The purpose of this study was to investigate the Staphylococcus aureus , methicillin-susceptible Staphylococcus epidermidis , other methicillin-susceptible coagulase-negative staphylococci , and vancomycin-susceptible Enterococcus faecalis (31). The isolates were collected primarily from pneumonia in hospitalized patients , urinary tract infections , and bloodstream infections . Organisms were tested using reference broth microdilution methods in a central laboratory. The susceptibility of 580 Gram-positive organisms were tested, including: methicillin-susceptible 90 value of 0.03 mg/L against MSSA and 0.015 mg/L against MSSE isolates. Ertapenem MIC90 values were 8-fold higher against MSSA  and 32-fold higher against MSSE . Tebipenem displayed an MIC90 value of 0.03 mg/L against MSCoNS species other than S. epidermidis. This result was 8- and 32-fold lower than those of meropenem  and ertapenem , respectively. Tebipenem inhibited all E. faecalis isolates at ≤1 mg/L , with an MIC90 value at least 2-fold lower than meropenem  and 16-fold lower than ertapenem .Tebipenem had an MICin vitro activity was greater than meropenem and ertapenem when tested against E. faecalis. These data indicate that tebipenem may be an option for treating urinary tract infections caused by these organisms or as an empiric option to provide broader coverage against Gram-negative and -positive organisms.Tebipenem displayed potent activity against methicillin susceptible staphylococci, including MSSA, MSSE, and other MSCoNS. Tebipenem S J Ryan Arends, PhD, AbbVie (formerly Allergan) (Research Grant or Support)GlaxoSmithKline, LLC (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Abby L. Klauer, n/a, Cidara Therapeutics, Inc. (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Nicole Cotroneo, Spero Therapeutics  Ian A. Critchley, Ph.D., Spero Therapeutics  Rodrigo E. Mendes, PhD, AbbVie (Research Grant or Support)AbbVie (formerly Allergan) (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)ContraFect Corporation (Research Grant or Support)GlaxoSmithKline, LLC (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support)


Influenza D virus (IDV), with bovines as a primary host, circulates widely in cattle populations across North America and Eurasia. Here we report the identification of a novel IDV group with broad antigenicity in U.S. bovine herds, which is genetically different from previously known lineages of IDV. Orthomyxoviridae. Since its first identification in the United States, IDV and its antibody prevalence have been reported in North America, Europe, Asia, and Africa [Influenza D virus (IDV) is a newly identified member of the family d Africa . IDV utid Africa . IDV infd Africa  and is ad Africa  with a md Africa ,9.Based on the nucleotide sequences of the Hemagglutinin-Esterase Fusion (HEF) protein that is the primary target of virus-neutralizing antibodies, IDV can be classified into four distinctive lineages, D/OK, D/660, D/Yama2016, and D/Yama2019 ,11. HereIn this study, total 100 nasal swabs were collected by the herd veterinarian from calves exhibiting respiratory disease at commercial operations in 2018–2019. Of them, 10 samples tested positive for IDV in RT–PCR assay  were inoculated individually onto human rectal tumour HRT-18G cells, then subsequently passaged to swine testicle ST cells. When a cytopathic effect (CPE) was observed in ST cells, supernatants were collected and tested for the presence of hemagglutination (HA) using 0.5% of turkey red blood cells. Following successful virus isolation and initial genome sequencing, six of them were further employed for full-genome sequencing by MiSeq. Sequences were submitted to GenBank: D/bovine/Michigan/0377/2019 (D/MI/0377/2019) (MW632171-MW632177), D/bovine/California/1490/2018 (D/CA/1490/2018) (MW632178-MW632184), D/bovine/Oklahoma/1544/2018 (D/OK/1544/2018) (MW632185-MW632191), D/bovine/California/0363/2019 (D/CA/19) (MW020305-MW020311), D/bovine/California/1908/2019 (D/CA/1908/2019) (MW020319-MW020325) and D/bovine/California/0894/2019 (D/CA/0894/2019) (MW020312-MW020318).To examine the evolutionary relationship of these new isolates to previously characterized IDVs, we performed phylogenetic analysis of the HEF segment sequences in MEGA-X, together with a total of 61genome sequences deposited in GenBank from 2013 to 2020. Three of six new isolates clustered together, forming a lineage that is genetically distinguishable from all the known IDV strains  assay using rabbit reference antisera raised against semi-purified virus particle preparations from three IDV lineage-representative strains, D/OK/11, D/660/13, and D/CA/19. As summarized in Antigenic variation between D/CA2019 and other two lineages was also further demonstrated in the HI assay using post-infection guinea antisera raised against three cell culture-propagated lineage-representative viruses as described above (In summary, we identified a novel phylogenetic group of IDV strains in diseased bovines in California. This new group, D/CA2019, represents the fifth genetic lineage of IDV (Click here for additional data file.Click here for additional data file.


SARS-CoV-2 vaccine efficacy (VE) against asymptomatic infection and impact on viral shedding during breakthrough infections have critical implications for pandemic control. AZD1222  demonstrated VE of 74.0%  against the primary endpoint of symptomatic RT-PCR-confirmed COVID-19 and safety in a Phase 3, 2:1 randomized, placebo-controlled study in the US, Chile and Peru . Here we present exploratory analyses on asymptomatic infections determined by nucleocapsid (N) seroconversion and time to viral clearance in participants with symptomatic infections determined by N seroconversion .N seroconversion was assessed at all scheduled and illness visits in the fully vaccinated analysis set (Table). In this analysis, symptomatic infections are defined as N seroconversion ≥ 15 days post second dose in participants who attended an illness visit with ≥ 1 qualifying COVID-19 symptom and had ≥ 1 positive RT-PCR result for SARS-CoV-2. Asymptomatic infections are defined as N seroconversion ≥ 15 days post second dose in participants who did not meet the criteria for symptomatic infections. In participants with symptomatic infections, viral shedding in saliva was assessed for 28 days and cumulative incidence of viral clearance was determined.Table. AZD1222 VE against symptomatic and potentially asymptomatic SARS-CoV-2 infections as determined by N seroconversionOverall, 358 participants had SARS-CoV-2 infections as determined by N seroconversion (Table). Incidences per 1000 person-years of symptomatic infections were 25.62 for AZD1222 vs 103.42 for placebo  and of asymptomatic infections were 51.24 vs 111.95  (Table). Sensitivity analyses for N seroconversion using the primary endpoint and CDC criteria for defining symptomatic/asymptomatic status were supportive. Median time to viral clearance in saliva in participants with symptomatic infections was 11 days  vs 16 days  .Figure. Viral clearance in saliva samples in participants with symptomatic infections as determined by N seroconversionAZD1222 resulted in lower yet meaningful VE against asymptomatic compared to symptomatic infections, as determined by N seroconversion, and shortened viral shedding in symptomatic SARS-CoV-2 breakthrough infections vs placebo, highlighting its potential contribution to reducing viral transmission.Funding StatementAnn R. Falsey, MD, AstraZeneca  Involved: Self): Grant/Research Support; BioFire Diagnostics  Involved: Self): Grant/Research Support; Janssen  Involved: Self): Grant/Research Support; Merck, Sharpe and Dohme  Involved: Self): Grant/Research Support; Novavax  Involved: Self): Other Financial or Material Support, Paid DSMB member; Pfizer  Involved: Self): Grant/Research Support Merlin L. Robb, M.D., Henry M. Jackson Foundation  Hong-Van Tieu, M.D, M.S., National Institutes of Health (Grant/Research Support) Lawrence Corey, MD, NIH (Grant/Research Support) Kathleen Neuzil, MD, MPH, NIH Pfizer (Grant/Research Support) Jill Maaske, M.D., AstraZeneca  Brett Jepson, n/a, AstraZeneca Cytel, Inc. (Employee) Stephanie Sproule, n/a, AstraZeneca  Elizabeth Kelly, n/a, AstraZeneca


Cell Discovery (2021) 7:62Correction to: 10.1038/s41421-021-00286-x Published online 10 August 20211 one of the author’s name was incorrect. In this correction article, the correct and incorrect name are indicated.In the original publication of this articlePrevious incorrect name:Hongqin YingCorrected name:Hongqing YinPrevious incorrect name:These authors contributed equally: Chuying Huang, Hongqin Ying, Xibiao Yang, Li Wang.Corrected name:These authors contributed equally: Chuying Huang, Hongqing Yin, Xibiao Yang, Li Wang.


Introduction: Cerebral palsy (CP) and spina bifida (SB) are congenital disabilities. Due to life-long disability, adults with CP/SB are with greater needs for preventative care. Little is known about racial/ethnic disparities in use of preventative services in this population. Our objective was to examine racial/ethnic disparities in use of preventative care. Methods: Using 2007-2017 private claims data, we identified White, Black, and Hispanic adults (18+) with CP/SB . We quantified the National Institute of Medicine (NAM) definition of disparity by matching health related variables  between Whites and each minority subpopulation. Generalized estimating equations were used and all models were adjusted for age, sex, comorbidities, income, education, and U.S. Census divisions. Outcomes of interest were: (1) any office visit; (2) any physical therapy/ occupational therapy (PT/OT); (3) annual wellness visit; (4) bone density screening; (5) cholesterol screening; (6) diabetes screening. Results: Rate of recommended services for all adults with CP/SB were low and no significant results were found for most preventative services across race/ethnicity. Compared with Whites, Hispanics had lower odds of annual wellness visit  but higher odds of diabetes screening . Blacks had lower odds of bone density screening , and annual wellness visit . Conclusions: There were no substantial racial/ethnic disparities in use of preventive services among privately insured adults with CP/SB who had a higher-than-average income and education level.


Originally published figures:Corrected figures Figs. , 3, 4:FiFollowing the publication of the original article , we wereThe original article has been corrected.


