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10.1101/2022.05.03.22274596 | The changing epidemiology of shigellosis in Australia, 2001-2019 | Shigellosis is an increasing cause of gastroenteritis in Australia, including prolonged outbreaks in remote Aboriginal and Torres Strait Islander (hereafter "First Nations") communities and among men who have sex with men (MSM) in major cities. To determine associations between Shigella species and demographic and geographic factors we used negative binomial regression to analyse national case notifications of shigellosis from 2001 to 2019.
S. sonnei and S. flexneri accounted for 42% and 29% of cases, respectively. Nationally, notification rates increased from 2001 to 2019 with yearly incidence rate ratios of 1.04 (95% CI 1.02-1.07) for S. boydii, 1.05 (95% CI 1.04-1.06) for S. sonnei and 1.04 (95% CI 1.04-1.06) for S. flexneri. Children aged 0-4 years had the highest burden of infection for S. flexneri, S. sonnei and S. boydii; and males had a higher notification rate for S. sonnei (incidence rate ratio 1.24, 95% CI 1.15-1.33), reflecting transmission among MSM. First Nations Australians were disproportionately affected by shigellosis, with the notification rate in this population peaking in 2018 at 92.1 cases per 100,000. The findings of this study provide important insights into the epidemiological characteristics of shigellosis in Australia, and can be used to inform targeted public health prevention and control strategies. | infectious diseases |
10.1101/2022.04.30.22274518 | Mortality during inpatient admissions for Takotsubo cardiomyopathy: can mortality be predicted with a scoring system? | IntroductionThis study aims to identify which comorbidities and demographic characteristics increase the inpatient mortality rate of patients with TCM and to establish a simple scoring system to help identify those at high risk for mortality.
MethodsA retrospective cross-sectional study using the Nationwide Inpatient Sample was conducted. Admissions with and without inpatient mortality were then compared. Univariate analyses were conducted to compare admission characteristics with and without inpatient mortality. A logistic regression analysis was conducted with inpatient mortality as the dependent variability and various admission characteristics as the independent variables in order to develop a model to predict inpatient mortality. The model was then used to calculate a score, the TCM mortality score, for each admission. A receiver operator curve analysis was conducted to determine the sensitivity, specificity, negative predictive value, and positive predictive value of the TCM mortality score in prediction of inpatient mortality.
ResultsA total of 19,454 admissions were included in the final analyses. Inpatient mortality was greater in patients that were older, males, Hispanics or Asian Pacific Islanders, and those with Medicare/Medicaid. In regards to comorbidities, inpatient mortality was greater in those with heart failure, arrhythmia, and acute kidney injury. Those with mortality were also more likely to have had an intra-aortic balloon pump or having had to be placed on extracorporeal membrane oxygenation. A mortality score was found to be 4.4 in the mortality group as compared to 1.6 for those in the non-mortality group.
ConclusionInpatient mortality with Takotsubo cardiomyopathy is approximately 4.0% and those presenting with certain demographic characteristics and comorbidities are at an increased risk for mortality. A simple scoring system can help identify those at high risk for mortality. | cardiovascular medicine |
10.1101/2022.05.03.22274606 | Validation of a Multi-Ancestry Polygenic Risk Score and Age-Specific Risks of Prostate Cancer: A Meta-analysis Within Diverse Populations | BackgroundWe recently developed a multi-ancestry polygenic risk score (PRS) that effectively stratifies prostate cancer risk across populations. In this study, we validated the performance of the PRS in the multi-ancestry Million Veteran Program (MVP) and additional independent studies.
MethodsWithin each ancestry population, the association of PRS with prostate cancer risk was evaluated separately in each case-control study and then combined in a fixed-effects inverse-variance-weighted meta-analysis. We further assessed the effect modification by age and estimated the age-specific absolute risk of prostate cancer for each ancestry population.
ResultsThe PRS was evaluated in 31,925 cases and 490,507 controls, including men from European (22,049 cases, 414,249 controls), African (8,794 cases, 55,657 controls), and Hispanic (1,082 cases, 20,601 controls) populations. Comparing men in the top decile (90-100% of the PRS) to the average 40-60% PRS category, the prostate cancer OR was increased 3.8-fold in European ancestry men (95% CI=3.62-3.96), 2.8-fold in African ancestry men (95% CI=2.59-3.03), and 3.2-fold in Hispanic men (95% CI=2.64-3.92). The PRS did not discriminate risk of aggressive versus non-aggressive prostate cancer. However, the OR diminished with advancing age (European ancestry men in the top decile: [≤]55 years, OR=7.11; 55-60 years, OR=4.26; >70 years, OR=2.79). Men in the top PRS decile reached 5% absolute prostate cancer risk [~]10 years younger than men in the 40-60% PRS category.
ConclusionsOur findings validate the multi-ancestry PRS as an effective prostate cancer risk stratification tool across populations. A clinical study of PRS is warranted to determine if the PRS could be used for risk-stratified screening and early detection.
FundingThis work was supported by the National Cancer Institute at the National Institutes of Health (grant numbers U19 CA214253 to C.A.H., U01 CA257328 to C.A.H., U19 CA148537 to C.A.H., R01 CA165862 to C.A.H., K99 CA246063 to B.F.D, and T32CA229110 to F.C), the Prostate Cancer Foundation (grants 21YOUN11 to B.F.D. and 20CHAS03 to C.A.H.), the Achievement Rewards for College Scientists Foundation Los Angeles Founder Chapter to B.F.D, and the Million Veteran Program-MVP017. This research has been conducted using the UK Biobank Resource under application number 42195. This research is based on data from the Million Veteran Program, Office of Research and Development, and the Veterans Health Administration. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. | epidemiology |
10.1101/2022.05.03.22274618 | Population-based Oral Cancer Service Screening Disrupted by COVID-19 Pandemic: Observational and Simulation Study | BackgroundIt is important for understanding the impact of COVID-19 pandemic on the missing opportunity for the early detection of oral cancer. This study aimed to assess the impact of COVID-19 pandemic on the existing population-based oral cancer (OC) service screening program in Taiwan.
MethodsBefore and after COVID-19 pandemic design was used to assess the impact of COVID-19 on the reduction of screening rate, referral rate, and the effectiveness of this OC service screening. Data and analysis after pandemic covered non-VOC period in 2020 and VOC period in 2021 compared to the historical control before pandemic in 2019.
ResultsThe screening rate decreased substantially from 26.6% before COVID-19 in 2019 to 16.7% in 2020 and 15.3% in 2021 after pandemic. The reduction of screening rate varied with months, being the most remarkable decline in March (RR=0.61, 95% CI (0.60-0.62)) and June (RR=0.09, 95% CI (0.09-0.10)) in 2021 compared with January. The referral rate was stable at 81.5% in 2020 but it was reduced to 73.1% in 2021. The reduction of screening and referral rate led to the attenuation of effectiveness of advance cancer and mortality attenuated by 4% and 5%, respectively.
ConclusionCOVID-19 pandemic disrupted the screening and the referral rate and further led to statistically significant reduction in effectiveness for preventing advanced cancer and death. Appropriate prioritized strategies must be adopted to ameliorate malignant transformation and tumor upstaging due to deference from participation in the screening.
FundingThis study was financially supported by Health Promotion Administration of the Ministry of Health and Welfare of Taiwan (A1091116). | epidemiology |
10.1101/2022.05.03.22274608 | Immunogenicity of BNT162b2 Vaccine Booster Dose in Patients with Inflammatory Bowel Disease Receiving Infliximab Combination Therapy: A Prospective Observational Study | IntroductionFew data exist regarding the immunogenicity of third dose of BNT162b2 relative to second dose in patients with inflammatory bowel disease (IBD) on different immunosuppressive therapies. We investigated the immunogenicity of BNT162b2 vaccine booster dose in patients with IBD on infliximab combination therapy.
MethodsThis is prospective single center observational study conducted between January 1st, 2022 until February 28th, 2022. Patients were recruited at the time of attendance at the infusion center. Eligibility criteria included patients with confirmed diagnosis of IBD who are receiving infliximab with azathioprine or 6-mercaptopurine and have received two or three-dose of BNT162b2 vaccine. Patients were excluded if they were infected or had symptoms of SARS-CoV-2 previously since the start of the pandemic or received other vaccines than the BNT162b2. Our primary outcome was the concentrations of SARS-CoV-2 antibodies Immunoglobulin G (IgG) and neutralizing antibodies 40-45 weeks from the first dose of BNT162b2 in patients with IBD receiving infliximab combination therapy. Medians with interquartile range (IQR) were calculated.
Results162 patients with IBD and receiving infliximab combination therapy were recruited and the number of patients in each group was 81. Median (IQR) SARS-CoV-2 IgG levels were significantly lower after the second dose [125 BAU/mL (43, 192)] compared to patients who received the third booster dose [207 BAU/mL (181, 234)] (p = 0.003). Neutralizing antibody levels were also lower after the second dose [80 BAU/mL (21, 95)] compared to patients who received the third booster dose [96 BAU/mL (93, 99)] (p = <0.001). The percentage of patients who achieved positive SARS-CoV-2 IgG levels in the third (booster) dose group was higher (96.3%) than those in second dose group (90%)(p = 0.026). Percentage of patients who received third (booster) dose and achieved positive SARS-CoV-2-neutralizing antibody level was 100%, whereas it was lower (88.9%) in patients who received second dose only (p=0.009).
ConclusionMost patients with IBD on infliximab combination therapy had positive SARS-CoV-2 IgG and neutralizing antibody concentrations 40-45 weeks post BNT162b2 vaccination. However, SARS-CoV-2 IgG and neutralizing antibody concentrations were lower in patients who received 2 doses only compared to patients who received a third dose. | gastroenterology |
10.1101/2022.05.03.22274414 | Attention Deficit Hyperactivity Disorder Symptoms and Brain Morphology: Examining Confounding Bias | BackgroundAssociations between attention-deficit/hyperactivity disorder (ADHD) and brain morphology have been reported, although with several inconsistencies. These may partly stem from confounding bias, which could distort associations and limit generalizability. We examined how associations between brain morphology and ADHD symptoms change with adjustments for potential confounders typically overlooked in the literature (aim 1), and for IQ, which is typically corrected for but plays an unclear role (aim 2).
MethodsParticipants were 10-year-old children from the Adolescent Brain Cognitive Development (N=7,961) and Generation R (N=2,531) studies. Cortical area and volume were measured with MRI and ADHD symptoms with the Child Behavior Checklist. Surface-based cross-sectional analyses were run.
ResultsADHD symptoms related to widespread cortical regions when solely adjusting for demographic factors. Additional adjustments for socioeconomic and maternal behavioral confounders (aim 1) generally attenuated associations, as cluster sizes halved and effect sizes substantially reduced. Cluster sizes were further reduced when including IQ (aim 2), however, we argue that adjustments could have introduced bias (e.g., by conditioning on a collider).
ConclusionsCareful confounder selection and control can help identify more robust and specific regions of associations for ADHD symptoms, across two cohorts. We provided guidance to minimizing confounding bias in psychiatric neuroimaging.
FundingAuthors are supported by an NWO-VICI grant (NWO-ZonMW: 016.VICI.170.200 to HT) for HT, LDA, SL, and the Sophia Foundation S18-20, and Erasmus University and Erasmus MC Fellowship for RLM. | psychiatry and clinical psychology |
10.1101/2022.05.03.22274530 | Solid fuel use in relation to dementia risk in middle-aged and older adults: A prospective cohort study | ObjectivesIt remains unknown whether household air pollution is associated with dementia risk. This study examined the associations between solid fuel use for cooking and heating (the main source of household air pollution) and dementia risk.
MethodsThis analysis included data on 11,352 participants (aged 45+ years) from the 2011 wave of China Health and Retirement Longitudinal Study, with follow-up to 2018. Dementia risk was assessed by a risk score using the Rotterdam Study Basic Dementia Risk Model (BDRM) and then standardized for analysis. Household fuel types of cooking and heating were categorized as solid (e.g., coal, crop residue) and clean (e.g., central heating, solar). Multivariable analyses were performed using generalized estimating equations. Moreover, we examined the joint associations of solid fuel use for cooking and heating with the BDRM score.
ResultsWe found an independent and significant association of solid (vs. clean) fuel use for cooking and heating with a higher BDRM score after adjusting for potential confounders (e.g., {beta} = 0.14 for solid fuel for cooking; 95% CI: 0.12, 0.17). Participants who used solid (vs. clean) fuel for both cooking and heating had the highest BDRM score ({beta} = 0.20; 95%CI: 0.16, 0.23). Subgroup analysis suggested stronger associations in participants living in rural areas.
ConclusionsSolid fuel use for cooking and heating was independently associated with increased dementia risk in Chinese middle-aged and older adults, particularly among those living in rural areas. Our findings call for more efforts to facilitate universal access to clean energy for dementia prevention. | public and global health |
10.1101/2022.05.03.22273718 | Associations of antidepressants and antipsychotics with lipid parameters: Do CYP2D6/CYP2C19 genes play a role? A UK population-based study. | BackgroundDyslipidaemia is an important risk factor for cardiovascular morbidity in people with severe mental illness and which contributes to premature mortality in this population. The link between antipsychotics and dyslipidaemia is well-established, whilst evidence on antidepressants is mixed.
AimsTo investigate (1) if antidepressant/antipsychotic use was associated with lipid parameters in UK Biobank participants, and (2) if CYP2D6 and CYP2C19 genetic variation plays a role.
MethodsReview of self-reported prescription medications identified participants taking antidepressants/antipsychotics. Total, low-, and high-density lipoprotein (L/HDL-C) cholesterol and triglycerides derived from blood samples. CYP2D6 and CYP2C19 metabolic phenotypes were assigned from genetic data. Linear regression investigated study aims.
ResultsOf 469,739 participants, 36,043 took antidepressants and 3,255 antipsychotics. Significant associations were found between use of amitriptyline, fluoxetine, citalopram/escitalopram, sertraline, paroxetine, and venlafaxine with worse levels of each lipid parameter (i.e., higher total cholesterol, LDL-C, and triglycerides and lower HDL-C). Venlafaxine was associated with the worst lipid profile (total cholesterol, mean difference: 0{middle dot}21 mmol/L, 95% confidence interval [CI]: 0{middle dot}17 to 0{middle dot}26, p<0{middle dot}001). Antipsychotic use was associated with lower HDL-C and higher triglycerides (0{middle dot}31 mmol/L, 95% CI 0{middle dot}28 to 0{middle dot}35, p<0{middle dot}001). In participants taking sertraline, the CYP2C19 intermediate metaboliser phenotype was associated with higher HDL-C (0{middle dot}05 mmol/L 95% CI: 0{middle dot}01 to 0{middle dot}09, p=0{middle dot}007) and lower triglycerides (-0{middle dot}17 mmol/L 95% CI: -0{middle dot}29 to -0{middle dot}05, p=0{middle dot}007).
ConclusionsAntidepressants are significantly associated with adverse lipid profiles, potentially warranting baseline and regular monitoring of lipids. Further research should investigate why the CYP2C19 intermediate metaboliser phenotype may be protective for HDL-C and triglycerides in people taking sertraline. | psychiatry and clinical psychology |
10.1101/2022.05.03.22274602 | Accident and emergency (AE) attendance in England following infection with SARS-CoV-2 Omicron or Delta | The SARS-CoV-2 Omicron variant is increasing in prevalence around the world. Accurate estimation of disease severity associated with Omicron is critical for pandemic planning. We found lower risk of accident and emergency (AE) attendance following SARS-CoV-2 infection with Omicron compared to Delta (HR: 0.39 (95% CI: 0.30 - 0.51; P<.0001). For AE attendances that lead to hospital admission, Omicron was associated with an 85% lower hazard compared with Delta (HR: 0.14 (95% CI: 0.09 - 0.24; P<.0001)).
Conflicts of InterestsNothing to declare.
Funding statementThis work was supported by the Medical Research Council MR/V015737/1. TPP provided technical expertise and infrastructure within their data centre pro bono in the context of a national emergency. Rosalind Eggo is funded by HDR UK (grant: MR/S003975/1), MRC (grant: MC_PC 19065), NIHR (grant: NIHR200908). | infectious diseases |
10.1101/2022.05.04.22274522 | Effect of Digoxin on Interstage Outcomes following Stage I Palliation for Functionally Univentricular Hearts: A Systematic Review and Meta-Analysis | ObjectivesThe goal of this systematic review and meta-analysis is to investigate the effects of digoxin on outcomes following stage I palliation for functionally univentricular hearts.
Data SourcesWe conducted electronic searches of PubMed, Ovid and Cochrane.
Study SelectionInclusion criteria included publication dates 1970-2018, children with functionally univentricular hearts between stage I and stage II palliation who received digoxin were compared to those who did not.
Data ExtractionWe identified 148 unique citations; 5 full-text articles were included in the final review. Data from 4 studies was pooled for meta-analysis.
Data SynthesisA total of 4 studies with 1,498 patients were included in the final analyses. Patient enrollment occurred between 2003 and 2013. A majority of patients were born full-term and approximately 25% were diagnosed with a syndrome. The most common cardiac diagnosis was hypoplastic left heart syndrome (70%). The most common initial surgical palliation was the Norwood procedure with a right ventricle to pulmonary artery conduit. The total amount of deaths was 121 (12 digoxin group versus 109 no digoxin group). The interstage mortality was reduced in the digoxin group [OR 0.25(95% CI 0.14 to 0.47)]. There was no statistically significant difference in the presence of arrhythmias or other complications.
ConclusionsThis systematic review and meta-analysis suggests that digoxin significantly decreases interstage period mortality with a concurrent significant decrease in weight for age. The odds of arrhythmia or other complications are not significantly different with digoxin based on current data. | cardiovascular medicine |
10.1101/2022.04.24.22272897 | Speed and accuracy of whole-genome nanopore sequencing for differential Neisseria gonorrhoeae strain detection in samples collected prospectively from a sexual health clinic | BackgroundAntimicrobial resistance (AMR) in Neisseria gonorrhoeae is a continuing global health challenge. Limitations to current national surveillance systems for reporting AMR trends, alongside reduction in culture-based diagnostics and susceptibility testing, has led to an increasing need for rapid diagnostics and identification of circulating N. gonorrhoeae strains. We investigated nanopore based sequencing time and depth needed to accurately identify closely related N. gonorrhoeae isolates, compared to Illumina MiSeq sequencing.
MethodsN. gonorrhoeae strains prospectively collected from a London Sexual Health clinic were sequenced on both Illumina MiSeq and Oxford Nanopore Technologies (ONT) MinION platforms. Accuracy was determined by comparing variant calls at 68 nucleotide positions representing 37 pre-characterised resistance associated markers in N. gonorrhoeae. Accuracy at varying MinION sequencing depths were determined through retrospective analysis of time-stamped reads.
ResultsOf the 22 MinION-MiSeq sequence pairs that reached sufficient depth of coverage for comparison, overall agreement of variant call positions passing quality control criteria was 185/185 (95% CI: 98.0-100.0), 502/503 (95% CI: 98.9-99.9) and 564/565 (95% CI: 99.0-100.0) at 10x, 30x and 40x MinION depth, respectively. Isolates found to be genetically closely related by MiSeq, that is within one yearly evolutionary distance of [≤]5 single nucleotide polymorphisms, were accurately identified as such via MinION.
ConclusionNanopore based sequencing shows utility for use as a rapid surveillance tool to correctly detect closely related N. gonorrhoeae strains, with just 10x sequencing depth, taking a median sequencing time of 29 minutes. This highlights its potential utility for tracking local gonorrhoea transmission and AMR markers. | sexual and reproductive health |
10.1101/2022.05.02.22273554 | Longitudinal analyses of depression and anxiety highlight greater prevalence during COVID-19 lockdowns in the Dutch general population and a continuing increase in suicidal ideation in young adults | ObjectiveThe pandemic of the coronavirus disease 2019 (COVID-19) has led to an increased burden on mental health. This study therefore investigated the development of major depressive disorder (MDD), generalized anxiety disorder (GAD), and suicidal ideation in the Netherlands during the first fifteen months of the pandemic and three nation-wide lockdowns.
MethodsParticipants of the Lifelines Cohort Study -a Dutch population-based sample-reported current symptoms of MDD and GAD, including suicidal ideation, according to DSM-IV criteria using a digital structured questionnaire. Between March 2020 and June 2021, 36,106 participants (aged 18-96) filled out a total of 629,811 questionnaires across 23 time points. Trajectories over time were estimated using generalized additive models and analyzed in relation to age, sex, and lifetime history of MDD/GAD to identify groups at risk.
ResultsWe found non-linear trajectories for MDD and GAD with a higher number of symptoms and prevalence rates during periods of lockdown. The point prevalence of MDD and GAD peaked during the third hard lockdown at 2.88% (95% CI: 2.71%-3.06%) and 2.92% (95% CI: 2.76%-3.08%), respectively, in March 2021. Women, younger adults, and participants with a history of MDD/GAD reported significantly more symptoms. For suicidal ideation, we found a linear increase over time in younger participants which continued even after the lockdowns ended. For example, 4.63% (95% CI: 3.09%-6.96%) of 20-year-old participants reported suicidal ideation at our last measured time point in June 2021, which represents a 4.14x increase since the start of the pandemic.
ConclusionsOur study showed greater prevalence of MDD and GAD during COVID-19 lockdowns suggesting that the pandemic and government enacted restrictions impacted mental health in the population. We furthermore found a continuing increase in suicidal ideation in young adults. This warrants for alertness in clinical practice and prioritization of mental health in public health policy. | psychiatry and clinical psychology |
10.1101/2022.04.11.22272364 | UB-612, a Multitope Universal Vaccine Eliciting a Balanced B and T Cell Immunity against SARS-CoV-2 Variants of Concern | ImportanceThe SARS-CoV-2 non-spike structural proteins of nucleocapsid (N), membrane (M) and envelope (E) are critical in the host cell interferon response and memory T-cell immunity and have been grossly overlooked in the development of COVID vaccines.
ObjectiveTo determine the safety and immunogenicity of UB-612, a multitope vaccine containing S1-RBD-sFc protein and rationally-designed promiscuous peptides representing sequence-conserved Th and CTL epitopes on the Sarbecovirus nucleocapsid (N), membrane (M) and spike (S2) proteins.
Design, setting and participantsUB-612 booster vaccination was conducted in Taiwan. A UB-612 booster dose was administered 6-8 months post-2nd dose in 1,478 vaccinees from 3,844 healthy participants (aged 18-85 years) who completed a prior placebo (saline)-controlled, randomized, observer-blind, multi-center Phase-2 primary 2-dose series (100-g per dose; 28-day apart) of UB-612. The interim safety and immunogenicity were evaluated until 14 days post-booster.
ExposureVaccination with a booster 3rd-dose (100-g) of UB-612 vaccine.
