bluuebunny/crossref_metadata_2025_split huggingface dataset:
National Increase but Pronounced Regional Disparities in Naloxone Prescribing to United States Medicaid and Medicare Patients
Authors: Manko Christopher D. , Ahmed Mohamed S. , Harrison Lavinia H. , Kodavatiganti Sree , Lugo Noelia , Konadu Jason O. , Khan Farrin , Massari Carrie A. , Sealey Tenisha K. , Addison Maame Efua , Mbah Celine N. , McCall Kenneth L. , Fraiman Joseph B. , Piper Brian J. 
Published: May 2023

AbstractBackgroundOpioid overdoses in the US have increased to unprecedented levels. Administration of the opioid antagonist naloxone can prevent overdoses. This study was conducted to reveal the pharmacoepidemiologic patterns in naloxone prescribing to Medicaid patients from 2018-2021 as well as Medicare in 2019.MethodsThe Medicaid State Drug Utilization Data File was utilized to extract information on number of prescriptions and amount prescribed of naloxone at a national and state level. States with naloxone prescription rates differing from the mean by ≥ 1.96 standard deviations were considered statistically significant. The Medicare Provider Utilization and Payment was also utilized to analyze prescription data from 2019.ResultsThe number of generic naloxone prescriptions per 100,000 Medicaid enrollees decreased 5.15% whereas brand naloxone prescriptions increased 245.00% from 2018-2021. There was a 33.14-fold difference in prescriptions between the highest (New Mexico = 1809.55) and lowest (South Dakota = 54.61) states in 2019. Medicare saw a 30.32-fold difference in prescriptions between the highest (New Mexico) and lowest states (also South Dakota) after correcting per 100,000 enrollees.ConclusionsThis pronounced increase in the number of naloxone prescriptions to Medicaid patients from 2018-2021 indicates a national response to this widespread public health emergency. Further research into the origins of the pronounced state-level disparities is warranted.
eoPred: Predicting the placental phenotype of early-onset preeclampsia using DNA methylation
Authors: Fernández-Boyano I. , Inkster A.M. , Yuan V. , Robinson W.P. 
Published: May 2023

AbstractBackgroundA growing body of literature has reported molecular and histological changes in the human placenta in association with preeclampsia (PE). Placental DNA methylation (DNAme) and transcriptomic patterns have revealed molecular subgroups of PE that are associated with placental histopathology and clinical phenotypes of the disease. However, the heterogeneity of PE both across and within subtypes, whether defined clinically or molecularly, complicates the study of this disease. PE is most strongly associated with placental pathology and adverse fetal and maternal outcomes when it develops early in pregnancy. We focused on placentae from pregnancies affected by preeclampsia that were delivered before 34 weeks of gestation to develop eoPred, a predictor of the DNAme signature associated with the placental phenotype of early-onset preeclampsia (EOPE).ResultsPublic data from 83 placental samples (HM450K), consisting of 42 EOPE and 41 normotensive preterm birth (nPTB) cases, was used to develop eoPred - a supervised model that relies on a highly discriminative 45 CpG DNAme signature of EOPE in the placenta. The performance of eoPred was assessed using cross-validation (AUC=0.95) and tested in an independent validation cohort (n=49, AUC=0.725). A subset of fetal growth restriction (FGR) and late-PE cases showed a similar DNAme profile at the 45 predictive CpGs, consistent with the overlap in placental pathology between these conditions. The relationship between the EOPE probability generated by eoPred and various phenotypic variables was also assessed, revealing that it is associated with gestational age, and it is not driven by cell composition differences.ConclusionseoPred relies on a 45 CpG DNAme signature to predict EOPE, and it can be used in a discrete or continuous manner. Using this classifier should 1) improve the consistency of future placental DNAme studies of PE and placental insufficiency, 2) facilitate identifying cases of EOPE in public data sets and 3) importantly, standardize the placental diagnosis to allow better cross-cohort comparisons. Lastly, classification of cases with eoPred should be useful for testing associations between placental pathology and genetic or environmental variables.
Trends in age, sex and racial differences in the incidence of infective endocarditis in Florida and New York
Authors: Anuforo Anderson , Aneni Ehimen , Akintoye Emmanuel , Anikpezie Nnabuchi , Patel Smit D. , Soipe Ayorinde , Olojakpoke Eloho , Burke Devin , Latorre Julius Gene , Khandelwal Priyank , Chaturvedi Seemant , Ovbiagele Bruce , Otite Fadar Oliver 
Published: May 2023

