bluuebunny/crossref_metadata_2025_split huggingface dataset:
Causal factors affecting gross motor function in children diagnosed with cerebral palsy
Authors: MacWilliams Bruce A. , Prasad Sarada , Shuckra Amy L. , Schwartz Michael H. 
Published: October 2020

AbstractCerebral palsy (CP) is a complex neuromuscular condition which may negatively impact gross motor function. Children diagnosed with CP often exhibit spasticity, weakness, reduced motor control, contracture, and bony malalignment. Despite many previous association studies, the causal impact of these impairments on motor function is unknown. In this study, we propose a causal model for motor function as measured by the 66-item Gross Motor Function Measure (GMFM-66), and estimate the direct and total effect sizes of these common impairments using linear regression based on covariate adjustment sets implied by the causal model. We evaluated 300/314 consecutive subjects with cerebral palsy who underwent routine clinical gait analysis. The largest effect sizes, as measured by standardized regression coefficients (standard error), were for static motor control (direct = 0.35 (0.04), total = = 0.40 (0.04)) and dynamic motor control (direct = 0.26 (0.04), total = 0.31 (0.04)), followed by strength (direct = 0.23 (0.04), total = 0.26 (0.04)). The next largest effect was found for gait deviations (direct = total = 0.15 (0.04)). In contrast, common treatment targets, such as spasticity (direct = 0.05 (0.03), total = 0.08 (0.03)) and orthopedic deformity (direct = 0.00 (0.03) to 0.08 (0.03), total = −0.01 (0.03) to 0.11 (0.03)), had relatively small effects. We also show that effect sizes estimated from bivariate models, which fail to appropriately adjust for other causal factors dramatically overestimate the total effect of spasticity (510%), strength (271%), and orthopedic deformity (192% to -2017%). Understanding the relative influences of impairments on gross motor function will allow clinicians to direct treatments at those impairments with the greatest influence on gross motor function and provide realistic expectations of the anticipated functional changes.
Sex-specific classification of drug-induced Torsade de Pointes susceptibility using cardiac simulations and machine learning
Authors: Iseppe Alex Fogli , Ni Haibo , Zhu Sicheng , Zhang Xianwei , Coppini Raffaele , Yang Pei-Chi , Srivatsa Uma , Clancy Colleen E. , Edwards Andrew G. , Morotti Stefano , Grandi Eleonora 
Published: October 2020

AbstractTorsade de Pointes (TdP), a rare but lethal ventricular arrhythmia, is a toxic side effect of many drugs. To assess TdP risk, safety regulatory guidelines require quantification of hERG channel blockin vitroand QT interval prolongationin vivofor all new therapeutic compounds. Unfortunately, these have proven to be poor predictors of torsadogenic risk, and are likely to have prevented safe compounds from reaching clinical phases. While this has stimulated numerous efforts to define new paradigms for cardiac safety, none of the recently developed strategies accounts for patient conditions. In particular, despite being a well-established independent risk factor for TdP, female sex is vastly underrepresented in both basic research and clinical studies, and thus current TdP metrics are likely biased toward the male sex. Here, we apply statistical learning to synthetic data, generated by simulating drug effects on cardiac myocyte models capturing male and female electrophysiology, to develop new sex-specific classification frameworks for TdP risk. We show that (1) TdP classifiers require different features in females vs. males; (2) malebased classifiers perform more poorly when applied to female data; (3) female-based classifier performance is largely unaffected by acute effects of hormones (i.e., during various phases of the menstrual cycle). Notably, when predicting TdP risk of intermediate drugs on female simulated data, male-biased predictive models consistently underestimate TdP risk in women. Therefore, we conclude that pipelines for preclinical cardiotoxicity risk assessment should consider sex as a key variable to avoid potentially lifethreatening consequences for the female population.
Deep Neural Network Models of Object Recognition Exhibit Human-Like Limitations when Performing Visual Search Tasks
Authors: Nicholson David A. , Prinz Astrid A. 
Published: October 2020

