While the second wave of COVID-19 pandemic almost reached its climax, unfortunately, new viral strains are rapidly spreading, and numbers of infected young adults are rising. Consequently, chest high-resolution computed tomography (HRCT) demands are increasing, regarding patients’ screening, initial evaluation and follow up. This study aims to evaluate the detection accuracy of ultra-low-dose chest CT in comparison with the routine low-dose chest CT to reduce the irradiation exposure hazards.-4.This study was prospectively conducted on 250 patients during the period from 15th December 2020 to 10th February 2021. All of the included patients were clinically suspected of COVID-19 infection. All patients were subjected to routine low-dose (45 mAs) and ultra-low-dose (22 mAs) chest CT examinations. Finally, all patients had confirmatory PCR swab tests and other dedicated laboratory tests. They included 149 males and 101 females (59.6%:40.4%). Their age ranged from 16 to 84 years (mean age 50 ± 34 SD). Patients were divided according to body weight; 104 patients were less than 80 kg, and 146 patients were more than 80 kg. HRCT findings were examined by two expert consultant radiologists independently, and data analysis was performed by other two expert specialist and consultant radiologists. The inter-observer agreement (IOA) was excellent (96–100%). The ultra-low-dose chest CT reached 93.53–96.84% sensitivity and 90.38–93.84% accuracy. The signal-to-noise ratio (SNR) is 12.8:16.1; CTDIvol (mGy) = 1.1 ± 0.3, DLP (mGy cm) = 42.2 ± 7.9, mean effective dose (mSv/mGy cm) = 0.59 and absolute cancer risk = 0.02 × 10Ultra-low-dose HRCT can be reliably used during the second wave of COVID-19 pandemic to reduce the irradiation exposure hazards. Real-time polymerase chain reaction (PCR) remains the gold standard tool for the diagnosis of the Novel coronavirus disease COVID-19) since it was first described in December 2019 and announced as a pandemic in February 2020 9 since i, 4.On the other hand, high-resolution computed tomography (HRCT) expressed more availability and more rapid results. Besides, HRCT sensitivity exceeded 90% in comparison with PCR sensitivity which could not exceed 75% –8. Low-dIn September 2019, the American Association of Physicists in Medicine (AAPM) suggested certain criteria for efficient low-dose CT during lung cancer screening among standard-sized persons (70–90 kg), including CTDIvol ≤ 3.0 mGy, DLP ≤ 75 mGy cm and effective dose ≤ 1.0 mSv . A dose While the second wave of COVID-19 pandemic almost reached its climax, unfortunately, new viral strains are rapidly spreading, and numbers of infected young adults are rapidly rising. Hence, chest HRCT demands are increasing.This study aims to evaluate the detection accuracy of ultra-low-dose chest CT in comparison with the routine low-dose chest CT during the assessment of COVID-19 patients in order to reduce the irradiation exposure hazards.This study was prospectively conducted on 250 patients who were clinically suspected of COVID-19 infection during the period from 15th December 2020 to 10th February 2021. The study was approved by the Ethics Committee of our University hospital. Patient verbal consent was accepted by the Ethics Committee respecting absolute safety of non-invasive non-therapeutic procedure without additional personal risk or burden to the public health, also assuring full respect of both patient and medical record confidentiality. The authors emphasize on the fact that the overall radiation dose in both low- and ultra-low-dose CT examinations together remains much lower than single routine chest CT examination.Patients included 149 males and 101 females (59.6%:40.4%). Their age ranged from 16 to 84 years (mean age 50 ± 34 SD). By definition of the American Association of Physicists in Medicine (AAPM), the standard bodyweight for an adult ranges from 70 to 90 kg  [2) [ of air] . The staair] [2) . By defiair] [2) .Fig. 1IThe prevalence rate of each HRCT finding (isolated or mixed) was estimated as the percentage of patients with each abnormal CT finding. This was done by each observer for both groups of patients regarding both low-dose and ultra-low-dose CT examinations.Similarly, the prevalence rate of the maximum attenuation of the pathological lesions was also estimated.Cohen’s Kappa test was utilized to calculate the “Inter-Observer Agreement” (IOA) coefficient regarding each HRCT characteristic and lung attenuation.https://www.medcalc.org/calc/diagnostic_test.php) was utilized to detect the mean value and 95% confidence interval (95% CI) regarding the sensitivity, specificity, positive predictive value (PPV), negative predictive value, positive likelihood ratio, negative likelihood ratio, and accuracy of both low-dose and ultra-low-dose CT protocols.An online calculator  in the ultra-low-dose CT was lower than that in the low-dose CT (12.8–16.1 compared with 17.5–24.4 respectively). This almost did not impact the diagnostic efficacy of CT as detailed later on.Ground-glass opacities were the most common findings among our patients. They were found alone in 173 patients (69.2%). They were found also surrounding a solid nodule  among 49 patients (19.6%) and associated with interlobular septal thickening (crazy paving pattern) also among 49 patients (19.6%). Consolidative changes with or without ground-glass opacities were detected among 84 patients (33.6%). The CT attenuation of these pathological CT findings ranged from + 40 to − 750 HU. The predominant CT attenuation among these CT findings ranged from – 300 to − 400 HU (157 patients/62.8%).In comparison with the low-dose CT, the ultra-low-dose CT protocol similarly detected all HRCT findings of COVID-19 , as well as their ranges of CT attenuation (+ 40 to − 750 HU). The inter-observer agreement was excellent (100%) Figs.  and 3.FIn comparison with the low-dose CT, the ultra-low-dose CT protocol only showed lower efficacy regarding detection of small GG nodules < 1 cm and nodules with ground-glass halo sign (ranging from 77 to 94% and 91 to 96% among both observers respectively). The CT attenuation of these lesions ranged from − 300 to − 600 HU. Otherwise, no absolute differences were found regarding the detection of the rest of the HRCT findings and their ranges of CT attenuation. Finally, the inter-observer agreement was collectively excellent (96–100%) Figs.  and 6.FA multi-compartmental flow chart Fig.  is summaCollectively the ultra-low-dose chest CT reached 93.53–96.84% sensitivity and 90.38–93.84% accuracy in comparison with the low-dose CT which showed 96.84–97.84% sensitivity and 90.38–95.21% accuracy.No differences were found between both observers at both low-dose and ultra-low-dose CT protocols regarding the final diagnosis. Ninety-two patients (88.5%) were truly positive and confirmed by PCR to have COVID-19. On the other hand, only 3 patients (3%) were false negative. Consequently, both CT protocols showed same statistical results: sensitivity (mean = 96.84% and CI 95% = 91.05 to 99.34%) and accuracy (mean = 90.38% and CI 95% = 83.03 to 95.29%).CT specificity was equally low (22.22%) for both low-dose and ultra-low-dose CT as 7/99 patients showed false-positive CT results with negative PCR swab tests and alternative diagnoses .Observer 1 truly detected 130 patients using ultra-low-dose CT compared with 136 patients using low-dose CT. Six cases were furtherly missed using the ultra-lose-dose CT. Consequently the low-dose CT showed sensitivity (mean = 97.84% and CI 95% = 93.82 to 99.55%) and accuracy (mean = 95.21% and CI 95% = 90.37 to 98.05%), while the ultra-low-dose CT showed sensitivity (mean = 93.53% and CI 95% = 88.06 to 97.00%) and accuracy (mean = 91.10% and CI 95% = 85.26 to 95.17%).Meanwhile, observer 2 truly detected 134 patients using ultra-low-dose CT compared with 136 patients using low-dose CT, while only two cases were furtherly missed using the ultra-low-dose CT. Consequently the low-dose CT showed sensitivity (mean = 97.84% and CI 95% = 93.82 to 99.55%) and accuracy (mean = 95.21% and CI 95% = 90.37 to 98.05%), while the ultra-low-dose CT showed sensitivity (mean = 96.40% and CI 95% = 91.81 to 98.82%) and accuracy (mean= 93.84% and CI 95%= 88.62 to 97.14%).CT specificity was equally low (42.86%) for both low-dose and ultra-low-dose CT as 4/146 patients showed false-positive CT results with negative PCR swab tests and alternative diagnoses .Comparison with other CT protocols is demonstrated in Table The second wave and even further crisis of COVID-19 pandemic are striking the world with increased demands for chest CT imaging .Similar to Chung et al.  and Song-4. These estimated radiation doses are 12.5:13.3 and 18.1:20 times more than that of the low-dose and the ultra-low-dose CT protocols in this study respectively. Additionally, the DLP and absolute cancer risk of the ultra-low-dose CT in this study were lower than those provided by Tabatabaei et al. [According to Kubo et al. , the DLPi et al.  and Bahri et al.   and iterative dose reduction (IDR).Ultra-low-dose HRCT can be reliably used during the second wave of COVID-19 pandemic to reduce irradiation exposure hazards.


Scientific Reportshttps://doi.org/10.1038/s41598-019-51090-3, published online 10 October 2019Correction to: The original version of this Article omitted Supplementary Table S1, Supplementary Table S2, and Supplementary Table S3.These Supplementary Information files now accompany the original Article.