Apodidae). Swifts are common resident and migratory birds throughout Saudi Arabia. Two chewing lice genera are known for parasitising swifts throughout the world: Dennyus Neumann, 1906 and Eureum Nitzsch, 1818, none of which have been recorded from the Kingdom before.Very little is known about the chewing lice fauna of Saudi Arabia especially from swifts (D. (Dennyus) hirundinis  and Dennyus sp. (Phthiraptera: Amblycera: Menoponidae) infesting the common swift Apusapus  and African palm swift Cypsiurusparvus , respectively. The described chewing lice species are considered as new country records. They will be added to the Saudi Arabia parasitic fauna. Taxonomical and ecological remarks were provided for the identified chewing lice through this work, along with notes on swift/chewing lice interaction.Two species of resident wild swifts were examined for chewing lice for the first time in Saudi Arabia. Two rare lice species were identified:  Apodiformes: Apodidae) are one of the fastest bird groups in the world and includes around 113 species  and three common swifts were examined at Aja Mountain, Ha’il ; however, only the African palm swift and one common swift were infested with lice. A standard mist net: (mesh: 1.8 cm × 0.12 mm and size: 2 m × 15 m) was used for capturing the examined birds. The live caught birds were first inspected visually, then a fumigation chamber was used for chewing lice collection using chloroform as a fumigant for 3 min .Known hosts: Cypsiurusparvus , African palm swift.D. (Dennyus) cypsiurus and, in this case, it will be the first record from Saudi Arabia. Not much is known about that species. The collected samples were found on the body feathers near the anus of the host.From my examination and description, as well as the host/parasite association, this species could be Linnaeus, 1761B23B1ED6-A010-50A4-A509-5CF9C0A909AEDennyus (Dennyus) hirundinisDennyus (Dennyus) hirundinisPediculushirundinis Linnaeus, 1761:479Nirmustruncatus Olfers, 1816:91Nitzschiaburmeisteri Denny, 1842:202Nitzschiatibialis Piaget, 1880:576Dennyusafricanus Büttiker, 1954:159Dennyusclayae Nakagawa, 1959a:164Dennyusmaritimus Buttiker, 1954:160Nitzschiaminor Kellogg & Pame, 1914:242Dennyusminutus Buttiker, 1954:160Dennyustruncatiformis Mokhehle, 1951:341Type status:Other material. Occurrence: recordedBy: Kholoud A. Al-Shammery; individualCount: 1; sex: 1 female; lifeStage: 1 adult; Taxon: kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Phthiraptera; family: Menoponidae; genus: Dennyus; subgenus: Dennyus; specificEpithet: hirundinis; Location: country: Saudi Arabia; stateProvince: Aja Mountain, Ha’il; Event: eventDate: February 2018Head trilobed triangular in shape, maxillary palp protruding out of the head, antenna very short, temple rectangular with characteristic highly chitinized out line, gula well developed with lateral row of four black spin-like seta and characteristic chitinization surrounding; thorax clearly divided, prothorax small quadrat shape, meso and meta thorax highly chitinized on lateral margin with acute ends; fore legs with large coxa and enlarged rounded femora, mid and hind legs slightly equal in length, ventral side of hind femora covered with elongated brush of short seta; abdomen elongated oval in shape with highly chitinized lateral margin with acute ends and two small thorn-like seta, the ventral brush appears in segment IV and V; the body of this species is highly pigmented Fig. .Measurements: Female HL: 0.47; HW: 0.64; HI: 0.73; TL: 0.57; AL: 1.94; TOL: 2.98 ± 0.2.Dennyus (Dennyus) hirundinis distribution: Palaearctic: Asia ; Europe ; Afrotropical: Africa .Local host: only one sample was collected from common swift, Apusapus.Known hosts: Apusapus , common swift (type host); Aerodramusunicolor , Indian swiftlet; Apusalexandri Hartert, 1901, Alexander´s swift; Apuspallidus , Pallid swift; Apusbarbatus , African swift; Apusbradfieldi , Bradfield´s swift; Apuspacificus , fork-tailed swift; Apusacuticauda , dark-rumped swift; Apusaffinis , little swift; Apushorus , Horus swift; Apuscaffer , white-rumped swift.D. (Dennyus) hirundinis from Saudi Arabia. This species is found throughout the body of the host; the collected sample was found feeding on the eye fluid of the host during the night.This report constitutes a new geographical record of Recently, several publications have focused on the taxonomic status of chewing lice infesting domestic, resident, migratory and exotic birds of Saudi Arabia . AlthougDennyus species from Saudi Arabia and the region. Therefore, the record of D. (Dennyus) hirundinis and unidentified Dennyus nymph are considered an addition to Saudi Arabia's parasitic fauna. Although Dennyus spp. are generally characterised by high degrees of host specificity (D. (Dennyus) cypsiurus Thompson, 1948 which is already known to infest African palm swift. There are likely more species of Dennyus waiting to be recorded from Saudi Arabia as additional louse samples from swifts become available  are considered migratory birds (The two species of swifts that have been examined in this work (the African palm swift, ry birds . This fa


Mean SBP at Baseline was 137.87 +18.8 mmHg (range 98-191). Menus were adapted to provide 20% daily DASH requirements at breakfast, 50% at lunch. Participants attended classes in nutrition and medication management and were provided with and trained to use an automated home BP monitor. Meal satisfaction scores dipped briefly then met or exceed pre-DASH levels. Home BP data was downloaded every 2-4 weeks with social/behavioral support. The COVID-19 closures interfered with BP outcome data collection and meal service ceased. Primary outcome: x2 change in SBP at Month 1 = -4.41 mmHg + 18 (n=61) (p=0.713). Significant associations will be reported. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our community-academic research partnership implemented the DASH diet in congregate-meal settings to address uncontrolled hypertension in seniors. COVID-19 interrupted the study, but encouraging trends were observed that may inform refinement to this community-based health intervention for seniors.ABSTRACT IMPACT: Our implementation model translates two evidence-based nutritional and behavioral interventions to lower blood pressure, into a community-based intervention program for seniors receiving congregate meals. OBJECTIVES/GOALS: The Rockefeller University, Clinical Directors Network, and Carter Burden Network received an Administration for Community Living Nutrition Innovation grant to test whether implementation of DASH-concordant meals and health education programs together lower blood pressure among seniors aging in place. METHODS/STUDY POPULATION: n=200, >60 yr, >4 meals/week at CBN; engagement of seniors/stakeholders in planning and conduct; Advisory Committee to facilitate dissemination; menus aligned with Dietary Approaches to Stop Hypertension (DASH) and NYC Department for the Aging nutritional guidelines; interactive sessions for education in nutrition, BP management, medication adherence. Training in use of automated daily home BP monitors (Omron 20). Validated surveys at M0, M1, M3, M6. Taste preference and cost assessed through Meal Satisfaction  and Plate Waste measures. Primary Outcome: Change in Systolic BP (SBP) at Month 1; change in %BP controlled. Secondary: validated cognitive, behavioral, nutritional measures , economics; staff/client satisfaction, trends and significant associations. RESULTS/ANTICIPATED RESULTS: n=94, x


Prevention, with widespread lifestyle risk reduction at the community-level, is currently considered an effective method to decrease Alzheimer’s disease (AD). As part of the Virginia Commonwealth University iCubed Health and Wellness in Aging Core, diverse older adults (60+) living in Richmond, VA, with incomes below $12,000/year and managing either diabetes/cardiovascular symptoms, were offered weekly lifestyle telephone-health coaching for 12-weeks, providing education, motivations, self-efficacy, and referral services for AD lifestyle risk. The study sample  was 88% African American/Black (n=35), 100% Non-Hispanic, and 45% males (n=18)). Thirty-nine (95%) of subjects successfully participated in coaching sessions; on average 91.9% (11) sessions/subject were completed. Participants provided positive anecdotal feedback and the need for continued health coaching during COVID. N=30 (75%) of the original sample consented for continued health coaching during the Covid pandemic, 63% female, 88% African American/Black, 60-77 age range (mean age 69 years), and 47% reporting memory problems. Baseline Covid interviews indicated poorer health status associated with reporting memory problems for poor physical health days ; poor mental health days ; total mental/physical health poor days ; sad days ; worried days ; tired days ; feelings of emptiness ; feelings of rejection ; feelings of failure ; little interest/pleasure ; and feeling down . In conclusion, this preliminary work creates the impetus for future large-scale AD prevention investigations to improve the lives of AD-risk, low-income, diverse older adults reporting memory problems. This research indicates the subjective reporting of memory problems requires health intervention.


Klebsiellae spp. arises through mutational and acquired mechanisms and is considered an “urgent threat” by the CDC. VNRX-5236 is a bicyclic boronate β-lactamase inhibitor (BLI) that combines oral bioavailability  and activity against all three Ambler classes of serine β-lactamases. VNRX-7145 is currently in development with the oral cephalosporin, ceftibuten (CTB) .Carbapenem resistance in Figure 1. Structures of VNRX-7145, VNRX-5236, and ceftibuten. The β-lactamase inhibitors are in red and the β-lactam antibiotic is in black.Klebsiellae from the Consortium on Resistance against Carbapenems in Klebsiella (CRACKLE) was assessed in this study. Among these, 193 expressed class A KPC enzymes, one expressed a class B NDM enzyme, and six expressed a class D OXA-48 or variant enzyme. Minimum inhibitory concentrations (MIC) were determined by broth microdilution (CLSI M07 Ed. 11) using the ThermoFisher Sensititre system with custom assay panels. MICs were interpreted using CLSI M100 Ed. 30, except the EUCAST breakpoint for CTB (S≤1 µg/mL) was used for CTB and was applied for comparative purposes to CTB/VNRX-5236 MICs where VNRX-5236 was fixed at 4 µg/mL. American Type Culture Collection strains were used for quality control.The activity of CTB/VNRX-5236 against 200 carbapenem-resistant 50s were in the susceptible range for CZA, MVB, and CTB/VNRX-5236; and resistant for CTB, ceftazidime (CAZ) and meropenem (MEM). MIC90s were in the susceptible range for CZA, MVB, and CTB/VNRX-5236 and resistant range for CAZ, MEM, and CTB (Table 1). One of four CZA-resistant and three of nine MVB non-susceptible strains were provisionally susceptible to CTB/VNRX-5236.92.5% of stains studied in this CRACKLE collection were provisionally susceptible to CTB/VNRX-5236. In comparison, strains were 95.5% and 98% susceptible to meropenem-vaborbactam (MVB) and ceftazidime-avibactam (CZA), respectively. MICMIC50 and MIC90 values (µg/mL) and percent susceptibility for Klebsiella pneumoniae strains (n=200). AMK, amikacin; CST, colistin; CAZ, ceftazidime; CZA, ceftazidime-avibactam; FEP, cefepime; MEM, meropenem; MVB, meropenem-vaborbactam; CTB, ceftibuten; TGC, tigecycline. * The breakpoint for CST is intermediate, as no susceptible breakpoint is available. ** The CTB breakpoint is valid only for urinary tract isolates. *** The breakpoint for CTB was provisionally used for CTB/VNRX-5236, where VNRX-5236 was fixed at 4 µg/mL.Klebsiella isolates tested, reaching a total of 92.5% susceptibility. The prodrug (VNRX-7145) allows for oral administration, making it a potential option for step-down therapy. Importantly, VNRX-5236 has a broader spectrum of activity than existing oral BLIs, opening new treatment options for resistant infections as a key addition to the existing antibiotic arsenal.The addition of VNRX-5236 enhanced the activity of CTB against the 200 Robin Patel, MD, 1928 Diagnostics (Consultant)BioFire Diagnostics (Grant/Research Support)ContraFect Corporation (Grant/Research Support)Curetis (Consultant)Hylomorph AG (Grant/Research Support)IDSA Infectious Diseases Board Review Course Mammoth Biosciences (Consultant)NBME Netflix (Consultant)Next Gen Diagnostics (Consultant)PathoQuest (Consultant)PhAST (Consultant)Qvella (Consultant)Samsung Selux Diagnostics (Consultant)Shionogi & Co., Ltd. (Grant/Research Support)Specific Technologies (Consultant)TenNor Therapeutics Limited (Grant/Research Support)Torus Biosystems (Consultant)Up-to-Date  Robin Patel, MD, BioFire  Involved: Self): Grant/Research Support; Contrafect  Involved: Self): Grant/Research Support; IDSA  Involved: Self): Editor’s stipend; NBME, Up-to-Date and the Infectious Diseases Board Review Course  Involved: Self): Honoraria; Netflix  Involved: Self): Consultant; TenNor Therapeutics Limited  Involved: Self): Grant/Research Support; to Curetis, Specific Technologies, Next Gen Diagnostics, PathoQuest, Selux Diagnostics, 1928 Diagnostics, PhAST, Torus Biosystems, Mammoth Biosciences and Qvella  Involved: Self): Consultant David van Duin, MD, PhD, Entasis (Advisor or Review Panel member)genentech (Advisor or Review Panel member)Karius (Advisor or Review Panel member)Merck Pfizer Qpex (Advisor or Review Panel member)Shionogi Utility (Advisor or Review Panel member) Vance G. Fowler, Jr., MD, MHS, Achaogen (Consultant)Advanced Liquid Logics (Grant/Research Support)Affinergy Affinium (Consultant)Akagera (Consultant)Allergan (Grant/Research Support)Amphliphi Biosciences (Consultant)Aridis (Consultant)Armata (Consultant)Basilea Bayer (Consultant)C3J (Consultant)Cerexa Contrafect Debiopharm Destiny (Consultant)Durata Genentech Green Cross Integrated Biotherapeutics (Consultant)Janssen Karius (Grant/Research Support)Locus (Grant/Research Support)Medical Biosurfaces (Grant/Research Support)Medicines Co. (Consultant)MedImmune Merck (Grant/Research Support)NIH (Grant/Research Support)Novadigm (Consultant)Novartis Pfizer (Grant/Research Support)Regeneron sepsis diagnostics Tetraphase (Consultant)Theravance Trius (Consultant)UpToDate Valanbio xBiotech (Consultant) Daniel D. Rhoads, MD, Becton, Dickinson and Company (Grant/Research Support) Michael Jacobs, MBBS, Venatorx Pharmaceuticals, Inc. (Grant/Research Support) Focco van den Akker, PhD, Venatorx Pharmaceuticals, Inc. (Grant/Research Support) David A. Six, PhD, Venatorx Pharmaceuticals, Inc. (Employee) Greg Moeck, PhD, Venatorx Pharmaceuticals, Inc. (Employee) Krisztina M. Papp-Wallace, Ph.D., Merck & Co., Inc. (Grant/Research Support)Spero Therapeutics, Inc. (Grant/Research Support)Venatorx Pharmaceuticals, Inc. (Grant/Research Support)Wockhardt Ltd.  Robert A. Bonomo, MD, entasis (Research Grant or Support)Merck (Grant/Research Support)NIH (Grant/Research Support)VA Merit Award (Grant/Research Support)VenatoRx (Grant/Research Support)


