offer chances for ‘delta zone’ shots,” says the journalist, referring to how the tapering of a pair of a woman’s underwear resembles the mouth of a river. “On the platforms, you can get good shots of office ladies and college gals sitting on benches.”
Of course, destinations like Yokohama and Shibuya are prime areas. But crackdowns by police have caused voyeurs to linger and wait in less-traveled areas not served by Japan Railways.
“The JR Saikyo Line is legendary,” says Tashiro. “Police always have their eye on that one.”
Tashiro advises women to be leery of express trains on private railways, including those operated by Odakyu, Keikyu, Seibu and Tokyu. The long spans between stations provide supreme opportunities for perverts.
“Recently, the Tokyu lines have been problematic,” says Tashiro, who cites the Dententoshi and Toyoko lines as especially worrisome. “Between Jiyugaoka and Nakameguro stations, there are a lot of girls going to art school who get off at Gakugei Daigaku Station,” he says. “This makes these stations prime spots.”
Then there is Shibuya…
“You’ve got a lot of college girls commuting through to Aoyama Gakuin University,” he says. “There is also a lot of nice-looking OLs working at IT companies nearby. Overall, it is a high-quality destination.”
Nikkan Gendai advises all women to stay alert.
Source: “Saikyo-sen ha mou furui chikan, tosatsu ma ga hisomu abunai supotto,” Nikkan Gendai (Dec. 11, page 9) |
package com.fxb.licensingservice.Entity;
import java.io.Serializable;
/**
* 类功能简述：
* 类功能详述：
*
* @author fanxb
* @date 2018/11/22 19:52
*/
public class Licensing implements Serializable {
private Organization organization;
private boolean isValid;
public Organization getOrganization() {
return organization;
}
public void setOrganization(Organization organization) {
this.organization = organization;
}
public boolean isValid() {
return isValid;
}
public void setValid(boolean valid) {
isValid = valid;
}
}
|
1. Introduction {#s0005}
===============
Dementia with Lewy bodies (DLB) is a common type of dementia after Alzheimer's disease, accounting for approximately 10--15% of cases at autopsy ([@b0200]). DLB is associated with quality of life and significant carer burden. It is frequently underdiagnosed and often misdiagnosed as AD, especially at early stages where both diseases manifest with similar cognitive deficits ([@b0225]). Estimates of sensitivity and specificity for DLB diagnosis using established clinical criteria ([@b0205]) have been quite variable but have a common tendency for relatively high specificity but lower sensitivity ([@b0170]). The fact that DLB patients are sensitive to neuroleptics ([@b0195]), and demonstrate a faster disease progression compared to other dementias ([@b0025]), underpin the necessity to improve diagnostic accuracy for this group of patients.
Cognitive fluctuations (CFs) are one of the core symptoms of DLB and refer to spontaneous alterations in cognition, attention and arousal ([@b0205]). CFs are of clinical importance as they have been correlated with visual hallucinations ([@b0285]), impairment in daily activities and care burden. Moreover, CFs are an important diagnostic feature for DLB as their prevalence reaches 90% of cases, compared to just 20% of AD and 29% of Parkinson's disease dementia (PDD; [@b0030]). CFs are also qualitatively different between DLB and AD as in the former case they relate more to executive and perceptual performance, while in the later they are primarily linked to memory impairment ([@b0300]). The Clinician Assessment of Fluctuation (CAF) is a clinical scale devised for the psychometric assessment of CFs ([@b0290]). Although CAF is regarded as a fairly reliable measure of CFs if used by an experienced clinician ([@b0125]), the high variability in fluctuation severity and duration of confusional episodes, along with difficulties for informants in separating out what are true intrinsic fluctuations from what are simply responses to external stressors, impose a considerable limitation in CF identification ([@b0085]).
Electroencephalography is an emerging modality for differential diagnosis between dementia subtypes as it is simple, cost-effective, easily accessible and non-invasive compared to imaging approaches. The most prominent QEEG finding in DLB and PDD is a shift of power and dominant frequency (DF) from the alpha frequency range towards high-theta, described as "EEG slowing". This EEG slowing is most prevalent posteriorly ([@b0090]) and although it is also observed in AD patients ([@b0175]), it is not as prominent as in the Lewy body diseases -- DLB and PDD. In studies quantifying differences between DLB or DLB/PDD, or AD and controls, QEEG variables such as coherence ([@b0270]), temporal dominant frequency variability (DFV) ([@b0015]), power ratio between bands and statistical measures such as Granger causality ([@b0150]), have all achieved high diagnostic sensitivity and specificity, reaching 100% in the latter study.
Previous investigations have found electrophysiological correlations of CFs in DLB patients. Early work using quantitative electroencephalography (QEEG) has shown a correlation between epoch-by-epoch DFV and CFs in DLB patients compared with healthy controls ([@b0290]). Later work also showed that DLB patients with CFs had greater DFV compared to AD patients in posterior brain regions, and used the DFV together with other QEEG measures to classify AD, PDD-CFs, PDD-without CFs and DLB patients and controls ([@b0075]). More recently, a multi-centre cohort analysis has verified these results ([@b0065]).
The aforementioned findings of QEEG signatures in DLB in addition to the fact that the QEEG measures were shown to be correlated with the clinical phenotype of DLB and specifically with CFs, suggest that the QEEG could be utilised to investigate for a neurophysiological divergence between DLB and other dementias. The QEEG investigations performed so far have not yet managed to identify differences ([@b0140], [@b0150]) between DLB and PDD. Generally, these Lewy body dementia (LBD) subtypes demonstrate great similarities in neuropathological processes, symptom manifestation and treatment. However, DLB is typically characterised by greater executive dysfunction, more psychiatric symptoms, poorer response to levodopa (L-DOPA) and greater amyloid burden compared to PDD ([@b0130]). Moreover, the onset of motor symptoms precedes that of dementia in PDD while in DLB, dementia appears concurrently or before motor symptoms ([@b0195]). These discrepancies may indicate differences in the spatio-temporal sequence of pathology, with a predominant brain-stem start and rostral progression in PDD and a cortical inception in DLB ([@b0050]). Potential QEEG differences between PDD and DLB are of research interest, as they could provide insight for better understanding these LBD subtypes.
Earlier QEEG studies focused on investigating the capacity of such measures in aiding DLB differential diagnosis in clinical settings. Hence, they utilized methods such as assessment by visual observation ([@b0075]), or attempted to develop an online method that performs analysis during and right-after EEG acquisition ([@b0150]). Here we took a less clinically-orientated approach, as our primary goal was to characterise and compare the resting EEG rhythm in AD, DLB and PDD patients and in relation to healthy controls, and to investigate for DLB specific signatures of CFs. Thus, we performed extensive pre-processing analysis of the EEG signal and a thorough analysis for differences in QEEG measures within different frequency ranges and brain regions, between diagnostic groups. Based on the literature, we hypothesized that dementia patients will exhibit a differential pattern in the distribution of QEEG measures of power and DF within different frequency ranges compared to healthy controls, and that these QEEG measures in addition to DF variability in time (DFV) will also differ between the dementia groups. We also hypothesized that greater DFV will only characterise LBDs and possibly only DLB, and that greater DFV will correlate with more CFs within these groups. Finally, to assess the possible utility of these measures in the development of biomarkers, the QEEG measures that were found to be significantly different between groups were used to predict dementia diagnosis.
2. Material and methods {#s0010}
=======================
2.1. Diagnostic groups {#s0015}
----------------------
Initially we pre-processed EEG data from 21 healthy controls, 19 AD, 20 DLB and 20 PDD participants ([Table 1](#t0005){ref-type="table"} for the demographic data of the final groups). Patients were individuals who were referred to local old age psychiatry and neurology services and diagnosis was determined by two independent experienced clinicians (Alan J. Thomas and John-Paul Taylor). Controls were age-matched volunteers. Patients with DLB fulfilled the 2005 and 2017 revised criteria for probable DLB ([@b0210], [@b0205]) and patients with PDD fulfilled the criteria for probable PDD ([@b0135]). Individuals with AD met the revised criteria of the National Institute of Neurological and Communicative Diseases and Stroke/AD and Related Disorders Association for probable AD ([@b0215]). The CAF score was assessed by the clinicians and CFs were defined on the basis that they were typical of those seen in DLB and internally driven rather than a response to external environmental factors. Healthy participants demonstrated no evidence of dementia as determined by the Cambridge Cognitive Examination (CAMCOG) score (\>80) and from clinical history. Exclusion criteria for all participants included significant history of neurological or psychiatric conditions. Prescriptions of acetylcholinesterase inhibitors (AChEIs), memantine and dopaminergic medications were allowed. Ethical approval was provided by the Northumberland Tyne and Wear NHS Trust and Newcastle University ethics committee.Table 1Demographics table for the healthy control (N = 21), Alzheimer's disease (AD; N = 18), dementia with Lewy bodies (DLB; N = 17) and Parkinson's disease dementia (PDD; N = 17) groups that were used for our analysis. L-DOPA = levo-dopa, LED = L-DOPA equivalent dose, AChEIs = acetylcholinesterase inhibitors, MMSE = Mini mental state examination, CAF = Clinician's assessment of fluctuations scale, UPDRS = Unified Parkinson's disease rating scale, NPI = Neuropsychiatric inventory total score. Although it is not shown in the table, 1 PDD patient (5.9%) was on memantine.Controls (N = 21)AD (N = 18)DLB (N = 17)PDD (N = 17)Age in yrs ± SD76.19 ± 5.3276.06 ± 7.8175.71 ± 5.3475.44 ± 4.66Males (%)66.7%88.9%88.2%100%L-DOPA--0%52.9%100%LED--0%348.94423.42AChEIs--94.4%88.2%76.5%Age at diagnosis (yrs ± SD)--74.64 ± 7.6373 ± 5.1174.07 ± 6.29Diagnosis duration (yrs ± SD)--1.5 ± 0.91.08 ± 0.700.94 ± 0.73MMSE29.19 ± 0.8723.67 ± 1.6825 ± 2.8923.94 ± 2.59CAF--0.47 ± 0.872.76 ± 3.786.59 ± 4.29NPI total--7.29 ± 7.618 ± 5.2720.35 ± 12.9UPDRS1.14 ± 1.421.67 ± 1.6113.82 ± 5.3227.06 ± 11.44
2.2. EEG recordings {#s0020}
-------------------
High-density, eyes-closed resting-state EEG recordings were obtained using 128 channel ANT Waveguard caps (ANT Neuro, Netherlands) with an Ag/AgCl electrode montage set according to the 10-5 placement system ([@b0240]). Electrode impedance with kept below 5 kΩ. A reference electrode (Fz) was used, no filters were applied during acquisition and the sampling frequency was set at 1024 Hz. The patients that received medication had normally taken AChEIs at least 4 h before while the time of the last Levodopa dose was 1--3 h prior to the EEG session.
2.3. Pre-processing {#s0025}
-------------------
Pre-processing of the EEG recordings was performed off-line after acquisition on the MATLAB environment (MATLAB 8.5, The MathWorks Inc., Natick, MA, 2015), using the EEGLAB toolbox version 13 ([@b0115]). The EEG signal was filtered with a 4 Hz high-pass and a 46 Hz low-pass filter. Lower frequencies were filtered out as they imposed noise on the higher frequencies that were of more interest, and because the EEG generally has a limited accuracy in estimating very low and very high frequencies ([@b0230]). A notch filter was applied at 50 Hz. Recordings from all electrodes were visually inspected in the power-time domain and rejected if they had a kurtosis value over 3, or if they contained clear and consistent artifacts such as electrooculogram (EOG) and electromyogram (EMG) artifacts. The number of channels removed was kept to the minimum possible (mean = 17.7 ± 6.7, min. = 0, max. = 33).
Independent component analysis (ICA) was used to accurately estimate and remove the presence of additional ocular, muscular, and other neuronal activity ([@b0185]). Individual recordings were reduced to 30 principal components and then decomposed using the extended RUNICA algorithm ([@b0045], [@b0115]). Components representing existing templates for muscular, ocular, and electrical (50 Hz line noise) artefacts ([@b0180]) were rejected (mean = 5.2 ± 1.6, min. = 0, max. = 9) and the remaining ICs remixed. The recordings were then segmented into 2-s long epochs and were inspected for any remaining artefacts. Epochs containing large artifacts were removed across channels, in a conservative manner. Finally, the removed channels were replaced using spherical spline interpolation ([@b0145]). As a final step, the EEG montage was changed to average reference.
2.4. Variable extraction {#s0030}
------------------------
The power spectral density (PSD) for each 2-s epoch was estimated using Bartlett's method ([@b0040]) with a 0.25 Hz frequency resolution using a 4-s FFT (fast Fourier transform) size and a Hamming window, for each electrode. To compensate for the between subject variability in factors such as brain neurophysiology, anatomy and physical tissue properties, the data were transformed to relative power spectral density (rPSD; Eq. [(1)](#e0005){ref-type="disp-formula"}; [@b0250]). The rPSD was extracted for each time point of each epoch (sampling frequency = 1024 Hz), and for each electrode. Then, for each epoch of a recording, the power was averaged across electrodes for each of four regions: frontal, central, posterior and lateral ([Fig. 1](#f0005){ref-type="fig"}). Seven subjects were rejected from further analysis due to an insufficient number of clean data (\<47 epochs). For the remaining 73 subjects (21 healthy controls, 18 AD, 17 DLB and 17 PDD; [Table 1](#t0005){ref-type="table"}), only the first 47 epochs of extracted power per region were utilised (total length of 94 s).$$\overline{g}(f) = \frac{g(f)}{\sum_{f}g(f)}$$Equation [(1)](#e0005){ref-type="disp-formula"}: Calculation of the relative PSD/power $(\overline{g})$ across the power spectrum (4--46 Hz). At each point in the frequency spectrum the amplitude ($g(f)$) is divided by the sum of all amplitudes across the frequency spectrum ($\sum_{f}g(f)$) ([@b0185]).Fig. 1Placement of the 128 electrodes according to the 10-5 placement system. The signal recorded from the electrodes indicated with black colour was selected out as it was deemed too noisy. The colours indicate the grouping of the electrodes into four regions: blue = frontal, green = central, purple = posterior, yellow = lateral. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
The mean power distributed in each of three frequency bands: theta (4--7.75 Hz), alpha (8--13.75 Hz), beta (14--20.75 Hz), was extracted as a percentage of the total power in that range, across epochs per region ([Table 2](#t0010){ref-type="table"}; [Fig. 2](#f0010){ref-type="fig"}). Higher frequencies were excluded as they are prone to contamination by electromyogram rhythms ([@b0295]). The DF -- the frequency with the highest power between 4 Hz and 20.75 Hz -- was extracted for each epoch to calculate the mean DF and DF variability (DFV; SD from the mean DF) across epochs, for the slow-theta (4--5.5 Hz), fast-theta (5.5--7.75 Hz; defined by others as pre-alpha; [@b0075]), theta, alpha and theta/alpha (4--13.75 Hz) frequency ranges ([Table 3](#t0015){ref-type="table"}; [Fig. 2](#f0010){ref-type="fig"}). Since the DF was limited within the theta-alpha range, beta band activity was excluded. The theta-alpha DF was used to calculate the Frequency Prevalence (FP) distribution, which is the percentage of epochs having a DF falling within the slow-theta, fast-theta and alpha frequency ranges ([Table 3](#t0015){ref-type="table"}; [Fig. 2](#f0010){ref-type="fig"}). These measures were calculated for each patient, for each diagnostic group and for each band and region combination.Fig. 2Schematic diagram illustrating the process of extracting each of the four main quantitative EEG variables used in this study, for one participant in the posterior region. The filtered, pre-processed EEG signal on each of the electrodes in posterior derivations (N = 35) is windowed in 2 s long epochs. The signal undergoes fast-Fourier transform (FFT) and using Bartlett's method the absolute power spectral density (PSD) is calculated for each epoch, for each electrode. The relative PSD (rPSD) is then calculated to normalize the signal. The mean rPSD is obtained across posterior electrodes, for each epoch (up to 47 epochs) of the recording, and the percentage of the total power in the 3--20.75 Hz range allocated to the theta (4--7.75 Hz), alpha (8--13.75 Hz) and beta (14--20.75 Hz) frequency ranges is calculated. The frequency with the highest power within the slow-theta (4--5.5 Hz), fast-theta (5.5--7.75 Hz), alpha and theta-alpha (4--13.75 Hz) frequency ranges was identified within each epoch, and that value corresponded to the dominant frequency (DF). The mean DF and the standard deviation of the mean DF (DF variability; DFV) across epochs were then calculated. Finally, the DF within each epoch was assessed and was characterised to be in the slow-theta, fast-theta or alpha range. The epochs that were characterised by a DF within each of these ranges are shown as a percentage of the total number of epochs. These percentages were the slow-theta, fast-theta and alpha frequency prevalence (FP). The same procedure was followed for the other three cortical regions.Table 2The mean percentage of the total power distributed in each of three frequency bands: theta (4--7.75 Hz), alpha (8--13.5 Hz), beta (14--30.75 Hz), in each region: frontal, central, posterior, lateral, for each group: healthy controls (N = 21), Alzheimer's disease (AD; N = 18), dementia with Lewy bodies (DLB; N = 17) and Parkinson's disease dementia (PDD; N = 17) patients.RegionsControlsADDLBPDDThetaFrontal20.19 ± 5.2224.57 ± 6.2637.63 ± 6.3635.89 ± 7.46Central19.18 ± 4.9623.02 ± 6.1336.90 ± 7.0535.33 ± 6.37Posterior19.79 ± 5.7723.51 ± 6.6339.62 ± 7.5339.10 ± 7.63Lateral19.32 ± 5.2924.39 ± 6.5336.96 ± 6.0735.35 ± 7.30
AlphaFrontal35.12 ± 5.6632.11 ± 4.3128.96 ± 5.1027.42 ± 2.57Central34.74 ± 5.1132.61 ± 4.4729.84 ± 4.9129.04 ± 2.28Posterior38.91 ± 6.0435.49 ± 5.8129.26 ± 5.7523.91 ± 2.50Lateral35.41 ± 5.1033.43 ± 4.0028.57 ± 4.9826.75 ± 2.34
BetaFrontal44.69 ± 7.0943.32 ± 7.0333.40 ± 3.7436.69 ± 7.52Central46.07 ± 6.7544.37 ± 6.7133.26 ± 3.8535.65 ± 6.20Posterior41.30 ± 7.0940.99 ± 8.3831.11 ± 5.3631.72 ± 7.67Lateral45.27 ± 7.7142.17 ± 6.5934.47 ± 5.5237.90 ± 7.80Table 3The mean dominant frequency (DF) ± DFV (mean SD of the DF), DFV ± SD and frequency prevalence (FP) ± SD for the theta (4--7.75 Hz), slow-theta (4--5.5 Hz), fast-theta (5.75--7 Hz), alpha (8--13.75 Hz) and theta-alpha (4--13.75 Hz) frequency ranges in each region: frontal, central, posterior, lateral, for each group: healthy controls (N = 21), Alzheimer's disease (AD; N = 18), dementia with Lewy bodies (DLB; N = 17) and Parkinson's disease dementia (PDD; N = 17) patients.RegionsVariablesControlsADDLBPDDThetaFrontalDF ± SD6.93 ± 0.46.57 ± 0.546.49 ± 0.606.26 ± 0.31DFV ± SD0.93 ± 0.250.98 ± 0.240.73 ± 0.240.80 ± 0.19FP ± SD19.55 ± 22.1444.92 ± 24.5482.48 ± 21.0091.36 ± 8.29CentralDF ± SD7.11 ± 0.336.67 ± 0.596.65 ± 0.526.51 ± 0.35DFV ± SD0.81 ± 0.280.86 ± 0.290.63 ± 0.220.67 ± 0.16FP ± SD18.84 ± 24.9641.02 ± 26.0780.60 ± 21.0290.49 ± 9.22PosteriorDF ± SD7.17 ± 0.356.71 ± 0.606.57 ± 0.666.31 ± 0.29DFV ± SD0.78 ± 0.330.86 ± 0.310.60 ± 0.210.72 ± 0.18FP ± SD16.72 ± 23.4934.99 ± 24.4583.35 ± 23.6894.99 ± 6.25LateralDF ± SD7.18 ± 0.316.80 ± 0.546.65 ± 0.536.51 ± 0.36DFV ± SD0.80 ± 0.300.83 ± 0.330.64 ± 0.260.72 ± 0.18FP ± SD17.53 ± 22.0639.24 ± 26.6883.35 ± 18.7689.36 ± 15.10
Slow-thetaFrontalDF ± SD4.88 ± 0.154.93 ± 0.175.01 ± 0.155.02 ± 0.14DFV ± SD0.55 ± 0.060.52 ± 0.070.49 ± 0.080.50 ± 0.08FP ± SD2.23 ± 4.2810.52 ± 13.2916.27 ± 21.0618.77 ± 11.56CentralDF ± SD4.95 ± 0.174.98 ± 0.185.16 ± 0.145.14 ± 0.13DFV ± SD0.52 ± 0.060.49 ± 0.060.42 ± 0.100.43 ± 0.10FP ± SD1.21 ± 3.059.46 ± 12.379.51 ± 1411.14 ± 12.28PosteriorDF ± SD4.91 ± 0.144.94 ± 0.185.11 ± 0.135.11 ± 0.15DFV ± SD0.54 ± 0.060.51 ± 0.060.45 ± 0.070.45 ± 0.10FP ± SD1.11 ± 3.346.97 ± 9.2513.77 ± 23.0316.15 ± 11.75LateralDF ± SD4.86 ± 0.184.94 ± 0.165.09 ± 0.155.09 ± 0.16DFV ± SD0.56 ± 0.050.51 ± 0.080.44 ± 0.110.46 ± 0.09FP ± SD0.51 ± 1.155.44 ± 6.7410.76 ± 17.4111.76 ± 11.99
Fast ThetaFrontalDF ± SD7.20 ± 0.276.98 ± 0.326.74 ± 0.416.55 ± 0.22DFV ± SD0.59 ± 0.140.62 ± 0.110.53 ± 0.120.55 ± 0.09FP ± SD17.32 ± 21.0234.4 ± 17.9566.21 ± 20.8672.59 ± 10.45CentralDF ± SD7.31 ± 0.227.02 ± 0.316.79 ± 0.436.69 ± 0.24DFV ± SD0.53 ± 0.160.60 ± 0.140.50 ± 0.110.52 ± 0.07FP ± SD17.62 ± 24.3031.56 ± 20.6871.09 ± 20.3479.35 ± 11.86PosteriorDF ± SD7.35 ± 0.217.06 ± 0.366.76 ± 0.476.54 ± 0.20DFV ± SD0.52 ± 0.170.58 ± 0.160.48 ± 0.110.52 ± 0.09FP ± SD15.60 ± 22.5128.01 ± 19.3569.59 ± 27.3778.85 ± 11.86LateralDF ± SD7.36 ± 0.197.09 ± 0.306.81 ± 0.416.70 ± 0.24DFV ± SD0.50 ± 0.150.58 ± 0.180.49 ± 0.130.52 ± 0.08FP ± SD17.02 ± 21.9533.81 ± 24.2672.59 ± 21.6477.60 ± 15.63
AlphaFrontalDF ± SD9.13 ± 0.579.40 ± 0.888.64 ± 0.219.01 ± 0.44DFV ± SD0.88 ± 0.401.07 ± 0.430.85 ± 0.321.19 ± 0.27FP ± SD80.45 ± 22.1455.08 ± 24.5417.52 ± 218.64 ± 8.29CentralDF ± SD9.13 ± 0.659.42 ± 0.908.48 ± 0.178.70 ± 0.39DFV ± SD0.82 ± 0.411.04 ± 0.400.60 ± 0.170.87 ± 0.37FP ± SD81.16 ± 24.9658.98 ± 26.0719.40 ± 21.029.51 ± 9.22PosteriorDF ± SD9.03 ± 0.631.06 ± 0.968.49 ± 0.188.72 ± 0.33DFV ± SD0.64 ± 0.350.86 ± 0.450.62 ± 0.250.93 ± 0.37FP ± SD83.28 ± 23.4965.01 ± 24.4516.65 ± 23.685.01 ± 6.25LateralDF ± SD9.12 ± 0.710.92 ± 0.828.48 ± 0.188.61 ± 0.41DFV ± SD0.82 ± 0.370.82 ± 0.400.65 ± 0.240.84 ± 0.35FP ± SD82.47 ± 22.0660.76 ± 26.6816.65 ± 18.7610.64 ± 15.10
Theta-alphaFrontalDF ± SD8.79 ± 0.758.24 ± 1.296.75 ± 0.806.45 ± 0.63DFV ± SD1.07 ± 0.461.29 ± 0.590.91 ± 0.270.98 ± 0.33CentralDF ± SD8.81 ± 0.828.36 ± 1.306.93 ± 0.716.68 ± 0.76DFV ± SD0.92 ± 0.471.30 ± 0.600.80 ± 0.250.82 ± 0.25PosteriorDF ± SD8.82 ± 0.798.65 ± 1.216.78 ± 0.866.41 ± 0.58DFV ± SD0.78 ± 0.381.21 ± 0.750.73 ± 0.230.84 ± 0.27LateralDF ± SD8.88 ± 0.818.42 ± 1.136.90 ± 0.716.74 ± 0.81DFV ± SD0.93 ± 0.411.13 ± 0.510.79 ± 0.310.88 ± 0.35
2.5. Statistical analysis {#s0035}
-------------------------
The mean power, theta-alpha DF and theta, alpha and theta-alpha DFV were statistically compared using repeated measures ANOVA, for region as the within-subjects factor and diagnosis as the between-subjects factor. When a significant interaction was found we followed up by univariate ANOVA and post hoc analysis with a Bonferonni correction. The DFV (for all frequency ranges) and the theta-alpha DF values were logarithmically transformed to achieve homogeneity of variance/homoscedasticity. Heteroscedasticity could not be solved for the theta and alpha DF and hence we performed Welch's ANOVA followed by the Games-Howell test. To statistically compare the distribution of the FP in the slow-theta, fast-theta and alpha frequency ranges we performed Kruskal-Wallis H test followed by post hoc analysis. Pearson's product-moment correlation and Spearman's rank correlation were used to investigate for correlations between these variables and the CAF score, the MMSE score and the levodopa equivalent dose (LED), for each diagnostic group. Manual correction for multiple comparisons by appropriating the level of α significance (α/N) was performed for the non-parametric statistical analyses and for the correlation analyses, where Bonferonni correction was not available with the statistical software.
In order to assess the capacity of the QEEG variables that were significantly different between the AD and DLB, and the DLB and PDD groups to predict diagnosis, the generalised estimating equations (GEE) procedure were used. This method allows the analysis of repeated measurements without the assumption for normal distribution ([@b0095]). The QEEG variables that introduce multicollinearity to the model (variance inflation factor \>5) were excluded from this analysis. Region was defined as the within-subjects variable, diagnosis as the between-subjects variable and the QEEG variables and the CAF score as the co-factors. The variables that significantly predicted diagnosis were then used to calculate the receiver operating characteristic (ROC) curve, and obtain the area under the curve (AUC), sensitivity and specificity with asymptotic confidence intervals. The sensitivity/specificity cut-off was determined using Youden\'s index.
3. Results {#s0040}
==========
3.1. Data and demographics {#s0045}
--------------------------
Data from a total of 73 individuals (21 healthy controls, 18 AD, 17 DLB, 17 PDD; [Table 1](#t0005){ref-type="table"}) were further analysed after data extraction. Participants were well matched for age at diagnosis and age at the time of the recording (p \> 0.05), as well as MMSE score (p \> 0.05). The PDD and DLB groups had significantly higher CAF scores than AD patients (p \< 0.01; p \< 0.05 respectively), with the PDD group also having a higher CAF score than the DLB group (p \< 0.01). Lastly, the neuropsychiatric inventory (NPI) total and Unified Parkinson's disease rating scale (UPDRS) scores were higher in the DLB/PDD subjects compared to the other groups, and in the PDD compared to the DLB group (p \< 0.01).
3.2. EEG slowing {#s0050}
----------------
We found a significant effect of diagnosis on the mean power in the theta: *F (3, 69) = 39.48, p \< 0.01,* alpha: *F (3, 69) = 14.49, p \< 0.01* and beta: *F (3, 69) = 12.825, p \< 0.01* ranges ([Table 2](#t0010){ref-type="table"}; [Fig. 3](#f0015){ref-type="fig"}). In all regions, PDD and DLB groups had higher theta power than AD patients and healthy controls (*p \< 0.01*). In the alpha and beta ranges the opposite pattern was observed. Specifically, in the alpha band, controls had significantly higher power than PDD patients in all regions (*p \< 0.01*), and compared to DLB patients frontally, posteriorly and laterally (*p \< 0.01*). Moreover, AD patients had greater alpha power than PDD patients posteriorly and laterally (*p \< 0.01*), and also to DLB patients frontally (*p \< 0.05*), posteriorly and laterally (*p \< 0.01*). In the beta range, DLB patients had lower power than AD patients and controls in all regions (*p \< 0.01*). PDD patients had lower power than healthy controls frontally and centrally (p \< 0.01) and posteriorly and laterally (p \< 0.05), and from AD patients frontally, posteriorly (*p \< 0.05*) and centrally (*p \< 0.01*).Fig. 3The mean percentage distribution of the total relative power in three frequency bands (Hz): theta (4--7.75), alpha (8--13.5) and beta 20.75), for each of four diagnostic groups: healthy controls (N = 21), Alzheimer's disease (AD; N = 18), dementia with Lewy bodies (DLB; N = 17) and Parkinson's disease dementia (PDD; N = 17) patients, for the posterior region. Similar observations were made in the frontal, central and lateral regions but are not shown. Error bards indicate the standard deviation.
We also found a significant effect of diagnosis in the second measure of interest, the mean theta-alpha DF (*F (3, 69) = 36.78, p \< 0.01),* which was significantly higher in all cortical regions in controls and AD patients compared to the other patient groups ([Table 3](#t0015){ref-type="table"}, [Fig. 4](#f0020){ref-type="fig"}). The mean theta DF was significantly higher in controls compared to the PDD group frontally, to the AD, DLB and PDD groups centrally and posteriorly*,* and to the DLB and PDD groups laterally. Significant differences were also found between groups in the alpha DF, in all regions. Specifically, the DLB group had significantly lower alpha DF than the control and AD group in all regions. The PPD group had higher alpha DF than the DLB group frontally, the AD group centrally and posteriorly and the control group laterally ([Fig. 4](#f0020){ref-type="fig"}). A trend for a greater alpha DF in the AD compared to the control group was observed, but was not verified by the statistical analysis.Fig. 4The mean dominant frequency (DF) in the theta-alpha (4--13.75 Hz), alpha (8--13.75 Hz) and theta (4--7.75 Hz) frequency ranges, for each of four diagnostic groups: healthy controls (N = 21), Alzheimer's disease (AD; N = 18), dementia with Lewy bodies (DLB; N = 17) and Parkinson's disease dementia (PDD; N = 17) patients, in the frontal, central, posterior and lateral regions. Error bars indicate the standard deviation (SD), ^\*\*^p \< 0.05, ^\*\*^p \< 0.01.
For measures of frequency prevalence (FP; the percentage distribution of the theta-alpha DF in time in the slow-theta, fast-theta and alpha frequency ranges; [Fig. 5](#f0025){ref-type="fig"}, [Table 3](#t0015){ref-type="table"}), the mean alpha FP was significantly higher in controls compared to all disease groups (*p \< 0.01*), and in AD patients compared to DLB and PDD patients (*p \< 0.01*), in all regions. In the fast-theta range the opposite pattern was observed, with controls exhibiting lower FP compared to AD patients frontally (*p \< 0.01*), and to DLB and PDD patients in all regions (*p \< 0.01*). Finally, in the slow-theta range controls had significantly lower FP than AD patients frontally (*p \< 0.01*), centrally and posteriorly (*p \< 0.05*), and to DLB and PDD patients in all regions (*p \< 0.01*). AD patients also have significantly lower slow-theta FP than PDD patients frontally and centrally (*p \< 0.05*).Fig. 5The mean frequency prevalence (FP; percentage distribution of the mean dominant frequency (DF) in each frequency point in the theta-alpha frequency range with 0.25 Hz resolution) for each of four diagnostic groups: healthy controls (N = 21), Alzheimer's disease (AD; N = 18), dementia with Lewy bodies (DLB; N = 17) and Parkinson's disease dementia (PDD; N = 17) patients, in the (a) frontal, (b) central, (c) posterior and (d) lateral regions.
3.3. Dominant frequency variability {#s0055}
-----------------------------------
Comparisons of the DFV between groups for different frequency band and region combinations revealed a significant effect of diagnosis in the theta/alpha (*F (3, 69) = 2.77, p \< 0.05* and alpha *(F (3, 69) = 6.29, p \< 0.01)* ranges ([Fig. 6](#f0030){ref-type="fig"}), but not in the theta range. In the theta-alpha band, the AD group had a significantly higher DFV compared to the control, DLB and PDD groups in the frontal, central and posterior regions, and only to the DLB group laterally. In the alpha band, AD patients had significantly higher DFV compared to the DLB group centrally, and to DLB and controls posteriorly. To further validate this finding we have included a short analysis on the effect of each electrode on the DFV in AD and DLB patients ([Supplementary Material 1](#s0100){ref-type="sec"}).Fig. 6The mean dominant frequency variability (DFV) in the (a) alpha (8--13.5 Hz) and (b) theta-alpha (4--13.75 Hz) frequency ranges, for each of four diagnostic groups: healthy controls (N = 21), Alzheimer's disease (AD; N = 18), dementia with Lewy bodies (DLB; N = 17) and Parkinson's disease dementia (PDD; N = 17) patients, in the frontal, central, posterior and lateral regions. Error bards indicate the standard deviation (SD), ^\*\*^p \< 0.05, ^\*\*^p \< 0.01.
3.4. Correlations {#s0060}
-----------------
We assessed correlations between CFs as measured by CAF and DFV measures similarly to previous studies ([@b0290]), and with QEEG measures of slowing for all the different diagnostic groups and each band and region. This analysis revealed that within the DLB group only, there was a strong correlation between the CAF score and the theta DFV in the central (*r = 0.789, p \< 0.000*), posterior (*r = 0.652, p \< 0.005*) and lateral regions (*r = 0.805, p \< 0.000*). A positive, DLB specific correlation with CAF was also found with slow-theta FP in the frontal (*r = 0.679, p = 0.003*), central (*r = 0.747, p = 0.001*), posterior (*r = 0.792, p \< 0.001*) and lateral (*r = 0.794, p = 0.001*) regions. A correlation between the CAF and MMSE score was only found in the PDD group (*r = −0.671, p \< 0.05*), while no significant correlation was found for any variable and the LED, for any group and region.
3.5. Exploratory GEE and ROC curve analysis {#s0065}
-------------------------------------------
GEE analysis was performed for the variables that were significantly different between the AD and DLB diagnostic groups (theta power, alpha power, theta-alpha DFV, alpha DFV, alpha DF and fast-theta FP). The alpha-theta DF and alpha FP were rejected from this analysis as they introduced marked multicollinearity. The QEEG variables that best predicted diagnosis were the theta power (%) (Wald chi-square = 15.74, df = 1, p \< 0.01), the fast-theta FP (Wald chi-square = 8.1, df = 1, p \< 0.01) and the theta-alpha SD (Wald chi-square = 7.549, df = 1, p \< 0.01). ROC analysis ([Fig. 7](#f0035){ref-type="fig"}) yielded AUC = 94% (90.4--97.9%), sensitivity = 92.26% (CI = 80.4--100%) and specificity = 83.3% (CI = 73.6--93%). Since no significant differences were found between the PDD and DLB groups for any of the QEEG variables in the variance analyses, all the QEEG variables were included in the GEE analysis. This analysis deviated from the analysis protocol and is therefore included in the [supplementary material (Supplementary Material 2)](#s0100){ref-type="sec"}, without drawing further conclusions.Fig. 7Receiver operating curves (ROC) for a model composed of fast-theta frequency prevalence (FP), theta power and theta-alpha dominant frequency variability (DFV), for differentiating between Alzheimer's disease (AD; N = 18) and dementia with Lewy bodies (DLB; N = 17) with mild dementia.