The prognostic value of bile duct invasion (BDI) remains controversial. We aimed to investigate the prognostic value of BDI and the stage of BDI in different staging systems.Patients with hepatocellular carcinoma (HCC) from nine hepatobiliary medical centers who underwent R0 resection were included. Overall survival (OS) was assessed using the Kaplan–Meier method and tested using the log-rank test. The prognostic effect of BDI was analyzed using univariate and multivariate Cox proportional hazard regression analyses. The predictive performance of these models was evaluated using the concordance index and time-dependent receiver operating characteristic curve (tdAUC).Of 1021 patients with HCC, 177 had BDI. OS was worse in the HCC with BDI group than in the HCC without BDI group (p<0.001); multivariate analysis identified BDI as an independent risk factor for OS. After adjustment for interference of confounding factors using the Cox proportional hazard regression model, HCC with BDI and without macrovascular invasion was classified as Barcelona Clinic Liver Cancer (BCLC) B, eighth edition American Joint Committee on Cancer (AJCC) IIIA, and China Liver Cancer (CNLC) IIb, respectively, whereas HCC with BDI and macrovascular was classified as BCLC C, AJCC IIIB, and CNLC IIIA, respectively. C-indexes and tdAUCs of the adjusted staging systems were superior to those of the corresponding current staging systems.We constructed adjusted staging systems with the BDI status, improved their predictive performance and facilitate clinical use. Hepatocellular carcinoma (HCC) is the sixth common cancer and fourth cancer-specific cause of death globally . HCC is th AJCC) staging system .HCC patients with microscopic or macroscopic BDI admitted to one of the nine Chinese hepatobiliary medical centers  between March 1, 2007 and March 1, 2018 were included. HCC patients without BDI were from the Mengchao Hepatobiliary Hospital of Fujian Medical University and Eastern Hepatobiliary Surgery Hospital of Second Military Medical University during the same period.The inclusion criteria were as follows: 1) both HCC and BDI were histopathologically confirmed, 2) tumors were treated with R0 resection, and 3) complete clinical data and postoperative follow-up records. The exclusion criteria were as follows: 1) recurrent or metastatic HCC, 2) combined HCC-intrahepatic cholangiocarcinoma, 3) other accompanying cancers, and 4) clinical data or survival data are missing. R0 resection was defined as the removal of all macroscopic tumors with a microscopically negative margin. The decision of treatment depends on the discussion of the multidisciplinary team in each center, whether perform surgical resection mainly considering the liver function, residual liver volume, tumor related factors such as if complicated with portal vein main trunk tumor thrombus or vena cava tumor thrombus or distant metastasis, and whether tumor and tumor thrombus can be completely removed.All patients were regularly followed up after discharge from the hospital. Follow-up visits were scheduled once every 2–3 months in the first 2 years, once every 6 months from 2 to 5 years, and once every year after 5 years. Follow-up examinations were conducted using laboratory tests , abdominal ultrasonography, and/or contrast-enhanced computed tomography magnetic resonance imaging. Overall survival (OS) was defined as the time of resection to the date of either death or the latest follow-up. Data including baseline and clinical characteristics and follow-up information were extracted and censored on September 31, 2020.via clinical diagnosis. PS (performance status) score refer to ECOG  PS score. Tumor differentiation was classified according to the Edmonson–Steiner grade. MVI was vascular invasion of small vessels only identifiable histologically. Major vascular invasion was defined as invasion of the branches of the main portal vein , one or more of the three hepatic veins , or the main branches of the proper hepatic artery (right or left hepatic artery) , major vascular invasion, macrovascular invasion (MaVI), preoperative serum gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP), total bilirubin (TBil), AFP, Child–Pugh grade, MELD (model for end-stage liver disease) score, BCLC stage, AJCC stage, and CNLC stage. Underlying liver diseases were categorized as viral liver disease (hepatitis B virus or hepatitis C virus), non-alcoholic fatty liver disease, alcoholic liver disease, and no underlying liver disease. Cirrhosis was confirmed histopathologically or  artery) . Major vhttp://www.r-project.org/); the R packages of “readxl,” “table1,” “rms,” “survminer,” “survival,” “ggplot2,” “CsChange,” and “timeROC” were used.Continuous variables are reported as medians with interquartile ranges and were compared using Student’s t-test or the Mann–Whitney test. Categorical data, presented as frequencies (%), were compared using the chi-square test or Fisher’s exact test. Kaplan–Meier survival curves were used to assess OS. Univariate and multivariate analyses were performed using the Cox proportional hazard regression model, and a backward stepwise selection method was used to identify independent prognostic factors and adjust for confounding factors. The Harrell’s concordance index (C-index)  and timeOf 1021 patients with HCC who were included, flowchart was shown in The median follow-up time of the whole cohort was 49.03 months . The median OS times (mOST) of patients without BDI and with BDI were 59.27 months (95%CI 50.7-67.17 months) and 23.3 months (95%CI 19.67-26.23 months), respectively (P<0.001) Figure 1The respective mOST of the BDI- and BDI+ groups were 76.87 months (95%CI 76.87- Not Available [NA] months) and 28.98 months (95%CI 18.53-NA months) in BCLC stage 0 (P=0.05), 75.53 months (95%CI 70.37-NA months) and 26.73 months (95%CI 20.27-35.9 months) in BCLC stage A (P<0.001), 40.33 months (95%CI 27.43-67.6 months) and 26.2 months (95%CI 23.07-NA months) in BCLC stage B (P=0.12), and 16.2 months (95%CI 12.67-20.87 months) and 16.3 months (95%CI 13.17-22.73 months) in BCLC stage C (P=0.45) D.The respective mOST of the BDI- and BDI+ groups were 76.87 months (95%CI 73.53-NA months) and 28.98 months (95%CI 23.43-NA months) in AJCC stage IA (P=0.03), 75.53 months (95%CI 70.07-NA months) and 31.8 months (95%CI 25.44-NA months) in AJCC stage IB (P<0.001), 44.97 months (95%CI 29.7-57.9 months) and 23.07 months (95%CI 19.67-26.53 months) in AJCC stage II (P<0.001), 26.93 months (95%CI 21.4-31.97 months) and 26.21 months (95%CI 12.6-NA months) in AJCC stage IIIA (P=0.35), 9.76 months (95%CI 7.57-12.63 months) and 10.23 months (95%CI 6.2-16.36 months) in AJCC stage IIIB (P=0.73) I.The mOST of the BDI- and BDI+ groups were 80.83 months (95%CI 76.87-NA months) and 28.98 months (95%CI 20.2-NA months) in CNLC stage Ia (P<0.001), 52.6 months (95%CI 48.27-67.13 months) and 24.17 months (95%CI 19.67-30.97 months) in CNLC stage Ib (P<0.001), 30.47 months (95%CI 22.93-NA months)and 26.53 months (95%CI 17.07-NA months) in CNLC stage IIa (P=0.43), 26.2 months (95%CI 19.0-40.33 months) and 24.77 months (95%CI 7.57-NA months) in AJCC stage IIIA (P=0.6), 11.77 months (95%CI 9.7-17.7 months) and 13.96 months (95%CI 7.54-16.37 months) in AJCC stage IIIB (P=0.27) N.OS curves stratified by different stages obtained from the multivariate Cox proportional hazard regression model adjusted for other covariates are shown in The BDI+ group was restaged according to the HR of each stage. BCLC stage 0/A/B BDI+ was integrated into BDI+MaVI- and classified as BCLC stage B, and BCLC stage C BDI+ was classified as BCLC stage C , Key Clinical Specialty Discipline Construction Program of Fuzhou, Fujian, P.R.C (Grant number: 201912002) and Fujian Provincial Medical Center of Hepatobiliary.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Patients with lymphoid malignancies are at high risk of severe COVID-19 disease and were not included in the phase 3 mRNA vaccine trials. Many patients with lymphoid malignancies receive immunosuppressive therapies, including B-cell depleting agents, that may negatively impact humoral response to vaccination.We recruited patients with lymphoid malignancies and healthy participants who planned to receive two doses of SARS-CoV-2 mRNA vaccine (BNT162b2 or mRNA-1273). Blood was drawn at baseline, prior to second dose of vaccine, and 28 days after last vaccination. Disease characteristics and therapies were extracted from patients’ electronic medical record. An ultrasensitive, single molecule array (Simoa) assay detected anti-Spike (S), anti-S1, anti-receptor binding domain (RBD), and anti-Nucleocapsid (N) IgG from plasma at each timepoint.23 healthy participants and 37 patients with lymphoid malignancies were enrolled (Table 1). Low titers of anti-N  demonstrate no prior exposure or acquisition of COVID-19 before vaccination or during the study. 37.8% of the lymphoid malignancy cohort responded to the vaccine, using an internally validated AEB cutoff of 1.07. A significantly higher magnitude of anti-S (p< 0.0001), anti-S1 (p< 0.0001) and anti-RBD (p< 0.0001) are present in the healthy as compared to lymphoid malignancy cohort at the second dose and day 28 post-series . Anti-S IgG titers were compared between the healthy cohort, treatment naïve, and treatment experienced groups . The treatment naïve cohort had high titers by series completion which were not significantly different from the healthy cohort (p=0.2259), although the treatment experienced group had significantly decreased titers (p< 0.0001). Of the 20 patients who had received CD20 therapy, there was no clear correlation of anti-S IgG response with time from CD20 therapy, although most patients who received CD20 therapies within 12 months from the vaccine had no response . Table 1. DemographicsFigure 1. Anti-N, Anti-S, Anti-S1, Anti-RBD and Anti-N Ig G for healthy v. lymphoid malignancy cohortThe dotted line at 1.07 marks in an internally validated threshold to mark anti-S IgG response. The black bars denote median with 95% CI.Figure 2: Anti-S IgG for healthy v. treatment naïve v. treatment experiencedThe dotted line at 1.07 marks in an internally validated threshold to mark antibody response. The black bars denote median with 95% CI.The vaccine-induced immune response was poor among treatment-experienced patients with lymphoid malignancies, especially among those who received CD20 therapies within 12 months.Figure 3. Months from CD20 therapy v. anti-S IgG titersThe dotted line at 1.07 marks in an internally validated threshold to mark antibody response.Jennifer Crombie, MD, AbbVie (Grant/Research Support)Bauer (Grant/Research Support)Karyopharm (Consultant)MorphoSys (Consultant) Philippe Armand, MD PhD, ADCT, Celgene, Morphosys, Daiichi, Miltenyi, Tessa, C4, Genmab, Enterome, Regeneron, Genentech, Epizyme, Astra Zeneca Affimed, Adaptive, BMS, Merck, Kite, IGM, Genentech  David Walt, PhD, Quanterix Corporation  Nicolas C. Issa, MD, AiCuris (Scientific Research Study Investigator)Astellas (Scientific Research Study Investigator)GSK (Scientific Research Study Investigator)Merck (Scientific Research Study Investigator)