AbstractBackgroundHow the incidence of infective endocarditis (IE) changed in various age, sex and racial/ethnic subgroups of the United States along with the worsening opioid epidemic over the last decade is unknown.MethodsWe utilized data from the 2007-2018 State Inpatient Databases (SID)) of two large demographically diverse states (Florida and New York) to conduct a retrospective cohort study. Cases of incident IE identified using validated International Classification of Diseases codes were combined with census data to compute age, sex- and race-specific incidence. Joinpoint regression was used to quantify the annualized percentage change (APC) in incidence over time.ResultsOf 98,221 incident IE admissions, 70.0% were Non-Hispanic White (NHW) and 60.6% were ≥ 65 years old (yo). The average annual age and sex-standardized incidence of IE in cases/100,000 population was 19.2 (95%CI 18.7-19.6) but this varied by age, sex and race. Incidence was ≈20% higher in men (20.9 [95%CI 20.2-21.7]) compared to women (17.5 [95%CI 16.8-18.2]) and increased with age in both sexes. Incidence was higher in Non-Hispanic Blacks (NHB); 22.5(95%CI 21.0-23.9) compared to NHW: 20.0(95%CI 19.3 to 20.6), Hispanic: 13.2(95%CI 12.3-14.1) and Asian/Pacific Islander patients: 5.9(95%CI 4.7 to 7.1). The age and sex-standardized incidence did not change over time (APC 0.5%,p=0.646). However, incidence increased in women 18-44 (APC 11.0%,p<0.001), men 18-44 (APC 7.3,p<0.001) and 45-64 yo (APC 1.5%,p=0.002) but declined in women ≥ 65 yo (APC −2.8,p=0.049). Most of this increased incidence occurred in NHW women 18-44 (APC 16.6%,p<0.001), NHW men 18-44 (APC 10.6%,p<0.001), NHW men 45-64 (APC 2.8%,p<0.001) and Hispanic Men 18-44 yo (APC 5.6%,p<0.001). Incidence did not change over time in these age/sex groups of NHB and in other age/sex groups. Prevalence of opioid use disorder increased by >2-fold in all age/sex groups over time but the pace of increase was faster in NHW women and men 18-44 yo compared to other races of similar demography (p-for-time interaction <0.001).ConclusionOver the last two decades, among residents of Florida and New York, incidence of IE increased in several demographic groups, but the most prominent rise was among young NHWs, particularly young NHW women.
The transcription factor OsbZIP48 governs rice responses to zinc deficiency
Authors: Hu Shubao , Du Binbin , Mu Guangmao , Jiang Zichen , Li Hui , Song Yuxinrui , Zhang Baolei , Xia Jixing , Rouached Hatem , Zheng Luqing 
Published: May 2023

AbstractZinc deficiency is the most prevalent micronutrient disorder in rice and leads to delayed development and decreased yield. Nevertheless, despite its primary importance, how rice responds to zinc deficiency remains poorly understood. Herein, we present genetic evidence that OsbZIP48 is essential for regulating rice responses to zinc deficiency. Using the reverse genetics approach, genetic inactivation ofOsbZIP48in rice seedlings caused a hyper sensitivity to zinc deficiency, associated with a significant decrease in the root-to-shoot translocation of zinc. Consistently,OsbZIP48was constitutively expressed in roots, slightly induced by zinc deficiency in shoots, and localized into nuclei induced by Zn deficiency. Comparative transcriptome analysis of the wild-type plants andosbzip48mutant grown under zinc deficiency enabled the identification of OsbZIP48 target genes, including key zinc transporter genes (OsZIP4andOsZIP8). We demonstrated that OsbZIP48 controlled the expressions of these genes by directly binding to their promoters, specifically to the zinc deficiency response element (ZDRE) motif. Collectively, we showed that theOsbZIP48gene encodes for a transcription factor in rice, and demonstrates its critical role in the response to zinc deficiency in this crop. This knowledge is crucial for the design of rice plants that are resilient to the globally prevalent zinc limitation through zinc bio-fortification programs.
HIV co-infection increases the risk of post-tuberculosis mortality among persons who initiated treatment for drug-resistant tuberculosis
Authors: Salindri Argita D. , Kipiani Maia , Lomtadze Nino , Tukvadze Nestani , Avaliani Zaza , Blumberg Henry M. , Masyn Katherine E. , Rothenberg Richard B. , Kempker Russell R. , Magee Matthew J. 
Published: May 2023

