bluuebunny/crossref_metadata_2025_split huggingface dataset:
From sequence data to patient result: a solution for HIV drug resistance genotyping with Exatype, end to end software for Pol-HIV-1 Sequence analysis and patient HIV drug resistance result generation
Authors: King’wara Leonard , Karanja Muthoni , Ngugi Catherine , Kangogo Geoffrey , Bera Kipkerich , Kimani Maureen , Bowen Nancy , Abuya Dorcas , Oramisi Violet , Mukui Irene 
Published: February 2020

AbstractIntroductionWith the rapid scale-up of antiretroviral therapy (ART) to treat HIV infection, there are ongoing concerns regarding probable emergence and transmission of HIV drug resistance (HIVDR) mutations. This scale-up has to lead to an increased need for routine HIVDR testing to inform the clinical decision on a regimen switch. Although the majority of wet laboratory processes are standardized, slow, labor-intensive data transfer and subjective manual sequence interpretation steps are still required to finalize and release patient results. We thus set out to validate the applicability of a software package to generate HIVDR patient results from raw sequence data independently.MethodsWe assessed the performance characteristics of Hyrax Bioscience’s Exatype (a sequence data to patient result, fully automated sequence analysis software, which consolidates RECall, MEGA X and the Stanford HIV database) against the standard method (RECall and Stanford database). Exatype is a web-based HIV Drug resistance bioinformatic pipeline available atsanger.exatype.com. To validate the exatype, we used a test set of 135 remnant HIV viral load samples at the National HIV Reference Laboratory (NHRL).ResultWe analyzed, and successfully generated results of 126 sequences out of 135 specimens by both standard and Exatype software. Result production using Exatype required minimal hands-on time in comparison to the standard (6 computation-hours using the standard method versus 1.5 Exatype computation-hours). Concordance between the two systems was 99.8% for 311,227 bases compared. 99.7 % of the 0.2% discordant bases, were attributed to nucleotide mixtures as a result of the sequence editing in Recall. Both methods identified similar (99.1%) critical antiretroviral resistance-associated mutations resulting in a 99.2% concordance of resistance susceptibility interpretations. Base calling comparison between the two methods had Cohen’s kappa (0.97 to 0.99) implying an almost perfect agreement with minimal base calling variation. On a predefined dataset, RECall editing displayed the highest probability to score mixtures accurately one vs. 0.71 and the lowest chance to inaccurately assign mixtures to pure nucleotides (0.002–0.0008). This advantage is attributable to the manual sequence editing in RECall.ConclusionThe reduction in hands-on time needed is a benefit when using the Exatype HIV DR sequence analysis platform and result generation tool. There is a minimal difference in base calling between Exatype and standard methods. Although the discrepancy has minimal impact on drug resistance interpretation, allowance of sequence editing in Exatype as RECall can significantly improve its performance.
A genetic model of ivabradine recapitulates results from randomized clinical trials
Authors: Legault Marc-André , Sandoval Johanna , Provost Sylvie , Barhdadi Amina , Perreault Louis-Philippe Lemieux , Shah Sonia , Lumbers R.Thomas , de Denus Simon , Tyl Benoit , Tardif Jean-Claude , Dubé Marie-Pierre 
Published: February 2020