4. Discussion {#s0070}
=============
Our analysis has revealed several novel findings, including greater theta-alpha DFV in AD patients compared to controls, DLB and PDD patients. Moreover, we did not identify any differences in the DFV between the DLB group compared to controls, as was previously reported ([@b0065], [@b0075]; [@b0290]). However, we found a significant, DLB specific positive correlation between the CAF score and the theta DFV, and the CAF score and slow-theta FP. Our findings confirm the widely reported shift of EEG power and dominant rhythm -- from the alpha towards the theta frequency range in the DLB and PDD groups compared to healthy controls and AD patients ([@b0090], [@b0035], [@b0075]). A subtler slowing of the EEG was also observed in AD patients compared to controls. Finally, a preliminary analysis investigating the possible diagnostic value of QEEG variables showed that the three QEEG variables describing the extent of EEG slowing and DFV (theta power, fast-theta FP and theta-alpha DFV) could predict a DLB versus an AD diagnosis with high sensitivity and specificity.
A more marked EEG slowing in DLB/PDD groups compared to healthy controls and AD patients has been extensively reported in the literature, mostly in posterior derivations ([@b0090], [@b0035], [@b0255]). In our analysis we looked within four different cortical regions compared to three regions previously reported ([@b0065], [@b0075]), and analysed three measures of EEG spectral distribution, the FP, DF and power, all of which indicated a greater EEG slowing in DLB/PDD patients compared to AD patients and controls.
In AD patients, EEG slowing of a lesser extent was observed, that was evident by a shift of FP from the alpha to the fast-theta and slow-theta ranges compared to healthy controls. This finding indicates that a higher percentage of measurements of the theta-alpha DF in time fell in the theta-band rather than in the alpha-band in AD patients compared to controls. This altered DF distribution towards lower frequencies in AD was "masked" with the calculation of the mean theta-alpha DF, as this measure does not account for variability. The DF in the AD group is highly variable and can take values towards the higher edge of the alpha band thus influencing the mean DF. This is evident by the significantly greater theta-alpha DFV and the trends for greater alpha DFV and alpha DF in the AD group.
A cholinergic deficit may partly account for the EEG slowing in LBDs and AD, as the administration of AChEIs can reverse the EEG slowing in both diseases ([@b0005], [@b0020], [@b0080]). However, the loss of cholinergic neurons projecting to the cortex is greater and has a faster progression in DLB and PDD compared to AD ([@b0190]) where the cholinergic deficit is not yet severe at mild stages of the disease ([@b0060]). Pathological protein-related synaptic dysfunction that occurs before neuronal degeneration has also been associated with cognitive decline in AD and is thought to be even greater in DLB ([@b0260], [@b0265]). Thus, a more advanced cholinergic deficit and synaptic dysfunction in the LBD groups could account for the greater extent of EEG slowing observed compared to the AD group, particularly given the relatively early disease stage/cognitive impairment that our participants exhibited.
Our analysis also revealed novel findings regarding temporal variability in the dominant rhythm as measured by DFV. Previous studies have shown a significant DFV increase in DLB patients compared to healthy controls, that correlated with CFs measured by CAF ([@b0075], [@b0290]). Although we did not find an increase in the DFV of DLB patients compared to controls, we did find a positive correlation between theta DFV and the CAF score within the DLB group ([@b0070]). This correlation was only significant in the theta frequency range, likely due to the shift of the DF towards these frequencies. A positive correlation was also found between slow-theta FP and the CAF score in DLB patients. Both these correlations were only seen in the DLB group and not in the PDD or AD groups.
Given the neuropathological similarities between PDD and DLB and the absence of other QEEG differences between these groups, the lack of a correlation between CAF and our QEEG measures in PDD was unexpected. Previous studies have reported that PDD patients with high CF scores show an EEG-slowing ([@b0075]) and have more DLB-like symptoms such as visual hallucinations, while patients with lower CF scores resemble PD ([@b0285]). This PDD heterogeneity may have affected our capacity to identify a correlation between the EEG measures and CAF score in this group. Moreover, DLB patients with parkinsonism have more impaired reaction times and vigilance measures that relate to CFs, compared to patients without motor symptoms, implying a connection between CFs and dopaminergic impairment ([@b0030]). Since PDD is characterised by greater dopaminergic impairment than DLB, this additional pathology could have a more dominant aetiological role in the CFs seen in PDD as compared to DLB and thus be less contingent on factors (e.g. cholinergic tone) which might drive a QEEG change that associates with CFs. Furthermore, fluctuations are likely to have at least two dimensions (arousal and attention; [@b0055]) which are not discriminated by the CAF scale but which may be differentially expressed in our DLB and PDD groups given arousal/sleepiness is strongly influenced by dopaminergic medications. Another factor may be the amyloid burden as this is significantly greater in DLB compared to PDD ([@b0120]) and the cortical amyloid-β deposition relates more to dementia severity, visual hallucinations and delusion in DLB than PDD ([@b0200]). DLB is also characterised by a greater amyloid load in the putamen ([@b0160]), which is involved in attentional networks and in DLB has altered functional connectivity that correlates with CAF ([@b0245]). Improved quantification scales of fluctuations may help unpick these challenges.
Previous studies have also shown that DLB patients had a significantly higher DFV compared to AD patients, which did not differ significantly from controls, and that a higher DFV was an accurate indicator of DLB versus AD diagnosis ([@b0075]). A QEEG analysis on the same patient cohorts as in this study, but with less spatial detail, also suggested a greater theta-alpha DFV in AD patients compared to the DLB/PDD groups, posteriorly ([@b9000]). Here, we found that AD patients had a significantly higher theta-alpha DFV compared to the other groups in most regions while DLB patients were not significantly different than PPD patients or controls. In the current study looking within smaller frequency bands in the theta-alpha range we also identified a greater alpha DFV in AD patients compared to controls and DLB patients posteriorly, and to DLB patients alone centrally. These findings could be part of the pathology or alternatively, the result of a compensation mechanism that may occur at early stages of AD. At rest, early stage AD patients may have increased activity and functional connectivity in resting state networks which correlate with a lower MMSE score ([@b9005]). However, at more advanced stages activity and connectivity decrease to levels lower than those seen in controls ([@b0010]). Therefore, increases in DFV may be associated with a compensation mechanism in early stage AD.
A number of other factors may account for the discrepancies between our findings and those of previous studies. The lack of a greater DFV in DLB patients compared to controls may be attributed to the fact that the majority of our DLB patients were on AChEIs, although we would argue that this adds to the clinical relevance of our findings, particularly from a diagnostic perspective; it is likely that any use of the EEG will be when patients are beginning or have already been initiated on treatment. In DLB patients, CFs have been shown to correlate with cholinergic imbalances in networks involved in the resting state ([@b0110]). AChEIs restore this imbalance and improve both the cognitive symptoms of DLB and the electrophysiological markers, including the EEG spectrum and connectivity ([@b0235]). That said, it is important to acknowledge that more AD (94.4%) than DLB (88.2%) patients were on AChEIs in our study groups and the former group showed greater DFV. However, as outlined above, cholinergic deficits are greater and occur earlier in DLB compared to AD ([@b0280]), while the brainstem cholinergic innervations of the thalamus are relatively spared in AD ([@b0220]) but not in DLB ([@b0275]). Hence, at the stage of mild dementia AChEIs could have a differential effect in DLB and AD. Although AChEIs may have normalized the DFV in DLB patients in relation to healthy individuals, the CAF/DFV correlation was still maintained within the DLB group. In previous studies, none ([@b0290]), or only a small proportion ([@b0075]) of the patients were on AChEIs. Differences in the participant cohorts, as well as methodological differences in the analysis of the recordings must also be considered. Specifically, we used a different pre-processing and spatial analysis approach, as well as a different way to estimate DFV; here DFV was defined as the standard deviation from the mean DF across epochs, in an epoch-by-epoch basis, while in [@b0075], [@b0065], DFV was defined using a visual rating of DF range on sequential EEG segments.
Finally, we proceeded with a preliminary analysis to investigate the capacity of the QEEG variables to correctly differentiate between AD and DLB patients with mild dementia. The theta power, fast-theta FP and theta-alpha DFV yielded accuracy of 94% (CI = 90.4--97.9%), sensitivity of 92.26% (CI = 80.4--100%) and specificity of 83.3% (73.6--93%). The high predictive accuracy of this model is in-line with previous classifications using QEEG variables, although different EEG pre-processing and analysis methods were used ([@b0015], [@b0150]).
A few issues relating to this study need to be considered and an important next step would be the confirmation of our findings in independent prospective cohorts, especially regarding the ROC analysis. We excluded the delta frequencies and hence, we might have missed changes in the QEEG variables within that range. In addition, the recordings were not always continuous as we focused on discarding as much of the noise as possible and preferred to occasionally reject epochs, across all channels. Moreover, the patients did not undergo post-mortem immunohistological examination and thus we did not account for mixed AD-DLB pathology that has been shown to relate to greater cognitive impairment in DLB patients ([@b0155]) and which may alter the QEEG pattern. However, our clinical diagnostic approaches were robust enough to enhance the specificity of our group selections. Evidence for this include DaT scans that were available for 9 of the DLB patients and were all positive, and a multi-modal MRI/EEG analysis on data from all the patients that were recruited in the same cohort as the patients included in this study, where AD and DLB patients were classified with 90% accuracy ([@b0100]).
5. Conclusions {#s0075}
==============
Our findings confirm the well-established slowing of the EEG in the Lewy body dementia groups compared to healthy controls and AD patients. Although we did not find higher DFV in DLB patients compared to controls as expected, theta DFV and slow-theta FP were positively correlated with CFs as measured by CAF. This DLB specific correlation suggests that a slower and more temporally variable DF specifically relates to the CFs seen in DLB, and could reveal differential mechanisms underlying CFs in dementia subtypes. Another novel finding was a significantly higher DFV in AD patients compared to the other groups. Exploratory analysis showed that QEEG measures could predict a DLB versus an AD diagnosis with high accuracy, sensitivity and specificity. In conclusion, this study supports the hypothesis that QEEG analysis can be a valuable tool for identifying CFs in DLB and for differential diagnosis between dementia subtypes, once replicated with low density EEG currently used in standard clinical practice after the feasibility and cost-effectiveness of these methodologies has been investigated.
Appendix A. Supplementary material {#s0100}
==================================
Supplementary data 1Supplementary data 2
Acknowledgements {#s0085}
================
We thank the Alzheimer's Society for funding this research as part of the Alzheimer's Society Doctoral Training center at Newcastle University. This research was supported by the NIHR Newcastle Biomedical Research Centre awarded to the Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, the Newcastle Hospitals NHS Charity, the Northumberland, Tyne and Wear NHS Foundation Trust, the Wellcome Trust (grant numbers: BH120812, BH120878) and by the Alzheimer's Research UK. S.G. was supported by the NIHR MedTech In Vitro Diagnostic Co-operatives scheme (ref MIC-2016-014).
Conflict of interest {#s0090}
====================
None.
Supplementary data associated with this article can be found, in the online version, at [https://doi.org/10.1016/j.clinph.2018.03.013](10.1016/j.clinph.2018.03.013){#ir005}.
[^1]: Current address: Baylor College of Medicine, Department of Neuropsychiatry, Houston, TX 77030, USA.
[^2]: These authors are joint senior authors.
|
[Preventive dentistry in France].
In France, oral prevention has recently progressed in various aspects of dental caries prophylaxis which is reviewed in this paper. A better knowledge of dental caries prevalence has been obtained at a national level and the French Government authorized in October 1985 salt fluoridation for a period of 5 years which in addition to other means of caries prevention such as fluoridated toothpastes and various local and topical procedures has increased the potentials of fluoride use in France. In addition a larger use of fissure sealants has been encouraged. It is hoped that the introduction of salt fluoridation in France will reduce the caries incidence to a DMFT not more than 3 for the 12 year old children thus fulfilling the WHO goals for oral health in the year 2000. |
Lecturers have been told to include more black and ethnic minority authors in the Cambridge University English curriculum, after students complained of “institutional racism.” Critics say excluding “old white male” authors will distort “historical truth.”
The debate was instigated by Lola Olufemi, a women’s officer for the Cambridge University Students’ Union, who wrote an open letter, co-signed by around 150 other students, asking for the curriculum to be “decolonized” and broadened to include Black and Minority Ethnic (BME) authors.
“For too long, teaching English at Cambridge has encouraged a ‘traditional’ and ‘canonical’ approach that elevates white male authors at the expense of all others. What we can no longer ignore, however, is the fact that the curriculum, taken as a whole, risks perpetuating institutional racism,” the letter states.
While Olufemi made no mention of actively excluding white male writers, the constraints of the course would mean that inclusion of new material by BME authors would inevitably mean the omission of existing texts.
The letter was discussed by the Cambridge English Faculty’s Teaching Forum, which decided to encourage academic staff to actively promote the reading of BME texts to their students, the Telegraph reports.
The decision has scandalized Britain’s establishment press. Both the Daily Mail and the Telegraph claimed academics will be “forced” to comply with the move.
Not all lecturers back the move either. Emeritus Professor Gill Evans complained the proposal would “distort” the curriculum. “[If you] lose sight of the historical truth that the West explored the world from the sixteenth century and took control – colonially or otherwise – of a very large part of it. It is false to pretend that never happened,” she told the Telegraph.
Read more
Other academics welcomed the move.
“Currently teaching of BME topics is largely restricted to the contemporary papers. In my view, such texts and topics need to be integrated much earlier and much more centrally,” said Priyamvada Gopa, a member of the forum.
In a statement, the University of Cambridge reaffirmed its support for the campaign. “Academic discussions are at a very early stage to look at how postcolonial literature is taught,” it said, noting that “changes will not lead any author being dropped in favor of others.”
“We condemn the related harassment directed towards our students on social media as a result of the recent coverage,” the university added.
First and second year students study English literature from 1300 to 1550, while choosing a second period of focus including present day literature. Students are also permitted to take papers from Anglo-Saxon, Norse and Celtic, Classics, or Modern and Medieval Languages for study.
The move follows widespread criticism of the university’s illustrious rival, Oxford, after one in three of the institution’s colleges failed to admit a single black A-level student in 2015. Labour MP David Lammy condemned the university for perpetuating “social apartheid.”
The data was the first of its kind released by Oxford since 2010. Cambridge released similar data, which revealed that six of its colleges failed to admit any black A-level students over the same time period. |
Q:
Mercurial distributed repositories
Having myself found in a role of a build engineer and a systems guy I had to learn end figure out a few things - namely how to set up our infrastructure. Before I came on board they didn't have any. With this in mind please excuse me if I ask anything that should have been obvious.
We currently have 3 level distributed mercurial repositories: level one on each of developer machines, level two on central (trunk) server - only accessible from local network and the third layer on BitBucket. Workflow is as follows:
Local development: developer pulls change-sets from local network server. developer commits to local and pushes to our local server once merge conflicts are resolved. A scheduled script overnight backs everything up to BitBucket.
Working from home: developer pulls change-sets from BitBucket. Developer comits to their local repo and push to BitBucket.
TeamCity picks up repo changes from local network server for each project and runs a build / automated deploy to test environment.
The issue I'm hitting is scenario 2: at the moment if someone pushes something to bitbucket it's their responsibility to merge it back when they're back in office. And it's a bit of a time waster if it could be automated.
In case you're wondering, the reason we have a central repo on local network is because it would be slow to run TeamCity builds of BitBucket repositories. Haven't tested so it's just an educated guess.
Anyhow, the script that is scheduled and pushes all changes from central repository on local network just runs a "hg push" for each of repositories. It would have to do a pull / merge beforehand. How do I do this right?
This is what the pull would have to use switches for:
- update after pull
- in case of merge conflicts, always take newer file
- in case of error, send an email to system administrator(s)
- anything extra?
Please feel free to share your own setup as long as it's not vastly different to what's described.
UPDATE: In light of recent answers I feel an important aspect if the intended approach needs to be clarified. The idea is not to force merges on our local network central repo. Instead it should resolve merge conflicts in same was as per using HgWorkbench on developer machines with post pull: update + merge. All developers have this on by default so it should be OK.
So the script / batch file on server would do the following:
pull from BitBucket
update + auto merge
Any merge auto conflicts?
3.1 Yes -> Send an email to administrators to manually merge -> Break
3.2 No -> Cary on
Get outgoing changesets. Will push create multiple heads? (This might be redundant because of pull / update)
4.1 Yes -> Prompt administrators. Break.
4.2 No -> Push changes
Hope this clears things up a bit. Now, can this be done using hg commands alone - batch - or do I have to script it? Specifically can it send emails?
Thanks.
A:
So all your work is available at BitBucket, right? Why not make BitBucket (as available from anywhere) you primary repo source and dropping your local servers? You can pull changes from BitBucket with TeamCity for your nightly builds and developers whould always work with current repo at BitBucket and resolve all merging problems themselves so there wouldn't be any subsequent merges for you.
|
First TC1 Release – 2/27/2018
Second TC1 Release – 3/14/2018
Third TC1 Release & Origin, Izumo, Baja Release – 3/28/2018
2nd Origin, Izumo, Baja Release – 4/3/2018
World Wide Release – 4/5/2018
Please note that the latest client patch is mandatory, so please be sure to patch your client before accessing any production server.
Latest Changes
Fixed issue with Global Chat where unicode text did not support all languages.
Global Chat
See the Global Chat page here.
Endless Journey Restrictions
Veteran Endless Journey Features Access Requirements Monthly Subscription New accounts or 120 days after a veteran account becomes inactive. No subscription required. Skill Cap 720 720 Ultima Store Yes Yes Veteran Rewards Can claim rewards in game and gain new rewards Cannot claim rewards in game or gain new rewards Use Veteran Reward Items Yes Yes Holiday Gifts Yes No Housing Placement Yes No Co-Owner or Traded/Friend Yes Cannot co-own or be traded a house. Can be friend to house only for wall safe security. Access Normal Public Houses Only Place Vendors Yes No Rental Vendors Yes No Wall Safe Yes Yes Lockdown/Secure Containers Yes No Access Mailboxes Yes No Interact with Player Vendors Yes Yes Drop logs/ingots (and other stackable items) on a locked down pile Yes No Safe logout in houses Yes Inns & Taverns Only Auction Safe Placement Yes No Dungeons Felucca Dungeons & Felucca T2A Yes Yes Chat General Chat Yes Yes Help Yes Yes Global Direct Messaging Yes Yes Character Character Transfer Tokens Yes, with purchase of token Yes, with purchase of token Character Creation All All shards, limited to 2 characters on new Endless Journey accounts Character Copy & TC1 Access Yes No/Yes Expansions, Boosters, and Theme Packs Up to Mondain’s Legacy Yes, included Yes, included Stygian Abyss Yes, included Yes, included (not active yet) High Seas If purchased If purchased Gothic/Rustic If purchased If purchased King’s Collection If purchased If purchased Time of Legends If purchased If purchased Miscellaneous Bank Box Yes Yes, limited to 20 items ( storage expansions can increase the max item count to 28). Any account over the max limit will be able to view their full banks but will not be able to remove any items at this time. Guilds Yes Cannot create new guilds but can join existing ones Resource Harvesting Restrictions None Yes -No 2x Felucca Bonus -Only basic ore & wood -No sand or stone Vice vs Virtue Yes Can participate in VvV but do not gain occupation points in active towns Do Repeatable Quests Yes Yes Use the Bag of Sending & Chest of Sending Yes No Use the Bracelet of Binding Yes Yes Use Pet Summoning Balls Yes Yes Do Community Collections Yes Yes Use Commodity Deeds Yes No Use Scrolls of Alacrity, Power, Stat, and Transcendence Yes Yes Protect or be Protected by Another Player via the Justice
Virtue Yes No Use the Justice Virtue Yes No Gain Justice Points Yes No Use Valor, Compassion, Honesty, Honor, Humility, Sacrifice,
and Spirituality Virtues Yes Yes Receive Scrolls from Champ Spawns Yes No Use Power Scrolls Yes Yes Receive Rewards, Monster Kill Points, or Virtue Points from
Champ Spawns Yes No Receive Mondain’s Legacy Resource Rewards Yes Yes EM Event Items Yes No Attack EM Event Creatures All None Board Ships All All, High Seas ships if purchased City Loyalty Yes Yes City Elections & Governorships Yes No Treasures of Tokuno Style Events Yes Yes Bulk Order Deeds Yes Yes, cannot bribe up. May only receive one BOD per day. Use Pack Animals Yes Yes, but may not mount pack animals with items in their pack. Cleanup Britannia Yes Yes Zoo Donations Yes Yes Covetous Void Pool Yes Yes
Town Crier Updates
Existing NPC Towncriers have been removed and respawned at all banks, starting inn locations, and the Eodon moongate.
Using the “news” speech command or double clicking a town crier NPC will now bring up the Town Cryer newspaper.
Town crier NPCs are updated in real time with the latest information. Non-NPC town criers (Sherry the Mouse & Coral the Owl) are updated once on server up if those objects are locked down or secure.
Town Cryer News & Quests
The “News” section of the Town Cryer offers a variety of quests designed to introduce players to new and existing content.
Quests can be accepted via the “Quest” button in each Town Cryer article.
Quests are non-repeatable.
Where appropriate, news articles have a “Learn More” button that will open a webpage to pertinent wiki-entries on UO.com.
Town Cryer quests are available for the following content areas, Animal Training updates The Wreck of the Ararat The Huntmaster’s Challenge Dungeon Shame Dungeon Wrong Castle Blackthorn Dungeon Treasure Hunting Dungeon Covetous Dungeon Despise
Town Cryer EM, City & Guild Events
EM event information, City Governor posts, and Guild Events are available in their respective sections of the Town Cryer.
Updates to the Town Cryer are done through a context menu accessed on NPC Town Criers.
Only the updates options the user has permissions for are displayed.
Governor Entries May be accessed by the Governor. Must have a headline, at least one paragraph entry, and an expiry between 1-14 days. May have up to 5 active articles at any time. Entries are cleaned up at the time of expiry.
Guild Events Guilds with 20 or more members may have 1 active event notice in the Town Cryer guild section. Guild Leaders & Warlords have permission to input, update, and delete event notices. A total of 150 guild event notices may be active at any given time. Events are sorted by date and cleaned up when the event date has passed. Guild event notices require a headline, event month, event day, event time, event timezone, event meeting place, and event description. Events may be posted for the current month and the following month. Inappropriate entries into the Town Cryer will result in guilds losing permission to input further events.
The Britain Commons
A new area has been added to Trammel Britain in the area southeast of the First Bank of Britain.
This open space makes for the perfect meeting place and offers nearby access to essential city services such as a pub, stable master, and crafting stations.
Ultima Store Items
The following items will be available in the Ultima Store. Keep an eye on UO.com and in-game for release dates!
Virtue Shield This shield grants a bonus to virtue points gained while equipped! The shield provides 8% to all resists, penalty free spell channeling, and 10% defense chance increase. Can be used by Humans, Elves, and Gargoyles and dyed with metallic, plant, and specialty pigments.
Deluxe Starter Pack This starter pack is a perfect way to jumpstart your journey in Britannia! This starter pack includes, A Runic Atlas (a high capacity runebook) that comes pre-loaded with recall runes to Britannia’s Vaults, Banks, and Points of Interest A Runic Hunter’s Atlas that allows recalling to a variety of hunting grounds friendly to the training adventurer, complete with location descriptions and tips A full complement of full spellbooks for all magic schools including Bushido, Chivalry, Magery, Mysticism, Necromancy, and Ninjitsu A Token of Skill Alacrity that allows you and your party members to experience an increased rate of skill gain for an entire week A Deluxe Journeyman’s Armor token that outfits the adventurer in a starter set of human/elf or gargish leather armor providing 70% in all resists, +15 Hit Points, +17 Mana, +17 Stamina, +30 Lower Mana Cost, +6 Hit Point Regeneration, +6 Mana Regeneration, +10 Stamina Regeneration, +5 Strength, +5 Dexterity, +5 Intelligence, and 100% Lower Reagent Cost A Community Collection Point Award token that can be redeemed at the Moonglow Zoo, Vesper Museum, or Britain Library for 500,000 points A Dungeon Point Award Point Token that can be redeemed for 100 Blackthorn Dungeon points, 1000 Dungeon Crystal Points of Despise, and 1000 Covetous Points A direct deposit of 100,000 gold into your currency account All items are account and shard bound.
Miscellaneous Updates
Existing city bulletin boards have been removed and new freestanding boards have been placed in each loyalty city. Only city citizens may interact with a city’s bulletin board.
Invisibility & Teleport Items Special moves can no longer be toggled while these items are casting These items can no longer be used while casting spells Invisibility items now have a 2 second casting delay Teleportation items now have a 1 second casting delay
Instanced Corpse Update Only 250 items will be re-consolidated back to a public corpse from all instances.
Added hitching post to Shadowguard lobby
Bug Fixes
All pets which have been exploited by releasing or death will have the following stats reset and incur a penalty to their advanced pet training. Strength, intelligence, dexterity, hit points, stamina, mana, base damage, and all resists will be reset to defaults. This change has been removed pending further development. Pets tamed before Publish 97 (Pre-Patch Pets) with pet slots lower than their true pet slots will no longer be able to start new advanced pet training. This is a temporary restriction to prevent further pets from entering a broken state prior to the resolution of the above referenced issue which will be resolved in Publish 100.
Fixed issue where quest text would get truncated in quest gumps.
Fixed issue where the New Haven Dark Knight quest could no longer be reached via rune.
Chicken coops are now shard bound and pets that have undergone animal training can no longer be placed in the coop.
Classic Client
Updated login screen
Cliloc changes
Art changes
Resolved issue where trading platinum & crimson drakes would result in classic client crashes.
Known Issue: The client crashes while trying to access the game credits.
Enhanced Client
Updated login screen
Cliloc changes
Art changes
Disabled the new player tutorial
Latest Changes
Fixed issue where monks in the Chamber of Virtue would not properly display a gump when doubled clicked.
Fixed issue with Animal Trainer quest where accepting the quest from the Town Cryer and continuing the quest with a female animal trainer vs a male animal trainer could break the quest.
Fixed issue where players could not use rune books or runic atlases if they were not in a player’s backpack.
Fixed issue where using the switch clothes command on a mannequin would be placed at the mannequin’s feet.
Pets tamed before Publish 97 (Pre-Patch Pets) with pet slots lower than their true pet slots will no longer be able to start new advanced pet training.
Improved Global Chat performance.
Issues resolved since Release 1 |
Q:
Python 2.7 AttributeError: 'ResultSet' object has no attribute 'replace'
I'm using BeautifulSoup and urllib to make a Wikipedia web scraper. I just keep getting the same annoying error.
My code:
from bs4 import BeautifulSoup
import urllib
page = urllib.urlopen("https://en.wikipedia.org/wiki/Donald_Trump").read()
soup = BeautifulSoup(page, "html.parser")
nickname = soup.find_all("span", class_="nickname")
nickname.replace('[<span class="nickname">','')
nickname.replace('</span>]','')
print(nickname)
The error:
AttributeError: 'ResultSet' object has no attribute 'replace'
A:
nickname has datatype ResultSet, you have to convert it to a string if you want to do some string operations on it.
from bs4 import BeautifulSoup
import urllib
page = urllib.urlopen("https://en.wikipedia.org/wiki/Donald_Trump").read()
soup = BeautifulSoup(page, "html.parser")
nickname = soup.find_all("span", class_="nickname")
nicknameStr = str(nickname)
nicknameStr.replace('[<span class="nickname">','')
nicknameStr.replace('</span>]','')
print(nicknameStr)
|
First Name is Required
Last Name is Required
Code is Required
Email is Required
Phone is Required |
[Eclipse retinopathy: three case reports].
We present the evolution of eclipse retinopathy in 3 patients who came to our hospital after the eclipse of October 2005 and had foveal lesions and visual field alterations. Eclipse retinopathy is a maculopathy that occurs after exposure to intense solar radiation, such as occurs during an eclipse, and is produced by a photochemical mechanism. Although the macular changes and symptoms are usually reversible, residual defects at the level of the EPR and scotoma in visual fields can occur. For these reasons the most appropriate treatment is prevention by means of public awareness campaigns. |
Small cell lung carcinoma: clinicopathological, immunohistochemical, and ultrastructural study.
Sixty-seven cases of small cell lung carcinoma (SCLA) in Tri-Service General Hospital (TSGH) during the past 16 years were studied. For patients with extensive stage of disease, the mean survival time and 2-year survival rate were 7.2 months and 3.1% versus 13.4 months and 16.7% for patients with limited stage. A better prognosis was obtained by treatment with a combination of intensive chemotherapy and radiotherapy. Immunohistochemical studies were performed by the peroxidase-antiperoxidase method. The positive rates in descending order were bombesin (80%), synaptophysin (74.3%), neurofilament (68.6%), neuron-specific enolase (60%), low molecular weight cytokeratin (54.3%), high molecular weight cytokeratin (25.7%), chromogranin-A (22.9%), adrenocorticotrophic hormone (0). Seven cases were examined and found to be ultrastructure; only 3 cases were found to contain neurosecretory granules. We emphasize that electron microscopy is not necessary as a routine diagnostic procedure, while light microscopy should be employed whenever possible; the immunohistochemical study should be considered within this context. |
Marsden Bay, New Zealand
Marsden Bay is a locality and bay at the south head of Whangarei Harbour in Northland, New Zealand. The western side of Marsden Bay is a coastal community called One Tree Point, and the eastern side is the industrial development of Marsden Point. Ruakaka lies about 9 km to the south.
The Māori name for the area is Te Poupouwhenua.
History
One Tree Point was called "Single Tree Point" by Captain Lort Stokes of the Acheron in 1849.
The town of Marsden, situated where Marsden Point is now, was originally intended to be the commercial centre for the district, due to the access to deep water, and because it was closer to Auckland than the area which is now Whangarei. The government purchased on the point in the mid-1850s and laid it out in quarter-acre sections. The development of the kauri gum industry changed the focus of settlement to Whangarei.
The Marsden Point oil refinery was built in the 1960s and expanded in the 1980s.
Education
One Tree Point School is a coeducational contributing primary (years 1-6) school with a decile rating of 4 and a roll of 181. The school was established in 1972.
Notes
External links
One Tree Point School website
Category:Whangarei District
Category:Populated places in the Northland Region |
Not sure if my facebook friends are unusually intelligent Or i've just unsubscribed from all of the idiots
155 shares |
The present invention relates to fluoro-alcohol additives for orientation control of block copolymers used in directed self-assembly applications, and more specifically to materials for top orientation-control of high-chi (χ) block copolymers containing a polycarbonate block.
Block copolymers (BCPs) find many applications in solution, bulk and thin films. Thin film applications of BCPs are particularly attractive for nanolithography and patterning due to the ability of some BCPs to form periodic self-assembled structures ranging in feature size from 5 nm to 50 nm. The thin-film self-assembly property of BCPs can be utilized with existing photolithographic techniques to provide a unique approach to long range order for semiconductor applications. This approach, called directed self-assembly (DSA) of block copolymers, promises to extend the patterning capabilities of conventional lithography.
BCPs for directed self-assembly (DSA) applications comprise two or more polymer blocks that can phase separate into domains characterized by ordered nanoscopic arrays of spheres, cylinders, gyroids, and lamellae. The ability of a BCP to phase separate depends on the Flory Huggins interaction parameter chi (χ) and degree of polymerization of the block copolymer. Poly(styrene)-b-poly(methyl methacrylate), abbreviated as PS-b-PMMA, is the most widely used block copolymer for DSA. For PS-b-PMMA, the poly(styrene) block (PS) and the poly(methyl methacrylate) block (PMMA) have similar surface energies at the polymer-air interface at elevated temperatures. In this instance, annealing a thin layer of the BCP, which is disposed on an orientation control layer, induces phase separation to produce BCP domains that are perpendicularly oriented to the orientation control layer. Typically, for PS-b-PMMA the orientation control layer is a crosslinkable or brush-type random copolymer formed with styrene and methyl methacrylate. The neutral wetting properties of the orientation control layer (underlayer) can be controlled by adjusting the composition of styrene and methyl methacrylate in order to enable perpendicular orientation of the BCP lamellar domains.
The minimum half-pitch of PS-b-PMMA is limited to about 10 nm because of the lower interaction and interaction parameter chi (χ) between PS and PMMA. Typically when the product of chi and N of the block copolymer is less than 10, such a block copolymer tends to form disordered aggregates rather than ordered phase-separated domains. To enable further feature miniaturization (i.e., using block copolymers having lower degree of polymerization), a block copolymer with higher interaction parameter between two blocks (higher chi) is desirable. Several block copolymers having higher interaction parameter between the two blocks have been studied to obtain smaller feature sizes. Of particular interest are block copolymers comprising a block derived from ring opening of a cyclic carbonyl monomer from a reactive end-group on the first polymer block. Block copolymers formed by ring opening polymerization (ROP) of cyclic monomers (e.g., lactides, lactones, ethylene oxide) have been used to generate sub-10 nm feature size for patterning application.
As the interaction parameter between the two blocks of the block copolymer increases, neutral underlayer properties alone may not be sufficient for forming perpendicularly oriented block copolymer domains due to the increased mismatch between the polymer-air surface energies of the two blocks. This causes parallel orientation of the block copolymer domains with only the lower surface energy block present at the polymer-air interface, rendering the thin-film undesirable for lithographic applications. Top-coat based orientation control strategies have been employed to control the surface energy at the polymer-air interface of the blocks. However, these strategies introduce additional process complexity in the integration of high-chi block copolymers into standard lithography processes.
There exists a need to develop a top-coat free method for perpendicularly orienting block copolymer domains of a high-chi block copolymer with sub-10 nm half-pitch. |
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Thursday, March 19, 2015
Annandale real estate market gaining strength
This 5,188-square foot house on Vellex Lane in the Wilburdale neighborhood is on the market for $1,169,888. It has five bedrooms, five bathrooms, a sun room, and much more. [Zillow]
The average price of a home sold in Annandale (zip code
22003) in February was $447,450, a 3.47 percent increase over the average home
sold here in February 2014, reports realtor Vivian Couts at Coldwell Banker.The median
price of homes sold last month, $481,000, is up 13.3 percent from February
2014.
Thirty six homes were sold in Annandale last month, compared
to just 28 in the same period a year ago. Home are also selling faster – the average
days on market are down from 59 in February 2014 to 5
+64 in February 2015.
While the number of detached houses sold last month are up
80 percent compared to February 2014, the number of attached units are down
30.8 percent.
The most expensive houses sold in Annandale last month were
in the $600,000 to $799,999 category; there were seven houses, all with four or more
bedrooms, sold in that category. There are 11 active listings for houses priced
in the $1 million to $2.49 million category.
Ellie I know that there are some better houses in this area to showcase for Annandale. Can you please pick some houses that are less garish. There is a really nice new renovation (my opinion) and a rather large one on Sleepy Hollow Road; sort of green taupe and unusual on a corner plot. This may be a much better example of how we may want to be represented.
Thank you, a concerned neighbor that would love for Annandale to have some good PR.
