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10.1101/2022.03.24.22272877 | Mass Homicide by Firearm in Canada: Effects of Legislation | Canada implemented a series of laws regulating firearms including background checks and licensing, references, psychological questionnaires, prohibition of paramilitary style rifles, and magazine capacity restrictions in order to decrease the incidences and deaths from mass shootings. The associated effects of these laws were examined over the years 1974 to 2020.
A model was constructed using difference-in-differences analysis of firearms and non-firearms mass homicide incidences and death rates. Mass homicides were defined as a homicide due to one event involving three or more deaths.
Incidence rates of mass homicide by firearm were found to be 0.11 (95%CI 0.08, 0.14) per million compared to a non-firearm mass homicide rate of 0.12 (95% CI 0.10, 0.15) per million. Mass homicide death rates by firearm were found to be 0.39 (95% CI 0.29, 0.49) per million compared to a non-firearm mass homicide rate of 0.47 (95% CI 0.34, 0.61) per million. Overall, there is a gradual declining trend in the incidence of mass homicide by firearm (IRR 0.97 (95% CI 0.96, 0.98)) and by non-firearm (IRR 0.97 (95% CI 0.97, 0.98)). The decline in mass homicide death rate by firearm and non-firearm is IRR 0.96 (95% CI 0.95, 0.97), and IRR 0.97 (95% CI 0.96, 0.98) respectively.
No associated decrease in mass homicide incidence rates or death rates with firearms legislation was found after the implementation of background checks and prohibition of full auto firearms in 1980, by the implementation of references and psychological questionnaires in 1994, by the restriction of magazine capacity in 1994, the prohibition of paramilitary rifles in 1994, or licensing in 2001. | health policy |
10.1101/2022.03.29.22273098 | Symptom Management When Non-Invasive Advanced Respiratory Support is Used During End-of-Life Care: A Systematic Review | Objectivesto narrate the canon of knowledge around symptom control at end of life for patients using, or having recently used, non-invasive advanced respiratory support (NARS) at end of life for respiratory failure.
MethodsA systematic review forming a narrative synthesis from a wide range of sample papers from Medline, Embase, CINAHL, Emcare, Cochrane and OpenGrey databases. A secondary search of grey literature was also performed with hand searching reference lists and author citations. The review was undertaken using the ENTREQ checklist for quality.
ResultsIn total 15 studies were included in the synthesis and four themes were generated: NARS as a buoy (NARS can represent hope and relief from the symptoms of respiratory failure), NARS as an anchor (NARS brings significant treatment burden), Impact on Staff (uncertainty over the balance of benefit and burden as well as complex patient care drives distress amongst staff providing care) and the Process of Withdrawal (withdrawal of therapy felt to be futile exists as discrete event in patient care but is otherwise poorly defined).
ConclusionNARS represents a complex interplay of hope, symptom control, unnaturally prolonged death and treatment burden. The literature captures the breadth of these issues but further, detailed, research is required in almost every aspect of practice around end-of-life care and NARS - especially how to manage symptoms at the end of life. | palliative medicine |
10.1101/2022.03.29.22273093 | Severe outcomes in unvaccinated COVID-19 cases <18 years during different variant waves in Norway | ObjectivesWe used linked individual-level data from national registries to compare the risk of severe outcomes among unvaccinated COVID-19 cases <18 years between waves of the SARS-CoV-2 Alpha, Delta and Omicron variants in Norway.
MethodsOur outcomes were hospitalisation with acute COVID-19 or multisystem inflammatory syndrome in children (MIS-C). We calculated adjusted risk ratios (aRR) with 95% confidence intervals (CIs) using multivariable log-binomial regression, adjusting for variant wave, demographic characteristics and underlying comorbidities.
ResultsWe included 10,538 Alpha (21 hospitalised with acute COVID-19, 7 MIS-C), 42,362 Delta (28 acute COVID-19, 14 MIS-C) and 82,907 Omicron wave cases (48 acute COVID-19, 7 MIS-C). The risk of hospitalisation with acute COVID-19 in cases <1 year was lower in the Delta (aRR: 0.28, 95% CI: 0.16-0.89) and Omicron wave (aRR: 0.41, 95% CI: 0.20-0.81), compared to the Alpha wave. We found no difference in the risk for this outcome for Omicron compared to Delta in any age group. The risk of MIS-C was lower in the Omicron wave compared to the Alpha (aRR: 0.09, 95% CI: 0.03-0.27) and Delta wave (aRR: 0.26, 95% CI: 0.10-0.63).
ConclusionsWe found no evidence of a difference in the risk of hospitalisation due to acute COVID-19 among unvaccinated cases <18 years for Omicron compared to Delta, but a reduced risk among cases <1 year in Omicron and Delta waves, compared to Alpha. Results also suggest a decrease in the risk of MIS-C in the Omicron wave compared to the Alpha and Delta waves.
Article SummaryWe compare the risk of severe outcomes in unvaccinated COVID-19 cases <18 years between waves of the SARS-CoV-2 Alpha, Delta and Omicron variant in Norway.
Whats Known on This SubjectCurrently, limited evidence suggests no clear difference in the risk of severe disease outcomes among children infected with different SARS-CoV-2 variants. The risk of multisystem inflammatory syndrome in children following infection with the Omicron variant has not been quantified.
What This Study AddsWe find a lower risk of hospitalisation due to acute COVID-19 among cases <1 year in the Delta and Omicron waves compared to the Alpha wave, and a lower risk of multisystem inflammatory syndrome in the Omicron wave, in Norway. | pediatrics |
10.1101/2022.03.29.22273086 | Age and product dependent vaccine effectiveness against SARS-CoV-2 infection and hospitalisation among adults in Norway: a national cohort study, July - November 2021. | BackgroundCOVID-19 vaccines have been crucial in the pandemic response and understanding changes in vaccines effectiveness is essential to guide vaccine policies. Though the Delta variant is no longer dominant, understanding vaccines effectiveness properties will provide essential knowledge to comprehend the development of the pandemic and estimate potential changes over time.
MethodsIn this population-based cohort study, we estimated vaccine effectiveness against SARS-CoV-2 infections, hospitalisations, intensive care admissions, and death using Cox proportional hazard models, across different vaccine product regimens and age groups, between 15 July and 31 November 2021 (Delta variant period). Vaccine status is included as a time-varying covariate and all models were adjusted for age, sex, comorbidities, county of residence, country of birth, and living conditions. Data from the entire adult Norwegian population were collated from the National Preparedness Register for COVID-19 (Beredt C19).
ResultsThe overall adjusted vaccine effectiveness against infection decreased from 81.3% (confidence interval (CI): 80.7 to 81.9) in the first two to nine weeks after receiving a second dose to 8.6% (CI:4.0 to 13.1) after more than 33 weeks, compared to 98.6% (CI: 97.5 to 99.2) and 66.6% (CI: 57.9 to 73.6) against hospitalisation respectively. After the third dose (booster), the effectiveness was 75.9% (CI: 73.4 to 78.1) against infection and 95.0% (CI: 92.6 to 96.6) against hospitalisation. Spikevax or a combination of mRNA products provided the highest protection, but the vaccine effectiveness decreased with time since vaccination for all vaccine regimens.
ConclusionsEven though the vaccine effectiveness against infection wanes over time, all vaccine regimens remained effective against hospitalisation after the second vaccine dose. For all vaccine regimens, a booster facilitated recovery of effectiveness. The results from this support the use of heterologous schedules, increasing flexibility in vaccination policy.
Fundingno external funding | public and global health |
10.1101/2022.03.29.22273094 | Systematic literature review examining the mere-measurement effect of patient reported measures: the interaction of emotional valence and frequency of exposure as an independent factor in patient change | The use of patient-reported outcome (PROs) have become increasingly commonplace across many healthcare settings over the past two decades. The value of PROs is now acknowledged by healthcare providers and patients alike. However, to date, little is known about the best practices for formulating PRO measures (PROMS), but even more specifically, the effect had on the responding patients as a result of item word choice, emotional valence, or frequency of use. That is, 1) does the positive or negative wording of items affect the patients perspective on the latent variable, 2) is there a degree of subliminal influence or measurement effects on their behaviour resulting from exposure to PROs, and finally, 3) is such an effect amplified with repeated exposure? | public and global health |
10.1101/2022.03.25.22272954 | Psychosocial factors affecting COVID-19 vaccine uptake in the UK: a prospective cohort study (CoVAccS - wave 3) | BackgroundWe investigated factors associated with COVID-19 vaccine uptake, future vaccination intentions, and changes in beliefs and attitudes over time.
MethodsProspective cohort study. 1500 participants completed an online survey in January 2021 (T1, start of vaccine rollout in the UK), of whom 1148 (response rate 76{middle dot}5%) completed another survey in October 2021 (T2, all UK adults offered two vaccine doses). Binary logistic regression analysis was used to investigate factors associated with subsequent vaccine uptake. Content analysis was used to investigate the main reasons behind future vaccine intentions (T2). Changes in beliefs and attitudes were investigated using analysis of variance.
FindingsAt T2, 90{middle dot}0% (95% CI 88{middle dot}2%-91{middle dot}7%) of participants had received two doses of a COVID-19 vaccine, 2{middle dot}2% (95% CI 1{middle dot}3%-3{middle dot}0%) had received one dose, and 7{middle dot}4% (95% CI 5{middle dot}9%-8{middle dot}9%) had not been vaccinated. Uptake was associated with higher intention to be vaccinated at T1, greater perceived vaccination social norms, necessity of vaccination, and perceived safety of the vaccine. People who had initiated vaccination reported being likely to complete it, while those who had not yet received a vaccine reported being unlikely to be vaccinated in the future. At T2, participants perceived greater susceptibility to, but lower severity of, COVID-19 (p<0.001), than T1. Perceived safety and adequacy of vaccine information were higher (p<0.001).
InterpretationTargeting modifiable beliefs about the safety and effectiveness of vaccination may increase uptake.
FundingData collection was funded by a Keele University Faculty of Natural Sciences Research Development award and a Kings COVID Appeal Fund award.
Research in contextO_ST_ABSEvidence before this studyC_ST_ABSCOVID-19 vaccination intention was high at the start of the vaccine rollout in the UK. Research suggests that psychosocial factors are associated with vaccine uptake. However, most research on uptake of the COVID-19 vaccine has investigated factors associated with vaccination intention, and used a cross-sectional design.
Added value of this studyWe used a prospective cohort study (T1 conducted in January 2021, the start of the UK vaccine rollout; T2 conducted in October 2021, all UK adults offered two vaccine doses) to investigate factors associated with subsequent COVID-19 vaccination. Qualitative data on the main supporting reasons for future vaccination intentions in those partially or not vaccinated were analysed using content analysis. Changes in vaccine beliefs and attitudes (generally and COVID-19 specific) were also analysed.
Implications of all the available evidenceIn our sample, more people reported having been vaccinated than had previously reported intending to be vaccinated. Vaccine uptake was strongly associated with previous vaccination intention, perceived social norms of vaccination, and greater perceived necessity and safety of vaccination. Those who had received at least one COVID-19 vaccine reported being likely to complete the schedule, whereas those who had not received a vaccine reported being unlikely to receive a vaccine. | public and global health |
10.1101/2022.03.30.22273165 | Effect of COVID-19 vaccination on menstrual periods in a prospectively recruited cohort | COVID-19 vaccination protects against the potentially serious consequences of SARS-CoV2 infection, but some people have been hesitant to receive the vaccine because of reports that it could affect menstrual bleeding. To determine whether this occurs, we prospectively recruited a cohort of 79 individuals, each of whom recorded details of at least three consecutive menstrual cycles, during which time they each received at least one dose of COVID-19 vaccine. We find that either dose of the COVID-19 vaccine is associated with a delay to the subsequent period in spontaneously cycling participants (2.3 days after dose 1; 1.3 days after dose 2) but this change rapidly reverses. No change to timing was detected in those on hormonal contraception. We detected no change in menstrual flow associated with either dose of the vaccine, in either spontaneously cycling participants or those on hormonal contraception. We detected no association between menstrual changes and other commonly-reported side effects of vaccination, such as sore arm, fever and fatigue. | sexual and reproductive health |
10.1101/2022.03.29.22273154 | Prediction of gestational diabetes mellitus using early oral glucose tolerance test | IntroductionGestational Diabetes Mellitus (GDM) is defined as diabetes first detected at the second or third trimester of pregnancy, excluding preexisting diabetes. We aimed to build a predictive model of GDM using booking oral glucose tolerance test (OGTT) values.
Materials and MethodsSeventy-five healthy mothers who underwent 75g OGTT at 12-14 weeks and at 24-28 weeks were recruited. GDM was diagnosed at 28 weeks by cutoffs proposed by the Hyperglycemia and Adverse Pregnancy Outcomes study.
Sensitivities and specificities for diagnosing GDM using different cut-offs for each of the three booking OGTT variables were measured. A series of multivariate binary logistic regression models were fitted using different combinations of the three booking OGTT variables. In-sample sensitivities and specificities for different cutoff probabilities of the models were calculated and Receiver Operating Characteristic (ROC) curves were constructed. The Area Under the Curve (AUC) of the ROC curve and the best cutoff value which maximized the sum of sensitivity and specificity of each model were computed.
ResultsAUC of ROC curves for isolated fasting, 1 hour and 2 hour booking OGTT values for the prediction of GDM were 69.8%, 67.1% and 61.0% respectively. However, the logistic regression model with fasting and 1 hour booking OGTT values as predictors out-performed all other models with an AUC of 76.3%, in-sample sensitivity of 87.5% and a negative predictive value of 95.12%.
ConclusionsThe future occurrence of GDM can be predicted utilizing a logistic model with fasting and 1 hour booking OGTT variables, which enables early identification and intervention. | obstetrics and gynecology |
10.1101/2022.03.30.22273183 | Design, Development, and Usability Evaluation of a Voice App Experience for Heart Failure Management | The use of digital therapeutics (DTx) in the prevention and management of medical conditions has increased through the years with an estimated 44 million people using one as part of their treatment plan in 2021, nearly double the amount from last year. DTx are commonly accessed through smartphone apps, but offering these treatments through an alternative input can improve the accessibility of these interventions. Voice apps are an emerging technology in the digital health field, and may be an appropriate alternative platform for some patients. This research aimed to identify the acceptability and feasibility of offering a voice app as an alternative input for a chronic disease self-management program. The objective of this project was to design, develop, and evaluate a voice app of an already existing smartphone-based heart failure self-management program, Medly, to be used as a case study. A voice app version of Medly was designed and developed through a user-centered design process. We conducted a usability study and semi-structured interviews with representative end users (n=8) at the Peter Munk Cardiac Clinic in Toronto General Hospital to better understand the user experience. A Medly voice app prototype was built using a software development kit in tandem with a cloud computing platform. Three out of the eight participants were successful in completing the usability session, while the rest of the participants were not due to various errors. Almost all (7 out of the 8) participants were satisfied with the voice app and felt confident using it. Half of the participants were unsure about using the voice app in the future, though. With these findings, design changes were made to better improve the user experience. With rapid advancements in voice user interfaces, we believe this technology will play an integral role when providing access to DTx for chronic disease management. | health informatics |
10.1101/2022.03.29.22273127 | Reproductive health needs of Human papillomavirus (HPV) Positive women: A systematic review | BackgroundHuman papillomavirus is one of the most important transmitted viruses that causes of cervical cancer.
In women undergoing cervical screening, it is important to be aware of ways to reduce anxiety. The present systematic review conducted to determine the reproductive health needs of women with HPV.