ABSTRACTBackgroundNaturally occurring human genetic variants provide a valuable tool to identify drug targets and guide drug prioritization and clinical trial design. Ivabradine is a heart rate lowering drug with protective effects on heart failure despite increasing the risk of atrial fibrillation. In patients with coronary artery disease without heart failure, the drug does not protect against major cardiovascular adverse events prompting questions about the ability of genetics to have predicted those effects. This study evaluates the effect of a mutation in HCN4, ivabradine’s drug target, on safety and efficacy endpoints.MethodsWe used genetic association testing and Mendelian randomization to predict the effect of ivabradine and heart rate lowering on cardiovascular outcomes.ResultsUsing data from the UK Biobank and large GWAS consortia, we evaluated the effect of a heart rate-reducing genetic variant at the HCN4 locus encoding ivabradine’s drug target. These genetic association analyses showed increases in risk for atrial fibrillation (OR 1.09, 95% CI: 1.06-1.13, P=9.3 ×10−9) in the UK Biobank. In a cause-specific competing risk model to account for the increased risk of atrial fibrillation, the HCN4 variant reduced incident heart failure in participants that did not develop atrial fibrillation (HR 0.90, 95% CI: 0.83-0.98, P=0.013). In contrast, the same heart rate reducing HCN4 variant did not prevent a composite endpoint of myocardial infarction or cardiovascular death (OR 0.99, 95% CI: 0.93-1.04, P=0.61).ConclusionGenetic modelling of ivabradine recapitulates its benefits in heart failure, promotion of atrial fibrillation, and neutral effect on myocardial infarction.CONDENSED ABSTRACTThe effects of drugs can sometimes be predicted from the effects of mutations in genes encoding drug targets. We tested the effect of a heart rate reducing allele at the HCN4 locus encoding ivabradine’s drug target and found results coherent with the SHIFT and SIGNIFY clinical trials of ivabradine. The genetic variant increased the risk of atrial fibrillation and cardioembolic stroke and protected against heart failure in a competing risk model accounting for the increased risk of atrial fibrillation. The variant had a neutral effect on a composite of myocardial infarction and cardiovascular death.
Collapsing the list of myocardial infarction-related differential expressed genes into a diagnostic signature
Authors: Osmak German , Baulina Natalia , Koshkin Philipp , Favorova Olga 
Published: February 2020

AbstractMyocardial infarction (MI) is one of the most severe manifestations of coronary artery disease (CAD) and the leading cause of death from non-infectious diseases worldwide. It is known that the central component of CAD pathogenesis is a chronic vascular inflammation. However, the mechanisms underlying the changes that occur in T, B and NK lymphocytes, monocytes and other immune cells during CAD and MI are still poorly understood. One of those pathogenic mechanisms might be the dysregulation of intracellular signaling pathways in the immune cells.In the present study we performed a transcriptome profiling in peripheral blood mononuclear cells of MI patients and controls. The machine learning algorithm was then used to search for MI-associated signatures, that could reflect the dysregulation of intracellular signaling pathways.The genes ADAP2, KLRC1, MIR21, PDGFD and CD14 were identified as the most important signatures for the classification model with L1-norm penalty function. The classifier output quality was equal to 0.911 by Receiver Operating Characteristic metric on test data. These results were validated on two independent open GEO datasets. Identified MI-associated signatures can be further assisted in MI diagnosis and/or prognosis.Thus, our study presents a pipeline for collapsing the list of differential expressed genes, identified by high-throughput techniques, in order to define disease-associated diagnostic signatures.
Apolipoprotein E genotype, lifestyle and coronary artery disease: gene-environment interaction analyses in the UK Biobank population
Authors: Bos Maxime M , de Vries Lina , Rensen Patrick CN , van Dijk Ko Willems , Blauw Gerard Jan , van Heemst Diana , Noordam Raymond 
Published: February 2020

AbstractBackgroundCarriers of theAPOE ε4genotype have an increased risk for developing coronary artery disease (CAD), but there is preliminary evidence that lifestyle factors interact withAPOEgenotype on CAD risk. Here, we assessed the interactions of physical activity, oily fish intake and polyunsaturated fatty acid (PUFA) intake withAPOEgenotype on risk of incident cardiovascular disease in a large population of middle-aged individuals.Methods and ResultsThe present study was embedded in the UK Biobank population and comprised 344,092 European participants (mean age: 56.5 years, 45.7% men) without a history of CAD. Information regarding physical activity, oily fish intake and PUFA intake was collected through questionnaires, and information on incident CAD through linkage with hospital admission records. Analyses were performed using Cox proportional hazard models adjusted for age and sex. From these analyses, higher physical activity level and a higher intake of oily fish were associated with a lower incidence of CAD. These associations were similar across all APOE isoform groups (p-values for interaction > 0.05). A higher PUFA intake was only associated with a lower CAD risk inAPOE ε4carriers (hazard ratio: 0.76, 95% confidence interval: 0.62,0.90), however, no statistically significant interaction was observed (p-valueinteraction= 0.137).ConclusionWhile higher physical activity, fish intake and PUFA intake all decreased the risk of CAD, no evidence for interaction of these lifestyle factors withAPOEgenotype was observed in UK Biobank participants. Interventions intended to reduce cardiovascular risk might therefore be similarly effective across the APOE isoform carriers.
Functional abnormalities in the cerebello-thalamic pathways in an animal model of dystonia
Authors: Margarint Elena Laura , Aïssa Hind Baba , Varani Andrés Pablo , Sala Romain , Menardy Fabien , Pelosi Assunta , Hervé Denis , Léna Clément , Popa Daniela 
Published: February 2020

