bluuebunny/crossref_metadata_2025_split huggingface dataset:
Causes of Outcome Learning: A causal inference-inspired machine learning approach to disentangling common combinations of potential causes of a health outcome
Authors: Rieckmann A , Dworzynski P , Arras L , Lapuschkin S , Samek W , Arah OA , Rod NH , Ekstrøm CT 
Published: December 2020

AbstractNearly all diseases can be caused by different combinations of exposures. Yet, most epidemiological studies focus on the causal effect of a single exposure on an outcome. We present the Causes of Outcome Learning (CoOL) approach, which seeks to identify combinations of exposures (which can be interpreted causally if all causal assumptions are met) that could be responsible for an increased risk of a health outcome in population sub-groups. The approach allows for exposures acting alone and in synergy with others. It involves (a) a pre-computational phase that proposes a causal model; (b) a computational phase with three steps, namely (i) analytically fitting a non-negative additive model, (ii) decomposing risk contributions, and (iii) clustering individuals based on the risk contributions into sub-groups based on the predefined causal model; and (c) a post-computational phase on hypothesis development and validation by triangulation on new data before eventually updating the causal model. The computational phase uses a tailored neural network for the non-negative additive model and Layer-wise Relevance Propagation for the risk decomposition through this model. We demonstrate the approach on simulated and real-life data using the R package ‘CoOL’. The presentation is focused on binary exposures and outcomes but can be extended to other measurement types. This approach encourages and enables epidemiologists to identify combinations of pre-outcome exposures as potential causes of the health outcome of interest. Expanding our ability to discover complex causes could eventually result in more effective, targeted, and informed interventions prioritized for their public health impact.
HEALTH OUTCOMES IN COPD SMOKERS USING HEATED TOBACCO PRODUCTS: A 3-YEAR FOLLOW-UP
Authors: Polosa R , Morjaria JB , Prosperini U , Busà B , Pennisi A , Gussoni G , Rust S , Maglia M , Caponnetto P 
Published: December 2020

ABSTRACTBackgroundGiven that many patients with chronic obstructive pulmonary disease (COPD) smoke despite their symptoms, it is important to understand the long term health impact of cigarette substitution with heated tobacco products (HTPs). We monitored health parameters for 3-years in COPD patients who substantially attenuated or ceased cigarette consumption after switching to HTPs.MethodsChanges in daily cigarette smoking, annualized disease exacerbations, lung function indices, patients reported outcomes (CAT scores) and 6-minute walk distance (6MWD) from baseline were measured in COPD patients using HTPs at 12, 24 and 36 months. These were compared to a group of age- and sex-matched COPD patients who continued smoking.ResultsComplete data sets were available for 38 patients (19 in each group). Subjects using HTPs had a substantial decrease in annualized COPD exacerbations within the group mean (±SD) from 2.1 (±0.9) at baseline to 1.4 (±0.8), 1.2 (±0.8) and 1.3 (±0.8) at 12-, 24- and 36-month follow-up (p<0.05 for all visits). In addition, substantial and clinically significant improvements in CAT scores and 6MWD were identified at all 3 time points in the HTP cohort. No significant changes were observed in COPD patients who continued smoking.ConclusionsThis study is the first to describe the long-term health effects of HTP use in COPD patients. Consistent improvements in respiratory symptoms, exercise tolerance, quality of life, and rate of disease exacerbations were observed in patients with COPD who abstained from smoking or substantially reduced their cigarette consumption by switching to HTP use.
Projecting the impact of a two-dose COVID-19 vaccination campaign in Ontario, Canada
Authors: Vilches Thomas N. , Zhang Kevin , Van Exan Robert , Langley Joanne M. , Moghadas Seyed M. 
Published: December 2020