MethodsIn this systematic review, articles without time constraints searched in PubMed, Scopus, Web of Science, Google Scholar and Iranian Magiran, SID and Iranmedex.
Keywords used: HPV, Information, Want, Need, Know, etc. and their Persian equivalents in the title and abstract of the articles.
Papers after identification by two researchers Contradictions evaluated and discussed with the third author.
ResultsAt first 1056articles retrieved which after removing,13articles published between2004-2021were entered. The studies were qualitative(N=9),quantitative(N=3), and one was unclear.Most qualitative studies collected data using individual interviews(N=7), two qualitative studies, narratives of HPV patients from a website of patient experiences and questions. The quality evaluation showed that good=8, Average=2, and one was of poor. There is not enough information about Friedman AL etal and Garland SM articles to check the quality, but since these studies were valuable, they included in the study according to the opinion of the research team.
ConclusionSurveys showed that the majority of women had unanswered questions about their HPV test results. The information that women thought was helpful in interpreting their test results included having a high-risk type of HPV, the risk of short-term and long-term cancer, and cancer survival statistics for the virus. Women also needed information about sexual transmission, how HPV tested positive in a long-term relationship, and the potential consequences for their partners and the risk of re-infection. Younger women had questions about whether HPV could affect fertility. | health systems and quality improvement |
10.1101/2022.03.28.22273033 | Key topics in pandemic health risk communication: A qualitative study of expert opinions and knowledge | BackgroundScience communication can provide people with more accurate information on pandemic health risks by translating complex scientific topics into language that helps people make more informed choices on how to protect themselves and others. During pandemics, experts in medicine, science, public health, and communication are important sources of knowledge for science communication. This study uses the COVID-19 pandemic to explore these experts opinions and knowledge of what to communicate to the public during a pandemic. The research question is: What are the key topics to communicate to the public about health risks during a pandemic?
MethodWe purposively sampled 13 experts in medicine, science, public health, and communication for individual interviews, with a range of different types of knowledge of COVID-19 risk and communication at the national, regional and hospital levels in Norway. The interview transcripts were coded and analysed inductively in a qualitative thematic analysis.
ResultsThe studys findings emphasise three central topics pertaining to communication about pandemic health risk during the first year of the COVID-19 pandemic in Norway: 1) how the virus enters the human body and generates disease; 2) how to protect oneself and others from being infected; and 3) pandemic health risk for the individual and the society.
ConclusionThe key topics emerging from the expert interviews relate to concepts originating from multiple disciplinary fields, and can inform frameworks for interprofessional communication about health risks during a pandemic. The study highlights the complexity of communicating pandemic messages, due to scientific uncertainty, fear of risk amplification, and heterogeneity in public health and scientific literacy. The study contributes with insight into the complex communication processes of pandemic health risk communication. | health systems and quality improvement |
10.1101/2022.03.24.22272837 | Prior vaccination enables a more robust immune response to Omicron infection | The antibody response following Omicron infection has been reported to be less robust than to other variants. Here we compared the immune-transcriptome and antibody responses following Omicron infection in unvaccinated and vaccinated individuals who experienced mild to moderate symptoms. The unvaccinated individuals showed a quantitatively greater transcriptional response but a muted antibody response than vaccinated individuals. Prior vaccination modifies the transcriptional response to Omicron infection with a more robust antibody response. | infectious diseases |
10.1101/2022.03.29.22273044 | Reduction in risk of death among patients admitted with COVID-19 between first and second epidemic waves in New York City | Many regions have experienced successive epidemic waves of COVID-19 since the emergence of SARS-CoV-2 with heterogeneous differences in mortality. Elucidating factors differentially associated with mortality between epidemic waves may inform clinical and public health strategies. We examined clinical and demographic data among patients admitted with COVID-19 during the first (March-June 2020) and second (December 2020-March 2021) epidemic waves at an academic medical center in New York City. Hospitalized patients (N=4631) had lower mortality during the second wave (14%) than the first (23%). Patients in the second wave had a lower 30-day mortality (Hazard Ratio (HR) 0.52, 95% CI 0.44, 0.61) than those in the first wave. The mortality decrease persisted after adjusting for confounders except for the volume of COVID-19 admissions (HR 0.88, 95% CI 0.70, 1.11), a measure of health system strain. Several demographic and clinical patient factors were associated with an increased risk of mortality independent of wave.
Article summaryUsing clinical and demographic data from COVID-19 hospitalizations at a tertiary New York City medical center, we show that a reduction in mortality during the second epidemic wave was associated with decreased strain on healthcare resources. | infectious diseases |
10.1101/2022.03.27.22273000 | Nationwide Effectiveness of First and Second SARS-CoV2 Booster Vaccines during the Delta and Omicron Pandemic Waves in Hungary (HUN-VE 2 Study) | BackgroundIn Hungary, the pandemic waves in late 2021 and early 2022 were dominated by the Delta and Omicron SARS-CoV-2 variants, respectively. Booster vaccines were offered with one or two doses for the vulnerable population during these periods.
Methods and FindingsThe nationwide HUN-VE 2 study examined the effectiveness of primary immunization, single booster, and double booster vaccination in the prevention of Covid-19 related mortality during the Delta and Omicron waves, compared to an unvaccinated control population without prior SARS-CoV-2 infection during the same study periods.
The risk of Covid-19 related death was 55% lower during the Omicron vs. Delta wave in the whole study population (n=9,569,648 and n=9,581,927, respectively; rate ratio [RR]: 0.45, 95% confidence interval [CI]: 0.44-0.48). During the Delta wave, the risk of Covid-19 related death was 74% lower in the primary immunized population (RR: 0.26; 95% CI: 0.25-0.28) and 96% lower in the booster immunized population (RR: 0.04; 95% CI: 0.04-0.05), vs. the unvaccinated control group. During the Omicron wave, the risk of Covid-19 related death was 40% lower in the primary immunized population (RR: 0.60; 95% CI: 0.55-0.65) and 82% lower in the booster immunized population (RR: 0.18; 95% CI: 0.16-0.2) vs. the unvaccinated control group. The double booster immunized population had a 93% lower risk of Covid-19 related death compared to those with only one booster dose (RR: 0.07; 95% CI. 0.01-0.46). The benefit of the second booster was slightly more pronounced in older age groups.
ConclusionsThe HUN-VE 2 study demonstrated the significantly lower risk of Covid-19 related mortality associated with the Omicron vs. Delta variant and confirmed the benefit of single and double booster vaccination against Covid-19 related death. Furthermore, the results showed the additional benefit of a second booster dose in terms of SARS-CoV-2 infection and Covid-19 related mortality. | infectious diseases |
10.1101/2022.03.30.22273175 | SARS-CoV-2 Omicron neutralization and risk of infection among elderly after a booster dose of Pfizer vaccine | BackgroundThe protective immunity against Omicron following a BNT162b2 Pfizer booster dose among elderly is not well characterized.
MethodsThirty-eight residents from three nursing homes were recruited for the study. Antibodies targeting the Spike protein of SARS-CoV-2 were measured with the S-Flow assay. Neutralizing activities in sera were measured as effective dilution 50% (ED50) with the S-Fuse assay using authentic isolates of Delta and Omicron.
ResultsAmong the 38 elderly included in the study, with median (inter-quartile range, IQR) age of 88 (81-92) years, 30 (78.9%) had been previously infected. The ED50 of neutralization were lower against Omicron than Delta, and higher among convalescent compared to naive residents. During an Omicron epidemic affecting two of the three nursing homes in December 2021-January 2022, 75% (6/8) of naive residents got infected, compared to 25% (6/24) of convalescents (P=0.03). Antibody levels to Spike and ED50 of neutralization against Omicron after the BNT162b2 booster dose were lower in those with breakthrough infection (n=12) compared to those without (n=20): median of 1256 vs 2523 BAU/mL (P=0.02) and median ED50 of 234 vs 1298 (P=0.0004), respectively.
ConclusionThis study confirmed the importance of receiving at least three antigenic exposures to the SARS-CoV-2 Spike protein for achieving satisfactory neutralizing antibody levels. In this population, protection against Omicron infection was increased in individuals who had been previously infected in addition to the three vaccine doses. Thus, a fourth antigenic exposure may be useful in the elderly population to prevent infection with Omicron, a variant known for its high escape immunity properties. | infectious diseases |
10.1101/2022.03.29.22272716 | SARS-CoV-2 and other respiratory pathogens are detected in continuous air samples from congregate settings. | Two years after the emergence of SARS-CoV-2, there is still a need for better ways to assess the risk of transmission in congregate spaces. We deployed active air samplers to monitor the presence of SARS-CoV-2 in real-world settings across communities in the Upper Midwestern states of Wisconsin and Minnesota. Over 29 weeks, we collected 527 air samples from 15 congregate settings and detected 106 SARS-CoV-2 positive samples, demonstrating SARS-CoV-2 can be detected in air collected from daily and weekly sampling intervals. We expanded the utility of air surveillance to test for 40 other respiratory pathogens. Surveillance data revealed differences in timing and location of SARS-CoV-2 and influenza A virus detection in the community. In addition, we obtained SARS-CoV-2 genome sequences from air samples to identify variant lineages. Collectively, this shows air surveillance is a scalable, cost-effective, and high throughput alternative to individual testing for detecting respiratory pathogens in congregate settings. | infectious diseases |
10.1101/2022.03.30.22273186 | Epidemiological and virological factors determining dengue transmission in Sri Lanka during the COVID-19 pandemic | BackgroundWith the onset of the COVID-19 pandemic in early 2020 there was a drastic reduction in the number of dengue cases in Sri Lanka, with an increase towards the end of 2021. We sought to study the contribution of virological factors, human mobility, school closure and mosquito factors in affecting these changes in dengue transmission in Sri Lanka during this time.
Methods and findingsTo understand the reasons for the differences in the dengue case numbers in 2020 to 2021 compared to previous years, we determined the association between the case numbers in Colombo (which has continuously reported the highest number of cases) with school closures, stringency index, changes in dengue virus (DENV) serotypes and vector densities.
There was a 79.4% drop in dengue cases from 2019 to 2020 in Colombo. A significant negative correlation was seen with the number of cases and school closures (Spearmans r=-0.4732, p=<0.0001) and a negative correlation, which was not significant, between the stringency index and case numbers (Spearmans r= -0.3755 p=0.0587). There was no change in the circulating DENV serotypes with DENV2 remaining the most prevalent serotype by early 2022 (65%), similar to the frequencies observed by end of 2019. The Aedes aegypti premise and container indices showed positive but insignificant correlations with dengue case numbers (Spearman r= 0.8827, p=0.93).
ConclusionsLockdown measures, especially school closures seemed to have had a significant impact on the number of dengue cases, while the vector indices had a limited effect. | infectious diseases |
10.1101/2022.03.28.22273040 | Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative | Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,048 severe disease cases and 571,009 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p=5.41x10-7). These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights. | infectious diseases |
10.1101/2022.03.28.22273040 | Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative | Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,048 severe disease cases and 571,009 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p=5.41x10-7). These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights. | infectious diseases |
10.1101/2022.03.25.22272944 | Enteric viruses isolates and rotavirus genotypes during the seasonal surge of acute watery childhood diarrhoea in South-Eastern Nigeria | Diarrhoea remains one of the top three causes of death in Africa. However, data on the molecular epidemiology of enteric viruses in Nigeria is rare.
Two hundred and forty three infants and children below the age of 5 years with acute watery diarrhoea were evaluated for the presence of enteric viruses in stool by real-time PCR (rtPCR) during the dry months of December to April 2017, which correspond to diarrhoea season in South-East Nigeria. At least one viral pathogen was detected in 95.1% (231/243) of the study population. Rotavirus, 231(95.1%) was the most common followed by adenovirus, 103(42.4%) and enterovirus 32(13.2%). Other viruses seen in the stool samples include astrovirus 7.3 % (11/151), parechovirus 3.5 % (4/113), sapovirus, 2.8 % (4/145), bocavirus 6.8% (5/73) and human coronavirus 13.9% (10/73). Norovirus and hepatitis A and E viruses were not detected. Children that consumed factory packaged water had the lowest prevalence of rotavirus infection (p=0.044). A significant association between the viral pathogen and home treatment of drinking water or exclusive breastfeeding was not observed. Randomly selected 46 samples were genotyped for rotavirus, which showed that G3P[6] (39.1%) was the most common, followed by G1P[8] (15.2%), G9P[8] (13.0%), G12P[8] (6.5%), G9P[6]P[8] (2.2%), and G12P[6] (2.2%).
This was the highest rotavirus prevalence in any published African study, and may be a reflection of inadequate water sanitation/hygiene in the study area, a peculiar epidemiological situation and/or the sensitivity of the diagnostic method used.
The present study suggests that the burden of rotavirus is bigger than previously reported; and that morbidity can be greatly reduced if rotavirus vaccine is included in Nigerian national immunization policy. | infectious diseases |
10.1101/2022.03.28.22272741 | Mechanistic models of Rift Valley fever virus transmission dynamics: A systematic review | Rift Valley fever (RVF) is a zoonotic arbovirosis which has been reported across Africa including the northernmost edge, South West Indian Ocean islands, and the Arabian Peninsula. The virus is responsible for high abortion rates and mortality in young ruminants, with economic impacts in affected countries. To this day, RVF epidemiological mechanisms are not fully understood, due to the multiplicity of implicated vertebrate hosts, vectors and ecosystems. In this context, mathematical models are useful tools to develop our understanding of complex systems, and mechanistic models are particularly suited to data-scarce settings. In this work, we performed a systematic review of mechanistic models studying RVF, to explore their diversity and their contribution to the understanding of this disease epidemiology. Researching Pubmed and Scopus databases (October 2021), we eventually selected 48 papers, which needed to provide a clear description of a mechanistic model with numerical application to RVF. We categorized models as theoretical, applied or grey, according to their will to represent a specific geographical context and their use of data to fulfill this intention. We discussed their contributions to the understanding of RVF epidemiology, and highlighted that theoretical and applied models can use different tools to meet common objectives. Through the examination of model features, we identified research questions left unexplored across scales, along with a substantial lack of justification when choosing a functional form for the force of infection. Overall, we showed a great diversity in RVF models, leading to substantial progress in our comprehension of epidemiological mechanisms. To go further, data gaps must be fulfilled, and modelers need to go the extra mile regarding transparency.
Authors summaryRift Valley fever (RVF) affects humans and livestock across Africa, South West Indian Ocean islands, and in the Arabian Peninsula. This disease is one of the World Health Organization priorities, and is caused by a virus transmitted by Aedes and Culex spp. mosquitoes, but also directly from livestock to humans. Mathematical models have been used in the last 20 years to disentangle RVF virus transmission dynamics. These models can further our understanding of processes driving outbreaks, test the efficiency of control strategies, or even anticipate possible emergence. Provided with detailed datasets, models can tailor their conclusions to specific geographical contexts and aid in decision-making in the field. This review provides a general overview of mathematical models developed to study RVF virus transmission dynamics. We describe their main results and methodological choices, and identify hurdles to be lifted. To offer innovative animal and public health value, we recommend that future models focus on the relative contribution of host species to transmission, and the role of animal mobility. | epidemiology |
10.1101/2022.03.29.22273085 | COVID-19 mortality among working-age Americans in 46 states, by industry and occupation | IntroductionA small body of epidemiological research suggests that working in an essential sector is a risk factor for SARS-CoV-2 infection or subsequent disease or mortality. However, there is limited evidence to date on the US, or on how the risks associated with essential work differ across demographic subgroups defined by age, sex, and race/ethnicity.