The 2017 IDSA CDI guideline update phased out metronidazole (MTZ) and recommended vancomycin (VAN) or fidaxomicin (FDX) for first-line use. This study examined changes in CDI antibiotic use and clinical outcomes among Medicare beneficiaries with CDI pre- vs. post- the guideline update.This retrospective claims analysis used 2016-2018 national Medicare claims data. The two study samples included continuously eligible fee-for-service Medicare beneficiaries aged ≥66 years with a new CDI diagnosis followed by an antibiotic fill in the pre-period (04/01/2017-09/30/2017) and post-period (04/01/2018-09/30/2018), respectively. Outcomes included type of CDI antibiotic received; sustained response and CDI recurrence. Multivariable regressions compared pre- vs. post-period outcomes while controlling for sociodemographic and clinical factors.The pre-period  and post-period  samples had similar characteristics . Post-guideline update, absolute rates of MTZ use declined 27.7%  and VAN use increased 26.9%  . While FDX use increased 0.8% , overall use remained low (1.63%). Surprisingly, clinical outcomes did not improve between the pre- and post-period (Table 1). Even after adjustment, overall sustained response rates decreased  and overall CDI recurrence rates increased  slightly in the post- vs. pre-period. Additional analyses by type of antibiotic showed that VAN (55.0% and 35.1%) was similar in outcomes to MTZ (54.2% and 33.0%), whereas FDX (71.4% and 20.9%) had higher sustained response and lower CDI recurrence rates, respectively .Figure 1. First-line use of CDI treatments, pre- vs. post- the guideline update, among Medicare beneficiaries with CDITable 1. Clinical outcomes, pre- vs. post- the guideline update, among Medicare beneficiaries with CDIFigure 2. Clinical outcomes* by type of index CDI treatment among Medicare beneficiaries with CDIPooled rates among patients on each index CDI treatment across the pre- and post-index periods.The 2017 IDSA guideline update was associated with a substantial increase in VAN use and decrease in MTZ use. FDX use rates remained low (< 2%). Overall CDI outcomes did not improve post guideline update despite the shift to guideline-indicated VAN. This may be because VAN was not associated with meaningfully improved outcomes relative to MTZ. However, improved outcomes seen with FDX relative to VAN and MTZ suggest potential benefits from its greater use in Medicare patients.Erik R. Dubberke, MD, MSPH, Ferring (Grant/Research Support)Merck (Consultant)Pfizer Seres (Consultant)Summit (Consultant) Justin T. Puckett, BA, COVIA Health Solutions (Employee) Engels N. Obi, PhD, Merck & Co.  Sachin Kamal-Bahl, PhD, AbbVie (Consultant)Arena Pharmaceuticals, Inc. (Consultant)COVIA Health Solutions (Employee)Janssen, Inc. (Consultant)Merck Novartis (Consultant)Pfizer, Inc. PhRMA (Consultant) Kaushal Desai, PhD, AstraZeneca Pharmaceuticals (Shareholder)Merck & Co. Inc. (Employee) Bruce Stuart, PhD, COVIA Health Solutions (Consultant) Jalpa A. Doshi, PhD, Acadia Allergan (Advisor or Review Panel member)Biogen (Grant/Research Support)Boehringer Ingelheim Catabasis (Consultant)Humana (Grant/Research Support)Janssen, Inc. MeiraGTX (Consultant)Merck Novartis (Grant/Research Support)Otsuka (Advisor or Review Panel member)Regeneron (Grant/Research Support)SAGE Therapeutics (Consultant)Sanofi (Grant/Research Support)Shire (Advisor or Review Panel member)The Medicines Company (Advisor or Review Panel member)


Here, we present 36 metagenomes, 59 metatranscriptomes, and 373 metagenome-assembled genomes (MAGs) from Chesapeake and Delaware Bay water samples. This data set will be useful for studying microbial biogeochemical cycling in estuaries. Sharp. Surface (∼1.5 m below the seafloor [mbsf]) water samples were collected using a rosette sampler with associated conductivity-temperature-depth (CTD) profiles. The sampling scheme (––https://www.bco-dmo.org/dataset/565451).Estuaries are productive aquatic environments harboring diverse flora, fauna, and microbial communities important for global carbon and nutrient cycling , 2. Omicg scheme , environg scheme –7 were d scheme ––7 and arhttps://doi.org/10.6084/m9.figshare.14173664 (metatranscriptomes).Cells were separated as large- and small-cell-size fractions by passing water samples through 0.8- and 0.22-μm-pore-size filters. Nucleic acids were extracted from size-fractionated cells using the Allprep DNA/RNA minikit  . A totalPrior to assembly, Cutadapt v1.11 and Sickle v1.33 were used to remove adapters from and quality trim (Q = 30) Illumina-sequenced reads . Nanoporhttps://doi.org/10.6084/m9.figshare.14179448) with >80% completion and <5% contamination were taxonomically annotated using Anvi’o and Microbial Genome Atlas (MiGA) v0.7.26.2 , Burkholderiales (n = 31), Flavobacteriales (n = 55), Microtrichales (n = 39), Nanopelagicales (n = 11), Pelagibacterales (n = 31), Pseudomonadales (n = 26), Rhodobacterales (n = 28), and Synechococcales (n = 13), as well as the archaeal phyla Crenarchaeota (n = 5) and Euryarchaeota (n = 2).For binning, trimmed reads from each Illumina-sequenced library were mapped to contigs ≥2,000 bp in the corresponding metagenome using the default parameters (end-to-end mode) of Bowtie 2 v2.2.7 . Alignme17–0.7.26.2 . They bePRJNA432171.The metagenomes, metatranscriptomes, and MAGs are available on NCBI under the umbrella project


Complicated urinary tract infections (cUTI) are one of the most common bacterial infections and represent substantial burden to the health care system. Here, we examine the epidemiology and treatment patterns associated with cUTI in a large US database containing longitudinal inpatient (IP) and outpatient (OP) patient-level data.We conducted a retrospective cohort study of adult patients in the IBM MarketScan® Commercial or Medicare Supplemental Databases with at least 1 IP or non-diagnostic OP claim with a diagnosis for cUTI between January 1, 2017 and June 30, 2019. Patients meeting the following criteria were included for analysis: (1) ≥18 years of age on the index date, (2) ≥6 months of continuous enrollment (CE) with medical and pharmacy benefits prior to the index date, (3) ≥12 months of CE following the index date or evidence of death, and (4) no evidence of a prior cUTI during the 6-month baseline period. Demographics and clinical characteristics were quantified. Patients were classified as IP if they were hospitalized during 30-day post index date; remaining patients were classified as OP. Antibiotics received in the OP setting in the 12-months post index date were examined. 95,423 patients met study criteria. Most (86.4%) patients were Commercially insured, mean (SD) age was 53.6 (18.1) and 70.4% were female. Mean baseline Charlson Comorbidity Index was 0.77. During the 30-day post index date, 22.2% were treated as IP and 77.8% were strictly treated as OP. In the 12-month OP follow-up period among index IP, 78.2% required ≥ 2 antibiotics, 38.2% required ≥4 antibiotics, and 41.6% received an IV antibiotic. In the 12-month OP follow-up period among index OP, 81.8% required ≥2 antibiotics, 38.2% required ≥4 antibiotics, and 46.8% received an IV antibiotic. For both IP and OP, fluoroquinolones were the most common oral antibiotic class (57.7%), followed by cephalosporins (39.2%), penicillins (30.3%), trimethoprim-sulfamethoxazole (29.8%), and nitrofurantoin (25.2%). Cephalosporins were the most common IV antibiotic class (38.5%).Regardless of index treatment setting, approximately 40% of all cUTI patients required ≥4 antibiotic therapy and almost half with receive an IV antibiotic in the outpatient setting in the 12-months post index date.Thomas Lodise, Jr., PharmD, PhD, Astra-Zeneca (Consultant)Bayer (Consultant)DoseMe ferring (Consultant)genentech (Consultant)GSK (Consultant)Melinta (Consultant)merck nabriva (Consultant)paratek shionogi Spero (Consultant)tetraphase (Consultant)Venatrox (Consultant) Thomas Lodise, Jr., PharmD, PhD, Melinta Therapeutics  Involved: Self): Consultant; Merck  Involved: Self): Consultant, Scientific Research Study Investigator; Paratek  Involved: Self): Consultant; Shionogi  Involved: Self): Consultant, Speakers’ bureau; Spero  Involved: Self): Consultant; Tetraphase Pharmaceuticals Inc.  Involved: Self): Consultant Janna Manjelievskaia, PhD, MPH, IBM Watson Health (Employee)Spero Therapeutics (Consultant) Matthew Brouillette, MPH, Spero Therapeutics, Inc.  Kate Sulham, MPH, Spero Therapeutics (Consultant)


Communications Biology 10.1038/s42003-021-02971-9, published online 10 January 2022.Correction to: The original version of this Article contained errors in Fig. 1 and Supplementary Fig. Updated Supplementary Information


Early bacterial co-infection is rare in hospitalized COVID-19 patients, yet antibiotics are commonly prescribed. Antibiotic stewardship (AS) intervention is needed, especially in small community hospitals (SCHs), which often lack access to AS expertise.We implemented daily remote multidisciplinary tele-COVID rounds (synchronous case review between SCH providers and ID clinicians) and tele-stewardship surveillance (ID pharmacist review of COVID patients on antibiotics) on 6/24/2020 in 17 SCHs. We retrospectively included adult symptomatic COVID-19 admissions between 3/2020 and 4/2021. The primary outcome was early use of antibiotics for pneumonia (started within 48 hours of admission); mean monthly days of therapy per 1,000 patient days (DOT) were compared pre- (3/2020-6/2020) and post-intervention (7/2020-4/2021). Secondary outcomes were early use of antibiotics for any indication, estimated days of antibiotics avoided (comparing pre- and post-intervention DOT), and in-hospital mortality. Analyses were conducted using a two-tailed unpaired t-test (antibiotic use) or Fisher’s exact test .Of the 1,976 patients included (124 pre- vs. 1852 post-intervention), 55.4% were male and 85.5% were white. Patients in the pre-intervention group were more likely to require hospital transfer [21.8% vs 8.8% (p< 0.001)] and ICU admission [18.5% vs. 9.7% (p=0.003)]. We observed a significant decrease in mean use of early antibiotics for pneumonia [656.9 vs. 240.1 DOT (p< 0.001)], including among non-ICU patients only [603.6 vs 240.2 DOT (p< 0.001)]. Early antibiotic use for any indication also decreased [686.2 vs. 359.3 DOT (p< 0.001)]. An estimated 3,697 days of unnecessary antibiotics for pneumonia were avoided in the 10-months post-intervention [370 days per month (95% CI 304 – 435)]. Unadjusted in-hospital mortality was not different pre- vs post-intervention , but was higher among those prescribed early antibiotics .A significant, sustained reduction in antibiotic use among COVID-19 patients at 17 SCHs was observed after implementation of tele-COVID rounds and tele-stewardship surveillance without an observed difference in mortality.All Authors: No reported disclosures


In Cohort A, baseline NT-proBNP > 3000 ng/L and cTnT-HS > 50 ng/L and a relative increase of NT-proBNP > 50% during follow-up were independent prognostic factors of EFS. The slopes of logs NT-proBNP and cTnT-HS increased with time before and stabilized after tafamidis. Conclusion: ATTR-CA patients with increasing NT-proBNP had an increased risk of EFS. Tafamidis stabilize NT-proBNP and cTnT-HS increasing, even if initial NT-proBNP levels were >3000 ng/L. Thus suggesting that all patients, irrespective of baseline NT-proBNP levels, may benefit from tafamidis.Background: We assesse the evolution and prognostic value of N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (cTnT-HS) in transthyretin amyloid cardiomyopathy (ATTR-CA) before and after tafamidis treatment. Methods and Results: 454 ATTR-CA patients without tafamidis (Cohort A) and 248 ATTR-CA with tafamidis (Cohort B) were enrolled. Event-free survival (EFS) events were death, heart transplant, or acute heart failure. In Cohort A, 27% of patients maintained NT-proBNP < 3000 ng/L and 14% cTnT-HS < 50 ng/L at 12 months relative to baseline levels. In Cohort B, the proportions were 49% and 29%, respectively. In Cohort A, among the 333 patients without an increased NT-proBNP > 50% relative to baseline EFS was extended compared to the 121 patients with an increased NT-proBNP > 50% (HR: 0.75 ;  Transthyretin amyloid cardiomyopathy (ATTR-CA) is a systemic life-threatening disease characterized by amyloid fibrils accumulating in the heart . There aIn the blood, TTR, mainly produced in the liver, transports the retinol-binding protein-vitamin A complex and to a lesser extent thyroxine. However, when TTR tetramer dissociates and the monomers misfolds TTR aggregates resulting in amyloidogenesis. Mutation of TTR (in ATTRv-CA) or aging (in ATTRwt-CA) destabilizers the tetramers and accelerate their dissociation into monomers. The TTR amyloid fibrils formed by the misfolding deposit in several tissues and organs in the body.Prior to the development of TTR stabilizers, ATTRv was treated by liver transplantation: replacing mutant TTR, in the liver, with wild-type TTR . CurrentThe phase III, double-blinded, placebo-controlled ATTR-ACT trial NCT01994889) assessed the benefit of tafamidis in ATTR patients. The all-cause mortality after 30 months was significantly lower in patients treated with tafamidis (30%) compared to those treated with placebo (43%), hazard ratio (HR): 0.70 (95% CI: 0.51–0.96)  (p < 0.0001)  and log (cTnT-HS) levels during follow up are shown in  0.0001) .n = 192/385) after 6 months, 30.6% (45/147) after 12 months, and 23.4% (30/128) after 18 months  and 14.5 months (95% CI: 10.9–19.0) in those with non-increased NT-proBNP (n = 333), HR: 0.75 (95% CI: 0.57–0.98); p = 0.032 (log-rank test) (p = 0.09) and 0.78 , respectively (figure not shown).At the cut-off date and after a median follow-up of 14.2 months (IQR: 3.1–40.4), 234 patients (52%) had reported EFS events (25 deaths and 209 acute heart failure). Among the 209 acute heart failures, 33 patients died after acute heart failure for a total number of deaths of 58 patients. 