bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prenatal and perinatal metabolic risk factors for autism: a review and integration of findings from population-based studies
Authors: Katz Julia , Reichenberg Abraham , Kolevzon Alexander 
Published: December 2020

Purpose of review
Given the ongoing rise in prevalence of autism spectrum disorder (ASD) and the challenges in developing and administering interventions to significantly alleviate ASD symptoms, there is an urgent need to identify modifiable risk factors for ASD. The goal of this review is to systematically evaluate the current evidence for an association between conditions related to maternal metabolic syndrome and risk for ASD in offspring focusing on methodically rigorous studies.

Recent findings
In recent years, multiple studies explored the association between various conditions related to maternal metabolic syndrome (obesity, hypertension, or diabetes prior to, or with onset during pregnancy) and ASD risk in the offspring.

Summary
Examining large, sufficiently powered, population-based epidemiological studies that explored the association between maternal metabolic syndrome and ASD, we found consistent evidence for an association between maternal preeclampsia and risk for ASD. Other conditions that are part of maternal metabolic syndrome, including maternal obesity, gestational weight gain, diabetes and gestational diabetes, should be studied further with careful attention paid to potential synergistic effects between different metabolic conditions. These findings highlight the need for rigorous, large, population-based epidemiological studies of potentially modifiable ASD risk factors that could inform public health interventions.
THE THERAPEUTIC POTENTIAL OF IVERMECTIN FOR COVID-19: A SYSTEMATIC REVIEW OF MECHANISMS AND EVIDENCE
Authors: Kalfas Stefanie , Visvanathan Kumar , Chan Kim , Drago John 
Published: December 2020

ABSTRACTIntroductionIvermectin is a commonly used antihelminthic agent with over 35 years of established safety data in humans. Recent data demonstrates antiviral activity in vitro against SARS-CoV-2, in addition to a range of viruses. In vitro and animal models also provide evidence of immunomodulatory action. These additional modes of action are supported by in silico modelling, which propose a number of viral and host targets that would mediate these effects.ObjectivesThe aim of this study is to systematically review the published and preprint clinical literature and study results that assessed the potential role of ivermectin as a COVID-19 therapeutic and prophylactic agent.MethodsWe conducted a comprehensive review of PubMed, medRxiv, ClinicalTrials.gov, Global Coronavirus COVID-19 Clinical Trial Tracker, World Health Organization International Clinical Trials Registry Platform, EU Clinical Trials Register, ANZ clinical trials registry, and references from relevant articles.ResultsSearch keywords- “COVID-19 (and synonyms) AND ivermectin”- generated 86 articles on PubMed, 48 on medRvix and 37 on clinicaltrials.gov at the time of writing. Twelve of these were listed as completed clinical trials and of these, 8 were included as investigators had released results. Positive mortality benefit, reduced time to clinical recovery, reduced incidence of disease progression and decreased duration of hospital admission were reported in patients across all stages of clinical severity.LimitationsDue to the time-critical nature of the COVID-19 pandemic our review included preprint data, which must be interpreted with caution while it awaits peer review.
Temporal Lobe Activation Predicts Episodic Memory Following Traumatic Brain Injury
Authors: Taing Abbie S. , Mundy Matthew E. , Ponsford Jennie L. , Spitz Gershon 
Published: December 2020

AbstractThe temporal lobes are critical for episodic memories and are preferentially affected following a traumatic brain injury (TBI). As such, episodic memory difficulties are common following TBI; however, the underlying neural changes that precipitate or maintain these difficulties in the early phase of recovery remains poorly understood. Here, we use functional magnetic resonance imaging (fMRI) to interrogate the relationship of temporal lobe activation in response to face, scene, and animal stimuli. Twenty-five patients with moderate to severe TBI were recruited an average of 2 months’ post-injury and compared with 21 demographically similar healthy controls. Findings indicate that memory for faces was preferentially impaired, compared to scene and animal stimuli. Decreased activity in temporal lobe structures was present for both face (right transverse temporal gyrus) and scene stimuli (right fusiform gyrus), but not for animals. Greater activation in these structures was associated with better long-term recognition. These findings provide evidence to suggest that TBI: a) preferentially affects memory for complex stimuli such as faces and scenes, and b) causes aberrant neuronal processes despite lack of evidence of significant impairment in behavioural performance. The mechanisms underpinning these findings are discussed in terms of differences in strategy use and reduced neural efficiency.
How to choose a time zero for patients in external control arms
Authors: Backenroth Daniel 
Published: December 2020