AbstractBackgroundA number of highly effective COVID-19 vaccines have been developed and approved for mass vaccination. We evaluated the impact of vaccination on COVID-19 outbreak and disease outcomes in Ontario, Canada.MethodsWe used an agent-based transmission model and parameterized it with COVID-19 characteristics, demographics of Ontario, and age-specific clinical outcomes. We implemented a two-dose vaccination program according to tested schedules in clinical trials for Pfizer-BioNTech and Moderna vaccines, prioritizing healthcare workers, individuals with comorbidities, and those aged 65 and older. Daily vaccination rate was parameterized based on vaccine administration data. Using estimates of vaccine efficacy, we projected the impact of vaccination on the overall attack rate, hospitalizations, and deaths. We further investigated the effect of increased daily contacts at different stages during vaccination campaigns on outbreak control.ResultsMaintaining non-pharmaceutical interventions (NPIs) with an average of 74% reduction in daily contacts, vaccination with Pfizer-BioNTech and Moderna vaccines was projected to reduce hospitalizations by 27.3% (95% CrI: 22.3% - 32.4%) and 27.0% (95% CrI: 21.9% - 32.6%), respectively, over a one-year time horizon. The largest benefits of vaccination were observed in preventing deaths with reductions of 31.5% (95% CrI: 22.5% - 39.7%) and 31.9% (95% CrI: 22.0% - 41.4%) for Pfizer-BioNTech and Moderna vaccines, respectively, compared to no vaccination. We found that an increase of only 10% in daily contacts at the end of lockdown, when vaccination coverage with only one dose was 6%, would trigger a surge in the outbreak. Early relaxation of population-wide measures could lead to a substantial increase in the number of infections, potentially reaching levels observed during the peak of the second wave in Ontario.ConclusionsVaccination can substantially mitigate ongoing COVID-19 outbreaks. Sustaining population-wide NPIs, to allow for a sufficient increase in population-level immunity through vaccination, is essential to prevent future outbreaks.
Common variants near the bradykinin receptor B2gene are associated with angioedema induced by angiotensin-converting-enzyme inhibitor treatment - a genome wide association study
Authors: Ghouse Jonas , Ahlberg Gustav , Andreasen Laura , Banasik Karina , Brunak Søren , Schwinn Michael , Larsen Ina Holst , Petersen Oscar , Sørensen Erik , Ullum Henrik , Rasmussen Eva Rye , Eriksson Niclas , Hallberg Pär , Wadelius Mia , Bundgaard Henning , Olesen Morten S. 
Published: December 2020

ABSTRACTObjectiveAngioedema is a rare, but potentially life-threatening adverse reaction, associated with angiotensin-converting-enzyme inhibitors (ACEi). Identification of potential genetic factors related to this adverse event may help identify at-risk patients.Design, Setting and ParticipantsA genome-wide association study (GWAS) involving patients of European descent, all taking ACEi was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as persons with an angioedema event and a filled prescription for an ACEi 180 days prior to the event. Controls were defined as persons with continuous treatment with ACEi without any history of angioedema. Odds ratios (ORs) and 95 % confidence intervals (95 % CI) were computed for angioedema risk by logistic mixed model regression analysis. Summary statistics from the discovery and the replication cohorts were analyzed with a fixed effects meta-analysis model.ExposureSingle-nucleotide polymorphisms associated with ACEi-associated angioedema.Main outcomeHospital record of angioedema.ResultsThe discovery cohort consisted of 462 cases and 53,391 ACEi-treated controls. The replication cohort consisted of 144 cases and 1,345 ACEi-treated controls. In the discovery cohort, we identified one locus, residing at chromosome 14q32.2, that was associated with angioedema at the genome-wide significance level ofP <5 × 10−8. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream ofBDKRB2(OR 1.62; 95 % CI 1.38 to 1.90;P= 4.3 × 10−9). This variant was validated in our replication cohort with similar direction and effect size (OR 1.60; 95 % CI 1.13 to 2.25;P= 7.2 × 10−3). We found that carriers of the risk allele had significantly lower systolic (−0.46 mmHg per T allele; 95 % CI −0.83 to −0.10;P= 0.013) and diastolic blood pressure (−0.26 mmHg per T allele; 95 % CI −0.46 to −0.05;P= 0.013).ConclusionIn this GWAS, involving individuals treated with ACEi, we found that common variants located in close proximity to the bradykinin receptor B2gene were associated with ACEi-related angioedema.BDKRB2genotype-directed therapy may aid in improving safety in evidence-based clinical decision-making.
QT Interval Prolongation in Patients Treated for COVID-19
Authors: Habibzadeh Parham , Sarami Abdollah , Yadollahie Mahboobeh , Hashemiasl Kourosh , Salahi Arezoo , Habibzadeh Farrokh 
Published: December 2020

