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10.1101/2022.02.25.22271516 | Rapid review of government issued documents relevant to mitigation of COVID-19 in the US food manufacturing and processing industry | We surveyed publicly available records published by the United States (US) government between the start of the Coronavirus Disease 2019 (COVID-19) pandemic and September 30th, 2021, to identify documents containing resources or guidelines about COVID-19 mitigation relevant to the US food manufacturing and processing industry (hereafter referred to as "the food processing industry"). Among 36 documents identified and reviewed (including 35 from government agencies and one from a relevant professional association), we extracted 19 categories of mitigation strategies covering the themes of employee biosafety, surveillance, vaccination, social distancing, and worker education. We concluded that the priority of COVID-19 mitigation in the food processing industry was to protect the health and safety of industry workers while maintaining food supply chain resilience to minimize disturbance in the food market and avoid food crisis. A collated list of the identified documents and their comprehensive review will (i) aid researchers and public health workers in interpreting the potential impacts of the recommended mitigations on the epidemiology of the disease among workers in the food processing industry and (ii) help the food processing industry sort out the most essential strategies to take in face of a pandemic. | health policy |
10.1101/2022.02.28.22271671 | A causal inference approach for estimating effects of non-pharmaceutical interventions during Covid-19 pandemic | In response to the outbreak of the coronavirus disease 2019 (Covid-19), governments worldwide have introduced multiple restriction policies, known as non-pharmaceutical interventions (NPIs). However, the relative impact of control measures and the long-term causal contribution of each NPI are still a topic of debate. We present a method to rigorously study the effectiveness of interventions on the rate of the time-varying reproduction number Rt and on human mobility, considered here as a proxy measure of policy adherence and social distancing. We frame our model using a causal inference approach to quantify the impact of five governmental interventions introduced until June 2020 to control the outbreak in 113 countries: confinement, school closure, mask wearing, cultural closure, and work restrictions. Our results indicate that mobility changes are more accurately predicted when compared to reproduction number. All NPIs, except for mask wearing, significantly affected human mobility trends. From these, schools and cultural closure mandates showed the largest effect on social distancing. We also found that closing schools, issuing face mask usage, and work-from-home mandates also caused a persistent reduction on Rt after their initiation, which was not observed with the other social distancing measures. Our results are robust and consistent across different model specifications and can shed more light on the impact of individual NPIs. | health policy |
10.1101/2022.02.28.22271674 | Assessment of Potential Risk Factors for COVID-19 among Health Care Workers in a Health Care Setting in Delhi, India -A Cohort Study | IntroductionHealth care workers (HCW) are among the most vulnerable for contracting the COVID-19 infection. Understanding the extent of human-to-human transmission of the COVID-19 infection among HCW is critical in management of this infection and for policy making. We did this study to observe seropositivity and estimate new infection by seroconversion among HCW and predict the risk factors for infection.
MethodsA cohort study was conducted at a tertiary dedicated COVID-19 hospital in New Delhi during first and second wave of the COVID-19 pandemic. All HCW working in the hospital during the study period who come in contact with the patients, were our study population. The data was collected by a detailed face to face interview along with serological assessment for anti-COVID-19 antibodies at baseline and endline, and assessment of daily symptoms. Prediction of potential risk factors for seroprevalence and seroconversion was done by logistic regression keeping the significance at p<0.05.
ResultsA total of 192 HCW were recruited in this study, out of which, 119 (61.97%) at baseline and 108 (77.7%) at endline were seropositive for COVID-19. About two-third (63.5%) had close contact, 5.2% had exposure during aerosol procedures, 30.2% had exposure with a patients body fluid while majority (85.4%) had exposure to contact surface around the patient. Almost all were wearing PPE and following IPC measures during their recent contact with a COVID-19 patient. Seroconversion was observed among 36.7% of HCWs while 64.0% had a serial rise in titer of antibodies during the follow-up period. Association of seropositivity was observed negatively with doctors [OR:0.353, CI:0.176-0.710], COVID-19 symptoms [OR:0.210, CI:0.054-0.820], comorbidities [OR:0.139, CI: 0.029 - 0.674], and recent Infection Prevention Control (IPC) training [OR:0.250, CI:0.072 - 0.864], while positively associated with partially [OR:3.303, CI: 1.256-8.685], as well as fully vaccination for COVID-19 [OR:2.428, CI:1.118-5.271]. Seroconversion was positively associated with doctor as profession [OR: 13.04, CI: 3.39 - 50.25] and with partially [OR: 4.35, CI: 1.070 - 17.647], as well as fully vaccinated for COVID-19 [OR: 6.08, CI: 1.729 - 21.40]. No significant association was observed between adherence to any of the IPC measures and PPE (personal protective equipment) adopted by the HCW during the recent contact with COVID-19 patients and seroconversion.
ConclusionA high seropositivity and seroconversion could be either due to exposure to COVID-19 patients or concurrent immunization against COVID-19 disease. In this study the strongest association of seropositivity and seroconversion was observed with recent vaccination. IPC measures were practiced by almost all the HCW in these settings, and thus were not found to be affecting seroconversion. Further study using anti N antibodies serology, which are positive following vaccination may help us to find out the reason for the seropositivity and seroconversion in HCW. | infectious diseases |
10.1101/2022.03.01.22271696 | COVID-19 in Tunisia (North Africa): IgG and IgG subclass antibody responses to SARS-CoV-2 according to disease severity | Coronavirus disease 2019 (COVID-19) expresses a wide spectrum of disease severity. We investigated the profile of IgG and IgG subclass antibody responses to SARS- CoV-2 in Tunisian patients with COVID-19 according to disease severity (86 patients with severe disease and 63 with mild to moderate disease). Two in house developed ELISA with excellent performance were used to test for antibodies to the nucleocapsid (N) protein and the receptor-binding domain of the spike antigen (S-RBD) of SARS-CoV-2. IgG, IgG1 and IgG3 antibodies were significantly higher in patients with severe disease compared to non-severe disease. Antibodies to S-RBD or the N protein were dominated by IgG1 and IgG3 or IgG1/IgG3 and IgG2 subclasses respectively. In patients with severe disease, IgG antibodies appearance to S-RBD was delayed compared to the N protein. IgG subclass imbalance may reflect the pathophysiology of COVID-19 and may herald disease aggravation. This study brings information on the immune responses to SARS-CoV-2 in North African patients and completes the picture drawn on COVID-19 in different African populations and worldwide. | allergy and immunology |
10.1101/2022.03.01.22271617 | A causal framework for assessing the transportability of clinical prediction models | BACKGROUNDMachine learning promises to support the diagnosis of dementia and Alzheimers Disease, but may not perform well in new settings. We present a framework to assess the transportability of models predicting cognitive impairment in external settings with different demographics.
METHODSWe mapped and quantified relationships between variables associated with cognitive impairment using causal graphs, structural equation models, and data from the ADNI study. These estimates generated datasets for training and validating prediction models. We measured transportability to external settings with interventions on age, APOE {varepsilon}4, and sex, using calibration metric differences.
RESULTSModels predicting with causes of the outcome were 1.3-12.8 times more transportable than those predicting with consequences. Logistic and lasso models had better calibration in internal validation settings than random forest and boosted models.
DISCUSSIONApplying a framework considering causal relationships is crucial to assess transportability. Future research could investigate more interventions and methods to quantify causal relationships in risk prediction.
Research in contextO_LISystematic Review: Machine learning models supporting the diagnosis of cognitive impairment may not perform well in external validation settings. Theoretical research established that models can be more transportable to external settings when predictors are causes of the outcome. Causal frameworks and practical examples to assess transportability are needed.
C_LIO_LIInterpretation: We developed and applied a causal framework to assess the transportability of models predicting cognitive impairment to settings with different demographics using a causal graph and interventions on semi-synthetic data. Our results add a practical example showing that models are more transportable when predicting with causes of the outcome rather than with its consequences. This supports using causal frameworks in prediction models to improve transportability.
C_LIO_LIFuture directions: Our framework can be extended to include more complex semi-synthetic data generation methods to quantify causal relationships. Further applications to risk prediction models could assess transportability under different interventions that simulate complex differences between populations.
C_LI | epidemiology |
10.1101/2022.03.01.22271617 | A causal framework for assessing the transportability of clinical prediction models | BACKGROUNDMachine learning promises to support the diagnosis of dementia and Alzheimers Disease, but may not perform well in new settings. We present a framework to assess the transportability of models predicting cognitive impairment in external settings with different demographics.
METHODSWe mapped and quantified relationships between variables associated with cognitive impairment using causal graphs, structural equation models, and data from the ADNI study. These estimates generated datasets for training and validating prediction models. We measured transportability to external settings with interventions on age, APOE {varepsilon}4, and sex, using calibration metric differences.
RESULTSModels predicting with causes of the outcome were 1.3-12.8 times more transportable than those predicting with consequences. Logistic and lasso models had better calibration in internal validation settings than random forest and boosted models.
DISCUSSIONApplying a framework considering causal relationships is crucial to assess transportability. Future research could investigate more interventions and methods to quantify causal relationships in risk prediction.
Research in contextO_LISystematic Review: Machine learning models supporting the diagnosis of cognitive impairment may not perform well in external validation settings. Theoretical research established that models can be more transportable to external settings when predictors are causes of the outcome. Causal frameworks and practical examples to assess transportability are needed.
C_LIO_LIInterpretation: We developed and applied a causal framework to assess the transportability of models predicting cognitive impairment to settings with different demographics using a causal graph and interventions on semi-synthetic data. Our results add a practical example showing that models are more transportable when predicting with causes of the outcome rather than with its consequences. This supports using causal frameworks in prediction models to improve transportability.
C_LIO_LIFuture directions: Our framework can be extended to include more complex semi-synthetic data generation methods to quantify causal relationships. Further applications to risk prediction models could assess transportability under different interventions that simulate complex differences between populations.
C_LI | epidemiology |
10.1101/2022.02.28.22271232 | Cerebrospinal fluid and brain α-synuclein seed amplification in autopsy-confirmed Lewy body disease relates to the distribution of pathology | ObjectiveTo determine the sensitivity and specificity of -synuclein seed amplification assay (Syn-SAA) in antemortem and postmortem CSF and brain homogenate samples of autopsy-confirmed patients with a spectrum of Lewy-related pathology (LRP).
MethodsAntemortem CSF samples were examined from 119 subjects with standardized neuropathological examinations from OHSU and UCSD (56 additional postmortem CSF samples available). The assay was also applied to frontal cortex and amygdala tissue to determine if the results could be explained by a regional variation in the propensity for seed aggregation. Sensitivity, specificity, and assay kinetics were compared across pathology groups and clinical data was compared across Syn-SAA positive and negative groups.
ResultsFifty-three LRP-individuals and 66 LRP+ individuals (neocortical (n=38), limbic (n=7), and amygdala-predominant (n=21)) were included. There was a sensitivity of 97.8% and specificity of 98.1% of the Syn-SAA to identify patients with limbic/neocortical pathology from antemortem CSF. Sensitivity to detect amygdala-predominant pathology was only 14.3%. Postmortem CSF and brain tissue Syn-SAA analyses showed a similar detection pattern, with higher positivity in samples from limbic/neocortical cases. Kinetic parameters of aggregation were significantly slower in amygdala-predominant cases compared to limbic and neocortical cases.
InterpretationIn this multicenter study of autopsy-confirmed subjects with a spectrum of Lewy-related pathology, we confirm that the Syn-SAA using CSF and brain tissue reliably identifies -synuclein seeds in patients with diffuse pathology and related cognitive symptoms. Pathological -synuclein in the amygdala appears less likely to form detectable seeds, which may result from differences in abundance, conformation, or strains of -synuclein.
Summary for Social Media If PublishedO_LITwitter handles of the authors: none
C_LIO_LIAlpha-synuclein seed amplification assays have shown high sensitivity and specificity in clinically defined DLB and PD cohorts
C_LIO_LIIt is less well known how well these assays detect synuclein seeds across a pathologically defined spectrum of Lewy body disease. Here we examine the ability of the Syn-SAA to detect alpha-synuclein seeds in a multicenter cohort of autopsy-validated cases with a spectrum of Lewy body related pathology.
C_LIO_LIHigh sensitivity and specificity of the Syn-SAA is confirmed in detecting alpha-synuclein seeds in spinal fluid and brain tissue in limbic and neocortical stage Lewy body stage pathology, but markedly decreased sensitivity is observed in detecting alpha-synuclein seeds in both spinal fluid and brain tissue in amygdala-predominant type Lewy body related pathology. A small number of these cases showed seeding capability from the amygdala that was not present in the frontal cortex, suggesting a topographic spread of alpha-synuclein seeds.
C_LIO_LIThe current generation of Syn-SAAs have a high sensitivity and specificity for detecting the most clinically relevant forms of Lewy body related pathology. Further study is needed to understand the differences in Lewy body related pathology between limbic/neocortical cases and amygdala-predominant cases that result in this difference in seeding capability.
C_LI | neurology |
10.1101/2022.02.28.22271320 | An Alzheimer's disease pathway uncovered by functional omics: the risk gene CELF1 regulates KLC1 splice variant E expression, which drives Aβ pathology | In an era when numerous disease-associated genes have been identified, determining the molecular mechanisms of complex diseases is still difficult. The CELF1 region was identified by genome-wide association studies as an Alzheimers disease (AD) risk locus. Using transcriptomics and cross-linking and immunoprecipitation sequencing (CLIP-seq), we found that CELF1, an RNA-binding protein, binds to KLC1 RNA and regulates its splicing. Analysis of two brain banks revealed that CELF1 expression is correlated with inclusion of KLC1 exons downstream of the CELF1-binding region identified by CLIP-seq. In AD, low CELF1 levels result in high levels of KLC1 splice variant E (KLC1_vE), an amyloid-{beta} (A{beta}) pathology-driving gene product. Cell culture experiments confirmed regulation of KLC1_vE by CELF1. Analysis of mouse strains with different propensities for A{beta} accumulation confirmed that Klc1_vE drives A{beta} pathology. Using omics methods, we revealedthe molecular pathway of a complex disease supported by human and mouse genetics. | neurology |
10.1101/2022.02.28.22271651 | Cost-effectiveness of implementing HIV and HIV/syphilis dual testing among key populations in Viet Nam: a modeling analysis | ObjectivesKey populations, including sex workers, men who have sex with men, and people who inject drugs, have a high risk of HIV and sexually transmitted infections (STIs). We assessed the health and economic impacts of different HIV and syphilis testing strategies among three key populations in Viet Nam using a dual HIV/syphilis rapid diagnostic test (RDT).
SettingWe used the Spectrum AIDS Impact Model to simulate the HIV epidemic in key populations in Viet Nam and evaluated five testing scenarios. We used a 15-year time horizon and all costs are from the providers perspective.
ParticipantsWe include the entire population of Viet Nam in the model.
InterventionsWe model five testing scenarios among key populations: 1) annual testing with an HIV rapid diagnostic test (RDT), 2) annual testing with a dual RDT, 3) biannual testing using dual RDT and HIV RDT, 4) biannual testing using HIV RDT, and 5) biannual testing using dual RDTs.
Primary and secondary outcome measuresThe primary outcome is incremental cost-effectiveness ratios (ICERS). Secondary outcomes include HIV and syphilis cases and costs for each proposed intervention.
ResultsAnnual testing using a dual HIV/syphilis RDT was cost saving and averted 3,206 HIV cases and treated 7,719 syphilis cases compared to baseline over 15 years. Biannual testing using one dual test and one HIV RDT, or two dual tests both averted an additional 875 HIV cases and were cost-effective ($1,024 and $2,518 per DALY averted, respectively). Annual or biannual HIV testing using HIV RDTs and separate syphilis tests were more costly and less effective than using one or two dual RDTs.
ConclusionsAnnual or biannual HIV and syphilis testing using dual RDTs among key populations can be cost-effective and support countries in reaching global reduction goals for HIV and syphilis.
STRENGTHS AND LIMITATIONS OF THIS STUDYO_LIStrength: Our model presents novel cost-effectiveness estimates for the use of dual HIV/syphilis testing in key populations that can inform health planners
C_LIO_LIStrength: We include five testing scale up scenarios using both HIV RDT and dual HIV/syphilis RDT
C_LIO_LIStrength: Our model is informed by demographic, behavioral, and biological data from government sources, surveys, surveillance, publicly available reports, databases, and peer-reviewed literature
C_LIO_LILimitation: We made some assumptions regarding the timing and uptake of HIV and syphilis testing among key populations that may be inaccurate.
C_LIO_LILimitation: Our model assumes that increased syphilis testing and treatment will not impact syphilis prevalence, however, it is unknown whether increased testing will reduce or increase syphilis prevalence.
C_LI | health economics |
10.1101/2022.03.01.22271685 | Patients with CLL have similar high risk of death upon the omicron variant of COVID-19 as previously during the pandemic. | Previous studies have shown that patients with chronic lymphocytic leukemia (CLL) and coronavirus disease 2019 (COVID-19) have high mortality rates. The omicron variant has been reported to give milder disease in the general population, but outcomes of infections with the omicron variant among immunocompromised patients have not previously been reported. In a population-based cohort we assessed rates of hospitalizations, ICU-admissions, and 30-day all-cause mortality among all patients with CLL from Eastern Denmark testing positive for severe adult respiratory syndrome coronavirus 2 (SARS-CoV-2) in time periods before and after dominance of the omicron variant. Rates of hospitalizations and ICU-admissions declined significantly, whereas 30-day mortality remained as high as 23% in the period with dominance of the omicron sublineage BA.2 variant. Thus, patients with CLL in general and in particular those above 70 years of age with one or more comorbidities should be considered for closer monitoring and pre-emptive antiviral therapy upon a positive SARS-CoV-2 test.
Key pointsO_LIThe omicron variant of COVID-19 leads to high fatality rates in CLL, despite milder disease in the background population
C_LIO_LIPatients with CLL who test positive for SARS-CoV-2 in the era of the omicron variant should be considered for pre-emptive antiviral therapy
C_LI
Explanation of noveltyThe omicron variant has been reported to give milder disease in the general population, but outcomes of infections with the omicron variant among immunocompromised patients have not previously been reported. These population-based data on outcome for patients with CLL upon infection with the omicron variant of SARS-CoV-2 warrants closer monitoring and pre-emptive antiviral therapy upon a positive SARS-CoV-2 test for patients with CLL. | hematology |
10.1101/2022.02.28.22271591 | Ammonium Sulfate Addition Reduces the Need for Guanidinium Isothiocyanate in the Denaturing Transport Medium Used for SARS-COV-2 RNA Detection | Rapid identification of SARS-CoV-2 infected individuals through viral RNA detection followed by effective personal isolation remains the most effective way to prevent the spread of this virus. Large-scale RNA detection involves mass specimen collection and transportation. For biosafety reasons, denaturing viral transport medium has been extensively used during the pandemic. But the high concentrations of guanidinium isothiocyanate (GITC) in such media have raised issues around sufficient GITC supply and laboratory safety. Here, we tested whether supplementing media containing low concentrations of GITC with ammonium sulfate (AS) would affect the throat-swab detection of SARS-CoV-2 pseudovirus or a viral inactivation assay targeting both enveloped and non-enveloped viruses. Adding AS to the denaturing transport media reduced the need for high levels of GITC and improved SARS-COV-2 RNA detection without compromising virus inactivation. | infectious diseases |
10.1101/2022.03.01.22271704 | First detection of Powassan Virus lineage I in field-collected Dermacentor variabilis from New York, USA | Powassan virus (POWV) is a tick-borne flavivirus that can cause lethal or debilitating neurological illness. It is canonically transmitted by Ixodes genus ticks but may interact with sympatric Dermacentor species. Here, we report the first detection of POWV lineage I from a pool of field-collected D. variabilis in New York state. | infectious diseases |
10.1101/2022.03.01.22271692 | Childhood meningitis in rural Gambia: 10 years of population-based surveillance | BackgroundThe introduction in many countries of conjugate vaccines against Haemophilus influenzae type-b, Streptococcus pneumoniae, and Neisseria meningitidis has led to significant reductions in acute bacterial meningitis (ABM) in children. However, recent population-based data on ABM in sub-Saharan Africa are limited.
MethodsPopulation-based surveillance for meningitis was carried out in a rural area of The Gambia under demographic surveillance from 2008 to 2017, using standardised criteria for referral, diagnosis and investigation. We calculated incidence using population denominators.
ResultsWe diagnosed 1,599 patients with suspected meningitis and collected cerebrospinal fluid (n=1,121) and/or blood (n=1,070) from 1,427 (88%) of cases. We detected 169 cases of ABM, 209 cases of non-bacterial meningitis and 1,049 cases of clinically suspected meningitis. The estimated average annual incidence of ABM was high at 145 per 100,000 population in the <2-month age group, 56 per 100,000 in the 2-23-month age group, but lower at 5 per 100,000 in the 5-14-year age group. The most common causes of ABM were Streptococcus pneumoniae (n=44), Neisseria meningitidis (n=42), and Gram-negative coliform bacteria (n=26). Eighteen of 22 cases caused by pneumococcal serotypes included in PCV13 occurred prior to vaccine introduction and four afterwards. The overall case fatality ratio for ABM was 29% (49/169) and highest in the <2-month age group 37% (10/27). The fatality rate was 8.6% (18/209) for non-bacterial meningitis cases.
ConclusionsGambian children continue to experience substantial morbidity and mortality associated with suspected meningitis, especially acute bacterial meningitis. Such severely ill children in sub-Saharan Africa require improved diagnostics and clinical care.