Join the conversation. The Annandale Blog covers redevelopment. land use, business openings and closings, schools, crime, politics (with a progressive viewpoint), transportation, recreation, and other issues in Annandale, Seven Corners, Bailey's Crossroads, Lincolnia, and other parts of the Mason District area of Fairfax County, VA. |
Q:
How to save Oracle DDL in an automated fashion
Oracle SQL Developer is able to export DDL through Tools -> Database Export... This works very well, but requires manual intervention.
I know of DBMS_METADATA.get_ddl(), what I want to do is save the generated DDL in client machine which I use to connect to the Oracle DB using Oracle SQL Developer, this can be done manually.
But, I am looking for an automatic/scriptable way to export (save to local machine) DDL identical to what is exported through the manual way.
This is the SQL command I used to get DDL.
select dbms_metadata.get_ddl('obJType','ObjName','Schema') from dual;
How can I do that?
A:
You can use spool and dbms_output.put_line to spool the results to your local machine.
You can see the link for an example utl-file-saving-in-local-machine spooling and tweak the same as per your requirement.
|
Hi all,
Chicken 4.8.0.2 is now available for download from the usual place:
http://code.call-cc.org/releases/4.8.0/chicken-4.8.0.2.tar.gz
=== What's new ===
4.8.0.2
- Interpreter - Fix regression in ,d for procedures, which resulted in an sprintf error.
- Compiler - Fix rewriting of newlines (~~) in printf.
- Runtime - Allow > 4GB heap on 64-bit systems (#974). - Added missing library (-lrt) on Solaris for nanosleep calls (#970).
- Build system - Use test -f instead of test -e in identify.sh to placate Solaris.
==================
The 4.8.0.x releases reside on the stability/4.8.0 branch in git,
which you can retrieve with:
git clone --branch stability/4.8.0 git://code.call-cc.org/chicken-core
Or browse my unofficial github mirror: https://github.com/ursetto/chicken-core-stability/tree/stability/4.8.0
Jim |
The effect of contrast on perceived speed and flicker.
Slowly moving low contrast patterns appear to drift more slowly than higher contrast patterns. It has been reported that this effect of contrast is reversed for flickering patterns such that they appear to flicker faster than high contrast patterns. This apparent difference in the effect of contrast on perceived speed and flicker may place important constraints upon models of speed encoding in the human visual system. We have measured perceived speed and flicker over a range of spatial and temporal frequencies. The results indicate that contrast has qualitatively (but not quantitatively) similar effects upon perceived speed and flicker. The results also indicate that the effect of contrast upon perceived speed is likely to be inherited from the effect of contrast upon perceived flicker. These findings allow a relaxation of previous constraints upon models of speed encoding. |
Fetal breasts in normal and Down syndrome fetuses.
To assess the validity of fetal breast size measurement as a sonographic marker in fetuses with Down syndrome. Fetal breasts were studied in 26 fetuses with trisomy 21 and 78 fetuses with normal chromosomes. Breasts were identified and measured in a cross-sectional plane of the fetal chest at the level of the four-chamber view of the heart. Normal fetuses had a mean breast size of 3.8 mm +/- 1.1 mm. Fetuses with Down syndrome had a mean breast size of 1.9 mm +/- 0.7 mm (p < or = 0.0001). Diminished breast size measured by ultrasound in the second trimester may be helpful in identifying fetuses with Down syndrome. |
MacSpeech's Dictate: high quality voice recognition for the Mac
MacSpeech at this week's Macworld Expo unveiled Dictate, its new speech recognition and voice command software currently in beta and slated for release mid February. The new product replaces and improves upon the existing iListen.
Dictate is now based upon the highly accurate speech recognition engine developed by Naturally Speaking; iListen was based upon technology licensed from Philips. MacSpeech supplies the user interface and rich integration with AppleScript and other Mac technologies.
A $29 crossgrade is available for any registered iListen customers who have purchased or obtain a copy of iListen in 2008. Any registered iLife customer from 2007 and earlier can pre-order a crossgrade for $79.
Speech Recognition Accuracy
Representatives demonstrated the accuracy and intelligence of the new system by dictating live into the system. After being switched on, the system allows the user to both dictate and issue voice commands. It determines which you are doing by analyzing the context of words. Dictate only requires a 5 minute profile creation session, which profiles the mic used and then analyzes the speaker's speech patterns and diction. In addition, the user can supply text that the software will analyze for unfamiliar words, and then speak those words to expand the system's dictionary.
The software's advanced recognition engine allows the software to accurately present natural speech dictation, correctly interpreting text such as "the patient was in a coma, comma" or "the end of the medieval period period." It also correctly formatted phone numbers and currency amounts, complete with a dollar sign, a thousands comma, and a decimal point, even when spoken in different ways, such as "five thousand dollars and twenty cents."
Dictate can enter text into any application that supports text entry from the keyboard, even including Windows apps running in a virtual environment such as Parallels or Fusion. To take a quick dictation without opening another application, Dictate also provides a simple text entry window of its own.
The software will support a variety of English language families, including American English, UK English, and Australian, Indian, and SE Asian variants. MacSpeech also has immediate plans to release German, Italian, Spanish, and French versions, and can match developments in new speech engine models released by Naturally Speaking.
Voice Control
In addition to entering text, Dictate can also be used to control the desktop interface. Reps demonstrated the software being used to launch applications, edit entered text, even open Safari bookmarks.
When a new application is installed, Dictate rapidly scans it to set up a table of commands, allowing the user to launch it by name and then activate any of its menu commands by voice. The voice command features can also be extended using AppleScript. Among other features, Dictate can also be used to launch Spotlight and rapidly search the system.
Dictation Hardware
Dictate ships with a microphone, but can be used with any standard mic. Company reps recommended against using a Bluetooth mic because that protocol limits the bandwidth of sound input to 8 KHz, reducing the overall accuracy of dictation. Other wireless microphones, such as professional quality RF equipment, can be used at full quality.
MacSpeech is using technology from Nuance and essentially the same technology currently present in the Dragon Naturally Speaking engine. Nothing too novel there I think
I wish Apple would realize the importance of speech recognition too and start investing money in it like it did back in the 90s. The potential of speech recognition for enabling voice commands and accurate dictation in devices like the iMac, iPhone and iPod is huge .
There were rumors that Microsoft's 1997 $150,000 investment in Apple came with some conditions including that Apple not compete in the area of voice recognition. I could imagine Apple agreeing to these terms given the state of the technology at that time. However, it's hard to believe, even if there was such an agreement, that there is not some sunset on the period of time until Apple can enter this arena. Hopefully, we will see voice recognition addressed by Apple soon.
There were rumors that Microsoft's 1997 $150,000 investment in Apple came with some conditions including that Apple not compete in the area of voice recognition. I could imagine Apple agreeing to these terms given the state of the technology at that time. However, it's hard to believe, even if there was such an agreement, that there is not some sunset on the period of time until Apple can enter this arena. Hopefully, we will see voice recognition addressed by Apple soon.
Since they no longer install IE as the default browser I'd say whatever deal was made is now complete.
edit: It was a 150,000 shared then valued at $150 million. MS sold those shares pretty much as soon as they could.
There were rumors that Microsoft's 1997 $150,000 investment in Apple came with some conditions including that Apple not compete in the area of voice recognition. I could imagine Apple agreeing to these terms given the state of the technology at that time. However, it's hard to believe, even if there was such an agreement, that there is not some sunset on the period of time until Apple can enter this arena. Hopefully, we will see voice recognition addressed by Apple soon.
That would explain why Microsoft has gotten really good on speech recognition lately
It's nice to see iListen drop that turd of a engine and move to Nuance technology. If Apple isn't interested in Spech Rec at a serious level they're on crack. I wince everytime I see a mini chiclet qwerty keyboard on a phone. Stone Age comes to mind.
I like the price of Dictate. It leads me to believe that they are basically delivering Dragon Preferred on Mac. However I'd love to see features that come in Professional. There needs to be robust support for scripting and creating Macros. That's where the fun...and efficiency really kick in. |
[Treatment results of surgical and radiologic therapy of penile cancer].
A retrospective analysis was made about the results achieved in 64 patients after combined surgical and radiotherapeutic treatment. The tumor areas were irradiated by fast electrons or cobalt 60 with 50 to 55 Gy, the lymph nodes received doses of 45 to 55 Gy. Local tumor control was achieved in 27 out of 28 patients irradiated immediately after surgery (96%). In case of demonstrated lymph node invasion, local control was achieved in 14 out of 19 cases (74%). The median survival was 9.6 years for patients in stage T1/2, N0, M0 and 2.5 years for patients in stage T1-4, N+, M0. The first two years following to therapy were decisive for the prognosis. Among those of our patients who developed recurrences during this period, not one could be cured in the long run. Two years after the end of therapy, the survival probability of patients without lymph node metastases becomes comparable to the survival curve of normal male population of the same age. In the treatment of penile carcinoma, a gradual proceeding depending on the stage is recommended for the combination of surgery and radiotherapy. In case of lymph node metastases, the application of adjuvant chemotherapy should be taken into consideration. |
OST file is an offline storage file which makes it possible to work when you are not online. You can perform task like emails, receive new messages from the other online mailboxes and you can also make changes to the emails and other items while you are offline. However sometime you face data lost problem because of modification in Exchange Server mailbox or some other reasons that time to overcome such situation, you need to use some result-oriented and appropriate third-party tool like OST Converter Tool. This tool helps you to convert OST to MS Outlook 2019, 2016, 2013, 2010 and so on.
Why you Need Outlook OST file to PST? Sometimes your mailbox gets vanished from the Exchange Server that time you need to use Outlook OST to Outlook PST file converter. Owing of data lost issue your works hamper a lot. In this situation you incline towards to use OST file converter to convert OST to Outlook items & get data back safely without any alteration.
Reason for Exchange Server Damage
There are various reasons for damaging Exchange Server owing of this, your crucial data get lost and you face serious problems. Some reasons are underwritten: |
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Транспортный самолет ВВС России Ил-76 подозревается в нарушении воздушного пространства Финляндии. Об этом сообщает пресс-служба Минобороны страны. Инцидент зафиксирован в 14:15 в пятницу недалеко от города Порвоо.
В пятницу МИД Эстонии вызвал российского посла Юрия Мерзлякова. Ему вручена нота протеста в связи с нарушением воздушного пространства Эстонии российским военно-транспортным самолетом Ан-26. Инцидент произошел в 12:50 в понедельник в районе острова Вайндлоо. Самолет находился в воздушном пространстве Эстонии больше минуты, сообщил штаб Сил обороны. Нарушение границы зарегистрировал операционный центр на авиабазе Эмари.
До этого был представлен план полета, согласно которому самолет должен был находиться в международном воздушном пространстве. Транспондер самолета был включен, пилот контактировал с диспетчерской службой Эстонии.
В российском Минобороны заявили, что самолет выполнял рейс Калининград - Петербург и на протяжении всего полета находился в международном воздушном пространстве.
11 марта истребители ВВС Италии, несущие службу в составе Балтийского воздушного патруля НАТО, были подняты на перехват российского самолета-заправщика Ил-78 над Балтикой. Ранее - 9, 13, 27 февраля и 5 марта - истребители НАТО поднимались на перехват разведывательных самолетов Ил-20, а 3 и 6 февраля - на перехват военно-транспортного самолета Ил-76 и противолодочного Ил-38.
Минобороны России неоднократно заявляло, что все полеты самолетов российских ВВС выполнялись и выполняются в строгом соответствии с международными правилами использования воздушного пространства над нейтральными водами, не нарушая границ других государств. При этом, как отмечают российские военные, активность ВВС НАТО вблизи российских границ сохранялась в течение всех предыдущих лет, и резко возросла в последние годы. |
We Did It! — Julie Scott, SRC
Soror Julie Scott, Grand Master of the English Grand Lodge for the Americas and Supreme Secretary of AMORC, reflects on the extraordinary projects that have been accomplished at Rosicrucian Park since the 75th Anniversary of the Park in 2002.
In 2002, on the occasion of the seventy-fifth anniversary of the founding of Rosicrucian Park, the Board of Directors of the English Grand Lodge announced the plans for the Future of Rosicrucian Park in a special issue of the Rosicrucian Digest. Some of the goals seemed formidable, however they were so important that we decided to include them all.
Today, most of these goals, plus many more, have been achieved, thanks to the exceptional vision and commitment of our Board and the generosity of thousands of Rosicrucian members around North America and the Caribbean.
This podcast describes some of the extraordinary projects that we have all accomplished together.
Thank you to everyone who has participated in the preservation and perpetuation of Rosicrucian Park. Your support has made all of this possible!
I hope that each of you will visit or re-visit Rosicrucian Park soon, to experience its beauty and tranquility. We look forward to welcoming you! With sincere appreciation for your support and my warmest wishes for Peace Profound, |
Q:
How to refer to a complex type in XML schema with no targetNamespace
At the moment, I'm implementing a number of interfaces to consume XML data from external systems. The data I'm supposed to receive are all well-formed XML documents. However, the problem is that they all come without namespaces like the sample below.
<ReturnOfFileApplicationDetails>
<ApplicationNo>APP-2015-1214-000847</ApplicationNo>
<CourtOrderRefNo></CourtOrderRefNo>
<SourceRequestNo></SourceRequestNo>
<Status>A</Status>
<RejectionReason></RejectionReason>
<CourtEventDetails>
<NextCourtNo>26</NextCourtNo>
<NextCourtDateTime>201601111500</NextCourtDateTime>
<NextCourtJOName></NextCourtJOName>
</CourtEventDetails>
<IODetails>
<Name>CPIB IO</Name>
<Designation>Special Investigation Officer</Designation>
<DivisionAgency>CPIB</DivisionAgency>
<ReportNo></ReportNo>
<IPNo></IPNo>
</IODetails>
</ReturnOfFileApplicationDetails>
Hence, from what I've learnt so far, I cannot use targetNamespace in the XSD schema I built to describe those data. For example, below is the XSD I created for the above payload.
<xsd:schema xmlns:xsd="http://www.w3.org/2001/XMLSchema"
xmlns="http://oscar.pactera.com/icms/schema">
<xsd:include schemaLocation="CourtEvent.xsd"/>
<xsd:include schemaLocation="InvestigationOfficer.xsd"/>
<xsd:complexType name="FileApplication">
<xsd:sequence>
<xsd:element name="ApplicationNo" type="xsd:string" minOccurs="0" nillable="true"/>
<xsd:element name="ApplicationType" type="xsd:string" minOccurs="0" nillable="true"/>
<xsd:element name="CourtOrderRefNo" type="xsd:string" minOccurs="0" nillable="true"/>
<xsd:element name="SourceRequestNo" type="xsd:string" minOccurs="0" nillable="true"/>
<xsd:element name="CaseNo" type="xsd:string" minOccurs="0" nillable="true"/>
<xsd:element name="Status" type="xsd:string" minOccurs="0" nillable="true"/>
<xsd:element name="RejectionCode" type="xsd:string" minOccurs="0" nillable="true"/>
<xsd:element name="RejectionReason" type="xsd:string" minOccurs="0" nillable="true"/>
<xsd:element name="CourtEventDetails" type="CourtEvent" minOccurs="0" maxOccurs="1"/>
<xsd:element name="IODetails" type="InvestigationOfficer" minOccurs="0" maxOccurs="1"/>
</xsd:sequence>
</xsd:complexType>
<xsd:element name="ReturnOfFileApplicationDetails" type="FileApplication"/>
</xsd:schema>
The problem I have now is that my IDE is complaining that it cannot find the complex type FileApplication I put in for the ReturnOfFileApplicationDetails element the even though they are literally in the same XSD. Since the CourtEvent.xsd and the InvestigationOfficer.xsd also come with no targetNamespace, my IDE cannot find the CourtEvent and the InvestigationOfficer complex types as well.
I'd be very grateful if you could show me I properly build my XSD without targetNamespace.
Cheers,
James Tran
A:
You need to remove the default namespace declaration
xmlns="http://oscar.pactera.com/icms/schema"
|
fileFormatVersion: 2
guid: cf498fc35b538884db557f7a9a2c0ef9
timeCreated: 1512062703
licenseType: Pro
NativeFormatImporter:
externalObjects: {}
mainObjectFileID: 0
userData:
assetBundleName:
assetBundleVariant:
|
Category: Historical
Winner of the 2010 Eudora Welty booklet Prize and the Mississippi Library Association's Non-fiction Author's Award for 2011, lower than Surge, less than Siege indicates how typhoon Katrina tore into Bay St. Louis, Mississippi, raking away lives, structures, and livelihoods in a spot identified for its picturesque, coastal perspectives; its laid-back, artsy downtown; and its deep-dyed southern cordiality. The tragedy additionally published the interior workings of a group with an indomitable middle and profound neighborly bonds. these connections frequently introduced out the simplest in humans lower than the worst of situations. In less than Surge, below Siege, Ellis Anderson, who rode out the hurricane in her Bay St. Louis domestic and sheltered many pals afterwards, bargains tales of generosity, heroism, and laughter in the course of terror and determined uncertainty.Divided into elements, this ebook invitations readers into the intimate enclave prior to, in the course of, and after the typhoon. "Under Surge" specializes in connections among citizens, then demonstrates how these bonds sustained them throughout the worst storm in U.S. heritage. "Under Siege" files the 1st 3 years of the grinding aftermath, detailing the unexpected burdens of pressure and melancholy, coverage scandals, and opportunists that threatened to accomplish the annihilation of the plucky town.A mix of memoir, own diary, and firsthand reportage, below Surge, lower than Siege creates a compelling American testomony to the power of the human spirit.
Aiming to provide the reader with the historic info to have interaction with the debates surrounding the Cameron government's 'Big Society' and civil society, this booklet offers the reader a better and extra educated historic recognition of ways the NGO region has grown and encouraged.
He might take her as his bride...but may she supply her center in return?
When Egan MacBain takes appealing Glenda MacKay as his bride, it seems that he is performed so for the noblest of purposes. honestly, he has vowed finally to say the girl he is continually loved--yet as soon as lost--to one other guy. however the rugged Highlander is set to maintain his ardour hidden whereas he woos her along with his mild caress and depraved kisses. For he'll no longer have an unwilling spouse and may in simple terms convey his tenderness as soon as she is tamed.
Although Glenda has agreed to the wedding, she's simply performed so that you could achieve the security of Egan's identify. but this younger widow of the once-powerful extended family MacKay by no means anticipated that vows of affection would go away her lips back, nor did she think she'd ever carry any guy so expensive. yet abruptly she reveals herself succumbing to the robust, silent warrior who fills her with trepidations and a fevered, forbidden craving to satisfy his depraved promise of the love--and the child--she aches for within the depths of the soul.
The significant query in felony philosophy is the connection among legislation and morality. The felony structures of many nations around the globe were inspired through the rules of the Enlightenment: freedom, equality and fraternity. the location is identical in terms of the accompanying nation excellent of the democratic constitutional nation in addition to the idea of a welfare kingdom. the basis of those ideas lies within the perfect of person autonomy. The legislation needs to during this view warrantly a social order which secures the equivalent freedom of all. This freedom is additionally primary simply because in smooth pluralistic societies an excellent variety of perspectives exist about the applicable lifestyle. This freedom excellent is in spite of the fact that additionally strongly contested. In legislation, Order and Freedom, a old assessment is given bearing on the query of the level to which the trendy Enlightenment values can function the common beginning of legislation and society.
For leave out Elizabeth Smith, sharing her first kiss with the captivating Lord Derek Creswell is little short of a dream come true...that is, till she is noticed by means of the most influential gossips of the ton. With scandal nipping at her heels, to prevent overall social smash, Elizabeth needs to current a fiancé by way of the tip of the Season. but if the viscount proves reluctant, Elizabeth is compelled to hire a seduction of a distinct sort...
He is decided to spoil her
Viscount Derek Creswell believes Elizabeth got down to seize him into marriage. in any case, her sister tried the exact same factor along with his brother six years ahead of. Now the delectable omit Smith expects a betrothal and a hoop, whereas Derek reveals her ruination infinitely extra appealing...
But as Derek units out to seduce merely her physique, Elizabeth is reason on claiming his jaded heart.
Few comprehend Morgan Drake's precise name—but many worry the ocean Wolf, the scourge of the sea, a fearless pirate who frees inspired American sailors from British vessels. Now a stunning reporter is prepared to threat her lifestyles, her innocence, and her middle to bare the secrets and techniques that Morgan is set to guard at any expense . . . A headstrong and brave younger girl in a man's global, Serenity James understands she is only tolerated in her father's newspaper place of work. An particular tale concerning the dreaded Sea Wolf, notwithstanding, will earn her the honour she so fervently wishes. yet she by no means anticipated to be abducted via the attractive and unsafe brigand whose daring exploits have fired her imagination—or to find the journey she's continually longed for in Morgan Drake's passionate caress. |
Q:
How to get lapply to output 2 objects obtained from a function
I'm trying to lapply a function over a list. Because my function intends to output 2 objects, I'm running into a problem. For each item in the list, running the function only outputs results from the second object.
Here is a vastly simplified example.
test<-function(x){
a<-x+4
b<-x/34
}
list<-c(3,4,5,6,6)
lapply(list,test)
# Outputs b:
[[1]]
[1] 0.08823529
[[2]]
[1] 0.1176471
[[3]]
[1] 0.1470588
[[4]]
[1] 0.1764706
[[5]]
[1] 0.1764706
How to I get the function to output both a and b?
A:
The function is returning just the last line as it should.
Try:
test<-function(x){
a<-x+4
b<-x/34
return(c(a,b))
}
list<-c(3,4,5,6,6)
lapply(list,test)
|
North American ECA – Today
By (Captain) Jeff CowanSeptember 21, 2012
On August 1, 2012, the North American Emissions Control Area (NAECA) took effect, mandating the use of 1.0% sulfur Heavy Fuel Oil (HFO) or residual fuel oil for ships within 200 miles of the continent of North America. California has mandated the use of distillate fuel when ships are within 24 miles of its coastline since July 1, 2009. Lessons learned from California’s experience with distillate fuels may benefit operators as the next phase of NAECA comes into effect (January 1, 2015) when the International Maritime Organization (IMO) will mandate the use of distillate fuel by ships within 200 miles of the coast of North America. As that time draws near, industry observers have bantered possible compliance scenarios.
Since June 2012, several developments have helped the ship operator comply with the August 1 mandate. Foremost, the Environmental Protection Agency (EPA) provided an interpretation of fuel requirements. In guidelines released in June 2012, the minimum standard for 1.0% sulfur fuel viscosity will be not less than 11 centistokes (cst). This is significant because at the time it was thought ship operators would have a difficult time sourcing the required 1.0% sulfur fuel and have to switch over to low sulfur distillate fuel with its assorted engine compatibility issues – the same issues that California experienced.
California experienced a 300% increase in loss of propulsion incidents since its distillate fuel (viscosity 1-2 cst) regulation came into effect in 2009. The engines used aboard modern ships over 10,000 gross tons use 3.0% sulfur HFO. This fuel must be heated to flow through the fuel lines because at normal ambient temperature HFO either low sulfur or high sulfur has the consistency of tar. Distillate fuel in contrast does not require the high temperatures, and the thermodynamics of cooling metal, gaskets and seals resulted in leaks, along with filter clogging from engine buildup scrubbing. In addition, the cost savings of using HFO are significant over the use of distillate fuel which is typically around US$300 more per ton. Before the days of slow steaming, a typical containership might burn 5 to 6 tons per hour. The 1.0% sulfur HFO must be heated just like the 3.0% HFO so the engine/fuel compatibility issue was solved, at least between 200 to 24 miles off the coast of California.
The EPA recognized there may be supply problems and allowed ship operators, if the required fuel was not available in ports outside the NAECA, to simply notify primarily the EPA and Coast Guard no less than 96 hours before entering the NAECA.
Unlike the fuel switchover required 24 miles off the coast of California which typically took one to two hours, the NAECA must switch over completely to the 1.0% sulfur fuel before entering the NAECA. Det Norske Veritas (DNV) and Lloyds, for example, have calculators for estimating fuel changeover times to remain in compliance. The use of the calculators should suffice for demonstrating compliance with the 1.0% regulation in terms of a timely switchover. The Bunker Delivery Note (BDN) supplied with the just loaded bunkers will demonstrate compliance with the 1.0% sulfur rule as well. If the overseeing regime (EPA) denotes suspicious fuel switch procedures or supply issues, they may take their own sample. The problems with shipboard samples, however, can be numerous. The ship has no control over the delivery medium which means the bunker oil delivery lines, bunker barge or ship fuel tanks could have residual amounts of the high sulfur fuel leftover that could increase the sulfur content of the oil sample. Beyond this, the question of where best to take a representative sample remains a matter for debate.
At a meeting held in Tacoma, WA to discuss the NAECA on June 26, the U.S. Coast Guard advised that LSFO should meet the ISO 4259 standard. This means the sulfur content could deviate in lab analysis results from .94% to 1.06% sulfur and remain in compliance. Meanwhile, the EPA insists that LSFO should not exceed the IMO mandated 1.0% sulfur. This determination by the EPA holds sway over compliance issues. Refinery fuel blenders most probably will take the sulfur percentage to .95%; allowing for a 5% margin in analysis repeatability.
Separately, the U.S. Coast Guard maintains that the use of an incinerator to incinerate sludge greater than 1% sulfur content generated on board ship is permitted by MARPOL Annex VI (Reg 16) including in the Emission Control Area (ECA). But, the US EPA says Reg 14 only applies to the use of fuel oil, so burning sludge in an incinerator is not regulated under Reg 14, but only under Reg 16. Fuel oil and sludge oil are clearly distinguished within the MARPOL definitions. In the spirit of the ECA, the EPA would not recommend that a ship burn sludge oil or other sludge with a sulfur content that might exceed 1% within the ECA. Upon further study, a consensus will be reached with a final determination.
In order to achieve the 1.0% sulfur content of LSFO, refinery blenders are using cutter stocks which tend to have high Aluminum (Al)+Silicone (Si) levels (cat fines). The issue with increased cat fines is the impact to filters and purifiers. With poor preventative maintenance, debris from the filters and purifiers ends up in the high pressure fuel system causing worn pumps and injectors and adverse piston ring and crown groove wear – all creating more costs for the ship operator.
With California’s regulations in effect, the following scenario may unfold aboard ships trying to comply with IMO and CA regulations at the same time. At 200 miles out, the ship will use LSFO with the increased metal wearing cat fines but with good fuel viscosity which is more forgiving to worn parts. Then, at 24 miles out from California, a switch to the less forgiving distillate fuel and its well documented increased incidence of loss of propulsion (LOP) incidents could take place. Bottom line: California will continue to face the risk of an increased rate of LOP incidents that could cause an oil spill due to allision, collision or grounding.
Article
"Offshore" refers to the discovery and development of oil and gas resources which lie underwater. Usually the term refers to ocean-based oil extraction , though the term can also apply to drilling in lakes and inland seas. The remote locations…
Maritime Reporter and Engineering News’ first edition was published in New York City in 1883 and became our flagship publication in 1939.
It is the world’s largest audited circulation magazine serving the global maritime industry, delivering more insightful editorial and news to more industry decision makers than any other source. |
Q:
Character classes using byte regex for characters encoded with multiple bit blocks
I would like to use regular expressions on bytestrings in python of which I know the encoding (utf-8). I am facing difficulties trying to use character classes that involve characters that are encoded using more than one bit block. They appear to become two or more 'characters' that are matched separately in the character class.
Performing the search on (unicode) strings instead is possible, but I would like to know if there is a solution to defining character classes for the case of bytestrings as well. Maybe it's just not possible!?
Below is a python 3 example that shows what happens when I try to replace different line breaks with '\n':
import re
def show_pattern(pattern):
print(f"\nPattern repr:\t{repr(pattern)}")
def test_sub(pattern, replacement, text):
print(f"Before repr:\t{repr(text)}")
result = re.sub(pattern, replacement, text)
print(f"After repr:\t{repr(result)}")
# Pattern for line breaks
PATTERN = '[' + "\u000A\u000B\u000C\u000D\u0085\u2028\u2029" + ']'
REPLACEMENT = '\n'
TEXT = "How should I replace my unicode string\u2028using utf-8-encoded bytes?"
show_pattern(PATTERN)
test_sub(PATTERN, REPLACEMENT, TEXT)
# expected output:
# Pattern repr: '[\n\x0b\x0c\r\x85\u2028\u2029]'
# Before repr: 'How should I replace my unicode string\u2028using utf-8-encoded bytes?'
# After repr: 'How should I replace my unicode string\nusing utf-8-encoded bytes?'
ENCODED_PATTERN = PATTERN.encode('utf-8')
ENCODED_REPLACEMENT = REPLACEMENT.encode('utf-8')
ENCODED_TEXT = TEXT.encode('utf-8')
show_pattern(ENCODED_PATTERN)
test_sub(ENCODED_PATTERN, ENCODED_REPLACEMENT, ENCODED_TEXT)
# expected output:
# Pattern repr: b'[\n\x0b\x0c\r\xc2\x85\xe2\x80\xa8\xe2\x80\xa9]'
# Before repr: b'How should I replace my unicode string\xe2\x80\xa8using utf-8-encoded bytes?'
# After repr: b'How should I replace my unicode string\n\n\nusing utf-8-encoded bytes?'
In the encoded version, I end up with three '\n''s instead of one. Similar things happen for a more complicated document where it's not obvious what the correct output should be.
A:
You may use an alternation based pattern rather than a character class, as you will want to match sequences of bytes:
PATTERN = "|".join(['\u000A','\u000B','\u000C','\u000D','\u0085','\u2028','\u2029'])
See the online demo.
If you prefer to initialize the pattern from a string use
CHARS = "\u000A\u000B\u000C\u000D\u0085\u2028\u2029"
PATTERN = "|".join(CHARS)
|
[Pituitary prolactinoma with severe erectile dysfunction as the initial symptom: diagnosis and treatment of 4 cases].
Pituitary prolactinoma with severe erectile dysfunction (ED) as the initial symptom is often misdiagnosed. This article explores the diagnosis and treatment of severe ED caused by pituitary prolactinoma. We retrospectively analyzed the diagnosis and treatment of 4 cases of pituitary prolactinoma with severe ED (IIEF-5 score 5 - 7) as the initial clinical symptom confirmed by MRI. The 4 cases of pituitary prolactinoma-induced severe ED, with serum prolactin 10 times above the maximum normal level, were misdiagnosed for 2 years. All failed to respond to the PDE5 inhibitor therapy, and then 3 of them underwent transnasal hypophysectomy. Twenty-four months of follow-up found the level of prolactin restored to normal in 1 case (IIEF-5 = 19), and reduced to 600 and 768 IU/L respectively (IIEF-5 = 15) in the other 2. Then administration of the PDE5 inhibitor was followed, which produced satisfactory efficacy. One case was treated with oral bromocriptine, which restored the prolactin level to normal at 12 months (IIEF-5 > 21). Prolactin detection and brain MRI can help to confirm pituitary prolactinoma with severe ED at the onset. As for its treatment, in case of an extremely high level of prolactin, simple administration of the PDE5 inhibitor is ineffective. When the prolactin level is reduced after surgery or medication, the symptom of ED can be improved and, in case of no obvious relief, administration of the PDE5 inhibitor can be followed, which may achieve satisfactory results. |
When you are in a daily fight against Donald Trump’s white supremacist agenda, it’s difficult to be thankful—even on Thanksgiving Day. Trump has made demonizing minorities his favorite pastime, from his racist demand that four women of color in Congress “go back” to their country to his demeaning of black Americans as “low IQ” and “unintelligent,” to dubbing Latino immigrants “rapists” and “invaders.”
Trump’s words, like all world leaders’, do more than just elicit cheers at campaign rallies. They inspire action. So it’s not surprising that the FBI earlier this month reported that violent hate crimes had reached a 16-year high in 2018.
Worse, 2018 saw the highest number of hate crime murders in 27 years. This follows three years of unprecedented annual increases in hate crimes, from 2015 to 2017, which—not coincidentally—matches the rise of Trump.
“ 2018 saw the highest number of hate crime murders in 27 years. ”
Alarmingly, Trump’s white supremacist views have an impact beyond our borders. For example, the terrorist who murdered 50 Muslims who were praying in their mosque in New Zealand referred to Trump as a “renewed symbol of white identity.”
It’s this foul climate that explains why what took place in London this past weekend is so moving. The London Underground, much like the New York City subway, carries a truly diverse cross-section of people around that great city, and last weekend was no exception.
But unfortunately for one orthodox Jewish family traveling with their three young children, all of whom wore yarmulkes, one anti-Semitic bigot tried to tell this family that they don’t belong in England. The incident, captured on video, shows the man reading loudly “anti-Jewish Bible passages” directed at the family in an effort to harass them.
But then something beautiful happened. A Muslim woman wearing a hijab, Asma Shuweikh, is seen on camera confronting the anti-Semite. Shuweikh told the local media she “had to confront him,” adding, “Being a mother-of-two, I know what it’s like to be in that situation, and I would want someone to help if I was in that situation.”
Shuweikh engaged the man and successfully distracted him so that he stopped harassing the Jewish family. After the video of the incident went viral, Shuweikh was praised as a “hero,” while the man was arrested by the police and charged with committing a “racially aggravated public order offence.”
To fully appreciate this event, you have to be aware that in the UK, both Muslims and Jews have been the target of increasing hate crimes. In 2018, as the British government reported, the groups suffering the most hate crimes were Muslims, followed by Jews, with both communities seeing a spike in violent attacks visited upon them.
Yet there was a person from a community being subject to hate standing up for another from a community enduring the same pain. As one witness to the incident so aptly put it, “In this day and age we are told how intolerant everyone is and all religions hate each other, and there you had a Muslim woman sticking up for some Jewish children.”
And thankfully we’ve seen increasing displays of Jews and Muslims standing up for each other. After the horrific attack by an anti-immigrant, white supremacist terrorist last November at the Tree of Life synagogue in Pittsburgh that resulted in 11 Jews being murdered, Muslim groups raised hundreds of thousands of dollars to help the Jewish community recover.
And when a few months later an anti-immigrant, white supremacist terrorist in New Zealand killed 50 Muslims praying in their mosque, that same Tree of Life community raised funds to help that Muslim community.
But a few heartwarming stories can’t alleviate the risks currently confronting Muslims and Jews going forward, not just in the United States, but in other Western democracies as well. People who hate Jews or Muslims tend to hate the other group as well.
A 2018 Pew Survey of 15 Western European countries found that “attitudes toward Jews and Muslims are highly correlated with each other. People who express negative opinions about Muslims are more likely than others to also express negative views of Jews.”
That poll also found that, “Western Europeans who identify with the far-right side of the ideological spectrum in their country are more likely to express negative feelings about minorities and immigrants.”
“ We should give thanks for the good things in our lives. But at same time prepare for a 2020 that may be the most challenging that Jews and Muslims have ever experienced in the United States. ”
Consequently, it’s not surprising that right-wing actors are attacking both communities. Even in Canada, which recently re-elected the progressive Justin Trudeau as prime minster, there has been an alarming 50 percent uptick in hate crimes in 2017 against minorities, with Jews being the number one group targeted followed closely by Muslims.
It’s becoming increasingly clear that for Muslims and Jews to thrive in the West, we need to stand with each other through these challenging times.
I get that some of us have strong differences over the Middle East conflict, but we are both minority faiths in a time where demonizing minorities is becoming not just acceptable, but a plank of politicians running for office from the United States to Europe—and winning a lot of votes and sometimes high office.
And as the Center for the Study of Hate & Extremism warns us, “Hate crimes have increased in every presidential election year since national FBI record keeping began in the early 1990s.”
That means 2020 could be even worse. So this Thanksgiving, we should give thanks for the good things in our lives. But at same time prepare for a 2020 that may be the most challenging that Jews and Muslims in the U.S. have ever experienced. |
Quinton Tellis is headed back to Louisiana this week to face charges there following a second Mississippi mistrial in the Jessica Chambers burning death.
