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10.1101/19000109 | Molecular profiling of neonatal dried blood spots reveals changes in innate and adaptive immunity following fetal inflammatory response | Daniel Costa; Nuria Bonet; Amanda Sole; Jose Manuel Gonzalez de Aledo-Castillo; Eduard Sabido; Ferran Casals; Carlota Rovira; Alfons Nadal; Jose Luis Marin; Teresa Cobo; Robert Castelo | Robert Castelo | Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain; Research Programme on Biomedical Informatics, Institut Hospita | 2019-06-25 | 1 | null | cc_by | genetic and genomic medicine | https://www.medrxiv.org/content/early/2019/06/25/19000109.source.xml | The fetal inflammatory response (FIR) increases the risk of perinatal brain injury, particularly in extremely low gestational age newborns (ELGANs, < 28 weeks of gestation). One of the mechanisms contributing to such a risk is a postnatal intermittent or sustained systemic inflammation (ISSI) following FIR. The link between prenatal and postnatal systemic inflammation is supported by the presence of well-established inflammatory biomarkers in the umbilical cord and peripheral blood. However, the extent of molecular changes contributing to this association is unknown. Using RNA sequencing and mass spectrometry proteomics, we profiled the transcriptome and proteome of archived neonatal dried blood spot (DBS) specimens from 21 ELGANs. Comparing FIR-affected and unaffected ELGANs, we identified 782 gene and 27 protein expression changes of 50% magnitude or more, and an experiment-wide significance level below 5% false discovery rate. These expression changes confirm the robust postnatal activation of the innate immune system in FIR-affected ELGANs and reveal for the first time an impairment of their adaptive immunity. In turn, the altered pathways provide clues about the molecular mechanisms triggering ISSI after FIR, and the onset of perinatal brain injury. | 10.1111/febs.15578 | medrxiv |
10.1101/19000109 | Molecular profiling of neonatal dried blood spots reveals changes in innate and adaptive immunity following fetal inflammatory response | Costa, D.; Bonet, N.; Sole, A.; Gonzalez de Aledo-Castillo, J. M.; Sabido, E.; Casals, F.; Rovira, C.; Nadal, A.; Marin, J. L.; Cobo, T.; Castelo, R. | Robert Castelo | Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain; Research Programme on Biomedical Informatics, Institut Hospita | 2019-07-09 | 2 | PUBLISHAHEADOFPRINT | cc_by_nc | genetic and genomic medicine | https://www.medrxiv.org/content/early/2019/07/09/19000109.source.xml | The fetal inflammatory response (FIR) increases the risk of perinatal brain injury, particularly in extremely low gestational age newborns (ELGANs, < 28 weeks of gestation). One of the mechanisms contributing to such a risk is a postnatal intermittent or sustained systemic inflammation (ISSI) following FIR. The link between prenatal and postnatal systemic inflammation is supported by the presence of well-established inflammatory biomarkers in the umbilical cord and peripheral blood. However, the extent of molecular changes contributing to this association is unknown. Using RNA sequencing and mass spectrometry proteomics, we profiled the transcriptome and proteome of archived neonatal dried blood spot (DBS) specimens from 21 ELGANs. Comparing FIR-affected and unaffected ELGANs, we identified 782 gene and 27 protein expression changes of 50% magnitude or more, and an experiment-wide significance level below 5% false discovery rate. These expression changes confirm the robust postnatal activation of the innate immune system in FIR-affected ELGANs and reveal for the first time an impairment of their adaptive immunity. In turn, the altered pathways provide clues about the molecular mechanisms triggering ISSI after FIR, and the onset of perinatal brain injury. | 10.1111/febs.15578 | medrxiv |
10.1101/19000109 | Genome-wide postnatal changes in immunity following fetal inflammatory response | Costa, D.; Bonet, N.; Sole, A.; Gonzalez de Aledo-Castillo, J. M.; Sabido, E.; Casals, F.; Rovira, C.; Nadal, A.; Marin, J. L.; Cobo, T.; Castelo, R. | Robert Castelo | Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain; Research Programme on Biomedical Informatics, Institut Hospita | 2020-03-16 | 3 | PUBLISHAHEADOFPRINT | cc_by | genetic and genomic medicine | https://www.medrxiv.org/content/early/2020/03/16/19000109.source.xml | The fetal inflammatory response (FIR) increases the risk of perinatal brain injury, particularly in extremely low gestational age newborns (ELGANs, < 28 weeks of gestation). One of the mechanisms contributing to such a risk is a postnatal intermittent or sustained systemic inflammation (ISSI) following FIR. The link between prenatal and postnatal systemic inflammation is supported by the presence of well-established inflammatory biomarkers in the umbilical cord and peripheral blood. However, the extent of molecular changes contributing to this association is unknown. Using RNA sequencing and mass spectrometry proteomics, we profiled the transcriptome and proteome of archived neonatal dried blood spot (DBS) specimens from 21 ELGANs. Comparing FIR-affected and unaffected ELGANs, we identified 782 gene and 27 protein expression changes of 50% magnitude or more, and an experiment-wide significance level below 5% false discovery rate. These expression changes confirm the robust postnatal activation of the innate immune system in FIR-affected ELGANs and reveal for the first time an impairment of their adaptive immunity. In turn, the altered pathways provide clues about the molecular mechanisms triggering ISSI after FIR, and the onset of perinatal brain injury. | 10.1111/febs.15578 | medrxiv |
10.1101/19000109 | Genome-wide postnatal changes in immunity following fetal inflammatory response | Costa, D.; Bonet, N.; Sole, A.; Gonzalez de Aledo-Castillo, J. M.; Sabido, E.; Casals, F.; Rovira, C.; Nadal, A.; Marin, J. L.; Cobo, T.; Castelo, R. | Robert Castelo | Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain; Research Programme on Biomedical Informatics, Institut Hospita | 2020-07-24 | 4 | PUBLISHAHEADOFPRINT | cc_by | genetic and genomic medicine | https://www.medrxiv.org/content/early/2020/07/24/19000109.source.xml | The fetal inflammatory response (FIR) increases the risk of perinatal brain injury, particularly in extremely low gestational age newborns (ELGANs, < 28 weeks of gestation). One of the mechanisms contributing to such a risk is a postnatal intermittent or sustained systemic inflammation (ISSI) following FIR. The link between prenatal and postnatal systemic inflammation is supported by the presence of well-established inflammatory biomarkers in the umbilical cord and peripheral blood. However, the extent of molecular changes contributing to this association is unknown. Using RNA sequencing and mass spectrometry proteomics, we profiled the transcriptome and proteome of archived neonatal dried blood spot (DBS) specimens from 21 ELGANs. Comparing FIR-affected and unaffected ELGANs, we identified 782 gene and 27 protein expression changes of 50% magnitude or more, and an experiment-wide significance level below 5% false discovery rate. These expression changes confirm the robust postnatal activation of the innate immune system in FIR-affected ELGANs and reveal for the first time an impairment of their adaptive immunity. In turn, the altered pathways provide clues about the molecular mechanisms triggering ISSI after FIR, and the onset of perinatal brain injury. | 10.1111/febs.15578 | medrxiv |
10.1101/19000109 | Genome-wide postnatal changes in immunity following fetal inflammatory response | Costa, D.; Bonet, N.; Sole, A.; Gonzalez de Aledo-Castillo, J. M.; Sabido, E.; Casals, F.; Rovira, C.; Nadal, A.; Marin, J. L.; Cobo, T.; Castelo, R. | Robert Castelo | Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain; Research Programme on Biomedical Informatics, Institut Hospita | 2020-09-25 | 5 | PUBLISHAHEADOFPRINT | cc_by | genetic and genomic medicine | https://www.medrxiv.org/content/early/2020/09/25/19000109.source.xml | The fetal inflammatory response (FIR) increases the risk of perinatal brain injury, particularly in extremely low gestational age newborns (ELGANs, < 28 weeks of gestation). One of the mechanisms contributing to such a risk is a postnatal intermittent or sustained systemic inflammation (ISSI) following FIR. The link between prenatal and postnatal systemic inflammation is supported by the presence of well-established inflammatory biomarkers in the umbilical cord and peripheral blood. However, the extent of molecular changes contributing to this association is unknown. Using RNA sequencing and mass spectrometry proteomics, we profiled the transcriptome and proteome of archived neonatal dried blood spot (DBS) specimens from 21 ELGANs. Comparing FIR-affected and unaffected ELGANs, we identified 782 gene and 27 protein expression changes of 50% magnitude or more, and an experiment-wide significance level below 5% false discovery rate. These expression changes confirm the robust postnatal activation of the innate immune system in FIR-affected ELGANs and reveal for the first time an impairment of their adaptive immunity. In turn, the altered pathways provide clues about the molecular mechanisms triggering ISSI after FIR, and the onset of perinatal brain injury. | 10.1111/febs.15578 | medrxiv |
10.1101/19000273 | Crohns disease and ulcerative colitis patient perspectives on clinical trials and participation | Orna G Ehrlich; James Testaverde; Caren Heller; Stuart Daman; Annick Anderson; Peter D.R. Higgins | Orna G Ehrlich | Crohn\'s & Colitis Foundation | 2019-06-25 | 1 | null | cc_by_nc_nd | gastroenterology | https://www.medrxiv.org/content/early/2019/06/25/19000273.source.xml | BackgroundClinical trial recruitment is often the rate-limiting step in the development of new treatments reaching patients across all disease states. With more than 1500 currently available clinical trials for inflammatory bowel diseases (IBD) patients, it is important to understand patient perceptions of clinical trial participation to improve recruitment and retention. This study aimed to examine the specific challenges and barriers that might be reducing IBD patient enrollment and potential methods to overcome these barriers.
MethodsFive in-person patient focus groups were conducted from February through May 2016 using two facilitation guides. Participants self-reported a diagnosis of Crohns disease or ulcerative colitis.
ResultsThe five focus groups included a total of 34 participants. Participants discussed several barriers, including fears, disease severity at trial onset, potential adverse effects, time constraints, and the influence of both their primary IBD provider and support network. Methods to improve participation included better communication to prospective patients, reduced length of trial and time commitment, lower placebo rates, the option of open label extension, and support of the patients primary IBD provider.
ConclusionsThis is the first study to examine patient perceptions for IBD clinical trial enrollment, including barriers to participation and methods to improve participation. Fear and misunderstanding of clinical trials, engagement with providers, limiting time demands, and limiting the impact on work and family were found to be barriers to participation. Creative solutions to these problems could lead to greater participation in trials and more rapid advancement of new therapies to clinical approval and use. | null | medrxiv |
10.1101/19000463 | Updating Insights into Rosiglitazone and Cardiovascular Risk through Shared Data: Individual Patient-and-Summary-Level Meta-Analyses | Joshua D Wallach; Kun Wang; Audrey D Zhang; Deanna Chang; Holly K Grossetta Nardini; Haiqun Lin; Michael B Bracken; Mayur Desai; Harlan Krumholz; Joseph S. Ross | Joshua D Wallach | Yale School of Public Health | 2019-06-25 | 1 | null | cc_by_nc | cardiovascular medicine | https://www.medrxiv.org/content/early/2019/06/25/19000463.source.xml | ObjectiveTo conduct a systematic review and meta-analysis of the effects of rosiglitazone therapy on cardiovascular risk and mortality using multiple data sources and varying analytical approaches.
DesignSystematic review and meta-analysis of randomized controlled trials.
Data sourcesGlaxoSmithKlines (GSK) Clinical Study Data Request (CSDR) and Study Register platforms, MEDLINE, PubMed, Embase, Web of Science, Cochrane Central Registry of Controlled Trials, Scopus, and ClinicalTrials.gov from inception to January 2019.
Study selection criteriaRandomized, controlled, phase II-IV clinical trials comparing rosiglitazone with any control for at least 24 weeks in adults.
Data extraction and synthesisFor analyses of trials for which individual patient-level data (IPD) were available, we examined a composite of the following events as our primary outcome: acute myocardial infarction, heart failure, cardiovascular-related deaths, and non-cardiovascular-related deaths. As secondary analyses, these four events were examined independently. When also including trials for which IPD were not available, we examined myocardial infarction and cardiovascular-related deaths, ascertained from summary-level data. Multiple meta-analyses were conducted, accounting for trials with zero events in one or all arms with two different continuity corrections (i.e., 0.5 constant and treatment arm comparator continuity correction), to calculate odds ratios and risk ratios with 95% confidence intervals.
ResultsThere were 33 eligible trials for which IPD were available (21156 participants) through GSKs CSDR. We also identified 103 additional trials for which IPD were not available from which we ascertained myocardial infarctions (23683 patients) and 103 trials for cardiovascular-related deaths (22772 patients). Among trials for which IPD were available, we identified a greater number of myocardial infarctions and fewer cardiovascular-related deaths reported in the IPD as compared to the summary-level data. When limited to trials for which IPD were available and accounting for trials with zero-events in only one arm using a constant continuity correction of 0.5, patients treated with rosiglitazone had a 39% increased risk of a composite event compared with controls (Mantel-Haenszel odds ratio 1.39, 95% CI 1.15 to 1.68). When examined separately, the odds ratios for myocardial infarction, heart failure, cardiovascular-related death, and non-cardiovascular-related death were 1.25 (0.99 to 1.60), 1.60 (1.20 to 2.14), 1.18 (0.64 to 2.17), and 1.13 (0.58 to 2.20), respectively. When all trials for which IPD were and were not available were combined for myocardial infarction and cardiovascular-related deaths, the odds ratios were attenuated (1.13 (0.92 to 1.38) and 1.10 (0.73 to 1.65), respectively). Effect estimates and 95% confidence intervals were broadly consistent when analyses were repeated including trials with zero events across all arms using constant continuity corrections of 0.5 or treatment arm continuity corrections.
ConclusionsResults of this comprehensive meta-analysis aggregating a multitude of trials and analyzed using a variety of statistical techniques suggest that rosiglitazone is consistently associated with an increased cardiovascular risk, likely driven by heart failure events, whose interpretation is complicated by varying magnitudes of myocardial infarction risk that were attenuated through aggregation of summary-level data in addition to IPD.
Systematic review registrationhttps://osf.io/4yvp2/
What is already known on this topic- Since 2007, there have been multiple meta-analyses, using various analytic approaches, that have reported conflicting findings related to rosiglitazones cardiovascular risk.
- Previous meta-analyses have relied primarily on summary-level data, and did not have access to individual patient-level data (IPD) from clinical trials.
- Currently, there is little consensus on which method should be used to account for sparse adverse event data in meta-analyses.
What this study adds- Among trials for which IPD were available, rosiglitazone use was consistently associated with an increased cardiovascular risk, likely driven by heart failure events.
- Interpretation of rosiglitazones cardiovascular risk is complicated by varying magnitudes of myocardial infarction risk that were attenuated through aggregation of summary-level data in addition to IPD.
- Among trials for which IPD were available, we identified a greater number of myocardial infarctions and fewer cardiovascular deaths reported in the IPD as compared to the summary-level data, which suggests that IPD may be necessary to accurately classify all adverse events when performing meta-analyses focused on safety. | 10.1136/bmj.l7078 | medrxiv |
10.1101/19000430 | Predicting epileptic seizures using nonnegative matrix factorization | Olivera Stojanovic; Gordon Pipa | Olivera Stojanovic | Institute of Cognitive Science, University of Osnabrueck | 2019-06-25 | 1 | null | cc_by | health informatics | https://www.medrxiv.org/content/early/2019/06/25/19000430.source.xml | 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. | 10.1371/journal.pone.0228025 | medrxiv |
10.1101/19000133 | Prospective and External Evaluation of a Machine Learning Model to Predict In-Hospital Mortality | Nathan Brajer; Brian Cozzi; Michael Gao; Mike Revoir; Marshall Nichols; Joseph Futoma; Jonathan Bae; Noppon Setji; Suresh Balu; Adrian Hernandez; Mark Sendak | Nathan Brajer | Duke University School of Medicine | 2019-06-25 | 1 | null | cc_by_nc_nd | health systems and quality improvement | https://www.medrxiv.org/content/early/2019/06/25/19000133.source.xml | The ability to accurately predict in-hospital mortality for patients at the time of admission could improve clinical and operational decision-making and outcomes. Few machine learning models have been developed to predict in-hospital death that are both broadly applicable to all adult patients across a health system and readily implementable, and, to the best of our knowledge, none have been implemented, evaluated prospectively, or externally validated.
The primary objective of this study was to prospectively and externally validate a machine learning model that predicts in-hospital mortality for all adult patients at the time of hospital admission. Model performance was quantified using the area under the receiver operating characteristic curve (AUROC) and area under the precision recall curve (AUPRC). Secondary objectives were to design the model using commonly available EHR data and accessible computational methods.
A total of 75,247 hospital admissions (median [IQR] age 59.5 [29.0] years; male [45.9%]) were included in the study. The in-hospital mortality rates for the training validation, retrospective validations at Hospitals A, B, and C, and prospective validation cohorts, respectively, were 3.0%, 2.7%, 1.8%, 2.1%, and 1.6%. The area under the receiver operating characteristic curves (AUROCs), respectively, were 0.87 (0.83-0.89), 0.85 (0.83-0.87), 0.89 (0.86 - 0.92), 0.84 (0.80-0.89), and 0.86 (0.83-0.90). The area under the precision recall curves (AUPRCs), respectively, were 0.29 (0.25-0.37), 0.17 (0.13-0.22), 0.22 (0.14-0.31), 0.13 (0.08-0.21), and 0.14 (0.09-0.21).
The results demonstrated accurate prediction of in-hospital mortality for adult patients at the time of admission. The data elements, methods, and patient selection make the model implementable at a system-level. | 10.1001/jamanetworkopen.2019.20733 | medrxiv |
10.1101/19000919 | Trends and variation in unsafe prescribing of methotrexate: a cohort study in English NHS primary care. | Brian MacKenna; Helen J Curtis; Alex J Walker; Richard Croker; Seb Bacon; Ben Goldacre | Ben Goldacre | University of Oxford | 2019-06-25 | 1 | null | cc_by | health systems and quality improvement | https://www.medrxiv.org/content/early/2019/06/25/19000919.source.xml | ObjectiveTo describe trends and geographical variation in methotrexate prescribing that breaches national safety recommendations; deaths from methotrexate poisoning; and associated litigation.
MethodsA 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.
ResultsOut 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.
ConclusionsThe 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. | 10.3399/bjgp20X710993 | medrxiv |
10.1101/19000919 | Trends and variation in unsafe prescribing of methotrexate: a cohort study in English NHS primary care. | MacKenna, B.; Curtis, H. J.; Walker, A. J.; Croker, R.; Bacon, S.; Goldacre, B. | Ben Goldacre | University of Oxford | 2019-07-02 | 2 | PUBLISHAHEADOFPRINT | cc_by | health systems and quality improvement | https://www.medrxiv.org/content/early/2019/07/02/19000919.source.xml | ObjectiveTo describe trends and geographical variation in methotrexate prescribing that breaches national safety recommendations; deaths from methotrexate poisoning; and associated litigation.
MethodsA 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.
ResultsOut 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.
ConclusionsThe 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. | 10.3399/bjgp20X710993 | medrxiv |
10.1101/19000596 | 18F-AV1451 PET imaging and white matter changes in progressive supranuclear palsy | Nicolas Nicastro; Patricia Vazquez Rodriguez; Maura Malpetti; W. Richard Bevan-Jones; P. Simon Jones; Luca Passamonti; Franklin I Aigbirhio; John T O'Brien; James B Rowe | Nicolas Nicastro | University of Cambridge | 2019-06-25 | 1 | null | cc_by_nc_nd | neurology | https://www.medrxiv.org/content/early/2019/06/25/19000596.source.xml | IntroductionProgressive supranuclear palsy (PSP) is characterized by deposition of straight filament tau aggregates in the grey matter of deep nuclei and cerebellum. White matter changes are increasingly documented as a feature of degenerative parkinsonism. We therefore examined the relationship between tau pathology (assessed via 18F-AV1451 positron emission tomography) and white matter integrity (using diffusion tensor imaging, DTI) in PSP.
MethodsTwenty-three people with clinically probable PSP-Richardsons syndrome (age 68.8 {+/-} 5.8 years, 39% female) and 23 controls underwent structural 3T brain MRI including DTI. Twenty-one patients also underwent 18F-AV145 PET imaging. DTI group comparisons were performed using Fractional Anisotropy (FA), Mean Diffusivity (MD) and Radial Diffusivity (RD). Voxel-wise white matter integrity was correlated with 18F-AV1451 binding in typical subcortical PSP regions of interest (i.e. putamen, pallidum, thalamus and midbrain). DTI and 18F-AV1451 imaging measures were correlated with clinical impairment.
ResultsWidespread DTI changes in PSP subjects relative to controls (family-wise error FWE p<0.01) were observed. In PSP, higher 18F-AV1451 binding correlated with reduced white matter integrity in the bilateral internal capsule, corona radiata, and superior longitudinal fasciculus (FWE p<0.05). Association between cognitive impairment (ACER score) and white matter deficits were found in the genu of corpus callosum and cingulum (p<0.005).
ConclusionThis cross-sectional study demonstrates an association between in vivo proxy measures of tau pathology and white matter degeneration in PSP. Longitudinal studies and more specific PET probes for non-Alzheimer tauopathies are warranted to assess the complex interplay between microstructural changes and protein deposition in PSP. | 10.1007/s00415-019-09566-9 | medrxiv |
10.1101/19000265 | Perception of whole-body motion during balance perturbations is impaired in Parkinson's disease and is associated with balance impairment | Sistania M Bong; JL McKay; Stewart A Factor; Lena H Ting | Lena H Ting | Emory University | 2019-06-25 | 1 | null | cc_by | neurology | https://www.medrxiv.org/content/early/2019/06/25/19000265.source.xml | BackgroundIn addition to motor deficits, Parkinsons disease (PD) may cause perceptual impairments. The role of perceptual impairments in sensorimotor function is unclear, and has typically been studied in single-joint motions. Research Question: We hypothesized that perception of whole-body motion is impaired in PD and contributes to balance impairments. We tested 1) whether directional acuity to whole body perturbations during standing was worse in people with PD compared to neurotypical older adults (NOA), and 2) whether balance ability, as assessed by the MiniBESTest, was associated with poor directional acuity in either group.
MethodsParticipants were exposed to pairs of support-surface translation perturbations in a two-alternative forced choice testing paradigm developed previously in a young healthy population. The first perturbation of each pair was directly backward and the second deviated to the left or right (1{degrees}-44{degrees}). Participants judged and reported whether the perturbations in each pair were in the "same" or "different" direction. This information was used to calculate directional acuity thresholds corresponding to "just-noticeable differences" in perturbation direction. Linear mixed models determined associations between directional thresholds and clinical variables including MDS UPDRS-III score, age, and MiniBESTest score. Results: 20 PD (64{+/-}7 y, 12 male, [>=]12 hours since last intake of antiparkinsonian medications) and 12 NOA (64{+/-}8, 6 male) were assessed. Directional thresholds were higher (worse) among PD participants (17.6{+/-}5.9{degrees} vs. 12.8{+/-}3.3{degrees}, P<0.01). Linear mixed models further showed that higher thresholds were associated with MDS UPDRS-III score (P<0.01), and were associated with poorer balance ability among PD participants (P<0.01), but not among NOA participants (P=0.40). Significance: Perception of whole-body motion is impaired in PD and may contribute to impaired balance and falls. | 10.1016/j.gaitpost.2019.10.029 | medrxiv |
10.1101/19000497 | Proximal and distal factors predicting timely initiation of breastfeeding in Ethiopia: a systematic review and meta-analysis | Tesfa Dejenie Habtewold; Shimels Hussien Mohammed; Aklilu Endalamaw; Henok Mulugeta; Getenet Dessie; Derbew Fikadu Berhe; Mulugeta Molla Birhanu; Md. Atiqul Islam; Andreas A. Teferra; Nigus Gebremedhin Asefa; Sisay Mulugeta Alemu | Tesfa Dejenie Habtewold | Department of Epidemiology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands | 2019-06-25 | 1 | null | cc_by_nc_nd | nutrition | https://www.medrxiv.org/content/early/2019/06/25/19000497.source.xml | BackgroundIn Ethiopia, the current coverage of timely initiation of breast feeding (TIBF) has fallen short of the national Health Sector Transformation Plan 2016-2020, National Nutrition Program 2016-2020 and WHO global target. This calls for the need to assess relevant proximal and distal factors that affect the rate of TIBF in Ethiopia.