Summary of the articles main pointPopulation-based surveillance in a health demographic surveillance area in Gambia showed a high incidence and mortality in clinically suspected, acute-bacterial, and non-bacterial meningitis among children 14-years of age. Findings revealed potential gaps in the diagnosis of meningitis in The Gambia requiring urgent attention. | infectious diseases |
10.1101/2022.03.01.22271576 | Transcriptomic clustering of critically ill COVID-19 patients | Infections caused by SARS-CoV-2 may cause a severe disease, termed COVID-19, with significant mortality. Host responses to this infection, mainly in terms of systemic inflammation, have emerged as key pathogenetic mechanisms, and their modulation is the only therapeutic strategy that has shown a mortality benefit. Herein, we used peripheral blood transcriptomes of critically-ill COVID-19 patients obtained at admission in an Intensive Care Unit (ICU), to identify two transcriptomic clusters characterized by expression of either interferon-related or immune checkpoint genes, respectively. These profiles have different ICU outcome, in spite of no major clinical differences at ICU admission. A transcriptomic signature was used to identify these clusters in an external validation cohort, yielding similar results. These findings reveal different underlying pathogenetic mechanisms and illustrate the potential of transcriptomics to identify patient endotypes in severe COVID-19, aimed to ultimately personalize their therapies. | intensive care and critical care medicine |
10.1101/2022.03.01.22271677 | Dual Guidance in Regional Anesthesia Influence of Needle Electrode Configuration on Stimulation Success at Sciatic Nerve; A Randomized, Controlled Pilot Trial | IntroductionIn contrast to ultrasound technology (US), peripheral nerve stimulation (PNS) for regional anesthesia was little improved in recent years. When using the combination of both techniques, PNS can give additional information for nerve localization to improve safety and success of regional anesthesia. There are influencing factors on the success rate of stimulation in PNS remaining uninvestigated in a clinical setting to date. This randomized controlled pilot trial evaluates the impact of shape and size of stimulation needles electrodes under dual guidance conditions.
MethodsIn a randomized controlled clinical trial 35 participants undergoing lower limb surgery received a preoperative proximal sciatic nerve block in dual guidance technique. Use of facet needles with point shaped electrodes (N=19, facet group) were compared with tuohy needles with large electroconductive tips (N=16, touhy group). Stimulation success at minimal distance between needle tip and nerve was recorded. Block success and complications of regional anesthesia were assessed.
ResultsIn 87% of successful stimulation (20 of 23) an ultrasound-proven contact of needle tip and sciatic nerve was necessary to elicit a motor response. More successful stimulations could performed using facet needles (84%, 16/19) compared to tuohy needles (44%, 7/16, p=0.03). If stimulation was successful the number of successful sensory blockades was increased (78%, 18/23, p=0.02). No serious complications of regional anesthesia were recorded.
DiscussionThis pilot trial suggests that stimulation needles with small electrodes may be more reliable in indicating a contact of needle and nerve, which may improve safety and success of proximal sciatic nerve blocks. | anesthesia |
10.1101/2022.02.28.22271632 | Blood-Based Brain Injury Biomarkers to Prognosticate Outcome after Pediatric Cardiac Arrest | BackgroundPrognostication after cardiac arrest in children is challenging due to a lack of validated methods to evaluate direct brain injury. The objective of this multicenter study was to analyze biomarker accuracy to prognosticate outcome 1 year post-arrest.
MethodsFourteen U.S. centers enrolled 164 children ages 48 h - 17 years with pre-arrest Pediatric Cerebral Performance Category score of 1-3 who were admitted to an intensive care unit after cardiac arrest. Glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal esterase-L1 (UCH-L1), neurofilament light (NfL), and Tau concentrations were measured in blood samples from post-arrest days 1-3 using Quanterix Simoa 4-Plex assay, Billerica, MA. Unfavorable outcome was death or survival with Vineland Adaptive Behavioral Scale-Third Edition score < 70 at 1 year. We analyzed area under receiver operator curve (AUROC) and performed multivariate logistic regressions to determine the association of each biomarker with outcome on days 1-3.
ResultsFifty of 120 children with primary outcomes available had an unfavorable outcome, including 43 deaths. Compared to those with favorable outcomes, more children with unfavorable outcome had out-of-hospital (36% vs. 70%) and unwitnessed (7% vs. 46%) events, p<0.05. For days 1-3, concentrations of all four measured biomarkers were increased in children with an unfavorable vs. favorable outcome, p<0.05. On post-arrest day 1, NfL demonstrated the best outcome classification (AUROC 0.731 [95% confidence interval 0.642, 0.820]) while UCH-L1 performed best on days 2 (0.860 [0.785, 0.935]) and 3 (0.837 [0.747, 0.926]). After covariate adjustment, NfL concentrations on day 1 (odds ratio 5.9 [95% confidence interval 1.8, 19.2], day 2 (11.9 [3.8, 36.9]), and day 3 (10.2 [3.1, 33.3]), UCH-L1 on day 2 (11.3 [3.0, 42.4]) and day 3 (7.6 [2.1, 27.1]), GFAP on day 2 (2.3 [1.2, 4.5]) and day 3 (2.2 [1.2, 4.0]), and tau on day 1 (2.4 [1.1, 5.3]), day 2 (2.3 [1.3, 4.0]), and day 3 (2.0 [1.2, 3.6]) were associated with unfavorable outcome, p<0.05.
ConclusionsBlood-based brain injury biomarkers accurately prognosticated death or unfavorable adaptive behavior composite outcome at 1 year after pediatric cardiac arrest. Accuracy of biomarkers to predict neurodevelopmental outcomes beyond 1 year should be evaluated.
Clinical Trial RegistrationURL: https://www.clinicaltrials.gov: Unique identifier: NCT02861534
Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIIn children who suffered a cardiac arrest, post-arrest blood levels of neurofilament light, ubiquitin carboxyl-terminal esterase-L1, glial fibrillary acidic protein, and tau predicted death or unfavorable adaptive behavior composite outcome at 1 year.
C_LIO_LINeurofilament light was the best performing biomarker to predict outcome on day 1 while ubiquitin carboxyl-terminal esterase-L1 performed best on days 1 and 2.
C_LI
What are the clinical implications?O_LIBlood-based brain injury biomarkers should be considered for clinical use to aid in prognostication after pediatric cardiac arrest.
C_LIO_LIBiomarker levels should be assessed as tools to aid in the prediction of neurodevelopmental outcomes beyond one year.
C_LI | pediatrics |
10.1101/2022.03.01.22271652 | Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium | BACKGROUNDLeft-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia (N = 11,095), using a single image analysis protocol.
METHODSWe included T1-weighted data from 46 datasets (5,080 affected individuals and 6,015 controls) from the ENIGMA Consortium. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Analyses were also performed with respect to the use of antipsychotic medication and other clinical variables, as well as age and sex. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029).
RESULTSSmall average differences between cases and controls were observed for asymmetries in cortical thickness, specifically of the rostral anterior cingulate (d = -0.08, pFDR = 0.047) and the middle temporal gyrus (d = -0.07, pFDR = 0.048), both driven primarily by thinner cortices in the left hemisphere in schizophrenia. These asymmetries were not significantly associated with the use of antipsychotic medication or other clinical variables. Older individuals with schizophrenia showed a stronger average leftward asymmetry of pallidum volume than older controls (d = 0.08, pFDR = 9.0 x 10-3). The multivariate analysis revealed that 7% of the variance across all structural asymmetries was explained by case-control status (F = 1.87, p = 1.25 x 10-5).
CONCLUSIONSAltered trajectories of asymmetrical brain development and/or lifespan asymmetry may contribute to schizophrenia pathophysiology. Small case-control differences of brain macro-structural asymmetry may manifest due to more substantial differences at the molecular, cytoarchitectonic or circuit levels, with functional relevance for lateralized cognitive processes. | psychiatry and clinical psychology |
10.1101/2022.03.01.22271652 | Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium | BACKGROUNDLeft-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia (N = 11,095), using a single image analysis protocol.
METHODSWe included T1-weighted data from 46 datasets (5,080 affected individuals and 6,015 controls) from the ENIGMA Consortium. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Analyses were also performed with respect to the use of antipsychotic medication and other clinical variables, as well as age and sex. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029).
RESULTSSmall average differences between cases and controls were observed for asymmetries in cortical thickness, specifically of the rostral anterior cingulate (d = -0.08, pFDR = 0.047) and the middle temporal gyrus (d = -0.07, pFDR = 0.048), both driven primarily by thinner cortices in the left hemisphere in schizophrenia. These asymmetries were not significantly associated with the use of antipsychotic medication or other clinical variables. Older individuals with schizophrenia showed a stronger average leftward asymmetry of pallidum volume than older controls (d = 0.08, pFDR = 9.0 x 10-3). The multivariate analysis revealed that 7% of the variance across all structural asymmetries was explained by case-control status (F = 1.87, p = 1.25 x 10-5).
CONCLUSIONSAltered trajectories of asymmetrical brain development and/or lifespan asymmetry may contribute to schizophrenia pathophysiology. Small case-control differences of brain macro-structural asymmetry may manifest due to more substantial differences at the molecular, cytoarchitectonic or circuit levels, with functional relevance for lateralized cognitive processes. | psychiatry and clinical psychology |
10.1101/2022.02.28.22271619 | Person-specific Characteristics of People with Low Back Pain Moderate the Preferred Movement Pattern within Motor Skill Training and Strength and Flexibility Exercise | BackgroundPeople with chronic low back pain (LBP) display an altered movement pattern where the lumbar spine moves more readily into its available range of motion relative to other joints when performing a movement. Recently a randomized controlled trial was completed to compare the effects of motor skill training (MST) to strength and flexibility exercise (SFE). MST improved the altered pattern to a greater extent than SFE. However, there was substantial variability in the baseline and the change over time in the pattern. Understanding factors that influence this variability may ultimately be used to better target treatment strategies to the person.
ObjectiveExamine if gender, age, LBP duration, and the movement pattern at baseline moderate the baseline movement pattern and the change over time in the pattern within MST and SFE. Design: Secondary analysis of kinematic data from a single-blind, randomized controlled clinical trial.
SettingInstitutional
Patients154 patients with chronic LBP.
InterventionsMotor skill training and strength and flexibility exercise.
Main outcome measureslumbar contribution (LC) to total movement.
ResultsThere was not a significant difference in baseline LC between MST and SFE ({beta}=-2.39, CI=[-7.74, 2.96], p=0.38). SFE did not change LC over time ({beta}=-0.11, CI=[-0.47, 0.24], p=0.53). However, there was a significant change over time in LC within MST ({beta}=-2.13, CI=[-2.54, -1.48], p<0.001). Irrespective of treatment group, there was a trend for gender ({beta}=-5.29, CI=[-10.34, 0.30], p=0.05) and age ({beta}=-0.22, CI=[-0.46, 0.00], p=0.05) to moderate baseline LC. Age ({beta}=0.01, CI=[0.00, 0.02], p = 0.04) and baseline LC ({beta}=-0.07, CI=[-0.10, -0.04], p<0.01) were associated with the change over time in LC within MST only.
ConclusionsPerson-specific characteristics moderate the baseline altered movement pattern within MST and SFE, as well as the change over time in the pattern within MST. | rehabilitation medicine and physical therapy |
10.1101/2022.03.01.22271684 | Viral cultures, Polymerase Chain Reaction Cycle Threshold Values and Viral Load Estimation for SARS-CoV-2 Infectious Potential Assessment in Hematopoietic Stem Cell and Solid Organ Transplant Patients: A Systematic Review | BackgroundOrgan transplant recipients are at increased vulnerability to SARS-CoV-2 due to immunosuppression and may pose a continued transmission risk especially within hospital settings. Detailed case reports including symptoms, viral load and infectiousness, defined by the presence of replication-competent viruses in culture, provide an opportunity to examine the relationship between clinical course, burden and contagiousness, and provide guidance on release from isolation.
ObjectivesWe performed a systematic review to investigate the relationship in transplant recipients between serial SARS-CoV-2 RT-PCR cycle threshold (Ct) value or cycle of quantification value (Cq), or other measures of viral burden and the likelihood and duration of the presence of infectious virus based on viral culture including the influence of age, sex, underlying pathologies, degree of immunosuppression, and/or vaccination on this relationship.
MethodsWe searched LitCovid, medRxiv, Google Scholar and WHO Covid-19 databases, from 1 November 2019 until 31 December 2021. We included studies reporting relevant data for transplantees with SARS-CoV-2 infection: results from serial RT-PCR testing and viral culture data from the same respiratory samples. We assessed methodological quality using five criteria, and synthesised the data narratively and graphically.
ResultsWe included 9 case reports and case series reporting on 30 transplantees. We observed a relationship between proxies of viral burden and likelihood of shedding replication-competent SARS-CoV-2 particles. Two individuals shed replication-competent particles over 100 days after infection onset. Lack of standardisation of testing and reporting precludes establishing a viral burden cutoff. Most transplantees stopped shedding competent particles when the RT-PCR cycle threshold was above 30, but there are differences across platforms.
ConclusionsViral burden is a reasonable proxy for infectivity when considered within the context of the clinical status of each patient. Standardised study design and reporting are essential to avoid research waste and generate guidance based on an increasing evidence base. | infectious diseases |
10.1101/2022.03.01.22271582 | Duration of viable virus shedding in SARS-CoV-2 omicron variant infection | Clinical features of SARS-CoV-2 Omicron variant infection, including incubation period and transmission rates, distinguish this variant from preceding variants. However, whether the duration of shedding of viable virus differs between omicron and previous variants is not well understood. To characterize how variant and vaccination status impact shedding of viable virus, we serially sampled symptomatic outpatients newly diagnosed with COVID-19. Anterior nasal swabs were tested for viral load, sequencing, and viral culture. Time to PCR conversion was similar between individuals infected with the Delta and the Omicron variant. Time to culture conversion was also similar, with a median time to culture conversion of 6 days (interquartile range 4-8 days) in both groups. There were also no differences in time to PCR or culture conversion by vaccination status. | infectious diseases |
10.1101/2022.02.28.22271633 | Analysis of Y Chromosome Haplogroups in Parkinson's Disease | Parkinsons disease is a complex neurodegenerative disorder that is about 1.5 times more prevalent in males than females. Extensive work has been done to identify the genetic risk factors behind Parkinsons disease on autosomes and more recently on chromosome X, but work remains to be done on the male specific Y chromosome. In an effort to explore the role of the Y chromosome in Parkinsons disease we analyzed whole genome sequencing data from the Accelerating Medicines Partnership - Parkinsons disease initiative (1,466 cases and 1,664 controls), genotype data from NeuroX (3,491 cases and 3,232 controls) and genotype data from UKBiobank (182,517 controls, 1,892 cases, and 3,783 proxy cases) all consisting of male European ancestry samples. We classified sample Y chromosomes by haplogroup using three different tools for comparison (Snappy, Yhaplo, Y-LineageTracker), and meta-analyzed this data to identify haplogroups associated with Parkinsons disease. This was followed up with a Y chromosome association study to identify specific variants associated with disease. We also analyzed blood based RNASeq data obtained from the Accelerating Medicines Partnership - Parkinsons disease initiative (1,020 samples) and RNASeq data obtained from the North American Brain Expression Consortium (171 samples) to identify Y chromosome genes differentially expressed in cases, controls, specific haplogroups, and specific tissues. RNASeq analyses suggest Y chromosome gene expression differs between brain and blood tissues but does not differ significantly in cases, controls or specific haplogroups. Overall, we did not find any strong associations between Y chromosome genetics and Parkinsons disease, suggesting the explanation for increased prevalence in males may lie elsewhere. | genetic and genomic medicine |
10.1101/2022.03.01.22271662 | High Viral Specific Antibody Convalescent Plasma Effectively Neutralizes SARS-CoV-2 Variants of Concern | The ongoing evolution of SARS-Co-V2 variants to omicron severely limits available effective monoclonal antibody therapies. Effective drugs are also supply limited. Covid-19 convalescent plasma (CCP) qualified for high antibody levels effectively reduces immunocompetent outpatient hospitalization. The FDA currently allows outpatient CCP for the immunosuppressed. Viral specific antibody levels in CCP can range ten-to hundred-fold between donors unlike the uniform viral specific monoclonal antibody dosing. Limited data are available on the efficacy of polyclonal CCP to neutralize variants. We examined 108 pre-delta/pre-omicron donor units obtained before March 2021, 20 post-delta COVID-19/post-vaccination units and one pre-delta/pre-omicron hyperimmunoglobulin preparation for variant specific virus (vaccine-related isolate (WA-1), delta and omicron) neutralization correlated to Euroimmun S1 IgG antibody levels. We observed a 2-to 4-fold and 20-to 40-fold drop in virus neutralization from SARS-CoV-2 WA-1 to delta or omicron, respectively. CCP antibody levels in the upper 10% of the 108 donations as well as 100% of the post-delta COVID-19/post-vaccination units and the hyperimmunoglobulin effectively neutralized all three variants. High-titer CCP neutralizes SARS-CoV-2 variants despite no previous donor exposure to the variants.
Key pointsAll of the post-delta COVID-19/post vaccination convalescent plasma effectively neutralizes the omicron and delta variants.
High-titer CCP and hyperimmunoglobulin neutralizes SARS-CoV-2 variants despite no previous donor exposure to the variants. | infectious diseases |
10.1101/2022.03.01.22271202 | Longitudinal monitoring of SARS-CoV-2 neutralizing antibody titers and its impact on employee personal wellness decisions | Virus neutralizing antibody (vnAb) titers are the strongest laboratory correlate of protection from SARS-CoV-2. Providing individuals with real-time measures of their vnAb titers is predicted to improve their ability to make personal wellness decisions. Yet, widespread commercial testing of SARS-CoV-2 vnAbs does not currently occur. Here, we examined whether knowing their vnAb titer impacted wellness decision-making among individuals. To this end, starting on January 1, 2021, we offered all employees from two companies free IMMUNO-COV testing and conducted a survey to assess their behaviors and decisions regarding booster vaccination. IMMUNO-COV is a clinically validated, surrogate virus assay that quantitates serum titers of SARS-CoV-2 vnAbs. To help participants gauge their level of protection based on their vnAb titer, we calibrated IMMUNO-COV titers to the World Health Organization (WHO) International Standard (IU/mL), making them comparable to published reports of correlates of protection, and we fit historical IMMUNO-COV vnAb titer values into predictive models of immune protection from COVID-19. As expected, data for the 56 program participants showed variability in vnAb titers post vaccination, rates vnAb decay, and fold-increases in vnAb titers after booster vaccination. Based on the participant survey, the majority (66%) of participants indicated that knowing their vnAb titer impacted their social behaviors and/or their decision on the timing of a booster vaccination. Several participants indicated that knowing their vnAb titer contributed to their peace of mind regarding their high level of protection from COVID-19. Together, these data demonstrate that regular determination of SARS-CoV-2 neutralizing antibody titers can significantly impact decisions regarding social interactions and timing of booster vaccinations. | infectious diseases |
10.1101/2022.03.01.22271708 | Racial/Ethnic Disparities in the Observed COVID-19 Case Fatality Rate Among the U.S. Population | PurposeDuring the initial 12 months of the pandemic, racial and ethnic disparities in COVID-19 death rates received considerable attention but it has been unclear whether disparities in death rates were due to disparities in case fatality rates (CFRs), incidence rates or both. We examined differences in observed COVID-19 case fatality rates (CFRs) between U.S. Whites, Blacks/African Americans and Latinx during this period.
MethodsUsing data from the COVID Tracking Project (CTP) and the CDCs COVID-19 Case Surveillance Public Use dataset, we calculated CFR ratios comparing minority groups to Whites, both overall and separately by age group. We also used a model of monthly COVID-19 deaths to estimate CFR ratios, adjusting for age, gender, and differences across states and time.
ResultsOverall Blacks and Latinx had lower CFRs than Whites. However, when adjusting for age, Blacks and Latinx had higher CFRs than Whites among those younger than 65. CFRs varied substantially across states and time.
ConclusionsDisparities in COVID-19 case fatality among U.S. Blacks and Latinx under age 65 were evident during the first year of the pandemic. Understanding racial/ethnic differences in COVID-19 CFRs is challenging due to limitations in available data. | infectious diseases |
10.1101/2022.03.01.22271618 | In vitro Characterization of SARS-CoV-2 Protein Translated from the Moderna mRNA-1273 Vaccine | Extensive research around mRNA vaccines and their proposed utility during the current COVID-19 pandemic resulted in many publications concerning the SARS-Cov-2 spike protein and angiotensin converting enzyme-2 receptor-binding domain of the virus, but none describe the characteristics of the full-length protein obtained from the modified/synthetic mRNA that is part of the Moderna and Pfizer-BioNTech vaccines. In this paper, we provide the first data characterizing the actual proteins produced by mouse and human cells in culture that had been incubated up to 30 minutes with the commercial vaccine produced by Moderna (i.e., Spikevax). The mRNA vaccine continues to produce proteins up to 12-14 days after introduction to the cells. The molecular weight of the SARS-CoV-2 encoded protein ranges from 135-200 kilodaltons depending on the extent of glycosylation. | allergy and immunology |
10.1101/2022.03.01.22271665 | Variability in SARS-Cov-2 IgG Antibody Affinity To Omicron and Delta Variants in Convalescent and Community mRNA Vaccinated Individuals | The emergence of Omicron and Delta variants of SARS-CoV-2 has begun a number of discussions regarding breakthrough infection, waning immunity, need and timing for vaccine boosters and whether existing mRNA vaccines for the wildtype strain are adequate. Our work leverages a biosensor-based technique to evaluate the binding efficacy of SARS-CoV-2 S1 specific salivary antibodies to the Omicron and Delta variants using a cohort of mRNA vaccinated (n=109) and convalescent (n=19) subjects. We discovered a wide range of binding efficacies to the variant strains, with a mean reduction of 60.5%, 26.7%, and 14.7% in measurable signal to the Omicron strain and 13.4%, 2.4%, and -6.4% percent mean reduction to the Delta Variant for convalescent, Pfizer, and Moderna vaccinated groups respectively. This assay may be an important tool in determining susceptibility to infection or need for booster immunization as the pandemic evolves.
