bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bacterial superinfection pneumonia in SARS-CoV-2 respiratory failure
Authors: Pickens Chiagozie O. , Gao Catherine A. , Cuttica Michael , Smith Sean B. , Pesce Lorenzo , Grant Rogan , Kang Mengjia , Morales-Nebreda Luisa , Bavishi Avni A. , Arnold Jason , Pawlowski Anna , Qi Chao , Budinger GR Scott , Singer Benjamin D. , Wunderink Richard G. ,   for the NU COVID Investigators
Published: January 2021

AbstractBackgroundSevere community-acquired pneumonia secondary to SARS-CoV-2 is a leading cause of death. Current guidelines recommend patients with SARS-CoV-2 pneumonia receive empirical antibiotic therapy for suspected bacterial superinfection, but little evidence supports these recommendations.MethodsWe obtained bronchoscopic bronchoalveolar lavage (BAL) samples from patients with SARS-CoV-2 pneumonia requiring mechanical ventilation. We analyzed BAL samples with multiplex PCR and quantitative culture to determine the prevalence of superinfecting pathogens at the time of intubation and identify episodes of ventilator-associated pneumonia (VAP) over the course of mechanical ventilation. We compared antibiotic use with guideline-recommended care.ResultsThe 179 ventilated patients with severe SARS-CoV-2 pneumonia discharged from our hospital by June 30, 2020 were analyzed. 162 (90.5%) patients had at least one BAL procedure; 133 (74.3%) within 48 hours after intubation and 112 (62.6%) had at least one subsequent BAL during their hospitalization. A superinfecting pathogen was identified within 48 hours of intubation in 28/133 (21%) patients, most commonly methicillin-sensitive Staphylococcus aureus or Streptococcus species (21/28, 75%). BAL-based treatment reduced antibiotic use compared with guideline-recommended care. 72 patients (44.4%) developed at least one VAP episode. Only 15/72 (20.8%) of initial VAPs were attributable to multidrug-resistant pathogens. The incidence rate of VAP was 45.2/1000 ventilator days.ConclusionsWith use of sensitive diagnostic tools, bacterial superinfection at the time of intubation is infrequent in patients with severe SARS-CoV-2 pneumonia. Treatment based on current guidelines would result in substantial antibiotic overuse. The incidence rate of VAP in ventilated patients with SARS-CoV-2 pneumonia are higher than historically reported.
A rare missense variant in theATP2C2gene is associated with language impairment and related measures
Authors: Martinelli Angela , Rice Mabel , Talcott Joel B. , Diaz Rebeca , Smith Shelley , Raza Muhammad Hashim , Snowling Margaret J. , Hulme Charles , Stein John , Hayiou-Thomas Marianna E. , Hawi Ziarih , Kent Lindsey , Pitt Samantha J. , Newbury Dianne F. , Paracchini Silvia 
Published: January 2021

ABSTRACTAt least 5% of children present unexpected difficulties in expressing and understanding spoken language. This condition is highly heritable and often co-occurs with other neurodevelopmental disorders such as dyslexia and ADHD. Through an exome sequencing analysis, we identified a rare missense variant (chr16:84405221, GRCh38.p12) in theATP2C2gene.ATP2C2was implicated in language disorders by linkage and association studies, and exactly the same variant was reported previously in a different exome sequencing study for language impairment (LI). We followed up this finding by genotyping the mutation in cohorts selected for LI and comorbid disorders. We found that the variant had a higher frequency in LI cases (1.8%, N=360) compared to cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24,046 gnomAD controls). Additionally, we observed that carriers of the rare variant identified from a general population cohort (N=42, ALSPAC cohort) presented, as a group, lower scores on a range of reading and language-related measures compared to controls (N=1825) (minimum p = 0.002 for nonword reading).ATP2C2encodes for an ATPase (SPCA2) that transports calcium and manganese ions into the Golgi lumen. Our functional characterization suggested that the rare variant influences the ATPase activity of SPCA2. Thus, our results further support the role ofATP2C2locus in language-related phenotypes and pinpoint the possible effects of a specific rare variant at molecular level.
Estimating the long-term health impact of nicotine exposure by dissecting the effects of nicotine versus non-nicotine constituents of tobacco smoke: A multivariable Mendelian randomisation study
Authors: Khouja J. N. , Sanderson E. , Wootton R.E. , Taylor A. E. , Church B. A. , Richmond R. C. , Munafo M. R. 
Published: January 2021