ObjectiveThe aim of this meta-analysis was to investigate the association between TIBF and educational status, household income, marital status, media exposure, and parity in Ethiopia.
MethodsDatabases used were PubMed, EMBASE, Web of Science, SCOPUS, CINAHL and WHO Global health library, and key terms were searched using interactive searching syntax. It was also supplemented by manual searching. Observational studies published between September 2000 and March 2019 were included. The methodological quality of studies was examined using the Newcastle-Ottawa Scale (NOS) for cross-sectional studies. Data were extracted using the Joanna Briggs Institute (JBI) data extraction tool. To obtain the pooled odds ratio (OR), extracted data were fitted in a random-effects meta-analysis model. Statistical heterogeneity was quantified using Cochrans Q test, {tau}2, and I2 statistics. Additional analysis conducted includes Jackknife sensitivity analysis, cumulative meta-analysis, and meta-regression analysis.
ResultsOut of 553 studies retrieved, 25 studies fulfilled our inclusion criteria. Almost all studies were conducted on mothers with newborn less than 23 months. Maternal educational status (OR = 1.82; p < 0.001; 95% CI = 1.35 - 2.45; I2 = 84.96%), paternal educational status (OR = 2.72; p = 0.001, 95% CI = 1.49 - 4.97 I2 = 62.50%), income (OR = 1.16; p = 0.002; 95% CI = 1.05 - 1.27; I2 = 0.00%), marital status (OR = 1.39; p = 0.001; 95% CI = 1.14 - 1.69; I2 = 9.17%) and parity (OR = 1.39; p = 0.01; 95% CI = 1.07 - 1.81; I2 = 74.43%) were found to be significantly associated with TIBF. We also observed a direct dose-response relationship of TIBF with educational status and income.
ConclusionsProximal and distal factors significantly predicting TIBF practice in Ethiopia, which needs integrated intervention by health professionals and healthcare policymakers. Health education, counselling and peer education targeting parents at antenatal and postnatal periods are needed. It is also relevant to improve the economic power of women and promote gender equality. | 10.1111/apa.15278 | medrxiv |
10.1101/19000497 | Proximal and distal factors predicting timely initiation of breastfeeding in Ethiopia: a systematic review and meta-analysis | Habtewold, T. D.; Mohammed, S. H.; Endalamaw, A.; Mulugeta, H.; Dessie, G.; Berhe, D. F.; Birhanu, M. M.; Islam, M. A.; Teferra, A. A.; Asefa, N. G.; Alemu, S. M. | Tesfa Dejenie Habtewold | Department of Epidemiology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands | 2019-07-08 | 2 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | nutrition | https://www.medrxiv.org/content/early/2019/07/08/19000497.source.xml | BackgroundIn Ethiopia, the current coverage of timely initiation of breast feeding (TIBF) has fallen short of the national Health Sector Transformation Plan 2016-2020, National Nutrition Program 2016-2020 and WHO global target. This calls for the need to assess relevant proximal and distal factors that affect the rate of TIBF in Ethiopia.
ObjectiveThe aim of this meta-analysis was to investigate the association between TIBF and educational status, household income, marital status, media exposure, and parity in Ethiopia.
MethodsDatabases used were PubMed, EMBASE, Web of Science, SCOPUS, CINAHL and WHO Global health library, and key terms were searched using interactive searching syntax. It was also supplemented by manual searching. Observational studies published between September 2000 and March 2019 were included. The methodological quality of studies was examined using the Newcastle-Ottawa Scale (NOS) for cross-sectional studies. Data were extracted using the Joanna Briggs Institute (JBI) data extraction tool. To obtain the pooled odds ratio (OR), extracted data were fitted in a random-effects meta-analysis model. Statistical heterogeneity was quantified using Cochrans Q test, {tau}2, and I2 statistics. Additional analysis conducted includes Jackknife sensitivity analysis, cumulative meta-analysis, and meta-regression analysis.
ResultsOut of 553 studies retrieved, 25 studies fulfilled our inclusion criteria. Almost all studies were conducted on mothers with newborn less than 23 months. Maternal educational status (OR = 1.82; p < 0.001; 95% CI = 1.35 - 2.45; I2 = 84.96%), paternal educational status (OR = 2.72; p = 0.001, 95% CI = 1.49 - 4.97 I2 = 62.50%), income (OR = 1.16; p = 0.002; 95% CI = 1.05 - 1.27; I2 = 0.00%), marital status (OR = 1.39; p = 0.001; 95% CI = 1.14 - 1.69; I2 = 9.17%) and parity (OR = 1.39; p = 0.01; 95% CI = 1.07 - 1.81; I2 = 74.43%) were found to be significantly associated with TIBF. We also observed a direct dose-response relationship of TIBF with educational status and income.
ConclusionsProximal and distal factors significantly predicting TIBF practice in Ethiopia, which needs integrated intervention by health professionals and healthcare policymakers. Health education, counselling and peer education targeting parents at antenatal and postnatal periods are needed. It is also relevant to improve the economic power of women and promote gender equality. | 10.1111/apa.15278 | medrxiv |
10.1101/19000638 | Transfer of Statistical Innovations of the 1990s-2000s in Oncology to the Biomedical Literature | Alexandre Vivot; Vincent Levy; Sylvie Chevret | Alexandre Vivot | APHP | 2019-06-25 | 1 | null | cc_no | oncology | https://www.medrxiv.org/content/early/2019/06/25/19000638.source.xml | IntroductionInnovations in the fields of clinical studies require time to generate and disseminate new knowledge. We aimed to specifically explore lag times between the introduction and widespread use of innovative statistical methods in oncology using the competing risks and phase I model-based clinical trials settings as examples.
MethodsFirst, we defined a set of closed articles for each setting based on two princeps papers (Gray, Annals of Statistics 1998 for the competing risks setting and OQuigley et al., Biometrics 1990 for the phase I setting). Secondly, we retrieved from the web of science all citations of the papers included in these sets. Each journal was classified as applied, semi-applied or methodological.
ResultsA total of 6,727 citations for the competing risks setting and 2,639 citations for the phase I setting were found. Time to reach 25 citations was 6.2 years for the Grays paper and 4.5 years for the Fine and Gray paper, while it ranged from 3.4 years up to at least 20.1 years and not reached for 6 papers from the competing risks setting. The vast majority (91%) of the citing papers for the competing risks setting originated from applied journals. In contrast, less than half (44%) of the citing papers for the phase I setting were published in applied journals.
ConclusionStatistical innovations in the competing risks setting have been widely diffused in the medical literature unlike the model-based designs for phase I trials, which are still seldom used 30 years after publication. | null | medrxiv |
10.1101/19000174 | Histopathologist Features Predictive of Diagnostic Concordance at Expert Level Amongst a Large International Sample of Pathologists Diagnosing Barrett′s Dysplasia Using Digital Pathology | Myrtle J Van der Wel; Helen G Coleman; Jacques JGHM Bergman; Marnix Jansen; Sybren L Meijer | Marnix Jansen | UCL Cancer Institute | 2019-06-25 | 1 | null | cc_no | oncology | https://www.medrxiv.org/content/early/2019/06/25/19000174.source.xml | ObjectiveGuidelines recommend expert pathology review of Barretts oesophagus (BO) biopsies that reveal dysplasia, but there are no evidence-based standards to corroborate expert reviewer status. We investigated BO concordance rates and pathologist features predictive of diagnostic discordance amongst a large international cohort of gastrointestinal pathologists to develop a quantitative model of BO expert review.
DesignPathologists (n=55) from over 20 countries assessed 55 digitised BO biopsies from across the diagnostic spectrum, before and after viewing matched p53 immunohistochemistry. Extensive demographic and clinical experience data were obtained via online questionnaire. We calculated discordance rates and applied multivariate regression analyses to identify predictors of concordance.
ResultsWe recorded over 6,000 individual case diagnoses. Of 2,805 H&E diagnoses, we found excellent concordance (>70%) for non-dysplastic Barretts oesophagus (NDBO) and high-grade dysplasia (HGD), and intermediate concordance for low-grade dysplasia (LGD, 42%) and indefinite for dysplasia (IND, 23%). Major diagnostic errors (i.e. NDBO overinterpreted as LGD/HGD or vice versa) were found in 248 diagnoses (8.8%), which reduced to 8.3% after viewing p53 labelled slides. At least 5 years of professional experience was protective against major diagnostic error for H&E slide review (OR 0.48, 95%CI 0.31-0.74). Working in a district general hospital was associated with increased odds of major diagnostic error (OR 1.76, 95%CI 1.15-2.69), however this was neutralised when pathologists viewed p53 labelled slides, suggesting a beneficial impact of p53 immunohistochemistry for this group.
ConclusionWe have developed an evidence-based quantitative model of BO histopathology diagnosis at expert consensus level that will inform guideline development. | 10.1136/gutjnl-2019-318985 | medrxiv |
10.1101/19000653 | Pain Reduction by Inducing Sensory-Motor Adaptation in Complex Regional Pain Syndrome (CRPS PRISMA): Protocol for a Double-blind Randomized Controlled Trial | Monika Halicka; Axel D Vittersø; Michael J Proulx; Janet H Bultitude | Monika Halicka | University of Bath | 2019-06-25 | 1 | null | cc_by_nc_nd | pain medicine | https://www.medrxiv.org/content/early/2019/06/25/19000653.source.xml | BackgroundComplex Regional Pain Syndrome (CRPS) presents as chronic, continuous pain and sensory, autonomic, and motor abnormalities affecting one or more extremities. People with CRPS can also show changes in their perception of and attention to the affected body part and sensory information in the affected side of space. Prism Adaptation (PA) is a behavioural intervention targeted at reducing attention deficits in post-stroke hemispatial neglect. PA also appears to reduce pain and other CRPS symptoms; however, these therapeutic effects have been demonstrated only in small unblinded studies. This paper describes the protocol for an ongoing double-blind, randomized, sham-controlled clinical trial that will evaluate the efficacy of PA treatment for CRPS. The secondary aims of the study are to examine the relationships between neuropsychological changes (such as spatial attention, space and body representation, and motor spatial performance) and clinical manifestations of CRPS, as well as symptom improvement.
MethodsForty-two participants with upper-limb CRPS type I will undergo two weeks of twice-daily PA treatment or sham treatment. The primary outcome measures are current pain intensity and CRPS severity score, measured immediately before and after the treatment period. Secondary outcome measures include the results of self-report questionnaires about pain, movement, symptoms interference, and body representation; clinical assessments of sensory, motor, and autonomic functions; and computer-based psychophysical tests of neuropsychological functions. Data are collected in four research visits: four weeks and one day before treatment, and one day and four weeks after the end of treatment. Additional follow-up through postal questionnaires is conducted three and six months post-treatment.
DiscussionIt is hypothesised that participants undergoing PA treatment, compared to those receiving sham treatment, will show greater reduction in pain and CRPS severity score, and improvements on other clinical and neuropsychological measures. Also, more pronounced neuropsychological symptoms are predicted to correlate with more severe clinical CRPS symptoms. This study will provide the first randomized double-blind evaluation of the therapeutic effects of PA that could be implemented as a rehabilitation method for CRPS, and will contribute to the understanding of how neuropsychological changes in body representation and attention pertain to the manifestation and treatment of CRPS. | 10.1186/s12883-020-1604-z | medrxiv |
10.1101/19000653 | Pain Reduction by Inducing Sensory-Motor Adaptation in Complex Regional Pain Syndrome (CRPS PRISMA): Protocol for a Double-blind Randomized Controlled Trial | Halicka, M.; Vitterso, A. D.; Proulx, M. J.; Bultitude, J. H. | Monika Halicka | University of Bath | 2020-01-03 | 2 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | pain medicine | https://www.medrxiv.org/content/early/2020/01/03/19000653.source.xml | BackgroundComplex Regional Pain Syndrome (CRPS) presents as chronic, continuous pain and sensory, autonomic, and motor abnormalities affecting one or more extremities. People with CRPS can also show changes in their perception of and attention to the affected body part and sensory information in the affected side of space. Prism Adaptation (PA) is a behavioural intervention targeted at reducing attention deficits in post-stroke hemispatial neglect. PA also appears to reduce pain and other CRPS symptoms; however, these therapeutic effects have been demonstrated only in small unblinded studies. This paper describes the protocol for an ongoing double-blind, randomized, sham-controlled clinical trial that will evaluate the efficacy of PA treatment for CRPS. The secondary aims of the study are to examine the relationships between neuropsychological changes (such as spatial attention, space and body representation, and motor spatial performance) and clinical manifestations of CRPS, as well as symptom improvement.
MethodsForty-two participants with upper-limb CRPS type I will undergo two weeks of twice-daily PA treatment or sham treatment. The primary outcome measures are current pain intensity and CRPS severity score, measured immediately before and after the treatment period. Secondary outcome measures include the results of self-report questionnaires about pain, movement, symptoms interference, and body representation; clinical assessments of sensory, motor, and autonomic functions; and computer-based psychophysical tests of neuropsychological functions. Data are collected in four research visits: four weeks and one day before treatment, and one day and four weeks after the end of treatment. Additional follow-up through postal questionnaires is conducted three and six months post-treatment.
DiscussionIt is hypothesised that participants undergoing PA treatment, compared to those receiving sham treatment, will show greater reduction in pain and CRPS severity score, and improvements on other clinical and neuropsychological measures. Also, more pronounced neuropsychological symptoms are predicted to correlate with more severe clinical CRPS symptoms. This study will provide the first randomized double-blind evaluation of the therapeutic effects of PA that could be implemented as a rehabilitation method for CRPS, and will contribute to the understanding of how neuropsychological changes in body representation and attention pertain to the manifestation and treatment of CRPS. | 10.1186/s12883-020-1604-z | medrxiv |
10.1101/19000562 | Limitations of machine learning in psychiatry: Participation in the PAC 2018 depression challenge | Fabian Eitel; Sebastian Stober; Lea Waller; Lena Dorfschmidt; Henrik Walter; Kerstin Ritter | Kerstin Ritter | Charite - Universitaetsmedizin Berlin | 2019-06-25 | 1 | null | cc_by_nc | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2019/06/25/19000562.source.xml | The authors have withdrawn this manuscript because the results were posted in error. The authors do not wish this work to be cited as reference for the project. Please contact the corresponding author if you have any questions. | null | medrxiv |
10.1101/19000562 | Limitations of machine learning in psychiatry: Participation in the PAC 2018 depression challenge | Eitel, F.; Stober, S.; Waller, L.; Dorfschmidt, L.; Walter, H.; Ritter, K. | Kerstin Ritter | Charite - Universitaetsmedizin Berlin | 2019-07-08 | 2 | PUBLISHAHEADOFPRINT | cc_by_nc | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2019/07/08/19000562.source.xml | The authors have withdrawn this manuscript because the results were posted in error. The authors do not wish this work to be cited as reference for the project. Please contact the corresponding author if you have any questions. | null | medrxiv |
10.1101/19000562 | Limitations of machine learning in psychiatry: Participation in the PAC 2018 depression challenge | Eitel, F.; Stober, S.; Waller, L.; Dorfschmidt, L.; Walter, H.; Ritter, K. | Kerstin Ritter | Charite - Universitaetsmedizin Berlin | 2019-08-05 | 3 | WITHDRAWN | cc_by_nc | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2019/08/05/19000562.source.xml | The authors have withdrawn this manuscript because the results were posted in error. The authors do not wish this work to be cited as reference for the project. Please contact the corresponding author if you have any questions. | null | medrxiv |
10.1101/19000166 | Gait differences in patients with multiple sclerosis who have low and high levels of disability. | John J Fraser; Jeannie Stephensen | John J Fraser | Physical Therapy Program, Department of Biology, The College of Staten Island City University of New York, Staten Island, NY | 2019-06-25 | 1 | null | cc0 | rehabilitation medicine and physical therapy | https://www.medrxiv.org/content/early/2019/06/25/19000166.source.xml | BackgroundMultiple Sclerosis (MS) often results in gait impairment and disability.
ObjectiveTo investigate differences in spatiotemporal gait characteristics of people with MS who have low versus high levels of disability. Between trial and inter-limb consistency and the association of gait variables with level of disability were also investigated.
MethodsParticipants with MS who had either low-disability [n=7; 3 females; EDSS mean: 2.7{+/-}0.5, range 2.0-4.5; BMI=26.9{+/-}6.6] or high-disability [n=11; 6 females; EDSS mean: 2.7{+/-}0.5, range 6.0-6.5; BMI=27.8{+/-}1.5) performed 2 trials of self-selected walking on an instrumented walkway. Differences in group, limb, and group by limb interactions were assessed using analysis of variance, independent-measures t-tests, and Cohens d effect sizes (ES). Between-trial consistency of gait were assessed with intra-class correlation coefficients (2, k).
ResultsParticipants in the high disability group had increased step time (ES=0.8), cycle time (ES=0.8), and ambulation time (ES=1.2) while taking shorter strides (ES=0.9) and more steps at a slower rate (ES=1.1). The high disability group demonstrated less between-trial consistency for 69% of gait variables when compared to the low disability group.
ConclusionPeople with MS who have high levels of disability walk differently and with less consistency than those with lower levels of disability. | null | medrxiv |
10.1101/19000356 | Metabolomics in juvenile-onset SLE: identifying new biomarkers to predict cardiovascular risk | George A Robinson; Leda Coelewij; Ania Radziszewska; Chris Wincup; Hannah Peckham; Kirsty Waddington; David A Isenberg; Yiannis Ioannou; Coziana Ciurtin; Ines Pineda-Torra; Elizabeth C Jury | Elizabeth C Jury | University College London | 2019-06-25 | 1 | null | cc_no | rheumatology | https://www.medrxiv.org/content/early/2019/06/25/19000356.source.xml | BACKGROUNDJuvenile-onset systemic lupus erythematosus (JSLE) is an autoimmune disorder characterised by immune dysregulation, chronic inflammation and increased cardiovascular risk (CVR). Cardiovascular disease is the leading cause of mortality in JSLE patients not attributable to disease flares. However, it is not possible to predict those patients at greatest risk using traditional CVR factors.
METHODSSerum metabolomic analysis was performed using a nuclear magnetic resonance spectroscopy-platform in 31 JSLE patients. Data was analysed using cluster, linear regression and receiver operating characteristic analysis. Results were validated in a second cohort of 31 JSLE patients and using data from a cohort of adult-onset SLE patients with known pre-clinical atherosclerotic plaque.
RESULTSUnbiased hierarchical clustering of metabolomic data identified three patient groups. Group-1 had decreased atheroprotective high density lipoproteins (HDL) and increased atherogenic very low and low density lipoproteins (VLDL/LDL); Group-2 had elevated HDL but reduced VLDL/LDL; and Group-3 had low HDL/VLDL/LDL levels. Notably, apolipoprotein(Apo)B1:ApoA1 ratio, a known CVR marker in adult cohorts, was elevated in Group-1 JSLE patients compared to Groups-2/3. The metabolomic signature was validated in a second JSLE cohort and compared with lipid biomarkers previously associated with pre-clinical atherosclerotic plaque in adult SLE patients. Linear regression analysis accounting for demographics, treatment, disease activity, lupus serological markers and body mass index confirmed that a unique metabolomic profile could differentiate between JSLE patients at high and low CVR.
CONCLUSIONSPatient stratification using ApoB:ApoA1 ratio and lipoprotein signatures could facilitate tailored lipid modification therapies and/or diet/lifestyle interventions to combat increased CVR in JSLE.
Key messagesO_LIWhat is already known about the subject?
Cardiovascular disease is the leading cause of mortality in juvenile-onset systemic lupus erythematosus (JSLE) not attributable to lupus flares; the cardiovascular risk of JSLE patients is 300 times higher than age matched healthy individuals. It is not possible to predict those patients at greatest risk using traditional risk factors.
C_LIO_LIWhat does this study add?
In depth lipoprotein-based metabolomic analysis identified Apolipoprotein(Apo)B :ApoA1 ratio as a potential biomarker for predicting increased cardiovascular risk in JSLE. This was validated in a second patient cohort and using metabolic signatures associated with pre-clinical atherosclerotic plaque development in adult SLE patients.
C_LIO_LIHow might this impact on clinical practice or future developments?
Predicting cardiovascular risk in young JSLE patients using ApoB:ApoA1 ratio could help to stratify patients and identify those who would benefit the most from existing lipid targeting therapies. Reducing cardiovascular risk at a young age could improve patients life expectancy and quality of life and reduce cardiovascular comorbidity in later life.
C_LI | 10.1016/j.ebiom.2021.103243 | medrxiv |
10.1101/19000687 | Electrocardiographic Changes After Completion of a Triathlon | Caroline Hosatte-Ducassy; Jose Correa; Francois Lalonde; Rohit Mohindra; Michael Chetrit; Gregory Marton; Audrey Marcotte; Francois Tournoux; Eileen Bridges | Caroline Hosatte-Ducassy | McGill University, Department of Emergency Medicine | 2019-06-25 | 1 | null | cc_by_nc_nd | sports medicine | https://www.medrxiv.org/content/early/2019/06/25/19000687.source.xml | ObjectivesGiven 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.
MethodsThis 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.
ResultsOf 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).
McNemars 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 athletes ECGs with acute exercise.
ConclusionLong-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 BOXO_LIThe acute effect of exercises on athletes electrocardiograms has not been well studied.
C_LIO_LIIn 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 athletes ECGs with acute exercise.
C_LIO_LICommon ECGs abnormalities found in those asymptomatic athletes were left ventricular hypertrophy, early repolarization and right bundle branch block.
C_LIO_LIPhysicians involved in the care of athletes should be prudent when interpreting ECGs in this population.
C_LI | 10.1002/tsm2.134 | medrxiv |
10.1101/19001024 | Disease overarching mechanisms that explain and predict outcome of patients with high cardiovascular risk: rationale and design of the Berlin Long-term Observation of Vascular Events (BeLOVE) study | Bob Siegerink; Joachim Weber; Michael Ahmadi; Kai-Uwe Eckardt; Frank Edelmann; Matthias Endres; Holger Gerhardt; Katrin Haubold; Norbert Hübner; Ulf Landmesser; david Leistner; Knut Mai; Dominik N. N. Müller; Burkert Pieske; Geraldine Rauch; Sein Schmidt; Kai Schmidt-Ott; Jeanette Schulz-Menger; Joachim Spranger; Tobias Pischon | Tobias Pischon | Berlin Institute of Health (BIH) & German Center for Cardiovascular Research (DZHK) & Charité Universitätsmedizin & Max-Delbrück Center for Molecular Medicine i | 2019-06-27 | 1 | null | cc_by_nc | cardiovascular medicine | https://www.medrxiv.org/content/early/2019/06/27/19001024.source.xml | BackgroundCardiovascular disease (CVD) is the leading cause of premature death worldwide. Effective and individualized treatment requires exact knowledge about both risk factors and risk estimation. Most evidence for risk prediction currently comes from population-based studies on first incident cardiovascular events. In contrast, little is known about the relevance of risk factors for the outcome of patients with established CVD or those who are at high risk of CVD, including patients with type 2 diabetes. In addition, most studies focus on individual diseases, whereas less is known about disease overarching risk factors and cross-over risk.
AimThe aim of BeLOVE is to improve short- and long-term prediction and mechanistic understanding of cardiovascular disease progression and outcomes in very high-risk patients, both in the acute as well as in the chronic phase, in order to provide the basis for improved, individualized management.