AbstractWhen a sponsor carries out a single-arm trial of a novel oncology compound, it may wish to assess the efficacy of the compound via comparison of overall survival to an external control arm, constructed using patients included in some retrospective registry. If efficacy of the novel compound is compared to efficacy of physician’s choice of chemotherapy, patients in the retrospective registry might qualify for inclusion in the external control arm at multiple different points in time, when they receive different chemotherapy treatments. For example, a patient might qualify at the start of their second, third and fourth lines of therapy. From the start of which line of therapy should this patient’s survival be compared to survival of participants in the single-arm trial?Some sponsors have elected to include patients in the external control arm from the last available line of therapy in the retrospective database. Another possibility is to randomly select a line of therapy for each external control arm patient from among those available. In this paper, we show, via probabilistic arguments and also via simulation based on real data, that both of these methods give rise to a bias in favor of the single-arm trial. We further show that this bias can be avoided by instead including external control arm patients multiple times in the external control arm, once for each time they receive qualifying treatment.
Elucidating the phenotypic variability associated with the polyT tract and TG repeats in CFTR
Authors: Nykamp Keith , Truty Rebecca , Riethmaier Darlene , Wilkinson Julia , Bristow Sara L. , Aguilar Sienna , Neitzel Dana , Faulkner Nicole , Kahan Stephanie , Aradhya Swaroop 
Published: December 2020

ABSTRACTPurposeTo evaluate the risk and spectrum of phenotypes associated in individuals with one or two of the CFTR T5 haplotype variants (TG11T5, TG12T5 and TG13T5) in the absence of the R117H variant.MethodsIndividuals who received testing with CFTR NGS results between 2014 and 2019 through Invitae at ordering provider discretion were included. TG-T repeats were detected using a custom-developed haplotype caller. Frequencies of the TG-T5 variants (biallelic or in combination with another CF-causing variant [CFvar]) were calculated. Clinical information reported by the ordering provider (via requisition form) or the individual (during genetic counseling appointments) was examined.ResultsAmong 548,300 individuals, the minor allele frequency of the T5 allele was 4.2% (TG repeat distribution: TG11=68.1%, TG12=29.5%, TG13=2.4%). When present with a CFvar, each of the TG[11-13]T5 variants were significantly enriched in individuals with a “high suspicion” of CF/CFTR-RD (personal/family history of CF/CFTR-RD) compared to those with very “low suspicion” for CF or CFTR-RD (hereditary cancer testing, CFTR not requisitioned). Compared to CFvar/CFvar individuals, TG[11-13]T5/CFvar individuals generally had single organ involvement, milder symptoms, variable expressivity, and reduced penetrance.DiscussionData from this study provides a better understanding of disease risks associated with inheriting TG[11-13]T5 variants and has important implications for reproductive genetic counseling.
Vaccine acceptance among college students in South Carolina: Do information sources and trust in information make a difference?
Authors: Qiao Shan , Friedman Daniela B. , Tam Cheuk Chi , Zeng Chengbo , Li Xiaoming 
Published: December 2020

