bluuebunny/crossref_metadata_2025_split huggingface dataset:
U.S. Food and Drug Administration utilization of postmarketing requirements and postmarketing commitments, 2009-2018
Authors: Skydel Joshua J. , Zhang Audrey D. , Dhruva Sanket S. , Ross Joseph S. , Wallach Joshua D. 
Published: September 2020

AbstractBackground/AimsThe U.S. Food and Drug Administration (FDA) outlines clinical studies as postmarketing requirements and commitments to be fulfilled following FDA approval of new drugs and biologics (“therapeutics”). As regulators have increasingly emphasized lifecycle evaluation of approved therapeutics, postmarketing studies are intended to advance our understanding of therapeutic safety and efficacy, yet little is known about how often clinical studies are outlined or the indications they investigate. Therefore, we characterized FDA postmarketing requirements and commitments for new therapeutics approved from 2009-2018.MethodsWe conducted a cross-sectional study of all novel therapeutics, including small molecule drugs and biologics, receiving original FDA approval from 2009-2018, using approval letters accessed through the Drug@FDA database. Outcomes included the number and characteristics of FDA postmarketing requirements and commitments for new therapeutics at original approval, including types of studies outlined, indications to be investigated, and clinical evidence to be generated.ResultsFrom 2009-2018, FDA approved 343 new therapeutics with 1978 postmarketing requirements and commitments. Overall, 750 (37.9%) postmarketing requirements and commitments outlined clinical studies. For 71 of 343 (20.7%) therapeutics, no postmarketing requirements nor commitments for clinical studies were outlined, while at least 1 was outlined for 272 (79.3%; median = 2 (IQR, 1-4)). Among these 272 therapeutics, the number of postmarketing requirements and commitments for clinical studies per therapeutic did not significantly change from 2009 (median 2 (IQR, 1-4)) to 2018 (median 2 (IQR, 1-3); P = .54). Among the 750 postmarketing requirements and commitments for clinical studies, 448 (59.7%) outlined new prospective cohort studies, registries, or clinical trials, while the remainder outlined retrospective studies, secondary analyses, or completion of ongoing studies. Although 455 (60.7%) clinical studies investigated only original approved therapeutic indications, 123 (16.4%) enrolled from an expansion of the approved disease population and 61 (8.1%) investigated diseases unrelated to approved indications.ConclusionsMost therapeutics are approved by FDA with at least 1 postmarketing requirement or commitment for a clinical study, which outline investigations of safety or efficacy for both approved and unapproved indications. However, the median number of 2 clinical studies outlined has remained relatively constant over the last decade, despite increasing emphasis on lifecycle evaluation of approved therapeutics.
Pathogenic SPTBN1 variants cause a novel autosomal dominant neurodevelopmental syndrome
Authors: Cousin Margot A. , Breau Keith A. , Creighton Blake A. , Spillmann Rebecca C. , Torti Erin , Dontu Sruthi , Tripathi Swarnendu , Ajit Deepa , Harper Kathryn M. , Stankewich Michael C. , Person Richard E. , Si Yue , Normand Elizabeth A. , Blevins Amy , May Alison S. , Bier Louise , Aggarwal Vimla , Mancini Grazia M. S. , van Slegtenhorst Marjon A. , Cremer Kirsten , Becker Jessica , Engels Hartmut , Aretz Stefan , MacKenzie Jennifer J. , Brilstra Eva , van Gassen Koen L. I. , van Jaarsveld Richard H. , Oegema Renske , Parsons Gretchen M. , Mark Paul , Helbig Ingo , McKeown Sarah E. , Stratton Robert , Cogne Benjamin , Isidor Bertrand , Cacheiro Pilar , Smedley Damian , Firth Helen V. , Bierhals Tatjana , Kloth Katja , Weiss Deike , Fairley Cecilia , Shieh Joseph T. , Kritzer Amy , Jayakar Parul , Kurtz-Nelson Evangeline , Bernier Raphael , Wang Tianyun , Eichler Evan E. , van de Laar Ingrid M.B.H. , McConkie-Rosell Allyn , McDonald Marie , Kemppainen Jennifer , Lanpher Brendan C. , Schultz-Rogers Laura E. , Gunderson Lauren B. , Pichurin Pavel N. , Yoon Grace , Zech Michael , Jech Robert , Winkelmann Juliane ,   Undiagnosed Diseases Network,   Genomics England Research Consortium, Zimmermann Michael T. , Temple Brenda , Moy Sheryl S. , Klee Eric W. , Tan Queenie K.-G. , Lorenzo Damaris N. 
Published: September 2020