Study designBeLOVE is an observational prospective cohort study of patients of both sexes aged >18 in selected Berlin hospitals, who have a high risk of future cardiovascular events, including patients with a history of acute coronary syndrome (ACS), acute stroke (AS), acute heart failure (AHF), acute kidney injury (AKI) or type 2 diabetes with manifest target-organ damage. BeLOVE includes 2 subcohorts: The acute subcohort includes 6500 patients with ACS, AS, AHF, or AKI within 2-8 days after their qualifying event, who undergo a structured interview about medical history as well as blood sample collection. The chronic subcohort includes 6000 patients with ACS, AS, AHF, or AKI 90 days after event, and patients with type 2 diabetes (T2DM) and target-organ damage. These patients undergo a 6-8 hour deep phenotyping program, including detailed clinical phenotyping from a cardiological, neurological and metabolic perspective, questionnaires including patient-reported outcome measures (PROMs)as well as magnetic resonance imaging. Several biological samples are collected (i.e. blood, urine, saliva, stool) with blood samples collected in a fasting state, as well as after a metabolic challenge (either nutritional or cardiopulmonary exercise stress test). Ascertainment of major adverse cardiovascular events (MACE) will be performed in all patients using a combination of active and passive follow-up procedures, such as on-site visits (if applicable), telephone interviews, review of medical charts, and links to local health authorities. Additional phenotyping visits are planned at 2, 5 and 10 years after inclusion into the chronic subcohort.
Future perspectiveBeLOVE provides a unique opportunity to study both the short- and long-term disease course of patients at high cardiovascular risk through innovative and extensive deep phenotyping. Moreover, the unique study design provides opportunities for acute and post-acute inclusion and allows us to derive two non-nested yet overlapping sub-cohorts, tailored for upcoming research questions. Thereby, we aim to study disease-overarching research questions, to understand crossover risk, and to find similarities and differences between clinical phenotypes of patients at high cardiovascular risk. | null | medrxiv |
10.1101/19001024 | Disease overarching mechanisms that explain and predict outcome of patients with high cardiovascular risk: rationale and design of the Berlin Long-term Observation of Vascular Events (BeLOVE) study | Siegerink, B.; Weber, J.; Ahmadi, M.; Eckardt, K.-U.; Edelmann, F.; Endres, M.; Gerhardt, H.; Haubold, K.; Hübner, N.; Landmesser, U.; Leistner, D.; Mai, K.; Müller, D. N.; Pieske, B.; Rauch, G.; Schmidt, S.; Schmidt-Ott, K. M.; Schulz-Menger, J.; Spranger, J.; Pischon, T. | Tobias Pischon | Berlin Institute of Health (BIH) & German Center for Cardiovascular Research (DZHK) & Charité Universitätsmedizin & Max-Delbrück Center for Molecular Medicine i | 2019-07-15 | 2 | PUBLISHAHEADOFPRINT | cc_by_nc | cardiovascular medicine | https://www.medrxiv.org/content/early/2019/07/15/19001024.source.xml | BackgroundCardiovascular disease (CVD) is the leading cause of premature death worldwide. Effective and individualized treatment requires exact knowledge about both risk factors and risk estimation. Most evidence for risk prediction currently comes from population-based studies on first incident cardiovascular events. In contrast, little is known about the relevance of risk factors for the outcome of patients with established CVD or those who are at high risk of CVD, including patients with type 2 diabetes. In addition, most studies focus on individual diseases, whereas less is known about disease overarching risk factors and cross-over risk.
AimThe aim of BeLOVE is to improve short- and long-term prediction and mechanistic understanding of cardiovascular disease progression and outcomes in very high-risk patients, both in the acute as well as in the chronic phase, in order to provide the basis for improved, individualized management.
Study designBeLOVE is an observational prospective cohort study of patients of both sexes aged >18 in selected Berlin hospitals, who have a high risk of future cardiovascular events, including patients with a history of acute coronary syndrome (ACS), acute stroke (AS), acute heart failure (AHF), acute kidney injury (AKI) or type 2 diabetes with manifest target-organ damage. BeLOVE includes 2 subcohorts: The acute subcohort includes 6500 patients with ACS, AS, AHF, or AKI within 2-8 days after their qualifying event, who undergo a structured interview about medical history as well as blood sample collection. The chronic subcohort includes 6000 patients with ACS, AS, AHF, or AKI 90 days after event, and patients with type 2 diabetes (T2DM) and target-organ damage. These patients undergo a 6-8 hour deep phenotyping program, including detailed clinical phenotyping from a cardiological, neurological and metabolic perspective, questionnaires including patient-reported outcome measures (PROMs)as well as magnetic resonance imaging. Several biological samples are collected (i.e. blood, urine, saliva, stool) with blood samples collected in a fasting state, as well as after a metabolic challenge (either nutritional or cardiopulmonary exercise stress test). Ascertainment of major adverse cardiovascular events (MACE) will be performed in all patients using a combination of active and passive follow-up procedures, such as on-site visits (if applicable), telephone interviews, review of medical charts, and links to local health authorities. Additional phenotyping visits are planned at 2, 5 and 10 years after inclusion into the chronic subcohort.
Future perspectiveBeLOVE provides a unique opportunity to study both the short- and long-term disease course of patients at high cardiovascular risk through innovative and extensive deep phenotyping. Moreover, the unique study design provides opportunities for acute and post-acute inclusion and allows us to derive two non-nested yet overlapping sub-cohorts, tailored for upcoming research questions. Thereby, we aim to study disease-overarching research questions, to understand crossover risk, and to find similarities and differences between clinical phenotypes of patients at high cardiovascular risk. | null | medrxiv |
10.1101/19000786 | Nutritional Supplementation during Pulmonary Rehabilitation in COPD: A Systematic Review | Abdulelah Aldhahir; John Hurst; Swapna Mandal; Ahmed Alrajeh; Yousef Aldabayan; Jaber Alqahtani; Salifu Drammeh; Vanitha Subbu | Abdulelah Aldhahir | University College London | 2019-06-28 | 1 | null | cc_by_nc_nd | nutrition | https://www.medrxiv.org/content/early/2019/06/28/19000786.source.xml | BackgroundUptake of nutritional supplementation during pulmonary rehabilitation (PR) for people with chronic obstructive pulmonary disease (COPD) has been limited by an absence of rigorous evidence-based studies supporting use. Our objective were to report and summarise the current evidence supporting use of nutritional supplementation to improve outcomes during pulmonary rehabilitation in stable COPD patients.
MethodsA systematic search was conducted up to May 7th, 2019 (registration number CRD42018089142). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used. Six databases were included: Medical Literature Analysis and Retrieval System Online or MEDLARS Online (Medline), Allied and Complementary Medicine Database (AMED), the Cochrane Database of Systematic Reviews, Excerpta Medica dataBASE (Embase), Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Web of Science.
ResultsThis systematic search generated 580 initial matches, of which 24 studies (1035 COPD participants) met the pre-specified criteria and were included. Our analysis does not confirm an impact of nutritional supplementation during PR, but studies, supplements and PR programmes were heterogeneous in nature.
ConclusionThere is currently insufficient evidence on the effect of nutritional supplementation on improving outcomes during PR in patients with COPD. Therefore, controversy remains and further research is needed. | 10.1177/1479973120904953 | medrxiv |
10.1101/19000661 | Comparative analysis of functional assay evidence use by ClinGen Variant Curation Expert Panels | Dona M. Kanavy; Shannon M. McNulty; Meera K. Jairath; Sarah E. Brnich; Chris Bizon; Bradford C. Powell; Jonathan S. Berg | Jonathan S. Berg | University of North Carolina at Chapel Hill | 2019-06-28 | 1 | null | cc_by_nc_nd | genetic and genomic medicine | https://www.medrxiv.org/content/early/2019/06/28/19000661.source.xml | BackgroundThe 2015 American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines for clinical sequence variant interpretation state that "well-established" 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.
MethodsWe 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.
ResultsUnsurprisingly, 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.
ConclusionsInterpretation 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. | 10.1186/s13073-019-0683-1 | medrxiv |
10.1101/19000521 | Association of puberty timing with Type 2 diabetes: Systematic review and meta-analysis | Tuck Seng Cheng; Felix R. Day; Rajalakshmi Lakshman; Ken K. Ong | Tuck Seng Cheng | University of Cambridge | 2019-06-28 | 1 | null | cc_by_nc_nd | epidemiology | https://www.medrxiv.org/content/early/2019/06/28/19000521.source.xml | OBJECTIVEWe aimed to systematically review published evidence on the association between puberty timing and Type 2 diabetes or impaired glucose tolerance (T2D/IGT), with and without adjustment for adiposity, and to estimate its potential contribution to the burden of T2D.
RESEARCH DESIGN AND METHODSWe searched PubMed, Medline and Embase databases for publications until February 2019 on the timing of any secondary sexual characteristic in boys or girls in relation to T2D/IGT. Inverse-weighted random-effects meta-analysis was used to pool reported estimates and meta-regression to explore sources of heterogeneity.
RESULTSTwenty eight observational studies were identified. All assessed age at menarche (AAM) in women (combined N=1,228,306); only one study additionally included men. In models without adjustment for adult adiposity, T2D/IGT risk was higher per year earlier AAM (relative risk (RR)=0.91, 95% confidence interval (CI)=0.89-0.93, 11 estimates, n=833,529, I2=85.4%) and for early versus later menarche (RR=1.41, 95% CI=1.28-1.55, 23 estimates, n=1,185,444, I2=87.8%). Associations were weaker but still evident in models adjusted for adiposity (AAM: RR=0.97 per year, 95% CI=0.95-0.98, 12 estimates, n=852,268, I2=51.8%; early menarche: RR=1.19, 95% CI=1.11-1.28, 21 estimates, n=890,583, I2=68.1%). Associations were stronger among Caucasians than Asians, and in populations with earlier average AAM. The estimated population attributable risk of T2D in UK Caucasians due to early menarche, unadjusted and adjusted for adiposity, was 12.6% (95% CI=11.0-14.3) and 5.1% (95% CI=3.6-6.7), respectively.
CONCLUSIONSA substantial proportion of T2D in women is attributable to early menarche timing. This will increase in light of global secular trends towards earlier puberty timing. | 10.1371/journal.pmed.1003017 | medrxiv |
10.1101/19001123 | Epigenetic prediction of major depressive disorder | Miruna C Barbu; Rosie M Walker; David M Howard; Kathryn L Evans; Heather C Whalley; David J Porteous; Stewart W Morris; Ian J Deary; Riccardo E Marioni; Toni-Kim Clarke; Andrew M McIntosh | Andrew M McIntosh | University of Edinburgh | 2019-06-28 | 1 | null | cc_by | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2019/06/28/19001123.source.xml | ObjectiveDNA methylation (DNAm) is associated with environmental risk factors for major depressive disorder (MDD) but has not yet been tested for its ability to discriminate individuals with MDD from unaffected individuals.
MethodsUsing penalized regression based on genome-wide CpG methylation, we trained a DNAm risk score of MDD (DNAm-RS) in 1,223 cases and 1,824 controls and tested in a second independent sample of 363 prevalent cases and 1,417 controls. Using DNA from 1,607 unaffected individuals, we tested whether DNAm-RS could discriminate the 190 incident cases of lifetime MDD from the 1,417 individuals who remained unaffected at follow-up.
ResultsA weighted linear combination of 196 CpG sites were derived from the training sample to form a DNAm-RS. The DNAm-RS explained 1.75% of the variance in MDD risk in an independent case-control sample and significantly predicted future incident episodes of MDD at follow up (R2=0.52%). DNAm-RS and MDD polygenic risk scores together additively explained 3.99% of the variance in prevalent MDD. The DNAm-RS was also significantly associated with lifestyle factors associated with MDD, including smoking status ({beta}=0.440, p=<2x10-16) and alcohol use ({beta}=0.092, p=9.85x10-5). The DNAm-RS remained significantly associated with MDD after adjustment for these environmental factors (independent association: {beta}=0.338, p=1.17x10-7 association post-adjustment: {beta}=0.081, p=0.0006).
ConclusionsA novel risk score of MDD based on DNAm data significantly discriminated MDD cases from controls in an independent dataset, and controls who would subsequently develop MDD from those who remained unaffected. DNAm-RS captured the effects of exposure to key lifestyle risk factors for MDD, revealing a potential role in risk stratification. | 10.1038/s41380-020-0808-3 | medrxiv |
10.1101/19001115 | Forecasting the impact of population ageing on tuberculosis incidence | Chu-Chang Ku; Peter J Dodd | Chu-Chang Ku | School of Health and Related Research, University of Sheffield | 2019-06-28 | 1 | null | cc_by | epidemiology | https://www.medrxiv.org/content/early/2019/06/28/19001115.source.xml | BackgroundTuberculosis (TB) disease reactivates from distant latent infection or recent (re)infection. Progression risks increase with age. Across the World Health Organisation Western Pacific region, many populations are ageing and have the highest per capita TB incidence rates in older age groups. However, methods for analysing age-specific TB incidence and forecasting epidemic trends while accounting for demographic change remain limited.
MethodsWe applied the Lee-Carter models, which were originally developed for mortality modelling, to model the temporal trends in age-specific TB incidence data from 2005 to 2018 in Taiwan. Females and males were modelled separately. We combined our demographic forecasts, and age-specific TB incidence forecasts to project TB incidence until 2035. We compared TB incidence projections with demography fixed in 2018 to projections accounting for demographic change.
ResultsOur models quantified increasing incidence rates with age and declining temporal trends. By 2035, the forecast suggests that the TB incidence rate in Taiwan will decrease by 54% (95% Prediction Interval (PI): 45%-59%) compared to 2015, while most age-specific incidence rates will reduce by more than 60%. In 2035, adults aged 65 and above will make up 78% of incident TB cases. Forecast TB incidence in 2035 accounting for demographic change will be 39% (95% PI: 36%-42%) higher than without population ageing.
ConclusionsAge-specific incidence forecasts coupled with demographic forecasts can inform the impact of population ageing on TB epidemics. The TB control programme in Taiwan should develop plans specific to older age groups and their care needs. | 10.1371/journal.pone.0222937 | medrxiv |
10.1101/19001008 | Current characteristics and outcomes of Cytomegalovirus Reactivation in kidney transplant seropositive recipients in the era of prophylaxis treatment. Lesson from single Moroccan center experience. | REZZOUK, B.; Bouattar, T.; Belkadi, B.; Razine, R.; Bayahia, R.; Ouzeddoun, N.; Benamar, L.; Rhou, H.; Bouihat, N.; Ibrahimi, A.; Seffar, M.; Kabbaj, H. | Bouchra REZZOUK | Laboratory of Microbiology and Molecular Biology, Faculty of Science, University Mohammed V, Rabat, Morocco. | 2019-06-28 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | infectious diseases | https://www.medrxiv.org/content/early/2019/06/28/19001008.source.xml | Despite the use of antiviral prophylaxis, the active cytomegalovirus (CMV) replication is still occurred in the seropositive kidney recipients. The aim of this study was to assess the incidence of CMV reactivation and potential risk factors associated with CMV disease. Data of sixty kidney transplant recipients who had received CMV prophylaxis were obtained between 2013 and 2017. Quantitative nucleic acid amplification testing for CMV viraemia was assessed using Abbott RealTime Polymerase Chain Reaction (PCR). Among the seropositive recipients, cumulative incidence for reactivation was 63%. In patients with quantitative viraemia, the time of active replication was significantly lower compared to those with detectable viraemia (141.5 {+/-} 96.9 vs 294.1 {+/-} 112.6 days, P < 0.001). During prophylactic treatment, 46.7% of patients with quantifiable viraemia had experienced active replication and none among patients with detectable viraemia (P= 0.017). Importantly, symptomatic reactivation was significantly observed in the younger patients with higher peak viraemia compared to those with symptoms free (28.8 {+/-} 5.12 vs. 38.1 {+/-} 12.34 years, P= 0.007) and 3.8 {+/-} 1.59 vs. 2.4 {+/-} 0. 79 log10IU/ml, P = 0.003, respectively). Furthermore, the median duration of viraemia (21.2, vs. 13.4 days, P= 0.028) and period of CMV therapy (24.3 vs 12.3 days, P <0.001) were significantly longer for this group. In addition, intercurrent infections (75% vs. 23%, P = 0.028) and acute rejection (50 % vs 0%, P = 0.003) were significantly more frequent in symptomatic reactivation group. In addition, peak viral load was a potential risk factor for development of symptomatic reactivation with odds ratio 3.39, 95%CI=1.21-9.53, P = 0.02). In conclusion, CMV reactivation remains serious problem for seropositive recipients who were expected to be on antiviral prophylaxis. Patients with high level of viraemia may be at an increased risk of progression to CMV disease and adverse outcomes. | 10.2147/trrm.s278655 | medrxiv |
10.1101/19001016 | Medication errors during simulated paediatric resuscitations: a prospective, observational human reliability analysis | Appelbaum, N.; Clarke, J.; Feather, C.; Franklin, B.; Sinha, R.; Pratt, P.; Maconochie, I.; Darzi, A. | Calandra Feather | NIHR-Imperial Patient Safety Translational Research Centre, Imperial College London | 2019-06-28 | 1 | PUBLISHAHEADOFPRINT | cc_by | pediatrics | https://www.medrxiv.org/content/early/2019/06/28/19001016.source.xml | IntroductionMedication errors during paediatric resuscitation are thought to be common. However, there is little evidence about the individual process steps that contribute to such medication errors in this context.
ObjectivesTo describe the incidence, nature and severity of medication errors in simulated paediatric resuscitations, and to employ human reliability analysis to understand the contributory role of individual process step discrepancies to these errors.
MethodsWe conducted a prospective observational study of simulated resuscitations subject to video micro-analysis, identification of medication errors, severity assessment and human reliability analysis in a large English teaching hospital. Fifteen resuscitation teams of two doctors and two nurses each conducted one of two simulated paediatric resuscitation scenarios.
ResultsAt least one medication error was observed in every simulated case, and a large magnitude or clinically significant error in 11 of 15 cases. Medication errors were observed in 29% of 180 simulated medication administrations, 40% of which considered to be moderate or severe. These errors were the result of 884 observed discrepancies at a number of steps in the drug ordering, preparation and administration stages of medication use, 8% of which made a major contribution to a resultant medication error. Most errors were introduced by discrepancies during drug preparation and administration.
ConclusionsMedication errors were common with a considerable proportion likely to result in patient harm. There is an urgent need to optimise existing systems and to commission research into new approaches to increase the reliability of human interactions during administration of medication in the paediatric emergency setting.
Strengths and limitations of this studyO_LIThis study is one of the first to use HRA methods to link task discrepancies with resultant medication errors, as well as to link these discrepancies directly to potential harm. This effort has demonstrated that a significant fraction of the burden of error in the paediatric emergency drug administration process originates during the preparation and administration phase and that most of these errors are likely to be undetected in clinical practice.
C_LIO_LIThis study was subject to a number of limitations. Although we went to considerable lengths to replicate the paediatric emergency environment, the simulation environment cannot truly reflect the clinical environment during a genuine emergency.
C_LIO_LIFurthermore, this study was conducted at a single site and participants were not blinded to the purpose of the study, so it is potentially subject to preparation bias.
C_LIO_LIParticipants were recruited from the paediatric emergency unit, intensive care unit and general paediatrics ward and had variable experience of emergency cases. However, all participants worked in clinical units that manage critically ill children.
C_LI | 10.1136/bmjopen-2019-032686 | medrxiv |
10.1101/19001016 | Medication errors during simulated paediatric resuscitations: a prospective, observational human reliability analysis | Appelbaum, N.; Clarke, J.; Feather, C.; Dean Franklin, B.; Sinha, R.; Pratt, P.; Maconochie, I.; Darzi, A. | Calandra Feather | NIHR-Imperial Patient Safety Translational Research Centre, Imperial College London | 2019-08-02 | 2 | PUBLISHAHEADOFPRINT | cc_by | pediatrics | https://www.medrxiv.org/content/early/2019/08/02/19001016.source.xml | IntroductionMedication errors during paediatric resuscitation are thought to be common. However, there is little evidence about the individual process steps that contribute to such medication errors in this context.
ObjectivesTo describe the incidence, nature and severity of medication errors in simulated paediatric resuscitations, and to employ human reliability analysis to understand the contributory role of individual process step discrepancies to these errors.
MethodsWe conducted a prospective observational study of simulated resuscitations subject to video micro-analysis, identification of medication errors, severity assessment and human reliability analysis in a large English teaching hospital. Fifteen resuscitation teams of two doctors and two nurses each conducted one of two simulated paediatric resuscitation scenarios.
ResultsAt least one medication error was observed in every simulated case, and a large magnitude or clinically significant error in 11 of 15 cases. Medication errors were observed in 29% of 180 simulated medication administrations, 40% of which considered to be moderate or severe. These errors were the result of 884 observed discrepancies at a number of steps in the drug ordering, preparation and administration stages of medication use, 8% of which made a major contribution to a resultant medication error. Most errors were introduced by discrepancies during drug preparation and administration.
ConclusionsMedication errors were common with a considerable proportion likely to result in patient harm. There is an urgent need to optimise existing systems and to commission research into new approaches to increase the reliability of human interactions during administration of medication in the paediatric emergency setting.
Strengths and limitations of this studyO_LIThis study is one of the first to use HRA methods to link task discrepancies with resultant medication errors, as well as to link these discrepancies directly to potential harm. This effort has demonstrated that a significant fraction of the burden of error in the paediatric emergency drug administration process originates during the preparation and administration phase and that most of these errors are likely to be undetected in clinical practice.
C_LIO_LIThis study was subject to a number of limitations. Although we went to considerable lengths to replicate the paediatric emergency environment, the simulation environment cannot truly reflect the clinical environment during a genuine emergency.
C_LIO_LIFurthermore, this study was conducted at a single site and participants were not blinded to the purpose of the study, so it is potentially subject to preparation bias.
C_LIO_LIParticipants were recruited from the paediatric emergency unit, intensive care unit and general paediatrics ward and had variable experience of emergency cases. However, all participants worked in clinical units that manage critically ill children.
C_LI | 10.1136/bmjopen-2019-032686 | medrxiv |
10.1101/19000422 | The nature of clusters of multimorbid patients in the UK: a latent class analysis. | Zhu, Y.; Edwards, D.; Payne, R. A.; Kiddle, S. | Yajing Zhu | MRC Biostatistics Unit, University of Cambridge | 2019-06-28 | 1 | PUBLISHAHEADOFPRINT | cc_by | epidemiology | https://www.medrxiv.org/content/early/2019/06/28/19000422.source.xml | BackgroundMultimorbidity 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.
MethodsLinked 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).
FindingsWe 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.
InterpretationThis 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+.
FundingUK Medical Research Council
Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed using the keyword list "multimorbidity, co-morbidity, disease patterns, clusters, service use, long-term conditions, chronic conditions" 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 studyThis 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 evidenceWe 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. | 10.1016/S0140-6736(19)32899-5 | medrxiv |
10.1101/19000422 | Characteristics, service use and mortality of clusters of multimorbid patients in England: a population-based study | Zhu, Y.; Edwards, D.; Mant, J.; Payne, R. A.; Kiddle, S. | Yajing Zhu | MRC Biostatistics Unit, University of Cambridge | 2019-12-02 | 2 | PUBLISHAHEADOFPRINT | cc_by | epidemiology | https://www.medrxiv.org/content/early/2019/12/02/19000422.source.xml | BackgroundMultimorbidity 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.
MethodsLinked 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).
FindingsWe 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.
InterpretationThis 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+.