Main outcomes and measuresSolicited local and systemic AEs were recorded for seven days in the e-diaries of study participants, while skin allergic reactions were recorded for fourteen days. The primary immunogenicity endpoints included viral-neutralizing antibodies against live SARS-CoV-2 wild-type (WT, Wuhan strain) and live Delta variant (VNT50), and against pseudovirus WT and Omicron variant (pVNT50). The secondary immunogenicity endpoints included anti-S1-RBD IgG antibody, S1-RBD:ACE2 binding inhibition, and T-cell responses by ELISpot and Intracellular Staining.
ResultsNo post-booster vaccine-related serious adverse events were recorded. The most common solicited adverse events were injection site pain and fatigue, mostly mild and transient. The UB-612 booster prompted a striking upsurge of neutralizing antibodies against live WT Wuhan strain (VNT50, 1,711) associated with unusually high cross-neutralization against Delta variant (VNT50, 1,282); and similarly with a strong effect against pseudovirus WT (pVNT50, 6,245) and Omicron variant (pVNT50, 1,196). Upon boosting, the lower VNT50 and pVNT50 titers of the elderly in the primary series were uplifted to the same levels as those of the young adults. The UB-612 also induced robust, durable VoC antigen-specific Th1-oriented (IFN-{gamma}+-) responses along with CD8+ T-cell (CD107a+-Granzyme B+) cytotoxicity.
Conclusions and relevanceWith a pronounced cross-reactive booster effect on B- and T-cell immunity, UB-612 may serve as a universal vaccine booster for comprehensive immunity enhancement against emergent VoCs.
Trial registration[ClinicalTrials.gov: NCT04773067]
KEY POINTSO_ST_ABSQuestionC_ST_ABSFacing ever-emergent SARS-CoV-2 variants and long-haul COVID, can composition-updated new vaccines be constructed capable of inducing striking, durable booster-recalled B/T-immunity to prevent infection by VoCs?
FindingsIn a Phase-2 extension study, a booster dose of UB-612 multitope protein-peptide vaccine prompted high viral-neutralizing titers against live wild-type virus (VNT50, 1,711), Delta variant (VNT50, 1,282); pseudovirus wild-type (pVNT50, 6,245) and Omicron variant (pVNT50, 1,196). Robust, durable Th1-IFN{gamma}+ responses and CD8+ T cell-(CD107a+-Granzyme B+) cytotoxic activity were both observed.
MeaningUB-612 RBD-sFc vaccine armed with T cell immunity-promoting conserved N, M and S2 Th/CTL epitope peptides may serve as a universal vaccine to fend off new VoCs. | infectious diseases |
10.1101/2022.05.03.22274640 | Determinants of maternal morbidity during pregnancy in urban Bangladesh: Negative binomial regression approach | AimTo investigate the prevalence of maternal morbidity during pregnancy and its determinants among the women from urban areas of Bangladesh.
MethodsThe secondary data were used and extracted from the latest Bangladesh Urban Health Survey (BUHS) 2013. Several statistical models: Poisson, negative binomial (NB) and mixed Poisson were adapted and compared to explore the best model for investigating potential determinants of maternal morbidity. Pearson chi-square statistic was used for the detection of overdispersion in the data.
ResultsOverall 13.5% of the urban women in Bangladesh suffered from at least two pregnancy complications. The study detected the overdispersion existing in the maternal morbidity count data and found the NB regression as the best choice for analyzing the data because of its smallest Akaike information criterion. Administrative division (Rangpur: p=0.003, IRR=1.34, 95% CI: 1.11 to 1.63; Sylhet: p=0.006, IRR=1.42, 95% CI: 1.11 to 1.82), wanted pregnancy (p<0.001, IRR=0.80, 95% CI: 0.71 to 0.90), place of delivery (p<0.001, IRR=0.60, 95% CI: 0.54 to 0.66) and wealth index (Rich: p<0.001, IRR=0.74, 95% CI: 0.66 to 0.84) were found to be statistically significant determinants for maternal morbidity during pregnancy among the urban women in Bangladesh.
ConclusionsThe urban women in Bangladesh with unwanted pregnancy, from poor/middle income group; and living in Rangpur and Sylhet divisional cities have higher risk of maternal morbidity during pregnancy. The women already suffering from major pregnancy related complications visit health centre to give birth. Study findings may help the government and relevant authorities to take necessary steps for reducing maternal morbidity and mortality due to pregnancy related complications. | health systems and quality improvement |
10.1101/2022.05.05.22274704 | Insomnia symptoms and risk of bloodstream infections: prospective data from the prospective population-based HUNT Study, Norway | ObjectivePrevious research suggest decreased immune function and increased risk of infections in persons with insomnia. We examined the effect of insomnia symptoms on risk of bloodstream infections (BSI) and BSI-related mortality in a population-based prospective study.
MethodsA total of 53,536 participants in the Norwegian HUNT2 study (1995-97) were linked to prospective data on clinically relevant BSIs until 2011. In Cox regression, we estimated hazard ratios (HRs) with 95% confidence interval (CI) for a first-time BSI and for BSI related mortality (BSI registered [≤]30 days prior to death) associated with insomnia symptoms.
ResultsCompared with participants who reported "no symptoms of insomnia", participants reporting having "difficulty initiating sleep" often/almost every night had a HR for a first-time BSI of 1.14 (95% CI 0.96-1.34). Participants reporting "difficulties maintaining sleep" often/almost every night had a HR of 1.19 (95% CI 1.01-1.40), whereas those having a "feeling of non-restorative sleep" once a week or more had a HR of 1.23 (95% CI 1.04-1.46). Participants experiencing all three above insomnia symptoms frequently had a HR of 1.39 (1.04-1.87) and being troubled by insomnia to a degree that affected work performance was associated with a HR of 1.41 (95% CI 1.08-1.84). The HRs for BSI related mortality suggest an increased risk with increasing insomnia symptoms, but confidence intervals are wide and inconclusive.
ConclusionsWe found that frequent insomnia symptoms and insomnia symptoms that affected work performance was associated with a weak positive increased risk of BSI. | infectious diseases |
10.1101/2022.05.02.22273844 | Multi-ancestry genome-wide analysis identifies effector genes and druggable pathways for coronary artery calcification | Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts symptomatic coronary artery disease. Identifying genetic risk factors for CAC may point to new therapeutic avenues for preventing clinical disease. Here, we conducted a multi-ancestry genome-wide association study in 26,909 individuals of European ancestry and 8,867 individuals of African American ancestry. We identified 11 independent risk loci, of which 8 are novel for CAC. Some novel loci harbor candidate causal genes supported by multiple lines of functional evidence. Together, these findings help refine the genetic architecture of CAC, extend our understanding of the biological pathways underlying CAC formation, as well as identify druggable targets for CAC. | cardiovascular medicine |
10.1101/2022.05.05.22274721 | Socioeconomic inequality in SARS-CoV-2 testing and COVID-19 outcomes in UK Biobank over the first year of the pandemic: can inequalities be explained byselection bias? | BackgroundStructural barriers to testing may introduce selection bias in COVID-19 research. We explore whether changes to testing and lockdown restrictions introduce time-specific selection bias into analyses of socioeconomic position (SEP) and SARS-CoV-2 infection.
MethodsUsing UK Biobank (N = 420 231; 55 % female; mean age = 56{middle dot}3 [SD=8{middle dot}01]) we estimated the association between SEP and i) being tested for SARS-CoV-2 infection versus not being tested ii) testing positive for SARS-CoV-2 infection versus testing negative and iii) testing negative for SARS-CoV-2 infection versus not being tested, at four distinct time-periods between March 2020 and March 2021. We explored potential selection bias by examining the same associations with hypothesised positive (ABO blood type) and negative (hair colour) control exposures. Finally, we conducted a hypothesis-free phenome-wide association study to investigate how individual characteristics associated with testing changed over time.
FindingsThe association between low SEP and SARS-CoV-2 testing attenuated across time-periods. Compared to individuals with a degree, individuals who left school with GCSEs or less had an OR of 1{middle dot}05 (95% CI: 0{middle dot}95 to 1{middle dot}16) in March-May 2020 and 0{middle dot}98 (95% CI: 0{middle dot}94 to 1{middle dot}02) in January-March 2021. The magnitude of the association between low SEP and testing positive for SARS-CoV-2 infection increased over the same time-period. For the same comparisons, the OR for testing positive increased from 1{middle dot}27 (95% CI: 1{middle dot}08 to 1{middle dot}50), to 1{middle dot}73 (95% CI: 1{middle dot}59 to 1{middle dot}87). We found little evidence of an association between both control exposures and all outcomes considered. Our phenome-wide analysis highlighted a broad range of individual traits were associated with testing, which were distinct across time-periods.
InterpretationThe association between SEP (and indeed many individual traits) and SARS-CoV-2 testing changed over time, indicating time-specific selection pressures in COVID-19. However, positive, and negative control analyses suggest that changes in the magnitude of the association between SEP and SARS-CoV-2 infection over time were unlikely to be explained by selection bias and reflect true increases in socioeconomic inequalities.
FundingUniversity of Bristol; UK Medical Research Council; British Heart Foundation; European Union Horizon 2020; Wellcome Trust and The Royal Society; National Institute of Health Research; UK Economic and Social Research Council | epidemiology |
10.1101/2022.05.05.22274697 | Asymptomatic SARS-CoV-2 infection by age: A systematic review and meta-analysis | ObjectivesThis systematic review and meta-analysis aimed to estimate the age-specific proportion of asymptomatic SARS-CoV-2 infected persons by year of age.
MethodsWe searched PubMed, Embase, medRxiv and Google Scholar on 10 September 2020 and 1 March 2021. We included studies conducted during January to October 2020, prior to routine vaccination against COVID-19. Since we expected the relationship between the asymptomatic proportion and age to be non-linear, multilevel mixed-effects logistic regression (QR decomposition) with a restricted cubic spline was used to model asymptomatic proportions as a function of age.
ResultsA total of 38 studies were included in the meta-analysis. In total, 6556 out of 14850 cases were reported as asymptomatic. The overall estimate of the proportion of people who became infected with SARS-CoV-2 and remained asymptomatic throughout infection was 44.1% (6556/14850, 95%CI 43.3%-45.0%). The asymptomatic proportion peaked in adolescents (36.2%, 95%CI 26.0%-46.5%) at 13.5 years, gradually decreased by age and was lowest at 90.5 years of age (8.1%, 95%CI 3.4%-12.7%).
ConclusionsGiven the high rates of asymptomatic carriage in adolescents and young adults and their active role in virus transmission in the community, heightened vigilance and public health strategies are needed among these individuals to prevent disease transmission. | epidemiology |
10.1101/2022.05.03.22274407 | Application of multilevel linear spline models for analysis of growth trajectories in a cohort with repeat antenatal and postnatal measures of growth: a prospective cohort study | IntroductionAntenatal and postnatal growth are important indicators of fetal and child health and development. Studies frequently have repeat antenatal and postnatal measures of growth available and require approaches that can maximise the use of these measures to examine growth trajectories. We demonstrate the use of multilevel linear spline modelling to model growth trajectories with repeated antenatal and postnatal measures of growth from 20 weeks gestation to five years in a cohort at high risk of macrosomia.
MethodsProspective follow-up data from 720-759 mother-child pairs from the ROLO study (initially a randomized controlled trial of a low glycemic index diet in pregnancy to prevent recurrence of macrosomia [birthweight > 4K]) were analysed. Fetal measurements were obtained from ultrasound scans performed on mothers at 20-and 34-weeks gestation, including abdominal circumference (AC) and head circumference (HC). An estimated fetal weight was obtained at 20-and 34-weeks gestation, calculated using the Hadlock 4-parameter formula. At delivery, AC, HC, weight and length were recorded. Follow-up anthropometry assessments (AC, HC, weight and length/height) were also obtained in childhood at six months, two years and five years. Linear spline multilevel models were used to examine trajectories of AC, HC and weight from 20 weeks gestation to five years and length/height from birth to five years.
Results754, 756 and 759 participants were included in analyses of AC, HC and weight respectively, while 720 participants were included in analysis of length/height. Over 50% of women had 3rd level education and over 90% were of White ethnicity. Women were a mean (SD) age of 32 (4.2) at recruitment. Following exploration of a series of different models for each growth measure, the best fitting model for AC, HC and weight included a model with knots at each measurement occasion giving rise to five linear spline periods from: 20 weeks to 34 weeks gestation, 34 weeks gestation to birth, birth to six months, six months to two years and two years to five years. The best fitting models for length/height included a model with three linear spline periods from birth to six months, six months to two years and two years to five years. Comparison of observed and predicted values for each model demonstrated good model fit. For all growth measures, fetal growth rates were generally fastest in pregnancy or immediately postpartum (for length/height), with rates of growth slowing after birth and becoming slower still as infancy and childhood progressed. We found little difference in growth trajectories between the intervention and control group. There was some evidence of slightly lower HC, weight and length among females compared with males at birth which appeared to widen by age five years due to slower postnatal growth rates among females.
ConclusionWe demonstrate the application of multilevel linear spline models for examining growth trajectories when both antenatal and postnatal measures of growth are available. The approach may be useful for cohort studies or randomised controlled trials with repeat prospective assessments of growth spanning pregnancy and childhood. | epidemiology |
10.1101/2022.05.04.22274653 | Which innovations can improve timeliness of investigations and address the backlog in endoscopy for patients with potential symptoms of upper and lower Gastrointestinal (GI) cancers? Rapid Review | TOPLINE SUMMARYO_ST_ABSWhat is a Rapid Review?C_ST_ABSOur rapid reviews use a variation of the systematic review approach, abbreviating or omitting some components to generate the evidence to inform stakeholders promptly whilst maintaining attention to bias. They follow the methodological recommendations and minimum standards for conducting and reporting rapid reviews, including a structured protocol, systematic search, screening, data extraction, critical appraisal, and evidence synthesis to answer a specific question and identify key research gaps. They take 1-2 months, depending on the breadth and complexity of the research topic/ question(s), extent of the evidence base, and type of analysis required for synthesis.
Background / Aim of Rapid ReviewMany patients were not able to access routine diagnostic care through 2020/21 because of extraordinary pressures on the NHS due to COVID-19 and the UK national lockdowns. For some patients this can have serious short and long-term consequences to their health and life expectancy. The NHS has limited resources and is looking for new ways to meet many demands and patient needs.
This Rapid Review Report aims to answer the question "Which innovations can be used to accelerate the patients journey through the endoscopic cancer diagnosis pathway?" The report highlights evidence of innovations and new ways to improve the timeliness of access to endoscopy and to address the backlog of unmet need for patients who have waited a long time for such tests and investigations by selecting those at highest for prioritisation. It does not evaluate in terms of effectiveness on clinical outcomes.
Key FindingsO_ST_ABSExtent of the evidence baseC_ST_ABS{blacksquare} Nine papers were included in the rapid review in total.
{blacksquare}Two reviews were identified. One review examined the novel colon capsule endoscopy (CCE) procedure and the second review summarised the effects of COVID-19 on colorectal cancer (CRC) screening, the potential long-term? outcomes, and ways to adapt CRC screening during the COVID-19 pandemic.
{blacksquare}Seven primary studies assessed innovations for the diagnosis of Gastrointestinal (GI) cancers. Five of these studies examined faecal immunochemical testing (FIT) for prioritising patients for further testing.
{blacksquare}Two studies reported pathways/innovations to triage patients e.g. from primary care. These methods of triage used interventions such as Cytosponge for oesophageal symptoms.
Recency of the evidence base{blacksquare} Of the primary studies, one was published in 2020 and six were published in 2021. Of the reviews, one was published in 2020 and one in 2021.
Evidence of effectiveness{blacksquare} The five studies investigating FIT found that it could help prioritise patients for further testing and improve targeting of high-risk patients.
{blacksquare}One review proposed CCE may offer a useful solution for investigating colorectal patients to reduce the need for some endoscopies following the pandemic.
{blacksquare}One review found a shift from current CRC screening and surveillance practices towards an individualized approach based on risk factors, could result in the allocation of resources to people with higher risks and prevent inappropriate use of healthcare resources for those with lower risks.
Best quality evidence{blacksquare} All studies were quality appraised using the relevant JBI checklist. Five studies were of low to moderate quality.
Policy Implications{blacksquare} Increased use of faecal immunochemical testing (FIT) could reduce the endoscopy backlog and save NHS resources if those with low FIT scores can be excluded from further testing.
{blacksquare}Policy in Wales supports prioritisation of potential gastrointestinal cancer patients for endoscopy using FIT test scores (NHS Wales 2021) although local implementation currently varies, so it is not yet fully utilised. The FIT test gives results which could be utilised by healthcare professionals to prioritise those who are most in need of urgent diagnosis. The viability of this method to prioritise those in greatest need of being referred for diagnosis through endoscopy is proven (though safety-netting is still required), and the FIT test is part of the diagnostic pathway already in Wales. It will be important to ensure all areas of Wales have equal access to the use of FIT testing for this purpose, and that clinical guidelines are harmonised and adhered to throughout Wales.
{blacksquare}Innovations to reduce backlog and speed up time to diagnosis should be explored including:
{circ}Triage in primary care settings such as GP surgeries using innovations such as the cytosponge for oesophageal symptoms (e.g. reflux).
{circ}Direct referral from primary care settings to specialist investigation, without the need for prior additional referrals in secondary care.
Strength of Evidence{blacksquare} The evidence presented in this review is recent, however with small samples (di Pietro et al., 2020), short-term follow up periods (Sagar et al., 2020) and assumptions required for modelling studies (Loveday et al., 2021). This reduces the generalisability and confidence of conclusions. The confidence in the strength of evidence about FIT testing is rated as low-moderate confidence. Cytosponge evidence is rated low confidence.
Review team and stakeholder involvementThis Rapid Review is being conducted as part of the Wales COVID-19 Evidence Centre Work Programme. The above question was developed in consultation with Cancer Research UKs identified research gaps and with Professor Tom Crosby OBE. Professor Crosby is a Consultant Oncologist, National Cancer Clinical Director for Wales and Clinical Lead for Transforming Cancer Services and acted as the expert stakeholder for this review.
The search questions were identified as a priority during the Cancer/COVID-19 Research Summit hosted by Cancer Research UK (CRUK), Public Health England (PHE) and the National Cancer Research Institute (NCRI). The stakeholder group supporting the review work here is Cancer Research Wales. | gastroenterology |
10.1101/2022.04.28.22274107 | Assessment of Alzheimer-related Pathologies of Dementia Using Machine Learning Feature Selection | Although a variety of brain lesions may contribute to the pathological diagnosis of dementia, the relationship of these lesions to dementia, how they interact and how to quantify them remain uncertain. Systematically assessing neuropathological measures in relation to the cognitive and functional definitions of dementia may enable the development of better diagnostic systems and treatment targets. The objective of this study is to apply machine learning approaches for feature selection to identify key features of Alzheimer-related pathologies associated with dementia. We applied machine learning techniques for feature ranking and classification as an unbiased comparison of neuropathological features and assessment of their diagnostic performance using a cohort (n=186) from the Cognitive Function and Ageing Study (CFAS). Seven feature ranking methods using different information criteria consistently ranked 22 out of the 34 neuropathology features for importance to dementia classification. Braak neurofibrillary tangle stage, Beta-amyloid and cerebral amyloid angiopathy features were the most highly ranked, although were highly correlated with each other. The best performing dementia classifier using the top eight ranked neuropathology features achieved 79% sensitivity, 69% specificity, and 75% precision. A substantial proportion (40.4%) of dementia cases was consistently misclassified by all seven algorithms and any combination of the 22 ranked features. These results highlight the potential of using machine learning to identify key indices of plaque, tangle and cerebral amyloid angiopathy burdens that may be useful for the classification of dementia. | pathology |
10.1101/2022.05.03.22274641 | Correlation of Suspected COVID-19 Symptoms with COVID-19 Positivity in Children | BackgroundEarly in the pandemic, COVID-19 was found to infect adults at higher rates than children, leaving limited data on disease presentation in children. Further understanding of the epidemiology of COVID-19 symptoms among children is needed. Our aim was to explore how symptoms vary between children testing positive for COVID-19 infection versus children testing negative.
MethodsData analysis of symptom prevalence among pediatric patients presenting to emergency departments (ED) in the Johns Hopkins Health System (JHHS) with concern for COVID-19 who subsequently received COVID-19 testing. Inclusion criteria included patients 0-17 years-of-age, ED evaluation between March 15th, 2020 - May 11th, 2020, and those who were ordered for COVID-19 testing. Chart review was performed to document symptoms using ED provider notes. Comparisons were made using chi-squared t-tests and Students t-tests.
ResultsFever (62.6%) and cough (47.9%) were the most prevalent symptoms among children with suspected COVID-19 infection. Compared to children with a negative COVID-19 test, children who tested positive had higher prevalence of myalgia (21.7% vs 6.0%) and loss of taste/smell (15.2% vs 0.9%). Over half of the children who tested positive for COVID-19 had public insurance (52.2%) and 58.7% of the positive tests occurred among children with Hispanic ethnicity.
ConclusionsMyalgia and loss of taste/smell were found to be significantly more prevalent among COVID-19 positive children compared to children testing negative. Additionally, children with public insurance and those with Hispanic ethnicity were more likely to test positive, emphasizing the importance of social factors in the screening and decision-making process. | pediatrics |
10.1101/2022.05.04.22274654 | The cost and cost-effectiveness of novel tuberculosis vaccines in low- and middle-income countries: a modelling study | BackgroundTuberculosis (TB) is preventable and curable but eliminating it has proven challenging. Safe and effective TB vaccines that can rapidly reduce disease burden are essential for achieving TB elimination. We assessed future costs, cost-savings, and cost-effectiveness of introducing novel TB vaccines in low- and middle-income countries (LMICs) for a range of product characteristics and delivery strategies.
MethodsWe developed a system of epidemiological and economic models, calibrated to demographic, epidemiological, and health service data in 105 LMICs. For each country, we assessed the likely future course of TB-related outcomes under several vaccine introduction scenarios, compared to a no-new-vaccine counterfactual. We estimated the incremental impact of vaccine introduction for a range of health and economic outcomes. In the base-case, we assumed a vaccine price of $4.60, and used a 1x per-capita GDP cost-effectiveness threshold (both varied in sensitivity analyses).
FindingsVaccine introduction was estimated to require substantial near-term resources, offset by future cost-savings from averted TB burden. From a health system perspective, vaccination was cost-effective in 65 of 105 LMICs. From a societal perspective (including productivity gains and averted patient costs), vaccination was projected to be cost-effective in 75 of 105 LMICs and cost-saving in 57 of 105 LMICs, including 96% of countries with higher TB burden. When considering the monetized value of health gains, we estimated that introduction of an adolescent/adult vaccine could produce $258-447 billion in economic benefits by 2050.