ABSTRACTTo find an object we are looking for, we must recognize it. Prevailing models of visual search neglect recognition, focusing instead on selective attention mechanisms. These models account for performance limitations that participants exhibit when searching highly simplified stimuli often used in laboratory tasks. However, it is unclear how to apply these models to complex natural images of real-world objects. Deep neural networks (DNN) can be applied to any image, and recently have emerged as state-of-the-art models of object recognition in the primate ventral visual pathway. Using these DNN models, we ask whether object recognition explains limitations on performance across visual search tasks. First, we show that DNNs exhibit a hallmark effect seen when participants search simplified stimuli. Further experiments show this effect results from optimizing for object recognition: DNNs trained from randomly-initialized weights do not exhibit the same performance limitations. Next, we test DNN models of object recognition with natural images, using a dataset where each image has a visual search difficulty score, derived from human reaction times. We find DNN accuracy is inversely correlated with visual search difficulty score. Our findings suggest that to a large extent visual search performance is explained by object recognition.
Race specific differences in DNA damage repair dysregulation in breast cancer and association with outcome
Authors: Mazumder Aloran , Jimenez Athena , Ellsworth Rachel E , Freedland Stephen J , George Sophia , Bainbridge Matthew , Haricharan Svasti 
Published: October 2020

AbstractIMPORTANCEAfrican American (AA) breast cancer patients have worse outcomes than Caucasian Americans (CAs). DNA damage repair (DDR) genes drive poor outcome in CA estrogen receptor (ER)+ breast cancer patients. Whether DDR genes similarly impact survival in AAs is unknown. Identifying AA-specific patterns of DDR dysregulation could change how we tailor predictive/prognostic biomarkers.OBJECTIVETo characterize DDR dysregulation in ER+ AA patient tumors and test associations with clinical outcome.DESIGN SETTINGS AND PARTICIPANTSThree independent tumor, and two normal breast datasets were analyzed. Tumor datasets: (1) GSE78958 (2) GSE18229 (3) The Cancer Genome Atlas (TCGA). Normal datasets: (4) GSE43973 (5) GSE50939.MAIN OUTCOME AND MEASURESUp/down-regulation of 104 DDR genes was assessed in AA samples vs CAs. Survival associations were assessed for genes dysregulated in multiple datasets.RESULTSOverall, RNA levels of single strand break repair (SSBR) genes were downregulated in AA tumors and double strand break repair (DSBR) genes were upregulated compared to CAs. While SSBR downregulation was mainly detected in tumors, DSBR upregulation was detectable in both tumor and normal breast AA samples. Seven specific DDR genes identified as dysregulated in AAs vs CAs in multiple datasets associated with poor survival. A subset of tumors with simultaneous dysregulation of homologous recombination and single strand break repair genes was enriched in AAs and had associated consistently with poor survival.CONCLUSION AND RELEVANCEOverall, these results constitute the first systematic analysis of differences in DDR regulation in AA ER+ tumors and normal tissue vs CAs. We identify a profile of DDR dysregulation enriched in AA patients, which associates with poor outcome. These results suggest a distinct molecular mechanism of DDR regulation in AAs that lays the groundwork for refining biomarker profiles by race and improving precision medicine for underserved populations.
ISG15-dependent Activation of the RNA Sensor MDA5 and its Antagonism by the SARS-CoV-2 papain-like protease
Authors: Liu GuanQun , Lee Jung-Hyun , Parker Zachary M. , Acharya Dhiraj , Chiang Jessica J. , van Gent Michiel , Riedl William , Davis-Gardner Meredith E. , Wies Effi , Chiang Cindy , Gack Michaela U. 
Published: October 2020

ABSTRACTActivation of the RIG-I-like receptors, RIG-I and MDA5, establishes an antiviral state by upregulating interferon (IFN)-stimulated genes (ISGs). Among these is ISG15 whose mechanistic roles in innate immunity still remain enigmatic. Here we report that ISGylation is essential for antiviral IFN responses mediated by the viral RNA sensor MDA5. ISG15 conjugation to the caspase activation and recruitment domains of MDA5 promotes the formation of higher-order assemblies of MDA5 and thereby triggers activation of innate immunity against a range of viruses including coronaviruses, flaviviruses and picornaviruses. The ISG15-dependent activation of MDA5 is antagonized through direct de-ISGylation mediated by the papain-like protease (PLpro) of SARS-CoV-2, a recently emerged coronavirus that causes the COVID-19 pandemic. Our work demonstrates a crucial role for ISG15 in the MDA5-mediated antiviral response, and also identifies a novel immune evasion mechanism of SARS-CoV-2, which may be targeted for the development of new antivirals and vaccines to combat COVID-19.
Genetic determinants of COVID-19 drug efficacy revealed by genome-wide CRISPR screens
Authors: Jiang Wei , Yang Ailing , Ma Jingchuan , Lv Dawei , Liu Mingxian , Xu Liang , Wang Chao , He Zhengjin , Chen Shuo , Zhao Jie , Chen Shishuang , Jiang Qi , Chu Yankai , Shan Lin , Zhou Zhaocai , Zhao Yun , Long Gang , Jiang Hai 
Published: October 2020