FundingUK Medical Research Council
Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed using the keyword list "multimorbidity, co-morbidity, disease patterns, clusters, service use, long-term conditions, chronic conditions" 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 studyThis 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 evidenceWe 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. | 10.1016/S0140-6736(19)32899-5 | medrxiv |
10.1101/19000646 | Big Five Personality Traits Influence Tinnitus Improvement Over Time | Simoes, J. P.; Schlee, W.; Schecklmann, M.; Langguth, B.; Farahmand, D.; Neff, P. | Jorge Piano Simoes | University of Regensburg | 2019-06-28 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2019/06/28/19000646.source.xml | Previous studies investigating the relation between personality and tinnitus distress showed that high neuroticism and low extraversion scores are related to higher tinnitus distress measured by the Tinnitus Handicap Inventory (THI) and the Tinnitus Questionnaire (TQ). However, little is known about the role of personality on tinnitus distress over time.
We collected the THI, TQ and Big Five Factor Index 2 of 388 patients who visited the Tinnitus Center Regensburg between 2012 and 2017, and filled in a survey with the same questionnaires in 2018. We used personality traits and facets to predict tinnitus distress cross-sectionally and longitudinally. Neuroticism and extraversion were significant predictors of THI and TQ scores in cross-sectional linear regression setups, and could explain up to 40% of the variance. However, the linear regressions could explain only little variance of both THI and TQ longitudinally. We clustered patients in three groups based in the difference THI and TQ between the two assessments: "clinically improved", "clinically stable" and "clinically worsened". The patients in the "clinically improved" and "clinically stable" groups scored statistically significantly lower in neuroticism and higher in extraversion than patients in the group "clinically worsened". We observed a similar trend among patients who tried at least one clinical treatment.
Our results suggest that personality traits, namely neuroticism and extraversion, are relevant markers of tinnitus distress over time and could be used to statistically distinguish patient groups with clinically relevant changes of tinnitus distress. These markers could inform both treatment responses from clinical studies and future choices on more efficient individual tinnitus treatments. | 10.1038/s41598-019-53845-4 | medrxiv |
10.1101/19000190 | Cost-Sensitive Machine Learning Classification for Mass Tuberculosis Screening | Septiandri, A. A.; Aditiawarman, A.; Tjiong, R.; Burhan, E.; Shankar, A. H. | Ali Akbar Septiandri | Inovasi Sehat Indonesia | 2019-06-28 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | health informatics | https://www.medrxiv.org/content/early/2019/06/28/19000190.source.xml | Active screening for Tuberculosis (TB) is needed to optimize detection and treatment. However, current algorithms for verbal screening perform poorly, causing misclassification that leads to missed cases and unnecessary and costly laboratory tests for false positives. We investigated the role of machine learning to improve the predefined one-size-fits-all algorithm used for scoring the verbal screening questionnaire. We present a cost-sensitive machine learning classification for mass tuberculosis screening. We compared score-based classification defined by clinicians to machine learning classification such as SVM-RBF, logistic regression, and XGBoost. We restricted our analyses to data from adults, the population most affected by TB, and investigated the difference between untuned and unweighted classifiers to the cost-sensitive ones. Predictions were compared with the corresponding GeneXpert MTB/Rif results. After adjusting the weight of the positive class to 40 for XGBoost, we achieved 96.64% sensitivity and 35.06% specificity. As such, sensitivity of our identifier increased by 1.26% while specificity increased by 13.19% in absolute value compared to the traditional score-based method defined by our clinicians. Our approach further demonstrated that only 2000 data points were sufficient to enable the model to converge. Our results indicate that even with limited data we can actually devise a better method to identify TB suspects from verbal screening. This approach may be a stepping stone towards more effective TB case identification, especially in primary health centres, and foster better detection and control of TB. | null | medrxiv |
10.1101/19000554 | Integrating Online Georeferenced Epidemiological Analysis and Visualization into a Telemedicine Infrastructure - First Results | von Wangenheim, A.; Savaris, A.; Borgatto, A. F.; Inacio, A. D. S. | Aldo von Wangenheim | Federal University of Santa Catarina - UFSC | 2019-06-28 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | health informatics | https://www.medrxiv.org/content/early/2019/06/28/19000554.source.xml | With the objective to perform a first evaluation of the impact of the integration of a graphic spatial epidemiology tool that allows quasi-realtime georeferenced data visualization into a telemedicine infrastructure, this work presents GISTelemed, an online module specialized on indexing structured and semi-structured data, as well as querying the indexed content using structured and free-text search.
We evaluated GISTelemed accordingly to the guidelines published by the US Centers for Disease Control and Prevention and input provided by a questionnaire customized according to AdEQUATE (questionnAire for Evaluation of QUAlity in TElemedicine systems).
39 healthcare professionals from 13 municipalities participated in the evaluation. We analyzed data from questionnaires using descriptive statistics, being Lernability and Comfort the characteristics that received the best evaluation. Quantitative evaluation based upon leprosis cases detected through tele-dermatology showed a sensitivity and PPV of respectively 77.2% and 95.3%. 22.8% of the cases detected were un-notified cases.
Results from our case study show a good evaluation regarding the perceived software quality". We conclude that the integration of spatial epidemiology tools to the STT/SC system, besides enabling visualization of data in maps, allowed users to analyze the evolution of morbidities and their co-occurrences. | null | medrxiv |
10.1101/19000570 | Maternal Mortality and Women's Political Participation | Bhalotra, S. R.; Clarke, D.; Gomes, J.; Venkataramani, A. S. | Atheendar S Venkataramani | University of Pennsylvania | 2019-06-28 | 1 | PUBLISHAHEADOFPRINT | cc_no | health policy | https://www.medrxiv.org/content/early/2019/06/28/19000570.source.xml | We show that large declines in maternal mortality can be achieved by raising womens political participation. We estimate that the recent wave of quotas for women in parliament in low income countries has resulted in a 9 to 12% decline in maternal mortality. Among mechanisms are that gender quotas lead to an 8 to 10% increase in skilled birth attendance, a 6 to 12% increase in prenatal care utilization and a 4 to 11% decrease in birth rates.
JEL codesI14, I15, O15. | null | medrxiv |
10.1101/19000844 | An acute bleomycin inflammatory and fibrotic mouse model of morphea is dependent upon CXCL9 and CXCR3 | Richmond, J. M.; Patel, D.; Watanabe, T.; Garelli, C.; Garg, M.; Dresser, K.; Deng, A.; Feghali-Bostwick, C. A.; Harris, J. E.; Jacobe, H. T. | Heidi T Jacobe | University of Texas Southwestern Medical Center | 2019-06-28 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | dermatology | https://www.medrxiv.org/content/early/2019/06/28/19000844.source.xml | Morphea, or localized scleroderma, is characterized by an inflammatory phase followed by cutaneous fibrosis, which may lead to disfigurement and/or disability. Previous work from our group showed that the CXCR3 ligands CXCL9 and CXCL10 are highly upregulated in lesional skin of morphea patients. Here, we used an acute inflammatory and fibrotic bleomycin mouse model of morphea to examine the role of the CXCR3 chemokine axis in pathogenesis. We first characterized which cells produce the CXCR3 ligands in the skin using the Reporter of Expression of CXCR3 ligands mouse (REX3). We found that fibroblasts contribute the bulk of CXCL9 and CXCL10, whereas endothelial cells are key dual chemokine producers. Macrophages, which have high MFI of chemokine expression, upregulated CXCL9 production over time, fibroblasts CXCL10 production, and T cells dual chemokine expression. To determine whether bleomycin treatment could directly induce expression of these chemokines, we treated cultured REX3 mouse dermis monolayers in vitro with bleomycin or IFN{gamma} with TNF and found that bleomycin could induce low amounts of CXCL9 directly in fibroblasts, whereas the cytokines were required for optimal CXCL9 and CXCL10 production. To determine whether these chemokines are mechanistically involved in pathogenesis, we induced fibrosis in CXCL9, CXCL10, or CXCR3 deficient mice and found that fibrosis is dependent on CXCL9 and CXCR3. Addition of recombinant CXCL9, but not CXCL10, to cultured mouse fibroblasts induces collagen 1a1 mRNA expression, indicating the chemokine itself can contribute to fibrosis. Taken together, our studies provide evidence that acute intradermal bleomycin administration in mice can model inflammatory morphea, and that CXCL9 and its receptor CXCR3 are mechanistically involved in pathogenesis.
One Sentence SummaryCXCL9 drives acute morphea pathogenesis in mice. | 10.1016/j.jid.2022.11.025 | medrxiv |
10.1101/19000851 | SEXUAL BEHAVIOURS AND EXPERIENCE OF SEXUAL COERCION AMONG IN-SCHOOL FEMALE ADOLESCENT IN SOUTHWESTERN NIGERIA | Owolodun, B. S.; Sanusi, R. A. | Babatunde Samuel Owolodun | University of Ibadan | 2019-07-03 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | public and global health | https://www.medrxiv.org/content/early/2019/07/03/19000851.source.xml | Most people begin their sexual relationship during adolescence and some get involved in risky life threatening behaviors such as unwanted pregnancies, abortions and sexually transmitted infections. This study was therefore designed to understand the patterns of female adolescents sexual behaviours and sexual coercion experience.
A descriptive cross-sectional study was carried out among 1227 in-school adolescents in the three senatorial district of Osun State, Southwestern Nigeria. Multi-stage sampling technique was used to select the respondents, and data were collected with pre-tested, semi-structured questionnaires. The data collected were analysed using Statistical Package for Social Sciences (SPSS version 21).
Three hundred and thirty seven (27.5%) were sexually exposed with a mean age of sexual initiation of 14.88{+/-}2. 46 years. Of the 337 that were sexually exposed 153(56.5%) initiated sex early between the ages of 10-15 years, while (4.7%) had uses drugs or take alcohol before sexual intercourse. Findings revealed that of those that were sexually exposed, 122(11%) were forced to have sex, 101(9.1%) played sex willingly, while 29(2.6%) felt threatened and 3(0.3%) were convinced with money. The proportion of the respondent who reported rape and abduction was (2.6%).
Finding from this study is consistent with earlier studies conducted in many other Nigerian cities which showed that in-school adolescents to be sexually active. There is the need to step up campaigns to address this noticed lapse in behavior among the students in order to arrest the usual consequences of such risky sexual behavior. | null | medrxiv |
10.1101/19000711 | Robotic middle ear access for cochlear implantation: first in man | Caversaccio, M.; Wimmer, W.; Anso, J.; Mantokoudis, G.; Gerber, N.; Rathgeb, C.; Schneider, D.; Hermann, J.; Wagner, F.; Scheidegger, O.; Huth, M.; Anschuetz, L.; Kompis, M.; Williamson, T.; Bell, B.; Gavaghan, K.; Weber, S. | Wilhelm Wimmer | Department of Otorhinolaryngology, Head and Neck Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland | 2019-07-03 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | otolaryngology | https://www.medrxiv.org/content/early/2019/07/03/19000711.source.xml | To demonstrate the feasibility of robotic middle ear access in a clinical setting, nine adult patients with severe-to-profound hearing loss indicated for cochlear implantation were included in this clinical trial. A keyhole access tunnel to the tympanic cavity and targeting the round window was planned based on preoperatively acquired computed tomography image data and robotically drilled to the level of the facial recess. Intraoperative imaging was performed to confirm sufficient distance of the drilling trajectory to relevant anatomy. Robotic drilling continued toward the round window. The cochlear access was manually created by the surgeon. Electrode arrays were inserted through the keyhole tunnel under microscopic supervision via a tympanomeatal flap. All patients were successfully implanted with a cochlear implant. In 9 of 9 patients the robotic drilling was planned and performed to the level of the facial recess. In 3 patients, the procedure was reverted to a conventional approach for safety reasons. No change in facial nerve function compared to baseline measurements was observed. Robotic keyhole access for cochlear implantation is feasible. Further improvements to workflow complexity, duration of surgery, and usability including safety assessments are required to enable wider adoption of the procedure. | 10.1371/journal.pone.0220543 | medrxiv |
10.1101/19000307 | Framework for rational donor selection in fecal microbiota transplant clinical trials | Duvallet, C.; Zellmer, C.; Panchal, P.; Budree, S.; Osman, M.; Alm, E. | Eric Alm | Massachusetts Institute of Technology | 2019-07-03 | 1 | PUBLISHAHEADOFPRINT | cc_by | gastroenterology | https://www.medrxiv.org/content/early/2019/07/03/19000307.source.xml | Early clinical successes are driving enthusiasm for fecal microbiota transplantation (FMT), the transfer of healthy gut bacteria through whole stool, as emerging research is linking the microbiome to many different diseases. However, preliminary trials have yielded mixed results and suggest that heterogeneity in donor stool may play a role in patient response. Thus, clinical trials may fail because an ineffective donor was chosen rather than because FMT is not appropriate for the indication. Here, we describe a conceptual framework to guide rational donor selection to increase the likelihood that FMT clinical trials will succeed. We argue that the mechanism by which the microbiome is hypothesized to be associated with a given indication should inform how healthy donors are selected for FMT trials, categorizing these mechanisms into four disease models and presenting associated donor selection strategies. We next walk through examples based on previously published FMT trials and ongoing investigations to illustrate how donor selection might occur in practice. Finally, we show that typical FMT trials are not powered to discover individual taxa mediating patient responses, suggesting that clinicians should develop targeted hypotheses for retrospective analyses and design their clinical trials accordingly. Moving forward, developing and applying novel clinical trial design methodologies like rational donor selection will be necessary to ensure that FMT successfully translates into clinical impact. | 10.1371/journal.pone.0222881 | medrxiv |
10.1101/19000307 | Framework for rational donor selection in fecal microbiota transplant clinical trials | Duvallet, C.; Zellmer, C.; Panchal, P.; Budree, S.; Osman, M.; Alm, E. | Eric Alm | Massachusetts Institute of Technology | 2019-09-26 | 2 | PUBLISHAHEADOFPRINT | cc_by | gastroenterology | https://www.medrxiv.org/content/early/2019/09/26/19000307.source.xml | Early clinical successes are driving enthusiasm for fecal microbiota transplantation (FMT), the transfer of healthy gut bacteria through whole stool, as emerging research is linking the microbiome to many different diseases. However, preliminary trials have yielded mixed results and suggest that heterogeneity in donor stool may play a role in patient response. Thus, clinical trials may fail because an ineffective donor was chosen rather than because FMT is not appropriate for the indication. Here, we describe a conceptual framework to guide rational donor selection to increase the likelihood that FMT clinical trials will succeed. We argue that the mechanism by which the microbiome is hypothesized to be associated with a given indication should inform how healthy donors are selected for FMT trials, categorizing these mechanisms into four disease models and presenting associated donor selection strategies. We next walk through examples based on previously published FMT trials and ongoing investigations to illustrate how donor selection might occur in practice. Finally, we show that typical FMT trials are not powered to discover individual taxa mediating patient responses, suggesting that clinicians should develop targeted hypotheses for retrospective analyses and design their clinical trials accordingly. Moving forward, developing and applying novel clinical trial design methodologies like rational donor selection will be necessary to ensure that FMT successfully translates into clinical impact. | 10.1371/journal.pone.0222881 | medrxiv |
10.1101/19000414 | The effectiveness of digital technology interventions to reduce loneliness in adult people: A protocol for a systematic review and meta-analysis | Shah, S. G. S.; Nogueras, D.; van Woerden, H. C.; Kiparoglou, V. | Syed Ghulam Sarwar Shah | NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK | 2019-07-03 | 1 | PUBLISHAHEADOFPRINT | cc_by | public and global health | https://www.medrxiv.org/content/early/2019/07/03/19000414.source.xml | IntroductionLoneliness is an emerging public health problem, which is associated with social, emotional, mental and physical health issues. The application of digital technology (DT) interventions to reduce loneliness has increased in recent years. The effectiveness of DT interventions needs to be assessed systematically.
Methods and analysisO_ST_ABSAimC_ST_ABSTo undertake a systematic review and meta-analysis on the effectiveness of digital technology interventions to reduce loneliness among adult people.
Designsystematic review and meta-analysis.
Data sourcesFive leading online bibliographic databases: PubMed, Medline, CINAHL, EMBASE, and Web of Science.
Publication period1 January 2010 to 30 April 2019.
Inclusion criteriaPrimary studies involving the application of digital technology interventions to reduce loneliness, involving adult participants (aged 18 years and more) and published in the English language.
Search strategyLiterature searches using a priory list of keywords, involvement of two independent researchers in article screening, short listing and data extraction using a predefined template based on the population, intervention(s), comparator(s) and outcome(s) (PICO) framework.
Synthesis and meta-analysisA narrative summary of the characteristics of included studies, findings by the type of DT intervention, and the age, gender and ethnicity of participants. A meta-analysis by the type of DT intervention and determination of effect sizes.
Quality of evidence and biasQuality of evidence assessed the RoB 2.0 (revised tool for Risk of Bias in randomized trials) and ROBINS-I (Risk Of Bias in Non-randomized Studies - of Interventions) tools for randomized control trials and non-randomized studies respectively. Heterogeneity between studies determined by the I2 and Cochrans Q statistics and publication bias checked with funnel plots and the Eggers test.
Patients and public involvementNone
Ethics and disseminationEthics approval was not required for writing this protocol. The findings will be disseminated through the publication of research articles and conference presentations.
PROSPERO Registration NumberCRD42019131524.
Article SummaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIThe main strength of this study includes a systematic assessment of evidence on the effectiveness of digital technology interventions to reduce loneliness, which is imperative from the health and social care and public health perspectives.
C_LIO_LIAnother strength of the study is the involvement of two independent researchers (and a third researcher as an arbitrator) involved in the identification, screening, inclusion and extraction of on a predefined template using the PICO framework.
C_LIO_LILimitations may include missing identification of additional relevant studies due to the application of selection filters such as the publication years and English as the publication language.
C_LI | 10.1136/bmjopen-2019-032455 | medrxiv |
10.1101/19000281 | LncRNA and predictive model for improving the diagnosis of clinically diagnosed pulmonary tuberculosis | Hu, X.; Zhang, J.; Liao, S.; Bai, H.; Gupta, S.; Zhou, Y.; Zhou, J.; Wu, Q.; Meng, Z.; Jiao, L.; Wu, L.; Wang, M.; Chen, X.; Zhou, Y.; Lu, X.; Zhang, Z.; Ying, B. | Binwu Ying | Department of Laboratory Medicine, West China Hospital, Sichuan University | 2019-07-03 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | infectious diseases | https://www.medrxiv.org/content/early/2019/07/03/19000281.source.xml | BackgroundClinically diagnosed pulmonary tuberculosis (PTB) patients lack Mycobacterium tuberculosis (MTB) microbiologic evidence, and misdiagnosis or delayed diagnosis often occurs as a consequence. We investigated the potential of lncRNAs and corresponding predictive models to diagnose these patients.
MethodsWe enrolled 1372 subjects, including clinically diagnosed PTB patients, non-TB disease controls and healthy controls, in three cohorts (Screening, Selection and Validation). Candidate lncRNAs differentially expressed in blood samples of the PTB and healthy control groups were identified by microarray and qRT-PCR in the Screening Cohort. Logistic regression models were developed using lncRNAs and/or electronic health records (EHRs) from clinically diagnosed PTB patients and non-TB disease controls in the Selection Cohort. These models were evaluated by AUC and decision curve analysis, and the optimal model was presented as a Web-based nomogram, which was evaluated in the Validation Cohort. The biological function of lncRNAs was interrogated using ELISA, lactate dehydrogenase release analysis and flow cytometry.
ResultsThree differentially expressed lncRNAs (ENST00000497872, n333737, n335265) were identified. The optimal model (i.e., nomogram) incorporated these three lncRNAs and six EHR variables (age, hemoglobin, weight loss, low-grade fever, CT calcification and TB-IGRA). The nomogram showed an AUC of 0.89, sensitivity of 0.86 and specificity of 0.82 in the Validation Cohort, which demonstrated better discrimination and clinical net benefit than the EHR model. ENST00000497872 may regulate inflammatory cytokine production, cell death and apoptosis during MTB infection.
ConclusionLncRNAs and the user-friendly nomogram could facilitate the early identification of PTB cases among suspected patients with negative MTB microbiologic evidence.
Key MessagesO_ST_ABSWhat is the key question?C_ST_ABSDoes integrating immune-related lncRNA signatures and electronic health records (EHRs) promote the early identification of PTB patients who are symptomatic but lack microbiologic evidence of Mycobacterium tuberculosis (MTB)?
What is the bottom line?We found three long non-coding RNAs (lncRNAs), i.e., ENST00000497872, n333737 and n335265, were potential diagnostic biomarkers for clinically diagnosed PTB patients; and we further developed and validated a novel nomogram incorporating these three lncRNAs and six electronic health records (EHRs), which were readily obtainable even in a resource-constrained setting and achieved a c-statistic of 0.89, sensitivity of 0.86 and specificity of 0.82 in a separate validation cohort.
Why read on?This study focuses on the challenge of accurately diagnosing PTB patients with negative MTB microbiological evidence and serves as the first proof-of-concept that integrating lncRNA signatures and EHR data could be a more promising diagnostic approach for clinically diagnosed PTB patients.
SUMMARYThis study developed and validated a novel nomogram that incorporated three lncRNAs and six EHR fields could be a useful predictive tool in identifying PTB patients who lack MTB microbiologic evidence. | 10.1128/jcm.01973-19 | medrxiv |
10.1101/19000281 | LncRNA and predictive model for improving the diagnosis of clinically diagnosed pulmonary tuberculosis | Hu, X.; Chen, H.; Liao, S.; Bai, H.; Gupta, S.; Zhou, Y.; Zhou, J.; Jiao, L.; Wu, L.; Wang, M.; Chen, X.; Zhou, Y.; Lu, X.; Hu, T. Y.; Zhang, Z.; Ying, B. | Binwu Ying | Department of Laboratory Medicine, West China Hospital, Sichuan University | 2019-11-05 | 2 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | infectious diseases | https://www.medrxiv.org/content/early/2019/11/05/19000281.source.xml | BackgroundClinically diagnosed pulmonary tuberculosis (PTB) patients lack Mycobacterium tuberculosis (MTB) microbiologic evidence, and misdiagnosis or delayed diagnosis often occurs as a consequence. We investigated the potential of lncRNAs and corresponding predictive models to diagnose these patients.
MethodsWe enrolled 1372 subjects, including clinically diagnosed PTB patients, non-TB disease controls and healthy controls, in three cohorts (Screening, Selection and Validation). Candidate lncRNAs differentially expressed in blood samples of the PTB and healthy control groups were identified by microarray and qRT-PCR in the Screening Cohort. Logistic regression models were developed using lncRNAs and/or electronic health records (EHRs) from clinically diagnosed PTB patients and non-TB disease controls in the Selection Cohort. These models were evaluated by AUC and decision curve analysis, and the optimal model was presented as a Web-based nomogram, which was evaluated in the Validation Cohort. The biological function of lncRNAs was interrogated using ELISA, lactate dehydrogenase release analysis and flow cytometry.
ResultsThree differentially expressed lncRNAs (ENST00000497872, n333737, n335265) were identified. The optimal model (i.e., nomogram) incorporated these three lncRNAs and six EHR variables (age, hemoglobin, weight loss, low-grade fever, CT calcification and TB-IGRA). The nomogram showed an AUC of 0.89, sensitivity of 0.86 and specificity of 0.82 in the Validation Cohort, which demonstrated better discrimination and clinical net benefit than the EHR model. ENST00000497872 may regulate inflammatory cytokine production, cell death and apoptosis during MTB infection.
ConclusionLncRNAs and the user-friendly nomogram could facilitate the early identification of PTB cases among suspected patients with negative MTB microbiologic evidence.
Key MessagesO_ST_ABSWhat is the key question?C_ST_ABSDoes integrating immune-related lncRNA signatures and electronic health records (EHRs) promote the early identification of PTB patients who are symptomatic but lack microbiologic evidence of Mycobacterium tuberculosis (MTB)?
What is the bottom line?We found three long non-coding RNAs (lncRNAs), i.e., ENST00000497872, n333737 and n335265, were potential diagnostic biomarkers for clinically diagnosed PTB patients; and we further developed and validated a novel nomogram incorporating these three lncRNAs and six electronic health records (EHRs), which were readily obtainable even in a resource-constrained setting and achieved a c-statistic of 0.89, sensitivity of 0.86 and specificity of 0.82 in a separate validation cohort.