220 patients have not reported an EFS event: 176 had initiated tafamidis including 28 patients enrolled in the ATTR-ACT study (NCT01994889), and 44 (9.7%) were without an EFS event . The median EFS was 8.8 months (95% CI: 6.2–14.2) in patients with 50% relative increased NT-proBNP levels (nk test) A. The sen = 48) and 12.6 months (95% CI: 8.3–16.6) in those with non-increased levels (n = 260), HR: 0.86 (95% CI: 0.60–1.25); p = 0.43 (log-rank test) (p = 0.40) and 0.91 , respectively (figure not shown).We also analysed median EFS in the 308 patients with at least two cTnT-HS assessments, according to whether patients had a 50% relative increased cTnT-HS levels. The median EFS was 12.2 months (95% CI: 5.1–15.4) in patients with 50% relative increased levels (nk test) B. Simila2) to be significantly associated with an extended EFS at a 5% level. Of these, the multivariate analysis, identified non-50% relative increased NT-proBNP levels , as well as baseline levels of NT-proBNP ≤ 3000 ng/L and cTnT-HS ≤ 50 ng/L to be significantly and independently associated with extended EFS , cTnT-HS (≤50 ng/L), and eGFR (>45 mL/min/mnded EFS .n = 248) was 17.5 months (IQR: 10.9–18.2).Among the 248 patients assessed in Cohort B, 63 (25%) had ATTRv and 185 (75%) had ATTRwt . The popn = 248), 194 patients (78.2%) were still being treated with tafamidis and 54 (21.8%) had discontinued tafamidis. In patients who discontinued tafamidis, 27 patients had died (including 25 before 18-month timepoint), 15 had aggravated disease, 8 had been enrolled in the ATTR-ACT study (NCT01994889), 1 had been enrolled in the APOLLO study (NCT01960348), 1 did not support the treatment, 1 refused to continue treatment, and 1 was non-compliant. In Cohort B (n = 248) the following proportions of patients had baseline levels of NT-proBNP maintained ≤3000 ng/L or decreased from >3000 ng/L to ≤3000 ng/L: 139/223 (62.3%) after 6 months, 89/162 (54.9%) after 12 months, and 80/145 (55.2%) after 18 months. At 18 months, 17% (25/145) of the patients were dead (In Cohort B (ere dead C.n = 248) the following proportions of patients had baseline levels of cTnT-HS maintained ≤50 ng/L or decreased from >50 ng/L to ≤50 ng/L: 90/204 (44.1%) after 6 months, 48/147 (32.7%) after 12 months, and 57/134 (42.5%) after 18 months. 19% (25/134) of the patients had died . We also generated the scatterplots for the subpopulations of patients that initiated tafamidis with NT-proBNP levels >3000 ng/L (p = 0.03). Similarly, for patients with NT-proBNP levels ≤3000 ng/L, the slope was 0.0007 (95% CI: −0.0070 to −0.0084) before tafamidis and 0.0080 (95% CI: 0.0025–0.0135) after tafamidis (p = 0.15). However, despite a stable positive slope of NT-proBNP levels after tafamidis, in patients with initial NT-proBNP levels ≤3000 ng/L, most of the individual NT-proBNP levels remain within a narrow logarithmic range (8 logs corresponding to 3000 ng/L).The scatterplots for log (NT-proBNP) before and after tafamidis treatment, are shown in 000 ng/L B and tho000 ng/L C. For pap < 0.01. In addition, we plotted the log (cTnT-HS) levels of patients with cTnT-HS levels >50 ng/L (p < 0.001). Similarly, for patients with cTnT-HS levels ≤50 ng/L, the slope was 0.0071 (95% CI: 0.0025–0.0118) before tafamidis and 0.0025 (95% CI: −0.0045–0.0094) after tafamidis (p = 0.35).The scatterplots for log (cTnT-HS) levels before and after tafamidis treatment, are shown in >50 ng/L E and tho>50 ng/L F. For paOur study is the first to describe the natural history of cardiac biomarkers in ATTR and their evolution after tafamidis treatment in a real-life cohort. Our results show that NT-proBNP and cTnT-HS levels increase in ATTR-CA natural history and that 50% relative increases in NT-proBNP levels significantly increases the risk of death, heart transplant, or acute heart failure in ATTR-CA patients. In contrast, increases in cTnT-HS levels were not associated with an increased risk of these events. Baseline levels of NT-proBNP ≤ 3000 ng/L and cTnT-HS ≤ 50 ng/L were found to be independently associated with extended EFS. Furthermore, our results show that tafamidis slows the increasing of NT-proBNP levels associated with amyloidosis evolution in ATTR-CA patients with NT-proBNP levels > 3000 ng/L when tafamidis is initiated. Similarly, tafamidis also slows the increasing of cTnT-HS levels in patients with cTnT-HS levels > 50 ng/L. The proportion of patients who maintained their baseline levels of NT-proBNP ≤ 3000 ng/L or decreased their NT-proBNP levels from >3000 ng/L to ≤3000 ng/L at 12 months was 31% for untreated patients and 55% for those treated with tafamidis.Amyloid formation is a progressive and dynamic process with cardiac biomarkers reflecting the pathophysiology of the disease. Our results show that cTnT-HS and NT-proBNP levels increase during the natural evolution of ATTR-CA.NT-proBNP is a cardiac biomarker indicative of cardiac wall stress and levels increase when heart ventricles become overloaded. NT-proBNP levels are used to diagnose congestive heart failure ,12,13,14In cardiac amyloidosis, fibrillogenesis is a dynamic process. An increase in biomarker levels may be linked to cardiomyopathy evolution, emphasizing the need to slow down their progression. Thus, increasing NT-proBNP levels may be linked with cardiac wall stress associated with amyloid infiltration. While, increasing troponin levels may be linked with the toxicity of amyloid fibrils .The prognostic value of baseline NT-proBNP and cardiac troponin levels in cardiac amyloidosis patients are well established ,21,22,23In our analysis of the cohort of patients treated with tafamidis we found that NT-proBNP levels continued to increase after initiating tafamidis but at a constant or reduced rate. We also found that tafamidis had a similar effect on cTnT-HS levels. The activity of tafamidis is reportedly due to its capacity to stabilise the TTR tetramer, reducing the build-up of amyloid fibrils in the heart . This meInteresting, our results correspond with an exploratory endpoint of the ATTR-ACT study showing a slightly higher NT-proBNP levels in patients, at 12 and 30 months  and one assessment before and another after tafamidis (Cohort B). However, a comparison of the patients included and those not included in the cohorts did not show any major imbalance. Secondly, the time intervals between NT-proBNP assessments were not control and varied. Our data were analysed using piecewise regression random model that generates slope models before and after treatment despite this variability in the time intervals. Thirdly, the cTnT-HS levels used for our analyses are different from the troponin assay usually used in cardiac amyloidosis literature. Recently, cTnT-HS assays have replaced the more traditional assays. These new assays detect the same proteins but with a much lower detection limit . It has Finally, this study was not designed to compare patients treated with tafamidis with those not treated. The patients in the two cohorts were not included during the same time period. Thus, untreated patients from Cohort A that were included in the Cohort B (tafamidis treated patients) may have less severe ATTR-CA. Indeed, a patient included in Cohort A with an EFS event would not have been included in Cohort B. Comparisons of the baseline characteristics of the cohorts support this hypothesis with lower level of NT-proBNP, cTnT-HS, Gillmore stage, and Grogan stage in treated patients. However, the sensitivity analyses that we performed gave results consistent with the results and conclusions herein reported. Nevertheless, this indirect comparison was not an objective of this study. We are currently indirectly comparing these cohorts using an adapted methodology, including the use of propensity scores and matching analysis.NT-proBNP and cTnT-HS are biomarkers for cardiac dysfunction that increase as ATTR-CA evolves. Increasing NT-proBNP levels, but not cTnT-HS levels, signal increasing cardiac dysfunction with an increased risk of death, heart transplant, or acute heart failure, in ATTR-CA patients. Our results seem to indicate that tafamidis slows disease evolution in ATTR-CA patients by stabilizing NT-proBNP and cTnT-HS levels.


Achillea santolinoides and Achillea aleppica aeral parts and root were extracted with ethyl acetate, methanol, and water. Detailed phytochemical profiles were obtained using UHPLC-MS, yielding the identification of hydroxybenzoic and hydroxycinnamic acids, phenolic acid glycosides and sugar esters, acylquinic acids, O-glycosyl flavones and flavonols, and flavonoid aglycons, among others. The antioxidant properties and enzyme inhibitory activities of the extracts were assayed with in vitro tests. The phenolic content of the water extracts was significantly higher as compared to the ethyl acetate and methanol ones. A. aleppica aerial parts methanol extract possessed highest flavonoid content . Antioxidant properties assessment revealed that the methanol extract of A. santolinoides roots actively scavenged DPPH (54.11 mg TE/g) and ABTS radicals (112.53 mg TE/g) and possessed highest reducing potential . The ethyl acetate extracts of aerial parts and roots of both species showed highest inhibition against BuCHE (6.07–6.76 mg GALAE/g). The ethyl acetate extract of A.santolinoides aerial part showed highest inhibition against tyrosinase (73.00 mg KAE/g). These results showed that the tested Achillea species might represent novel phytotherapeutic avenues for the management of Alzheimer’s disease and epidermal hyperpigmentation conditions, which are both associated with oxidative stress. This paper could shed light into future potential industrial applications using the tested Achillea species.In the current study,  Achillea genus, one of the most important genera of the Asteraceae family with ethnopharmacological significance, consists of approximately 85 species mainly distributed in Middle East regions, such as Iran, Turkey, and Serbia and Eastern regions of Europe − at m/z 357.084) were obtained (m/z 195.050 (C6H11O7−) corresponding to the [gluconic acid-H]− supported by the fragment ions at m/z 177.040 [GA-H-H2O]−, 87.007 [GA-H-C3H8O4]− and 59.012 [GA-H-C3H8O4-CO]−  and four hydroxycinnamic acids  together with extracts . In addiobtained . They yi8O4-CO]− .O-(6-caffeoyl)-hexoside (32) was deduced from the loss of vanillic acid (168 Da) at m/z 323.077 and a subsequent transition 323.077→221.046 [M-H-102]− arising from the hexose cross ring cleavage . The latter ion points out to the caffeoyl moiety at Hex C-6. Regarding 42, the prominent ion at m/z 323.077 [M-H-C7H6O3]− and a base peak at m/z 137.023 [salicylic acid-H]− together with m/z 93.033 [salicylic acid-H-CO2]− were in accordance with caffeic acid-O--hexoside (Tanacetum vulgare [Vanillic acid-4-hexoside . Both 32 vulgare .A. santolinoides. Syringic acid-hexoside (6) was presented mainly in A. allepica roots  afforded prominent ions at m/z 353.088 and 191.055 indicating the subsequent losses of a caffeoyl moiety (diCQA 33 and 37 were witnessed by the “dehydrated” ion of quinic acid at m/z 173.044 (100%) supported by the diagnostic ions at m/z 335.0771 [CQA-H-H2O]− and 135.044 [caffeic acid-H-CO2]− in 3,4-diCQA (33) (diCQA as suggested by the lack of ion at m/z 335 and the chromatographic behavior on the reverse phase (the most lipophilic diCQA isomer). The base peak at m/z 191.055 evidenced 1,3-diCQA (24a), 1,5-diCQA (34) and 3,5-diCQA (35) supported by the relative abundance of the ions at m/z 179.034 and m/z 135.044: 73.2% and 58.7% (24a), 6.2% and 6.6% (34), and 53.1% and 52.7% (35), respectively.Five peaks 24, 33–35, and 37 ([M-H]l moiety . The vicCQA (33) . The secp-coumaroyl-caffeoylquinic acids (p-CoCQA) isomers 41 and 44 at m/z 499.122 (C25H23O11) were deduced from the distinctive fragments at m/z 337.093 [M-H-caffeoyl]−, m/z 163.039 [p-CoA-H]− and m/z 119.049 [p-CoA-H-CO2]− for p-coumaric acid (m/z 337.093 (83.6%) indicating a loss of caffeoyl residue before the p-coumaroyl one. This assignment was also supported by the base peak at m/z 163.039 as was registered in 3-p-CoQA − and m/z 353.270 [M-H-feruloyl]− for feruloyl-caffeolylquinic