AbstractSPTBN1 encodes βII-spectrin, the ubiquitously expressed member of the β-spectrin family that forms micrometer-scale networks associated with plasma membranes. βII-spectrin is abundantly expressed in the brain, where it is essential for neuronal development and connectivity. Mice deficient in neuronal βII-spectrin expression have defects in cortical organization, global developmental delay, dysmorphisms, and behavioral deficiencies of corresponding severity. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous variants in this gene may also present with measurable compromise of neural development and function. Here we report the identification of heterozygous SPTBN1 variants in 29 individuals who present with global developmental, language and motor delays, mild to severe intellectual disability, autistic features, seizures, behavioral and movement abnormalities, hypotonia, and variable dysmorphic facial features. We show that these SPTBN1 variants lead to loss-of-function, gain-of-function, and dominant negative effects that affect protein stability, disrupt binding to key protein partners, and disturb cytoskeleton organization and dynamics. Our studies define the genetic basis of this new neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and neural development, and underscore the critical role of βII-spectrin in the central nervous system.
Comparative performance of five commercially available serologic assays to detect antibodies to SARS-CoV-2 and identify individuals with high neutralizing titers
Authors: Patel Eshan U. , Bloch Evan M. , Clarke William , Hsieh Yu-Hsiang , Boon Denali , Eby Yolanda , Fernandez Reinaldo E. , Baker Owen R. , Keruly Morgan , Kirby Charles S. , Klock Ethan , Littlefield Kirsten , Miller Jernelle , Schmidt Haley A. , Sullivan Philip , Piwowar-Manning Estelle , Shrestha Ruchee , Redd Andrew D. , Rothman Richard E. , Sullivan David , Shoham Shmuel , Casadevall Arturo , Quinn Thomas C. , Pekosz Andrew , Tobian Aaron A.R. , Laeyendecker Oliver 
Published: September 2020

ABSTRACTAccurate serological assays to detect antibodies to SARS-CoV-2 are needed to characterize the epidemiology of SARS-CoV-2 infection and identify potential candidates for COVID-19 convalescent plasma (CCP) donation. This study compared the performance of commercial enzyme immunoassays (EIAs) to detect IgG or total antibodies to SARS-CoV-2 and neutralizing antibodies (nAb). The diagnostic accuracy of five commercially available EIAs (Abbott, Euroimmun, EDI, ImmunoDiagnostics, and Roche) to detect IgG or total antibodies to SARS-CoV-2 was evaluated from cross-sectional samples of potential CCP donors that had prior molecular confirmation of SARS-CoV-2 infection for sensitivity (n=214) and pre-pandemic emergency department patients for specificity (n=1,102). Of the 214 potential CCP donors, all were sampled >14 days since symptom onset and only a minority had been hospitalized due to COVID-19 (n=16 [7.5%]); 140 potential CCP donors were tested by all five EIAs and a microneutralization assay. When performed according to the manufacturers’ protocol to detect IgG or total antibodies to SARS-CoV-2, the sensitivity of each EIA ranged from 76.4% to 93.9%, and the specificity of each EIA ranged from 87.0% to 99.6%. Using a nAb titer cutoff of ≥160 as the reference positive test (n=140 CCP donors), the empirical area under receiver operating curve of each EIA ranged from 0.66 (Roche) to 0.90 (Euroimmun). Commercial EIAs with high diagnostic accuracy to detect SARS-CoV-2 antibodies did not necessarily have high diagnostic accuracy to detect high nAbs. Some but not all commercial EIAs may be useful in the identification of individuals with high nAbs in convalescent individuals.
A comprehensive analysis of recovered COVID-19 patients and dynamic trend in antibodies over 3 months using ELISA and CLIA methods
Authors: Dehgani-Mobaraki Puya , Zaidi Asiya Kamber , Floridi Alessandro , Lepri Alessandro , Floridi Emanuela , Gherardi Alessia , Bernini-Carri Enrico , D’urzo Eleonora , Dehgani-Mobaraki Massoud 
Published: September 2020