Why read on?This study focuses on the challenge of accurately diagnosing PTB patients with negative MTB microbiological evidence and serves as the first proof-of-concept that integrating lncRNA signatures and EHR data could be a more promising diagnostic approach for clinically diagnosed PTB patients.
SUMMARYThis study developed and validated a novel nomogram that incorporated three lncRNAs and six EHR fields could be a useful predictive tool in identifying PTB patients who lack MTB microbiologic evidence. | 10.1128/jcm.01973-19 | medrxiv |
10.1101/19000927 | Acceleration of chemical shift encoding-based water fat MRI for liver proton density fat fraction and T2* mapping using compressed sensing | Lohoefer, F. K.; Kaissis, G. A.; Mueller-Leisse, C.; Franz, D.; Katemann, C.; Hock, A.; Peeters, J. M.; Rummeny, E. J.; Karampinos, D.; Braren, R. | Rickmer Braren | TU Muenchen, Institute for diagnostic and interventional Radiology | 2019-07-03 | 1 | PUBLISHAHEADOFPRINT | cc_no | radiology and imaging | https://www.medrxiv.org/content/early/2019/07/03/19000927.source.xml | ObjectivesTo evaluate proton density fat fraction (PDFF) and T2* measurements of the liver with combined parallel imaging (sensitivity encoding, SENSE) and compressed sensing (CS) accelerated chemical shift encoding-based water-fat separation.
MethodsSix-echo Dixon imaging was performed in the liver of 89 subjects. The first acquisition variant used acceleration based on SENSE with a total acceleration factor equal to 2.64 (acquisition labeled as SENSE). The second acquisition variant used acceleration based on a combination of CS with SENSE with a total acceleration factor equal to 4 (acquisition labeled as CS+SENSE). Acquisition times were compared between acquisitions and proton density fat fraction (PDFF) and T2*-values were measured and compared separately for each liver segment.
ResultsTotal scan duration was 14.5 sec for the SENSE accelerated image acquisition and 9.3 sec for the CS+SENSE accelerated image acquisition. PDFF and T2* values did not differ significantly between the two acquisitions (paired Mann-Whitney and paired t-test P>0.05 in all cases). CS+SENSE accelerated acquisition showed reduced motion artifacts (1.1%) compared to SENSE acquisition (12.3%).
ConclusionCS+SENSE accelerates liver PDFF and T2*mapping while retaining the same quantitative values as an acquisition using only SENSE and reduces motion artifacts.
Strengths of this studyO_LICompressed sensing allows accelerated imaging with reduction of motion artifacts without alteration of quantitative measurements
C_LIO_LIRobust results in fat and iron quantification in a heterogeneous patient cohort
C_LI
Limitations of this studyO_LINo histopathological validation of the MR findings was performed
C_LIO_LIThe study was not performed at different field strengths
C_LI | 10.1371/journal.pone.0224988 | medrxiv |
10.1101/19001149 | Aerobic capacity predicts skeletal but not cardiac muscle damage after a full distance Ironman triathlon - the Iron(wo)man-study | Danielsson, T.; Carlsson, J.; Ten Siethoff, L.; Ahnesjo, J.; Bergman, P. | Patrick Bergman | Linnaeus University | 2019-07-03 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | sports medicine | https://www.medrxiv.org/content/early/2019/07/03/19001149.source.xml | PurposeThis study examines the association between aerobic capacity and biomarkers of skeletal- and cardiac muscle damage among amateur triathletes after a full distance Ironman.
MethodsMen 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.
ResultA 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 r2 values, than when aerobic capacity was expressed in relative terms.
ConclusionA 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. | 10.1038/s41598-020-57842-w | medrxiv |
10.1101/19001073 | Machine learning to predict early recurrence after oesophageal cancer surgery | Rahman, S.; Walker, R. C.; LLoyd, M. A.; Grace, B. L.; van Boxel, G. I.; Kingma, F. B.; Ruurda, J. P.; van Hillegersberg, R.; Harris, S.; Parsons, S.; Mercer, S.; Griffiths, E. A.; O'Neill, J. R.; Turkington, R.; Fitzgerald, R.; Underwood, T. J.; OCCAMS Consortium, | Timothy J Underwood | Cancer Sciences Unit, University of Southampton, Southampton, UK | 2019-07-03 | 1 | PUBLISHAHEADOFPRINT | cc_no | surgery | https://www.medrxiv.org/content/early/2019/07/03/19001073.source.xml | ObjectiveTo develop a predictive model for early recurrence after surgery for oesophageal adenocarcinoma using a large multi-national cohort.
Summary Background DataEarly cancer recurrence after oesophagectomy is a common problem with an incidence of 20-30% despite the widespread use of neoadjuvant treatment. Quantification of this risk is difficult and existing models perform poorly. Machine learning techniques potentially allow more accurate prognostication and have been applied in this study.
MethodsConsecutive patients who underwent oesophagectomy for adenocarcinoma and had neoadjuvant treatment in 6 UK and 1 Dutch oesophago-gastric units were analysed. Using clinical characteristics and post-operative histopathology, models were generated using elastic net regression (ELR) and the machine learning methods random forest (RF) and XG boost (XGB). Finally, a combined (Ensemble) model of these was generated. The relative importance of factors to outcome was calculated as a percentage contribution to the model.
ResultsIn total 812 patients were included. The recurrence rate at less than 1 year was 29.1%. All of the models demonstrated good discrimination. Internally validated AUCs were similar, with the Ensemble model performing best (ELR=0.785, RF=0.789, XGB=0.794, Ensemble=0.806). Performance was similar when using internal-external validation (validation across sites, Ensemble AUC=0.804). In the final model the most important variables were number of positive lymph nodes (25.7%) and vascular invasion (16.9%).
ConclusionsThe derived model using machine learning approaches and an international dataset provided excellent performance in quantifying the risk of early recurrence after surgery and will be useful in prognostication for clinicians and patients.
DRAFT VISUAL ABSTRACT
O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/19001073v1_ufig1.gif" ALT="Figure 1">
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org.highwire.dtl.DTLVardef@1d0693corg.highwire.dtl.DTLVardef@1acea40org.highwire.dtl.DTLVardef@1472e5borg.highwire.dtl.DTLVardef@34841a_HPS_FORMAT_FIGEXP M_FIG C_FIG Icons taken from www.flaticon.com, made by Freepik, smashicons, and prettycons. Reproduced under creative commons attribution license
MINI-ABSTRACTEarly recurrence after surgery for adenocarcinoma of the oesophagus is common. We derived a risk prediction model using modern machine learning methods that accurately predicts risk of early recurrence using post-operative pathology | 10.1002/bjs.11461 | medrxiv |
10.1101/19001222 | Predicting Residual Function in Hemodialysis and Hemodiafiltration : A Population Kinetic, Decision Analytic Approach | Achakzai, M.; Argyropoulos, C.; Roumelioti, M. - E. | Christos Argyropoulos | Department of Internal Medicine, Division of Nephrology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA | 2019-07-03 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | nephrology | https://www.medrxiv.org/content/early/2019/07/03/19001222.source.xml | In this study, we introduce a novel framework for the estimation of residual renal function (RRF), based on the population compartmental kinetic behavior of Beta 2 Microglobulin (B2M) and its dialytic removal. Using this model, we simulated a large cohort of patients with various levels of RRF receiving either conventional high-flux hemodialysis or on-line hemodiafiltration. These simulations were used to estimate a novel population kinetic (PK) equation for RRF (PK-RRF) that was validated in an external public dataset of real patients. We assessed the performance of the resulting equation(s) against their ability to estimate urea clearance using cross-validation. Our equations derived entirely from computer simulations and advanced statistical modeling, and had extremely high discrimination (AUC 0.888 - 0.909) when applied to a human dataset of measurements of RRF. A clearance-based equation that utilized pre and post dialysis B2M measurements, patient weight, treatment duration and ultrafiltration had higher discrimination than an equation previously derived in humans. Furthermore, the derived equations appeared to have higher clinical usefulness as assessed by Decision Curve Analysis, potentially supporting decisions that for individualizing dialysis frequency in patients with preserved RRF. | 10.3390/jcm8122080 | medrxiv |
10.1101/19001222 | Predicting Residual Function in Hemodialysis and Hemodiafiltration : A Population Kinetic, Decision Analytic Approach | Achakzai, M.; Argyropoulos, C.; Roumelioti, M. - E. | Christos Argyropoulos | Department of Internal Medicine, Division of Nephrology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA | 2019-07-09 | 2 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | nephrology | https://www.medrxiv.org/content/early/2019/07/09/19001222.source.xml | In this study, we introduce a novel framework for the estimation of residual renal function (RRF), based on the population compartmental kinetic behavior of Beta 2 Microglobulin (B2M) and its dialytic removal. Using this model, we simulated a large cohort of patients with various levels of RRF receiving either conventional high-flux hemodialysis or on-line hemodiafiltration. These simulations were used to estimate a novel population kinetic (PK) equation for RRF (PK-RRF) that was validated in an external public dataset of real patients. We assessed the performance of the resulting equation(s) against their ability to estimate urea clearance using cross-validation. Our equations derived entirely from computer simulations and advanced statistical modeling, and had extremely high discrimination (AUC 0.888 - 0.909) when applied to a human dataset of measurements of RRF. A clearance-based equation that utilized pre and post dialysis B2M measurements, patient weight, treatment duration and ultrafiltration had higher discrimination than an equation previously derived in humans. Furthermore, the derived equations appeared to have higher clinical usefulness as assessed by Decision Curve Analysis, potentially supporting decisions that for individualizing dialysis frequency in patients with preserved RRF. | 10.3390/jcm8122080 | medrxiv |
10.1101/19001362 | The impact of involving young children in improving the understanding of a new eye test | Casanova, T.; Black, C.; Rafiq, S.; Hugill, J.; Read, J. C. A.; Vancleef, K. | Kathleen Vancleef | Newcastle University, University of Oxford | 2019-07-03 | 1 | PUBLISHAHEADOFPRINT | cc_by | ophthalmology | https://www.medrxiv.org/content/early/2019/07/03/19001362.source.xml | BackgroundAlthough considered important, the involvement of young children in research is rare and its impact has never been measured. We aim to provide a good practice example of involvement of young children in the development of a tablet-based 3D eye test or stereotest, ASTEROID. We focus on improving understanding of test instructions.
MethodsAfter a pre-measure of understanding was taken, we explored issues with the test instructions in patient and public involvement (PPI) sessions. Feedback was collected via observations, rating scales and childrens comments. An interdisciplinary panel reviewed the feedback and decided on the implementation. Subsequently, a post-measure was collected. In Study 1, 650 children (2-11.8 years old) took part in the pre-measure, 111 children (1-12 years old) in the PPI sessions, and 52 children (4-6 years old) in the post-measure which also served as a pre-measure for Study 2. PPI sessions for Study 2 attracted 122 children (1-12 years old) and adults. 53 people (2-39 years old) participated in the post-measure of Study 2.
ResultsFollowing feedback in Study 1, we added a frame cue and included a shuffle animation. This increased the percentage of correct practice trials from 76% to 97% (t(231)=14.29, p<.001). After adding a cardboard demo in Study 2, the percentage of correct trials remained stable but the number of additional instructions given decreased (t(103)=3.72, p<.001).
ConclusionsOur study demonstrates impact of involvement of very young children in research through accessible activities. It can encourage researchers to involve young children and contribute to developing guidelines. | 10.1186/s40900-020-00194-6 | medrxiv |
10.1101/19000877 | A Needs Analysis of Parents Following Sudden Cardiac Death in the Young | McDonald, K.; Sharpe, L.; Yeates, L.; Semsarian, C.; Ingles, J. | Jodie Ingles | Centenary Institute, The University of Sydney | 2019-07-03 | 1 | PUBLISHAHEADOFPRINT | cc_no | cardiovascular medicine | https://www.medrxiv.org/content/early/2019/07/03/19000877.source.xml | 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 ([≤]45 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 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 "To have the option of whether or not you would pursue genetic testing for yourself or family members" and "To understand what happened". 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 QUESTIONSO_ST_ABSWhat is already known about this subject?C_ST_ABSThere 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. | 10.1136/openhrt-2019-001120 | medrxiv |
10.1101/19001321 | Accuracy of ECG Chest Electrode Placements by Paramedics; an observational study | Gregory, P.; Lodge, S.; Kilner, T.; Paget, S. | Pete Gregory | University of Wolverhampton | 2019-07-03 | 1 | PUBLISHAHEADOFPRINT | cc_no | emergency medicine | https://www.medrxiv.org/content/early/2019/07/03/19001321.source.xml | BackgroundThe use of the 12-lead ECG is common in UK paramedic practice but its value depends upon accurate placement of the ECG-electrodes. Several studies have shown widespread variation in the placement of chest electrodes by other health professionals but no studies have addressed the accuracy of paramedics. The main objective of this study was to ascertain the accuracy of the chest lead placements by registered paramedics.
MethodsRegistered paramedics who attended the Emergency Services Show in Birmingham in September 2018 were invited to participate in this observational study. Participants were asked to place the chest electrodes on a male model in accordance with their current practice. Correct positioning was determined against the Society for Cardiological Science & Technologys Clinical Guidelines for recording a standard 12-lead electrocardiogram (2017) with a tolerance of 19mm being deemed acceptable based upon previous studies.
Results52 eligible participants completed the study. Measurement of electrode placement in the craniocaudal and mediolateral planes showed a high level of inaccuracy with 3/52 (5.8%) participants able to accurately place all chest leads. In leads V1 - V3, the majority of incorrect placements were related to vertical displacement with most participants able to identify the correct horizontal position. In V4, the tendency was to place the lead too low and to the left of the pre-determined position whilst V5 tended to be below the expected positioning but in the correct horizontal alignment. There was a less defined pattern of error in V6 although vertical displacement was more likely than horizontal displacement.
ConclusionsOur study identified a high level of variation in the placement of chest ECG electrodes which could alter the morphology of the ECG. From a patient safety perspective, we would advocate that paramedics leave the chest electrodes in situ to allow hospital staff to assess the accuracy of the placements.
Key messagesWhat is already known on this subject
O_LIThe recording of a prehospital ECG has become increasingly common in sophisticated Emergency Medical Services across the world
C_LIO_LIThe accuracy of precordial ECG electrode placement has been studied with other health professionals and has highlighted varying degrees of accuracy.
C_LIO_LIInaccurate electrode placement can lead to aberrant ECG readings and application of unnecessary treatment or the withholding of indicated treatment
C_LI
What this study adds
O_LIIn this observational cohort study, we found significant variation in the placement of the precordial ECG electrodes by UK registered paramedics
C_LIO_LIWe recommend that paramedics leave the prehospital ECG electrodes in situ to allow hospital staff to assess the accuracy of the placements.
C_LI | 10.29045/14784726.2019.12.4.3.51 | medrxiv |
10.1101/19000539 | Health workers experiences of coping with the Ebola epidemic in the Democratic Republic of the Congo health system: a qualitative study of variables of hospital activities on infection control practices in Kinshasa city | Tshima, G. K.; Kalala, K. T. | Guyguy Kabundi Tshima | Universite de Kinshasa | 2019-07-03 | 1 | PUBLISHAHEADOFPRINT | cc_by | epidemiology | https://www.medrxiv.org/content/early/2019/07/03/19000539.source.xml | Health workers play an important role during epidemics, but there is limited research on hospital activities on infection control practices in the Democratic Republic of the Congo and how health workers can cope during a probable health epidemic in Kinshasa city. The determinants of the current Ebola Virus Disease in the geographical distribution remain poorly understood. The World Health Organizations Health Regulation Committee decided on Wednesday July 17th, 2019 to declare the Ebola haemorrhagic fever epidemic in the provinces of North Kivu and Ituri as a health emergency of international concern. The country struggles to control it against a backdrop of a health system that is already overburdened. To test the influence of the challenges of a contamination in the context of an Ebola outbreak that may face health workers and their coping strategies in thirteen hospitals of reference in Kinshasa, we conducted a survey hoping to educate or remember good practices for health workers in Kinshasa that is also available for health workers in the East Area of the country in which the ongoing Ebola outbreak progress is spreading (North Kivu and Ituri). For the ongoing outbreak, we obtained data from the Ministere de la Sante Publique of the Democratic Republic of the Congo where cases are classified as suspected, probable, or confirmed using national case definitions. We found that the ongoing Ebola virus outbreak in the Democratic Republic of the Congo has similar epidemiological features to previous Ebola virus disease outbreak in Sierra Leone that was well described. For the qualitative study about the biosecurity in thirteen hospitals of reference in Kinshasa, we found that the Bondeko-Ngaliema Monkole group has occupied the first rank, while the group Kintambo-King Baudouin-Ndjili-Makala occupied the other end of the scale; the other health facilities occupied an intermediate position. Among the 7 hospitals which were placed at the top of this classification of biosecurity, 5 were massively subsidized by international NGO, which explains to a great extent their performances in one hand, another hand finding its explanation in the quality of their management. It is the case of Bondeko, Monkole, Kalembe-Lembe, St Joseph and Kingasani 2.
Author summaryThe determinants of the transmission are poorly understood, but a growing body of evidence supports an important role of the lack of prevention in the dissemination of Ebola virus. The results of our study conducted in 13 hospitals of reference in Kinshasa suggest that the biosecurity measures--which were introduced in Kinshasa hospitals policies through prevention since Ebola outbreaks--have been respected by 75% and had 25% of parameters to be improved. Biosecurity is an important concept; it seems to be a vector for the prevention of Ebola Virus Disease. In addition, the lack of biosecurity observation may have a role in the contamination of Ebola Virus Disease in local populations found in invaded areas. This study provides knowledge into the preventive measures influencing Ebola Virus Disease populations, thereby determining in perspective a study on meat consumption of animals found dead in forests that will be a risk for human infection as the Democratic Republic of the Congo has many forests. | null | medrxiv |
10.1101/19000539 | Show solidarity with the Congolese people in the 10th Ebola outbreak declared a health emergency of international concern: understand a qualitative study of variables of hospital activities on infection control practices in Kinshasa city | Tshima, G. K.; Kalala, K. T. | Guyguy Kabundi Tshima | Universite de Kinshasa | 2019-07-23 | 2 | PUBLISHAHEADOFPRINT | cc_by | epidemiology | https://www.medrxiv.org/content/early/2019/07/23/19000539.source.xml | Health workers play an important role during epidemics, but there is limited research on hospital activities on infection control practices in the Democratic Republic of the Congo and how health workers can cope during a probable health epidemic in Kinshasa city. The determinants of the current Ebola Virus Disease in the geographical distribution remain poorly understood. The World Health Organizations Health Regulation Committee decided on Wednesday July 17th, 2019 to declare the Ebola haemorrhagic fever epidemic in the provinces of North Kivu and Ituri as a health emergency of international concern. The country struggles to control it against a backdrop of a health system that is already overburdened. To test the influence of the challenges of a contamination in the context of an Ebola outbreak that may face health workers and their coping strategies in thirteen hospitals of reference in Kinshasa, we conducted a survey hoping to educate or remember good practices for health workers in Kinshasa that is also available for health workers in the East Area of the country in which the ongoing Ebola outbreak progress is spreading (North Kivu and Ituri). For the ongoing outbreak, we obtained data from the Ministere de la Sante Publique of the Democratic Republic of the Congo where cases are classified as suspected, probable, or confirmed using national case definitions. We found that the ongoing Ebola virus outbreak in the Democratic Republic of the Congo has similar epidemiological features to previous Ebola virus disease outbreak in Sierra Leone that was well described. For the qualitative study about the biosecurity in thirteen hospitals of reference in Kinshasa, we found that the Bondeko-Ngaliema Monkole group has occupied the first rank, while the group Kintambo-King Baudouin-Ndjili-Makala occupied the other end of the scale; the other health facilities occupied an intermediate position. Among the 7 hospitals which were placed at the top of this classification of biosecurity, 5 were massively subsidized by international NGO, which explains to a great extent their performances in one hand, another hand finding its explanation in the quality of their management. It is the case of Bondeko, Monkole, Kalembe-Lembe, St Joseph and Kingasani 2.
Author summaryThe determinants of the transmission are poorly understood, but a growing body of evidence supports an important role of the lack of prevention in the dissemination of Ebola virus. The results of our study conducted in 13 hospitals of reference in Kinshasa suggest that the biosecurity measures--which were introduced in Kinshasa hospitals policies through prevention since Ebola outbreaks--have been respected by 75% and had 25% of parameters to be improved. Biosecurity is an important concept; it seems to be a vector for the prevention of Ebola Virus Disease. In addition, the lack of biosecurity observation may have a role in the contamination of Ebola Virus Disease in local populations found in invaded areas. This study provides knowledge into the preventive measures influencing Ebola Virus Disease populations, thereby determining in perspective a study on meat consumption of animals found dead in forests that will be a risk for human infection as the Democratic Republic of the Congo has many forests. | null | medrxiv |
10.1101/19000968 | Liver function tests and fibrosis scores in a rural population in Africa: estimation of the burden of disease and associated risk factors | O'Hara, G.; Mokaya, J.; Hau, J. P.; Downs, L. O.; McNaughton, A. L.; Karabarinde, A.; Asiki, G.; Seeley, J.; Matthews, P. C.; Newton, R. | Philippa C Matthews | Nuffield Department of Medicine, University of Oxford, Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, UK | 2019-07-03 | 1 | PUBLISHAHEADOFPRINT | cc_by | gastroenterology | https://www.medrxiv.org/content/early/2019/07/03/19000968.source.xml | IntroductionLiver 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.
MethodologyA 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.
ResultsData 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).
ConclusionFurther 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 FINDINGSO_ST_ABSWhat is already known?C_ST_ABSO_LILiver 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.
C_LIO_LINon-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.
C_LIO_LIAppropriate reference ranges for LFTs are crucial for optimising the sensitivity and specificity of the detection of underlying liver disease.
C_LI
What are the new findings?O_LIThere is a disparity in the prevalence of abnormal LFTs in our study cohort when comparing two references ranges (American vs. local reference ranges).
C_LIO_LIBased 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.
C_LIO_LIAlcohol consumption accounted for 64% of abnormal S-index scores, 32% of elevated FIB-4 scores, and 19% of GPR abnormalities.
C_LI
What do the new findings imply?O_LIAppropriate reference ranges for LFTs are necessary to contribute to an understanding of the burden and aetiology of liver disease.
C_LIO_LIAlcohol, HIV and HBV are risk factors for deranged LFTs and liver fibrosis, with alcohol making the most significant and striking contribution.
C_LIO_LIFurther investigation is needed to determine other factors that contribute to liver disease in this setting.
