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] | {"Title": "Genetic determinants of trehalose utilization are not associated with severe Clostridium difficile infection", "Authors": "Saund Katie, Rao Krishna, Young Vincent B., Snitkin Evan S.", "Abstract": "ABSTRACT In a case-control study of patients with C. difficile infection we found no statistically significant association between the presence of trehalose utilization variants in infecting C. difficile strains and development of severe infection. These results do not support trehalose utilization conferring enhanced virulence in the context of human C. difficile infections.", "URL": "https://doi.org/10.1101/19008342"} |
10.1101/2019.12.10.19014423 | [
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] | {"Title": "Optically Pumped Magnetoencephalography in Epilepsy", "Authors": "Vivekananda Umesh, Mellor Stephanie, Tierney Tim M, Holmes Niall, Boto Elena, Leggett James, Roberts Gillian, Hill Ryan, Litvak Vladimir, Brookes Matthew J., Bowtell Richard, Barnes Gareth R, Walker Matthew C", "Abstract": "Abstract Our aim was to demonstrate the first use of Optically Pumped Magnetoencephalography (OP-MEG) in an epilepsy patient with unrestricted head movement. Current clinical MEG uses a traditional SQUID system for recording MEG signal, where sensors are cryogenically cooled and housed in a helmet in which the patient\u2019s head is fixed. Here we use a different type of sensor (OPM), which operates at room temperature and can be placed directly on the patient\u2019s scalp, permitting free head movement. We performed two 30 minute OP-MEG recording sessions in a patient with refractory focal epilepsy and compared these with clinical scalp EEG performed earlier. OP-MEG was able to identify analogous interictal activity to scalp EEG, and source localise this activity to an appropriate brain region. This is the first application of OP-MEG in human epilepsy. Future directions include simultaneous EEG/OP-MEG recording and prolonged OP-MEG telemetry.", "URL": "https://doi.org/10.1101/2019.12.10.19014423"} |
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] | {"Title": "Measuring Baseline Health with Individual Health-Adjusted Life Expectancy (iHALE)", "Authors": "Johansson Kjell Arne, \u00d8kland Jan-Magnus, Kr\u00fcger Skaftun Eirin, Bukhman Gene, Norheim Ole Frithjof, Coates Matthew M., Haaland \u00d8ystein Ariansen", "Abstract": "ABSTRACT Objectives At any point of time, a person\u2019s baseline health is the number of healthy life years they are expected to experience during the course of their lifetime. In this article we propose an equity-relevant health metric, illness-specific individual Health Adjusted Life Expectancy (iHALE), that facilitates comparison of baseline health for individuals at the onset of different medical conditions, and allows for the assessment of which patient groups are worse off. A method for calculating iHALE is presented, and we use this method to rank four conditions in six countries according to several criteria of \u201cworse off\u201d as a proof of concept. Methods iHALE measures baseline health at an individual level for specific conditions, and consists of two components: past health (before disease onset) and future expected health (after disease onset). Four conditions (acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), schizophrenia, and epilepsy) are analysed in six countries (Ethiopia, Haiti, China, Mexico, United States and Japan). Data for all countries and for all diseases in 2017 were obtained from the Global Burden of Disease Study database. In order to assess who are the worse off, we focus on four measures: the proportion of affected individuals who are expected to attain less than 20 healthy life years (T20), the 25 th and 75 th percentiles of healthy life years for affected individuals (Q1 and Q3, respectively), and the average iHALE across all affected individuals. Results Even in settings where average iHALE is similar for two conditions, other measures may vary. One example is AML (average iHALE=58.7, T20=2.1, Q3-Q1=15.3) and ALL (57.7, T20=4.7, Q3-Q1=21.8) in the US. Many illnesses, such as epilepsy, are associated with higher baseline health in high-income settings (average iHALE in Japan=64.3) than in low-income settings (average iHALE in Ethiopia=36.8). Conclusion iHALE allows for the estimation of the distribution of baseline health of all individuals in a population. Hence, baseline health can be incorporated as an equity consideration in setting priorities for health interventions.", "URL": "https://doi.org/10.1101/19003814"} |
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] | {"Title": "Quality of care at safety-net hospitals and the impact on pay-for-performance reimbursement", "Authors": "Sarkar Reith R., Courtney Patrick T., Bachand Katie, Sheridan Paige, Riviere Paul, Guss Zachary D., Lopez Christian R., Brandel Michael G., Banegas Matthew P., Murphy James D.", "Abstract": "Abstract Background Pay-for-performance reimbursement ties hospital payments to standardized quality of care metrics. The impact of pay-for-performance reimbursement models on safety-net hospitals, which care primarily for uninsured or underinsured patients, remains poorly defined. This study evaluates how standardized quality of care metrics vary by a hospital\u2019s safety-net status, and helps us better understand the potential impact that pay-for-performance reimbursement could have on funding of safety-net hospitals. Methods We identified 1,703,865 bladder, breast, cervix, colon, endometrium, gastric, lung, ovary, or rectum cancer patients treated at 1,344 hospitals diagnosed between 2004 and 2015. Safety-net burden was defined for each hospital as the percentage of uninsured or Medicaid patients cared for by that hospital. Hospitals were grouped into low-, medium-, and high-burden hospitals. We evaluated the impact of safety-net burden on concordance with 20 standardized quality of care measures, adjusting for differences in patient age, gender, stage at diagnosis, and comorbidity. Results Patients seen at high-burden hospitals were more likely to be young, male, black, Hispanic, and to reside in a low-income and low-educated region. High-burden hospitals had lower adherence to 13 of 20 quality measures compared to low-burden hospitals (all p<0.05). Among the 350 high-burden hospitals, the quality measures were lowest for those caring for the highest fraction of uninsured or Medicaid patients, minority serving hospitals, and those caring for less educated patients (all p<0.001). Discussion Cancer care at safety-net hospitals was associated with lower concordance to standardized quality of care measures. Under a pay-for-performance reimbursement model these lower quality of care scores could decrease payments to safety-net hospitals, potentially increasing health disparities for at-risk cancer patients.", "URL": "https://doi.org/10.1101/19010843"} |
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] | {"Title": "fMRI as an outcome measure in clinical trials: A systematic review in clinicaltrials.gov", "Authors": "Sadraee Alaleh, Paulus Martin P., Ekhtiari Hamed", "Abstract": "Abstract Background Functional magnetic resonance imaging (fMRI) is quickly becoming a significant outcome measure for clinical trials and as more than one thousand trials with fMRI as an outcome measure were registered in clinicaltrials.gov at the time of writing this article. However, 93% of these registered trials are still not completed with published results and there is no picture available about methodological dimensions of these ongoing trials with fMRI as an outcome measure. Methods We collected trials that use fMRI as an outcome measure by searching \u201cfMRI\u201d in the ClinicalTrials.gov registry on October 13 2018 and reviewing each trial\u2019s record entry. Eligible trials\u2019 characteristics were extracted and summarized. Results In total, 1386 clinical trials were identified that reported fMRI in their outcome measures with fMRI as the only primary outcome in 33% of them. 82% of fMRI trials were started after 2011. The most frequent intervention was drug (29%). 57% of trials had parallel assignment design and 20% were designed for cross over assignment. For task-based fMRI, cognitive systems (46%) based on RDoC was the most frequent domain of tasks, followed by positive valence systems (19%), systems for social processing (10%) and sensorimotor systems (5%). Less than one-third of trials (28%) registered at least one region of interest for their analysis. Food cue reactivity task, pain perception task, n-back task and monetary incentive delay task were recruited in more than 25 registered trials. Conclusion The number of fMRI trials (fMRI as an outcome measure) with both task and rest protocols is growing rapidly. Different RDoC domains are covered by various tasks in fMRI trials. However, our study suggests the need of greater harmony and better standardization for registration of fMRI details on both methods and analysis which would allow for more effective comparison across studies in systematic reviews and also help the validation of results towards having fMRI as a biomarker in the future.", "URL": "https://doi.org/10.1101/19002972"} |
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] | {"Title": "Generating Evidence for Chronic Obstructive Pulmonary Disease (COPD) Clinical Guidelines Using EHR Data", "Authors": "Johnson Amber M., Bikak Marvi, Griffin Paul M., Adibuzzaman Mohammad", "Abstract": "ABSTRACT Objectives The aim of this research was to develop data-driven models using electronic health records (EHRs) to conduct clinical studies for predicting clinical outcomes through probabilistic analysis that considers temporal aspects of clinical data. We assess the efficacy of antibiotics treatment and the optimal time of initiation for in-hospitalized diagnosed with acute exacerbation of COPD (AECOPD) as an application to probabilistic modeling. Materials and Methods We developed a semi-automatic Markov Chain Monte Carlo (MCMC) modeling and simulation approach that encodes clinical conditions as computable definitions of health states and exact time duration as input for parameter estimations using raw EHR data. We applied the MCMC approach to the MIMIC-III clinical database, where ICD-9 diagnosis codes (491.21, 491.22, and 494.1) were used to identify data for 697 AECOPD patients of which 25.9% were administered antibiotics. Results The average time to antibiotic administration was 27 hours, and 32% of patients were administered vancomycin as the initial antibiotic. The model simulations showed a 50% decrease in mortality rate as the number of patients administered antibiotics increased. There was an estimated 5.5% mortality rate when antibiotics were initially administrated after 48 hours vs 1.8% when antibiotics were initially administrated between 24 and 48 hours. Discussion Our findings suggest that there may be a mortality benefit in initiation of antibiotics early in patient with severe respiratory failure in settings of COPD exacerbations warranting an ICU admission. Conclusion Probabilistic modeling and simulation methods that considers temporal aspects of raw clinical patient data can be used to adequately generate evidence for clinical guidelines.", "URL": "https://doi.org/10.1101/19006023"} |
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] | {"Title": "Identification of newborns at risk for autism using electronic medical records and machine learning", "Authors": "Rahman Rayees, Kodesh Arad, Levine Stephen Z, Sandin Sven, Reichenberg Abraham, Schlessinger Avner", "Abstract": "Abstract Importance Current approaches for early identification of individuals at high risk for autism spectrum disorder (ASD) in the general population are limited, where most ASD patients are not identified until after the age of 4. This is despite substantial evidence suggesting that early diagnosis and intervention improves developmental course and outcome. Objective Develop a machine learning (ML) method predicting the diagnosis of ASD in offspring in a general population sample, using parental electronic medical records (EMR) available before childbirth Design Prognostic study of EMR data within a single Israeli health maintenance organization, for the parents of 1,397 ASD children (ICD-9/10), and 94,741 non-ASD children born between January 1st, 1997 through December 31st, 2008. The complete EMR record of the parents was used to develop various ML models to predict the risk of having a child with ASD. Main outcomes and measures Routinely available parental sociodemographic information, medical histories and prescribed medications data until offspring\u2019s birth were used to generate features to train various machine learning algorithms, including multivariate logistic regression, artificial neural networks, and random forest. Prediction performance was evaluated with 10-fold cross validation, by computing C statistics, sensitivity, specificity, accuracy, false positive rate, and precision (positive predictive value, PPV). Results All ML models tested had similar performance, achieving an average C statistics of 0.70, sensitivity of 28.63%, specificity of 98.62%, accuracy of 96.05%, false positive rate of 1.37%, and positive predictive value of 45.85% for predicting ASD in this dataset. Conclusion and relevance ML algorithms combined with EMR capture early life ASD risk. Such approaches may be able to enhance the ability for accurate and efficient early detection of ASD in large populations of children. Key points Question Can autism risk in children be predicted using the pre-birth electronic medical record (EMR) of the parents? Findings In this population-based study that included 1,397 children with autism spectrum disorder (ASD) and 94,741 non-ASD children, we developed a machine learning classifier for predicting the likelihood of childhood diagnosis of ASD with an average C statistic of 0.70, sensitivity of 28.63%, specificity of 98.62%, accuracy of 96.05%, false positive rate of 1.37%, and positive predictive value of 45.85%. Meaning The results presented serve as a proof-of-principle of the potential utility of EMR for the identification of a large proportion of future children at a high-risk of ASD.", "URL": "https://doi.org/10.1101/19008367"} |
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] | {"Title": "Genetic Polymorphisms, Adherence to Mediterranean Diet and Microbiota-Associated Urolithin Metabotypes: A Complex Cocktail to Predict the Obesity in Childhood-Adolescence", "Authors": "Cort\u00e9s-Mart\u00edn Adri\u00e1n, Colmenarejo Gonzalo, Selma Mar\u00eda Victoria, Esp\u00edn Juan Carlos", "Abstract": "Environmental and genetic factors are associated with pandemic obesity since childhood. However, the association of overweight-obesity with these factors, acting as a consortium, has been scarcely studied in children. We aimed here to assess the probabilities of being overweighed-obese in a randomly recruited cohort of Spanish children and adolescents ( n =415, 5\u201317 years-old) by estimating the odds ratios for different predictor variables, and their relative importance in the prediction. The predictor variables were ethnicity, age, sex, adherence to the Mediterranean diet (KIDMED), physical activity, urolithin metabotypes (UM-A, UM-B and UM-0) as biomarkers of the gut microbiota, and 53 single-nucleotide polymorphisms (SNPs) from 43 genes mainly related to obesity and cardiometabolic diseases. A proportional-odds logistic ordinal regression, validated through bootstrap, was used to model the data. While every variable was not independently associated with overweight-obesity, however, the ordinal logistic model revealed that overweight-obesity prevalence was related to being a young boy with either UM-B or UM-0, low KIDMED score and high contribution of a consortium of 24 SNPs, being rs1801253- ADRB1 , rs4343- ACE , rs8061518- FTO , rs1130864- CRP , rs659366- UCP2 , rs6131- SELP , rs12535708- LEP , rs1501299- ADIPOQ , rs708272- CETP and rs2241766- ADIPOQ the top-ten contributing SNPs. Additional research should confirm and complete this model by including dietary interventions and the individuals\u2019 gut microbiota composition.", "URL": "https://doi.org/10.1101/2019.12.11.19014431"} |
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] | {"Title": "Defining predatory journals and responding to the threat they pose: a modified Delphi consensus process", "Authors": "Cukier Samantha, Lalu Manoj M., Bryson Gregory L., Cobey Kelly D., Grudniewicz Agnes, Moher David", "Abstract": "ABSTRACT Background Posing as legitimate open access outlets, predatory journals and publishers threaten the integrity of academic publishing by not following publication best practices. Currently, there is no agreed upon definition of predatory journals, making it difficult for funders and academic institutions to generate practical guidance or policy to ensure their members do not publish in these channels. Methods We conducted a modified three-round Delphi survey of an international group of academics, funders, policy makers, journal editors, publishers and others, to generate a consensus definition of predatory journals and suggested ways the research community should respond to the problem. Results A total of 45 participants completed the survey on predatory journals and publishers. We reached consensus on 18 items out of a total of 33, to be included in a consensus definition of predatory journals and publishers. We came to consensus on educational outreach and policy initiatives on which to focus, including the development of a single checklist to detect predatory journals and publishers, and public funding to support research in this general area. We identified technological solutions to address the problem: a \u2018one-stop-shop\u2019 website to consolidate information on the topic and a \u2018predatory journal research observatory\u2019 to identify ongoing research and analysis about predatory journals/publishers. Conclusions In bringing together an international group of diverse stakeholders, we were able to use a modified Delphi process to inform the development of a definition of predatory journals and publishers. This definition will help institutions, funders and other stakeholders generate practical guidance on avoiding predatory journals and publishers.", "URL": "https://doi.org/10.1101/19010850"} |
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] | {"Title": "Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents Over Three Decades, 1995-2017: Cross-Sectional Analysis", "Authors": "Zhang Audrey D, Puthumana Jeremy, Downing Nicholas S, Shah Nilay D, Krumholz Harlan M, Ross Joseph S", "Abstract": "ABSTRACT Objective To evaluate whether characteristics of pivotal efficacy trials supporting US Food and Drug Administration (FDA) approval of novel therapeutic agents have changed over the past three decades. Design Cross-sectional study. Setting and population Publicly available data on novel therapeutics approved by the FDA between 1995-1997, 2005-2007, and 2015-2017. Main outcome measures Use of randomization, blinding, types of comparators and primary endpoints, number of treated patients, and trial duration in pivotal trials supporting novel therapeutic approval, both individually and aggregated by each indication approval. Analyses were repeated stratifying by use of orphan designation and use of special regulatory programs. Results There were 273 novel therapeutics approved by the FDA in these 3 periods (107 in 1995-1997, 57 in 2005-2007, 109 in 2015-2017), representing 339 indications (157, 64, and 118, respectively). Overall, the proportion of indication approvals supported by at least 2 pivotal trials decreased (80.6% in 1995-1997, 60.3% in 2005-2007, 52.8% in 2015-2017; p<0.001). The proportion supported by only single-arm pivotal trials increased (4.0% in 1995-1997, 12.7% in 2005-2007, 17.0% in 2015-2017; p=0.001), as did the proportion supported by at least one pivotal trial of 6 months\u2019 duration (25.8% in 1995-1997, 34.9% in 2005-2007, 46.2% in 2015-2017; p=0.001). When stratified by use of special regulatory programs, pivotal trial characteristics changed over time in divergent ways, both individually and when aggregated by indication approvals. Conclusion More recent FDA approvals of novel therapeutics were based on fewer pivotal trials, with less rigorous designs but longer trial durations. These findings reinforce the importance of FDA\u2019s strategy for requiring ongoing evaluation of therapeutic safety and efficacy after approval. What is already known on this topic - Pivotal trial characteristics supporting US Food and Drug Administration approval of novel therapeutic agents vary widely across therapeutic characteristics. - A growing number of approvals make use of special regulatory programs that expedite the development and review of potentially transformative drugs, such as Fast Track, Priority Review, Accelerated Approval, and Breakthrough Designation. - Special regulatory programs often offer more flexible requirements for approval, such as requiring only a single pivotal trial or trials using surrogate endpoints. What this study adds - Over the past three decades, the characteristics of the aggregate pivotal trials supporting new drug approvals has changed, with more recent approvals requiring fewer trials of less rigorous design. - Differences in pivotal trial characteristics over time persist after accounting for the increasing use of special regulatory programs. - Divergent patterns are observed among approvals making use of special regulatory programs, for which more recent approvals have required fewer trials of less rigorous design, as compared to approvals using the standard pathway, for which more recent approvals have required trials of more rigorous design.", "URL": "https://doi.org/10.1101/19007047"} |
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] | {"Title": "Is There a Health Inequality in Gambling Related Harms? A Systematic Review", "Authors": "Raybould J. N, Larkin M, Tunney R. J", "Abstract": "ABSTRACT Objective Here we present a systematic review of the existing research into gambling harms, in order to determine whether there are differences in the presentation of these across demographic groups such as age, gender, culture, and socioeconomic status, or gambling behaviour categories such as risk severity and play frequency. Primary and Secondary Outcome Measures: Inclusion criteria were: 1) focus on gambling harms; 2) focus on harms to the gambler rather than affected others; 3) discussion of specific listed harms and not just harms in general terms. Exclusion criteria were: 1) research of non-human subjects; 2) not written in English; 3) not an empirical study; 3) not available as a full article. Search We conducted a systematic search using the Web of Science and Scopus databases in February 2020. Assessment of quality took place using Standard Quality Assessment Criteria. Results 56 studies published between 1994 and 2019 met the inclusion criteria. These were categorised into thematic groups for comparison and discussion. There were replicated differences found in groups defined by age, socioeconomic status, education level, ethnicity and culture, risk severity, and gambling behaviours. Conclusion Harms appear to be dependent on specific social, demographic and environmental conditions that suggests there is a health inequality in gambling related harms. Further investigation is required to develop standardised measurement tools and to understand confounding variables and co-morbidities. With a robust understanding of harms distribution in the population, Primary Care Workers will be better equipped to identify those who are at risk, or who are showing signs of Gambling Disorder, and to target prevention and intervention programmes appropriately.", "URL": "https://doi.org/10.1101/19012104"} |
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] | {"Title": "Validation of Serum Neurofilaments as Prognostic & Potential Pharmacodynamic Biomarkers for ALS", "Authors": "Benatar Michael, Zhang Lanyu, Wang Lily, Granit Volkan, Statland Jeffrey, Barohn Richard, Swenson Andrea, Ravits John, Jackson Carlayne, Burns Ted M, Trivedi Jaya, Pioro Erik P, Caress James, Katz Jonathan, McCauley Jacob L, Rademakers Rosa, Malaspina Andrea, Ostrow Lyle W, Wuu Joanne", "Abstract": "Abstract Objective Identify preferred neurofilament assays, and clinically validate serum NfL and pNfH as prognostic and potential pharmacodynamic biomarkers relevant to ALS therapy development. Methods Prospective, multi-center, longitudinal observational study of patients with ALS (n=229), primary lateral sclerosis (PLS, n=20) and progressive muscular atrophy (PMA, n=11). Biological specimens were collected, processed and stored according to strict standard operating procedures (SOPs) 1 . Neurofilament assays were performed in a blinded manner by independent contract research organizations (CROs). Results For serum NfL and pNfH measured using the Simoa assay, missing data (i.e. both technical replicates below the lower limit of detection (LLD) was not encountered. For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in \u223c4% and \u223c10% of serum samples respectively. Mean coefficients of variation (CVs) for pNfH in serum and CSF were \u223c4-5% and \u223c2-3% respectively in all assays. Baseline NfL concentration, but not pNfH, predicted the future ALSFRS-R slope and survival. Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of \u223c8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings. Conclusions Serum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, have potential utility as pharmacodynamic biomarkers of treatment effect.", "URL": "https://doi.org/10.1101/19002998"} |
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] | {"Title": "Real-world Drug Regimens for Multiple Myeloma in a Swiss Population (2012 to 2017): cost-outcome description", "Authors": "Eichler Klaus, Rapold Roland, Wieser Simon, Reich Oliver, Blozik Eva", "Abstract": "Abstract Background Novel drugs are dynamically changing current treatment regimens for multiple myeloma (MM). Novel drugs have improved prognosis of MM patients in clinical studies but are expensive. Little is known about up-to-date real-world application and costs. Methods We performed a retrospective observational cohort analysis (cost-outcome description; 2012-2017) in a claims database of a major Swiss health insurance company which covers 14% of the Swiss population (Helsana Versicherungen AG).We used primary (MM diagnoses via ICD-10) and secondary features (prescribed MM-specific drugs) as inclusion criteria and defined a hierarchy of drug regimens to classify treatments as: 1) proteasome inhibitor (PI)-based regimen (e.g. bortezomib); 2) IMID-based regimen (e.g. lenalidomide); 3) chemotherapy (CHEMO)-based regimen (e.g. bendamustin); 4) monoclonal antibody (MAB)-based regimen (e.g. daratunumab). Direct medical costs of mandatory health insurance were analysed in 2017 Swiss Francs (CHF; third party payer perspective). Results Overall, we identified n=1054 prevalent MM patients (2012-2017) and n=378 incident MM patients (2015-2017; men: 47.1%; age group <=75 years: 48.7%). The number of prevalent patients per year increased over time (from n=314 in 2012 to n=645 in 2017). PI-based regimens were the most frequent first line approach for incident patients (76.0%), followed by IMID-based (21.9%) and CHEMO-based regimens (2.1%). Only four patients were treated with MAB-drugs. For later lines, IMID-based regimens were most often used (2 nd line: 56.4%; 3 rd line: 2 of 3 patients), followed by PI-based regimens (43.6% and 1 of 3 patients, respectively). 161 of 1054 prevalent MM patients (15.3%) were treated with autologous hematopoietic stem cell transplantation (HSCT), 4 patients with allogeneic HSCT. Average costs per patient per treatment line varied considerably (reliable data available from 2012 to 2014; mean duration of lines between 112 and 388 days): PI-based regimens: CHF 81\u2019352; IMID-based: CHF 73\u2019495; CHEMO-based: CHF 683. Mean daily costs under MM treatment stepwise increased from CHF 209 in 2012 to CHF 254 in 2017 (relative increase: 21.5%). Annual direct medical costs in Switzerland for seven novel MM drugs were extrapolated to be 60.1 Mio CHF in 2012 and 118.6 Mio CHF in 2017 (relative increase: 97.3%), corresponding to mean annual outpatient MM drug costs per patient of CHF 28\u2019000 in 2017. Annual death rates decreased systematically from 18.6% in 2012 to 15.5% in 2017 (p for trend: 0.03). No statistically significant difference in death rates emerged for 2017 compared with 2012 (risk ratio: 0.83; 95%-CI: 0.63 to 1.10; absolute risk reduction: 3.1%). Conclusions Current treatment patterns for MM patients in Switzerland show variation concerning applied drug regimens as well as costs. An increasing prevalent population of MM patients in combination with increasing costs per day under treatment lead to a substantial and growing budget impact for the Swiss social insurance system.", "URL": "https://doi.org/10.1101/19008383"} |
10.1101/2019.12.11.19014449 | [