AbstractBackgroundMany of the drugs commonly used for the treatment of COVID-19 cause QT interval prolongation and increase the risk of life-threatening cardiac arrhythmias. It has been shown that maintaining serum potassium and magnesium levels above 4 and 3 mg/dL, respectively, would prevent the QTc prolongation.ObjectiveTo determine if keeping only the serum magnesium level above 3 mg/dL could be considered an effective measure to prevent QTc prolongation in patients with COVID-19 receiving these drugs.MethodsIn a retrograde observational study, QTc interval was measured in 14 patients diagnosed with COVID-19 before and 3 days after initiation of treatment with either hydroxychloroquine or lopinavir-ritonavir, while their serum magnesium levels were kept ≥3 mg/dL.ResultsThe baseline QTc interval of 412 (SD 36) ms significantly increased by an average of 34 (95% CI 13 to 55) ms after 3 days of treatment. 5 patients, mostly those with lower serum potassium levels, had QTc prolongation ≥60 ms.ConclusionAlthough it seems that the risk of fatal cardiac arrhythmias in this setting is not high, it is prudent to monitor the serum electrolytes, particularly potassium, in patients with COVID-19 who are treated with either hydroxychloroquine or lopinavir-ritonavir.
Kinetics of SARS-CoV-2 antibody responses pre- and post- COVID-19 convalescent plasma transfusion in patients with severe respiratory failure: an observational case-control study
Authors: Klein Matthew N. , Wang Elizabeth Wenqian , Zimand Paul , Beauchamp Heather , Donis Caitlin , Ward Matthew D. , Martinez-Hernandez Aidaelis , Tabatabai Ali , Baddley John W. , Bloch Evan M. , Mullins Kristin E. , Fontaine Magali J. 
Published: December 2020

ABSTRACTOBJECTIVESTo investigate if COVID-19 convalescent plasma (CCP) transfusion in patients with severe respiratory failure will increase plasma levels of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) antibody titers while improving survival and clinical outcomes.DESIGNObservational, retrospective, control study of anti-Receptor binding domain (RBD) of SARS-CoV-2 IgG and IgM titers from serial plasma samples drawn before and after CCP administration. Clinical improvement in CCP recipients is assessed and compared to COVID-19 control patients.SETTINGPatients hospitalized with severe COVID19, United States, between April 17 and July 19, 2020PARTICIPANTS34 patients hospitalized with severe or life threatening COVID-19 and who consented and received a CCP transfusion, 95 control patients with COVID-19 not transfused with CCP. 34 out the 95 control patients were matched for age, sex, and the level of respiratory support required. Patients less than 18 years old were excluded.MAIN OUTCOME MEASURESSerial trends of anti-RBD of SARS-CoV-2 IgG and IgM titers in CCP recipients are compared to those in control patients. The primary outcome is survival at 30 days, and the secondary outcomes are length of ventilatory and/or extracorporeal membrane oxygenation (ECMO) support, length of stay (LOS) in the hospital, and LOS in the ICU.RESULTSCCP transfusion occurred in 34 patients at a median of 12 days following COVID-19 symptom onset. Immediately prior to CCP transfusion, patients median anti-RBD SARS-CoV-2 IgG and IgM titers were 1:3200 (IQR, 1:50 to 1:9600) and 1:320 (IQR, 1:40 to 1:640) respectively. Following a Loess regression analysis, the kinetics and distribution of anti-RBD of SARS-CoV-2 IgG and IgM in plasma from CCP recipients were comparable to those from a control group of 68 patients who did not receive CCP. CCP recipients presented with similar survival, similar duration on ventilatory and/or ECMO support, as well as ICU and hospital LOS, compared to a matched control group of 34 patients.CONCLUSIONIn the present study, hospitalized COVID-19 patients with severe respiratory failure transfused with CCP presented with high titers of SARS-CoV-2 IgG antibodies before transfusion and did not show improved survival at 30 days.
Understanding Suicide in Our Community Through the Lens of the Pediatric ICU: An Epidemiological Review (2011-2017) of One Midwestern City in the US
Authors: Kampfschulte Andrew , Oram Matthew , Escobar Vasco Alejandra M. , Essenmacher Brittany , Herbig Amy , Behere Aniruddh , Leimanis-Laurens Mara L. , Rajasekaran Surender 
Published: December 2020