C_LI | 10.1136/bmjopen-2019-032890 | medrxiv |
10.1101/19001255 | A CALCIUM-RICH MULTI-MINERAL INTERVENTION TO MODULATE COLONIC MICROBIAL COMMUNITIES AND METABOLOMIC PROFILES IN HUMANS:Results from a 90-day trial | Aslam, M. N.; Bassis, C. M.; Bergin, I. L.; Knuver, K.; Zick, S.; Sen, A.; Turgeon, D. K.; Varani, J. | Muhammad N Aslam | University of Michigan Medical School | 2019-07-03 | 1 | PUBLISHAHEADOFPRINT | cc_no | gastroenterology | https://www.medrxiv.org/content/early/2019/07/03/19001255.source.xml | Aquamin, a calcium-, magnesium-, and multiple trace element-rich natural product has polyp prevention efficacy based on preclinical studies. The overall goal of this study was to determine the safety and tolerability of Aquamin when used as a dietary chemopreventative in humans. Additionally, we determined the effects of Aquamin on the colonic microbial community and attendant metabolomic profile. Thirty healthy male and female human participants were enrolled in a 90-day trial in which the effects of Aquamin (delivering 800 mg of calcium per day) were compared to those of calcium alone or placebo. Before and after the interventional period, colonic biopsies and stool specimens were obtained. All 30 participants completed the study without serious adverse events. There were no changes in liver function markers. Compared to pretreatment values, intervention with Aquamin led to a reduction in total bacterial DNA and a shift in the microbial community. Treatment with calcium alone also produced a decline in total bacteria, but smaller than seen with Aquamin, while no reduction was observed with placebo. In parallel with microbial changes, a reduction in bile acid levels and a slight increase in the level of the short chain fatty acid (SCFA) acetate in stool specimens from Aquamin-treated participants was noted. No change in bile acids or SCFAs was observed with calcium alone or placebo. We conclude from these studies that Aquamin is safe and tolerable in healthy human participants and may produce beneficial alterations in the colonic microbial community and the attendant metabolomic profile. | 10.1158/1940-6207.CAPR-19-0325 | medrxiv |
10.1101/19000489 | Misclassification of a whole genome sequence reference defined by the Human Microbiome Project: a detrimental carryover effect to microbiome studies | Bandoy, D. D. R.; Huang, B. C.; Weimer, B. C. | Bart C Weimer | UC Davis | 2019-07-06 | 1 | PUBLISHAHEADOFPRINT | cc_no | infectious diseases | https://www.medrxiv.org/content/early/2019/07/06/19000489.source.xml | Taxonomic classification is an essential step in the analysis of microbiome data that depends on a reference database of whole genome sequences. Taxonomic classifiers are built on established reference species, such as the Human Microbiome Project database, that is growing rapidly. While constructing a population wide pangenome of the bacterium Hungatella, we discovered that the Human Microbiome Project reference species Hungatella hathewayi (WAL 18680) was significantly different to other members of this genus. Specifically, the reference lacked the core genome as compared to the other members. Further analysis, using average nucleotide identity (ANI) and 16s rRNA comparisons, indicated that WAL18680 was misclassified as Hungatella. The error in classification is being amplified in the taxonomic classifiers and will have a compounding effect as microbiome analyses are done, resulting in inaccurate assignment of community members and will lead to fallacious conclusions and possibly treatment. As automated genome homology assessment expands for microbiome analysis, outbreak detection, and public health reliance on whole genomes increases this issue will likely occur at an increasing rate. These observations highlight the need for developing reference free methods for epidemiological investigation using whole genome sequences and the criticality of accurate reference databases. | null | medrxiv |
10.1101/19001305 | Using collaboration networks to identify authorship bias in meta-analyses | Moulin, T. C.; Amaral, O. B. | Thiago C Moulin | Uppsala University | 2019-07-08 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc | epidemiology | https://www.medrxiv.org/content/early/2019/07/08/19001305.source.xml | Meta-analytic methods are powerful resources to summarize the existing evidence concerning a given research question, and are widely used in many academic fields. However, meta-analyses can be vulnerable to various sources of bias, which should be considered to avoid inaccuracies. Many of these sources can be related to study authorship, as both methodological choices and researcher bias may lead to deviations in results between different research groups. In this work, we describe a method to objectively attribute study authorship within a given meta-analysis to different research groups by using graph cluster analysis of collaboration networks. We then provide empirical examples of how the research group of origin can impact effect size in distinct types of meta-analyses, demonstrating how non-independence between within-group results can bias effect size estimates if uncorrected. Finally, we show that multilevel random-effects models using research group as a level of analysis can be a simple tool for correcting biases related to study authorship. | 10.1002/jrsm.1430 | medrxiv |
10.1101/19001305 | Using collaboration networks to identify authorship bias in meta-analyses | Moulin, T. C.; Amaral, O. B. | Thiago C Moulin | Uppsala University | 2019-12-16 | 2 | PUBLISHAHEADOFPRINT | cc_by_nc | epidemiology | https://www.medrxiv.org/content/early/2019/12/16/19001305.source.xml | Meta-analytic methods are powerful resources to summarize the existing evidence concerning a given research question, and are widely used in many academic fields. However, meta-analyses can be vulnerable to various sources of bias, which should be considered to avoid inaccuracies. Many of these sources can be related to study authorship, as both methodological choices and researcher bias may lead to deviations in results between different research groups. In this work, we describe a method to objectively attribute study authorship within a given meta-analysis to different research groups by using graph cluster analysis of collaboration networks. We then provide empirical examples of how the research group of origin can impact effect size in distinct types of meta-analyses, demonstrating how non-independence between within-group results can bias effect size estimates if uncorrected. Finally, we show that multilevel random-effects models using research group as a level of analysis can be a simple tool for correcting biases related to study authorship. | 10.1002/jrsm.1430 | medrxiv |
10.1101/19001230 | The effect of the genetic liability to autism spectrum disorder on emotion recognition in young unaffected probands from a population-based cohort | Wendt, F. R.; Muniz Carvalho, C.; Gelernter, J.; Polimanti, R. | Renato Polimanti | Yale School of Medicine | 2019-07-08 | 1 | PUBLISHAHEADOFPRINT | cc_no | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2019/07/08/19001230.source.xml | We investigated how ASD genetic risk relates to neurodevelopmental features (491 traits tested) via polygenic risk scoring (PRS) in 4,309 young non-ASD probands from the Philadelphia Neurodevelopmental Cohort. ASD PRS most strongly associated with the ability to correctly identify angry facial emotions in youths aged 11-17 years (R2=1.06%, p=1.38x10-7) and replicated similarly in older probands (>18 years) (R2=0.55%, p=0.036). The association in 11- to-17-year-old probands was independent of other psychiatric disorders, brain imaging phenotypes, and educational attainment. ASD PRS also associated with proband-reported emotionality and connectedness with others. The proband-reported irritability trait was highly correlated with angry facial emotion recognition (r2=0.159, p=2.74x10-5) but was independently associated with ASD PRS (R2=1.20%, p=1.18x10-4). Several informant-reported (i.e., typically mother-reported) traits were predicted by the probands ASD PRS, including duration of fear (R2=0.156%, p=0.001). These data indicate how genetic liability to ASD may influence neurodevelopment in the general population, especially the development of emotional intelligence. | 10.1016/j.euroneuro.2019.08.213 | medrxiv |
10.1101/19001156 | Intermittent Lactobacilli-containing Vaginal Probiotic or Metronidazole Use to Prevent Bacterial Vaginosis Recurrence: Safety and Preliminary Efficacy by Microscopy and Sequencing | van de Wijgert, J.; Verwijs, M. C.; Agaba, S. K.; Bronowski, C.; Mwambarangwe, L.; Uwineza, M.; Lievens, E.; Nivoliez, A.; Ravel, J.; Darby, A. | Janneke van de Wijgert | Institute of Infection and Global Health, University of Liverpool, Liverpool, UK | 2019-07-08 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | sexual and reproductive health | https://www.medrxiv.org/content/early/2019/07/08/19001156.source.xml | Bacterial vaginosis (BV) is associated with HIV acquisition and adverse pregnancy outcomes. Recurrence after metronidazole treatment is high. HIV-negative, non-pregnant Rwandan BV patients were randomized to four groups (n=17/group) after seven-day oral metronidazole treatment: behavioral counseling only (control), or counseling plus intermittent use of oral metronidazole, Ecologic Femi+ vaginal capsule (containing multiple Lactobacillus and one Bifidobacterium species), or Gynophilus LP vaginal tablet (L. rhamnosus 35) for two months. Vaginal microbiota assessments at all visits included Gram stain Nugent scoring and 16S rRNA gene qPCR and HiSeq sequencing. All interventions were safe. BV (Nugent 7-10) incidence was 10.18 per person-year at risk in the control group, and lower in the metronidazole (1.41/person-year; p=0.004), Ecologic Femi+ (3.58/person-year; p=0.043), and Gynophilus LP groups (5.36/person-year; p=0.220). In mixed effects models adjusted for hormonal contraception/pregnancy, sexual risk-taking, and age, metronidazole and Ecologic Femi+ users, each compared to controls, had higher Lactobacillus and lower BV-anaerobes concentrations and/or relative abundances, and were less likely to have a dysbiotic vaginal microbiota type by sequencing. Inter-individual variability was high and effects disappeared soon after intervention cessation. Lactobacilli-based vaginal probiotics warrant further evaluation because, in contrast to antibiotics, they are not expected to negatively affect microbiota or cause antimicrobial resistance. | 10.1038/s41598-020-60671-6 | medrxiv |
10.1101/19001537 | Phenome-wide association study of TTR and RBP4 genes in 361,194 individuals reveals novel insights in the genetics of hereditary and senile systemic amyloidoses | De Lillo, A.; De Angelis, F.; Di Girolamo, M.; Luigetti, M.; Frusconi, S.; Manfellotto, D.; Fuciarelli, M.; Polimanti, R. | Renato Polimanti | Yale University | 2019-07-08 | 1 | PUBLISHAHEADOFPRINT | cc_no | genetic and genomic medicine | https://www.medrxiv.org/content/early/2019/07/08/19001537.source.xml | Transthyretin (TTR) gene has a causal role in a hereditary form of amyloidosis (ATTRm) and is potentially involved in the risk of senile systemic amyloidosis (SSA). To understand the genetics of ATTRm and SSA, we conducted a phenome-wide association study of TTR gene in 361,194 participants of European descent testing coding and non-coding variants. Among the 382 clinically-relevant phenotypes tested, TTR non-coding variants were associated with 26 phenotypic traits after multiple testing correction. These included signs related to both ATTRm and SSA such as chronic ischaemic heart disease (rs140226130, p=2.00x10-6), heart failure (rs73956431, p=2.74x10-6), atrial fibrillation (rs10163755, p=4.63x10-6), dysphagia (rs2949506, p=3.95x10-6), intestine diseases (rs970866, p=7.14x10-6) and anxiety (rs554521234, p=8.85x10-6). Consistent results were observed for TTR disease-causing mutation Val122Ile (rs76992529) with respect to carpal tunnel syndrome (p=6.41x10-6) and mononeuropathies of upper limbs (p=1.22x10-5). Sex differences were also observed in line with ATTRm and SSA epidemiology. Additionally, we explored possible modifier genes related to TTR function, observing convergent associations of RBP4 variants with the clinical phenotypes associated with TTR locus. In conclusion, we provide novel insights regarding the molecular basis of ATTRm and SSA based on large-scale cohort, expanding our understanding of the phenotypic spectrum associated with TTR gene variation. | 10.1007/s00439-019-02078-6 | medrxiv |
10.1101/19001693 | Automated interpretation of the coronary angioscopy with deep convolutional neural networks | Miyoshi, T.; Higaki, A.; Kawakami, H.; Yamaguchi, O. | Akinori Higaki | Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC, Canada | 2019-07-08 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | cardiovascular medicine | https://www.medrxiv.org/content/early/2019/07/08/19001693.source.xml | BackgroundCoronary angioscopy (CAS) is a useful modality to assess atherosclerotic changes, but interpretation of the images requires expert knowledge. Deep convolutional neural networks (DCNN) can be used for diagnostic prediction and image synthesis.
Methods107 images from 47 patients, who underwent coronary angioscopy in our hospital between 2014 and 2017, and 864 images, selected from 142 MEDLINE-indexed articles published between 2000 and 2019, were analyzed. First, we developed a prediction model for the angioscopic findings. Next, we made a generative adversarial networks (GAN) model to simulate the CAS images. Finally, we tried to control the output images according to the angioscopic findings with conditional GAN architecture.
ResultsFor both yellow color (YC) grade and neointimal coverage (NC) grade, we could observe strong correlations between the true grades and the predicted values (YC grade, average r value = 0.80 {+/-} 0.02, p-value <0.001; NC grade, average r value = 0.73 {+/-} 0.02, p < 0.001). The binary classification model for the red thrombus yielded 0.71 {+/-} 0.03 F1-score and the area under the ROC curve (AUC) was 0.91 {+/-} 0.02. The standard GAN model could generate realistic CAS images (average Inception score = 3.57 {+/-} 0.06). GAN-based data augmentation improved the performance of the prediction models. In the conditional GAN model, there were significant correlations between given values and the experts diagnosis in YC grade and NC grade.
ConclusionDCNN is useful in both predictive and generative modeling that can help develop the diagnostic support system for CAS. | 10.1136/openhrt-2019-001177 | medrxiv |
10.1101/19001693 | Automated interpretation of the coronary angioscopy with deep convolutional neural networks | Miyoshi, T.; Higaki, A.; Kawakami, H.; Yamaguchi, O. | Akinori Higaki | Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC, Canada | 2019-12-17 | 2 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | cardiovascular medicine | https://www.medrxiv.org/content/early/2019/12/17/19001693.source.xml | BackgroundCoronary angioscopy (CAS) is a useful modality to assess atherosclerotic changes, but interpretation of the images requires expert knowledge. Deep convolutional neural networks (DCNN) can be used for diagnostic prediction and image synthesis.
Methods107 images from 47 patients, who underwent coronary angioscopy in our hospital between 2014 and 2017, and 864 images, selected from 142 MEDLINE-indexed articles published between 2000 and 2019, were analyzed. First, we developed a prediction model for the angioscopic findings. Next, we made a generative adversarial networks (GAN) model to simulate the CAS images. Finally, we tried to control the output images according to the angioscopic findings with conditional GAN architecture.
ResultsFor both yellow color (YC) grade and neointimal coverage (NC) grade, we could observe strong correlations between the true grades and the predicted values (YC grade, average r value = 0.80 {+/-} 0.02, p-value <0.001; NC grade, average r value = 0.73 {+/-} 0.02, p < 0.001). The binary classification model for the red thrombus yielded 0.71 {+/-} 0.03 F1-score and the area under the ROC curve (AUC) was 0.91 {+/-} 0.02. The standard GAN model could generate realistic CAS images (average Inception score = 3.57 {+/-} 0.06). GAN-based data augmentation improved the performance of the prediction models. In the conditional GAN model, there were significant correlations between given values and the experts diagnosis in YC grade and NC grade.
ConclusionDCNN is useful in both predictive and generative modeling that can help develop the diagnostic support system for CAS. | 10.1136/openhrt-2019-001177 | medrxiv |
10.1101/19001693 | Automated interpretation of the coronary angioscopy with deep convolutional neural networks | Miyoshi, T.; Higaki, A.; Kawakami, H.; Yamaguchi, O. | Akinori Higaki | Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC, Canada | 2020-01-08 | 3 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | cardiovascular medicine | https://www.medrxiv.org/content/early/2020/01/08/19001693.source.xml | BackgroundCoronary angioscopy (CAS) is a useful modality to assess atherosclerotic changes, but interpretation of the images requires expert knowledge. Deep convolutional neural networks (DCNN) can be used for diagnostic prediction and image synthesis.
Methods107 images from 47 patients, who underwent coronary angioscopy in our hospital between 2014 and 2017, and 864 images, selected from 142 MEDLINE-indexed articles published between 2000 and 2019, were analyzed. First, we developed a prediction model for the angioscopic findings. Next, we made a generative adversarial networks (GAN) model to simulate the CAS images. Finally, we tried to control the output images according to the angioscopic findings with conditional GAN architecture.
ResultsFor both yellow color (YC) grade and neointimal coverage (NC) grade, we could observe strong correlations between the true grades and the predicted values (YC grade, average r value = 0.80 {+/-} 0.02, p-value <0.001; NC grade, average r value = 0.73 {+/-} 0.02, p < 0.001). The binary classification model for the red thrombus yielded 0.71 {+/-} 0.03 F1-score and the area under the ROC curve (AUC) was 0.91 {+/-} 0.02. The standard GAN model could generate realistic CAS images (average Inception score = 3.57 {+/-} 0.06). GAN-based data augmentation improved the performance of the prediction models. In the conditional GAN model, there were significant correlations between given values and the experts diagnosis in YC grade and NC grade.
ConclusionDCNN is useful in both predictive and generative modeling that can help develop the diagnostic support system for CAS. | 10.1136/openhrt-2019-001177 | medrxiv |
10.1101/19001545 | Bayesian spatial modelling of childhood cancer incidence in Switzerland using exact point data: A nationwide study during 1985-2015. | Konstantinoudis, G.; Schuhmacher, D.; Ammann, R.; Diesch, T.; Kuehni, C.; Spycher, B. D. | Ben Daniel Spycher | Institute of social and preventive medicine, University of Bern | 2019-07-08 | 1 | PUBLISHAHEADOFPRINT | cc_by | epidemiology | https://www.medrxiv.org/content/early/2019/07/08/19001545.source.xml | BackgroundThe aetiology of most childhood cancers is largely unknown. Spatially varying environmental factors such as traffic-related air pollution, background radiation and agricultural pesticides might contribute to the development of childhood cancer. We investigated the spatial variation of childhood cancers in Switzerland using exact geocodes of place of residence.
MethodsWe included 5,947 children diagnosed with cancer during 1985-2015 at age 0-15 from the Swiss Childhood Cancer Registry. We modelled cancer risk using log-Gaussian Cox processes and indirect standardization to adjust for age and year of diagnosis. We examined whether the modelled spatial variation of risk can be explained by ambient air concentration of NO2, natural background radiation, area-based socio-economic position (SEP), linguistic region, years of existing general cancer registration in the canton or degree of urbanization.
ResultsFor all childhood cancers combined, the posterior median relative risk (RR), compared to the national level, varied by location from 0.83 to 1.13 (min to max). Corresponding ranges were 0.96 to 1.09 for leukaemia, 0.90 to 1.13 for lymphoma, and 0.82 to 1.23 for CNS tumours. The covariates considered explained 72% of the observed spatial variation for all cancers, 81% for leukaemia, 82% for lymphoma and 64% for CNS tumours. There was evidence of an association of background radiation and SEP with incidence of CNS tumours, (1.19;0.98-1.40) and (1.6;1-1.13) respectively.
ConclusionOf the investigated diagnostic groups, childhood CNS tumours show the largest spatial variation in Switzerland. The selected covariates only partially explained the observed variation of CNS tumours suggesting that other environmental factors also play a role. | 10.1186/s12942-020-00211-7 | medrxiv |
10.1101/19001545 | Bayesian spatial modelling of childhood cancer incidence in Switzerland using exact point data: A nationwide study during 1985-2015. | Konstantinoudis, G.; Schuhmacher, D.; Ammann, R.; Diesch, T.; Kuehni, C.; Spycher, B. D. | Ben Daniel Spycher | Institute of social and preventive medicine, University of Bern | 2019-07-15 | 2 | PUBLISHAHEADOFPRINT | cc_by | epidemiology | https://www.medrxiv.org/content/early/2019/07/15/19001545.source.xml | BackgroundThe aetiology of most childhood cancers is largely unknown. Spatially varying environmental factors such as traffic-related air pollution, background radiation and agricultural pesticides might contribute to the development of childhood cancer. We investigated the spatial variation of childhood cancers in Switzerland using exact geocodes of place of residence.
MethodsWe included 5,947 children diagnosed with cancer during 1985-2015 at age 0-15 from the Swiss Childhood Cancer Registry. We modelled cancer risk using log-Gaussian Cox processes and indirect standardization to adjust for age and year of diagnosis. We examined whether the modelled spatial variation of risk can be explained by ambient air concentration of NO2, natural background radiation, area-based socio-economic position (SEP), linguistic region, years of existing general cancer registration in the canton or degree of urbanization.
ResultsFor all childhood cancers combined, the posterior median relative risk (RR), compared to the national level, varied by location from 0.83 to 1.13 (min to max). Corresponding ranges were 0.96 to 1.09 for leukaemia, 0.90 to 1.13 for lymphoma, and 0.82 to 1.23 for CNS tumours. The covariates considered explained 72% of the observed spatial variation for all cancers, 81% for leukaemia, 82% for lymphoma and 64% for CNS tumours. There was evidence of an association of background radiation and SEP with incidence of CNS tumours, (1.19;0.98-1.40) and (1.6;1-1.13) respectively.
ConclusionOf the investigated diagnostic groups, childhood CNS tumours show the largest spatial variation in Switzerland. The selected covariates only partially explained the observed variation of CNS tumours suggesting that other environmental factors also play a role. | 10.1186/s12942-020-00211-7 | medrxiv |
10.1101/19001578 | Public knowledge and attitude towards epilepsy and its associated factors in Debre Berhan, North Shoa, Amhara Region, Ethiopia, 2018/19. Community based cross sectional study | dargie, a. w.; engidaw, n. a.; basha, e. a. | abate wubetu dargie Jr. | Debre Berhan University | 2019-07-08 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | epidemiology | https://www.medrxiv.org/content/early/2019/07/08/19001578.source.xml | IntroductionEpilepsy is chronic brain disorder characterized by recurrent derangement of the nervous system due to the sudden excessive disorderly discharge of the cerebral neurons. People living with epilepsy continue to suffer from enacted or perceived stigma that is based on myths, misconceptions, and misunderstandings that have persisted for many years. Therefore, this study aimed to assess the community general knowledge and attitude towards epilepsy.
MethodsCommunity-based cross-sectional study was conducted to assess public general knowledge and attitude towards epilepsy and its associated factors using structured pretested questionnaire. Data were entered into Epi data version 3.1 and transported to SPSS version 21 further analysis. Both Bivariable and Multivariable Logistic Regression was done to identify associated factors. Odds Ratios and their 95% Confidence interval were computed and variables with p-value less than 0.05 was considered significantly associated factors.
Results596 study participants participated in a response rate of 98%. Among the study participants, 43.6 (95% CI: 39.6, 47.5) had poor knowledge and 41.3 (95% CI: 37.4, 45.1) had an unfavorable attitude. Being secondary education, marital status, witnessed a seizure and heard the term epilepsy were showed statistically significant association with poor knowledge about epilepsy. Level of education, low average monthly income, not witnessed a seizure, not heard the term epilepsy and distant from health facility showed statically significant association with the unfavorable attitude.
ConclusionIn this study, Debre Berhan communities were found to have deficits in terms of general knowledge and attitude about epilepsy; and it should be given due attention. | null | medrxiv |
10.1101/19001578 | Public knowledge and attitude towards epilepsy and its associated factors in Debre Berhan, North Shoa, Amhara Region, Ethiopia, 2018/19. Community based cross sectional study | dargie, a. w.; engidaw, n. a.; basha, e. a. | abate wubetu dargie Jr. | Debre Berhan University | 2019-07-15 | 2 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | epidemiology | https://www.medrxiv.org/content/early/2019/07/15/19001578.source.xml | IntroductionEpilepsy is chronic brain disorder characterized by recurrent derangement of the nervous system due to the sudden excessive disorderly discharge of the cerebral neurons. People living with epilepsy continue to suffer from enacted or perceived stigma that is based on myths, misconceptions, and misunderstandings that have persisted for many years. Therefore, this study aimed to assess the community general knowledge and attitude towards epilepsy.
MethodsCommunity-based cross-sectional study was conducted to assess public general knowledge and attitude towards epilepsy and its associated factors using structured pretested questionnaire. Data were entered into Epi data version 3.1 and transported to SPSS version 21 further analysis. Both Bivariable and Multivariable Logistic Regression was done to identify associated factors. Odds Ratios and their 95% Confidence interval were computed and variables with p-value less than 0.05 was considered significantly associated factors.
Results596 study participants participated in a response rate of 98%. Among the study participants, 43.6 (95% CI: 39.6, 47.5) had poor knowledge and 41.3 (95% CI: 37.4, 45.1) had an unfavorable attitude. Being secondary education, marital status, witnessed a seizure and heard the term epilepsy were showed statistically significant association with poor knowledge about epilepsy. Level of education, low average monthly income, not witnessed a seizure, not heard the term epilepsy and distant from health facility showed statically significant association with the unfavorable attitude.