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] | {"Title": "Determining factors for pertussis vaccination policy: A study in 5 EU countries", "Authors": "Wong Anabelle, Opinel Annick, Combes Simon Jean-Baptiste, Toubiana Julie, Brisse Sylvain", "Abstract": "Abstract Pertussis vaccination policy varies across Europe, not only in the type of vaccine \u2013 whole cell (wP) vs. acellular (aP1/2/3/5) \u2013 but also in the schedule and recommendation for parents. This study aims to investigate the determining factors for the type of vaccine, immunization schedule and maternal immunization recommendation. From March to May 2019, experts in national health agencies and major academic or research institutions from Denmark, France, Poland, Sweden and the UK were invited to a semi-structured interview. Thematic analysis was performed on the transcripts using a codebook formulated by 3 coders. Inter-coder agreement was assessed. Fifteen expert interviews were conducted. The identified driving factors for pertussis vaccine policy were classified into three domains: scientific factors, sociological factors, and pragmatic factors. The determining factors for the type of vaccine were prescriber\u2019s preference, concern of adverse events following immunization (AEFI), effectiveness, and consideration of other vaccine components in combined vaccines. The determining factors for infant schedule were immunity response and the potential to improve coverage and timeliness. The determining factors for maternal immunization were infant mortality and public acceptability. To conclude, socio-political and pragmatic factors were, besides scientific factors, important in determining the vaccine type, schedule of childhood immunization and recommendations for parents.", "URL": "https://doi.org/10.1101/2019.12.11.19014449"} |
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] | {"Title": "Analyzing the Reversal Hypothesis of Obesity with Education: A Cross-Sectional Study of Adult Females in 34 Low- and Lower-Middle-Income Countries", "Authors": "Tang Cynthia Y., Woldu Henok G., Sheets Lincoln R.", "Abstract": "Abstract Setting Obesity, once considered an epidemic of the developed world, is now becoming an even more prominent problem than underweight in low and lower middle income countries (LLMICs). Ample literature has shown that as a country\u2019s income increases, the burden of obesity shifts from the rich to the poor. This is known as the \u201cReversal Hypothesis.\u201d Many studies have explored the effects of various social determinants of health on obesity, but few have studied education as an independent variable on female obesity across LLMICs. Objective Globally, adult females have a higher prevalence of obesity and the obesity shift occurs more quickly for women than for men. We aim to address this disparity and contribute towards the reversal hypothesis by exploring the association of education and obesity in women in LLMICs. Design In this cross-sectional study, we used a multi-national and multi-year database from the publicly available Demographic and Health Surveys program with data from 34 LLMICs. Education levels are standardized across countries during survey collection. Results Our age-adjusted prevalence ratio (AA-PR) analysis shows that women in LLMICs with higher education have a significantly greater prevalence of obesity than women with no education. We analyzed this phenomenon by individual nations, continents, and income classifications. Educated women living in low income countries are 5.12 times more obese than uneducated women (AA-PR, 95% CI=4.75, 5.53) and 3.42 times more obese in lower middle income countries (AA-PR, 95% CI=3.31, 3.54). Conclusion These findings highlight a need for more studies and policy attention focusing on female education levels, among other factors, to understand, predict, and prevent obesity in LLMICs. ARTICLE SUMMARY Strengths and limitations of this study A rigorous sample size of 943,947 adult females in 34 LLMIC countries was utilized to study the association between adult female obesity and education level. Age-adjusted and age-and-wealth-adjusted prevalence ratios of obesity were analyzed based on 34 individual nations, three continents, and two major income categories. This study includes the most recent data available through the Demographic and Health Surveys program, which standardizes education levels during data collection, allowing for comparison between all surveyed countries. This study is limited by the relatively small number of countries for which data is available through the DHS dataset, and thus, further research will be needed to show whether these results are generalizable to other LLMICs.", "URL": "https://doi.org/10.1101/19003004"} |
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] | {"Title": "Validity of using cancer registry data for comparative effectiveness research", "Authors": "Kumar Abhishek, Guss Zachary D, Courtney Patrick T, Nalawade Vinit, Sheridan Paige, Sarkar Reith R, Banegas Matthew P, Rose Brent S, Xu Ronghui, Murphy James D", "Abstract": "Abstract Purpose Researchers often analyze cancer registry data to assess for differences in survival among cancer treatments. However, the retrospective non-random design of these analyses raise questions about study validity. The purpose of this study was to determine the extent to which comparative effectiveness analyses using cancer registry data produces results concordant with randomized clinical trials. Methods We identified 141 randomized clinical trials referenced in the National Comprehensive Cancer Network Clinical Practice Guidelines for 8 common solid tumor types. For each trial we identified subjects from the National Cancer Database (NCDB) matching the eligibility criteria of the randomized trial. With each trial we used three Cox regression models to determine hazard ratios (HRs) for overall survival including univariable, multivariable, and propensity score adjusted models. Multivariable and propensity score analyses controlled for potential confounders including demographic, comorbidity, clinical, treatment, and tumor-related variables. Each NCDB survival analysis was defined as discordant if the HR for the NCDB analysis fell outside the 95% confidence interval of the corresponding randomized trial. Results NCDB analyses produced HRs for survival discordant with randomized trials in 62 (44%) univariable analyses, 43 (30%) multivariable analyses, and 51 (36%) propensity score models. NCDB analyses produced p-values discordant with randomized trials in 83 (59%) univariable analyses, 76 (54%) multivariable analyses, and 78 (55%) propensity score models. We did not identify any clinical trial characteristic associated with discordance between NCDB analyses and randomized trials including disease site, type of clinical intervention, or severity of cancer. Conclusion Comparative effectiveness research with cancer registry data often produces survival outcomes discordant to randomized clinical data. These findings help provide context for providers interpreting observational comparative effectiveness research in oncology.", "URL": "https://doi.org/10.1101/19010876"} |
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] | {"Title": "Behavioral effects of multiple-dose oxytocin treatment in autism: A randomized, placebo-controlled trial with long-term follow-up", "Authors": "Bernaerts Sylvie, Boets Bart, Bosmans Guy, Steyaert Jean, Alaerts Kaat", "Abstract": "ABSTRACT Background Intranasal administration of the \u2018prosocial\u2019 neuropeptide oxytocin is increasingly explored as a potential treatment for targeting the core characteristics of autism spectrum disorder (ASD). However, long-term follow-up studies, evaluating the possibility of long-lasting retention effects are currently lacking. Methods Using a double-blind, randomized, placebo-controlled, parallel design, this pilot clinical trial explored the possibility of long-lasting behavioral effects of four weeks of intranasal oxytocin treatment (24 International Units once daily in the morning) in 40 adult men with ASD. To do so, self-report and informant-based questionnaires assessing core autism symptoms and characterizations of attachment were administered at baseline, immediately after four weeks of treatment (approximately 24 hours after the last nasal spray administration), and at two follow-up sessions, four weeks and one year post-treatment. Results No treatment-specific effects were identified in the primary outcome assessing social symptoms (Social responsiveness scale, self- and informant-rated). In particular, with respect to self-reported social responsiveness, improvements were evident both in the oxytocin and in the placebo group, yielding no significant between-group difference (p= .37). Also informant-rated improvements in social responsiveness were not significantly larger in the oxytocin, compared to the placebo group (between-group difference: p= .19). Among the secondary outcome measures, treatment-specific improvements were identified in the Repetitive Behavior Scale and State Adult Attachment Measure, indicating reductions in self-reported repetitive behaviours (p= .04) and reduced feelings of avoidance towards others (p= .03) in the oxytocin group compared to the placebo group, up to one month and even one year post-treatment. Treatment-specific effects were also revealed in screenings of mood states (Profile of Mood States), indicating higher reports of \u2018vigor\u2019 (feeling energetic, active, lively) in the oxytocin, compared to the placebo group (p= .03). Conclusions While no treatment-specific improvements were evident in terms of core social symptoms, the current observations of long-term beneficial effects on repetitive behaviors and feelings of avoidance are promising and suggestive of a therapeutic potential of oxytocin treatment for ASD. However, given the exploratory nature of this pilot study, future studies are warranted to evaluate the long-term effects of OT administration further. Trial Registration The trial was registered with the European Clinical Trial Registry (Eudract 2014-000586-45) on January 22, 2014 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-000586-45/BE ).", "URL": "https://doi.org/10.1101/19012112"} |
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] | {"Title": "Patient Preferences to Undergo Low-Value CT Coronary Angiography in the Emergency Department", "Authors": "Winkels Jessica L., Smith Chelsea Morrow, Iyengar Rahul, Meka Arjun P., Porath Jonathan D., Meurer William J.", "Abstract": "Abstract Background Low-value diagnostic testing adds billions of dollars to the cost of health care in the US annually. Addressing patient preference for these tests is one possible strategy to limit overuse. In previous work, we showed that patient preference for testing can be influenced by test benefit, risk, and financial measures. Our objective was to examine the effect of these variables in another clinical scenario involving chest pain. Methods In this cross-sectional survey of patients at the University of Michigan Emergency Department (ED), participants were given a hypothetical scenario involving an ED visit for chest pain, along with information regarding potential benefit (detecting a life-threatening condition; 0.1 or 1%) and risk (developing cancer; 0.1 or 1%) of CTCA, as well as an incentive of $0 or $100 to forego testing. Values for risk, benefit, and financial incentive varied across participants. Our primary outcome was patient preference to undergo testing. We also obtained demographic and numeracy information. Then, we used logistic regression to estimate odds ratios, adjusting for multiple potential confounders. Our sample size was designed to find at least 300 events (test acceptance) to allow for up to 30 covariates in fully adjusted models. We had 85-90% power to detect a 10% absolute difference in testing rate across groups, assuming a 95% significance level. Results 913 patients were surveyed. A $100 financial incentive (adjusted OR [AOR] 0.57; 95% Confidence Interval [CI] 0.42-0.78) and increased test risk (AOR 0.61; 95% CI 0.44-0.84) both significantly decreased test acceptance in fully adjusted models, whereas increased test benefit significantly increased test acceptance (AOR 2.45; 95% CI 1.79-3.36). Conclusions Offering a financial incentive deterred patients from accepting testing despite varying levels of risk and benefit. In the context of previous work, we provide preliminary evidence supporting that financial interventions may impact patient preference more than test risk and benefit.", "URL": "https://doi.org/10.1101/19008391"} |
10.1101/2019.12.11.19014472 | [
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] | {"Title": "Urate, blood pressure and cardiovascular disease: updated evidence from Mendelian randomization and meta-analysis of clinical trials", "Authors": "Gill Dipender, Cameron Alan C., Burgess Stephen, Li Xue, Doherty Daniel J., Karhunen Ville, Abdul-Rahim Azmil H, Taylor-Rowan Martin, Zuber Verena, Tsao Philip S., Klarin Derek, Evangelou Evangelos, Elliott Paul, Damrauer Scott M., Quinn Terence J, Dehghan Abbas, Theodoratou Evropi, Dawson Jesse, Tzoulaki Ioanna", "Abstract": "Abstract Aims To investigate the effect of serum urate on blood pressure and cardiovascular disease (CVD) risk by updating evidence from Mendelian randomization (MR) analysis and meta-analysis of randomized controlled trials (RCTs). Methods and Results Using recently available data from the Million Veterans Program and UK Biobank, the main MR analyses showed that every 1-standard deviation increase in genetically predicted serum urate was associated with an increased risk of coronary heart disease (odds ratio 1.19, 95% confidence interval 1.10-1.30, P =4\u00d710 \u22125 ), peripheral artery disease (1.12, 95%CI 1.03 to 1.21, P =9\u00d710 \u22123 ), and stroke (1.11, 95%CI 1.05 to 1.18, P =2\u00d710 \u22124 ). In MR mediation analyses, SBP was estimated to mediate approximately one third the effect of urate on CVD risk. Systematic review and meta-analysis of RCTs showed a favorable effect of urate-lowering treatment on SBP (mean difference -2.55mmHg, 95%CI -4.06 to -1.05, P =1\u00d710 \u22123 ) and major adverse cardiovascular events (MACE) in those with previous CVD (OR 0.40, 95%CI 0.22 to 0.73, P =3\u00d710 \u22123 ), but no significant effect on MACE in all individuals (OR 0.73, 95%CI 0.48 to 1.09, P =0.12). Conclusion MR and clinical trial data support an effect of higher serum urate on increasing blood pressure, which may mediate a consequent effect on CVD risk. High-quality trials are necessary to provide definitive evidence on the specific clinical contexts where urate-lowering may be of cardiovascular benefit.", "URL": "https://doi.org/10.1101/2019.12.11.19014472"} |
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] | {"Title": "Self-reported Morisky 8 item medication adherence scale to statins concords with pill count method and correlates with serum lipid profile parameters and Serum HMGCoA Reductase levels", "Authors": "Grover Abhinav, Oberoi Mansi, Rehan Harmeet, Gupta Lalit, Yadav Madhur", "Abstract": "ABSTRACT Background It is imperative that non-compliance to statins be identified and addressed to optimize the clinical benefit of statins. Patient self-reporting methods are convenient to apply in clinical practice but need to be validated. Objective We studied the concordance of a patient self-report method, MMAS (Morisky eight item medication adherence scale) with pill count method in measuring adherence to statins and their correlation with extended lipid profile parameters and serum HMGCoA-R (hydroxymethylglutaryl coenzyme A reductase) enzyme levels. Methods MMAS and pill count method were used to measure the adherence to statins in patients on statins for any duration. Patients were subjected to estimation of extended lipid profile and serum HMGCoA-R levels at the end of 3 months follow-up. Results Out of a total of 200 patients included in the study, 117 patients had low adherence (score less than 6 on MMAS) whereas 65 and 18 patients had medium (score 6 to less than 8) and high adherence (score of 8) respectively. Majority of patients who had low adherence to statins by MMAS were nonadherent by pill count method yielding concordance of 96.5%. Medium or high adherence to statins by MMAS method had concordance of 89.1% with pill count method. The levels of total cholesterol, low density lipoprotein-cholesterol, apolipoprotein B and HMGCoA-R were significantly negatively correlated with compliance measured by pill count and MMAS with similar correlation coefficients. HMGCoA-R levels demonstrated a plateau phenomenon with levels being 9-10 ng/ml when compliance to statin therapy was greater than 60% by pill count and greater than 6 on Morisky scale. Conclusion In conclusion, MMAS and pill count methods showed concordance in measuring adherence to statins. These methods need to be explored further for their interchangeability as surrogates for biomarker levels.", "URL": "https://doi.org/10.1101/19006148"} |
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] | {"Title": "Improvements in the incidence and survival of cancer and cardiovascular but not infectious disease have driven recent mortality improvements in Scotland: nationwide cohort study of linked hospital admission and death records 2001\u20132016", "Authors": "Timmers Paul RHJ, Kerssens Joannes J, Minton Jon W, Grant Ian, Wilson James F, Campbell Harry, Fischbacher Colin M, Joshi Peter K", "Abstract": "Abstract Objectives To identify the causes and future trends underpinning improvements in life expectancy in Scotland and quantify the relative contributions of disease incidence and survival. Design Population-based study. Setting Linked secondary care and mortality records across Scotland. Participants 1,967,130 individuals born between 1905 and 1965, and resident in Scotland throughout 2001\u20132016. Main outcome measures Hospital admission rates and survival in the five years following admission for 28 diseases, stratified by sex and socioeconomic status. Results The five hospital admission diagnoses associated with the greatest burden of death subsequent to admission were \u201cInfluenza and pneumonia\u201d, \u201cSymptoms and signs involving the circulatory and respiratory systems\u201d, \u201cMalignant neoplasm of respiratory and intrathoracic organs\u201d, \u201cSymptoms and signs involving the digestive system and abdomen\u201d, and \u201cGeneral symptoms and signs\u201d. Using disease trends, we modelled a mean mortality hazard ratio of 0.737 (95% CI 0.730\u20130.745) across decades of birth, equivalent to a life extension of \u223c3 years per decade. This improvement was 61% (30%\u201393%) accounted for by improvements in disease survival after hospitalisation (principally cancer) with the remainder accounted for by a fall in hospitalisation incidence (principally heart disease and cancer). In contrast, deteriorations in the incidence and survival of infectious diseases reduced mortality improvements by 9% (\u223c3.3 months per decade). Overall, health-driven mortality improvements were slightly greater for men than women (due to greater falls in disease incidence), and generally similar across socioeconomic deciles. We project mortality improvements will continue over the next decade but will slow down by 21% because much of the progress in disease survival has already been achieved. Conclusion Morbidity improvements broadly explain observed improvements in overall mortality, with progress on the prevention and treatment of heart disease and cancer making the most significant contributions. The gaps between men and women\u2019s morbidity and mortality are closing, but the gap between socioeconomic groups is not. A slowing trend in improvements in morbidity may explain the stalling in improvements of period life expectancies observed in recent studies in the UK. However, our modelled slowing of improvements could be offset if we achieve even faster improvements in the major diseases contributing to the burden of death, or if we improve prevention and survival of diseases which have deteriorated recently, such as infectious disease, in the future. Summary box What is already known on this topic Long term improvements in Scottish mortality have slowed down recently, while life expectancy inequalities between socioeconomic classes are increasing. Deaths attributed to ischaemic heart disease and stroke in Scotland have declined in the last two decades. What this study adds Gains in life expectancy can largely be attributed to improvements in cancer survival and falls in incidence of cancer and cardiovascular disease. The hospitalisation rate and survival of several infectious diseases have deteriorated, and for urinary infections, this decline has been more rapid in more socioeconomically deprived classes. Improvements in morbidity are projected to slow down, with much progress in survival of heart disease and cancer already achieved, and align with the recently observed slow-down in mortality improvements.", "URL": "https://doi.org/10.1101/19003012"} |
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] | {"Title": "The role of prison-based interventions for hepatitis C virus (HCV) micro-elimination among people who inject drugs in Montr\u00e9al, Canada", "Authors": "Godin Arnaud, Kronfli Nadine, Cox Joseph, Alary Michel, Maheu-Giroux Mathieu", "Abstract": "Abstract Background In Canada, hepatitis C virus (HCV) transmission primarily occurs among people who inject drugs (PWID) and people with experience in the prison system bare a disproportionate HCV burden. These overlapping groups of individuals have been identified as a priority populations for HCV micro-elimination in Canada, a country currently not on track to achieve its elimination targets. Considering the missed opportunities to intervene in provincial prisons, this study aims to estimate the population-level impact of prison-based interventions and post-release risk reduction strategies on HCV transmission among PWID in high HCV-burdened Canadian city, Montr\u00e9al. Methods A dynamic HCV transmission model among PWID was developed and calibrated to community and prison bio-behavioural surveys in Montr\u00e9al. The, the relative impact of prison-based testing and treatment or post-release linkage to care, alone or in combination with risk reduction strategies, was estimated from 2018 to 2030, and compared to counterfactual status quo scenario. Results Testing and linkage to care interventions implemented over 2018-30 could lead to the greatest declines in prevalence (23%; 95% Credible interval(CrI):17\u201331%), incidence (20%; 95%CrI: 10\u201328%), and prevent the most new chronic infections (8%; 95%CrI: 4\u201311%). Testing and treatment in prison could decrease prevalence, incidence, and fraction of prevented new chronic infections. Combining test and linkage to care with risk reduction measures could further its epidemiological impact, preventing 10% (95%CrI: 5\u201316%) of new chronic infections. When implemented concomitantly with community-based treatment scale-up, both prison-based interventions had synergistic effects, averting a higher fraction of new chronic infections. Conclusion Offering HCV testing and post-release linkage to care in provincial prisons, where incarcerations are frequent and sentences short, could change the course of the HCV epidemic in Montr\u00e9al. Integration of post-release risk reduction measures and community-based treatment scale-up could also increase the impact of these interventions.", "URL": "https://doi.org/10.1101/19008409"} |
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] | {"Title": "A Systematic Review on Psychological and Biological Mediators Between Adversity and Psychosis: Potential Targets for Treatment", "Authors": "Alameda Luis, Rodriguez Victoria, Carr Ewan, Aas Monica, Trotta Giulia, Marino Paolo, Vorontsova Natasha, Herane-Vives Andr\u00e9s, Spinazzola Edoardo, Di Forti Marta, Morgan Craig, Murray Robin M", "Abstract": "Abstract Various psychological and biological pathways have been proposed as mediators between childhood adverse events (CA) and psychosis. A systematic review of the evidence in this domain is needed. The aim of this work is to systematically review the evidence on psychological and biological mediators between CA and psychosis across the psychosis spectrum. This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (registration number: CRD42018100846). Articles published between 1979 and July 2019 were identified through a literature search in OVID (PsychINFO; Medline and Embase). The evidence by each analysis and each study results are presented by group of mediator categories found in the review. The percentage of total effect mediated was calculated. 47 studies were included, with a total of 79,668 from general population (GP) and 3,189 from clinical samples. The quality of studies was judged as \u201cfair\u201d. Our results showed (i) solid evidence of mediation between CA and psychosis by negative cognitive schemas about the self, the world, and others (NS); by dissociation and other PTSD symptoms; (ii) evidence of al mediation through an affective pathway (affective dysregulation, anxiety, and depression) in GP; (iii) lack of studies exploring biological mediators. To conclude, we found evidence suggesting that various overlapping and not competing pathways contribute partially to the link between adversity and psychosis. Experiences of adversity, along with relevant mediators such as PTSD and mood related symptoms and NS, should be routinely assessed in patients with psychosis. Targeting such mediators through cognitive behavioural aproaches using trauma-focused therapy and/or pharmacological means could be a useful addition to the traditional treatment of positive symptoms.", "URL": "https://doi.org/10.1101/2019.12.14.19014506"} |
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] | {"Title": "Unsupervised clustering of missense variants in the HNF1A gene using multidimensional functional data aids clinical interpretation", "Authors": "Althari Sara, Najmi Laeya A., Bennett Amanda J., Aukrust Ingvild, Rundle Jana K., Colclough Kevin, Molnes Janne, Kaci Alba, Nawaz Sameena, van der Lugt Timme, Hassanali Neelam, Molven Anders Prof., Ellard Sian Prof., McCarthy Mark I. Prof., Bj\u00f8rkhaug Lise Prof., Nj\u00f8lstad P\u00e5l Rasmus Prof., Gloyn Anna L. Prof.", "Abstract": "Summary Background Exome sequencing in diabetes presents a diagnostic challenge as depending on frequency, functional impact and genomic and environmental contexts, HNF1A variants can cause Maturity-onset Diabetes of the Young (MODY), increase type 2 diabetes risk, or be benign. A correct diagnosis matters as it informs on treatment, progression, and family risk. We describe a multi-dimensional functional dataset of 73 HNF1A missense variants identified in exomes of 12,940 individuals. Our aim was to develop an analytical framework for stratifying variants along the HNF1A phenotypic continuum to facilitate diagnostic interpretation. Methods HNF1A variant function was determined by 4 different molecular assays. Structure of the multi-dimensional dataset was explored using principal component analysis, k-means, and hierarchical clustering. Weights for tissue-specific isoform expression and functional domain were integrated. Functionally annotated variant subgroups were used to re-evaluate genetic diagnoses in national MODY diagnostic registries. Findings HNF1A variants demonstrated a range of behaviours across the assays. The structure of the multi-parametric data was shaped primarily by transactivation. Using unsupervised learning methods, we obtained high-resolution functional clusters of the variants which separated known causal MODY variants from benign and type 2 diabetes risk variants and led to reclassification of 4% and 9% of HNF1A variants identified in the UK and Norway MODY diagnostic registries, respectively. Interpretation Our proof-of-principle analyses facilitated informative stratification of HNF1A variants along the continuum, allowing improved evaluation of clinical significance, management and precision medicine in diabetes clinics. Transcriptional activity appears a superior readout supporting pursuit of transactivation-centric experimental designs for high-throughput functional screens. Funding Wellcome Trust, National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), European Research Council, Norwegian Research Council, Stiftelsen Kristian Gerhard Jebsen, Western Norway Regional Health Authority, Novo Nordisk Fonden, Royal Norwegian Diabetes Foundation. Research in context Evidence before the study Molecular characterisation pipelines for studying the function of transcription factors consist primarily of in vitro cellular assays which interrogate transcriptional activity, protein abundance, localisation of the transcription factor to the nucleus, and binding to relevant DNA recognition sequences. The experimental techniques used to explore these mechanisms in vitro vary in robustness and reliability. There exist a wide variety of reported functional consequences of HNF1A variants in the literature, a gene causing the most common form of Maturity-onset Diabetes of the Young (HNF1A-MODY). The standard approach for analysing multi-tiered functional datasets has been to evaluate each functional parameter independently. Data from functional characterisation efforts of the HNF-1A protein encoded by the HNF1A gene, support that the degree of HNF-1A disruption tends to correlate positively with phenotypic severity: MODY-causing protein-altering variants impair HNF-1A transcriptional activity more severely (\u226430% vs . wild-type) than HNF1A variants associated with increased risk for developing type 2 diabetes in population-specific contexts (40-60% vs . wild-type). Rare variants which demonstrated intermediate function (between MODY-casual and wild-type) in transactivation and nuclear localisation assays were shown to be associated with a 6-fold increase in type 2 diabetes predisposition. Added value of this study We have developed a proof-of-principle analytical framework for robust and unbiased variant stratification using multi-dimensional functional follow-up data from a large number of exome-identified missense variants in HNF1A . Through our analytical approach we were able to perform a comprehensive assessment of molecular function by utilising data from as many mechanistic dimensions as possible, avoiding arbitrarily determined cut-offs based on 1D functional data. Our method facilitated informative spatial organization of variants along the HNF1A molecular-phenotypic spectrum and an exploration of the contributions of each in vitro molecular mechanism on meaningful functional, and therefore clinical, stratification. Further, we were able to perform sensitive mapping of variant effects on molecular function with phenotypic outcome using clinical and genetic data from national MODY diagnostic registries of UK and Norway. This effort allowed us to annotate functional clusters with clinical knowledge and identify discordant classifications between functional genotype and clinical phenotype. Implications of all the available evidence Our novel approach towards analysing large functional datasets enables sensitive variant-phenotype mapping and multi-layered variant annotation. It also assists in prioritisation of functional elements and signatures for Multiplexed Assays of Variant Effects (MAVEs) whilst they largely remain limited to a single functional readout. Indeed, comprehensively annotated HNF1A variant clusters can aid in the interpretation and clinical classification of variants, and can also be utilised to calibrate supervised variant classification models built with high-throughput-derived experimental data.", "URL": "https://doi.org/10.1101/19010900"} |