MethodsUsing publicly available data from the National Center for Health Statistics on deaths occurring in the US in 2020, we calculated per-capita COVID-19 mortality by industry and occupation. We additionally calculated per-capita COVID-19 mortality by essential industry--essential or not--by age group, sex, and race/ethnicity.
ResultsAmong non-military individuals and individuals with a known industry or occupation, there were 48,030 reported COVID-19 deaths, representing 25.1 COVID-19 deaths per 100,000 working-age individuals after age standardization. Per-capita age-standardized COVID-19 mortality was 1.96 times higher among essential workers than among workers in non-essential industries, representing an absolute difference of 14.9 per 100,000. Across industry, per-capita age-standardized COVID-19 mortality was highest in the following industries: accommodation and food services (45.4 per 100,000); transportation and warehousing (43.4); agriculture, forestry, fishing and hunting (42.3); mining (39.6); and construction (38.7).
DiscussionGiven that SARS-CoV-2 is an airborne virus, we call for collaborative efforts to ensure that workplace settings are properly ventilated and that workers have access to effective masks. We also urge for paid sick leave, which can help increase vaccine access and minimize disease transmission. | epidemiology |
10.1101/2022.03.29.22273085 | COVID-19 mortality among working-age Americans in 46 states, by industry and occupation | IntroductionA small body of epidemiological research suggests that working in an essential sector is a risk factor for SARS-CoV-2 infection or subsequent disease or mortality. However, there is limited evidence to date on the US, or on how the risks associated with essential work differ across demographic subgroups defined by age, sex, and race/ethnicity.
MethodsUsing publicly available data from the National Center for Health Statistics on deaths occurring in the US in 2020, we calculated per-capita COVID-19 mortality by industry and occupation. We additionally calculated per-capita COVID-19 mortality by essential industry--essential or not--by age group, sex, and race/ethnicity.
ResultsAmong non-military individuals and individuals with a known industry or occupation, there were 48,030 reported COVID-19 deaths, representing 25.1 COVID-19 deaths per 100,000 working-age individuals after age standardization. Per-capita age-standardized COVID-19 mortality was 1.96 times higher among essential workers than among workers in non-essential industries, representing an absolute difference of 14.9 per 100,000. Across industry, per-capita age-standardized COVID-19 mortality was highest in the following industries: accommodation and food services (45.4 per 100,000); transportation and warehousing (43.4); agriculture, forestry, fishing and hunting (42.3); mining (39.6); and construction (38.7).
DiscussionGiven that SARS-CoV-2 is an airborne virus, we call for collaborative efforts to ensure that workplace settings are properly ventilated and that workers have access to effective masks. We also urge for paid sick leave, which can help increase vaccine access and minimize disease transmission. | epidemiology |
10.1101/2022.03.29.22273146 | Endemicity is not a victory: the unmitigated downside risks of widespread SARS-CoV-2 transmission | We have entered a new phase of the ongoing COVID-19 pandemic, as the strategy of relying solely on the current SARS-CoV-2 vaccines to bring the pandemic to an end has become infeasible. In response, public-health authorities in many countries have advocated for a strategy of using the vaccines to limit morbidity and mortality while permitting unchecked SARS-CoV-2 spread ("learning to live with the disease"). The feasibility of this strategy is critically dependent on the infection fatality rate (IFR) of COVID-19. An expectation exists, both in the lay public and in the scientific community, that future waves of the virus will exhibit decreased IFR, either due to viral attenuation or the progressive buildup of immunity. In this work, we examine the basis for that expectation, assessing the impact of virulence on transmission. Our findings suggest that large increases in virulence for SARS-CoV-2 would result in minimal loss of transmission, implying that the IFR may be free to increase or decrease under neutral evolutionary drift. We further examine the effect of changes in the IFR on the steady-state death toll under conditions of endemic COVID-19. Our modeling suggests that endemic SARS-CoV-2 implies vast transmission resulting in yearly US COVID-19 death tolls numbering in the hundreds of thousands under many plausible scenarios, with even modest increases in the IFR leading to an unsustainable mortality burden. Our findings thus highlight the critical importance of enacting a concerted strategy (involving for example global access to vaccines, therapeutics, prophylactics and nonpharmaceutical interventions) to suppress SARS-CoV-2 transmission, thereby reducing the risk of catastrophic outcomes. Our findings also highlight the importance of continued investment in novel biomedical interventions to prevent viral transmission. | epidemiology |
10.1101/2022.03.29.22273134 | The complex relationship of air pollution and neighborhood socioeconomic deprivation and their association with cognitive decline | BackgroundAir pollution and neighborhood socioeconomic status (nSES) have been shown to affect cognitive decline in older adults. In previous studies, nSES acts as both a confounder and an effect modifier between air pollution and cognitive decline.
ObjectivesThis study aims to examine the individual and joint effects of air pollution and nSES on cognitive decline on adults 50 years and older in Metro Atlanta, USA.
MethodsPerceived memory and cognitive decline was assessed in 11,897 participants aged 50+ years from the Emory Healthy Aging Study (EHAS) using the cognitive function instrument (CFI). Three-year average air pollution concentrations for 12 pollutants and 16 nSES characteristics were matched to participants using census tracts. Individual exposure linear regression and LASSO models explore individual exposure effects. Environmental mixture modeling methods including, self-organizing maps (SOM), Bayesian kernel machine regression (BKMR), and quantile-based G-computation explore joint effects, and effect modification between air pollutants and nSES characteristics on cognitive decline.
ResultsParticipants living in areas with higher air pollution concentrations and lower nSES experienced higher CFI scores (beta: 0.121; 95% CI: 0.076, 0.167) compared to participants living in areas with low air pollution and high nSES. Additionally, the BKMR model showed a significant overall mixture effect on cognitive decline, indicating synergy between air pollution and nSES. These joint effects explain protective effects observed in single-pollutant linear regression models, even after adjustment for confounding by nSES (e.g., an IQR increase in CO was associated with a 0.038-point decrease (95% CI: -0.06, -0.01) in CFI score).
DiscussionObserved protective effects of single air pollutants on cognitive decline can be explained by joint effects and effect modification of air pollutants and nSES. Researchers must consider nSES as an effect modifier if not a co-exposure to better understand the complex relationships between air pollution and nSES in urban settings. | epidemiology |
10.1101/2022.03.28.22273071 | Association between HIV co-infection and delayed diagnosis with tuberculosis bacterial load in setting with widespread antiretroviral therapy use | HIV co-infection has been shown to be associated with lower tuberculosis (TB) bacterial load in studies conducted prior to widespread availability of antiretroviral therapy (ART). The purpose of this study was to determine associations between HIV co-infection and TB bacterial load, accounting for differences in time to TB diagnosis, in a high prevalence setting with widespread ART use. In Gaborone, Botswana, 186 sputum samples from people with newly diagnosed TB were tested with Xpert MTB/RIF (Xpert). TB bacterial load and time to TB diagnosis were estimated using mean Xpert cycle threshold (CT) and symptom duration, respectively. Multiple linear regression models were used to determine the associations between HIV and Xpert CT with and without controlling for symptom duration. Mean CT values were higher in people living with HIV compared to people without HIV (21.8 vs 18.6, p < 0.001). Among those living with HIV, there was a negative correlation between CD4 count and mean CT value (Spearmans rho -0.27, p = 0.023). After controlling for gender, age, and symptom duration, HIV status remained an independent predictor of CT value, with an average increase of 2.0 cycles (p = 0.004) among people with HIV and CD4 count > 200 cells/mm3 and 2.8 cycles (p < 0.001) in those with a CD4 count [≤] 200 cells/mm3 compared to individuals without HIV. Increased HIV-associated immunosuppression is associated with decreased bacterial burden even in settings with widespread ART use. | epidemiology |
10.1101/2022.03.30.22273179 | Effect of seizures on developmental trajectories in children with autism | The effect of seizures in 2 to 5-year-old children with ASD was investigated in the largest and the longest observational study to-date. Parents assessed the development of 8461 children quarterly for three years on five orthogonal subscales: combinatorial receptive language, expressive language, sociability, sensory awareness, and health. Seizures were reported in 11% of children. Children with no seizures developed faster compared to matched children with seizures in all subscales. On an annualized basis, participants with no seizures improved their receptive language 1.5-times faster than those with seizures; expressive language: 1.3-times faster; sociability: 2.3-times faster; sensory awareness: 6.2-times faster; and health: 20.0-times faster. This study confirms a high prevalence of seizures in ASD children and points to the need for more systematic approach to the development of treatment strategies. | pediatrics |
10.1101/2022.03.29.22273140 | Telomere length and its associations with mental disorders, age and genetic risk for mental disorders | BackgroundMental disorders are associated with substantially increased morbidity and reduced life expectancy. Accelerated biological ageing might contribute to excess mortality of individuals with mental disorders. The aim of this study was to characterise telomere length, a biological hallmark of ageing, in individuals with mental disorders, and to examine associations between telomere length, age and genetic risk for mental disorders.
MethodsThe UK Biobank is a multicentre, community-based observational study that recruited >500,000 middle-aged and older adults across England, Scotland and Wales. Average leukocyte telomere length (T/S ratio) was measured using quantitative polymerase chain reaction. Polygenic risk scores (PRS) were calculated for individuals of European ancestry. We estimated differences in T/S ratio and age-related changes in T/S ratio between individuals with anxiety disorder, depression or bipolar disorder and people without mental disorders. We also estimated associations between T/S ratio and PRS for these three disorders.
ResultsThe analyses included up to 308,725 participants. Individuals with depression had shorter telomeres than people without mental disorders (adjusted {beta} = -0.011, 95% CI -0.019 to -0.004, pBonf. = 0.027). There was only limited evidence of case-control differences in telomere length for anxiety disorders or bipolar disorders. Age-related changes in telomere length did not differ between individuals with and without mental disorders. PRS for depression were associated with shorter telomeres ({beta} = -0.006, 95% CI -0.010 to -0.003, pBonf. = 0.001). There was no evidence that PRS for anxiety disorder or bipolar disorder were associated with telomere length.
ConclusionAlthough telomere length is a biological hallmark of ageing, we observed limited evidence that leukocyte telomere length is a clinically useful marker to quantify accelerated biological ageing in middle-aged and older adults with a lifetime history of anxiety disorder, depression or bipolar disorder. | psychiatry and clinical psychology |
10.1101/2022.03.28.22273027 | Unravelling the link between sleep and mental health during the COVID-19 pandemic | BackgroundThe emergence of COVID-19 brought unparalleled changes in peoples lifestyle, including sleep. We aimed to assess the bidirectional association between sleep quality and mental health and describe how sleep and mental health were affected in Sweden during the COVID-19 pandemic (between June 2020 and September 2021).
MethodsData were obtained from the Omtanke2020 study. Participants who completed the baseline survey and 8 monthly follow-up surveys were included (N=9035). We described the distribution of sleep and mental health in the different Swedish regions using maps and over the study period with longitudinal graphs adjusting for sex, age, recruitment type (self-recruitment or invitation), and COVID-19 status. The inner relationships between mental health, sleep and covid infection were described through relative importance networks. Finally, we modelled how mental health affects sleep and vice versa using generalized estimating equations with different adjustments.
ResultsSeasonal and north-south regional variations were found in sleep and mental health outcomes at baseline and attenuated over time. The seasonal variation of sleep and mental health correlated moderately with the incidence rate of COVID-19 in the sample. Networks indicate that the relationship between COVID-19 incidence and mental health varies over time. We observed a bidirectional relationship between sleep quality and quantity at baseline and mental health at follow-up and vice versa.
ConclusionSleep quality and quantity at baseline was associated with adverse symptom trajectories of mental health at follow-up, and vice versa, during the COVID-19 pandemic. There is also a weak relationship between COVID-19 incidence, sleep, and mental health. | public and global health |
10.1101/2022.03.28.22273027 | Unravelling the link between sleep and mental health during the COVID-19 pandemic | BackgroundThe emergence of COVID-19 brought unparalleled changes in peoples lifestyle, including sleep. We aimed to assess the bidirectional association between sleep quality and mental health and describe how sleep and mental health were affected in Sweden during the COVID-19 pandemic (between June 2020 and September 2021).
MethodsData were obtained from the Omtanke2020 study. Participants who completed the baseline survey and 8 monthly follow-up surveys were included (N=9035). We described the distribution of sleep and mental health in the different Swedish regions using maps and over the study period with longitudinal graphs adjusting for sex, age, recruitment type (self-recruitment or invitation), and COVID-19 status. The inner relationships between mental health, sleep and covid infection were described through relative importance networks. Finally, we modelled how mental health affects sleep and vice versa using generalized estimating equations with different adjustments.
ResultsSeasonal and north-south regional variations were found in sleep and mental health outcomes at baseline and attenuated over time. The seasonal variation of sleep and mental health correlated moderately with the incidence rate of COVID-19 in the sample. Networks indicate that the relationship between COVID-19 incidence and mental health varies over time. We observed a bidirectional relationship between sleep quality and quantity at baseline and mental health at follow-up and vice versa.
ConclusionSleep quality and quantity at baseline was associated with adverse symptom trajectories of mental health at follow-up, and vice versa, during the COVID-19 pandemic. There is also a weak relationship between COVID-19 incidence, sleep, and mental health. | public and global health |
10.1101/2022.03.29.22273151 | Substance use and associated factors among Adolescents during the Covid-19 pandemic in Eastern Ethiopia: A cross-sectional study | IntroductionThe effects of the COVID-19 pandemic have been dramatic and wide-reaching, affecting many more than those who become ill, including reports of increased substance use among adolescents may be due to various restrictions of social life that disrupted adolescents daily lives. However, up to now, no data is showing the extent of substance use among adolescents in the study area.
PurposeThis study aimed to assess the prevalence of substance use and associated factors during the Covid-19 pandemic among school adolescents of west hararghe, Eastern Ethiopia to guide possible intervention and public policy.
MethodsA School-based cross-sectional study design was conducted from 10 to 30, October 2021. A multi-stage sampling technique was used to select 788 students from ten public secondary schools in the West Hararge zone, Eastern Ethiopia. The data were collected using a self-administered pre-tested semi-structured questionnaire. Data was entered into Epidata version and then exported to SPSS version 26 software for further analysis. Descriptive analysis was done. Multi variables binary logistic regression was done and a p-value less than 0.05 were used to declare statistical significance.
ResultsIn this study, the response rate of 98.46% were complete fill the questionnaires. More than 1 in 2 of the adolescent students were self-reported substances (alcohol, khat (Catha edulis) and/or cigarette) users (prevalence = 58.6%) during the Covid-19 pandemic. Specifically, chewing khat (Catha edulis) (57.87%), followed by alcohol user (21.73%), Cigarette smoking (14.85%) and, hashish consumption (5.54%). Age of students, family history of drinking alcohol, availability of substances were factors positively associated with substance use. On the other hand, family management is negatively associated with substance use.
ConclusionsThe prevalence of substance users among adolescents was dramatically increased during the covid-19 pandemic in the west hararghe zone, Ethiopia. Hence, the authors hoped that these findings provide preliminary insights for refining mental health and addiction policies that are targeted at adolescent and their parents in these settings and guidance for further research. | public and global health |
10.1101/2022.03.29.22273114 | Understanding Barriers toward Interventions for Childhood Obesity in Minority Communities: A Rapid Review | BackgroundIt is well documented that racial/ethnic minorities have higher attrition rates from pediatric weight manage programs than their white counterparts. This review aimed to identify barriers facing minority families when seeking to complete weight management programs for their children to develop strategies to keep these families engaged. Maintaining engagement through program completion could improve health outcomes and overall quality of life for minority children.