A third Chambers trial — if it happens — won't be for quite some time, District Attorney John Champion said.
Champion, who unsuccessfully prosecuted both trials in Chambers' 2014 death, wasn't sure exactly when Tellis will leave Mississippi or where he is being held in the interim. He said, however, that the transfer to Louisiana authorities will happen this week.
Quinton Tellis retrial:Jessica Chambers trial jury hangs again
Quinton Tellis hung jury:Did Jessica Chambers talk or did responders misunderstand? Jury could not decide
Louisiana officials said in the immediate aftermath of the second Chambers mistrial earlier this week in Batesville that they would wait to confer with Mississippi prosecutors before deciding what to do.
But, Champion said: "We actually borrowed him from Louisiana, so before we do anything, Louisiana will have to finish their case."
Asked if that means a possible third Chambers trial was quite some time away, Champion replied: "That's correct."
After Circuit Judge Gerald Chatham declared a mistrial Monday, Champion said on the Panola County Courthouse steps that he wouldn't speculate on trying the case a third time. He told reporters he and his team would have to confer at some point and decide what to do next.
Champion said late Wednesday there's no timetable for his team getting together since Louisiana now needs to take the next step, anyway.
In Louisiana, Tellis is charged with first-degree murder for the July 2015 stabbing death of Ming-Chen Hsiao, a Taiwanese exchange student at the University of Louisiana at Monroe.
He is accused of stabbing her more than 30 times, many of the wounds superficial in order to torture her until she gave Tellis the PIN number for her debit card.
Tellis had moved to Monroe following the 2014 death of Chambers in Panola County's Courtland community, where both Tellis and Chambers lived.
In addition to the murder charge, Tellis faces Louisiana charges for the theft of the debit card and an unrelated charge of possession of a controlled dangerous substance with intent to distribute.
In Mississippi, Tellis was incarcerated at the Mississippi State Penitentiary at Parchman before the Chambers trial, serving a sentence for an unrelated charge of burglarizing an unoccupied building. |
Our latest update to Prospect Pro lets users export a list of flagged elements as a CSV file for later review. This feature can help you and your team have more efficient review sessions using your BIM model. Below, we outline the steps to get started and specific workflows for Revit, Dynamo, and Navisworks to VR.
Update as of November 2018: We now have a plugin for Navisworks - click here to learn more. Additionally, with the release of Prospect 2.4, you can automatically create a Report during your design review session or VR Meeting and download it as a PDF. Reports contain screenshots, flagged elements, notes, and action items. Read more about Reports here.
Step 1: Inspect and Flag Elements in VR
Prospect allows you to select elements using the Inspect Element tool and flag them in red so that you can document what needs further review. We have full support to inspect the properties of elements for all of the formats we have integrations with, including SketchUp, Rhino, Grasshopper, and OBJ, though this post will focus on Revit.
To start, perform a walkthrough of your model and use the Inspect Element tool to flag elements that need to be reviewed. They will turn red once they're flagged, like below.
Step 2: Generate A Report of Flagged Elements
Once you're out of VR, go into your Prospect Library and select the Revit file you were viewing. When you open the Flagged Elements setting, you'll see a list of element IDs and their names. From there, you can export the report as a CSV. The CSV will contain the element ID, the family and element names of each element, the time it was flagged, and the username of the individual who flagged the element.
Step 3: Use the Report in Revit, Dynamo, or Navisworks
Once you've generated the report, you can use it easily in Revit, Dynamo, or Navisworks.
Using the report with Revit:
Using this list, you can copy the element IDs into Revit to find the objects there. Go to Manage > the Inquiry tab > Select by Id and paste the element IDs. This allows you to quickly identify the elements in your model.
Using the report with Dynamo:
If you are a Dynamo user, you can create a simple definition that can read all the flagged elements from your review session.
Use a File Path node and browse to the location where you saved your CSV file. Next, add an ImportFromCSV node. Select the first list, which represents the column with the Element IDs, by using the List.FirstItem node. Finally, install the Clockwork Package and use the Element.ByID node to find the flagged elements in the Revit file.
The Navisworks workflow:
To find the flagged Revit elements in Navisworks, simply click on View > Workspace > Windows and check Find Items in the dropdown.
In the dialog, select Element ID under Category, select Value under Property, set Condition to =, and under Value paste the element ID of the object you'd like to find. After that, click on Find First. Once the element is selected, you can click on Zoom Selected in the dropdown under Viewpoint > Navigate > Zoom Window.
In the future, we’ll continue to add additional support and modifications to this feature that will make your VR review sessions more productive, and in the meantime we’d love to hear your feedback. Please reach out to our team directly if you have any questions or comments! |
using System.Runtime.CompilerServices;
[assembly: InternalsVisibleTo("Unity.ML-Agents.Extensions.EditorTests")]
[assembly: InternalsVisibleTo("Unity.ML-Agents.Extensions.Editor")]
|
1. Technical Field
The present disclosure relates to the field of unmanned aerial vehicles, and more particularly to presentation of events or objects captured by the vehicles.
2. Discussion of Related Art
An unmanned aerial vehicle (UAV), commonly known as a drone is an aircraft without a human pilot on board. Its flight is either controlled autonomously by computers in the vehicles, or under the remote control of a pilot on the ground or in another vehicle. UAVs are predominantly deployed for military applications, but are also used in a small but growing number of civil applications, such surveillance of pipelines, natural resource exploration, livestock monitoring, wildfire mapping, transport of medical supplies, etc.
A UAV may be fitted with one or more high definition cameras that can send streaming video to a remote computer for storage thereon. An operator of the remote computer can then review the stored video to determine whether any events of interest have occurred. For example, if the UAV is being used by police to investigate a drug smuggling operation, an event of interest might include images of armed people moving containers into a suspected drug storage facility. While the entire video captured by the UAV may include several hours or days worth of footage, the event of interest may only comprise a few minutes. Thus, it could take an operator manually reviewing the video several hours to determine whether the event of interest has occurred. Further, since the event of interest may occur in a short period of time, the operator can easily miss the event.
Accordingly, there is a need for methods and systems that can automatically summarize the events of interest. |
[Lemierre syndrome: pediatric case report].
We report a case of Lemierre syndrome with extensive thrombophlebitis of the internal jugular and subclavian veins with multiple septic emboli to the lungs and pericardium. This report illustrates a case of this forgotten disease in a child and the unusual presence of pericardial involvement. |
McKay Valley
McKay Valley () is the central of three largely ice-free valleys that trend east from Midnight Plateau in the Darwin Mountains of Antarctica. It was named after physicist Christopher P. McKay, of the NASA Ames Research Center, Moffett Field, California, who carried out investigations in the McMurdo Dry Valleys concerning micrometeorology, thickness of ice in frozen lakes, stability of ground ice, in 15 austral summers beginning in about 1980.
References
Category:Valleys of Oates Land |
Structural characterization of Cu(I) and Zn(II) sites in neuronal-growth-inhibitory factor by extended X-ray absorption fine structure (EXAFS).
Neuronal-growth-inhibitory factor (GIF) is a metalloprotein specific to the central nervous system which has been linked to Alzheimer's disease. The high metal content, approximately seven metal atoms/protein molecule, and 70% sequence identity to mammalian metallothioneins (MT), including a preserved array of 20 cysteinyl residues, place GIF in the family of MT. In contrast to MT, native GIF isolated from human or bovine brain contains an unusual metal composition, viz. four Cu(I) and three Zn(II) per polypeptide chain. Cu and/or Zn K-edge X-ray absorption spectra have been recorded for native Cu, Zn-GIF, Zn-substituted GIF, and these metals bound to the 32-residue N-terminal domain, Cu4-, Cu6- or Zn3-GIF-(1-32) at 77 K. The results are consistent with the metals being bound to the protein by cysteinyl residues in every case. The Cu-S distance is approximately 2.25 A and the EXAFS is considered to be consistent with primarily trigonal coordination of the Cu(I); Cu...Cu backscattering is observed at approximately 2.67 A, indicative of the formation of Cu(x)(Scys)y clusters. Thus, the Cu(I) environment is similar to that observed in MT. This is also the case for Zn(II), with 4 S at approximately 2.34 A. However, in contrast to Zn-MT for Zn-substituted GIF and Zn3-GIF-(1-32), Zn...Zn backscattering is observed at approximately 3.28 A. The significance of these results are discussed with respect to the specific biological activity of GIF. |
Comparing Waste-to-Energy technologies by applying energy system analysis.
Even when policies of waste prevention, re-use and recycling are prioritised, a fraction of waste will still be left which can be used for energy recovery. This article asks the question: How to utilise waste for energy in the best way seen from an energy system perspective? Eight different Waste-to-Energy technologies are compared with a focus on fuel efficiency, CO(2) reductions and costs. The comparison is carried out by conducting detailed energy system analyses of the present as well as a potential future Danish energy system with a large share of combined heat and power as well as wind power. The study shows potential of using waste for the production of transport fuels. Biogas and thermal gasification technologies are hence interesting alternatives to waste incineration and it is recommended to support the use of biogas based on manure and organic waste. It is also recommended to support research into gasification of waste without the addition of coal and biomass. Together the two solutions may contribute to alternate use of one third of the waste which is currently incinerated. The remaining fractions should still be incinerated with priority to combined heat and power plants with high electric efficiency. |
Q:
Android - Retrieve Selected Items in a CheckBox
I'm trying to retrieve the selected item from a list to be added to the user's List.
The user would select the project that would be added to the user in a different activity then return to main activity with the newly added projects to the list.
The functionality of adding should be done when the user select multiple or single item from the list when the use click on the floating button presented in the activity.
Activity
public class ProjectSelectionActivity extends AppCompatActivity {
private ArrayList<Project> Projects;
private Player Player;
private ProjectSelectionAdapter Adapter;
private ListView ProjectSelectionLV;
private FloatingActionButton AddProject;
@Override
protected void onCreate(Bundle savedInstanceState) {
super.onCreate(savedInstanceState);
setContentView(R.layout.activity_project_selection);
AddProject = (FloatingActionButton) findViewById(R.id.ProjectSelectionFloatingActionButton);
Player = (Player)getIntent().getSerializableExtra("Player");
Projects = (ArrayList<Project>) getIntent().getSerializableExtra("Projects");
Adapter = new ProjectSelectionAdapter(getApplicationContext(), Projects);
ProjectSelectionLV = (ListView)findViewById(R.id.ProjectSelectionListView);
ProjectSelectionLV.setAdapter(Adapter);
AddProject.setOnClickListener(new View.OnClickListener() {
@Override
public void onClick(View v) {
}
});
}
}
Adapter:
public class ProjectSelectionAdapter extends BaseAdapter {
private Context context;
private ArrayList<Project> projects;
private LayoutInflater inflator;
private View view;
public ProjectSelectionAdapter(Context context, ArrayList<Project> projects) {
this.context = context;
this.projects = projects;
}
@Override
public int getCount() {
return projects.size();
}
@Override
public Object getItem(int position) {
return projects.get(position);
}
@Override
public long getItemId(int position) {
return position;
}
@Override
public View getView(int position, View convertView, ViewGroup parent) {
inflator = (LayoutInflater)context.getSystemService(context.LAYOUT_INFLATER_SERVICE);
if(convertView == null){
view = new View(context);
view = inflator.inflate(R.layout.project_selection_view, null);
TextView Title = (TextView)view.findViewById(R.id.ProjectSelectionTitleTextView);
TextView Value = (TextView)view.findViewById(R.id.ProjectSelectionValueTextView);
TextView Revenue = (TextView)view.findViewById(R.id.ProjectSelectionRevenueTextView);
ImageView Image = (ImageView)view.findViewById(R.id.ProjectSelectionImage);
Title.setText(projects.get(position).getTitle());
Value.setText("التكلفة: " + Integer.toString(projects.get(position).getValue()));
Revenue.setText("الربح: " + Integer.toString(projects.get(position).getRevenue()));
Image.setImageResource(projects.get(position).getImage());
}
return view;
}
}
Item view
<?xml version="1.0" encoding="utf-8"?>
<RelativeLayout xmlns:android="http://schemas.android.com/apk/res/android"
xmlns:app="http://schemas.android.com/apk/res-auto"
android:orientation="vertical" android:layout_width="match_parent"
android:layout_height="match_parent"
android:paddingLeft="5dp"
android:paddingBottom="5dp"
android:paddingTop="5dp"
android:paddingRight="5dp">
<TextView
android:id="@+id/ProjectSelectionTitleTextView"
android:layout_width="match_parent"
android:layout_height="wrap_content"
android:text="Title"
android:layout_alignParentTop="true"
android:layout_toLeftOf="@+id/ProjectSelectionImage"
android:layout_alignParentLeft="true"
android:layout_alignParentStart="true" />
<ImageView
android:id="@+id/ProjectSelectionImage"
android:layout_width="100sp"
android:layout_height="100sp"
app:srcCompat="@drawable/farm_fruit"
android:layout_alignParentTop="true"
android:layout_toLeftOf="@+id/ProjectSelectionCheckbox"
android:layout_toStartOf="@+id/ProjectSelectionCheckbox" />
<TextView
android:id="@+id/ProjectSelectionValueTextView"
android:layout_width="wrap_content"
android:layout_height="wrap_content"
android:text="Value"
android:layout_marginBottom="24dp"
android:layout_above="@+id/ProjectSelectionRevenueTextView"
android:layout_toLeftOf="@+id/ProjectSelectionImage"
android:layout_alignParentLeft="true"
android:layout_alignParentStart="true" />
<TextView
android:id="@+id/ProjectSelectionRevenueTextView"
android:layout_width="wrap_content"
android:layout_height="wrap_content"
android:text="Revenue"
android:layout_alignBottom="@+id/ProjectSelectionImage"
android:layout_toLeftOf="@+id/ProjectSelectionImage"
android:layout_alignParentLeft="true"
android:layout_alignParentStart="true" />
<CheckBox
android:id="@+id/ProjectSelectionCheckbox"
android:layout_width="wrap_content"
android:layout_height="wrap_content"
android:layout_alignBaseline="@+id/ProjectSelectionValueTextView"
android:layout_alignBottom="@+id/ProjectSelectionValueTextView"
android:layout_alignParentRight="true"
android:layout_alignParentEnd="true" />
</RelativeLayout>
A:
Make another Arraylist which will store all the selected projects in your activity.
private ArrayList<Project> selectedProjects;
2.You can add onItemClickListener() on your Listview like this -
ProjectSelectionLV.setOnItemClickListener(new AdapterView.OnItemClickListener() {
@Override
public void onItemClick(AdapterView<?> parent, View view, int position, long id) {
//inside this check if your checkbox corresponding to this item is selected or not. You can do this by taking checkbox from **parent** which you are getting in this method and checking if this checkbox is selected or not.
//If the checkbox is selected, then add the project of this position to your selectedProjects ArrayList -
//selectedProjects.add(Projects.get(position));
//Make sure to check that selectedProjects does not contain this already to avoid duplicates
}
});
When user clicks the floating button, inside its onClick() method, you can pass the selectedProjects ArrayList using intent extras. Refer this link to see how to pass objects between activities.
Finally, in your other activity, use selectedProjects Arraylist to add new projects. Call notifyDataSetChanged() when you have added the new projects from selectedProjects.
EDIT - To get the checkbox in 2nd step, you can do -
RelativeLayout rl = (RelativeLayout) parent.getAdapter().getItem(position);
CheckBox cb = (CheckBox) rl.getChildAt(4);
|
Over the weekend, Bill Childs of Spare the Rock Spoil the Child wrote, quite simply, that he was plotting his family’s Summer road trip. That’s all…no details, no dreamy locale mentioned. I read this sentence and my mind quickly began to roam…where can we go?! Is Mouse, at 2, ready for a long road trip? Can we fly somewhere far away (say, Santa Fe), rent a car and meander home?
It took much of Sunday, but we think we’ve figured it out. Using Pete Seeger’s Clearwater Music Festival along the Hudson River as a launching pad, we will head north to Lake Placid for a night, then off to Montreal for nearly a week before heading west in Canada to Kingston/Belleville for a quick tour of the 1000 Islands Region in the St. Lawrence River. From there we bypass Toronto (where the Blue Jays play the Phillies but the big ugly dome there + insane ticket prices do nothing to inspire me enough incorporate it) on the way to Niagara Falls. We have a beautiful room with a huge window overlooking both the American and Canadian Falls. We finish up in Pittsburgh, where we will see a Pirates game at lovely PNC Park and visit the underrated Pittsburgh Zoo.
12 nights overall, 1500 miles, yet no single day of driving will be longer than 4.5 hours. Not too shabby!
All we need is the price of gas to stay stable (or drop, that’d be fine as well!) and the Canadian dollar to stay where it is in relation to the greenback.
I wish were leaving right now.
Thanks Bill for inspiring the Mrs. and I to dream up this wild summer ride. A trip that will finally get me to Montreal, a city that has enchanted me from a far for so, so long! The girls are watching Muzzy right now…time to re-learn a little French!
No Comments
sounds like a great trip. like the sound of the clearwater music festival. montreal for nearly a week will give you lots of time to explore– the public pools in the parks here are free on weekends, and when it’s hot the big library at the Berri metro has an amazing kids’ section. (yes, i am a library tourist. big geek.) cheers! |
The paper, co-authored by researchers from Inovio and
collaborators from University of Pennsylvania School of Medicine,
notes that co-delivery of Inovio's immunoadjuvant, a DNA plasmid
encoding interleukin (IL)-28B, with an Inovio optimized
SynCon™ DNA vaccine using its proprietary electroporation
(EP) technology significantly enhanced antigen-specific killer T
cell responses in rhesus monkeys.
Dr. J. Joseph Kim, Inovio's president and CEO, said:
“Inovio's goal is to revolutionalize the way new vaccine
blockbusters are developed utilizing our DNA vaccine development
platform, comprised of our SynCon™ optimized DNA vaccine
constructs, novel formulations, electroporation delivery systems,
and DNA manufacturing processes. In addition, Inovio has been
developing novel gene immunoadjuvants able to safely and
efficiently improve immune responses generated by DNA vaccines.
Inovio's IL-28B has demonstrated these characteristics in non-human
primates, the closest animal model for humans in terms of testing
vaccines' immunological effects. The gene immunoadjuvant program
complements our existing technology and will further enhance our
dominant position in the field of optimized DNA
vaccines.”
An adjuvant is a pharmacological or immunological agent that
improves the effect of a vaccine while having few if any direct
effects when administered alone. They are often included in
vaccines to enhance immune responses and/or reduce the amount of
vaccine required and keep the injected foreign material at a
minimum. Conventional adjuvants are composed of chemicals like
aluminum and lipids (fatty acids), which often are not naturally
found in the body. In contrast, a gene immunoadjuvant is a DNA
plasmid encoded with the genetic blueprint of an important,
naturally occurring immune molecule such as IL-28B. When this DNA
plasmid is co-delivered with a DNA vaccine, both the vaccine and,
in this case, IL-28B proteins are produced by the same cell. The
presence of an immunoadjuvant such as IL-28B may enhance the
attraction of particularly important immune cells such as dendritic
cells or killer T cells. Generation of CD8+ killer T cells are
considered instrumental in clearing cancerous or infected cells
from the body and imperative to achieving sufficient potency of new
vaccines against cancers and chronic infectious diseases such as
HIV and hepatitis C.
Inovio has already demonstrated superior advantages in the
magnitude and breadth of killer T cell immune responses induced in
non-human primates by one of its optimized SynCon™ DNA
vaccines delivered using its proprietary electroporation
technology, without the use of an immunoadjuvant. The study
results, recently
published in Molecular Therapy, compared Inovio's
platform with Merck's adenovirus serotype 5 (Ad5) vaccine,
considered to be the most immunogenic among viral vectors. Inovio
has also reported from its phase I clinical study of a
SynCon™ DNA vaccine against HPV/cervical cancer the
achievement of T cell response levels thought sufficient to provide
therapeutic benefit.
The purpose of the IL-28B study was to assess the incremental
benefit of a gene immunoadjuvant added to a DNA-based vaccine. This
was the first study of IL-28B in non-human primates. The study
compared an antigen alone, antigen delivered in combination with an
IL-12 immunoadjuvant, and antigen delivered in combination with
IL-28B. The antigen/IL-28B combination achieved the most
significant and long-lived responses in generating CD8+ T cells.
The level of T cell immune enhancement was significantly greater
than for IL-12, a previously tested potent immunoadjuvant. The
potent T cell immunoadjuvanting effects of IL-28B were first
identified in small animals by scientists at the University of
Pennsylvania. The university filed patent applications covering its
IL-28B product and its use as an immunoadjuvant, and licensed
exclusive worldwide rights to these patents to Inovio. Inovio also
has IL-15, RANTES, and other gene immunoadjuvants in its
pipeline.
This study was funded in part by grants and contracts from the
Division of AIDS, National Institute of Allergy and Infectious
Diseases (NIAID) to Inovio and University of Pennsylvania. Inovio
is further testing IL-28B as an immunoadjuvant in its efforts to
develop a globally-targeted HIV vaccine candidate,
PENNVAX™-GP, via a multi-year $23.5 million NIAID HIV Vaccine
Design and Development (HVDDT) contract and in a novel malaria
vaccine development program funded by the Malaria Vaccine
Initiative/PATH.
About Inovio Pharmaceuticals, Inc.
Inovio is developing a new generation of vaccines, called DNA
vaccines, to treat and prevent cancers and infectious diseases. The
company's SynCon™ “universal” vaccines are
designed to provide broad cross-strain protection against known as
well as newly emergent strains of pathogens such as influenza. When
delivered with Inovio's proprietary electroporation delivery
devices the vaccines have been shown to be safe and to generate
significant immune responses. Inovio's clinical programs include
HPV/cervical cancer (therapeutic), avian flu, and HIV vaccines
(both preventive and therapeutic). Inovio is developing its
universal influenza vaccines in collaboration with scientists from
the University of Pennsylvania and National Microbiology Laboratory
of the Public Health Agency of Canada. Other partners and
collaborators include Merck, ChronTech, University of Southampton,
National Cancer Institute, HIV Vaccines Trial Network, and Malaria
Vaccine Initiative/PATH. More information is available at
www.inovio.com.
This press release contains certain forward-looking
statements relating to our business, including our plans to develop
electroporation-based drug and gene delivery technologies and DNA
vaccines and our capital resources. Actual events or results may
differ from the expectations set forth herein as a result of a
number of factors, including uncertainties inherent in pre-clinical
studies, clinical trials and product development programs
(including, but not limited to, the fact that pre-clinical and
clinical results referenced in this release may not be indicative
of results achievable in other trials or for other indications,
that results from one study may not necessarily be reflected or
supported by the results of other similar studies and that results
from an animal study may not be indicative of results achievable in
human studies), the availability of funding to support continuing
research and studies in an effort to prove safety and efficacy of
electroporation technology as a delivery mechanism or develop
viable DNA vaccines, the adequacy of our capital resources, the
availability or potential availability of alternative therapies or
treatments for the conditions targeted by the company or its
collaborators, including alternatives that may be more efficacious
or cost-effective than any therapy or treatment that the company
and its collaborators hope to develop, evaluation of potential
opportunities, issues involving patents and whether they or
licenses to them will provide the company with meaningful
protection from others using the covered technologies, whether such
proprietary rights are enforceable or defensible or infringe or
allegedly infringe on rights of others or can withstand claims of
invalidity and whether the company can finance or devote other
significant resources that may be necessary to prosecute, protect
or defend them, the level of corporate expenditures, assessments of
the company's technology by potential corporate or other partners
or collaborators, capital market conditions, our ability to
successfully integrate Inovio and VGX Pharmaceuticals, the impact
of government healthcare proposals and other factors set forth in
our Annual Report on Form 10-K for the year ended
December 31, 2009, our Form 10-Q for the three months ended
March 31, 2010, and other regulatory filings from time to time.
There can be no assurance that any product in Inovio's pipeline
will be successfully developed or manufactured, that final results
of clinical studies will be supportive of regulatory approvals
required to market licensed products, or that any of the
forward-looking information provided herein will be proven
accurate.
Drugs.com provides accurate and independent information on more than 24,000 prescription drugs, over-the-counter medicines and natural products. This material is provided for educational purposes only and is not intended for medical advice, diagnosis or treatment. |
When we are not sure of ourselves, we often turn to family, friends and mentors for advice. We ask them what we should do about our jobs, relationships, opportunities and dilemmas. We often seek the approval of the majority, and use the opinions of others to make assessments of ourselves.
While we love the people in our lives from whom we seek advice, they are not always objective. In fact, it’s pretty hard for anyone to be objective and truly offer great guidance. That’s why great mentors and coaches are such game-changers: they help silence the noise of society and unearth your own truth.
I believe it’s easier to find your truth than you expect. The answer always lies within us–it just takes some time to excavate. Asking questions is a great way to be more objective about your situation and to discover new things about yourself and the path you want to be on.
These 100 questions will help you understand where you are in your career versus where you want to be and help you to identify actionable steps towards making a powerful vision a reality. Answer them honestly. Step away and then come back and read your answers with a fresh slate. You’ll know what you need to do.
What do you like to learn?
What do you do in your spare time for fun?
Do you do certain activities because you think it’s what you have to do?
Are you creating a career for your parents, society, from your own excitement or for money?
Do you believe that making money will make you happy?
What is your definition of work?
Do you believe that you can love what you do and make money doing it?
What is your dream?
Is that dream realistic?
Do you believe in yourself?
What challenge excites you the most in your life right now?
What impact do you want to have on other people’s lives or in the world?
Do you feel confident that you are exceptional at something?
Who can you count on for support?
Do you believe that with hard work and focus that you can do whatever you set your mind to?
Do you think your intelligence is set?
If you think it is, how does that affect your career choices?
If you think it’s not, how does that affect your career choices?
Who do you get career advice from?
Can these people be objective about you? (i.e. they are not family or friends)
When you were in college, what did you envision for yourself and your career?
What do you want: more joy or more power?
Do you want to be like your parents?
Why or why not?
What do you do that builds your confidence?
Can you do that more often?
If you can’t, why not?
Do you exercise, eat healthy and take care of yourself?
If not, why not?
Do you like your job?
Do you feel like you are valued?
Do you trust your superiors and your colleagues?
Do you wake up excited to be working in this job?
If no, why not?
What excites you about the work you are doing?
How often are you bored?
Are you pro-active about sharing your ideas with your team and managers?
How would you describe the work culture?
Does that culture work for you?
Do you laugh at work frequently?
Are you inspired by the leaders in the organization?
Do the leaders talk to you?
Are you clear what the next level is for you at this organization?
Does that excite you?
How important is loving your job to you?
How important is it that people you work with love what they do?
Do you have a career vision?
Do you think of that vision often?
How important is security to you?
Are you willing to take a risk with your career and your comfort zone?
When was the last time you did something that scared you?
Was that exhilarating?
Do you feel fulfilled by your work?
Do you care about being fulfilled?
What is the advantage of being purpose driven, if you are not currently?
Who do you admire most?
Are they passionate and purpose driven by their work?
Do you think you deserve to have a job you love and get paid well?
Are you confident most of the time?
What is your number one confidence barrier?
What can you do to work on that barrier?
What is your greatest fear?
What new behavior would help you achieve your goals?
Do you think you are the best at what you do?
Why or why not?
Do you care what other people think of your success?
When you make decisions about your career, do you often consider what other people will think of your decision?
Are you money or power driven?
Why or why not?
What advice would you give to yourself today about where you are in your career based on where you want to go?
If you are an entrepreneur, have you always believed you were meant to be an entrepreneur?
What is your favorite part of running your own business?
Least favorite?
Are you in your dream job?
If not, do you know what your dream job is?
Do you feel confident most of the time or do you struggle a lot?
Do you enjoy working alone?
How do you do your best thinking?
Where do you do your best thinking?
Do you feel fulfilled by the work you are doing?
If you don’t, why not?
Do you give yourself time to think?
Do you feel like you are efficient with your time?
If not, what is your main distraction?
How can you eliminate that distraction?
Do you have a clear vision for yourself and your business?
Is the work you are doing a reflection of your greatest strength?
If not, can you hire someone to support you in doing work that is not in line with your strengths?
What do you think your performance barriers are? What behaviors are holding you back?
Do you have a plan for eliminating the performance barriers?
If no, why not?
If yes, what is it? Can you start that today?
Are you pushing your comfort zone at least once a week?
What can you do to ensure you are getting out of your comfort zone more regularly?
Do you feel successful?
What does success mean to you?
What is driving you?
Do you use that driving force in your business?
If you don’t, how can you bring more of that to your daily work-life?
What have you learned about yourself and your status by answering the above questions? |
Q:
Why the node.js script is call twice?
I am a beginner in Node.js
I write the first script in Node.js like the below:
var count = 0;
var http = require('http');
var serv = http.createServer(function (req, res) {
count++;
console.log("why two?:" + count);
res.writeHead(200,{'Content-Type': 'text/html'});
require('colors');
if (count % 2 == 0) {
console.log('count:' + count);
console.log('smashing node'.rainbow);
res.end('<marquee>Smashing Node</marquee>');
} else {
console.log('count:' + count);
console.log('WTF'.rainbow);
res.end('<h4>Smashing Node</h4>');
}
});
serv.listen(3000);
Then I run this script
node first.js
In browser, access http://localhost:3000
And the result in console is:
why two?:1
count:1
WTF
why two?:2
count:2
smashing node
Why the code is called twice?
Thanks
A:
Because two requests are being made.
Probably one is for / and the other is for /favicon.ico.
Your code doesn't care what the path is when it handles a request.
You can test that by looking in the Net tab of your browser's developer tools or examining the contents of the req object.
|
Q:
Render data from PHP DB query in HTML
I am a newbie to PHP but trying to learn it to enhance my programming skillset
So far i have the following PHP code in my page to return some data from my Database:
<?php
//code missing to retrieve my data
while($row = mysql_fetch_array($result))
{
echo '$row['Name']';
}
mysql_close($connection);
?>
This is working in that I can see the names from my database displayed on screen. I have seen as well that I can include html in the echo to format the data. However if I have the html code like below in a jQuery accordion outside my PHP code in the page - how can I dynamically place the Names in the specific h3 tags - so the first name in my table is Joe so that comes back in [0] element of array - is there a way I can reference this from my html code outside the php?
<div id="accordion">
<h3>Joe</h3>
<div>
<p>
Some blurb about Joe
</p>
</div>
<h3>Jane</h3>
<div>
<p>
Some blurb about Jane
</p>
</div>
<h3>John</h3>
<div>
<p>
Some Blurb about John.
</p>
</div>
</div>
A:
Try something like this:
<?php while($row = mysql_fetch_array($result)) { ?>
<h3><?php echo $row['name']; ?></h3>
<div>
<p>Some blurb about Joe</p>
</div>
<?php } ?>
I'm assuming 'Some blurb about Joe' would also have to be replaced by a field in the DB, which you can accomplish in the same manner as the name.
@Gert is correct - the original mysql API is deprecated and should not be used anymore. Look into mysqli or PDO, instead.
|
The cover for my upcoming book, The Elves of Uteria!
If you like it enough, you can even buy a print! The Elves of Uteria print at the Aradani storefront. |
Q:
ConcurrentModificationException with 2 Iterators and one ArrayList
I have a quick question that involves one ArrayList, 2 Iterators, and some nested for loops. Im trying to make a bit of a gravity engine using multiple gravity wells pulling on each other and moving around. To do this, Iv made an ArrayList of these gravity wells, all randomly places on the screen with a random size. Here it is for reference.
for(int i = 0; i < amount; i++){ // makes all
int mass = rand.nextInt(45,65);
int locX = rand.nextInt(50, getWidth()-100);
int locY = rand.nextInt(50, getHeight()-100);
Color cColor = rand.nextColor();
if(mass%8==0){
mass = rand.nextInt(25,35);
}
else if(mass%7==0){
mass = rand.nextInt(75,85);
}
Body body = new Body((double)locX,(double)locY,mass);
body.setFilled(true);
body.setColor(Color.WHITE);
body.setFillColor(cColor);
add(body);
bodys.add(body);
}
bodys is the name of the ArrayList containing everything. So my real problem comes to the Iterators. Heres the code thats giving me trouble:
public void move(){
Iterator<Body> eIter = bodys.iterator();
while(eIter.hasNext()){ // finding the thing we edit
Body edit = eIter.next();
int addX = 0, addY = 0;
int totalX = 0, totalY = 0;
double ex = edit.getX(), ey = edit.getY();
double eMass = edit.getMass(), eSize = edit.getHeight();
double eMoveX = edit.getMoveX(), eMoveY = edit.getMoveY();
int placeInArrayEdit = bodys.indexOf(edit);
Iterator<Body> fIter = bodys.iterator();
while(fIter.hasNext()){ // iterating through the force pulling the edit body
Body force = fIter.next(); /// ConcurrentModificationException is thrown
int placeInArrayForce = bodys.indexOf(force);
if(placeInArrayForce != placeInArrayEdit){ // making sure the 2 bodys arent the same
double fx = force.getX(), fy = force.getY();
double fMass = force.getMass();
double fMoveX = force.getMoveX(), fMoveY = force.getMoveY();
double difX = (ex-fx);
double difY = (ey-fy);
double distX = distanceP(ex, fx);
double distY = distanceP(ey, fy);
double vecX = (difX/distX);
double vecY = (difY/distY);
if(distance(fx,ex,fy,ey) <= eSize/3){ // if they are colliding
if(eMass >= fMass){
remove(edit);
edit.addMass((int)(fMass));
eIter.remove(); // problem
}
if(eMass < fMass){
remove(force);
force.addMass((int)(eMass));
fIter.remove();
}
}
double grav = (eMass/fMass);
grav -= (grav*.50);
addX -= (vecX/grav)/2; // this determines movement which means i
addY -= (vecY/grav)/2; // need to edit this with fMass
}
edit.setVelX(addX/(eMass + (eMass*.75)));
edit.setVelY(addY/(eMass + (eMass*.75)));
edit.addMoveX(edit.getVelX());
edit.addMoveY(edit.getVelY());
edit.move(edit.getMoveX(),edit.getMoveY());
}
}
}
The code above is moving the gravity wells and testing for collision. The problem is that ConcurrentModificationException is thrown where iv commented it to be thrown.
Iv spent about an hour or so looking around for a solution and nothing iv tried has worked. The code works up until the wells actually hit each other, then the error is thrown. Is there a way to avoid this error while still testing for collision like this, or is my code just too broken?
Thanks for all the help! Please let me know if you need anything clarified as this is my first question on StackOverflow
A:
See javadoc of ArrayList:
The iterators returned by this class's iterator and listIterator methods are fail-fast: if the list is structurally modified at any time after the iterator is created, in any way except through the iterator's own remove or add methods, the iterator will throw a ConcurrentModificationException. Thus, in the face of concurrent modification, the iterator fails quickly and cleanly, rather than risking arbitrary, non-deterministic behavior at an undetermined time in the future.
So, you have 2 iterators: eIter for the outer loop, and fIter for the inner loop.
When you call eIter.remove(), fIter will go bad.
When you call fIter.remove(), eIter will go bad.
(If you had called bodys.remove(index), both would go bad.)
Either way, one of the iterators will be stale, and will throw ConcurrentModificationException when you call next().
Also, when you call eIter.remove(), you don't break out of the inner loop, so you run the risk of trying to do it again in another iteration of the inner loop.
In short, you need to find another way, e.g. using indexes and get(index) calls, or something like that.
|
Wednesday, March 19, 2008
The Middle East's first women-only hotel was officially opened in the capital of the ultra-conservative kingdom of Saudi Arabia on Tuesday.