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] | {"Title": "Psychiatric comorbid disorders of cognition: A machine learning approach using 1,175 UK Biobank participants", "Authors": "Li Chenlu, Gheorghe Delia A., Gallacher John E.J., Bauermeister Sarah", "Abstract": "Abstract Background Conceptualising comorbidity is complex and the term is used variously. Here, it is the coexistence of two or more diagnoses which might be defined as \u2018chronic\u2019 and, although they may be pathologically related, they may also act independently 1 . Of interest here is the comorbidity of common psychiatric disorders and impaired cognition. Objectives To examine whether anxiety and/or depression are important longitudinal predictors of cognitive change. Methods UK Biobank participants used at three time points (n= 502,664): baseline, 1 st follow-up (n= 20,257) and 1 st imaging study (n=40,199). Participants with no missing data were 1,175 participants aged 40 to 70 years, 41% female. Machine learning (ML) was applied and the main outcome measure of reaction time intraindividual variability (cognition) was used. Findings Using the area under the Receiver Operating Characteristic (ROC) curve, the anxiety model achieves the best performance with an Area Under the Curve (AUC) of 0.68, followed by the depression model with an AUC of 0.63. The cardiovascular and diabetes model, and the covariates model have weaker performance in predicting cognition, with an AUC of 0.60 and 0.56, respectively. Conclusions Outcomes suggest psychiatric disorders are more important comorbidities of long-term cognitive change than diabetes and cardiovascular disease, and demographic factors. Findings suggest that psychiatric disorders (anxiety and depression) may have a deleterious effect on long-term cognition and should be considered as an important comorbid disorder of cognitive decline. Clinical implications Important predictive effects of poor mental health on longitudinal cognitive decline should be considered in secondary and also primary care. Summary Box What is already known about this subject? 3-4 bullet points Poor mental health is associated with cognitive deficits. One in four older adults experience a decline in affective state with increasing age. ML approaches have certain advantages in identifying patterns of information useful for the prediction of an outcome. What are the new findings? 3-4 bullet points Psychiatric disorders are important comorbid disorders of long-term cognitive change. Machine-learning methods such as sequence learning based methods are able to offer non-parametric joint modelling, allow for multiplicity of factors and provide prediction models that are more robust and accurate for longitudinal data The outcome of the RNN analysis found that anxiety and depression were stronger predictors of change IIV over time than either cardiovascular disease and diabetes or the covariate variables. How might it impact on clinical practice in the foreseeable future? The important predictive effect of mental health on longitudinal cognition should be noted and, its comorbidity relationship with other conditions such as cardiovascular disease likewise to be considered in primary care and other clinical settings", "URL": "https://doi.org/10.1101/19006189"} |
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] | {"Title": "Phylodynamics of pertussis in the vaccine era: transition to re-emergence", "Authors": "Bento Ana I., Taujale Rahil, Schot Corrie, Bosch Thijs, Mariman Rob, King Aaron A., Rohani Pejman", "Abstract": "This manuscript has been withdrawn following a formal investigation by the Indiana University Research Integrity Office.", "URL": "https://doi.org/10.1101/19012138"} |
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] | {"Title": "Quantification of Optical Coherence Tomography Angiography in Age and Age-related Macular Degeneration using Vessel Density analysis", "Authors": "Vaghefi Ehsan, Hill Sophie, Kersten Hannah M, Squirrell David", "Abstract": "Abstract Purpose To determine whether vessel density (VD) as measured by optical coherence tomography angiography (OCT-A) provide insights into retinal and choriocapillaris vascular changes with ageing and intermediate dry age related macular degeneration (AMD). Methods Seventy-five participants were recruited into three cohorts; young healthy (YH) group, old healthy (OH) and those at high-risk for exudative AMD. Raw OCT and OCT-A data from TOPCON DRI OCT Triton were exported using Topcon IMAGENET 6.0 software, and 3D datasets were analysed to determine retinal thickness and vessel density. Results Central macular thickness measurements revealed a trend of overall retinal thinning with increasing age. VD through the full thickness of the retina was highest in ETDRS sector 4 (the inferior macula) in all the cohorts. Mean VD was significantly higher in the deep capillary plexus than the superficial capillary plexus in all ETDRS sectors in all cohorts but there was no significant difference noted between groups. Choriocapillaris VD was significantly lower in all ETDRS sectors in the in the AMD group compared with the YH and the OH groups. Conclusions Retinal vessel density maps, derived from the retinal plexi are not reliable biomarkers for assessing the ageing macular. Our non-proprietary analysis of the vascular density of the choriocapillaris revealed a significant drop off of VD with age and disease but further work is required to corroborate this finding. If repeatable, choriocapillaris VD may provide a non-invasive biomarker of healthy ageing and disease. Brief Summary In this manuscript, we have studied the potential of retinal vessel density as measured by optical coherence tomography angiography (OCT-A), as a biomarker for detection of high-risk of developing exudative age-related macular degeneration (AMD).", "URL": "https://doi.org/10.1101/19003053"} |
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] | {"Title": "Physicians\u2019 learning in the workplace: use of informal feedback cues in daily practice", "Authors": "Sehlbach Carolin, Teunissen Pim W, Driessen Erik W, Mitchell Sharon, Rohde Gernot GU, Smeenk Frank WJM, Govaerts Marjan JB", "Abstract": "ABSTRACT Purpose We expect physicians to be lifelong learners. Learning from clinical practice is an important potential source for that learning. To support physicians in this process, a better understanding of how they learn in clinical practice is necessary. This study investigates how physicians use informal feedback as learning cues to adjust their communication from interactions with patients in the outpatient setting. Methods To understand physicians\u2019 use of informal feedback, we combined non-participant ethnographic observations with semi-structured interviews. We enrolled 10 respiratory physicians and observed 100 physician-patient interactions at one academic and one non-academic hospital in the Netherlands. Data collection and analysis were performed iteratively according to the principles of constructivist grounded theory. Our conceptual model describes how physicians use cues to reflect on and adjust their communication as well as to further develop their adaptive expertise. Results In addition to vast variations within and across patient encounters, we observed recurring patterns in physicians\u2019 communications in reaction to specific learning cues. Physicians had learnt to recognise and use different cues to adjust their communication in patient encounters. They established a \u2018communication repertoire\u2019 based on multiple patient interactions, which many saw as learning opportunities, contributing to the development of adaptive expertise. Our findings show differences in physicians\u2019 sensitivity to recognising learning opportunities in daily practice which was further influenced by contextual, personal and interpersonal factors. Whereas some reported to have little inclination to change, others used critical incidents to fine-tune their communication repertoire, while others constantly reshaped it, seeking learning opportunities in their daily work. Conclusions There is a large variation in how physicians use learning cues from daily practice. Learning from daily practice is a collaborative effort and requires a culture that promotes lifelong learning. Raising physicians\u2019 awareness of experiences as potential learning opportunities might enhance their development of adaptive expertise.", "URL": "https://doi.org/10.1101/19010926"} |
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] | {"Title": "Quantifying the success of measles vaccination campaigns in the Rohingya refugee camps", "Authors": "Chin Taylor, Buckee Caroline O., Mahmud Ayesha S.", "Abstract": "Abstract In the wake of the Rohingya population\u2019s mass migration from Myanmar, one of the world\u2019s largest refugee settlements was constructed in Cox\u2019s Bazar, Bangladesh to accommodate nearly 900,000 new refugees. Refugee populations are particularly vulnerable to infectious disease outbreaks due to many population and environmental factors. A large measles outbreak, with over 2,500 cases, occurred among the Rohingya population between September and December 2017. Here, we estimate key epidemiological parameters and use a dynamic mathematical model of measles transmission to evaluate the effectiveness of the reactive vaccination campaigns in the refugee camps. We also estimate the potential for subsequent outbreaks under different vaccination coverage scenarios. Our modeling results highlight the success of the vaccination campaigns in rapidly curbing transmission and emphasize the public health importance of maintaining high levels of vaccination in this population, where high birth rates and historically low vaccination coverage rates create suitable conditions for future measles outbreaks.", "URL": "https://doi.org/10.1101/19008417"} |
10.1101/2019.12.11.19014522 | [
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] | {"Title": "Mendelian randomization of smoking behavior on cognitive status among older Americans", "Authors": "Fu Mingzhou, Faul Jessica D., Jin Yuan, Ware Erin B., Bakulski Kelly M.", "Abstract": "Abstract Background Smoking is a likely risk factor for dementia, and smoking behavior has a strong genetic component. In this study, we jointly test the associations between cumulative genetic risk for smoking, smoking behavior, and cognitive status using a Mendelian randomization framework. Methods We conducted a cross-sectional study using the 2010 wave of the Health and Retirement Study database. Individuals aged between 50 and 90 were included. Smoking status was self-reported. Polygenic scores (PGSs) were calculated by weighting participant genotype by published smoking genome-wide association estimates. Cognitive status (normal, impaired, dementia) was measured using multiple assessments. A Mendelian randomization framework was used to infer causal relationships between smoking behavior and cognitive status via genetic instruments. Results Among European ancestry participants (N = 8,735), current smoking behavior was positively associated with cognitive impairment (OR = 1.62, 95% CI: 1.29, 2.01) relative to normal cognition. Using smoking PGS as an instrumental variable, a causal relationship was observed between current smoking and cognitive impairment (OR = 1.53, 95% CI: 1.07, 2.18). There were no associations between smoking PGS, smoking behaviors and cognitive status in the African ancestry study sample (N = 2,511). Conclusions Current smoking is a modifiable risk factor which causes cognitive impairment. Promotion of smoking cessation is important for public health. Further studies on dose and duration of smoking behaviors on cognitive impairment are critically needed, as well as in research other ancestries.", "URL": "https://doi.org/10.1101/2019.12.11.19014522"} |
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] | {"Title": "Prevalence of diabetic foot ulcer and its association with duration of illness and residence in Ethiopia: a systematic review and meta-analysis", "Authors": "Mulugeta Henok, Wagnew Fasil, Zeleke Haymanot, Tesfaye Bekele, Amha Haile, Leshargie Cheru Tesema, Biresaw Henok, Dessie Getenet, Belay Yihalem Abebe, Habtewold Tesfa Dejenie", "Abstract": "Abstract Background Diabetic foot ulcer (DFU), devastating complications of diabetes mellitus, is a major public health problem, and one of the leading reasons for hospital admission, amputations, and even death among diabetic patients in Ethiopia. Despite its catastrophic health consequences, the national burden of diabetic foot ulcer remains unknown in Ethiopia. Hence, the objective of this systematic review and meta-analysis was to estimate the national prevalence of diabetic foot ulcer and investigate the association with duration of illness and patient residence among diabetic patients. Methods We searched PubMed, Google Scholar, Cochrane Library, CINAHL, EMBASE, and PsycINFO databases for studies of diabetic foot ulcers prevalence that published from conception up to June 30, 2019. Quality of each article was assessed using a modified version of the Newcastle-Ottawa Scale for cross-sectional studies. All statistical analyses were done using STATA version 14 software for Windows, and meta-analysis was carried out using a random-effects method. The pooled national prevalence of diabetic foot ulcers was presented using a forest plot. Results A total of 10 studies with 3,029 diabetic patients were included. The pooled national prevalence of diabetic foot ulcers among Ethiopian diabetic patients was 11.27% (95% CI 7.22, 15.31%, I 2 =94.6). Duration of illness (OR: 3.91, 95%CI 2.03, 7.52, I 2 =63.4%) and patients\u2019 residence (OR: 3.40, 95%CI 2.09, 5.54, I 2 =0.0%) were significantly associated with a diabetic foot ulcer. Conclusion In Ethiopia, at least one out of ten diabetic patients had diabetic foot ulcers. Healthcare policymakers (FMoH) need to improve the standard of diabetic care and should design effective preventive strategies to improve health care delivery for people with diabetes and reduce the risk of foot ulceration.", "URL": "https://doi.org/10.1101/19003061"} |
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] | {"Title": "Using Mobile Phones For Computer Aided Detection Of Anomalies On Chest Radiographs: Proof Of Concept", "Authors": "Mitini-Nkhoma Steven", "Abstract": "Abstract Mastering the art of interpreting chest radiographs can be a long and daunting process. We trained a neural network to classify photographs of chest radiographs into 6 groups. The trained model is hosted on a webserver. The model receives and processes photographs of chest radiographs taken using mobile phones. The system then informs the user the most probable diagnosis. Such systems could prove useful in low resource settings which do not have enough highly trained medical personnel and cannot afford the new generation of CAD based radiology equipment.", "URL": "https://doi.org/10.1101/19012146"} |
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] | {"Title": "LncRNA and predictive model for improving the diagnosis of clinically diagnosed pulmonary tuberculosis", "Authors": "Hu Xuejiao, Zhang Jingwei, Liao Shun, Bai Hao, Gupta Shubham, Zhou Yi, Zhou Juan, Wu Qian, Meng Zirui, Jiao Lin, Wu Lijuan, Wang Minjin, Chen Xuerong, Zhou Yanhong, Lu Xiaojun, Zhang Zhaolei, Ying Binwu", "Abstract": "ABSTRACT Background Clinically diagnosed pulmonary tuberculosis (PTB) patients lack Mycobacterium tuberculosis (MTB) pathogenic evidence, and misdiagnosis or delayed diagnosis often occurs in clinical practice. We aimed to investigate the potential of lncRNAs and corresponding predictive models to diagnose these patients. Methods and Findings We totally enrolled 1372 subjects in three cohorts and conducted this study through a prospective four-step approach. In the Screening Step, we discovered five lncRNA candidates from blood samples using microarray on a small cohort. In the Selection Step, we used qRT-PCR to test five lncRNAs on the Selection Cohort (141 clinically diagnosed PTB patients, 159 non-TB disease controls, 578 healthy subjects) and determined three differentially expressed lncRNAs ( ENST00000497872, n333737, n335265 ). In the Model Training Step, we developed logistic regression models to distinguish clinically diagnosed PTB cases from suspected patients of the Selection Cohort, by combining these three lncRNAs with patients\u2019 electronic health records (EHRs). The model with the best c-statistic of 0.91 was presented as a Web-based nomogram (nine variables: ENST00000497872, n333737, n335265 , age, hemoglobin, weight loss, low-grade fever, CT calcification, TB-IGRA; available at https://xuejiao.shinyapps.io/shiny/ ). In the Validation Step, the nomogram was evaluated in the independent Validation Cohort, with good calibration and discrimination (c-statistic: 0.89, sensitivity: 0.80 and specificity: 0.85). A higher clinical net benefit was observed in the nomogram as compared with the EHR model using decision curve analysis. Additionally, The biological function of the most significant lncRNA was interrogated using ELISA, lactate dehydrogenase release analysis and flow cytometry. The results indicated that ENST00000497872 may involve in regulating inflammatory cytokine production, cell death and apoptosis during MTB infection. Conclusions LncRNAs ( ENST00000497872, n333737, n335265 ) could be potential diagnostic biomarkers for clinically diagnosed PTB. The nomogram incorporating lncRNAs and EHRs showed good performance in identifying clinically diagnosed PTB patients. Utilizing the user-friendly nomogram could facilitate the rapid identification of PTB cases among highly suspected patients with negative MTB pathogenic evidence, and thereby help to optimize TB diagnostic procedure.", "URL": "https://doi.org/10.1101/19000281"} |
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] | {"Title": "Mendelian randomization analysis of smoking behavior and cognitive ability on the Big Five", "Authors": "Adams Charleen D.", "Abstract": "Abstract Tobacco smoke, a mutagen that can thin the brain\u2019s cortex, might influence the Big Five (neuroticism, conscientiousness, agreeableness, extraversion, and openness). Cognitive ability, however, is a potential confounder, since it is associated with who smokes and with personality. Mendelian randomization (MR), which uses genetic variants as instrumental variables, can be used to probe the causal nature of these factors on personality. Here, MR was used to appraise smoking and cognitive ability on the Big Five and cognitive ability and neuroticism on social disparity. The results seem to suggest that smoking, independent of cognitive ability, leads people to be more neurotic and less extraverted and conscientious. Higher cognitive ability appears to make people less neurotic and more open, when accounting for smoking. Neuroticism appears to increase disparity, and higher cognitive ability appears to decrease it. Smoking may enhance disparity between those of lower and higher cognitive ability by exacerbating personality differences.", "URL": "https://doi.org/10.1101/2019.12.11.19014530"} |
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] | {"Title": "Host genetic variants near the PAX5 gene locus associate with susceptibility to invasive group A streptococcal disease", "Authors": "Parks Tom, Auckland Kathryn, Lamagni Theresa L., Mentzer Alexander, Elliott Katherine, Guy Rebecca, Cartledge Doreen, Strakova Lenka, O\u2019Connor Daniel, Pollard Andrew J, Chapman Stephen J., Thomas Matthew, Brodlie Malcolm, Colot Julien, D\u2019Ortenzio Eric, Baroux No\u00e9mie, Mirabel Mariana, Gilchrist James J., Scott J. Anthony G., Williams Thomas N., Knight Julian, Steer Andrew C., Hill Adrian V. S., Sriskandan Shiranee", "Abstract": "Abstract We undertook a genome-wide association study of susceptibility to invasive group A streptococcal (GAS) disease combining data from distinct clinical manifestations and ancestral populations. Amongst other signals, we identified a susceptibility locus located 18kb from PAX5 , an essential B-cell gene, which conferred a nearly two-fold increased risk of disease (rs1176842, odds ratio 1.8, 95% confidence intervals 1.5-2.3, P=3.2\u00d710 \u22127 ). While further studies are needed, this locus could plausibly explain some inter-individual differences in antibody-mediated immunity to GAS, perhaps providing insight into the effects of intravenous immunoglobulin in streptococcal toxic shock.", "URL": "https://doi.org/10.1101/19003087"} |
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] | {"Title": "Obstetrical safety indicators for preventing hospital harms: a scoping review protocol", "Authors": "Conway A, Reszel J, Walker MC, Grimshaw JM, Dunn SI", "Abstract": "Abstract Introduction Optimizing the safety of obstetric patient care is a primary concern for many hospitals. Identifying performance indicators that measure aspects of patient care processes related to preventable harms can present opportunities to improve health systems. In this paper, we present our protocol for a scoping review to identify performance indicators for obstetric safety. We aim to identify a comprehensive list of obstetric safety indicators which may help reduce the number of preventable patient harms, to summarize the data and to synthesize the results. Methods and analysis We will use the methodological framework described by Arksey and O\u2019 Malley and further expanded by Levac. We will search multiple electronic databases such as Medline, Embase, CINAHL and the Cochrane Library as well as websites from professional bodies and other organisations, using an iterative search strategy. We will include indicators that relate to preventable harms in the process of obstetric care. Two reviewers will independently screen titles and abstracts of search results to determine eligibility for inclusion. For records where eligibility is not clear, the reviewers will screen the full text version. If reviewers\u2019 decisions regarding eligibility differ, a third reviewer will review the full text record. Two reviewers will independently extract data from records that meet our inclusion criteria using a standardized data collection form. We will narratively describe quantitative data, such as the frequency with which indicators are identified, and conduct a thematic analysis of the qualitative data. We will compile a comprehensive list of patient safety indicators identified during our scoping review and organise them according to concepts that best suit the data such as the Donabedian model or the Hospital Harm Framework. We will discuss the implications of the indicators for future research, clinical practice and policy making. We will report the conduct of the review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA ScR) Checklist. Ethics and Dissemination The sources of information included in this scoping review will be available to the public. Therefore, ethical review for this research is not warranted. We will disseminate our research results using multiple modes of delivery such as a peer-reviewed publication, conference presentations and stakeholder communications. Strengths and limitations of this study We will use systematic methods to conduct and report this scoping review based on established methods introduced by Arksey and O\u2019 Malley and further developed by Levac. We will report the conduct of the review using guidance from the PRISMA Extension for Scoping Reviews (PRISMA-ScR). We will limit the focus of this review to patient safety indicators from English language resources aimed at health system processes in developed countries. We will not assess the risk of bias or certainty of the evidence in the included records because this is a scoping review to identify potential obstetrical safety indicators. After the scoping review, we will present the identified indicators to key informants in a consensus process to create a shortlist that may not be suitable for inclusion in a future obstetrical safety dashboard for BORN (Better Outcomes Registry and Network) Ontario. BORN collects and safeguards data, and shares information to improve the delivery of maternal, neonatal and child healthcare across the province.", "URL": "https://doi.org/10.1101/19012153"} |
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] | {"Title": "A target product profile for electronic clinical decision support algorithms combined with point-of-care diagnostic test results to support evidence-based decisions during patient consultations by health workers", "Authors": "Pell\u00e9 Karell G., Rambaud-Althaus Clotilde, D\u2019Acremont Val\u00e9rie, Moran Gretchen, Sampath Rangarajan, Katz Zach, Moussy Francis, Mehl Garrett L., Dittrich Sabine", "Abstract": "ABSTRACT Health workers in low-resource settings often lack the support and tools to follow evidence-based clinical recommendations for diagnosing, treating and managing sick patients. Digital technologies, by combining patient health information and point of care diagnostics with evidence-based clinical protocols, can help improve the quality of care, the rational use of resources (humans, diagnostics and medicines) and save patient lives. The development of a target product profile for electronic clinical decision support algorithms (CDSAs) aimed at guiding preventive or curative consultations, and that integrate diagnostic test results will help align developer and implementer processes and specifications with the needs of end-users, in terms of quality, safety, performance and operational functionality. To identify characteristics for a CDSA, experts from academia, research institutions, and industry as well as policy makers with expertise in diagnostic and CDSA development, and implementation in LMICs were convened. Experts discussed the critical characteristics of a draft TPP which was revised and finalised through a Delphi process to facilitate consensus building. Experts were in overwhelming agreement that, given that CDSAs provide patients\u2019 management recommendations, the underlying clinical algorithms should be available in human readable format and evidence-based. Whenever possible, the algorithm output should take into account pre-test disease probabilities, diagnostic likelihood ratios of clinical or laboratory predictors and disease probability thresholds to test and to treat. Validation processes should at a minimum ensure the CDSA are implementing faithfully the evidence-based algorithm they are based on (internal validation through clinical association and analytical validation). Additionally, clinical validation, bringing practice evidence about the impact of the CDSA use on health outcomes, was recognized as a good to have. The CDSAs should be designed to fit within clinic workflows, connectivity challenges and high volume settings. Data collected through the tool should conform to local patient privacy regulations and international data standards.", "URL": "https://doi.org/10.1101/19008433"} |
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] | {"Title": "Detection of parasite-derived transrenal DNA for the diagnosis of chronic Trypanosoma cruzi infection", "Authors": "Madrigal Ana G., Marcus Rachel, Gilman Robert, Scott Alan L., Shiff Clive", "Abstract": "Abstract Chagas disease, caused by the protozoan parasite Trypanosoma cruzi , is a potentially life-threatening infection endemic to Latin America that has emerged as a global public health issue due to globalization and emigration patterns. Diagnosis of T. cruzi infection is complex, especially for the chronic phase of the disease that is characterized by a low to moderate burden of the difficult to detect, tissue-dwelling, intracellular form of the parasite. Diagnosis relies on a multistep indirect serological detection approach that requires positive results in at least two independent anti- T. cruzi antibody tests. With no gold standard diagnostic method for chronic T. cruzi , new approaches are needed that can more directly test for the presence of the parasite. Here, we report on of the potential utility of a noninvasive diagnostic approach that specifically detects T. cruzi -derived cell-free repeat DNA in the urine of patients who are both serologically positive and negative.", "URL": "https://doi.org/10.1101/19010934"} |