Of 159 family caregivers participants, the mean age was 57.9, 85.4% were female, 51.9% were African-American, and 65.2% were the patient’s spouse/partner. DISCUSSION/SIGNIFICANCE OF IMPACT: Limited data describes HF symptom pattern trajectories.How co-occurring symptoms affect quality of life or are affected by personal or situational factors are not well-understood. This study will help to identify factors and symptom phenotypes that may serve as targets for future interventions.OBJECTIVES/GOALS: This work-in-progress aims to: 1) identify and differentiate symptom pattern trajectories in a sample of older adult heart failure (HF) patients over 24 weeks, and 2) examine associations between sociodemographic/clinical/physiological characteristics, dyadic health, and symptom trajectories. METHODS/STUDY POPULATION: ENABLE CHF-PC, a palliative care RCT (NCT02505425), was conducted at a Southeastern US medical center. Between 2016-2018, 415 older adult HF patients and 159 family caregivers were randomized to receive a psychoeducational intervention or usual care. Baseline sociodemographic information  were collected. Outcome variables of interest include symptoms (Kansas City Cardiomyopathy Questionnaire (KCCQ), Functional Assessment of Chronic Illness Therapy-Palliative 14, Hospital Anxiety and Depression Scale (HADS)) and dyadic health . We have calculated baseline descriptive statistics. Future work includes latent growth mixture modeling to identify distinct symptom trajectories and univariate associations with patient level factors. RESULTS/ANTICIPATED RESULTS: Of 415 patient participants, mean age was 64, 53% were male; 55% were African American; 26% were rural dwellers; 46% had


Pseudomonas aeruginosa (PSA) Carbapenem (Carb) interpretive breakpoint minimum inhibitory concentrations (MICs) in 2012. It often takes several years for commercial test manufacturers and microbiology labs to incorporate revised breakpoints. We compare facility-reported rates of Carb-NS PSA to the 2012 CLSI MIC breakpoints, using a large nationwide database for isolates tested in 2016-2020 at United States (US) facilities.CLSI lowered Table. Imipenem (IPM)/meropenem (MEM)/doripenem (DOR) interpretation  results for PSA.All adults with a positive non-contaminant PSA culture  in ambulatory and inpatient settings from 298 US hospitals from Q1 2016-Q4 2020 were evaluated . Facility-reported Carb-non susceptible (NS) was defined as lab information system feed designations of susceptible (S), intermediate (I) or resistant (R) to imipenem (IPM), meropenem (MEM) and/or doripenem (DOR) per commercial panels. Where available, MICs were interpreted using CLSI 2012 Carb breakpoints (µg/ml) of ≤2 (S), 4 (I), ≥8 (R) for IPM/MEM/DOR. For evaluable PSA isolates we compared susceptibility results as reported by the facility to those using CLSI MIC breakpoints.Overall, 86.9%  of non-duplicate PSA isolates with facility-reported IPM/MEM/DOR susceptibility interpretations also had interpretable MIC results. S rates were 84.9% and 83.3% as reported by facilities and determined by CLSI criteria, respectively (Table). Facilities under-reported Carb-NS by 9.8%, using CLSI criteria as the standard .Systematic application of CLSI breakpoints in 2016-20 would have had minimal impact on PSA S rates in the US. However, facility reporting failed to identify ~10% of Carb-NS isolates. The clinical implications of this observation are unknown. Facilities should know their local epidemiology, decide if under-reporting might be an issue, and assess if there is any impact on their patients. Vikas Gupta, PharmD, BCPS, Becton, Dickinson and Company  Kalvin Yu, MD, BD (Employee) Jason M Pogue, PharmD, BCPS, BCIDP, Merck (Consultant)QPex (Consultant)Shionogi (Consultant)Utility Therapeutics (Consultant)VenatoRX (Consultant) Janet Weeks, PhD, Becton, Dickinson and Company (Employee) Cornelius J. Clancy, MD, Merck (Grant/Research Support)


The COVID-19 pandemic had a considerable impact on US healthcare systems, straining hospital resources, staff, and operations. Our objective was to evaluate the impact of COVID-19 pandemic on incidence and trends of healthcare-associated infections (HAIs) in a network of hospitals.This was a retrospective review of central-line-associated bloodstream infections (CLABSIs), catheter-associated urinary tract infections (CAUTIs), C. difficile infections (CDI), and ventilator-associated events (VAE) in 51 hospitals from 2018 to 2021. Descriptive statistics were reported as mean hospital-level monthly incidence rates (IR) and compared using Poisson regression GEE models with period as the only covariate. Segmented regression (SR) analysis was performed to estimate changes in monthly IR of CAUTIs, CLABSIs and CDI in the baseline period (01/2018 – 02/2020) and the Pandemic period (03/2020 – 03/2021). SR model was not appropriate for VAE based on the plot. All models were constructed using SAS v.9.4 .Compared to the baseline period, CLABSIs increased significantly by 50% from 0.6 to 0.9/ 1000 catheter days (P< 0. 001). In contrast, no significant changes were identified for CAUTI (P=0.87). Similar trends were seen in SR models for CLABSI and CAUTI . While overall CDIs decreased significantly from 3.5 to 2.5/10,000 patient days in the pandemic period (P< 0.001), SR model showed increasing pandemic trend change . VAEs increased > 700% from 6.9 to 59.7/1000 ventilator days (P=0.15), but displayed considerable variation during the pandemic period . Compared to baseline period, there was a significant increase in central line days , ventilator days , but no change in urinary catheter days  during the pandemic period.Figure 1: Segmented Regression model showing baseline and pandemic period trends of CLABSIFigure 2: Segmented Regression model showing baseline and pandemic period trends of CAUTIFigure 3: Segmented Regression model showing baseline and pandemic period trends of C. difficile (HO-CDI) infectionsThe COVID-19 pandemic was associated with substantial increases in CLABSIs and VAEs, no change in CAUTIs, and an increasing trend in CDI incidence. These variations in trends of different HAIs are likely due, in part, to unique characteristics of the underlying infection, resource shortages, staffing concerns, increased device use, changes in testing practices, and the limitations of surveillance definitions. Figure 4: Trend of Ventilator-Associated Events (VAE) in the baseline and pandemic period (Segmented Regression model not appropriate)Sonali D. Advani, MBBS, MPH, Nothing to disclose David J. Weber, MD, MPH, Merck  Involved: Self): Consultant; PDI  Involved: Self): Consultant; Pfizer  Involved: Self): Consultant; Sanofi  Involved: Self): Consultant; UVinnovators  Involved: Self): Consultant


Although hospice care benefits seriously ill patients and their families, growing evidence suggests anxiety, depression, and altered quality of life are prevalent among family hospice caregivers. It is unknown if Black and white family hospice caregivers experience differences in mental health, quality of life, caregiver burden, or quality of hospice communication. In this secondary analysis of baseline data collected from 717 family hospice caregivers in two randomized clinical trials, we compared anxiety (GAD-7), depression (PHQ-9), quality of life (CQLI-R), caregiver burden (Zarit), and caregiver-reported quality of hospice team communication (CCCQ) between Black and white caregivers. Black and white caregivers differed demographically across multiple variables. In bivariate analysis, we found no differences in depression (P=0.3536), anxiety (P=0.0733), caregiver burden (P=0.6680), and perceptions of caregiver-centered hospice communication (P=0.4549). White caregivers reported lower quality of life than Blacks (P=0.0386), specifically in emotional (P=0.0321) and social (P=0.0002) domains. Financial and physical quality of life did not differ. In multivariate regression analyses controlling for caregiver and patient factors, we found no racial differences in depression (P= 0.5071), anxiety (P = 0.7288), quality of life (P=0.0584), caregiver burden (P=0.9465), or hospice communication (P=0.8779). Variables explained 7.7% to 20% of variability in outcomes, suggesting research is needed to understand which other factors contribute to hospice caregiver coping and communication experiences. Results suggest Black and white informal hospice caregivers experience similar levels of anxiety, depression, burden, and perceptions of hospice team communication quality. Interventions to support hospice caregivers across racial groups are needed.


The correct citation is: Guglielmini C, Baron Toaldo M, Chiesa A, Contiero B, Berlanda M, Poser H (2020) Effect of temperature variation on hospital admissions and outcomes in dogs with myxomatous mitral valve disease and new onset pulmonary edema. PLoS ONE 15(1): e0227807.


Procalcitonin (PCT) and serum lactate (L) are measures of bacterial infection and tissue hypoxia, respectively, but also used to discern sepsis from infection negative systemic inflammation (INSI). However, improved tools are needed to enhance this differentiation. A previously validated gene signature assay (SeptiCyte RAPID) and its correlated score (SeptiScore (SS)) has been reported to effectively differentiate sepsis from INSI.To compare early L, PCT and SS results  in differentiating sepsis from INSI in adult intensive care unit (ICU) patients (Pt).≥ 2 signs of systemic inflammatory response syndrome; (ii) Therapeutic antibiotic administration; (iii) external 3-physician clinical review classifying each Pt as sepsis or INSI with ≥ 2 reviewer agreement; (iv) L, PCT & SS values within 24 hrs of ICU admission; (v) Statistical Analysis; (iv) Area under the receiving operator curve (AUROC), 95% confidence intervals (CI) via generalized linear models for: (i) Each parameter alone ; (ii) Combinations ; (iii) AUROC discriminated Sepsis from INSI model: (a) < 0.7 Sub-Optimal; (b) 0.7-0.8 Good; (c) > 0.8 Excellent. Comparisons conducted via paired t-test.Data from a previously reported, prospective study (8 sites). Inclusion criteria: (i) ICU admission with 222 pts, sepsis=113; INSI=109 Similar demographics between groups (NS). Mean age (SD) = 57.9 (17.1) yrs; 58.1% male). Overall mechanically ventilated 60.8% and hospital mortality 17.1%. AUCROC (95% CI) in Table and Figure; AUCROC of L, PCT or SS alone or in combinationL, PCT, SS Comparison of Sepsis vs INSIL is sub-optimal in discriminating sepsis from INSI. PCT with or without L was acceptable but not as robust as SS. SS alone or in any combination provided superior and significant discrimination between sepsis and INSI. Incorporation of SS into the clinical assessment process for suspected sepsis pts should be evaluated to determine the impact on early detection and Pt management.Erkan Hassan, Pharm.D., FCCM, Immunexpress (Consultant) Roy Davis, M.D>, Immunexpress (Consultant)Immunexpress  Dayle Sampson, Ph.D., Immunexpress