MethodsEligible studies were identified through searching PubMed, PsychINFO and CENTRAL databases. Articles had to focus on reasons for attrition from pediatric weight management among minority groups to be included. We extracted data on attrition from each study and narratively summarized the results.
ResultsFrom the 302 articles screened, five met the inclusion criteria. Four of the five studies predicted attrition factors from attendance or past survey data. Only one study surveyed parents to identify potential barriers. Among these studies, most sociodemographic factors analyzed had no significant effect on early dropout. Program structure, logistical barriers, and parental negative self and child body image were all identified as predictors of attrition.
ConclusionMore studies need to directly investigate why minority families discontinue weight management treatments early. Directly interviewing or surveying parents to ascertain their concerns can lead to the development of programs that retain and better meet the needs of these groups. | public and global health |
10.1101/2022.03.29.22273099 | Association between central blood pressure, arterial stiffness and low cognitive scores in South African adults | BackgroundThe burden of hypertension in South Africa, as well as the successive cardiovascular morbidity and mortality is increasing. Hypertension presents a risk for subsequent cognitive impairment with age. This study sought to determine the association between blood pressure, arterial stiffness, using pulse wave velocity and pulse amplification pressure, and cognitive function in younger and older adults from a 30yr old urban South African birth cohort study.
MethodsWe conducted a cross-sectional study among n=93 index children (now age 29yr) and their mothers (all women). We collected peripheral and central blood pressure (BP) variables, and conducted a cognitive assessment using the Montreal Cognitive Assessment (MoCA) instrument and analysed the association of BP variables with global cognitive tests and specific domains.
ResultsForty percent of the pooled sample had low MoCA total scores, and 32% of the total sample had hypertension. No associations were found in the regression analysis between BP related variables and total MoCA scores. Also, no associations were found between peripheral and central BP variables with individual cognitive domains when stratified by age. A significant relationship was found between mean pressure and low visual perception (i.e. the ability to interpret information that is seen and give it meaning; p=0.02).
ConclusionCentral mean pressure is associated with low visual perception domain among black women. These findings add to the growing evidence which suggests that central BP variables are important to explore as exposure proxies for studying the association of BP and cognitive decline especially at mid-life. | public and global health |
10.1101/2022.03.25.22272948 | Labor market position and depression during the COVID-19 epidemic among young adults (18 to 30 years): a nationally representative study in France. | ObjectiveTo examine the relationship between young adults labor force participation and depression in the context of the COVID-19 pandemic.
Design, Setting, ParticipantsData come from the nationally-representative EPICOV cohort study set up in France, and were collected in 2020 and 2021 (3 waves of online or telephone interviews) among 2217 participants aged 18-30 years. Participants with prior mental health disorder (n=50) were excluded from the statistical analyses.
ResultsUsing Generalized Estimating Equation (GEE) models controlled for participants socio-demographic and health characteristics and weighted to be nationally-representative, we found that compared to young adults who were employed, those who were studying or unemployed were significantly more likely to experience depression assessed using the PHQ-9 (multivariate ORs respectively: OR: 1.29, 95% CI 1.05-1.60 and OR: 1.50, 1.13-1.99). Stratifying the analyses by age, we observed than unemployment was more strongly associated with depression among participants 25-30 years than among those who were 18-24 years (multivariate ORs respectively 1.78, 95% CI 1.17-2.71 and 1.41, 95% CI 0.96-2.09). Being out of the labor force was, to the contrary, more significantly associated with depression among participants 18-24 years (multivariate OR: 1.71, 95% CI 1.04-2.82, vs. 1.00, 95% CI 0.53-1.87 among participants 25-30 years). Stratifying the analyses by sex, we found no significant differences in the relationships between labor market characteristics and depression (compared to participants who were employed, multivariate ORs associated with being a student: men: 1.33, 95% CI 1.01-1.76; women: 1.19, 95% CI 0.85-1.67, multivariate ORs associated with being unemployed: men: 1.60, 95% CI 1.04-2.45; women: 1.47, 95% CI 1.01-2.15).
Conclusions and relevanceOur study shows that in addition to students, young adults who are unemployed also experience elevated levels of depression in the context of the COVID-19 pandemic. These two groups should be the focus of specific attention in terms of prevention and mental health treatment. Supporting employment could also be a propitious way of reducing the burden of the Covid-19 pandemic on the mental health of young adults.
Key PointsO_ST_ABSQuestionC_ST_ABSIs labor force participation associated with young adults likelihood of depression during the COVID-19 pandemic?
FindingsIn a nationally-representative cohort study in France, compared to young adults who are employed, those who are studying or experience unemployment had elevated odds of depression in 2020 and 2021.
MeaningYoung people are experiencing the highest burden of mental health problems in the context of the COVID-19 epidemic - our study implies that those who are studying or are unemployed are at especially high risk and should be the focus of attention in terms of prevention and treatment. | public and global health |
10.1101/2022.03.28.22273066 | Ivacaftor, not ivacaftor/lumacaftor, is associated with lower pulmonary inflammation in preschool cystic fibrosis | Airway inflammation is a key driver of cystic fibrosis (CF) lung disease. The advent of cystic fibrosis transmembrane conductance regulator (CFTR) modulators has the potential to transform the care of CF, however the direct effect of these therapies on lung inflammation is unknown. Here, we profile airway inflammation in bronchoalveolar lavage (BAL) of preschool aged children with CF on CFTR modulator therapy (ivacaftor or ivacaftor/lumacaftor), untreated children with CF, and age-matched healthy controls. We show that children treated with ivacaftor have lower pulmonary concentrations of inflammatory mediators CCL3, CXCL9, CCL2, IL-8, IL-1{beta}, and IL-6 relative to untreated children with CF. Conversely, there was no significant effect of lumacaftor/ivacaftor treatment on airway inflammation. This is the first work to illustrate a difference in early life airway inflammation with CFTR treatment, highlights the effectiveness of ivacaftor in early life, and suggests that BAL inflammatory profile may represent a biomarker of therapeutic response to treatment. | respiratory medicine |
10.1101/2022.03.28.22272832 | Genome-wide analysis of longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis | BackgroundIdiopathic pulmonary fibrosis (IPF) is an incurable disease characterised by progressive scarring of the lungs. This leads to the lungs becoming stiffer, reducing lung capacity, and impeding gas transfer. We aimed to identify genetic variants associated with either declining lung capacity or gas transfer after diagnosis of IPF.
MethodsWe performed a genome-wide meta-analysis of longitudinal measures of forced vital capacity (FVC) and diffusing capacity for lung of carbon monoxide (DLco) in individuals diagnosed with IPF from three studies. Suggestively significant variants were investigated further in an additional study. Variants were defined as significantly associated if they had a meta-analysis p<5x10-8, had consistent direction of effects across all studies and were nominally significant (p<0.05) in each study.
Findings1,048 individuals with measures of longitudinal FVC and 729 individuals with longitudinal measures of DLco passed quality control. In total, 4,560 measures of FVC and 2,795 measures of DLco and over 7 million genetic variants were included in the analysis. One variant located in an antisense RNA gene for Protein Kinase N2 (PKN2) showed a genome-wide significant association with FVC decline (-140 ml/year per risk allele, 95% CI [-180, -100], p=9.14x10-12).
InterpretationThese results identify a possible druggable target involved in promoting IPF disease progression.
FundingAction for Pulmonary Fibrosis, Medical Research Council, Wellcome Trust, National Institute of Health/National Heart, Lung and Blood Institute
Research in contextO_ST_ABSEvidence before this studyC_ST_ABSIdiopathic pulmonary fibrosis (IPF) is a devastating disease where the lungs become scarred, this scarring leads to a reduced lung capacity, poorer rates of gas transfer and is eventually fatal. However, disease progression is highly variable and it is not clear why this is. To date, genome-wide association studies (GWAS) have identified 20 genetic loci associated with susceptibility to IPF. These genetic loci implicate genes involved with host defence, regulation of TGF{beta} signalling, telomere maintenance, cell-cell adhesion and spindle assembly as important biological processes involved in the pathogenesis of IPF. The GWAS variant with the strongest effect on disease risk is found in the promoter region of the MUC5B gene (rs35705950). Generally, the variants associated with IPF susceptibility show little or no association with disease progression, apart from the risk allele at rs35705950 which has been reported as having an association with improved survival times.
Added value of this studyAlthough genetic variants associated with disease risk have been widely studied, little has been reported to investigate the effect of genetics on progression of IPF. Here we present a GWAS of progressive IPF by identifying genetic variants associated longitudinal measures of lung health after diagnosis of IPF. We identify a genetic locus associated with a more rapid decline in lung capacity that lies in the RNA antisense gene of PKN2.
Implications of all available evidenceThe novel genetic locus associated with a more rapid decline in lung capacity in individuals with IPF implicates a Rho/RAC effector protein. Effective treatments for IPF are desperately needed. There are currently PKN2 inhibitors under development meaning this analysis highlights a potential therapeutic target for IPF. We also show the genetic determinants of IPF progression appear to be distinct from those that drive IPF susceptibility. | respiratory medicine |
10.1101/2022.03.28.22273029 | Healthcare workers perceptions and medically approved COVID-19 infection risk: understanding the mental health dimension of the pandemic. A German hospital case study | IntroductionThis study analyses how healthcare workers (HCWs) perceived risks, protection and preventive measures during the COVID-19 pandemic in relation to medically approved risks and organisational measures. The aim is to explore blind spots of pandemic protection and make mental health needs of HCWs visible.
MethodsWe have chosen an optimal-case scenario of a high-income country with a well-resourced hospital sector and low HCW infection rate at the organisational level to explore governance gaps in HCW protection. A German multi-method hospital study at Hannover Medical School served as empirical case; document analysis, expert information and survey data (n=1163) were collected as part of a clinical study into SARS-CoV-2 serology testing during the second wave of the pandemic (November 2020-February 2021). Selected survey items included perceptions of risks, protection and preventive measures. Descriptive statistical analysis and regression were undertaken for gender, profession and COVID-19 patient care.
ResultsThe results reveal a low risk of 1% medically approved infections among participants, but a much higher mean personal risk estimate of 15%. The majority (68.4%) expressed some to very strong fear of acquiring infection at the workplace. Individual protective behaviour and compliance with protective workplace measures were estimated as very high. Yet only about half of the respondents felt strongly protected by the employer; 12% even perceived no or little protection. Gender and contact with COVID-19 patients had no significant effect on the estimations of infection risks and protective workplace behaviour, but nursing was correlated with higher levels of personal risk estimations and fear of infection.
ConclusionsA strong mismatch between low medically approved risk and personal risk perceptions of HCWs brings stressors and threats into view, that may be preventable through better information and risk communication and through investment in mental health and inclusion in pandemic preparedness plans. | rheumatology |
10.1101/2022.03.29.22273128 | Faster, Higher, Stronger - Together? A bibliometric analysis of author distribution in top medical education journals | BackgroundWithin medical education research, issues of equity, absence, and marginalization of diverse perspectives are becoming a growing area of scholarly focus. One area of absence that has been under-explored is that of published voices from low- and middle-income countries and non-English speaking scholars. Bibliometric analyses are one way to identify absences. We undertook a bibliometric analysis of five top medical education journals to determine which countries were represented in prestigious first and last authorship positions.
MethodsWeb of Science was searched for all articles and reviews that were published between 2012 and 2018 within Academic Medicine, Medical Education, Advances in Health Sciences Education, Medical Teacher, and BMC Medical Education. Country of origin was identified for the first and last author of each publication, and the number of publications originating from each country were counted.
ResultsOur analysis revealed a dominance of first and last authors from five countries: USA, Canada, United Kingdom, Netherlands, and Australia. Authors from these five countries had first or last authored 74% of publications. Of the 195 countries in the world, 53% were not represented by a single publication. Journals varied in their inclusion of authors from outside of these five dominant countries, with BMC Medical Education including more geographic diversity than other journals. There was a slight increase in the percentage of publications from outside of these five countries, from 22% in 2012 to 29% in 2018.
ConclusionsThe dominance of wealthy nations within spaces that claim to be international is a finding that requires attention. As a bibliometric analysis, we were unable to unearth the reasons behind this dominance. However, we draw upon analogies from modern Olympic sport and our own collaborative research process to show how academic publishing continues to be a colonized space that advantages those from wealthy and English-speaking countries. | medical education |
10.1101/2022.03.27.22272998 | Screening of plasma IL-6 and IL-17 in Bangladeshi lung cancer patients | Cancer is the second leading cause of death globally, where most cancer deaths occur in low- and middle-income countries. Lung cancer is the most prevalent in men and the third most prevalent in women among all cancer types. Globally, 1.8 million new lung cancer cases were recorded in 2012, which increased to 2 million in 2018. Cancer disease burden can be diminished, and life expectancy profoundly increases when diagnosis and prognosis are made at an earlier stage. Although biopsy is the gold standard in cancer diagnosis, it is invasive, inconvenient, and expensive. Liquid biopsy, which identifies cancer biomarkers in blood, is an active area of cancer research. Recent evidence suggests that interleukins (ILs), a class of cytokines involved in diverse cellular processes such as inflammation, growth, and proliferation, play critical roles in cancer initiation, progression, and resistance to therapy. Interestingly, many studies found the association of plasma IL-6 and IL-17 levels with lung cancer prognosis. In this study, we analyzed plasma levels of IL-6 and IL-17 in lung cancer patients and healthy volunteers. We have also studied the demographic and medical records of the participants. Among the participants, 42.9% and 57.1% were female in the control group and the disease group, respectively. The age of the participants was 22-65 years, with a mean of 46.5 (SD, {+/-} 19.7) years. Plasma IL-6 levels were strikingly different between healthy volunteers (mean {+/-} SEM, 0.97 {+/-} 0.15 pg/mL) and patients (mean {+/-} SEM, 7.42 {+/-} 1.45 pg/mL). Notably, the range was narrow in the control group (0.32-2.10 pg/mL) but wide in the disease group (0.42-23.20 pg/mL). Plasma IL-17 levels were slightly lower in the disease group (mean {+/-} SEM, 9.40 {+/-} 2.82 pg/mL) compared to the control group (mean {+/-} SEM, 12.40 {+/-} 4.41 pg/mL), although the difference was not statistically significant. Intriguingly, the mean IL-17 value reduced dramatically with chemotherapy, and further reduction occurred with radiotherapy in lung cancer patients. Together, our study supports the use of plasma IL-6 and IL-7 levels as prognostic markers in lung cancer. | oncology |
10.1101/2022.03.29.22273133 | Human gain-of-function variants in HNF1A confer protection from diabetes but independently increase hepatic secretion of multiple cardiovascular disease risk factors | Loss-of-function mutations in Hepatocyte Nuclear Factor 1A (HNF1A) are known to cause rare forms of diabetes and alter hepatic physiology through unclear mechanisms. In the general population, 1:100 individuals carry a rare protein-coding variant in HNF1A, most of unknown functional consequence. To characterize the full allelic series, we performed deep mutational scanning of 11,970 protein-coding HNF1A variants in human hepatocytes and clinical correlation with 553,246 exome-sequenced individuals. Surprisingly, we found [~]1:5 rare protein-coding HNF1A variants found in the general population cause molecular gain-of-function (GOF), increasing the transcriptional activity of HNF1A by up to 50%. GOF in HNF1A conferred protection from type 2 diabetes (T2D) (OR=0.60, p=8.4 x 10-7), but not against coronary artery disease. Independently of T2D, increased hepatic expression of HNF1A promoted a pro-inflammatory and pro-atherogenic serum profile mediated in part by enhanced transcription of risk genes including PCSK9. In summary, [~]1:300 individuals carry a GOF variant in HNF1A that protects carriers from diabetes but enhances hepatic secretion of metabolic disease risk factors. | genetic and genomic medicine |
10.1101/2022.03.28.22273077 | Insights into the limited global spread of the immune evasive SARS-CoV-2 variant Mu | SARS-CoV-2 Variants of Concern (VOCs) continue to reshape the trajectory of the COVID-19 pandemic. However, why some VOCs, like Omicron, become globally dominant while the spread of others is limited is not fully understood. To address this question, we investigated the VOC Mu, which was first identified in Colombia in late 2020. Our study demonstrates that, although Mu is less sensitive to neutralization compared to variants that preceded it, it did not spread significantly outside of South and Central America. Additionally, we find evidence that the response to Mu was impeded by reporting delays and gaps in the global genomic surveillance system. Our findings suggest that immune evasion alone was not sufficient to outcompete highly transmissible variants that were circulating concurrently with Mu. Insights into the complex relationship between genomic and epidemiological characteristics of previous variants should inform our response to variants that are likely to emerge in the future. | epidemiology |
10.1101/2022.03.28.22273062 | External Validation of the Predicting Asthma Risk in Children (PARC) tool in a clinical cohort | RationaleThe Predicting Asthma Risk in Children (PARC) tool uses questionnaire-based respiratory symptoms collected from preschool children to predict their risk of asthma 5 years later. The tool was originally developed and externally validated in population-based settings and has not yet been validated in a clinical setting.