AbstractThe detrimental health effects of smoking are well-known, but the impact of long-term nicotine use without exposure to the other constituents of tobacco is less clear. Given the increasing long-term use of alternative nicotine delivery systems, such as e-cigarettes, it is increasingly important to understand and separate the effects of long-term nicotine use from the impact of tobacco smoke exposure. Using a multivariable Mendelian randomisation framework, we explored the direct effects of nicotine compared with the non-nicotine constituents of tobacco smoke on health outcomes (lung cancer, chronic obstructive pulmonary disease [COPD], forced expiratory volume in one second [FEV-1], forced vital capacity [FVC], coronary heart disease [CHD], and heart rate [HR]). The results suggest that these smoking-related outcomes are not due to nicotine exposure but are caused by the other components of tobacco smoke; however, there are multiple potential sources of bias, and the results should be triangulated using evidence from a range of methodologies.
Variation in waiting times by diagnostic category: an observational study of 1951 referrals to a neurology outpatient clinic
Authors: Biggin Fran , Howcroft Timothy , Davies Quinta , Knight Jo , Emsley Hedley 
Published: January 2021

ABSTRACTObjectiveTo investigate the frequency of diagnoses seen among new referrals to neurology outpatient services; to understand how these services are used through exploratory analysis of diagnostic tests and follow-up appointments; and to examine the waiting times between referral and appointment.MethodsRoutine data from new NHS appointments at a single consultant-delivered clinic between Sept 2016 and January 2019 were collected. These clinical data were then linked to hospital administrative data. The combined data were assigned diagnostic categories based on working diagnoses to allow further analysis using descriptive statistics.ResultsFive diagnostic categories accounted for 62% of all patients seen within the study period, the most common of which was headache disorders. Following a first appointment, 50% of all patients were offered at least one diagnostic test, and 35% were offered a follow-up appointment, with variation in both measures by diagnostic category. Waiting times from referral to appointment also varied by diagnostic category. 65% of patients with a seizure/epilepsy disorder were seen within the 18 week referral to treatment target, compared to 38% of patients with a movement disorder.ConclusionsA small number of diagnostic categories account for a large proportion of new patients. This information could be used in policy decision making to describe a minimum subset of categories for diagnostic coding. We found significant differences in waiting times by diagnostic category, as well as tests ordered, and follow-up offered; further investigation could address causes of variation.
Understanding non-adherence to tuberculosis medications in India using urine drug metabolite testing: a cohort study
Authors: Subbaraman Ramnath , Thomas Beena E. , Kumar J. Vignesh , Thiruvengadam Kannan , Khandewale Amit , Kokila S. , Lubeck-Schricker Maya , Kumar M. Ranjith , Gaurkhede Gunjan Rahul , Walgude Apurva Shashikant , Mercy J. Hephzibah , Kumbhar Jagannath Dattatraya , Eliasziw Misha , Mayer Kenneth H. , Haberer Jessica E. 
Published: January 2021