InterpretationTB vaccination would be highly impactful and cost-effective in most LMICs.
FundingWorld Health Organization (2020/985800-0)
Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPrevious studies have highlighted the economic impact of tuberculosis disease and mortality, and the potential economic impact that novel tuberculosis vaccines could have on reducing this burden in specific low- and middle-income countries (LMICs). The cost and cost-effectiveness of novel tuberculosis vaccines will depend on vaccine price and delivery strategy, which may vary by country. No modelling studies have estimated cost and cost-effectiveness with country-specific assumptions for medical and non-medical costs, indirect costs, vaccine delivery costs, and delivery strategies across a wide range of LMICs.
Added value of this studyWe estimated the costs, cost-effectiveness, and incremental net monetary benefit of tuberculosis vaccine introduction from both the health system and societal perspective in order to inform global-level decision-making for novel tuberculosis vaccine investment and introduction. Using mathematical and economic models, we assessed scenarios for the introduction of novel vaccines with a wide range of characteristics and a diverse set of health and economic outcomes. We assumed country-specific introduction years from 2028-2047, determined based on indicators for disease burden, immunization capacity, classification of the country as an "early adopter/leader," lack of regulatory barriers, and commercial prioritization. We varied vaccination coverage, vaccine delivery strategy, vaccine price, duration of protection, and future trends in tuberculosis incidence in scenario analysis.
Our analysis projected that an effective new tuberculosis vaccine could offer large potential health and economic benefits over 2028-2050. From a societal perspective, vaccination was projected to be cost-effective in 75 LMICs compared to a 1x per-capita gross domestic product threshold. When considering the monetized value of health gains, we estimated that introduction of an adolescent/adult vaccine could produce $258-447 billion in economic benefits by 2050, with greater benefits in LMICs with elevated tuberculosis incidence.
Implications of all the available evidenceIntroduction of a new tuberculosis vaccine was found to be impactful and cost-effective for a range of assumptions on vaccine price and delivery strategies, with aggregate health and economic benefits of similar scale to the most influential health interventions in LMIC settings in recent years. The results of these analyses can be used by global and country stakeholders to inform vaccine policy and introduction preparedness, as well as decision-making around future development, adoption, and implementation of novel tuberculosis vaccines. | public and global health |
10.1101/2022.05.03.22274629 | Childhood Stunting and Its Associated Factors in Ethiopia | Child malnutrition is the root cause of nearly half (45%) of all child deaths, especially in low-income nations. Ethiopia has the highest frequency of stunting among Sub-Saharan African countries, at 38 percent. The studys major goal was to use cluster specific models to identify risk factors for stunting in Ethiopian children under the age of five. The data was gathered from the EDHS 2016, a nationally representative survey of children aged 0 to 59 months. The research was carried out using generalized linear mixed models from the cluster specific model family. The variables childs age, mothers education level, mothers BMI, place of residence, wealth index, and prior birth interval were determined to be important drivers of child malnutrition in Ethiopia as a result of the analysis. According to the findings, children with a shorter previous birth interval (less than 24 months) were more likely to be stunted than those with a longer previous birth interval. Rural Ethiopian children were more likely than urban Ethiopian children to be stunted. It is advised that in order to reduce childhood malnutrition, parents awareness and implementation of proper young child feeding practices, as well as frequent growth monitoring and appropriate and timely interventions, should be prioritized. | public and global health |
10.1101/2022.05.04.22274659 | What innovations can address inequalities experienced by women and girls due to the COVID-19 pandemic across the different areas of life/domains: work, health, living standards, personal security, participation and education? Rapid Review | TOPLINE SUMMARYO_ST_ABSWhat is a Rapid Review?C_ST_ABSOur rapid reviews use a variation of the systematic review approach, abbreviating or omitting some components to generate the evidence to inform stakeholders promptly whilst maintaining attention to bias. They follow the methodological recommendations and minimum standards for conducting and reporting rapid reviews, including a structured protocol, systematic search, screening, data extraction, critical appraisal and evidence synthesis to answer a specific question and identify key research gaps. They take one to two months, depending on the breadth and complexity of the research topic/question(s), the extent of the evidence base and type of analysis required for synthesis.
Background / Aim of Rapid ReviewThe COVID-19 pandemic has led to differential economic, health and social impacts illuminating prevailing gender inequalities (WEN Wales, 2020). This rapid review investigated evidence for effectiveness of interventions to address gender inequalities across the domains of work, health, living standards, personal security, participation, and education.
Key FindingsO_ST_ABSExtent of the evidence baseC_ST_ABSO_LI21 studies were identified: 7 reviews, 6 commentaries and 8 primary studies
C_LIO_LILimited evidence for the effectiveness of identified innovations in minority groups
C_LIO_LIA lack of evaluation data for educational interventions
C_LIO_LIA lack of evidence for cost-effectiveness of the identified interventions
C_LIO_LI14 additional articles were identified in the grey literature but not used to inform findings (apart from the Education domain, where there was a lack of peer-reviewed evidence).
C_LI
Recency of the evidence baseO_LIAll studies were published in 2020-2021
C_LI
Summary of findingsSome evidence supported interventions/innovations related to work: O_LIPermanent contracts, full-time hours, and national childcare programmes to increase income for women and thereby decrease the existing gender wage gap.
C_LIO_LIMore frequent use of online platforms in the presentation of professional work can reduce gender disparities due to time saved in travel away from home.
C_LI Some evidence supported interventions/innovations related to health: O_LILeadership in digital health companies could benefit from women developing gender-friendly technology that meets the health needs of women.
C_LIO_LICreate authentic partnerships with black women and female-led organisations to reduce maternal morbidity and mortality (Bray & McLemore, 2021).
C_LI Some evidence supported interventions/innovations related to living standards including: O_LIMulti-dimensional care provided to women and their children experiencing homelessness.
C_LI Limited evidence supported interventions/innovations related to personal security including: O_LISpecific training of social workers, psychologists and therapists to empower women to use coping strategies and utilise services to gain protection from abusive partners.
C_LIO_LIHelplines, virtual safe spaces smart phone applications and online counselling to address issues of violence and abuse for women and girls.
C_LI Very limited evidence supported interventions/innovations related to participation including: O_LIUse of online platforms to reduce gender disparities in the presentation of academic/professional work.
C_LIO_LIEnsuring equal representation, including women and marginalised persons, in pandemic response and recovery planning and decision-making.
C_LI Limited evidence from the grey literature described interventions/innovations related to education including: O_LITeacher training curricula development to empower teachers to understand and challenge gender stereotypes in learning environments.
C_LIO_LIEducation for girls to enable participation in STEM.
C_LI
Policy ImplicationsThis evidence can be used to map against existing policies to identify which are supported by the evidence, which are not in current policy and could be implemented and where further research/evaluation is needed.
Further research is needed to evaluate the effectiveness of educational innovations, the effectiveness of the innovations in minority groups and the social value gained from interventions to address gender inequalities.
Strength of EvidenceOne systematic review on mobile interventions targeting common mental disorders among pregnant and postpartum women was rated as high quality (Saad et al., 2021). The overall confidence in the strength of evidence was rated as low due to study designs. Searches did not include COVID specific resources or pre-prints. There may be additional interventions/innovations that have been implemented to reduce inequalities experienced by women and girls due to the COVID-19 pandemic but have not been evaluated or published in the literature and are therefore not included here. | public and global health |
10.1101/2022.05.02.22274589 | WHO TARGETS FOR CERVICAL CANCER CONTROL BY 2030: A BASELINE ASSESSMENT IN SIX AFRICAN COUNTRIES | AimWe present and analyze the findings of a survey of the readiness of the healthcare systems in Eswatini, Guinea, Malawi, Rwanda, Uganda and Zambia, to implement the necessary measures for attaining the targets for cervical cancer control, set by WHO, by the year 2030.
MethodsA questionnaire with 129 questions with preset answer options was completed in 2020, by ministries of health program coordinators for non-communicable diseases, cancer control and/or reproductive health, and by WHO country offices, in the six countries selected.
ResultsThe findings on demographics, burden of disease, governance and management, laboratory services, equipment, supplies and medicines, as well as on personnel and training will be presented here.
The burden of cervical cancer in the countries studied is considerable, based on the IARC estimations. The incidence of the disease is augmented by the high prevalence of HIV infection, in most of the countries surveyed. Most of the population live in rural areas, where access to the health services is far from ideal. Facilities for screening with HPV tests and for histopathology are limited. One pathologist covers the diagnostic needs of between 0.5 million and 4 million inhabitants. Most other categories of health professionals are under-represented, and the capacity to train them is inadequate.
ConclusionsStrong country commitment and leadership, innovative solutions and extensive international cooperation would be needed to attain the targets of cervical cancer control set by WHO, in these countries. | public and global health |
10.1101/2022.05.02.22274588 | A Framework for Advancing Sustainable MRI Access in Africa | MRI technology has profoundly transformed current healthcare and research systems globally. The rapidly growing burden of non-communicable diseases in Africa has underscored the importance of improving access to MRI equipment as well as training and research opportunities on the continent. The Consortium for Advancement of MRI Education & Research in Africa (CAMERA) is a network of African experts, global partners, and ISMRM/ESMRMB members implementing novel strategies to advance MRI access and research in Africa. To identify challenges to MRI usage and provide a framework for addressing MRI needs in the region, CAMERA conducted a Needs Assessment Survey (NAS) and a series of symposia at international MRI society meetings over a 2-year period. The 68-question NAS was distributed to MRI users in Africa and completed by 157 clinicians and scientists from across Sub-Saharan Africa (SSA). On average, the number of MRI scanners per million people remained at <1, of which, 39% were obsolete low-field systems yet still in use to meet clinical needs. The feasibility of coupling stable energy supplies from various sources has contributed to the growing number of higher-field (1.5T) MRI scanners in the region. However, these systems are underutilized with only 8% of facilities reporting clinical scans of 15 or more patients daily per scanner. The most frequently reported MRI scans were neurological and musculoskeletal. Our NAS combined with the World Health Organization and International Atomic Energy Agency data provides the most up-to-date data on MRI density in Africa and offers unique insight into Africas MRI needs. Reported gaps in training, maintenance, and research capacity indicate ongoing challenges in providing sustainable high-value MRI access in SSA. Findings from the NAS and focused discussions at ISMRM and ESMRMB provided the basis for the framework presented here for advancing MRI capacity in SSA.
Graphical Abstract
O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=62 SRC="FIGDIR/small/22274588v1_ufig1.gif" ALT="Figure 1">
View larger version (15K):
[email protected]@ec4fdorg.highwire.dtl.DTLVardef@1a6c74eorg.highwire.dtl.DTLVardef@66d5ce_HPS_FORMAT_FIGEXP M_FIG C_FIG Africa has a massive population with few infrastructural resources and an untapped potential to effect transformative change in healthcare. To advance MRI access across all African countries and meet the sustainable development goals of improving health and wellbeing in low-resource settings over the next decade, the MRI community is called to partner with CAMERA to create enabling clinical and research MRI environments that will utilize the rich intellectual resources in Africa to realize lasting and equitable MRI for all Africans and the world at large. | radiology and imaging |
10.1101/2022.05.02.22274456 | Change in stroke presentations during COVID-19 pandemic in South-Western Sydney. | BackgroundAustralia managed relatively well during the global COVID-19 pandemic owing to our swift mandated public health response. During the NSW lockdown restrictions, we noted a decrease in acute stroke presentations at our institution, similar to what was subsequently reported worldwide.
AimsWe aimed to test our hypothesis that (i) the true numbers of ischaemic strokes did not change, however patients were presenting later and (ii) the proportion of TIAs decreased.
MethodsWe conducted a retrospective audit of all stroke and TIA presentations in 2020 and compared these with data from 2019. We collected information about stroke subtype, severity, time from stroke/TIA onset to presentation and acute reperfusion therapies.
ResultsBetween January-February and April-March 2020, there was a 15% drop in acute stroke presentations (128 vs. 109). In the same period "stroke mimic" presentations dropped by 22%. The proportion of patients attending the emergency department within 4.5hrs was only 36% compared with 48% over the similar period in 2019.
ConclusionsAlthough the raw numbers of ischemic stroke presentations remained stable during NSW Covid lockdown, the proportion of patients presenting within time window for acute reperfusion therapies fell. The number of TIAs similarly fell suggesting COVID-19 discouraged patients from presenting to hospital which placed them at higher risk of disabling stroke. The opportunity cost of lockdown restrictions on stroke outcome should be considered in future policy directives. | neurology |
10.1101/2022.05.04.22274088 | Presence of Major Depressive Disorder influences both neuropsychiatric symptoms and the cognitive profile in Mild Cognitive impairment and Alzheimers disease | ObjectivesThe impact of depression, as quantified with specific tests, and neuropsychiatric symptoms (NPS) on mnesic and executive performance has been documented previously. However, the depression can be also diagnosed as Major Depressive Disorder (MDD) based on the DSM-V. We aimed to determine how MDD influences NPS and cognitive performance in Alzheimers disease (AD), Mild Cognitive Impairment (MCI) and Healthy Controls (CH).
Participants647 HC, 291 patients with MCI and 208 patients with AD were extracted from the National Alzheimers Coordinating Center database.
MeasurementsDuring their inclusion in the cohort, each patient was assessed by a physician to distinguish those with a diagnosis of MDD from those without MDD. Patients were assessed with the NeuroPsychiatric Inventory and a comprehensive cognitive assessment. We performed logistic regression and a MANCOVA models respectively with NPS and cognitive performance as variables of interest and MDD as fixed factors within each group. The MANCOVA was controlled for the effects of age, sex, and education.
ResultsOur results exhibited that: MDD was associated with and predicted psychotic, affective and behavioral NPS in MCI, and affective/behavioral NPS in CH and AD; MCI with MDD had lower performance of selective attention and mental flexibility whereas AD with MDD had better working memory performance, than those without MDD.
ConclusionsMDD was mainly associated with higher prevalence of NPS in CH and both level of cognitive decline. This suggest that early treatment of MDD could reduce essentially neuropsychiatric symptomatology and caregiver mental burden. | neurology |
10.1101/2022.05.03.22273437 | Effect of a 12-mo milk-based micronutrient-fortified drink intervention on children: a systemic analysis of placebo-controlled study dataset | BackgroundNutritional deficiencies have many immediate and long-term effects on physical and cognitive development outcomes, with the children not achieving their full potential. A milk-based health drink fortified with micronutrients as a part of a daily balanced diet can promote physical and cognitive growth in children by increasing macronutrients and micronutrients availability in the body. The systematic analysis aims to quantify the effect of a formulated health drink on childrens physical, clinical, and cognitive development outcomes.
MethodsThe dataset used in the analysis was obtained from literature and consisted of 900 children between 7 to 12 years of age. These children were distributed equally into the Control group (no micronutrient-fortified health drink is given), Group I (micronutrient-fortified health drink in water), and Group II (micronutrient-fortified health drink in the toned milk).
ResultsThe analysis shows that micronutrient-fortified health drinks in water (by 2.1-fold) and toned milk (by 2.5-fold) improve the height gain velocities and anthropometric and body composition parameters. It helped children achieve healthy IAP growth percentiles compared to the control group. The analysis also shows a 1.6- and 2-fold change in the cognitive tests grades in groups I & II, respectively, compared to the control group.
ConclusionsThe analysis indicates that two servings of 33g micronutrient-fortified health drink in water and toned milk for a year significantly improved the gain velocities of anthropometric and body composition parameters, reduced time taken to complete the physical activity task, reduced the number of anaemia and morbidity cases among groups, and improved the scoring grades in cognitive assessment test in studied children population. The IAP data benchmarking clearly indicated that a micronutrient fortified milk-protein-based powder significantly improved childrens overall growth with better health. | nutrition |
10.1101/2022.05.04.22274624 | Genetic effects on the timing of parturition and links to fetal birth weight | The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of the timing of parturition, identifying 22 loci associated with gestational duration (n = 195,555) and 6 with preterm delivery (cases = 18,797, controls = 260,246). We observed modest differences in the genetic effects between gestational duration and preterm delivery, with most loci shared between the two. Analysis of the transmitted and non-transmitted parental alleles (n = 136,833) shows that 15 of the identified variants act through the maternal genome, while nine have fetal or both maternal and fetal effects. We observe a sex-specific genetic link between testosterone (negative) and sex hormone-binding globulin (positive) on the timing of parturition, likely due to pleiotropic effects. Finally, we provide evidence of maternal-fetal antagonistic effects on gestational duration and birth weight: maternal alleles that increase gestational duration have negative effects on birth weight when present in the fetus. | genetic and genomic medicine |
10.1101/2022.05.04.22274624 | Genetic effects on the timing of parturition and links to fetal birth weight | The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of the timing of parturition, identifying 22 loci associated with gestational duration (n = 195,555) and 6 with preterm delivery (cases = 18,797, controls = 260,246). We observed modest differences in the genetic effects between gestational duration and preterm delivery, with most loci shared between the two. Analysis of the transmitted and non-transmitted parental alleles (n = 136,833) shows that 15 of the identified variants act through the maternal genome, while nine have fetal or both maternal and fetal effects. We observe a sex-specific genetic link between testosterone (negative) and sex hormone-binding globulin (positive) on the timing of parturition, likely due to pleiotropic effects. Finally, we provide evidence of maternal-fetal antagonistic effects on gestational duration and birth weight: maternal alleles that increase gestational duration have negative effects on birth weight when present in the fetus. | genetic and genomic medicine |
10.1101/2022.05.04.22274657 | Have infection control and prevention measures resulted in any adverse outcomes for care home and domiciliary care residents and staff? | TOPLINE SUMMARYO_ST_ABSWhat is a Rapid Review?C_ST_ABSOur rapid reviews use a variation of the systematic review approach, abbreviating or omitting some components to generate the evidence to inform stakeholders promptly whilst maintaining attention to bias. They follow the methodological recommendations and minimum standards for conducting and reporting rapid reviews, including a structured protocol, systematic search, screening, data extraction, critical appraisal and evidence synthesis to answer a specific question and identify key research gaps. They take 1-2 months, depending on the breadth and complexity of the research topic/question(s), the extent of the evidence base and type of analysis required for synthesis.
Background / Aim of Rapid ReviewCare for older and vulnerable people must sustain core infection prevention and control (IPC) practices and remain vigilant for COVID-19 transmission to prevent virus spread and protect residents and healthcare professionals from severe infections, hospitalisations and death.
However, these measures could potentially lead to adverse outcomes such as decreased mental wellbeing in patients and staff. A recent publication by Public Health England examines the effectiveness of IPC practices for reducing COVID-19 transmission in care homes (Duval et al., 2021). We explore evidence relating to adverse outcomes from IPC practices to help inform policy recommendations and identify gaps within the literature where further research can be prioritised.
Key FindingsO_ST_ABSExtent of the evidence baseC_ST_ABSO_LI15 studies were identified: 14 primary studies and one rapid review
C_LI
Recency of the evidence baseO_LIOf the primary studies, six were published in 2020 and eight were published in 2021
C_LIO_LIThe rapid review was published in 2021.
C_LI
Summary of findingsThis rapid review focuses on adverse outcomes resulting from increased IPC measures put in place during the COVID-19 pandemic. Whilst there is some evidence to show that there may be a link between IPC measures and adverse outcomes, causation cannot be assumed.
O_LIDuring the COVID-19 restrictions, the cognition, mental wellbeing and behaviour of residents in care homes were negatively affected
C_LIO_LIIncreased IPC procedures during the COVID-19 pandemic increased stress and burden among care staff because of increased workload and dilemmas between adhering well to IPC procedures and providing the best care for the care recipients
C_LIO_LICOVID-19 IPC procedures were not well developed at the beginning of the COVID-19 pandemic, but evidence from 2021 suggests that good adherence to IPC measures can enable visitations by family members and medical professionals into care homes
C_LIO_LIOnly one study investigating domiciliary care was found. Therefore, it is difficult to make conclusions related specifically to this care setting
C_LIO_LINo published studies have reported on the costs or cost-effectiveness of IPC measures or have explored the cost implications of adverse outcomes associated with IPC measures
C_LI
Best quality evidenceOnly one study was deemed as high quality based on the quality appraisal checklist ranking. This was a mixed methods study design (Tulloch et al., 2021).
Policy ImplicationsSince March 2020, there have been many changes to government guidelines relating to procedures to keep the population safe from COVID-19 harm. Policies vary according to country, even within the UK. Important issues such as care home visitation policies have changed in such a way that care home staff have felt it difficult to keep up with the changes, which in itself increased the burden on those staff. The following implications were identified from this work:
O_LIIPC policies should be clear, concise and tailored to care homes and domiciliary care settings
C_LIO_LIIncreased attention to workforce planning is needed to ensure adequate staffing and to reduce individual burden
C_LIO_LIRestrictions (e.g. visitation) for care home residents needs to be balanced by additional psychological support
C_LIO_LIFurther research with robust methods in this area is urgently needed especially in the domiciliary care setting
C_LI
Strength of EvidenceOne limitation is the lack of high-quality evidence from the included studies. Confidence in the strength of evidence about adverse outcomes of COVID-19 IPC procedures was rated as low overall. Whilst the majority of studies achieved a moderate score based on the quality appraisal tools used, due to the nature of the methods used, the overall quality of evidence is low. | health systems and quality improvement |
10.1101/2022.05.03.22274592 | Durability of the immune response to a third BNT162b2 dose; five months follow-up | BackgroundTwo doses of the BNT162b2 vaccine yielded high effectiveness that wanes within several months. The third dose was effective in mounting a significant humoral and cellular immune response..
MethodsWe followed BNT162b2-vaccinated health-care workers monthly for IgG and neutralizing antibody (NeutAb) titers. Avidity, T-cell activation and microneutralization of sera against different variants of concern (VOC) were assessed for a sub-cohort. Linear mixed models were used to compare the durability of the second and third doses, and to assess if Omicron breakthrough infections were associated with waning dynamics.
ResultsOverall 3972 participants with a third dose were followed, the rate of waning of IgG and NeutAb was slower after the third (1.32%/day and 1.32%/day, respectively) compared to the second (2.26%/per day and 3.34%/day) dose. Live-neutralization of Omicron VOC was lower compared to previous strains and demonstrated similar waning from 111 (95%CI:75-166) to 26 (95%CI:16-42) within 4 months. Mean T cell activity decreased from 98{+/-}5.4 T cells/106 PBMC to 59{+/-}9.3, within 3-5 months. Omicron breakthrough infections were associated with lower IgG peak (ratio of means 0.86 95%CI 0.80-0.91), and among participants over 65y with faster waning of both IgG and NeutAb (ratio of mean rates 1.40 95% CI 1.13-1.68 and 3.58 95% CI 1.92-6.67). No waining in IgG avidity was obsereved during 112 days after the 3rd dose.