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] | {"Title": "High frequency of Exon 20 S768I EGFR mutation detected in malignant pleural effusions: a poor prognosticator of NSCLC?", "Authors": "D\u2019Souza George, Dhar Chirag, Kyalanoor Vishal, Yadav Lokendra, Sharmra Mugdha, Nawaz S Mohammad, Srivastava Sweta", "Abstract": "Abstract Lung cancer is the cause of a fourth of all cancer-related deaths. About a third of all lung adenocarcinoma tumours harbour mutations on exons 18, 19, 20 and 21 of the epidermal growth factor receptor ( EGFR ) gene. Detection of these mutations allows for targeted therapies in the form of EGFR Tyrosine kinase inhibitors. In our study, we utilized malignant pleural effusions (MPEs) as \u201cliquid biopsies\u201d to detect EGFR mutations when tissue biopsies were unavailable. We showed that a direct sequencing approach was likely to miss SNVs in MPEs. We then optimized an EGFR mutant-specific quantitative polymerase chain reaction-based assay and piloted it on n=10 pleural effusion samples (1 non-malignant pleural effusion as a negative control). 5/9 (55.55%) samples harboured EGFR mutations with 2/9 (22.22%) being exon 19 deletions and 3/9 (33.33%) had the S768I exon 20 mutation. The frequency of the S768I SNV in our study was significantly higher than that observed in other studies (\u223c0.3%). Utilizing publicly available cBioPortal data, we report that patients with the S768I SNV had a shorter median survival time, progression-free survival time and lower tumor mutation count compared to patients with other EGFR mutations. These data suggest that this point mutation predicts poor prognosis as a result of aggressive disease, though studies in larger cohorts are necessary to confirm these findings. The high frequency of S768I mutations seen in our study also suggests that cancer cells harbouring these mutations may be superior in their ability to migrate, home or reside in pleural fluid.", "URL": "https://doi.org/10.1101/2019.12.08.19014167"} |
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] | {"Title": "A study of knowledge, experience and beliefs about hepatitis B virus (HBV) infection in south western Uganda", "Authors": "Mugisha Joseph, Mokaya Jolynne, Bukenya Dominic, Ssembajja Fatuma, Mayambala Denis, Newton Robert, Matthews Philippa C, Seeley Janet", "Abstract": "ABSTRACT Introduction United Nations sustainable development goals aim for the elimination of viral hepatitis as a public health threat by 2030, leading to efforts to upscale the availability and accessibility of hepatitis B virus (HBV) vaccination, diagnosis and treatment globally. However, a variety of societal factors, including beliefs, traditions, and stigma, can be a major obstacle to all of these interventions. We therefore set out to investigate how HBV is understood and described in communities in Uganda, and whether there is evidence of potential stigma. Method We carried out a qualitative formative study in two sites in South Western Uganda: a village in Kalungu district (site A) and an area on the outskirts of Masaka town (site B). We undertook a rapid assessment to investigate how adults describe HBV infection and their perceptions about the infection. We collected data by conducting a transect walk, observations, community group discussions, and in-depth interviews, sampling a total of 131 individuals. We used inductive content analysis to extract key themes associated with HBV. Results There is no specific word for HBV infection in local languages, and knowledge about this infection is varied. While some individuals were completely unfamiliar with HBV infection, some had heard of HBV. Radio was a common source of information. There was awareness of HBV as a cause of liver disease, limited knowledge regarding the cause, mode of transmission and treatment. Stigma in HBV may be rare in this community due to limited understanding and experience of HBV. Conclusion There is an ongoing need to improve awareness and understanding of HBV in this community. Careful dissemination of accurate information is required to promote acceptance of interventions for prevention, diagnosis and treatment.", "URL": "https://doi.org/10.1101/19003129"} |
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] | {"Title": "Characteristics, service use and mortality of clusters of multimorbid patients in England: a population-based study", "Authors": "Zhu Yajing, Edwards Duncan, Mant Jonathan, Payne Rupert A, Kiddle Steven", "Abstract": "Abstract Background Multimorbidity is one of the principal challenges facing health systems worldwide. To help understand the changes to services and policies that are required to deliver better care, we used a novel approach to investigate which diseases co-occur and how combinations are associated with mortality and service use. Methods Linked primary and secondary care electronic health records contributed by 382 general practices in England to the Clinical Practice Research Datalink (CPRD) were used. The study included a representative set of multimorbid adults (18 years old or more) with two or more long-term conditions (N=113,211). A random set of 80% of the multimorbid patients (N=90,571) were stratified by age and clustered using latent class analysis. Consistency between obtained disease profiles, classification quality and associations with demographic characteristics and primary outcomes (hospitalisation, polypharmacy and mortality) was validated in the remaining 20% of multimorbid patients (N=22,640). Findings We identified twenty patient clusters across four age strata. The clusters with the highest mortality comprised psychoactive substance and alcohol misuse (aged 18-64), coronary heart disease, depression and pain (aged 65-84) and coronary heart disease, heart failure and atrial fibrillation (aged 85+). The clusters with the highest service use coincided with those with highest mortality for people aged over 65. For people aged 18-64, the cluster with the highest service use comprised depression, anxiety and pain. The majority of 85+ year olds multimorbid patients belonged to the cluster with the lowest service use and mortality for that age range. Pain featured in thirteen clusters. Interpretation This work has highlighted patterns of multimorbidity that have implications for health services. These include the importance of psychoactive substance and alcohol misuse in people under the age of 65; of co-morbid depression and coronary heart disease in people aged 65-84, and of cardiovascular disease in people aged 85+. Funding UK Medical Research Council Research in context Evidence before this study We searched PubMed using the keyword list \u201cmultimorbidity, co-morbidity, disease patterns, clusters, service use, long-term conditions, chronic conditions\u201d for studies published in English. We also reviewed multiple systematic reviews of multimorbidity patterns, and the policy report of multimorbidity research issued by the Academy of Medical Sciences in 2018. Most studies have focused on older populations (aged 60+) and often used a small list of long-term conditions. Multimorbidity clusters composed of more than two conditions have not been well profiled mostly due to non-representative and small samples. There is substantial heterogeneity in the number of conditions considered (often less than 20) and in the statistical methods. Most studies focused on grouping diseases rather than patients, making it less straightforward to relate patients to outcomes in order to facilitate patient-centred care. Added value of this study This study is the first to describe and validate clusters of multimorbid patients across the adult lifecourse using a patient-centred probabilistic clustering approach. This leads to a more nuanced understanding of the relationship between age, multimorbidity and mortality and new insights into the importance of different clusters. For example, contrary to perceived wisdom, we show that the majority of 85+ year old multimorbid patients belong to a cluster with relatively low service use and mortality for that age group. We identify a cluster of younger multimorbid patients with psychoactive substance misuse that have a mortality rate 18 times higher than their non-multimorbid peers. Implications of all the available evidence We have validated and added to the list of disease combinations where tailored approaches could be attempted to better manage multimorbid patients and develop effective interventions. For example, the high mortality of younger multimorbid patients with psychoactive substance misuse might be reduced by addressing risk factors (e.g. drug use, smoking, deprivation) which are amenable to intervention.", "URL": "https://doi.org/10.1101/19000422"} |
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] | {"Title": "Opening the Black Box of Artificial Intelligence for Clinical Decision Support: A Study Predicting Stroke Outcome", "Authors": "Zihni Esra, Madai Vince Istvan, Livne Michelle, Galinovic Ivana, Khalil Ahmed A., Fiebach Jochen B., Frey Dietmar", "Abstract": "Abstract Background State-of-the-art machine learning (ML) artificial intelligence methods are increasingly leveraged in clinical predictive modeling to provide clinical decision support systems to physicians. Modern ML approaches such as artificial neural networks (ANNs) and tree boosting often perform better than more traditional methods like logistic regression. On the other hand, these modern methods yield a limited understanding of the resulting predictions. However, in the medical domain, understanding of applied models is essential, in particular, when informing clinical decision support. Thus, in recent years, interpretability methods for modern ML methods have emerged to potentially allow explainable predictions paired with high performance. Methods To our knowledge, we present in this work the first explainability comparison of two modern ML methods, tree boosting and multilayer perceptrons (MLPs), to traditional logistic regression methods using a stroke outcome prediction paradigm. Here, we used clinical features to predict a dichotomized 90 days post-stroke modified Rankin Scale (mRS) score. For interpretability, we evaluated clinical features\u2019 importance with regard to predictions using deep Taylor decomposition for MLP, Shapley values for tree boosting and model coefficients for logistic regression. Results With regard to performance as measured by AUC values on the test dataset, all models performed comparably: Logistic regression AUCs were 0.82, 0.82, 0.79 for three different regularization schemes; tree boosting AUC was 0.81; MLP AUC was 0.81. Importantly, the interpretability analysis demonstrated consistent results across models by rating age and stroke severity consecutively amongst the most important predictive features. For less important features, some differences were observed between the methods. Conclusions Our analysis suggests that modern machine learning methods can provide explainability which is compatible with domain knowledge interpretation and traditional method rankings. Future work should focus on replication of these findings in other datasets and further testing of different explainability methods.", "URL": "https://doi.org/10.1101/19010975"} |
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] | {"Title": "Asthma Exacerbation Prediction and Interpretation based on Time-sensitive Attentive Neural Network: A Retrospective Cohort Study", "Authors": "Xiang Yang, Ji Hangyu, Zhou Yujia, Li Fang, Du Jingcheng, Rasmy Laila, Wu Stephen, Zheng Wenjin.Jim, Xu Hua, Zhi Degui, Zhang Yaoyun, Tao Cui", "Abstract": "Abstract Background Asthma exacerbation is an acute or sub-acute episode of progressive worsening of asthma symptoms and can have significant impacts on patients\u2019 daily life. In 2016, 12.4 million current asthmatics (46.9%) in the U.S. had at least one asthma exacerbation in the previous year. Objective The objectives of this study were to predict the risk of asthma exacerbations and to explore potential risk factors involved in progressive asthma. Methods We proposed a time-sensitive attentive neural network to predict asthma exacerbation using clinical variables from electronic health records (EHRs). The clinical variables were collected from the Cerner Health Facts\u00ae database between 1992 and 2015 including 31,433 asthmatic adult patients. Interpretations on both the patient level and the cohort level were investigated based on the model parameters. Results The proposed model obtains an AUC value of 0.7003 through 5-fold cross-validation, which outperforms the baseline methods. The results also demonstrate that the addition of elapsed time embeddings considerably improves the performance on this dataset. Through further analysis, it was witnessed that risk factors behaved distinctly along the timeline and across patients. We also found supporting evidence from peer-reviewed literature for some possible cohort-level risk factors such as respiratory syndromes and esophageal reflux. Conclusions The proposed time-sensitive attentive neural network is superior to traditional machine learning methods and performs better than state-of-the-art deep learning methods in realizing effective predictive models for the prediction of asthma exacerbation. We believe that the interpretation and visualization of risk factors can help the clinical community to better understand the underlying mechanisms of the disease progression.", "URL": "https://doi.org/10.1101/19012161"} |
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] | {"Title": "Brain-Computer Interface Robotics for Hand Rehabilitation After Stroke: A Systematic Review", "Authors": "Baniqued Paul Dominick E, Stanyer Emily C, Awais Muhammad, Alazmani Ali, Jackson Andrew E, Mon-Williams Mark A, Mushtaq Faisal, Holt Raymond J", "Abstract": "Abstract Background Hand rehabilitation is core to helping stroke survivors regain activities of daily living. Recent studies have suggested that the use of electroencephalography-based brain-computer interfaces (BCI) can promote this process. Here, we report the first systematic examination of the literature on the use of BCI-robot systems for the rehabilitation of fine motor skills associated with hand movement and profile these systems from a technical and clinical perspective. Methods A search for January 2010-October 2019 articles using Ovid MEDLINE, Embase, PEDro, PsycINFO, IEEE Xplore and Cochrane Library databases was performed. The selection criteria included BCI-hand robotic systems for rehabilitation at different stages of development involving tests on healthy participants or people who have had a stroke. Data fields include those related to study design, participant characteristics, technical specifications of the system, and clinical outcome measures. Results 30 studies were identified as eligible for qualitative review and among these, 11 studies involved testing a BCI-hand robot on chronic and subacute stroke patients. Statistically significant improvements in motor assessment scores relative to controls were observed for three BCI-hand robot interventions. The degree of robot control for the majority of studies was limited to triggering the device to perform grasping or pinching movements using motor imagery. Most employed a combination of kinaesthetic and visual response via the robotic device and display screen, respectively, to match feedback to motor imagery. Conclusion 19 out of 30 studies on BCI-robotic systems for hand rehabilitation report systems at prototype or pre-clinical stages of development. We identified large heterogeneity in reporting and emphasise the need to develop a standard protocol for assessing technical and clinical outcomes so that the necessary evidence base on efficiency and efficacy can be developed.", "URL": "https://doi.org/10.1101/2019.12.11.19014571"} |
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] | {"Title": "The Human Leukocyte Antigen Locus and Susceptibility to Rheumatic Heart Disease in South Asians and Europeans", "Authors": "Auckland Kathryn, Mittal Balraj, Cairns Benjamin J, Garg Naveen, Kumar Surendra, Mentzer Alexander J, Kado Joseph, Perman Mai Ling, Steer Andrew C, Hill Adrian V S, Parks Tom", "Abstract": "Abstract Background Rheumatic heart disease (RHD) remains an important cause of morbidity and mortality globally. Several reports have linked the disease to the human leukocyte antigen (HLA) locus but with negligible consistency. Methods We undertook a genome-wide association study (GWAS) of susceptibility to RHD in 1163 South Asians (672 cases; 491 controls) recruited in India and Fiji. We analysed directly obtained and imputed genotypes, and followed-up associated loci in 1459 Europeans (150 cases; 1309 controls) from the UK Biobank study. For fine-mapping, we used HLA imputation to define classical alleles and amino acid polymorphisms. Results A single signal situated in the HLA class III region reached genome-wide significance in the South Asians, and replicated in the Europeans (rs201026476; combined odds ratio 1.81, 95% confidence intervals 1.51-2.18, P =3.48\u00d710 \u221210 ). While the signal fine-mapped to specific amino acid polymorphisms within HLA-DQB1 and HLA-B , with conditioning, the lead class III variant remained associated with susceptibility ( P =3.34\u00d710 \u22124 ), suggesting an independent effect. Conclusions A complex HLA signal, likely comprising at least two underlying causal variants, strongly associates with susceptibility to RHD in South Asians and Europeans. Crucially, the involvement of the class III region may partly explain the previous inconsistency, while offering important new insight into pathogenesis.", "URL": "https://doi.org/10.1101/19003160"} |
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] | {"Title": "Living alone, loneliness and lack of emotional support as predictors of suicide and self-harm: a nine-year follow up of the UK Biobank cohort", "Authors": "Shaw Richard J., Cullen Breda, Graham Nicholas, Lyall Donald M., Mackay Daniel, Okolie Chukwudi, Pearsall Robert, Ward Joey, John Ann, Smith Daniel J.", "Abstract": "Abstract Background The association between loneliness and suicide is poorly understood. We investigated how living alone, loneliness and emotional support were related to suicide and self-harm in a longitudinal design. Methods Between 2006 and 2010 UK Biobank recruited and assessed in detail over 0.5 million people in middle age. Data were linked to prospective hospital admission and mortality records. Adjusted Cox regression models were used to investigate relationships between living arrangements, loneliness and emotional support, and both suicide and self-harm as outcomes. Results For men, both living alone (Hazard Ratio (HR) 2.16, 95%CI 1.51-3.09) and living with non-partners (HR 1.80, 95%CI 1.08-3.00) were associated with death by suicide, independently of loneliness, which had a modest relationship with suicide (HR 1.43, 95%CI 0.1.01-2.03). For women, there was no evidence that living arrangements, loneliness or emotional support were associated with death by suicide. Associations between living alone and self-harm were explained by health for women, and by health, loneliness and emotional support for men. In fully adjusted models, loneliness was associated with hospital admissions for self-harm in both women (HR 1.89, 95%CI 1.57-2.28) and men (HR 1.74, 95%CI 1.40-2.16). Limitations Loneliness and emotional support were operationalized using single item measures. Conclusions For men - but not for women - living alone or living with a non-partner increased the risk of suicide, a finding not explained by subjective loneliness. Overall, loneliness may be more important as a risk factor for self-harm than for suicide. Loneliness also appears to lessen the protective associations of cohabitation. Highlights First cohort study to investigate loneliness\u2019s relationship with deaths by suicide Loneliness is associated with a modest increased risk of death by suicide for men For men, living with a partner reduces the risk of death by suicide Loneliness increases the risk of hospitalization for self-harm for men and women", "URL": "https://doi.org/10.1101/19008458"} |
10.1101/2019.12.12.19014555 | [
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] | {"Title": "A brief report: de novo copy number variants in children with attention deficit hyperactivity disorder", "Authors": "Martin Joanna, Hosking Grace, Wadon Megan, Agha Sharifah Shameem, Langley Kate, Rees Elliott, Owen Michael J, O\u2019Donovan Michael, Kirov George, Thapar Anita", "Abstract": "Abstract Background Recent case-control genetic studies of attention deficit hyperactivity disorder (ADHD) have implicated common and rare genetic risk alleles, highlighting the polygenic and complex aetiology of this neurodevelopmental disorder. Studies of other neurodevelopmental disorders, such as autism spectrum disorder (ASD), Tourette disorder, developmental delay/intellectual disability, and schizophrenia indicate that identification of specific risk alleles and additional insights into disorder biology can be gained by studying non-inherited de novo variation. In this study, we aimed to identify large de novo copy number variants (CNVs) in children with ADHD. Methods Children with a confirmed diagnosis of ADHD and their parents were genotyped and included in this sample. We used PennCNV to call large (>200kb) CNVs and identified those calls that were present in the proband and absent in both biological parents. Results In 305 parent-offspring trios, we detected 14 de novo CNVs in 13 probands, giving a mutation rate of 4.6% and a per individual rate of 4.3%. This rate is higher than published reports in controls and similar to those observed for ASD, schizophrenia and Tourette disorder. We also identified de novo mutations at 4 genomic loci (15q13.1-13.2 duplication, 16p13.11 duplication, 16p12.2 deletion and 22q11.21 duplication) that have previously been implicated in other neurodevelopmental disorders, two of which (16p13.11 and 22q11.21) have also been implicated in case-control ADHD studies. Conclusions Our study complements ADHD case-control genomic analyses and demonstrates the need for larger parent-offspring trio genetic studies to gain further insights into the complex aetiology of ADHD.", "URL": "https://doi.org/10.1101/2019.12.12.19014555"} |
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] | {"Title": "Predicting epileptic seizures using nonnegative matrix factorization", "Authors": "Stojanovi\u0107 Olivera, Pipa Gordon", "Abstract": "Abstract This paper presents a procedure for the patient-specific prediction of epileptic seizures. To this end, a combination of nonnegative matrix factorization (NMF) and smooth basis functions with robust regression is applied to power spectra of intracranial electroencephalographic (iEEG) signals. The resulting time and frequency components capture the dominant information from power spectra, while removing outliers and noise. This makes it possible to detect structure in preictal states, which is used for classification. Linear support vector machines (SVM) with L1 regularization are used to select and weigh the contributions from different number of not equally informative channels among patients. Due to class imbalance in data, synthetic minority over-sampling technique (SMOTE) is applied. The resulting method yields a computationally and conceptually simple, interpretable model of EEG signals of preictal and interictal states, which shows a good performance for the task of seizure prediction.", "URL": "https://doi.org/10.1101/19000430"} |
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] | {"Title": "GBA variants in REM sleep behavior disorder: a multicenter study", "Authors": "Krohn Lynne, Ruskey Jennifer A., Rudakou Uladzislau, Leveille Etienne, Asayesh Farnaz, Hu Michele T.M., Arnulf Isabelle, Dauvilliers Yves, H\u00f6gl Birgit, Stefani Ambra, Monaca Christelle Charley, Beatriz Abril, Plazzi Giuseppe, Antelmi Elena, Ferini-Strambi Luigi, Heidbreder Anna, Boeve Bradley F., Espay Alberto J., De Cock Val\u00e9rie Cochen, Mollenhauer Brit, Sixel-D\u00f6ring Friederike, Trenkwalder Claudia, Sonka Karel, Kemlink David, Figorilli Michela, Puligheddu Monica, Dijkstra Femke, Viaene Mineke, Oertel Wolfgang, Toffoli Marco, Gigli Gian Luigi, Valente Mariarosaria, Gagnon Jean-Fran\u00e7ois, Desautels Alex, Montplaisir Jacques Y., Postuma Ronald B., Rouleau Guy A., Gan-Or Ziv", "Abstract": "Abstract Objective To study the role of GBA variants in the risk for isolated rapid-eye-movement (REM)-sleep behavior disorder (iRBD) and conversion to overt neurodegeneration. Methods A total of 4,147 individuals were included: 1,061 iRBD patients and 3,086 controls. GBA was fully sequenced using molecular inversion probes and Sanger sequencing. We analyzed the effects of GBA variants on the risk for iRBD, age at onset (AAO) and conversion rates. Results GBA variants were found in 9.5% of iRBD patients compared to 4.1% in controls (odds ratio [OR]=2.45, 95% CI=1.87\u20133.22, p =1\u00d710 \u221210 ). The estimated OR for mild p.N370S variant carriers was 3.69, 95% CI=1.90\u20137.14, p =3.5\u00d710 \u22125 , while for severe variant carriers it was 17.55, 95% CI=2.11\u2013145.9, p =0.0015. Carriers of severe GBA variants had an average AAO of 52.8 years, 7-8 years earlier than those with mild variants or non-carriers ( p =0.029). Of the GBA variant carriers with available data, 52.5% had converted, compared to 35.6% in non-carriers ( p =0.011), with a trend for faster conversion among severe GBA variant carriers. However, the results on AAO and conversion were based on small numbers and should be taken with caution. Conclusions GBA variants robustly and differentially increase the risk of iRBD. The rate of conversion to neurodegeneration is also increased and may be faster among severe GBA variant carriers, although confirmation will be required in larger samples. Screening for RBD in healthy carriers of GBA variants should be studied as a potential way to identify GBA variant carriers who will develop a synucleinopathy in the future.", "URL": "https://doi.org/10.1101/19010991"} |
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] | {"Title": "Insomnia, excessive daytime sleepiness, anxiety, depression and socioeconomic status among customer service employees in Canada", "Authors": "Sosso FA Etindele", "Abstract": "ABSTRACT Objectives The present study alerts on the potential effect of working full time in a call center as a risk factor for neuropsychiatric illnesses. It is the first study investigating deeply presence of anxiety, depression, insomnia and excessive daytime sleepiness among a large population of customer service employees. It has 3 specifics goals which were (1) document presence of sleep disorders among customer service advisors (2) document presence of anxiety and depression in this population (3) determine the influence of the socioeconomic status, duration in position and full time or part-time shift on the diseases above. Findings It was found that the majority of people working in customer service are undergraduate students or at a secondary/high school degree. They worked full time, are single and have reported at least two of the neuropsychiatric disorders assessed in the present study. Among customer service advisors enrolled in this study, all neuropsychiatric disorders investigated were present and significantly higher for those working full time. Perceived socioeconomic status (pSES) was almost similar for full time and part time workers with a mean score of 4.8 on the MacArthur scale of subjective social status. Results revealed that duration in position was an excellent predictor of insomnia, sleepiness and anxiety (respectively with R2=91,83%, R2=81,23% and R2=87,46%) but a moderate predictor of depression (R2=69,14%). The pSES was a moderate predictor of sleep disorders (respectively R2=62,04% for insomnia and R2=53,62% for sleepiness) but had a strong association with anxiety and depression (R2=82,95% for anxiety and R2=89,77% for depression). It was found that insomnia and anxiety are more prevalent for immigrants and international students compared to Canadians, while depression was similarly higher for Canadian and immigrants compared to international students. It was found that sleepiness has the same trend in the three subgroups. Conclusion Customer service employees are exposed to a continuous stimulation of their cognitive functions in addition to different stressors which can progressively and silently damage the nervous system. Investigations on mental and physical health of customer service advisors are worthy of interest, and understanding how their work, their rotating shifts and their socioeconomic status influence their resilience and their performance at work; may help comprehension of similar health issues emerging in similar populations with similar occupations.", "URL": "https://doi.org/10.1101/19003194"} |
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] | {"Title": "Joint modelling of individual trajectories, within-individual variability and a later outcome: systolic blood pressure through childhood and left ventricular mass in early adulthood", "Authors": "Parker Richard M.A., Leckie George, Goldstein Harvey, Howe Laura D., Heron Jon, Hughes Alun D., Phillippo David M., Tilling Kate", "Abstract": "ABSTRACT Within-individual variability of repeatedly-measured exposures may predict later outcomes: e.g. blood pressure (BP) variability (BPV) is an independent cardiovascular risk factor above and beyond mean BP. Since two-stage methods, known to introduce bias, are typically used to investigate such associations, we introduce a joint modelling approach, examining associations of both mean BP and BPV across childhood to left ventricular mass (indexed to height; LVMI) in early adulthood with data from the UK\u2019s Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Using multilevel models, we allow BPV to vary between individuals (a \u201crandom effect\u201d) as well as to depend on covariates (allowing for heteroscedasticity). We further distinguish within-clinic variability (\u201cmeasurement error\u201d) from visit-to-visit BPV. BPV was predicted to be greater at older ages, at higher bodyweights, and in females, and was positively correlated with mean BP. BPV had a positive association with LVMI (10% increase in SD(BP) was predicted to increase LVMI by mean = 0.42% (95% credible interval: \u22120.47%, 1.38%)), but this association became negative (mean = \u22121.56%, 95% credible interval: \u22125.01%, 0.44%)) once the effect of mean BP on LVMI was adjusted for. This joint modelling approach offers a flexible method of relating repeatedly-measured exposures to later outcomes.", "URL": "https://doi.org/10.1101/19008474"} |