AbstractImmunomodulatory agents dexamethasone and colchicine, antiviral drugs remdesivir, favipiravir and ribavirin, as well as antimalarial drugs chloroquine phosphate and hydroxychloroquine are currently used in the combat against COVID-191–16. However, whether some of these drugs have clinical efficacy for COVID-19 is under debate. Moreover, these drugs are applied in COVID-19 patients with little knowledge of genetic biomarkers, which will hurt patient outcome. To answer these questions, we designed a screen approach that could employ genome-wide sgRNA libraries to systematically uncover genes crucial for these drugs’ action. Here we present our findings, including genes crucial for the import, export, metabolic activation and inactivation of remdesivir, as well as genes that regulate colchicine and dexamethasone’s immunosuppressive effects. Our findings provide preliminary information for developing urgently needed genetic biomarkers for these drugs. Such biomarkers will help better interpret COVID-19 clinical trial data and point to how to stratify COVID-19 patients for proper treatment with these drugs.
Exact Matching of Trabectome-Mediated Ab Interno Trabeculectomy to Conventional Trabeculectomy with Mitomycin C Followed for Two Years
Authors: Strzalkowska A. , Strzalkowski P. , Al Yousef Y. , Grehn F. , Hillenkamp J. , Loewen N. A. 
Published: October 2020

AbstractPurposeWe used exact matching for a highly balanced comparison of ab interno trabeculectomy (AIT) with the trabectome to trabeculectomy with mitomycin C (TRAB).Methods5485 patients who underwent AIT were exact-matched to 196 TRAB patients by baseline intraocular pressure (IOP), number of glaucoma medications, and glaucoma type. Nearest-neighbor-matching was applied to age. Success was defined as a final IOP of less than 21 mmHg, IOP reduction of at least 20% reduction from baseline, and no secondary surgical interventions. Outcomes were measured at 1, 3, 6, 12, 18, and 24 months.Results165 AIT could be matched to 165 TRAB. The mean baseline IOP was 22.3±5.6 mmHg, and the baseline number of glaucoma medications was 2.7±1.1 in both groups. At 24 months, IOP was reduced to 15.8±5.2 mmHg in AIT and 12.4±4.7 mmHg in TRAB. IOP was lower than baseline at all visits (p<0.01) and lower in TRAB than AIT (p<0.01). Glaucoma medications were reduced to 2.1 ± 1.3 in AIT and 0.2 ± 0.8 in TRAB. Compared to baseline, patients used fewer drops postoperatively (p<0.01) and more infrequently in TRAB than in AIT (p>0.01). Secondary surgical interventions had the highest impact on success and became necessary in 15 AIT and 59 TRAB patients. Thirty-two challenging events occurred in TRAB and none in AIT.ConclusionBoth AIT and TRAB reduced IOP and medications. This reduction was more significant in TRAB but at the expense of four times as many secondary interventions.Key messagesDespite vastly different IOP reduction and safety profile, ab interno trabeculectomy with the Trabectome and trabeculectomy with mitomycin C are both used as primary glaucoma surgeries. Exact matching allowed us to strictly focus on identical IOP and medications to create highly similar patient pairs for a balanced comparison that cannot be accomplished short of a randomized controlled trial. We found that trabeculectomy could achieve low IOPs and independence from drops, but trabeculectomies often required postoperative interventions. Trabectome patients had a lesser reduction of IOP and drops but needed far fewer interventions.
Knowledge, attitudes, and perceptions of long-acting reversible contraceptive (LARC) methods among healthcare workers in sub-Saharan Africa: a systematic review and meta-analysis
Authors: Rouncivell Laura , Takuva Simbarashe , Ledibane Neo , Musekiwa Alfred , Leong Trudy D 
Published: October 2020