ConclusionThe third dose is more durable than the second dose, yet Omicron is relatively resistant to direct neutralization. The level of humoral response may predict breakthrough infections. | infectious diseases |
10.1101/2022.05.04.22274668 | Antibody responses to AZD1222 vaccination in West Africa | BackgroundThere are no real world data on vaccine elicited neutralising antibody responses for the worlds most widely used vaccine, AZD1222, in African populations following scale up. Here, we measured i) baseline SARS-CoV-2 seroprevalence and levels of protective neutralizing antibodies prior to vaccination rollout using both flow cytometric based analysis of binding antibodies to nucleocapsid (N), coupled with virus neutralisation approaches and ii) neutralizing antibody responses to VOC prior to vaccination (January 2021) and after two-doses of AZD1222 vaccine administered between June and July 2021 in Lagos, Nigeria - a period when the Delta variant was circulating.
MethodsHealth workers at multiple sites in Lagos were recruited to the study. For binding antibody measurement, IgG antibodies against SARS-COV-2 Wuhan-1 receptor-binding domain (RBD), trimeric spike protein (S), nucleocapsid protein (N) and Omicron S1 were measured using the Luminex-based SARS-CoV-2-IgG assay by flow cytometry. For plasma neutralising antibody measurement, SARS-CoV-2 lentiviral pseudovirus (PV) were prepared by transfecting 293T cells with Wuhan-614G wild type (WT), B.1.617.2 (Delta) and BA.1 (Omicron) plasmids in conjunction with HIV-1 expression vectors and luciferase encoding genome flanked by LTRs. We performed serial plasma dilutions from each time point and mixed plasma with PV before infecting HeLa-ACE2 cell lines, reading out luminescence and calculating ID50 (reciprocal dilution of sera required to inhibit 50% of PV infection).
ResultsOur study population receiving at least one dose of vaccine comprised 140 participants with a median age of 40 (interquartile range: 33, 48). 62/140 (44%) participants were anti-N IgG positive prior to administration of first vaccine dose. 49 had plasma samples available at baseline prior to vaccination and at two follow-up timepoints post vaccination for neutralization assays. Half of the participants, 25/49 (51%) were IgG anti-N positive at baseline. Of the 24 individuals anti-N Ab negative at baseline, 12/24 had ID50 above the cut-off of 20. In these individuals, binding antibodies to S were also detectable, and neutralisation correlated with IgG anti-S, suggesting waning of N antibody after infection. Overall, neutralizing Ab titres to WT 1 month after second dose were 2579 and at 3 months post second-dose were 1695. As expected, lower levels of neutralization were observed against the Delta GMT 549 and Omicron variants 269 at 1 month. Positive anti-N IgG Ab status at baseline was associated with significantly higher titres of neutralizing antibodies following vaccination across all tested VOC. Those with anti-N Abs present at baseline did not experience waning of responses between months 1 and 3 post second dose. When data were analysed for negative anti-N IgG status at any timepoint, there was a significant decline in neutralization and binding antibodies between 1 month and 3 months post second-dose. The GMT in these individuals for Delta and Omicron was approximately 100, nearly a log lower in comparison to WT. We tested anti-N IgG in subjects who were anti-N IgG negative at baseline (n=78) and became positive between 1- and 3-months post second dose and found 7/49 (14%) with de-novo infection, with one additional participant demonstrating both reinfection and breakthrough infection to yield a total breakthrough rate of 8/49 (16%). Neutralising and binding Ab titres 1 month post vaccine, prior to breakthrough, were not associated with breakthrough infection. Neutralizing titres were higher at the last time point in individuals who had experienced vaccine breakthrough infection (with no evidence of infection prior to vaccine), indicating a boosting effect of infection in addition to vaccine. The increase in titres against Delta PV observed in breakthrough was significantly greater than the increase for WT and Omicron PVs, coincident with in the Delta wave of infection during the sampling period.
ConclusionsAZD1222 is immunogenic in this real world west African cohort with significant background seroprevalence and incidence of breakthrough infection over a short time period. Prior infection and breakthrough infection induced higher anti-SARS-CoV-2 Ab responses at 3 months post vaccine against all widely circulating VOC. However, responses to Omicron BA.1 were low at three months regardless of prior exposure or breakthrough infection. Booster doses after AZD1222 should be considered for those at high risk in the African setting, even after natural infection, as future variants may be more pathogenic as well as immune evasive in the context of waning immunity. | infectious diseases |
10.1101/2022.05.03.22274622 | SARS-CoV-2 neutralizing antibodies in Chile after a vaccination campaign with five different schemes | Using levels of neutralizing antibodies (nAbs), we evaluate the successful Chilean SARS-CoV-2 vaccine campaign, which combines technologies and heterologous boosters. In 120 randomly selected seropositive individuals from a population-based study, we conclude that the booster dose, regardless of vaccine technology or natural infection, and mRNA vaccines significantly improve nAbs response. | infectious diseases |
10.1101/2022.05.03.22274395 | Development and evaluation of low-volume tests to detect and characterise antibodies to SARS-CoV-2 | Low-volume antibody assays can be used to track SARS-CoV-2 infection rates in settings where active testing for virus is limited and remote sampling is optimal. We developed 12 ELISAs detecting total or antibody isotypes to SARS-CoV-2 nucleocapsid, spike protein or its receptor binding domain (RBD), 3 anti-RBD isotype specific luciferase immunoprecipitation system (LIPS) assays and a novel Spike-RBD bridging LIPS total-antibody assay. We utilised pre-pandemic (n=984) and confirmed/suspected recent COVID-19 sera taken pre-vaccination rollout in 2020 (n=269). Assays measuring total antibody discriminated best between pre-pandemic and COVID-19 sera and were selected for diagnostic evaluation. In the blind evaluation, two of these assays (Spike Pan ELISA and Spike-RBD Bridging LIPS assay) demonstrated >97% specificity and >92% sensitivity for samples from COVID- 19 patients taken >21 days post symptom onset or PCR test. These assays offered better sensitivity for the detection of COVID-19 cases than a commercial assay which requires 100-fold larger serum volumes. This study demonstrates that low-volume in- house antibody assays can provide good diagnostic performance, and highlights the importance of using well-characterised samples and controls for all stages of assay development and evaluation. These cost-effective assays may be particularly useful for seroprevalence studies in low and middle-income countries. | infectious diseases |
10.1101/2022.05.03.22274000 | IDENTIFICATION OF GENOTYPE III OF HEPATITIS DELTA VIRUS IN ANDEAN AND AMAZONIAN COMMUNITIES OF PERU | Objectivesto identify the genotypes of Hepatitis Delta Virus (HDV) circulating in populations of the inter-Andean valley of Huanta and three indigenous peoples of the Peruvian Amazon.
Materials and MethodsObservational and cross-sectional study, from 582 reactive samples for anti-HBc-HBV antibodies in inhabitants of the andean province of Huanta (Ayacucho) and the Amazonian towns of Matses, Kandozi and Chapra (Loreto). Analysis was performed for HDV infection markers: anti-HDV IgM and anti-HDV IgG by ELISA using Wantai brand kits. Anti-HDV positive samples by ELISA were processed with the nRT-PCR method for the detection of HDV RNA. HDV genotype was determined by direct Sanger-type sequencing and phylogenetic analysis of the R0 fragment. 111 reference sequences from GenBank were used. The 42 sequences of the study were edited, assembled and cut with the programs Chromas 2.6.5, Bioedit v7.2, ClustalW v.1.6 of Mega v.7.0 and the Gblocks server. Phylogenetic and evolutionary analysis was performed with the following software: Beast V2.5.2, Jmodeltest v2.1.10, Tracer v1.7.1, Tree Annotator and Figtree v1.4.4. The Bayesian Yule and Birth Death skyline serial models were used, the MCMC at 30 and 80 million respectively, with the relaxed uncorrelated Exponential molecular clock. Summary and central tendency measures were calculated using the program in STATA 14.0.
ResultsThe mean age was 38 years (0 to 86 years), 52.75% (N=307) were women. 582 blood samples positive for anti-HBc were analyzed for anti-HVD antibodies using the ELISA method, with 101 positive samples being found. HDV RNA was detected in 49.50% of the anti-HDV ELISA reactive samples. Phylogenetic analysis determined the presence of genotype 3.
ConclusionsThe presence of HDV genotype 3 in Andean and Amazonian communities of Peru is evidenced. | infectious diseases |
10.1101/2022.05.05.22274716 | Statin intolerance - Prevalence and practical management in a specialized lipid clinic | AimsStatins are recommended as first-line treatment to prevent cardiovascular disease, but high rates of adverse events and subsequent discontinuation can prevent effective treatment in some patients. We aimed to describe the intensity, nature and frequency of adverse effects caused by statins and other lipid-lowering drugs, and to assess their association with clinical predictors and treatment strategies.
MethodsThis is a retrospective study of 121 consecutive unselected patients followed at a specialized lipid referral clinic in Lausanne University Hospital, Switzerland, in 2018 whose clinical data spanned 2016 until 2019.
ResultsAdverse effects were reported by 58% of patients, causing musculoskeletal (72%), neurologic (40%), gastrointestinal (25%) and other (25%) symptoms. Gastrointestinal symptoms affected 35% of women, but only 12% of men (p=0.06). Statins caused more adverse effects than other drugs, with atorvastatin (63%) and simvastatin (64%) achieving the lowest rates, pravastatin (87%) and fluvastatin (100%) the highest. Fenofibrate was associated with significantly less frequent adverse effects than statins (22% vs. 57%, p=0.006). Adaptation and termination of the treatment led to 86% and 88% lower intensity of symptoms, respectively.
ConclusionWhile the predominance of musculoskeletal symptoms caused by lipid-lowering drugs is known, symptoms affecting other organ systems should not be ignored. Statins were the lipid-lowering drug class with the highest rates of adverse effects. To maintain compliance and cardiovascular prevention, treatment strategies such as a change of dosage, frequency of administration, daily timing, or switching active substance can contribute to better tolerance of statin treatment. Further investigation is needed to establish specific treatment strategies for individual patient profiles. | cardiovascular medicine |
10.1101/2022.05.03.22274594 | Optimal thromboprophylaxis strategies in non-critically ill patients with COVID-19 pneumonia. The PROTHROMCOVID Randomized Controlled Trial. | BackgroundHospitalized patients with COVID-19 are at increased risk for thrombosis, acute respiratory distress syndrome and death. The optimal dosage of thromboprophylaxis is unknown.
ObjectiveTo evaluate the efficacy and safety of tinzaparin in prophylactic, intermediate, and therapeutic doses in non-critical patients admitted for COVID-19 pneumonia.
Design, setting, and participantsRandomized controlled, multicenter trial (PROTHROMCOVID) enrolling non-critical, hospitalized adult patients with COVID-19 pneumonia.
InterventionsPatients were randomized to prophylactic (4500 IU), intermediate (100 IU/kg), or therapeutic (175 IU/kg) doses of tinzaparin during hospitalization, followed by 7 days of prophylactic tinzaparin at discharge.
MeasurementsThe primary efficacy outcome was a composite endpoint of symptomatic systemic thrombotic events, need for invasive or non-invasive mechanical ventilation, or death within 30 days. The main safety outcome was major bleeding at 30 days.
ResultsOf the 311 subjects randomized, 300 were included in the analysis (mean [SD] age, 56.7 [14.6] years; males, 182 [60.7%]. The composite endpoint at 30 days from randomization occurred in 58 patients (19.3%) of the total population; 19 (17.1 %) in the prophylactic group, 20 (22.1%) in the intermediate group, and 19 (18.5%) in the therapeutic dose group (P= 0.72). No major bleeding event was reported; non-major bleeding was observed in 3.7% of patients, with no intergroup differences.
ConclusionsIn non-critically ill COVID-19 patients, intermediate or full-dose tinzaparin compared to standard prophylactic doses did not appear to increase benefit regarding the likelihood of thrombotic event, non-invasive ventilation or high-flow oxygen, or death.
Trial RegistrationClinicalTrials.gov Identifier (NCT04730856).
FundingThis independent research initiative was supported by Leo-Pharma; Tinzaparin was provided by Leo Pharma. | cardiovascular medicine |
10.1101/2022.05.05.22274498 | Cutaneous surgical wounds have distinct microbiomes from intact skin | BackgroundInfections are relatively rare following cutaneous surgical procedures, despite the potential for wound exposure to pathogens both during surgery and throughout the healing process. Although gut commensals are believed to reduce the risk of intestinal infections, an analogous role for skin commensals has not been described. In fact, the microbiome of normally healing surgical skin wounds has not yet been profiled using culture-independent techniques.
ResultsWe characterized the wound microbiome in 52 patients who underwent skin cancer surgery and healed without signs or symptoms of infection. A week after surgery, several bacterial species displayed significant differences in relative abundance when compared to control, non-operated skin from the same patient. The most common bacteria found on intact skin, Cutibacterium acnes, was depleted in wounds 5-fold. Surprisingly, Staphylococcus aureus, a frequent cause of postoperative skin infections, was enriched 6.4-fold in clinically non-infected wounds, suggesting active suppression of this pathogen. Finally, members of the Corynebacterium genus were the dominant organism is postoperative wounds, making up 37% of the average wound microbiome.
ConclusionsWe observed distinct bacterial communities in acute wounds a week after surgery and anatomically-matched normal skin from the same patient. Future studies focused on the biological and clinical significance of the wound microbiome may shed light on normal wound healing and potential therapeutic opportunities to mitigate infection risk. | dermatology |
10.1101/2022.05.03.22274632 | Assessment of Standard HIV Testing Services Delivery to Injured Persons Seeking Emergency Care in Nairobi, Kenya: A Prospective Observational Study | Emergency departments (EDs) in Africa are contact points for key groups for HIV testing services (HTS) but understanding of ED-testing delivery is limited which may impeded program impacts. This study evaluated the offering and uptake of standard HTS among injured persons seeking ED care at Kenyatta National Hospital (KNH) in Nairobi, Kenya.
An ED population of adult injured persons was prospectively enrolled (1 March - 25 May 2021) and followed through ED disposition. Participants requiring admission were followed through hospital discharge and willing participants were contacted at 28-days for follow up. Data on population characteristics and HTS were collected by personnel distinct from clinicians responsible for standard HTS. Descriptive analyses were performed and prevalence values with 95% confidence intervals (CI) were calculated for HIV parameters.
The study enrolled 646 participants. The median age was 29 years with the majority male (87.8%). Most ED patients were discharged (58.9%). A prior HIV diagnosis was reported by 2.3% of participants and 52.7% reported their last testing as >6 months prior. Standard ED-HTS were offered to 49 or 8.6% of participants (95% CI: 5.8-9.9%), among which 89.8% accepted. For ED-tested participants 11.4% were newly diagnosed with HIV (95% CI: 5.0-24.0%). Among 243 participants admitted, testing was offered to 6.2% (95% CI: 3.9-9.9%), with 93.8% accepting. For admitted participants tested 13.3% (95% CI: 4.0-35.1%) were newly diagnosed (all distinct from ED cases). At 28-day follow up an additional 22 participants reported completing testing since ED visitation, with three newly diagnosed. During the full follow-up period the HIV prevalence in the population tested was 10.3% (95% CI: 5.3-19.0%); all being previously undiagnosed.
Offering of standard HTS was infrequent, however, when offered, uptake and identification of new HIV diagnoses were high. These data suggest that opportunities exist to improve ED-HTS which could enhance identification of undiagnosed HIV. | emergency medicine |
10.1101/2022.05.04.22274692 | The spread and burden of the COVID-19 pandemic in sub-Saharan Africa: comparison between predictions and actual data and lessons learned. | IntroductionSub-Saharan Africa (SSA) was predicted to be severely affected by the coronavirus disease 2019 (COVID-19) pandemic, but the actual data seem to have contradicted these forecasts. This study attempted to verify this observation by comparing predictions against actual data on the spread and burden of the COVID-19 pandemic in SSA.
MethodsFocused on the period from March 1st to September 30th, 2020, we compared (1) the predicted interval dates when each SSA country would report 1 000 and 10 000 COVID-19 cases, to the actual dates when these numbers were attained, as well as (2) the daily number of predicted versus actual COVID-19 cases.
Further, we calculated the case fatality ratio of the COVID-19 infection in SSA, and the correlation coefficient between the weekly average number of confirmed COVID-19 cases reported by each country and the weekly average stringency index of its anti-COVID-19 policy measures.
Results84.61% (33) and 100% (39) of the 39 SSA countries for which predictions were made did not reach a total of 1 000 and 10 000 confirmed COVID-19 cases at the predicted interval dates. The daily number of confirmed COVID-19 cases was lower than the one projected for all SSA countries. The case fatality ratio of the COVID-19 infection in SSA was 3.42%. Among the 44 SSA countries for which the correlation could be estimated, it was negative for 17 (38.6 %) of them.
ConclusionsThe natural characteristics of SSA and the public health measures implemented might partly explain that the actual data were lower than the predictions on the COVID-19 pandemic in SSA, but the low case ascertainment and the numerous asymptomatic cases did significantly influence this observation. | epidemiology |
10.1101/2022.05.03.22274614 | Predicting Oncogene Mutations of Lung Cancer Using Deep Learning and Histopathologic Features on Whole-Slide Images | Lung cancer is a leading cause of death in both men and women globally. The recent development of tumor molecular profiling has opened opportunities for targeted therapies for lung adenocarcinoma (LUAD) patients. However, the lack of access to molecular profiling or cost and turnaround time associated with it could hinder oncologists willingness to order frequent molecular tests, limiting potential benefits from precision medicine. In this study, we developed a weakly supervised deep learning model for predicting somatic mutations of LUAD patients based on formalin-fixed paraffin-embedded (FFPE) whole-slide images (WSIs) using LUAD subtypes-related histological features and recent advances in computer vision. Our study was performed on a total of 747 hematoxylin and eosin (H&E) stained FFPE LUAD WSIs and the genetic mutation data of 232 patients who were treated at Dartmouth-Hitchcock Medical Center (DHMC). We developed our convolutional neural network-based models on 172 training cases and tested on 60 independent cases to analyze whole slides and predict five major genetic mutations, i.e., BRAF, EGFR, KRAS, STK11, and TP53. We additionally used 111 cases from the LUAD dataset of the CPTAC-3 study for external validation. Our model achieved an AUROC of 0.799 (95% CI: 0.686-0.904) and 0.686 (95% CI: 0.620-0.752) for predicting EGFR genetic mutations on the DHMC and CPTAC-3 test sets, respectively. Predicting TP53 genetic mutations also showed promising outcomes. Our results demonstrated that H&E stained FFPE LUAD whole slides could be utilized to predict oncogene mutations, such as EGFR, indicating that somatic mutations could present subtle morphological characteristics in histology slides, where deep learning-based feature extractors can learn such latent information. | pathology |
10.1101/2022.05.04.22274647 | Protection against omicron severe disease 0-7 months after BNT162b2 booster | Following a rise in cases due to the delta variant and evidence of waning immunity after 2 doses of the BNT162b2 vaccine, Israel began administering a third BNT162b2 dose (booster) in July 2021. Recent studies showed that the 3rd dose provides a much lower protection against infection with the omicron variant compared to the delta variant and that this protection wanes quickly. In this study, we used data from Israel to estimate the protection of the 3rd dose against severe disease up to 7 months from receiving the booster dose. The analysis shows that protection conferred by the 3rd dose against omicron did not wane over a 7-month period and that a 4th dose further increased protection, with a severe disease rate approximately 3-fold lower than in the 3-dose cohorts. | public and global health |
10.1101/2022.05.03.22274645 | Pregnant women's knowledge of obstetrical danger signs: A cross-sectional survey in Kigali, Rwanda | BACKGROUNDMaternal mortality remains critically high worldwide, particularly in sub-Saharan Africa. The leading causes of maternal death in Rwanda include postpartum hemorrhage and obstructed labor. Maternal recognition of obstetrical danger signs is critical for timely access to emergency care, in order to reduce maternal mortality.
OBJECTIVETo assess the knowledge of obstetrical danger signs among pregnant women attending antenatal care in Kigali, Rwanda.
METHODSA cross-sectional study was conducted between September and December 2018 at five health centers and one district hospital in Kigali, Rwanda. Pregnant women attending antenatal care (ANC) services completed a structured questionnaire. Data were analyzed using descriptive statistics.
RESULTSA total of 382 pregnant women were included in the study. The majority of women (67.8%) were aged 23-35 years, and 44.5% had completed secondary education. Almost half (43.2%) reported traveling more than 30 minutes to reach the health facility; only 23.3% were within 15 minutes of the health facility. Over half (57%) reported attending three or more ANC visits during pregnancy. The majority (85.6%) knew at least one obstetrical danger sign, with nearly half (46.1%) obtaining knowledge of danger signs from midwives and nurses.
CONCLUSIONKnowledgeability was significantly associated with the parity and number of ANC visits, though CHW was also a good source of information for pregnant women. We encourage a systematically designed curriculum to teach mothers during their follow-up visits for ANC. | sexual and reproductive health |
10.1101/2022.05.03.22274642 | Development and Validation of Audio-based Guided Imagery and Progressive Muscle Relaxation Tools for Functional Bloating | Mind-body techniques, including Guided Imagery (GI) or Progressive Muscle Relaxation (PMR), may effectively manage bloating. The current study aimed to develop and validate (psychometric and psychological responses) audio-based GI and PMR techniques for bloating. Audio scripts were first developed from literature reviews and in-depth interviews of participants with bloating diagnosed based on the Rome IV criteria. Scripts were validated using psychometric (content & face validity index) and physiological approaches (brain event-related potentials & heart rate variability). 45/63 participants completed the in-depth interview, and balloon emerged as the synonymous imagery description for bloating, of which inflation correlated with a painful sensation. The final tools consisted of narrated audio scripts in the background of a validated choice of music. Overall, content and face validity index for PMR and GI ranged from 0.92 - 1.00. For ERP and HRV, 17/20 participants were analysed. For ERP, there was significant difference between GI and PMR for alpha waves (p=0.029), delta waves (p=0.029) and between PMR and control for delta waves (p=0.014). For HRV, both GI and PMR exhibited similar autonomic responses over controls (overall p<0.05). The newly developed GI and PMR audio-based tools have been validated using psychometric and physiological approaches. | gastroenterology |
10.1101/2022.05.04.22274208 | Decreased cerebral blood flow in non-hospitalized adults who self-isolated due to COVID-19 | The long-term consequences of coronavirus disease 2019 (COVID-19) on brain physiology and function are not yet well understood. From the recently described NeuroCOVID-19 study, we examined cerebral blood flow (CBF) in 50 participants recruited to one of two groups: 1) adults who previously self-isolated at home due to COVID-19 (n = 39; 116.5 {+/-} 62.2 days since positive diagnosis), or 2) adults who experienced flu-like symptoms but had a negative COVID-19 diagnosis (n = 11). Participants underwent arterial spin labeling magnetic resonance imaging at 3 Tesla to yield measures of CBF. Voxel-wise analyses of CBF were performed to assess for between-group differences, after controlling for age and sex. Relative to controls, the COVID-19 group exhibited decreased CBF in the thalamus, orbitofrontal cortex, and regions of the basal ganglia. Within the COVID-19 group, CBF differences in occipital and parietal regions were observed between those with (n = 11) and without (n = 28) self-reported on-going fatigue. These results suggest long-term changes in brain physiology in adults across the post-COVID-19 timeframe. Moreover, CBF may aid in understanding the heterogeneous symptoms of the post-COVID-19 condition. Future longitudinal studies are needed to further characterize the consequences of COVID-19 on the brain. | neurology |
10.1101/2022.05.05.22274740 | Uganda Genome Resource: A rich research database for genomic studies of communicable and non-communicable diseases in Africa | The Uganda Genome Resource (UGR) is a well characterised genomic database, with a range of phenotypic communicable and non-communicable diseases and risk factors generated from the Uganda General Population Cohort (GPC) - a population-based open cohort study established in 1989 by the Medical Research Council (MRC) UK in collaboration with the Uganda Virus Research Institute (UVRI).