acids (FCQA). The fragment ion at m/z 335.0754 [M-H-FA]− accompanied by the “dehydrated” form of quinic acid suggested 3F-4CQA (40) [m/z 193.050 together with the abundant ion at m/z 134.036 (74.4%) as was registered in 3-FQA (m/z 161.023 [CA-H-H2O]− accompanied by the abundant ions at m/z 179.034 [CA-H]− (42.3%) and 367.104 (34.1%) − at m/z 327.051 (54) and 311.056 (57) supported by the relevant ions at m/z 299.056 0,2X/CO− [(M-H)-120–28]− and m/z 283.061, respectively. This fragmentation pathway was consistent with C-8 hexosyl luteolin/apigenin [C-6 hexosyl isomers 52 and 58 was shown by the ions at m/z 447.094 [M-H]− (100%) and 431.099, as well as 0,3X− at m/z 357.062 and 341.067, and 0,2X− at m/z 327.051 and 311.056. The aglycones luteolin  and apigenin  were discernable by the RDA ions 1,3A− (m/z 151.022), 0,4A− (m/z 107.012), 1,3B− at m/z 133.028  and 117.033 . Based on the comparison with reference standards, compounds 52, 54, 57, and 58 were identified as homoorientin, orientin, vitexin, and isovitexin, respectively.MS/MS spectra of the acquired . In the apigenin . In cont− at m/z 593.152 (C-glycosyl flavon pathway were produced at m/z 473.109 [(M-H)-120]−, 383.077 [(M-H)-90–120]− and 353.067 [(M-H)-2 × 120]− suggesting the presence of two C-hexosyl moieties on the flavonoid skeleton − at m/z 413.088 [(M-H)-60–120]− and − at 323.057 [(M-H)-120-150]− suggesting the presence of both C-pentosyl (X0) and C-hexosyl (X1) moieties. Additionally, methylluteolin was assigned on the basis of specie at m/z 299.560 [MeLu-H]− and 298.048 Y0/0,2X1/•CH3/CO [m/z 323.057 ([(M-H)-(132 + H2O)-120]− and 443.097 ([(M-H)-(132 + H2O)]− suggesting O-pentosyl unit at 2″ of the primary hexose  593.152 . Concerny hexose . Diagnos− at 609.147, 47 was annotated as 6, 8-diC-hexosyl-luteolin, while 48 was assigned to O, C-dihexosyl-luteolin. The latter structure was shown by a series of diagnostic ions at m/z 447.093 [M-H-Hex]−, 357.062 [M-H-Hex-90]− and 327.051 [M-H-Hex-120]−. Additionally, ions at m/z 298.048 , 175.039  and 133.028 1,3A− indicated luteolin. The sugar chain of 56 was consistent with rutinose (308 Da); aglycone quercetin was witnessed by a series of fragments including RDA ions at m/z 178.998 −, 163.003 −, 151.002 −, 121.028 −, 107.012 −. Based on comparison with reference standard, 56 (rutin), 60 (luteolin-7-glucoside), 65 (kaempferol-3-glucoside), 66 (isorhamnetin-3-glucoside), 67 (apigenin-7-glucoside), luteolin (50), quercetin (72), apigenin (75), kaempferol (77) and chrysoeriol (78) were unambiguously identified , 299.056  and 329.067 (71) [(M-H)-HexA]−, respectively, indicating flavonoid hexuronides  was deduced from the fragment ions at m/z 243.030 [(M-H)-HexA-CH3-HCO•-CO]−, 227.035 [(M-H)-HexA-CH3-HCO•-CO2]− as well as RDA ions at m/z 133.028 . Compound 69 was ascribed to chrysoeriol-O-hexuronide , while 70 was consistent with jaceosidin-O-hexuronide flavones . In (−) llea sp. .1,3A−) at m/z 165.990 , 139.039 , 136.986  and 1,2 B− at m/z 121.028. Within this group, compounds 73 (patuletin), 74 (axillarin), and quercetagetin-3,6,3′(4′)-trimethyl ether (80) were quercetagetin derivatives, while compounds 77 (hispidulin) and 81 (cirsimaritin) were scutellarein derivatives , 164.981 , 163.002 , 136.987 . Moreover,  at m/z 132.020 indicated 2 methoxy groups either in C-3, C-4′ or C-3′, C-4′, as was observed in santin and eupatilin, respectively + and 243.101 [M + H-2H2O]+ and a base peak at m/z 237.111 [M + H-H2O-CH2]+. This fragmentation pathway could be associated with the presence of peroxide group and 84 was tentatively ascribed to tanaparthin-peroxide, previously isolated from Achillea nobilis (+ at m/z 307.153 gave a base peak at m/z 247.132 [M + H-CH3COOH]+ which is in accordance with the structure of achillicin/matricin. Compound 87 differs from 85 for 60 Da (CH3COOH) and revealed the same fragmentation patterns as 85. Thus, compound 87 was tentatively annotated as achillin/leucodin , 2xH2O (−36 Da), CO (−28 Da), as well as concomitant loss of H2O + CO (−46 Da), 2H2O + CO (−64 Da), 88 and 89 were ascribed to artabsin and dihydrosantamarin, respectively, and were previously isolated from Achillea collina [MS/MS spectrum of 84 [M + H] nobilis  44]. Co. Co+ at leucodin . Similarm/z 280.263 (C18H33NO) together with distinctive fragments at m/z 263.236 [M + H-NH3]+ and m/z 245.225 [M + H-NH3-H2O]+, suggesting amide of octadecadienoic acid. Additionally, the suggested structure was supported by the fragments at m/z 81.070 (C6H9), 69.070 (C5H9), 57.070 (C6H9)  . Thus, 9ectively  46]..m/z 280.A. aleppica aerial parts (55.15 mg TE/g) and A. santolinoides roots (54.11 mg TE/g) showed highest scavenging activity against DPPH. In contrast A. aleppica roots water extract (101.88 mg TE/g) and A. santolinoides roots methanol extract (112.53 mg TE/g) were most potent in scavenging ABTS. Protocatechuic acid and its derivatives identified in the A. aleppica roots water extract, A. aleppica aerial parts methanol extract, and A. santolinoides roots methanol extract, has been reported to exhibit radical scavenging activity [A. aleppica aerial parts and A. santolinoides roots showed highest reducing capabilities  and ethyl acetate and water extract of the aerial parts of A. santolinoides (27.37 and 26.06 mg EDTAE/g), respectively possessed strong chelating ability. Caffeic acid, chlorogenic acid, and protocatechuic acid were identified in aerial parts of A. aleppica water and A. santolinoides ethyl acetate extracts. Interestingly, a study conducted by Andjelković, et al. [A.santolinoides was previously reported to possess antioxidant effect on brain tissues in pentylenetetrazole-induced seizures Wistar rat models [A.santolinoides was also found to exhibit antioxidant potential against DPPH radical (IC50 = 129–372 mg/mL) [The total antioxidant capacity of the extracts was determined using the phosphomolybdenum assay. As shown in activity ,48. Neocactivity . The redbilities . The che, et al.  has asset models . The ess2 mg/mL) .Achillea species against enzymes targeted in the management of diabetes mellitus type II, Alzheimer’s disease, and skin hyperpigmentation problems was investigated. Alzheimer’s disease has escalated to epidemic proportions and the need for complementary therapeutic agents to effectively manage this debilitating condition is of paramount importance. From A. aleppica aerial parts ethyl acetate extract and A. santolinoides roots methanol exhibited highest inhibition against AChE. A previous molecular docking study confirmed the interaction of orientin with AChE which showed least binding energy and highest binding affinity [A. aleppica roots and A. santolinoides aerial parts was previously reported to inhibit BuChE in an in silico study. On the other hand, the ethyl acetate extracts of A. aleppica aerial parts and roots (6.07 and 6.73 mg GALAE/g) and as well as that of A. santolinoides aerial parts (6.76 and 6.70 mg GALAE/g) were most active against BuChE. The inhibition of BuChE has been advocated in the later stage of Alzheimer’s disease. During the progression of the disease, BuChE level increases, exacerbating the conditions of the patient [A. aleppica and A. santolinoides aerial parts and roots possessed weak anti-diabetic properties. Tyrosinase, a rate limiting enzyme responsible for the biosynthesis of melanin, is considered to be a key therapeutic strategy for the management of skin hyperpigmentation conditions. In the present study, methanol extracts of A. aleppica aerial parts and roots showed the highest inhibitory activity against tyrosinase. In other side, ethyl acetate and methanol extracts of both studied parts of A. santolinoides displayed strongest anti-tyrosinase activity. Hispidulin, isolated from Phyla nodiflora and identified in extracts which actively inhibited tyrosinase was previously reported to exhibit inhibitory action against tyrosinase with an IC50 value of 146 µM [The inhibitory ability of extracts prepared from the aerial parts and roots of the selected affinity . Vitexinaffinity . Acacetiaffinity . However patient . The abif 146 µM .A. aleppica roots EA and MeOH and A. santolinoides roots EA were grouped together. Similarly, in PC1 vs PC2 and PC1 vs. PC3, A. A. santolinoides roots MeOH and A. aleppica aerial parts MeOH were close together. Following PCA, a hierarchical classification was done to obtain a clearer picture of the different group. Based on the scores of samples on the three PCs, the hierarchical analysis revealed two principal clusters, each of which was divided into two sub-clusters  were characterized by higher antioxidant activity while samples of the second cluster  were marked by stronger enzyme inhibitory activity.Subsequent to comparison of the bioactivities of the samples of each species, principal component analysis (PCA) was used in order to uncover the similarities/differences among the extracts of both species, in light of assessed antioxidant and enzyme inhibitory activities. The results of PCA were displayed in clusters B. The sa2X) and biological activities (R2Y) respectively, indicating the good performance of the model.The relationship between the metabolites and biological activities Partial was assessed and result was reported in Achillea species. In respect of the genes modulation, 73, 122, 280, 122, 113, 122, 57, 57, 254, 287 and 272 mRNA were found to be up-regulated and down-regulated by artabsin, dehydroleucodin, dihydrosantamarin, leucodin, matricin, tanaparthin peroxide, neochlorogenic acid, chlorogenic acid, homoorientin, vitexin and isovitexin respectively (Artemisia capillaries, it has been demonstrated that leucodin dose dependently enhances phosphorylation of AMPK in alcohol-exposed HepG2 cells [After the phytochemical screening and in vitro evaluation of biological properties of the samples, we have been engaged in the investigation of KEGG pathway enrichment analysis of identified sesquiterpene lactones and derivatives and five of the main phenolics of ectively . As regaectively . StructuG2 cells . FurtherG2 cells . While tG2 cells . This fiA.aleppica and A. santolinoides roots and aerial part. Chlorogenic acid was the main derivative in aerial parts of both the species. 3,5-diCQA was the most important diCQA derivative in A. aleppica while 1,3diCQA was the most significant in A santolinoides. Sesquiterpene lactone and fatty acid amides have been also detected showing large chemical diversity in the constituents of the plant. The extraction with ethyl acetate, methanol and water allowed to prepare samples with different composition that were used to assess their in vitro bioactivity on several antioxidant and enzyme inhibition assays. The methanol extract of A. santolinoides roots possessed significant antioxidant activities. The ethyl acetate extracts of the aerial parts and roots of both Achillea species showed significant inhibition against butyrylcholinesterase while the ethyl acetate extract of A. santolinoides aerial part actively inhibited tyrosinase. The detailed phytochemical investigation, the evaluation of in vitro bioactivity, of the two Achillea species indicate these plants as valuable starting point for potential future studies and possible applications extracts in cosmetic, pharmaceuticals and nutraceuticals products. KEGG mapping using some of the phenolics and sesquiterpenes of the plants allowed to predict some of the possible molecular targets for significant bioactivities. This information opens new opportunities of research and application for A. aleppica and A. santolinoides extracts and isolated compounds.This study allowed obtaining a detailed phytochemical fingerprint of


Staphylococcus aureus (MRSA) SCCmec IV[2B] has become one of the most common community-associated MRSA clones in Australia. We report the complete genome sequence of one of the earliest isolated Australian S. aureus ST1-MRSA-IV strains, WBG8287, isolated from an Indigenous Australian patient living in the remote Kimberley region of Western Australia.Sequence type 1 (ST1) methicillin-resistant  Staphylococcus aureus (CA-MRSA) first emerged in Australia in the 1980s . WBG8287 was additionally sequenced using the Illumina NextSeq 500 platform, the Nextera XT DNA library preparation kit (paired-end format) , and the NextSeq 500/550 kit v2.5 (300-cycle format) (Illumina). The Illumina sequencing produced 2,083,742 reads, with a maximum read length of 151 bp and a mean read length of 147 bp. The Nesoni clip tool (github.com/Victorian-Bioinformatics-Consortium/nesoni) was used to remove adaptor sequences and quality filter reads. The assembly was polished with the Illumina reads 5× using Minimap2 v2.17-r941 , using MinKNOW v20.10.3 and MinKNOW Core v4.1.2 software. Base calling was performed using Guppy v4.4.1 + 1c81d62 (ONT) with the dna_r9.4.1_450bps_hac.cfg model. Sequencing produced 470,277 reads and a read-length CP070986.1 (chromosome), CP070987.1 (pWBG750), and CP070988.1 (pWBG751). The sequencing reads have been deposited in the Sequence Read Archive under accession numbers SRX11246054 and SRX11246053.The WBG8287 sequences are deposited in NCBI GenBank under accession numbers