ABSTRACTDystonia is often associated with functional alterations in the cerebello-thalamic pathways, which have been proposed to contribute to the disorder by propagating pathological firing patterns to the forebrain. Here, we examined the function of the cerebello-thalamic pathways in a model of DYT25 dystonia, mice carrying a heterozygous invalidation ofGnalgene which notably disrupts striatal function, exhibiting dystonic movements and postures following systemic or striatal administration of oxotremorine. Theta-burst optogenetic stimulations of the cerebellar nuclei evoked a potentiation of the responses to cerebellar stimulations in the thalamus and motor cortex in WT mice, without evident motor function disruption. In contrast, theta burst stimulations evoked a depression of these responses only in dystonia-manifestingGnal+/− mice after oxotremorine administration, decreased the disabling dystonia attacks, and increased normal active wake behaviour inGnal+/− mice. The cerebellum could thus offer a gateway for a corrective treatment of motor impairments in dystonia including striatal dysfunction.One sentence summaryA mouse model of DYT25 dystonia, carrying aGnalmutation disrupting striatal neurotransmission, exhibits anomalous cerebello-thalamic plasticity in the non-manifesting state, but theta-burst cerebellar stimulations during cholinergic-induced dystonia depress the cerebello-thalamic transmission and reduce the severity of the motor symptoms.
Improving esophageal protection during AF ablation: The IMPACT study
Authors: Leung Lisa WM , Bajpai Abhay , Zuberi Zia , Li Anthony , Norman Mark , Kaba Riyaz , Akhtar Zaki , Evranos Banu , Gonna Hanney , Harding Idris , Sohal Manav , Al-Subaie Nawaf , Louis-Auguste John , Hayat Jamal , Gallagher Mark M 
Published: February 2020

ABSTRACTBackgroundThermal injury to the esophagus is a known complication of ablation for atrial fibrillation (AF) and accounts for most procedure-related mortality. Thermal protection of the esophageal lumen by infusing cold liquid can reduce thermal injury to a limited extent. A method to control the local luminal esophageal temperature is investigated by this study.ObjectiveTo investigate the ability of a powerful temperature control device to protect the esophagus from ablation-related thermal injury.MethodsA single-center, prospective, double-blinded randomized controlled trial was used to investigate the ability of the ensoETM device to protect the esophagus from thermal injury. This method was compared in a 1:1 randomization to a control group of standard practice utilizing a single-point temperature probe. In the study group, the device was used to keep the luminal temperature at 4°C during radiofrequency (RF) ablation for AF. Endoscopic examination was performed at 7 days post-ablation and esophageal injury was scored. The patient and the endoscopist were blinded to the randomization.ResultsWe recruited 188 patients, of whom 120 underwent endoscopy. Thermal injury to the mucosa was significantly more common in the control group than in those receiving esophageal protection (12/60 versus 2/60; P=0.008), with a trend toward reduction in gastroparesis (6/60 Vs 2/60, p=0.27). There was no difference between groups in RF duration, force, power and combined ablation index (P value range= 0.2-0.9). Procedure duration and fluoroscopy duration were similar (P=0.97, P=0.91 respectively).ConclusionThermal protection of the esophageal lumen significantly reduces ablation-related thermal injury compared to standard care. This method of esophageal protection is safe and does not compromise the efficacy of the ablation procedure.CONDENSED ABSTRACTThermal injury to the esophagus causes most ablation-related deaths. We investigated the ability of a powerful method of esophageal temperature control to protect from thermal lesions during ablation, using a double-blinded randomized clinical trial to compare this to standard care. Patients randomised to receive thermal protection experienced significantly fewer lesions to the esophageal mucosa and a trend towards reduction in gastroparesis. Procedure efficacy and efficiency were not compromised.
Is mammography screening beneficial: An individual-based stochastic model for breast cancer incidence and mortality
Authors: Le Thuy T. T. , Adler Frederick R. 
Published: February 2020