In 2011, UGR was launched with genotype data on [~]5000 and whole genome sequence data on [~]2000 Ugandan individuals from 9 ethno-linguistic groups. Leveraging other available platforms at the MRC Uganda such as Biorepository centre for sample storage, Clinical Diagnostic Laboratory Service (CDLS) for sample diagnostic testing, sequencing platform for DNA extraction, Uganda Medical informatics Unit (UMIC) for large-scale data analysis, GPC for additional sample collection, UGR is strategically poised to expand and generate scientific discoveries.
Here, we describe UGR and highlight the important genetic findings thus far including how UGR is providing opportunities to: (1) discover novel disease susceptibility genetic loci; (2) refine association signals at new and existing loci; (3) develop and test Polygenic Risk Score (PRS) to determine individuals disease risk; 4) assess how some risk factors including infectious diseases are causally related to non-communicable diseases (NCDs) in Africa; (5) develop research capacity for genomics in Africa; and (6) enhance African participation in the global genomics research arena. Leveraging established research infrastructure, expertise, local genomic leadership, global collaboration and strategic funding, we anticipate that UGR can develop further to a comparable level of European and Asian large-scale genomic initiatives. | genetic and genomic medicine |
10.1101/2022.05.06.22274705 | PCSK6 and Survival in Idiopathic Pulmonary Fibrosis | RationaleIdiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. Novel therapies and prognostic biomarkers are needed.
ObjectiveTo identify and validate molecular determinants of IPF survival.
MethodsA staged genome-wide association study (GWAS) was performed using paired genomic and survival data. Stage I cases were drawn from centers across the US and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplant-free survival (TFS). Stage I variants with nominal significance (p<5x10-5) were advanced for stage II testing and meta-analyzed to identify those reaching genome-wide significance (p<5x10-8). Downstream analyses were performed for genes and proteins associated with variants reaching genome-wide significance.
Main ResultsAfter quality controls, 1481 stage I cases and 397 stage II cases were included in the analysis. After filtering, 9,075,629 variants were tested in stage I, with 158 meeting advancement criteria. Four variants associated with TFS with consistent effect direction were identified in stage II, including one in an intron of proprotein convertase subtilisin/kexin type 6 (PCSK6) reaching genome-wide significance (HR 4.11; 95%CI 2.54-6.67; p=9.45x10-9). PCSK6 protein was highly expressed in IPF lung parenchyma and negatively correlated with survival. Peripheral blood PCSK6 gene expression and plasma concentration were associated with reduced transplant-free survival.
ConclusionsWe identified four novel variants associated with IPF survival, including one in PCSK6 that reached genome-wide significance. Downstream analyses suggested that PCSK6 protein may serve as prognostic biomarker in IPF and potential therapeutic target. | genetic and genomic medicine |
10.1101/2022.05.04.22274650 | Supporting the revision of the health benefits package in Uganda: a constrained optimisation approach | This study demonstrates how the linear constrained optimization approach can be used to design a health benefits package (HBP) which maximises the net disability adjusted life years (DALYs) averted given the health system constraints faced by a country, and how the approach can help assess the marginal value of relaxing health system constraints. In the analysis performed for Uganda, 58 interventions were included in the HBP in the base scenario, resulting in a total of 49.9 million net DALYs averted. When task shifting of pharmacists and nutrition officers tasks to nurses is allowed, 68 interventions were included in the HBP resulting in a total of 53.8 million net DALYs averted (a 7.8% increase). Further, investing only $39 towards hiring additional nutrition officers time could avert one net DALY; this increased to $55, $56, and $123 for nurses, pharmacists and doctors respectively, and $971 for expanding the consumable budget. | health economics |
10.1101/2022.05.06.22274658 | STIMULATE-ICP-CAREINEQUAL - Defining usual care and examining inequalities in Long Covid support: protocol for a mixed-methods study (part of STIMULATE-ICP: Symptoms, Trajectory, Inequalities and Management: Understanding Long-COVID to Address and Transform Existing Integrated Care Pathways). | IntroductionIndividuals with Long Covid represent a new and growing patient population. In England, fewer than 90 Long Covid clinics deliver assessment and treatment informed by NICE guidelines. However, a paucity of clinical trials or longitudinal cohort studies means that the epidemiology, clinical trajectory, healthcare utilisation and effectiveness of current Long Covid care are poorly documented, and that neither evidence-based treatments nor rehabilitation strategies exist. In addition, and in part due to pre-pandemic health inequalities, access to referral and care varies, and patient experience of the Long Covid care pathways can be poor.
In a mixed methods study, we therefore aim to: (1) describe the usual healthcare, outcomes and resource utilisation of individuals with Long Covid; (2) assess the extent of inequalities in access to Long Covid care, and specifically to understand Long Covid patients experiences of stigma and discrimination.
Methods and analysisA mixed methods study will address our aims. Qualitative data collection from patients and health professionals will be achieved through surveys, interviews and focus group discussions, to understand their experience and document the function of clinics. A patient cohort study will provide an understanding of outcomes and costs of care. Accessible data will be further analysed to understand the nature of Long Covid, and the care received.
Ethics and disseminationEthical approval was obtained from South Central - Berkshire Research Ethics Committee (reference 303958). The dissemination plan will be decided by the patient and public involvement and engagement (PPIE) group members and study Co-Is, but will target 1) policy makers, and those responsible for commissioning and delivering Long Covid services, 2) patients and the public, and 3) academics. | health systems and quality improvement |
10.1101/2022.05.04.22274662 | Asymptomatic carriage of Plasmodium falciparum in children living a hyperendemic area occurs independently of IgG responses but is associated with induction of IL-10 | BackgroundMalaria immuno-epidemiological data suggest that two key immunological processes, including anti-parasite and anti-disease immunity, may be implicated in the maintenance of asymptomatic infections. However, in highly exposed persons where the duration of chronic malaria infection could range from a few weeks to several years, the host immunological factors that determine the persistence of asymptomatic parasitemia remain poorly understood. This study therefore aimed to define the association between antibody or cytokine responses with asymptomatic malarial parasitemia amongst highly exposed individuals in Cameroon.
MethodsAn initial cross-sectional study was carried out (week 1) and individuals were classified as having asymptomatic Plasmodium parasitemia with no fever (AS), symptomatic Plasmodium parasitemia with an axillary temperature [≥]37.5{degrees}C (SY) and non-infected (NI) (no Plasmodium parasitemhia and a normal body temperature). Asymptomatic individuals were followed for 10 weeks before being treated with artemisinin-based combination treatment (ACT) and a final sample taken at week 16, 5 weeks after treatment. Those who continued to carry Plasmodium parasites with no measureable fever were defined as having chronic asymptomatic malaria. Antibody levels to P. falciparum schizont extract (SE), merozoite extract (ME), erythrocyte binding antigen-175 (EBA-175) and merozoite surface protein-1 (MSP-1) were quantified by ELISA. The growth inhibitory activities of circulating anti-parasite antibodies were quantified using the 3D7 laboratory strain of P. falciparum and a Sybr Green-I based parasite growth inhibition assay. Plasma levels of 38 cytokines were measured by Luminex technology.
ResultsAmongst infected individuals, parasitemia significantly decreased with increased age although this decrease in parasitemia with age was only observed until age 20. Individuals older than 20 years of age had low parasitemia and this remained constant between the ages of 20 and 80. Although there was no difference in the magnitude of the antibody response between AS, SY and NI groups to any of the antigens tested, median levels of antibody against P. falciparum crude extracts and recombinant proteins EBA-175 and MSP-1 were significantly higher in those older than 20 years of age compared with the younger age group as might be expected from lower parasite levels. Parasite densities and P. falciparum clones fluctuated widely over the 10-week follow-up period in individuals with persistent asymptomatic parasitemia but collectively there was no change in the antibody levels over time within this group. Similar to antibody levels, many levels of the cytokines measured were stable over time. However, IL-10 levels decreased after treatment indicating that this cytokine was associated with parasite carriage in asymptomatic individuals. The ratio of IL-10 to pro-inflammatory cytokines, tumor necrosis factor- (TNF-) and lymphotoxin- (LT-) ratios were higher in the symptomatic group compared to the asymptomatic individuals but only in the younger (<20 years old) age group.
ConclusionTaken together, the above findings indicate that asymptomatic carriage of Plasmodium falciparum in children living in a hyperendemic area occurs independently of antibody responses, but is associated with induction of IL-10. | infectious diseases |
10.1101/2022.05.05.22274610 | Repurposing EEG monitoring of general anaesthesia for building biomarkers of brain ageing: An exploratory study | BackgroundEEG is a common tool for monitoring anaesthetic depth but is rarely reused at large for biomedical research. This study sets out to explore repurposing of EEG during anaesthesia to learn biomarkers of brain ageing.
MethodsWe focused on brain age estimation as an example. Using machine learning, we reanalysed 4-electrodes EEG of 323 patients under propofol and sevoflurane. We included spatio-spectral features from stable anaesthesia for EEG-based age prediction applying recently published reference methods. Anaesthesia was considered stable when 95% of the total power was below a frequency between 8Hz and 13Hz.
ResultsWe considered moderate-risk patients (ASA <= 2) with propofol anaesthesia to explore predictive EEG signatures. Average alpha-band power (8-13Hz) was informative about age. Yet, state-of-the-art prediction performance was achieved by analysing the entire power spectrum from all electrodes (MAE = 8.2y, R2 = 0.65). Clinical exploration revealed that brain age was systematically linked with intra-operative burst suppression - commonly associated with age-related postoperative cognitive issues. Surprisingly, the brain age was negatively correlated with burst suppression in high-risk patients (ASA = 3), pointing at unknown confounding effects. Secondary analyses revealed that brain-age EEG signatures were specific to propofol anaesthesia, reflected by limited prediction performance under sevoflurane and poor cross-drug generalisation.
ConclusionsEEG from general anaesthesia may enable state-of-the-art brain age prediction. Yet, differences between anaesthetic drugs can impact the effectiveness of repurposing EEG from anaesthesia. To unleash the dormant potential of repurposing EEG-monitoring for clinical and health research, collecting larger datasets with precisely documented drug dosage will be key enabling factors. | anesthesia |
10.1101/2022.05.04.22274698 | Trends in Diabetes Biomarkers and Treatment Statuses of Non-Institutionalized Canadians: Canadian Health Measures Survey 2007 to 2015 | BackgroundDiabetes has been a major source of disease burden in Canada. Moreover, untreated diabetes can lead to complications and severe conditions. A few studies exist on the prevalence of diabetes and the adequacy of diabetes management for the Canadian population, and so this study aims to estimate the diabetes prevalence rates using biomarkers and the treatment statuses of non-institutionalized Canadian patients.
MethodsThe Canadian Health Measures Survey (CHMS) cycles 1 to 4 were conducted between 2007 and 2015 as interviews with non-institutionalized Canadians. Four blood diabetic markers were measured: insulin, glycosylated hemoglobin percentages, random-spot glucose, and fasting glucose. Subjects with levels higher than normal ranges were considered to have pre-diabetes or diabetes. Treatment statuses were categorized into treated (using anti-diabetic agents or diagnosed with diabetes), probably treated (taking prescriptions or diagnosed with chronic conditions), potentially treated (taking any medications or diagnosed with chronic conditions), and untreated (not taking any medications and not diagnosed with chronic conditions). Weights were applied to generate nationally representative statistics.
ResultsThe blood insulin levels in cycle 4 were significantly higher than those in cycle 1 (ratio = 1.42, 95% CI = 1.04 to 1.79). The proportions of patients with pre-diabetes and diabetes were estimated differently at 0.75% using random-spot glucose and 42.17% using glycosylated hemoglobin percentages, respectively. The proportions of Canadians with uncontrolled pre-diabetes or diabetes varied from 0.59% using random-spot glucose levels to 4.63% using fasting glucose levels, respectively. Through cycles 1 to 4, the proportions of untreated Canadians with pre-diabetes or diabetes ranged from 3.86% to 3.73%. More than 93% of those with high fasting glucose levels were taking prescription medications or had been diagnosed with chronic conditions (probably treated). Less than 33% of those with high fasting glucose levels were diagnosed or actively being treated with anti-diabetic agents (treated).
ConclusionDiabetes biomarkers might be useful for screening untreated and undertreated patients with pre-diabetes or diabetes. The treatment categories we used indicated different intensities of intervention that might be useful for determining levels of patient outreach and for planning targeted screening in Canada. | endocrinology |
10.1101/2022.05.06.22274782 | Post-acute health care burden after SARS-CoV-2 infection: A retrospective cohort study among 530,892 adults | Importance: The SARS-CoV-2 pandemic portends a significant increase in health care use related to post-acute COVID sequelae, but the magnitude is not known. Objective: To assess the burden of post-acute health care use after a positive versus negative polymerase chain reaction (PCR) test for SARS-CoV-2. Design, Setting, and Participants: Retrospective cohort study of community-dwelling adults January 1, 2020 to March 31, 2021 in Ontario, Canada, using linked population-based health data. Follow-up began 56 days after PCR testing. Exposures: Individuals with a positive SARS-CoV-2 PCR test were matched 1:1 to individuals who tested negative based on hospitalization, test date, public health unit, sex, and a propensity score of socio-demographic and clinical characteristics. Main Outcomes and Measures: The health care utilization rate was the number of outpatient clinical encounters, homecare encounters, emergency department visits, days hospitalized, and days in long-term care per person-year. Mean health care utilization for test-positive versus negative individuals was compared using negative binomial regression, and rates at 95th and 99th percentiles were compared. Outcomes were also stratified by sex. Results: Among 530,232 unique, matched individuals, mean age was 44 years (sd 17), 51% were female, and 0.6% had received [≥]1 COVID-19 vaccine dose. The mean rate of health care utilization was 11% higher in test-positive individuals (RR 1.11, 95% confidence interval [CI] 1.10-1.13). At the 95th percentile, test-positive individuals had 2.1 (95% CI 1.5-2.6) more health care encounters per person-year, and at the 99th percentile 71.9 (95% CI 57.6-83.2) more health care encounters per person-year. At the 95th percentile, test-positive women had 3.8 (95% CI 2.8-4.8) more health care encounters per person-year while there was no difference for men. At the 99th percentile, test-positive women had 76.7 (95% CI 56.3-89.6) more encounters per person-year, compared to 37.6 (95% CI 16.7-64.3) per person-year for men. Conclusions and Relevance: Post-acute health care utilization after a positive SARS-CoV-2 PCR test is significantly higher compared to matched test-negative individuals. Given the number of infections worldwide, this translates to a tremendous increase in use of health care resources. Stakeholders can use these findings to prepare for health care demand associated with long COVID. | epidemiology |
10.1101/2022.05.04.22274686 | Post-translational modifications glycosylation and phosphorylation of the major hepatic plasma protein fetuin-A are associated with severity of CNS inflammation in children | BackgroundFetuin-A is a liver derived plasma protein showing highest serum concentrations in utero, preterm infants and neonates. Fetuin-A is also present in cerebrospinal fluid (CSF). The origin of CSF fetuin-A, blood-derived via the blood brain barrier or synthesized intrathecally, is presently unclear. Fetuin-A prevents ectopic calcification by stabilizing calcium and phosphate as colloidal calciprotein particles mediating their transport and clearance. Thus, fetuin-A plays a suppressive role in inflammation. Fetuin-A is a negative acute-phase protein, serving as a biomarker for MS. Here we studied the association of pediatric inflammatory CNS diseases with fetuin-A glycosylation and phosphorylation.
MethodsPaired blood and CSF samples from 66 children were included in the study. Concentration measurements were performed using a commercial human fetuin-A/AHSG ELISA. Of 60 pairs, 23 pairs were analyzed by SDS-PAGE following glycosidase digestion with PNGase-F and Sialidase-AU. Phosphorylation was analyzed in 30 pairs by Phos-Tag acrylamide electrophoresis following alkaline phosphatase digestion.
Results and DiscussionMean serum and CSF fetuin-A levels were 0.30 {+/-} 0.06 mg/ml and 0.644 {+/-} 0.55 {micro}g/ml, respectively. This study showed that serum fetuin-A levels decreased in inflammation corroborating its role as a negative acute-phase protein. Blood-brain barrier disruption was associated with elevated fetuin-A in CSF. A strong positive correlation was found between the CSF fetuin-A/serum fetuin-A ratio and the CSF albumin/serum albumin ratio, suggesting predominantly transport across the blood-brain barrier rather than intrathecal fetuin-A synthesis. Sialidase digestion showed increased asialofetuin-A levels in serum and CSF samples from children with neuroinflammatory diseases. Desialylation enhanced hepatic fetuin-A clearance via the asialoglycoprotein receptor thus rapidly reducing serum levels during inflammation. Phosphorylation of fetuin-A was more abundant in serum samples than in CSF, suggesting that phosphorylation may regulate fetuin-A influx into the CNS. These results may help establish Fetuin-A as a potential biomarker for neuroinflammatory diseases. | pediatrics |
10.1101/2022.05.05.22274710 | Clinical prediction models for treatment outcome in newly diagnosed epilepsy: Protocol for a systematic review | Epilepsy, characterised by a predisposition towards unprovoked seizures, is one of the most common neurological disorders globally. Whilst 60-70% of individuals diagnosed with epilepsy will gain seizure control through anti-seizure medication, the mechanisms underlying seizure persistence are unclear. Intractability can significantly degrade a patients quality of life amongst other things; the use of predictive modelling of epilepsy outcomes in deciding on treatment therefore offers a tangible benefit to the patient. Early indicators of pharmacoresistance may discourage certain treatment options, and save time in what has been indicated to be a critical stage for newly-diagnosed epilepsy. Primarily, this paper aims to evaluate existing predictive models to identify demographic, clinical, physiological (e.g. EEG), and neuroimaging (e.g. MRI) factors that may be predictive of treatment outcomes in newly-diagnosed epilepsy. Two electronic databases, MEDLINE and EMBASE, will be searched with terms related to prognosis in newly-diagnosed epilepsy, and identified studies will be included for review if they have combined at least two demographic, clinical, neuroimaging, and/or physiological factors to predict treatment outcome in people with newly-diagnosed epilepsy. Papers will be screened by two independent reviewers via titles, abstracts and then full text against the inclusion criteria for eligibility. Data will be extracted by reviewers using standardised forms, assessed for risk of bias using the PROBAST tool and synthesised narratively. If considered appropriate the authors will carry out a meta-analysis on the available data.
Prospero registration number- | pharmacology and therapeutics |
10.1101/2022.05.05.22273234 | Changes in English medication safety indicators throughout the COVID-19 pandemic: a federated analysis of 57 million patients' primary care records in situ using OpenSAFELY | ObjectiveTo describe the impact of the COVID-19 pandemic on safe prescribing, using the PINCER prescribing indicators; to implement complex prescribing indicators at national scale using GP data.
DesignPopulation based cohort study, with the approval of NHS England using the OpenSAFELY platform.
SettingElectronic health record data from 56.8 million NHS patients general practice records.
ParticipantsAll NHS patients registered at a GP practice using TPP or EMIS computer systems and recorded as at risk of at least one potentially hazardous PINCER indicator between September 2019 and September 2021.
Main outcome measureMonthly trends and between-practice variation for compliance with 13 PINCER measures between September 2019 and September 2021.
ResultsThe indicators were successfully implemented across GP data in OpenSAFELY. Hazardous prescribing remained largely unchanged during the COVID-19 pandemic, with only small reductions in achievement of the PINCER indicators. There were transient delays in blood test monitoring for some medications, particularly ACE inhibitors. All indicators exhibited substantial recovery by September 2021. We identified 1,813,058 patients at risk of at least one hazardous prescribing event.
ConclusionGood performance was maintained during the COVID-19 pandemic across a diverse range of widely evaluated measures of safe prescribing.
Summary box O_TEXTBOXWHAT IS ALREADY KNOWN ON THIS TOPICO_LIPrimary care services were substantially disrupted by the COVID-19 pandemic.
C_LIO_LIDisruption to safe prescribing during the pandemic has not previously been evaluated.
C_LIO_LIPINCER is a nationally adopted programme of activities that aims to identify and correct hazardous prescribing in GP practices, by conducting manual audit on subgroups of practices.
C_LI
WHAT THIS STUDY ADDSO_LIFor the first time, we were able to successfully generate data on PINCER indicators for almost the whole population of England, in a single analysis.
C_LIO_LIOur study is the most comprehensive assessment of medication safety during the COVID-19 pandemic in England, covering 95% of the population using well-validated measures.
C_LIO_LIGood performance was maintained across many PINCER indicators throughout the pandemic.
C_LIO_LIDelays in delivering some medication-related blood test monitoring were evident though considerable recovery was made by the end of the study period.
C_LI
C_TEXTBOX | primary care research |
10.1101/2022.05.05.22274709 | Testing the Triple Network Model of Psychopathology in a Transdiagnostic Neurodevelopmental Cohort | BackgroundThe triple network model of psychopathology posits that altered connectivity between the Salience (SN), Central Executive (CEN), and Default Mode Networks (DMN) may underlie neurodevelopmental conditions. However, this has yet to be tested in a transdiagnostic sample of youth.
MethodsWe investigated triple network connectivity in a sample of 175 children (60 girls) that represent a heterogeneous population who are experiencing neurodevelopmental difficulties in cognition and behavior, and 60 comparison children (33 girls) without such difficulties. Hyperactivity/impulsivity and inattention were assessed by parent-report and resting-state functional Magnetic Resonance Imaging data were acquired. Functional connectivity was calculated between independent network components and regions of interest. We then examined whether connectivity between the SN, CEN and DMN was dimensionally related to hyperactivity/impulsivity and inattention, whilst controlling for age, gender, and motion.