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] | {"Title": "Temporal trends in public mass shootings: high-capacity magazines significantly increase fatality counts, and are becoming more prevalent", "Authors": "Towers Sherry, Wallace Danielle, Hemenway David", "Abstract": "Abstract Background There has been disagreement in the literature regarding whether public mass shootings are becoming more frequent, or more deadly, and whether high-capacity magazine (HCM) weaponry is associated with increased fatalities. Objective We examined the 85 non-felony- and non-gang-related mass shootings with at least four people shot and killed that occurred in public places between 1995 to 2018 to examine the frequency and deadliness of public mass shootings, as well as the role of HCM weaponry in fatalities. Findings The per-capita rate of public mass shootings with at least four people killed has not significantly increased since 1995 (Negative Binomial linear regression p=0.20), but public mass shootings with at least six people killed have been increasing by 6.9% per year (p=0.01). Public mass shootings are becoming significantly more deadly, with fatalities per incident increasing by 4.5% per year (truncated Negative Binomial log-linear regression p<0.001). Use of HCM weaponry banned during the 1994 to 2004 Federal Assault Weapons Ban (FAWB) increased fatality counts on average by 1.9 times, and total number shot by 3.3 times (non-parametric bootstrap comparison of means (NPBCM), p < 0.001 in both cases). In these incidents, HCM pistols were as deadly as assault rifles. The fraction of firearms involving HCMs used by perpetrators more than doubled after the lapse of the federal ban, from 25% during the ban to 59% after (Binomial factor regression, p<0.001). Our online visual analytics application, https://mass-shooting-analytics.shinyapps.io/mass_shootings/ , allows interested parties to examine and download our data, replicate our analysis results and explore the analysis with alternate selections. Policy recommendations A re-instatement of the federal ban on high-capacity magazines in pistols and rifles, or special taxes on such weaponry, may reduce public mass shooting fatalities.", "URL": "https://doi.org/10.1101/2019.12.12.19014738"} |
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] | {"Title": "Risk of Inflammatory Bowel Disease in Psoriasis Patients Treated with Anti-Interleukin-17 Agents: A Bayesian Metaanalysis", "Authors": "Gill N., Pietrosanu M., Gniadecki R.", "Abstract": "Abstract Background Use of interleukin-17 inhibitors (IL-17i) in psoriasis has been associated with an increased risk of inflammatory bowel disease (IBD). However, the clinical significance of this association is not understood. Objectives To quantify the absolute risk of IBD in patients with psoriasis treated with IL-17i, stratified by known IBD risk factors. Methods Literature searches were performed to identify known IBD risk factors and the prevalences were quantified by a meta-analysis of proportions. The Bayesian model was used to estimate the probability of a new-onset or a flare of IBD in patients with psoriasis. Results The prevalence of Crohn\u2019s disease (CD) or ulcerative colitis (UC) in the general psoriasis population was 0.0010. Use of IL-17i increased the risk of CD to 0.0037 and UC to 0.0028, translating to a number needed to harm (NNH) of 373 for CD and 564 for UC. In patients who had concomitant hidradenitis suppurativa, the use of IL-17i was associated with a decrease in NNH for CD and UC to 18 and 76, respectively, whereas for patients with a family history of IBD, the NNH values were 6 (for CD) and 10 (for UC). Conclusions In patients with no risk factors, the probability of IBD flare or onset during IL-17i treatment is negligible and additional IBD screening procedures are not indicated. In contrast, the patients with psoriasis who have hidradenitis suppurativa or first-degree family history of IBD as risk factors should be monitored for signs and symptoms of CD and UC during IL-17i therapy.", "URL": "https://doi.org/10.1101/19012179"} |
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] | {"Title": "Childhood immune imprinting to influenza A shapes birth year-specific risk during seasonal H1N1 and H3N2 epidemics", "Authors": "Gostic Katelyn M, Bridge Rebecca, Brady Shane, Viboud C\u00e9cile, Worobey Michael, Lloyd-Smith James O", "Abstract": "Abstract Across decades of co-circulation in humans, influenza A subtypes H1N1 and H3N2 have caused seasonal epidemics characterized by different age distributions of cases and mortality. H3N2 causes the majority of relatively severe, clinically attended cases in high-risk elderly cohorts, and the majority of overall deaths, whereas H1N1 causes fewer deaths overall, and cases shifted towards young and middle-aged adults. These contrasting age profiles may result from differences in childhood exposure to H1N1 and H3N2 or from differences in evolutionary rate between subtypes. Here we analyze a large epidemiological surveillance dataset to test whether childhood immune imprinting shapes seasonal influenza epidemiology, and if so, whether it acts primarily via immune memory of a particular influenza subtype or via broader immune memory that protects across subtypes. We also test the impact of evolutionary differences between influenza subtypes on age distributions of cases. Likelihood-based model comparison shows that narrow, within-subtype imprinting shapes seasonal influenza risk alongside age-specific risk factors. The data do not support a strong effect of evolutionary rate, or of broadly protective imprinting that acts across subtypes. Our findings emphasize that childhood exposures can imprint a lifelong immunological bias toward particular influenza subtypes, and that these cohort-specific biases shape epidemic age distributions. As a result, newer and less \u201csenior\u201d antibody responses acquired later in life do not provide the same strength of protection as responses imprinted in childhood. Finally, we project that the relatively low mortality burden of H1N1 may increase in the coming decades, as cohorts that lack H1N1-specific imprinting eventually reach old age. Author Summary Influenza viruses of subtype H1N1 and H3N2 both cause seasonal epidemics in humans, but with different age-specific impacts. H3N2 causes a greater proportion of cases in older adults than H1N1, and more deaths overall. People tend to gain the strongest immune memory of influenza viruses encountered in childhood, and so differences in H1N1 and H3N2\u2019s age-specific impacts may reflect that individuals born in different eras of influenza circulation have been imprinted with different immunological risk profiles. Another idea is that H3N2 may be more able to infect immunologically experienced adults because it evolves slightly faster than H1N1 and can more quickly escape immune memory. We analyzed a large epidemiological data set and found the clearest signal that birth year-specific differences in childhood immune imprinting, not differences in evolutionary rate, explain differences in H1N1 and H3N2\u2019s age-specific impacts. These results can help epidemiologists understand how epidemic risk from specific influenza subtypes is distributed across the population and predict how population risk may shift as differently imprinted birth years grow older. Further, these results provide immunological clues to which facets of immune memory become biased in childhood, and then later play a strong role in protection during seasonal influenza epidemics.", "URL": "https://doi.org/10.1101/19001834"} |
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] | {"Title": "Identification of de novo mutations in prenatal neurodevelopment-associated genes in schizophrenia in two Han Chinese patient-sibling family-based cohorts", "Authors": "Jiang Shan, Zhou Daizhan, Wang Yin-Ying, Jia Peilin, Wan Chunling, Li Xingwang, He Guang, Cao Dongmei, Jiang Xiaoqian, Kendler Kenneth S., Tsuang Ming, Mize Travis, Wu Jain-Shing, Lu Yimei, He Lin, Chen Jingchun, Zhao Zhongming, Chen Xiangning", "Abstract": "Abstract Schizophrenia (SCZ) is a severe psychiatric disorder with a strong genetic component. High heritability of SCZ suggests a major role for transmitted genetic variants. Furthermore, SCZ is also associated with a marked reduction in fecundity, leading to the hypothesis that alleles with large effects on risk might often occur de novo. In this study, we conducted whole-genome sequencing for 23 families from two cohorts with matched unaffected siblings and parents. Two nonsense de novo mutations (DNMs) in GJC1 and HIST1H2AD were identified in SCZ patients. Ten genes ( DPYSL2, NBPF1, SDK1, ZNF595, ZNF718, GCNT2, SNX9, AACS, KCNQ1 and MSI2 ) were found to carry more DNMs in SCZ patients than their unaffected siblings by burden test. Expression analyses indicated that these DNM implicated genes showed significantly higher expression in prefrontal cortex in prenatal stage. The DNM in the GJC1 gene is highly likely a loss function mutation (pLI = 0.94), leading to the dysregulation of ion channel in the glutamatergic excitatory neurons. Analysis of rare variants in independent exome sequencing dataset indicates that GJC1 has significantly more rare variants in SCZ patients than in unaffected controls. Data from genome-wide association studies suggested that common variants in the GJC1 gene may be associated with SCZ and SCZ-related traits. Genes co-expressed with GJC1 are involved in SCZ, SCZ-associated pathways and drug targets. These evidence suggest that GJC1 may be a risk gene for SCZ and its function may be involved in prenatal and early neurodevelopment, a vulnerable period for developmental disorders such as SCZ.", "URL": "https://doi.org/10.1101/19011007"} |
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] | {"Title": "Comparative analysis of functional assay evidence use by ClinGen Variant Curation Expert Panels", "Authors": "Kanavy Dona M., McNulty Shannon M., Jairath Meera K., Brnich Sarah E., Bizon Chris, Powell Bradford C., Berg Jonathan S.", "Abstract": "ABSTRACT Background The 2015 American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines for clinical sequence variant interpretation state that \u201cwell-established\u201d functional studies can be used as evidence in variant classification. These guidelines articulated key attributes of functional data, including that assays should reflect the biological environment and be analytically sound; however, details of how to evaluate these attributes were left to expert judgment. The Clinical Genome Resource (ClinGen) designates Variant Curation Expert Panels (VCEPs) in specific disease areas to make gene-centric specifications to the ACMG/AMP guidelines, including more specific definitions of appropriate functional assays. We set out to evaluate the existing VCEP guidelines for functional assays. Methods We evaluated the functional criteria (PS3/BS3) of six VCEPs ( CDH1 , Hearing Loss, Inherited Cardiomyopathy- MYH7, PAH, PTEN , RASopathy). We then established criteria for evaluating functional studies based on disease mechanism, general class of assay, and the characteristics of specific assay instances described in primary literature. Using these criteria, we extensively curated assay instances cited by each VCEP in their pilot variant classification to analyze VCEP recommendations and their use in the interpretation of functional studies. Results Unsurprisingly, our analysis highlighted the breadth of VCEP-approved assays, reflecting the diversity of disease mechanisms among VCEPs. We also noted substantial variability between VCEPs in the method used to select these assays and in the approach used to specify strength modifications, as well as differences in suggested validation parameters. Importantly, we observed discrepancies between the parameters VCEPs specified as required for approved assay instances and the fulfillment of these requirements in the individual assays cited in pilot variant interpretation. Conclusions Interpretation of the intricacies of functional assays often requires expert-level knowledge of the gene and disease and current VCEP recommendations for functional assay evidence are a useful tool to improve the accessibility of functional data. However, our analysis suggests that further guidance is needed to standardize this process and ensure consistency in the application of functional evidence.", "URL": "https://doi.org/10.1101/19000661"} |
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] | {"Title": "Association of Kras mutation with tumor deposit status and overall survival of colorectal cancer", "Authors": "Zhang Meifang, Hu Wenwei, Hu Kun, Lin Yong, Feng Zhaohui, Yun Jing-Ping, Gao Nan, Zhang Lanjing", "Abstract": "Abstract Background The recent staging manual upstages Node-negative tumor-deposit positive colorectal cancer (CRC) from N0 to N1c category, while the development of tumor-deposit presence is poorly understood. Meanwhile, Kras mutation is associated with progression of CRC, but its link to tumor-deposit status is unclear. Method This retrospective cohort study included the patients with incidental CRC diagnosed during 2010-2014 in the National Cancer Database and recorded statuses of Kras and tumor deposit. We conducted multivariable logistic regression and Cox regression analyses to investigate the factors associated with tumor-deposit status and overall-survival, respectively. Results A total of 48,200 CRC patients with Kras status were included in the study (25,407 [52.7%] men, 25,648[46.8%] <65 years old, 18 381 [38.1%] with Kras mutation). Adjusted for microsatellite instability, age, pathologic stage and tumor grade, Kras mutation (versus wild-type) was associated with tumor-deposit presence (n=15,229, odds ratio=1.11, 95% CI 1.02 to 1.20). Kras mutation was also independently linked to a worse overall survival of CRC patients regardless of tumor-deposit status (n=8,110, adjusted Hazard ratio=1.40, 95% CI 1.09 to 1.79 for CRC with tumor deposits, and n=2,618, adjusted HR=1.63, 95% CI 1.16 to 2.28 for CRC without), but a better survival in CRC with no known/applicable tumor-deposit status (n=457, adjusted Hazard ratio =0.32, 95% CI 0.11 to 0.95). Conclusion Kras mutation is independently associated with tumor-deposit presence, and a worse overall survival of CRC with or without tumor-deposit. Therefore, it may play a role in the development of tumor deposits and serve as a target for CRC treatment.", "URL": "https://doi.org/10.1101/19003210"} |
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] | {"Title": "Identifying 31 novel breast cancer susceptibility loci using data from genome-wide association studies conducted in Asian and European women", "Authors": "Shu Xiang, Long Jirong, Cai Qiuyin, Kweon Sun-Seog, Choi Ji-Yeob, Kubo Michiaki, ParK Sue K., Bolla Manjeet K., Dennis Joe, Wang Qin, Yang Yaohua, Shi Jiajun, Guo Xingyi, Li Bingshan, Tao Ran, Aronson Kristan J., Chan Kelvin Y.K., Chan Tsun L., Gao Yu-Tang, Hartman Mikael, Ho Weang Kee, Ito Hidemi, Iwasaki Motoki, Iwata Hiroji, John Esther M., Kasuga Yoshio, Khoo Ui Soon, Kim Mi-Kyung, Kurian Allison W., Kwong Ava, Li Jingmei, Lophatananon Artitaya, Low Siew-Kee, Mariapun Shivaani, Matsuda Koichi, Matsuo Keitaro, Muir Kenneth, Noh Dong-Young, Park Boyoung, Park Min-Ho, Shen Chen-Yang, Shin Min-Ho, Spinelli John J., Takahashi Atsushi, Tseng Chiuchen, Tsugane Shoichiro, Wu Anna H., Xiang Yong-Bing, Yamaji Taiki, Zheng Ying, Milne Roger L., Dunning Alison M., Pharoah Paul D.P., Garc\u00eda-Closas Montserrat, Teo Soo-Hwang, Shu Xiao-ou, Kang Daehee, Easton Douglas F., Simard Jacques, Zheng Wei", "Abstract": "ABSTRACT Common genetic variants in 183 loci have been identified in relation to breast cancer risk in genome-wide association studies (GWAS). These risk variants combined explain only a relatively small proportion of breast cancer heritability, particularly in Asian populations. To search for additional genetic susceptibility loci for breast cancer, we performed a meta-analysis of data from GWAS conducted in Asians (24,206 cases and 24,775 controls). Variants showing an association with breast cancer risk at P < 0.01 were evaluated in GWAS conducted in European women including 122,977 cases and 105,974 controls. In the combined analysis of data from both Asian and European women, the lead variant in 28 loci not previously reported showed an association with breast cancer risk at P < 5 \u00d710 \u22128 . In the meta-analysis of all GWAS data from Asian and European descendants, we identified SNPs in three additional loci in association with breast cancer risk at P < 5 \u00d710 \u22128 . The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women ( P < 0.05). Expression quantitative trait locus (eQTL) and gene-based analyses provided evidence for the possible involvement of the YBEY, MAN2C1, SNUPN, TBX1, SEMA4A, STC1, MUTYH, LOXL2 , and LINC00886 genes underlying the associations observed in eight of these 28 newly identified risk loci. In addition, we replicated the association for 78 of the 166 previously reported risk variants at P < 0.05 in women of Asian descent using GWAS data. These findings improve our understanding of breast cancer genetics and etiology and extend to Asian populations previous findings from studies of European women.", "URL": "https://doi.org/10.1101/19003855"} |
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] | {"Title": "Integrated Bioinformatic Approach to Identify Potential Biomarkers against Idiopathic Pulmonary Fibrosis", "Authors": "Ullah Md. Asad, Sarkar Bishajit, Araf Yusha, Islam Prottoy Md. Nazmul, Saha Ananna, Jahan Tanjila, Boby Aisha Siddiqua, Islam Md. Shariful", "Abstract": "Abstract Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive lung disease that leads to gradual decline in lung function. The molecular mechanism and risk factors of this disease are still obscure. Poorly understood etiology of this disease is the major obstacle in the identification of potential biomarkers and drug targets. In this study, microarray gene expression data of normal and IPF patient has been utilized for the statistical analysis of differentially expressed genes (DEGs) with a view to identifying potential molecular signatures using network-based system. Then their functional enrichment analysis revealed their predominant involvement in transcription, protein acetylation, extracellular matrix organization, apoptic process, inflammatory response etc. Protein-Protein Interaction (PPI) network revealed (UBC, PTEN, SOS1, PTK2, FGFR1, YAP1, FOXO1, RACK1, BMP4 and CD44) as hub proteins in IPF. Subsequent regulatory network analysis suggested (E2F1, STAT3, PPARG, MEF2A, FOXC1, GATA3, YY1, GATA2, NFKB1, and FOXL1) as the best regulatory transcriptional signatures and (hsa-mir-155-5p, hsa-mir-16-5p, hsa-mir-17-5p, hsa-mir-19a-3p, hsa-mir-192-5p, hsa-mir-92a-3p, hsa-mir-26b-5p, hsa-mir-335-5p, hsa-mir-124-3p, and hsa-let-7b-5p) as the best post-transcriptional signatures. This study represents proteome and RNA signatures of IPF which might be useful to uphold the present efforts in the discovery of potential biomarkers and treatments of this disease.", "URL": "https://doi.org/10.1101/2019.12.12.19014746"} |
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] | {"Title": "Evaluating the utility of tumour mutational signatures for identifying hereditary colorectal cancer and polyposis syndrome carriers", "Authors": "Georgeson Peter, Pope Bernard J., Rosty Christophe, Clendenning Mark, Mahmood Khalid, Joo Jihoon E., Walker Romy, Hutchinson Ryan, Preston Susan, Como Julia, Joseland Sharelle, Win Aung K., Macrae Finlay A., Hopper John L., Mouradov Dmitry, Gibbs Peter, Sieber Oliver M., O\u2019Sullivan Dylan E., Brenner Darren R., Gallinger Steve, Jenkins Mark A., Winship Ingrid M., Buchanan Daniel D.", "Abstract": "ABSTRACT Objective Germline pathogenic variants (PVs) in the DNA mismatch repair (MMR) genes and in the base excision repair gene MUTYH underlie hereditary colorectal cancer (CRC) and polyposis syndromes. We evaluated the robustness and discriminatory potential of tumour mutational signatures in CRCs for identifying germline PV carriers. Design Whole exome sequencing of formalin-fixed paraffin embedded (FFPE) CRC tissue was performed on 33 MMR germline PV carriers, 12 biallelic MUTYH germline PV carriers, 25 sporadic MLH1 methylated MMR-deficient CRCs (MMRd controls) and 160 sporadic MMR-proficient CRCs (MMRp controls) and included 498 TCGA CRC tumours. COSMIC V3 single base substitution (SBS) and indel (ID) mutational signatures were assessed for their ability to differentiate CRCs that developed in carriers from non-carriers. Results The combination of mutational signatures SBS18 and SBS36 contributing >30% of a CRC\u2019s signature profile was able to discriminate biallelic MUTYH carriers from all other non-carrier control CRCs with 100% accuracy (area under the curve (AUC) 1.0). SBS18 and SBS36 were associated with specific MUTYH variants p.Gly396Asp (p=0.025) and p.Tyr179Cys (p=5\u00d710 \u22125 ), respectively. The combination of ID2 and ID7 could discriminate the 33 MMR PV carrier CRCs from the MMRp control CRCs (AUC 0.99), however, SBS and ID signatures, alone or in combination, could not provide complete discrimination (AUC 0.79) between CRCs from MMR PV carriers and sporadic MMRd controls. Conclusion Assessment of SBS and ID signatures can discriminate CRCs from biallelic MUTYH carriers and MMR PV carriers from non-carriers with high accuracy, demonstrating utility as a potential diagnostic and variant classification tool. SIGNIFICANCE OF THE STUDY What is already known about this subject? Identifying carriers of pathogenic variants (PVs) in moderate/high-risk colorectal cancer (CRC) and polyposis susceptibility genes has clinical relevance for diagnosis, targeted screening and prevention strategies, prognosis, and treatment options. However, challenges still remain in the identification of carriers and the classification of rare variants in these genes. Previous studies have identified tumour mutational signatures that result from defective DNA repair including DNA mismatch repair (MMR) deficiency and base excision repair defects, DNA repair mechanisms that underlie the common hereditary CRC and polyposis syndromes but their diagnostic utility in CRC is unknown. What are the new findings? Single base substitution (SBS)-related mutational signatures derived from whole exome sequencing of formalin-fixed paraffin embedded (FFPE)-derived CRC tissue DNA can effectively discriminate CRCs that developed in biallelic MUTYH PV carriers from CRC-affected non-carriers. CRCs that develop in MMR PV carriers (Lynch syndrome) can be effectively differentiated from sporadic MMR-proficient CRC by a combination of indel (ID) signatures, but the SBS and ID tumour mutational signatures are less effective at discriminating Lynch syndrome-related CRC from sporadic MMR-deficient CRC resulting from MLH1 gene promoter hypermethylation. The SBS and ID mutational signatures associated with biallelic MUTYH PV carriers and MMR PV carriers are robust to changes in experimental settings. We demonstrate the optimal experimental settings for calculating mutational signatures and define thresholds that optimise sensitivity and specificity for classifying CRC aetiology as hereditary or non-hereditary. How might it impact on clinical practice in the foreseeable future? Deriving SBS- and ID-related mutational signatures from CRCs can identify carriers of PVs in hereditary CRC and polyposis susceptibility genes. The application of mutational signatures has the potential to improve the diagnosis of hereditary CRC and aid in variant classification, leading to improved clinical management and CRC prevention.", "URL": "https://doi.org/10.1101/2019.12.11.19014597"} |
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] | {"Title": "The Genetic Links to Anxiety and Depression (GLAD) Study: online recruitment into the largest recontactable study of depression and anxiety", "Authors": "Davies Molly R., Kalsi Gursharan, Brailean Anamaria, Cleare Anthony J., Coleman Jonathan R.I., Curtis Charles J., Curzons Susannah C.B., Davis Katrina A.S., Goldsmith Kimberley A., Bennett Megan Hammond, Hotopf Matthew, H\u00fcebel Christopher, Leng Jennifer, Mason Bethany D., McAtarsney-Kovacs Monika, Monssen Dina, Palaiologou Elisavet, Pariante Carmine, Parikh Shivani, Peel Alicia J., Rimes Katharine A., Rogers Henry C., Skelton Megan, Spaul Anna, Suarez Eddy L.A., Sykes Bronte L., White Katie M., Young Allan H., Vassos Evangelos, Veale David, Wingrove Janet, Eley Thalia C., Breen Gerome", "Abstract": "Abstract Background Anxiety and depression are common, debilitating and costly. These disorders are influenced by multiple risk factors, from genes to psychological vulnerabilities and environmental stressors but research is hampered by a lack of sufficiently large comprehensive studies. We are recruiting 40,000 individuals with lifetime depression or anxiety, with broad assessment of risks to facilitate future research. Methods The Genetic Links to Anxiety and Depression (GLAD) Study ( www.gladstudy.org.uk ) recruits individuals with depression or anxiety into the NIHR Mental Health BioResource. Participants invited to join the study (via media campaigns) provide demographic, environmental and genetic data, and consent for medical record linkage and recontact. Results Online recruitment was effective; 41,892 consented and 26,877 participants completed the questionnaire by July 2019. Participants\u2019 questionnaire data identified very high rates recurrent depression, severe anxiety and comorbidity. Participants reported high rates of treatment receipt. The age profile of sample is biased toward young adults, with higher recruitment of females and the better educated, especially at younger ages. Discussion This paper describes the study methodology and descriptive data for GLAD, which represents a large, recontactable resource that will enable future research into risks, outcomes and treatment for anxiety and depression. Highlights Online recruitment of 40,000 individuals with lifetime depression or anxiety (77 characters) Detailed online phenotyping combined with genetic and clinical data (66 characters) The study sample is severe, highly comorbid, with chronic psychopathology (62 characters) The study protocol enables recall of participants for future research and trials (82 characters)", "URL": "https://doi.org/10.1101/19002022"} |
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] | {"Title": "Does the metabolic syndrome exist? The identification of cardio-metabolic profiles in a South Asian population study", "Authors": "Harber-Aschan Lisa, Bakolis Ioannis, Glozier Nicholas, Ismail Khalida, Jayaweera Kaushalya, Pannala Gayani, Pariante Carmine, Rijsdijk Fruhling, Siribaddana Sisira, Sumathipala Athula, Zavos Helena M.S., Zunszain Patricia, Hotopf Matthew", "Abstract": "Abstract OBJECTIVE Research testing the validity of the metabolic syndrome (MetS) as a clinical construct associated with cardiovascular disease risk has produced inconsistent results. This study tested the existence of the MetS, explored alternative cardiometabolic risk characterisations, and examined the relative influence of genetic and environmental factors in a South Asian sample. RESEARCH DESIGN AND METHODS Data came from the Colombo Twin and Singleton follow-up Study, CoTaSS-2 (N=3969). Latent class analysis tested the clustering of MetS indicators (waist circumference, high-density-lipoprotein cholesterol (HDL-C), triglycerides (TG), blood pressure, fasting plasma glucose (FPG), medications and diabetes). Regression analyses tested cross-sectional associations between identified latent classes and covariates. Structural equation modelling estimated genetic and environmental influences on these classes. Analyses were stratified by gender (n=1681 men, n=2288 women). RESULTS Three classes were identified in men: 1) \u201cHealthy\u201d (52.3%), 2) \u201cCentral obesity, high TG, high FPG\u201d (40.2%), and 3) \u201cCentral obesity, high TG, diabetes\u201d (7.6%). Four classes were identified in women: 1) \u201cHealthy\u201d (53.2%), 2) \u201cVery high central obesity, low HDL-C, raised FPG\u201d (32.8%), 3) \u201cVery high central obesity, diabetes\u201d (7.2%) and 4) \u201cCentral obesity, hypertension, raised FPG\u201d (6.8%). Older age in men and women, and high socioeconomic status in men, was associated with cardiometabolic risk categories, compared to the \u201cHealthy\u201d classes. In men, individual differences in cardiometabolic class membership were due to environmental effects. In females, genetic differences significantly predicted class membership. CONCLUSIONS The findings did not support the MetS construct. Instead, distinct clinical profiles were identified in men and women, suggesting different aetiological pathways.", "URL": "https://doi.org/10.1101/19012195"} |