Prince Sultan bin Salman bin Abdul Aziz, secretary general of the Supreme Commission for Tourism, attended the inauguration of the Luthan Hotel and Spa in Riyadh.
Saudi Arabia, which applies a rigorous doctrine of Islam known as Wahhabism, strictly enforces the separation of the sexes in public, and the 25-room hotel said it can offer its female-only guests 150 types of spa treatments as well as fine dining and conference facilities.
Princess Madawi Bint Mohammad Bin Abdullah, who chairs the board of partners that set up the hotel, said the project was an important step forward for women in the kingdom.
"One of the aims of the Luthan ... is to support the achievements of women in general and particularly those in Saudi Arabia," the statement quoted her as saying at a news conference during the hotel's official opening.
Women in Saudi Arabia face a host of constraints. They are banned from driving, forced to cover from head to toe in public, prohibited from mixing with men other than relatives and prevented from travelling without written permission from their male guardian.
*************************************************************
Comments:
Agence France_Presse is one of Europe’s most leftist news organizations.
It often reports on such steps “forward for woman” in Saudi Arabia.
But I can’t recall a single instance when AGF reported the reaction of one or a few feminist leaders in France or America to its stories reporting steps “forward for women” in Saudi Arabia.
However, I can recall many times when I’ve been in France and read or heard AGF reports in which feminists on both sides of the pond expressed their “outrage” at the Catholic Chruch’s refusal to ordain women as priests.
J-in-C, I don't recall ever seeing how to contact you "off-blog"; however, you might find the following URL interesting:
http://blog.kir.com/archives/2008/03/the_stench_of_p.asp
this relates to some withholding of exculpatory evidence in a _Federal_ trial; specifically, part(s) of the Enron litigation. It does, however, address issues of prosecutors run amok, and why/how they can usually get away with their misdeeds. |
Q:
How to search parenthesis by ack
I want to search for a parentheis ( using ack, but neither using ( nor \( worked.
The first one ("(") is recognized as a multiple line command.
The second one ("\(") is treated as an invalid regular expression.
How can I search for a parenthesis character with ack?
Error message
% ack foo\(
Invalid regex 'foo(':
Unmatched ( in regex; marked by <-- HERE in m/foo( <-- HERE / at /usr/local/bin/ack line 332.
A:
To search for a parenthesis character, pass backslash+parenthesis to ack.
Both backslash and parentheses are special in the shell, so you need to quote them when you're entering them in a shell script or on the command line. The simplest form of quoting is with single quotes: this tells the shell to pass everything through literally except single quotes themselves.
ack '\('
You can also use backslashes to protect special characters from shell expansion, but it tends to be less readable:
ack \\\(
The first backslash quotes the second one in the shell, so that the first character of the argument to ack is \. The third backslash quotes the parenthesis, so the second character of the argument to ack is (. Like in the case with single quotes above, the argument that ack sees is the two-character string \(.
ack ( doesn't work because the shell sees an opening parenthesis and treats it as shell syntax. ack \( doesn't work because the shell passes ( as the argument to ack, and ack interprets the parenthesis in the regular expression as indicating the start of a group.
|
Q:
Using stored procedure to insert data from selection
I need to insert data into another table using stored procedure that looks something like this:
CREATE PROCEDURE T.countnum
AS
Insert into T1 values(select count(*) from T.countTable)
But it isn't working I saw several example but not with selection. Any example?
A:
use db;
CREATE PROCEDURE T.countnum
AS
Insert into T1 ([column_name])
select count(*)
from T.countTable
go
or
use db;
CREATE PROCEDURE T.countnum
AS
declare @counting int
select @counting = count(*)
from T.countTable
Insert into T1 ([column_name]) values (@counting)
go
And you should specify the column to count like select count(id) from T.countTable
|
Nos primeiros nove meses deste ano foram celebrados 834,4 mil contratos de trabalho, o que revela um crescimento de 10,6% face ao mesmo período do ano passado. Daquele total, 39,4% tinham uma remuneração equivalente ao valor do salário mínimo – que no início do ano foi fixado em 557 euros.
O relatório de acompanhamento da Remuneração Mínima Mensal Garantida (RMMG) relativo ao terceiro trimestre deste ano, que foi divulgado esta terça-feira, mostra ainda que em setembro 21,6% do total dos trabalhadores com remunerações declaradas à segurança social recebiam o salário mínimo nacional. Traduzindo em número, isto significa que há 713 mil trabalhadores a auferir 557 euros mensais.
Na comparação em cadeia, setembro regista um decréscimo do número de trabalhadores por conta de outrem e membros de órgãos estatutários a receber o SMN (em junho eram 728 mil e cerca de 22,7% do total), mas a evolução homóloga revela que a subida do salário mínimo em 2017 fez aumentar o universo de pessoas contratadas por este valor. Por comparação com o 3º trimestre de 2016, há agora mais cerca de 61,5 mil pessoas nesta situação.
A publicação deste relatório coincide com a reunião da Concertação Social em que deverá ficar definido o valor do SMN para 2018. Na última reunião, o ministro Vieira da Silva indicou que deveria apresentar hoje aos parceiros sociais a proposta do governo e a expectativa é que formalize os 580 euros que constam do acordo político entre o PS e o Bloco de Esquerda.
Na ocasião Vieira da Silva não quis falar de valores para 2018, optando antes por sublinhar que em 2019 o SMN chegará aos 600 euros – o patamar que a CGTP exige desde 2016.
As confederações patronais recusaram até agora propor valores e a UGT tem defendido uma subida para os 585 euros. |
// Copyright 2017 The Go Authors. All rights reserved.
// Use of this source code is governed by a BSD-style
// license that can be found in the LICENSE file.
// Functions to access/create device major and minor numbers matching the
// encoding used in Darwin's sys/types.h header.
package unix
// Major returns the major component of a Darwin device number.
func Major(dev uint64) uint32 {
return uint32((dev >> 24) & 0xff)
}
// Minor returns the minor component of a Darwin device number.
func Minor(dev uint64) uint32 {
return uint32(dev & 0xffffff)
}
// Mkdev returns a Darwin device number generated from the given major and minor
// components.
func Mkdev(major, minor uint32) uint64 {
return (uint64(major) << 24) | uint64(minor)
}
|
Camps return after Rim Fire
Two Yosemite-area summer camps, which draw thousands of tourists yearly to economically hard-hit southern Tuolumne County, are readying to reopen for the season following last year’s destructive Rim Fire.
Camp Tawonga plans to install four or five yurts to make up for two staff cabins that burned in the fire, said Aaron Mandel, assistant director of the Jewish camp which serves children from throughout the state.
The fire also damaged a ropes course and outdoor amphitheater used for prayer services and camp gatherings.
“Those are in the process of being rebuilt and will be ready for summer programs,” Mandel said.
The 160-acre camp is located off Mather Road along the Middle Fork of the Tuolumne River in the Stanislaus National Forest.
As the Rim Fire approached the camp last August, staffers were asked to grab “memory books” and a special Holocaust-era Torah, the Jewish holy book, as a precaution.
Those items will return, along with campers, this May.
Nearby, the City of San Jose’s family camp, which goes by the name of Family Camp at Yosemite, plans to open in June.
The Rim Fire burned the outskirts of the camp, which sits on 47 acres leased from the Forest Service off Cherry Lake Road.
Art Catbagan, recreation superintendent for the City of San Jose, estimated 90 to 95 percent of the camp is “undamaged.”
“A lot of the damage was sustained in areas where we don’t have campers,” he said. “If you’re sitting in the middle of camp, you can’t even tell (a fire came through).”
The Rim Fire burned 14 of the camp’s canvas tent cabins. Of those 14, four were for volunteers and 10 were among the 72 tent cabins rented to campers.
The fire also burned an outbuilding and damaged the camp’s well infrastructure. The wells have been repaired, and workers are in the process of replacing the tent cabins. |
Identification of rubella virus T-cell epitopes recognized in anamnestic response to RA27/3 vaccine: associations with boost in neutralizing antibody titer.
Rubella virus (RV)-specific cell-mediated immunity (CMI) and antibodies were measured in healthy adolescents reimmunized with measles-mumps-rubella (MMR) vaccine. Lymphocyte proliferation to RV synthetic peptides was determined before and at 2, 4 and 10 weeks after, MMR. After MMR, increased CMI was observed with 16 peptides, including six containing antibody neutralization (NT) domains. Positive CMI (stimulation index > or =2.0) to E1(254-285) and C(1-29) before vaccination was significantly associated with a boost in NT titers, while positive CMI at weeks 2 or 4 to E1(254-285), E1(301-314), E1(389-408), E1(462-481), E2(134-150), E2(140-156), E2(168-179), C(1-29) and C(88-111) showed the same association. |
Thursday, 28 January, 2010
The extended take is a cinematic hire-wire act that pushes the director, actors, cinematographer, art department, sound design, and every other department to their limits. They take a very long time to set-up, and are very easy to mess up. The longer the take, the more pressure is added to get it right.
Thursday, 28 January, 2010
TakeOutWithOut aims to encourage us to reduce the amount of wrapping, packing, and accessories (napkins, plastic utensils, etc) that are offered to us with takeaway meals.
Think about the spoons, forks, straws, and napkins that you get served (why do they give you enough for a family of 20 when eating alone?). Ask yourself before accepting all these items, “Do I really need all of this?”, “Am I going to be eating this right away?” (If so, why take the bag or the napkins)… just enjoy your muffin – and be neat so the napkin isn’t needed!
Every content website I’ve ever worked on has proclaimed the death of print, but the truth is, they’ve all been secretly jealous of old media. Why? Consumers pay for print. Advertisers pay more for print. Print, for all its ink stains and dead trees still makes money. Meanwhile, every print organization I’ve ever worked with has been head-to-toe freaked about the web. The web is the hot, new thing that all the kids are excited about.
Thursday, 28 January, 2010
Even though the second full Moon in a month is not actually a Blue Moon it seems the misconception is so ingrained there is little point in putting people right any more, with Sydney Observatory advising that both January and March of this year are Blue Moon months.
In Australia, the first full Moon in 2010 is on Jan 1st at 6:13am while the Blue Moon occurs on the 30th at 5:18pm. The second blue Moon month is March with the first full Moon on the 1st at 3:38am and the second or blue Moon on the 30th at 1:25pm.
The article that told me I was wrong about what “blue moon” means (and hilariously refers to that definition as “trendy”) explains that the “two full moons in a month” definition is due to a misreading of the Maine Farmers’ Almanac: the real Blue Moon is the third full moon in a season that has four full moons.
If it’s unusual astronomical phenomena you’re after though, February will not have a Full Moon at all, while Mars will be in “opposition” – the closest the planet will be to Earth for sometime – this Saturday night.
Wednesday, 27 January, 2010
The premise
Invictus, Clint Eastwood’s adaptation of John Carlin’s book, “Playing the Enemy: Nelson Mandela and the Game that Made a Nation”, is set in post apartheid South Africa shortly after Mandela (Morgan Freeman) assumes the presidency, as the country prepares to host the 1995 Rugby World Cup tournament.
The play
Mandela sees rugby as a game that could go along way to uniting the tense and fractured new nation, more so a win in the World Cup. He begins to take a personal interest in the game, the Springboks, and goes onto befriend captain Francois Pienaar (Matt Damon).
The wrap
Despite being heavy on emotion, tension, and drama, ingredients which work well during the World Cup final play, but not always at other times, Invictus is, by way of Mandala’s “we must become the change we want to see in the world” philosophy, an uplifting story of the early days of the new South Africa. |
Chondroitin 4-sulfotransferase
In enzymology, a chondroitin 4-sulfotransferase () is an enzyme that catalyzes the chemical reaction
3'-phosphoadenosine-5'-phosphosulfate + chondroitin adenosine 3',5'-bisphosphate + chondroitin 4'-sulfate
Thus, the two substrates of this enzyme are 3'-phosphoadenylyl sulfate and chondroitin, whereas its two products are adenosine 3',5'-bisphosphate and chondroitin 4'-sulfate.
This enzyme belongs to the family of transferases, to be specific, the sulfotransferases, which transfer sulfur-containing groups. The systematic name of this enzyme class is 3'-phosphoadenylyl-sulfate:chondroitin 4'-sulfotransferase. This enzyme is also called chondroitin sulfotransferase. This enzyme participates in 3 metabolic pathways: chondroitin sulfate biosynthesis, sulfur metabolism, and the biosynthesis of glycan structures.
References
Category:EC 2.8.2
Category:Enzymes of unknown structure |
---------------------- Forwarded by David M Gagliardi/TTG/HouInd on
08/28/2000 08:19 AM ---------------------------
"Michael Gagliardi" <[email protected]> on 08/28/2000 07:10:39 AM
To: [email protected], [email protected],
[email protected]
cc:
Subject: True Orange Fax/E-Mail #79
---------------------- Forwarded by Michael
Gagliardi/Hou-ComOps/EnergyTrading/PEC on 08/28/2000 07:19 AM
---------------------------
[email protected] on 08/26/2000 03:09:12 PM
To: [email protected]
cc: (bcc: Michael Gagliardi/Hou-ComOps/EnergyTrading/PEC)
Subject: True Orange Fax/E-Mail #79
True Orange Fax/E-Mail Service
Volume 8, Fax/E-Mail #79,Saturday, August 26, 2000
Jerry Scarbrough's True Orange, P. O. Box 26530, Austin, Texas 78755 -
Phone
512-795-8536
Freshmen Score 3 TDs in Saturday Scrimmage
The Longhorns scored four touchdowns in their Saturday scrimmage, and three
of them were scored by true freshmen. And, no, Roy Williams was not one of
the TD makers. Williams has been the freshman star of the early practices,
but fellow freshmen B. J. Johnson, Nathan Vasher and Sloan Thomas showed
Saturday they are ready for prime time, too.
Chris Simms connected with senior Brandon Healy for a 63-yard pass-and-run
play to open the scoring, but then the freshmen took over. Major Applewhite
found Johnson just breaking past CB Quentin Jammer for a 75-yard
pass-and-run
touchdown against the first-team defense. It was the first touchdown the
second-team has scored against the defensive starters in their two
scrimmages.
Johnson made a great catch in traffic, then turned on the speed to complete
the long scoring play.
Vasher, however, had the longest scoring jaunt of the day, bolting 79 yards
on a punt return. He made a couple of great moves to get started, then used
his speed to outrun the pursuit.
Beau Trahan, who was moved from safety to quarterback last week, threw a
beautiful pass to Thomas for a 15-yard scoring play.
Simms again took all the snaps for the first team and Applewhite, last
year's
co-Big 12 Offensive Player of the Year, again worked with the second team.
Brown said no decision has been made on which QB will be the starter in the
season opener, but he did say no significance should be given to the fact
the
Simms has worked with the first team throughout the first two scrimmages.
He
said the coaches know what Applewhite can do with the first team, and they
want to see what Simms can do with the first team.
Simms, leading the starters against the second-team defense, had only
slightly better statistics than Applewhite, who went against the defensive
starters all day. Simms completed 7 of 17 passes for 142 yards, with the
63-yard touchdown pass to Healy. He also gave up an interception by backup
linebacker O. J. McClintock. Applewhite completed 6 of 18 passes for 119
yards, including the TD pass to Johnson. He also allowed a pick by walk-on
defensive back Chad Davis.
Backup TBs Victor Ike and Ivan Williams led the rushers with 34 and 25
yards,
respectively. Ike had seven carries and Williams had five.
The first-team defense, which was No. 6 in the nation last year in yardage
allowed, has been very stingy against the run throughout the fall drills.
Healy led the receivers with four catches for 102 yards, but Johnson was
close behind with two grabs for 94 yards.
Coach Mack Brown thanked the approximately 2,000 Longhorn fans who attended
the 9:30 a.m. scrimmage, and he said the players were tired, but still gave
a
great effort.
He said Williams hurt his shoulder, but it was not serious and did not
prevent him from going back in the game. He also said Vasher showed "great
quickness" on his scoring punt return, and said he will "probably be used
on
some punt returns this year."
The first-team offense scored on its first possession against the
second-team
defense when Simms found Healy open all alone down the middle, but the
second-team defenders held the starters without another score. The
second-team defense is much more talented this year than it was last year,
and defensive coordinator Carl Reese said that will allow him to rest the
starters more and keep his players fresher.
Fan appreciation day begins at 2 p.m. Sunday at Royal Memorial Stadium.
Brown
urged all Longhorn fans to show up. Players and coaches will be available
for
autographs.
* * * *
RECRUITING NOTE: Getting a commitment from Midland Lee running back Cedric
Benson, Texas Football Magazine's first high school cover boy, is going to
help the Longhorns snare some more top players. It may not help with
running
backs, but it always helps to get a super star at a skill position. Since
Benson rushed for 3,526 yards and scored 51 touchdowns in Class 5A last
year,
he definitely qualifies as a super star.
* * * *
My next fax will be whenever events warrant.
* * * *
The True Orange Fax Service includes at least 99 faxes a year and costs
$99 ($79 by E-Mail). The True Orange Newsletter includes 26 newsletters
and
is published weekly during football season and twice monthly during most of
the other months. It costs $45. Save by subscribing to both for $130 (or
$110
if you take the faxes via E-Mail or $99 if you take the faxes and
newsletter
via E-Mail). Send check to address at the top of page. I also update my
900 number
- 1-900-288-8839
- frequently with recruiting news. My E-Mail
address is: [email protected] |
Reception: “Women’s Work”
Artists’ Reception: March 22, 6-8 p.m. – free and open to the public. See the exhibit, meet the artists, and enjoy light refreshments.
The AAC gallery is open Monday-Thursday 9 a.m.- 8 p.m., Friday 9 a.m. – 3 p.m., & Saturday 9 a.m. -noon. The gallery is also open before performances and during intermission.
Admission to the gallery is free. |
An Essex girl walks into the local dry cleaners. She places a garment on the counter."I'll be back tomorrow afternoon to pick up my dress," she says."Come again?" says the clerk, cupping his ear."No" she replies. "This time it's mayonnaise."
Monica Lewinski goes into her cleaners with a dress to be cleaned. As she enters, she sees that Mr. Lee, (the owner of the cleaners and whom is hard of hearing), is in the back.She yells, " Mr. Lee, Mr. Lee, It's Monica. I have a dress to be cleaned."Mr. Lee yells, "Come again"Monica says, "No, it is gravy this time."
Monica needed to get one of her dresses cleaned so she takes it to thedry cleaners. The man working there was an elderly man and was hard ofhearing.Monica said,"I need this dress cleaned."The man said, "Come again?"Monica replied, "No, it's just mustard."
Monica needed to get one of her dresses cleaned so she takes it to thedry cleaners. The man working there was an elderly man and was hard ofhearing.Monica said,"I need this dress cleaned." The man said, "Come again?"Monica replied, "No, it's just mustard." |
/*
* Copyright 2013 the original author or authors.
*
* Licensed under the Apache License, Version 2.0 (the "License");
* you may not use this file except in compliance with the License.
* You may obtain a copy of the License at
*
* http://www.apache.org/licenses/LICENSE-2.0
*
* Unless required by applicable law or agreed to in writing, software
* distributed under the License is distributed on an "AS IS" BASIS,
* WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
* See the License for the specific language governing permissions and
* limitations under the License.
*/
package org.grails.web.databinding
import grails.databinding.errors.BindingError;
import grails.databinding.events.DataBindingListener;
import groovy.transform.CompileStatic
import groovy.util.logging.Commons
/**
* @author Jeff Brown
* @author Graeme Rocher
* @since 2.3
*/
@CompileStatic
@Commons
class DataBindingEventMulticastListener implements DataBindingListener {
protected final List<DataBindingListener> listeners
DataBindingEventMulticastListener(List<DataBindingListener> listeners) {
this.listeners = listeners
}
boolean supports(Class<?> clazz) {
true
}
Boolean beforeBinding(target, errors) {
boolean bind = true
for (DataBindingListener listener in listeners) {
try {
if (!listener.beforeBinding(target, errors)) {
bind = false
}
} catch (Exception e) {
log.error "An error occurred invoking beforeBinding on the ${listener.getClass().getName()} listener.", e
}
}
bind
}
@Override
Boolean beforeBinding(obj, String propertyName, value, errors) {
boolean bind = true
for (DataBindingListener listener in listeners) {
try {
if (!listener.beforeBinding(obj, propertyName, value, errors)) {
bind = false
}
} catch (Exception e) {
log.error "An error occurred invoking beforeBinding on the ${listener.getClass().getName()} listener.", e
}
}
bind
}
@Override
void afterBinding(obj, String propertyName, errors) {
if(listeners) {
for(DataBindingListener listener : listeners) {
try {
listener.afterBinding obj, propertyName, errors
} catch (Exception e) {
log.error "An error occurred invoking afterBinding on the ${listener.getClass().getName()} listener.", e
}
}
}
}
@Override
void afterBinding(target, errors) {
if(listeners) {
for(DataBindingListener listener : listeners) {
try {
listener.afterBinding target, errors
} catch (Exception e) {
log.error "An error occurred invoking afterBinding on the ${listener.getClass().getName()} listener.", e
}
}
}
}
@Override
void bindingError(BindingError error, errors) {
if(listeners) {
for(DataBindingListener listener : listeners) {
try {
listener.bindingError error, errors
} catch (Exception e) {
log.error "An error occurred invoking bindingError on the ${listener.getClass().getName()} listener.", e
}
}
}
}
} |
Image copyright Reuters Image caption Navy Secretary Richard Spencer said he and Trump did not have the same view of "discipline"
US Navy chief Richard Spencer has been fired over his handling of the case of a Navy Seal demoted for misconduct.
The case of Edward Gallagher, who was convicted for posing with a corpse, had sparked tensions between US President Donald Trump and military officials.
The navy officer had been due to face a disciplinary review where he could have been stripped of his Seals membership.
There have been differing accounts as to why Richard Spencer was asked to resign.
US Defence Secretary Mark Esper said he had lost confidence in the navy secretary because his private conversations with the White House contradicted his public position.
However, Mr Trump said he was not happy with "cost overruns" and how Chief Petty Officer Gallagher's trial was run, and suggested this was why Mr Spencer was fired.
Meanwhile, in a strongly worded letter, Mr Spencer said it was apparent that he and Mr Trump did not have the same view of "good order and discipline".
"The lives of our Sailors, Marines and civilian teammates quite literally depend on the professional execution of our many missions," he said.
Mr Trump has drawn criticism from parts of the military after pardoning army officers convicted of war crimes.
How did we get here?
Gallagher was accused of stabbing an unarmed 17-year-old Islamic State group prisoner to death and randomly shooting civilians while serving in Iraq in 2017.
He was acquitted of those charges and convicted only of the lesser charge of posing with the IS prisoner's corpse.
For that, he was demoted, but President Trump later reinstated his rank.
Gallagher was formally notified by navy leaders last week that he would face a disciplinary review which could result in his being stripped of his membership of the Seals.
Mr Trump tweeted his disapproval of this on Thursday, saying the navy would "NOT be taking away Warfighter and Navy SEAL Eddie Gallagher's Trident Pin".
Why was Spencer fired?
On Sunday, the defence department said Mr Esper had asked Mr Spencer to resign due to "his lack of candour".
Mr Spencer had made private proposals to the White House, which he did not share with Mr Esper, and had contradicted his public position, Pentagon spokesman Jonathan Hoffmann said in a statement.
According to the Washington Post, Mr Spencer had privately suggested to White House officials that if they did not interfere with proceedings against Edward Gallagher, he would ensure that the officer retired as a Navy Seal.
However, the New York Times quoted defence officials as saying Mr Trump had been angered by reports that Mr Spencer had threatened to resign if the president intervened in the case.
Mr Trump tweeted on Sunday he was not happy with how the navy had handled Gallagher's trial, and high costs in the navy's contracting procedures.
"Therefore, Secretary of the Navy Richard Spencer's services have been terminated," he said, adding: "Eddie will retire peacefully with all of the honours that he has earned, including his Trident pin."
In his resignation letter to President Trump, Mr Spencer wrote: "The rule of law is what sets us apart from our adversaries. Good order and discipline is what has enabled our victory against foreign tyranny time and again."
"Unfortunately, it has become apparent that in this respect, I no longer share the same understanding with the Commander in Chief who appointed me, in regards to the key principle of good order and discipline.
"I cannot in good conscience obey an order that I believe violates the sacred oath I took."
Senior Democratic Senator Chuck Schumer commended Richard Spencer for "standing up to President Trump when he was wrong, something too many in this administration and the Republican Party are scared to do".
What does this mean for Gallagher?
Image copyright Reuters Image caption Navy Seal Special Operations Chief Edward Gallagher was accused of war crimes in Iraq
Mr Esper has instructed that Gallagher be allowed to retire as a Navy Seal, retaining his Trident pin which symbolises membership of the elite unit.
While Mr Esper had wanted the disciplinary process to "play itself out objectively", he had decided to let Gallagher keep his pin "given the events of the last few days", defence spokesman Jonathan Hoffman said in a statement.
He had concluded Gallagher could not receive fair treatment in his case from the navy, AP news reported.
"Secretary Esper will meet with Navy Under Secretary (now Acting Secretary) Thomas Modley and the Chief of Naval Operations, Admiral Michael Gilday, on Monday morning to discuss the way ahead," the statement said.
Gallagher told the conservative Fox News channel on Sunday that he intends to retire next Saturday.
You might also be interested in: |
Vector-Borne Zoonotic Pathogens in Eurasian Moose (Alces alces alces).
Climate change, with warmer temperatures and altered precipitation patterns, has affected the distribution of vectors and vector-borne diseases. In the northern hemisphere, vectors are spreading north, and with them, pathogens of zoonotic and animal health impact. Eurasian moose (Alces alces alces) are physiologically and anatomically adapted for cold climate, and are rarely considered ideal hosts of vectors, apart from deer keds (Lipoptena cervi). To investigate the presence of vector-borne pathogens, spleen samples from 615 moose were collected in southern Sweden from 2008 to 2015. The samples were analyzed with a high-throughput PCR method for 24 bacterial, and 12 parasitic pathogens. Anaplasma (82%), Borrelia (3%), Babesia (3%), and Bartonella (1%) DNA was found, showing that moose are exposed to, and can act as hosts of some of these pathogens, which can have an impact of both animal and human health. These results show that Swedish moose are exposed to pathogens that in some instances are more commonly found in regions with warmer climate, and highlights the importance of also considering moose as sentinels of vector-borne pathogens. Further research is needed to understand the effect of these pathogens on the health of individual moose and to elucidate whether climate change and moose population density interact to create the pattern observed. |
Tap out a few hundred words on some local mobster, and I can expect several phone calls — at least one of them life-threatening.
Take up the columnist’s sling and hurl a rhetorical pebble against the castle of a Strip casino titan, and I might receive a higher volume of response — and a letter threatening litigation.
Pen a political piece about one of our keepers of the public trust, and there’s likely to be no response at all.
But write one story about spotting a lowly deceased beaver during a recent walk outside Boulder City, and dozens of you folks can’t stop slapping me with your tales of similar sightings.
Talk about beaver fever. This subject has really given you something to chew on.
Diane Pouch can barely contain herself.
“We have also seen beavers!” she writes. “Last summer our family took the boat through the Narrows and stopped somewhere before hitting the upper lake. We were eating lunch in an outlet that had a small cave-like opening. We dared our then-11-year-old to swim in. He swam up to the entrance and swam back as fast he could muttering, ‘Something’s in there.’ We laughed and teased him as I said ‘I’ll handle it.’ I swam up to the opening and to my surprise was met by a large beaver face hunched over and grunting.”
After returning to the boat faster than Michael Phelps, Pouch and her family discovered they had come across another family: a mother beaver and three little ones.
The River Walk area in Laughlin on the Colorado River is Noreen Nash’s favorite place to catch the cute little critters. “And I, too, was stunned the first time I saw a beaver swimming along the shore down there. Now, I’m disappointed when I don’t see one. (On my last visit, I enjoyed watching a set-to between one of the beavers and one of the many resident raccoons.)”
Joe Merritt has seen them there, too, while camping in 2006 during the annual Laughlin River Run.
“Like you, I was of the belief that beavers had been trapped out years ago,” Merritt says. “I later ran into an employee of the campground and asked him about the beavers. He said that they had to watch them because they were always trying to cut down the tree on the property.”
Longtime reader Julie Bare from Bullhead City, Ariz., first saw the creatures back in 1965 south of Davis Dam on the Colorado.
“Beavers were on the Nevada side of the riverbank, busy trying to build some sort of lodge or hut-looking device,” she writes.
When civilization crept close, the beavers moved on.
Which brings us to another issue where beavers are concerned. Given the chance, they’ll expand their condos without the proper permits.
A reader named Mark, who works at the wetlands nature preserve near Sam Boyd Stadium, notes that “part of our morning job that we have to do is break down beaver dams.” He estimates that 60 to 80 beavers live near the stadium, which in recent seasons would constitute a good crowd for a Rebels football game.
As the Southern Nevada Water Authority’s engineering project manager in charge of stabilizing Las Vegas Wash from Lake Las Vegas to the Clark County Wetlands Park Nature Center, Gary Hester is a beaver believer.
“Just read your column,” he writes. “You better sit down for this.
“We often see the workings of beaver in the Wash and periodically catch a glimpse of them. Just three weeks ago, one of my contractors spotted one on his work site, near Lake Las Vegas. Beavers have been known to chew on trees all the way up to the Nature Center. There is a reason most of the young trees have wire around them at the Nature Center!”
As president and founder of Worth A Dam, Heidi Perryman speaks for the beavers, or at least notes their importance to our water system.
“Just remember, the more beaver sightings you have in Nevada the better news it will be for your water supply. February is ‘dispersal’ month so it is not uncommon to see 2-year-old beavers walking distances to find their own habitat.”
Some columnists would be put off by all this chatter about an oversized rodent. I say gnaw. |
13C CP/MAS NMR studies of vitamin E model compounds.
13C cross-polarization magic angle spinning (CP/MAS) NMR data for 2,2,5,7,8-pentamethylchroman-6-ol (2), 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox c) (3) and its acetate (4), 2-methoxy-2,2,5,7,8-pentamethylchroman-6-ol (5), 2-hydroxy-2,2,5,7,8-pentamethylchroman-6-ol (6) and 2,2,5,7,8-pentamethylchroman (7) are reported. A deshielding of 7.7 ppm for the carboxylic carbon was observed in solid Trolox due to formation of intermolecular hydrogen bonds within cyclic dimers. Such crystal packing permits effective cross-polarization and fast relaxation (short T1rho(H)). The impact of the proton concentration on the CP dynamics is reflected by the longer T(CP) and T1rhoH for Trolox-d2 (deuterated at mobile proton sites). The calculated GIAO RHF shielding constants are sensitive to intramolecular effects: rotation around the C-6-O bond (changes of sigma up to 8 ppm) and conformation at C-2. |
Introduction {#s1}
============
Allogeneic hematopoietic cell transplantation (HCT) remains a curative approach for many patients with malignant and non-malignant hematologic indications ([@B1]). However, timely availability of a suitable HLA-matched sibling donor (MSD) or adequately HLA-matched unrelated donor (MUD) remains a significant challenge in providing access to HCT. The likelihood of finding an optimal donor varies significantly among racial and ethnic groups with the chances of finding an appropriate donor ranging from 75% for whites of European descent to 16% for blacks of South or Central American descent ([@B2]). Although most candidates for HCT will have a donor or cord blood unit considered suitable (HLA-matched or minimally mismatched), even single allele mismatches negatively impact patient outcomes after HCT ([@B3]). Additionally, proceeding with an unrelated donor is a time- and cost-consuming process that can result in delay or suboptimal timing of HCT.
In contrast, haploidentical donors are available for \>95% of patients in need of HCT ([@B4]). Biological children, parents, siblings, and frequently more distant family members who share one haplotype potentially qualify as donors ([Figure 1](#F1){ref-type="fig"}). They can be readily identified and are typically available and motivated to donate bone marrow (BM) or peripheral blood stem cells (PBSC) to their family member in a timely fashion. This is particularly beneficial when unexpected events delay or expedite the need for HCT. Moreover, haploidentical donors can readily be tested in situations where there is concern for an underlying familiar predisposition syndrome and are typically available for a repeat stem cell collection, donor lymphocyte infusion or other cell therapeutic approaches which may be indicated if post-transplant complications such as graft failure, relapse, or infectious complications arise. Finally, if the selected family member had a poor stem cell mobilization for a PBSC graft or the optimal graft composition was not achieved then a different family member can be approached to serve as a haploidentical donor.
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Historically, haploidentical HCT (haplo-HCT) was associated with high rates of graft vs. host disease (GVHD) and graft failure ([@B5]--[@B7]). With the introduction of efficient T-cell depletion (TCD) of the graft ([@B8]), haplo-HCT became feasible from a GVHD perspective. However, TCD led to an imbalance between host and donor T cells resulting in high rates of graft failure. This imbalance was overcome with the use of T-cell depleted "megadose" stem cell grafts ([@B9], [@B10]). Since then, nuanced *ex vivo* approaches to optimize the immunological composition of haploidentical grafts have been developed as outlined in this review.
A major milestone in promoting the wide-spread use and cost-efficient accessibility of haplo-HCT, including in resource-poor countries, was reached with the use of high-dose post-transplant cyclophosphamide (PTCy) to achieve *in vivo* attenuation of T cell alloreactivity ([@B11]). A different strategy using Granulocyte-colony stimulating factor (G-CSF) mobilized bone marrow grafts with extensive immunosuppression has been similarly feasible ([@B12]). In addition, a special emphasis is being placed on using natural killer (NK) cells to harness both innate and adaptive immunity in haplo-HCT. NK cells are uniquely regulated by activating and inhibitory receptors and can mediate a critical graft-vs.-leukemia (GVL) effect, also referred to as NK-cell alloreactivity, without mediating GVHD ([@B13]--[@B15]).
These approaches have contributed to a surge in the use of haplo-HCT in recent years ([@B16]). Furthermore, dramatic advances in the field of adoptive immune cell transfer have been applied to the haplo-HCT platform whereby donors could be readily approached for additional cell collections to enhance immunity against infections and relapse ([@B17], [@B18]). As haplo-HCT evolves to refine and establish its role in the field of transplantation, it is critical to examine the immunobiological properties unique to haplo-HCT and the effect of *ex vivo* or *in vivo* graft manipulation on the immunological content and trajectory of immune reconstitution.
Challenges of the Hla-Barrier in Haplo-Hct {#s2}
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Early trials of T-cell-replete haplo-HCT were associated with poor outcomes due to a high incidence of GVHD and graft rejection, resulting in \~10% long-term survival ([@B5]--[@B7], [@B19], [@B20]). In the setting of grafting across a haploidentical HLA barrier, \~2% of donor T cells mediate alloreactive reactions resulting in GVHD while residual host T cells mount host-vs.-graft responses leading to graft rejection ([@B21]--[@B23]). The ability to overcome the problem of GVHD despite the large HLA-disparity in haplo-HCT was first demonstrated by Reisner and colleagues with the successful transplantation of children with severe combined immunodeficiency (SCID) using T-cell depleted haploidentical grafts which differed at three major HLA loci ([@B8]). However, when this approach was extended to other indications in which a patient\'s underlying immune system is generally functional, the minimal T-cell content in the graft resulted in unopposed host-vs.-graft rejections and a high rate of graft failure. The latter was mediated by recipient anti-donor T lymphocyte precursors that survived the conditioning regimen ([@B22], [@B24], [@B25]), as well as anti-donor HLA antibodies ([@B26]) ([Figure 2](#F2){ref-type="fig"}).