ConclusionIn this study, Debre Berhan communities were found to have deficits in terms of general knowledge and attitude about epilepsy; and it should be given due attention. | null | medrxiv |
10.1101/19001719 | Antihypertensive medications as repurposed treatments for mood disorders: analysis of linked healthcare data for 1.8 million patients | Shaw, R. J.; Mackay, D.; Pell, J. P.; Padmanabhan, S.; Bailey, D. S.; Smith, D. J. | Richard John Shaw | University of Glasgow | 2019-07-08 | 1 | PUBLISHAHEADOFPRINT | cc_no | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2019/07/08/19001719.source.xml | BackgroundRecent work suggests that antihypertensive medications may be useful as repurposed treatments for mood disorders. Using large-scale linked healthcare data we investigated whether certain classes of antihypertensive, such as angiotensin antagonists and calcium channel blockers, were associated with reduced risk of new-onset Major Depressive Disorder (MDD) or bipolar disorder.
MethodTwo cohorts of patients treated with antihypertensives were identified from Scottish prescribing (2009-2016) and hospital admission (1981-2016) records. Eligibility for cohort membership was determined by receipt of a minimum of four prescriptions for antihypertensives within a 12-month window. One treatment cohort (n=538,730) included patients with no previous history of mood disorder, whereas the other (n=262,278) included those who did. Both cohorts were matched by age, sex and area deprivation to untreated comparators. Associations between antihypertensive treatment and new-onset MDD or bipolar episodes were investigated using Cox regression.
ResultsFor patients without a history of mood disorder, antihypertensives were associated with increased risk of new-onset MDD. For angiotensin antagonist monotherapy, the hazard ratio (HR) for new-onset MDD was 1.17 (95%CI 1.04-1.31). Beta blockers association was stronger (HR 2.68; 95%CI 2.45-2.92), possibly indicating pre-existing anxiety. Some classes of antihypertensive were associated with protection against bipolar disorder, particularly angiotensin antagonists (HR 0.46; 95%CI 0.30-0.70). For patients with a past history of mood disorders, all classes of antihypertensives were associated with increased risk of future episodes of MDD.
ConclusionsThere was no evidence that antihypertensive medications prevented new episodes of MDD but angiotensin antagonists may represent a novel treatment avenue for bipolar disorder. | 10.1017/S0033291719004094 | medrxiv |
10.1101/19001719 | The relationship between antihypertensive medications and mood disorders: analysis of linked healthcare data for 1.8 million patients. | Shaw, R. J.; Mackay, D.; Pell, J. P.; Padmanabhan, S.; Bailey, D. S.; Smith, D. J. | Richard John Shaw | University of Glasgow | 2019-12-20 | 2 | PUBLISHAHEADOFPRINT | cc_no | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2019/12/20/19001719.source.xml | BackgroundRecent work suggests that antihypertensive medications may be useful as repurposed treatments for mood disorders. Using large-scale linked healthcare data we investigated whether certain classes of antihypertensive, such as angiotensin antagonists and calcium channel blockers, were associated with reduced risk of new-onset Major Depressive Disorder (MDD) or bipolar disorder.
MethodTwo cohorts of patients treated with antihypertensives were identified from Scottish prescribing (2009-2016) and hospital admission (1981-2016) records. Eligibility for cohort membership was determined by receipt of a minimum of four prescriptions for antihypertensives within a 12-month window. One treatment cohort (n=538,730) included patients with no previous history of mood disorder, whereas the other (n=262,278) included those who did. Both cohorts were matched by age, sex and area deprivation to untreated comparators. Associations between antihypertensive treatment and new-onset MDD or bipolar episodes were investigated using Cox regression.
ResultsFor patients without a history of mood disorder, antihypertensives were associated with increased risk of new-onset MDD. For angiotensin antagonist monotherapy, the hazard ratio (HR) for new-onset MDD was 1.17 (95%CI 1.04-1.31). Beta blockers association was stronger (HR 2.68; 95%CI 2.45-2.92), possibly indicating pre-existing anxiety. Some classes of antihypertensive were associated with protection against bipolar disorder, particularly angiotensin antagonists (HR 0.46; 95%CI 0.30-0.70). For patients with a past history of mood disorders, all classes of antihypertensives were associated with increased risk of future episodes of MDD.
ConclusionsThere was no evidence that antihypertensive medications prevented new episodes of MDD but angiotensin antagonists may represent a novel treatment avenue for bipolar disorder. | 10.1017/S0033291719004094 | medrxiv |
10.1101/19001719 | The relationship between antihypertensive medications and mood disorders: analysis of linked healthcare data for 1.8 million patients. | Shaw, R. J.; Mackay, D.; Pell, J. P.; Padmanabhan, S.; Bailey, D. S.; Smith, D. J. | Richard John Shaw | University of Glasgow | 2020-01-23 | 3 | PUBLISHAHEADOFPRINT | cc_no | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2020/01/23/19001719.source.xml | BackgroundRecent work suggests that antihypertensive medications may be useful as repurposed treatments for mood disorders. Using large-scale linked healthcare data we investigated whether certain classes of antihypertensive, such as angiotensin antagonists and calcium channel blockers, were associated with reduced risk of new-onset Major Depressive Disorder (MDD) or bipolar disorder.
MethodTwo cohorts of patients treated with antihypertensives were identified from Scottish prescribing (2009-2016) and hospital admission (1981-2016) records. Eligibility for cohort membership was determined by receipt of a minimum of four prescriptions for antihypertensives within a 12-month window. One treatment cohort (n=538,730) included patients with no previous history of mood disorder, whereas the other (n=262,278) included those who did. Both cohorts were matched by age, sex and area deprivation to untreated comparators. Associations between antihypertensive treatment and new-onset MDD or bipolar episodes were investigated using Cox regression.
ResultsFor patients without a history of mood disorder, antihypertensives were associated with increased risk of new-onset MDD. For angiotensin antagonist monotherapy, the hazard ratio (HR) for new-onset MDD was 1.17 (95%CI 1.04-1.31). Beta blockers association was stronger (HR 2.68; 95%CI 2.45-2.92), possibly indicating pre-existing anxiety. Some classes of antihypertensive were associated with protection against bipolar disorder, particularly angiotensin antagonists (HR 0.46; 95%CI 0.30-0.70). For patients with a past history of mood disorders, all classes of antihypertensives were associated with increased risk of future episodes of MDD.
ConclusionsThere was no evidence that antihypertensive medications prevented new episodes of MDD but angiotensin antagonists may represent a novel treatment avenue for bipolar disorder. | 10.1017/S0033291719004094 | medrxiv |
10.1101/19001610 | Impact of a regional educational advertising campaign on harm perceptions of e-cigarettes, prevalence of e-cigarette use, and quit attempts among smokers | Tattan-Birch, H.; Jackson, S. E.; Ide, C.; Bauld, L.; Shahab, L. | Harry Tattan-Birch | University College London, UK | 2019-07-08 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc | public and global health | https://www.medrxiv.org/content/early/2019/07/08/19001610.source.xml | BackgroundWe evaluated how effective an advertising campaign that was piloted by Cancer Research UK in January/February 2018 was at promoting quit attempts by increasing awareness of the relative harms of e-cigarettes compared with smoking.
MethodsAdults ([≥]16 years, n = 2217) living in Greater Manchester (campaign region) and Yorkshire & Humber and the North East of England (control regions) completed cross-sectional surveys immediately before and after the campaign period. Surveys measured socio-demographics, perceptions and use of e-cigarettes, and motivation and attempts to quit smoking. We tested interactions between time (pre, post) and region (campaign, control).
Results36.7% (95% CI 33.0% - 40.6%) of those in the intervention region recognised the campaign. In the general population, interactions were non-significant for all outcomes except for perception of e-cigarettes as effective cessation aids, with smaller increases from pre-to post-campaign in the campaign (49.9% to 54.0%) compared with the control region (40.5% to 55.0%; OR = 0.66, 95% CI 0.45 - 0.98). Among smokers, motivation to quit increased in the intervention region (44.0% to 48.0%) but decreased in the control region (40.5% to 21.5%; OR = 2.97, 95% CI 1.25 - 7.16), with no other significant differences between regions over time. A Bayesian analysis confirmed that non-significant results were inconclusive.
ConclusionsCompared with the control region, the campaign was associated with an increase in smokers motivation to quit but a smaller increase in adults perception of e-cigarettes as an effective cessation aid. There was insufficient evidence to determine whether the campaign affected other outcomes. | 10.1093/ntr/ntz236 | medrxiv |
10.1101/19001594 | Plasma Itaconate elevation following successful cDMARD treatment in early rheumatoid arthritis patients elucidates disease activity associated macrophage activation | Daly, R.; Blackburn, G.; Mudaliar, M.; Burgess, K.; Stirling, A.; Porter, D.; McInnes, I.; Barrett, M. P.; Dale, J. | James Dale | University of Glasgow | 2019-07-08 | 1 | PUBLISHAHEADOFPRINT | cc_no | rheumatology | https://www.medrxiv.org/content/early/2019/07/08/19001594.source.xml | ObjectiveTo characterize changes in the plasma metabolic profile in newly diagnosed rheumatoid arthritis (RA) patients upon commencement of conventional disease modifying anti-rheumatic drug (cDMARD) therapy.
MethodsPlasma samples collected in an early RA randomized strategy study (NCT00920478) that compared clinical (DAS) disease activity assessment with musculoskeletal ultrasound assessment (MSUS) to drive treatment decisions were subjected to untargeted metabolomic analysis. Metabolic profiles were collected at pre- and 3 months post commencement of non-biologic cDMARD. Metabolites that changed in association with changes in the DAS44 score were identified at the 3 month timepoint.
ResultsA total of ten metabolites exhibited a clear correlation with reduction in DAS44 score following cDMARD commencement, particularly itaconate, its derived anhydride and a derivative of itaconate coA. Increasing itaconate correlated with improved DAS44 score and decreasing levels of CRP.
ConclusioncDMARD treatment effects invoke consistent changes in plasma detectable metabolites, that in turn implicate clinical disease activity with macrophages. Such changes inform RA pathogenesis and reveal for the first time a link between itaconate production and resolution of an inflammatory disease in humans. Quantitative metabolic biomarker based tests of clinical change in state are feasible and should be developed around the itaconate pathway.
Key MessagesO_ST_ABSWhat is already known about this subject?C_ST_ABSRheumatoid arthritis is associated with perturbations in metabolic activity, which have also been associated with response to certain treatments. In vitro work on immunometabolism has recently revealed itaconate as a key metabolite controlling macrophage activation.
What does this study add?In newly diagnosed RA, commencement of csDMARD therapy is associated with changes in the levels of ten metabolites (especially itaconate and its derivatives) that correlate to a corresponding fall in disease activity Pathway analyses suggest these metabolites are associated with macrophage activation.
How might this impact on clinical practice?Changes in metabolite levels in response to treatment provide additional new insights into RA pathogenesis that suggest a focus on macrophage activation state. The association of increased itaconate with decreased inflammation point to possible routes of intervention in RA. | 10.3390/metabo10060241 | medrxiv |
10.1101/19001511 | Cluster analysis successfully identifies clinically meaningful knee valgus moment patterns: Frequency of early peaks reflects sex-specific ACL injury incidence | Sigurthsson, H. B.; Briem, K. | Haraldur Björn Sigurðsson | University of Iceland | 2019-07-08 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | sports medicine | https://www.medrxiv.org/content/early/2019/07/08/19001511.source.xml | BackgroundBiomechanical studies of ACL injury risk factors report heterogenous results, analyze only a fraction of the data, and do not analyze data in accordance with the injury mechanism. Extracting a peak value of relevance to ACL injuries is challenging due to differences in the relative timing of the peak value.
Aims/HypothesesThe aim was to cluster analyze the knee valgus moment time series curve shape in the early stance phase. We hypothesized that 1a) There would be few discrete curve shapes, 1b) there would be an early peak pattern, 2a) youth athletes of both sexes would show similar frequencies of early peaks, 2b) adolescent girls would have higher early peak frequencies.
MethodsN=213 (39% boys) youth soccer and team handball athletes (phase 1) and N=35 (45% boys) with 5 year follow-up data (phase 2) were recorded performing a change of direction task with 3D motion analysis and a force plate. The time series of the first 30% of stance phase were cluster analyzed based on Euclidean distances in two steps; shape-based main clusters with a transformed time series, and magnitude based sub-clusters with body weight normalized time series. Group differences (sex, phase) in curve shape frequencies, and shape-magnitude frequencies were tested with chi-squared test.
Results6 discrete shape-clusters and 14 magnitude based sub-clusters were formed. Phase 1 boys had higher frequencies of early peaks than phase 1 girls (38% vs 25% respectively, P<0.001 for full test). Phase 2 girls had higher frequencies of early peaks than phase 2 boys (42% vs 21% respectively, P<0.001 for full test).
ConclusionsCluster analysis can reveal different patterns of curve shapes in biomechanical data. The early peak shape is relatable to the ACL injury mechanism as the timing of its peak moment is consistent with the timing of injury. Higher frequency of early peaks demonstrated by Phase 2 girls is consistent with their higher incidence of ACL injury. | 10.1186/s40634-019-0205-5 | medrxiv |
10.1101/19000760 | Reduced survival in COPD patients who received long-term oxygen therapy without meeting prescription criteria: a preliminary study | Alexandre, F.; Varray, A.; Stephan, Y.; Hayot, M.; Heraud, N. | Francois Alexandre | Les Cliniques du Souffle, groupe 5-Sante | 2019-07-08 | 1 | PUBLISHAHEADOFPRINT | cc_by_nd | respiratory medicine | https://www.medrxiv.org/content/early/2019/07/08/19000760.source.xml | BackgroundRandomized clinical trials have provided clear evidence that long-term oxygen therapy (LTOT) increases life expectancy in severely hypoxemic COPD patients. However, in real-life settings, in global COPD cohorts, a paradoxical 2-3-fold increased risk of death has been reported in patients under LTOT. This discrepancy could be explained by a subgroup of patients under LTOT who do not meet the current guidelines and for whom LTOT would be associated with poor prognosis. This retrospective study of a global COPD cohort therefore sought to: (1) determine if a subgroup of patients under LTOT without severe hypoxemia could be distinguished, and (2) compare the mortality risk according to hypoxemia severity and LTOT prescription.
MethodThe sample was taken from a database (NCT02055885) on 191 stable COPD patients (age: 65.1{+/-}9.8 years, 85 women) admitted for a pulmonary rehabilitation program between 2009 and 2012 and followed until 1 January 2018. Uni- and multivariate Cox proportional hazard ratio (HR) models were used to examine the associations between clinical characteristics (age, sex, blood gases, etc.), LTOT according to PaO2 level, and mortality.
ResultsForty patients (21%) were under LTOT at PR entry despite not meeting the O2 prescription criteria. Patients under LTOT had a nearly 2-fold higher mortality risk adjusted by covariates (HRmultivariate=1.83; p=0.009). Furthermore, the higher mortality risk under LTOT was specific to the patients under LTOT without severe hypoxemia (HRmultivariate=2.39; p=0.04).
ConclusionThe association between LTOT and mortality might be attributed to a subgroup under LTOT despite not/no longer meeting the LTOT criteria. Further studies are needed to identify the physiological basis of this phenomenon. | null | medrxiv |
10.1101/19000950 | Oncofetal Protein Cripto-1 in a new clinical role: a potential tumor marker for Oral Squamous Cell Carcinoma. | Jain, A.; Mallupattu, S. K.; Thakur, R.; Mohindra, S.; Bal, A.; Das, A.; Ghoshal, S.; Pal, A. | Arnab Pal | Department of Biochemistry, Post Graduate Institute of Medical Education and Research | 2019-07-08 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc | oncology | https://www.medrxiv.org/content/early/2019/07/08/19000950.source.xml | PURPOSECR-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.
METHODSCR-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.
RESULTSPre-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.
CONCLUSIONThis 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. | 10.1007/s12291-020-00898-2 | medrxiv |
10.1101/19000232 | Optimising the use of molecular tools for the diagnosis of yaws | Munson, M.;Cresswell, B.;Kondobala, K.;Gainwu, B.;Lomotey,R. D.;Oppong, P.;Agyeman, F. O.;Kotye, N.;Diwura, M.;Ako, E. P.;Simpson, S. V.;Addo, K. K.;
Pickering, H.;Handley, R.;Houghton, J.;Kwakye, C.;Marks, M.; | Michael Marks | London School of Hygiene and Tropical Medicine | 2019-06-25 | 1 | null | cc_by | infectious diseases | https://www.medrxiv.org/content/early/2019/06/25/19000232.source.xml | IntroductionYaws is a neglected tropical disease and results in lesions of skin, soft tissues and bones. PCR plays an important part in surveillance.
MethodsChildren suspected to have yaws were enrolled. From the largest lesion paired swabs were collected; one into transport medium and one as a dry swab. In children with multiple lesions we collected additional swabs from up to four subsequent lesions. Swabs in transport medium were maintained in a cold-chain whilst dry swabs were stored at ambient temperature. Swabs were tested by PCR for Treponema pallidum and Haemophilus ducreyi.
ResultsOf 55 individuals, 10 (18%) had at least 1 positive PCR for T. pallidum and 12 (22%) had at least 1 positive result for H. ducreyi. Concordance was 100% between swabs in transport medium and dry swabs. One patient had PCR-confirmed yaws on the swab of a third lesion when both the first and second lesions were PCR-negative.
DiscussionStoring swabs in transport medium and transporting in a cold chain did not improve yield, however detection of T. pallidum is increased by swabbing additional lesions. As the target for yaws is eradication approaches to sample collection need revisiting to ensure cases are not missed. | 10.1093/trstmh/trz083 | medrxiv |
10.1101/19000232 | Optimising the use of molecular tools for the diagnosis of yaws | Munson, M.; Cresswell, B.; Kondobala, K.; Gainwu, B.; Lomotey, R. D.; Oppong, P.; Agyeman, F. O.; Kotye, N.; Diwura, M.; Ako, E. P.; Simpson, S. V.; Addo, K. K.; Pickering, H.; Handley, R.; Houghton, J.; Kwakye, C.; Marks, M. | Michael Marks | London School of Hygiene and Tropical Medicine | 2019-07-09 | 2 | PUBLISHAHEADOFPRINT | cc_by | infectious diseases | https://www.medrxiv.org/content/early/2019/07/09/19000232.source.xml | IntroductionYaws is a neglected tropical disease and results in lesions of skin, soft tissues and bones. PCR plays an important part in surveillance.
MethodsChildren suspected to have yaws were enrolled. From the largest lesion paired swabs were collected; one into transport medium and one as a dry swab. In children with multiple lesions we collected additional swabs from up to four subsequent lesions. Swabs in transport medium were maintained in a cold-chain whilst dry swabs were stored at ambient temperature. Swabs were tested by PCR for Treponema pallidum and Haemophilus ducreyi.
ResultsOf 55 individuals, 10 (18%) had at least 1 positive PCR for T. pallidum and 12 (22%) had at least 1 positive result for H. ducreyi. Concordance was 100% between swabs in transport medium and dry swabs. One patient had PCR-confirmed yaws on the swab of a third lesion when both the first and second lesions were PCR-negative.
DiscussionStoring swabs in transport medium and transporting in a cold chain did not improve yield, however detection of T. pallidum is increased by swabbing additional lesions. As the target for yaws is eradication approaches to sample collection need revisiting to ensure cases are not missed. | 10.1093/trstmh/trz083 | medrxiv |
10.1101/19000232 | Optimising the use of molecular tools for the diagnosis of yaws | Munson, M.; Cresswell, B.; Kondobala, K.; Gainwu, B.; Lomotey, R. D.; Oppong, P.; Agyeman, F. O.; Kotye, N.; Diwura, M.; Ako, E. P.; Simpson, S. V.; Addo, K. K.; Pickering, H.; Handley, R.; Houghton, J.; Kwakye, C.; Marks, M. | Michael Marks | London School of Hygiene and Tropical Medicine | 2019-07-15 | 3 | PUBLISHAHEADOFPRINT | cc_by | infectious diseases | https://www.medrxiv.org/content/early/2019/07/15/19000232.source.xml | IntroductionYaws is a neglected tropical disease and results in lesions of skin, soft tissues and bones. PCR plays an important part in surveillance.
MethodsChildren suspected to have yaws were enrolled. From the largest lesion paired swabs were collected; one into transport medium and one as a dry swab. In children with multiple lesions we collected additional swabs from up to four subsequent lesions. Swabs in transport medium were maintained in a cold-chain whilst dry swabs were stored at ambient temperature. Swabs were tested by PCR for Treponema pallidum and Haemophilus ducreyi.
ResultsOf 55 individuals, 10 (18%) had at least 1 positive PCR for T. pallidum and 12 (22%) had at least 1 positive result for H. ducreyi. Concordance was 100% between swabs in transport medium and dry swabs. One patient had PCR-confirmed yaws on the swab of a third lesion when both the first and second lesions were PCR-negative.
DiscussionStoring swabs in transport medium and transporting in a cold chain did not improve yield, however detection of T. pallidum is increased by swabbing additional lesions. As the target for yaws is eradication approaches to sample collection need revisiting to ensure cases are not missed. | 10.1093/trstmh/trz083 | medrxiv |
10.1101/19001248 | Higher energy requirement during weight-loss maintenance on a low- versus high-carbohydrate diet: secondary analyses from a randomized controlled feeding study | Ebbeling, C. B.; Bielak, L.; Lakin, P. R.; Klein, G. L.; Wong, J. M.; Luoto, P. K.; Wong, W. W.; Ludwig, D. S. | David S Ludwig | Boston Children\'s Hospital, Harvard Med School | 2019-07-11 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | nutrition | https://www.medrxiv.org/content/early/2019/07/11/19001248.source.xml | BackgroundLonger-term feeding studies suggest that a low-carbohydrate diet increases energy expenditure, consistent with the carbohydrate-insulin model of obesity. However, the validity of methodology utilized in these studies, involving doubly-labeled water, has been questioned.
ObjectiveThe aim of this study was to determine whether dietary energy requirement for weight-loss maintenance is higher on a low-versus high-carbohydrate diet.
MethodsThe study reports secondary outcomes and exploratory analyses from a feeding study in which the primary outcome was total energy expenditure. After attaining a mean Run-in weight loss of 10.5%, 164 adults with pre-weight-loss BMI of [≥]25 were randomly assigned to Test diets containing Low (20%), Moderate (40%) or High (60%) carbohydrate for 20 weeks. Calorie content of Test diets was adjusted to maintain individual body weight within 2 kg of the post-weight-loss value. In analyses by Intention-to-Treat (ITT, study completers, n=148) and Per Protocol (PP, those achieving the weight-loss maintenance target, n=110), we compared estimated energy requirement from 10 to 20 weeks on the Test diets using ANCOVA. Insulin secretion was assessed pre-weight-loss as insulin concentration 30 minutes following 75 grams oral glucose (Insulin-30).
ResultsEstimated energy requirement was higher in the Low vs High group by models involving ITT (ranging from 181 [CI 8-353] to 223 [40-406] kcal/d; P[≤]0.04) and PP (ranging from 245 [43-446] to 295 [91-499] kcal/d; P[≤]0.02). This difference remained significant in sensitivity analyses accounting for change in adiposity and possible non-adherence. In observational analyses, pre-weight loss Insulin-30 predicted adverse change in body composition following weight loss.
ConclusionsEnergy requirement was higher on a low-versus high-carbohydrate diet during weight-loss maintenance, commensurate with total energy expenditure. These data are consistent with the carbohydrate-insulin model and lend qualified support for the validity of the doubly-labeled water method with diets varying in macronutrient composition. | 10.1093/jn/nxaa150 | medrxiv |
10.1101/19001206 | Detection of malaria parasites in dried human blood spots using mid-infrared spectroscopy and logistic regression analysis | Mwanga, E. P.; Minja, E. G.; Mrimi, E.; Gonzalez Jimenez, M.; Swai, J. K.; Abbas, S.; Ngowo, H. S.; Siria, D. J.; Mapua, S. A.; Stica, C.; Maia, M. F.; Olotu, A.; Sikulu-Lord, M. T.; Baldini, F.; Ferguson, H. M.; Wynne, K.; Selvaraj, P.; Babayan, S. A.; Okumu, F. O. | Fredros O Okumu | Environmental Health and Ecological Sciences Department, Ifakara Health Institute, Morogoro, Tanzania; Institute of Biodiversity, Animal Health and Comparative | 2019-07-12 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | infectious diseases | https://www.medrxiv.org/content/early/2019/07/12/19001206.source.xml | BackgroundEpidemiological surveys of malaria currently rely on microscopy, polymerase chain reaction assays (PCR) or rapid diagnostic test kits for Plasmodium infections (RDTs). This study shows that mid-infrared (MIR) spectroscopy coupled with supervised machine learning could constitute an alternative method for rapid malaria screening, directly from dried human blood spots.