ObjectiveTo externally validate the PARC tool in children seen in paediatric pulmonology clinics.
MethodsThe Swiss Paediatric Airway Cohort (SPAC) is a prospective study of children seen in respiratory outpatient clinics across Switzerland. This analysis included children seen at ages 1-6 years for cough or wheeze at baseline and who completed the follow-up questionnaire 2 years later. The outcome was defined as current wheeze plus use of asthma medication. In sensitivity analyses, we explored effects of varied inclusion criteria and outcomes. We assessed performance by describing sensitivity, specificity, negative and positive predictive value (NPV, PPV), area under the curve (AUC), scaled Briers score and Nagelkerkes R2 scores and compared performance in SPAC to that achieved in the original population, the Leicester Respiratory Cohort (LRC).
ResultsAmong the 346 children included, 125 (36%) reported the outcome after 2 years. At a PARC score cut-off of 4, sensitivity was higher (95% vs 79%) but specificity lower (14% vs 57%) in SPAC compared to LRC. NPV was comparable (0.84 vs. 0.87) as was PPV (0.37 vs.0.42). Discrimination was lower in SPAC (AUC of 0.71 vs 0.78), as were Nagelkerkes R2 (0.18 vs 0.28) and scaled Briers scores (0.13 vs 0.22). When the outcome was changed to moderately severe asthma (>4 attacks plus use of asthma medication), there were improvements in AUC (0.74), sensitivity (0.97), specificity (0.22) and NPV (0.99), but some deterioration in PPV (0.13), R2 (0.15) and scaled Brier score (0.09).
ConclusionWhile the PARC tool performs well in a population-based setting and has some clinical utility, in particular for ruling out the development of asthma, this study highlights the need for new prognostic prediction tools to be developed specifically for the clinical setting.
FundingSNSF:320030_182628, SLA2019-03_641670 | epidemiology |
10.1101/2022.03.25.22272952 | Rapid increase in SARS-CoV-2 seroprevalence during the emergence of Omicron variant, Finland | ObjectivesThe aim of this study was to assess changes in exposure and prevalence of SARS-CoV-2 infection during the first months of emergence of Omicron variant in the Greater Helsinki area, Finland.
MethodsA prospective seroepidemiological survey of SARS-CoV-2 was conducted on 1,600 serum specimens sent to Helsinki University Hospital Laboratory (HUSLAB) for HIV serology between 15 November 2021 and 6 March 2022 (calendar weeks 46/2021 - 9/2022). For each calendar week, 100 serum specimens were randomly selected and analysed for SARS-CoV-2 IgG antibodies against nucleocapsid (N) and spike 1 (S1) protein with Abbott SARS-CoV-2 IgG (N protein) and SARS-CoV-2 IgG II Quant (S protein) tests, respectively.
ResultsThe prevalence of N antibodies increased from 5.2% (weeks 46-50/2021) to 28.2% (weeks 5-9/2022) during the study period. The proportion of seronegative samples as well as anti-N negative, anti-S1 positive samples decreased correspondingly from 11.6% to 3.8%, and 84.2% to 68.2%, respectively. Anti-N positive samples that were anti-S1 negative only began to appear as of week 2/2022.
ConclusionsA rapid increase in the N antibody prevalence was observed over the study period, suggesting a high transmission rate. A substantial proportion of COVID-19 cases remained undiagnosed during the emergence of Omicron variant in the Greater Helsinki Area, Finland. | epidemiology |
10.1101/2022.03.29.22273100 | The impact of human mobility and reactive case detection on malaria transmission in Zanzibar | Malaria persists at low levels on Zanzibar despite the use of vector control and case management. We use a metapopulation model to investigate the role of human mobility in malaria persistence on Zanzibar, and the impact of reactive case detection. The model was parameterized using survey data on malaria prevalence, reactive case detection, and travel history. We find that in the absence of imported cases from mainland Tanzania, malaria would likely cease to persist on Zanzibar. We also investigate potential intervention scenarios that may lead to elimination, especially through changes to reactive case detection. While we find that some additional cases are removed by reactive case detection, a large proportion of cases are missed due to many infections having a low parasite density that go undetected by rapid diagnostic tests, a low rate of those infected with malaria seeking treatment, and a low rate of follow up at the household level of malaria cases detected at health facilities. While improvements in reactive case detection would lead to a reduction in malaria prevalence, none of the intervention scenarios tested here were sufficient to reach elimination. Imported cases need to be treated to have a substantial impact on prevalence. | epidemiology |
10.1101/2022.03.28.22273039 | Optimal epidemic control under uncertainty: trade-offs between information collection and other actions | BackgroundRecent epidemics and measures taken to control them - through vaccination or other actions - have highlighted the role and importance of uncertainty in public health. There is generally a trade-off between information collection and other uses of resources. Explicitly or more implicitly, the concept of expected value of perfect information (EVPI) is central in order to inform policy makers in an uncertain environment.
MethodWe use a simple SIR disease emergence and transmission model with vaccination that can be administered as one or two doses. The disease parameters and vaccine characteristics are uncertain. We study the trade-offs between information acquisition and two other measures: bringing vaccination forward, and acquiring more vaccine doses. To do this, we quantify the EVPI under different constraints faced by public health authorities, i.e. the time of the vaccination campaign implementation and the number of vaccine doses available.
ResultsWe discuss the appropriateness of different responses under uncertainty. We show that in some cases, vaccinating later or with less vaccine doses but more information may bring better results than vaccinating earlier or with more doses and less information respectively.
ConclusionIn the present methodological paper, we show in an abstract setting how clearly defining and treating the trade-off between information acquisition and the relaxation of constraints can improve public health decision making. | public and global health |
10.1101/2022.03.29.22273120 | Adherence to and enforcement of non-pharmaceutical interventions (NPIs) for COVID-19 prevention in Nigeria, Rwanda, and Zambia: A mixed-methods analysis | IntroductionIn the early parts of the COVID-19 pandemic, non-pharmaceutical interventions (NPIs) were implemented worldwide, including in sub-Saharan Africa, to prevent and control SARS-CoV-2 transmission. This mixed-methods study examines adherence to and enforcement of NPIs implemented to curb COVID-19 in Nigeria, Rwanda, and Zambia, leading up to the 10,000th case of laboratory-confirmed COVID-19 in each country. Additionally, we aim to evaluate the relationship between levels and changes of NPIs over time and changes in COVID-19 cases and deaths.
MethodsThis mixed-methods analysis utilized semi-structured interviews and a quantitative dataset constructed using multiple open data sources, including the Oxford COVID-19 Government Response Tracker. To understand potential barriers and facilitators in implementing and enforcing NPIs qualitative data were collected from those involved in the COVID-19 response and analyzed using NVivo. Quantitative results were analyzed using descriptive statistics, plots, ANOVA, and post hoc Tukey.
ResultsIndividual indicator scores varied with the COVID-19 response in all three countries. Nigeria had sustained levels of strict measures for containment and closure NPIs, while in Rwanda there was substantial variation in NPI score as it transitioned through the different case windows for the same measures. Zambia implemented moderate stringency throughout the pandemic using gathering restrictions and business/school closure measures but maintained low levels of strictness for other containment and closure measures. Rwanda had far more consistent and stringent measures compared to Nigeria and Zambia. Rwandas success in implementing COVID-related measures was partly due to strong enforcement and having a population that generally obeys its government.
ConclusionVarious forces either facilitated or hindered adherence and compliance to COVID-19 control measures. This research highlights important lessons, including the need to engage communities early and create buy-in, as well as the need for preparation to ensure that response efforts are proactive rather than reactive when faced with an emergency. | public and global health |
10.1101/2022.03.26.22272613 | Persistent health issues, adverse events of significant concern, and effectiveness of COVID-19 vaccination- findings from a real-world cohort study of healthcare workers in north India | BackgroundThere is paucity of real-world data on COVID-19 vaccine effectiveness and safety from cohort designs. The current study aimed to evaluate vaccine performance during second wave in India. It also aimed to determine adverse events of significant concern (AESCs), and to ascertain the effect of vaccination on persistent health issues in individuals post COVID-19.
MethodsA cohort study was conducted from July-2021 to December-2021 in a tertiary hospital of north India. The primary outcome was vaccine-effectiveness against COVID-19. Secondary outcomes were AESCs, and persistent health issues in those receiving vaccine. Regression analyses were performed to determine risk factors.
ResultsIn 2760 healthcare workers (HCWs) included, 1033 COVID-19 events were reported. Around 6-17% vaccine effectiveness was observed against COVID-19 occurrence. One dose-recipients were at 1.6-times increased risk of COVID-19. Prior SARS-CoV-2 infection was a strong independent protective factor against COVID-19 (aOR 0.66). Full vaccination reduced moderate-severe COVID-19 by 57%. Those with lung disease were at 2.5-times increased risk of moderate-severe COVID-19. AESCs were observed in 1.3% including one case each of myocarditis and severe hypersensitivity. Individuals with hypothyroidism were at 5-times and those receiving vaccine after recovery from COVID-19 were at 3-times higher risk of persistent health issues.
ConclusionCOVID-19 vaccination reduced COVID-19 severity but offered marginal protection against occurrence. Relationship of asthma and hypothyroidism with COVID-19 outcomes necessitates focused research. Independent protection of prior SARS-CoV-2 infection was high and persistent health issues were common in individuals receiving vaccine post COVID-19. Recommendations of vaccinating those recovered from COVID-19 need further studies. | infectious diseases |
10.1101/2022.03.28.22273068 | SARS-CoV-2 spike-binding antibody longevity and protection from re-infection with antigenically similar SARS-CoV-2 variants | AO_SCPLOWBSTRACTC_SCPLOWThe PARIS (Protection Associated with Rapid Immunity to SARS-CoV-2) cohort follows health care workers with and without documented coronavirus disease 2019 (COVID-19) since April 2020. We report our findings regarding SARS-CoV-2 spike binding antibody stability and protection from infection in the pre-variant era. We analyzed data from 400 healthcare workers (150 seropositive and 250 seronegative at enrollment) for a median of 84 days. The SARS-CoV-2 spike binding antibody titers were highly variable with antibody levels decreasing over the first three months, followed by a relative stabilization. We found that both more advanced age (>40 years) and female sex were associated with higher antibody levels (1.6-fold and 1.4-fold increases, respectively). Only six percent of the initially seropositive participants "seroreverted". We documented a total of 11 new SARS-CoV-2 infections (ten naive participants, one previously infected participant without detectable antibodies, p<0.01) indicating that spike antibodies limit the risk of re-infection. These observations, however, only apply to SARS-CoV-2 variants antigenically similar to the ancestral SARS-CoV-2 ones. In conclusion, SARS-CoV-2 antibody titers mounted upon infection are stable over several months in most people and provide protection from infection with antigenically similar viruses.
summaryThe levels of SARS-CoV-2 spike binding antibodies mounted upon infection with ancestral SARS-CoV-2 variants are highly variable, stabilize at an individual level after three months and provide protection from infection with homologous virus. | infectious diseases |
10.1101/2022.03.29.22273041 | Emerging Therapies for COVID-19: the value of information from more clinical trials | ObjectivesThe COVID-19 pandemic necessitates time-sensitive policy and implementation decisions regarding new therapies in the face of uncertainty. The aim of this study was to quantify consequences of approving therapies or pursuing further research: either immediate approval, use only in research, approval with research (e.g., Emergency Use Authorization), or reject.
MethodsUsing a cohort state-transition model for hospitalized COVID-19 patients, we estimated quality-adjusted life years (QALYs) and costs associated with the following interventions: Hydroxychloroquine, Remdesivir, Casirivimab-Imdevimab, Dexamethasone, Baricitinib-Remdesivir, Tocilizumab, Lopinavir-Ritonavir, and Interferon beta-1a, and usual care. We used the model outcomes to conduct cost-effectiveness and value of information analyses from a US healthcare perspective and a lifetime horizon.
ResultsAssuming a $100,000-per-QALY willingness-to-pay-threshold, only Remdesivir, Casirivimab-Imdevimab, Dexamethasone, Baricitinib-Remdesivir and Tocilizumab were (cost-) effective (incremental net health benefit 0.252, 0.164, 0.545, 0.668 and 0.524 QALYs and incremental net monetary benefit $25,249, $16,375, $54,526, $66,826 and $52,378). Our value of information analyses suggest that most value can be obtained if these 5 therapies are approved for immediate use rather than requiring additional RCTs (net value $20.6 Billion, $13.4 Billion, $7.4 Billion, $54.6 Billion and $7.1 Billion); Hydroxychloroquine (net value $198 Million) only used in further RCTs if seeking to demonstrate decremental cost-effectiveness, and otherwise rejected; and Interferon beta-1a and Lopinavir-Ritonavir are rejected (i.e., neither approved nor additional RCTs).
Conclusions and RelevanceEstimating the real-time value of collecting additional evidence during the pandemic can inform policymakers and clinicians about the optimal moment to implement therapies and whether to perform further research. | health economics |
10.1101/2022.03.28.22273056 | Feeding practices and cost of diet of six-month-old HIV exposed uninfected compared to HIV unexposed uninfected infants in a peri-urban community in South Africa | BackgroundThe increasing population of HIV-exposed-uninfected (HEU) infants are known to be at risk of poor nutritional status and suboptimal growth, with biological risk factors implicated, yet the cost to families of feeding infants is often overlooked.
ObjectiveThe study compared the infant feeding practices and costs and macronutrient intake of HEU vs HIV-unexposed-uninfected (HUU) six-month-old infants in the Gauteng Province of South Africa.
MethodsA cross-sectional study investigated 46 HEU and 55 HUU infants aged six months and utilised a single quantified 24-hr recall and the FoodFinder program for meal analysis. The estimation of diet cost utilised supermarket food prices based on the 24-hr recall method.