ResultsHyperactivity/impulsivity was associated with decreased segregation between the SN, CEN, and DMN in at-risk children, whereas it was associated with increased segregation of the CEN and DMN in comparison children. We replicated these effects in networks and regions derived from an adult parcellation of brain function and when using increasingly stringent exclusion criteria for in-scanner motion.
ConclusionsTriple network connectivity characterizes transdiagnostic neurodevelopmental difficulties with hyperactivity/impulsivity. This may arise from delayed network segregation, difficulties sustaining CEN activity to regulate behavior, and/or a heightened developmental mismatch between neural systems implicated in cognitive control relative to those implicated in reward/affect processing. | psychiatry and clinical psychology |
10.1101/2022.05.05.22274733 | Pre- and post-operative psychological interventions to prevent pain and fatigue after breast cancer surgery (PREVENT): a randomized controlled trial | BackgroundBreast cancer is the most common cancer type among women worldwide with over a million new cases each year. More than 40% of these women will struggle with chronic pain and fatigue after surgery, regardless of surgical procedure. These consequences are detrimental and result in distress and disability, including work disability. Few attempts have been made to prevent chronic pain and fatigue after surgery by applying a psychological approach, despite psychological risk factors being crucial in the development of both chronic pain and fatigue. In this study, we aim to develop and test an easily implementable strategy of preventing chronic pain and fatigue after breast cancer surgery. The intervention strategy involves a pre-operative hypnosis session and a web-based post-operative Acceptance and Commitment Therapy (ACT). The hypnosis has previously been found effective in alleviating acute post-operative pain and fatigue in breast cancer patients, while ACT is well suited to cancer populations as it offers a model of healthy adaptation to difficult circumstances. Together they form an intervention strategy with both a preventive and a rehabilitative focus.
Methods/designThis randomized controlled trial aims to estimate the effects of the pre- and post-operative interventions compared to attentional control and treatment as usual (TAU) and will also include a qualitative process evaluation. Participants will be randomized to receive either a pre-operative brief hypnosis session and a post-operative web-based psychological intervention (iACT) or a pre-operative one-session mindfulness through an audio file and post-operative TAU. Self-reported questionnaire data and biomarker data will be assessed pre-surgery, post-surgery and 3 and 12 months after surgery. In addition, we will assess registry data on sick leave and prescriptions until 2-year follow-up. In the qualitative process evaluation, data will be collected from participants from both study arms (through interviews and a diary) and two different analyses performed (socio-narrative and Grounded Theory) with the objective to describe the development of chronic post-surgical pain and fatigue and the potential influence of the interventions on these processes. The study is set-up to demonstrate a minimum difference in pain of 1 point on NRS (0-10) and 3 points on FACIT-F (0-52) between the groups at 3-months follow-up by including 200 breast cancer patients in total.
DiscussionThis trial will be the first study to estimate the effect of a combined pre-operative hypnosis with a post-operative iACT to prevent pain and fatigue after breast cancer surgery. The results from our study might i) help the large group of women affected by chronic pain and fatigue after breast cancer surgery, ii) shed light on the mechanisms involved in chronic pain and fatigue development, and iii) serve as a model for other surgical procedures.
Trial registrationClinicaltrials.gov, registration number NCT04518085. Registered on January 29th, 2020. | psychiatry and clinical psychology |
10.1101/2022.05.05.22274713 | Impaired visual processing in psychosis patients with a predisposition for visual hallucinations | Psychosis is frequently associated with the occurrence of visual hallucinations (VH), but their etiology remains largely unknown. While patients with psychosis show deficits on various behavioral visual and attentional tasks, previous studies have not specifically related these deficits to the presence of VH. This suggests that tasks used in these studies do not target the visual-cognitive neural mechanisms that mediate VH, which in turn limits the development of effective therapies. We therefore designed a study to target these mechanisms directly. In this case control study we asked patients with psychosis who had previously experienced VH to indicate when they recognized objects that were gradually emerging from dynamic visual noise, while scanning their brains using functional Magnetic Resonance Imaging. In a previous study, this recognition task was used to identify the neural basis of VH in patients with Parkinsons Disease. Based on this earlier work, we decided to test the following hypothesis: when compared to psychosis patients not experiencing VH and age-matched healthy controls, psychosis patients with VH show reduced occipital activity and frontal activity around the moment of recognition (known as pop-out). For all groups, neuroimaging revealed increased activity in all examined visual areas around pop-out. However, psychosis patients with VH showed reduced occipital responsiveness, especially in the inferior part of the bilateral lateral occipital complex, a region known to play a key role in object recognition. We did not observe altered frontal or prefrontal activity before pop-out in this group. A possible explanation is that the relatively sustained activation of the visual memory-related angular gyri around pop-out may have compensated for the impaired early visual processing in psychosis patients with VH. We discuss our results in terms of current theories of visual hallucinations, such as predictive coding and contextual modulation. Our study is the first to show that visual processing deficits contribute to the occurrence of VH in psychosis. These findings could be used to develop tests to identify the visual-cognitive mechanisms that mediate VH in this group. | psychiatry and clinical psychology |
10.1101/2022.05.06.22274770 | Time-specific effects of a multifaceted intervention on accelerometer-measured physical activity in primary school children: A cluster-randomized controlled trial | Background It is unclear whether intervention effects on school-aged children's physical activity differ across specific periods of the week or day. This study aimed to assess the time-specific intervention effects on accelerometer-measured physical activity in primary school children. Methods This was a nested study in a cluster-randomized controlled trial conducted from September 2018 to June 2019 in China. The intervention group included 4 schools (119 children) and the control group included 4 schools (99 children) in Beijing. The obesity prevention intervention engaged schools and families to improve children's physical activity. Outcome measures included accelerometer-assessed intensity and amounts of physical activity within specific periods of a week (weekday/weekend day) or a day (in-school/out-of-school periods). Linear mixed models were used to estimate intervention effects. Subgroup analyses were also conducted to examine potential moderators including sex, age, body mass index, physical activity, and accelerometer compliance. Results The intervention lead to an increase in time engaged in moderate-to-vigorous physical activity (MVPA) within in-school periods of a day (adjusted mean difference: 0.54 minutes/hour; 95% confidence interval: 0.13, 0.94, P = 0.012) but it did not improve physical activity within out-of-school periods (P > 0.05) compared with the control group. There was no difference in the effect size across most of the moderators except for age, as younger children appeared to benefit more from the intervention in the improvement of in-school MVPA (Pinteraction = 0.035). No between-group differences were observed in physical activity within the whole weekday or weekend day (P > 0.05). Conclusion The intervention effectively increased MVPA within in-school periods but did not improve out-of-school physical activity. Findings support the tailoring of intervention components to specific periods of a day to improve school-aged children's whole pattern of physical activity. | public and global health |
10.1101/2022.05.05.22274737 | Factors associated with repeat childbirth among Adolescent Mothers in Soroti District, Teso sub-region, Uganda: A cross-sectional study | The percentage of adolescent mothers aged 15 to 19 years with a repeat childbirth in Uganda (26.1%) is higher than the global estimate (18.5%). Soroti district tops Teso (a region with highest adolescent childbearing rate nationally) in adolescent childbearing. Adolescent repeat childbearing (ARC) is associated with poor health outcomes, increased risk of stillbirth, maternal and child mortality, thus a public health concern. The factors associated with, and the burden, of ARC remains unknown in Soroti district. Consequently, interventions which combat ARC in Soroti district have not been informed by empirical data. This study determined the proportion of adolescent mothers with, and factors associated with, repeat childbirth among adolescent mothers in Soroti district.
We conducted a cross-sectional study involving mixed methods of data collection. Interviewer-administered structured interviews were conducted amongst 422 adolescent mothers.
Demographic and socio-economic data of respondents, data regarding respondents family and peer related factors was collected. Chi-square was the test statistics used. Multivariate analysis was by logistic regression.
Of the 422 respondents, 31.28% (132) were married. Proportion of respondents with repeat childbirth was at 30.81% (95%CI: 26.57%-35.39%). Risk factors of ARC were (a) being married, AOR 5.74 (95%CI: 3.08-10.68), (b) incorrect knowledge of rhythm method, AOR 2.15 (95%CI: 1.21-3.82), (c) Age at first birth, AOR 0.48 (95%CI: 0.36-0.63). Protective factors of ARC included (a) not drinking alcohol, AOR 0.41(95%CI: 0.21-0.77), not being raped, AOR 0.19(95%CI: 0.06-0.55), having first childbirth from health facility, AOR 0.38 (95%CI: 0.18-0.78) and father of first baby without multiple sexual partners, AOR 0.40(95%CI: 0.22-0.72).
In conclusion, sexual partner characteristics were associated with ARC suggesting male involvement (for example in family planning) in prevention of ARC. In addition, strengthening the implementation of anti-teen marriage programs and alcohol consumption policies, and instating measures to delay age at first delivery among adolescent mothers are required. Further research is needed to validate these findings. | sexual and reproductive health |
10.1101/2022.05.06.22274768 | Novel visualization of the spatiotemporal relationship between ictal spiking and LFP supports the involvement of mid-range excitatory circuits during human focal seizures | The relationship between action potentials and the associated local field potential (LFP) in neural recordings is typically studied only in the temporal domain using the spike-triggered average (STA). In this study, we present a novel approach, termed the spatiotemporal spike-centered average (st-SCA), that allows for visualization of the spike-LFP relationship in both the temporal and spatial domains. In this method, a 3D spatiotemporal topography of spike-associated LFP is calculated from a 2D spatial average of the LFP centered around the time and location of individual spikes. We applied this method to 25 microelectrode array (MEA) recordings obtained from seven patients with pharmacoresistant focal epilepsy during ictal and interictal states. Five patients in this dataset had MEA implants in recruited cortex, and two had implants in unrecruited cortex. Of the five patients with arrays implanted in recruited territory, three showed STAs that resembled sine cardinal (sinc) functions, and two showed non-sinc functions. Using the st-SCA, we found that the patients who showed a sinc-function pattern in the temporal domain showed a donut-shaped ring of LFP activity in the spatial domain. This observation was corroborated by a theoretical model describing an ictal spike as measured by a macroelectrode. The model also revealed a special symmetry wherein temporal component of the st-SCA predicts the spatial component when they both approximate sinc-functions. Supporting this theoretical derivation, a radial cut of the donut-shaped st-SCA showed a spatial pattern consistent with a sinc-function. This spatial sinc-function had peaks separated by [~]2.5mm--a measurement that supports the role of mid-range excitatory connections during ictal activity. In sum these findings suggest that patients whose seizures engage mid-range connections may be identifiable by the spatiotemporal features of ictal spike-associated LFP activity. | neurology |
10.1101/2022.05.04.22274689 | Conceptualization of Health Literacy from A Nursing Perspective | Health as an inseparable part of human beings needs to be maintained to achieve a complete human health degree. The role of health literacy in attaining optimum health is significant. When associated with nursing, health literacy must be interpreted as a part of the role and function of nursing. However, to understand health literacy, it is necessary to study it from the aspect of scientific formation itself and a nursing perspective. This review proposes an alternative conceptualization of health literacy from a nursing perspective. This review used an integrative search through four databases: ScienceDirect, ProQuest, SAGE Journal, and Google Scholar. Search using various combinations of keywords with the help of Boolean operators, including: health literacy, nursing perspective, nursing, and conceptualization combined as MESH terms. The inclusion criteria are peer-reviewed articles in English that discuss health literacy and nursing perspective. Articles published within the last six years (2017-2022). Research such as literature reviews, dissertations, editorials, commentaries, and other expert opinions are excluded. Ten articles were considered in this literature review. We describe the conceptualization of health literacy from the nurses point of view, the predictors that influence it, the dimensions surrounding health literacy, the implication of health literacy, and how nurses will participate in supporting this health literacy. In the end, this conceptualization will be used as an illustration material to integrate the concept of health literacy into various problems that become nursing tasks. | nursing |
10.1101/2022.05.04.22274673 | Increased Prevalence of Rare Copy Number Variants in Treatment-Resistant Psychosis | BackgroundIt remains unknown why [~]30% of patients with psychotic disorders fail to respond to treatment. Previous genomic investigations into treatment-resistant psychosis have been inconclusive, but some evidence suggests a possible link between rare disease-associated copy number variants (CNVs) and worse clinical outcomes in schizophrenia. Here, we test whether schizophrenia-associated CNVs are more prevalent in patients with treatment-resistant psychotic symptoms compared to previously published schizophrenia cases not selected for treatment-resistance.
MethodsCNVs were identified using chromosomal microarrays and exome sequencing in 509 patients with treatment-resistant psychosis (a lack of clinical response to [≥] 3 adequate antipsychotic medication trials over at least five years of psychiatric hospitalization). Prevalence of schizophrenia-associated CNVs in this sample was compared against a previous large schizophrenia cohort study.
ResultsIn total, 47 cases (9.2%) carried at least one CNV with known or possible neuropsychiatric risk. The prevalence of schizophrenia-associated CNVs (n=21; 4.1%) was significantly increased compared to a previous schizophrenia cohort study (p = 0.005322; OR = 1.93). This increase in prevalence was primarily due to duplications at 15q11.2-q13.1 and 16p11.2, which were independently associated with treatment-resistance in pairwise loci-based analysis.
ConclusionsThese findings suggest that rare schizophrenia-associated CNVs, particularly duplications of 15q11.2-q13.1 and 16p11.2, may serve as biological entry points for studying treatment resistance. Further investigation will be necessary to elucidate the spectrum of phenotypic characteristics observed in adult psychiatric patients with disease-associated CNVs. | genetic and genomic medicine |
10.1101/2022.05.04.22274667 | Screening for safe opening of universities under Omicron and Delta variants of COVID-19: When less is more | As new COVID-19 variants emerge, and disease and population characteristics change, screening strategies may also need to change. We develop screening guidelines for the safe opening of college campuses, considering COVID-19 infections/hospitalizations/deaths; peak daily hospitalizations; and the tests required. Our compartmental model simulates disease spread on a college campus under co-circulating variants with different disease dynamics, considering: (i) the heterogeneity in disease transmission and outcomes for faculty/staff and students based on vaccination status and level of natural immunity; and (ii) variant- and dose-dependent vaccine efficacy. Using the Spring 2022 academic semester as a case study, we study various routine screening strategies, and find that screening the faculty/staff less frequently than the students, and/or the boosted and vaccinated less frequently than the unvaccinated, may avert a higher number of infections per test, compared to universal screening of the entire population at a common frequency. We also discuss key policy issues, including the need to revisit the mitigation objective over time, effective strategies that are informed by booster coverage, and if and when screening alone can compensate for low booster coverage. | health policy |
10.1101/2022.05.05.22274702 | Managing COVID-19 in an Australian designated isolation facility: Implications for current and future healthcare crises | The lived experiences of healthcare workers (HCWs) and their perceptions of the pandemic can prove to be a valuable resource in the face of a seemingly persistent Novel coronavirus disease 2019 (COVID-19) to inform ongoing efforts, as well as identify components essential to a crisis preparedness plan and the issues pertinent to supporting relevant change. We employed a phenomenological approach and using purposive sampling conducted 39 semi-structured interviews with senior healthcare professionals who were employed at a designated COVID-19 facility in New South Wales (NSW), Australia during the height of the pandemic in 2020. Participants comprised administrators, heads of department and clinicians. We obtained from these HCWs (i) perspectives of their lived experience on what was done well and what could have been done differently and (ii) recommendations on actions for current and future crisis response. Four themes encapsulated insights of respondents that should inform our capacity to meet current needs, direct meaningful and in situ change, and prepare us for future crises. Observations and recommendations of respondents are informative for decision-makers tasked with mobilising an efficacious approach to the next health crisis and, in the interim, would aid the governance of a more robust workforce to effect high quality patient care in a safe environment. | health systems and quality improvement |
10.1101/2022.05.05.22274731 | Deep learning identified genetic variants associated with COVID-19 related mortality | Analysis of host genetic components provides insights into the susceptibility and response to viral infection such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). To reveal genetic determinants of susceptibility to COVID-19 related mortality, we train a deep learning model to identify groups of genetic variants and their interactions that contribute to the COVID-19 related mortality risk using the UK Biobank data. We refer to such groups of variants as super variants. We identify 15 super variants with various levels of significance as susceptibility loci for COVID-19 mortality. Specifically, we identify a super variant (OR=1.594, p=5.47x10-9) on Chromosome 7 that consists of the minor allele of rs76398985, rs6943608, rs2052130, 7:150989011_CT_C, rs118033050 and rs12540488. We also discover a super variant (OR=1.353, p=2.87x10-8) on Chromosome 5 that contains rs12517344, rs72733036, rs190052994, rs34723029, rs72734818, 5:9305797_GTA_G and rs180899355. | infectious diseases |
10.1101/2022.05.04.22274681 | Longitudinal analysis reveals elevation then sustained higher expression of autoantibodies for six months after SARS-CoV-2 infection | High autoantibody levels are found in individuals hospitalized for COVID-19. The temporal trajectories and levels of these autoantibodies months into convalescence after SARS-CoV-2 infection are unclear. It is also unknown if the composite autoantibody signatures of convalescent SARS-CoV-2-infected individuals resemble those with diagnosed autoimmune diseases. We measured the circulating levels of 17 autoantibodies associated with autoimmune connective tissue diseases from SARS-CoV-2 hospitalized and outpatient participants, as well as from individuals with scleroderma (SSc), systemic lupus erythematosus (SLE), and uninfected pre-pandemic controls. Seven of the 17 autoantibodies measured were higher in hospitalized and/or outpatient SARS-CoV-2 individuals an average of six months after symptom onset compared with controls, with multivariate analyses revealing links between SARS-CoV-2 infection and positivity of SSB-La, Sm, Proteinase 3, Myleoperoxidase, Jo-1, and Ku reactive IgG six months post-symptom onset. Autoantibody levels from SARS-CoV-2 infected individuals were followed over time from initial symptom onset for an average of six months, and different temporal autoantibody trajectories were classified. A negative, then positive expression pattern was found for at least one autoantibody in 18% of the outpatient and 53% of the hospitalized participants, indicating initiation and durable expression of self-reactive immune responses post-infection, particularly with severe acute illness. Analysis of individual participant autoantibody expression patterns revealed similar patterns between pre-pandemic and convalescent SARS-CoV-2 infected groups that are distinct from participants with both the SSc and SLE. As autoantibody positivity can occur years prior to autoimmune disease onset, the possibility that SARS-CoV-2-associated autoantibodies are a herald of future autoimmune disorders requires further investigation.
One Sentence SummaryAutoantibody levels rise after acute SARS-CoV-2 infection and remain elevated for at least six months after symptom onset in participants with mild or severe COVID-19. | infectious diseases |
10.1101/2022.05.05.22274646 | Impact of COVID-19 non-pharmaceutical interventions on pneumococcal carriage prevalence and density in Vietnam | Non-pharmaceutical interventions (NPIs) implemented to contain SARS-CoV-2 have decreased invasive pneumococcal disease. We undertook an observational study to evaluate the impact of NPIs on pneumococcal carriage and density, drivers of transmission and disease, during the COVID-19 pandemic in Ho Chi Minh City, Vietnam. While NPIs did not significantly impact pneumococcal carriage, mean capsular pneumococcal density decreased by up to 91.5% (1.07 log10genome equivalents/mL, 95% Confidence Interval: 0.74-1.41) after NPI introduction compared with the pre-COVID-19 period. As higher pneumococcal density is a risk factor for disease, the observed decline provides a plausible mechanism for the reductions in invasive pneumococcal disease. | infectious diseases |
10.1101/2022.05.06.22274771 | Covid-19 vaccine effectiveness against general SARS-CoV-2 infection from the omicron variant: A retrospective cohort study | ObjectiveTo estimate the effectiveness of 2-dose and 3-dose mRNA vaccination (BNT162b2 and mRNA-1273) against general SARS-CoV-2 infection (asymptomatic or symptomatic) caused by the omicron variant.
DesignPropensity-score matched retrospective Cohort Study.
SettingLarge public university undergoing weekly Covid-19 testing in South Carolina, USA.
ParticipantsPopulation consists of 24,145 university students and employees undergoing weekly Covid-19 testing between January 3rd and January 31st, 2022. The analytic sample was constructed via propensity score matching on vaccination status: Unvaccinated, completion of 2-dose mRNA series within previous 5 months, and receipt of mRNA booster dose within previous 5 months. The resulting analytic sample consists of 1,944 university students and 658 university employees.
InterventionVaccination with a two dose or 3 dose regimen of the BNT162b2 or mRNA-1273 vaccine.
ResultsBooster protection against any SARS-CoV-2 infection was 66.4% among employees (95% CI: 46.1-79.0%; P<.001) and 45.4% among students (95% CI: 30.0-57.4%; P<.001). Compared to the 2-dose mRNA series, estimated increase in protection from the booster dose was 40.8% among employees (P=.024) and 37.7% among students (P=.001). We did not have enough evidence to conclude a statistically significant protective effect of the 2-dose mRNA vaccination series, nor did we have enough evidence to conclude that protection waned in the 5-month period after receipt of the 2nd or 3rd mRNA dose. Furthermore, we did not find evidence that protection varied by manufacturer.