ABSTRACTLittle is known regarding the relationship between common comorbidities in persons with tuberculosis (TB) (including human immunodeficiency virus [HIV], diabetes, and hepatitis C virus [HCV]) with post-TB mortality. We conducted a retrospective cohort study among persons who initiated treatment for rifampicin-resistant and multi/extensively drug-resistant (RR and M/XDR) TB reported to the country of Georgia’s TB surveillance during 2009-2017. Exposures included HIV serologic status, diabetes, and HCV status. Our outcome was all-cause post-TB mortality determined by cross-validating vital status with Georgia’s death registry through November 2019. We estimated adjusted hazard rate ratios (aHR) and 95% confidence intervals (CI) of post-TB mortality among participants with and without comorbidities using cause-specific hazard regressions. Among 1032 eligible participants, 34 (3.3%) died during treatment and 87 (8.7%) died post-TB treatment. Among those who died post-TB treatment, the median time to death was 21 months (interquartile range 7–39) post-TB treatment. After adjusting for confounders, the hazard rates of post-TB mortality were higher among participants with HIV co-infection (aHR=3.74, 95%CI 1.77–7.91) compared to those without HIV co-infection. In our cohort, post-TB mortality occurred most commonly in the first three years post-TB treatment. Linkage to care for common TB comorbidities post-treatment may reduce post-TB mortality rates.
Lack of univariate, clinically-relevant biomarkers of autism in resting state EEG: a study of 776 participants
Authors: Dede Adam J. O , Xiao Wenyi , Vaci Nemanja , Cohen Michael X , Milne Elizabeth 
Published: May 2023

ABSTRACTMental health conditions are difficult to diagnose, requiring expert clinicians and subjective judgements. There has been interest in finding quantitative biomarkers using resting state electroencephalogram (EEG) data. Here, we focus on resting state EEG biomarkers of autism. Although many previous reports have pointed to differences between autistic and neurotypical participants, results have often failed to replicate and sample sizes have typically been small. Taking a big-data, open-science approach, we combined data from 5 studies to create a large sample of autistic and neurotypical individuals (n=776) and used high-power computing to extract 942 variables from each participant’s data. Using a systematic, preregistered analysis pipeline, we failed to identify even a single EEG-based variable that could serve as a practically useful biomarker of autism clinical diagnosis. Our results highlight that a biomarker for autism drawn from EEG data is an elusive construct that may not exist.
ECG predictors of AF: a systematic review (Predicting AF in Ischaemic Stroke-PrAFIS)
Authors: Berry-Noronha Alexander , Bonavia Luke , Song Edmund , Grose Daniel , Johnson Damian , Maylin Erin , Oqueli Ernesto , Sahathevan Ramesh 
Published: May 2023

AbstractIn 25% of patients presenting with embolic stroke, a cause is not determined. Atrial fibrillation (AF) is a commonly identified mechanism of stroke in this population, particularly in older patients. Conventional investigations are used to detect AF, but can we predict AF in this population and generally? We performed a systematic review to identify potential predictors of AF on 12-lead electrocardiogram (ECG).MethodWe conducted a search of EMBASE and Medline databases for prospective and retrospective cohorts, meta-analyses or case-control studies of ECG abnormalities in sinus rhythm predicting subsequent atrial fibrillation. We assessed quality of studies based on the Newcastle-Ottawa scale and data were extracted according to PRISMA guidelines.ResultsWe identified 42 studies based on our criteria. ECG patterns that predicted the risk of developing AF included interatrial block, P-wave terminal force lead V1, P-wave dispersion, abnormal P-wave-axis, abnormal P-wave amplitude, prolonged PR interval, left ventricular hypertrophy, QT prolongation, ST-T segment abnormalities and atrial premature beats. Furthermore, we identified that factors such as increased age, high CHADS-VASC, chronic renal disease further increase the positive-predictive value of some of these parameters. Several of these have been successfully incorporated into clinical scoring systems to predict AF.ConclusionThere are several ECG abnormalities that can predict AF both independently, and with improved predictive value when combined with clinical risk factors, and if incorporated into clinical risk scores. Improved and validated predictive models could streamline selection of patients for cardiac monitoring and initiation of oral anticoagulants.
Preregistration and Credibility of Clinical Trials*
Authors: Decker Christian , Ottaviani Marco 
Published: May 2023