ResultsMothers of HEU infants had significantly lower income (p<0.01) and educational attainment (p=0.03). The infant feeding practices differed between HEU vs HUU infants (p=0.05): exclusive breastfeeding (50.0% vs 34.0%) and mixed breastfeeding (38.1% vs 64.2%). Common complementary foods for HEU versus HUU infants included commercial infant cereals (CIC) (48.7% vs 70.9%; p=0.04); fruits and vegetables (33.3% vs 15.7%; p=0.05) and maize meal porridge (25.6% vs 15.7%; p=0.24), respectively. The mean daily cost of diet of HEU vs HUU infants was 8.55{+/-}7.35ZAR ($0.68{+/-}0.59USD) vs 10.97{+/-}7.92ZAR($0.88{+/-}0.63 USD); (p=0.10). Regarding the complementary feeding, there were non-significant differences in protein, fat, and carbohydrate intakes (p>0.05) and their costs per daily intake (p>0.05) between the groups.
ConclusionThere are no significant differences in cost, feeding and macronutrient intakes between HEU and HUU. Suboptimal breastfeeding practices remains an issue within the first six months. More sustained effort is required to support and promote exclusive breastfeeding. | nutrition |
10.1101/2022.03.28.22273043 | Examining impacts of approval of home use of misoprostol in England on access to medical abortion | ObjectivesTo assess the impact of the December 2018 approval of home administration of misoprostol in England on access to medical abortion.
DesignTime series analysis
SettingBritish Pregnancy Advisory Service (BPAS), independent-sector abortion provider in England
Participants145,529 abortions carried out by BPAS across England between 2018 and 2019.
InterventionApproval of home administration of misoprostol in early medical abortions (EMA) in December 2018
Main outcome measureGestational age at abortion and EMAs as a proportion of all abortions. The analysis was stratified by key sociodemographic characteristics to assess differential impacts of the approval
Results99,008 abortions took place in the period before the approval or during its implementation phase (January 2018 - June 2019) and 46,521 took place after (July 2019 - Dec 2019). Compared to if former trends had continued, the actual proportion of EMAs was 4.2% higher in December 2019 and the mean gestational age 3.4 days lower.
ConclusionFollowing the approval of home use of misoprostol, we saw an acceleration in the trends towards increasing proportion of all abortions that were EMAs and decreasing gestational age at abortion, especially in more deprived areas of England. Some inequities remain across race/ethnicity groups that require further investigation. Policymakers should take the positive results of this study into consideration when reviewing rules for home management of medical abortions, including with home use of mifepristone.
What is already known on this topicIn 2018 in England, a womans "home" was designated as a class of place where misoprostol could be used to induce abortion up to 10 weeks gestation following administration of mifepristone in a medical facility. This model of abortion care has been shown in numerous international studies to be highly effective, safe, and preferred by women over in-clinic use. Existing data anticipated positive clinical and acceptability outcomes with implementation of home use, but whether or how the change would impact access particularly in relation to barriers such as area-level deprivation, race/ethnicity, and disability was uncertain.
What this study addsThe approval of home use of misoprostol as part of a medical abortion regimen in England was associated with material and equitable improvements in abortion access as evidenced by a higher proportion of medical abortions provided, lower gestational age at treatment, and higher odds of having a medical abortion across all racial/ethnic groups and socioeconomic groups. Pre-approval trends toward greater uptake of medical abortion and declining gestational age were accelerated post-approval and were greatest in the most deprived quintiles but not across all racial/ethnic groups.
Patient and Public Involvement StatementThis study was a quantitative data analysis of existing clinical data and patients were not directly involved in the research.
Authors note on terminologyThe authors would like to note that abortions are experienced not only by cis-women, but also by trans, non-binary and intersex people, who should be recognised and treated as equal recipients of abortion care. The term women will be used in this project for simplicity and in acknowledgment of the fact that the majority of the patients identify as women. | sexual and reproductive health |
10.1101/2022.03.27.22273001 | A COMPARATIVE EVALUATION OF NON-INCISED PAPILLAE AND ENTIRE PAPILLA PRESERVATION SURGICAL APPROACHES IN TREATMENT OF INTRABONY DEFECTS. A CLINICAL AND RADIOGRAPHIC STUDY | Aim & ObjectivesThe aim of the present study was to clinically and radiographically compare and evaluate the NIPSA (Non-Incised Papillae Surgical Approach) and EPP (Entire Papilla Preservation) techniques in the treatment of intra bony defects.
Patients and methodsFrom this initial patient pool of 156 patients, 44 individuals satisfying the inclusion criteria were selected. One site in each subject was assigned into each of the following experimental groups which were treated with the relevant procedure; NIPSA and EPP groups. Clinical parameters included the recording of pocket probing depths (PPD), clinical attachment levels (CAL) and papilla loss. The evaluation of bone fill was performed at the end of 3 & 6-months by using Image J(R) software.
ResultsNIPSA and EPP resulted in highly significant CAL gains (4.00{+/-}1.00 vs 5.25 {+/-} 1.47mm; p[≤]0.001) and PPD reductions (3.352{+/-}0.70 vs 3.625{+/-}1.024mm; p[≤]0.001) at 6-months post-surgery. From the start to the end of study period, NIPSA resulted in almost no papilla loss (1.71{+/-}0.47 to 1.73{+/-}0.77mm) while EPP technique showed minimal and insignificant (1.57{+/-}0.52 to 1.48{+/-}0.71mm; p[≥]0.05) papilla loss. The EPP group revealed a highly significant (0.459{+/-}0.16 vs 0.269{+/-}0.16cm2; p[≤]0.001) bone fill over NIPSA group at 6-months.
ConclusionFrom this trial conducted over a period of 6-months, NIPSA and EPP both resulted in significant improvements in clinical outcomes. NIPSA and EPP showed favourable outcomes in terms papilla loss and bone fill respectively. Both the techniques achieve the aims outlined earlier and broaden the choice available to a periodontist in the management of intrabony defects. | dentistry and oral medicine |
10.1101/2022.03.25.22272961 | Serum DNA methylome of the colorectal cancer serrated pathway | ObjectiveThe clinical relevance of the serrated pathway of colorectal carcinogenesis is evident but the screening of serrated lesions remains challenging. We aimed to characterize the serum methylome of the serrated pathway, and to evaluate circulating cell-free DNA (cfDNA) methylation as a source of biomarkers for the non-invasive screening and diagnosis of serrated lesions.
DesignWe collected serum samples from individuals with serrated adenocarcinoma (SAC), traditional serrated adenomas, sessile serrated lesions, hyperplastic polyps and with no colorectal findings. First, epigenome-wide methylation was quantified in cfDNA pooled samples with the MethylationEPIC array. Then, methylation profiles were compared to tissue and serum cfDNA datasets. Finally, biomarker utility of serum cfDNA methylation was evaluated.
ResultsWe identified a differential methylation profile that can distinguish high-risk serrated lesions from the absence of serrated neoplasia, showing concordance with tissue methylation from SAC and sessile serrated lesions (external datasets). We report that the methylation profiles in serum cfDNA are pathway-specific, clearly separating serrated lesions from conventional adenomas. Among the differentially methylated regions (DMR) we report, the combination of two DMRs within the genes NINJ2 and ERICH1 discriminated high-risk serrated lesions and SAC with 91.4% sensitivity and 64.4% specificity, while methylation from a DMR within ZNF718 reported 100% sensitivity for the detection of SAC at 96% specificity.
ConclusionThis is the only study available to date exploring the serum methylome of serrated lesions. We have identified a differential methylation profile in serum specific to the serrated pathway. The serum methylome may serve as a source of non-invasive biomarkers for screening and detection of high-risk serrated lesions. | gastroenterology |
10.1101/2022.03.28.22273054 | Weakly supervised learning for multi-organ adenocarcinoma classification in whole slide images | The primary screening by automated computational pathology algorithms of the presence or absence of adenocarcinoma in biopsy specimens (e.g., endoscopic biopsy, transbronchial lung biopsy, and needle biopsy) of possible primary organs (e.g., stomach, colon, lung, and breast) and radical lymph node dissection specimen is very useful and should be a powerful tool to assist surgical pathologists in routine histopathological diagnostic workflow. In this paper, we trained multi-organ deep learning models to classify adenocarcinoma in biopsy and radical lymph node dissection specimens whole slide images (WSIs). We evaluated the models on seven independent test sets (stomach, colon, lung, breast, lymph nodes) to demonstrate the feasibility in multiorgan and lymph nodes specimens from different medical institutions and international public datasets, achieving receiver operating characteristic areas under the curves (ROC-AUCs) in the range of 0.91-0.99. | pathology |
10.1101/2022.03.28.22273069 | Multimodal neuroimaging correlates of physical-cognitive covariation in Chilean adolescents. The Cogni-Action Project | Health-related behaviours have been related to brain structural features; however, most literature in this domain comes from developed countries. In developing settings, such as Latin America, high social inequality is associated inversely with several health-related behaviours affecting brain development. Understanding the relationship between health behaviours and brain structure in such settings is particularly important during adolescence when key habits are acquired and ingrained. In this cross-sectional study, we carry out a multimodal analysis identifying a brain region associated with health-related behaviours (i.e., fatness, fitness, sleep problems and others) and cognitive/academic performance independent of socioeconomic status in a large sample of Chilean adolescents. Our findings suggest that the relationship between health behaviours and cognitive/academic performance involves a particular brain phenotype that could play a mediator role. These findings raise the possibility of promoting healthy behaviours in adolescence as a means to influence brain structure and thereby cognitive/academic achievement, independently of socioeconomic factors. | pediatrics |
10.1101/2022.03.28.22272995 | Speech disturbances in schizophrenia: assessing cross-linguistic generalizability of NLP automated measures of coherence | IntroductionLanguage disorders - disorganized and incoherent speech in particular - are distinctive features of schizophrenia. Natural language processing (NLP) offers automated measures of incoherent speech as promising markers for schizophrenia. However, the scientific and clinical impact of NLP markers depends on their generalizability across contexts, samples, and languages, which we systematically assessed in the present study relying on a large, novel, cross-linguistic corpus.
MethodsWe collected a Danish (DK), German (GE), and Chinese (CH) cross-linguistic dataset involving transcripts from 187 participants with schizophrenia (111DK, 25GE, 51CH) and 200 matched controls (129DK, 29GE, 42CH) performing the Animated Triangle task. Fourteen previously published NLP coherence measures were calculated, and between-groups differences and association with symptoms were tested for cross-linguistic generalizability.
ResultsOne coherence measure robustly generalized across samples and languages. We found several language-specific effects, some of which partially replicated previous findings (lower coherence in German and Chinese patients), while others did not (higher coherence in Danish patients). We found several associations between symptoms and measures of coherence, but the effects were generally inconsistent across languages and rating scales.
ConclusionsUsing a cumulative approach, we have shown that NLP findings of reduced semantic coherence in schizophrenia have limited generalizability across different languages, samples, and measures. We argue that several factors such as sociodemographic and clinical heterogeneity, cross-linguistic variation, and the different NLP measures reflecting different clinical aspects may be responsible for this variability. Future studies should take this variability into account in order to develop effective clinical applications targeting different patient populations. | psychiatry and clinical psychology |
10.1101/2022.03.28.22272995 | Speech disturbances in schizophrenia: assessing cross-linguistic generalizability of NLP automated measures of coherence | IntroductionLanguage disorders - disorganized and incoherent speech in particular - are distinctive features of schizophrenia. Natural language processing (NLP) offers automated measures of incoherent speech as promising markers for schizophrenia. However, the scientific and clinical impact of NLP markers depends on their generalizability across contexts, samples, and languages, which we systematically assessed in the present study relying on a large, novel, cross-linguistic corpus.
MethodsWe collected a Danish (DK), German (GE), and Chinese (CH) cross-linguistic dataset involving transcripts from 187 participants with schizophrenia (111DK, 25GE, 51CH) and 200 matched controls (129DK, 29GE, 42CH) performing the Animated Triangle task. Fourteen previously published NLP coherence measures were calculated, and between-groups differences and association with symptoms were tested for cross-linguistic generalizability.
ResultsOne coherence measure robustly generalized across samples and languages. We found several language-specific effects, some of which partially replicated previous findings (lower coherence in German and Chinese patients), while others did not (higher coherence in Danish patients). We found several associations between symptoms and measures of coherence, but the effects were generally inconsistent across languages and rating scales.
ConclusionsUsing a cumulative approach, we have shown that NLP findings of reduced semantic coherence in schizophrenia have limited generalizability across different languages, samples, and measures. We argue that several factors such as sociodemographic and clinical heterogeneity, cross-linguistic variation, and the different NLP measures reflecting different clinical aspects may be responsible for this variability. Future studies should take this variability into account in order to develop effective clinical applications targeting different patient populations. | psychiatry and clinical psychology |
10.1101/2022.03.25.22272956 | No magic bullet: limiting in-school transmission in the face of variable SARS-CoV-2 viral loads | In the face of a long-running pandemic, understanding the drivers of ongoing SARS-CoV-2 transmission is crucial for the rational management of COVID-19 disease burden. Keeping schools open has emerged as a vital societal imperative during the pandemic, but in-school transmission of SARS-CoV-2 can contribute to further prolonging the pandemic. In this context, the role of schools in driving SARS-CoV-2 transmission acquires critical importance. Here we model in-school transmission from first principles to investigate the effectiveness of layered mitigation strategies on limiting in-school spread. We examine the effect of masks and air quality (ventilation, filtration and ionizers) on steady-state viral load in classrooms, as well as on the number of particles inhaled by an uninfected person. The effectiveness of these measures in limiting viral transmission is assessed for variants with different levels of mean viral load (Wuhan, Delta, Omicron). Our results suggest that a layered mitigation strategy can be used effectively to limit in-school transmission, with certain limitations. First, poorly designed strategies (insufficient ventilation, no masks, staying open under high levels of community transmission) will permit in-school spread even if some level of mitigation is ostensibly present. Second, for viral variants that are sufficiently contagious, it may be difficult to construct any set of interventions capable of blocking transmission once an infected individual is present, underscoring the importance of other measures. Our findings provide several practical recommendations: the use of a layered mitigation strategy that is designed to limit transmission, with other measures such as frequent surveillance testing and smaller class sizes (such as by offering remote schooling options to those who prefer it) as needed. | public and global health |
10.1101/2022.03.25.22272941 | Attitudes and Experiences Surrounding Female Genital Mutilation/Cutting in the United States: A Scoping Review | In recent decades, growing migration to the United States from countries where female genital mutilation/cutting (FGM/C) is widely practiced has caused a rise in the number of women and girls in the United States who could have potentially experienced FGM/C. A scoping review was conducted to identify research and gaps in literature about FGM/C-related attitudes and experiences among individuals from FGM/C-practicing countries living in the United States. This scoping review identified 40 articles meeting inclusion criteria. The findings of this review suggest that both women and men from FGM/C-practicing countries living in the United States generally oppose FGM/C, and that women with FGM/C have significant physical and mental health needs and have found US healthcare providers to lack understanding of FGM/C. Future research can improve measurement of FGM/C by applying a health equity lens and taking into account the sociocultural influences on FGM/C-related attitudes and experiences. | public and global health |
10.1101/2022.03.25.22272900 | Can electroencephalography (EEG) identify ADHD subtypes? A systematic review. | Attention Deficit/Hyperactivity Disorder (ADHD) has been associated with atypical patterns of neural activity measured by electroencephalography (EEG). However, the identification of EEG diagnostic biomarkers has been complicated by the disorders heterogeneity. The objective of this review was to synthesize the literature investigating EEG variation in patients diagnosed with ADHD, addressing the following questions: 1) Are the diagnostic ADHD subtypes associated with different EEG characteristics? 2) Are EEG measures correlated with ADHD traits and/or symptom severity? and 3) Do classification techniques using EEG measures reveal different clinical presentations of ADHD? Outcomes highlight the potential for electrophysiological measures to provide meaningful insights into the heterogeneity of ADHD, although direct translation of EEG biomarkers for diagnostic purposes is not yet supported. Key measures that show promise for the discrimination of existing ADHD subtypes and symptomatology include: resting state and task-related modulation of alpha, beta and theta power, and the event-related N2 and P3 components. Prescriptions are discussed for future studies that may help to bridge the gap between research and clinical application. | neurology |
10.1101/2022.03.31.22273227 | Identification of carcinogenesis and tumor progression processes in pancreatic ductal adenocarcinoma using high-throughput proteomics | Pancreatic adenocarcinoma (PDAC) is an aggressive disease with an overall 5 year-survival rate of just 5%. A better understanding of both the carcinogenesis processes and the mechanisms of progression of PDAC disease is mandatory. Proteomics offers complementary information to genomics, measuring the direct effectors of the biological processes.