AbstractSuicide frequency has tripled for some pediatric age groups over the last decade, of which, serious attempts result in pediatric intensive care unit (PICU) admissions. We paired clinical, aggregate geospatial, and temporal demographics to understand local community variables to determine if epidemiological patterns emerge that associate with risk for PICU admission. Data was extracted at an urban, high-volume, quaternary care facility from January 2011 to December 2017 via ICD 10 codes associated with suicide. Clinical, socioeconomic, geographical, and temporal variables were reviewed. 1,036 patients over age 9 were included, of which n=161 were PICU admissions. Females represented higher proportions of all suicide-related hospital admissions (67.9%). Looking at race/ethnicity, PICU admissions were largely Caucasian (83.2%); Blacks and Hispanics had lower odds of PICU admissions (OR: 0.49; 0.17, respectively). PICU-admitted patients were older (16.0 vs. 15.5; p=0.0001), with lower basal metabolic index (23.0 vs. 22.0; p=0.0013), and presented in summer months (OR: 1.51, p = 0.044). Time-series decomposition showed seasonal peaks in June and August. Local regions outside city limits identified higher numbers of PICU admissions. PICUs serve discrete geographical regions and are a source of information, when paired with clinical-geospatial/seasonal analyses, highlighting clinical and societal risk factors associated with PICU admissions.
Mathematical modelling projections versus the actual course of the COVID-19 epidemic following the nationwide lockdown in Kyrgyzstan
Authors: Moldokmatova Ainura , Estebesova Aida , Dooronbekova Aizhan , Zhumalieva Chynar , Mukambetov Aibek , Abdyldaev Talant , Kubatova Aisuluu , Ibragimov Shamil , Usenbaev Nurbolot , Kutmanova Ainura , White Lisa J 
Published: December 2020

AbstractKyrgyzstan was placed under a two-month, nationwide lockdown due to the COVID-19 epidemic, starting on March 25, 2020. Given the highly disruptive effects of the lockdown on the national economy and people’s lives, the government decided not to extend lockdown beyond the initially planned date of May 10, 2020. The strategy chosen by the government was close to the input parameters of our model’s baseline scenario, ‘full lockdown release’, which we presented to policymakers in April 2020, along with various other hypothetical scenarios with managed lockdown release options. To explore whether our model could accurately predict the actual course of the epidemic following the release of lockdown, we compared the outputs of the baseline scenario, such as new cases, deaths, and demand for and occupancy of hospital beds, with actual official reports. Our analysis revealed that the model could accurately predict the timing of the epidemic peak, with a difference of just two weeks, although the magnitude of the peak was overestimated compared with the official statistics. However, it is important to note that the accuracy of the official reports remains debatable, so outputs relating to the size of the epidemic and related pressures on the health system will need to be updated if new evidence becomes available.
Signal and noise in circRNA translation
Authors: Hansen TB 
Published: December 2020

AbstractWithin recent years, circular RNAs (circRNAs) have been an attractive new field of research in RNA biology and disease. Consequently, numerous studies have been published towards the disclosure of circRNA biogenesis and function. Initially, circRNAs were described as a subclass of cytoplasmic non-coding RNA, however, a few recent observations have proposed that circRNAs may instead be templates for protein production. The extent to which this is the case is currently debated, and therefore using rigorous data analysis and proper experimental setups is instrumental to settle the current controversies. Here, the conventional experiments used for detecting circRNA translation are outlined, and guidelines to distinguish signal from the inherent noise are discussed. While these guidelines are specific for circRNA translation, most also apply to all other aspects of non-canonical translation.
Metabolic potential for reductive acetogenesis and a novel energy-converting [NiFe] hydrogenase inBathyarchaeiafrom termite guts – a genome-centric analysis
Authors: Loh Hui Qi , Hervé Vincent , Brune Andreas 
Published: December 2020