Macrolides are a significant family of natural products with diverse structures and bioactivities. Considerable effort has been made in recent decades to isolate additional macrolides and characterize their chemical and bioactive properties. The majority of macrolides are obtained from marine organisms, including sponges, marine microorganisms and zooplankton, cnidarians, mollusks, red algae, bryozoans, and tunicates. Sponges, fungi and dinoflagellates are the main producers of macrolides. Marine macrolides possess a wide range of bioactive properties including cytotoxic, antibacterial, antifungal, antimitotic, antiviral, and other activities. Cytotoxicity is their most significant property, highlighting that marine macrolides still encompass many potential antitumor drug leads. This extensive review details the chemical and biological diversity of 505 macrolides derived from marine organisms which have been reported from 1990 to 2020. Lamellomorpha strongylata (La. strongylata) [Symbiodinium sp. [The term “macrolide” was coined by Woodward in 1957 ,3,4. Thengylata) , and thenium sp. . MacroliThis literature review from 1990 to 2020 highlights 505 new macrolides derived from marine organisms  . CompareTheonella sp. (T. sp.) sponges produced a series of dimeric macrolides called swinholides A–G (1–7) and isoswinholide A (8) [9), isobistheonellide A (10), and bistheonellic acids A (11) and B (12)—are also produced by Okinawan T. sp. sponges [13), which is weakly cytotoxic and obtained from Japanese sponge Polyfibrospongia sp., was elucidated by X-ray single crystal diffraction [14) was isolated from Mycale adhaerens (M. adhaerens) and identified by spectroscopic analysis [The Okinawan de A (8) ,17,18,19 sponges . The strfraction . 13-Deoxanalysis . 15) and halistatin 2 (16) were isolated from Phakellia carteri from the Comoros Islands and Axinella cf. carteri (Dendy) from the Western Indian Ocean [17) was produced in extremely small quantities by Phakellia sponges collected at Chuuk [The antimitotic macrolides halistatin 1 , 2 (19), and 3 (20), which were isolated from Spongia sp. in the Republic of Maldives and identified via spectral data without stereochemistry [21), 5 (22), 6 (23), 7 (24), 8 (25), and 9 (26) from Spirastrella spinispirulfera (S. spinispirulfera) on the southeast coast of Africa [Independent groups have reported the potent antitumor macrolides spongiastatins 1 , C (28), and D (29) have been isolated from the Caledonian sponge Neosiphoniu superstes [Three macrolides sphinxolides B (uperstes . 30), B (31), and C (32), were reported without stereochemical data in an Okinawan Juspis sponge [Three new trisoxazole macrolides, jaspisamides A (30), B , and C (33) was isolated from a Republic of Maldives Spongia sponge and exhibited significant cytotoxicity towards murine P388 lymphocytic leukemia [34) and B (35), have been produced by the marine sponge Reidispongia coerulea (R. coerulea) [A new 22-membered macrocyclic lactone named dictyostatin 1 (leukemia . The rel4) and B , have beoerulea) . The reloerulea) . 36) and superstolide B (37) have been isolated from the deep-water marine sponge Neosiphonia superstes (N. superstes) [38), was produced by the shallow-water Caribbean sponge Forcepia sp. [39), belonging to the halichondrin family, was isolated from the New Zealand deep-water sponge Lissodendoryx sp. (Li. sp.) [40) and B (41) have an unprecedented scaffold and were isolated from the Indian Ocean sponge Phorbas sp. (P. sp.), with complete stereochemistry and absolute configuration determined by spectroscopy and partial synthesis [42) and laulimalide B (43) isolated from Okinawan sponge Fasciospongia rimosa were determined by X-ray analysis [44), neolaulimalide (45) and zampanolide (46), have been produced by the F. rimosa genus [47), isolated from the marine sponge Halichodria okadai, exhibited significant inhibition of vascular cell adhesion molecule 1 (VCAM-1) [Cytotoxic superstolide A (perstes) ,39. Anotepia sp. . IsohomoLi. sp.) . Phorboxynthesis ,43. The analysis . Other climalide  and zamppanolide , have be48), exhibiting antifungal and cytotoxic activities, was obtained from the sponge Leucascandra caveolata (Le. caveolata) [Callipelta sp.  contains the first member of a new class of marine-derived macrolides, callipeltoside A (49), which incorporates an unusual chlorocyclopropyl group and an amino sugar [50–52) and 5-desacetylaltohyrtin A (53) were isolated from the sponge Hyrtios altum and their absolute stereochemistries were determined by spectroscopy [La. strongylata for cytotoxicity towards the P388 cell line yielded swinholide H (54) [Leucascandrolide A , exhibittoside A , which ino sugar ,51,52. Chyrtin A  were isotroscopy . Screenie H (54) .Li. produced the antitumor macrolides neonorhalichondrin B (55), neohomohalichondrin B (56), 55-methoxyisohomohalichondrin (57), 53-methoxyneoisohomohalichondrin B (58a) and 53-epi-53-methoxyneoisohomohalichondrin B (58b) [Another deep-water (> 100 m) sponge of the genus ondrin B , neohomo59) and B (60) were isolated from the Haliclona sponge, representing a potentially important new class of antitumor leads [61) and C (62), two members of a novel class of marine glycoside macrolides, were isolated from the sponge Cal. sp. [Macrolide salicylihalamides A  and B  were iso63–66), were isolated from an Okinawan marine sponge, Halichondria sp. [Four new oxazole-containing compounds, halishigamides A–D , showing modest cytotoxicity [68), 32-hydroxymycalolide A (69), and 38-hydroxymycalolide B (70), were isolated from the marine sponge M. magellanica and showed cytotoxicity towards L1210 cells [A Palau toxicity . Three m10 cells . 71), a thiazole-containing macrolide with an unique dilactone functionality, was isolated from M. sp. sponge [72–75), were produced by the marine sponge Amphimedon spp. collected in the Great Australian Bight [Pateamine 1 (. sponge . Four nean Bight . 76), NB (77), NC (78), ND (79) and NE (80) were isolated from the New Caledonian Litbistida sponges N. superstes and R. Coerulea [81–83) and reidispongiolide C (84) are new cytotoxic macrolides from Okinawan species of Ircinia [85) is a 16-membered macrolide from the calcareous sponge Le. caveolata from the northeastern waters of New Caledonia [M. sp. contained the polyoxygenated, pyranose ring-containing, 16-membered macrolide peloruside A (86) [Cytotoxic macrolides haterumalides NA  , which we A (86) . 87) has been isolated from the Vanuatu marine sponge Spongia sp. [88), was isolated from a marine sponge of the genus Dactylospongia. This has been synthesized and the relative stereochemistry of the acyloxymethine and the absolute configuration of the whole molecule have been determined [Ha. sp. was found to contain the cyclic metabolite haliclamide (89) [Cytotoxic spongidepsin (ngia sp. . A new ctermined . The Vanide (89) .90–93) have been found in sponge Myriastra clavosa [94–100) are antimitotic macrolides isolated from the Caribbean marine sponge S. coccinea [Clavosolides A–D  and (19Z)-halichondramide (102), and the open ringed secohalichondramide. Neohalichondramide and (19Z)-halichondramide exhibited significant cytotoxicity and antifungal activity toward the human leukemia cell-line K562 and Candida albicans  [The sponge lbicans) .103), 32-hydroxymycalolide A (104) and 38-hydroxymycalolide B (105), have been isolated from a Japanese M. magellanica [106–110) were isolated from Forcepia sponge collected in the U.S. Gulf of Mexico [111), isolated from the marine sponge Geodia exigua, was reported to inhibit fertilization of sea urchin (Hemicentrotus pulcherrimus) gametes but not embryogenesis [Three cytotoxic mycalolides, 30-hydroxymycalolide A (ellanica . The fivf Mexico . Exiguologenesis . The absogenesis .112) and B (113) were obtained from a deep-water (>200 m) Leiodermatium sponge [114), isolated from Ircinia sp. (Papua New Guinea), was found to be potently cytotoxic, causing S-phase arrest, suggestive of protein synthesis inhibition [115–118) were produced by Pachastrissa nux (P. nux) (Gulf of Thailand) [Cytotoxic macrolides leiodolides A  . 119), was isolated from P. nux sponge [120) and the related hurghadolide A (121), with cytotoxicity towards human colon cancer cells, were produced by T. swinhoei  [An antiplasmodial macrolide, kabiramide L  .122) was isolated from Red Sea sponge Negombata corticata and showed significant antifungal and anticancer activities, suggesting it as a potential member of the bioactive latrunculin family [123) with potential cytotoxic and antifungal activities. This compound was synthesized to determine its absolute configuration and the relative stereochemistry of C-13 [124), a complex mixture of acyl esters of a macrolide related to tedanolide, was isolated from Candidaspongia sp. (Can. sp.) (Papua New Guinea) and Can. flabellata  [125–130) were produced by sponge Cacospongia mycofijiensis (Cac. mycofijiensis)  [131–135) are chlorocyclopropane macrolides isolated from marine sponge P. sp. [Oxalatrunculin B  . FijianoVanuatu) . Phorbase P. sp. ,97. 136–138), 18-epi-latrunculol (139) and latrunculones A (140) and B (141), were obtained from Cac. mycofijiensis [142), salarin B (143) and tulearin A (144) were obtained from repeated collections of the Madagascan sponge Fascaplysinopsis sp. (F. sp.) [Latrunculin analogs, latrunculol A–C  . 145), which was considered to be the precursor of salarins A and B [Siliquariaspongia mirabilis contained an antitumor macrolide lactam named mirabilin (146) [147) was isolated from the Madagascar sponge F. sp. and was found to inhibit proliferation of K562 leukemia cells [148), containing a rare hexahydro-1H-isoindolone and trichlorocarbinol ester, was isolated from marine sponge of the genus Phorbas [A further collection led to the isolation of salarin C ( A and B . Marine in (146) . The nitia cells . Muirono Phorbas . 149), B-1092 (150), B-1020 (151) and B-1076 (152), were extracted from the Poecilosclerid sponge Li. sp. in microgram quantities and their structures were elucidated by capillary NMR spectroscopy [Four variants of halichondrin B, B-1140 (troscopy . 153) and two analogs, 15-O-methylenigmazole A (154) and 13-hydroxy-15-O-methylenigmazole A (155), were extracted from the marine sponge Cinachyrella enigmatica collected in Papua New Guinea [Cytotoxic phosphate-containing macrolide enigmazole A (w Guinea  and theiw Guinea .156–162) were obtained from the Madagascan F. sp. sponge. Scalarins D, E, H, and J inhibited cell proliferation in a dose- and time-dependent manner [163–165) were obtained from the Okinawan marine sponge T. sp. and absolute configurations were determined by combining a JBCA method, a universal NMR database, and a 13C-acetonide method [Seven scalarin analogs D–J  and swinholide K (167) [168), with strong cytotoxicity towards human Jurkat J16 T and Ramos B lymphocytes, was isolated from marine sponge Cal. sp. [169) and C (170) were isolated from Petrosiidae sponge with stereochemical assignment via enantioselective synthesis of the macrocyclic core [171), F (172), and G (173) were isolated from the marine sponge Poecillastra sp. [The Indonesian sponge  K (167) . An unusCal. sp. . Cytotoxlic core . Cytotoxstra sp. .Periconia byssoides (Per. byssoides), obtained from the sea hare Aplysia kurodai (Ap. sp.), was reported to produce the cytotoxic triols pericosides A and B, and four new macrolides, macrosphelides E–H (174–177) [178) and macrosphelides E–H from Per. byssoides isolated from Ap. kurodai were also reported elsewhere [179) and H produced by Per. byssoides from Ap. kurodai, and the cytotoxic macrosphelide M (180) [Penicillum verruculosum (IMI352119) was reported to produce three macrolides with antifungal activity: BK223-A (181), BK223-B (182) and BK223-C (183) [Varicosporina ramulosa has been reported to produce -colletodiol (184), -colletodiol (185) and colletoketol (186) [187) and pandangolide 2 (188) were extracted from an unidentified fungus isolated from marine sponge collected in Indonesia [The fungus 174–177) . Macrosplsewhere . Macrosplsewhere . The synlsewhere ,118. Abs M (180) ,119,120.