Maximum intensity projection images (MIP) of PET (D) demonstrate its superior resolution compared with SPECT (H). Furthermore, two separate lymph vessels can be identified on PET/CT lymphoscintigraphy (D), which are not visualized on SPECT/CT (H). Also note that the activity in a SLN in level Ib on the right site is better visible on axial (A), sagittal (B), and coronal (C) PET/CT lymphoscintigraphic images compared with corresponding SPECT/CT reconstructions . Surgically, five SLNs were localized and harvested , using a conventional gammaprobe. Histopathological assessment showed metastasis in one SLN located in level IIa. Complementary neck dissection of level I-IV showed no additional lymphatic metastasis  procedure is routinely performed for nodal staging in several malignancies, including early-stage oral cancer. In oral cancer, the SLN imaging procedure usually consists of peritumoral injections with a [SPECT/CT , 2. A frSPECT/CT , 4. PET/SPECT/CT . Here, w


Polycystic ovary syndrome (PCOS) affects up to 18% of reproductive-age females. The prevalence of obesity in PCOS patients reaches up to 80%, which is 2-fold higher than the general population.The present study aimed to compare the effectiveness of 55 pharmacological interventions across 17 different outcomes in overweight/obese PCOS patients with hyperandrogenism manifestations for both short- and long-term follow-ups. A comprehensive literature search was performed on PubMed, Scopus, Embase, Science Direct, Web of Science, and Cochrane CENTRAL for randomized controlled trials comparing any conventional pharmacological intervention as a monotherapy or a combination in overweight/obese patients with polycystic ovary syndrome and hyperandrogenism manifestations. Extracted data included three main parameters; I. Anthropometric parameters , II. Hormonal parameters , and III. Metabolic parameters . Critical appraisal and risk of bias assessments were performed using the modified Jadad scale, and the overall quality of this network meta-analysis was evaluated according to the CINeMA framework. We performed both a pairwise meta-analysis and a network meta-analysis to evaluate the effect sizes with 95% CI, and we calculated the surface under the cumulative ranking curve (SUCRA) for each intervention.th 2021 retrieved 23,305 unique citations from searching six electronic databases. Eventually, 101 RCTs of 108 reports with a total of 8,765 patients were included in our systematic review and multi-treatments meta-analysis. 55 different interventions were included: 22 monotherapies, and 33 combinations. The two-dimensional cluster ranking of the average SUCRA values for metabolic and hormonal parameters with significant estimates revealed flutamide  as the highest and rosiglitazone  as the lowest, in terms of the overall efficacy in reducing weight and hyperandrogenism. However, cyproterone-acetate+ethinylestradiol exhibited a higher ranking in improving hormonal parameters (71.1%), but even a lower-ranking regarding metabolic parameters (34.5%).Our final search on May 15Current evidence demonstrated the superiority of flutamide in improving both metabolic and hormonal parameters, and the higher efficacy of cyproterone-acetate+ethinylestradiol only in improving hormonal parameters. Nearly all interventions were comparable in female hormones, FGS, HDL, glucose, and insulin levels improvements. Polycystic ovary syndrome (PCOS) is a complex endocrinal disorder affecting up to 18% of young females . While pThe pathophysiology of PCOS is still unclear, but evidence suggests a mixture of environmental factors and genetic susceptibility . One of Pharmacological interventions mainly involve: oral contraceptives, antiandrogens, oral hypoglycemics, insulin sensitizers, ovulation induction agents, and conventional obesity treatments . The recStill, long-term use of these agents increases the risk of venous thrombosis and disrupts the metabolic parameters . HypotheGiven that the symptoms upon diagnosis are usually confined to irregular menstruation or infertility, physicians may disregard the possible long-term metabolic and anthropometric disturbances . SubsequAccordingly, we performed this network meta-analysis to compare the effectiveness of 55 pharmacological interventions across 17 different clinical and biochemical outcomes in overweight PCOS patients for both short- and long-term follow-ups.We followed the PRISMA statement guidelines —PRISMA  during tth 2021 and May 15th 2021 covering all selected databases  OR (polycystic ovary syndrome[Title/Abstract])) OR (PCOS[Title/Abstract])) OR ) OR ) OR (anovulation[MeSH Terms])) OR (anovulation[Title/Abstract])) OR (amenorrhea[MeSH Terms])) OR (amenorrhea[Title/Abstract])) OR (ovarian dysfunction[Title/Abstract])) OR (ovarian failure[Title/Abstract])) OR (Oligo-amenorrhea[Title/Abstract]))) AND (metformin[Title/Abstract])) OR (metformin[MeSH Terms])) OR (liraglutide[Title/Abstract])) OR (orlistat[Title/Abstract])) OR (orlistat[MeSH Terms])) OR (inositol[MeSH Terms])) OR (inositol[Title/Abstract])) OR ) OR ) OR (Ethinyl estradiol[MeSH Terms])) OR (Ethinyl estradiol[Title/Abstract])) OR (ethinylestradiol[MeSH Terms])) OR (ethinylestradiol[Title/Abstract])) OR (diane[Title/Abstract])) OR (cyproterone[MeSH Terms])) OR (cyproterone[Title/Abstract])) OR ) OR ) OR (OCP[Title/Abstract])) OR (CC[Title/Abstract])) OR (marvelon[MeSH Terms])) OR (marvelon[Title/Abstract])) OR (desogestrel[MeSH Terms])) OR (desogestrel[Title/Abstract])) OR (yasmin[Title/Abstract])) OR (drospirenone[Title/Abstract])) OR (letrozole[MeSH Terms])) OR (letrozole[Title/Abstract])) OR (FSH[Title/Abstract])) OR (hMG[Title/Abstract])) OR (menotropin[MeSH Terms])) OR (menotropin[Title/Abstract])) OR (pioglitazone[MeSH Terms])) OR (pioglitazone[Title/Abstract])) OR (rosiglitazone[MeSH Terms])) OR (rosiglitazone[Title/Abstract])) OR (troglitazone[MeSH Terms])) OR (troglitazone[Title/Abstract])) OR (litraglutide[Title/Abstract])) OR (flutamide[MeSH Terms])) OR (flutamide[Title/Abstract])) OR (clomiphene[MeSH Terms])) OR (clomiphene[Title/Abstract])) OR (clomifene[Title/Abstract])) OR (clomifene[MeSH Terms])) OR (chlormadinone[MeSH Terms])) OR (chlormadinone[Title/Abstract])) OR (gonadotropin[Title/Abstract])) OR (gonadotropin[MeSH Terms])) OR (simvastatin[MeSH Terms])) OR (simvastatin[Title/Abstract])) OR (atorvastatin[Title/Abstract])) OR (atorvastatin[MeSH Terms])) OR (acarbose[MeSH Terms])) OR (acarbose[Title/Abstract])) OR ) OR (anastrozole[MeSH Terms])) OR (anastrozole[Title/Abstract])) OR (clomiphene citrate[Title/Abstract])) OR (clomiphene citrate[MeSH Terms])) OR (exenatide[MeSH Terms])) OR (exenatide[Title/Abstract])) OR (folic acid[Title/Abstract])) OR (folic acid[MeSH Terms])) OR (pure follicle-stimulating hormone[MeSH Terms])) OR (pure follicle-stimulating hormone[Title/Abstract])) OR ) OR ) OR (letrozole[MeSH Terms])) OR (letrozole[Title/Abstract])) OR (liraglutide[Title/Abstract])) OR (medroxyprogesterone acetate[MeSH Terms])) OR (medroxyprogesterone acetate[Title/Abstract])) OR (N-acetyl cysteine[Title/Abstract])) OR (N-acetyl cysteine[MeSH Terms])) OR (pioglitazone[MeSH Terms])) OR (pioglitazone[Title/Abstract])) OR (rosiglitazone[Title/Abstract])) OR (rosiglitazone[MeSH Terms])) OR (sibutramine[Title/Abstract])) from inception till 28 August 2020 and search update was conducted on March 28atabases . All pubWe included all studies satisfying the following criteria:2) with polycystic ovary syndrome defined by Rotterdam, NIH, or Androgen Excess Society criteria for PCOs with a mutual presentation of obesity and hyperandrogenism across criteria;  Intervention and Comparison: any conventional pharmacological intervention; (4) Outcomes: Extracted data included three main parameters; I. Anthropometric parameters , II. Hormonal parameters , and III. Metabolic parameters , and (5) Study design: blinded randomized controlled trials (RCTs). We excluded the following: 1) non-randomized trials, 2) open-label and cross-over studies 3) surgical, herbal, and supplemental interventions, and 4) studies whose data were unreliable for extraction and analysis including post hoc analyses and preliminary reports. Duplicates were removed and retrieved references were screened in two steps: the first step was to screen titles/abstracts for matching our inclusion criteria and the second step was to screen the full-text articles of eligible abstracts for eligibility to meta-analysis. Given the challenges in this unique design of the network-meta analysis, we included comparable RCTs in their methodology and quality to guarantee the assumption of transitivity and the lowest possible heterogeneity. We analyzed only well-designed blinded RCTs that applied globally recognized diagnostic criteria for PCOS. Regarding the BMI, we considered both the mean and the standard deviation (SD) in determining the eligibility of the studies’ population. For instance, studies that had an average BMI above 25 but had a standard deviation that crosses the 25-mean into a lower value for some patients were excluded. Also, we separated studies with short-term follow-ups from those with long-term follow-ups in the statistical combinations. Eventually, each included intervention was administered as primary therapy in its original study. So, a critical distinction has to be made between a tertiary/off-label use of a drug and the primary use of the same drug.Population: overweight/obese patients , so it would not be fair to compare these agents to each other regarding the same outcome. With that in mind, we had two prospects when planning for this study. Firstly, we could have focused the study on the used interventions a particular PCOS phenotype  only. Even though this option would have been much simpler to handle, the work would have contributed more to widening the current knowledge gap. Given that PCOS has a progressive nature, it does not restrain itself to the presented phenotype, let alone that the borders that should determine different managements between various phenotypes are inevitably interleaving -implying a dire need for a much comprehensive investigation. Alternatively, we selected 17 measurable parameters that are mutual between various phenotypes and grouped them into anthropometric, metabolic, and hormonal parameters. Following, we examined the effect of each intervention on each parameter of these 17 parameters . That is how even when intervention X has primary use for the first five parameters (with a secondary or tertiary effect on the rest) and intervention Y has primary use for the last five parameters (with secondary or tertiary effect on the rest), we can still draw an overall performance across parameters between the two interventions in an objective manner. Eventually, the data of this extensive analysis would help in drawing step-wise management for different phenotypes based on the best performing intervention across the prioritized parameters of that phenotype . This algorithm will further promote the clinical practice to be more data-driven instead of theory-driven regarding PCOS management.Eight independent authors extracted the relevant data from the included studies, four authors  performed the literature search and validation, then, another four authors  re-performed the search and validation. Disagreements were resolved through discussion and consensus among the reviewers. The screening and de-duplication were conducted through Endnote X7 and Microsoft Excel 2016. The extracted data included the following:Baseline characteristics Study outcomes: I. Anthropometric parameters, II. Hormonal, and III. Metabolic parameters -as previously defined.Critical appraisal and risk of bias assessments of the included RCTs were performed using the modified Jadad scale from Oxford University . This eiStatistical analyses were performed using Stata 16.0 software. First, we conducted a pair-wise meta-analysis employing the IVhet random-effects model. All reported units were converted to standard SI units. All data were continuous (means and standard deviations "SD") and were pooled as weighted mean differences (MD) with 95% confidence intervals. Missing SD was calculated from the standard error or 95% CI or range according to Wan et al.  or obtaiSecond, a network meta-analysis was performed with a frequentist framework to compare different interventions that have no direct comparisons. We applied the node-splitting and loop-specific approaches to verify