Key PointsO_LIAMPERIAL assay developed to quantify salivary SARS-CoV-2 S1 IgG antibodies to Omicron and Delta variants
C_LIO_LIThere was a reduction in affinity to both Delta and Omicron Variants
C_LIO_LIThe reduction in affinity was more pronounced to Omicron than for Delta Variants
C_LIO_LIThere was a significant difference between IgG affinities in Individuals vaccinated with Pfizer versus Moderna Vaccines
C_LI | allergy and immunology |
10.1101/2022.03.01.22271686 | Association of the medical therapy with beta-blockers or inhibitors of renin-angiotensin system with clinical outcomes in patients with mildly reduced left ventricular ejection fraction after acute myocardial infarction | In the era of the initial optimal interventional and medical therapy for acute myocardial infarction (AMI), a number of patients with mildly reduced left ventricular ejection fraction (EF) (41 - 49%) have been increasing. This observational study aimed to investigate the association between the medical therapy with oral beta-blockers or inhibitors of renin-angiotensin system (RAS) and 2-year clinical outcomes in patients with mildly reduced EF after AMI. Among patients enrolled in the Korea Acute Myocardial Infarction Registry-National Institute of Health, propensity-score matched patients who survived the initial attack and had mildly reduced EF were selected according to beta-blocker or RAS inhibitor therapy at discharge. Beta-blocker therapy at discharge was associated with lower 2-year major adverse cardiac events which was a composite of cardiac death, myocardial infarction, revascularization and re-hospitalization due to heart failure (8.7 vs. 12.8/100 patient-years; hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.50-0.93; P=0.015), and no significant interaction between EF [≤]45% and >45% was observed (Pinteraction=0.354). This association was mainly driven by lower myocardial infarction in patients with beta-blockers (HR 0.50; 95% CI 0.26-0.95; P=0.035). Inhibitors of RAS at discharge were associated with lower re-hospitalization due to heart failure (1.8 vs. 3.5/100 patient-years; HR 0.53; 95% CI 0.33-0.86; P=0.010) without a significant interaction between EF [≤]45% and >45% (Pinteraction=0.333). In patients with mildly reduced EF after AMI, the medical therapy with beta-blockers or RAS inhibitors at discharge was associated with better 2-year clinical outcomes. | cardiovascular medicine |
10.1101/2022.03.01.22271713 | Comparing Waves of COVID-19 in the US: Scale of response changes over time | Local response to the SARS-CoV-2 pandemic differed spatially across the United States but the drivers of this spatial variation remain unclear. We approach this open question by studying the relationship between the growth rate of subsequent waves of the pandemic at the county level during the first year of the pandemic, asking whether state or county demographics better explain variation in this relationship. We found clear spatiotemporal patterns in the relationship between the slopes of subsequent waves in a given county. Generally the standardized difference between the growth rates of waves 1 and 2 and waves 2 and 3 were strongly positively correlated over short distances and shifted to a weak negative correlation at intermediate distances. We also found that peer county health group (a categorization of counties by demographic information relevant to public health) explained variation in response better between wave 1 and 2, while state identity was most important between wave 2 and 3. Taken together, we suggest that there are identifiable spatial patterns in pandemic response across the US but that the nature of these patterns change over the course of the pandemic. | epidemiology |
10.1101/2022.03.01.22271715 | Understanding multimorbidity trajectories in Scotland: an application of sequence analysis. | BACKGROUNDAlthough understanding how multiple conditions develop over time is of growing interest, there is currently little methodological development on the topic, especially in understanding how multimorbidity (the co-existence of at least two chronic conditions) develops longitudinally and in which order diseases occur. Therefore, we aim to describe how a longitudinal method, sequence analysis, can be used to understand the sequencing of common chronic diseases that lead to multimorbidity and the socio-demographic factors and health outcomes associated with typical disease trajectories.
METHODSWe use the Scottish Longitudinal Study (SLS) linking the Scottish census 2001 to disease registries, hospitalisation and mortality records. SLS participants aged 40-74 years at baseline were followed over a 10-year period (2001-2011) for the onset of three commonly occurring diseases: diabetes, cardiovascular disease (CVD), and cancer. We focused on participants who transitioned to at least two of these conditions over the follow-up period (N=6,300). We use sequence analysis with optimal matching and hierarchical cluster analysis to understand the process of disease sequencing and to distinguish typical multimorbidity trajectories. Socio-demographic differences between specific disease trajectories were evaluated using multinomial logistic regression. Poisson and Cox regressions were used to assess differences in hospitalisation and mortality outcomes between typical trajectories.
RESULTSIndividuals who transitioned to multimorbidity over 10 years were more likely to be older and living in more deprived areas than the rest of the population. We found seven typical trajectories: later fast transition to multimorbidity, CVD start with slow transition to multimorbidity, cancer start with slow transition to multimorbidity, diabetes start with slow transition to multimorbidity, fast transition to both diabetes and CVD, fast transition to multimorbidity and death, fast transition to both cancer and CVD. Those who quickly transitioned to multimorbidity and death were the most vulnerable, typically older, less educated, and more likely to live in more deprived areas. They also experienced higher number of hospitalisations and overnight stays while still alive.
CONCLUSIONSSequence analysis can strengthen our understanding of typical disease trajectories when considering a few key diseases. This may have implications for more active clinical review of patients beginning quick transition trajectories. | epidemiology |
10.1101/2022.03.01.22271714 | Describing a complex primary health care population in a learning health system to support future decision support and artificial intelligence initiatives | BackgroundLearning health systems (LHS) use data to improve care. Descriptive epidemiology to reveal health states and needs of the LHS population is essential for informing LHS initiatives. To properly characterize complex populations, both simple statistical and artificial intelligence techniques, applied with an epidemiological lens, can be useful. We present the first large-scale description of the population served by one of the first primary care LHS in Canada.
MethodsWe use electronic health record data from 2009-2019 to describe sociodemographic, clinical, and health care use characteristics of adult primary care clients served by the Alliance for Healthier Communities. In addition to simple summary statistics, we apply unsupervised leaning techniques to explore patterns of common condition co-occurrence, care provider teams, and care frequency.
ResultsThere are 221 047 eligible clients. Clients at community health centres that primarily serve those most at risk (homeless, mental health, addictions) and clients with multimorbidity tended to have more social determinants of health and chronic conditions. Most care is provided by physician and nursing providers, with heterogeneous combinations of other provider types. A subset of clients have many issues addressed within single-visits and there is notable within- and between-client variability in care frequency.
ConclusionsThis population-level overview of clients served by the Alliance provides a foundation for future LHS initiatives. In addition to substantive findings, we demonstrate the use of methods from statistics and artificial intelligence to describe a complex primary care population. We discuss implications for future initiatives, including development of decision support tools.
Key messagesO_LIThe Alliance for Healthier Communities serves clients with barriers to care and complex health needs through Community Health Centres across Ontario; we provide the first large-scale description of sociodemographic, clinical, and health care use characteristics of their primary care population using electronic health record data.
C_LIO_LIWe demonstrate the use of both simple statistical techniques traditionally used in descriptive epidemiology and artificial intelligence techniques, applied with an epidemiological lens, to account for complexity.
C_LIO_LIImplications for future learning health system initiatives, including the development of decision support tools, are discussed.
C_LI | primary care research |
10.1101/2022.03.01.22271714 | Describing a complex primary health care population in a learning health system to support future decision support and artificial intelligence initiatives | BackgroundLearning health systems (LHS) use data to improve care. Descriptive epidemiology to reveal health states and needs of the LHS population is essential for informing LHS initiatives. To properly characterize complex populations, both simple statistical and artificial intelligence techniques, applied with an epidemiological lens, can be useful. We present the first large-scale description of the population served by one of the first primary care LHS in Canada.
MethodsWe use electronic health record data from 2009-2019 to describe sociodemographic, clinical, and health care use characteristics of adult primary care clients served by the Alliance for Healthier Communities. In addition to simple summary statistics, we apply unsupervised leaning techniques to explore patterns of common condition co-occurrence, care provider teams, and care frequency.
ResultsThere are 221 047 eligible clients. Clients at community health centres that primarily serve those most at risk (homeless, mental health, addictions) and clients with multimorbidity tended to have more social determinants of health and chronic conditions. Most care is provided by physician and nursing providers, with heterogeneous combinations of other provider types. A subset of clients have many issues addressed within single-visits and there is notable within- and between-client variability in care frequency.
ConclusionsThis population-level overview of clients served by the Alliance provides a foundation for future LHS initiatives. In addition to substantive findings, we demonstrate the use of methods from statistics and artificial intelligence to describe a complex primary care population. We discuss implications for future initiatives, including development of decision support tools.
Key messagesO_LIThe Alliance for Healthier Communities serves clients with barriers to care and complex health needs through Community Health Centres across Ontario; we provide the first large-scale description of sociodemographic, clinical, and health care use characteristics of their primary care population using electronic health record data.
C_LIO_LIWe demonstrate the use of both simple statistical techniques traditionally used in descriptive epidemiology and artificial intelligence techniques, applied with an epidemiological lens, to account for complexity.
C_LIO_LIImplications for future learning health system initiatives, including the development of decision support tools, are discussed.
C_LI | primary care research |
10.1101/2022.03.01.22270897 | Descriptive and Narrative Study of Long Covid Cases in General Practice and Diagnostic Value of Single Photon Emission Computed Tomography | Primary care is under great pressure from patients with Covid -19 and those affected by Long Covid. The issue of Long Covid, its diagnosis and therapeutic approach are discussed here in detail. The Long Covid is described on the basis of a review of the literature and also on the basis of clinical experience in general practice. The main characteristics of thirty four cases (twenty five women) of Long Covid encountered in 2021 and early 2022 are outlined. The experience of six of them is reported on the basis of notes from their medical records. These six patients were interviewed and each was asked to reread and correct the texts concerning them. This is therefore a descriptive study based on clinical and narrative experience, verified by the patients.
Long Covid, the first disease in the history of medicine to be described first by patients themselves on social networks, is not yet precisely defined and the multi -systemic symptoms may be non-specific or vary according to the organs affected.
Diagnosis is based on careful listening to the patients history. Previously unknown irrepressible fatigue, brain fog, working memory disorders with possible anomia, anosmia, dysgeusia or other muli-systemic symptoms occurring after an acute Covid are varying characteristics of Long Covid. Biological evidence of Covid is missing in fourteen patients as PCRs may have been not done or came back negative in the acute phase of the disease. Anti-SARS-CoV-2 antibodies are not always present or are indistinguishable from post-vaccine antibodies. In fourteen severe cases presented, Single Photon Emission Computed Tomography (SPECT scan) after intravenous administration of Technetium-99m (Tc-99m HM-PAO) were able to demonstrate a disorder of cerebral perfusion. Two follow -up brain SPECT at three months showed significant improvement. Further genetic and immunologic study is ongoing for all patient with the help of the international consortium COVID Human Genetic Effort. A patient who presents after a Covid with medically unexplained symptoms may well be a Long Covid. Despite some interesting hypothesis, there is no known specific treatment. Neurocognitive revalidation and physiotherapy may help those patients who need long -term empathic support to cope with their condition.
Key messages{square} Long Covid is a recent onset, multi-systemic, long-term condition that can be very debilitating.
{square}The main symptoms are severe fatigue, exertional exhaustion, and cognitive and memory problems, among others.
{square}Patients who suffer from it may not realize it, may not talk about it, or may attribute their problem to other causes.
{square}Single Photon Emission Computed Tomography (SPECT CT) contributes to the hypothesis of a vascular perfusion disorder induced by SARS -coV-2 and should be validated as a diagnostic tool in neurological Long Covid.
{square}Tissue immunity should be available to prove Long Covid in case of humoral seronegativity
{square}There is no identified treatment that can be recommended yet. Careful listening, empathic support and cognitive and physical rehabilitation are suggested and should be organised or supported by the Belgian state. | primary care research |
10.1101/2022.02.28.22270969 | Development and validation of a quantitative instrument for measuring temporal and social disorientation in the Covid-19 crisis | We developed a quantitative Instrument for measuring Temporal and Social Disorientation (ITSD), aimed at major crises such as the Covid-19 pandemic. Disorientation has been identified as one of the central elements of the psychological impact of the Covid-19 era on the general public, but so far, the question has only been approached qualitatively. This paper offers an empirical, quantitative approach to the multi-faceted disorientation of the Covid-19 pandemic by operationalising the issue with the help of the ITSD. The ITSD was developed through multiple stages involving a preliminary open-ended questionnaire followed by a coder-based thematic analysis. This paper establishes the reliability and validity of the resulting ITSD using a 3-step validation process on a sample size of 3306. | public and global health |
10.1101/2022.02.24.22271449 | Healthcare services access, use, and barriers among migrants in Europe: a systematic review | BackgroundThe issue of migrants health and access to health services is dynamic and complex posing a challenge to health systems worldwide.
AimTo investigate migrants access to health services in European countries, the use of health services by migrants and the barriers encountered by migrants in the use of health services.
Material and methodsThe search was conducted in January 2022 in five databases; PubMed, Medline, Web of science, Scopus and Cinahl. We used the following keywords: migrants, immigrants, use, access, utilization, healthcare services, services, needs, health, difficulties, barriers. The inclusion criteria were the following: (a) the studies investigated the access of migrants to health services, the use of health services by migrants and the barriers encountered by migrants in using health services. (b) migrants self-assessed access, use and barriers. (c) studies were conducted in European countries. (d) studies included adult migrants. (e) the language of articles was English.
ResultsSixty-five studies were met our inclusion criteria. among studies, 89.2% were quantitative and 11.8% were qualitative. All quantitative studies were cross-sectional. for data collection, 58.5% of studies used questionnaires and 30.8% used historical files. Also, personal interviews were performed in 9.2% of studies and focus groups in 1.5% of studies. in our studies, 73.8% of natives stated that they had better access to health services and used health services better than migrants, while 26.2% found that migrants stated that they had better access to health services and used health services better. The most common barriers were the following: inability to understand the language and communicate, lack of insurance, lack of information and knowledge, lack of family support, low educational level, short duration of stay in the country of migration, low income, lack of a family doctor and high costs.
ConclusionsMigrants face several barriers both in accessing and using health services in Europe. Intensive efforts are needed to increase migrants knowledge, implement culturally sensitive interventions in migrant communities and better inform healthcare professionals so that they can approach migrants more effectively. | public and global health |
10.1101/2022.03.01.22271688 | No impact of sex on surgical site infections in abdominal surgery: A multi-center study | ObjectiveMale sex is controversially discussed as a risk factor for surgical site infections (SSI). The aim of the present study was to evaluate the impact of sex on SSI in abdominal surgery under elimination of relevant confounders.
MethodsClinicopathological data of 6603 patients undergoing abdominal surgery from a multi-center prospective database of four Swiss hospitals including patients between 2015 and 2018 were assessed. Patients were stratified according to postoperative SSI and risk factors for SSI were assessed using univariate and multivariate analysis.
ResultsIn 649 of 6603 patients SSI was reported (9.8%). SSI was significantly associated with reoperation (22.7% vs. 3.4%, p <0.001), higher mortality rate (4.6% vs. 0.9%, p <0.001) and higher rate of length of hospital stay over the 75th percentile (57.0 % vs. 17.9 %, p <0.001). In univariate analysis male sex was a significant risk factor for SSI (p = 0.01). In multivariate analysis including multiple confounders such as comorbidities and perioperative factors there was no association between male sex and risk of SSI (odds ratio (OR) 1.1 [CI 0.8 - 1.4]). Independent risk factors for SSI in multivariate analysis were BMI [≥] 30 kg/m2 (OR 1.8 [CI 1.3 - 2.3]), duration of surgery > 75th percentile (OR 2.3 [1.8 - 2.9]), high contamination level (OR 1.3 [1.0 - 1.6]), laparotomy (OR 1.3 [1.0 - 1.7]), pervious laparotomy (OR 1.4 [1.1 - 1.7]), blood transfusion (OR 1.7 [1.2 - 2.4]), cancer (OR 1.3 [1.0-1.8], malnutrition (OR 2.5 [1.8 - 3.4]).
ConclusionUnder elimination of relevant confounders there is no significant correlation between sex and risk of SSI after abdominal surgery. | surgery |
10.1101/2022.03.01.22271687 | Efficacy of bladder training in adults with overactive bladder: A systematic review protocol | IntroductionThe aim of this systematic review will be to investigate and update whether bladder training can promote improvement of symptoms of overactive bladder syndrome with or without urgency urinary incontinence in adults.
MethodsWe will perform a systematic review according to the Cochrane methodology of randomized controlled trials. An overall search strategy will be developed and adapted for each database. A bibliographic search will be conducted in eight databases - PubMed, PEDro, SciELO, LILACS, Cochrane Library, Web of Science, EMBASE, CINAHL, by manual searching. The MeSH terms will be "Bladder Training", "Bladder Drill", "Bladder Re-education", "Bladder Retraining", "Bladder Discipline", "Overactive Bladder", "Bladder, Overactive", "Overactive Urinary Bladder", "Urinary Bladder", "Overactive, Urinary Bladder", "Bladder, Urinary", "Urinary Bladder Disease", "Bladder Disease", "Bladder Detrusor Muscle" and "Detrusor Muscle, Bladder". Meta-analysis, if plausible, will be performed by the software Review Manager 5.4. Primary outcomes: symptoms of overactive bladder syndrome (urinary urgency with daytime voiding frequency, nocturia with or without urgency urinary incontinence), and cure/improvement assessed by instruments. Secondary outcomes: quality of life, functional assessment, validated scale/questionnaire and adverse events. Quality assessment will be performed by Cochrane instrument and quality of evidence will be assessed by GRADE.
DiscussionThis study is a review of randomized controlled studies to analyze the efficacy of bladder training in improving the symptoms of adults with overactive bladder syndrome. The study design of randomized controlled trials for a higher level of scientific evidence was chosen. The aim is to obtain results that allow further studies and evidence that this intervention generates beneficial effects in the sample studied.
Trial registration
Systematic review registrationPROSPERO CRD42022301522. | urology |
10.1101/2022.02.18.22271039 | Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and signs of neurodegeneration: a prospective cross-sectional study | ImportanceGrowing evidence suggests that coronavirus disease 2019 (COVID-19) is associated with neurological sequelae. However, the underlying pathophysiological mechanisms resulting in central nervous system (CNS) derogation remain unclear.
ObjectiveTo identify severity-dependent immune mechanisms in the cerebrospinal fluid (CSF) and plasma of COVID-19 patients and their association with brain imaging alterations.
DesignProspective cross-sectional cohort study.
SettingThis study was performed from August 2020 to April 2021. Participants were enrolled in the outpatient clinics, hospital wards and intensive care units (ICU) of two clinical sites in Basel and Zurich, Switzerland.
ParticipantsAge >18 years and a positive SARS-CoV-2 test result were inclusion criteria. Potentially matching individuals were identified (n=310), of which 269 declined to participate and 1 did not match inclusion criteria. Paired CSF and plasma samples, as well as brain images, were acquired. The COVID-19 cohort (n=40; mean [SD] age, 54 [20] years; 17 women (42%)) was prospectively assorted by neurological symptom severity (classes I, II and III). Age/sex-matched inflammatory (n=25) and healthy (n=25) CSF and plasma control samples were obtained. For volumetric brain analysis, a healthy age/sex-matched control cohort (n=36) was established.
ExposuresLumbar puncture, blood sampling and cranial MRI and/or CT.
Main outcomes and measuresProteomics, standard parameters and antibody profiling of paired CSF and plasma samples in COVID-19 patients and controls. Brain imaging and gray matter volumetric analysis in association with biomarker profiles. Follow-up after 10-months.
ResultsCOVID-19 patients displayed a plasma cytokine storm but a non-inflammatory CSF profile. Class III patients displayed signs of blood-brain barrier (BBB) impairment and a polyclonal B cell response targeting self- and non-self antigens. Decreased regional brain volumes were present in COVID-19 patients and associated with specific CSF and plasma parameters.
Conclusion and relevanceNeuro-COVID class III patients had a strong, peripheral immune response resulting in (1) BBB impairment (2) ingress of (auto-)antibodies, (3) microglia activation and neuronal damage signatures. Our data point towards several potentially actionable targets that may be addressed to prevent COVID-19-related neurological sequelae.
Trial registrationThe trial (NCT04472013) was registered on clinicaltrials.gov.
Key pointsO_ST_ABSQuestionC_ST_ABSDoes a severity-dependent pattern of immune mechanisms exist in the cerebrospinal fluid (CSF) and plasma of COVID-19 patients and are these associated with clinical and brain imaging findings?
FindingsNeuro-COVID patients display a robust class III-specific peripheral immune response resulting in (1) blood-brain barrier (BBB) impairment, (2) ingress of (auto-)antibodies, (3) microglia activation and neuronal damage signatures. Integration of MRIs, brain volumetry and proteomics identified biomarkers associated with regional brain volume loss in severe Neuro-COVID.