From a cohort of 110 PDAC patients treated with surgery and adjuvant therapy, 52 patients, of which primary tumor and normal tissue, preneoplastic lesions (PanIN), and/or lymph node metastases were available, were selected for the study. Proteins were extracted from small punches obtained from formalin fixed, paraffin embedded tissue, and analyzed by LC-MS/MS using a data-independent acquisition approach. Protein expression data was analyzed using probabilistic graphical models, allowing functional characterization. Functional node activities were calculated as the mean of expression of those proteins related to the main function of each node. Comparisons between groups were done using linear mixed models.
First, analyzing the tumor tissue, three proteomics subtypes were defined: T1 (32% of patients) presented higher activity of adhesion and complement activation nodes, T2 (34%) had higher mitochondrial and metabolic node activity, and T3 (34%) had higher nucleoplasm node activity. Second, relevant biological processes related to carcinogenesis and tumor progression were studied in each subtype. We found differences between T1 PanIN and primary tumors in adhesion, translation, mitochondria and pancreatic secretion nodes, suggesting an involvement of these processes in tumor development. Differences between tumors and lymph nodes, related to tumor progression, were identified in nucleoplasm, translation, adhesion, extracellular matrix, and complement activation nodes. Mitochondria and metabolism nodes had differential activity between T2 normal tissue, PanIN and tumors, and also between tumors and lymph nodes. T3 analyses point out that nucleoplasm, metabolism and mitochondria, and extracellular matrix nodes could be involved in T3 tumors carcinogenesis. Interestingly, identified processes were different between the three proteomics subtypes suggesting that the motor of the disease is characteristic of each subtype. Additionally, these proteomics subtypes were validated into the PDAC TCGA cohort.
In this study, three PDAC proteomics subtypes were defined, an adhesion-related subtype (T1), a metabolic-related subtype (T2), and a nucleoplasm subtype (T3). We also suggest several biological processes involved in tumor development and progression exclusive of each proteomics subtype. These biological processes could be relevant as a guide to select candidates for future tailored therapeutics treatments in PDAC. Proteomics data are available via ProteomeXchange with identifier PXD032076. | oncology |
10.1101/2022.03.31.22273227 | Identification of carcinogenesis and tumor progression processes in pancreatic ductal adenocarcinoma using high-throughput proteomics | Pancreatic adenocarcinoma (PDAC) is an aggressive disease with an overall 5 year-survival rate of just 5%. A better understanding of both the carcinogenesis processes and the mechanisms of progression of PDAC disease is mandatory. Proteomics offers complementary information to genomics, measuring the direct effectors of the biological processes.
From a cohort of 110 PDAC patients treated with surgery and adjuvant therapy, 52 patients, of which primary tumor and normal tissue, preneoplastic lesions (PanIN), and/or lymph node metastases were available, were selected for the study. Proteins were extracted from small punches obtained from formalin fixed, paraffin embedded tissue, and analyzed by LC-MS/MS using a data-independent acquisition approach. Protein expression data was analyzed using probabilistic graphical models, allowing functional characterization. Functional node activities were calculated as the mean of expression of those proteins related to the main function of each node. Comparisons between groups were done using linear mixed models.
First, analyzing the tumor tissue, three proteomics subtypes were defined: T1 (32% of patients) presented higher activity of adhesion and complement activation nodes, T2 (34%) had higher mitochondrial and metabolic node activity, and T3 (34%) had higher nucleoplasm node activity. Second, relevant biological processes related to carcinogenesis and tumor progression were studied in each subtype. We found differences between T1 PanIN and primary tumors in adhesion, translation, mitochondria and pancreatic secretion nodes, suggesting an involvement of these processes in tumor development. Differences between tumors and lymph nodes, related to tumor progression, were identified in nucleoplasm, translation, adhesion, extracellular matrix, and complement activation nodes. Mitochondria and metabolism nodes had differential activity between T2 normal tissue, PanIN and tumors, and also between tumors and lymph nodes. T3 analyses point out that nucleoplasm, metabolism and mitochondria, and extracellular matrix nodes could be involved in T3 tumors carcinogenesis. Interestingly, identified processes were different between the three proteomics subtypes suggesting that the motor of the disease is characteristic of each subtype. Additionally, these proteomics subtypes were validated into the PDAC TCGA cohort.
In this study, three PDAC proteomics subtypes were defined, an adhesion-related subtype (T1), a metabolic-related subtype (T2), and a nucleoplasm subtype (T3). We also suggest several biological processes involved in tumor development and progression exclusive of each proteomics subtype. These biological processes could be relevant as a guide to select candidates for future tailored therapeutics treatments in PDAC. Proteomics data are available via ProteomeXchange with identifier PXD032076. | oncology |
10.1101/2022.03.31.22273249 | Rigorous benchmarking of T cell receptor repertoire profiling methods for cancer RNA sequencing | The ability to identify and track T cell receptor (TCR) sequences from patient samples is becoming central to the field of cancer research and immunotherapy. Tracking genetically engineered T cells expressing TCRs that target specific tumor antigens is important to determine the persistence of these cells and quantify tumor responses. The available high-throughput method to profile T cell receptor repertoires is generally referred to as TCR sequencing (TCR-Seq). However, the available TCR-Seq data is limited compared to RNA sequencing (RNA-Seq). In this paper, we have benchmarked the ability of RNA-Seq-based methods to profile TCR repertoires by examining 19 bulk RNA-Seq samples across four cancer cohorts including both T cell rich and poor tissue types. We have performed a comprehensive evaluation of the existing RNA-Seq-based repertoire profiling methods using targeted TCR-Seq as the gold standard. We also highlighted scenarios under which the RNA-Seq approach is suitable and can provide comparable accuracy to the TCR-Seq approach. Our results show that RNA-Seq-based methods are able to effectively capture the clonotypes and estimate the diversity of TCR repertoires, as well as to provide relative frequencies of clonotypes in T cell rich tissues and monoclonal repertoires. However, RNA-Seq-based TCR profiling methods have limited power in T cell poor tissues, especially in polyclonal repertoires of T cell poor tissues. The results of our benchmarking provide an additional appealing argument to incorporate the RNA-Seq into immune repertoire screening of cancer patients as it offers broader knowledge into the transcriptomic changes that exceed the limited information provided by TCR-Seq. | oncology |
10.1101/2022.03.25.22272958 | Genetically personalised organ-specific metabolic models in health and disease | Understanding how genetic variants influence disease risk and complex traits (variant-to-function) is one of the major challenges in human genetics. Here we present a model-driven framework to leverage human genome-scale metabolic networks to define how genetic variants affect biochemical reaction fluxes across major human tissues, including skeletal muscle, adipose, liver, brain and heart. As proof of concept, we build personalised organ-specific metabolic flux models for 524,615 individuals of the INTERVAL and UK Biobank cohorts and perform a fluxome-wide association study (FWAS) to identify 4,411 associations between personalised flux values and the concentration of metabolites in blood. Furthermore, we apply FWAS to identify 97 metabolic fluxes associated with the risk of developing coronary artery disease, many of which are linked to processes previously described to play in role in the disease. Our work demonstrates that genetically personalised metabolic models can elucidate the downstream effects of genetic variants on biochemical reactions involved in common human diseases. | genetic and genomic medicine |
10.1101/2022.03.27.22273019 | DraculR: A web based application for in silico haemolysis detection in high throughput small RNA sequencing data | MotivationThe search for novel microRNA (miRNA) biomarkers in plasma is hampered by haemolysis, the lysis and subsequent release of red blood cell (RBC) contents, including miRNAs, into surrounding fluid. The biomarker potential of miRNAs comes in part from their multi-compartment origin, and the long-lived nature of miRNA transcripts in plasma, giving researchers a functional window for tissues that are otherwise difficult or disadvantageous to sample. The inclusion of RBC derived miRNA transcripts in downstream analysis introduces a source of error that is difficult to identify post hoc and may lead to spurious results. Where access to a physical specimen is not possible, our tool will provide an in silico approach to haemolysis prediction.
ResultsWe present DraculR, an interactive Shiny/R application that enables a user to upload microRNA expression data from short read sequencing of human plasma as a raw read counts table and interactively calculate a metric that indicates the degree of haemolysis contamination.
Availability and implementationDraculR and its tutorial are freely available from (https://mxhp75.shinyapps.io/shinyVamp/). Code is available from (https://github.com/mxhp75/shinyVamp.git). | genetic and genomic medicine |
10.1101/2022.03.28.22272580 | A cystic fibrosis lung disease modifier locus harbors tandem repeats associated with gene expression | Variable number of tandem repeats (VNTRs) are major source of genetic variation in human. However due to their repetitive nature and large size, it is challenging to genotype them by short-read sequencing. Therefore, there is limited understanding of how they contribute to complex traits such as cystic fibrosis (CF) lung function. Genome-wide association study (GWAS) of CF lung disease identified two independent signals near SLC9A3 displaying a high density of VNTRs and CpG islands. Here, we used long-read (PacBio) phased sequence (N=58) to identify the boundaries and lengths of 49 common (frequency >2%) VNTRs in the region. Subsequently, associations of the VNTRs with gene expression were investigated in CF nasal epithelia using RNA sequencing (N=46). Two VNTRs tagged by the two GWAS signals and overlapping CpG islands were independently associated with SLC9A3 expression in CF nasal epithelia. The two VNTRs together explained 24% of SLC9A3 gene expression variation. One of them was also associated with TPPP expression. We then showed that the VNTR lengths can be estimated with good accuracy in short-read sequence in a subset of individuals with data on both long (PacBio) and short-read (10X Genomics) technologies (N=52). VNTR lengths were then estimated in the Genotype-Tissue Expression project (GTEx) and their association with gene expression was investigated. Both VNTRs were associated with SLC9A3 expression in multiple non-CF GTEx tissues including lung. The results confirm that VNTRs can explain substantial variation in gene expression and be responsible for GWAS signals, and highlight the critical role of long-read sequencing. | genetic and genomic medicine |
10.1101/2022.03.27.22273017 | Using Genomic data to Investigate the Anti-Depressive Effects of Statins | Cholesterol-lowering statins, which are widely prescribed for treating and preventing cardiovascular diseases, have previously been reported to show anti-depressive properties. However, there is conflicting evidence on the association of statins with depression, and the molecular mechanisms that govern their potential anti-depressive effects remain largely veiled. We evaluated the anti-depressive activities of statins using a combined approach of transcriptomic signature matching and genetic association analysis. We interrogated pre-compiled Connectivity Map (CMap) perturbational gene expression signatures and found that compounds with highly similar signatures to statins (average connectivity score > 90) were enriched for antidepressants (p < 1E-05). Genes perturbed in the same direction by both statins and antidepressants were significantly enriched for various immune pathways, while genes perturbed in the opposite direction were enriched for lipid metabolism pathways. Using publicly available expression quantitative trait loci (eQTL) and genome-wide association summary data, we performed Mendelian randomisation analysis to infer association of genetically predicted statin target inhibition with various depression, immune and disease traits. Genetically proxied HMGCR inhibition was significantly associated with extensive changes in immune cell traits, particularly platelet-related indices, and while we observed no genetic association between HMGCR expression and depression risk (p = 0.21), we found nominal association with depression-related worrying symptoms (p = 0.042). Our analyses provide genomic evidence for the association between statins and extensive alterations in immune-related processes, which have been linked to depression. Our findings carry clinical relevance, both for treating the increasing prevalence of individuals with comorbid cardiovascular diseases and depression, and for exploring the potential of repurposing statins for modulating depression symptoms. | genetic and genomic medicine |
10.1101/2022.03.28.22273024 | Detection of mosaic chromosomal alterations in children with severe developmental disorders recruited to the DDD study | PurposeStructural mosaicism has been previously implicated in developmental disorders. We aim to identify rare mosaic chromosomal alterations (MCAs) in probands with severe undiagnosed developmental disorders.
MethodsWe identified MCAs in SNP array data from 12,530 probands in the Deciphering Developmental Disorders (DDD) study using MoChA.
ResultsWe found 61 MCAs in 57 probands, many of these were tissue specific. In 23/26 (88.5%) cases for which the MCA was detected in saliva where blood was also available for analysis, the MCA could not be detected in blood. The MCAs included 20 polysomies, comprising either one arm of a chromosome or a whole chromosome, for which we were able to show the timing of the error (25% mitosis, 40% meiosis I, 35% meiosis II). Only 2/57 (3.5%) of the probands in whom we found MCAs had another likely genetic diagnosis identified by whole exome sequencing, despite an overall diagnostic yield of [~]40% across the cohort.
ConclusionOur results show that identification of MCAs provides candidate diagnoses for previously undiagnosed patients with developmental disorders, potentially explaining [~]0.45% of cases in the DDD study. Nearly 90% of these MCAs would have remained undetected by analysing DNA from blood and no other tissue. | genetic and genomic medicine |
10.1101/2022.03.28.22273024 | Detection of mosaic chromosomal alterations in children with severe developmental disorders recruited to the DDD study | PurposeStructural mosaicism has been previously implicated in developmental disorders. We aim to identify rare mosaic chromosomal alterations (MCAs) in probands with severe undiagnosed developmental disorders.
MethodsWe identified MCAs in SNP array data from 12,530 probands in the Deciphering Developmental Disorders (DDD) study using MoChA.
ResultsWe found 61 MCAs in 57 probands, many of these were tissue specific. In 23/26 (88.5%) cases for which the MCA was detected in saliva where blood was also available for analysis, the MCA could not be detected in blood. The MCAs included 20 polysomies, comprising either one arm of a chromosome or a whole chromosome, for which we were able to show the timing of the error (25% mitosis, 40% meiosis I, 35% meiosis II). Only 2/57 (3.5%) of the probands in whom we found MCAs had another likely genetic diagnosis identified by whole exome sequencing, despite an overall diagnostic yield of [~]40% across the cohort.