AbstractBackgroundSince the Coronavirus disease-2019 outbreak, most studies have focused on etiopathogenic aspects and treatment strategies. Acquired immunity still remains a dilemma. The aim of our study included a comprehensive analysis of patient characteristics, evaluation of antibody response, and its trend over a period of three months in recovered patients.MethodsMonocentric investigator-initiated pilot longitudinal observational study conducted by the Association Naso Sano, on a cohort of 30 COVID recovered patients based in the Umbria region, followed up from April to June 2020 for baseline blood counts, IgM and IgG trends using two different serological assays-ELISA and CLIA. The demographics, blood group, co-morbidities and treatment modalities were recorded from each patient along with an analysis of clinical profile, dates concerning symptom onset, first positive and two consecutive negative swabs using an online questionnaire followed by serological testing. Descriptive and Bivariate (Pearson correlation coefficient) statistics were conducted to detect statistically significant correlations.FindingsThe study involved 30 patients with a M:F ratio of 0.57 and a distribution of mild (67%), moderate (30%) and critical (3%). Majority of the patients were healthcare workers (40%) and the mean viral shedding duration was 20.13 ± 6.17 days. The IgG levels offered long-standing protection as long as 3 months in some cases. A statistically significant, directly proportional correlation (Pearson) exists between ELISA and CLIA values for IgM. Some patients also expressed titers lower than the detection threshold and therefore a positive RT-PCR test does not necessarily guarantee a high IgG response in the recovery period.InterpretationThe data presented in our study provides a relative long-term analysis and possible explanation regarding the protection developed by patients recovered from COVID-19.
Risk Factors for ICU Admission, Mechanical Ventilation and Mortality in Hospitalized Patients with COVID-19 in Hubei, China
Authors: Ren Hong Gang , Guo Xingyi , Blighe Kevin , Zhu Fang , Martin Janet , Safdar Luqman Bin , Yang Pengcheng , Wang Dao Wen , Hu Qinyong , Huo Nan , Stebbing Justin , Cheng Davy 
Published: September 2020

PurposeTo examine the risk factors for Intensive Care Unit (ICU) admission, mechanical ventilation and mortality in hospitalized patients with COVID-19.MethodsThis was a retrospective cohort study including 432 patients with laboratory-confirmed COVID-19 who were admitted to three medical centers in Hubei province from January 1st to April 10th 2020. Primary outcomes included ICU admission, mechanical ventilation and death occurring while hospitalized or within 30 days.ResultsOf the 432 confirmed patients, 9.5% were admitted to the ICU, 27.3% required mechanical ventilation, and 33.1% died. Total leukocyte count was higher in survivors compared with those who died (8.9 vs 4.8 × 109/l), but lymphocyte counts were lower (0.6 vs 1.0 × 109/l). D-dimer was significantly higher in patients who died compared to survivors (6.0ug/l vs 1.0ug/l, p<0.0001. This was also seen when comparing mechanically versus non-mechanically-ventilated patients. Other significant differences were seen in AST, ALT, LDH, total bilirubin and creating kinase. The following were associated with increased odds of death: age > 65 years (adjusted hazard ratio (HR 2.09, 95% CI 1.02-4.05), severe disease at baseline (5.02, 2.05-12.29), current smoker (1.67, 1.37-2.02), temperature >39° C at baseline (2.68, 1.88-4.23), more than one comorbidity (2.12, 1.62-3.09), bilateral patchy shadowing on chest CT or X-ray (3.74, 1.78-9.62) and organ failure (6.47, 1.97-26.23). The following interventions were associated with higher CFR: glucocorticoids (1.60, 1.04-2.30), ICU admission (4.92, 1.37-17.64) and mechanical ventilation (2.35, 1.14-4.82).ConclusionDemographics, including age over 65 years, current smoker, diabetes, hypertension, and cerebrovascular disease, were associated with increased risk of mortality. Mortality was also associated with glucocorticoid use, mechanical ventilation and ICU admission.Take-Home MessageCOVID-19 patients with risk factors were more likely to be admitted into ICU and more likely to require mechanical ventilation.
Time in blood glucose range 70 to 180 mg/dL and survival rate in critically ill patients: A retrospective observational study
Authors: Naraba Hiromu , Goto Tadahiro , Shirakawa Toru , Sonoo Tomohiro , Kanda Naoki , Nakano Hidehiko , Takahashi Yuji , Hashimoto Hideki , Nakamura Kensuke 
Published: September 2020