AbstractBackgroundTo control the COVID-19 pandemic, governments need to ensure a successful large-scale administration of COVID-19 vaccines when safe and efficacious vaccines become available. Vaccine acceptance could be a critical factor influencing vaccine uptake. Health information has been associated with vaccine acceptance. For college students who are embracing a digital era and being exposed to multimedia, the sources of COVID-19 vaccine information and their trust in these sources may play an important role in shaping their acceptance of vaccine uptake.MethodsIn September 2020, we conducted an online survey among 1062 college students in South Carolina to understand their perceptions and attitudes toward COVID-19 vaccination. Descriptive analysis and linear regression analysis were used to investigate vaccine information sources among college students and examine how COVID-19 vaccine acceptance was associated with information source and trust level in each source.ResultsThe top three sources of COVID-19 vaccine information were health agencies (57.7%), mass media (49.5%), and personal social networks (40.5%). About 83.1% of the participants largely or always trusted scientists, 73.9% trusted healthcare providers, and 70.2% trusted health agencies. After controlling for key demographics, vaccine acceptance was positively associated with scientists as information sources but negatively associated with pharmaceutical companies as sources. Higher trust levels in mass media, health agencies, scientists, and pharmaceutical companies was significantly associated with higher COVID-19 vaccine acceptance. However, trust in social media was negatively associated with vaccine acceptance.DiscussionCollege students use multiple sources to learn about upcoming COVID-19 vaccines including health agencies, personal networks, and social media. The level of trust in these information sources play a critical role in predicting vaccine acceptance. Trust in health authorities and scientists rather than social media is related to higher level vaccine acceptance. Our findings echo the call for restoring trust in government, healthcare system, scientists, and pharmaceutical industries in the COVID-19 era and highlight the urgency to dispel misinformation in social media. Effective strategies are needed to disseminate accurate information about COVID-19 vaccine from health authorities and scientific research to improve vaccine communication to the public and promote COVID-19 vaccine uptake.
Detailed disease progression of 213 patients hospitalized with Covid-19 in the Czech Republic: An exploratory analysis
Authors: Modrák Martin , Bürkner Paul-Christian , Sieger Tomáš , Slisz Tomáš , Vašáková Martina , Mesežnikov Grigorij , Casas-Mendez Luis Fernando , Vajter Jaromír , Táborský Jan , Kubricht Viktor , Suk Daniel , Horejsek Jan , Jedlička Martin , Mifková Adriana , Jaroš Adam , Kubiska Miroslav , Váchalová Jana , Šín Robin , Veverková Markéta , Pospíšil Zbyšek , Vohryzková Julie , Pokrievková Rebeka , Hrušák Kristián , Christozova Kristína , Leos-Barajas Vianey , Fišer Karel , Hyánek Tomáš 
Published: December 2020

AbstractWe collected a multi-centric retrospective dataset of patients (N = 213) who were admitted to ten hospitals in Czech Republic and tested positive for SARS-CoV-2. The dataset contains baseline patient characteristics, breathing support required, pharmacological treatment received and multiple markers on daily resolution. Patients in the dataset were treated with hydroxychloroquine (N = 108), azithromycin (N = 72), favipiravir (N = 9), convalescent plasma (N = 7), dexamethasone (N = 4) and remdesivir (N = 3), often in combination. Most patients were admitted during the first wave of the epidemic. To explore association between treatments and patient outcomes we performed multiverse analysis, observing how the conclusions change between defensible choices of statistical model, predictors included in the model and other analytical degrees of freedom. Weak evidence to constrain the potential efficacy of azithromycin and favipiravir can be extracted from the data. Additionally, we performed external validation of several proposed prognostic models for Covid-19 severity showing that they mostly perform unsatisfactorily on our dataset.
Genome-wide analysis of 944,133 individuals provides insights into the etiology of hemorrhoidal disease
Authors: Zheng Tenghao , Ellinghaus David , Juzenas Simonas , Cossais François , Burmeister Greta , Mayr Gabriele , Jørgensen Isabella Friis , Teder-Laving Maris , Skogholt Anne Heidi , Banasik Karina , Becker Thomas , Bokelmann Frank , Brunak Søren , Buch Stephan , Clausnizer Hartmut , Datz Christian ,   DBDS Consortium, Degenhardt Frauke , Doniec Marek , Erikstrup Christian , Esko Tõnu , Forster Michael , Frey Norbert , Fritsche Lars G. , Gabrielsen Maiken Elvestad , Gräßle Tobias , Gsur Andrea , Gross Justus , Hampe Jochen , Hendricks Alexander , Hinz Sebastian , Hveem Kristian , Jongen Johannes , Junker Ralf , Karlsen Tom Hemming , Hemmrich-Stanisak Georg , Kruis Wolfgang , Kupcinskas Juozas , Laubert Tilman , Laudes Matthias , Leendertz Fabian H. , Lieb Wolfgang , Limperger Verena , Margetis Nikolaos , Mätz-Rensing Kerstin , Németh Christopher Georg , Ness-Jensen Eivind , Nowak-Göttl Ulrike , Pandit Anita , Pedersen Ole Birger , Günter Peleikis Hans , Peuker Kenneth , Rodríguez Cristina Leal , Rühlemann Malte , Schniewind Bodo , Schulzky Martin , Skieceviciene Jurgita , Tepel Jürgen , Thomas Laurent , Uellendahl-Werth Florian , Ullum Henrik , Vogel Ilka , Völzke Henry , Fersen Lorenzo von , Schoenfels Witigo von , Vanderwerff Brett , Wilking Julia , Wittig Michael , Zeissig Sebastian , Zobel Myrko , Zawistowski Matthew , Vacic Vladimir , Sazonova Olga , Noblin Elizabeth S. ,   The 23andMe Research Team, Wedel Thilo , Kahlke Volker , Schafmayer Clemens , D’Amato Mauro , Franke Andre 
Published: December 2020