inconsistencies across the network, where a p<0.05 indicated a significant inconsistency. When no significant inconsistency was detected, we employed a consistency model; otherwise, an inconsistency model was adopted. We also utilized a global inconsistency test based on a random-effects design-by-treatment interaction model. Additionally, the surface under the curve ranking area (SUCRA) was calculated to rank different interventions for each outcome. Further, a meta-regression was conducted to examine the relationship between anthropometric, hormonal, and metabolic parameters.Our updated search retrieved 23,305 unique citations from searching electronic databases. Following title and abstract screening, 408 full-text articles were retrieved and screened for eligibility. Of them, 307 articles were excluded, and 101 RCTs , 111–12055 different interventions were included: 22 monotherapies, and 33 combinations. The monotherapies included acarbose (ACR), alfacalcidol (ALF), anastrozole (ANZ), clomiphene citrate (CC), exenatide (EXN), folic acid (FA), flutamide (FLT) pure follicle-stimulating hormone (FSH), human menopausal gonadotropins (HMG), inositol (INS), letrozole (LET), liraglutide (LIR), metformin (MET), medroxyprogesterone acetate (MPA), N-acetyl cysteine (NAC), orlistat (ORL), pioglitazone (PGZ), placebo (PLC), rosiglitazone (RGZ), sibutramine (SBT), simvastatin (SMV), and troglitazone (TGZ).The combinations included acarbose+clomiphene citrate (ACR+CC), alfacalcidiol+metformin (ALF+MET), atorvastatin+metformin (ATR+MET), bromocriptine+clomiphene citrate (BRM+CC), bromocriptine+metformin (BRM+MET), clomiphene citrate+dexamethasone (CC+DEX), clomiphene citrate+ketoconazole (CC+KTZ), clomiphene citrate+l-carnitine (CC+LC), clomiphene citrate+l-carnitine+metformin (CC+LC+MET), clomiphene citrate+metformin (CC+MET), clomiphene citrate+N-acetylcysteine (CC+NAC), clomiphene citrate+rosiglitazone (CC+RGZ), chlormadinone acetate+ethinylestradiol (CHA+EE), cyproterone acetate+ethinylestradiol (CPA+EE), cyproterone acetate+ethinylestradiol+metformin (CPA+EE+MET), cyproterone acetate+ethinylestradiol+metformin+orlistat (CPA+EE+MET+ORL), cyproterone acetate+ethinylestradiol+orlistat (CPA+EE+ORL), cyproterone acetate+ethinylestradiol+spironolactone (CPA+EE+SPR), dexamethasone+metformin (DEX+MET), desogestrel+ethinylestradiol (DGT+EE), drospirenone+ethinylestradiol (DPN+EE), drospirenone+ethinylestradiol+metformin (DPN+EE+MET), ethinylestradiol+flutamide+levonorgestrel (EE+FLT+LVT), ethinylestradiol+gestodene (EE+GTN), ethinylestradiol+metformin+norgestimate (EE+MET+NRG), ethinylestradiol+norgestimate (EE+NRG), folic acid+inositol (FA+INS), flutamide+metformin (FLT+MET), human menopausal gonadotropins+ leuprolide (HMG+LPR), inositol+monacolin k (INS+MNK), letrozole+metformin (LET+MET), metformin+rosuvastatin (MET+RSV), and metformin+simvastatin (MET+SMV).A network map was formed to visually display the size of studies involved in each direct comparison for each outcome , and a sAll of the included studies were randomized, blinded, and were treated as an intention to treat (ITT) analysis; thus, exhibiting a low risk of bias. The funnel plot was visually symmetrical , indicatWe performed a pairwise meta-analysis for RCTs that compared the same interventions employing the random-effects IVhet model. The results of these analyses are displayed in For BMI, only the following comparisons revealed significance: CPA+EE+MET+ORL# vs. CPA+EE# , CPA+EE+MET+ORL# vs. CPA+EE+ORL# , FLT vs. MET , FLT vs. PLC , and FLT+MET vs. PLC . Pooled analysis was homogenous .(mIU/ml), only the following comparisons revealed significance: MET vs. PLC . LIR was inferior to PLC in reducing LH levels . Pooled analysis was moderately heterogeneous , and heterogeneity did not resolve after further sensitivity analysis.For LH (nmol/L), only the following comparisons revealed significance: CPA+EE vs. MET , CPA+EE vs. RGZ , D(ng/dl), only the following comparisons revealed significance: CPA+EE vs. MET , DGT+EE vs. MET , DGT+EE vs. PLC , and CC+DEX# vs. PLC . Pooled analysis was homogenous .For Total Testosterone (μg/dl), only the following comparisons revealed significance: FLT vs. MET , FLT vs. PLC , INS# vs. PLC , and MET+RSV# vs. MET# . Pooled analysis was homogenous .For DHEAS (mg/dl), only the following comparisons revealed significance: MET+SMV# vs. MET# . Pooled analysis was homogenous .For Total Cholesterol (mg/dl), only the following comparisons revealed significance: INS+MNK vs. INS , INS+MNK vs. MET , MET vs. DGT+EE , MET# vs. PLC , MET+SMV# vs. MET# , and ORL# vs. PLC . Pooled analysis was moderately heterogeneous , and heterogeneity did not resolve after further sensitivity analysis.For LDL (mg/dl), only the following comparisons revealed significance: FLT vs. MET , FLT vs. PLC , and MET+RSV# vs. MET# . DPN+EE was inferior to RGZ in reducing Triglycerides levels . Pooled analysis was homogenous .For Triglycerides (mg/dl), only the following comparisons revealed significance: MET# vs. PLC , and MET# vs. ORL# . Pooled analysis was homogenous .For Fasting Glucose (pmol/L), only the following comparisons revealed significance: CC+MET vs. CC , and MET vs. CC . CPA+EE and DPN+EE were inferior to RGZ in reducing Fasting Insulin levels  and ; respectively. Pooled analysis was moderately heterogeneous , and heterogeneity did not resolve after further sensitivity analysis.For Fasting Insulin For HOMA-IR, only the following comparisons revealed significance: ALF vs. ALF+MET , CC+MET vs. CC , CPA+EE+MET# vs. CPA+EE# , DGT+EE vs. CPA+EE , DGT+EE vs. DPN+EE , MET vs. ALF+MET , MET vs. CC , MET vs. CPA+EE , PGZ vs. PLC , and RGZ vs. CPA+EE . Pooled analysis was moderately heterogeneous , and heterogeneity did not resolve after further sensitivity analysis.Additionally, we performed a frequentist network meta-analysis. Following the results of node-splitting analyses, we adopted the consistency model. The estimated value of between-study variance in the network ranged from 2.2 to 309.7. Among indirect comparisons, significant inconsistencies were identified in the closed-loop of MET#-ORL#-PLC and DGT+EE-DPN+EE-MET-RGZ . FurtherResults of each direct and indirect comparison in the network meta-analysis are detailed extensively in The ranking probabilities of the highest and lowest intervention for each outcome are available in We further employed multiple regression models to assess the interaction between anthropometric, metabolic, and hormonal parameters with significant estimates. The results of these meta-regressions are available in In contrast, LDL and Triglyceride levels showed no significant associations with Total Testosterone  or DHEAS levels . However, changes in LDL and Triglyceride levels were significantly associated with changes in SHBG  and ; respectively. The inversed regression for the effect of LDL and Triglycerides on SHBG was not significant . Likewise, no significant associations were detected between HOMA-IR and either SHBG (P = 0.9) or Total Testosterone (P = 0.95) or DHEAS (P = 0.97).In the present systematic review and network meta-analysis: 55 interventions were evaluated for efficacy in reducing weight and hyperandrogenism through 7,858 comparisons across 17 outcomes. The included interventions can be categorized pharmacologically into ten categories: Oral contraceptives, Gonadotropins modulators, Estrogen modulators, Aromatase inhibitors, Catecholamines modulators, Antiandrogens, Antidiabetics, Cholesterol modulators, Antioxidants, and Anti-inflammatories. After a long chain of analyses, the competition settled between Antiandrogens, Oral contraceptives, Anti-diabetics, Cholesterol modulators, and combinations in-between categories.Flutamide, an antiandrogen, proved efficacy in improving anthropometric, androgenic, and lipid parameters. Cyproterone acetate+ethinylestradiol, an antiandrogen with an oral contraceptive, demonstrated the highest efficacy in improving androgenic parameters. However, it did not exhibit any superiority in the remaining parameters. Inositol+monacolin K, an antidiabetic and a cholesterol modulator, displayed efficacy in improving androgenic and lipid parameters. Likewise, metformin+simvastatin/rosuvastatin and orlistat, an antidiabetic and cholesterol modulators, significantly improved lipid parameters. Nonetheless, these improvements were only observable in the short term follow-up.Ideally, all interventions were comparable in female hormones, FGS, HDL, glucose, and insulin levels improvements. As an exception, liraglutide, an antidiabetic, showed a significantly lower efficacy in reducing LH levels. Clomiphene citrate, an estrogen modulator, was the least effective agent in improving insulin levels. Eventually, pioglitazone, an antidiabetic, demonstrated efficacy in reducing HOMA-IR.Meanwhile, results of meta-regression revealed no significant associations between changes in hormonal and metabolic parameters. Even those few significant associations had a very small R-squared. This finding indicates that a drug’s action on hormonal parameters does not necessarily modify metabolic parameters and vice versa. Also, this finding is counter-intuitive to previous studies that attributed PCOS progression to lipid metabolism disturbance , 138. ThOn the other hand, meta-regression revealed a significant effect of hormonal parameters on anthropometric parameters. This finding could explain why traditional obesity interventions show limited efficacy and limited duration in obese PCOS patients , 140. FuGiven the high prevalence of obesity among PCOS patients, effective treatments that improve both obesity and reproductive functions are urgently needed , 142. EvFlutamide works by inhibiting androgen uptake or nuclear binding in the target tissues . HoweverThe mainstream literature approaches PCOS either as a mere metabolic disturbance or a fertility challenge –150. FurIn our systematic review and network meta-analysis: we assessed multi-dimensional outcomes, developed strict inclusion criteria, separated short-term from long term comparisons, and analyzed only well-designed RCTs in the past 30 years. Our findings settle a group of assumptions and advocate a reliable reference for future clinical decisions and guidelines. To the best of our knowledge: this is the first meta-analysis to investigate this size of outcomes with this number of interventions in the management of PCOS. The findings for various treatments involved were consistent for all measured outcomes, and the evidence presented was highly rated.Even so, some limitations can be identified in our work: most RCTs had relatively small sample sizes; thus, the wide 95% CI of most comparisons indicates insufficient power. Also, we restricted the average BMI to over 25; hence, the implications can only apply to overweight/obese PCOS patients. The modifications in the clinical definitions and diagnostic criteria of PCOS may contribute to the clinical heterogeneity.Overall, the current evidence demonstrated the superiority of flutamide in improving both metabolic and hormonal parameters. And the higher efficacy of cyproterone acetate+ethinylestradiol only in improving hormonal parameters. Nearly all interventions were comparable in female hormones, FGS, HDL, glucose, and insulin levels improvements. Even though inositol+monacolin K, metformin+simvastatin/rosuvastatin, and orlistat ranked higher in improving lipid parameters, their efficacy lasted only for short-term follow-ups. Liraglutide exhibited the lowest efficacy in reducing LH levels, and clomiphene citrate was the least effective agent in improving insulin levels. Pioglitazone demonstrated the highest efficacy in reducing HOMA-IR on the long-term follow-up. In the management of PCOS: a drug’s action on hormonal parameters does not necessarily modify metabolic parameters and vice versa. Obesity in PCOS is a unique case of obesity that should not be merely addressed by traditional weight-loss interventions. Prospective large-scale clinical trials are crucially required to study the appropriate dosage of flutamide and to assess the efficacy of combined flutamide+cyproterone acetate+ethinylestradiol.S1 File(DOCX)Click here for additional data file.S2 File(XLSX)Click here for additional data file.S3 File(XLSX)Click here for additional data file.S4 File(PDF)Click here for additional data file.S5 File(DOCX)Click here for additional data file.S6 File(DOCX)Click here for additional data file.