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] | {"Title": "Inconsistent Addiction Treatment for Patients Undergoing Cardiac Surgery for Injection Drug Use-Associated Infective endocarditis", "Authors": "Tiako Max Jordan Nguemeni, Hong Seong, Mahmood Syed Usman Bin, Mori Makoto, Mangi Abeel, Yun James, Juthani-Mehta Manisha, Geirsson Arnar", "Abstract": "Abstract Introduction Cases of injection drug use-related infective endocarditis (IDU-IE) requiring surgery are rising in the setting of the current U.S. opioid epidemic. We thus aimed to determine the nature of addiction interventions in the perioperative period. Methods This is a retrospective review of surgical IDU-IE from 2011 to 2016 at a tertiary care center in New Haven, Connecticut. The data collected included substances consumed recreationally, consultations by social work (SW), psychiatry, pharmacotherapy for addiction, and evidence of enrollment in a drug rehabilitation program upon discharge. Among patients with active drug use (ADU), we compared the 24-month survival of those who received at least one form of addiction intervention to that of those who did not. Results Forty-two patients (75%) had active drug use. Among them, 22 used heroin. Forty-one patients (73.2%) saw SW, 17 (30.4%) saw psychiatry; 14 (25%) saw neither SW nor psychiatry. Twenty-one patients (37.5%) received methadone, 6 (10.7%) received buprenorphine, 1 (0.02%) received naltrexone; 26 (46.4%) did not receive any pharmacotherapy. Fifteen patients (26.8%) attended a drug rehabilitation program, 13 (86.7%) of whom had seen SW and 8 (53%) psychiatry. Among patients with ADU, there was no statistically significant difference in survival between those who received at least one intervention and those who did not (p=0.1 by log rank). Conclusion Addiction interventions are deployed inconsistently for patients with surgical IDU-IE. Untreated substance use disorder and recurrent endocarditis are the leading cause of death in this population. Studying best-practices for perioperative interventions in IDU-IE and establishing protocols are of the upmost importance.", "URL": "https://doi.org/10.1101/19008482"} |
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] | {"Title": "Electrocardiographic Changes After Completion of a Triathlon", "Authors": "Hosatte-Ducassy Caroline, Correa Jos\u00e9 A., Lalonde Fran\u00e7ois, Mohindra Rohit, Marton Gregory, Chetrit Michael, Marcotte Audrey, Tournoux Fran\u00e7ois, Bridges Eileen", "Abstract": "ABSTRACT Objectives Given the increasing popularity of long-distance triathlon events amongst amateur athlete and the difficulty for emergency physician to address cardiovascular complaints in the context of exercise, this study aims to: - Identify the prevalence of electrocardiographic abnormalities before and after a long distance triathlon in a cohort of participants using the Seattle criteria. - Identify the acute changes that occur on their ECGs at the finish line of a long-distance triathlon. Methods This prospective observational study examines the prevalence of selected standard 12-lead ECG findings, the Seattle criteria, in asymptomatic athletes before and after the completion of a long-distance triathlon. Results Of 99 ECGs obtained prior to the race, 28 were abnormal, for a pre-race prevalence of 28.3% (95% CI (20.4, 37.8)). Of the 72 ECGs post-race, 12 were abnormal, for a post-race prevalence of 16.7% (95% CI (9.8, 26.9)). We did not observe any athletes with marked repolarization abnormalities. Common findings were increased QRS voltage significant for left ventricular hypertrophy (LVH) (24 (24.2%) pre-race, 10 (14.1%) post-race), early repolarization (21 (21.2%) pre-race, 19 (26.8%) post-race) and incomplete right bundle branch block (RBBB) (8 (8.1%) pre-race, 11 (15.5%) post-race). McNemar\u2019s test showed no agreement between the ECG pre and post results (Chi-square =6.54, p = 0.01), suggesting a possible effect of the race on ECG findings. We observed a trend to normalization of athlete\u2019s ECGs with acute exercise. Conclusion Long-distance endurance exercise might acutely affect the ECGs findings in asymptomatic athletes and abnormal ECG findings were common in our cohort of athletes. Physicians providing care to long-distance athletes should interpret ECGs in this population prudently. SUMMARY BOX The acute effect of exercises on athlete\u2019s electrocardiograms has not been well studied. In our cohort of long-distance triathlon finishers, 28.3% of athletes had abnormal ECGs pre-race and 16.7% had abnormal ECGs post-race according to the Seattle Criteria. We observed a trend toward normalization of athlete\u2019s ECGs with acute exercise. Common ECGs abnormalities found in those asymptomatic athletes were left ventricular hypertrophy, early repolarization and right bundle branch block. Physicians involved in the care of athletes should be prudent when interpreting ECGs in this population.", "URL": "https://doi.org/10.1101/19000687"} |
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] | {"Title": "A genome-wide association study of polycystic ovary syndrome identified from electronic health records", "Authors": "Zhang Yanfei, Ho Kevin, Keaton Jacob M., Hartzel Dustin N., Day Felix, Justice Anne E., Josyula Navya S., Pendergrass Sarah A., Actkins Ky\u2019Era, Davis Lea K., Velez Edwards Digna R., Holohan Brody, Ramirez Andrea, Stanaway Ian B., Crosslin David R., Jarvik Gail P., Sleiman Patrick, Hakonarson Hakon, Williams Marc S., Michael Lee Ming Ta", "Abstract": "Abstract Background Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. Previous studies have identified genetic variants associated with PCOS identified by different diagnostic criteria. The Rotterdam Criteria is the broadest and able to identify the most PCOS cases. Objectives To identify novel associated genetic variants, we extracted PCOS cases and controls from the electronic health records (EHR) based on the Rotterdam Criteria and performed a genome-wide association study (GWAS). Study Design We developed a PCOS phenotyping algorithm based on the Rotterdam criteria and applied it to three EHR-linked biobanks to identify cases and controls for genetic study. In discovery phase, we performed individual GWAS using the Geisinger\u2019s MyCode and the eMERGE cohorts, which were then meta-analyzed. We attempted validation of the significantly association loci (P<1\u00d710 \u22126 ) in the BioVU cohort. All association analyses used logistic regression, assuming an additive genetic model, and adjusted for principal components to control for population stratification. An inverse-variance fixed effect model was adopted for meta-analyses. Additionally, we examined the top variants to evaluate their associations with each criterion in the phenotyping algorithm. We used STRING to identify protein-protein interaction network. Results We identified 2,995 PCOS cases and 53,599 controls in total (2,742cases and 51,438 controls from the discovery phase; 253 cases and 2,161 controls in the validation phase). GWAS identified one novel genome-wide significant variant rs17186366 (OR=1.37 [1.23,1.54], P=2.8\u00d710 \u22128 ) located near SOD2 . Additionally, two loci with suggestive association were also identified: rs113168128 (OR=1.72 [1.42,2.10], P=5.2 x10 \u22128 ), an intronic variant of ERBB4 that is independent from the previously published variants, and rs144248326 (OR=2.13 [1.52,2.86], P=8.45\u00d710 \u22127 ), a novel intronic variant in WWTR1 . In the further association tests of the top 3 SNPs with each criterion in the PCOS algorithm, we found that rs17186366 was associated with polycystic and hyperandrogenism, while rs11316812 and rs144248326 were mainly associated with oligomenorrhea or infertility. Besides ERBB4, we also validated the association with DENND1A1 . Conclusion Through a discovery-validation GWAS on PCOS cases and controls identified from EHR using an algorithm based on Rotterdam criteria, we identified and validated a novel association with variants within ERBB4 . We also identified novel associations nearby SOD2 and WWTR1 . These results suggest the eGFR and Hippo pathways in the disease etiology. With previously identified PCOS-associated loci YAP1 , the ERBB4-YAP1-WWTR1 network implicates the epidermal growth factor receptor and the Hippo pathway in the multifactorial etiology of PCOS.", "URL": "https://doi.org/10.1101/2019.12.12.19014761"} |
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] | {"Title": "Ethnicity and acculturation: Asian American substance use from early adolescence to mature adulthood", "Authors": "Ahmmad Zobayer, Adkins Daniel E.", "Abstract": "Abstract Research on Asian American substance use has, to date, been limited by monolithic conceptions of Asian identity, inadequate attention to acculturative process, and a dearth of longitudinal analyses spanning developmental periods. Using five waves of the National Longitudinal Study of Adolescent to Adult Health, this study addresses these limitations by longitudinally investigating disparities in substance use from early adolescence into mature adulthood among Asian American ethnic groups, including subjects identifying as multiple Asian ethnicities and multiracial Asians. The conditional effects of acculturation indicators (e.g., nativity generation, co-ethnic peer networks, co-ethnic neighborhood concentration) on the substance use outcomes were also examined. Results indicate significant variation across Asian ethnicities, with the lowest probabilities of substance use among Chinese and Vietnamese Americans, and the highest among multiracial Asian Americans. Acculturation indicators were also strongly, independently associated with increased substance use, and attenuated many of the observed ethnic disparities, particularly for multiracial, multiethnic, and Japanese Asian Americans. This study argues that ignoring the diversity of Asian ethnicities masks the presence of high-risk Asian American groups. Moreover, results indicate that, among Asian Americans, substance use is strongly positively associated with acculturation to U.S. cultural norms, and generally peaks at later ages than the U.S. average.", "URL": "https://doi.org/10.1101/19002048"} |
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] | {"Title": "Traditional Healers as Client Advocates in the HIV-endemic Region of Maputo, Mozambique: Results from a qualitative study", "Authors": "Sundararajan Radhika, Langa Patr\u00edcio V., Morshed Trisha, Manuel Sandra", "Abstract": "Traditional healers are commonly utilized throughout sub-Saharan Africa instead of \u2013 and in concert with \u2013 biomedical facilities. Traditional healers are trusted providers and prominent community members, and could be important partners in improving engagement with HIV services in endemic contexts. Our study sought to understand the roles of healers in the urban setting of Maputo, Mozambique, where HIV prevalence is high and testing rates are low. Qualitative data were gathered through minimally-structured interviews with 36 healers. Analysis followed an inductive, grounded theory approach. Data reveal three themes relevant to improving engagement with HIV services in this endemic region: 1) healers have positive attitudes towards biomedicine; 2) healers advocate for their sick clients; and 3) clients are reticent to present to biomedical facilities. Healers describe their roles as \u2018cooperative\u2019 with biomedical providers to provide healthcare for their clients. Results suggest that healers could be considered critical enablers to effective HIV programs in communities. They have social and symbolic capital that positions them to beneficially influence clients, and are natural partners for interventions to improve uptake of HIV services.", "URL": "https://doi.org/10.1101/19008490"} |
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] | {"Title": "Esophageal Cooling For Protection During Left Atrial Ablation: A Systematic Review And Meta- Analysis", "Authors": "Leung Lisa, Gallagher Mark, Santangeli Pasquale, Tschabrunn Cory, Guerra Jose, Campos Bieito, Hayat Jamal, Atem Folefac, Mickelsen Steven, Kulstad Erik", "Abstract": "ABSTRACT Background Thermal damage to the esophagus is a risk from radiofrequency (RF) ablation of the left atrium for the treatment of atrial fibrillation (AF), with the most extreme type of thermal injury resulting in atrio-esophageal fistula (AEF), with a correspondingly high mortality rate. Various approaches have been developed to reduce esophageal injury, including power reduction, avoidance of greater contact-force, esophageal deviation, and esophageal cooling. One method of esophageal cooling involves direct instillation of cold water or saline into the esophagus during RF ablation. Although this method provides limited heat-extraction capacity, studies of it have suggested potential benefit. Objective We sought to perform a meta-analysis of existing studies evaluating esophageal cooling via direct liquid instillation for the reduction of thermal injury. Methods We reviewed Medline for existing studies involving esophageal cooling for protection of thermal injury during RF ablation. A meta-analysis was then performed using random effects model to calculate estimated effect size with 95% confidence intervals, with outcome of esophageal lesions, stratified by severity, as determined by post-procedure endoscopy. Results A total of 9 studies were identified and reviewed. After excluding pre-clinical and mathematical model studies, 3 were included in the meta-analysis, totaling 494 patients. Esophageal cooling showed a tendency to shift lesion severity downward, such that total lesions did not show a statistically significant change (OR 0.6, 95% CI 0.15 to 2.38). For high grade lesions, a significant OR of 0.39 (95% CI 0.17 to 0.89) in favor of esophageal cooling was found, suggesting that esophageal cooling, even utilizing a low-capacity thermal extraction technique, reduces lesion severity from RF ablation. Conclusions Esophageal cooling reduces lesion severity encountered during RF ablation, even when using relatively low heat extraction methods such as direct instillation of cold liquid. Further investigation of this approach is warranted.", "URL": "https://doi.org/10.1101/19003228"} |
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] | {"Title": "A Needs Analysis of Parents Following Sudden Cardiac Death in the Young", "Authors": "McDonald Kristie, Sharpe Louise, Yeates Laura, Semsarian Christopher, Ingles Jodie", "Abstract": "ABSTRACT The sudden cardiac death (SCD) of a young person is a devastating event for any parent. Inherited heart disease is often either identified or assumed to be the cause. Few studies have explored the psychosocial impact to the surviving at-risk family members. We sought to investigate the needs of parents who have experienced the SCD of their child (\u226445 years). A quantitative needs analysis questionnaire was developed based on semi-structured interviews, including one focus group, and a review of relevant literature. There were 38 parents who completed a cross-sectional quantitative survey. Parents\u2019 perceived needs for information and support spanned medical, psychosocial, spiritual and financial domains. Medical information and support needs were identified as the most important domains, followed by psychosocial, spiritual and financial information and support needs. Importantly, psychosocial information and support needs were reported as the most unmet need, endorsed by 54% of parents. Medical information and support needs were reported as unmet by almost one third of parents. The two most endorsed needs were \u201cTo have the option of whether or not you would pursue genetic testing for yourself or family members\u201d and \u201cTo understand what happened\u201d. This work demonstrates for the first time, the multifactorial needs of parents after SCD in the young. With the greatest unmet need reported as psychosocial needs, there is clear necessity to find ways of integrating psychological support in to the care of families after SCD in the young. KEY QUESTIONS What is already known about this subject? There is currently very little known about the needs of families following a sudden cardiac death due to inherited heart diseases. We know there is significant risk of poor psychological outcomes including posttraumatic stress and prolonged grief, even years after the death, however this is one of the first studies to formally evaluate the needs of parents during this time. What does this study add? We show that medical information and support needs are ranked very highly, but psychosocial support needs are the most unmet. Our findings provide a platform for developing an approach to delivering psychosocial support interventions in this population. How might this impact on clinical practice? Currently clinical and research efforts in this setting focus on clinical and genetic aspects of care. Here we show the critical need to also focus on the psychological care needs in this population. These data will help to guide services in integrating psychological support in to their multidisciplinary clinic models.", "URL": "https://doi.org/10.1101/19000877"} |
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] | {"Title": "Deficient goal-directed control in a population characterized by extreme goal pursuit", "Authors": "Foerde Karin, Daw Nathaniel D., Rufin Teresa, Walsh B Timothy, Shohamy Daphna, Steinglass Joanna E.", "Abstract": "A bstract Computational neuroscience has contributed to understanding compulsive behavior by distinguishing habitual from goal-directed choice through model-free and model-based learning. Yet, questions remain about applying this approach to psychiatric conditions that are characterized by complex behaviors that occur outside the laboratory. Here, we compared individuals with anorexia nervosa (AN), whose self-starvation appears both excessively goal-directed and habitual, with healthy controls (HC) to assess: 1) whether their behavior is characterized by enhanced or diminished model-based behavior, 2) the domain specificity of any abnormalities by comparing learning in a food-specific context as well as in a monetary context, and 3) whether impairments are secondary to starvation by comparing learning before and after initial treatment. Across all conditions, individuals with AN showed an impairment in model-based, but not model-free, learning, suggesting a general and persistent contribution of habitual over goal-directed control, across domains and timepoints.", "URL": "https://doi.org/10.1101/19002089"} |
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] | {"Title": "Exceptionally low likelihood of Alzheimer\u2019s dementia in APOE2 homozygotes", "Authors": "Reiman Eric M., Arboleda-Velasquez Joseph F., Quiroz Yakeel T., Huentelman Matthew J., Beach Thomas G., Caselli Richard J., Chen Yinghua, Su Yi, Myers Amanda J., Hardy John, Vonsattel Jean Paul, Younkin Steven G., Bennett David A., De Jager Philip L., Larson Eric B., Crane Paul K., Keene C. Dirk, Kamboh M. Ilyas, Kofler Julia K., Duque Linda, Gilbert John R., Gwirtsman Harry E., Buxbaum Joseph D., Dickson Dennis W., Frosch Matthew P., Ghetti Bernardino, Lunetta Kathryn L., Wang Li-San, Hyman Bradley T., Kukull Walter A., Foroud Tatiana, Haines Jonathan L., Mayeux Richard P., Pericak-Vance Margaret A., Schneider Julie A., Trojanowski John Q., Farrer Lindsay A., Schellenberg Gerard D., Beecham Gary W., Montine Thomas J., Jun Gyungah R.", "Abstract": "ABSTRACT Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer\u2019s dementia, such that APOE4 homozygotes have a particularly high risk. While the APOE2 allele is associated with a lower risk of Alzheimer\u2019s dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer\u2019s dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer\u2019s dementia cases and controls. APOE2/2 was associated with exceptionally low Alzheimer\u2019s dementia odds ratios compared to APOE2/3, 3/3 and 4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer\u2019s disease could have a major impact on the understanding, treatment and prevention of this terrible disease.", "URL": "https://doi.org/10.1101/19011015"} |
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] | {"Title": "A conceptual model for pluralistic healthcare behavior: results from a qualitative study in southwestern Uganda", "Authors": "Sundararajan Radhika, Mwanga-Amumpaire Juliet, King Rachel, Ware Norma C.", "Abstract": "ABSTRACT Introduction Medical pluralism , or concurrent utilization of multiple therapeutic modalities, is common in various international contexts, and has been characterized as a factor contributing to poor health outcomes in low-resource settings. Traditional healers are ubiquitous providers in most regions, including the study site of southwestern Uganda. It is not well understood why patients in pluralistic settings continue to engage with both therapeutic healthcare modalities, rather than simply selecting one or the other. The goal of this study was to identify factors that motivate pluralistic healthcare utilization, and create a general, conceptual framework of pluralistic health behavior. Methods In-depth interviews were conducted between September 2017 and February 2018 with patients seeking care at traditional healers (N=30) and at an outpatient medicine clinic (N=30) in Mbarara, Uganda; the study is nested within a longitudinal project examining HIV testing engagement among traditional healer-utilizing communities. Inclusion criteria included age \u226518 years, and ability to provide informed consent. Participants were recruited from healer practices representing the range of healer specialties. Following an inductive approach, interview transcripts were reviewed and coded to identify conceptual categories explaining healthcare utilization. Results We identified three broad categories relevant to healthcare utilization among study participants: 1) traditional healers treat patients with \u201ccare\u201d; 2) biomedicine uses \u201cmodern\u201d technologies; and 3) peer \u201ctestimony\u201d influences healthcare engagement. These categories describe variables at the healthcare provider , healthcare system , and peer levels that interrelate to motivate individual engagement in pluralistic health resources. Conclusions Patients perceive clear advantages and disadvantages to biomedical and traditional care in medically pluralistic settings. We identified factors at the healthcare provider, healthcare system, and peer levels which influence patients\u2019 therapeutic itineraries. Our findings provide a basis to improve health outcomes in medically pluralistic settings, and underscore the importance of recognizing traditional healers as important stakeholders in community health. STRENGTHS AND LIMITATIONS OF THIS STUDY Medical pluralism is common in both high- and low-resource settings, and has been characterized as a factor leading to poor health outcomes for both infectious and non-communicable diseases This study identifies factors that motivate utilization of healthcare in a medically pluralistic community Patients in pluralistic settings perceive clear advantages and disadvantages of both traditional care and biomedicine; characteristics of healthcare providers, the healthcare system, and peer influences motivate patients to engage with particular healthcare modalities Patients often prefer traditional healing instead of biomedicine; this utilization is not simply a function of limited access to biomedical resources Traditional healers should be considered important stakeholders in community health", "URL": "https://doi.org/10.1101/19008508"} |
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] | {"Title": "Toward Automated Classification of Pathological Transcranial Doppler Waveform Morphology via Spectral Clustering", "Authors": "Thorpe Samuel G., Thibeault Corey M., Canac Nicolas, Jalaleddini Kian, Dorn Amber, Wilk Seth J., Devlin Thomas, Scalzo Fabien, Hamilton Robert B.", "Abstract": "Abstract Cerebral Blood Flow Velocity waveforms acquired via Transcranial Doppler (TCD) can provide evidence for cerebrovascular occlusion and stenosis. Thrombolysis in Brain Ischemia (TIBI) flow grades are widely used for this purpose, but require subjective assessment by expert evaluators to be reliable. In this work we seek to determine whether TCD morphology can be objectively assessed using an unsupervised machine learning approach to waveform categorization. TCD beat waveforms were recorded at multiple depths from the Middle Cerebral Arteries of 106 subjects; 33 with CTA-confirmed Large Vessel Occlusion (LVO). From each waveform, three morphological variables were extracted, quantifying absolute peak onset, number/prominence of auxiliary peaks, and systolic canopy length. Spectral clustering identified groups implicit in the resultant three-dimensional feature space, with gap-statistic criteria establishing the optimal cluster number. We found that gap-statistic disparity was maximized at four clusters, referred to as flow types I, II, III, and IV. Types I and II were primarily composed of control subject waveforms, whereas types III and IV derived mainly from LVO patients. Cluster morphologies for types I and IV aligned clearly with Normal and Blunted TIBI flows, respectively. Types II and III represented commonly observed flow-types not delineated by TIBI, which nonetheless deviate quantifiably from normal and blunted flows. We conclude that important morphological variability exists beyond that currently quantified by TIBI in populations experiencing or at-risk for acute ischemic stroke, and posit that the observed flow-types provide the foundation for objective methods of real-time automated flow type classification.", "URL": "https://doi.org/10.1101/19003236"} |
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] | {"Title": "Structural and functional MRI changes associated with cognitive impairment and dementia in Parkinson disease", "Authors": "Owens-Walton Conor, Jakabek David, Power Brian D., Walterfang Mark, Hall Sara, van Westen Danielle, Looi Jeffrey C.L., Shaw Marnie, Hansson Oskar", "Abstract": "Abstract Objective Cognitive impairment in Parkinson disease (PD) places a high burden on patients and the pathophysiological mechanisms that differentiate patients with cognitive impairment from those without it are still incompletely understood. Methods We conducted a resting-state seed region-of-interest approach to investigate functional connectivity (FC) of important subdivisions of the caudate nucleus, putamen and thalamus in controls (n=33), cognitively unimpaired subjects (PD-CU, n=33), PD subjects with mild cognitive impairment (PD-MCI, n=22) and subjects with dementia (PDD, n=17). We then investigated how the morphology of these structures differed between groups. Results PD-CU subjects, compared to controls, displayed increased and decreased FC of caudate, putamen and thalamic subdivisions. PD-MCI subjects demonstrated reduced FC of the mediodorsal thalamus with the paracingulate cortex, compared to PD-CU, and reduced FC of the mediodorsal thalamus with the posterior cingulate cortex compared to PDD. Extensive volumetric and surface-based deflation was found in subjects with dementia. Conclusions Our research suggests that cognitive impairment and dementia in PD may be associated with a breakdown in FC of the mediodorsal thalamus with para- and posterior cingulate regions of the brain, respectively. Significance Cognitive impairment and dementia in PD may relate to pathophysiological changes in FC of the mediodorsal thalamus.", "URL": "https://doi.org/10.1101/19002147"} |
10.1101/19012203 | [
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] | {"Title": "Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia", "Authors": "Tsvetanov Kamen A., Gazzina Stefano, Jones P. Simon, Swieten John van, Borroni Barbara, Sanchez-Valle Raquel, Moreno Fermin, Laforce Robert Jr, Graff Caroline, Synofzik Matthis, Galimberti Daniela, Masellis Mario, Tartaglia Maria Carmela, Finger Elizabeth, Vandenberghe Rik, de Mendon\u00e7a Alexandre, Tagliavini Fabrizio, Santana Isabel, Ducharme Simon, Butler Chris, Gerhard Alexander, Danek Adrian, Levin Johannes, Otto Markus, Frisoni Giovanni, Ghidoni Roberta, Sorbi Sandro, Rohrer Jonathan D., Rowe James B.", "Abstract": "Abstract INTRODUCTION The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy. We investigate this phenomenon in familial Frontotemporal dementia (FTD). METHODS We studied 121 presymptomatic FTD mutation carriers and 134 family members without mutations, using multivariate data-driven approach to link cognitive performance with both structural and functional magnetic resonance imaging. Atrophy and brain network connectivity were compared between groups, in relation to the time from expected symptom onset. RESULTS There were group differences in brain structure and function, in the absence of differences in cognitive performance. Specifically, we identified behaviourally-relevant structural and functional network differences. Structure-function relationships were similar in both groups, but coupling between functional connectivity and cognition was stronger for carriers than for non-carriers, and increased with proximity to the expected onset of disease. DISCUSSION Our findings suggest that maintenance of functional network connectivity enables carriers to maintain cognitive performance.", "URL": "https://doi.org/10.1101/19012203"} |
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] | {"Title": "Motivational Strategies for Stroke Rehabilitation: A Descriptive Cross-sectional Study", "Authors": "Oyake Kazuaki, Suzuki Makoto, Otaka Yokei, Tanaka Satoshi", "Abstract": "Abstract Background and Purpose The addition of motivational strategies to a rehabilitation program is thought to enhance patient adherence and improve outcomes. However, little is known about how rehabilitation professionals motivate stroke patients during rehabilitation. The primary objective of this study was to provide a comprehensive and quantitative list of motivational strategies for stroke rehabilitation. In addition, we aimed to examine (1) whether professionals with more clinical experience used a higher number of motivational strategies, (2) the purpose for using each strategy, and (3) the information considered when choosing strategies. Methods This descriptive, cross-sectional study was conducted using a web survey with a random sample of 407 rehabilitation professionals including physicians, nurses, physical therapists, occupational therapists, and speech-language-hearing therapists. Results We received data for 362 participants. Fifteen strategies were found to be used by more than 75% of the respondents reported using to motivate their patients. Almost all of the respondents reported that they actively listen to and praise their patients to increase patient adherence to rehabilitation programs. Respondents with more clinical experience tended to use a higher number of motivational strategies (rho = 0.208, p < 0.001). For 11 of the 15 strategies selected by more than 75% of respondents, the highest percentage of respondents reported that they used the strategies to make rehabilitation worthwhile for their patients. The majority of respondents reported that they decide which motivational strategy to use by considering comprehensive information regarding the patient health condition, environmental factors, and personal factors. Conclusions The comprehensive list of motivational strategies obtained may be useful for increasing patient adherence to rehabilitation, especially for professionals with less clinical experience. Furthermore, our findings regarding the purpose for using each strategy and the information used to choose strategies might help rehabilitation professionals to utilize the motivational strategy list.", "URL": "https://doi.org/10.1101/19011023"} |