ABSTRACTObjectiveTo assess the knowledge, attitudes, and perceptions (KAP) of long-acting reversible contraceptive (LARC) methods among healthcare workers (HCWs) in sub-Saharan Africa (SSA).MethodsA systematic review and meta-analysis were conducted following the PRISMA methodology. Two authors independently searched three electronic databases for studies published between 2000 and January 2020 reporting on the KAP of LARC methods among HCWs in SSA. Titles and abstracts were screened against eligibility criteria, data were extracted and the included studies were assessed for risk of bias. A meta-analysis of proportions for 11 pre-determined questions relating to LARC KAP was performed. Heterogeneity was explored using the I2-statistic and publication bias investigated using funnel plots and Egger’s tests.ResultsTwenty-two studies comprising of 11 272 HCWs from 11 SSA countries were included. Forty-one percent (95% CI: 20%, 61%) of HCWs had received intrauterine contraceptive device (IUCD) insertion training while 63% (95% CI: 44%, 81%) expressed a desire for training. Only 27% (95% CI: 18%, 36%) deemed IUCD appropriate for HIV-infected women. Restrictions for IUCD and injectables based on a minimum age were imposed by 56% (95% CI: 33%, 78%) and 60% (95% CI: 36%, 84%), respectively. Minimum parity restrictions were observed among 29% (95% CI: 9%, 50%) of HCWs for IUCDs and 36% (95% CI: 16%, 56%) for injectable contraceptives. Heterogeneity was high and publication bias was present in two of the 11 questions.ConclusionThe systematic review and meta-analysis indicate that unnecessary provider-imposed restrictions may hinder the uptake of LARC methods by women in SSA.Conflicts of InterestNone.Ethics approvalEthical approval was received from the Faculty of Health Sciences Research Ethics Committee (REC) at the University of Pretoria, School of Health Systems and Public Health. Reference Number: 640/2019Authors ContributionsAll authors contributed to the design of the study and the preparation of the manuscript. LR, ST and AM contributed toward the statistical analysis. All authors read and approved the content of the manuscript.
Corona-Independent Excess Mortality Due to Reduced Use of Emergency Medical Care in the Corona Pandemic: A Population-Based Observational Study
Authors: Kortüm S. , Frey P. , Becker D. , Ott H.-J. , Schlaudt H-P. 
Published: October 2020

AbstractBackgroundA significant decrease in the number of cases of emergency medical care during the first phase of the Corona pandemic has been reported from various regions of the world. Due to the lack of or delayed use of medical assistance, particularly in the case of time-critical clinical pictures (myocardial infarction, stroke), a corona collateral damage syndrome is postulated regarding possible health consequences. The present study investigates changes in the use of preclinical and clinical emergency care and effects on overall mortality in a rural area.MethodsThe number of patients in the emergency department at the Klinikum Hochrhein and the ambulance service were retrospectively aggregated and analyzed regarding the total number and selected tracer diagnoses and alarm keywords. The investigation period was the 9th to 22nd calendar week 2020 compared to the identical period of the previous year. In addition, the death rates in the district were collected directly from the registries and related to the number of patients in emergency care.ResultsOverall, the number of patients in clinical and preclinical emergency care declined significantly during the investigation period. This concerned in particular emergency inpatient treatment of patients with exacerbations or complications of severe chronic diseases. At the same time, excess mortality occurred in April 2020, which was still highly significant even after excluding deaths on or with COVID-19.DiscussionOnly about 55 % of the excess mortality in April 2020 can be attributed to COVID-19 and is associated with the decline in inpatient emergency treatment, especially of chronically ill patients. Since a drift of patients with the use of other service providers is unlikely, we assume that fears of infection in overburdened hospitals, one-sided public communication and reporting, and the extent of contact restrictions have contributed significantly to the decline in case numbers and to excess mortality (collateral damage).ConclusionFor similar situations in the future, it is strongly recommended to make crisis communication and media coverage more balanced so as not to prevent people with acute health problems from receiving medical assistance. Contact restrictions should be critically reviewed and limited to the objectively necessary minimum.
Prevalence and outcomes of co-infection and super-infection with SARS-CoV-2 and other pathogens: A Systematic Review and Meta-analysis
Authors: Musuuza Jackson , Watson Lauren , Parmasad Vishala , Putman-Buehler Nathan , Christensen Leslie , Safdar Nasia 
Published: October 2020