Vascular reactivity (VR), defined as blood vessels’ capability to actively modify the diameter and flow resistances can be non-invasively assessed analyzing vascular response to forearm occlusion. Several VR indexes can be quantified: (i) ´microvascular´, which consider variables that depend almost exclusively on changes in distal resistances, (ii)´ macrovascular´, that evaluate the changes in brachial artery (BA) diameter, adjusting for blood flow stimulus, and (iii) ´macro/micro´, whose values depend on the micro and macrovascular response without discriminating each one´s contribution. VR indexes could not be associated. Many VR indexes have been used without availability of adequate normative data . Aims: (1) to evaluate macro, macro/micro and micro VR indexes obtained in a cohort of healthy children, adolescents and adults, (2) to evaluate the association between VR indexes, (3) to determine the need for age and/or sex-specific RIs, and (4) to define RIs for VR indexes. Methods: Ultrasound (B-mode/Doppler) and automatic computerized analysis were used to assess BA diameter, blood flow velocity and distal resistances, at rest and in conditions of decreased and increased blood flow. Macro, macro/micro and micro VR indexes were quantified (n = 3619). RIs-subgroups were defined according to European Reference Values for Arterial Measurements Collaboration Group  and HUNT3-Fitness Study Group  criteria. Mean value and standard deviation equations were obtained for VR indexes. The need for age or sex-specific RIs was analyzed. Percentile curves were defined and data were compared with those obtained in other populations. Conclusion: Macro and macro/micro VR indexes showed no association (or it was very weak) with microvascular indexes. Age- and sex-related profiles and RIs for macro, macro/micro and micro VR indexes were defined in a large population of healthy subjects (3–85 y). Equations for mean, standard deviation and percentiles values (year-to-year) were included in text and spreadsheet formats. Vascular reactivity (VR) defined as blood vessels’ capability to actively modify the diameter and resistance in response to a stimulus  can be non-invasively assessed following post-ischemic vascular response to forearm occlusion –5. SchemVR assessment has been considered useful in early detection of cardiovascular (CV) disease and risk stratification, which accounts for the interest in VR evaluation in clinical practice ,9–12. HoThis work’s aims were: (1) to evaluate macro, macro/micro and micro VR indexes obtained in a cohort of healthy children, adolescents and adults from South America, (2) to evaluate the association between indexes used to assess VR, (3) to determine the need for age and/or sex-specific RIs (normative data), and (4) to define RIs for the different VR indexes.The study was carried out in the context of the Centro Universitario de Investigación, Innovación y Diagnóstico Arterial (CUiiDARTE) project –27, a poA clinical interview, together with the anthropometric evaluation enabled us to assess CRFs exposure. A family history of CVD was defined by the presence of first-degree  and/or second-degree (for subjects ≤18 y) relatives with early  CVD. Body weight (BW) and height (BH) were measured with the participant wearing light clothing and no shoes. Standing BH was measured using a portable stadiometer and recorded to the nearest 0.1 cm. BW was measured with an electronic scale  and recorded to the nearest 0.1 kg. Body mass index (BMI) was calculated as BW-to-squared BH ratio. In children and adolescents z-scores for the BMI were calculated using the World Health Organization software .Participants were asked to avoid exercise, tobacco, alcohol, caffeine and food-intake four hours before the evaluation. All haemodynamic measurements were performed in a temperature-controlled environment (21–23˚C), with the subject in supine position and after resting for at least 10–15 minutes, which enabled reaching steady hemodynamic conditions. Using a validated oscillometric device , heart rate (HR), and brachial systolic and diastolic blood pressure (BP) levels (bSBP and bDBP) were recorded in supine position simultaneously and/or immediately before or after each VR recording. Then, brachial pulse pressure  and mean BP  were obtained.CV evaluation in CUiiDARTE project includes assessing: (i) peripheral  and central  BP levels; central  pulse wave analysis and wave separation analysis-derived parameters , (ii) carotid, femoral and BA diameter waveforms and intima-media thickness, (iii) VR indexes, (iv) carotid, femoral and BA Doppler-derived blood velocity profiles and indexes , (v) ankle-brachial index, (vi) screening for carotid and femoral atherosclerotic plaques, (vii) carotid, femoral and BA local stiffness , (viii) hemodynamic evaluation  using BA pulse contour analysis and/or impedance cardiography, and (ix) regional stiffness . In this work, the analysis was focused on VR data ,23.Left and right common, internal and external carotid arteries, vertebral arteries and common femoral arteries were examined  ,27. TranVascular reactivity was evaluated by means of standardized methods ,5,12 Fi.Left shoulder and arm were positioned on a support, ensuring comfort and stability, thus avoiding muscle tension development and subsequent movement. In turn, forearm and wrist were placed on a support to minimize motion and artifacts in the records (e.g. due to cuff inflation). Then, BA was interrogated in longitudinal plane . To ensure adequate records the transducer was fixed using a stereotactic probe holder ,3. DopplRecorded videos were stored for blinded off-line analysis. Automatic wall-detection and Doppler velocity tracing software  were used ,28. OnceThe beginning and end of the arterial occlusion were identified on the flow velocity signal. That made it easier to assess the vascular parameters in the different conditions : (i) peak systolic, mean and end-diastolic diameter , (ii) peak systolic , mean and end-diastolic flow velocity , and (iii) resistive index (RI), a measure of pulsate flow that reflects the resistance associated with distal microvessels . RI was 2) and a parabolic velocity profile, wall shear stress (WSS) can be obtained as a function of local centre-stream velocity  and diameter   and relative ☯ %] terms), can be quantified as :ΔDDPea−DDBasalDDRatiectively . FMD% waectively –33:FMDDifferent FMD% temporal-patterns, have been described, which show differences in the kinetics of the dilatory response ,34–36. TDifferent ways to include the stimulus in the analysis have been proposed. The way to determine the stimulus more accurately is still discussed . Some ofFMD% was also normalized by WSS levels ,7,37:FPrre-release is the BA diameter at the end of vascular occlussion (pre-release)  estimated from the regression for the mean FMD% curve, and likewise from the SD curve. Continuing the example, FPs with powers Fig 12], in vivo physiological conditions .per se, but by sex-related differences in arterial sensitivity to CRFs and/or by the age of the studied subjects. On the other hand, it should be noted that sex-related differences were in many cases defined on the basis of statistical results , disregard of the true ´effect size´. Additionally, in some cases the definition and/or analysis of sex-related differences was done without taking into account cofactors   reference intervals: All (European criteria). Table S11. DD Ratio Peak_Basal [%] reference intervals: All (European criteria). Table S12. FMD% [%] reference intervals: All (European criteria). Table S13. TPD FMD% [seconds] reference intervals: All (European criteria). Table S14. ΔDD Peak-Basal/ΔVPeak-Basal [mm/cm/s] reference intervals: All (European criteria). Table S15. FMD/ΔVPeak_Basal [1/cm/s] reference intervals: All (European criteria). Table S16. pFMDv reference intervals: All (European criteria). Table S17. FMD% WSS reference intervals: All (European criteria). Table S18. ΔDPrerelease_Basal [mm] reference intervals: All (European criteria). Table S19. DD Ratio Prerelease_Basal [%] reference intervals: All (European criteria). Table S20. L-FMC% [%] reference intervals: All (European criteria). Table S21. ΔDDPrerelease_Basal/ΔEDVPrelease_Basal reference intervals: All (European criteria). Table S22. L-FMC/ΔVPrerelease_Basal [1/cm/s] reference intervals: All (European criteria). Table S23. pL-FMCv reference intervals: All (European criteria). Table S24. L-FMC%/WSS reference intervals: All (European criteria). Table S25. TVR [%] reference intervals: All (European criteria). Table S26. TVR [%] reference intervals: Female (European criteria). Table S27. TVR [%] reference intervals: Male (European criteria). Table S28. ΔVPeak_Basal [cm/s] reference intervals: Male (European criteria). Table S29. ΔWSSPeak_Basal [dyn/cm2] reference intervals: All (European criteria). Table S30. ΔWSSPeak_Basal [dyn/cm2] reference intervals: Female (European criteria). Table S31. ΔWSSPeak_Basal [dyn/cm2] reference intervals: Male (European criteria). Table S32. ΔRIPeak_Basal reference intervals: All (European criteria). Table S33. ΔRIPeak_Basal reference intervals: Female (European criteria). Table S34. ΔRIPeak_Basal reference intervals: Male (European criteria). Table S35. ΔRI%Peak_Basal [%] reference intervals: Male (European criteria). Table S36. ΔDD Peak_Basal [mm] reference intervals: All (HUNT-FIT criteria). Table S37. DD Ratio Peak_Basal [%] reference intervals: All (HUNT-FIT criteria). Table S38. FMD% [%] reference intervals: All (HUNT-FIT criteria). Table S39. TPD FMD% [seconds] reference intervals: All (HUNT-FIT criteria). Table S40. ΔDD Peak-Basal/ΔVPeak-Basal [mm/cm/s] reference intervals: All (HUNT-FIT criteria). Table S41. FMD/ΔVPeak_Basal [1/cm/s] reference intervals: All (HUNT-FIT criteria). Table S42. pFMDv reference intervals: All (HUNT-FIT criteria). Table S43. FMD%WSS reference intervals: All (HUNT-FIT criteria). Table S44. ΔDPrerelease_Basal [mm] reference intervals: All (HUNT-FIT criteria). Table S45. DD Ratio Prerelease_Basal [%] reference intervals: All (HUNT-FIT criteria). Table S46. L-FMC% [%] reference intervals: All (HUNT-FIT criteria). Table S47. ΔDDPrerelease_Basal/ΔEDVPrelease_Basal reference intervals: All (HUNT-FIT criteria). Table S48. L-FMC/ΔVPrerelease_Basal [1/cm/s] reference intervals: All (HUNT-FIT criteria). Table S49. pL-FMCv reference intervals: All (HUNT-FIT criteria). Table S50. L-FMC%/WSS reference intervals: All (HUNT-FIT criteria). Table S51. TVR [%] reference intervals: All (HUNT-FIT criteria). Table S52. TVR [%] reference intervals: Female (HUNT-FIT criteria). Table S53. TVR [%] reference intervals: Male (HUNT-FIT criteria). Table S54. ΔVPeak_Basal [cm/s] reference intervals: All (HUNT-FIT criteria). Table S55. ΔWSSPeak_Basal [dyn/cm2] reference intervals: All (HUNT-FIT criteria). Table S56. ΔWSSPeak_Basal [dyn/cm2] reference intervals: Female (HUNT-FIT criteria). Table S57. ΔWSSPeak_Basal [dyn/cm2] reference intervals: Male (HUNT-FIT criteria). Table S58. ΔRIPeak_Basal reference intervals: All (HUNT-FIT criteria). Table S59. ΔRIPeak_Basal reference intervals: Female (HUNT-FIT criteria). Table S60. ΔRIPeak_Basal reference intervals: Male (HUNT-FIT criteria). Table S61. ΔRI%Peak_Basal [%] reference intervals: All (HUNT-FIT criteria). Table S62. ΔRI%Peak_Basal [%] reference intervals: Female. (HUNT-FIT criteria). Table S63. ΔRI%Peak_Basal [%] reference intervals: Male (HUNT-FIT criteria).(XLSX)Click here for additional data file.S2 FileFigure S1. Age-related profiles for vascular reactivity indexes: ´European criteria. Figure S2. Age-related profiles for vascular reactivity indexes: ´HUNT.FIT criteria.(DOCX)Click here for additional data file.


Correction to: BMC Medical Education 20, 464 (2020)https://doi.org/10.1186/s12909-020-02377-xFunding section. The corrected text should read as follows:Following publication of the original article , the autFundingThis study was supported by National Medical Research Council (NMRC) Health Services Research Grant (NMRC/HSRG/0093/2018).


The author and Publisher would like to correct the following references:Reference 9 should be listed as:Zisman-Ilani, Y, Lysaker, P., Hasson-Ohayon, I. Shared Risk Taking: Shared Decision Making in Serious Mental Illness. Psychiatr Serv 2021; 72(4): 461–463.The Publisher apologises for this error.