MeaningWe provide a multidimensional framework of mechanisms associated with severe Neuro-COVID and present possible targets to prevent COVID-19-related neurological sequelae. | neurology |
10.1101/2022.03.01.22271733 | Impact and cost-effectiveness of frequent HIV re-testing among key populations in Viet Nam: a modeling study | BackgroundHIV testing and counseling is a key component of HIV prevention and the entry point into the treatment cascade, which improves for individual clinical outcomes and reduces onward HIV transmission. Current guidelines recommend at least annual testing for key populations. More frequent testing could provide health benefits, but these additional services increase the program the cost-effectiveness is not well-evaluated.
MethodsWe used a compartmental mathematical model to simulate the health and economic impact of HIV testing one to four times per year for men who have sex with men, people who inject drugs, and female sex workers in Viet Nam. Model outcomes included costs, HIV infections, HIV-related deaths, and disability-adjusted life years (DALYs) associated with each scenario. We used an opportunity cost-based cost-effectiveness threshold of US $2,255 per DALY averted, discounted costs and health benefits at 3% annually, and used a time horizon from 2021 to 2030 to calculate incremental cost-effectiveness ratios (ICERs).
ResultsCompared to the baseline scenario, more frequent HIV testing was estimated to incrementally avert 10.2%, 5.2%, 3.0%, and 1.6% discounted infections for one-, two-, three-, and four-tests per year, respectively. ICERs associated with each scenario ranged from $464, $1,190, $1,762, and $2,727 per DALY averted for one-, two-, three-, and four-tests per year, respectively.
ConclusionsIncreased HIV testing frequency for key populations was projected to avert HIV incidence, mortality, and disability in Viet Nam and was cost-effective. Settings with a similar context should consider strategies on how to optimize retesting among key populations. | hiv aids |
10.1101/2022.03.01.22271740 | Treatment Outline and Clinical Outcome of Hospitalized COVID-19 Patients: Experiences from a Combined Military Hospital of Bangladesh | BackgroundGlobal knowledge of treatment and outcomes of COVID-19 has been evolving since the onset of the pandemic.
Materials and MethodsThe objective of this cross-sectional study was to explore treatment and outcome of COVID-19 patients admitted in a Combined Military Hospital of Bangladesh. Data were collected from treatment records of patients of the CMH Bogura during the period of June 2020 to August 2020. Total 219 RT-PCR positive admitted patients were included as study population.
ResultAmong 219 patients, 78.6% were male and 21.5% were female, mean age of patients was 34.3 {+/-} 12.2. About14.6% patients had one or more comorbidities. Most (83.1%) of the admitted patients were diagnosed as mild cases. Antimicrobials were used in 98.8% cases, and frequent use of doxycycline (80.4%) and ivermectine (77.2%) was found. Anticoagulant and steroid therapy were used in 42.0% and 15.5% patients respectively. O2 therapy was required in 6.0% cases and intensive care unit (ICU) support was needed in 2.3% cases.Duration of hospital stay was 12.1{+/-} 4.4 days and 100% of patients were discharged from hospital. There was no single mortality during the study period.
ConclusionHigh prevalence of antimicrobials use was observed among the hospitalized COVID-19 patients in this single center study.Supportive care was effective with no incidence of mortality. | infectious diseases |
10.1101/2022.03.02.22271385 | Impact of Delta and Vaccination on SARS-CoV-2 transmission risk: Lessons for Emerging Breakthrough infections | With the continuous emergence of SARS-CoV-2 variants of concern and implementation of mass-scale interventions like vaccination, understanding factors affecting disease transmission has critical implications for control efforts. Here we used a simple adapted N95 mask sampling method to demonstrate the impact of circulating SARS-CoV-2 variants and vaccination on 92 COVID-19 patients to expel virus into the air translating to a transmission risk. Between July and September 2021, when the Delta was the dominant circulating strain in Mumbai, we noted a two-fold increase in the proportion of people expelling virus (95%), about an eighty-fold increase in median viral load and a three-fold increase in high emitter type (41%; people expelling >1000 viral copy numbers in 30 minutes) compared to initial strains of 2020. Eight percent of these patients continued to be high emitters even after eight days of symptom onset, suggesting a probable increased transmission risk for Delta strain even at this stage. There was no significant difference in expelling pattern between partial, full and un-vaccinated individuals suggesting similar transmission risk. We noted significantly more infections among vaccinated study patients and their household members than unvaccinated, probably due to increased duration from vaccination and/or increased risk behaviour upon vaccination due to lower perceived threat. This study provides biological evidence for possible continued transmission of the Delta strain even with vaccination, emphasizing the need to continue COVID-19 appropriate behaviour. The study also indicates that the mask method may be useful for screening future vaccine candidates, therapeutics or interventions for their ability to block transmission. | infectious diseases |
10.1101/2022.03.01.22271735 | Comparison of the reactogenicity and immunogenicity of a reduced and standard booster dose of the mRNA COVID-19 vaccine in healthy adults after two doses of inactivated vaccine. | The coronavirus disease 2019 (COVID-19) pandemic has been a serious healthcare problem worldwide since December 2019. The third dose of heterologous vaccine was recently approved by World Health Organization. The present study compared the reactogenicity and immunogenicity of the reduced and standard third booster dose of the BNT162b2 and mRNA-1273 vaccine in adults who previously received the two-dose CoronaVac vaccine. Results showed that headache, joint pain, and diarrhea were more frequent in the 15 g-than the 30 g-BNT162b2 groups, whereas joint pain and chilling were more frequent in the 100 g-than the 50 g-mRNA-1273 groups. No significant differences in immunogenicity were detected. These findings demonstrate that the reduced dose of the mRNA vaccines elicited antibody responses against the SARS-CoV-2 delta and omicron variants that were comparable to the standard dose. The reduced dose could be used to increase vaccine coverage in situations of limited global vaccine supply.
HighlightsO_LIThe 15 g- and 30 g-BNT162b2, and 50 g- and 100 g-mRNA-1273 booster doses were compared
C_LIO_LIBooster vaccination with the mRNA vaccine elicits high Ig and IgG anti-RBD in CoronaVac-vaccinated adults
C_LIO_LINo differences were observed in antibody responses after the reduced or standard booster dose of the mRNA vaccine in CoronaVac-vaccinated adults
C_LIO_LINeutralizing antibodies against the delta and omicron variants were significantly higher after the booster dose
C_LIO_LINeutralizing antibody titers were lower against the omicron variant than the delta variant in all vaccinated adults
C_LI | allergy and immunology |
10.1101/2022.03.01.22271738 | When Diagnosis Is Made By Playing Shuffled Cards: A Non-Invasive, Real-Time, Adaptive Method to Functionally Evaluate Coronary Artery Based on Coronary Angiography | AimsThe great value concealed in the sequence of coronary angiography frames is not discovered in the world. We discovered and demonstrated the "Sequence Value" concealed in the coronary angiography and proposed DZL (Disarranged Zone Learning) to realize the sequence value in functional evaluation of coronary artery disease. Furthermore, we automated the DZL using a deep learning model to release huge medical resources.
Methods and ResultsWe gave a novel definition of TIMI flow grade using the term temporal and spatial coupling tightness (TSCT) of the antegrade contrast agent. We used the TSCT to model the myocardial ischemia in a functional perspective and used the PCI conduction after CAG as the outcome event of myocardial ischemia. We proposed a novel method (Disarranged Zone Learning) to measure TSCT and we designed an experiment to validate its effectiveness. We further automated the novel method using an unsupervised deep learning model. The prediction accuracy of the model was applied as a proxy of myocardial ischemia. We further proposed Difference DZL to quantify the functional capability of any specific vessel segment. DZL overall AUC reaches 0.92. DZL automation reveals an AUC of 0.84 (95%CI, 0.81-0.87).
ConclusionWe unprecedentedly discovered the "Sequence Value" concealed in coronary angiography. We then proposed a novel method termed DZL to functionally evaluate the coronary artery in a non-invasive, real-time and adaptive manner.
DisclosureThe Authors declare that there is no conflict of interest. | cardiovascular medicine |
10.1101/2022.03.02.22271753 | Non-occupational physical activity and risk of 22 cardiovascular disease, cancer, and mortality outcomes: a dose-response meta-analysis of large prospective studies | ObjectiveTo estimate dose-response associations between non-occupational physical activity and multiple chronic disease outcomes in the general adult population.
Eligibility criteriaProspective cohort studies with (a) general population samples >10,000 adults, (b) [≥]3 exposure categories, and (c) risk measures and confidence intervals for all-cause mortality, total cardiovascular disease, coronary heart disease, stroke, heart failure, total cancer, and site-specific cancers (head and neck, myeloid leukemia, myeloma, gastric cardia, lung, liver, endometrium, colon, breast, bladder, rectum, esophagus, prostate, kidney).
Information sourcesPubMed, Scopus, Web of Science, and reference lists of published studies, searched in February 2019.
Data extraction and synthesisIndependent extraction and double-checking of study characteristics, exposure, and outcome assessment by two reviewers for each paper. Primary exposure was non-occupational physical activity volume, harmonized to physical activity energy expenditure in marginal MET-hours per week (mMET-h/week). The current minimum recommendations for physical activity (150 min/week of moderate-to-vigorous physical activity) equate to 8.75 mMET-h/week. Outcomes were risks of mortality, cardiovascular diseases, and cancers. We used restricted cubic splines in random-effects meta-analyses. Potential population impact was quantified using impact fractions.
Results196 articles were included, covering 94 cohorts. The evidence base was largest for all-cause mortality (50 independent results; 163,415,543 person-years; 811,616 events), and incidence of cardiovascular disease (37 independent results; 28,884,209 person-years; 74,757 events) and cancer (31 independent results; 35,500,867 person-years; 185,870 events). In general, inverse non-linear associations were observed, steeper between 0 and 8.75 mMET-h/week, with smaller marginal reductions in risk above this level to 17.5 mMET-h/week, beyond which additional reductions were small and uncertain. Associations were stronger for all-cause and cardiovascular disease mortality than for cancer mortality. If all insufficiently active individuals had met the recommended physical activity level, 15.7% (95%CI: 13.1 to 18.2%) of all premature deaths would have been averted.
ConclusionsInverse non-linear dose-response associations suggest substantial protection against a range of chronic disease outcomes from small increases in non-occupational physical activity in inactive adults.
Review registrationPROSPERO CRD42018095481. | epidemiology |
10.1101/2022.03.02.22271743 | Persisting decreases in state and trait anxiety post-psilocybin: A naturalistic, observational study among retreat attendees | Anxiety disorders are the most common type of psychiatric disorders among Western countries. Evidence-based treatment modalities including pharmacological and cognitive-behavioral therapy result in relatively low response rates (average range: 51 - 58%). Historical and recent research suggests psychedelic drugs may be efficacious in alleviating anxiety-related symptoms among healthy and clinical populations. The main aim of the present study was investigation of the effects of psilocybin-containing truffles, when taken in a supportive group setting, on ratings of state and trait anxiety across self-reported healthy volunteers. Attendees of psilocybin ceremonies were asked to complete a test battery at three separate occasions: before the ceremony (baseline), the morning after, and one week after the ceremony. The test battery included questionnaires assessing state and trait anxiety (State-Trait Anxiety Inventory), mindfulness capacities (Five Facet Mindfulness Questionnaire), and personality (Big Five Inventory). Additionally, the psychedelic experience was quantified with the Persisting Effects Questionnaire and the Ego Dissolution Inventory. The total amount of psilocybin-containing truffles consumed by each participant was recorded, and a sample of the truffles was analyzed to determine psilocin concentrations. Fifty-two attendees (males= 25; females= 25; others= 2) completed parts of the baseline assessment, 46 (males= 21; females= 24; others= 1) completed assessments the morning after the ceremony, and 23 (males= 10; females= 13) completed assessments at the one-week follow-up. Average psilocin consumption across individuals was 27.1 mg. We observed medium to large reductions in anxiety measures (both state and trait) compared to baseline which persisted over a one-week period post-ceremony. At one week post-ceremony, the non-judging facet of the mindfulness scale was increased, while the personality trait neuroticism decreased, when compared to baseline. Additionally, we found neuroticism and ratings of ego dissolution to be the strongest predictors of reductions in trait and state anxiety, respectively. In sum, results indicate rapid and persisting (up to one week) anxiolytic effects in psilocybin retreat attendees, which are related to the acute experience of ego dissolution, as well as lasting changes in trait neuroticism. To understand whether these effects extend to wider populations suffering from heightened anxiety, and the mechanisms involved, further experimental research is needed. | pharmacology and therapeutics |
10.1101/2022.03.01.22271659 | Structural deviations of the posterior fossa and the cerebellum and their cognitive links in a neurodevelopmental deletion syndrome | BackgroundHigh-impact genetic variants associated with neurodevelopmental disorders provide biologically defined entry points for etiological discovery. The 3q29 deletion (3q29Del) is one such variant that confers a [~]40-fold increased risk for schizophrenia, and a [~]30-fold increased risk for autism. However, the specific neural mechanisms underlying this link remain largely unknown.
MethodsHere, we report the first in vivo quantitative neuroimaging study in 3q29Del individuals (N=24) and healthy controls (N=1,608) using structural MRI. Given prior reports of posterior fossa abnormalities in 3q29Del, we focus our investigation on the cerebellum and its primary tissue-types. Additionally, we compare the prevalence of cystic/cyst-like malformations of the posterior fossa between 3q29Del participants and controls, and examine the association between neuroanatomical findings and standardized behavioral measures to probe gene-brain-behavior relationships.
Results3q29Del participants had smaller cerebellar cortex volumes than controls, both before and after correction for intracranial volume (ICV). 3q29Del participants also had larger cerebellar white matter volumes than controls following ICV-correction. The 3q29Del group displayed an elevated rate of posterior fossa arachnoid cysts and mega cisterna magna findings independent of cerebellar volume. Sex played a moderating role in a subset of findings. Cerebellar white matter volume was positively associated with visual-motor integration skills and cognitive ability, while cystic/cyst-like malformations yielded no behavioral link.
ConclusionsAbnormal development of posterior fossa structures may represent neuroimaging-based biomarkers in 3q29Del. Results reveal cerebellar associations with sensorimotor and cognitive deficits in 3q29Del and present a novel point of genetic convergence with cerebellar pathology reported in idiopathic forms of neurodevelopmental disease. | psychiatry and clinical psychology |
10.1101/2022.03.01.22271659 | Structural deviations of the posterior fossa and the cerebellum and their cognitive links in a neurodevelopmental deletion syndrome | BackgroundHigh-impact genetic variants associated with neurodevelopmental disorders provide biologically defined entry points for etiological discovery. The 3q29 deletion (3q29Del) is one such variant that confers a [~]40-fold increased risk for schizophrenia, and a [~]30-fold increased risk for autism. However, the specific neural mechanisms underlying this link remain largely unknown.
MethodsHere, we report the first in vivo quantitative neuroimaging study in 3q29Del individuals (N=24) and healthy controls (N=1,608) using structural MRI. Given prior reports of posterior fossa abnormalities in 3q29Del, we focus our investigation on the cerebellum and its primary tissue-types. Additionally, we compare the prevalence of cystic/cyst-like malformations of the posterior fossa between 3q29Del participants and controls, and examine the association between neuroanatomical findings and standardized behavioral measures to probe gene-brain-behavior relationships.
Results3q29Del participants had smaller cerebellar cortex volumes than controls, both before and after correction for intracranial volume (ICV). 3q29Del participants also had larger cerebellar white matter volumes than controls following ICV-correction. The 3q29Del group displayed an elevated rate of posterior fossa arachnoid cysts and mega cisterna magna findings independent of cerebellar volume. Sex played a moderating role in a subset of findings. Cerebellar white matter volume was positively associated with visual-motor integration skills and cognitive ability, while cystic/cyst-like malformations yielded no behavioral link.
ConclusionsAbnormal development of posterior fossa structures may represent neuroimaging-based biomarkers in 3q29Del. Results reveal cerebellar associations with sensorimotor and cognitive deficits in 3q29Del and present a novel point of genetic convergence with cerebellar pathology reported in idiopathic forms of neurodevelopmental disease. | psychiatry and clinical psychology |
10.1101/2022.03.01.22271659 | Structural deviations of the posterior fossa and the cerebellum and their cognitive links in a neurodevelopmental deletion syndrome | BackgroundHigh-impact genetic variants associated with neurodevelopmental disorders provide biologically defined entry points for etiological discovery. The 3q29 deletion (3q29Del) is one such variant that confers a [~]40-fold increased risk for schizophrenia, and a [~]30-fold increased risk for autism. However, the specific neural mechanisms underlying this link remain largely unknown.
MethodsHere, we report the first in vivo quantitative neuroimaging study in 3q29Del individuals (N=24) and healthy controls (N=1,608) using structural MRI. Given prior reports of posterior fossa abnormalities in 3q29Del, we focus our investigation on the cerebellum and its primary tissue-types. Additionally, we compare the prevalence of cystic/cyst-like malformations of the posterior fossa between 3q29Del participants and controls, and examine the association between neuroanatomical findings and standardized behavioral measures to probe gene-brain-behavior relationships.
Results3q29Del participants had smaller cerebellar cortex volumes than controls, both before and after correction for intracranial volume (ICV). 3q29Del participants also had larger cerebellar white matter volumes than controls following ICV-correction. The 3q29Del group displayed an elevated rate of posterior fossa arachnoid cysts and mega cisterna magna findings independent of cerebellar volume. Sex played a moderating role in a subset of findings. Cerebellar white matter volume was positively associated with visual-motor integration skills and cognitive ability, while cystic/cyst-like malformations yielded no behavioral link.
ConclusionsAbnormal development of posterior fossa structures may represent neuroimaging-based biomarkers in 3q29Del. Results reveal cerebellar associations with sensorimotor and cognitive deficits in 3q29Del and present a novel point of genetic convergence with cerebellar pathology reported in idiopathic forms of neurodevelopmental disease. | psychiatry and clinical psychology |
10.1101/2022.03.01.22271717 | Prevalence of Chronic Diseases, Depression, and Stress among U.S. Child Care Professionals during the COVID-19 Pandemic | ImportanceThere is no published national research reporting child care professionals physical health, depression, or stress during the COVID-19 pandemic. Given their central role in supporting childrens development, child care professionals overall physical and mental health is important.
ObjectivesTo evaluate the prevalence of chronic diseases, depression, and stress levels during the COVID-19 pandemic among U.S. child care professionals.
DesignIn this large-scale national survey, data were collected through an online survey from May 22, 2020 to June 8, 2020. We analyzed the association of sociodemographic characteristics with four physical health conditions (asthma, heart disease, diabetes, and obesity), depression, and stress weighted to national representativeness. Sociodemographic characteristics included race, ethnicity, age, gender, medical insurance status, and child care type.
SettingCenter- and home-based child care.
ParticipantsChild care professionals (n = 81,682) from all U.S. states and the District of Columbia.
ResultsMean age was 42.1 years (standard deviation = 14.1); 96.0% (n = 78,725) were female, 2.5% (n = 2,033) were male, and 0.3% (n = 225) were non-binary. For physical health conditions, 14.3% (n = 11,717) reported moderate to severe asthma, 6.5% (n = 5,317) diabetes, 4.9% (n = 3,971) heart disease, and 19.8% (n = 16,207) being obese. Regarding mental health, 45.7% (n = 37,376) screened positive for depression and 66.5% (n = 54,381) reported moderate to high stress levels. Race, ethnicity, and gender disparities were evidenced for physical health conditions of child care professionals, but not for mental health during the pandemic.
Conclusions and RelevanceOur findings highlight that child care professionals depression rates during the pandemic were much higher than before the pandemic, and depression, stress and asthma rates were higher than U.S. adult depression rates during the pandemic. Given the essential work child care professionals provide during the pandemic, policy makers and public health officials should consider what can be done to support the physical and mental health of child care professionals.
Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the prevalence of chronic diseases, depression, and stress among U.S. child care professionals during the COVID-19 pandemic?
FindingsIn this survey of 81,682 U.S. child care professionals, 14.3% reported moderate to severe asthma, 6.5% diabetes, 4.9% heart disease, 19.8% being obese, 45.7% screening positive for depression, and 66.5% moderate to high stress levels.
MeaningDuring the pandemic, child care professionals reported depression rates much higher than before the pandemic, and asthma, stress, and depression much greater than U.S. adult estimates, highlighting a need for effective supports for the wellbeing of this essential workforce. | public and global health |
10.1101/2022.03.01.22271496 | Development of a vocal biomarker for fatigue monitoring in people with COVID-19 | ObjectiveTo develop a vocal biomarker for fatigue monitoring in people with COVID-19.
DesignProspective cohort study.
SettingPredi-COVID data between May 2020 and May 2021.
ParticipantsA total of 1772 voice recordings was used to train an AI-based algorithm to predict fatigue, stratified by gender and smartphones operating system (Android/iOS). The recordings were collected from 296 participants tracked for two weeks following SARS-CoV-2 infection.
primary and secondary outcome measuresFour machine learning algorithms (Logistic regression, k-nearest neighbors, support vector machine, and soft voting classifier) were used to train and derive the fatigue vocal biomarker. A t-test was used to evaluate the distribution of the vocal biomarker between the two classes (Fatigue and No fatigue).