AbstractHemorrhoidal disease (HEM) affects a large fraction of the population but its etiology including suspected genetic predisposition is poorly understood. We conducted a GWAS meta-analysis of 218,920 HEM patients and 725,213 controls of European ancestry, demonstrating modest heritability and genetic correlation with several other diseases from the gastrointestinal, neuroaffective and cardiovascular domains. HEM polygenic risk scores validated in 180,435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harboring genes whose expression is enriched in blood vessels and gastrointestinal tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses of affected tissue from HEM patients highlighted HEM gene co-expression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organization of the extracellular matrix. We conclude HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.
Knowledge, attitude and willingness to accept the RTS,S malaria vaccine among mothers in Abuja Nigeria
Authors: Musa-Booth Tolulope O. , Enobun Blessing E. , Agbomola Adewumi J. , Shiff Clive J. 
Published: December 2020

ABSTRACTObjectiveTo assess mothers’ knowledge, attitude, and practices to malaria and its prevention as well as mothers’ willingness to accept the RTS,S/AS01 malaria vaccine.MethodsA cross-sectional study design was used to administer questionnaires to 180 mothers within six public secondary health facilities in Abuja, Nigeria. Regression analyses were used to assess the effect of maternal demographics and exposure to malaria related messages on the outcome measures.ResultsKnowledge of malaria preventive measures was approximately 59% (124/180). Multivariate logistic regression analyses indicated ethnicity, education and number of messages or training on malaria were associated with mother’s knowledge of 3 or more preventive measures against malaria. About 30% (36/180) of respondents were aware of malaria vaccines but only four percent (7/180) had heard of RTS,S. Young maternal age (OR, 2.4; p = 0.03), self-employment (OR, 2.55; p = 0.04) and formal employment (OR, 3.74; p = 0.03) were associated with no prior knowledge of malaria vaccine. Ninety-one percent (163/180) had positive attitude to malaria vaccine and 98% (176/180) were willing to allow their child(ren) to be immunized with RTS,S despite the efficacy of the vaccine, route of administration and number of doses.ConclusionKnowledge of malaria preventive measures does not correlate with knowledge of RTS,S. Although willingness to accept RTS,S is high, consistent targeted messaging on RTS,S would be required to improve community knowledge and attitude prior to implementation to ensure maximum uptake.
Repeated measures ASCA+ for analysis of longitudinal intervention studies with multivariate outcome data
Authors: Madssen Torfinn S. , Giskeødegård Guro F. , Smilde Age K. , Westerhuis Johan A. 
Published: December 2020