The list of materials covered in this Section includes: protective nanocomposite coatings; self-healing nanocomposites; shape memory and shape switching nanocomposite layers; piezoelectric, magnetocaloric, magnetoelectric, or halochromic nanocomposites; metamaterials; multifunctional core-shell nanoparticles ; organic


We reported the S. aureus (n=315) and CoNS (n=100) clinical isolates expressing various resistance phenotypes. The isolates were collected in 2002-2019 from medical centers located in the United States , Europe , Asia-Pacific region , and Latin America . These isolates originated mostly from the year 2019 (n=323).The isolates were susceptibility tested by the CLSI broth microdilution method. MIC interpretations were based on CLSI and EUCAST criteria where available.LSVT-1701 and comparators were tested against 415 S. aureus and CoNS isolates with MIC90 values of 2 mg/L for all S. aureus, methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), and CoNS (Table). The highest LSVT-1701 MIC values were 4 and 8 mg/L among S. aureus and CoNS, respectively. LSVT-1701 retained potent activity against S. aureus isolates showing resistance or decreased susceptibility to oxacillin, vancomycin, teicoplanin, telavancin, linezolid, daptomycin, ceftaroline, or lefamulin; MIC50 values ranged from 0.5 to 1 mg/L and MIC90 values ranged from 1 to 4 mg/L among S. aureus resistant subsets.LSVT-1701 was highly active against Summary of LSVT-1701 activity against S. aureus, CoNS and resistant subsetsin vitro activity against contemporary clinical isolates of S. aureus and CoNS collected from medical centers worldwide and against resistant S. aureus isolates with uncommon resistance phenotypes. The results of this study support further clinical development of LSVT-1701 to treat staphylococcal infections.LSVT-1701 demonstrated potent David Huang, MD, PhD, Lysovant (Consultant) Helio S. Sader, MD, PhD, FIDSA, AbbVie (formerly Allergan) (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Department of Health and Human Services Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Paul R Rhomberg, Cidara Therapeutics, Inc. (Research Grant or Support)Pfizer, Inc. (Research Grant or Support) Katyna Borroto-Esoda, PhD, Lysovant (Consultant) Eric Gaukel, BS, Lysovant (Employee)


Scientific Reports 10.1038/s41598-019-51770-0, published online 29 October 2019Retraction of:  The authors have retracted this Article.Figure 3A: The H&E/PI panel looks identical to the PI/H&E (day 20) panel in Figure 4.Figure 3A: The MT/NT panel looks identical to the PI/MT (day 60) panel in Figure 4.Figure 4: The APN + PBS/PAS (day 50) panel was edited to bring the glomeruli closer together.After publication, the authors reported several irregularities in the histopathology images presented, specifically:Amin Ahmadi, Vahid Ezzatizadeh, Mehdi Alikhani, Fatemeh Hadi, and Hossein Baharvand agree to this retraction. Seyed Mahdi Nassiri does not agree with this retraction. Reza Moghadasali, Zeinab Taghizadeh, Mohammad Hassan Asghari-Vostikolaee, Reza Rahbarghazi, Reza Salman Yazdi, and Nasser Aghdami did not respond to correspondence relating to this retraction.


In animals, the biogenesis of some lipoprotein classes requires members of the ancient large lipid transfer protein (LLTP) superfamily, including the cytosolic large subunit of microsomal triglyceride transfer protein (MTP), vertebrate apolipoprotein B (apoB), vitellogenin (Vtg), and insect apolipophorin II/I precursor (apoLp-II/I). In most oviparous species, Vtg, a large glycolipoprotein, is the main egg yolk precursor protein.This report clarifies the phylogenetic relationships of LLTP superfamily members and classifies them into three families and their related subfamilies. This means that the generic term Vtg is no longer a functional term, but is rather based on phylogenetic/structural criteria. In addition, we determined that the main egg yolk precursor protein of decapod crustaceans show an overall greater sequence similarity with apoLp-II/I than other LLTP, including Vtgs. This close association is supported by the phylogenetic analysis, i.e. neighbor-joining, maximum likelihood and Bayesian inference methods, of conserved sequence motifs and the presence of three common conserved domains: an N-terminal large lipid transfer module marker for LLTP, a DUF1081 domain of unknown function in their central region exclusively shared with apoLp-II/I and apoB, and a von Willebrand-factor type D domain at their C-terminal end. Additionally, they share a conserved functional subtilisin-like endoprotease cleavage site with apoLp-II/I, in a similar location.The structural and phylogenetic data presented indicate that the major egg yolk precursor protein of decapod crustaceans is surprisingly closely related to insect apoLp-II/I and vertebrate apoB and should be known as apolipocrustacein (apoCr) rather than Vtg. These LLTP may arise from an ancient duplication event leading to paralogs of Vtg sequences. The presence of LLTP homologs in one genome may facilitate redundancy, e.g. involvement in lipid metabolism and as egg yolk precursor protein, and neofunctionalization and subfunctionalization, e.g. involvement in clotting cascade and immune response, of extracellular LLTP members. These protein-coding nuclear genes may be used to resolve phylogenetic relationships among the major arthropod groups, especially the Pancrustacea-major splits. This lipoprotein turned out to be serologically identical to oocyte lipovitellin. The term "vitellogenin" (Vtg) was proposed over thirty-five years ago [Diptera [In 1967, Wallace et al.  identifiears ago  to descrears ago , and is ears ago -8. Howevears ago  and lipa[Diptera . Multipl[Diptera . Regions[Diptera ,14. The [Diptera ,16.Knowledge of molecular structure and expression of Vtg in oviparous animals has increased impressively over the past two decades ,17. RecePenaeus semisulcatus, Penaeus monodon, Metapenaeus ensis, Marsupenaeus japonicus, Litopenaeus vannamei, Feneropenaeus merguiensis, Cherax quadricarinatus, Machrobrachium rosenbergii, Charybdis feriatus, Pandalus hypsinotus. and Portunus trituberculatus. In Penaeus semisulcatus and Marsupenaeus japonicus, the same apoCr cDNA was isolated from ovary and hepatopancreas tissues [Metapenaeus ensis, two apoCr cDNAs, apoCr1 and apoCr2, were isolated from these two tissues [Metapenaeus lineage. A recent phylogeny of penaeid shrimps, performed on two mitochondrial genes, indicated that Metapenaeus may be representative of the ancient Penaeus genus but distant from the other penaeid species [Penaeus semisulcatus revealed a sequence identity ranging from 92% with Feneropenaeus merguiensis to 34% with Charybdis feriatus [see Dendrobranchiata suborder were grouped together and the Pleocyemata suborder species, crab (Charybdis feriatus), crayfish (Cherax quadricarinatus) and prawn  were outside this monophyletic group. It is interesting to note that phylogenetic results correlated with the expression pattern of apoCr transcripts. Dendrobranchiata suborder species express apoCr transcripts in both ovaries and hepatopancreas [Metapenaeus ensis [Pleocyemata suborder species is apparently restricted to the hepatopancreas [Full-length apoCr cDNA sequences, annotated as Vtg in the GenBank™/EBI Data Bank (see the Methods section), are currently available for eleven decapod species:  tissues ,32. In M tissues ,25. They species . Alignmeatus see . The phypancreas ,24,28,29pancreas ,21,26,27Penaeus semisulcatus apoCr as a target sequence revealed high BLAST scores and expected (E) values with other decapod apoCr, from the full-length sequence of Feneropenaeus merguiensis  to Charybdis feriatus . There were also similarities with other extracellular LLTP: insect apoLp-II/I, from Locusta migratoria  to Anopheles gambiae , and vertebrate apoB, from Gallus gallus  to Danio rerio , including Homo sapiens apoB-100 precursor protein . Lower scores and E values were retrieved with Vtg of oviparous animals, ranging from Crassostrea gigas mollusks  to Samia cynthia ricini insects . BLAST scores and E values of intracellular MTP family members overlapped with Vtg family members, as shown with Strongylocentrotus purpuratus echinoderms  or Homo sapiens . Even if BLAST analysis represents an over simplification of reality, the results obtained by this method, i.e. so-called crustacean Vtg are more closely-related to insect apoLp-II/I than to insect Vtg, as indicated by BLAST scores, was not seriously taken into account, as the term Vtg was already used for these sequences.A BLASTP  search oCrustacean apoCr  is of intermediate length between insect, nematode, mollusk, and vertebrate Vtg, which are generally shorter , and insect apoLp-II/I, which are larger . Consistent with BLAST scores, crustacean apoCrs confidently align with insect apoLp-II/Is see . ApoLp-IPenaeus semisulcatus and other crustacean apoCr include three conserved structural domains , between conserved motifs N19 and N20, and aligns very well between crustacean apoCrs and insect apoLp-II/Is [see Penaeus semisulcatus [Penaeus semisulcatus 74-kDa apoCr-II subunit displays 22%–43% identity-similarity with Locusta migratoria apoLp-II, while Locusta migratoria apoLp-II displays no more than 33%–55% and 28%–47% identity-similarity with Manduca sexta and Drosophila melanogaster apoLp-II, respectively. A similar consensus cleavage site is present in most insect Vtgs, but at a different location, in the extended region between motifs N6 and N7 [Crassostrea gigas Vtgs.In insects, the apoLp-II/I is cleaved before its secretion into apoLp-II and apoLp-I  at a consensus cleavage site, RX(R/K)R, for dibasic endoprotease processing ,37, and I/Is see . The N-tsulcatus  and othesulcatus ,37. For 6 and N7 . HoweverMetapenaeus ensis apoCr sequences were clustered together and therefore both belonged to the apoCr subfamily. The second group of sequences named the Vtg/CP family supported by a BI posterior probability of 0.82 grouped with confidence in separate clusters: vertebrate, mollusk, nematode, and insect Vtg, and crustacean CP .The evolutionary relationship of genes in the LLTP superfamily was evaluated after aligning the twenty-two conserved N-terminal sequence motifs of the LLT module of selected LLTP sequences see  and the Daphnia magna, a species belonging to the class of Branchiopoda, and CP from decapod crustaceans, belonging to the class of Malacostraca, tend to be grouped with insect Vtg . It should be noted that Daphnia magna Vtg is fused with a superoxide dismutase module at the N-terminal end [Arthropoda Vtg than decapod apoCr. Vtg, CP, apoCr, and apoLp-II/I members contain a VWD domain at their C-terminal end , and of both apoLp-II/I and Vtg in honey bees (Apis mellifera), from separate clusters according to our phylogenetic analysis  and both apoLp-II/I and Vtg from insect species (e.g. Apis mellifera), suggest that, in addition to their involvement in the lipid metabolism, extracellular LLTP may have acquired other functions during metazoan evolution, e.g. involvement in clotting cascade and immune response. The findings of this study may be also a starting point for using LLTP phylogeny and their functional role to clarify the controversial relationships among Pancrustacean constituent lineages.Observation of modular architecture and phylogenetic analyses demonstrated that the main egg yolk precursor protein of decapod crustaceans is a member of the LLTP superfamily, is homologous to insect apoLp-II/I and vertebrate apoB, and would be more appropriately called apolipocrustacein (apoCr) rather than Vtg. The presence of apoCr and a clotting protein structurally related to Vtg from the same shrimp species (e.g. AY051318 (Penaeus semisulcatus), GenBank:AB033719 (Marsupenaeus japonicus), GenBank:AY103478 (Vg1) and GenBank:AY530205 (Vg2) (Metapenaeus ensis), GenBank:AY321153 (Litopenaeus vannamei), GenBank:AY499620 (Fenneropenaeus merguiensis), and GenBank:DQ288843 (Penaeus monodon) for Crustacea Decapoda Penaeidae apoCr sequences; GenBank:AB117524 , GenBank:AF306784 (Cherax quadricarinatus), GenBank:AB056458 (Macrobrachium rosenbergii), GenBank:AY724676 (Charybdis feriatus), and GenBank:AAX94762 (Portunus trituberculatus) for Crustacea Decapoda Pleocyemata apoCr sequences; UniProt:Q9U943 for locust (Locusta migratoria), UniProt:Q25490 for tobacco hornworm (Manduca sexta), UniProt:Q9V496 for fruit fly (Drosophila melanogaster), GenBank:XP_392490 for honey bee (Apis mellifera), GenBank:XP_321226 for African malaria mosquito (Anopheles gambiae), and GenBank:BAB32641 for silk moth (Samia cynthia ricini) apoLp-II/I sequences; GenBank:XP_694827 for zebrafish (Danio rerio), GenBank:XP_419979 for chicken , and UniProt:X04714 for human (Homo sapiens) apoB sequences; GenBank:AAD16454 for freshwater crayfish (Pacifastacus leniusculus), and GenBank:AAF19002 for shrimp (Penaeus monodon) CP sequences; GenBank:NP_610075 for fruit fly (Drosophila melanogaster), GenBank:XP_319421 for African malaria mosquito (Anopheles gambiae), GenBank:AAR27937 for nematode (Caenorhabditis elegans), GenBank:XP_788526 for sea urchin (Strongylocentrotus purpuratusthe), UniProt:Q8AXV7 for zebrafish (Danio rerio), UniProt:X78567 for bovine (Bos taurus), and UniProt:P55157 for human (Homo sapiens) large subunit of MTP sequences; GenBank:BAC22716 for oyster (Crassostrea gigas), GenBank:BAB63260  for Yesso scallop (Mizuhopecten yessoensis), UniProt:P55155 (Vtg2), UniProt:P06125 (Vtg5), UniProt:P18948 (Vtg6) for nematode (Caenorhabditis elegans), UniProt:T18561 (Vtg6) for nematode , UniProt:Q91062 for lamprey (Ichthyomyzon unicuspis), UniProt:Q90243 for sturgeon (Acipenser transmontanus), UniProt:U07055 for mummichog (Fundulus heteroclitus), UniProt:Q92093 for rainbow trout (Oncorhynchus mykiss), UniProt:P18709 for Xenopus (Xenopus laevis), and UniProt:P87498 for chicken  (Vtg1) Vtg sequences. As previously demonstrated, using the NJ method [Bombyx mori), UniProt:U60186 for gypsy moth (Lymantria dispar), UniProt:U02548 for yellow fever mosquito (Aedes aegypti), UniProt:Q05808 for boll weevil (Anthonomus grandis), UniProt:U97277 for bean bug (Riptortus clavatus), GenBank:NP_001011578 for honey bee (Apis mellifera), and GenBank:AF026789 for parasitoid wasp (Pimpla nipponica).Accession numbers for LLTP sequences used from GenBank™/EBI or UniProt databases are GenBank:Penaeus semisulcatus [The deduced amino acid sequence of sulcatus  was subjsulcatus . Amino asulcatus . Sequencsulcatus . The twesulcatus  resultinsulcatus .sump and sumt commands in MrBayes and the computer program Tracer version 3.1 [The phylogenetic tree and branch support values were estimated using three different methodologies of phylogenetic reconstruction: 1) NJ, 2) ML and 3) BI. NJ algorithm was based on the number of amino acid substitutions per site with the Poisson-correction distance method and pairwise-deletion option for gap sites, and bootstrap support values were obtained with 5,000 pseudoreplicates. The distance analysis was carried out with MEGA 3.1 . ML analsion 3.1 . Stationsion 3.1 . In the apoB, apolipoprotein B; apoCr, apolipocrustacein; apoLp-II/I, apolipophorin II/I; APO, apolipocrustacein/apolipophorin/apolipoprotein monophyletic group; BI, Bayesian inference; CP, clotting protein; LLT, large lipid transfer; LLTP, large lipid transfer proteins; MCMC, Markov Chain Monte Carlo; ML, maximum likelihood; MTP, large subunit of microsomal triglyceride transfer protein; neighbor-joining, NJ; very high density lipoprotein, (VHDL); Vtg, vitellogenin; VWD, von Willebrand factor type D; vWF, von Willebrand factor.J-C.A, E.L and P.J.B. designed research; J-C.A. and P.J.B performed research; J-C.A., E.L. and P.J.B analyzed data; and J-C.A., E. L. and P.J.B wrote the paper. All authors read and approved the final manuscript.Alignment of deduced amino acid sequences from crustacean apolipocrustaceins (apoCr) and insect apolipophorins II/I (apoLp-II/I). The conservative substitutions allowed were colored and defined as follows: A, G; S, T; E, D; R, K, H; Q, N; V, I, L, M; Y, F, W; P; and C. Gaps inserted to optimize alignments are indicated by dashes. Sites of identical or conserved amino acids in all sequences are highlighted in red and gray, respectively. The conserved functional subtilisin-like endoprotease cleavage site is highlighted in yellow. The name of each domain and of each conserved motif, from N1 to N22, of the LLT module [T module  is indicClick here for fileAlignment of LLT module conserved protein sequence motifs extracted from LLTP superfamily members. The conservative substitutions allowed were colored and defined as in Click here for file