AbstractBackgroundSuboptimal adherence to tuberculosis (TB) treatment is associated with increased disease recurrence and death. Little research has been conducted in India to understand TB medication non-adherence.MethodsWe enrolled adult drug-susceptible TB patients, about half of whom were people living with HIV (PLHIV), in Chennai, Vellore, and Mumbai. We conducted a single unannounced home visit to administer a survey assessing reasons for non-adherence and collect a urine sample that was tested for isoniazid content. We described patient-reported reasons for non-adherence and identified factors associated with non-adherence (negative urine test) using multivariable logistic regression. We also assessed the association between non-adherence and unfavorable treatment outcomes.ResultsOf 650 patients in the cohort, 77 (11.8%) had a negative urine test result. Non-adherence was independently associated with daily wage labor (aOR 3.1, CI: 1.3—7.7), smear-positive pulmonary disease (aOR 2.1, CI: 1.1—4.1), alcohol use (aOR 2.3, CI: 1.1—4.8), and spending 60 minutes or more picking up medication refills (aOR 9.1, CI: 1.8—45.4). PLHIV reported greater barriers to picking up medications than non-PLHIV. Among 167 patients who reported missing doses, common reasons reported included traveling away from home, forgetting, feeling depressed, and running out of pills. The odds of non-adherence was 3.8 (CI: 2.1—6.9) times higher among patients with unfavorable treatment outcomes compared to those with favorable outcomes.ConclusionAddressing structural and psychosocial barriers will be critical to improve TB treatment adherence in India. Urine isoniazid testing may help identify non-adherent patients to facilitate early intervention during treatment.Key pointsWe evaluated adherence to tuberculosis medications in 650 Indian patients by conducting urine isoniazid tests collected during unannounced home visits. Structural barriers to collecting medication refills and psychosocial barriers emerged as the most important factors contributing to medication non-adherence.
New and Increasing Rates of Adverse Events Can be Found in Unstructured Text in Electronic Health Records using the Shakespeare Method
Authors: Bright Roselie A. , Dowdy Katherine , Rankin Summer K. , Blok Sergey V. , Palmer Lee Anne , Bright-Ponte Susan J. 
Published: January 2021

ABSTRACTBackgroundText in electronic health records (EHRs) and big data tools offer the opportunity for surveillance of adverse events (patient harm associated with medical care) (AEs) in the unstructured notes. Writers may explicitly state an apparent association between treatment and adverse outcome (“attributed”) or state the simple treatment and outcome without an association (“unattributed”). We chose to study EHRs from 2006-2008 because of known heparin contamination during this timeframe. We hypothesized that the prevalence of adulterated heparin may have been widespread enough to manifest in EHRs through symptoms related to heparin adverse events, independent of clinicians’ documentation of attributed AEs.ObjectiveUse the Shakespeare Method, a new unsupervised set of tools, to identify attributed and unattributed potential AEs using the unstructured text of EHRs.MethodsWe studied 21,287 adult critical care admissions divided into three time periods. Comparisons of period 3 (7/2007 to 6/2008) to period 2 (7/2006 to 6/2007) were used to find admissions notes to review for new or increased clinical events by generating Latent Dirichlet Allocation topics among words in period 3 that were distinct from period 2. These results were further explored with frequency analyses of periods 1 (7/2001 to 6/2006) through 3.ResultsTopics represented unattributed heparin AEs, other medical AEs, rare medical diagnoses, and other clinical events; all were verified with EHRs notes review and frequency analysis. The heparin AEs were not attributed in the notes, diagnosis codes, or procedure codes. Somewhat different from our hypothesis, heparin AEs increased in prevalence from 2001 through 2007, and decreased starting in 2008 (when heparin AEs were being published).ConclusionsThe Shakespeare Method could be a useful supplement to AE reporting and surveillance of structured EHRs data. Future improvements should include automation of the manual review process.
Developing research knowledge through special study module: Notes from year 2 medical students
Authors: Rahman S M Niazur , Alam Nazmun Nahar , Alam Tanbira 
Published: January 2021

AbstractIntroductionSpecial Study Module is a mandatory research project implemented in some medical curriculum. For the successful application of evidence-based practice, physicians must understand research methodology before the appraisal of relevant evidence. The objective of this paper is to provide a brief overview of the effectiveness of student research modules in enhancing research understanding.MethodsSecond-year students of undergraduate medical programs were included in this study. At the beginning and after completion of literature review type research projects, the same student cohort completed a questionnaire comprising sections on perceived competency, attitude, and knowledge on research skills. Data from 163 participants who completed both pre and post-survey were analyzed.ResultsPaired t-test revealed significant differences in self-perceived knowledge, attitude, and assessed knowledge of the subjects before and after completing the research modules. Multivariate analysis also displayed a significant increase in self-perceived and assessed knowledge by carrying out the project. No significant association was exhibited by gender and ethnicity.ConclusionsIn summary, the research module improved students’ understanding of research methodology as well as the structure of scientific communication. Further studies to assess the effect of various types of research modules in different study populations are warranted.
PIWI silencing mechanism involving the retrotransposonnimbusorchestrates resistance to infection withSchistosoma mansoniin the snail vector,Biomphalaria glabrata
Authors: Smith Michael , Yadav Swara , Akinyele Olayemi , Pels Nana Adjoa , Horton Daniel , Alsultan Nashwah , Borns Andrea , Cousin Carolyn , Dixon Freddie , Mann Victoria H. , Lee Clarence , Brindley Paul J. , El-Sayed Najib M. , Bridger Joanna M. , Knight Matty 
Published: January 2021