AbstractBACKGROUNDThe benefits of mammography screening have been controversial, with conflicting findings from various studies.METHODSWe hypothesize that unmeasured heterogeneity in tumor aggressiveness underlies these conflicting results. Based on published data from the Canadian National Breast Screening Study (CNBSS), we develop and parameterize an individual-based mechanistic model for breast cancer incidence and mortality that tracks five stages of breast cancer progression and incorporates the effects of age on breast cancer incidence and all-cause mortality.RESULTSThe model accurately reproduces the reported outcomes of the CNBSS. By varying parameters, we predict that the benefits of mammography depend on the effectiveness of cancer treatment and tumor.CONCLUSIONSIn particular, patients with the most rapidly growing or potentially largest tumors have the highest benefit and least harm from the screening, with only a relatively small effect of age. However, the model predicts that confining mammography populations with a high risk of acquiring breast cancer increases the screening benefit only slightly compared with the full population.
Circulating lipids associate with future weight gain in individuals with an at-risk mental state and in first-episode psychosis
Authors: Lamichhane Santosh , Dickens Alex M. , Sen Partho , Laurikainen Heikki , Suvisaari Jaana , Hyötyläinen Tuulia , Howes Oliver , Hietala Jarmo , Orešič Matej 
Published: February 2020

AbstractPatients with schizophrenia have a lower than average life span, largely due to the increased prevalence of cardiometabolic co-morbidities. Identification of individuals with psychotic disorders with a high risk of rapid weight gain, and the associated development of metabolic complications, is an unmet need as regards public health. Here, we applied mass spectrometry-based lipidomics in a prospective study comprising 48 controls (CTR), 44 first-episode psychosis (FEP) patients and 22 individuals at clinical-high-risk (CHR) for psychosis, from two study centers (Turku/Finland and London/UK). Baseline serum samples were analyzed by lipidomics, while body mass index (BMI) was assessed at baseline and after 12 months. We found that baseline triacylglycerols with low double bond counts and carbon numbers were positively associated with the change in BMI at follow-up. In addition, a molecular signature comprised of two triacylglycerols (TG(48:0) and TG(45:0)), was predictive of weight gain in individuals with a psychotic disorder, with an area under the receiver operating characteristic curve (AUROC) of 0.74 (95% CI: 0.60–0.85). When independently tested in the CHR group, this molecular signature predicted said weight change with AUROC = 0.73 (95% CI: 0.61–0.83). We conclude that molecular lipids may serve as a predictor of weight gain in psychotic disorders in at-risk individuals, and may thus provide a useful marker for identifying individuals who are most prone to developing cardiometabolic co-morbidities.
Association of the use of hearing aids with the conversion from mild cognitive impairment to dementia and progression of dementia: a longitudinal retrospective study
Authors: Bucholc Magda , McClean Paula L. , Bauermeister Sarah , Todd Stephen , Ding Xuemei , Ye Qinyong , Wang Desheng , Huang Wei , Maguire Liam P. 
Published: February 2020

AbstractINTRODUCTIONHearing aid usage has been linked to improvements in cognition, communication, and socialization, but the extent to which it can affect the incidence and progression of dementia is unknown. Such research is vital given the high prevalence of dementia and hearing impairment in older adults, and the fact that both conditions often coexist. In this study, we examined for the first time the effect of the use of hearing aids on the conversion from mild cognitive impairment (MCI) to dementia and progression of dementia.METHODSWe used a large referral-based cohort of 2114 hearing-impaired patients obtained from the National Alzheimer’s Coordinating Center. Survival analyses using multivariable Cox proportional hazards regression model and weighted Cox regression model with censored data were performed to assess the effect of hearing aid use on the risk of conversion from MCI to dementia and risk of death in hearing-impaired participants. Disease progression was assessed with CDR® Dementia Staging Instrument Sum of Boxes (CDRSB) scores. Three types of sensitivity analyses were performed to validate the robustness of the results.RESULTSMCI participants that used hearing aids were at significantly lower risk of developing all-cause dementia compared to those not using hearing aids (hazard ratio [HR] 0.73, 95%CI, 0.61-0.89; false discovery rate [FDR]P=0.004). The mean annual rate of change (standard deviation) in CDRSB scores for hearing aid users with MCI was 1.3 (1.45) points and significantly lower than for individuals not wearing hearing aids with a 1.7 (1.95) point increase in CDRSB per year (P=0.02). No association between hearing aid use and risk of death was observed. Our findings were robust subject to sensitivity analyses.DISCUSSIONAmong hearing-impaired adults, hearing aid use was independently associated with reduced dementia risk. The causality between hearing aid use and incident dementia should be further tested.HighlightsHigh prevalence of dementia and hearing impairment in older adultsHearing aid (HA) use associated with a lower risk of incident dementiaSlower cognitive decline in users than non-users of HA with mild cognitive impairmentThe relationship between hearing impairment and dementia should be further tested
Exploring the potential for collaborative use of an app-based platform for n-of-1 trials among healthcare professionals that treat patients with insomnia
Authors: Bobe Jason R. , De Freitas Jessica K. , Glicksberg Benjamin S. 
Published: February 2020