Volvox carteri possesses only two cell types: mortal, motile somatic cells and potentially immortal, immotile reproductive cells. It is therefore an attractive model system for studying how cell-autonomous cytodifferentiation is programmed within a genome. Moreover, there are ongoing genome projects both in Volvox carteri and in the closely related unicellular alga Chlamydomonas reinhardtii. However, gene sequencing is only the beginning. To identify cell-type specific expression and to determine relative expression rates, we evaluate the potential of real-time RT-PCR for quantifying gene transcript levels.The multicellular alga Here we analyze a diversified pool of 39 target genes by real-time RT-PCR for each cell type. This gene pool contains previously known genes with unknown localization of cellular expression, 28 novel genes which are described in this study for the first time, and a few known, cell-type specific genes as a control. The respective gene products are, for instance, part of photosynthesis, cellular regulation, stress response, or transport processes. We provide expression data for all these genes.Volvox, which can be extended to a much larger number of genes or to developmental or metabolic mutants. Our expression data also provide a basis for a detailed analysis of individual, previously unknown, cell-type specifically expressed genes.The results show that quantitative real-time RT-PCR is a favorable approach to analyze cell-type specific gene expression in  Volvox carteri has a level of complexity representing an ideal model system for studies of multicellularity and cellular differentiation , klpA [GenBank:EF123073],fer1 [GenBank:EF123074], nab1 [GenBank:EF123075],rap41 [GenBank:EF123076], fbp1 [GenBank: EF123077],cp12 [GenBank: EF123078], prfA [GenBank: EF123079],fsd1 [GenBank: EF123080], rpl37 [GenBank: EF123081],glu1 [GenBank: EF123082], hsp70B [GenBank: EF123083],hsp40A [GenBank: EF123084], ubcA [GenBank: EF123085],ponA [GenBank: EF123086], mat3 [GenBank: EF123087],vpeA [GenBank: EF123088], sac1 [GenBank: EF123089],rcd1 [GenBank: EF123090], adcA [GenBank: EF123091],nipA [GenBank: EF123092], lciB [GenBank: EF123093],upf1 [GenBank: EF123094], upf2 [GenBank: EF123095],upf3 [GenBank: EF123096], upf4 [GenBank: EF123097],upf5 [GenBank: EF123098], and upf6 [GenBank: EF123099].t – cycle threshold; EST – expressed sequence tag; gDNA – genomic DNA; PCR – polymerase chain reaction; RT-PCR – reverse transcription-polymerase chain reactionBLAST – basic local alignment search tool; cDNA – complementary DNA; CGN and AK were responsible for homology search, sequence analysis, primer design, and realization of all experiments. AH (corresponding author) conceived and coordinated the study, critically evaluated the data, did the final calculations, and wrote the manuscript. All authors read and approved the final manuscript.


Mitochondrial genomes form units of genetic information replicating indepentently from nuclear genomes. Sequence data (most often from protein-coding genes) and other features  of mitochondrial genomes are often used in phylogenetic studies of metazoan animals from population to phylum level. Pycnogonids are primarily marine arthropods, often considered closely related to chelicerates . However, due to their aberrant morphology and to controversial results from molecular studies, their phylogenetic position is still under debate.Nymphon gracile, class Pycnogonida). Gene order derives from that of other arthropods so that presumably 10 single tRNA gene translocations, a translocation of the mitochondrial control region, and one large inversion affecting protein-coding genes must have happened in the lineage leading to Nymphon gracile. Some of the changes in gene order seem not to be common to all pycnogonids, as those were not found in a partial mitochondrial genome of another species, Endeis spinosa. Four transfer RNAs of Nymphon gracile show derivations from the usual cloverleaf secondary structure (truncation or loss of an arm). Initial phylogenetic analyses using mitochondrial protein-coding gene sequences placed Pycnogonida as sister group to Acari. However, this is in contrast to the majority of all other studies using nuclear genes and/or morphology and was not recovered in a second analysis where two long-branching acarid species were omitted.This is the first report of a complete mitochondrial genome sequence from a sea spider , as found in phylogenetic analyses using mitochondrial genes, may rather be due to long-branch attraction and independently derived nucleotide composition and amino acid frequency, than to a real sister group relationship.Extensive gene rearrangement characterizes the mitochondrial genome of  Due to their evolutionary history as derived endosymbionts, mitochondria have retained genetic material – the mitochondrial genome. Much of their original gene content was eliminated or transferred to the nucleus , while otrnL2 is changed in crustaceans and hexapods, but not in chelicerates and myriapods . All 37 genes expected for animal mitochondrial genomes have been identified. Gene overlaps (7 bp) exist between nad4 and nad4L, as well as between atp8 and atp6, as is reported for many other mitochondrial genomes. Six out of thirteen protein-coding genes show incomplete stop codons (T or TA), which is probably compensated by posttranscriptional polyadenylation , was published recently ; Triops cancriformis, [Genbank:NC_004465]; Tricholepidion gertschi, [Genbank:NC_005437]; Locusta migratoria, [Genbank:NC_001712]; Narceus annularius, [Genbank:NC_003343]; Lithobius forficatus, [Genbank:NC_002629]; Limulus polyphemus, [Genbank:NC_003057]; Centruroides limpidus, [Genbank:NC_006896]; Heptathela hangzhouensis, [Genbank:NC_005924]; Ornithoctonus huwena, [Genbank:NC_005925]; Habronattus oregonensis, [Genbank:NC_005942]; Leptotrombidium pallidum, [Genbank:NC_007601]; Varroa destructor, [Genbank:NC_004454]; Ornithodoros moubata, [Genbank:NC_004357]; Carios capensis, [Genbank:NC_005291]; Ixodes hexagonus, [Genbank:NC_002010]; Haemaphysalis flava, [Genbank:NC_005292]; Rhipicephalus sanguineus, [Genbank:NC_002074]; Amblyomma triguttatum, [Genbank:NC_005963].Two different analyses were performed on both alignments. (1) A maximum likelihood tree was computed using PAUP* ver. 4.0b10 . The moddatabase . NCBI Geatp6, atp8, ATP synthase subunits 6 and 8; cob, cytochrome oxidase b; cox1-3, cytochrome oxidase subunit I-III; nad1-6, nad4L, NADH dehydrogenase subunits 1–6, 4L; rrns, rrnl, small (12S) and large (16S) subunit ribosomal RNA; transfer RNA (tRNA) genes are listed as trnX, where X is replaced by the one letter amino acid code of the corresponding amino acid; CR, mitochondrial control region. EF-1α/EF-2, elongation factor-1α/-2; RNA-Pol II, RNA polymerase II. BI, Bayesian inference; ML, maximum likelihood; bp, base pairs.Mitochondrial genes: LP was primarily responsible for design and coordination of the study and conducted all the laboratory work. Analyses and manuscript draft was done in equal parts by both authors.