ABSTRACTObjectiveTime in targeted blood glucose range (TIR) 70-140 mg/dL has been associated with an increased risk of mortality in critically ill patients. Nevertheless, it remains unclear whether TIR is associated with 28-day mortality in critically ill patients under glycemic control with a less tight target glucose range of 70-180 mg/dL. We aimed to assess whether TIR 70-180 mg/dL was associated with 28-day mortality and to identify the optimal TIR.DesignA retrospective observational study.SettingData from a tertiary care centre in Japan, from 1 January 2016 through 31 October 2019.Participants1,230 adult patients admitted to the intensive care unit for more than three days.Outcome measureThe primary outcome was 28-day mortality.ResultsOf 1,230 patients, patients with HbA1c ≥6.5% had a higher 28-day mortality than those with <6.5% (32.0% vs. 22.7%; p=0.003). In the multivariate logistic regression, TIR <80% was associated with an increased risk of 28-day mortality in patients with HbA1c <6.5% with an adjusted odds ratio (OR) of 1.88 (95% confidence interval [CI]: 1.36-2.61). When using 10% incremental TIR as a categorical variable, lower TIR was associated with worse 28-day mortality compared to TIR ≥90% in patients with HbA1c <6.5% (e.g., adjusted OR of TIR <60%, 3.62 [95%CI 2.36-5.53]). Similar associations were found in the analyses using the COX proportional hazards model. In addition, sensitivity analyses using TIR of the first three days showed that the overall associations were consistent with primary analyses.ConclusionsOur study demonstrated that lower TIR 70-180 mg/dL was associated with higher 28-day mortality in nondiabetic critically ill patients.Article SummaryStrengths and limitations of this studyThis is the first study to evaluate the association between less tight TIR (70-180 mg/dl) and mortality in critically ill patients.We found consistent results in the analyses using logistic regression model and Cox proportional hazard model.The primary findings were also observed in the analysis using TIR in the first three days.We did not use a continuous glucose monitoring device to calculate TIR.Due to the nature of the single-centre study design, the generalizability of the findings might be limited.
Asymptomatic cases and limited transmission of SARS-CoV-2 in residents and healthcare workers in three Dutch nursing homes
Authors: van Buul Laura W. , van den Besselaar Judith H. , Koene Fleur M.H.P.H. , Buurman Bianca M. , Hertogh Cees M.P.M. ,   the COVID-19 NH-STUDY GROUP
Published: September 2020

ABSTRACTPurposeMany nursing homes worldwide have been hit by outbreaks of the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to assess the contribution of a- and presymptomatic residents and healthcare workers in transmission of SARS-CoV-2 in three nursing homes.MethodsTwo serial point-prevalence surveys, 1 week apart, among residents and healthcare workers of three Dutch nursing homes with recent SARS-CoV-2 introduction. Nasopharyngeal and oropharyngeal testing for SARS-CoV-2, including reverse-transcriptase polymerase chain reaction (rRT-PCR) was presymptomatic or asymptomatic with standardized symptom assessment.ResultsIn total, 297 residents and 542 healthcare workers participated in the study. At the first point-prevalence survey, 15 residents tested positive of which one was presymptomatic (Ct value>35) and three remained asymptomatic (Ct value of 23, 30 and 32). At the second point-prevalence survey one resident and one healthcare worker tested SARS-CoV-2 positive (Ct value >35 and 24, respectively) and both remained asymptomatic.ConclusionThis study confirms a-and presymptomatic occurrence of Covid-19 among residents and health care workers. Ct values below 25 suggested that these cases have the potential to contribute to viral spread. However, very limited transmission impeded the ability to answer the research question. We describe factors that may contribute to the prevention of transmission and argue that the necessity of large-scale preemptive testing in nursing homes may be dependent of the local situation regarding prevalence of cases in the surrounding community and infection control opportunities.KEY SUMMARY POINTSAimTo assess the contribution of a- and presymptomatic residents and healthcare workers in transmission of SARS-CoV-2 in three nursing homes by facility wide preemptive testing.FindingsOccurrence of a-and presymptomatic residents and healthcare workers with Ct values below 25 was confirmed. However, evaluation of contribution to transmission of the virus was not possible because of limited positive cases in the follow-up.MessageNecessity of large-scale preemptive testing for a- and presymptomatic SARS-CoV-2 cases in nursing homes may be dependent on prevalence of cases in the surrounding community and infection control opportunities.
Accelerated aging in the brain, epigenetic aging in blood, and polygenic risk for schizophrenia
Authors: Teeuw Jalmar , Ori Anil , Brouwer Rachel M. , de Zwarte Sonja M.C. , Schnack Hugo G. , Pol Hilleke E. Hulshoff , Ophoff Roel A. 
Published: September 2020