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A second breakthrough that paved the way toward the broad application of haplo-HCT was the use of "megadose" grafts, targeting the infusion of a stem cell product containing on the order of ≥10 × 10^6^/kg CD34^+^ hematopoietic stem cells while retaining the threshold dose of ≤4 × 10^4^/kg T cells established in the SCID patients ([@B9], [@B10], [@B27], [@B28]). The underlying immunologic effect of megadose grafting was attributed to tolerance induction of host anti-donor cytotoxic T cell precursors by donor CD34^+^ stem cells or by CD34^+^ derived regulatory immune cells endowed with a "veto"-effect in a TNFα mediated mechanism ([@B29], [@B30]). Intensified myeloablative conditioning (MAC) with 8 Gy total body irradiation (TBI), thiotepa, rabbit anti-thymocyte globulin (ATG) and fludarabine (replacing cyclophosphamide after 1995) ([@B31]) to eliminate host T cells, followed by G-CSF mobilized megadose T-cell depleted PBSC grafts (initially using soybean agglutination and erythrocyte resetting and later immunomagnetic selection of CD34^+^ HSCs) without any additional post-transplant immunosuppression was refined over the years ([@B28], [@B32]). This approach ultimately demonstrated primary engraftment in 95% of patients with acute leukemia (*n* = 104), with 6 of 7 patients who initially experienced graft failure engrafting successfully after second transplantation. Although acute and chronic GVHD were largely prevented, a significant non-relapse mortality (NRM) of 36.5% was observed largely owing to post-transplant infections (27 of the 38 patients died of infectious complications) and substantial relapse risk. The 2-year event-free survival (EFS) probability among patients receiving transplantation in any complete remission (CR) was 47%, while the EFS for those transplanted in relapse was 4% ([@B27]).
Despite the tremendous advances toward clinical feasibility of haplo-HCT, these early studies embodied the challenge of achieving a sensitive immunologic balance during transplantation across haploidentical HLA-barriers. This challenge is reflective of the need for extensive T-cell depletion and immunosuppression to control GVHD on the one hand, and facilitation of engraftment, immune reconstitution, protection from infections, and prevention of relapse on the other ([Figure 2](#F2){ref-type="fig"}). This conundrum has fueled the iterative improvement of modulating immunity in the context of haplo-HCT as outlined below.
Current HAPLO-HCT Platforms {#s3}
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*In vivo* Haplo-HCT Strategies With Unmanipulated Stem Cell Grafts
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### Post-transplantation Cyclophosphamide (PTCy)
Post-transplantation high-dose cyclophosphamide (PTCy), when administered in a specific time-frame after graft infusion, efficiently attenuates alloreactive T cells from both donor and host and prevents GVHD and graft rejection. This immunological effect of PTCy was first observed in the 1960s in animal models of allogeneic skin grafts whereby cyclophosphamide administration within a window of up to 4 days after grafting delayed rejection ([@B33]). Subsequent preclinical studies defined the role of PTCy in the setting of allogeneic HCT and showed the benefits of its use with respect to engraftment and GVHD ([@B34]--[@B36]). Importantly the concurrent immunosuppression of T cells with cyclosporine or steroids interfered with PTCy-tolerogenic effects ([@B37], [@B38]), indicating that high proliferative rates are critical for the PTCy immunomodulatory mechanism ([@B39]).
Initial mechanistic studies based on murine skin allografting models attributed the PTCy-effect to the selective depletion of alloreactive T cells. Based on these hypotheses, the presumed depletion was dependent on the heightened cytotoxic sensitivity of newly primed and highly proliferative alloreactive T cells (particularly CD4^+^ T cells) at the peak of anti-host and anti-donor T cell expansion, aided by a favorable balance between effector T cells and regulator T cells (Tregs) as well as an additional intrathymic clonal deletion of alloreactive T cell precursors ([@B40]--[@B44]). Suppressive immune cells were only felt to have an adjunct role in maintaining tolerance ([@B45], [@B46]). However, recent work by Kanakry and colleagues formally tested the putative immunologic mechanisms (selective destruction of alloreactive T cells, intrathymic clonal deletion of alloreactive T cells and induction of suppressor T cells) in dedicated murine PTCy haplo-HCT models ([@B47]). These studies suggest that PTCy reduces CD4^+^ T cell proliferation but does not eliminate alloreactive T cells and instead functionally impairs the T-cell response to alloantigens and induces the rapid and preferential recovery and expansion of regulatory T cells (Treg). Treg resistance to PTCy is based on their differential expression of aldehyde dehydrogenase (ALDH) ([@B48]). Evidence for the importance of the role of Tregs after PTCy is exemplified by the development of severe and fatal GVHD in the context of Foxp3^+^ Treg depletion, as well as additional data showing that Tregs are required for PTCy-mediated protection against GVHD ([@B49]). Studies in thymectomized mice also suggested the dispensability of the thymus in this process ([@B47]). Advances in this active field of preclinical and clinical study are poised to further elucidate and facilitate adaption of the PTCy platform for different clinical scenarios. Increasing experience with this platform and the potential for PTCy-mediated bi-directional tolerance induction also lends itself to further exploration of this approach in the setting of combined solid organ and bone marrow transplantation ([@B44]).
The first clinical study of unmanipulated haplo-HCT with PTCy was conducted in the setting of non-myeloablative (NMA) conditioning with administration of PTCy at 50 mg/kg on day +3 and an added immunosuppressive regimen of mycophenolate mofetil (MMF) and tacrolimus starting on day +4 in 13 patients ([@B50]) ([Figures 3A](#F3){ref-type="fig"}, [4C](#F4){ref-type="fig"}). Subsequent prospective clinical trials, administering PTCy either on day +3 or on days +3 and +4, demonstrated rates of graft failure and GVHD comparable to those reported with reduced intensity conditioning (RIC) HLA-matched sibling and MUD HCTs with a trend toward a lower risk of extensive chronic GVHD among recipients of two doses of PTCy ([@B50]). These studies paved the way for the increased investigation and clinical use of haplo-HCT with PTCy ([Figure 3B](#F3){ref-type="fig"}).
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{ref-type="fig"}; Tregs are depicted in bright yellow).](fimmu-11-00191-g0004){#F4}
### GIAC Approach ([G]{.ul}-CSF-Mobilization, [I]{.ul}ntensified Post-transplant Immunosuppression, [A]{.ul}TG and [C]{.ul}ombination of PBSC and BM Allografts)
The GIAC approach using T-cell replete haploidentical grafts was pioneered at Peking University ([@B12], [@B51]). This approach uses ATG as part of the conditioning regimen, which affects recipient T cells and facilitates engraftment. Owing to its long half-life, it also exerts effects on donor T cells and therefore impacts GVHD and post-transplant immunity. The graft consists of a combination of G-CSF-primed bone marrow and PBSC, thereby combining the advantages of both elements. PBSC grafts contain 2--3-fold higher CD34^+^ cells and a log-fold higher T cell dose than are typically contained in a steady-state bone marrow graft ([@B52]), and this has been shown to accelerate engraftment and decrease the relapse rate ([Figures 3C](#F3){ref-type="fig"}, [4B](#F4){ref-type="fig"}).
The higher T cell dose in PBSC grafts adversely affects chronic GVHD but not acute GVHD rates in unrelated donor HCT ([@B53]). Multiple mechanisms may contribute to why acute GVHD rates are not drastically higher despite the high T cell dose. These include preferential dendritic cell mobilization and T cell polarization ([@B54], [@B55]), attenuating effects on costimulatory molecules such as CD86 on APCs and CD28 on CD4^+^ T cells ([@B56], [@B57]), as well as IL-10 mediated T-cell suppression by monocytes ([@B58]). Several studies underscored the benefit of utilizing G-CSF mobilized bone marrow, leading to less acute and chronic GVHD while maintaining engraftment rates comparable to PBSC ([@B59]) and have attributed these effects to differences in cytokine milieu, T-cell polarization and T-cell hypo-responsiveness ([@B60]--[@B62]).
In the initial study of 171 patients using GIAC, most of whom had ALL, AML, or CML, all patients engrafted with sustained full donor chimerism. The rates of leukemia-free survival and incidences of grade II-IV acute GVHD and extensive chronic GVHD were comparable to MUD HCT ([@B12], [@B53]). A prospective multicenter study of AML patients has demonstrated that transplant outcomes with the GIAC strategy have also been comparable to MSD HCT ([@B63]). Although a modified approach using G-CSF primed haploidentical bone marrow and extensive GVHD prophylaxis has also been applied in Europe ([@B64]), the GIAC strategy has been used most extensively in China and therefore patients transplanted with this strategy represent a large cohort of haploidentical transplants HCT treated to date ([@B65]).
Haploidentical Hct With *ex vivo* T Cell Depletion or Anergy Induction Strategies
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### CD34^+^ Cell Selection
The establishment of procedures for the *ex vivo* removal of T cells from the graft in the late 1970s by Reisner, O\'Reilly and colleagues, represented a tremendous breakthrough toward the feasibility of utilizing haploidentical donors. In the initial approach, T cells were eliminated from the bone marrow by first rosetting with sheep red blood cells followed by differential soybean agglutination of residual T lymphocytes in the non-rosetting population. This yielded an un-agglutinated fraction containing a high proportion of colony-forming cells without any detectable T cell alloreactivity, and abrogated lethal GVHD in murine models ([@B66], [@B67]). This strategy was applied in the first clinically successful haploidentical HCT of an infant with AML, leading to sustained hematopoietic engraftment without GVHD until relapse occurred 11 weeks after HCT ([@B68]). Three infants with SCID were also treated with this approach of whom 2 had sustained engraftment and none developed GVHD ([@B8]).
CD34^+^ selection, now in wide-spread use in TCD transplants, was first introduced in the 1990s. This process utilizes a CD34^+^ directed antibody coupled to immunomagnetic beads to positively select CD34^+^ cells and isolate them over a magnetic column. This effectively eliminates all other immune cells, including T-, B-, NK-cells, dendritic cells and monocytes from the graft ([@B69], [@B70]). This process was further refined with the use of micromagnetic beads, which had the advantages of high purity selection via attachment to single cells and safe infusion into patients ([@B71]). Aversa and colleagues of the Perugia group pioneered a novel haploidentical HCT platform incorporating an intensified conditioning regimen to eliminate host T cells and administering megadose T cell depleted grafts without additional post-grafting immunosuppression ([@B28], [@B72]). Handgretinger et al. tested this approach with G-CSF mobilized megadose PBSC grafts in 39 children lacking suitable donors and observed low rates of GVHD, but significant relapse and treatment-related mortality (TRM) ([@B73]). Investigators from Perugia further evaluated this system in adults with high-risk leukemia using megadose haplo-HCT, demonstrating 91% primary engraftment and low rates of GVHD without post-transplant GVHD prophylaxis ([@B27]) ([Figure 4A](#F4){ref-type="fig"}, top panel).
### CD3^+^ Cell Depletion
To improve post-transplant immune reconstitution, control of infections and prevention of relapse, further iterations of immunomagnetic graft engineering were developed ([@B74]). This included the elimination of CD3^+^ T cells and CD19^+^ B cells using a negative immunomagnetic selection method to deplete these subsets from the graft. Stem cells, NK cells, myeloid precursors, monocytes, and other progenitor cells important for engraftment are preserved ([@B75]). This strategy maintains innate immunity in the graft while removing CD3^+^ T cells capable of inducing GVHD. Depletion of CD19^+^ B cells was introduced to reduce the risk of post-transplant lymphoproliferative disease (PTLD) ([@B73]) and GVHD ([@B76]). While the depletion of donor B-cells reduces the risk of PTLD, it does not address PTLD arising from residual host B cells. Instead, this can be addressed with the inclusion of rituximab or Campath (but not the T cell directed agents ATG or OKT3) into the conditioning regimen ([@B77], [@B78]). Several centers established CD3^+^/CD19^+^ depletion as a feasible approach for patients lacking a suitable donor, with excellent primary engraftment and reduced rates of GVHD correlating with the remaining CD3^+^ cell/kg content of the graft. However, the low OS rate of 31% remains primarily attributable to infections and relapse, suggesting that further improvement of TCD haplo-HCT is needed ([@B79], [@B80]) ([Figure 4A](#F4){ref-type="fig"}, second panel).
### αβT-Cell/B-Cell Depletion
With emerging recognition of γδT cells ([@B81]), a yet more sophisticated approach was developed for GVHD prevention. In contrast to αβ-T-cell receptor (TCR) expressing T cells, γδ-TCR expressing T-cells are not implicated in mediating GVHD ([@B82]) but do exhibit important functions characteristic of innate immune recognition and anti-tumor effects ([@B83], [@B84]). These cells represent 1--20% of all CD3^+^ circulating T lymphocytes in human peripheral blood and the majority of resident T cells in skin and mucosa. Their TCR heterodimer consists of a γ and δ chain encoded by a limited repertoire of V, D, and J gene segments. The two major Vδ1 and Vδ2 subsets are distinguished based on their TCRδ composition. Whereas, Vδ1^+^ cells are typically associated with a Vγ1/2/3/5/8 chain, the majority of Vδ2^+^ T cells express an invariant TCR harboring Vγ9. The Vγ9δ2 TCR is expressed by the majority of peripheral γδ T cells, whereas γδ T cells including other Vδ elements are predominantly enriched at epithelial surfaces and the skin ([@B81], [@B84]). Analogous to NK cell biology, γδT cells are fine-tuned by activating and inhibitory receptors and recognize conserved non-peptide antigens that signal potential danger or cellular stress. The activating receptor NKG2D is broadly expressed in γδT cells and functions synergistically with the γδ-TCR as a costimulatory receptor ([@B85], [@B86]).
γδT cells have heterogenous functions, ranging from protection against intra- and extracellular pathogens or malignant cells to modulation of the immune response and tissue homeostasis. They contribute to pathogen clearance through the production of granulysin, defensins, and cytotoxic effector molecules such as perforin and granzymes ([@B84]). γδT cells secrete proinflammatory cytokines involved in protective immunity against viruses, intracellular pathogens (TNF-α and IFN-γ), extracellular bacteria, fungi (IL-17), and extracellular parasites (IL4, IL5, IL13), and have been shown to exhibit lytic activities against leukemia, lymphoma and carcinoma cells ([@B87]--[@B89]). Indeed, increased γδT-cell numbers after allogeneic HCT were associated with a lower incidence of infections and improved disease-free survival (DFS) in several studies ([@B90]--[@B92]).
In a pediatric trial using αβ-T cell/B-cell depleted haplo-HCT, γδ-T cells were the predominant T-cell population in the initial weeks after transplantation, specifically expanded in response to CMV reactivation, and displayed cytotoxicity and degranulation when challenged with primary leukemia blasts *in vitro* ([@B93]). These effects were increased after exposure to zoledronic acid, suggesting that the anti-leukemic capacity of γδ-T cells could further be enhanced ([@B94]). Outcomes with the αβ-T cell/B-cell depleted haplo-HCT approach in which no additional GVHD prophylaxis was employed appear promising both in children with malignant ([@B95]) and non-malignant conditions ([@B96]), and when compared with MUD and MMUD HCTs in a retrospective analysis of children transplanted for acute leukemias ([@B97]). However, the high incidence of viral infections reported by some groups highlights the potential to further improve *ex vivo* T-cell depletion strategies ([@B98]) ([Figure 4A](#F4){ref-type="fig"}, third panel).
### CD45RA-Depletion
As our understanding of T cell differentiation status and phenotype has become increasingly sophisticated, so have approaches to tailor graft composition further ([@B99], [@B100]). αβ-T cells exist as distinct subsets that can be differentiated by cell surface phenotype: naïve (T~N~), stem cell memory (T~SCM~), effector (T~E~), effector memory (T~EM~), and central memory (T~CM~). The CD45RA^+^CD62L^+^ T~N~ subset is antigen inexperienced, has a more diverse TCR repertoire than memory T cells and clonally expands following T cell priming to execute short-lived effector functions. They ultimately differentiate into memory subsets, which is associated with downregulation of CD45RA and upregulation of CD45RO. Studies in mouse models demonstrated that T~N~ mediated severe GVHD, whereas T~CM~ induced milder GVHD and T~EM~ were devoid of GVH activity ([@B101]--[@B105]). Importantly memory T cells transferred infectious immunity and GVL activity in these models ([@B106]).
Based on the premise that elimination of T~N~ from the graft could significantly reduce GVHD while maintaining pathogen- and tumor-specific immunity, Bleakley and colleagues developed a novel graft-engineering strategy using immunomagnetic beads coupled to a monoclonal Ab targeting CD45RA. The latter antigen is expressed on all T~N~, but absent on Treg, T~CM~ and most T~M~ ([@B107]). This strategy was initially studied in patients with high risk hematologic malignancies undergoing MSD HCT, utilizing a 2-step selection procedure with a CD34^+^ selection of stem cells (a minor subset of which expresses CD45RA) followed by depletion of CD45RA^+^ cells from the CD34^−^ fraction. This study demonstrated engraftment in all patients (*n* = 35), prompt immune recovery without excessive rates of infection or relapse and low chronic GVHD, but interestingly no reduction in acute GVHD although the latter was readily steroid-responsive ([@B108]).
Clinical results with CD45RA-depletion in the context of haplo-HCT are so far limited. A study of 17 pediatric patients with high risk hematologic malignancies using a RIC conditioning with total lymphoid irradiation (TLI) but without TBI or serotherapy, administered a CD34^+^ selected PBSC product on day 0, followed by a CD45RA-depleted PBSC product which had been collected the following day, and ultimately a donor NK cell product administered on day +6 with the use of Sirolimus or MMF post-transplant. Rapid neutrophil engraftment and memory T-cell reconstitution was observed, without any infectious deaths and with 76.5% of patients alive at a median of 225 days after HCT. Grade III-IV acute GVHD and chronic GVHD were seen in 3 and 6 of 17 patients, respectively ([@B109]). In a second small study, 5 children with combined immunodeficiency and chronic viral infections received a combination of a CD34^+^ selected product and the CD45RA-depleted fraction of the CD34-negative product with post-HCT prophylaxis consisting of Cyclosporine and MMF. One patient died with graft failure. In the 4 engrafted patients, viral infections cleared within 2 months after HCT and an early T cell response against viral pathogens was documented in 2 patients ([@B110]). Further studies will be needed to further define the role of this approach in haplo-HCT ([Figure 4A](#F4){ref-type="fig"}, bottom panel).
### *Ex vivo* Induction of T Cell Anergy With CTLA-4Ig
An early strategy to minimize T-cell alloreactivity by interfering with the priming of alloreactive T cells in haplo-HCT was explored in a pediatric trial. This involved collection of patients\' peripheral blood mononuclear cells (PBMC) prior to the start of myeloablation and a 36-h *in vitro* incubation of the recipient cells with non-mobilized donor bone marrow in a mixed lymphocyte reaction (MLR) setting in the presence of CTLA-4Ig, a fusion protein which inhibits priming of alloreactive T cells by inhibiting costimulatory signaling between the B7 protein family (CD80/CD86) on APCs and CD28 on T cells ([@B111]). This reduced the frequency of T cells recognizing alloantigens of the recipient while preserving responsiveness to alloantigens of other persons. In this trial of 11 evaluable patients most of which had persistent disease at the time of HCT, 5 were alive and in CR at 4.5--29 months after transplant with 3 patients developing steroid-responsive acute GVHD of the gut only. There were no deaths attributable to GVHD ([@B112]). However, this approach has not been explored further.
### Photodynamic Purging of Adoptive T Cell Therapy Following TCD Haplo-Hct
A different approach to augment the TCD graft with an adoptive T cell therapy product devoid of alloreactive T cells is a process termed photoallodepletion. Prior to G-CSF mobilization of the PBSC graft, donors undergo non-mobilized leukapheresis to obtain T cells. Donor T cells are then incubated with recipient PBMC in an MLR in the presence of TH9402, a photosensitizer similar to rhodamine. T cell activation in the MLR, which occurs selectively in the alloreactive T cells but spares Tregs and pathogen-specific T cells, is associated with P-glycoprotein pump inhibition leading to mitochondrial accumulation of TH9402 in alloreactive T cells ([@B113], [@B114]). Subsequent activation of TH9402 with visible light leads is then selectively toxic to and eliminates alloreactive T cells via an oxidative damage mechanism ([@B115]). Early results from a clinical trial in which patients received the photodynamically allodepleted T-cell product subsequent to a CD34^+^ selected graft appear promising ([@B116]).
Role of Innate Immunity in HAPLO-Hct {#s4}
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NK-cells are an important component of the innate immune system providing protection against infectious pathogens and cancer. Recent studies have elucidated that human NK cell diversity is much broader than the traditional distinction via CD56^bright^ and CD56^dim^ subsets reflective of differentiation stage and cytotoxic potential. The ability of NK cells to differentiate into long-lived cells with memory capacity ([@B117]) and the discovery of non-NK innate lymphoid cells has highlighted the complexity and potential roles of innate immune cells after HCT ([@B118], [@B119]). NK cells have potent anti-leukemia effector capacity, respond to viral infections via release of toxic granules, and facilitate engraftment without mediating GVHD. This is particularly important in the setting of heavily T cell-depleted grafts or T-cell directed post-transplant immunosuppression and has inspired a rich field of investigation to augment NK cell immunity in the context of HCT to develop leukemia-directed NK-cell based cellular therapies.
NK-cell activity is governed by the balance of a system of activating and inhibitory NK cell receptors ([@B120]). Activating signals are provided by receptors such as NKG2D, CD94/NKG2C and Natural Cytotoxicity Receptor (NCRs) including NKp30, 44, and 46 and by activating killer-cell Ig-like receptors (KIR). NKG2D recognizes MHC-class I related stress-ligands that can be upregulated by tissues in response to infection, inflammation, DNA-damage, and malignant transformation ([@B121]), while CD94/NKG2C binds to the non-classical HLA-E molecules and senses overall HLA-Class I expression on cells ([Figure 5A](#F5){ref-type="fig"}). NK cells utilize a unique process to balance tolerance to self under steady state conditions with the ability to mediate an immune response to pathogens or malignant cells. This is referred to as NK-cell education or licensing ([@B122]), is in large part regulated by inhibitory KIR receptors and impacts NK-cell alloreactivity in the setting of haplo-HCT and allogeneic NK-cell therapies ([@B123]).
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KIRs are either activating or inhibitory based on their structure. The KIR nomenclature incorporates the number of extracellular Ig-like domains (two in KIR2D vs. three in KIR3D) and whether the KIR contains a long or short tail (KIR2DL vs. KIR2DS). KIRs are further numbered in order of their discovery within their structural group (KIR2DL1 vs. KIR2DL2). KIRs with long tails are generally inhibitory (with exception of KIR2DL4) and KIRs with short tails function as activating receptors according to presence or absence of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) ([@B124]). There is tremendous variability within the KIR repertoire owing to a high degree of polymorphism among individual KIR genes as well as their organization and recombination within haplotypes ([Figures 5B,C](#F5){ref-type="fig"}) ([@B125]). An individual\'s genetic KIR repertoire is determined by the inherited composition of centromeric and telomeric A and B haplotypes ([Figure 5B](#F5){ref-type="fig"}). Group A haplotypes contain fewer genes and predominantly those encoding for inhibitory KIRs. Additionally, the activating KIR2DS4 gene exist as an inactive deletion variant, termed KIR1D in the majority of Caucasians, leaving the framework gene KIR2DL4 as the sole receptor on this haplotype with any activating function ([@B126], [@B127]). In contrast, Group B haplotypes are enriched for activating KIRs. Two groups of KIR haplotype can be assigned based on the combination of the centromeric and telomeric motifs. Presence of a centromeric or telomeric B-haplotype constitutes a KIR B haplotype whereas the combination of a centromeric and a telomeric A-haplotype results in a KIR A haplotype ([Figure 5C](#F5){ref-type="fig"}). Although more than 50 different haplotypes have been described, there are 11 common haplotypes derived by reciprocal recombination, which collectively account for 94% of Caucasian haplotypes examined by Jiang et al. ([@B128]). Distribution of a KIR gene in the centromeric or telomeric region of chromosome 19q13.4 is further thought to impact KIR-mediated regulation of NK-cell activity ([@B129]). Additionally, KIR-cell surface expression at the protein level may vary substantially from the inherited KIR gene profile. This is attributable to the fact that KIRs are stochastically expressed on NK cells and each NK cell may therefore display a different cell-surface profile of inhibitory or activating KIRs ([@B130]). For the most accurate prediction of NK-cell alloreactivity between haploidentical donor and recipient, KIR-genotyping alone is insufficient and determination of the KIR phenotype (by flow cytometry) should also be pursued.
The majority of inhibitory KIRs recognize classical (HLA- A, B, and C) or non-classical HLA-class I molecules (HLA-G) as their cognate ligands ([Figure 5A](#F5){ref-type="fig"}) ([@B131]). KIR genes are located on chromosome 19 whereas HLA-genes are located on chromosome 6. KIR and HLA genes therefore segregate independently, and an individual may or may not express the cognate HLA-ligand for any given KIR. This forms the basis for the concept of "education" or "licensing" of NK-cells, which allows NK-cells to maintain self-tolerance under physiologic conditions, while retaining the ability to mount an immune response ([@B132]). When NK cells encounter the matching HLA-class I ligand for their inhibitory KIR (based on the requisite germline inheritance of the appropriate HLA and KIR genes and their expression patterns on individual NK cells), they are considered "educated" or "licensed" and refrain from an attack on healthy tissues under steady state. However, when NK cells are accustomed to this inhibitory signal and subsequently encounter a cell that does not express the appropriate KIR-ligand ("missing ligand"), this situation renders them functional to mount an effector response, if the target also expresses stress-ligands that trigger activating NK-cell receptors ([@B133]). A missing ligand may be encountered on malignant cells due to HLA-class I downregulation, or HLA-mismatched allogeneic transplantation such as haplo-HCT, when the recipient does not express the corresponding HLA-ligand ([Figure 6](#F6){ref-type="fig"}). NK-cells are considered "unlicensed" when they do not encounter the matching HLA-class I ligand for their given inhibitory KIR. Due to the lack of exposure to their corresponding ligand, unlicensed NK-cells are "un-educated" and hyporesponsive at steady state rather than being triggered by self-tissues lacking the ligand ([@B134]). Unlicensed NK cells require a higher threshold for activation. However, in the absence of KIR inhibition, they can mediate higher levels of effector function when they receive strong stimulatory signals under inflammatory conditions (such as CMV infection or in the posttransplant setting) or when triggered for antibody-dependent cellular cytotoxicity (ADCC) ([@B135], [@B136]). Given that NK cells may surface-express variable combinations and densities of inhibitory KIRs, NK-cell education occurs on a continuum along which individual NK cells display graded levels of responsiveness based on their KIR profile and engagement of cognate HLA-class I ligands ([@B122], [@B137], [@B138]).
{#F6}
Since the model of NK-cell alloreactivity in the context of mismatched HCT was first proposed, a number of studies have evaluated its clinical impact ([@B139]). For the interpretation of HCT studies evaluating the role of NK-cell alloreactivity it is critical to consider the definition of the KIR-mismatch model employed in each study ([@B131], [@B140]) ([Figure 6](#F6){ref-type="fig"}). The "KIR ligand-ligand mismatch model" is based on the hypothesis that the presence of the corresponding HLA-ligand prevents NK-cell alloreactivity, whereas a missing ligand in the HCT recipient triggers NK cell alloreactivity. However, while this model accounts for HLA-class I mismatches, it does not consider KIR-genotype or phenotype. In contrast, the "KIR receptor-ligand mismatch model" accounts for the fact that a missing ligand is irrelevant if NK cells do not express the corresponding KIR for a mismatched HLA-class I ligand. Therefore, this model incorporates the HLA-ligand repertoire in the recipient as well as the donor KIR genotype and ideally phenotype. Other groups have employed the "KIR-haplotype model" which takes into consideration the presence or absence of a B-KIR haplotype in the donor, as a measure of enrichment for activating vs. inhibitory KIRs. Use of this model demonstrated a reduced risk of leukemia relapse when patients were transplanted from donors with centromeric B-haplotypes ([@B141]--[@B143]). Similarly, more recent approaches have focused on the predicted overall degree of inhibitory and activating KIR-KIR ligand interactions between the recipient and potential donors with a highly variable KIR repertoire. This allows for selection of an optimal donor, even when the transplant recipient\'s HLA-class I repertoire is such that all KIR ligands are expressed and a missing-ligand scenario is unachievable.
Ruggeri et al. first established that a NK-cell alloreactivity of the donor toward recipient (based on KIR receptor-ligand mismatch in the GVL direction and presence of alloreactive clones against recipient targets) lowered the AML relapse risk in the context of *ex vivo* depleted haplo-HCT ([@B72]). These results were subsequently consolidated in a larger cohort of 112 AML patients, where transplantation from a NK-cell alloreactive donor was associated with a significantly lower relapse rate (3% compared to 47%) when transplanted in complete remission and better EFS when transplanted in relapse (34% compared to 6%) or CR (67% compared to 18%) ([@B144]). Subsequent studies of sibling donor, unrelated donor (URD), and umbilical cord blood (UCB) donor sources have yielded variable results ([@B14]). Some studies showed no benefit or even inferior survival resulting from a mismatch in the KIR/KIR-ligand system. This may be partly related to the variable definition of KIR-mismatch models and transplant regimens used. In contrast, a large analysis in AML patients undergoing 9/10 or 10/10 URD employed an algorithm to predict the strength of inhibition between the ubiquitous KIR3DL1 and its ligand HLA-B and found that combinations with absent of weak inhibition were associated with significantly lower rates of relapse and overall mortality ([@B145]). The extent of T-cell depletion may also play an important role, since the presence of T cells in the graft affects NK cell reconstitution leading to lower KIR-receptor expression ([@B146]). Lastly, given that a KIR ligand-ligand mismatch implies an absence of a KIR ligand in the host that is present in the donor, it equates with the presence of a major HLA-class I mismatch. It is therefore not unexpected that such mismatch leads to significant T-cell alloreactivity and poor survival unless T-cell reactivity is minimized with methods such as TCD.
A retrospective analysis of 161 patients receiving TCD haploidentical allografts confirmed a beneficial role of NK cell alloreactivity. In the presence of KIR-receptor-ligand mismatches in the GVL direction, expression of activating KIR2DS1 or KIR3DS1 was associated with a significant reduction in NRM, largely owing to 50% reduction in infection rates ([@B147]). While much of the benefits of NK cell alloreactivity are reported for myeloid indications, a pediatric study of 85 patients undergoing TCD haplo-HCT showed that patients transplanted for ALL from a KIR B-haplotype donor had a significantly better EFS than those with KIR haplotype A donors. Additionally, a higher KIR B-content score (based on the number of centromeric and telomeric KIR B motifs) was associated with a significant reduction in relapse risk ([@B148]). Although limited by use of a KIR ligand-ligand model, a study of haplo-HCT with PTCy for various hematologic malignancies found that KIR-ligand mismatch was associated with a lower incidence of relapse and better PFS for patients transplanted in relapse but had no significant impact on those transplanted in CR ([@B149]). A growing ability to navigate the complexities of the KIR-system, such as recognition of varied strengths of inhibition among subtypes of inhibitory KIRs and its ligands resulting in discrete hierarchies of anti-leukemic cytotoxicity will aid in further revealing how donor selection based on KIR-compatibility may improve outcomes ([@B145]). While the beneficial effects of NK-cell alloreactivity are mostly documented in the context of *ex vivo* T cell-depleted haplo-HCT, the growing adaptation of T-cell replete haplo-HCT affords the opportunity to carefully study the role of NK-cell alloreactivity in these platforms.
Immune Reconstitution After HAPLO-Hct {#s5}
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Transplant outcomes are directly related to the achievement of an acceptable restoration of the immune system. Several cell subsets play a key role in the protection toward infections and disease recurrence. In general, innate immunity recovers early after transplant and represents the first line of defense against pathogens. Specifically, monocytes followed by neutrophils and NK cells arise in the first month after transplant. Adaptive immunity mediated by T and B cell lymphocytes recovers later and is crucial for both immune tolerance maintenance and long-term protection against infections and disease relapse. T cell reconstitution can occur through two different mechanisms: thymus-independent T cell peripheral expansion of infused donor memory T cells and thymus-dependent *de novo* generation of donor T cells from donor hematopoietic progenitors ([@B150]).
While the kinetics of immune reconstitution and its correlation with HCT outcomes are well-established in the setting of matched donor transplant, more studies are needed in the setting of haplo-HCT. Different donor sources do not represent the only cause of possible differences in immune reconstitution kinetics. Specific haplo-HCT platforms and GVHD prophylaxis approaches are also crucial factors to consider ([@B151]). As detailed above, two major haplo-platforms are currently used: T- cell replete haplo-HCT that use an *in vivo* T-cell depletion with ATG or PTCY, and TCD haplo-HCT in which the graft is *ex vivo* manipulated with a CD34-positive selection or a T-cell negative selection. Here, we review the immune reconstitution of different blood cell subsets after different types of haplo-HCT ([Figure 7](#F7){ref-type="fig"}).
.](fimmu-11-00191-g0007){#F7}
Monocytes
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Monocytes are the first immune subset to recover after HCT. Rapid and robust monocyte CD14^+^ cell reconstitution has been correlated with the improvement of transplant outcomes in the setting of MSD ([@B152]) and UCB-HCT ([@B153]). Recently, a study by Turcotte and colleagues showed that higher absolute monocyte count (AMC) and higher classic monocyte subsets (CD14^bright^ CD16^−^) at day +28 were associated with a reduced risk of relapse and TRM, better 2-yr OS, and improved 2-yr PFS in a cohort of patients transplanted for different hematological malignancies using both RIC or MAC regimens and different stem cell sources ([@B154]). AMC was influenced by the graft origin, with a higher AMC found in UCB but no differences between BM and PBSC. However, no haplo-HCTs were included in this study. In a separate cohort of 144 patients treated with MAC conditioning for hematological malignancies, receiving a T-cell replete graft consisting of G-CSF-mobilized BM and PBSC from HLA-haploidentical or MSDs, the monocytes recovered rapidly, and the AMC was above the normal range starting from the first month to the first year after transplant. Both patient groups received GVHD prophylaxis with Methotrexate, Tacrolimus, MMF, and Cyclosporine with the addition of ATG in the haploidentical group (GIAC protocol). Monocyte reconstitution was comparable between recipients after HLA-matched and haplo-HCT on days +30, 90, and 180 after transplantation. None of the patient transplant characteristics impacted monocyte recovery in the multivariable analysis ([@B155]). Finally, in a pediatric cohort of 40 patients receiving TCD haplo-HCT using CD34 positive selection or CD3/CD19 cell depletion, monocyte expansion was rapid, reaching normal values for age within 30 days of transplant. Moreover, no differences in monocyte recovery were seen between different graft purification and conditioning intensity regimens ([@B156]).
Neutrophils
-----------
Depending on the study, neutrophil engraftment is defined by the presence of more than 500 or 1,000 neutrophils/μL of blood and represents a crucial step in the early phase after transplant. Prolonged neutropenia is associated with severe infection and increased TRM ([@B157]). In the setting of a T-cell replete transplant, neutrophil recovery occurs quickly. With GIAC protocols, the median neutrophil engraftment was achieved at 14 days (range 9--25) ([@B158], [@B159]), whereas with the RIC PTCY platform using BM grafts and Tacrolimus and MMF GVHD-based prophylaxis, the median time to neutrophil recovery was 15 days (range 11--42) ([@B11]). For both protocols, patients received recombinant human granulocyte colony-stimulating factor (rhG-CSF) from day +6 or +4 to engraftment, respectively.