AbstractSymbiotic digestion of lignocellulose in the hindgut of higher termites is mediated by a diverse assemblage of bacteria and archaea. During a large-scale metagenomic study, we reconstructed 15 metagenome-assembled genomes (MAGs) ofBathyarchaeiathat represent two distinct lineages in subgroup 6 (formerly MCG-6) unique to termite guts. One lineage (TB2;CandidatusTermitimicrobium) encodes all enzymes required for reductive acetogenesis from H2and CO2via an archaeal variant of the Wood–Ljungdahl pathway. This includes a novel 11-subunit hydrogenase, which possesses the genomic architecture of the respiratory Fpo-complex of other archaea but whose catalytic subunit is phylogenetically related to and shares the conserved [NiFe] cofactor-binding motif with [NiFe] hydrogenases of subgroup 4g. We propose that this novel Fpo-like hydrogenase provides the reduced ferredoxin required for CO2reduction and is driven by the electrochemical membrane potential generated from the ATP conserved by substrate-level phosphorylation. Members of the other lineage (TB1;CandidatusTermiticorpusculum) are not capable of lithotrophic acetogenesis because they consistently lack hydrogenases and/or methylene-tetrahydromethanopterin reductase, a key enzyme of the pathway. Both lineages have the genomic capacity to reduce ferredoxin by oxidizing amino acids and might conduct methylotrophic acetogenesis using unidentified methylated compound(s). Our results indicate thatBathyarchaeiaof subgroup 6 contribute to acetate formation in the guts of higher termites and substantiate the genomic evidence for reductive acetogenesis from organic substrates, including methylated compounds, in other uncultured representatives of the phylum.
Multi-omics insights into host-viral response and pathogenesis in Crimean-Congo Hemorrhagic Fever Viruses for novel therapeutic target
Authors: Neogi Ujjwal , Elaldi Nazif , Appelberg Sofia , Ambikan Anoop T. , Kennedy Emma , Dowall Stuart , Bagci Binnur K. , Gupta Soham , Rodriguez Jimmy E. , Svensson-Akusjärvi Sara , Monteil Vanessa M. , Végvári Ákos , Benfeitas Rui , Banerjea Akhil C. , Weber Friedemann , Hewson Roger , Mirazimi Ali 
Published: December 2020

AbstractThe pathogenesis and host-viral interactions of the Crimean–Congo hemorrhagic fever orthonairovirus (CCHFV) are convoluted and not well evaluated. Application of the multi-omics system biology approaches including biological network analysis in elucidating the complex host-viral response, allow for interrogating the viral pathogenesis. The present study aimed to fingerprint the system-level alterations during acute CCHFV-infection and the cellular immune responses during productive CCHFV-replicationin vitro. We used system-wide network-based system biology analysis of peripheral blood mononuclear cells (PBMCs) from a longitudinal cohort of CCHF patients during the acute phase of infection and after one year of recovery (convalescent phase) and untargeted quantitative proteomics analysis of the most permissive CCHFV-infected Huh7 and SW13 cells. In the RNAseq analysis of the PBMCs, comparing the acute and convalescent-phase, we observed system-level host’s metabolic reprogramming towards central carbon and energy metabolism (CCEM) with distinct upregulation of oxidative phosphorylation (OXPHOS) during CCHFV-infection. Upon application of network-based system biology methods, negative coordination of the biological signaling systems like FOXO/Notch axis and Akt/mTOR/HIF-1 signaling with metabolic pathways during CCHFV-infection were observed. The temporal quantitative proteomics in Huh7 showed a dynamic change in the CCEM over time and was in agreement with the cross-sectional proteomics in SW13 cells. By blocking the two key CCEM pathways, glycolysis and glutaminolysis, viral replication was inhibitedin vitro. Activation of key interferon stimulating genes during infection suggested the role of type I and II interferon-mediated antiviral mechanisms both at system-level and during progressive replication.Significance StatementA combination of multi-modal systems-wide host-immune response andin vitrotemporal analysis identified molecular re-arrangement in CCEM and fingerprinting the interferon-mediated antiviral mechanism during CCHFV-infection. Using the newly gained insights, we then modulated the key pathways of CCEM by drugs and inhibited the productive CCHFV-replication inin vitroinfection models. Our study thus provides a comprehensive, system-level picture of the regulation of cellular and metabolic pathways during productive CCHFV-infection for the first time that aids in identifying novel therapeutic targets and treatment strategies.