AbstractBackgroundN-of-1 trials are single patient, multiple crossover, comparative effectiveness experiments. Despite their rating as “level 1” evidence, they are not routinely used in clinical medicine to evaluate the effectiveness of treatments.ObjectiveWe explored the potential for implementing a mobile app-based n-of-1 trial platform for collaborative use by clinicians and patients to support data-driven decisions around the treatment of insomnia.MethodsA survey assessing awareness and utilization of n-of-1 trials was administered to healthcare professionals that frequently treat patients with insomnia at the Icahn School of Medicine at Mount Sinai in New York City. 1M electronic health records were analyzed to evaluate evidence for a comorbid relationship between insomnia and dementia or Alzheimer’s disease among a patient population that may benefit from n-of-1 trials for the selection of optimal sleep treatments.ResultsA total of 45 healthcare professionals completed the survey and were included in the analysis. We found that 64% of healthcare professionals surveyed had not heard of n-of-1 trials. After a brief description of these methods, 75% of healthcare professionals reported that they are likely or highly likely to use an app-based n-of-1 trial at least once in the next year if the service were free and easy to offer to their patients.ConclusionsAn app-based n-of-1 trials platform might be a valuable tool for clinicians and patients to identify the best treatments for insomnia. Educational interventions that raise awareness and provide training are also likely necessary. The electronic health record (EHR) may help identify eligible patients.
Loss of COX4i1 leads to combined respiratory chain deficiency and impaired mitochondrial proteosynthesis
Authors: Kristýna Čunátová , David Pajuelo Reguera , Marek Vrbacký , Erika Fernández-Vizarra , Shujing Ding , Ian Fearnley , Massimo Zeviani , Josef Houštěk , Tomáš Mráček , Petr Pecina 
Published: February 2020

ABSTRACTOxidative phosphorylation (OXPHOS) system localized in the inner mitochondrial membrane secures production of the majority of ATP in mammalian organisms. Individual OXPHOS complexes were shown to form supramolecular assemblies termed supercomplexes. It has been repeatedly shown that complexes are not linked only by their function but also by interdependence of individual complex biogenesis or maintenance. For instance, cytochromecoxidase (cIV, COX) or cytochromebc1complex (cIII) deficiencies affect the level of fully assembled NADH dehydrogenase (cI) in monomer as well as within supercomplexes. It was hypothesized that cI is affected at the level of enzyme assembly as well as at the level of cI stability and maintenance. However, the true nature of interdependency between cI and cIV is not fully understood yet. We used HEK293 cellular model with complete knockout of COX4 subunit, which serves as an ideal system to study interdependency of cI and cIV, as early phases of cIV assembly process are disrupted. Total absence of cIV was accompanied by profound deficiency of cI, documented by selective decrease in cI subunits amount and significantly reduced amount of assembled cI. Supercomplexes assembled from cI, cIII and cIV were missing in COX4dKO due to loss of cIV and decrease in cI amount. Pulse-chase metabolic labelling of mtDNA-encoded proteins uncovered decrease of cIV and cI subunits translation. Moreover, partial impairment of mitochondrial proteosynthesis correlated with decreased level of mitochondrial ribosomal proteins. In addition, complexome profiling approach uncovered accumulation of cI assembly intermediates indicating that cI biogenesis was affected rather than stability. We propose that impairment of mitochondrial proteosynthesis caused by cIV deficiency represents one of the mechanisms which may couple biogenesis of cI and cIV.