ABSTRACTBackgroundSchistosomiasis remains widespread in many regions despite efforts at its elimination. By examining changes in the transcriptome at the host-pathogen interface in the snailBiomphalaria glabrataand the blood flukeSchistosoma mansoni,we previously demonstrated that an early stress response in juvenile snails, manifested by induction of heat shock protein 70 (Hsp 70) and Hsp 90 and of the reverse transcriptase (RT) domain of theB. glabratanon-LTR-retrotransposon,nimbus, were critical forB. glabratasusceptibility toS. mansoni. Subsequently, juvenileB. glabrataBS90 snails, resistant toS. mansoniat 25°C become susceptible by the F2 generation when maintained at 32°C, indicating an epigenetic response.Methodology/Principal FindingsTo better understand this plasticity in susceptibility of the BS90 snail, mRNA sequences were examined fromS. mansoniexposed juvenile BS90 snails cultured either at 25°C (permissive temperature) or 32°C (non-permissive). Comparative analysis of transcriptomes from snails cultured at the non-permissive and permissive temperatures revealed that whereas stress related transcripts dominated the transcriptome of susceptible BS90 juvenile snails at 32°C, transcripts encoding proteins with a role in epigenetics, such as PIWI (BgPiwi), chromobox protein homolog 1 (BgCBx1), histone acetyl transferase histone deacetylase (HDAC) and metallotransferase (MT) were highly expressed in those cultured at 25°C. To further determine a role forBgPiwiinB. glabratasusceptibility toS. mansoni, siRNA corresponding to theBgPiwiencoding transcript was utilized to suppress expression ofBgPiwi, rendering the resistant BS90 juvenile snail susceptible to infection at 25°C. Given transposon silencing activity of PIWI as a facet of its role as guardian of the integrity of the genome, we examined the expression of thenimbusRT encoding transcript at 120 min after infection of resistant BS90piwi-siRNA treated snails. We observed thatnimbusRT was upregulated, indicating that modulation of the transcription of thenimbusRT was associated with susceptibility toS. mansoniinBgPiwi-siRNA treated BS90 snails. Furthermore, treatment of susceptible snails with the RT inhibitor lamivudine, before exposure toS. mansoni, blockedS. mansoniinfection concurrent with downregulation of thenimbusRT transcript and upregulation of theBgPiwiencoding transcript in the lamivudine-treated, schistosome-exposed susceptible snails.Conclusions and SignificanceThese findings support a role for the interplay ofBgPiwiandnimbusin the epigenetic modulation of plasticity of resistance/susceptibility in the snail-schistosome relationship.
Proximal and Distal Nephron-specific Adaptation to Furosemide
Authors: Krauson Aram J. , Schaffert Steven , Walczak Elisabeth M. , Nizar Jonathan M. , Holdgate Gwen M. , Iyer Sonali , Elsayed Ragwa , Gaudet Alexandre , Khatri Purvesh , Bhalla Vivek 
Published: January 2021