ResultsThe final study population included 56% of women and had a mean ({+/-}SD) age of 40 ({+/-}13) years. Women were more likely to report fatigue (P<.001). We developed four models for Android female, Android male, iOS female, and iOS male users with a weighted AUC of 79%, 85%, 86%, 82%, and a mean Brier Score of 0.15, 0.12, 0.17, 0.12, respectively. The vocal biomarker derived from the prediction models successfully discriminated COVID-19 participants with and without fatigue (t-test P<.001).
ConclusionsThis study demonstrates the feasibility of identifying and remotely monitoring fatigue thanks to voice. Vocal biomarkers, digitally integrated into telemedicine technologies, are expected to improve the monitoring of people with COVID-19 or Long-COVID. | public and global health |
10.1101/2022.03.02.22271697 | Recurrent SARS-CoV-2 Mutations in Immunodeficient Patients | Long-term SARS-CoV-2 infections in immunodeficient patients are an important source of variation for the virus but are understudied. Many case studies have been published which describe one or a small number of long-term infected individuals but no study has combined these sequences into a cohesive dataset. This work aims to rectify this and study the genomics of this patient group through a combination of literature searches as well as identifying new case series directly from the COG-UK dataset. The spike gene receptor binding domain (RBD) and N-terminal domains (NTD) were identified as mutation hotspots. Numerous mutations associated with variants of concern were observed to emerge recurrently. Additionally a mutation in the envelope gene, - T30I was determined to be the most recurrent frequently occurring mutation arising in persistent infections. A high proportion of recurrent mutations in immunodeficient individuals are associated with ACE2 affinity, immune escape, or viral packaging optimisation.
There is an apparent selective pressure for mutations which aid intra-host transmission or persistence which are often different to mutations which aid inter-host transmission, although the fact that multiple recurrent de novo mutations are considered defining for variants of concern strongly indicates that this potential source of novel variants should not be discounted. | infectious diseases |
10.1101/2022.03.02.22271441 | Collecting mortality data via mobile phone surveys: a non-inferiority randomized trial in Malawi | IntroductionDespite the urgent need for timely mortality data in low-income and lower-middle-income countries, mobile phone surveys rarely include questions about recent deaths. There are concerns that such questions might a) be too sensitive, b) prompt negative/adverse reactions among respondents, c) take too long to ask and/or d) generate unreliable data. We assessed the feasibility of mortality data collection during mobile phone surveys.
MethodsWe conducted a non-inferiority trial among a random sample of mobile phone users in Malawi. Participants were allocated 3:1 to an interview about recent deaths in their family (treatment group) or about their economic activity (control group). In the treatment group, half of the respondents completed a short mortality questionnaire, focused on information necessary to calculate recent mortality rates, whereas the other half completed an extended questionnaire that also included questions about symptoms and healthcare use. The primary trial outcome was the cooperation rate. Secondary outcomes included the completion rate, self-reports of negative feelings and stated intentions to participate in future interviews. We also documented the amount of time required to collect mortality data, and we explored the quality of death reports.
ResultsThe difference in cooperation rates between treatment and control groups was 0.9 percentage points (95% CI = -2.3, 4.1), which satisfied the non-inferiority criterion. Similarly, the mortality questionnaire was non-inferior to the control questionnaire on all secondary outcomes. Collecting mortality data required approximately 2 to 4 additional minutes per reported death, depending on the inclusion of questions about symptoms and healthcare use. More than half of recent deaths elicited during mobile phone interviews had not been reported to the national civil registration system.
ConclusionIncluding mortality-related questions in mobile phone surveys appears acceptable and feasible. It might help strengthen the surveillance of mortality trends in low-income and lower-middle-income countries with limited civil registration systems.
KEY QUESTIONSO_ST_ABSWhat is already known?C_ST_ABSO_LIIn many low-income and lower-middle-income countries, civil registration systems only record a fraction of all deaths. The excess mortality associated with health crises is thus not known in near real-time.
C_LIO_LIMobile phone surveys are increasingly common in low-income and lower-middle-income countries. They could help fill mortality-related data gaps, but there are concerns that asking questions about recent deaths over the phone might be too sensitive, might take too long, and/or might generate unreliable data.
C_LI
What are the new findings?O_LIIn a randomized trial conducted with mobile phone users in Malawi, asking questions about recent deaths was not less acceptable than asking questions about economic activity and household livelihoods.
C_LIO_LIFew participants reported experiencing negative feelings during the interview, and these feelings were temporary.
C_LIO_LIMore than half of the deaths reported during mobile phone interviews had not been previously registered with the national civil registration system.
C_LI
What do the new findings imply?O_LIIncluding questions about recent deaths in mobile phone surveys appears feasible and acceptable.
C_LIO_LIIt might help strengthen the surveillance of mortality trends in low-income and lower-middle-income countries with limited civil registration systems.
C_LI | infectious diseases |
10.1101/2022.02.21.22270929 | Gaussian-Enveloped Tones (GET): a vocoder that can simulate pulsatile stimulation in cochlear implants | Acoustic simulations of cochlear implants allow comprehensive evaluation of not only perceptual performance under impoverished listening conditions but also relative contributions of classical spectral and temporal cues to speech recognition. Conventional simulations use continuous sinusoidal or noise carriers, lacking the vital pulsatile characteristics in a typical cochlear-implant processing strategy. The present study employed Gaussian-enveloped tones (GETs) as a discrete carrier to simulate the electric pulse train in modern cochlear implants. Two types of GET vocoders were implemented and evaluated in normal-hearing listeners to compare their performance to actual cochlear-implant performance. In the first implementation, GETs with different durations were used to simulate electric current interaction across channels that produced vowel and consonant recognition similar to the actual cochlear-implant result. In the second implementation, a direct mapping from electric pulses to GETs was developed to simulate a widely-used clinical n-of-m strategy in cochlear implants. The GET processing simulated the actual implant speech in noise perception in terms of the overall trend, the absolute mean scores, and their standard deviations. The present results demonstrated that the pulsatile GET vocoders simulate the cochlear implant performance more accurately than the conventional sinusoid or noise vocoders. | otolaryngology |
10.1101/2022.02.21.22270929 | Gaussian-Enveloped Tones (GET): a vocoder that can simulate pulsatile stimulation in cochlear implants | Acoustic simulations of cochlear implants allow comprehensive evaluation of not only perceptual performance under impoverished listening conditions but also relative contributions of classical spectral and temporal cues to speech recognition. Conventional simulations use continuous sinusoidal or noise carriers, lacking the vital pulsatile characteristics in a typical cochlear-implant processing strategy. The present study employed Gaussian-enveloped tones (GETs) as a discrete carrier to simulate the electric pulse train in modern cochlear implants. Two types of GET vocoders were implemented and evaluated in normal-hearing listeners to compare their performance to actual cochlear-implant performance. In the first implementation, GETs with different durations were used to simulate electric current interaction across channels that produced vowel and consonant recognition similar to the actual cochlear-implant result. In the second implementation, a direct mapping from electric pulses to GETs was developed to simulate a widely-used clinical n-of-m strategy in cochlear implants. The GET processing simulated the actual implant speech in noise perception in terms of the overall trend, the absolute mean scores, and their standard deviations. The present results demonstrated that the pulsatile GET vocoders simulate the cochlear implant performance more accurately than the conventional sinusoid or noise vocoders. | otolaryngology |
10.1101/2022.02.24.22271443 | Investigating automatic speech emotion recognition for children with autism spectrum disorder in interactive intervention sessions with the social robot Kaspar | In this contribution, we present the analyses of vocalisation data recorded in the first observation round of the European Commissions Erasmus Plus project "EMBOA, Affective loop in Socially Assistive Robotics as an intervention tool for children with autism". In total, the project partners recorded data in 112 robot-supported intervention sessions for children with autism spectrum disorder. Audio data were recorded using the internal and lapel microphone of the H4n Pro Recorder. To analyse the data, we first utilise a child voice activity detection (VAD) system in order to extract child vocalisations from the raw audio data. For each child, session, and microphone, we provide the total time child vocalisations were detected. Next, we compare the results of two different implementations for valence- and arousal-based speech emotion recognition, thereby processing (1) the child vocalisations detected by the VAD and (2) the total recorded audio material. We provide average valence and arousal values for each session and condition. Finally, we discuss challenges and limitations of child voice detection and audio-based emotion recognition in robot-supported intervention settings. | health informatics |
10.1101/2022.03.02.22271623 | Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis | BackgroundWe evaluated the use of baricitinib, a Janus kinase (JAK) 1/2 inhibitor, for the treatment of patients admitted to hospital because of COVID-19.
MethodsThis randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was conducted that included the results from the RECOVERY trial and all previous randomised controlled trials of baricitinib or other JAK inhibitor in patients hospitalised with COVID-19. The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936).
FindingsBetween 2 February 2021 and 29 December 2021, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomisation, 95% of patients were receiving corticosteroids and 23% receiving tocilizumab (with planned use within the next 24 hours recorded for a further 9%). Overall, 513 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0{middle dot}87; 95% CI 0{middle dot}77-0{middle dot}98; p=0{middle dot}026). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of 8 previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths) in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0.57; 95% CI 0.45-0.72). Including the results from RECOVERY into an updated meta-analysis of all 9 completed trials (involving 11,888 randomised patients and 1484 deaths) allocation to baricitinib or other JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0.80; 95% CI 0.71-0.89; p<0.001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no excess of thrombosis, or other safety outcomes.
InterpretationIn patients hospitalised for COVID-19, baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth.
FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056). | infectious diseases |
10.1101/2022.02.24.22271475 | Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19 | Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease including MIS-C and chilblain-like lesions (CLL), otherwise known as "COVID toes", remains unclear. Studying multinational cohorts, we found that, in CLL, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs post-disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased levels of NETs when compared to other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients.
SummaryNET formation and degradation are dysregulated in pediatric and symptomatic adult patients with various complications of COVID-19, in association with disease severity. NET degradation impairments are multifactorial and associated with natural inhibitors of DNase 1, G-actin and anti-DNase1L3 and anti-NET antibodies. Infection with the Omicron variant is associated with decreased levels of NETs when compared to other SARS-CoV-2 strains. | infectious diseases |
10.1101/2022.02.23.22271355 | Genomic epidemiology offers high resolution estimates of serial intervals for COVID-19 | Estimating key aspects of transmission is crucial in infectious disease control. Serial intervals - the time between symptom onset in an infector and infectee - are fundamental, and help to define rates of transmission, estimates of reproductive numbers, and vaccination levels needed to prevent transmission. However, estimating the serial interval requires knowledge of individuals contacts and exposures (who infected whom), which is typically obtained through resource-intensive contact tracing efforts. We develop an alternate framework that uses virus sequences to inform who infected whom and thereby estimate serial intervals. The advantages are many-fold: virus sequences are often routinely collected to support epidemiological investigations and to monitor viral evolution. The genomic approach offers high resolution and cluster-specific estimates of the serial interval that are comparable with those obtained from contact tracing data. Our approach does not require contact tracing data, and can be used in large populations and over a range of time periods. We apply our techniques to SARS-CoV-2 sequence data from the first two waves of COVID-19 in Victoria, Australia. We find that serial interval estimates vary between clusters, supporting the need to monitor this key parameter and use updated estimates in onward applications. Compared to an early published serial interval estimate, using cluster-specific serial intervals can cause estimates of the effective reproduction number Rt to vary by a factor of up to 2-3. We also find that serial intervals estimated in settings such as schools and meat processing/packing plants tend to be shorter than those estimated in healthcare facilities. | epidemiology |
10.1101/2022.02.25.22270246 | Comprehensive characterization of Candida isolates in a given geographical area for the determination of prevalence and drug sensitivity. | PurposeAn alarming increase in Candidiasis infections has been observed worldwide and in India. This increase is attributed to increase in immune-compromised individuals and an increase in plethora of species causing the disease. The emergence of drug resistance of isolates has further worsened the situation.
Materials & MethodsCandida isolates causing infections were obtained from patients and evaluated for their macroscopic and microscopic characteristics by colony morphology and staining procedures. The patients demography was also analyzed to identify any correlation between the isolates. Doubling time was determined to analyze growth characteristics of these isolates. Isolates were also characterized biochemically for their ability to assimilate carbon and nitrogen sources and for fermentative capabilities. Additionally, drug sensitivity profiles of these isolates were analyzed towards Azoles.
ResultsDemographic analysis of the isolates suggested that all age groups were affected by Candida via both albicans and non-albican species. The infections were not gender biased but majority isolates were obtained from urine samples suggesting Candida as an important species causing urine-genital infections. Macroscopic and microscopic analysis showed cream colored circular colonies with smooth surface and entire margins with cells in single and budding stage. The doubling time ranged between 40 mins to 180 mins with 81 mins being the average. Biochemical characterization showed sucrose to be the most metabolizable sugar with maximum fermentative capacity with glucose. Surprisingly, very low nitrogen assimilation capacity was observed with all the nitrogen sources tested (nitrate, urea and glycine). Drug sensitivity towards Azoles suggested almost 50% and 90% isolates were resistant to Fluconazole and Itraconazole respectively, the most common Azoles used against fungal infections in the current scenario.
ConclusionsThe results obtained from the study suggested differential characteristics of the isolates towards various parameters thereby indicating the relevance of isolate characterization, for appropriate control and prevention of the disease.
Graphical abstract
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10.1101/2022.02.23.22271408 | Using Twitter Data for Cohort Studies of Drug Safety in Pregnancy: A Proof-of-Concept with Beta-Blockers | BackgroundDespite that medication is taken during more than 90% of pregnancies, the fetal risk for most medications is unknown, and the majority of medications have no data regarding safety in pregnancy.
ObjectiveUsing beta-blockers as a proof-of-concept, the primary objective of this study was to assess the utility of Twitter data for a cohort study design--in particular, whether we could identify (1) Twitter users who have posted tweets reporting that they took a beta-blocker during pregnancy and (2) their associated pregnancy outcomes.
MethodsWe searched for mentions of beta-blockers in 2.75 billion tweets posted by 415,690 users who announced their pregnancy on Twitter. We manually reviewed the matching tweets to first determine if the user actually took the beta-blocker mentioned in the tweet. Then, to help determine if the beta-blocker was taken during pregnancy, we used the timestamp of the tweet reporting intake and drew upon an automated natural language processing (NLP) tool that estimates the date of the users prenatal time period. For users who posted tweets indicating that they took or may have taken the beta-blocker during pregnancy, we drew upon additional NLP tools to help identify tweets that report their adverse pregnancy outcomes, including miscarriage, stillbirth, preterm birth, low birth weight, birth defects, and neonatal intensive care unit admission.
ResultsWe retrieved 5114 tweets, posted by 2339 users, that mention a beta-blocker, and manually identified 2332 (45.6%) tweets, posted by 1195 (51.1%) of the users, that self-report taking the beta-blocker. We were able to estimate the date of the prenatal time period for 356 pregnancies among 334 (27.9%) of these 1195 users. Among these 356 pregnancies, we identified 257 (72.2%) during which the beta-blocker was or may have been taken. We manually verified an adverse pregnancy outcome--preterm birth, neonatal intensive care unit admission, low birth weight, birth defects, or miscarriage--for 38 (14.8%) of these 257 pregnancies.
ConclusionsOur ability to detect pregnancy outcomes for Twitter users who posted tweets reporting that they took or may have taken a beta-blocker during pregnancy suggests that Twitter can be a complementary resource for cohort studies of drug safety in pregnancy. | health informatics |
10.1101/2022.02.28.22271668 | Utilization of Pharmacy Value-Added Services and Its Association with Waiting Time for Medication Collection in Public Health Institutions across Malaysia | BackgroundPharmacy value-added services (PVAS) have long been offered in public health institutions across Malaysia as an alternative to conventional counter services for prescription refills, with the aim to reduce the waiting time.
ObjectiveTo assess the utilization of the PVAS in individual health institutions, and its association with the achievement of the key performance indicator (KPI) set for the pharmacy waiting time.
MethodThis was a cross-sectional study based on the data contributed by 142 hospitals and 648 health clinics throughout 2018. The availability and uptake of the PVAS were summarized as percentages. The impacts of the PVAS uptake and the other institution-related factors on the KPI achievement were further explored using the logistic regression analysis.
ResultsApproximately 2.9 million (17.1%) of the refill prescriptions were dispensed via the PVAS. The appointment-and-pickup services (42.7%) and the Integrated Drug Dispensing System (23.7%) emerged as the most commonly used types of PVAS. A higher PVAS uptake was associated with a better KPI achievement (OR=0.91, 95% CI: 0.84-0.98). In contrast, adding a new type of PVAS to the existing services yielded an opposite outcome (OR=1.48, 95% CI: 1.15-1.89). Both the prescription load and location of health institutions were also found have influenced the KPI achievement.
ConclusionThe PVAS are generally well accepted in Malaysia and showed to have reduced the pharmacy waiting time. However, strategies to optimize the PVAS uptake are warranted. | health systems and quality improvement |
10.1101/2022.02.24.22271438 | Pegylated-interferon-{lambda} treatment-induced peripheral interferon stimulated genes are associated with SARS-CoV-2 viral load decline despite delayed T cell response in older individuals | Interferons (IFNs) are antiviral cytokines induced very early after SARS-CoV-2 infection and are crucial for viral clearance, shaping immunity, and preventing the development of severe COVID-19. We previously demonstrated that a single injection of peginterferon-lambda1 (PEG-IFN-{lambda}) accelerated viral clearance in COVID-19 patients. To determine if the rapid viral decline was mediated by enhanced immunity, we assessed in vivo responses to PEG-IFN-{lambda} by single cell RNA sequencing and measured SARS-CoV-2-specific T cell and antibody responses between placebo and PEG-IFN-{lambda}-treated patients. PEG-IFN-{lambda} treatment induced interferon stimulated genes in peripheral immune cells expressing IFNLR1, with plasmacytoid dendritic cells having the greatest response, followed by B cells. PEG-IFN-{lambda} did not significantly affect SARS-CoV-2-specific antibody levels in plasma or the magnitude or functionality of virus-specific T cells. However, we identified a delayed T cell response in older adults, suggesting that PEG-IFN-{lambda} can overcome the delay in adaptive immunity to accelerate viral clearance in patients most at risk for severe disease. Taken together, PEG-IFN-{lambda} offers an early COVID-19 treatment option for outpatients to boost innate antiviral defenses without dampening peripheral SARS-CoV-2 adaptive immunity | allergy and immunology |
10.1101/2022.02.17.22270791 | Vaccine effectiveness and duration of protection against symptomatic and severe Covid-19 during the first year of vaccination in France | BackgroundSARS-CoV-2 continues to spread despite fast vaccine rollout, which could be attributed to waning immunity or to a reduced protection against some variants. A thorough characterization of vaccine protection and its duration in time is needed to inform vaccination policies and enhance public trust.
MethodsWe matched three national databases with exhaustive information on screening, vaccination and hospitalizations in France over the year 2021. We performed a two-step analysis to estimate vaccine effectiveness against severe forms of Covid-19 in people aged 50 years or over, combining: (i) a test-negative case-control design to assess vaccine effectiveness against symptomatic infections; and (ii) a survival analysis to assess the additional protection against severe outcomes (hospitalizations and inpatient deaths) in infected individuals.
ResultsWe found a high vaccine effectiveness in people aged 50 years or more, reaching 82% against symptomatic infections and 94% against severe outcomes, after a full vaccination scheme.
Vaccine effectiveness against symptomatic infections strongly decreased over time, dropping to 53% after six months, but remained high against severe forms (90% after six months). The booster dose allowed restoring high protection levels. Vaccine protection and its evolution in time, showed little difference against the variants that circulated prior to December 2021 in France, including the Delta variant.
ConclusionThough vaccine immunity decreases over time, vaccination remains crucial to provide individual protection against severe diseases. This decline can be reversed by the injection of a booster dose. | epidemiology |
10.1101/2022.02.20.22271250 | Electronic Nicotine Delivery Systems (ENDS) use during a five-year period is not associated with self-reported chronic obstructive pulmonary disease (COPD) after adjustment of cigarette smoking history: A longitudinal analysis of PATH data. | BackgroundUnderstanding the relationship between electronic nicotine delivery systems (ENDS) use and chronic obstructive pulmonary disease (COPD) and other respiratory conditions is critical. However, previous studies have not adequately controlled for history of cigarette smoking.
Research QuestionTo examine the prospective association between ENDS use and self-reported incident COPD after adjusting for cigarette smoking history.
Study Design and MethodsUsing waves 1-5 of the US Population Assessment of Tobacco and Health (PATH) study, we examined the association between ENDS use and self-reported incident COPD among adults aged 40+ using discrete time survival models. Current ENDS use was measured as a time-varying covariate, lagged by one wave, defined as established daily or some days use. We controlled for baseline demographics (age, sex, race/ethnicity, education), health characteristics (asthma, obesity, exposure to second-hand smoke), and smoking history (smoking status and cigarette pack-years).
ResultsIncident COPD was self-reported by 925 respondents during the five-year follow-up period. Prior to adjusting for other covariates, time-varying ENDS use appeared to nearly double the risk of incident COPD (HR 1.98, 95% CI 1.44-2.74). However, ENDS use was no longer significantly associated with COPD (aHR 1.10, 95% CI 0.78-1.57) after adjusting for current cigarette smoking and cigarette pack-years. The risk of self-reported incident COPD increased with cigarette pack-years and was higher for respondents who were older, female, less educated, and had baseline asthma or obesity.