In the context of TCD HCT using the Perugia protocol with CD34^+^ selected megadose grafts, the median time to neutrophil recovery was 11 days (range 9--30) without G-CSF support ([@B27]). Studies using CD3/CD19 cell depletion in adult patients also showed rapid neutrophil recovery, with a median time of 12 days (range 9--50) without the addition of G-CSF ([@B79], [@B80]). Similar results were seen in a cohort of pediatric patients with acute leukemia undergoing MAC transplant. Specifically, patients in the αβ-T cell-depleted haplo-HCT had a faster neutrophil recovery compared to MUD, mismatch unrelated donors (mMUD), and those treated with Methotrexate and Calcineurin-inhibitors, with median time to neutrophil engraftment of 13 (range 6--23), 19 (range 9--46), and 20 days (range 10--120), respectively ([@B97]). All three groups received ATG during the conditioning for prevention of graft failure and GVHD, and none of the patients received G-CSF to accelerate neutrophil recovery. Taken together, these data show that haplo-HCT provides a comparable or even expedited neutrophil recovery compared to standard matched donor-HCT.
Dendritic Cells
---------------
Dendritic cells (DCs) represent a rare population in the peripheral blood, accounting for 0.15--0.7% of mononuclear cells ([@B160]). In the context of T-cell replete haplo-HCT using the GIAC protocol, Wang and colleagues measured the frequencies of DCs and their subsets among white blood cells (WBCs) after haplo-HCT, including CD123^+^ plasmacytoid DCs (pDCs) and CD11c^+^ myeloid DCs (mDCs). Recipients had strikingly decreased proportions of DCs (0.49% vs. 0.27%, *P* = 0.025), mDCs (0.27% vs. 0.14%, *P* \< 0.001), and pDCs (0.04% vs. 0.02%, *P* = 0.008) in the WBC compartment at \~180 days post-haplo-HCT compared to healthy subjects. Since, it was reported that primary human DCs were the most potent expander of the γδ T cell subset Vδ2^+^ ([@B161]), the authors also investigated whether the recovery levels of Vδ2^+^ T cells were associated with the DC content following transplantation. Bivariate correlation analysis showed that the proportion of mDCs, but not DCs and pDCs, in WBCs was significantly correlated with the recovery of Vδ2^+^ T cells after haplo-HCT. Specifically, slow recovery of mDCs was associated with a slow recovery of Vδ2^+^ T cells in this haplo-HCT setting ([@B162]).
Chang and colleagues also described a slower DCs recovery at +15 and 30 days after HCT compared to those in the HLA-matched recipients in another study ([@B158]). In their protocol, ATG was administrated only in the haplo-group. Indeed, it was described that ATG not only induced a tolerogenic phenotype in human DCs ([@B163]), but was also able to mediate a complement-mediated lysis of DCs ([@B164]). In summary, these findings may explain the delay in DC recovery in the setting of the haplo-HCT using the GIAC protocol. The kinetics of DC reconstitution in other haplo-HCT settings, remain to be fully characterized.
Natural Killer (NK) Cells
-------------------------
Due to the need to perform an extensive T cell depletion in haplo-HCT, anti-tumor efficacy is largely dependent on the graft-vs.-leukemia effect exerted by NK cells that eradicate residual leukemic blasts surviving the preparative regimen ([@B72], [@B165]--[@B167]). In the haplo-HCT setting performed through the infusion of positively selected CD34^+^ cells, the first emergence of fully functioning, KIR alloreactive NK cells from hematopoietic progenitors may require at least 6--8 weeks, and therefore the benefit offered by their anti-leukemia effect is delayed ([@B168]--[@B171]). In the setting of αβ-T-cell/CD19 depletion, generation of NK cells from donor HSC takes \~8 weeks but circulating NK cells can be detected earlier after transplant due to infusion with the graft ([@B172]). Moreover, CMV reactivation in this setting was associated with an expansion of memory-like NK cells (NKG2C^+^, CD57^+^, KIR^+^) as early as 3 months after HCT ([@B173]). Surprisingly, in a pediatric comparison between TCD haplo-HCT performed with CD34 positive selection or CD3/19 negative selection, NK-cell recovery was faster in patients receiving PBSC from CD34^+^ positive selection in the first 4 months after transplant ([@B156]).
In the T-cell replete haplo-HCT setting using PTCY, Russo and colleagues described that donor alloreactive NK cells infused with the graft were killed by cyclophosphamide ([@B174]). This translated into a delay of NK recovery and maturation resulting from a profound reduction after cyclophosphamide administration following a robust proliferation of donor-NK cells in the early phase after graft infusion. The absence of aldehyde dehydrogenase (ALDH)-positive NK cells suggested that they were susceptible to cyclophosphamide cytotoxicity, and this was then confirmed using an *in vitro* assay of mafosfamide-induced cell death ([@B174]). On the other hand, Russo et al. reported an IL-15 peak in patient sera at day +15 after transplant that was associated with a progressive increase of NK cells expressing an immature phenotype (CD62L^+^, NKG2A^+^, KIR^−^) between day +15 and day +30 ([@B174]). The normal distribution of NK phenotypes was achieved only between 9 and 12 months after transplant, with a decrease of CD56^bright^, NKG2A, and CD62L expression and an increase of maturation markers (CD16, CD57, and KIR). KIR expression returned to normal levels around day +60, but NKG2A expression decreased only after 6 months. Interestingly, in this cohort of patients, there was no difference in PFS between patients with or without a predicted KIR alloreactivity, suggesting that the protective anti-tumor activity of NK cells is dampened after T-cell replete haplo-HCT using the PTCY platform ([@B174]).
Another group described the transient and predominant expansion of an unconventional subset of NK cells characterized by a specific phenotype: NKp46^neg/low^, CD56^dim^, CD16^neg^, CD94/NKG2A^high^ starting from the second week after transplant and maintained until the 7th week ([@B175]). This unconventional population retained its proliferative capacity and the ability to differentiate into the CD56^bright^ subsets (NKp46^+^, CD56^bright^, CD16^−^ cells) in response to IL-15 and IL-18. Despite the unconventional NK cells expressing a high level of activating receptors (NKG2D and NKp30), Granzyme-B and Perforin, they displayed a defective *in vitro* cytotoxicity highlighting again the need to improve NK reconstitution after PTCy haplo-HCT ([@B175]). Similar results were reported in the GIAC protocol in which early and higher expression of CD94/NKG2A was inversely correlated with KIR expression, and was associated with worse survival ([@B176]). The same group showed that NK cells from patients who developed GVHD had a lower expression of NKG2A, lower proliferative capacity and an increased rate of apoptosis, but retained their cytotoxicity after *in vitro* co-culture with the K562 cell line ([@B177]).
Finally, in contrast to TCD haplo-HCT, KIR-mismatch analysis between donor-recipient pairs when using only HLA and KIR genotyping without consideration of the KIR phenotype, was unable to predict post-transplantation outcomes in multivariate analyses in the setting of haplo-HCT using the GIAC protocol ([@B178]). However, it has been reported that KIR-driven NK cell alloreactivity is better predicted if donor KIR genotype is considered in conjunction with KIR cell surface expression ([@B130]). Moreover, in haplo-HCT using the GIAC protocol, the higher number of T-cells infused in the graft contributed to the high incidence of acute GVHD ([@B178]). This resulted in a need for increased immune suppression, thereby affecting NK alloreactivity.
T Cells
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Achievement of an acceptable T cell reconstitution after HCT represents a crucial goal and correlates with better transplant outcomes. Impairment of T cell reconstitution is more pronounced after T cell depletion ([@B152]). In the context of T-cell replete haplo-HCT using the GIAC protocol, CD3^+^ T cell counts were 125, 883, 1,163, and 1,308 cells/μL at 30, 90, 180, and 360 days after HCT, respectively ([@B158]). A lower median CD3^+^ T cell count was reported after NMA haplo-HCT using a BM graft with PTCy, Tacrolimus and MMF based GVHD prophylaxis, with 206 cells/μL at day 40 and 219 cells/μL at day 100 ([@B179]). On the other hand, CD3^+^ T-cell recovery was more rapid with 338 cells/uL at day +30 after MAC haplo-HCT using PBSC grafts with PTCy, MMF, and sirolimus GVHD-based prophylaxis ([@B180]).
In the setting of T-cell replete haplo-HCT with both GIAC and PTCy-based protocols, CD8^+^ T cells recovered earlier than CD4^+^ T cells ([@B158], [@B181]--[@B183]). Faster CD8^+^ T cell recovery at day +90 correlated with higher CD3^+^ cells in the graft but was not associated with a higher incidence of GVHD ([@B184]). The same studies highlighted that the recovery of CD4^+^ T cells was impaired for the whole first year after transplant, but failed to demonstrate a correlation between delay in CD4^+^ T cell reconstitution and NRM as was shown in the HLA-matched donor setting ([@B185]). Notably, in the GIAC experience the delay of CD4^+^ T-cell reconstitution was compensated by the proportional increase of the CD8^+^ T cell- and monocyte fractions, and the NRM was relatively low (19.5% in the haplo group vs. 17.4% for the matched-sibling donor cohort). This was likely due to patient care improvements, especially the management of CMV reactivation ([@B158]).
A retrospective EBMT registry study including both adult and pediatric patients undergoing haplo-HCT found an association between higher CD3^+^, CD4^+^, and CD8^+^ T-cell counts and better OS with less NRM ([@B186]). However, in the multivariable analysis only higher CD3^+^ and CD8^+^ T-cell counts correlated with lower NRM. No association was found between any of the T-cell, B-cell, or NK-cell subset counts with relapse-related mortality. In this study, the majority of patients were treated with TCD haplo-HCT using both CD34^+^ selection and CD3/19 depletion ([@B186]). In the context of αβ T-cell depleted haplo-HCT, CD3^+^, and CD3^+^/CD8^+^ T-cell recovery was slower compared to MUD or MMUD-HCT until 6 months after transplant ([@B97]). Recovery of CD4^+^ T cells was delayed only in the first 3 months and became even better at 1 year after haplo-HCT compared to MUD and MMUD. In this pediatric experience, haplo-HCT patients did not receive any additional pharmacological GVHD prophylaxis, whereas MUD and MUD HCT were performed using standard calcineurin-based GVHD prophylaxis and short-term methotrexate ([@B97]).
T memory stem cells (T~SCM~) represent a subset of early-differentiated human memory T cells with stem cell-like properties. T~SCM~ and naïve T cells (T~N~) both express naïve markers such as CD45RA, CCR7, and CD62L, but in distinction to T~N~ and similar to other memory subsets, T~SCM~ are characterized by CD95 expression. In the context of haplo-HCT using PTCy, two different groups elegantly showed that donor-derived T~SCM~ reconstitute early after transplant, representing the majority of both CD4 and CD8 T cells at day +8. At the polyclonal, antigen-specific, and clonal level, T~SCM~ lymphocytes were preferentially derived from differentiation of T~N~ infused within the graft, whereas most memory infused lymphocytes are purged by PTCy ([@B182], [@B187]).
Regulatory T (Treg) Cells
-------------------------
Treg cells play a key role in the modulation of immune tolerance after HCT. Higher Treg content in the graft has been associated with better OS and lower aGVHD ([@B188]), whereas a reduced frequency of Tregs contributed to cGVHD incidence after matched-donor transplant ([@B189]). In the matched donor setting, Kanakry and colleagues showed that Treg, especially memory CD45RA-Treg, were preserved and recovered rapidly while conventional T (Tcon) naïve cells were reduced when PTCy was used as the sole method of GVHD prophylaxis ([@B48]). This was ascribed to the high levels of aldehyde dehydrogenase (ALDH), as the major *in vivo* mechanism of Cyclophosphamide resistance in the Treg population. In addition, murine studies demonstrated the importance of Tregs for GVHD reduction in the context of the PTCy-based GVHD prophylaxis ([@B49]).
In the T-cell replete haplo-HCT setting using PTCy, naïve Tregs increased after cyclophosphamide administration. This was attributed to the lower Ki67 levels compared to the memory subsets at day +3. In addition, Tregs exhibited a lower proliferation profile compared to Tcons, suggesting a lower susceptibility to PTCy in the haploidentical setting ([@B182]). This effect seems to be enhanced when PTCy is combined with sirolimus instead of a calcineurin inhibitor ([@B180]). Cieri et al. showed an expansion of CD25^+^CD127^−^FoxP3^+^ Tregs early after transplant, relative to the donor leukapheresis content and to the quantity in healthy subjects. Interestingly, patients who did not experience acute GVHD had a higher percentage of circulating Tregs at day +15 compared to patients who developed acute GVHD ([@B180]). Notably, the ability of Sirolimus to boost Treg reconstitution has also been reported outside of the PTCy platform. Indeed, Peccatori and colleagues reported an expansion of Treg after haplo-HCT using a combination of ATG, sirolimus and MMF as GVHD prophylaxis ([@B190]). Moreover, in the Baltimore experience with a cohort of patients undergoing MAC haplo-HCT using PTCy, MMF, and tacrolimus-based GVHD prophylaxis, Tregs achieved normal donor levels at all time-points examined (day +30, +90, +180, and +365) ([@B181]). Finally, in haplo-HCT using the GIAC protocol, patients with a higher day +30 percentage of naive Treg, defined as CD4^+^CD25^+^CD45RA^+^, had a significantly lower incidence of grades II--IV acute GVHD ([@B191]). This highlights the importance of reaching a satisfactory Treg reconstitution for the achievement of immune tolerance after haplo-HCT.
γδ T Cells
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γδ T cells combine conventional adaptive immunity features with innate-like MHC-independent tumor recognition ([@B192]). In healthy donors the majority of circulating γδ T cells expresses the Vδ2 chain, whereas the minority expresses the Vδ1 chain. The former subgroup is able to recognize non-peptide phosphoantigens and to perform direct killing of tumor cells ([@B193]). The Vδ1 γδ T-cell subgroup on the other hand is associated with control of CMV infection and also retains antitumor activity ([@B194]). Both subgroups play a key role in the setting of haplo-HCT because they do not induce GVHD but can exert immunological surveillance. In patients undergoing αβ-TCD haplo-HCT, γδ-T cells were the predominant T-cell subset for the first 2--3 weeks after transplant (91.5% of CD3^+^ lymphocytes), while αβ T cells became the most prevalent population at 1 month ([@B93]). Moreover, patients had a higher proportion of γδ-T cells, especially the Vδ2^+^ subset for the first 3 months. However, CMV reactivation (but not infection with other viruses) was associated with an expansion of Vδ1 γδ-T cells ([@B93]). Interestingly, the authors showed that zolendronic acid was able to potentiate Vδ2^+^ killing against leukemia blasts after *in vitro* culture, indicating that the cytotoxicity was dependent on phosphoantigen recognition and providing a rationale for the development of future clinical trials to boost the γδ T anti-tumor effect ([@B93]). The same group tested the *in vivo* ability of zolendronic acid (ZOL) to enhance γδ T-cell recovery and function, by administrating the drug to pediatric patients undergoing αβ-TCR/CD19 depleted haplo-HCT. An induction of Vδ2-cell differentiation paralleled by increased cytotoxicity of both Vδ1 and Vδ2 cells against primary leukemia blasts was associated with ZOL treatment. Patients given three or more ZOL infusions had a better probability of survival in comparison to those given one or two treatments (86% vs. 54%, respectively, *p* = 0.008), suggesting that ZOL infusion promotes γδ T-cell differentiation and cytotoxicity and may influence the outcome of patients in this transplant setting ([@B94]).
B Cells
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B cell recovery occurs late after HCT. B cells are almost undetectable during the first and second months and normal values are only reached around 12 months after transplant ([@B195]). In the setting of NMA haplo-BMT using PTCy, MMF and Tacrolimus as GVHD prophylaxis, B cells were undetectable until day +28. Recovery of B cells started from week 5 with an immature CD38^bright^ CD10^+^ Ki-67 negative phenotype, suggesting that the increase in B-cell number was not due to the homeostatic proliferation of transferred B cells but to *de novo* generation ([@B196]). Maturation of B cells was characterized by different expression of both transitional (T) markers CD5 and CD21: T0 (CD5^−^CD21^−^), T1 (CD5^+^CD21^−^), T2 (CD5^+^CD21^+^), and the CD5^−^CD21^+^ subset. Starting at week 9, mature B cells (CD38^dim^ CD10^−^) began to increase with a naïve phenotype (IgD^+^, IgM^+^). Overall, B cell maturation took 6 months to complete in the setting of a T-cell replete PTCy-based haplo-HCT ([@B196]).
With haplo-HCT using the GIAC protocol, median B cell counts did not differ from HLA-matched HCT at any of the time points examined ([@B158]). In an analysis comparing CD34 positive selection and CD3/CD19 cell depletion, B cells reconstituted more rapidly in the former group ([@B156]). Furthermore, recovery of B cells after αβ T cell-depleted haplo-HCT was delayed for the first 6 months compared to a cohort of patients transplanted with a MUD or MMUD using standard calcineurin-based GVHD prophylaxis. However, this is at least in part attributable to the fact that in the αβ T-cell depletion setting, patients received one dose of Rituximab as part of the conditioning regimen in order to prevent post-transplant lymphoproliferative disorders ([@B97]).
Relapse and Immune Evasion Mechanisms After HAPLO-Hct {#s6}
=====================================================
Recent data has highlighted the critical role of the immune system in the control of myeloid leukemia after HCT and elucidated our understanding regarding the immunologic mechanisms underlying relapse after haplo-HCT. Work by Vago and colleagues revealed that a substantial proportion of AML and MDS relapses after haplo-HCT are attributable to acquired uniparental disomy of chromosome 6p (copy-neutral loss of heterozygosity eliminating the incompatible HLA alleles without decreasing the overall level of expression of HLA class I molecules). This was shown to result in loss of the mismatched HLA molecules on leukemia cells and immune escape from leukemia control exerted by haploidentical donor T cells via the major histocompatibility mismatch ([@B197]). The maintained overall expression of class I molecules in this study also evaded activation of NK-cell mediated anti-leukemic responses which could potentially be based on a newly missing ligand to an inhibitory KIR receptor ([@B197]). Clinical suspicion for an immune evasion phenomenon was first raised when patients relapsing after haplo-HCT had discrepant findings in host chimerism monitoring between short-tandem-repeat amplification but not HLA typing ([@B198]). Recognition of this leukemia escape mechanism has therapeutic importance for patients who are candidates for subsequent haplo-HCT in whom a different donor is available who is mismatched for the HLA haplotype retained in the relapsed leukemic cells and/or is predicted to mediate NK-cell alloreactivity based on the newly missing KIR-ligand. The development of routine diagnostic methods is expected to facilitate this ([@B198]). Importantly, \~30% of relapses after haplo-HCT are attributable to this mechanism of the elimination of the incompatible HLA alleles irrespective of the GVHD prophylaxis or platform used to control T-cell alloreactivity ([@B190], [@B199], [@B200]).
To identify other drivers of post-HCT relapse Toffalori et al. analyzed transcriptional signatures specific for post-transplant AML relapses ([@B201]). This study demonstrated deregulation of the costimulatory interface between donor T cells and host leukemia cells, with loss of costimulatory interactions and enforcement of inhibitory ones (PD-1/PDL-1) as evidenced by both changes in leukemic cells and donor T cells ([Figure 8](#F8){ref-type="fig"}). Additionally, the study documented downregulation of surface expression of HLA class II molecules on leukemia cells due to the downregulation of the HLA class II regulator CIITA ([@B201]). Patients with AML relapse after HCT were found to have a higher proportion of BM---infiltrating T cells expressing inhibitory receptors (IR) compared to patients remaining in CR. The exhausted BM-T cell phenotype was associated with a restricted TCR repertoire, impaired effector functions and leukemia-reactive specificities. Furthermore, early detection of severely exhausted BM-memory stem T cells predicted relapse ([@B202]). Interestingly, IR-positive T cells infiltrating the BM of AML patients at relapse displayed a greater ability to recognize matched leukemic blasts after *in vitro* expansion compared with their IR-negative counterparts. This suggest that IR expression marks lymphocytes enriched for tumor specificity whose activity could be unleashed with therapeutic check-point blockade, although innovative targeted strategies will be required to avoid exacerbation of GVHD in the HCT context ([@B202]).
.](fimmu-11-00191-g0008){#F8}
HAPLO-Hct as a Platform for Post-Transplant Immune Therapies {#s7}
============================================================
Numerous scientific advances have contributed to the resurgence of haplo-HCT as a viable transplant option for patients requiring HCT and have achieved similar outcomes to those from other donor sources. The ability to perform haplo-HCT without costly *ex-vivo* T-cell depletion approaches, which require extensive cell manufacturing expertise frequently limited to large transplant centers, has been a major advance in transplant accessibility for patients in resource-limited countries that frequently do not perform unrelated donor transplantation ([@B203]). However, further efforts are required to improve immune reconstitution, control infectious complications and decrease relapse rates in patients after haplo-HCT. Fortunately, haplo-HCT provides an ideal platform characterized by unique immunologic properties and ready accessibility of the donor for additional cell products. This offers tremendous opportunities for the development and implementation of innovative adoptive immune cell therapies to augment infectious and antitumor immunity and further improve outcomes ([Figure 9](#F9){ref-type="fig"}).
{#F9}
Suicide Mechanisms for Defined T-Cell Content in the Graft and Post-transplant
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*Ex-vivo* TCD haplo-HCT affords opportunities not only for the dose-titration but also the manipulation of the T cell product prior to infusion into the patient. Rather than *in-* or *ex-vivo* approaches to selectively deplete or attenuate T cells, a different approach is the infusion of polyclonal T cells that have been genetically engineered to include an inducible suicide gene. With this strategy, a defined dose of T cells can be administered to aid in engraftment and immune reconstitution, mediate a GVL effect, and provide infectious immunity while being selectively susceptible to an externally inducible suicide mechanism in the event of significant GVHD ([@B204]).
The first such approach was pioneered by Bonini and colleagues with the introduction of a herpes simplex virus thymidine kinase (HSV-TK) suicide gene into T cells using γ-retroviral transduction in which the transgene also contained the truncated selection marker ΔLNGFR. This allowed for the isolation and infusion of transduced cells bearing the suicide gene ([@B205]). With this strategy, administration of the drug ganciclovir activated the suicide mechanism and successfully controlled GVHD in several patients after infusion ([@B204]). Interestingly, the first wave of circulating TK^+^ cells after infusion facilitated thymic renewal and was followed by a second wave of long-term immune reconstitution with naïve lymphocytes. This was supported by an increase in TCR excision circles, CD31^+^ recent thymic emigrants and expansion of thymic tissue on imaging and was further associated with an increase in serum IL-7 levels following each infusion ([@B206]).
Since then, other approaches have been developed, such as transduction of T-cells with the iCasp-9 suicide gene. This gene can be activated by an otherwise inert drug ([@B207], [@B208]). Novel approaches have also included the use of a different transduction marker such as truncated CD19 that allows for the confirmation of transduction and if desired positive isolation of transduced T cells prior to infusion. Brenner and colleagues first utilized this approach in children undergoing haplo-HCT and demonstrated impressively how iCasp-9 transduced T cells expressing the truncated CD19 aid in immune reconstitution and contribute to infectious immunity ([@B207], [@B208]). Activation of the suicide gene led to resolution of GVHD symptoms within hours ([@B209], [@B210]). Interestingly, while alloreactivity was rapidly abrogated, suicide-gene transduced T cells were not permanently eliminated and able to reconstitute again without causing GVHD. Pediatric studies are underway to investigate suicide-gene equipped T-cell infusions after αβ-TCR/CD19 depleted haplo-HCT.
Haploidentical Donor Lymphocyte Infusions
-----------------------------------------
A common approach to address relapse early after HCT is the infusion of donor lymphocyte infusions (DLI) to exert a GVL effect, but this is frequently accompanied by significant rates of GVHD. Zeidan and colleagues demonstrated the feasibility of this approach after haplo-HCT with PTCy in a retrospective analysis of a dose escalation approach at their center ([@B211]). Forty patients received 52 haplo-DLI doses initially at 1 × 10^5^ CD3^+^/kg and most commonly starting at 1 × 10^6^ CD3^+^/kg. Ten patients (25%) developed GVHD with Grade III-IV acute GVHD in 6 and chronic GVHD in 3 patients. Twelve patients (30%) achieved a CR with a median duration of 11.8 months ([@B211]).
Sun et al. reported on haplo-DLI following a number of different chemotherapy regimens (FLAG, Methotrexate and others) for relapse after haplo-HCT with the GIAC protocol. Of 86 patients, 20 developed Grade III-IV aGVHD and 41 developed cGHVD. NRM was 10.3%, and 62% of patients achieved a CR after chemo-DLI of which 50% experienced re-relapse at a median duration of 92 days ([@B212]). A modified GIAC backbone was also utilized to assess preemptive DLI at a median of 77 days post haplo-HCT in high risk patients to prevent relapse. With a sizeable median CD3^+^ dose of 1.8 × 10^7^/kg, the 100-day incidences of acute GVHD were 55.3% for Grade II--IV and 10.2% for Grade III--IV, respectively. Two-year incidence of chronic GVHD was 52%, among which 18.2% were severe. With this regimen, 2-year NRM was high at 33.1% with a 2-year relapse incidence of 32% ([@B213]). Approaches to reduce GVHD while optimizing the GVL effect of preemptive or therapeutic DLI are likely to evolve over time and include the infusion of IL-10 anergized DLI ([@B214]), CD45-RA depleted DLI ([@B215]) and adoptive transfer of gene modified cells as described in this section. Although experience in the haplo-HCT setting is limited to date, azacitidine or decitabine in conjunction with DLI have shown promising overall response rates on the order of 25--33% for patients with AML or MDS relapsing after allogeneic HCT ([@B216], [@B217]).
CAR- T or CAR-NK-Cell Infusion
------------------------------
Chimeric antigen receptor (CAR) T cells targeting CD19 have revolutionized the treatment of relapsed/refractory B-cell acute lymphoblastic leukemias and aggressive B-cell lymphomas, with complete remission rates ranging from 70--90% in ALL ([@B218], [@B219]) and \~60% for refractory large B-cell lymphoma ([@B220], [@B221]). CAR-T cells have been successfully manufactured from donor T cells in patients with relapse after allogeneic HCT and infused without mediating GVHD. Autoimmune complications have not been observed after infusion of CAR-T cells derived from autologous T cells suggesting that the CAR-signal overrides TCR-based recognition. The use of third-party CAR-T cells has been explored with concurrent transcription activator-like effector nuclease (TALEN)-based gene editing of the endogenous TCR. These CAR-T cells did mediate GVHD in a limited study of three patients ([@B222]). The use of CAR-NK cells is also being explored in the relapse setting, and although long-term persistence may be more limited than that of CAR-T cells, this approach may be beneficial when there is a higher degree of HLA-mismatch such as after haplo-HCT ([@B223]). While the therapeutic success of CD19-targeting CAR-T cell therapy to date is limited to B-cell malignancies and multiple myeloma ([@B224]), studies are underway to investigate the safety, feasibility, and preliminary efficacy of CAR-T cells directed against AML and MDS ([@B225]--[@B227]). Given this rapidly evolving field, the established efficacy potential of CAR-T cells and ability to utilize donor cells for CAR-T cell manufacture post-HCT, haploidentical HCT donors represent a readily available post-transplant cell source for donor-derived CAR-T cell or CAR-NK cell therapies for relapsed leukemia.
Antiviral Cytotoxic T Lymphocyte (CTL) Infusion
-----------------------------------------------
Infectious complications and particularly end-organ viral disease after HCT remain a challenge, particularly in haplo-HCT where *ex-* or *in*- vivo T-cell depletion is necessary. For example, the incidence of BK-virus hemorrhagic cystitis is higher in haplo-HCT ([@B228]). As demonstrated by Leen and Bollard the infusion of virus-specific CTL lines, generated by stimulating PBMC from adenovirus and EBV-seropositive donors, can safely be performed without inducing GVHD and can result in clearance of adenoviral disease and prevention of EBV-associated PTLD ([@B229]). The successful use of off-the-shelf multi-virus-specific T cells to treat viral infections after allogeneic HCT with minimal risk of GVHD has since been confirmed in a larger study and has the potential to mitigate serious viral disease after haplo-HCT either with third-party or haploidentical antiviral CTLs ([@B230]).
TCR-Edited T Cell Infusions
---------------------------
Whereas, CAR-transduced T cells recognize extracellular peptides on the surface of target cells in an MHC-independent manner, TCR-mediated T cell recognition mediates T cell immunity against MHC-restricted, intracellular targets and minor histocompatibility antigens. With the advent of sophisticated strategies to optimize T cell transduction and prevent mis-coupling of transduced and endogenous TCR chains, TCR-edited T cells have successfully entered clinical trials for patients with an HLA-type required for the HLA-restricted expression of the antigen. Greenberg and colleagues cloned a high affinity TCR targeting the HLA-A2 restricted tumor antigen WT-1 from healthy donors and inserted this TCR into EBV-specific donor CD8^+^ T cells (to minimize the GVHD risk and enhance persistence). The WT1-TCR modified donor T cells were then infused prophylactically into the HLA-A^\*^0201+ recipients after they had received an allogeneic HCT from the same donor. This approach resulted in 100% relapse free survival in the WT-1 TCR-T cell group at 44 months as compared to a comparative group of similar risk AML patients with a 54% relapse-free survival after HCT ([@B231]). A separate approach is currently under investigation to target the HLA-A^\*^0201-restricted minor histocompatibility antigen HA-1, which is exclusively expressed on hematopoietic cells ([@B232]). When the immunogenic single-nucleotide polymorphic variant of HA-1 is expressed on hematopoietic cells of the HLA-A2+HCT-recipient, donor T cells that have been transduced to encode a high-avidity TCR recognizing HA-1 can effectively eliminate leukemia and lymphoma cells *in vitro* ([@B233]). Given the facile availability of donor T cells, haplo-HCT can and should serve as a beneficial platform to explore new approaches to reduce relapse after HCT.
NK Cell Product Infusion to Augment Graft vs. Tumor Effect
----------------------------------------------------------
As previously described, NK-cells can mediate GVL effects due to KIR-mediated alloreactivity in the haplo-HCT setting. In addition to selecting the donor based on predicted NK-cell alloreactivity, the availability of haploidentical donors for additional cell product collection affords the unique opportunity to utilize NK-cell infusions to provide for additional GVL or GVT effects after HCT prophylactically or in the face of relapse ([@B234]). Generation of adequate numbers of NK cells for post-transplant therapies can be challenging given the relatively low NK cell frequency in the blood but can be overcome by *in vitro* expansion such as with membrane-bound IL-21 expressing feeder cells (mbIL21). A Phase 1 study evaluated prophylactic NK cell infusions after haplo-HCT with PTCy on days −2, +7, and +28. Of 11 enrolled patients who received all 3 planned NK cell doses, 54% developed Grade I-II aGVHD, and none developed Grade III-IV aGVHD, chronic GVHD or dose-limiting toxicities. Only 1/11 patient relapsed. All others were alive and in remission at a median follow-up of 14.7 months ([@B235]). Administration of cytokines can facilitate NK cell expansion, but certain cytokines such as IL-2 also preferentially expand Tregs based on their constitutive expression of high-affinity IL-2R (CD25). These Tregs in turn inhibit NK cell proliferation ([@B236]). A study treating AML patients with haploidentical NK cell infusions after lymphodepletion with cyclophosphamide and fludarabine demonstrated that NK cell expansion was most pronounced and effective when IL-2-diphteria toxin fusion protein was administered to achieve host Treg depletion ([@B237]).
A recent trial administering haploidentical NK cells with rhIL15 for relapsed AML after lymphodepleting chemotherapy showed that rhIL-15 achieved better rates of *in vivo* NK-cell expansion and remission compared to previous trials utilizing IL-2, but also observed steroid- and tocilizumab-responsive cytokine release syndrome and neurologic toxicity which was associated with high levels of IL-6 ([@B238]). Cytokine-induced memory-like (CIML) NK cells from haploidentical donors were able to induce complete remissions in relapsed/refractory AML patients outside of the transplant setting without any toxicities ([@B239]). This GVL effect may be even more durable when NK cells from the same haploidentical donor are infused after haplo-HCT because no immunologic rejection of the CIML NK cells from the same donor is expected. Studies to date have suggested that KIR-reactivity is less important when NK cells are cytokine-induced ([@B240]). Studies are now underway to evaluate the safety and efficacy of CIML NK cells for relapse after haplo-HCT.
Cytokine Support to Enhance NK-Cell Alloreactivity After Hct
------------------------------------------------------------
An alternative strategy to address relapse after HCT is the administration of cytokines aimed at enhancing the anti-leukemic function of the existing post-transplant immune environment. One such approach employed ALT-803, an IL-15 superagonist complex designed to extend the *in vivo* half-life of IL-15 and mimic the physiologic *trans*-presentation of IL-15 ([@B241]). In contrast to IL-2 that can promote the survival, proliferation, and activation of lymphocytes, but that also stimulates Tregs, IL-15 preferentially expands CD8^+^ T cells and NK cells via trans-presentation to the IL-2/15Rβγ~c~-receptor while avoiding the stimulation of Tregs. In a recent Phase 1 trial ALT-803 was well-tolerated, particularly when administered subcutaneously, and induced responses of 19% in patients relapsed after HCT ([@B241]), suggesting that such agents may also be explored in the haplo-HCT setting. Efforts are underway to test use of IL-15 or IL-15 superagonist complex alone or in combination with NK cell- based therapy to target relapse after haplo-HCT.
Conclusion {#s8}
==========
The initial immunologic barriers to haplo-HCT, namely GVHD and graft failure, have been overcome with different platforms that can be utilized to control T cell alloreactivity post-transplant. Comparable clinical outcomes have now been achieved relative to alternative donor sources and depending on the specific scenario, haplo-HCT can offer a lower risk of GVHD and/or improved control against relapse. The GVL effect in haplo-HCT is particularly intriguing given the concept of NK-cell alloreactivity based on the KIR/KIR-ligand system and ability to select donors accordingly. An emerging body of literature is elucidating immunologic mechanisms of GVHD and relapse that are potentially targetable and highlight the immune pressure exerted by donor immune cells after HCT. Given ready accessibility of the donor, haplo-HCT offers a unique platform for post-transplant cell-based immune therapies aimed at expediting immune reconstitution, improving thymic function, providing infectious immunity, and treating or protecting against relapse, while maintaining therapeutic control of those cell immunotherapies with methods such as suicide mechanisms. The rapid advancements in our understanding of the immunobiology of haplo-HCT are therefore poised to lead to increasingly sophisticated strategies to fine-tune the transplant process and to further improve outcomes after haplo-HCT.
Author Contributions {#s9}
====================
SB, BR, RS, and RR helped review the literature and wrote this manuscript.
Conflict of Interest
--------------------
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: Antonio Pierini, University of Perugia, Italy
[^2]: Reviewed by: Daniela Pende, San Martino Hospital (IRCCS), Italy; Jacopo Peccatori, San Raffaele Hospital (IRCCS), Italy
[^3]: This article was submitted to Alloimmunity and Transplantation, a section of the journal Frontiers in Immunology
|
Avance La Casa De Al Lado Capítulo 139 Telenovela Online will be broadcast on telemundo Wednesday 13 December 2011. The videos are linked immediately after the live broadcast and are high quality, enjoys replacing Clone your favorite novels and all novel here. I hope you enjoy all of this video and dont forget to come back again to follow the next episode because each episode has a story interesting and suspenseful
Sinopsis Of La Casa De Al Lado Online : Mysterious events begin to envelop the Conde family suggesting that Adolfo's presence is alive and well. Is he haunting the family? Is someone else keeping his name alive? Could he even be alive? Gonzalo realizes that nothing is as it seems in the Conde mansion, or the house next door. He vows to uncover the layers of intrigue that surround him. Next door, live Pilar Arismendi (Maritza Rodríguez) and her husband, Javier Ruiz (Miguel Varoni), with their two children. Behind the gloss of success and family felicity lurks a dark reality and secrets that threaten to devastate both the Ruiz and Conde families. Javier is a highly regarded and influential attorney, who, for years, is employed by the Condes. Javier's privileged position becomes threatened by Gonzalo, who is appointed Javier's business associate by his powerful father in law, Renato Conde (Daniel Lugo). |
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Thank you LA, dowloading. May I install any gapps or cm gapps only in the 05/05 build?