ConclusionsCovid-19 mRNA booster doses offer moderate protection against any SARS-CoV-2 infection caused by the omicron variant and provide a substantial increase in protection relative to the 2-dose mRNA vaccination series. | infectious diseases |
10.1101/2022.05.06.22274719 | Antibody responses to known and unknown SARS-CoV-2 infections after mRNA vaccine booster | We followed a fully-vaccinated (two mRNA vaccine doses) community cohort (n=41) without prior COVID-19 diagnosis from September 2021 through March 2022 through the Omicron wave following a booster mRNA vaccination. 19.5% of participants reported a known SARS-CoV-2 infection during the Omicron wave, which was confirmed by anti-nucleocapsid IgG. An additional 36.5% also developed anti-nucleocapsid IgG after the boost, consistent with unknown, asymptomatic SARS-CoV-2 infection during this period. Infection defined by anti-nucleocapsid IgG, whether known to participant or not, increased anti-spike IgG levels, relative to those lacking anti-nucleocapsid IgG, at 120 days post-booster. | infectious diseases |
10.1101/2022.05.06.22274611 | Implication of DNA methylation changes at chromosome 1q21.1 in the brain pathology of Primary Progressive Multiple Sclerosis | Multiple Sclerosis (MS) is a highly heterogenous inflammatory and neurodegenerative disease of the central nervous system with unpredictable course towards progressive disability. Understanding and treating progressive forms of MS remains extremely challenging due to the limited knowledge of the underlying mechanisms. We examined the molecular changes that associate with primary progressive MS (PPMS) using a cross-tissue (blood and post-mortem brain) and multilayered data (genetic, epigenetic, transcriptomic) from independent cohorts. We first identified and replicated hypermethylation of an intergenic region within the chromosome 1q21.1 locus in the blood of PPMS patients compared to other MS patients and healthy individuals using Illumina 450K arrays and pyrosequencing. We next revealed that methylation is under the control of genetic variation within the extended locus both in the blood and brain. Several genetic variants also affected expression of proximal genes (CHD1L, PRKAB2 and FMO5) in the brain and displayed evidence of the association with the risk of developing PPMS, suggesting a genetic-epigenetic-transcriptional interplay in PPMS pathogenesis. We next addressed the causal link between DNA methylation and gene expression using reporter systems and dCas9-TET1-induced demethylation of CpGs in the identified region, which resulted in upregulation of CHD1L and PRKAB2 genes in SH-SY5Y neuron-like cells. Independent exploration using unbiased correlation network analysis, confirmed the putative implication of CHD1L and PRKAB2 in brain processes in PPMS patients. We provide several lines of evidence suggesting distinct molecular changes in the 1q21.1 region, known to associate with brain development and disorders, associated with genetic predisposition to high methylation in PPSM patients that regulates the expression of genes within the extended locus. | allergy and immunology |
10.1101/2022.05.05.22274728 | Association of socioeconomic status with arterial stiffness in older African American and White Adults: The ARIC Study Cohort | Background: The contributions of traditional CVD risk factors do not fully explain the racial and socioeconomic disparities in arterial stiffness. The extent to which the association of socioeconomic status (SES) with subclinical CVD is different for older African American and White adults is unclear. Methods and Results: Cross-section associations of individual SES [education and income] with carotid femoral pulse wave velocity (cfPWV), a subclinical marker of arterial stiffness, and modification of this relationship by race were examined among 3,342 participants of the Atherosclerosis Risk in Communities (ARIC) Study (age=75plus-or-minus sign 4.9 years, 64% female, 23% African American, free of CVD in 2011-2013) using multivariable linear regression. Post-graduate education compared to less than high school, was associated with lower cfPWV (less stiffness) in African Americans (lower case Greek beta = -1.28 m/s; 95% CI, -1.97, -0.59), but not in Whites (lower case Greek beta = -0.69 m/s; 95% CI, -1.39, 0.01). Income [≥]$50K as compared to <$25K, was associated with lower cfPWV both in African Americans (lower case Greek beta = -0.82 m/s; 95% CI, -1.42, -0.22) and Whites (lower case Greek beta = -0.76 m/s; 95% CI, -1.19, -0.32). However, interaction of race with individual measures of SES on cfPWV in African American and White adults were not statistically significant (p-value for interaction >0.05). Conclusions: Higher SES was cross-sectionally associated with lower arterial stiffness in this cohort; the data did not support differences by race. Prospective studies of SES and cfPWV among a racially socioeconomically diverse cohort merit further study. | cardiovascular medicine |
10.1101/2022.05.03.22274582 | Use of c-peptide as a measure of cephalic phase insulin release in humans | Cephalic phase insulin release (CPIR) is a rapid pulse of insulin secreted within minutes of food-related sensory stimulation. Understanding the mechanisms underlying CPIR in humans has been hindered by its small observed effect size and high variability within and between studies. One contributing factor to these limitations may be the use of peripherally measured insulin as an indicator of secreted insulin, since a substantial portion of insulin is metabolized by the liver before delivery to peripheral circulation. Here, we investigated the use of c-peptide, which is co-secreted in equimolar amounts to insulin from pancreatic beta cells, as a proxy for insulin secretion during the cephalic phase period. Changes in insulin and c-peptide were monitored in 18 adults over two repeated sessions following oral stimulation with a sucrose-containing gelatin stimulus. We found that on average, insulin and c-peptide release followed a similar time course over the cephalic phase period, but that c-peptide showed a greater effect size. Importantly, when insulin and c-peptide concentrations were compared across sessions, we found that changes in c-peptide were significantly correlated at the 2 minute (r = 0.50, p = 0.03) and 4 minute (r = 0.65, p = 0.003) time points, as well as when individuals peak c-peptide concentrations were considered (r = 0.64, p = 0.004). In contrast, no significant correlations were observed for changes in insulin measured from the sessions (r = -0.06-0.35, p < 0.05). Herein, we detail the individual variability of insulin and c-peptide release during the cephalic phase period, and discuss why c-peptide may be a more appropriate metric to represent insulin secretion. | endocrinology |
10.1101/2022.05.04.22274677 | A statistical definition of epidemic waves | The timely identification of expected surges of cases during infectious disease epidemics is essential for allocating resources and preparing interventions. This study describes a simple way to evaluate whether an epidemic wave is likely to be present based on daily new case count data. The proposed measure compares two models that assume exponential or linear dynamics, respectively. Technically, the output of two regression analyses is used to approximate a Bayes factor, which quantifies the support for the exponential over the linear model and can be used for epidemic wave detection. The trajectory of the coronavirus epidemic in three countries is analyzed and discussed for illustration. The proposed measure detects epidemic waves at an early stage, which are otherwise visible only by inspecting the development of case count data retrospectively. In addition to informing public health decision making, the outlined approach may serve as a starting point for scientific discussions on epidemic waves. | epidemiology |
10.1101/2022.05.04.22274664 | Adherence trajectory as an on-treatment risk indicator among drug- resistant TB patients in the Philippines | IntroductionHigh levels of treatment adherence are critical for achieving optimal treatment outcomes among patients with tuberculosis (TB), especially for drug-resistant TB (DR TB). Current tools for identifying high-risk non-adherence are insufficient. Here, we apply trajectory analysis to characterize adherence behavior early in DR TB treatment and assess whether these patterns predict treatment outcomes.
MethodsWe conducted a retrospective analysis of Philippines DR TB patients treated between 2013 and 2016. To identify unique patterns of adherence, we performed group-based trajectory modelling on adherence to the first 12 weeks of treatment. We estimated the association of adherence trajectory group with six-month and final treatment outcomes using univariable and multivariable logistic regression. We also estimated and compared the predictive accuracy of adherence trajectory group and a binary adherence threshold for treatment outcomes.
ResultsOf 596 patients, 302 (50.7%) had multidrug resistant TB, 11 (1.8%) extremely drug-resistant (XDR) TB, and 283 (47.5%) pre-XDR TB. We identified three distinct adherence trajectories during the first 12 weeks of treatment: a high adherence group (n=483), a moderate adherence group (n=93) and a low adherence group (n=20). Similar patterns were identified at 4 and 8 weeks. Being in the 12-week moderate or low adherence group was associated with unfavorable six-month (adjusted OR [aOR] 3.42, 95% CI 1.90 - 6.12) and final (aOR 2.71, 95% 1.73 - 4.30) treatment outcomes. Adherence trajectory group performed similarly to a binary threshold classification for the prediction of final treatment outcomes (65.9 % vs. 65.4 % correctly classified), but was more accurate for prediction of six-month treatment outcomes (79.4% vs. 60.0% correctly classified).
ConclusionsAdherence patterns are strongly predictive of patient treatment outcomes. Trajectory-based analyses represent an exciting avenue of research into TB patient adherence behavior seeking to inform interventions which rapidly identify and support patients with high-risk adherence patterns. | epidemiology |
10.1101/2022.05.05.22274743 | Interactions between seasonal temperature variation and temporal synchrony drive increased arbovirus co-infection incidence | Though instances of arthropod-borne (arbo)virus co-infection have been documented clinically, the overall incidence of arbovirus co-infection and its drivers are not well understood. Now that dengue, Zika, and chikungunya viruses are all in circulation across tropical and subtropical regions of the Americas, it is important to understand the environmental and biological conditions that make co-infections more likely to occur. To understand this, we developed a mathematical model of cocirculation of two arboviruses, with transmission parameters approximating dengue, Zika, and/or chikungunya viruses and co-infection possible in both humans and mosquitoes. We examined the influence of seasonal timing of arbovirus cocirculation on the extent of co-infection. By undertaking a sensitivity analysis of this model, we examined how biological factors interact with seasonality to determine arbovirus co-infection transmission and prevalence. We found that temporal synchrony of the co-infecting viruses and average temperature were the most influential drivers of co-infection incidence. For seasonal patterns typical of a tropical region, we observed non-negligible incidence irrespective of arrival time when two arboviruses arrived simultaneously. Under our default parameter settings, this corresponded to a maximum co-infection cumulative incidence of 83 per 1,000 individuals and a minimum cumulative incidence of 32 per 1,000 individuals in the year following arrival. For seasonal patterns typical of a more temperate region, co-infections only occurred if arrivals took place near the seasonal peak, and even then, did not reach 0.01 co-infections per 1,000 individuals. Our model highlights the synergistic effect of co-transmission from mosquitoes, which leads to more than double the number of co-infections than would be expected in a scenario without co-transmission. Our results show that arbovirus co-infections are unlikely to occur in appreciable numbers unless epidemics overlap in space and time and in a tropical region. | epidemiology |
10.1101/2022.05.04.22274661 | Alcohol Use Disorder Is Associated with Higher Risks of Adverse Brain Outcomes | Alcohol use disorder (AUD) is on the ascendancy in the US older adult population, while the association between AUD and adverse brain outcomes remains inconclusive. The objective of this work is to investigate the associations between AUD with the onset of Alzheimers disease and Parkinsons disease. In a retrospective cohort design using US insurance claim data (2007-2020), 129,182 patients with AUD were matched with 129,182 controls by age, sex, race, and clinical characteristics. After adjusting for covariates, AUD was associated with a higher risk of Alzheimers disease (female adjusted HR=1.78, 95% CI: 1.68-1.90, P<0.001; male adjusted HR=1.80, 95% CI: 1.71-1.91, P<0.001) and a higher risk of Parkinsons disease (female adjusted HR=1.49, 95% CI: 1.32-1.68 P<0.001; male adjusted HR=1.42, 95% CI: 1.32-1.52, P<0.001) in the overall sample. In separate analyses of Black, White, and Hispanic patients, those with AUD had higher risk of Alzheimers disease (adjusted HRs[≥]1.58; Ps[≤]0.001). A significantly elevated risk for Parkinsons disease was found only in the White subpopulation (female adjusted HR=1.55, 95% CI: 1.36-1.77, P<0.001; male adjusted HR=1.45, 95% CI: 1.33-1.57, P<0.001). Alcohol use disorder is associated with Alzheimers disease. Alcohol use disorder is associated with Parkinsons disease in White persons. Cognitive screening and neurological examination among older adults with severe problematic alcohol use hold the promise for early detection of Alzheimers disease and Parkinsons disease. | epidemiology |
10.1101/2022.05.06.22274762 | Rapid growth in disposable e-cigarette vaping among young adults in Great Britain from 2021 to 2022: a repeat cross-sectional survey | Aims: To estimate recent trends in the prevalence of disposable e-cigarette vaping in Great Britain, overall and across ages. Design: The Smoking Toolkit Study, a monthly representative cross-sectional survey. Setting: Great Britain. Participants: 29,976 adults ([≥]18 years) completed telephone interviews from January 2021 to January 2022. Measurements: Current e-cigarette vapers were asked which type of device they mainly use. We estimated age-specific time trends in the prevalence of current disposable e-cigarette use among vapers and inhaled nicotine use (vaping/smoking) among adults. Findings: From January 2021 to January 2022, there was a 14-fold increase in the percentage of vapers that used disposables, rising from 1.2% to 16.7% (prevalence ratio [PR], 14.4; 95%CI, 6.6-49.0). Growth in disposable e-cigarette vaping was most pronounced in younger adults (interaction p-value, .0.007): for example, the percentage of 18-year-old vapers using of disposables rose from 0.89% to 56.7% (PR, 64; 95%CI, 15-5790) while it rose from 1.3% to 6.2% (PR, 4.7; 95%CI, 1.7-144) among 45-year-old vapers. However, the overall percentage people currently using any inhaled nicotine, vaped or smoked, remained stable over time both among all adults (20.1% vs. 20.6%; PR, 1.03; 95%CI, 0.88-1.20) and among 18-year-olds (29.6% vs. 29.6%; PR, 1.00; 95%CI, 0.79-1.26). Conclusions: Use of disposable e-cigarettes in Great Britain grew rapidly between 2021 and 2022, especially among younger adults, but the overall prevalence of inhaled nicotine use -- smoked or vaped -- was stable over time. Most young adult vapers in Great Britain now use disposable products. | epidemiology |
10.1101/2022.05.06.22274701 | COVID-19 vaccine effectiveness during a prison outbreak when the Omicron was the dominant circulating variant, Zambia, December 2021 | During a COVID-19 outbreak in a prison in Zambia from 14th to 19th December 2021, a case control study was done to measure vaccine effectiveness (VE) against infection and symptomatic infection, when the Omicron variant was the dominant circulating variant. Among 382 participants, 74.1% were fully vaccinated and the median time since full vaccination was 54 days. There were no hospitalizations or deaths. COVID-19 VE against any SARS-CoV-2 infection was 64.8% and VE against symptomatic SARS-CoV-2 infection was 72.9%. COVID-19 vaccination helped protect incarcerated persons against SARS-CoV-2 infection during an outbreak while Omicron was the dominant variant in Zambia. | epidemiology |
10.1101/2022.05.06.22274684 | The role of corticospinal and extrapyramidal pathways in motor impairment after stroke | Anisotropy of descending motor pathways has repeatedly been linked to the severity of motor impairment following stroke-related damage to the corticospinal tract (CST). Despite promising findings consistently tying anisotropy of the ipsilesional CST to motor outcome, anisotropy is not yet utilized as a biomarker for motor recovery in clinical practice as a conclusive understanding of degenerative processes in the ipsilesional CST and compensatory roles of other descending motor pathways is hindered by methodological constraints such as estimating anisotropy in voxels with multiple fiber directions, sampling biases, and confounds due to aging-related atrophy. The present study addressed these issues by combining diffusion spectrum imaging (DSI) with a novel compartmentwise analysis approach differentiating voxels with one dominant fiber direction (one-directional voxels) from voxels with multiple fiber directions. Compartmentwise anisotropy for bihemispheric CST and extrapyramidal tracts was compared between chronic stroke patients (N=25), age-matched controls (N=22), and young controls (N=24) and its associations with motor performance of the upper and lower limbs were assessed. Our results provide direct evidence for Wallerian degenration along the entire length of the ipsilesional CST reflected by decreased anisotropy in descending fibers compared to age-matched controls, while aging-related atrophy was observed more ubiquitously across compartments. Anisotropy of descending ipsilesional CST voxels showed a highly robust correlation with various aspects of upper and lower limb motor impairment, highlighting the behavioral relevance of Wallerian degeneration. Moreover, anisotropy measures of two-directional voxels within bihemispheric rubrospinal and reticulospinal tracts were linked to lower limb deficits, while anisotropy of two-directional contralesional rubrospinal voxels explained gross motor performance of the affected hand. Of note, the relevant extrapyramidal structures contained fibers crossing the midline, fibers potentially mitigating output from brain stem nuclei, and fibers transferring signals between the extrapyramidal system and the cerebellum. Thus, specific parts of extrapyramidal pathways seem to compensate for impaired gross arm and leg movements incurred through stroke-related CST lesions, while fine motor control of the paretic hand critically relies on ipsilesional CST integrity. Importantly, our findings suggest that the extrapyramidal system may serve as a compensatory structural reserve independent of post-stroke reorganization of extrapyramidal tracts. In summary, compartment-specific anisotropy of ipsilesional CST and extrapyramidal tracts explained distinct aspects of motor impairment, with both systems representing different pathophysiological mechanisms contributing to motor control post-stroke. Considering both systems in concert may help develop diffusion imaging biomarkers for specific motor functions after stroke. | neurology |
10.1101/2022.05.04.22274475 | Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2 | BackgroundSchaaf-Yang syndrome (SYS) is caused by truncating mutations in MAGEL2, mapping to the Prader-Willi region (15q11-q13), with an observed phenotype partially overlapping that of Prader-Willi syndrome. MAGEL2 plays a role in retrograde transport and protein recycling regulation. Our aim is to contribute to the characterization of SYS pathophysiology at clinical, genetic and molecular levels.
MethodsWe performed an extensive phenotypic and mutational revision of previously reported SYS patients. We analysed the secretion levels of amyloid-{beta} 1-40 peptide (A{beta}1-40), and performed targeted metabolomic and transcriptomic profiles in SYS patients fibroblasts (n=7) compared to controls (n=11). We also transfected cell lines with vectors encoding wild-type (WT) or truncated MAGEL2 to assess stability and subcellular localization of the truncated protein.
ResultsFunctional studies show significantly decreased levels of secreted A{beta}1-40 and intracellular glutamine in SYS fibroblasts compared to wild-type. We also identified 132 differentially expressed genes, including ncRNAs such as HOTAIR, many of them related to developmental processes and mitotic mechanisms. The truncated form of MAGEL2 displayed a stability similar to the wild-type but it was significantly switched to the nucleus, compared to a mainly cytoplasmic distribution of the wild-type MAGEL2. Based on updated knowledge we offer guidelines for clinical management of SYS patients.
ConclusionA truncated MAGEL2 protein is stable and localises mainly in the nucleus, where it might exert a pathogenic gain of function effect. A{beta}1-40 secretion levels and HOTAIR mRNA levels might be promising biomarkers for SYS. Our findings may improve SYS understanding and clinical management.
Key MessagesMAGEL2 truncating mutations cause Schaaf-Yang syndrome (SYS) but the functional effects of the truncated MAGEL2 protein have been poorly defined. By expressing truncated MAGEL2 in cell lines, we now know that a truncated version of the protein is retained in the nucleus, thus exerting a gain-of-function behaviour in addition to the loss of some of its main functions. Patients fibroblasts show reduced levels of excreted amyloid beta 1-40 and intracellular glutamine as well as an altered transcriptomic profile, including overexpression of the major regulator HOTAIR. Based on a comprehensive review of genetic and clinical aspects of all reported cases, families and physicians will benefit from the Clinical Management Recommendations that we provide here. | neurology |
10.1101/2022.05.05.22274567 | PERFORMANCE OF αSYNUCLEIN RT-QUIC IN RELATION TO NEUROPATHOLOGICAL STAGING OF LEWY BODY DISEASE | Currently, there is a need for diagnostic markers in Lewy body disorders (LBD). Syn RT-QuIC has emerged as a promising assay to detect misfolded -synuclein in clinically or neuropathologically established patients with various synucleinopathies. In this study, Syn RT-QuIC was used to analyze lumbar CSF in a clinical cohort from the Swedish BioFINDER study and postmortem ventricular CSF in a neuropathological cohort from the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program (AZSAND/BBDP). The BioFINDER cohort included 64 PD/PDD, 15 MSA, 15 PSP, 47 controls and two controls who later converted to PD/DLB. The neuropathological cohort included 101 cases with different brain disorders, including LBD and controls. In the BioFINDER cohort Syn RT-QuIC identified LBD (i.e. PD, PDD and converters) vs. controls with a sensitivity of 95% and a specificity of 83%. The two controls that converted to LBD were Syn RT-QuIC positive. Within the AZSAND/BBDP cohort, Syn RT-QuIC identified neuropathologically verified "standard LBD" (i.e. PD, PD with AD and DLB; n=25) vs. no LB pathology (n=53) with high sensitivity (100%) and specificity (94%). Only 57% were Syn RT-QuIC positive in the subgroup with "non-standard" LBD (i.e., AD with Lewy Bodies not meeting criteria for DLB or PD, and incidental LBD, n=23). Furthermore, Syn RT-QuIC reliably identified cases with LB pathology in the cortex (97% sensitivity) vs. cases with no LBs or LBs present only in the olfactory bulb (93% specificity). However, the sensitivity was low, only 50%, for cases with LB pathology restricted to the brainstem or amygdala, not affecting the allocortex or neocortex. In conclusion, Syn RT-QuIC of CSF samples is highly sensitive and specific for identifying cases with clinicopathologically-defined Lewy body disorders and shows a lower sensitivity for non-standard LBD or asymptomatic LBD or in cases with modest LB pathology not affecting the cortex. | neurology |
10.1101/2022.05.04.22274679 | Synaptic resilience is associated with maintained cognition during ageing | INTRODUCTIONIt remains unclear why age increases risk of Alzheimers disease and why some people experience age-related cognitive decline in the absence of dementia. Here we test the hypothesis that resilience to molecular changes in synapses contribute to healthy cognitive ageing.
METHODSWe examined post-mortem brain from people in mid-life (n=15), healthy ageing with either maintained cognition (n=8) or lifetime cognitive decline (n=7), and Alzheimers disease (n=13). Synapses were examined with high resolution imaging, proteomics, and RNA sequencing. Stem cell-derived neurons were challenged with Alzheimers brain homogenate.
RESULTSSynaptic pathology increased, and expression of genes involved in synaptic signalling decreased between mid-life, healthy ageing and Alzheimers. In contrast, brain tissue and neurons from people with maintained cognition during ageing exhibited decreases in synaptic signalling genes compared to people with cognitive decline.
DISCUSSIONEfficient synaptic networks without pathological protein accumulation may contribute to maintained cognition during ageing. | neurology |
10.1101/2022.05.05.22274419 | Deep-PheWAS: a pipeline for phenotype generation and association analysis for phenome-wide association studies. | SummaryDeep-PheWAS is a platform for phenome wide association studies that creates clinically-curated composite phenotypes, and integrates quantitative phenotypes from primary care data, longitudinal trajectories of quantitative measures, disease progression, and drug response phenotypes. Tools are provided for efficient analysis of association with any genetic input, under any genetic model, with optional sex-stratified analysis, and for developing novel phenotypes.
Availability and ImplementationThe Deep-PheWAS pipeline is freely available under GNU general public licence v3.0 at https://github.com/Richard-Packer/Deep-PheWAS.