AbstractIntroductionThe recovery of other respiratory viruses in patients with SARS-CoV-2 infection has been reported, either at the time of a SARS-CoV-2 infection diagnosis (co-infection) or subsequently (superinfection). However, data on the prevalence, microbiology and outcomes of co-infection and super infection are limited. The purpose of this study was to examine occurrence of respiratory co-infections and superinfections and their outcomes among patients with SARS-CoV-2 infection.Patients and MethodsWe searched literature databases for studies published from October 1, 2019, through June 11, 2020. We included studies that reported clinical features and outcomes of co-infection or super-infection of SARS-CoV-2 and other pathogens in hospitalized and non-hospitalized patients. We followed PRISMA guidelines and we registered the protocol with PROSPERO as: CRD42020189763.ResultsOf 1310 articles screened, 48 were included in the random effects meta-analysis. The pooled prevalence of co-infection was 12% (95% confidence interval (CI): 6%-18%, n=29, I2=98%) and that of super-infection was 14% (95% CI: 9%-21%, n=18, I2=97%). Pooled prevalence of pathogen type stratified by co- or super-infection: viral co-infections, 4% (95% CI: 2%-7%); viral super-infections, 2% (95% CI: 0%-7%); bacterial co-infections, 4% (95% CI: 1%-8%); bacterial super-infections, 6% (95% CI: 2%-11%); fungal co-infections, 4% (95% CI: 1%-8%); and fungal super-infections, 4% (95% CI: 0%-11%). Compared to those with co-infections, patients with super-infections had a higher prevalence of mechanical ventilation [21% (95% CI: 13%-31%) vs. 7% (95% CI: 2%-15%)] and greater average length of hospital stay [mean=12.5 days, standard deviation (SD) =5.3 vs. mean=10.2 days, SD= 6.7].ConclusionsOur study showed that as many as 14% of patients with COVID-19 have super-infections and 12% have co-infections. Poor outcomes were associated with super-infections. Our findings have implications for diagnostic testing and therapeutics, particularly in the upcoming respiratory virus season in the Northern Hemisphere.
Genome-wide Association Study of Non-syndromic Orofacial Clefts in a Multiethnic Sample of Families and Controls Identifies Novel Regions
Authors: Mukhopadhyay Nandita , Feingold Eleanor , Moreno-Uribe Lina , Wehby George , Valencia-Ramirez Luz Consuelo , Restrepo Muñeton Claudia P. , Padilla Carmencita , Deleyiannis Frederic , Christensen Kaare , Poletta Fernando A. , Orioli Ieda M , Hecht Jacqueline T. , Buxó Carmen J. , Butali Azeez , Adeyemo Wasiu L. , Vieira Alexandre R. , Shaffer John R. , Murray Jeffrey C. , Weinberg Seth M. , Leslie Elizabeth J. , Marazita Mary L. 
Published: October 2020

AbstractOrofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic and vary in prevalence by ethnicity. Africans have the lowest prevalence of OFCs (∼ 1/2,500), Asians have the highest prevalence (∼1/500), European and Latin Americans lie somewhere in the middle (∼1/800 and 1/900 respectively). Thus, ethnicity appears to be a major determinant of the risk of developing OFC. The Pittsburgh Orofacial Clefts Multiethnic study was designed to explore this ethnic variance, comprising a large number of families and individuals (∼12,000 individuals) from multiple populations worldwide: US and Europe, Asians, mixed Native American/Caucasians, and Africans. In this current study, we analyzed 2,915 OFC cases, 6,044 unaffected individuals related to the OFC cases, and 2,685 controls with no personal or family history of OFC. Participants were grouped by their ancestry into African, Asian, European, and Central and South American subsets, and genome-wide association run on the combined sample as well as the four ancestry-based groups. We observed 22 associations to cleft lip with or without cleft palate at 18 distinct loci with p-values < 1e-06, including 10 with genome-wide significance (< 5e-08), in the combined sample and within ancestry groups. Three loci - 2p12 (rs62164740, p=6.27e-07), 10q22.2 (rs150952246, p=3.14e-07), and 10q24.32 (rs118107597, p=8.21e-07) are novel. Nine were in or near known OFC loci - PAX7, IRF6, FAM49A, DCAF4L2, 8q24.21, NTN1, WNT3-WNT9B, TANC2, and RHPN2. The majority of the associations were observed only in the combined sample, European, and Central and South American groups. We investigated whether the observed differences in association strength were a) purely due to sample sizes, b) due to systematic allele frequency difference at the population level, or (c) due to the fact certain OFC-causing variants confer different amounts of risk depending on ancestral origin, by comparing effect sizes to observed allele frequencies of the effect allele in our ancestry-based groups. While some of the associations differ due to systematic differences in allele frequencies between groups, others show variation in effect size despite similar frequencies across ancestry groups.