InterpretationENDS use did not significantly increase the risk of self-reported incident COPD over a five-year period once current smoking status and cigarette pack-years were taken into account. Cigarette pack-years, on the other hand, remained associated with a net increase in the risk of self-reported incident COPD. These findings highlight the importance of using prospective longitudinal data and properly controlling for cigarette smoking history to assess the independent health effects of ENDS. | epidemiology |
10.1101/2022.02.22.22271323 | Variation in hospital cost trajectories at the end of life by age, multimorbidity and cancer type | BackgroundApproximately thirty thousand people in Scotland are diagnosed with cancer annually, of whom a third live less than one year. The timing, nature and value of hospital-based healthcare for patients with advanced cancer are not well understood. The aim of this study was to describe patterns of hospital-based healthcare use and associated costs in the last year of life for patients with a cancer diagnosis.
MethodsWe undertook a Scottish population-wide administrative data linkage study of hospital-based healthcare use for individuals with a cancer diagnosis aged 60 years and over on their date of death, who died between 2012 and 2017. Hospital admissions, length of stay (LOS), number and nature of outpatient and day case appointments were analysed for all cancer types. Generalised linear models were used to adjust costs for age, gender, socioeconomic deprivation status, rural-urban (RU) status and comorbidity.
ResultsThe study included 85,732 decedents with a cancer diagnosis, for whom 64,553 (75.3%) cancer was the primary cause of death. Mean age at death was 80.01 (SD 8.15) years. The mean number of inpatient stays in the last year of life was 5.88 (SD 5.68), with a mean LOS of 7 days. Mean total inpatient, outpatient and daycase costs per patient were {pound}10261, {pound}1275 and {pound}977 respectively. Admission rates rose sharply in the last month of life. One year adjusted and unadjusted costs decreased with increasing age. A higher comorbidity burden was associated with higher costs and major cost differences between cancer types were also observed.
ConclusionsPeople in Scotland in their last year of life with cancer are high users of secondary care. Hospitalisation accounts for a high proportion of costs, particularly in the last month of life. Further research is needed to examine triggers for unplanned hospitalisation and to identify modifiable reasons for variation in hospital use among different cancer cohorts. | health economics |
10.1101/2022.02.24.22270908 | Are Dutch General Practitioners willing to prescribe mifepristone and misoprostol?: a mixed-methods study | BackgroundThe World Health Organization (WHO) indicates that General Practitioners (GPs) can effectively and safely provide mifepristone and misoprostol for medical termination of pregnancy (TOP). Dutch GPs are permitted to treat miscarriages with mifepristone and misoprostol, but in practice only guide spontaneous miscarriages. Current Dutch abortion law forbids GPs to prescribe these medications for medical TOP. Medical TOP is limited to the specialized settings of abortion clinics and hospitals. A shift to primary care is debated in the House of Representative, following the example of France and Ireland. It would improve reproductive health care and choices for women. Little is known about GPs willingness to provide medical TOP and miscarriage management.
AimThis study aimed to gain insight into Dutch GPs willingness and anticipated obstacles to prescribing mifepristone and misoprostol for medical TOP and miscarriages.
Design and SettingThis is a mixed-method study among Dutch GPs.
MethodA questionnaire provided quantitative data that was analysed using descriptive methods. Thematic analyses were performed on qualitative data collected by in-depth interviews.
ResultsThe questionnaire was sent to 575 GPs, the response rate was 22.1%. Of the responders, 84.3% were willing to prescribe mifepristone and misoprostol and 58.3% were willing to provide both medical TOP and miscarriage management. 57.5% indicated a need for training. The main barriers influencing GPs willingness were lack of experience, knowledge, time and a restrictive abortion law.
ConclusionOver 80% of the respondents were willing to prescribe mifepristone and misoprostol for medical TOP or miscarriages. Training, (online) education and a revision of the abortion law are recommended.
How this fits inMedical TOP in the Netherlands can only be provided in abortion clinics and hospitals. GPs may prescribe these same medications for miscarriage management, but in practice only guide spontaneous miscarriages. To improve access to woman-centred care, it is important to allow GPs by law to provide medical TOP. Our study is the first to assess Dutch GPs willingness to provide mifepristone and misoprostol and aims to understand enablers and barriers that give insight into the feasibility of a shift in care. Our results illustrate the need to revise laws and to provide training and education in the similar procedure of medical TOP and miscarriage management. | primary care research |
10.1101/2022.03.02.22271415 | Differences in Genetic Correlations between Posttraumatic Stress Disorder and Alcohol Use Disorder-Related Phenotypes Compared to Alcohol Consumption-Related Phenotypes | BackgroundPosttraumatic Stress Disorder (PTSD) tends to co-occur with greater alcohol consumption as well as alcohol use disorder (AUD). However, it is unknown whether the same etiologic factors that underlie PTSD-AUD comorbidity also contribute to PTSD-alcohol consumption.
MethodsWe used summary statistics from large-scale genome-wide association studies (GWAS) of European-ancestry (EA) and African-ancestry (AA) participants to estimate genetic correlations between PTSD (both the diagnosis and re-experiencing symptoms) and a range of alcohol consumption-related and AUD-related phenotypes (e.g., drinks per week, max drinks, consumption, AUD).
ResultsIn EAs, there were positive genetic correlations between PTSD phenotypes and AUD-related phenotypes (i.e., Alcohol Use Disorders Identification Test (AUDIT) problem score, maximum alcohol intake, AUD, and alcohol dependence) (rGs: .132-.533, all FDR adjusted p<.05). However, the genetic correlations between PTSD phenotypes and alcohol consumption -related phenotypes (i.e., drinks per week, AUDIT consumption score, AUDIT total score, and a combination of consumption and problems) were negatively associated or non-significant (rGs: -.417- -.042, FDR adjusted p: <.05-NS). For AAs, the direction of correlations was sometimes consistent and sometimes inconsistent with that in EAs, and the ranges were larger (rGs for AUD--related: -.275 -.266, FDR adjusted p: NS, alcohol consumption-related: .145-.699, FDR adjusted p: NS).
ConclusionsThese findings illustrate that the genetic associations between consumption and problem alcohol phenotypes and PTSD differ in both strength and direction. Thus, the genetic factors that may lead someone to develop PTSD and consume large quantities of alcohol are not the same as those that lead someone to develop PTSD-AUD. | genetic and genomic medicine |
10.1101/2022.03.01.22271722 | Validating and automating learning of cardiometabolic polygenic risk scores from direct-to-consumer genetic and phenotypic data: implications for scaling precision health research. | IntroductionA major challenge to enabling precision health at a global scale is the bias between those who enroll in state sponsored genomic research and those suffering from chronic disease. More than 30 million people have been genotyped by direct-to-consumer (DTC) companies such as 23andMe, Ancestry DNA, and MyHeritage, providing a potential mechanism for democratizing access to medical interventions and thus catalyzing improvements in patient outcomes as the cost of data acquisition drops. However, much of these data are sequestered in the initial provider network, without the ability for the scientific community to either access or validate. Here, we present a novel geno-pheno platform that integrates heterogeneous data sources and applies learnings to common chronic disease conditions including Type 2 diabetes (T2D) and hypertension.
MethodsWe collected genotyped data from a novel DTC platform where participants upload their genotype data files, and were invited to answer general health questionnaires regarding cardiometabolic traits over a period of 6 months. Quality control, imputation and genome-wide association studies were performed on this dataset, and polygenic risk scores were built in a case-control setting using the BASIL algorithm.
ResultsWe collected data on N=4,550 (389 cases / 4,161 controls) who reported being affected or previously affected for T2D; and N=4,528 (1,027 cases / 3,501 controls) for hypertension. We identified 164 out of 272 variants showing identical effect direction to previously reported genome-significant findings in Europeans. Performance metric of the PRS models was AUC=0.68, which is comparable to previously published PRS models obtained with larger datasets including clinical biomarkers.
DiscussionDTC platforms have the potential of inverting research models of genome sequencing and phenotypic data acquisition. Quality control (QC) mechanisms proved to successfully enable traditional GWAS and PRS analyses. The direct participation of individuals has shown the potential to generate rich datasets enabling the creation of PRS cardiometabolic models. More importantly, federated learning of PRS from reuse of DTC data provides a mechanism for scaling precision health care delivery beyond the small number of countries who can afford to finance these efforts directly.
ConclusionsThe genetics of T2D and hypertension have been studied extensively in controlled datasets, and various polygenic risk scores (PRS) have been developed. We developed predictive tools for both phenotypes trained with heterogeneous genotypic and phenotypic data generated outside of the clinical environment and show that our methods can recapitulate prior findings with fidelity. From these observations, we conclude that it is possible to leverage DTC genetic repositories to identify individuals at risk of debilitating diseases based on their unique genetic landscape so that informed, timely clinical interventions can be incorporated. | genetic and genomic medicine |
10.1101/2022.03.01.22271722 | Validating and automating learning of cardiometabolic polygenic risk scores from direct-to-consumer genetic and phenotypic data: implications for scaling precision health research. | IntroductionA major challenge to enabling precision health at a global scale is the bias between those who enroll in state sponsored genomic research and those suffering from chronic disease. More than 30 million people have been genotyped by direct-to-consumer (DTC) companies such as 23andMe, Ancestry DNA, and MyHeritage, providing a potential mechanism for democratizing access to medical interventions and thus catalyzing improvements in patient outcomes as the cost of data acquisition drops. However, much of these data are sequestered in the initial provider network, without the ability for the scientific community to either access or validate. Here, we present a novel geno-pheno platform that integrates heterogeneous data sources and applies learnings to common chronic disease conditions including Type 2 diabetes (T2D) and hypertension.
MethodsWe collected genotyped data from a novel DTC platform where participants upload their genotype data files, and were invited to answer general health questionnaires regarding cardiometabolic traits over a period of 6 months. Quality control, imputation and genome-wide association studies were performed on this dataset, and polygenic risk scores were built in a case-control setting using the BASIL algorithm.
ResultsWe collected data on N=4,550 (389 cases / 4,161 controls) who reported being affected or previously affected for T2D; and N=4,528 (1,027 cases / 3,501 controls) for hypertension. We identified 164 out of 272 variants showing identical effect direction to previously reported genome-significant findings in Europeans. Performance metric of the PRS models was AUC=0.68, which is comparable to previously published PRS models obtained with larger datasets including clinical biomarkers.
DiscussionDTC platforms have the potential of inverting research models of genome sequencing and phenotypic data acquisition. Quality control (QC) mechanisms proved to successfully enable traditional GWAS and PRS analyses. The direct participation of individuals has shown the potential to generate rich datasets enabling the creation of PRS cardiometabolic models. More importantly, federated learning of PRS from reuse of DTC data provides a mechanism for scaling precision health care delivery beyond the small number of countries who can afford to finance these efforts directly.
ConclusionsThe genetics of T2D and hypertension have been studied extensively in controlled datasets, and various polygenic risk scores (PRS) have been developed. We developed predictive tools for both phenotypes trained with heterogeneous genotypic and phenotypic data generated outside of the clinical environment and show that our methods can recapitulate prior findings with fidelity. From these observations, we conclude that it is possible to leverage DTC genetic repositories to identify individuals at risk of debilitating diseases based on their unique genetic landscape so that informed, timely clinical interventions can be incorporated. | genetic and genomic medicine |
10.1101/2022.02.18.22270926 | Ultrarare missense and frameshift variants in the TECTA gene may involve tectorial membrane in familial Meniere disease | BackgroundMenieres disease (MD) is an inner ear disease defined by episodes of vertigo associated with sensorineural hearing loss initially affecting low- to medium frequencies, tinnitus, and aural fullness. Familial aggregation has been reported in 9-10% of MD patients showing, mostly, an autosomal dominant inheritance pattern with incomplete penetrance. However, familial MD is a genetically heterogeneous disorder and other inheritance patterns have been recently proposed, such as recessive and digenic inheritance involving rare variants in OTOG and MYO7A genes, respectively. In this study, a familial MD cohort was recruited to identify new candidate genes.
MethodsExome sequencing was performed in 99 individuals (from 77 families) diagnosed with MD according to the diagnostic criteria defined by the Barany Society. Candidate variants were classified based on the ACMG/AMP guidelines, and their effects were evaluated by protein modeling. Standard audiometric evaluations were retrieved, and a case report was made of each family to assess the genotype-phenotype correlations.
ResultsThe TECTA gene, which encodes -tectorin, was highlighted as a candidate for four multicase MD families carrying rare missense heterozygous variants and a short deletion in this gene. Variants in -tectorin were also found in two additional families with one MD patient and relatives with partial syndromes carrying a missense heterozygous variant and a short deletion. According to the predicted protein model, these variants could affect the stability of -tectorin.
ConclusionsSeveral MD families were identified carrying rare variants and deletions in the TECTA gene, which encodes one of the main proteins of the tectorial membrane (TM). The TM is an extracellular matrix localized over the sensory epithelium mediating the mechanical stimulation of cochlear hair cells, a critical role in the process of hearing. Modifications on the TM stability and the micromechanics involved in the sound-evoked motion of stereocilia might be involved in familial MD. | genetic and genomic medicine |
10.1101/2022.03.02.22271760 | Mathematical Analysis of a Zika Model with reservoirs and Human Movement | A mathematical model for Zika virus is proposed describing the spread of the disease in three interacting populations, namely, human, vector (mosquitoes) and non-human primate (monkeys) inhabiting forests area. Human movement between rural and forest areas has been also considered. It is assumed that Zika virus spreads within non-human primate population, which in turn acts as a reservoir of infection, and then transmitted to the human population through infected mosquitoes. The proposed model incorporates vertical transmission and direct transmission in all populations. The proposed model has been first normalized. The normalized model has been then fully analyzed both qualitatively and quantitatively to investigate the role of the interaction between forest mosquitoes and primates on the ZIKV transmission dynamics. The mathematical analysis includes positivity and boundedness of solutions, derivation of the basic reproduction number R0 using the next generation matrix method, sensitivity analysis, existence and stability analysis of all equilibria and bifurcation analysis. Finally, numerical simulations have been carried out to illustrate the obtained theoretical results and to demonstrate the effect of some model parameters in the disease transmission dynamics. The results show that the interaction between forest mosquitoes and primates has a significant impact on the ZIKV transmission dynamics among human population through the fraction of susceptible moving to forest areas. Furthermore, the results highlight that the transmission probabilities are as important as the ratios of population size between vector population and human or primate populations in the disease transmission dynamics. | epidemiology |
10.1101/2022.03.02.22271346 | Exploring the experiences of loneliness in adults with mental health problems: a co-produced participatory qualitative interview study | BackgroundMany mental health conditions are associated with loneliness, which is both a potential trigger and an exacerbating factor in mental health conditions. Richer evidence about how people with mental health problems experience loneliness, and about what exacerbates or alleviates it, is needed to underpin research on strategies to help with loneliness in this context.
MethodsOur aim was to explore experiences of loneliness, as well as what contributes to or helps address it, among a diverse sample of adults living with mental health problems in the UK. We recruited purposively via online networks and community organisations. Qualitative semi-structured interviews were conducted with 59 consenting participants by video call or telephone. Researchers with relevant lived experience were involved at all stages, including design, data collection, analysis and writing up of results.
FindingsAnalysis led to identification of four overarching themes: 1. What the word "lonely" meant to participants, 2. Contributory factors to ongoing loneliness, 3. Connections between loneliness & mental health, 4. Ways of reducing loneliness. Central aspects of loneliness were lack of meaningful connections with others and lack of a sense of belonging to valued groups and communities. Some drivers of loneliness, such as losses and transitions, were universal, but specific links were made between living with mental health problems and being lonely. These included direct effects of psychiatric symptoms, the need to withdraw to cope with mental health problems, and impacts of stigma and poverty.
ConclusionsThe multiplicity of contributors to loneliness that we identified, and of potential strategies for reducing it, suggest that a variety of approaches are relevant to reducing loneliness among people with mental health problems, including peer support and supported self-help, psychological and social interventions, and strategies to facilitate change at community and societal levels. The views and experiences of adults living with mental health problems are a rich source for understanding why loneliness is a frequent experience in this context and what may address it. Co-produced approaches to developing and testing interventions have potential to draw on this experiential knowledge in formulating effective approaches to loneliness. | psychiatry and clinical psychology |
10.1101/2022.03.02.22271346 | Exploring the experiences of loneliness in adults with mental health problems: a participatory qualitative interview study | BackgroundMany mental health conditions are associated with loneliness, which is both a potential trigger and an exacerbating factor in mental health conditions. Richer evidence about how people with mental health problems experience loneliness, and about what exacerbates or alleviates it, is needed to underpin research on strategies to help with loneliness in this context.
MethodsOur aim was to explore experiences of loneliness, as well as what contributes to or helps address it, among a diverse sample of adults living with mental health problems in the UK. We recruited purposively via online networks and community organisations. Qualitative semi-structured interviews were conducted with 59 consenting participants by video call or telephone. Researchers with relevant lived experience were involved at all stages, including design, data collection, analysis and writing up of results.
FindingsAnalysis led to identification of four overarching themes: 1. What the word "lonely" meant to participants, 2. Contributory factors to ongoing loneliness, 3. Connections between loneliness & mental health, 4. Ways of reducing loneliness. Central aspects of loneliness were lack of meaningful connections with others and lack of a sense of belonging to valued groups and communities. Some drivers of loneliness, such as losses and transitions, were universal, but specific links were made between living with mental health problems and being lonely. These included direct effects of psychiatric symptoms, the need to withdraw to cope with mental health problems, and impacts of stigma and poverty.
ConclusionsThe multiplicity of contributors to loneliness that we identified, and of potential strategies for reducing it, suggest that a variety of approaches are relevant to reducing loneliness among people with mental health problems, including peer support and supported self-help, psychological and social interventions, and strategies to facilitate change at community and societal levels. The views and experiences of adults living with mental health problems are a rich source for understanding why loneliness is a frequent experience in this context and what may address it. Co-produced approaches to developing and testing interventions have potential to draw on this experiential knowledge in formulating effective approaches to loneliness. | psychiatry and clinical psychology |
10.1101/2022.03.02.22271610 | Optimal vaccination with time-varying based on immunity barrier in Hunan Province, China | The current outbreak of novel coronavirus disease 2019 (COVID-19) is already causing a serious disease burden worldwide, this paper analyzed data of a delta variant Covid-19 outbreak in Hunan, China, and proposed an optimal dose-wise dynamical vaccinating process based on local contact pattern and vaccine coverage that minimize the accumulative cases in a certain future time interval. The optimized result requires an immediate vaccination to that none vaccinated at age group 30 to 39, which is coherent to the prevailing strategies. The dose-wise optimal vaccinating process can be directive for countries or regions where vaccines are not abundant. We recommend that vaccination should be further intensified to increase the coverage of booster shots, thus effectively reducing the spread of COVID-19. | public and global health |
10.1101/2022.03.02.22271765 | Development and validation of a modified Cambridge Multimorbidity Score for use with internationally recognized electronic health record clinical terms (SNOMED CT) | BackgroundPeople with multiple health conditions are more likely to have poorer health outcomes and greater care and service needs; a reliable measure of multimorbidity would inform management strategies and resource allocation. This study aims to develop and validate a modified version of the Cambridge Multimorbidity Score in an extended age range, using clinical terms which are routinely used in electronic health records across the world (SNOMED CT).
Methods and FindingsWe curated new variables describing 37 health conditions and modelled the associations between these and 1-year mortality risk using the Cox proportional hazard model in a development dataset (n=300,000). We then developed two simplified models - a 20-condition model as per the original Cambridge Multimorbidity Score, and a variable reduction model using backward elimination with Akaike information criterion as the stopping criterion. The results were compared and validated for 1-year mortality in a synchronous validation dataset (n=150,000), and for 1-year and 5-year mortality in an asynchronous validation dataset (n=150,000).
Our final variable reduction model retained 21 conditions, and the conditions mostly overlapped with those in the 20-condition model. The model performed similarly to the 37- and 20-condition models, showing high discrimination and good calibration following recalibration.
ConclusionsThis modified version of the Cambridge Multimorbidity Score allows reliable estimation using clinical terms which can be applied internationally across multiple healthcare settings. | public and global health |
10.1101/2022.03.02.22271269 | Multiple sclerosis cortical lesion detection with deep learning at ultra-high-field MRI | Manually segmenting multiple sclerosis (MS) cortical lesions (CL) is extremely time-consuming, and past studies have shown only moderate inter-rater reliability. To accelerate this task, we developed a deep learning-based framework (CLAIMS: Cortical Lesion Artificial Intelligence-based assessment in Multiple Sclerosis) for the automated detection and classification of MS CL with 7T MRI.
Two 7T datasets, acquired at different sites, were considered. The first consisted of 60 scans that include 0.5mm isotropic MP2RAGE acquired 4 times (MP2RAGEx4), 0.7mm MP2RAGE, 0.5mm T2*-weighted GRE, and 0.5mm T2*-weighted EPI. The second dataset consisted of 20 scans including only 0.75x0.75x0.9 mm MP2RAGE. CLAIMS was first evaluated using 6-fold cross-validation with single and multi-contrast 0.5mm MRI input. Second, performance of the model was tested on 0.7mm MP2RAGE images after training with either 0.5mm MP2RAGEx4, 0.7mm MP2RAGE, or alternating the two. Third, its generalizability was evaluated on the second external dataset and compared with a state-of-the-art technique based on partial volume estimation and topological constraints (MSLAST). CLAIMS trained only with MP2RAGEx4 achieved comparable results to the multi-contrast model, reaching a CL true positive rate of 74% with a false positive rate of 30%. Detection rate was excellent for leukocortical and subpial lesions (83%, and 70%, respectively), whereas it reached 53% for intracortical lesions. The correlation between disability measures and CL count was similar for manual and CLAIMS lesion counts. Applying a domain-scanner adaptation approach and testing CLAIMS on the second dataset, the performance was superior to MSLAST when considering a minimum lesion volume of 6L (lesion-wise detection rate of 71% vs 48%).