-C (183) . The mitol (186) ,123. Thendonesia . 189), macrolide dimer pandangolide 4 (190), and a new acetyl derivative of 5-hydroxymethylfuran-2-carboxylic acid were produced by the fungus Cladosporium herbarum (Cla. herbarum), associated with the sponge Callyspongia aerizusa  and collected in Bali [191) was obtained from an extract of the marine fungus Myrothecium roridum (M. roridum) [192–196) were isolated from the mangrove fungus Aigialus parvus BCC 5311 [197) and 15G256ѡ (198) were obtained from the marine fungus Hypoxylon oceanicum LL-15G256 [199) and B (200), were produced by the fungus Cladosporium isolated from the brown alga Actinotrichia fragilis  [Pandangolide 3  . The 14-BCC 5311 . PotentiL-15G256 . Two cyt, Japan) . Sargassum sp.  was the source of two 12-membered ring lactones (201–202) [203), roridin Q (204) and 2,3-deoxyroritoxin D (205) were obtained from M. roridum on submerged wood in Palau [Gliocladium sp. isolated from the alga Durvillaea antarctica  yielded 4-ketoclonostachydiol (206) [An unidentified endophytic fungus from the brown alga 201–202) . 12-Hydrin Palau . Glioclaol (206) . 207) and 2′-hydroxyzearalanol (208) were isolated from the marine-derived fungus Penicillium sp. (Pen. sp.) [209) was obtained from the culture broth of the fungus Fusarium sp. 05ABR26 [210–212) were isolated from the culture broth of the marine sponge-derived fungus Aspergillus ostianus (As. ostianus)  [The 14-membered resorcylic acid lactone derivatives 8′-hydroxyzearalanone (en. sp.) . β-resor 05ABR26 . The cytronesia) .As. sp. SCSGAF 0076 was reported to produce the 16-membered macrolide aspergillide D (213) [214) and enantiomers of curvularin (215–220) were isolated from Curvularia sp. (Cur. sp.) [221) was produced by Cur. sp. isolated from the marine alga Gracilaria folifera and inhibited the growth of B. subtilis, Microbotryum violaceum, Septoria tritici, and Chlorella fusca [The marine-derived fungus  D (213) . Apralacur. sp.) ,138. Thela fusca . 222–224), were purified from an ethyl acetate extract of Corynespora cassiicola isolated from leaf tissues of the Chinese mangrove medicinal plant Laguncularia racemose [225) and B (226) (as the diacetate) were isolated from the fungus Pestalotiopsis spp., which is associated with mangrove twigs of Rhizophora mucronata [227–229), 15G256α (230), and 15G256β (231) were obtained from crude extracts of the fungus Calcarisporium sp. KF525 isolated from German Wadden Sea water samples [Three decalactones, xestodecalactones D–F , were obtained from the fungus Dendrodochium sp. derived from sea cucumber Holothuria nobilis Selenka in the South China Sea [Thirteen new 12-membered macrolides, dendrodolides A–M  was produced by the gorgonian-derived fungus Cochliobolus lunatus (Coc. lunatus) [Cochliomycin C (lunatus) , its abslunatus) .Pen. sumatrense MA-92, associated with the mangrove Lumnitzera racemose, yielded the sulfur-containing curvularin derivatives sumalarins A−C (246–248) [Coc. lunatus (TA26-46) with histone deacetylase inhibitors led to the elucidation of two 14-membered resorcylic acid lactones: 5-bromozeaenol (249) and 3,5-dibromozeaenol (250) [251–255) were obtained from a sponge-derived fungus Gliomastix sp. ZSDS1-F7-2, their structures being determined by spectroscopy and single crystal X-ray diffraction [256–257) were isolated from the marine-derived fungus Pen. meleagrinum var. viridiflavum [Penicillium sp. DRF2 led to the isolation of cyclothiocurvularins (258–260) and cyclosulfoxicurvularins (261–262) [263) was produced by the mangrove endophytic fungus Cladosporium sp. (Cla. sp.) SCNU-F0001 and its absolute configuration was determined by X-ray diffraction [264–268) were isolated from another mangrove-derived endophytic fungus species in the same Cla. genus [269) was isolated from endophytic fungus Aplosporella javeedii [270–271), were obtained from the endophytic fungus Paramyrothecium roridum isolated from the medicinal plant Morinda officinalis [The fungus 246–248) . Chemicaol (250) . Gliomasfraction . Two 13-diflavum . Applica261–262) . Thioclafraction . Thioclaa. genus . The macjaveedii . Two triicinalis .272) was isolated from a marine bacterium in the order Actinomycetales [273) was produced by Streptomyces hygroscopicus (S. hygroscopicus) isolated from the marine fish Halichoeres bleekeri [O-Succinyl macrolactin F (274) and 7-O-succinyl macrolactin A (275) were isolated from a culture of marine Bacillus sp. (B. sp.) Sc026 [The 24-membered macrolide maduralide  Sc026 .276) was obtained from marine actinomycete L-25-ES25-008 [277) was isolated from marine Streptomycete isolate B7064 and was bioactive in both microorganisms and microalgae [278–279) have been extracted from culture broths of bacteria isolated from the surface of the Caribbean brown alga Lobophora variegata  [280–282) were produced by Micromonospora sp. (M. sp.) and demonstrated inhibition of gastrulation in starfish embryos [Cytotoxic macrolide IB-96212  . Micromo embryos ,164. 283–286) were isolated from actinomycete “Marinispora”. These marinomycins showed antibacterial activity towards methicillin-resistant S. aureus (MRSA), while marinomycin A inhibited vancomycin-resistant S. faecium (VREF) and C. albicans (weakly). Marinomycins A–C demonstrated cytotoxic activity against a panel of 60 tumor cell lines, including six of the eight melanoma cell lines [Marinomycins A–D , with arenicolides A showing moderate cytotoxicity [290) has been reported in a culture of marine Bacillus sp. [Marinispora” yielded polyene macrolides marinisporolides A (291) and B (292), which photoisomerized to the geometric isomers marinisporolides C–E, suggesting that they may be artefacts [S. hygroscopicus  produced halichoblelides B (293) and C (294), which are cytotoxic to tumor cells [Marine actinomycete toxicity . Macrolallus sp. . The actrtefacts . S. hygror cells .295–296), were obtained from the culture of a marine actinomycete S. sp. isolated from a sediment sample collected at North Cat Cay in the Bahamas [Two 36-membered macrolides, bahamaolides A and B ( Bahamas . B. subtilis isolated from marine sediment collected at Gageocho (Republic of Korea) was a source of three new glycosylated methoxy-macrolactins (297–299) [300–302), featuring an oxetane, an epoxide, and a tetrahydropyran ring, were isolated from an ethyl acetate extract of a marine B. sp. [303) was produced by a marine-derived actinomycete strain (CNJ-878) [M. strain FIM07-0019 isolated from shallow coastal waters near the island of Chiloe (Chile) produced a 20-membered macrolide, levantilide C (304) [297–299) . Three ne B. sp. . CytotoxCNJ-878) . The M.  C (304) . S. sp. in sediment from Heishijiao Bay  yielded 11′,12′-dehydroelaiophylin (305) and 11,11′-O-dimethyl-14′-deethyl-14′-methylelaiophylin (306)—both 6-deoxyhexose-containing antibiotics—with the former exhibiting inhibition of MRSA and vancomycin-resistant Enterococci pathogens [307), was produced by a marine-derived filamentous sulfur bacteria, Thioploca sp. [308), was isolated from marine sediment-derived actinomycete S. sp.  [309) and B (310) were identified in marine-derived bacteria of the genus Nocardiopsis and demonstrated inhibition towards TNF-α-induced NFκB activation (fijiolide A to a greater extent than fijiolide B) [311) and B (312) were obtained from S. hygroscopicus in the alkaline soil of the Saratov region of Russia. They exhibited significant cytotoxicity towards doxorubicin-resistant human leukemia cells [313) and B (314), were isolated from the actinobacterium Catenulispora sp. KCB13F192 [Investigation of a athogens . A rare loca sp. . A poten U.S.A.) . Fijioliolide B) . Astolidia cells . Two hygCB13F192 . Scytonema mirabile BY-8-1, S. burmanicum DO-4-1, and S. ocellatum DD-8-1, FF-65-1 and FF-66-3 have been reported to produce tolytoxin (315). S. burmanicum DO-4-1 also yielded scytophycin B (316), 6-hydroxyscytophycin B (317), 19-O-demethylscytophycin C (318), 6-hydroxy-7-O-methylscytophycin E (319), and scytophycin E (320) [321), was isolated from Japanese Oscillatoria sp. and demonstrated inhibition towards fertilized echinoderm eggs [Lyngbya bouillonii (L. bouillonii) collected on Laing Island (Papua New Guinea) produced lyngbyaloside (322) [323), madangolide (324), and laingolide A (325) [326), for which the configuration of C-11 was later revised [Cyanobacteria  E (320) . A macroerm eggs . The marde (322)  in addit A (325) ,185, and revised ,187.327) and B (328), together with swinholide A previously obtained from the marine sponge T. swinhoei [Geitlerinema sp. collected in Madagascar [329), demonstrating significant molluscicidal activity towards the snail vector Biomphalaria glabrata, was also isolated from L. bouillonii from Papua New Guinea [330) was isolated from L. sp. and showed strong apoptosis-inducing activity in HeLa S3 and HL60 cells [331–333), were produced by another L. cyanobacterium sampled on Tokunoshima Island (Japan) [2+ concentration in HeLa S3 cells [Two glycosylated swinholides, ankaraholides A  . BiselynS3 cells . 334) [335–338), have been isolated from Leptolyngbya sp. collected in Okinawa [The Caribbean Okeania cyanobacterium VQR28MAR11-2 has been reported to produce polycavernoside D (334) , while f Okinawa .339) was isolated from the Okinawan flatworm Amphiscolops sp. (Amphis. sp.) and exhibited cytotoxicity towards murine leukemia cells L1210 and L5178Y [340), G (341) and H (342) were produced by dinoflagellate Amphidinium sp. (Amphid. sp.) associated with the Okinawan flatworm Amphis. breviviridis [Amphidinolide E  and K (344) were isolated from symbiotic dinoflagellate Amphid. sp. and later synthesized [345), B2 (346) and B3 (347) were also isolated from Amphid. sp. [348), M (349) and N (350) [Amphidinolides G and H were elucidated by X-ray diffraction analysis and interconversion . Amphidithesized ,200. Amphid. sp. ,202,203, N (350) ,205,206.351) and P (352), were also isolated from Amphis. sp. [353), showing moderate cytotoxicity towards murine lymphoma L1210 cells in vitro (IC50 6.4 μg/mL), was obtained from the symbiotic flatworm Amphis. sp. of dinoflagellate Amphid. sp. [R, 7R, 9S, 11R, and 13R on the basis of NMR analysis and a modified Mosher’s method [354) and S (355) were also isolated from Amphid. sp. [356) was obtained from a cultured Amphid. sp. Y-56 isolated from the flatworm Amphis. sp. in Okinawa [357), was also obtained from the Y-56 dinoflagellate strain and exhibited cytotoxicity towards P388, L1210 and KB cells [358) [A. sp. Y-5 produced the 14-membered polyene amphidinolide V (359) [360), T3 (361), T4 (362), and T5 (363) were produced by Amphid. sp. [364), H3 (365), H4 (366), H5 (367), G2 (368), and G3 (369) were produced by Amphid. sp. strain Y-42 isolated from marine acoel flatworms Amphis. sp. The absolute configurations of these compounds were determined by coupling constant data, distance geometry calculations, and chemical means [S)-lactate via a 16-step linear sequence [370) was isolated from an Amphid. sp. and the absolute stereochemistry determined by a combination of J-based configuration analysis and modified Mosher’s method [371) and Y (372) were produced by symbiotic dinoflagellate Amphid. sp. strain Y-42 from Okinawan Amphis. species. Amphidinolide Y exists as a 9:1 equilibrium mixture of the 6-keto- and 6(9)-hemiacetal forms (373). Both amphidinolides X and Y showed significant cytotoxicity against murine lymphoma L1210 and human epidermoid carcinoma KB cells in vitro [374) and B7 (375), were isolated from a culture of a symbiotic dinoflagellate Amphid. sp. from Amphis. sp. and demonstrated cytotoxicity against human B lymphocyte DG-75 cells [376) was isolated from dinoflagellate Amphid. sp. (Y-71 strain) [The structure of amphidinolide N was later revised and stereochemistry assigned . Cytotoxhis. sp. . The abshis. sp. . The 12-hid. sp. . The abss method . Cytotoxhid. sp. . The 20- Okinawa . A 25-meKB cells . Y-56 hals [358) , while t V (359) . Total s V (359) . Analogshid. sp. ,220. Ampal means . Amphidisequence . Amphidis method . Total ss method . Amphidiin vitro ,226. Two75 cells . Amphidi strain) . Amphid. strain S1-36-5 yielded the highly cytotoxic 26-membered caribenolide I (377) [The  I (377) .378) and a 26-membered macrolide amphidinolactone B (379) have been isolated from cultures of Amphid. sp. Amphidinolactone A was synthesized totally via a ring-closing metathesis reaction and the absolute configuration was elucidated [380) and B (381) were isolated from a symbiotic dinoflagellate Symbiodinium sp. (Y-6 strain), which was associated with Amphis. sp. [Prorocentrum maculosum Faust yielded the fast-acting toxin prorocentrolide B (382) [383) was identified in the marine dinoflagellate P. hoffmannianum [384), -1b (385) and -1c (386) were isolated from a marine benthic dinoflagellate Amphid. sp. (strain HYA024) [The 13-membered macrolide amphidinolactone A 37 and a 26ucidated ,231. Thehis. sp. ,233. Bio B (382) . Hoffmanannianum . The 20- HYA024) ,237. 