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I think any gapps for 5.1.1 can be used, I'm using PA gapps and it is OK
Hello. I have a stock GT-N8010 that is currently on 4.0.4 Would the steps to come up to this rom be to get a recovery on here via odin, root it and then use the recovery to flash this rom? Would I lose IR blaster functionality in this rom? I t...
XDA Developers was founded by developers, for developers. It is now a valuable resource for people who want to make the most of their mobile devices, from customizing the look and feel to adding new functionality.Are you a developer? |
Wednesday, January 21, 2009
Confusion from the Harper crew on Guantanamo
Obama, his presidency just hours old, ordered prosecutors to request the hiatus late Tuesday in order to allow for time to review the case of Khadr and 244 other detainees held at this infamous prison, according to prosecution documents.
That move prompted signals from Defence Minister Peter MacKay that the federal Conservative government would take Obama's cue and re-examine its oft-repeated position that due process in the U.S. should be allowed to run its course.
"Everyone involved in these cases will be reassessing their positions," MacKay said in Ottawa.
That appeared to bring out Kory Teneycke, a spokesman for Prime Minister Stephen Harper, who reiterated the government's more familiar message: Khadr faces serious charges and the U.S. process must run its course.
"We are just not going to get into hypotheticals around different scenarios," Teneycke said.
"We'll simply wait and see what comes forward from the United States around this issue. We'll address other questions if and when they arise."
Scott Newark, a former Crown Prosecutor who has also served as a security advisor to both the Government of Ontario and former Public Safety Minister Stockwell Day, said in an interview with the Toronto Star said that he agreed now is the best time to exert influence over Khadr's fate.
Calling Khadr a "low level foot soldier with a high level pedigree," due to his late father's connections to Al Qaeda, he said a plan should be in place to slowly re-integrate Khadr back to Canada.
"The Canadian government better realize one way or another, the ball is coming back to our court and this government and Prime Minister Harper should be asked: `Are we prepared?' "
Now's the time for leadership and an evolution in the Canadian government's position on Guantanamo Bay. Off the mark, we're just seeing more hesitation and now, perhaps internal disagreement between the PM's office and MacKay. |
A user interface facilitates the interaction between a computer and computer user by enhancing the user's ability to utilize application programs. The traditional interface between a human user and a typical personal computer is implemented with graphical displays and is generally referred to as a graphical user interface (GUI). Input to the computer or particular application program is accomplished through the presentation of graphical information on the computer screen and through the use of a keyboard and/or mouse, trackball or other similar implements. Many systems employed for use in public areas utilize touch screen implementations whereby the user touches a designated area of a screen to effect the desired input. Airport electronic ticket check-in kiosks and rental car direction systems are examples of such systems. There are, however, many applications where the traditional user interface is less practical or efficient.
The traditional computer interface is not ideal for a number of applications. Providing stand-up presentations or other type of visual presentations to large audiences, is but one example. In this example, a presenter generally stands in front of the audience and provides a verbal dialog in conjunction with the visual presentation that is projected on a large display or screen. Manipulation of the presentation by the presenter is generally controlled through use of awkward remote controls, which frequently suffer from inconsistent and less precise operation, or require the cooperation of another individual. Traditional user interfaces require the user either to provide input via the keyboard or to exhibit a degree of skill and precision more difficult to implement with a remote control than a traditional mouse and keyboard. Other examples include control of video, audio, and display components of a media room. Switching between sources, advancing fast fast-forward, rewinding, changing chapters, changing volume, etc., can be very cumbersome in a professional studio as well as in the home. Similarly, traditional interfaces are not well suited for smaller, specialized electronic gadgets.
Additionally, people with motion impairment conditions find it very challenging to cope with traditional user interfaces and computer access systems. Such conditions include Cerebral Palsy, Muscular Dystrophy, Friedrich's Ataxia, and spinal injuries or disorders. These conditions and disorders are often accompanied by tremors, spasms, loss of coordination, restricted range of movement, reduced muscle strength, and other motion impairing symptoms.
Similar symptoms exist in the growing elderly segment of the population. As people age, their motor skills decline and impact the ability to perform many tasks. It is known that as people age, their cognitive, perceptual and motor skills decline, with negative effects in their ability to perform many tasks. The requirement to position a cursor, particularly with smaller graphical presentations, can often be a significant barrier for elderly or afflicted computer users. Computers can play an increasingly important role in helping older adults function well in society.
Graphical interfaces contribute to the ease of use of computers. WIMP (Window, Icon, Menu, Pointing device (or Pull-down menu)) interfaces allow fairly non-trivial operations to be performed with a few mouse motions and clicks. However, at the same time, this shift in the user interaction from a primarily text-oriented experience to a point-and-click experience has erected new barriers between people with disabilities and the computer. For example, for older adults, there is evidence that using the mouse can be quite challenging. There is extensive literature demonstrating that the ability to make small movements decreases with age. This decreased ability can have a major effect on the ability of older adults to use a pointing device on a computer. It has been shown that even experienced older computer users move a cursor much more slowly and less accurately than their younger counterparts. In addition, older adults seem to have increased difficulty (as compared to younger users) when targets become smaller. For older computer users, positioning a cursor can be a severe limitation.
One solution to the problem of decreased ability to position the cursor with a mouse is to simply increase the size of the targets in computer displays, which can often be counter-productive since less information is being displayed, requiring more navigation. Another approach is to constrain the movement of the mouse to follow on-screen objects, as with sticky icons or solid borders that do not allow cursors to overshoot the target. There is evidence that performance with area cursors (possibly translucent) is better than performance with regular cursors for some target acquisition tasks.
One method to facilitate computer access for users with motion impairment conditions and for applications, in which the traditional user interfaces are cumbersome, is through use of perceptual user interfaces. Perceptual user interfaces utilize alternate sensing modalities, such as the capability of sensing physical gestures of the user, to replace or complement traditional input devices such as the mouse and keyboard. Perceptual user interfaces promise modes of fluid computer-human interaction that complement and/or replace the mouse and keyboard, particularly in non-desktop applications such as control for a media room.
One study indicates that adding a simple gesture-based navigation facility to web browsers can significantly reduce the time taken to carry out one of the most common actions in computer use, i.e., using the “back” button (or function) to return to previously visited pages. Subjective ratings by users in experiments showed a strong preference for a “flick” system, where the users would flick the mouse left or right to go back or forward in the web browser.
In the simplest view, gestures play a symbolic communication role similar to speech, suggesting that for simple tasks gesture may enhance or replace speech recognition. Small gestures near the keyboard or mouse do not induce fatigue as quickly as sustained whole arm postures. Previous studies indicate that users find gesture-based systems highly desirable, but that users are also dissatisfied with the recognition accuracy of gesture recognizers. Furthermore, experimental results indicate that a user's difficulty with gestures is in part due to a lack of understanding of how gesture recognition works. The studies highlight the ability of users to learn and remember gestures as an important design consideration.
Even when a mouse and keyboard are available, users may find it attractive to manipulate often-used applications while away from the keyboard, in what can be called a “casual interface” or “lean-back” posture. Browsing e-mail over morning coffee might be accomplished by mapping simple gestures to “next message” and “delete message”.
Gestures may compensate for the limitations of the mouse when the display is several times larger than a typical display. In such a scenario, gestures can provide mechanisms to restore the ability to quickly reach any part of the display, where once a mouse was adequate with a small display. Similarly, in a multiple display scenario it is desirable to have a fast comfortable way to indicate a particular display. For example, the foreground object may be “bumped” to another display by gesturing in the direction of the target display.
However, examples of perceptual user interfaces to date are dependent on significant limiting assumptions. One type of perceptual user interface utilizes color models that make certain assumptions about the color of an object. Proper operation of the system is dependent on proper lighting conditions and can be negatively impacted when the system is moved from one location to another as a result of changes in lighting conditions, or simply when the lighting conditions change in the room. Factors that impact performance include sun light versus artificial light, florescent light versus incandescent light, direct illumination versus indirect illumination, and the like. Additionally, most attempts to develop perceptual user interfaces require the user to wear specialized devices such as gloves, headsets, or close-talk microphones. The use of such devices is generally found to be distracting and intrusive for the user.
Thus perceptual user interfaces have been slow to emerge. The reasons include heavy computational burdens, unreasonable calibration demands, required use of intrusive and distracting devices, and a general lack of robustness outside of specific laboratory conditions. For these and similar reasons, there has been little advancement in systems and methods for exploiting perceptual user interfaces. However, as the trend towards smaller, specialized electronic gadgets continues to grow, so does the need for alternate methods for interaction between the user and the electronic device. Many of these specialized devices are too small and the applications unsophisticated to utilize the traditional input keyboard and mouse devices. Examples of such devices include TabletPCs, Media center PCs, kiosks, hand held computers, home appliances, video games, and wall sized displays, along with many others. In these, and other applications, the perceptual user interface provides a significant advancement in computer control over traditional computer interaction modalities.
In light of these findings, what is needed is to standardize a small set of easily learned gestures, the semantics of which are determined by application context. A small set of very simple gestures may offer significant bits of functionality where they are needed most. For example, dismissing a notification window may be accomplished by a quick gesture to the one side or the other, as in shooing a fly. Another example is gestures for “next” and “back” functionality found in web browsers, presentation programs (e.g., PowerPoint™) and other applications. Note that in many cases the surface forms of these various gestures may remain the same throughout these examples, while the semantics of the gestures depends on the application at hand. Providing a small set of standard gestures eases problems users have in recalling how gestures are performed, and also allows for simpler and more robust signal processing and recognition processes. |
San Diego Police apparently will not allow this father to stand up while being detained at a local beach. The father, who was walking with his daughter and a small dog, was allegedly being detained for having "a dog on the beach".He was apparently allowed to go, once he signed the citation correctly, instead of "FUCK YOU PIGS" in the signature box. |
The value of ultrasound screening for proximal vein thrombosis after total hip arthroplasty--a prospective cohort study.
The role of ultrasound screening for proximal deep-vein thrombosis (DVT) following major hip surgery is controversial. 202 consecutive patients, who had received warfarin prophylaxis after total hip arthroplasty underwent a bilateral ultrasound assessment of the proximal vein system (using the criterion of vein compressibility) before hospital discharge. In the 9 patients (4.5%; 95% CI, 2.1-8.3%) with positive test anticoagulant treatment was successfully continued for three months. In all the remaining 193 patients the warfarin treatment was withdrawn. A second ultrasound test was performed 15 days later, and showed a new (asymptomatic) abnormality compatible with proximal DVT in 2 patients (1.0%; 95% CI, 0.1-3.7%). All other 191 patients remained asymptomatic until the completion of a 3-month follow-up period (rate of symptomatic thromboembolism, 0/191, 0%; 95% CI, 0-1.9%). Because of the relatively high incidence of proximal DVT in patients undergoing major orthopaedic surgery under warfarin prophylaxis, screening for proximal DVT at hospital discharge in these patients is indicated. The negativity of this test has the potential of safely preventing the extension of anticoagulation beyond hospital stay. A larger controlled study in which the value of this strategy is tested against the prolongation of oral anticoagulation in patients with a negative ultrasound screening at discharge is indicated. |
A digital phased array includes a plurality of antennas formed into an array. The phased array works by forming abeam with an array of antenna elements in a certain direction, thus causing a high gain relative to a signal of interest. The signal of interest could be a desired signal originating from a target for which tracking using the phased array is desired or an interference signal. In some cases, the interference signal may be intentionally provided in the form of a jamming signal. Thus, one challenge associated with operation of a digital phased array is to accurately preserve a signal coming from a target, white minimizing the effects of interfering signals coming from other directions.
Conventional digital phased arrays may employ a signal processor to facilitate cancellation of interference signals. Two relatively well known solutions for interference cancellation include a Side-Lobe Canceller (SLC) and the Linearly Constrained Minimum Variance (LCMV) beamformer. SLC employs a low gain auxiliary channel with a near uniform gain pattern over the steerable range of the main beam. With this configuration, any interference in the side lobe of the main beam can be subtracted out of the desirable signal in the main beam using the information in the auxiliary channel. Of course, the signal of interest wilt also be present in the auxiliary channel and some signal loss will occur when subtracting from the main beam. However, the loss is generally expected to be relatively small because the gain in the main beam is much larger than the gain of the auxiliary channel.
In contrast to SLC, LCMV beamformer is a method for calculating the beamforming weights of an array. In conventional beamforming, the typical weights are just those that will introduce a progressive time delay to each unit such that the array is steered in a certain direction. LCMV adaptively computes weights that will steer the array in the desired direction, but also have nulls in the directions of interference while minimizing main beam losses. Thus, LCMV achieves the same objective as SLC with respect to interference removal. However, LCMV also minimizes loss to the signal of interest.
Both SLC and LCMV were introduced decades ago. However, SLC has remained the dominant algorithm employed in large systems having hundreds of elements due to the computational cost associated with LCMV. While SLC may be more practical for implementation, SLC does not necessarily perform as well as LCMV due to the fact that SLC causes signal loss and has difficulty performing for main-beam interference. Computing hardware is much more mature today, and thus it may be more practical to implement LCMV than it had been in the past. However, LCMV still presents significant computational challenges for signals with a wide bandwidth and when the array has a large number of elements. Thus, it may be desirable to develop an algorithm that can perform interference cancellation while avoiding some of the performance degradations described above. |
Factors associated with failure in managing pelvic sepsis after ileal pouch-anal anastomosis (IPAA)--a multivariate analysis.
Pelvic sepsis is known to cause a detrimental outcome after ileal pouch-anal anastomosis (IPAA). The aim of this study was to examine potential factors associated with failure in managing pelvic sepsis after IPAA. We performed univariate and multivariate logistic regression analysis on 2518 IPAA patients between 1983 and 2005. Failure was defined as pouch failure, the need for a permanent ileostomy, or mortality as a result of sepsis. There were 157 patients (6.2%) with pelvic sepsis after IPAA. These involved anastomotic leak 34% (54/157) and fistula 25% (40/157). There were 5 mortalities related to sepsis. Mean age at surgery was 38.1 +/- 14.4 years and mean follow-up was 5.5 +/- 4.7 years. Pouches were saved in 75.8% patients. Univariate analysis identified early sepsis (P = .040), preoperative steroid use (P = .007), and need for percutaneous drainage (P = .004) as significant factors associated with treatment success. Factors associated with failure were hypertension (P = .026), hand-sewn anastomosis (P = .038), associated fistula (P = .0003), need for transanal drainage (P = .0002), need for laparotomy to control septic complications (P < .0001), delayed ileostomy closure (P = .0003), and need for a new diverting ileostomy (P < .0001). By using multivariate analysis with selected covariates, significant factors associated with failure were associated fistula (P = .0013), need for transanal drainage (P = .003), delayed ileostomy closure (P = .022), need for a new ileostomy diversion (P = .004), and hypertension (P = .039). We developed a predictive scoring system for failure to use in management plans and decision-making for the treatment of septic complications of IPAA. Pelvic sepsis after IPAA has a significant impact on pouch failure. This predictive model for failure may play an important role in providing risk estimates for successful outcomes. |
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About Tales from the Borderlands Wallpaper
My first Tales from the Borderlands Wallpaper featuring Rhys & Fiona. These two are the wannabe vault hunters, you follow their story as you play through the game. Although each character will remember the story in a different way. Like all Telltale games, the choices you make during the game will affect the outcome of the story. This will gives players a unique story based on which path they take. Tales from the Borderlands is part of the official Borderlands timeline and takes place after Borderlands 2. As most of the Tales from the Borderlands artwork is presented on a greenish backdrop i implied the same on this wallpaper, giving it the Borderlands grunge background. Originally this wallpaper had the logo on the top left, but recently i changed it and moved it over Rhys’s hand. Changing the look of the logo giving it the more hologram look so it fits vault logo projection. Hopefully you like my fanart with this Tales from the Borderlands Wallpaper and set it as your wallpaper to decorate as your background theme. Don’t forget to rate, follow and share.
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A practical approach to intraoperative evaluation of sentinel lymph node biopsy in breast carcinoma and review of the current methods.
Sentinel lymph node (SLN) biopsy is increasingly becoming an alternative method for assessing axillary status in breast carcinoma patients. Intraoperative SLN evaluation can potentially select patients for immediate axillary clearance and spare most of them a second surgical procedure. Nevertheless, no standard protocol for intraoperative SLN evaluation has been developed. The aims of this study were to establish the reliability of SLN intraoperative evaluation in breast carcinoma staging, to review the published methods currently used, and to propose a standard protocol. One hundred fifty-two SLNs were collected from 86 patients. Lymphoscintigraphy, blue dye, and gamma camera intraoperative controls were used for localization. Each SLN was sliced 2 mm thick and was intraoperatively evaluated by using the combination of frozen section and imprint cytology. The final examination included standard hematoxylin and eosin staining, and, in case of persistent negativity, further sectioning, including hematoxylin and eosin combined with immunohistochemistry (CAM5.2 cytokeratin), was performed. The combination of frozen section and imprint cytology for intraoperative SLN evaluation yielded an intraoperative sensitivity of 78% and a specificity of 100%. All macrometastases (>2 mm) were detected during surgery, as were 2 micrometastases. Final examination detected seven more micrometastases, six of which consisted of isolated tumor cells. We propose a fast, cost-effective, and accurate procedure for SLN evaluation that is useful for making intraoperative decisions, feasible for most institutions, and reliable because of its high sensitivity (100% for macrometastases) and specificity. |
• FOLKLORE AND FACTS:Chinese Feng Shui suggests that Chrysanthemum will bring happiness into the home. • During the years of Imperial Reign in China, common people were not permitted to grow Chrysanthemum, only Nobility had that privilege. • Chrysanthemum is a sacred flower in Asia. • In Malta and in Italy it is considered to be unlucky to have Chrysanthemum in the house. |
c, 1 n, and 1 w?
1/110
Two letters picked without replacement from nquxkvqnnknnqnvkv. What is prob of picking 1 x and 1 q?
3/136
What is prob of picking 2 o and 2 a when four letters picked without replacement from {o: 5, a: 2}?
2/7
Four letters picked without replacement from {u: 3, o: 3, a: 1, k: 2, y: 2, r: 3}. Give prob of picking 1 o, 1 y, 1 r, and 1 a.
18/1001
What is prob of picking 1 i and 1 n when two letters picked without replacement from oitootoonddgoddt?
1/120
Two letters picked without replacement from {u: 6, k: 2, d: 4}. What is prob of picking 2 u?
5/22
Calculate prob of picking 2 d and 1 z when three letters picked without replacement from {d: 3, z: 2, x: 3}.
3/28
Two letters picked without replacement from {m: 3, e: 1, x: 3, f: 7, v: 3, y: 2}. Give prob of picking 1 e and 1 x.
1/57
Three letters picked without replacement from kkmmktmztlkklkkmt. Give prob of picking 1 m, 1 t, and 1 l.
3/85
What is prob of picking 1 s and 2 e when three letters picked without replacement from zqqqzeqyqzqezzzese?
1/136
Two letters picked without replacement from {a: 2, w: 1, q: 2, f: 2, e: 5, b: 1}. Give prob of picking 1 a and 1 f.
2/39
Calculate prob of picking 1 o and 2 r when three letters picked without replacement from {y: 4, o: 3, r: 2, j: 2}.
1/55
Two letters picked without replacement from {d: 2, n: 1, v: 4}. What is prob of picking 2 v?
2/7
Calculate prob of picking 1 h and 2 n when three letters picked without replacement from {h: 5, n: 4, j: 6}.
6/91
Four letters picked without replacement from {m: 2, v: 7}. Give prob of picking 2 m and 2 v.
1/6
Four letters picked without replacement from {y: 4, x: 15}. What is prob of picking 1 x and 3 y?
5/323
Two letters picked without replacement from {j: 1, y: 3, d: 1, f: 3, k: 3, m: 2}. Give prob of picking 2 m.
1/78
What is prob of picking 4 s when four letters picked without replacement from {j: 2, s: 5, k: 7, a: 4}?
1/612
Three letters picked without replacement from czccczcczczzccccccc. Give prob of picking 3 z.
10/969
What is prob of picking 1 j, 1 m, and 1 o when three letters picked without replacement from iijoooooonjomo?
4/91
Two letters picked without replacement from crvvvcvssmsr. What is prob of picking 2 c?
1/66
Three letters picked without replacement from cacaaubkakdd. Give prob of picking 1 a, 1 k, and 1 b.
2/55
Three letters picked without replacement from {a: 2, f: 1, e: 1, y: 2}. What is prob of picking 1 f, 1 a, and 1 y?
1/5
What is prob of picking 2 j and 1 u when three letters picked without replacement from ijjijiiiiijum?
3/143
What is prob of picking 1 v and 3 j when four letters picked without replacement from {v: 3, j: 7, d: 2, c: 1, s: 5}?
7/204
Two letters picked without replacement from vvvqqvvvvqvqq. What is prob of picking 2 q?
5/39
Four letters picked without replacement from {o: 13, x: 6}. What is prob of picking 3 o and 1 x?
143/323
Three letters picked without replacement from {s: 4, n: 3, a: 2, l: 6}. What is prob of picking 1 a and 2 s?
12/455
Two letters picked without replacement from eeeebeeeebee. Give prob of picking 1 b and 1 e.
10/33
Three letters picked without replacement from {t: 3, f: 4, q: 2, r: 10}. Give prob of picking 1 t, 1 r, and 1 q.
20/323
Two letters picked without replacement from vrrgvvr. What is prob of picking 1 g and 1 r?
1/7
Four letters picked without replacement from {g: 3, a: 4, p: 4}. Give prob of picking 4 a.
1/330
Two letters picked without replacement from {m: 1, u: 3}. Give prob of picking 1 u and 1 m.
1/2
What is prob of picking 1 y and 1 r when two letters picked without replacement from {y: 10, m: 4, r: 2}?
1/6
Two letters picked without replacement from {w: 9, u: 2}. What is prob of picking 1 u and 1 w?
18/55
Three letters picked without replacement from {u: 15, m: 3}. Give prob of picking 1 u and 2 m.
15/272
Four letters picked without replacement from {g: 7, p: 3}. Give prob of picking 1 p and 3 g.
1/2
Four letters picked without replacement from iieieeeieeieiiee. Give prob of picking 3 e and 1 i.
21/65
Four letters picked without replacement from mmelmmfmefembmym. What is prob of picking 1 y, 1 l, and 2 e?
3/1820
What is prob of picking 3 n when three letters picked without replacement from {t: 12, n: 6}?
5/204
Calculate prob of picking 1 g and 1 x when two letters picked without replacement from {p: 2, x: 2, g: 4}.
2/7
Two letters picked without replacement from dmdjvxdvjxxxvdc. Give prob of picking 1 x and 1 j.
8/105
What is prob of picking 1 a and 1 p when two letters picked without replacement from {z: 1, a: 4, v: 4, p: 2, u: 6}?
1/17
Three letters picked without replacement from lauzulllllulu. Give prob of picking 1 z, 1 u, and 1 l.
14/143
Calculate prob of picking 2 k and 1 s when three letters picked without replacement from sksrkrkr.
3/28
Calculate prob of picking 1 t and 3 k when four letters picked without replacement from {t: 3, k: 13}.
33/70
Two letters picked without replacement from {k: 7, a: 7}. What is prob of picking 1 a and 1 k?
7/13
Three letters picked without replacement from bwwbd. What is prob of picking 1 d and 2 w?
1/10
Four letters picked without replacement from fffeffffefwfwefe. What is prob of picking 4 f?
3/26
Four letters picked without replacement from lllzblzbzzllzblblll. What is prob of picking 4 l?
35/646
Calculate prob of picking 2 z and 1 j when three letters picked without replacement from {z: 5, j: 13}.
65/408
What is prob of picking 2 j when two letters picked without replacement from {s: 4, v: 6, e: 1, m: 2, j: 3}?
1/40
Two letters picked without replacement from esaad. What is prob of picking 1 d and 1 s?
1/10
Two letters picked without replacement from olosqnq. What is prob of picking 1 s and 1 q?
2/21
Calculate prob of picking 2 r and 1 p when three letters picked without replacement from {r: 4, p: 1, o: 2, n: 2, e: 5}.
3/182
Three letters picked without replacement from {h: 4}. What is prob of picking 3 h?
1
Three letters picked without replacement from ltbtbbbwtbtgbbt. What is prob of picking 1 l, 1 w, and 1 g?
1/455
Calculate prob of picking 1 d and 1 c when two letters picked without replacement from {d: 2, c: 2, s: 1}.
2/5
Calculate prob of picking 2 x, 1 e, and 1 p when four letters picked without replacement from xxeeedxexepx.
10/99
Three letters picked without replacement from dllllllddddd. What is prob of picking 3 l?
1/11
Two letters picked without replacement from zcjckhckjvzczccck. Give prob of picking 1 j and 1 z.
3/68
Two letters picked without replacement from wyxbsysszxbwbs. Give prob of picking 1 s and 1 w.
8/91
Calculate prob of picking 1 y and 1 l when two letters picked without replacement from {y: 6, l: 2, i: 1, n: 2}.
12/55
Four letters picked without replacement from {t: 4, v: 7, c: 2, d: 5}. Give prob of picking 2 t and 2 v.
7/170
Three letters picked without replacement from {a: 11, y: 8, z: 1}. What is prob of picking 2 y and 1 z?
7/285
Calculate prob of picking 1 y and 2 h when three letters picked without replacement from hyynhnthymn.
3/55
What is prob of picking 1 e, 1 n, and 1 s when three letters picked without replacement from {s: 3, e: 3, n: 2}?
9/28
Calculate prob of picking 1 g and 1 s when two letters picked without replacement from syggsgkgyygsfyypg.
9/68
Calculate prob of picking 1 i, 1 k, and 1 z when three letters picked without replacement from {z: 2, e: 1, i: 1, k: 2}.
1/5
Calculate prob of picking 2 g when two letters picked without replacement from {g: 2, c: 1}.
1/3
Calculate prob of picking 1 w, 1 q, and 1 e when three letters picked without replacement from {e: 1, q: 1, w: 1, z: 2}.
1/10
What is prob of picking 2 p and 1 q when three letters picked without replacement from uqquuoqummpmom?
0
Four letters picked without replacement from aaaaa. What is prob of picking 4 a?
1
Three letters picked without replacement from {x: 2, y: 3, u: 6, z: 2, r: 1, g: 5}. What is prob of picking 2 g and 1 y?
10/323
What is prob of picking 1 a and 1 t when two letters picked without replacement from {a: 2, t: 2}?
2/3
Three letters picked without replacement from {k: 2, j: 1, v: 7}. What is prob of picking 1 v, 1 j, and 1 k?
7/60
What is prob of picking 2 r when two letters picked without replacement from {r: 5, h: 15}?
1/19
What is prob of pi |
Cold exposure: human immune responses and intracellular cytokine expression.
It is commonly believed that exposure to cold environmental temperatures depresses immune function and increases the risk for infection. This review paper will 1) present an overview of human physiological responses to cold exposure, 2) present the human studies examining the effects of cold exposure on immune responses, and 3) summarize recent experiments from our laboratories examining the effects of exercise and fatigue on immune responses during subsequent cold exposure. Based on the review of the literature, there is no support for the concept that cold exposure depresses immune function. |
//
// BMKType.h
// MapPlatform
//
// Created by BaiduMapAPI on 13-3-26.
// Copyright (c) 2013年 baidu. All rights reserved.
//
#import <CoreGraphics/CoreGraphics.h>
#import <CoreLocation/CoreLocation.h>
#import <UIKit/UIKit.h>
typedef enum
{
BMK_COORDTYPE_GPS = 0, ///GPS设备采集的原始GPS坐标
BMK_COORDTYPE_COMMON, ///google地图、soso地图、aliyun地图、mapabc地图和amap地图所用坐标
} BMK_COORD_TYPE;
enum {
BMKMapTypeStandard = 1, ///< 标准地图
BMKMapTypeSatellite = 2, ///< 卫星地图
};
typedef NSUInteger BMKMapType;
typedef enum {
BMKErrorOk = 0, ///< 正确，无错误
BMKErrorConnect = 2, ///< 网络连接错误
BMKErrorData = 3, ///< 数据错误
BMKErrorRouteAddr = 4, ///<起点或终点选择(有歧义)
BMKErrorResultNotFound = 100, ///< 搜索结果未找到
BMKErrorLocationFailed = 200, ///< 定位失败
BMKErrorPermissionCheckFailure = 300, ///< 百度地图API授权Key验证失败
BMKErrorParse = 310 ///< 数据解析失败
}BMKErrorCode;
//鉴权结果状态码
typedef enum {
E_PERMISSIONCHECK_CONNECT_ERROR = -300,//链接服务器错误
E_PERMISSIONCHECK_DATA_ERROR = -200,//服务返回数据异常
E_PERMISSIONCHECK_OK = 0, // 授权验证通过
E_PERMISSIONCHECK_KEY_ERROR = 101, //ak不存在
E_PERMISSIONCHECK_MCODE_ERROR = 102, //mcode签名值不正确
E_PERMISSIONCHECK_UID_KEY_ERROR = 200, // APP不存在，AK有误请检查再重试
E_PERMISSIONCHECK_KEY_FORBIDEN= 201, // APP被用户自己禁用，请在控制台解禁
/*
*更多鉴权状态码请参考：
*http://developer.baidu.com/map/index.php?title=lbscloud/api/appendix
*/
}BMKPermissionCheckResultCode;
//检索结果状态码
typedef enum{
BMK_SEARCH_NO_ERROR = 0,///<检索结果正常返回
BMK_SEARCH_AMBIGUOUS_KEYWORD,///<检索词有岐义
BMK_SEARCH_AMBIGUOUS_ROURE_ADDR,///<检索地址有岐义
BMK_SEARCH_NOT_SUPPORT_BUS,///<该城市不支持公交搜索
BMK_SEARCH_NOT_SUPPORT_BUS_2CITY,///<不支持跨城市公交
BMK_SEARCH_RESULT_NOT_FOUND,///<没有找到检索结果
BMK_SEARCH_ST_EN_TOO_NEAR,///<起终点太近
BMK_SEARCH_KEY_ERROR,///<key错误
BMK_SEARCH_NETWOKR_ERROR,///网络连接错误
BMK_SEARCH_NETWOKR_TIMEOUT,///网络连接超时
BMK_SEARCH_PERMISSION_UNFINISHED,///还未完成鉴权，请在鉴权通过后重试
}BMKSearchErrorCode;
//调起百度地图结果状态码
typedef enum{
BMK_OPEN_NO_ERROR = 0,///<正常
BMK_OPEN_WEB_MAP,///打开的是web地图
BMK_OPEN_OPTION_NULL,///<传入的参数为空
BMK_OPEN_NOT_SUPPORT,///<没有安装百度地图，或者版本太低
BMK_OPEN_POI_DETAIL_UID_NULL,///<poi详情 poiUid为空
BMK_OPEN_POI_NEARBY_KEYWORD_NULL,///<poi周边 keyWord为空
BMK_OPEN_ROUTE_START_ERROR,///<路线起点有误
BMK_OPEN_ROUTE_END_ERROR,///<路线终点有误
}BMKOpenErrorCode;
///表示一个经纬度范围
typedef struct {
CLLocationDegrees latitudeDelta; ///< 纬度范围
CLLocationDegrees longitudeDelta; ///< 经度范围
} BMKCoordinateSpan;
///表示一个经纬度区域
typedef struct {
CLLocationCoordinate2D northEast; ///< 东北角点经纬度坐标
CLLocationCoordinate2D southWest; ///< 西南角点经纬度坐标
} BMKCoordinateBounds;
///表示一个经纬度区域
typedef struct {
CLLocationCoordinate2D center; ///< 中心点经纬度坐标
BMKCoordinateSpan span; ///< 经纬度范围
} BMKCoordinateRegion;
///表示一个经纬度坐标点
typedef struct {
int latitudeE6; ///< 纬度，乘以1e6之后的值
int longitudeE6; ///< 经度，乘以1e6之后的值
} BMKGeoPoint;
///地理坐标点，用直角地理坐标表示
typedef struct {
double x; ///< 横坐标
double y; ///< 纵坐标
} BMKMapPoint;
///矩形大小，用直角地理坐标表示
typedef struct {
double width; ///< 宽度
double height; ///< 高度
} BMKMapSize;
///矩形，用直角地理坐标表示
typedef struct {
BMKMapPoint origin; ///< 屏幕左上点对应的直角地理坐标
BMKMapSize size; ///< 坐标范围
} BMKMapRect;
///地图缩放比例
typedef CGFloat BMKZoomScale;
/// 经过投影后的世界范围大小，与经纬度（-85，180）投影后的坐标值对应
UIKIT_EXTERN const BMKMapSize BMKMapSizeWorld;
/// 经过投影后的世界矩形范围
UIKIT_EXTERN const BMKMapRect BMKMapRectWorld;
/// 空的直角坐标矩形
UIKIT_EXTERN const BMKMapRect BMKMapRectNull;
///线路检索节点信息,一个路线检索节点可以通过经纬度坐标或城市名加地名确定
@interface BMKPlanNode : NSObject{
NSString* _cityName;
NSString* _name;
CLLocationCoordinate2D _pt;
}
///节点所在城市
@property (nonatomic, strong) NSString* cityName;
///节点名称
@property (nonatomic, strong) NSString* name;
///节点坐标
@property (nonatomic) CLLocationCoordinate2D pt;
@end
|
megagrumpycat ,
The UI is somewhat complicated even though the app itself has lots of options. My initial experience was rather negative because of constant crashes. Turned out it was because of lack of space on my iPad (something to think about, dear developers). But once that issue was solved, the app is stable. Focus stacking takes some time, but results in many cases are very good |
Conventional detergents used in food and beverage (e.g., the dairy, cheese, sugar, meat, food, and brewery and other beverage industries), warewashing and laundry industries include alkaline detergents. Alkaline detergents, particularly those intended for institutional and commercial use, generally contain phosphates, nitrilotriacetic acid (NTA) and ethylenediaminetetraacetic acid (EDTA). Phosphates, NTA and EDTA are components commonly used in detergents to remove soils and to sequester metal ions such as calcium, magnesium and iron.
In particular, NTA, EDTA or polyphosphates such as sodium tripolyphosphate and their salts are used in detergents because of their ability to solubilize preexisting inorganic salts and/or soils. When calcium, magnesium and iron salts precipitate, the crystals may attach to the surface being cleaned and cause undesirable effects. For example, calcium carbonate precipitation on the surface of ware can negatively impact the aesthetic appearance of the ware, giving an unclean look. In the laundering area, if calcium carbonate precipitates and attaches onto the surface of fabric, the crystals may leave the fabric feeling hard and rough to the touch. In the food and beverage industry, the calcium carbonate residue can affect the acidity levels of foods. The ability of NTA, EDTA and polyphosphates to remove metal ions facilitates the detergency of the solution by preventing hardness precipitation, assisting in soil removal and/or preventing soil redeposition into the wash solution or wash water.
While effective, phosphates and NTA are subject to government regulations due to environmental and health concerns. Although EDTA is not currently regulated, it is believed that government regulations may be implemented due to environmental persistence. Therefore, there is a need in the art for an alternative, and preferably environmentally friendly, cleaning composition that can replace the properties of phosphorous-containing compounds such as phosphates, phosphonates, phosphites, and acrylic phosphinate polymers, as well as non-biodegradable aminocarboxylates such as NTA and EDTA. |