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] | {"Title": "Trends and variation in unsafe prescribing of methotrexate: a cohort study in English NHS primary care", "Authors": "MacKenna Brian, Curtis Helen J, Walker Alex J, Croker Richard, Bacon Seb, Goldacre Ben", "Abstract": "Abstract Objective To describe trends and geographical variation in methotrexate prescribing that breaches national safety recommendations; deaths from methotrexate poisoning; and associated litigation. Methods A retrospective cohort study of English NHS primary care prescribing data, complemented by information obtained through Freedom of Information (FOI) requests. The main outcome measures were: (1) variation in ratio of breaching / adherent prescribing, geographically and over time, between General Practices and Clinical Commissioning Groups; (2) description of responses to FOI requests. Results Out of 7349 NHS General Practices in England, 1689 practices prescribed both 2.5mg and 10mg tablets to individual patients in 2017, breaching national guidance. In April 2018, 697 practices (at the 90th centile and above) prescribed at least 14.3% of all methotrexate as 10mg tablets, breaching national guidance. The 66 practices at the 99th percentile and above gave at least 52.4% of all prescribed methotrexate in the form of 10 mg tablets. The prescribing of 10mg tablets has fallen over 7 years, with 10mg tablets as a proportion of all methotrexate tablets falling from 9.1% to 3.4%. 21 deaths caused by methotrexate poisoning have been reported from 1993-2017. Conclusions The prevalence of unsafe methotrexate prescribing has reduced but it remains common, with substantial variation between organisations. We recommend the NHS invests in better strategies around implementation of safety recommendations. 21 deaths have been attributed to methotrexate poisoning but with no further details easily available: the full coroners reports for these deaths should be reviewed to identify recurring themes.", "URL": "https://doi.org/10.1101/19000919"} |
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] | {"Title": "Local socioeconomic status and paramedic students\u2019 academic performance", "Authors": "Hamel Lydia, Procum Ashley, Hunter Justin, Gridley Donna, O\u2019Connor Kathleen, Fentress Thomas, Goenner Christopher, Khalsa Sahaj, Batt Alan M.", "Abstract": "Abstract Research indicates students of lower socioeconomic status (SES) are educationally disadvantaged. We sought to examine differences in paramedic student academic performance from counties with varying SES in the United States. Student performance data and SES data were combined for counties within the states of California, Mississippi, Louisiana, Texas and Virginia. Linear multiple regression modelling was performed to determine the relationship between income, high school graduation rate, poverty and food insecurity with first-attempt scores on the Fisdap Paramedic Readiness Exam (PRE) versions 3 and 4. Linear regression models indicated that there was a significant relationship between county-level income, poverty, graduation rate, food insecurity, and paramedic student academic performance. It remains unclear what type of relationship exists between individual SES and individual academic performance of paramedic students. These findings support the future collection of individual student level SES data in order to identify issues and mitigate impact on academic performance.", "URL": "https://doi.org/10.1101/19008516"} |
10.1101/2019.12.12.19014621 | [
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] | {"Title": "Hepatitis C Core Antigen test as an alternative for diagnosing HCV infection: mathematical model and cost-effectiveness analysis", "Authors": "Sadeghimehr Maryam, Keiser Olivia, Negro Francesco, Butsashvili Maia, Shilton Sonjelle, Tskhomelidze Irina, Tsereteli Maia, Bertisch Barbara, Estill Janne", "Abstract": "Abstract Background The cost and complexity of polymerase chain reaction (PCR) testing is a significant barrier for the diagnosis and treatment of patients infected with hepatitis C virus (HCV). We investigated the cost-effectiveness of various testing strategies using antigen as an alternative to PCR. Methods We developed a mathematical model for HCV to estimate the number of newly diagnosed individuals and cases of different stages of liver disease. We compared the following testing strategies: antibody test followed by PCR in case of positive antibody (baseline strategy); antibody test followed by HCV-antigen test (antibody-antigen); antigen test alone; and PCR test alone. We conducted cost-effectiveness analyses considering the costs of HCV testing (of both infected and uninfected individuals) (A1), liver-related complications (A2) and all costs including HCV treatment (A3). The model was parameterized for the country of Georgia, and several sensitivity analyses were conducted to generalize the findings for different settings. Results Using the current standard of testing, 89% of infected individuals were detected. Comparatively, antibody-antigen and antigen testing alone detected 86% and 88% of infected individuals, respectively. PCR testing alone detected 91% of the infected individuals with the remaining 9% dying or spontaneously recovering before testing. In analysis A1, antibody-antigen testing was not found to be essentially cheaper compared to the baseline strategy. In analysis A2, strategies using PCR were cheaper than antigen-based strategies. In analysis A3, antibody-antigen testing was the cheapest strategy, followed by the baseline strategy, and PCR testing alone. Conclusion Antigen testing, either following a positive antibody test or alone, performed almost as well as the current practice of HCV testing. The cost-effectiveness of these strategies strongly depends on the inclusion of treatment costs. Lay summary Core antigen testing is a reliable alternative test for diagnose HCV infection. Antigen-based strategies may be cost-effective, in particular if treatment costs are considered. Highlights Strategies using an antigen test to diagnose HCV infection performed reasonably well compared with the traditional antibody- and PCR based approach. According to our study, antigen test alone missed about 3%, and antibody followed by PCR test 2% of HCV infected individuals. The maximum difference in quality-adjusted life expectancy across the different strategies of diagnosing HCV was only one month.", "URL": "https://doi.org/10.1101/2019.12.12.19014621"} |
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] | {"Title": "Acute ischemic stroke alters the brain\u2019s preference for distinct dynamic connectivity states", "Authors": "Bonkhoff Anna K., Espinoza Flor A., Gazula Harshvardhan, Vergara Victor M., Hensel Lukas, Michely Jochen, Paul Theresa, Rehme Anne, Volz Lukas J., Fink Gereon R., Calhoun Vince D., Grefkes Christian", "Abstract": "Abstract Acute ischemic stroke disturbs healthy brain organization, prompting subsequent plasticity and reorganization to compensate for loss of specialized neural tissue and function. Static resting-state functional magnetic resonance imaging (fMRI) studies have already furthered our understanding of cerebral reorganization by estimating stroke-induced changes in network connectivity aggregated over the duration of several minutes. In this study, we utilized dynamic resting-state fMRI analyses to increase temporal resolution to seconds and explore transient configurations of motor network connectivity in acute stroke. To this end, we collected resting-state fMRI data of 31 acute ischemic stroke patients and 17 age-matched healthy controls. Stroke patients presented with moderate to severe hand motor deficits. By estimating dynamic connectivity within a sliding window framework, we identified three distinct connectivity configurations of motor-related networks. Motor networks were organized into three regional domains, i.e. a cortical, subcortical and cerebellar domain. Temporal connectivity patterns of stroke patients markedly diverged from those of healthy controls depending on the severity of the initial motor impairment. Moderately affected patients (n=18) spent significantly more time in a weakly connected configuration that was characterized by low levels of connectivity, both locally as well as between distant regions. In contrast, severely affected patients (n=13) showed a significant preference for transitions into a spatially segregated connectivity configuration. This configuration featured particularly high levels of local connectivity within the three regional domains as well as anti-correlated connectivity between distant networks across domains. A third connectivity configuration represented an intermediate connectivity pattern compared to the preceding two, and predominantly encompassed decreased inter-hemispheric connectivity between cortical motor networks independent of individual deficit severity. Alterations within this third configuration thus closely resembled previously reported ones originating from static resting-state fMRI studies post-stroke. In summary, acute ischemic stroke not only prompted changes in connectivity between distinct functional networks, yet also caused severe aberrations in temporal properties of large-scale network interactions depending on the individual deficit severity. These findings offer new vistas on the dynamic neural mechanisms underlying acute neurological symptoms, cortical reorganization and treatment effects in stroke patients.", "URL": "https://doi.org/10.1101/19011031"} |
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] | {"Title": "Oncofetal Protein CR-1 in a new clinical role: a potential tumor marker for Oral Squamous Cell Carcinoma", "Authors": "Anu Jain, Kumar Mallupattu Sumanth, Reetu Thakur, Satyawati Mohindra, Amanjit Bal, Ashim Das, Sushmita Ghoshal, Arnab Pal", "Abstract": "Abstract PURPOSE CR-1 (CR-1) is an oncofetal protein with its role as a key factor in early process of carcinoma has been evaluated in cases of various cancers. However, very few studies have reported its role in oral cancers, which is the sixth most common cancer around the world, particularly with high prevalence in developing countries. Oral squamous cell carcinoma (OSCC) is the most predominant (90%) of all the histological types of oral cancer. Late detection, associated with increased morbidity and mortality, is mainly attributed to non-availability of a suitable biomarker for the disease. In the present pilot study we have evaluated the role of soluble CR-1, in serum as a potential tumor marker for OSCC. METHODS CR-1 was estimated using sandwich ELISA in serum samples of 50 biopsy proven OSCC patients (pre and post treatment) along with age and gender matched healthy controls. Immunohistochemistry was also done in corresponding tumor tissue sections to check the expression of CR-1. RESULTS Pre-treatment CR-1 was found to be 2.25 fold higher in serum of OSCC patients as compared to control (p<0.0001***), which was reduced to 1.6 folds post treatment (p=0.0006***). CR-1 levels were comparatively higher in early stage of disease. Upon IHC 80% of the cases were found to be positive for CR-1. CONCLUSION This study provides evidence that serum levels of CR-1 are elevated in patients of Oral Squamous Cell Carcinoma, which decrease post treatment. Also, the association of expression of protein with tumor progression predicts CR-1 as a molecule that can be further evaluated as a potential tumor maker in OSCC.", "URL": "https://doi.org/10.1101/19000950"} |
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] | {"Title": "The Effects of Metronome Frequency Differentially Affects Gait on a Treadmill and Overground in People with Parkinson\u2019s Disease", "Authors": "Wygand Madelon, Chawla Guneet, Browner Nina, Lewek Michael D", "Abstract": "Abstract Objective To determine the effect of different metronome cue frequencies on spatiotemporal gait parameters when walking overground compared to walking on a treadmill in people with Parkinson\u2019s disease Design Repeated-measures, within-subject design Setting Research laboratory Participants Twenty-one people with Parkinson\u2019s disease (Hoehn & Yahr stage 1-3) Interventions Participants walked overground and on a treadmill with and without metronome cues of 85%, 100%, and 115% of their baseline cadence for one minute each. Main Outcome Measures Gait speed, step length, and cadence Results An interaction effect between cue frequency and walking environment revealed that participants took longer steps during the 85% condition on the treadmill only. When walking overground, metronome cues of 85% and 115% of baseline cadence yielded decreases and increases, respectively, in both cadence and gait speed with no concomitant change in step length. Conclusions These data suggest that people with PD are able to alter spatiotemporal gait parameters immediately when provided the appropriate metronome cue and walking environment. We propose to target shortened step lengths by stepping to the beat of slow frequency auditory cues while walking on a treadmill, whereas the use of fast frequency cues during overground walking can facilitate faster walking speeds.", "URL": "https://doi.org/10.1101/19003251"} |
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] | {"Title": "Genome-wide investigation of DNA methylation in congenital adrenal hyperplasia", "Authors": "Karlsson Leif, Barbaro Michela, Ewing Ewoud, Gomez-Cabrero David, Lajic Svetlana", "Abstract": "Abstract Background Patients with congenital adrenal hyperplasia (CAH) are at risk of long-term cognitive and metabolic sequelae with some of the effects being attributed to the chronic glucocorticoid treatment that they receive. This study investigates genome-wide DNA methylation in patients with CAH to determine whether there is evidence for epigenomic reprogramming as well as any relationship to patient outcome. Methods We analysed CD4+ T cell DNA from 28 patients with CAH (mean age=18.5 \u00b16.5 years [y]) and 37 population controls (mean age=17.0 \u00b16.1 y) with the Infinium-HumanMethylation450 BeadChip array to measure genome-wide locus-specific DNA methylation levels. Effects of CAH, phenotype and CYP21A2 genotype on methylation were investigated as well as the association between differentially methylated CpGs, glucose homeostasis, blood lipid profile and cognitive functions. In addition, we report data on a small cohort of 11 patients (mean age=19.1, \u00b16.0 y) with CAH who were treated prenatally with dexamethasone (DEX) in addition to postnatal glucocorticoid treatment. Results We identified two CpGs to be associated with patient phenotype: cg18486102 (located in the FAIM2 gene; rho=0.58, adjusted p=0.027) and cg02404636 (located in the SFI1 gene; rho=0.58, adjusted p=0.038). cg02404636 was also associated with genotype (rho=0.59, adjusted p=0.024). Higher levels of serum C-peptide was also observed in patients with CAH (p=0.044). Additionally, levels of C-peptide and HbA1c were positively correlated with patient phenotype (p=0.044 and p=0.034) and genotype (p=0.044 and p=0.033), respectively. No significant association was found between FAIM2 methylation and cognitive or metabolic outcome. However, SFI1 TSS methylation was associated with fasting plasma HDL cholesterol levels (p=0.035). Conclusion In conclusion, higher methylation levels in CpG sites covering FAIM2 and SFI1 were associated with disease severity. Hypermethylation in these genes may have implications for long-term cognitive and metabolic outcome in patients with CAH.", "URL": "https://doi.org/10.1101/19008524"} |
10.1101/2019.12.12.19014647 | [
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] | {"Title": "Retrospective Assessment of Deep Neural Networks for Skin Tumor Diagnosis", "Authors": "Han Seung Seog, Moon Ik Jun, Na Jung-Im, Kim Myoung Shin, Park Gyeong Hun, Kim Seong Hwan, Kim Kiwon, Lee Ju Hee, Chang Sung Eun", "Abstract": "ABSTRACT BACKGROUND The aim of this study was to validate the performance of algorithm ( http://rcnn.modelderm.com ) for the diagnosis of benign and malignant skin tumors. METHODS With external validation dataset (43 disorders; 40,331 clinical images from 10,426 patients; January 1, 2008 \u2013 March 31, 2019), we compared the prediction of algorithm with the clinical diagnosis of 65 attending physicians at the time of biopsy request. RESULTS For binary-task classification of determining malignancy, the AUC of the algorithm was 0.863(95% CI 0.852-0.875) with unprocessed clinical photographs. The sensitivity/specificity of the algorithm at the predefined high-sensitivity and high-specificity threshold were 79.1%(76.9-81.4)/76.9%(76.1-77.8) and 62.7%(59.9- 65.5)/90.0%(89.4-90.6), respectively. The sensitivity/specificity calculated by the clinical diagnosis of attending physicians were 88.1%/83.8%(Top-3) and 70.2%/95.6%(Top-1), which were superior to those of algorithm. For multi-task classification, the mean Top-1,2,3 accuracies of the algorithm were 42.6\u00b120.7%, 56.1\u00b122.8%, 61.9\u00b122.9%, and those of clinical diagnosis were 65.4\u00b117.7%, 73.9\u00b116.6%, 74.7\u00b116.6%, respectively. In the reader test with images from 30-patients batches, the sensitivity / specificity of the algorithm at the predefined threshold were 66.9%\u00b130.2% / 87.4%\u00b116.5%. The sensitivity / specificity derived from the first diagnosis of 44 the participants were 65.8%\u00b133.3% / 85.7%\u00b111.0%, which were comparable with those of the algorithm (Wilcoxon signed-rank test; P=0.61 / 0.097). CONCLUSIONS Our algorithm could diagnose skin tumors at dermatologist-level when diagnosis was made solely with photographs, demonstrating its potential as a mass screening tool in telemedicine setting. However, due to limited data relevancy, the performance was inferior to that of actual medical examination. Clinical information should be integrated with imaging information to achieve more accurate predictions.", "URL": "https://doi.org/10.1101/2019.12.12.19014647"} |
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] | {"Title": "Individuals with Parkinson\u2019s Disease Retain Spatiotemporal Gait Control With Music and Metronome Cues", "Authors": "Chawla Guneet, Wygand Madelon, Browner Nina, Lewek Michael D", "Abstract": "Abstract Background Parkinson\u2019s disease (PD) is marked by a loss of motor automaticity, resulting in decreased control of step length during gait. Rhythmic auditory cues (metronomes or music) may enhance automaticity by adjusting cadence. Both metronomes and music may offer distinct advantages, but prior attempts at quantifying their influence on spatiotemporal aspects of gait have been confounded by altered gait speeds from overground walking. We hypothesized that when gait speed is fixed, individuals with PD would experience difficulty in modifying cadence due to the concomitant requirement to alter step length, with greater changes noted with metronomes compared to music cues. Research Question Can a metronome or music promote spatiotemporal adjustments when decoupled from changes in gait speed in individuals with PD? Methods 21 participants with PD were instructed to time their steps to a metronome and music cues (at 85%, 100%, and 115% of overground cadence) during treadmill walking. We calculated cadence, cadence accuracy, and step length during each cue condition and an uncued control condition. We compared the various cue frequencies and auditory modalities. Results At fixed gait speeds, participants were able to increase and decrease cadence in response to auditory cues. Music and metronome cues produced comparable results in cadence manipulation with greater cadence errors noted at slower intended frequencies. Nevertheless, the induced cadence changes created a concomitant alteration in step length, with music and metronomes producing comparable changes. Notably, longer step lengths were induced with both music and metronome during slow frequency cueing. Significance This important change conflicts with conventional prescriptive approaches, which advocate for faster cue frequencies, if applied on a treadmill. The music and metronome cues produced comparable changes to gait, suggesting that either cue may be effective at overcoming the shortened step lengths during treadmill walking if slower frequencies are used.", "URL": "https://doi.org/10.1101/19003269"} |
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] | {"Title": "An international multicenter examination of MOG antibody assays", "Authors": "Reindl Markus, Schanda Kathrin, Woodhall Mark, Tea Fiona, Ramanathan Sudarshini, Sagen Jessica, Fryer Jim, Mills John, Teegen Bianca, Mindorf Swantje, Ritter Nora, Krummrei Ulrike, St\u00f6cker Winfried, Eggert Juliane, Flanagan Eoin P., Ramberger Melanie, Hegen Harald, Rostasy Kevin, Berger Thomas, Leite Maria Isabel, Palace Jacqueline, Irani Sarosh R., Dale Russell C., Probst Christian, Probst Monika, Brilot Fabienne, Pittock Sean, Waters Patrick", "Abstract": "Abstract Objectives To compare the reproducibility of 11 antibody assays for IgG and IgM myelin oligodendrocyte glycoprotein antibodies (MOG-IgG, MOG-IgM) from five international centers. Methods The following samples were analyzed: MOG-IgG clearly positive sera (n=39), MOG-IgG low positive sera (n=39), borderline negative sera (n=13), clearly negative sera (n=40), and healthy blood donors (n=30). As technical controls, 18 replicates (9 MOG-IgG positive and 9 negative) were included. All samples and controls were re-coded, aliquoted, and distributed to the five testing centers which performed the following antibody assays: five live and one fixed immunofluorescence cell-based assays (CBA-IF, five MOG-IgG, one MOG-IgM), three live flow cytometry cell-based assays (FACS-CBA, all MOG-IgG), and two enzyme-linked immunosorbent assays (ELISA, both MOG-IgG). Results We found excellent agreement (96%) between the live CBAs for MOG-IgG for samples previously identified as clearly positive or negative from four different national testing centers. The agreement was lower with fixed CBA-IF (90%) and the ELISA showed no concordance with CBAs for detection of human MOG-IgG. All CBAs showed excellent inter-assay reproducibility. The agreement of MOG-IgG CBAs for borderline negative (77%) and particularly low positive (33%) samples was less good. Finally, most samples from healthy blood donors (97%) were negative for MOG-IgG in all CBAs. Conclusion Live MOG-IgG CBAs showed excellent agreement for high positive and very good agreement for negative samples at four international testing centers. Low positive samples were more frequently discordant than in similar assays for other autoantigens. Further research is needed to improve international standardization for clinical care.", "URL": "https://doi.org/10.1101/19011049"} |
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] | {"Title": "Liver function tests and fibrosis scores in a rural population in Africa: estimation of the burden of disease and associated risk factors", "Authors": "O\u2019Hara Geraldine A, Mokaya Jolynne, Hau Jeffrey P, Downs Louise O, McNaughton Anna L, Karabarinde Alex, Asiki Gershim, Seeley Janet, Matthews Philippa C, Newton Robert", "Abstract": "ABSTRACT Introduction Liver disease is a major cause of morbidity and mortality in sub-Saharan Africa. However, its prevalence, distribution and aetiology have not been well characterised. We examined liver function tests (LFTs) and calculated liver fibrosis scores in a rural population in Uganda. Methodology A cross-sectional survey of LFTs was undertaken in 2011 in a rural population cohort in South-Western Uganda. We classified abnormal LFTs based on reference ranges set in America and in Africa. We derived fibrosis scores (AST to Platelet Ratio Index, fibrosis-4, GGT to platelet ratio, red cell distribution width to platelet ratio, and S-index) to evaluate the potential prevalence of liver disease. We collected information about alcohol intake, and infection with HIV, HBV and HCV, to determine the contribution made by these factors to liver inflammation or fibrosis. Results Data were available for 8,099 participants (median age 30 years; 56% female). The prevalence of HBV, HCV and HIV infection were 3%, 0.2% and 8%, respectively. The prevalence of abnormal LFTs was higher based on the American reference range compared to the African reference range (e.g. for AST 13% vs 3%, respectively). The prevalence of AST/ALT ratio >2 was 11%, suggestive of alcoholic hepatitis. The highest prevalence of fibrosis was suggested by the GPR score, with 24% of the population falling above the threshold for fibrosis. By multivariate analysis, elevated LFTs and fibrosis scores were most consistently associated with older age, male sex, being under-weight, infection with HIV or HBV, and alcohol consumption. Based on population attributable risk, the highest proportion of elevated fibrosis scores was associated with alcohol use (e.g. 64% of elevated S-index scores). Conclusion Further work is required to determine normal reference ranges for LFTs in this setting, to evaluate the specificity and sensitivity of fibrosis scores, and to determine aetiology of liver disease. KEY FINDINGS What is already known? Liver disease is not well characterised in many parts of sSA despite the high prevalence of chronic viral infections (HIV, HBV and HCV), and potential exposure to hepatotoxins including alcohol, aflatoxins and traditional herbal medicine. Non-invasive blood tests for markers of fibrosis are relatively simple and offer a safe route to assess for liver fibrosis, however, their diagnostic accuracy is not well established in sSA. Appropriate reference ranges for LFTs are crucial for optimising the sensitivity and specificity of the detection of underlying liver disease. What are the new findings? There is a disparity in the prevalence of abnormal LFTs in our study cohort when comparing two references ranges (American vs. local reference ranges). Based on GPR score, there is a high prevalence of liver fibrosis (almost 1 in 4 of this population) and elevated GPR score is associated with older age, male sex, being under-weight, infection with HIV or HBV, and alcohol consumption. Alcohol consumption accounted for 64% of abnormal S-index scores, 32% of elevated FIB-4 scores, and 19% of GPR abnormalities. What do the new findings imply? Appropriate reference ranges for LFTs are necessary to contribute to an understanding of the burden and aetiology of liver disease. Alcohol, HIV and HBV are risk factors for deranged LFTs and liver fibrosis, with alcohol making the most significant and striking contribution. Further investigation is needed to determine other factors that contribute to liver disease in this setting.", "URL": "https://doi.org/10.1101/19000968"} |
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] | {"Title": "Memory recovery is related to default mode network impairment and neurite density during brain tumours treatment", "Authors": "Romero-Garcia R, Suckling J, Owen M, Assem M, Sinha R, Coelho P, Woodberry E, Price SJ, Burke GAA, Santarius T, Erez Y, Hart MG", "Abstract": "ABSTRACT Surgical resection is an effective treatment to delay brain tumour progression and improve survival. Nevertheless, a large proportion of patients have treatment-induced memory deficits that dramatically reduce their life quality. Our aim is to test brain tumour interactions with brain networks thereby identifying protective features and risk factors for memory recovery. Seventeen patients with diffuse glioma (aged 22-56 years) were MRI-scanned and cognitively assessed before and after surgery, and during a 12-months recovery period (47 MRI in total after exclusion). Using structural MRI and Neurite Orientation Dispersion and Density Imaging (NODDI) derived from diffusion-weighted images, we respectively estimated lesion overlap and Neurite Density with brain networks derived from normative data in healthy participants. Non-local effects of tumours were evident on neurite density, which was reduced not only within the tumour, but also beyond the tumour boundary. In contrast, high preoperative neurite density outside the tumour, but within the DMN, was associated with better memory recovery. Furthermore, follow-up neurite density within the DMN and Frontoparietal network were also associated with memory recovery. Preoperative tumour, and post-operative lesion, overlap with the DMN showed a significant negative association with memory recovery. Our findings suggest that brain tumours and their corresponding treatment affecting brain networks that are fundamental for memory functioning such as the DMN can have a major impact on patient\u2019s memory recovery.", "URL": "https://doi.org/10.1101/19008581"} |