AbstractLongitudinal intervention studies with repeated measurements over time are an important type of experimental design in biomedical research. Due to the advent of “omics”-sciences (genomics, transcriptomics, proteomics, metabolomics), longitudinal studies generate increasingly multivariate outcome data. Analysis of such data must take both the longitudinal intervention structure and multivariate nature of the data into account. The ASCA+-framework combines general linear models with principal component analysis, and can be used to separate and visualize the multivariate effect of different experimental factors. However, this methodology has not yet been developed for the more complex designs often found in longitudinal intervention studies, which may be unbalanced, involve randomized interventions, and have substantial missing data. Here we describe a new methodology, repeated measures ASCA+ (RM-ASCA+), and show how it can be used to model metabolic changes over time, and compare metabolic changes between groups, in both randomized and non-randomized intervention studies. Tools for both visualization and model validation are discussed. This approach can facilitate easier interpretation of data from longitudinal clinical trials with multivariate outcomes.Author summaryClinical trials are increasingly generating large amounts of complex biological data. Examples can include measuring metabolism or gene expression in tissue or blood sampled repeatedly over the course of a treatment. In such cases, one might wish to compare changes in not one, but hundreds, or thousands of variables simultaneously. In order to effectively analyze such data, both the study design and the multivariate nature of the data should be considered during data analysis. ANOVA simultaneous component analysis+ (ASCA+) is a statistical method which combines general linear models with principal component analysis, and provides a way to separate and visualize the effects of different factors on complex biological data. In this work, we describe how repeated measures linear mixed models, a class of models commonly used when analyzing changes over time and treatment effects in longitudinal studies, can be used together with ASCA+ for analyzing clinical trials in a novel method called repeated measures-ASCA+ (RM-ASCA+).
A first-in-human evaluation of the safety and immunogenicity of SCB-2019, an adjuvanted, recombinant SARS-CoV-2 trimeric S-protein subunit vaccine for COVID-19 in healthy adults; a phase 1, randomised, double-blind, placebo-controlled trial
Authors: Richmond Peter , Hatchuel Lara , Dong Min , Ma Brenda , Hu Branda , Smolenov Igor , Li Ping , Liang Peng , Han Htay Htay , Liang Joshua , Clemens Ralf 
Published: December 2020

ABSTRACTBackgroundAs part of the accelerated development of prophylactic vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) we report a first-in-human dose-finding and adjuvant justification study of SCB-2019, a novel protein subunit vaccine candidate composed of a stabilised trimeric form of the spike (S)-protein produced in CHO-cells, combined with two different adjuvants.MethodsThis phase 1 study was done in one centre in Western Australia in 151 healthy adult volunteers in two age groups (18–54 and 55–75 years), allocated to 15 groups (nine young and six older adults) to receive two doses, 21 days apart, of placebo, or 3 μg, 9 μg or 30 μg SCB-2019, alone or adjuvanted with AS03 or CpG/Alum. Reactogenicity was assessed for 7 days after each vaccination. Humoral responses were measured as SCB-2019 binding and ACE2-competitive binding IgG antibodies by ELISA, and as neutralising antibodies by wild-type SARS-CoV-2 microneutralisation assay; cellular responses to pooled S-protein peptides were measured by flow-cytometric intracellular cytokine staining.FindingsWe report on 148 participants with at least 4 weeks follow-up post dose 2. Three participants withdrew, two for personal reasons and one with an unrelated SAE (pituitary adenoma). Vaccination was well tolerated, with few Grade 3 solicited adverse events (AE). Most local AEs were mild injection site pain, which were more frequent with formulations containing AS03 than CpG/Alum or unadjuvanted SCB-2019. Systemic AEs, mostly transient headache, fatigue or myalgia, were more frequent in young adults than older adults after the first dose, but similar after second doses. Unadjuvanted SCB-2019 elicited minimal immune responses, but SCB-2019 with fixed doses of AS03 or CpG/Alum induced high titres and seroconversion rates of binding and neutralising antibodies in both young and older adults. Titres were higher than those observed in a panel of COVID-19 convalescent sera in all AS03 groups and high dose CpG/Alum groups. Both adjuvanted formulations elicited Th1-biased CD4+ T cell responses.InterpretationSCB-2019 trimeric protein formulated with AS03 or CpG/Alum adjuvants elicited robust humoral and cellular immune responses against SARS-CoV-2 with high viral neutralising activity. Both adjuvanted formulations were well tolerated and are suitable for further clinical development.Clinical trial registrationClinicalTrials.gov identifier NCT04405908.