The proposed framework outperforms previous state-of-the-art methods for automated CL detection across scanners and protocols. In the future, CLAIMS may be useful to support clinical decisions at 7T MRI, especially in the field of diagnosis and differential diagnosis of multiple sclerosis patients. | neurology |
10.1101/2022.03.02.22271741 | Low Haemoglobin Levels are Associated with Reduced Psychomotor and Language Abilities in Young Ugandan Children. | Children living in Sub-Saharan Africa are vulnerable to developmental delay, particularly in the critical first five years due to various adverse exposures including disease and nutritional deficiencies. Anaemia and iron deficiency (ID) are highly prevalent in pregnant mothers and young children and are implicated in abnormal brain development. However, available evidence on the association between anaemia, ID and neurodevelopment in Sub-Saharan Africa is limited. Using data from the Entebbe Mother and Baby Study prospective birth cohort, we examined the effect of maternal and child haemoglobin (Hb) levels and child iron status on developmental scores in 933 and 530 pre-school Ugandan children respectively. Associations between Hb levels, iron status and developmental scores were assessed using regression analyses adjusting for potential confounders. Lower maternal and child Hb levels were associated with reduced psychomotor scores at 15 months, while only lower Hb levels in infancy were associated with reduced language scores. We found no evidence that anaemia or ID was associated with cognitive or motor scores at five years. This study emphasizes the importance of managing anaemia in pregnancy and infancy and highlights the need for further studies on the effects of anaemia and ID in children living in Sub-Saharan Africa. | nutrition |
10.1101/2022.03.02.22271367 | Altered brain reward response to monetary incentives in fibromyalgia: A replication study | Dysregulated brain reward systems have been observed in chronic pain. Using functional magnetic resonance imaging (fMRI) and a monetary incentive delay (MID) task, Martucci et al. (2018) showed that neural responses to reward anticipation and outcome are altered in patients with fibromyalgia. The current study aimed to replicate these results in a separate cohort of patients with fibromyalgia recruited at a new location using a similar study design. Twenty patients with fibromyalgia and 20 healthy controls were included in the replication study. Group fMRI analyses revealed a solid and consistent trend of main findings similar to the previous results. Specifically, in the replication cohort of patients with fibromyalgia, medial prefrontal cortex (MPFC) activity was reduced during gain anticipation and increased during no-loss (non-punishment) outcomes, as compared to controls. Similar to the Martucci et al. results, again in the replication cohort, nucleus accumbens activity during gain anticipation did not differ in patients compared to controls. The same behavioral, correlational, and exploratory analyses that were conducted in the Martucci et al. study were conducted in the present replication study, with prior results largely replicated here. Thus, the present replication study results solidify observations of altered cortico-striatal processing to monetary rewards in chronic pain, which underscore relevance of altered brain reward circuits, particularly as related to the MPFC in patients with fibromyalgia. | pain medicine |
10.1101/2022.03.02.22271552 | A predictive model for hospitalization and survival to COVID-19 in a retrospective population-based study | The severe acute respiratory syndrome coronavirus (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) is highly transmissible and has been responsible for a pandemic associated with a high number of deaths. The clinical management of patients and the optimal use of resources are two important factors in reducing this mortality, especially in scenarios of high incidence. To this end, it is necessary to develop tools that allow early triage of patients with the minimal use of diagnostic tests and based on readily accessible data, such as electronic medical records. This work proposes the use of a machine learning model that allows the prediction of mortality and risk of hospitalization using simple demographic characteristics and comorbidities, using a COVID-19 dataset of 86867 patients. In addition, we developed a new method designed to deal with data imbalance problems. The model was able to predict with high accuracy (89-93%, ROC-AUC = 0.94) the patients final status (expired/discharged) and with medium accuracy the risk of hospitalization (71-73%, ROC-AUC = 0.75). These models were obtained by assembling and using easily obtainable clinical characteristics (2 demographic characteristics and 19 predictors of comorbidities). The most relevant features of these models were the following patient characteristics: age, sex, number of comorbidities, osteoarthritis, obesity, depression, and renal failure. | health informatics |
10.1101/2022.03.02.22271694 | Evidence of co-infection during Delta and Omicron variants of concern co-circulation, weeks 49-2021 to 02-2022, France | We report evidence of Delta/Omicron SARS-CoV-2 co-infections during the fifth wave of COVID-19 pandemics in France for 7 immunocompetent and epidemiologically unrelated patients. These co-infections were detected by PCR assays targeting SARS-CoV-2 S-gene mutations K417N and L452R and confirmed by whole genome sequencing which allowed the proportion estimation of each subpopulation. For 2 patients, the analyses of longitudinal samples collected 7 to 11 days apart showed that Delta or Omicron can outcompete the other variant during dual infection. | infectious diseases |
10.1101/2022.03.02.22271731 | Vaccine Breakthrough Infection with the SARS-CoV-2 Delta or Omicron (BA.1) Variant Leads to Distinct Profiles of Neutralizing Antibody Responses | There is increasing evidence that the risk of SARS-CoV-2 infection among vaccinated individuals is variant-specific, suggesting that protective immunity against SARS-CoV-2 may differ by variant. We enrolled vaccinated (n = 39) and unvaccinated (n = 11) individuals with acute, symptomatic SARS-CoV-2 Delta or Omicron infection and performed SARS-CoV-2 viral load quantification, whole-genome sequencing, and variant-specific antibody characterization at the time of acute illness and convalescence. Viral load at the time of infection was inversely correlated with antibody binding and neutralizing antibody responses. Increases in antibody titers and neutralizing activity occurred at convalescence in a variant-specific manner. Across all variants tested, convalescent neutralization titers in unvaccinated individuals were markedly lower than in vaccinated individuals. For individuals infected with the Delta variant, neutralizing antibody responses were weakest against BA.2, whereas infection with Omicron BA.1 variant generated a broader response against all tested variants, including BA.2. | infectious diseases |
10.1101/2022.03.02.22271759 | SARS-CoV-2 IgG seroprevalence in the Okinawa Main Island and remote islands in Okinawa, Japan, 2020-2021. | We estimated the seroprevalence of anti-SARS-COV-2 IgG in different island groups in Okinawa and described its changes over time. A cross-sectional sero-survey was repeated in three distinct periods between July 2020 and February 2021. A total of 2683 serum samples were collected from six referral medical centers, each covering a separate region in Okinawa. Patients who visited the emergency department for any reason and underwent blood collection were eligible for the study. Samples were analyzed using an FDA-authorized two-step enzyme-linked immunosorbent assay (ELISA) protocol. The case detection ratio was computed by dividing the seroprevalence by the attack rate obtained from publicly available surveillance data. In the main island, the seroprevalence was 0.0% (0/392, 95% CI: 0.0-0.9), 0.6% (8/1448, 0.2-1.1), and 1.4% (8/582, 0.6-2.7) at the 1st, 2nd, and 3rd sero-survey, respectively. In the remote islands, the seroprevalence was 0.0% (0/144, 95% CI: 0.0-2.5) and 1.6% (2/123, 0.2-5.8) at the 2nd and 3rd survey, respectively. The overall case detection ratios at the 3rd survey were 2.7 (95% CI: 1.3-5.3) in the main island and 2.8 (0.7-11.1) in the remote islands. The highest age-specific case detection ratio was observed in people aged 20-29 years (8.3, 95% CI: 3.3-21.4) in the main island and in those aged 50-59 years (14.1, 2.1-92.7) in the remote islands. The low seroprevalence at the latest survey suggested that a large-scale epidemic had not yet occurred in Okinawa by February 2021. The case detection ratios imply that the cumulative number of incident cases in Okinawa should be 2-3 times higher than that reported by routine surveillance. The ratio was particularly high in young people probably due to a frequent asymptomatic/mild COVID-19 disease in this age group. To accurately measure the scale of the COVID-19 epidemic, it is crucially important to conduct a sero-survey targeting the young. | infectious diseases |
10.1101/2022.03.01.22271660 | Examining the Impact of ICU Population Interaction Structure on Modeled Colonization Dynamics of Staphylococcus aureus | BackgroundComplex transmission models of healthcare-associated infections provide insight for hospital epidemiology and infection control efforts; however, many are difficult to implement and come at high computational costs. Structuring more simplified models to incorporate the heterogeneity of the intensive care unit (ICU) patient-provider interactions, we explore how methicillin-resistant Staphylococcus aureus (MRSA) dynamics and acquisitions may be better represented and approximated.
MethodsUsing a stochastic compartmental model of an 18-bed ICU, we compared the rates of MRSA acquisition across three ICU population interaction structures: a model with nurses and physicians as a single staff type (SST), a model with separate staff types for nurses and physicians (Nurse-MD model), and a Metapopulation model where each nurse was assigned a group of patients. The proportion of time spent with the assigned patient group ({gamma}) within the Metapopulation model was also varied.
ResultsThe SST, Nurse-MD, and Metapopulation models had a mean of 40.6, 32.2 and 19.6 annual MRSA acquisitions respectively. All models were sensitive to the same parameters in the same direction, although the Metapopulation model was less sensitive. The number of acquisitions varied non-linearly by values of{gamma} , with values below 0.40 resembling the Nurse-MD model, while values above that converged toward the metapopulation structure.
DiscussionComplex population interactions of a modeled hospital ICU has considerable impact on model results, with the SST model having more than double the acquisition rate of the more structured metapopulation model. While the direction of parameter sensitivity remained the same, the magnitude of these differences varied, producing different colonization rates across relatively similar populations. The non-linearity of the models response to differing values of a parameter gamma ({gamma}) suggests only a narrow space of relatively dispersed nursing assignments where simple model approximations are appropriate.
ConclusionSimplifying assumptions around how a hospital population is modeled, especially assuming random mixing, may overestimate infection rates and the impact of interventions. In many, if not most cases, more complex models that represent population mixing with higher granularity are justified.
Author SummarySome models of healthcare-associated infection assume random mixing between healthcare workers and patients - that is, all healthcare workers care for all patients in the model at equal frequency. This paper explores the impact of that assumption, creating a model of an 18-bed intensive care unit that compares a model with random mixing with one that segments patients into distinct groups with a single nurse assigned to them while a dedicated critical care physician continues to see all patients. Higher rates of segmentation result in lower rates of predicted acquisitions of methicillin-resistant Staphylococcus aureus, as well as more modest predicted impacts of interventions - represented by changes in parameter values. These findings suggest that the simpler random mixing models that are used for analytical tractability or computational speed may not be appropriate approximations in settings where healthcare workers are not uniformly distributed among patients due to scheduling, patient complexity or cohorting, the built environment, or hospital policy, and that balancing the computational costs with the trend toward more complex models in hospital epidemiology is justified. | epidemiology |
10.1101/2022.03.02.22271758 | Self-Care, Health Literacy and Their Associations Amongst Patients with Chronic Kidney Disease (CKD) in Primary Care | AimThe study objective was to determine the levels of self-care (including domains of behaviour, motivation, self-efficacy) and health literacy, and study their associations amongst patients with chronic kidney disease (CKD) in primary care setting in Singapore.
MethodA cross-sectional, questionnaire-based study was conducted in one public-sector primary care clinic. Participants aged 21 to 80 years with hypertension were recruited from the clinic CKD register with 5,500 patients. Self-care profile (including behaviour, motivation and self-efficacy) were measured using Hypertension Self-Care Profile (HTN-SCP, range 0-240, domain range 0-80). Health literacy was measured using Short-Form Health Literacy Scale (HLS-SF12, range 0-50, limited literacy [≤]33).
ResultsA total of 347 out of 354 randomly selected patients consented to participate in the study. Two hundred and eighty-nine fully-completed responses were analysed. The mean self-care (HTN-SCP) score was 182.7 (SD 23.2), while mean scores were 55.3 (SD 8.6), 63.3 (SD 8.7), 64.0 (SD 9.3), for behaviour, self-efficacy and motivation domains respectively. The mean health literacy score was 36.1 (SD 7.7), and 31.1% of participants had limited health literacy. Limited health literacy was associated with self-efficacy (OR= -7.2, 95%CI=-9.1 to -5.2, p<0.001), motivation (OR= -6.1, 95%CI=-8.3 to -3.9, p<0.001) and behaviour (OR= -4.5, 95%CI=-6.6 to -2.4, p<0.001). Self-care was not associated with age, CKD status, household income and education but was associated with gender and limited health literacy. In the final regression model only limited health literacy was associated with self-care scores (Adjusted beta -17.4, p<0.001).
ConclusionOne-third of the patients with CKD in primary care had limited health literacy. Self-care was not associated with age, gender, CKD status, household income or education. Limited health literacy was associated with self-care, with strongest association with self-efficacy, followed by motivation and behaviour. More targeted approach can be adopted to improve self-care and health literacy amongst patients with CKD. | primary care research |
10.1101/2022.02.20.22271260 | A Progeroid Syndrome Caused by RAF1 deficiency Underscores the importance of RTK signaling for Human Development | Somatic and germline gain-of-function point mutations in RAF, the first oncogene to be discovered in humans, delineate a group of tumor-prone syndromes known as RASopathies. In this study, we document the first human phenotype resulting from the germline loss of function of the proto-oncogene RAF1 (a.k.a. CRAF). In a consanguineous family, we uncovered a homozygous p.Thr543Met mutation segregating with a neonatal lethal progeroid syndrome with cutaneous, craniofacial, cardiac and limb anomalies. Structure-based prediction and functional tests using human knock-in cells showed that threonine 543 is essential to: 1) ensure RAF1s stability and phosphorylation, 2) maintain its kinase activity towards substrates of the MAPK pathway and 3) protect from stress-induced apoptosis. When injected in Xenopus embryos mutant RAF1T543M failed to phenocopy the effects of overactive FGF/MAPK signaling confirming its hypomorphic activity. Collectively, our data disclose the genetic and molecular etiology of a novel segmental progeroid syndrome which highlights the importance of RTK signaling for human development and homeostasis.
Short summaryA germline homozygous recessive loss-of-function mutation p.T453M in RAF1 causes a neonatal lethal progeroid syndrome. In vitro and in vivo tests demonstrate that Thr543 is necessary for RAF1s protein stability, to transduce signaling to the MAPK pathway and to respond to stress-induced apoptosis. | genetic and genomic medicine |
10.1101/2022.02.22.22271222 | NOVEL RT-qPCR ASSAYS ENABLE RAPID DETECTION AND DIFFERENTIATION BETWEEN SARS-COV-2 OMICRON (BA.1) AND BA.2 VARIANTS | In this report, we describe the development and initial validation of novel SARS-COV-2 Omicron-specific reactions that enable the identification of Omicron (BA.1) and BA.2 variants. Mutations that are either shared by both BA.1 and BA.2, or are exclusive for BA.1 or for BA.2 were identified by bioinformatic analysis, and corresponding probe-based quantitative PCR reactions were developed to identify them. We show that multiplex combinations of these reactions provide a single-reaction identification of the sample as BA.1, BA.2, or as non-Omicron SARS-COV-2. All four reactions described herein have a sensitivity of less than ten copies per reaction, and are amendable for multiplexing. The results of this study suggest that the new assays may be useful for testing both clinical and environmental samples to differentiate between these two variants. | infectious diseases |
10.1101/2022.03.02.22271710 | Daily tenofovir disoproxil fumarate/emtricitabine and hydroxychloroquine for pre-exposure prophylaxis of COVID-19: a double-blind placebo controlled randomized trial in healthcare workers | ObjectiveTo assess the effect of hydroxychloroquine (HCQ), Tenofovir disoproxil fumarate/Emtricitabine (TDF/FTC), and their combination as pre-exposure prophylaxis on the risk of symptomatic COVID-19.
MethodsEPICOS is a double-blind, placebo-controlled randomized trial conducted in 51 hospitals in Spain, Bolivia, and Venezuela. Healthcare workers with negative SARS-CoV-2 IgM/IgG test were randomly assigned to: daily TDF/FTC plus HCQ for 12 weeks, TDF/FTC plus HCQ placebo, HCQ plus TDF/FTC placebo and TDF/FTC placebo plus HCQ placebo. The primary outcome was laboratory-confirmed, symptomatic COVID-19. We also studied any (symptomatic or asymptomatic) COVID-19 infection. We compared group-specific 14-week risks via differences and ratios with 95% confidence intervals (CI).
ResultsOf 1002 individuals screened, 926 (92.4%) were eligible; 64.2% recruited in Spain, 22.3% in Bolivia, and 13.6% in Venezuela. Median age was 38 years (range 18 - 68), 62.5% were female, 62.3% worked at inpatient care, and comorbidities were rare. Compared with the placebo group, 14-week risk ratios (95% CI) of symptomatic COVID-19 were 0.39 (0.00, 1.98) for TDF+HCQ, 0.34 (0.00, 2.06) for TDF, and 0.49 (0.00, 2.29) for HCQ. Corresponding risk ratios of any COVID-19 were 0.51 (0.21, 1.00) for TDF+HCQ, 0.81 (0.44, 1.49) for TDF, and 0.73 (0.41, 1.38) for HCQ. Adverse events were generally mild.
ConclusionA beneficial effect of TDF/FTC and HCQ, alone or in combination, as pre-exposure prophylaxis for COVID-19 cannot be ruled out but effect estimates are imprecise because the target sample size was not met. These findings support launching randomized trials of TDF/FTC for the early treatment of COVID-19. | infectious diseases |
10.1101/2022.03.01.22271638 | Identifying risk factors associated with death among patients with MDR-TB in KwaZulu-Natal, South Africa: an illustration using Weibull parametric model. | BackgroundThis study aim was to identify the risk factors associated with multidrug-resistant tuberculosis (MDR-TB) disease. The Weibull model has shown to perform better than the Cox proportional models with respect to the accuracy and efficient of the estimates. Therefore, a Weibull parametric model was employed to identify predictors of death in patients with MDR-TB and the efficiency of the models using current dataset.
MethodsPatients diagnosed with MDR-TB were studied in four decentralised sites located in rural areas and one centralised hospital in KwaZulu-Natal, South Africa from July 2008 to July 2012. Patients were followed from the date of MDR-TB diagnosis until death or the last follow-up date.
ResultsA total of 1 542 patients were included in the analyses: 812 and 730 from the centralised hospital and decentralised sites, respectively. Of the 1 542 enrolled, 15.9% patients died. We found that the hazard of death was significantly higher among patients treated in decentralised sites (aHR) = 1.84, 95% CI = 1.38 - 2.75; SE = 0.81 than that of those who were treated in the centralised hospital. However, the results from the Cox PH model showed an insignificant hazard of death between the decentralised sites and the centralised hospital (aHR = 1.46, 95% CI = 0.69 - 2.36; SE = 0.92). Patients who are between 31 - 40 years of age had increased hazard of death compared to those between 18 - 30 years (aHR = 1.52, 95% CI = 1.04 - 2.23). The hazard of death in female patients was 24% higher compared to male patients (aHR = 1.24, 95% CI = 0.93 - 1.63). Furthermore, patients with previous MDR-TB episodes had an increased hazard of death (aHR = 1.79, 95% CI = 0.23 - 0.62) compared to those with no previous MDR-TB episodes. The hazard of death in HIV negative patients was low compared to those who were HIV positive (aHR = 0.95, 95% CI = 0.57 - 0.77).
ConclusionMore health facilities are needed especially in decentralised places and that can help the 2030 World Health Organisation strategy to reduce or end TB infection. | health informatics |
10.1101/2022.03.01.22271720 | A gene expression map of host immune response in human brucellosis | Brucellosis is a common zoonotic disease caused by intracellular pathogens of the genus Brucella. Brucella infects macrophages and evades clearance mechanisms, which results in chronic parasitism. Herein, we studied the molecular changes that take place in human brucellosis both in vitro and in vivo. RNA sequencing was performed in primary human macrophages (M{varphi}) and polymorphonuclear neutrophils (PMNs) infected with clinical strains of B. melitensis. We observed a downregulation in the expression of genes involved in host response, such as TNF signaling, IL-1{beta} production and phagosome formation in M{varphi}, and phosphatidylinositol signaling and TNF signaling in PMNs, being in line with the ability of the pathogen to survive within phagocytes. Further transcriptomic analysis of isolated peripheral blood mononuclear cells (PBMCs) and PMNs from patients with acute brucellosis before treatment initiation and after successful treatment revealed a positive correlation of the molecular signature of active disease with pathways associated with response to interferons (IFN). We identified 24 common genes that were significantly altered in both PMNs and PBMCs, including genes involved in IFN signaling that were downregulated after treatment in both cell populations, and IL1R1 that was upregulated. The levels of several inflammatory mediators were evaluated in the serum of these patients, and we observed increased levels of IFN-{gamma}, IL-1{beta} and IL-6 before the treatment of acute brucellosis. An independent cohort of patients with chronic brucellosis also revealed the increased levels of IFN-{gamma} during relapse compared to remissions. Taken together, this study provides for the first time an in-depth analysis of the molecular alterations that take place in human phagocytes upon infection, and in peripheral blood immune populations during active disease. | infectious diseases |
10.1101/2022.03.02.22271673 | Predictive Model of Risk Factors of High Flow Nasal Cannula Using Machine Learning in COVID-19 | BackgroundWith the rapid increase in the number of COVID-19 patients in Japan, the number of patients receiving oxygen at home has also increased rapidly, and some of these patients have died. An efficient approach to identify high-risk patients with slowly progressing and rapidly worsening COVID-19, and to avoid missing the timing of therapeutic intervention will improve patient prognosis and prevent medical complications.