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] | {"Title": "Interdependence between confirmed and discarded cases of dengue, chikungunya and Zika viruses in Brazil: A multivariate time-series analysis", "Authors": "Oliveira Juliane F, Rodrigues Moreno S., Skalinski Lacita M., Santos Aline ES, Costa Larissa C., Cardim Luciana L., Paix\u00e3o Enny S., da Concei\u00e7\u00e3o N. Costa Maria, Oliveira Wanderson K., Barreto Maur\u00edcio L., Gl\u00f3ria Teixeira Maria, Andrade Roberto F. S.", "Abstract": "Abstract The co-circulation of different arboviruses in the same time and space poses a significant threat to public health given their rapid geographic dispersion and serious health, social, and economic impact. Therefore, it is crucial to have high quality of case registration to estimate the real impact of each arboviruses in the population. In this work, a Vector Autoregressive (VAR) model was developed to investigate the interrelationships between discarded and confirmed cases of dengue, chikungunya, and Zika in Brazil. We used data from the Brazilian National Notifiable Diseases Information System (SINAN) from 2010 to 2017. There were two waves in the series of dengue notification in this period, one occurring in 2013 and the second in 2015. The series of reported cases of both Zika and chikungunya reached their peak in late 2015 and early 2016. The VAR model shows that the Zika series have a significant impact on the dengue series and vice versa, suggesting that several discarded and confirmed cases of dengue could actually have been cases of Zika. The model also suggests that the series of confirmed chikungunya cases is almost independent of the cases of dengue and Zika. In conclusion, co-circulation of arboviruses with similar symptoms could lead to misdiagnosed diseases in the surveillance system. We argue that the use of mathematical and statistical models routinely in association with traditional symptom-surveillance could help to decrease such errors and to provide early indication of possible future outbreaks. These findings address the challenges regarding notification biases and shed new light on how to handle reported cases based only in clinical-epidemiological criteria when multiples arboviruses co-circulate in the same population. Author summary Arthropod-borne viruses (arboviruses) transmission is a growing health problem worldwide. The real epidemiological impact of the co-circulation of different arboviruses in the same urban spaces is a recent phenomenon and there are many issues to explore. One of this issue is the misclassification due to the scarce availability of confirmatory laboratory tests. This establishes a challenge to identify, distinguish and estimate the number of infections when different arboviruses co-circulate. We propose the use of multivariate time series analysis to understand how the weekly notification of suspected cases of dengue, chikungunya and Zika, in Brazil, affected each other. Our results suggest that the series of Zika significantly impact on the series of dengue and vice versa, indicating that several discarded and confirmed cases of dengue might actually have been Zika cases. The results also suggest that the series of confirmed cases of chikungunya are almost independent of those of dengue and Zika. Our findings shed light on yet hidden aspects on the co-circulation of these three viruses based on reported cases. We believe the present work provides a new perspective on the longitudinal analysis of arboviruses transmission and call attention to the challenge in dealing with biases in the notification of multiple arboviruses that circulate in the same urban environment.", "URL": "https://doi.org/10.1101/19002246"} |
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] | {"Title": "Dysmetabolic circulating tumor cells are prognostic in metastatic breast cancer", "Authors": "Brisotto Giulia, Biscontin Eva, Rossi Elisabetta, Bulfoni Michela, Piruska Aigars, Spazzapan Simon, Poggiana Cristina, Vidotto Riccardo, Steffan Agostino, Colombatti Alfonso, Huck Wilhelm T. S., Cesselli Daniela, Zamarchi Rita, Turetta Matteo, Ben Fabio Del", "Abstract": "ABSTRACT The prognostic value of the circulating tumor cells (CTCs), defined as EpCAM+, Cytokeratin (8, 18, 19)+ and CD45-nucleated cells, has been provided in metastatic breast cancer (mBC), with Level I of evidence. However, CTCs belong to a heterogeneous pool of rare cells, and there isn\u2019t consensus on an univocal definition of CTCs. Here, we present a definition of metabolically altered CTCs (MBA-CTC) as CD45-negative cells with an increased extracellular acidification rate (iECAR), supported by the presence of iECAR among the hallmarks of cancer. We tested the prognostic value of MBA-CTC present in mBC patients before starting a new systemic therapy (T0) and 3-4 weeks after (T1). Samples were analyzed in parallel with CellSearch platform (CS). Standard RECIST criteria were used to determine patients\u2019 responses to treatment. In our cohort of n=31 mBC patients, a level of MBA-CTCs above the cut-off was associated with: i) a shorter median PFS both pre-therapy (123 days vs 306; p<0.0001) and during therapy (139 vs 266 days; p= 0.0009); ii) a worse OS both pre-therapy (p=0.0003, 82% survival vs 20%) and during therapy (p=0.0301, 67% survival vs 38%); iii) good agreement with therapy response (kappa=0.685). Both the trend of MBA-CTCs over time and the combined results of the two assays (MBA and CS) enabled more accurate stratification. MBA and CS results showed fair (K=0.33) and poor (K=0.077) agreement at T0 and T1, respectively. This fact and the increased accuracy in combining results suggest that the assays detect different CTC subsets. In conclusion, MBA-CTCs does provide prognostic information at least equivalent to CS, and are even more informative when analyzed over time or combined with CS-CTCs.", "URL": "https://doi.org/10.1101/19012211"} |
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] | {"Title": "Real-time Hearing Threshold Determination of Auditory Brainstem Responses by Cross-correlation Analysis", "Authors": "Wang Haoyu, Li Bei, Lu Yan, Han Kun, Sheng Haibin, Zhou Jialei, Qi Yumeng, Wang Xueling, Huang Zhiwu, Song Lei, Hua Yunfeng", "Abstract": "Summary Auditory brainstem response (ABR) serves as an objective indication of auditory perception at given sound level and is nowadays widely used in hearing function assessment. Despite efforts for automation over decades, hearing threshold determination by machine algorithm remains unreliable and thereby still rely on visual identification by trained personnel. Here, we described a procedure for automatic threshold determination that can be used in both animal and human ABR tests. The method terminates level averaging of ABR recordings upon detection of time-locked waveform through cross-correlation analysis. The threshold level was then indicated by a dramatic increase in the sweep numbers required to produce \u201cqualified\u201d level averaging. A good match was obtained between the algorithm outcome and the human readouts. Moreover, the method varies the level averaging based on the cross-correlation, thereby adapting to the signal-to-noise ratio of single sweep recordings. These features empower a robust and fully automated ABR test.", "URL": "https://doi.org/10.1101/19003301"} |
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] | {"Title": "Interactive web application for plotting personalized prognosis prediction curves in allogeneic hematopoietic cell transplantation using machine learning", "Authors": "Okamura Hiroshi, Nakamae Mika, Koh Shiro, Nanno Satoru, Nakashima Yasuhiro, Koh Hideo, Nakane Takahiko, Hirose Asao, Hino Masayuki, Nakamae Hirohisa", "Abstract": "ABSTRACT Background Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for malignant hematological disorders. Transplant clinicians estimate patient-specific prognosis empirically in clinical practice based on previous studies on similar patients. However, this approach does not provide objective data. The present study primarily aimed to develop a tool capable of providing accurate personalized prognosis prediction after allo-HCT in an objective manner. Methods We developed an interactive web application tool with a graphical user interface capable of plotting the personalized survival and cumulative incidence prediction curves after allo-HCT adjusted by eight patient-specific factors, which are known as prognostic predictors, and assessed their predictive performances. A random survival forest model using the data of patients who underwent allo-HCT at our institution was applied to develop this application. Results We succeeded in showing the personalized prognosis prediction curves of 1-year overall survival (OS), progression-free survival (PFS), relapse/progression, and non-relapse mortality (NRM) interactively using our web application ( https://predicted-os-after-transplantation.shinyapps.io/RSF_model/ ). To assess its predictive performance, the entire cohort (363 cases) was split into a training cohort (70%) to develop the predictive model and test cohort (30%) to confirm its performance time-sequentially. The areas under the receiver-operating characteristic curves for 1-year OS, PFS, relapse/progression, and NRM in test cohort were 0.70, 0.72, 0.73, and 0.77, respectively. Conclusions The new web application could allow transplant clinicians to inform a new allo-HCT candidate of the objective personalized prognosis prediction and facilitate decision-making.", "URL": "https://doi.org/10.1101/2019.12.14.19014654"} |
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] | {"Title": "Factors associated with risk of developmental delay in preschool children in a setting with high rates of malnutrition: a cross-sectional analysis of data from the IHOPE study, Madagascar", "Authors": "Miller Ann C., Garchitorena Andres, Rabemananjara Faramalala, Cordier Laura, Randriamanambintsoa Marius, Rabeza Victor, Razanadrakoto Hery-Tiana Rahaniraka, Ramakasoa Ranaivozafindary Rakoto, RamahefarisonTiana Olivier, Ratsimbazafy Baolova Nathaline, Ouenzar Mohammed Ali, Bonds Matthew H., Ratsifandrihamanana Lisy", "Abstract": "Background Nearly two hundred eighty million children in low and middle income countries are at risk for not achieving their full developmental potential( 1 ). Poor development can lead to reduced scholastic ability( 2 ) or opportunity (promoting and entrenching inequity), and has been associated with lower adult earning potential( 3 ), and poorer health( 4 ), thus potentially contributing to intergenerational poverty traps. While the entire period of childhood is important for development, the first 1000 days (conception to age 2) are critically important for brain development; with the most rapid and prolific development of neural pathways, first in sensory development, then language skills and then higher cognitive functioning( 5 ). Experiences during this period \u2013 positive or negative \u2013 can substantially impact the architecture of the developing brain. Adverse events such as exposure to familial or societal violence, toxins such as lead or arsenic, illness (anemia, diarrhea, HIV, chronic malnutrition, maternal depression), or lack of a developmentally stimulating and nurturing environment can all act as toxic stressors on young children that negatively impact cognitive development throughout the life-course( 6 ). Infants and young children in settings of poverty are often faced with many of these stressors( 7 ).", "URL": "https://doi.org/10.1101/19011064"} |
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] | {"Title": "Periodic Testing and Estimation of STD-HIV Association", "Authors": "M\u00e2sse B.R., Guibord P., Boily M.-C., Alary M.", "Abstract": "Abstract Background The validity of measures used in follow-up studies to estimate the magnitude of the HIV-STD association will be the focus of this paper. A recent simulation study by Boily et al [1] based on a model of HIV and STD transmission showed that the relative risk ( RR ), estimated by the hazard rate ratio ( HRR ) obtained by the Cox model had poor validity, either in absence or in presence of a real association between HIV and STD. The HRR tends to underestimate the true magnitude of a non-null association. These results were obtained from simulated follow-up studies where HIV was periodicaly tested every three months and every month for the STD. Aims and Methods This paper extends the above results by investigating the impact of using different periodic testing intervals on the validity of HRR estimates. Issues regarding the definition of exposure to STDs in this context are explored. A stochastic model for the transmission of HIV and other STDs is used to simulate follow-up studies with different periodic testing intervals. HRR estimates obtained with the Cox model with a time-dependent STD exposure covariate are compared to the true magnitude of the HIV-STD association. In addition, real data are reanalysed using the STD exposure definition described in this paper. The data from Laga et al [2] are used for this purpose. Results (1) Simulated data: independently of the magnitude of the true association, we observed a greater reduction of the bias when increasing the frequency of HIV testing than that of the STD testing. (2) Real data: The STD exposure definition can create substantial differences in the estimation of the HIV-STD association. Laga et al [2] have found a HRR of 2.5 (1.1 - 6.4) for the association between HIV and genital ulcer disease compared to an estimate of 3.5 (1.5 - 8.3) with our improved definition of exposure. Conclusions Results on the simulated data have an important impact on the design of field studies. For instance when choosing between two designs; one where both HIV and STD are screened every 3 months versus one where HIV and STD are screened every 3 months and monthly, respectively. The latter design is more expensive and involves more complicated logistics. Furthermore, this increment in cost may not be justified considering the relatively small gain in terms of validity and variability.", "URL": "https://doi.org/10.1101/19002345"} |
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] | {"Title": "Aerobic capacity predicts skeletal but not cardiac muscle damage after a full distance Ironman triathlon - the Iron(wo)man-study", "Authors": "Danielsson Tom, Carlsson J\u00f6rg, Siethoff Lasse Ten, Ahnesj\u00f6 Jonas, Bergman Patrick", "Abstract": "Abstract Purpose This study examines the association between aerobic capacity and biomarkers of skeletal- and cardiac muscle damage among amateur triathletes after a full distance Ironman. Methods Men and women (N=55) were recruited from local sport clubs. One month before an Iron-man triathlon, they conducted a 20m shuttle run test to determine aerobic capacity. Blood samples were taken immediately after finishing the triathlon, and analyzed for biomarkers of cardiac- and skeletal muscle damage. Regression models examining the association between aerobic capacity expressed in both relative terms (mLO2*kg-1*min-1) and absolute terms (LO2*min-1) controlled for weight and were fitted. Result A total of 39 subjects (26% females) had complete data and were included in the analysis. No association between aerobic capacity and cardiac muscle damage but a significant negative association between aerobic capacity and skeletal muscle damage was observed. This association was independent of how aerobic capacity was expressed, although the model with aerobic capacity expressed in absolute terms and controlled for weight resulted in slightly higher r 2 values, than when aerobic capacity was expressed in relative terms. Conclusion A negative association between aerobic capacity and skeletal muscle damage was seen but despite the well-known cardio-protective health effect of high aerobic fitness no such association could be observed in this study.", "URL": "https://doi.org/10.1101/19001149"} |
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] | {"Title": "Toric Intraocular Lens Implantation in Cataract Patients with Corneal Opacity", "Authors": "Ra Ho, Kim Hyun Seung, Kim Man Soo, Kim Eun Chul", "Abstract": "Abstract Aims To evaluate the effect of toric intraocular lens implantation in cataract patient with corneal opacity and high astigmatism. Methods 31 eyes of 31 patients who underwent cataract surgery with toric intraocular lens implantation were included. All patients had corneal opacity with regular astigmatism. Preoperative total corneal astigmatism was determined considering posterior astigmatism using a rotating Scheimpflug camera (Pentacam\u00ae: Oculus, Wetzlar, Germany). At 2 months after toric intraocular lens implantation, we evaluated residual astigmatism, uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA). Results Postoperative UCVA and BCVA (0.30 \u00b1 0.17, 0.22 \u00b1 0.16LogMAR) statistically improved compared to preoperative UCVA and BCVA (1.2 \u00b1 0.34, 1.1 \u00b1 0.30LogMAR, respectively) (P<0.01). Postoperative residual refractive astigmatism (1.2 \u00b1 0.35D) was statistically reduced compared to preoperative refractive astigmatism (2.4 \u00b1 0.65D) (P<0.05). Preoperative and postoperative total corneal astigmatism values were not statistically different. All cases achieved visual acuity were as good as or better than that preoperatively. The percentage of corneal opacity covering pupillary area had significant negative correlation with postoperative UCVA and BCVA (logMAR) (R=-0.88 P<0.00001 and R=-0.87 P<0.00001, respectively) Conclusion Toric intraocular lens implantation can improve UCVA, BCVA, and refractive astigmatism in cataract patient with corneal opacity. The percentage of central corneal opacity covering pupillary area is the major prognostic factor for postoperative visual improvement. Therefore, toric intraocular lens implantation should be considered for cataract patients who have corneal opacity with high astigmatism.", "URL": "https://doi.org/10.1101/19003319"} |
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] | {"Title": "ULCERATIVE COLITIS-DERIVED COLONOID CULTURE: A Multi-Mineral-Approach to Improve Barrier Protein Expression", "Authors": "Aslam Muhammad N, McClintock Shannon D, Attili Durga, Pandya Shailja, Rehman Humza, Nadeem Daniyal M, Jawad-Makki Mohamed Ali H, Rizvi Areeba H, Berner Maliha M, Dame Michael K, Turgeon Danielle Kim, Varani James", "Abstract": "ABSTRACT Background Recent studies demonstrated that Aquamin \u00ae , a calcium-, magnesium-, and multiple trace element-rich natural product, improves barrier structure and function in colonoids obtained from tissue of healthy subjects. The goal of the present study was to determine if the colonic barrier could be improved in tissue from subjects with ulcerative colitis (UC). Methods Colonoid cultures were established with tissue from 9 individuals with UC. The colonoids were then incubated for a 2-week period under control conditions (i.e., in culture medium with a final calcium concentration of 0.25 mM) or in the same medium supplemented with Aquamin \u00ae to provide 1.5 \u2013 4.5 mM calcium. Effects on differentiation and barrier protein expression were determined using several approaches: phase-contrast & scanning electron microscopy, quantitative histology & immunohistology, mass spectrometry-based proteome assessment and transmission electron microscopy. Results Aquamin \u00ae -treated colonoids demonstrated a modest up-regulation of tight junctional proteins but stronger induction of adherens junction proteins and desmosomal proteins. Increased desmosomes were seen at the ultrastructural level. Proteomic analysis also demonstrated increased expression of basement membrane proteins and hemidesmosomal components. Proteins expressed at the apical surface (mucins and trefoils) were also increased as were several additional proteins with anti-microbial activity or that modulate inflammation. Conclusion A majority of individuals including patients with UC do not reach the recommended daily intake for calcium and other minerals. The findings presented here suggest that adequate mineral intake might improve the colonic barrier.", "URL": "https://doi.org/10.1101/2019.12.12.19014662"} |
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] | {"Title": "Achieving coordinated national immunity and cholera elimination in Haiti through vaccination", "Authors": "Lee Elizabeth C., Chao Dennis L., Lemaitre Joseph, Matrajt Laura, Pasetto Damiano, Perez-Saez Javier, Finger Flavio, Rinaldo Andrea, Sugimoto Jonathan D., Halloran M. Elizabeth, Longini Ira M. Jr., Ternier Ralph, Vissieres Kenia, Azman Andrew S., Lessler Justin, Ivers Louise C.", "Abstract": "Summary Background Cholera was introduced into Haiti in 2010. Since, there have been over 820,000 reported cases and nearly 10,000 deaths. The year 2019 has seen the lowest reported number of cases since the epidemic began. Oral cholera vaccine (OCV) is safe and effective, but has generally not been seen as a primary tool for cholera elimination due to a limited period of protection and constrained supplies. Regionally, epidemic cholera is contained to the island of Hispaniola. Hence, Haiti may represent a unique opportunity to eliminate cholera by use of OCV. Methods We assess the probability of elimination and the potential health impact of OCV use in Haiti by leveraging simulations from four independent modeling teams. For a 10-year projection period, we compared the impact of five vaccination campaign scenarios, differing in geographic scope, vaccination coverage, and rollout duration to a status quo scenario without vaccination. Teams used common calibration data and assumptions for vaccine efficacy and vaccination scenarios, but all other model features and assumptions were determined independently. Findings A two-department OCV campaign proposed in Haiti\u2019s national plan for elimination had less than 50% probability of elimination across models, and only ambitious, nationwide campaigns had a high probability of reaching this goal. Despite their low probability of elimination, two-department campaigns averted a median of 13-58% of infections across models over the five years after the start of vaccination campaigns; a nationwide campaign implemented at the same coverage and rollout duration averted a median of 58-95% of infections across models. Interpretation Despite recent declines in cholera cases in Haiti, bold action is needed to promote elimination of cholera from the region. Large-scale cholera vaccination campaigns in Haiti offer the opportunity to synchronize nationwide immunity, providing near-term protection to the population while improvements to water and sanitation infrastructure create an environment favorable to long-term cholera elimination. Research in Context Evidence before this study We searched PubMed without language or date restrictions on October 4, 2019 for all records matching (\u201ccholera*\u201d AND \u201cHaiti\u201d AND (\u201cvaccin*\u201d OR \u201celim*\u201d)) in any field and added one known article on the probability of elimination of cholera that was not indexed by PubMed to our review. Of 94 results, four articles were not about the cholera outbreak in Haiti or the use of cholera vaccination, and 34 were not original research articles. Fourteen articles presented research on cholera biology or cholera vaccine biology, either through discussion of Vibrio cholerae genetics, immunogenicity of oral cholera vaccine (OCV), or prospective vaccine candidate antigens. Twenty articles assessed OCV vaccine effectiveness, evaluated OCV campaign implementation or attitudes and knowledge about cholera control, or presented lessons learned on outbreak response and policy as a result of the Haiti cholera outbreak. Seven articles were about general cholera outbreak epidemiology in Haiti, and six articles were related to cholera transmission models outside our research scope. Of the nine remaining articles, five examined the impact of potential OCV campaigns at an early time point when Haiti\u2019s cholera outbreak still exhibited epidemic dynamics, and one other projected the impact of the OCV campaigns planned after Hurricane Matthew in 2016. Two of the articles considered prospects for cholera elimination in Haiti in 2013 and 2014 and found that further targeted interventions were needed. One final study from 2017 modeled the possibility for OCV campaigns to eliminate cholera transmission in the Ouest department within a few years. Added value of this study Previous assessments of the impact of OCV use in Haiti occurred during early points of the outbreak when OCV campaigns were unlikely to lead to cholera elimination. Our study projects cholera transmission in Haiti with multiple years of more recent data, and directly examines prospect of cholera elimination in the status quo and under various mass OCV campaign scenarios. In bringing together results from multiple modeling teams, our study provides robust evidence about the current state of cholera transmission across Haiti and the potential impact of multiple mass OCV campaign scenarios. Implications of all of the available evidence While 2019 has seen the lowest number of cholera cases in Haiti since the outbreak began, model simulations suggest that it may be possible for cholera transmission to persist without additional cholera control interventions.While a single two-department vaccination campaign may avert roughly 13-58% of infections with V. cholerae over a five year period, only a nationwide campaign led to a high probability of cholera elimination. Ambitious nationwide vaccination campaigns may break the cycle of endemic cholera transmission in Haiti as long-term improvements to water and sanitation infrastructure, which will limit the effects of potential re-introductions of Vibrio cholerae , are being made.", "URL": "https://doi.org/10.1101/19011072"} |
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] | {"Title": "Mental Health in UK Biobank Revised \u2013 development, implementation and results from an online questionnaire completed by 157,366 participants", "Authors": "Davis Katrina A. S., Coleman Jonathan R. I., Adams Mark, Allen Naomi, Breen Gerome, Cullen Breda, Dickens Chris, Fox Elaine, Graham Nick, Holliday Jo, Howard Louise M, John Ann, Lee William, McCabe Rose, McIntosh Andrew, Pearsall Robert, Smith Daniel J., Sudlow Cathie, Ward Joey, Zammit Stan, Hotopf Matthew", "Abstract": "Abstract This paper corrects and updates a paper published in BJPsych Open 2018 \u201cMental Health in UK Biobank\u201d ( https://doi.org/10.1192/bjo.2018.12 ) that was voluntarily retracted following the finding of errors in the coding of the variable for alcohol use disorder. Notably, the percentage of participants reaching threshold for alcohol use disorder on the Alcohol Use Disorder Identification Tool increased from 7% to 21%. Background UK Biobank is a well-characterised cohort of over 500,000 participants that offers unique opportunities to investigate multiple diseases and risk factors. An online mental health questionnaire completed by UK Biobank participants expands the potential for research into mental disorders. Methods An expert working group designed the questionnaire, using established measures where possible, and consulting with a service user group regarding acceptability. Operational criteria were agreed for defining likely disorder and risk states, including lifetime depression, mania/hypomania, generalised anxiety disorder, unusual experiences and self-harm, and current post-traumatic stress and alcohol use disorders. Results 157,366 completed online questionnaires were available by August 2017. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status. Lifetime depression was the most common finding in 24% of participants (37,434), with current alcohol use disorder criteria met by 21% (32,602), while other criteria were met by less than 8% of the participants. There was extensive comorbidity among the syndromes. Mental disorders were associated with a high neuroticism score, adverse life events and long-term illness; addiction and bipolar affective disorder in particular were associated with measures of deprivation. Conclusions The questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed due to selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health.", "URL": "https://doi.org/10.1101/19001214"} |
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] | {"Title": "A Multiomics Approach to Heterogeneity in Alzheimer\u2019s Disease: Focused Review and Roadmap", "Authors": "Badhwar AmanPreet, McFall G. Peggy, Sapkota Shraddha, Black Sandra E., Chertkow Howard, Duchesne Simon, Masellis Mario, Li Liang, Dixon Roger A., Bellec Pierre", "Abstract": "Abstract Etiological and clinical heterogeneity is increasingly recognized as a common characteristic of Alzheimer\u2019s disease and related dementias. This heterogeneity complicates diagnosis, treatment, and the design and testing of new drugs. An important line of research is discovery of multimodal biomarkers that will facilitate the targeting of subpopulations with homogeneous pathophysiological signatures. High-throughput \u2018omics\u2019 are unbiased data driven techniques that probe the complex etiology of Alzheimer\u2019s disease from multiple levels (e.g. network, cellular, and molecular) and thereby account for pathophysiological heterogeneity in clinical populations. This review focuses on data reduction analyses that identify complementary disease-relevant perturbations for three omics techniques: neuroimaging-based subtypes, metabolomics-derived metabolite panels, and genomics-related polygenic risk scores. Neuroimaging can track accrued neurodegeneration and other sources of network impairments, metabolomics provides a global small-molecule snapshot that is sensitive to ongoing pathological processes, and genomics characterizes relatively invariant genetic risk factors representing key pathways associated with Alzheimer\u2019s disease. Following this focused review, we present a roadmap for assembling these multiomics measurements into a diagnostic tool highly predictive of individual clinical trajectories, to further the goal of personalized medicine in Alzheimer\u2019s disease.", "URL": "https://doi.org/10.1101/19008615"} |