ABSTRACTFurosemide, a widely prescribed diuretic for edema-forming states, inhibits sodium reabsorption in the thick ascending limb of the nephron. Tubular adaptation to diuretics has been observed, but the range of mechanisms along the nephron has not been fully explored. Using morphometry, we show that furosemide induces renal tubular epithelial hyperplasia selectively in distal nephron segments. By comparison, we find progressive cellular hypertrophy in proximal and distal nephron segments. We next utilize single cell RNA sequencing of vehicle- and furosemide-treated mice to define potential mechanisms of diuretic resistance. Consistent with distal tubular cell hyperplasia, we detect a net increase in DCT cell number andBirc5, an anti-apoptotic and pro-growth gene, in a subset of DCT cells, as the most prominently up-regulated gene across the nephron. We also map a gradient of cell-specific transcriptional changes congruent with enhanced distal sodium transport. Furosemide stimulates expression of the mitogen IGF-1. Thus, we developed a mouse model of inducible deletion of renal tubular IGF-1 receptor and show reduced kidney growth and proximal, but not distal, tubular hypertrophy by furosemide. Moreover, genes that promote enhanced bioavailability of IGF-1 includingIgfbp1andIgfbp5are significantly and differentially expressed in proximal tubular segments and correspond to IGF-1R-dependent hypertrophy. In contrast, downstream PI3-kinase signaling genes includingPdk1, Akt1, Foxo3, FKBP4, Eif2BP4, andSpp1are significantly and differentially expressed in distal nephron segments and correspond to IGF-1R-independent hypertrophy. These findings highlight novel mechanisms of tubular remodeling and diuretic resistance, provide a repository of transcriptional responses to a common drug, and expand the implications of long-term loop diuretic use for human disease.
Mutational impact and signature of ionizing radiation
Authors: Youk Jeonghwan , Kwon Hyun Woo , Lim Joonoh , Kim Eunji , Kim Ryul , Park Seongyeol , Yi Kijong , Jeon Sara , Choi Jinwook , Na Hyelin , Lee Eun-Seok , Cho Young-Won , Min Dong-Wook , Kim Hyojin , Kang Yeong-Rok , Choi Si Ho , Bae Min Ji , Lee Chang Geun , Kim Joon-Goon , Kim Young Seo , Lee Dong Soo , Kim Tae You , Ku Taeyun , Kim Su Yeon , Lee Joo-Hyeon , Koo Bon-Kyoung , Lee Hyunsook , Yi On Vox , Han Eon Chul , Chang Ji Hyun , Kim Kyung Su , Son Tae Gen , Ju Young Seok 
Published: January 2021

AbstractWhole-genome sequencing (WGS) of human tumors and normal cells exposed to various carcinogens has revealed distinct mutational patterns that provide deep insights into the DNA damage and repair processes. Although ionizing radiation (IR) is conventionally known as a strong carcinogen, its genome-wide mutational impacts have not been comprehensively investigated at the single-nucleotide level. Here, we explored the mutational landscape of normal single-cells after exposure to the various levels of IR. On average, 1 Gy of IR exposure generated ∼16 mutational events with a spectrum consisting of predominantly small nucleotide deletions and a few characteristic structural variations. In ∼30% of the post-irradiated cells, complex genomic rearrangements, such aschromoplexy, chromothripsis, and breakage-fusion-bridge cycles, were resulted, indicating the stochastic and chaotic nature of DNA repair in the presence of the massive number of concurrent DNA double-strand breaks. These mutational signatures were confirmed in the genomes of 22 IR-induced secondary malignancies. With high-resolution genomic snapshots of irradiated cells, our findings provide deep insights into how IR-induced DNA damage and subsequent repair processes operate in mammalian cells.
Predicting lifestyle and host from positive selection data and genome properties in oomycetes
Authors: Gómez-Pérez Daniel , Kemen Eric 
Published: January 2021

AbstractBackgroundHost and niche shifts are a source of genomic and phenotypic diversification as evidenced in parasitism. Exemplary is core metabolism reduction as parasites adapt to a particular host, while the accessory genome often maintains a high degree of diversification. However, selective pressures acting on the genome of organisms that have undergone lifestyle or host change have not been fully investigated.ResultsHere, we developed a comparative genomics approach to study underlying adaptive trends in oomycetes, a eukaryotic phylum with a broad range of economically important plant and animal parasitic lifestyles. Our analysis reveals converging evolution on biological processes for oomycetes that have similar lifestyle. Besides, we find that certain functions, in particular carbohydrate metabolism, transport, and signaling, are important for host and environmental adaption in oomycetes.DiscussionGiven the high correlation between lifestyle and genome properties in our oomycete dataset and the convergent evolution of fungal and oomycete genomes, we have developed a model that predicts plant pathogen lifestyles with high accuracy based on functional annotations. Understanding how genomes and selective pressures correlate with lifestyle may be crucial to identify new emerging diseases and pandemic threats.