[email protected]
Supplementary informationSupplementary methods and results are available at Bioinformatics online. | genetic and genomic medicine |
10.1101/2022.05.06.22274754 | Use of Low-Dose Decitabine with or without Tyrosine Kinase Inhibitors in Advanced Phase Chronic Myelogenous Leukemia: A Systemic Review and Metaanalysis | Subject Area: Hematology Title: USE OF LOW-DOSE DECITABINE WITH OR WITHOUT TYROSINE KINASE INHIBITORS IN ADVANCED PHASE CHRONIC MYELOGENOUS LEUKEMIA: A SYSTEMIC REVIEW AND METAANALYSIS Author List: Maureen Via M. Comia, MD, FPCP, Charles Eryll S. Sy, MD, FPCP, Jomell C. Julian, MD, FPCP, FPCHTM1 1Section of Clinical Hematology, University of Santo Tomas Hospital, Espana, Manila Philippines 1008 ABSTRACT Rationale: Progression of Chronic Myelogenous Leukemia (CML) to more advanced phases can involve hypermethylation, which is correlated to resistance or intolerance to imatinib. This hypermethylation has also been found to be a negative prognostic factor independent of imatinib response and from CML phase, thus decitabine, a hypomethylating agent, can be an attractive treatment option for advanced phase CML. Objective: This systemic review and meta-analysis aims to investigate the role of low-dose decitabine among patients with advanced phase CML. Methodology: This was performed according to the statement of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Results: Four (4) studies from 86 articles screened were eligible to be assessed in this systemic review and meta-analysis. These were phase I/II trials involving 81 advanced phase CML patients and used low-dose decitabine (5 to 20 mg/m2), with two studies using tyrosine kinase inhibitors. Outcomes of hematologic and cytogenetic response, and survival were assessed in the meta-analysis; with hematologic response being favored among advanced phase CML patients upon exposure with low-dose decitabine (p=0.05). Survival was also favored among responders to low-dose decitabine, however this was not significant. Discussion and Conclusion: Low-dose decitabine can be an effective and safe treatment option in advanced phase CML, especially in more frail patients that could not tolerate more intensive chemotherapy regimens. However, this study is limited by few studies available on this topic, thus further randomized controlled trials can be investigated to define the role of decitabine and its optimal dose among this subset of patients. Keywords: Chronic myelogenous leukemia, Decitabine, Advanced phase Conflict of Interest: The authors have no conflict of interest to declare regarding the publication of this article. Funding Source: None Corresponding Author: Maureen Via M. Comia, MD, FPCP [email protected] +639178396329 | hematology |
10.1101/2022.05.04.22274665 | School immunization coverage during the COVID-19 pandemic: A retrospective cohort study | Few studies have assessed the impact of the COVID-19 pandemic on immunization coverage for adolescents, and little is known about how coverage has changed throughout the pandemic. We aimed to: (1) assess the change in coverage for school-based vaccines in Alberta, Canada resulting from the pandemic; (2) determine whether coverage differed by geographic health zone and school type; and (3) ascertain whether coverage has returned to pre-pandemic levels. Using a retrospective cohort design, we used administrative health data to compare coverage for human papillomavirus (HPV) and meningococcal conjugate A, C, Y, W-135 (MenC-ACYW) vaccines in Alberta, Canada between pre-pandemic (2017-2018 school year) and pandemic (2019-2020 and 2020-2021 school years) cohorts (N=289,420). Coverage was also compared by health zone and authority type. The 2019-2020 cohort was followed over one year to assess catch-up. Compared to 2017-2018, immunization coverage for HPV was significantly lower in the 2019-2020 (absolute difference: 60.8%; 95% CI: 60.4-61.3%) and 2020-2021 cohorts (absolute difference: 59.9%; 95% CI: 59.4-60.3%). There was a smaller, significant decline in MenC-ACYW coverage comparing 2017-2018 to 2019-2020 (absolute difference: 6.1%; 95% CI: 5.6-6.5%) and 2020-2021 (absolute difference: 32.2%; 95% CI: 31.6-32.7%). Private schools had low coverage overall, while coverage fluctuated by zone. During follow-up of the 2019-2020 cohort, coverage for HPV and MenC-ACYW increased from 5.6% to 50.2%, and 80.7% to 83.0%, respectively. There was a substantial decrease in school-based immunization coverage during the COVID-19 pandemic, and coverage has not returned to pre-pandemic levels, suggesting further catch-up is needed. | epidemiology |
10.1101/2022.05.05.22274583 | A blueprint for biobanking in everyday clinical practice in psychiatry: The Munich Mental Health Biobank | Translational research on complex, multifactorial mental health disorders, such as bipolar disorder, major depressive disorder, schizophrenia, and substance use disorders requires databases with large-scale, harmonized, and integrated real-world and research data.
The Munich Mental Health Biobank (MMHB) is a mental health-specific biobank that was established in 2019 to collect, store, connect, and supply such high-quality phenotypic data and biospecimens from patients and study participants, including healthy controls, recruited at the Department of Psychiatry and Psychotherapy and the Institute of Psychiatric Phenomics and Genomics, University Hospital of the Ludwig-Maximilians-University (LMU), Munich, Germany. Participants are asked to complete a questionnaire that assesses sociodemographic and cross-diagnostic clinical information, provide blood samples, and grant access to their existing medical records. The generated data and biosamples are available to both academic and industry researchers. In the current manuscript, we outline the workflow and infrastructure of the MMHB, describe the clinical characteristics and representativeness of the sample collected so far, and reveal future plans for expansion and application.
As of October 31, 2021, the MMHB contains a continuously growing set of data from 578 patients and 104 healthy controls (46.37% female; median age, 38.31 years). The five most common mental health diagnoses in the MMHB are recurrent depressive disorder (38.78%; ICD-10: F33), alcohol-related disorders (19.88%; ICD-10: F10), schizophrenia (19.69%; ICD-10: F20), depressive episode (15.94%; ICD-10: F32), and personality disorders (13.78%; ICD-10: F60). Compared with the average patient treated at the recruiting hospitals, MMHB participants have significantly more mental health-related contacts, less severe symptoms, and a higher level of functioning. The distribution of diagnoses is also markedly different in MMHB participants compared with individuals who did not participate in the biobank.
After establishing the necessary infrastructure and initiating recruitment, the major tasks for the next phase of the MMHB project are to improve the pace of participant enrollment, diversify the sociodemographic and diagnostic characteristics of the sample, and improve the utilization of real-world data generated in routine clinical practice. | psychiatry and clinical psychology |
10.1101/2022.05.06.22274666 | Impaired functional connectivity in patients with psychosis and visual hallucinations | Backgroundmore than one-third of patients with psychosis experience visual hallucinations, but the underlying pathomechanism remains largely unknown. Although schizophrenia is related to altered brain functional connectivity, it is unknown how this could predispose patients to experience visual hallucinations. Previous work suggested that this predisposition is caused by alterations in vision-related networks, including the Visual Network, possibly with a specific focus on the Ventral Attention Network 1. This network responds to salient stimuli from the Visual Network and operates as a switch between the internally-focused Default Mode Network and the outside-world-focused Dorsal Attention Network.
Methodsin this case control study we investigated the role of these networks in three groups: 14 participants with a psychotic disorder and visual hallucinations, 15 participants with a psychotic disorder without visual hallucinations, and 16 healthy controls. All patients underwent resting state functional Magnetic Resonance Imaging after which we determined the intra- and inter-network functional connectivity of these networks in all participants. We also used fast Eigenvector Centrality Mapping to determine the most central regions, i.e. the most functionally communicating regions, within these networks.
Resultscompared to healthy controls, patients with visual hallucinations had lower functional connectivity, both intra-network and inter-network, in all vision-related networks. This decrease was most prominent for the Ventral Attention Network and the Dorsal Attention Network for intra-network functional connectivity. Moreover, Eigenvector Centrality Mapping showed a severe decrease in functional communication within the Visual Network in the right intracalcarine sulcus, with a simultaneous increase in functional communication in the lateral part of the left middle occipital gyrus, a region involved in object recognition. The results of patients without hallucinations were generally in between patients with visual hallucinations and healthy controls.
Discussionour study shows that widespread dysconnectivity of predominantly vision-related functional networks may predispose patients with psychosis to generate visual hallucinations. These results are in line with previous models of hallucinations in psychosis which suggested that the processing deficits in the Visual Network may cause or exacerbate inadequate co-functioning and switching between the Default Mode Network and the Dorsal Attentional Network, possibly due to impaired Ventral Attention Network functioning. In combination with impaired attending of visual signals by the Dorsal Attentional Network, this may lead to inappropriate saliency processing and wrongly attributing an external origin to internally generated events and, consequently, to visual hallucinations. The often complex nature of psychotic visual hallucinations may be explained by the more central role of object processing regions. | psychiatry and clinical psychology |
10.1101/2022.05.06.22274674 | Grey matter morphometric biomarkers for classifying early schizophrenia and PD psychosis: a multicentre study | BackgroundPsychotic symptoms occur in a majority of schizophrenia patients, and in approximately 50% of all Parkinsons disease (PD) patients. Altered grey matter (GM) structure within several brain areas and networks may contribute to their pathogenesis. Little, however, is known about transdiagnostic similarities when psychotic symptoms occur in different disorders, such as schizophrenia and PD.
MethodsThe present study investigated a large, multicenter sample containing 722 participants: 146 patients with first episode psychosis, FEP; 106 individuals at-risk mental state for developing psychosis, ARMS; 145 healthy controls matching FEP and ARMS, Con-Psy; 92 PD patients with psychotic symptoms, PDP; 145 PD patients without psychotic symptoms, PDN; 88 healthy controls matching PDN and PDP, Con-PD. We applied source-based morphometry in association with receiver operating curves (ROC) analyses to identify common GM structural covariance networks (SCN) and investigated their accuracy in identifying the different patient groups. We assessed group-specific homogeneity and variability across the different networks and potential associations with clinical symptoms.
ResultsSCN-extracted GM values differed significantly between FEP and Con-Psy, PDP and Con-PD as well as PDN and Con-PD, indicating significant overall grey matter reductions in PD and early schizophrenia. ROC analyses showed that SCN-based classification algorithms allow good classification (AUC[~]0.80) of FEP and Con-Psy, and fair performance (AUC[~]0.72) when differentiating PDP from Con-PD. Importantly, best performance was found in partly overlapping networks including the precuneus. Finally, reduced GM volume in SCN with increased variability was linked to increased psychotic symptoms in both FEP and PDP.
ConclusionAlterations within selected SCNs seem to be related to the presence of psychotic symptoms in both early schizophrenia and PD psychosis, indicating some commonality of underlying mechanisms. Furthermore, results provide first evidence that GM volume within specific SCNs may serve as a biomarker for identifying FEP and PDP. | psychiatry and clinical psychology |
10.1101/2022.05.06.22274712 | A quasi-experimental cohort study evaluating a conditional economic incentive on first-dose COVID-19 vaccination rates among older adults in South Africa | Importance: COVID-19 vaccination coverage in South Africa remains low despite increased access to vaccines. On November 1, 2021, South Africa introduced the Vooma Voucher program, which provided a small guaranteed financial incentive, a Vooma Voucher redeemable at grocery stores, for COVID-19 vaccination among older adults, a population most vulnerable to serious illness, hospitalization, and death. However, the association of financial incentives with vaccination coverage remains unclear. Objective: To evaluate the association of the conditional economic incentive program with first-dose vaccination rates among older adults (aged [≥]60 years) in South Africa. Design: A quasi-experimental cohort study using daily data on first doses administered. We ran interrupted time series (ITS) models to evaluate the Vooma Voucher program, launched on November 1, 2021, at national and provincial levels. We used data between October 1, 2021 and November 27, 2021 in models estimated at the daily level. Setting and participants: The Vooma Voucher program was a nationwide vaccination incentive program implemented for adults aged [≥]60 years from November 1, 2021 to February 28, 2022. Intervention: Individuals who received their first vaccine dose received a text message to access a ~$7 (ZAR100) voucher that was redeemable at nationwide chain of grocery stores. Main outcome: Daily first COVID-19 vaccine doses administered per 10,000 individuals aged [≥]60 years. Results: The Vooma Voucher program was associated with a of 7.15-12.01% increase in daily first-dose vaccination in November 2021 compared to late October 2021. The incentive accounted for 6,476-10,874 additional first vaccine doses from November 1-27, 2021, or 8.31-13.95% of all doses administered to those aged [≥]60 years during that period. This result is robust to the inclusion of controls for the number of active vaccine delivery sites and for the nationwide Vooma weekend initiative (November 12-14), both of which also increased vaccinations through expanded access to vaccines and demand creation activities. Conclusions/Relevance: Financial incentives for COVID-19 vaccination led to a modest increase in first dose vaccinations among older adults in South Africa. In addition to financial incentives, expanded access to vaccines may also results in higher vaccination coverage. | public and global health |
10.1101/2022.05.06.22274712 | A quasi-experimental cohort study evaluating a conditional economic incentive on first-dose COVID-19 vaccination rates among older adults in South Africa | Importance: COVID-19 vaccination coverage in South Africa remains low despite increased access to vaccines. On November 1, 2021, South Africa introduced the Vooma Voucher program, which provided a small guaranteed financial incentive, a Vooma Voucher redeemable at grocery stores, for COVID-19 vaccination among older adults, a population most vulnerable to serious illness, hospitalization, and death. However, the association of financial incentives with vaccination coverage remains unclear. Objective: To evaluate the association of the conditional economic incentive program with first-dose vaccination rates among older adults (aged [≥]60 years) in South Africa. Design: A quasi-experimental cohort study using daily data on first doses administered. We ran interrupted time series (ITS) models to evaluate the Vooma Voucher program, launched on November 1, 2021, at national and provincial levels. We used data between October 1, 2021 and November 27, 2021 in models estimated at the daily level. Setting and participants: The Vooma Voucher program was a nationwide vaccination incentive program implemented for adults aged [≥]60 years from November 1, 2021 to February 28, 2022. Intervention: Individuals who received their first vaccine dose received a text message to access a ~$7 (ZAR100) voucher that was redeemable at nationwide chain of grocery stores. Main outcome: Daily first COVID-19 vaccine doses administered per 10,000 individuals aged [≥]60 years. Results: The Vooma Voucher program was associated with a of 7.15-12.01% increase in daily first-dose vaccination in November 2021 compared to late October 2021. The incentive accounted for 6,476-10,874 additional first vaccine doses from November 1-27, 2021, or 8.31-13.95% of all doses administered to those aged [≥]60 years during that period. This result is robust to the inclusion of controls for the number of active vaccine delivery sites and for the nationwide Vooma weekend initiative (November 12-14), both of which also increased vaccinations through expanded access to vaccines and demand creation activities. Conclusions/Relevance: Financial incentives for COVID-19 vaccination led to a modest increase in first dose vaccinations among older adults in South Africa. In addition to financial incentives, expanded access to vaccines may also results in higher vaccination coverage. | public and global health |
10.1101/2022.05.05.22274448 | Definition of normal vertebral morphology using NHANES-II radiographs | BackgroundA robust definition of normal is required to confidently identify vertebral abnormalities such as fractures. Between 1976 and 1980, the 2nd National Health and Nutrition Examination Survey (NHANES-II) was conducted. Justified by the prevalence of neck and back pain, approximately 10,000 lateral cervical spine and 7,000 lateral lumbar spine X-rays were collected. Demographic, anthropometric, health, and medical history data were also collected. This resource can be used for establishing normative reference data that can subsequently be used to diagnose abnormal vertebral morphology.
Purpose1) Develop normative reference data for vertebral morphology using the lateral spine radiographs from NHANES-II. 2) Document sources of variability.
Subject SampleNationwide probability sample to document health status of the United States.
MethodsThe coordinates of the four vertebral body corners were obtained using previously validated, automated technology consisting of a proprietary pipeline of neural networks and coded logic. These landmarks were used to calculate six vertebral body morphology metrics: 1) anterior/posterior vertebral body height ratio (VBHR); 2) superior/inferior endplate width ratio (EPWR); 3) forward/backward diagonal ratio (FBDR); 4) height/width ratio (HWR); 5: angle between endplates (EPA); 6) Angle between posterior wall and superior endplate (PSA). Descriptive statistics were generated and used to identify and trim outliers from the data and obtain a gaussian distribution for each metric. Descriptive statistics were tabulated using the trimmed data for use in quantifying deviation from average for each metric. The dependency of these metrics on sex, age, race, nation of origin, height, weight, and BMI was also assessed.
ResultsComputer generated lumbar landmarks were obtained for 42,980 vertebrae from lumbar radiographs and 54,093 vertebrae from cervical radiographs for subjects 25 to 74 years old. After removing outliers, means and standard deviations for the remaining 35,275 lumbar and 44,938 cervical vertebrae changed only slightly, suggesting that normal morphology and intervertebral alignment is dominant in the data. There was low variation in vertebral morphology after accounting for vertebra (L1, L2, etc.), and the R2 was high for analyses of variance. The EPWR, FBDR and PSA generally had the lowest coefficients of variation. Excluding outliers, Age, sex, race, nation of origin, height, weight, and BMI were statistically significant for most of the variables, though the F-statistic was very small compared to that for vertebral level. Excluding all variables except vertebra changed the R2 very little (e.g. for the lumbar data, VBHR R2 went from 0.804 to 0.795 and FBDR R2 went from 0.9005 to 0.9000). Reference data were generated that can be used to produce standardized metrics in units of standard deviation from average. This allows for easy identification of abnormalities resulting from vertebral fractures, atypical vertebral body morphologies, and other congenital or degenerative conditions. Standardized metrics also remove the effect of vertebra thereby enabling data for all vertebrae to be pooled in research studies.
ConclusionsThe NHANES-II collection of spine radiographs and associated data may prove to be a valuable resource that can facilitate standardized spine metrics useful for objectively identifying abnormalities. The data may be particularly valuable for identification of vertebral fractures, although X-rays taken early in life would be needed in some cases to differentiate between normal anatomic variants, fractures, and vertebral shape remodeling. | radiology and imaging |
10.1101/2022.05.05.22274628 | The I-SPY COVID Adaptive Platform Trial for COVID-19 Acute Respiratory Failure: Rationale, Design and Operations | IntroductionThe COVID-19 pandemic brought an urgent need to discover novel effective therapeutics for patients hospitalized with severe COVID-19. The ISPY COVID trial was designed and implemented in early 2020 to evaluate investigational agents rapidly and simultaneously on a phase 2 adaptive platform. This manuscript outlines the design, rationale, implementation, and challenges of the ISPY COVID trial during the first phase of trial activity from April 2020 until December 2021.
Methods and analysisThe ISPY COVID Trial is a multi-center open label phase 2 platform trial in the United States designed to evaluate therapeutics that may have a large effect on improving outcomes from severe COVID-19. The ISPY COVID Trial network includes academic and community hospitals with significant geographic diversity across the country. Enrolled patients are randomized to receive one of up to four investigational agents or a control and are evaluated for a family of two primary outcomes--time to recovery and mortality. The statistical design uses a Bayesian model with "stopping" and "graduation" criteria designed to efficiently discard ineffective therapies and graduate promising agents for definitive efficacy trials. Each investigational agent arm enrolls to a maximum of 125 patients per arm and is compared to concurrent controls. As of December 2021, 11 investigational agent arms had been activated, and 8 arms were complete. Enrollment and adaptation of the trial design is ongoing.
Ethics and disseminationISPY COVID operates under a central institutional review board via Wake Forest School of Medicine IRB00066805. Data generated from this trial will be reported in peer reviewed medical journals.
Trial registration numberClinicaltrials.gov registration number NCT04488081
Strengths and limitations of this studyO_LIThe ISPY COVID Trial was developed in early 2020 to rapidly and simultaneously evaluate therapeutics for severe COVID-19 on an adaptive open label phase 2 platform
C_LIO_LIThe ISPY COVID Adaptive Platform Trial Network is an academic-industry partnership that includes academic and community hospitals spanning a wide geographic area across the United States
C_LIO_LIOf December 2021, 11 investigational agent arms have been activated on the ISPY COVID Trial Platform
C_LIO_LIThe ISPY COVID Trial was designed to identify therapeutic agents with a large clinical effect for further testing in definitive efficacy trials--limitations to this approach include the risk of a type 2 error
C_LI | respiratory medicine |
10.1101/2022.05.05.22274750 | Reduced motor unit discharge rates in gastrocnemius lateralis, but not in gastrocnemius medialis or soleus, in runners with Achilles tendinopathy | ObjectivesDeficits in muscle performance could be a consequence of a reduced ability of a motor neuron to increase the rate in which it discharges. This study aimed to investigate motor unit (MU) discharge properties of each Triceps surae muscle (TS), and TS torque steadiness during submaximal intensities in runners with Achilles tendinopathy (AT).
MethodsWe recruited runners with (n=12) and without (n=13) mid-portion AT. MU discharge rate was analysed for each of the TS muscles, using High-Density surface electromyography during 10 and 20% isometric plantar flexor contractions.
ResultsMU mean discharge rate was lower in the Gastrocnemius lateralis (GL) in AT compared to controls. In AT, GL MU mean discharge rate did not increase as torque increased from 10% peak torque, 8.24pps (95%CI: 7.08 to 9.41) to 20%, 8.52pps (7.41 to 9.63, p=0.540); however, in controls, MU discharge rate increased as torque increased from 10%, 8.39pps (7.25 to 9.53) to 20%, 10.07pps (8.89 to 11.25, p<0.001). There were no between-group difference in Gastrocnemius medialis (GM) or Soleus (SOL) MU discharge rates. We found no between-groups differences in coefficient of variation of MU discharge rate in any of the TS muscles nor in TS torque steadiness.
ConclusionOur data demonstrates that runners with AT may have a reduced neural drive to GL, failing to increase MU discharge rate to adjust for the increase in torque demand. Further research is needed to understand how interventions focusing on increasing neural drive to GL would affect muscle function in runners with AT. | sports medicine |
10.1101/2022.05.06.22274708 | HOXA Amplification Defines a Genetically Distinct Subset of Angiosarcomas | Angiosarcoma is a rare, devastating malignancy with few curative options for disseminated disease. We analyzed a recently published genomic data set of 48 angiosarcomas and noticed recurrent amplifications of HOXA cluster genes in 33% of patients. HOXA genes are master regulators of embryonic vascular development and adult neovascularization, which provides a molecular rationale to suspect that amplified HOXA genes act as oncogenes in angiosarcoma. HOXA amplifications typically affected multiple pro-angiogenic HOXA genes and co-occurred with amplifications of CD36 and KDR, whereas the overall mutation rate in these tumors was relatively low. HOXA amplifications were found most commonly in angiosarcomas located in the breast, and were rare in angiosarcomas arising in sun-exposed areas on the head, neck, face and scalp. Our data suggest that HOXA amplified angiosarcoma is a distinct molecular subgroup. Efforts to develop therapies targeting oncogenic HOX gene expression in AML and other sarcomas may have relevance for HOXA amplified angiosarcoma. | oncology |
10.1101/2022.05.06.22274773 | Comparing human and AI performance in medical machine learning: An open-source Python library for the statistical analysis of reader study data | In seeking to understand the potential effects of artificial intelligence (AI) on the practice of diagnostic medicine, many investigations involve collecting interpretations from several human experts on a common set of cases. In an effort to standardize the process of analyzing the data emerging from such studies, we have released an open-source Python library to perform applicable statistical procedures. The software implements the industry-standard Obuchowski-Rockette-Hillis (ORH) method for multi-reader multi-case (MRMC) studies. The tools can be used to compare a standalone algorithm against a panel of readers, or compare readers operating in two modalities (for example, with and without algorithmic assistance). The software supports both nonequivalence and noninferiority tests. Functions are also provided to simulate reader and model scores, useful for Monte Carlo power analysis. The code is publicly available in our Gitub repository at https://github.com/Google-Health/google-health/tree/master/analysis. | health informatics |