MethodsFilter papers containing dried blood spots (DBS) were obtained from a cross-sectional malaria survey in twelve wards in south-eastern Tanzania in 2018/19. The DBS were scanned using attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectrometer to obtain high-resolution MIR spectra in the range, 4000 cm-1 to 500 cm-1. The spectra were cleaned to compensate for atmospheric water vapor and CO2 interference bands and used to train different classification algorithms to distinguish between malaria-positive and malaria-negative DBS papers based on PCR test results as reference. The analysis considered 296 individuals, including 123 PCR-confirmed malaria-positives and 173 negatives. Model training was done using 80% of the dataset, after which the best-fitting model was optimized by bootstrapping of 80/20 train/test stratified splits. The trained models were evaluated by predicting Plasmodium falciparum positivity in the 20% validation set of DBS.
ResultsLogistic regression was the best-performing model. Considering PCR as reference, the models attained overall accuracies of 92% for predicting P. falciparum infections (specificity = 91.7%; sensitivity = 92.8%) and 85% for predicting mixed infections of P. falciparum and P. ovale (specificity = 85%, sensitivity = 85%) in the field-collected specimen.
ConclusionThese results demonstrate that mid-infrared spectroscopy coupled with supervised machine learning (MIR-ML) could be used to screen for malaria parasites in dried human blood spots. The approach could have potential for rapid and high-throughput screening of Plasmodium infections in both non-clinical settings (e.g. field surveys) and clinical settings (diagnosis to aid case management). However, full utility will require further advances in classification algorithms, field validation of this technology in other study sites and an in-depth evaluation of the biological basis of the observed test results. Training the models on larger datasets could also improve specificity and sensitivity of the technique. The MIR-ML spectroscopy system is robust, low-cost, and requires minimum maintenance. | 10.1186/s12936-019-2982-9 | medrxiv |
10.1101/19001396 | Post-Exposure Effects of Vaccines on Infectious Diseases | Gallagher, T. E.; Lipsitch, M. | Tara E Gallagher | Dartmouth College | 2019-07-12 | 1 | PUBLISHAHEADOFPRINT | cc_by_nd | infectious diseases | https://www.medrxiv.org/content/early/2019/07/12/19001396.source.xml | Many available vaccines have demonstrated post-exposure effectiveness, but no published systematic reviews have synthesized these findings. We searched the PubMed database for clinical trials and observational human studies concerning the post-exposure vaccination effects, targeting infections with an FDA-licensed vaccine plus dengue, hepatitis E, malaria, and tick borne encephalitis, which have licensed vaccines outside of the U.S. Studies concerning animal models, serologic testing, and pipeline vaccines were excluded. Eligible studies were evaluated by definition of exposure, and their attempt at distinguishing pre- and post-exposure effects was rated on a scale of 1-4. We screened 4518 articles and ultimately identified 14 clinical trials and 31 observational studies for this review, amounting to 45 eligible articles spanning 7 of the 28 vaccine-preventable diseases. For secondary attack rate, this body of evidence found the following medians for post-exposure vaccination effectiveness: hepatitis A: 85% (IQR: 28; 5 sources), hepatitis B: 85% (IQR: 22; 5 sources), measles: 83% (IQR: 21; 8 sources), varicella: 67% (IQR: 48; 9 sources), smallpox: 45% (IQR: 39; 4 sources), and mumps: 38% (IQR: 7; 2 sources). For case fatality proportions resulting from rabies and smallpox, the vaccine efficacies had medians of 100% (IQR: 0; 6 sources) and 63% (IQR: 50; 8 sources) post-exposure. Although mainly used for preventive measures, many available vaccines can modify or preclude disease if administered after exposure. This post-exposure effectiveness could be important to consider during vaccine trials and while developing new vaccines. | 10.1093/epirev/mxz014 | medrxiv |
10.1101/19002014 | Epigenetic field cancerization in breast cancer using subject-matched tumor, ipsilateral-normal, and contralateral-normal tissues | Muse, M. E.; Titus, A. J.; Salas, L. A.; Wilkins, O. M.; Mullen, C.; Gregory, K. J.; Schneider, S. S.; Crisi, G. M.; Jarwale, R. M.; Otis, C. N.; Christensen, B. C.; Arcaro, K. F. | Kathleen F. Arcaro | University of Massachusetts, Amherst, MA | 2019-07-12 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | epidemiology | https://www.medrxiv.org/content/early/2019/07/12/19002014.source.xml | BackgroundEmerging work has demonstrated that histologically normal (non-tumor) tissue adjacent to breast tumor tissue shows evidence of molecular alterations related to tumorigenesis, referred to as field cancerization effects. Although changes in DNA methylation are known to occur early in breast carcinogenesis and the landscape of breast tumor DNA methylation is profoundly altered compared with normal tissue, there have been limited efforts to identify DNA methylation field cancerization effects in histologically normal breast tissue adjacent to tumor.
MethodsMatched tumor, histologically normal tissue of the ipsilateral breast (ipsilateral-normal), and histologically normal tissue of the contralateral breast (contralateral-normal) were obtained from nine women undergoing bilateral mastectomy. Laser capture microdissection was used to select breast epithelial cells from normal tissues, and neoplastic cells from tumor specimens for genome-scale measures of DNA methylation with the Illumina HumanMethylationEPIC array.
ResultsWe identified substantially more CpG loci that were differentially methylated between contralateral-normal breast and tumor tissue (63,271 CpG loci q < 0.01), than between ipsilateral-normal tissue and tumor (38,346 CpG loci q < 0.01). In addition, we identified differential methylation in ipsilateral-normal relative to contralateral-normal tissue (9,562 CpG loci p < 0.01). Hypomethylated loci in ipsilateral normal relative to contralateral were significantly enriched for breast cancer-relevant transcription factor binding sites including those for ESR1, FoxA1, and GATA3. Hypermethylated loci in ipsilateral-normal relative to contralateral-normal tissue were significantly enriched for CpG island shore regions.
ConclusionsOur results indicate that early hypermethylation events in breast carcinogenesis are more likely to occur in the regions immediately surrounding CpG islands than CpG islands per se, reflecting a field effect of the tumor on surrounding histologically normal tissue. This work offers an opportunity to focus investigations of early DNA methylation alterations in breast carcinogenesis and potentially develop epigenetic biomarkers of disease risk. | null | medrxiv |
10.1101/19001404 | The fecal microbiome in diverticulitis and asymptomatic diverticulosis: A case-control study in the US | Hullar, M. A.; Sandstrom, R. S.; Stamatoyannopoulos, J. A.; Lampe, J. W.; Strate, L. L. | Lisa L Strate | University of Washington School of Medicine | 2019-07-12 | 1 | PUBLISHAHEADOFPRINT | cc_no | gastroenterology | https://www.medrxiv.org/content/early/2019/07/12/19001404.source.xml | ObjectiveThe intestinal microbiota are hypothesized to play a role in the pathogenesis of diverticulitis. We compared fecal microbial communities in individuals with diverticulitis to those with uncomplicated diverticulosis.
MethodsWe used 16S ribosomal RNA gene sequencing to assess and compare the microbiota composition of fecal samples from 10 patients presenting with acute diverticulitis (cases) and 10 controls with asymptomatic diverticulosis matched on age and sex.
ResultsWe found differences in the distribution of relative abundances of bacterial phyla and genera in diverticulitis cases versus diverticulosis controls. At the phyla level, Verrucomicrobia was more abundant on average in diverticulitis cases at the time of diagnosis than in diverticulosis controls (p=0.07). Univariate analysis identified a significant increase in the genera Coriobacteria (p=0.050), Anaerotruncus (0.046), Subdoliganulum (p=0.034), Marvinabryantia (p=0.006), and Akkermansia (p=0.04), and a decrease in Barnesiella (p=0.035) and Coprococcus (p=0.035) in diverticulitis cases at the time of diagnosis compared to diverticulosis controls. However, after correction for multiple comparisons, these differences were no longer significant. Partial least squares discriminant analysis on all microbial genera showed partial separation of diverticulitis cases at diagnosis and diverticulosis controls. The microbial alpha diversity was higher in diverticulitis cases at time of diagnosis vs controls but this was not significant (Shannon diversity index 7.4{+/-}0.6 vs 6.8{+/-}0.7, p=0.08).
ConclusionsIndividuals with diverticulitis differ from those with asymptomatic diverticulosis based on components of the fecal microbiome. | null | medrxiv |
10.1101/19001495 | Why so many significant Phase 3 results in clinical trials? | Adda, J.; Decker, C.; Ottaviani, M. | Marco Ottaviani | Bocconi University | 2019-07-12 | 1 | PUBLISHAHEADOFPRINT | cc_no | health economics | https://www.medrxiv.org/content/early/2019/07/12/19001495.source.xml | Clinical research should conform to high standards of ethical and scientific integrity, given that human lives are at stake. However, economic incentives can generate conflicts of interest for investigators, who may be inclined to withhold unfavorable results or even tamper with data in order to achieve desired outcomes. To shed light on the integrity of clinical trial results, this paper systematically analyzes the distribution of p-values of primary outcomes for phase II and phase III drug trials reported to the ClinicalTrials.gov registry. First, we detect no bunching of results just above the classical 5% threshold for statistical significance. Second, a density discontinuity test reveals an upward jump at the 5% threshold for phase III results by small industry sponsors. Third, we document a larger fraction of significant results in phase III compared to phase II. Linking trials across phases, we find that early favorable results increase the likelihood of continuing into the next phase. Once we take into account this selective continuation, we can explain almost completely the excess of significant results in phase III for trials conducted by large industry sponsors. For small industry sponsors, instead, part of the excess remains unexplained. | 10.1073/pnas.1919906117 | medrxiv |
10.1101/19001495 | Why so many significant Phase III results in clinical trials? | Adda, J.; Decker, C.; Ottaviani, M. | Marco Ottaviani | Bocconi University | 2019-11-25 | 2 | PUBLISHAHEADOFPRINT | cc_no | health economics | https://www.medrxiv.org/content/early/2019/11/25/19001495.source.xml | Clinical research should conform to high standards of ethical and scientific integrity, given that human lives are at stake. However, economic incentives can generate conflicts of interest for investigators, who may be inclined to withhold unfavorable results or even tamper with data in order to achieve desired outcomes. To shed light on the integrity of clinical trial results, this paper systematically analyzes the distribution of p-values of primary outcomes for phase II and phase III drug trials reported to the ClinicalTrials.gov registry. First, we detect no bunching of results just above the classical 5% threshold for statistical significance. Second, a density discontinuity test reveals an upward jump at the 5% threshold for phase III results by small industry sponsors. Third, we document a larger fraction of significant results in phase III compared to phase II. Linking trials across phases, we find that early favorable results increase the likelihood of continuing into the next phase. Once we take into account this selective continuation, we can explain almost completely the excess of significant results in phase III for trials conducted by large industry sponsors. For small industry sponsors, instead, part of the excess remains unexplained. | 10.1073/pnas.1919906117 | medrxiv |
10.1101/19001495 | P-hacking in clinical trials and how incentives shapethe distribution of results across phases | Adda, J.; Decker, C.; Ottaviani, M. | Marco Ottaviani | Bocconi University | 2020-03-27 | 3 | PUBLISHAHEADOFPRINT | cc_no | health economics | https://www.medrxiv.org/content/early/2020/03/27/19001495.source.xml | Clinical research should conform to high standards of ethical and scientific integrity, given that human lives are at stake. However, economic incentives can generate conflicts of interest for investigators, who may be inclined to withhold unfavorable results or even tamper with data in order to achieve desired outcomes. To shed light on the integrity of clinical trial results, this paper systematically analyzes the distribution of p-values of primary outcomes for phase II and phase III drug trials reported to the ClinicalTrials.gov registry. First, we detect no bunching of results just above the classical 5% threshold for statistical significance. Second, a density discontinuity test reveals an upward jump at the 5% threshold for phase III results by small industry sponsors. Third, we document a larger fraction of significant results in phase III compared to phase II. Linking trials across phases, we find that early favorable results increase the likelihood of continuing into the next phase. Once we take into account this selective continuation, we can explain almost completely the excess of significant results in phase III for trials conducted by large industry sponsors. For small industry sponsors, instead, part of the excess remains unexplained. | 10.1073/pnas.1919906117 | medrxiv |
10.1101/19001487 | Cardiac arrest outcomes after targeted temperature management with an esophageal cooling device | Wayne, M. A.; Anderson, C.; Fisher, R.; Berry, D.; Diestelhorst, J. B. | Marvin A Wayne | PeaceHealth St. Joseph Medical Center | 2019-07-12 | 1 | PUBLISHAHEADOFPRINT | cc_no | intensive care and critical care medicine | https://www.medrxiv.org/content/early/2019/07/12/19001487.source.xml | ObjectiveTo assess the efficacy of an esophageal device to provide TTM (Target Temperature Management) post Cardiac Arrest
DesignA chart review of all patients treated with ETTM, following cardiac arrest. Initial patient temperature, time to target, supplemental methods (water blankets, head wraps, or ice packs), and patient survival were extracted for analysis.
SettingCommunity Medical Center Intensive Care Unit
PatientsAll patients receiving TTM via an esophageal device post Cardiac Arrest from August 2016 to November 2018
InterventionsTTM both cooling and warming via an esophageal device
Measurements and ResultsA total of 54 patients were treated from August 2016 to November 2018; 30 received ETM only, 22 received supplemental cooling, and 2 had treatment discontinued prior to reaching target due to recovery. Target temperatures ranged from 32 to 36 degrees. The median time to target temperature for the entire cohort was 219 minutes (IQR 81-415). For the cohorts without, and with, supplemental cooling modalities, the median time to attain target temperature was 128 minutes (IQR 71-334), and 285 minutes (IQR 204-660), respectively. Survival to ICU discharge was 51.9% for the entire cohort.
ConclusionsETM attains target temperature at a rate consistent with current guidelines and with similar performance to alternative modalities. This may provide a more cost-effective and approachable core cooling option to community hospitals that only use water blankets or other surface methods. | null | medrxiv |
10.1101/19001487 | Cardiac arrest outcomes after targeted temperature management with an esophageal cooling device | Wayne, M. A.; Anderson, C.; Fisher, R.; Berry, D.; Diestelhorst, J. B. | Marvin A Wayne | PeaceHealth St. Joseph Medical Center | 2019-07-15 | 2 | PUBLISHAHEADOFPRINT | cc_no | intensive care and critical care medicine | https://www.medrxiv.org/content/early/2019/07/15/19001487.source.xml | ObjectiveTo assess the efficacy of an esophageal device to provide TTM (Target Temperature Management) post Cardiac Arrest
DesignA chart review of all patients treated with ETTM, following cardiac arrest. Initial patient temperature, time to target, supplemental methods (water blankets, head wraps, or ice packs), and patient survival were extracted for analysis.
SettingCommunity Medical Center Intensive Care Unit
PatientsAll patients receiving TTM via an esophageal device post Cardiac Arrest from August 2016 to November 2018
InterventionsTTM both cooling and warming via an esophageal device
Measurements and ResultsA total of 54 patients were treated from August 2016 to November 2018; 30 received ETM only, 22 received supplemental cooling, and 2 had treatment discontinued prior to reaching target due to recovery. Target temperatures ranged from 32 to 36 degrees. The median time to target temperature for the entire cohort was 219 minutes (IQR 81-415). For the cohorts without, and with, supplemental cooling modalities, the median time to attain target temperature was 128 minutes (IQR 71-334), and 285 minutes (IQR 204-660), respectively. Survival to ICU discharge was 51.9% for the entire cohort.
ConclusionsETM attains target temperature at a rate consistent with current guidelines and with similar performance to alternative modalities. This may provide a more cost-effective and approachable core cooling option to community hospitals that only use water blankets or other surface methods. | null | medrxiv |
10.1101/19001529 | Stem Cell Transplantation Patients and Situational Meaning: A Prospective and Longitudinal View | Blosser, J.; Sabo, R.; Candler, K.; Mullin, K.; Toor, A.; Chaber, D. | Jennifer Blosser | VCU Health | 2019-07-12 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | transplantation | https://www.medrxiv.org/content/early/2019/07/12/19001529.source.xml | BackgroundThough there is thorough examination of psychosocial issues in SCT, there are few longitudinal studies examining the meaning SCT patients attribute to their treatment.
ObjectiveThe object of this study was to examine change in situational appraisal over time, and to explore potential modifiers of that change.
MethodsA prospective, longitudinal study of 146 autologous and allogeneic stem cell transplant (SCT) patients at Virginia Commonwealth University (VCU) was conducted to measure situational appraisal over time as per the meaning making model of Park and Folkman (1997) utilizing the Illness Perception Questionnaire-Revised (IPQ-R; Moss-Morris et al., 2002). Participants were administered the instrument prior to transplant, at one, three and six months, and at one-year post-transplant.
ResultsChange over time was seen in different diagnoses, donor types, reduced intensity and standard pre-transplant preparative regimens, and between the two major ethnic groups (Caucasian and African American) studied. Many of the patient subgroups had statistically significant findings in measures of illness attribution.
ConclusionThe appraisals SCT patients made of their situation in treatment revealed a complex process of appraisal affected by illness, treatment and patient characteristics including disease type, donor type, race, and pre-transplant regimen. | null | medrxiv |
10.1101/19001925 | Prediagnostic breast milk DNA methylation alterations in women who develop breast cancer | Salas, L. A.; Lundgren, S. N.; Browne, E. P.; Punska, E. C.; Anderton, D. L.; Karagas, M. R.; Arcaro, K. F.; Christensen, B. C. | Brock C. Christensen | Geisel School of Medicine at Dartmouth | 2019-07-12 | 1 | PUBLISHAHEADOFPRINT | cc_no | genetic and genomic medicine | https://www.medrxiv.org/content/early/2019/07/12/19001925.source.xml | BackgroundPrior candidate gene studies have shown tumor suppressor DNA methylation in breast milk related with history of breast biopsy, an established risk factor for breast cancer. To further establish the utility of breast milk as a tissue-specific biospecimen for investigations of breast carcinogenesis we measured genome-wide DNA methylation in breast milk from women with and without a diagnosis of breast cancer in two independent cohorts.
MethodsDNA methylation was assessed using Illumina HumanMethylation450k in 87 breast milk samples. After quality control, 368,171 autosomal CpG loci were analyzed. Cell type proportion estimates from RefFreeCellMix were calculated and adjusted for in this Epigenome Wide Association Study using linear mixed effects models adjusted for history of breast biopsy, age, time of delivery, cell type proportion estimates, array chip, and subject as random effect.
ResultsEpigenome-wide analyses identified 58 differentially methylated CpG sites associated with a breast cancer diagnosis in the prospectively collected milk samples from the breast that would develop cancer compared with women without a diagnosis of breast cancer (q-value < 0.05). Nearly all CpG sites associated with a breast cancer diagnosis were hypomethylated in cases compared with controls, and were enriched for CpG islands. In addition, inferred repeat element methylation was lower in breast milk DNA from cases compared to controls, and cases exhibited increased estimated epigenetic mitotic tick rate as well as DNA methylation age compared with controls.
ConclusionBreast milk has utility as a biospecimen for prospective assessment of disease risk, for understanding the underlying molecular basis of breast cancer risk factors, and improving primary and secondary prevention of breast cancer. | 10.1093/hmg/ddz301 | medrxiv |
10.1101/19002022 | The Genetic Links to Anxiety and Depression (GLAD) Study: online recruitment into the largest recontactable study of depression and anxiety | Davies, M.; Kalsi, G.; Brailean, A.; Cleare, A. J.; Coleman, J. R.; Curtis, C. J.; Curzons, S. C.; Davis, K. A. S.; Goldsmith, K. A.; Hammond Bennett, M.; Hotopf, M.; Huebel, C.; Leng, J.; Mason, B. D.; McAtarsney-Kovacs, M.; Monssen, D.; Palaiologou, E.; Pariante, C.; Parikh, S.; Peel, A. J.; Rimes, K.; Rogers, H.; Skelton, M.; Spaul, A.; Almira Suarez, E. L.; Sykes, B. L.; White, K.; Young, A.; Vassos, E.; Veale, D.; Wingrove, J.; Eley, T.; Breen, G. | Gerome Breen | Institute of Psychiatry, Psychology and Neuroscience, King\'s College London | 2019-07-12 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2019/07/12/19002022.source.xml | BackgroundAnxiety 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.
MethodsThe 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.
ResultsOnline recruitment was effective; 41,892 consented and 26,877 participants completed the questionnaire by July 2019. Participants 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.
DiscussionThis 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.
HighlightsO_LIOnline recruitment of 40,000 individuals with lifetime depression or anxiety (77 characters)
C_LIO_LIDetailed online phenotyping combined with genetic and clinical data (66 characters)
C_LIO_LIThe study sample is severe, highly comorbid, with chronic psychopathology (62 characters)
C_LIO_LIThe study protocol enables recall of participants for future research and trials (82 characters)
C_LI
The views expressed are those of the authors and not necessarily those of the NHS, NIHR, Department of Health or Kings College London | 10.1016/j.brat.2019.103503 | medrxiv |
10.1101/19002022 | The Genetic Links to Anxiety and Depression (GLAD) Study: online recruitment into the largest recontactable study of depression and anxiety | Davies, M. R.; Kalsi, G.; Brailean, A.; Cleare, A. J.; Coleman, J. R.; Curtis, C. J.; Curzons, S. C.; Davis, K. A. S.; Goldsmith, K. A.; Hammond Bennett, M.; Hotopf, M.; Hübel, C.; Leng, J.; Mason, B. D.; McAtarsney-Kovacs, M.; Monssen, D.; Palaiologou, E.; Pariante, C.; Parikh, S.; Peel, A. J.; Rimes, K.; Rogers, H.; Skelton, M.; Spaul, A.; Almira Suarez, E. L.; Sykes, B. L.; White, K.; Wingrove, J.; Young, A.; Vassos, E.; Veale, D.; Eley, T.; Breen, G. | Gerome Breen | Institute of Psychiatry, Psychology and Neuroscience, King\'s College London | 2019-07-22 | 2 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2019/07/22/19002022.source.xml | BackgroundAnxiety 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.
MethodsThe 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.
ResultsOnline recruitment was effective; 41,892 consented and 26,877 participants completed the questionnaire by July 2019. Participants 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.
DiscussionThis 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.
HighlightsO_LIOnline recruitment of 40,000 individuals with lifetime depression or anxiety (77 characters)
C_LIO_LIDetailed online phenotyping combined with genetic and clinical data (66 characters)
C_LIO_LIThe study sample is severe, highly comorbid, with chronic psychopathology (62 characters)
C_LIO_LIThe study protocol enables recall of participants for future research and trials (82 characters)
C_LI
The views expressed are those of the authors and not necessarily those of the NHS, NIHR, Department of Health or Kings College London | 10.1016/j.brat.2019.103503 | medrxiv |
10.1101/19002089 | Deficient goal-directed control in a population characterized by extreme goal pursuit | Foerde, K.; Daw, N.; Rufin, T.; Walsh, B. T.; Shohamy, D.; Steinglass, J. | Karin Foerde | NYSPI | 2019-07-14 | 1 | PUBLISHAHEADOFPRINT | cc_by_nd | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2019/07/14/19002089.source.xml | AO_SCPLOWBSTRACTC_SCPLOWComputational 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. | 10.1162/jocn_a_01655 | medrxiv |