387) was also obtained from Amphid. sp. [388) containing an allyl epoxide was obtained from Amphid. sp. strain HYA024 and was potently cytotoxic to human B lymphocyte DG-75 cells and Epstein–Barr virus (EBV)-infected Raji cells [389) and -5a (390) were isolated from a benthic dinoflagellate Amphid. sp. (strain HYA024) and showed moderate cytotoxicity towards human B lymphocytes DG-75 [391) and -11a (392) were cytotoxic towards human cervix adenocarcinoma HeLa and murine hepatocellular carcinoma MH134 cells [The cytotoxic 23-membered iriomoteolide-2a (hid. sp. . The 15-ji cells . Iriomotes DG-75 . The 15-34 cells .393) and -12a (394) were isolated from a marine dinoflagellate Amphid. sp. (KCA09053 strain) with iriomoteolide-10a being cytotoxic to human cervix adenocarcinoma HeLa and murine hepatocellular carcinoma MH134 cells [395) was isolated from the symbiotic dinoflagellate Symbiodinium sp. (S. sp.) and showed significant voltage-dependent N-type Ca2+ channel-opening activity at 7 nM and immediately ruptured the surface tissue of the acoel flatworm Amphis. sp. at 2.5 mM [S,18R,21R) configurations were determined by synthesis [S,40S) and (C-1′–C-25′) [396) caused potent stimulation of actomyosin ATPase activity [397) was isolated from cultures of the marine dinoflagellate Prorocentrum belizeanum [398) was extracted and purified from a culture of dinoflagellate Alexandrium ostenfeldii from the Baltic Sea [399) was isolated from a culture of the symbiotic marine dinoflagellate S. sp. [Iriomoteolide-10a  ,244,245.activity . The 25-lizeanum . Gymnodiltic Sea . Symbiode S. sp. .Polycavernosa tsudai (Gracilaria edulis) contained the macrolide polycavernoside A (400), which led to human illness and death in Guam [401), A3 (402), B (403) and B2 (404) were also obtained from Polycavernosa red algae [ in Guam . The rel in Guam ,252. Its in Guam . Polycaved algae . 405) and C2 (406), were isolated from the red alga Gracilaria edulis (G. edulis) [407–409) were isolated from extracts of red alga G. coronopifolia [410) and manauealide C were extracted from Hawaiian G. coronopifolia [Callophycus serratus (C. serratus) led to the isolation of three diterpene-benzoate natural products: bromophycolides A (411) and B (412), and a nonhalogenated compound (413). Bromophycolides A and B exhibited moderate antibacterial and antifungal properties while bromophycolides A demonstrated potent anti-HIV and moderate cytotoxic activities [414–420) were also isolated from extracts of C. serratus. All the bromophycolides exhibited modest antineoplastic activity towards a range of human tumor cell lines while bromophycolides F and I showed weak antifungal activity [Two analogs of polycavernosolide A, polycavernosides C ( edulis) . Manaueaopifolia . Anhydroopifolia . Investitivities . Bromophactivity . C. serratus extract yielded a series of unusual antimalarial diterpene-benzoate macrolides, bromophycolides J–Q (421–428), with a range of moderate to strong antimicrobial and anticancer properties [C. serratus was also a source of the diterpene-benzoate macrolides bromophycolides R–U (429–432). These demonstrated modest cytotoxicity toward selected human cancer cell lines while bromophycolide S was active (at submicromolar concentrations) against the human malaria parasite Plasmodium falciparum  [Further investigation of the operties . C. serrciparum) . 433) and B (434) were obtained from the Fijian red alga Neurymenia fraxinifolia [Ecklonia stolonifera produced ecklonialactones C (435) and D (436) containing a 14-membered lactone moiety, and ecklonialactones E (437) and F (438), with a 16-membered moiety [439–446) with a macrolide scaffold and one cymathere-type oxylipin with an open ring were isolated from the brown alga Eisenia bicyclis. The absolute configurations of compounds 439–443 and 446 were determined by NMR spectroscopy with the relative stereochemistry at C-9 in 446 remaining unassigned [447) was isolated from the crustose coralline alga Hydrolithon reinboldii and its absolute relative configuration was determined by NMR spectroscopy with the relationships of the two side chains to the macrolide ring remaining unassigned [The α-pyrone macrolides neurymenolides A  and B1e (449), exhibiting moderate antifouling activity were obtained from Anthrogorgia caerulea collected in the South China Sea [Two avermectin congeners, avermectins B1c (hina Sea .450) from the marine bryozoan Bugula neritina (L.) was carried out to provide material for clinical study [451) has been converted to bryostatin 1 and bryostatin 12 (452) by selective protection and deprotection involving the C-26 hydroxyl group [p-bromobenzoate (453) [1H- and 13C-NMR were later revised [B. neritina and reinvestigation of 2D NMR spectroscopic data revised the structure of bryostatin 3 to structure 454 [Large-scale isolation of bryostatin 1  , while t revised . Bryostature 454 .B. neritina led to the identification of bryostatins 14 (455) and 15 (456) [457) have been elucidated by NMR spectroscopy [458) was determined to be the major cytotoxic component of B. neritina [459), 17 (460), and 18 (461), were isolated in trace amounts from B. neritina from the Gulf of Mexico [462) was isolated from B. neritina collected from the South China Sea [463), was produced by the larvae of B. neritina and its structure determined by spectral comparison with previously described bryostatins [464), which was cytotoxic towards the P388 lymphocytic leukemia cell line [Further investigation of 15 (456) . The strtroscopy ,273,275.troscopy . Bryostaneritina . Three af Mexico . Antineohina Sea . A furthostatins . Bioassaell line .465) was isolated from an extract of the sea hare Stylocheilus longicauda and synthesized [Aplysia kurodai Baba contained the novel and potently cytotoxic macrolides aplyronines A (466), B (467) and C (468). The absolute configuration of aplyronine A was assigned following enantioselective synthesis of its degradation products and total synthesis was also reported [469–473), were also isolated from the Japanese sea hare Aplysia kurodai [474) and the diacetyl derivative dolabelide B (475), both cytotoxins, were obtained from the Japanese sea hare Dolobella auricularia [476) and D (477) were also isolated from Dolabella auricularia, the originally assigned structure of dolabelide D being confirmed by total synthesis [478–482) were found in the skin of the marine mollusk Aplysia depilans, and were ichthyotoxic to the mosquito fish Gambusia affinis [483) and 7 (484) were isolated from Patinopecten yessoensis scallops [485) as a pectenotoxin accumulating in Norwegian blue mussels (Mytilus edulis) and cockles (Cerastoderma edule) [486), containing a 14-membered macrocyclic lactone linked to a 2,4-di-O-methyl-L-R-rhamnopyranoside, was found in the Gulf of California in the shell-less mollusk Dolabella auricularia [Aplysiatoxin  . Dolastaicularia . The steicularia .487) and D (488), were isolated from the Okinawan tunicate Eudistoma cf. rigida [489) and B (490), were reported in the tunicate Aplidium lobatum [A. lobatum from shallow waters in Australia, A. sp. from deep water, and an unidentified Philippine ascidian have been reported as sources of a series of macrolides, lobatamides C–F (491–494), demonstrating cytotoxicity towards human tumor cell lines [495) was obtained from an Okinawan ascidian L. sp. by bioassay-guided isolation and was shown to inhibit the first cleavage of fertilized sea urchin eggs at 0.01 μg/mL [Didemnidae sp. was the source of the macrolides biselides A (496) and B (497) [D. sp. led to the isolation of biselides C (498), D (499) and E (500) which exhibited cytotoxicity against human cancer cells NCI-H460 and MDA-MB-231 [501) was obtained from the Antarctic tunicate Synoicum adareanum [Two 24-membered macrolide sulfates showing antineoplastic activity, iejimalides C  . FurtherA-MB-231 . Cytotoxdareanum  and its dareanum ,307. 502–505) were isolated from Lissoclinum ascidian collected in Algoa Bay near Port Elizabeth and the surrounding Nelson Mandela Metropole in South Africa [Glycosylated macrolides mandelalides A−D (h Africa .The biological activities of marine-derived macrolides have been studied extensively. As listed in This review presents a summary of 505 marine-derived macrolides reported from 1990 to 2020 and highlights their chemical and biological diversity. As shown in For macrolides with larger macrocyclic rings, such as reidispongiolides A and B , symbiod


ADG20 is a fully human IgG1 monoclonal antibody engineered to have potent and broad neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-like CoVs with pandemic potential as well as an extended-half-life. ADG20 is administered intramuscularly (IM). A QSP/PBPK model was constructed to support dose selection for a COVID-19 Phase 2/3 prevention trial (EVADE: NCT04859517).90]) for authentic SARS-CoV-2 were also evaluated.A QSP/PBPK model and a CDC reference adult body weight distribution (45–150 kg) were used to simulate 1000 concentration-time profiles for candidate single-dose regimens of ADG20 (150–450 mg IM). As serum virus neutralizing antibody (sVNA) titers are reportedly a key correlate of protection from COVID-19, a regression equation between time-matched serum ADG20 concentrations (following a 300 mg IM dose) and sVNA titers was developed using measured titers against authentic SARS-CoV-2 determined by a plaque reduction neutralization assay. Projected ADG20 serum concentrations relative to neutralization potency in vitro .The measured 50% neutralization titer  was 1382 (32.7%) 13 days after a single 300 mg IM dose of ADG20. This was within the range of peak sVNA titers reported for COVID-19 vaccine recipients. Using the linear equation relating serum ADG20 concentration to time matched individual MN50 titers and the QSP/PBPK median PK prediction, the anticipated median MN50 exceeded the threshold for protection from SARS-CoV-2 infection established in a non-human primate adoptive transfer model for up to 52 weeks. Based on the QSP/PBPK median PK prediction, median ADG20 serum concentrations are projected to remain >100-fold above the ADG20 ICFollowing administration of a single 300 mg IM dose, sVNA titers and concentrations of ADG20 are projected to remain above thresholds anticipated to be required for protection against COVID-19 for up to 52 weeks. These data support the evaluation of a single ADG20 300 mg IM dose for the prevention of COVID-19.Figure. QSP/PBPK model forecast of ADG20 300 mg IM in adults.Predicted median serum ADG20 concentration is shown with the dotted line representing 100× in vitro IC90 of 0.011 mg/L or 1.1 mg/L; the solid black line represents the simulated median; the shaded area represents the 90% prediction interval. The predicted median half-life of ADG20 300 mg IM exceeded 74 days. PBPK model inputs include Ln-normal Kd,FcRn of 9.55 nM (10% IIV); IM bioavailability of 100%; 15% IIV on muscle lymph RC; and Centers for Disease Control and Prevention weight distribution of 45–150 kg. FcRn, neonatal Fc receptor; IIV, inter-individual variability; Kd, dissociation constant; Ln, log-normal; RC, reflection coefficient.Scott A. Van Wart, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Evan D. Tarbell, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Kristin Narayan, PhD, Adagio Therapeutics, Inc. (Employee) Laura M. Walker, PhD, Adagio Therapeutics, Inc.  Lynn E. Connolly, MD, PhD, Adagio Therapeutics, Inc. (Employee) Paul G. Ambrose, PharmD, Adagio Therapeutics, Inc. (Employee)