AbstractPreregistration at public research registries is considered a promising solution to the credibility crisis in science, but empirical evidence of its actual benefit is limited. Guaranteeing research integrity is especially vital in clinical research, where human lives are at stake and investigators might suffer from financial pressure. This paper analyzes the distribution of p-values from pre-approval drug trials reported toClinicalTrials.gov, the largest registry for research studies in human volunteers, conditional on the preregistration status. The z-score density of non-preregistered trials displays a significant upward discontinuity at the salient 5% threshold for statistical significance, indicative of p-hacking or selective reporting. The density of preregistered trials appears smooth at this threshold. With caliper tests, we establish that these differences between preregistered and non-preregistered trials are robust when conditioning on sponsor fixed effects and other design features commonly indicative of research integrity, such as blinding and data monitoring committees. Our results suggest that preregistration is a credible signal for the integrity of clinical trials, as far as it can be assessed with the currently available methods to detect p-hacking.
Vaccine-mediated protection against merbecovirus and sarbecovirus challenge in mice
Authors: Martinez David R. , Schaefer Alexandra , Gavitt Tyler D. , Mallory Michael L. , Lee Esther , Catanzaro Nicholas J. , Chen Haiyan , Gully Kendra , Scobey Trevor , Korategere Pooja , Brown Alecia , Smith Lena , Parks Rob , Barr Maggie , Newman Amanda , Bowman Cindy , Powers John M. , Mansouri Katayoun , Edwards Robert J. , Baric Ralph S. , Haynes Barton F. , Saunders Kevin O. 
Published: May 2023

SUMMARYThe emergence of three distinct highly pathogenic human coronaviruses – SARS-CoV in 2003, MERS-CoV in 2012, and SARS-CoV-2 in 2019 – underlines the need to develop broadly active vaccines against theMerbecovirusandSarbecovirusbetacoronavirus subgenera. While SARS-CoV-2 vaccines are highly protective against severe COVID-19 disease, they do not protect against other sarbecoviruses or merbecoviruses. Here, we vaccinate mice with a trivalent sortase-conjugate nanoparticle (scNP) vaccine containing the SARS-CoV-2, RsSHC014, and MERS-CoV receptor binding domains (RBDs), which elicited live-virus neutralizing antibody responses and broad protection. Specifically, a monovalent SARS-CoV-2 RBD scNP vaccine only protected against sarbecovirus challenge, whereas the trivalent RBD scNP vaccine protected against both merbecovirus and sarbecovirus challenge in highly pathogenic and lethal mouse models. Moreover, the trivalent RBD scNP elicited serum neutralizing antibodies against SARS-CoV, MERS-CoV and SARS-CoV-2 BA.1 live viruses. Our findings show that a trivalent RBD nanoparticle vaccine displaying merbecovirus and sarbecovirus immunogens elicits immunity that broadly protects mice against disease. This study demonstrates proof-of-concept for a single pan-betacoronavirus vaccine to protect against three highly pathogenic human coronaviruses spanning two betacoronavirus subgenera.
StructuralDPPIV: A novel deep learning model based on atom-structure for predicting dipeptidyl peptidase-IV inhibitory peptides
Authors: Wang Ding , Jin Junru , Li Zhongshen , Wang Yu , Fan Mushuang , Liang Sirui , Su Ran , Wei Leyi 
Published: May 2023

AbstractMotivationDiabetes is a chronic metabolic disorder that has been a major cause of blindness, kidney failure, heart attacks, stroke, and lower limb amputation across the world. To alleviate the impact of diabetes, researchers have developed the next generation of anti-diabetic drugs, known as dipeptidyl peptidase IV inhibitory peptides (DPP-IV-IPs). However, the discovery of these promising drugs has been restricted due to the lack of effective peptide-mining tools.ResultsHere, we presented StructuralDPPI V, a deep learning model designed for DPP-IV-IP identification, which takes advantage of both molecular graph features in amino acid and sequence information. Experimental results on the independent test dataset and two wet experiment datasets show that our model outperforms the other state-of-art methods. Moreover, to better study what StructuralDPPIV learns, we used CAM technology and perturbation experiment to analyze our model, which yielded interpretable insights into the reasoning behind prediction results.AvailabilityThe project code is available athttps://github.com/WeiLab-BioChem/Structural-DPP-IV.Contactweileyi@sdu.edu.cn,ran.su@tju.edu.cn
GASOLINE: detecting germline and somatic structural variants from long-reads data
Authors: Magi Alberto , Mattei Gianluca , Mingrino Alessandra , Caprioli Chiara , Ronchini Chiara , Frigè GianMaria , Semeraro Roberto , Bolognini Davide , Colombo Emanuela , Mazzarella Luca , Pelicci Pier Giuseppe 
Published: May 2023