AbstractSchizophrenia patients show signs of accelerated aging in cognitive and physiological domains. Both schizophrenia and accelerated aging, as measured by MRI brain images and epigenetic clocks, are correlated with increased mortality. However, the association between these aging measures have not yet been studied in schizophrenia patients.In schizophrenia patients and healthy subjects, accelerated aging was assessed in brain tissue using a longitudinal MRI (N=715 scans; mean scan interval 3.4 year) and in blood using two epigenetic age clocks (N=172). Differences (‘gaps’) between estimated ages and chronological ages were calculated, as well as the acceleration rate of brain aging. The correlations between these aging measures as well as with polygenic risk scores for schizophrenia (PRS; N=394) were investigated.Brain aging and epigenetic aging were not significantly correlated. Polygenic risk for schizophrenia was significantly correlated with brain age gap, brain age acceleration rate, and negatively correlated with DNAmAge gap, but not with PhenoAge gap. However, after controlling for disease status and multiple comparisons correction, these effects were no longer significant. Our results imply that the (accelerated) aging observed in the brain and blood reflect distinct biological processes. Our findings will require replication in a larger cohort.
COVID-19 Myocardial Pathology Evaluated Through scrEening Cardiac Magnetic Resonance (COMPETE CMR)
Authors: Clark Daniel E. , Parikh Amar , Dendy Jeffrey M. , Diamond Alex B. , George-Durrett Kristen , Fish Frank A. , Fitch Warne , Hughes Sean G. , Soslow Jonathan H. 
Published: September 2020

AbstractBackgroundMyocarditis is a leading cause of sudden cardiac death among competitive athletes and may occur without antecedent symptoms. COVID-19-associated myocarditis has been well-described, but the prevalence of myocardial inflammation and fibrosis in young athletes after COVID-19 infection is unknown.ObjectivesThis study sought to evaluate the prevalence and extent of cardiovascular involvement in collegiate athletes that had recently recovered from COVID-19.MethodsWe conducted a retrospective cohort analysis of collegiate varsity athletes with prior COVID-19 infection, all of whom underwent cardiac magnetic resonance (CMR) prior to resumption of competitive sports in August 2020.ResultsTwenty-two collegiate athletes with prior COVID-19 infection underwent CMR. The median time from SARS-CoV-2 infection to CMR was 52 days. The mean age was 20.2 years. Athletes represented 8 different varsity sports. This cohort was compared to 22 healthy controls and 22 tactical athlete controls. Most athletes experienced mild illness (N=17, 77%), while the remainder (23%) were asymptomatic. No athletes had abnormal troponin I, electrocardiograms, or LVEF < 50% on echocardiography. Late gadolinium enhancement was found in 9% of collegiate athletes and one athlete (5%) met formal criteria for myocarditis.ConclusionsOur study suggests that the prevalence of myocardial inflammation or fibrosis after an asymptomatic or mild course of ambulatory COVID-19 among competitive athletes is modest (9%), but would be missed by ECG, Ti, and strain echocardiography. Future investigation is necessary to further phenotype cardiovascular manifestations of COVID-19 in order to better counsel athletes on return to sports participation.Condensed AbstractCOVID-19-associated myocarditis has been well-described, but the prevalence of myocardial inflammation and fibrosis in athletes after COVID-19 is unknown. We conducted a retrospective cohort analysis of 22 collegiate athletes with prior COVID-19 infection who underwent electrocardiography, troponin I, echocardiography with strain, and CMR. The median time from SARS-CoV-2 infection to CMR was 52 days. All athletes experienced mild illness or were asymptomatic. Late gadolinium enhancement was found in 9%. This suggests the prevalence of myocardial inflammation or fibrosis after an asymptomatic or mild course of COVID-19 among competitive athletes is modest, but would be missed without CMR screening.