MethodsPatients admitted to medical institutions in Japan from November 14, 2020 to April 11, 2021 and registered in the COVID-19 Registry Japan were included. Risk factors for patients with High Flow Nasal Cannula invasive respiratory management or higher were comprehensively explored using machine learning. Age-specific cohorts were created, and severity prediction was performed for the patient surge period and normal times, respectively.
ResultsWe were able to obtain a model that was able to predict severe disease with a sensitivity of 57% when the specificity was set at 90% for those aged 40-59 years, and with a specificity of 50% and 43% when the sensitivity was set at 90% for those aged 60-79 years and 80 years and older, respectively. We were able to identify lactate dehydrogenase level (LDH) as an important factor in predicting the severity of illness in all age groups.
DiscussionUsing machine learning, we were able to identify risk factors with high accuracy, and predict the severity of the disease. Using machine learning, we were able to identify risk factors with high accuracy, and predict the severity of the disease. We plan to develop a tool that will be useful in determining the indications for hospitalisation for patients undergoing home care and early hospitalisation. | infectious diseases |
10.1101/2022.03.01.22271254 | COVID-SAFER: Deprescribing Guidance for Nirmatrelvir-ritonavir Drug Interactions in Older Adults | ImportanceOlder adults, at high-risk of developing complications from COVID-19, could benefit from nirmatrelvir-ritonavir, an oral antiviral treatment for outpatients at high risk of complications from COVID-19; however, due to its potent CYP3A4 inhibition, nirmatrelvir-ritonavir is associated with many drug-drug interactions (DDI).
ObjectivesIdentify how common DDIs are between nirmatrelvir-ritonavir, common medications, and PIMs in older adults with polypharmacy. Craft anticipatory deprescribing guidance for PIMs that interact with nirmatrelvir-ritonavir to help prioritize deprescribing resources, and increase the proportion of older adults potentially benefitting from treatment.
DesignIn this secondary analysis, we retrospectively analyzed all patients in the MedSafer cluster randomized deprescribing trial (N=5698 participants) to investigate the proportion of older adults (age >65) with polypharmacy ([≥]5 usual home medications) who would be ineligible for treatment with nirmatrelvir-ritonavir due to pre-existing DDIs.
SettingThe setting of the primary study was in medical inpatient units at 11 Canadian acute care hospitals.
ParticipantsHospitalized persons, age 65 years and older, on 5 or more daily home medications, with an expected survival of 3 months or longer were included in this secondary analysis.
Main outcomes and measuresWe identified the prevalence of (PIMs), as defined by the MedSafer software. We then developed deprescribing guidance, so clinicians could proactively deprescribe in an effort to increase the proportion of older adults eligible for safe treatment with nirmatrelvir-ritonavir in the event of a SARS-CoV-2 infection.
ResultsOf 5698 participants, a total of 3869 (68%) were taking a medication with a known nirmatrelvir-ritonavir DDI, and of these 823 (21%) had at least one PIM. Of 823 PIMs, 627 (76%) were medications with a known high risk DDI and 213 (26%) were considered moderate risk DDIs with nirmatrelvir-ritonavir. Many of the PIMs required "advanced deprescribing" and could not simply be stopped, held, or adjusted at the time of nirmatrelvir-ritonavir receipt.
Conclusions and relevanceOlder adults are at high risk of developing severe complications from COVID-19. Deprescribing PIMs in advance of a COVID-19 infection could increase the proportion of older adults who can safely receive nirmatrelvir-ritonavir, in addition to the usual benefits observed with medication management.
Impact StatementWe certify that this work is novel. This timely clinical investigation explores the unforeseen consequences of polypharmacy and the use of potentially inappropriate medication in older adults during the COVID-19 pandemic. This manuscript addresses the many drug-drug interactions between nirmatrelvir-ritonavir, an antiviral treatment for COVID-19, and potentially inappropriate medications in older adults with polypharmacy from the MedSafer cluster randomized trial. Our work highlights that the pandemic has created an even greater urgency to examine the medication lists of older adults and proactively deprescribe to improve the safety and tolerability of different COVID-19 treatments.
Key PointsO_LIQuestion: How does polypharmacy affect the eligibility of older adults to receive Nirmatrelvir-ritonavir?
C_LIO_LIFindings: 68% of older adults in the MedSafer cluster randomized trial had a DDI with nirmatrelvir-ritonavir, and 21% were taking at least 1 potentially inappropriate medication.
C_LIO_LIMeaning: Due to its potent CYP3A4 inhibition, nirmatrelvir-ritonavir is associated with many drug-drug interactions (DDI).
C_LI | infectious diseases |
10.1101/2022.03.02.22271664 | Serum levels of the novel adipokine isthmin-1 are associated with obesity in pubertal boys | PurposeThe aims of this study were; 1) to evaluate if there is an association between the serum levels of the novel insulin-like adipokine isthmin-1 (ISM1) and obesity-related phenotypes in a population of Spanish children, 2) to investigate the plausible molecular alterations behind the alteration of the serum levels of this protein in children with obesity.
MethodsThe study population is a sub-cohort of the PUBMEP research project, consisting of a cross-sectional population of 119 pubertal children with overweight (17 boys, 19 girls), obesity (20 boys, 25 girls) and normal weight (17 boys, 21 girls). All subjects were classified into experimental groups according to their sex, obesity and insulin resistance (IR) status. They counted on anthropometry, glucose, and lipid metabolism, inflammation and cardiovascular biomarkers as well as ISM1 serum levels measured. This population was intended as a discovery population in which to elucidate the relationship between obesity and ISM1 levels in children. Furthermore, the study population had blood whole-genome DNA methylation allowing deepening into the obesity-ISM1 molecular relationship.
ResultsHigher serum levels of ISM1 were observed in boys with obesity when compared with normal-weight (P=0.004), and overweight (P=0.007). ISM1 serum levels were positively associated with BMI Z-score (P=0.005), and negatively with myeloperoxidase (MPO) (p=0.043) in boys. Nevertheless, we did not find associations between ISM1 serum levels and metabolic outcomes in girls, indicating a putative sexual dimorphism. DNA methylation levels in two-enhancer-related CpG sites of ISM1 (cg03304641 and cg14269097) were associated with serum levels of ISM1 in children.
DiscussionWe report an unprecedented study that provides a major step forward showing that ISM1 is robustly associated with obesity in pubertal boys, elucidating how this protein might be of special relevance as a new biomarker of obesity in children. | endocrinology |
10.1101/2022.03.02.22271762 | Disparities in SARS-CoV-2 case rates by ethnicity, religion, measures of socio-economic position, English proficiency, and self-reported disability: cohort study of 39 million people in England during the Alpha and Delta waves | ObjectiveTo examine socio-demographic disparities in SARS-CoV-2 case rates during the second (Alpha) and third (Delta) waves of the COVID-19 pandemic.
DesignRetrospective, population-based cohort study.
SettingResident population of England.
Participants39,006,194 people aged 10 years and over who were enumerated at the 2011 Census, registered with the National Health Service (NHS) and alive on 1 September 2020.
Main outcome measuresTesting positive for SARS-CoV-2 during the second wave (1 September 2020 to 22 May 2021) or third wave (23 May to 10 December 2021) of the pandemic. We calculated age-standardised case rates by socio-demographic characteristics and used logistic regression models to estimate adjusted odds ratios (ORs).
ResultsDuring the study period, 5,767,584 individuals tested positive for SARS-CoV-2. In the second wave, the fully-adjusted odds of having a positive test, relative to the White British group, were highest for the Bangladeshi (OR: 1.88, 95% CI 1.86 to 1.90) and Pakistani (1.81, 1.79 to 1.82) ethnic groups. Relative to the Christian group, Muslim and Sikh religious groups had fully-adjusted ORs of 1.58 (1.57 to 1.59) and 1.74 (1.72 to 1.76), respectively. Greater area deprivation, disadvantaged socio-economic position, living in a care home and low English language proficiency were also associated with higher odds of having a positive test. However, the disparities between groups varied over time. Being Christian, White British, non-disabled, and from a more advantaged socio-economic position were all associated with increased odds of testing positive during the third wave.
ConclusionThere are large socio-demographic disparities on SARS-CoV-2 cases which have varied between different waves of the pandemic. Research is now urgently needed to understand why these disparities exist to inform policy interventions in future waves or pandemics.
What is already known on this topicPeople with pre-existing health conditions or disability, ethnic minority groups, the elderly, some religious groups, people with low socio-economic status, and those living in deprived areas have been disproportionately affected by the COVID-19 pandemic in terms of risk of infection and adverse outcomes.
What this study addsUsing linked data on 39 million people in England, we found that during the second wave, COVID-19 case rates were highest among the Bangladeshi and Pakistani ethnic groups, the Muslim religious group, individuals from deprived areas and of low socio-economic position; during the third wave, being Christian, White British, non-disabled, and from a more advantaged socio-economic position were all associated with increased odds of receiving a positive test
Adjusting for geographical factors, socio-demographic characteristics, and pre-pandemic health status explained some, but not all, of the excess risk
When stratifying the dataset by broad age groups, the odds of receiving a positive test remained higher among the Bangladeshi and Pakistani ethnic groups aged 65 years and over during the third wave, which may partly explain the continued elevated mortality rates in these groups | epidemiology |
10.1101/2022.03.02.22271767 | Estimating relative generation times and relative reproduction numbers of Omicron BA.1 and BA.2 with respect to Delta in Denmark | The Omicron variant is the most transmissible variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) we had so far. The BA.1 and BA.2 sublineages of Omicron are circulating in Europe and it is urgent to evaluate the transmissibility of these sub-lineages. Using a mathematical model describing trajectories of variant frequencies that assumes a constant ratio in generation times and a constant ratio in effective reproduction numbers among variants, trajectories of variant frequencies in Denmark from November 22, 2021 to February 26, 2022 were analyzed. We found that the generation times of Omicron BA.1 and BA.2 are 0.60 (95%CI: 0.59-0.62) and 0.51 (95%CI: 0.50-0.52) of the length of that of Delta, respectively. We also found that the effective reproduction number of Omicron BA.1 is 1.99 (95% CI: 1.98-2.02) times and that of Omicron BA.2 is 2.51 (95% CI: 2.48- 2.55) times larger than the effective reproduction number of Delta. The generation times of Omicron BA.2 is 0.85 (95% CI:0.84-0.86) the length of that of BA.1 and that the effective reproduction number of Omicron BA.2 is 1.26 (95% CI:1.25-1.26) times larger than that of Omicron BA.1. These estimates on the ratio of generation times and the ratio of effective reproduction numbers has epidemiologically important implications. The duration of quarantine for people who contacted with an Omicron BA.1 and BA.2 patient can be reduced to 60% and 51% of that for Delta, respectively. The control measures against Omicron BA.1 and BA.2 need to reduce contacts between infectious and susceptible people respectively by 50% (95% CI: 49-50%) and 60% (95% CI: 60-61%) compared to that against Delta to achieve the same effect on their control. | epidemiology |
10.1101/2022.03.02.22271755 | Introducing riskCommunicator: an R package to obtain interpretable effect estimates for public health | Common statistical modeling methods do not necessarily produce the most relevant or interpretable effect estimates to communicate risk. Overreliance on the odds ratio and relative effect measures limit the potential impact of epidemiologic and public health research. We created a straightforward R package, called riskCommunicator, to facilitate the presentation of a variety of effect measures, including risk differences and ratios, number needed to treat, incidence rate differences and ratios, and mean differences. The riskCommunicator package uses g-computation with parametric regression models and bootstrapping for confidence intervals to estimate effect measures in time-fixed data. We demonstrate the utility of the package using data from the Framingham Heart Study to estimate the effect of prevalent diabetes on the 24-year risk of cardiovascular disease or death.
The absolute 24-year risk of cardiovascular disease or death was 30% (95% confidence interval (CI): 22, 38) higher among subjects with diabetes compared to subjects without diabetes at baseline. The relative 24-year risk was 55% (95% CI: 40, 70) higher. Because the outcome was common (41.8%), the odds ratio (4.55) is highly inflated compared to the risk ratio (1.55). An expected 4 additional persons would need to have diabetes at baseline to observe an increase in the number of cases of cardiovascular disease or death by 1 over 24 years of follow-up.
The package promotes the communication of public-health relevant effects and is accessible to a broad range of epidemiologists and health researchers with little to no expertise in causal inference methods or advanced coding. | epidemiology |
10.1101/2022.03.01.22271646 | A gain-of-function GRIA2 variant associated with neurodevelopmental delay and seizures: functional characterization and targeted treatment | AMPA-type glutamate receptors (AMPARs) are tetrameric ligand-gated ion channels formed as different combinations of GluA1-4 subunits encoded by the genes GRIA1-4. Various pathogenic variants of these genes have been described in patients with developmental delay, intellectual disability, autistic spectrum disorder and seizures. Here we report a heterozygous de novo pathogenic missense mutation in GRIA2 (c.1928 C>T, p.A643V) identified in a one-year-old male patient with seizures, developmental delay and failure to thrive. Electrophysiological investigation of heterologously expressed receptors showed GluA2 A643V to exhibit greatly slowed deactivation, and a markedly reduced extent of desensitization, compared with wild-type GluA2. When GluA2 A643V was coexpressed with the transmembrane AMPAR regulatory protein (TARP) {gamma}2, or with both GluA1 and {gamma}2 to generate TARPed heteromeric receptors, the slowed deactivation and decreased desensitization persisted. We found that the AMPAR negative allosteric modulator perampanel was able to fully block currents from GluA2 A643V/{gamma}2 receptors, albeit with reduced potency compared with wild-type GluA2/{gamma}2. The introduction of perampanel to the patients treatment regimen, alongside a modified Atkins diet, was associated with a marked reduction in seizure number, a resolution of failure to thrive, and clear developmental gains. Our study suggests that AMPAR gain-of-function (GoF) underlies the effect of the GRIA2 variant in our patient, and that perampanel may be beneficial in other patients with GRIA GoF variants.
Author summaryRapid communication between brain cells is mediated by the excitatory neurotransmitter glutamate. Mutations affecting genes that encode glutamate-gated ion channels can result in neurodevelopmental disorders and seizures. In a young male patient, we identified a mutation in the gene responsible for production of GluA2, a key subunit of AMPA-type glutamate receptors. We showed that receptors containing GluA2 produced by this GRIA2 A643V variant were more sensitive to glutamate and gave rise to unusually prolonged or sustained responses, thus causing gain-of-function. We found that receptors affected by this mutation could, nonetheless, be inhibited by the AMPA receptor-targeting antiseizure medication, perampanel. Prompted by this finding we introduced perampanel alongside the patients ongoing antiseizure medication. This coincided with a decrease in the patients seizures and clear developmental gains. Taken together, our findings suggest that a GRIA2 gain-of-function mutation can cause neurological disease, that perampanel can be used to directly counteract the effect of the mutation, and that it may be beneficial in other GRIA gain-of-function patients. | pharmacology and therapeutics |
10.1101/2022.03.03.22271772 | Sex-specific genetic and transcriptomic liability to neuroticism | BackgroundThe presentation, etiology, and relative risk of psychiatric disorders are strongly influenced by biological sex. Neuroticism is a transdiagnostic feature of psychiatric disorders displaying prominent sex differences. We performed genome-wide association studies (GWAS) of neuroticism separately in males and females to identify sex-specific genetic and transcriptomic profiles.
MethodsNeuroticism scores were derived from the Eysenck Personality Inventory Neuroticism scale. GWAS were performed in 145,669 females and 129,229 males from the UK Biobank considering autosomal and X-chromosomal variation. Two-sided Z-tests were used to test for sex-specific effects of discovered loci, genetic correlates (N=673 traits), tissue and gene transcriptomic profiles, and polygenic associations across health outcomes in the Vanderbilt University Biobank (BioVu, 39,692 females and 31,268 males).
ResultsThe SNP-heritability of neuroticism was not statistically different between males (h2=10.6%) and females (h2=11.85%). Four female-specific (rs10736549-CNTN5, rs6507056-ASXL3, rs2087182-MMS22L, and rs72995548-HSPB2) and two male-specific (rs10507274-MED13L and rs7984597) neuroticism risk loci reached genome-wide significance. Male- and female-specific neuroticism polygenic scores were most significantly associated with "mood disorders" (male OR=1.11, P=1.40x10-9; female OR=1.14, P=6.05x10-22). They also associated with sex-specific laboratory measures related to erythrocyte count, distribution, and hemoglobin concentration. Gene expression variation in the pituitary was enriched for neuroticism loci in males (males {beta}=0.026, P=0.002) and genetically-regulated transcriptomic changes highlighted the effect of RAB7L1, TEX26, and PLOT1.
ConclusionsThrough a comprehensive assessment of genetic risk for neuroticism and the associated biological processes, this study identified several molecular pathways that can partially explain the known sex differences in neurotic symptoms and their psychiatric comorbidities. | psychiatry and clinical psychology |
10.1101/2022.03.02.22271656 | Analyzing county-wide trends in Tennessee Covid-19 rates, Median Household Income, and Presence of Hospital | The Covid-19 pandemic has caused millions of deaths and infections worldwide. Recent studies suggest that Covid-19 may be disproportionately affecting certain groups. The Tennessee Department of Health regularly publishes data on Covid infections and vaccinations. This data alongside data published from the 2010 census was used to analyze trends in Covid-19 rates for the State of Tennessee. The census data for the average household income of each county was cross-referenced with the covid data. A positive correlation between population of the county and the number of new cases reported on January 3rd, 2022, appeared when observing the data. A regression analysis (ANOVA) revealed that the data on population and covid rate was significant (P-value: 2.69E-10). The results from comparing the covid rates in a county with a hospital and a county without a hospital seemed to be the most significant. The data reported by the Sycamore institute on the Tennessee counties without a hospital was used to identify trends unique to these counties. The counties lacking a hospital were compared with counties with a similar population. 7 hospital-less counties were used for comparison, 6 counties (Fayette, Grainger, Haywood, Chester, Sequatchie, Clay) reported a greater number of cases than counties of a similar population. Of the 20 counties lacking a hospital, 16 fell within the bottom 50% of median household incomes, with 9 in the bottom 25% and 4 in the bottom 10%. Healthcare sites in rural areas may lack fundamental infrastructure. These areas may require unique interventions to address the healthcare concerns present. | public and global health |
10.1101/2022.03.01.22271611 | Predicting missed health care visits during the COVID-19 pandemic using machine learning methods: Evidence from 55,500 individuals from 28 European Countries | BackgroundThe COVID-19 pandemic has led many individuals to miss essential care. Machine-learning models that predict which patients are at greatest risk of missing care visits can help health administrators prioritize retentions efforts towards patients with the most need. Such approaches may be especially useful for efficiently targeting interventions for health systems overburdened by the COVID-19 pandemic.
MethodsWe compare the performance of four machine learning algorithms to predict missed health care visits based on common patient characteristics available to most health care providers. We use data from 55,500 respondents of the Survey of Health, Ageing and Retirement in Europe (SHARE) COVID-19 survey (June - September 2020) in conjunction with longitudinal data from waves 1-8 (April 2004 - March 2020). We use stepwise selection, group lasso, random forest and neural network algorithms and employ 5-fold cross-validation to test the prediction accuracy, sensitivity, and specificity of the selected models.
FindingsWithin our sample, 15.5% of the respondents reported any missed essential health care visit due to the COVID-19 pandemic. All four machine learning methods perform similarly in their predictive power. When classifying all individuals with a predicted probability for missed care above 17% as at risk of a missed visit, they correctly identify between 41% and 53% of the respondents at risk, while correctly identifying between 74% and 64% of the individuals not at risk. We find that the sensitivity and specificity of the models are strongly related to the risk threshold used to classify individuals; thus, the models can be calibrated depending on users resource constraints and targeting approach. All models had an area under the curve around 0.62, indicating that they outperform random prediction.
InterpretationPandemics such as COVID-19 require rapid and efficient responses to reduce disruptions in health care. Based on characteristics available to health insurance providers, machine learning algorithms can be used to efficiently target efforts to reduce missed essential care.
FundingResearch in this article is a part of the European Unions H2020 SHARE-COVID19 project (Grant Agreement No. 101015924). | public and global health |
10.1101/2022.03.02.22271563 | VALIDATION OF AN INSTRUMENTED MOUTHGUARD | The purpose of this study was to determine the validity of an raw and filtered acceleration time-series data from an instrumented mouthguard system against an anthropometric testing device. Testing was conducted in a laboratory using a standard impact protocol utilising the head-form of reference system and the mouthguard system. Testing occurred at 5 impact locations: facemask, front, oblique, side and back, and at four velocities (3.6, 5.5, 7.4, and 9.3 m/s) to attain a total of 55 impacts. A 160 Hz Low-pass 4th order Butterworth filter was applied to the time-series data, and was reported as raw and filtered. Peak linear acceleration, peak rotational velocity and peak rotational acceleration was statistically compared to the reference measurement system. Total concordance correlation coefficient was 90.7% and 96.9%, for raw and filtered data set. Raw and filtered had intraclass correlation coefficients of 0.85 and 0.95 for peak linear acceleration, 0.99 and 0.99 for peak rotational velocity and 0.94 and 0.95 peak rotational acceleration respectively. The instrumented mouthguard displayed high accuracy when measuring head impact kinematics in a laboratory setting. The results presented in this study provide the basis on which the instrumented mouthguard can be further developed for deployment and application within sport quantify head impact collision dynamics in order to optimise performance and brain health. | sports medicine |