AbstractLong-read sequencing allows analyses of single nucleic-acid molecules and produces sequences in the order of tens to hundreds kilobases. Its application to whole-genome analyses allows identification of complex genomic structural-variants (SVs) with unprecedented resolution. SV identification, however, requires complex computational methods, based on either read-depth or intra- and inter-alignment signatures approaches, which are limited by size or type of SVs. Moreover, most currently available tools only detect germline variants, thus requiring separate computation of sample pairs for comparative analyses. To overcome these limits, we developed a novel tool (Germline And SOmatic structuraL varIants detectioN and gEnotyping; GASOLINE) that groups SV signatures using a sophisticated clustering procedure based on a modified reciprocal overlap criterion, and is designed to identify germline SVs, from single samples, and somatic SVs from paired test and control samples. GASOLINE is a collection of Perl, R and Fortran codes, it analyzes aligned data in BAM format and produces VCF files with statistically significant somatic SVs. Germline or somatic analysis of 30x sequencing coverage experiments requires 4-5 hours with 20 threads. GASOLINE outperformed currently available methods in the detection of both germline and somatic SVs in synthetic and real long-reads datasets. Notably, when applied on a pair of metastatic melanoma and matched-normal sample, GASOLINE identified 6 genuine somatic SVs that were missed using five different sequencing technologies and state-of-the art SV calling approaches. Thus, GASOLINE identifies germline and somatic SVs with unprecedented accuracy and resolution, outperforming currently available state-of-the-art WGS long-reads computational methods.
Conditional control of universal CAR T cells by cleavable OFF-switch adaptors
Authors: Kvorjak Michael , Ruffo Elisa , Tivon Yaniv , So Victor , Parikh Avani B. , Deiters Alexander , Lohmueller Jason 
Published: May 2023

AbstractAs living drugs, engineered T cell therapies are revolutionizing disease treatment with their unique functional capabilities. However, they suffer from limitations of potentially unpredictable behavior, toxicities, and non-traditional pharmacokinetics. Engineering conditional control mechanisms responsive to tractable stimuli such as small molecules or light is thus highly desirable. We and others previously developed “universal” chimeric antigen receptors (CARs) that interact with co-administered antibody adaptors to direct target cell killing and T cell activation. Universal CARs are of high therapeutic interest due to their ability to simultaneously target multiple antigens on the same disease or different diseases by combining with adaptors to different antigens. Here, we further enhance the programmability and potential safety of universal CAR T cells by engineering OFF-switch adaptors that can conditionally control CAR activity, including T cell activation, target cell lysis, and transgene expression, in response to a small molecule or light stimulus. Moreover, in adaptor combination assays, OFF-switch adaptors were capable of orthogonal conditional targeting of multiple antigens simultaneously following Boolean logic. OFF-switch adaptors represent a robust new approach for precision targeting of universal CAR T cells with potential for enhanced safety.
A single-cell atlas of the single versus multiple parous Hu Sheep ovary
Authors: Ge Ting , Wen Yifan , Li Bo , Huang Xiaoyu , Jiang Shaohua , Zhang Enping 
Published: May 2023

AbstractIn the modern sheep production system, the reproductive performance of ewes determines the economic profitability of farming. The mechanism of difference in litter size is important for the selection and breeding of high-fecundity ewes. Hu sheep is a high-quality sheep breed with high fecundity in China and is ideal for investigating high reproductive traits. In the current study, the sheep with lambing number ≥3 in three consecutive lambing records were assigned to the HLS group, and lambing number = 1 as the LLS group selected from the same farm with three consecutive lambing. Three randomly picked ewes were slaughtered within 12 h of estrus, and unilateral ovarian tissue was collected and analyzed by single-cell RNA sequencing in each group. A total of five types of somatic cells were identified, and corresponding expression profiles were mapped in the ovaries of the Hu sheep. Additionally, the results of the difference in ovary somatic cell expression profiles between HLS and LLS present that the differences between multiples vs. singleton Hu sheep were mainly clustered in the GCs. In addition, 4 granulosa cell subtypes were identified. GeneSwitches results revealed the opening ofJPH1expression and the closure ofLOC101112291, which leads to different evolutionary directions of the granular cells. The expression levels ofFTH1andFTLin GCs of Hu sheep in the HLS group were significantly higher, which inhibited necroptosis and ferroptosis of mural– GCs from decreasing follicular atresia. This study constructed the cellular atlas of the ovary and revealed related biological characteristics at the cellular molecular level. It provides a theoretical basis for the mechanisms underlying the differences in ovulation numbers, which contributes to breeding high-fertility sheep and molecular genetics-based selection.