ConclusionOur results show that identification of MCAs provides candidate diagnoses for previously undiagnosed patients with developmental disorders, potentially explaining [~]0.45% of cases in the DDD study. Nearly 90% of these MCAs would have remained undetected by analysing DNA from blood and no other tissue. | genetic and genomic medicine |
10.1101/2022.03.28.22273021 | A Wide-bandwidth Nanocomposite-Sensor Integrated Smart Mask for Tracking Multi-phase Respiratory Activities for COVID-19 Endemic | A global sentiment in early 2022 is that the COVID-19 virus could become endemic just like common cold flu viruses soon. The most optimistic view is that, with minimal precautions, such as vaccination, boosters and optional masking, life for most people will proceed as normal soon. However, as warned by A. Katzourakis of Oxford University recently [1], we must set aside lazy optimism, and must be realistic about the likely levels of death, disability and sickness that will be brought on by a COVID-19 endemic. Moreover, the world must also consider that continual circulation of the virus could give rise to new variants such as the new BA.2 variant (a subvariant of Omicron) continues to spread across the US and parts of Europe. Data from the CDC is already showing that BA.2 has been tripling in prevalence every two weeks [2]. Hence, globally, we must use available and proven weapons to continue to fight the COVID-19 viruses, i.e., effective vaccines, antiviral medications, diagnostic tests and stop an airborne virus transmission through social distancing, and mask wearing. For this work, we have demonstrated a smart mask with an optimally-coupled ultra-thin flexible soundwave sensors for tracking, classifying, and recognizing different respiratory activities, including breathing, speaking, and two-/tri-phase coughing; the masks functionality can also be augmented in the future to monitor other human physiological signals. Although researchers have integrated sensors into masks to detect respiratory activities in the past, they only based on measuring temperature and air flow during coughing, i.e., counting only the number of coughs. However, coughing is a process consisting of several phases, including an explosion of the air with glottal opening producing some noise-like waveform, a decrease of airflow to decrease sound amplitude, and a voiced stage which is the interruption of the air flow due to the closure of glottal and periodical vibration of partly glottis, which is not always present. Therefore, sensors used for cough detection should not be only sensitive to subtle air pressure but also the high-frequency vibrations, i.e., a pressure sensor that needs to be responsive to a wide input amplitude and bandwidth range, in order to detect air flows between hundreds of hertz from breath, and acoustic signals from voice that could reach [~] 8000 Hz. Respiratory activities data from thirty-one (31) human subjects were collected. Machine learning methods such as Support Vector Machines and Convolutional Neural Networks were used to classify the collected sensor data from the smart mask, which show an overall macro-recall of about 93.88% for the three respiratory sounds among all 31 subjects. For individual subjects, the 31 human subjects have the average macro-recall of 95.23% (ranging from 90% to 100%) for these 3 respiratory activities. Our work bridges the technological gap between ultra-lightweight but high-frequency response sensor material fabrication, signal transduction and conditioning, and applying machining learning algorithms to demonstrate a reliable wearable device for potential applications in continual healthy monitoring of subjects with cough symptoms during the eventual COVID-19 endemic. The monitoring and analysis of cough sound should be highly beneficial for human health management. These health monitoring data could then be shared with doctors via cloud storage and transmission technique to help disease diagnosis more effectively. Also, communication barriers caused by wearing masks can be alleviated by combining with the speech recognition techniques. In general, this research helps to advance the wearable device technology for tracking respiratory activities, similar to an Apple Watch or a Fitbit smartwatch in tracking physical and physiological activities. | health informatics |
10.1101/2022.03.28.22273063 | The responsiveness of health service provider and quality of services when provided at three selected urban primary health care sites in Dhaka city, Bangladesh: a cross-sectional study | 1IntroductionResponsiveness of Health Service Provider (HSP) and quality of services when provided resembles basic professional and social duties of HSP towards their clients. Because of poor responsiveness and quality of services when provided, clients lose their trust towards HSP. These factors are very important to improve relationship between HSP and clients, clients satisfaction, quality of care and finally increase utilization of Urban Primary Health Care Centre services (UPHC).
ObjectivesThis study was done to determine the responsiveness of health service provider and quality of services when provided at selected UPHCs in Dhaka city.
MethodologyA cross sectional quantitative study was conducted in three UPHCs in Dhaka city from November to December 2017. 257 exit interviews were conducted by systematic random sampling for responsiveness and quality of services when provided. 49 observations of client-provider interactions were conducted using Responsiveness of Physician (ROP) scale. For exit interview, dichotomous variable was used. Descriptive analysis was done using Stata v 12.1.
FindingsMajority (90%) of HSP listen carefully, explained about the diseases, facilitated about follow-up, and client understood information clearly. More than 70% of the clients found the providers approach were friendly though only 37% had social talk with the clients. 41% of the clients reported that the providers shared emergency contact number. Around 67% of clients were not asked allergic history and in 47% case consent was not taken before procedure. Being urban area, for more than 39% clients services were not given similar in terms of social status like gender, ethnicity, economic and social status.
For tangible items like gloves (80%) and thermometer (55%) were mostly missing in all UPHCs. 88% of the HSP were reliable, 93% assured the client and 91% showed empathy in all facilities. Clients were mostly satisfied with doctors behaviour and dissatisfied about the long waiting time (average 37 minutes) in all UPHCs.
ConclusionThis study has highlighted some important gaps in responsiveness of HSP which translate into the quality of care being provided to clients seeking care from UPHC. Friendliness of HSP should be increased and services should be provided with respect. | health systems and quality improvement |
10.1101/2022.03.31.22273221 | Immunogenicity and reactogenicity of SARS-CoV-2 vaccines in people living with HIV: a nationwide prospective cohort study in the Netherlands | BackgroundVaccines can be less immunogenic in people living with HIV (PLWH), but for SARS-CoV-2 vaccinations this is unknown.
Methods and FindingsA prospective cohort study to examine the immunogenicity of BNT162b2, mRNA-1273, ChAdOx1-S and Ad26.COV2.S vaccines in adult PLWH, without prior COVID-19, compared to HIV-negative controls. The primary endpoint was the anti-spike SARS-CoV-2 IgG response after mRNA vaccination. Secondary endpoints included the serological response after vector vaccination, anti-SARS-CoV-2 T-cell response and reactogenicity.
Between February-September 2021, 1154 PLWH (median age 53 [IQR 44-60], 86% male) and 440 controls (median age 43 [IQR 33-53], 29% male) were included. 884 PLWH received BNT162b2, 100 mRNA-1273, 150 ChAdOx1-S, and 20 Ad26.COV2.S. 99% were on antiretroviral therapy, 98% virally suppressed, and the median CD4+T-cell count was 710 cells/{micro}L [IQR 520-913]. 247 controls received mRNA-1273, 94 BNT162b2, 26 ChAdOx1-S and 73 Ad26.COV2.S. After mRNA vaccination, geometric mean concentration was 1418 BAU/mL in PLWH (95%CI 1322-1523), and after adjustment for age, sex, and vaccine type, HIV-status remained associated with a decreased response (0.607, 95%CI 0.508-0.725). In PLWH vaccinated with mRNA-based vaccines, higher antibody responses were predicted by CD4+T-cell counts 250-500 cells/{micro}L (2.845, 95%CI 1.876-4.314) or >500 cells/{micro}L (2.936, 95%CI 1.961-4.394), whilst a viral load >50 copies/mL was associated with a reduced response (0.454, 95%CI 0.286-0.720). Increased IFN-{gamma}, CD4+, and CD8+T-cell responses were observed after stimulation with SARS-CoV-2 spike peptides in ELISpot and activation induced marker assays, comparable to controls. Reactogenicity was generally mild without vaccine-related SAE.
ConclusionAfter vaccination with BNT162b2 or mRNA-1273, anti-spike SARS-CoV-2 antibody levels were reduced in PLWH. To reach and maintain the same serological responses and vaccine efficacy as HIV-negative controls, additional vaccinations are probably required. | hiv aids |
10.1101/2022.03.28.22273010 | A 21L/BA.2-21K/BA.1 MixOmicron SARS-CoV-2 hybrid undetected by qPCR that screen for variant in routine diagnosis | Among the multiple SARS-CoV-2 variants identified since summer 2020, several have co-circulated, creating opportunities for coinfections and potentially genetic recombinations that are common in coronaviruses. Viral recombinants are indeed beginning to be reported more frequently. Here, we describe a new SARS-CoV-2 recombinant genome that is mostly that of a Omicron 21L/BA.2 variant but with a 3 tip originating from a Omicron 21K/BA.1 variant. Two such genomes were obtained in our institute from adults sampled in February 2022 in university hospitals of Marseille, southern France, by next-generation sequencing carried out with the Illumina or Nanopore technologies. The recombination site was located between nucleotides 26,858-27,382. In the two genomic assemblies, mean sequencing depth at mutation-harboring positions was 271 and 1,362 reads and mean prevalence of the majoritary nucleotide was 99.3{+/-}2.2% and 98.8{+/-}1.6%, respectively. Phylogeny generated trees with slightly different topologies according to whether genomes were depleted or not of the 3 tip. This 3 terminal end brought in the Omicron 21L/BA.2 genome a short transposable element of 41 nucleotides named S2m that is present in most SARS-CoV-2 except a few variants among which the Omicron 21L/BA.2 variant and may be involved in virulence. Importantly, this recombinant is not detected by currently used qPCR that screen for variants in routine diagnosis. The present observation emphasizes the need to survey closely the genetic pathways of SARS-CoV-2 variability by whole genome sequencing, and it could contribute to gain a better understanding of factors that lead to observed differences between epidemic potentials of the different variants. | infectious diseases |
10.1101/2022.03.25.22272599 | Safety and immunogenicity of a reduced dose of the BNT162b2 mRNA COVID-19 vaccine (REDU-VAC): a single blind, randomized, non-inferiority trial | 1BackgroundThe use of fractional dose regimens of COVID-19 vaccines has the potential to accelerate vaccination rates in low-income countries. Dose-finding studies of the mRNA vaccine BNT162b2 (Pfizer-BioNTech) have suggested that a fractional dose induces comparable antibody responses to the full, licensed dose in people below 55 years old. Here, we report the safety and immunogenicity of a fractional dose regimen of the BNT162b2 vaccine.
MethodsREDU-VAC is a participant-blinded, randomised, phase 4, multicentre, non-inferiority study investigating safety, reactogenicity and immunogenicity of BNT162b2. Adults aged between 18 and 55 years, without uncontrolled co-morbidities, either previously infected or infection naive, were eligible and recruited at five sites across Belgium. Participants were randomly assigned to receive 20{micro}g/20{micro}g (fractional dose) or 30{micro}g/30{micro}g (full dose) of BNT162b2, administered intra-muscularly at a three-week interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-RBD IgG titres at 28 days post second dose between the reduced and the full dose regimens. The reduced dose was considered non-inferior to the full dose if the lower limit of the two-sided 95% CI of the GMR was greater than 0.67. The primary analysis was done on the per-protocol population, including infection naive participants only.
FindingsBetween April 19 and April 23, 2021, 145 participants were enrolled in the study and randomized, of whom 141 were vaccinated and reached the primary endpoint. Participants were mostly female (69.5%), of European origin (95%), with a mean age of 40.4 years (SD 7.9). At 28 days post second dose, the geometric mean titre (GMT) of SARS-CoV-2 anti-RBD IgG of the reduced dose regimen (1,705 BAU/mL) was not non-inferior to the full dose regimen (2,387 BAU/mL), with a GMR of 0.714 (two-sided 95% CI 0.540-0.944). No serious adverse events occurred.
ConclusionsWhile non-inferiority of the reduced dose regimen was not demonstrated, the SARS-CoV-2 anti-RBD IgG titre was only moderately lower than that of the full dose regimen and, importantly, still markedly higher than the reported antibody response to the licensed adenoviral vector vaccines. These data suggest that reduced doses of the BNT162b2 mRNA vaccine may offer additional benefit as compared to the vaccines currently in use in most low and middle-income countries, warranting larger immunogenicity and effectiveness trials. The trial is registered at ClinicalTrials.gov (NCT04852861). | infectious diseases |
10.1101/2022.03.24.22272732 | Transcriptomic profiling of cardiac tissues from SARS-CoV-2 patients identifies DNA damage | The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to present with pulmonary and extra-pulmonary organ complications. In comparison with the 2009 pandemic (pH1N1), SARS-CoV-2 infection is likely to lead to more severe disease, with multi-organ effects, including cardiovascular disease. SARS-CoV-2 has been associated with acute and long-term cardiovascular disease, but the molecular changes govern this remain unknown.
In this study, we investigated the landscape of cardiac tissues collected at rapid autopsy from SARS-CoV-2, pH1N1, and control patients using targeted spatial transcriptomics approaches. Although SARS-CoV-2 was not detected in cardiac tissue, host transcriptomics showed upregulation of genes associated with DNA damage and repair, heat shock, and M1-like macrophage infiltration in the cardiac tissues of COVID-19 patients. The DNA damage present in the SARS-CoV-2 patient samples, were further confirmed by {gamma}-H2Ax immunohistochemistry. In comparison, pH1N1 showed upregulation of Interferon-stimulated genes (ISGs), in particular interferon and complement pathways, when compared with COVID-19 patients.
These data demonstrate the emergence of distinct transcriptomic profiles in cardiac tissues of SARS-CoV-2 and pH1N1 influenza infection supporting the need for a greater understanding of the effects on extra-pulmonary organs, including the cardiovascular system of COVID-19 patients, to delineate the immunopathobiology of SARS-CoV-2 infection, and long term impact on health. | infectious diseases |
10.1101/2022.03.27.22273007 | Global Reports of Myocarditis Following COVID-19 Vaccination: A Systematic Review and Meta-Analysis | In December 2020, the FDA granted emergency approval to Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) COVID-19 vaccines. There have been recent media reports of myocarditis after receiving COVID-19 vaccines, particularly the messenger RNA (mRNA) vaccines, causing public concern. This review summarizes information from published case series and case reports, with a strong emphasis on reporting patient and disease characteristics, investigation, and clinical outcome, to provide a comprehensive picture of the condition. Forty studies, including 147 cases, participated in this systematic review. The median age was 28.9 years; 93.9% were male and 6.1% were female. 72.1% of patients received the Pfizer-BioNTech (BNT162b2) vaccine, 24.5% of patients received the Moderna COVID-19 Vaccine (mRNA-1273), and the rest of the 3.3% received other types of vaccines. Furthermore, most myocarditis cases (87.1%) occurred after the second vaccine dose, after a median time interval of 3.3 days. The most frequently reported symptoms were chest pain, myalgia/body aches and fever. Troponin levels were consistently elevated in 98.6%. The admission ECG was abnormal in 88.5% of cases, and the left LVEF was lower than 50% in 26.5% of cases. The vast majority of patients (93.2%) resolved symptoms and recovered, and only 3 patients died. These findings may help public health policy to consider myocarditis in the context of the benefits of COVID-19 vaccination as well as to assess the cardiac condition before the choice of vaccine, which is offered to male adults. In addition, it must be carefully weighed against the very substantial benefit of vaccination. | cardiovascular medicine |
10.1101/2022.03.31.22273230 | Impact of spatiotemporal heterogeneity in COVID-19 disease surveillance on epidemiological parameters and case growth rates | SARS-CoV-2 case data are primary sources for estimating epidemiological parameters and for modelling the dynamics of outbreaks. Understanding biases within case based data sources used in epidemiological analyses are important as they can detract from the value of these rich datasets. This raises questions of how variations in surveillance can affect the estimation of epidemiological parameters such as the case growth rates. We use standardised line list data of COVID-19 from Argentina, Brazil, Mexico and Colombia to estimate delay distributions of symptom-onset-to-confirmation, -hospitalisation and -death as well as hospitalisation-to-death at high spatial resolutions and throughout time. Using these estimates, we model the biases introduced by the delay from symptom-onset-to-confirmation on national and state level case growth rates (rt) using an adaptation of the Richardson-Lucy deconvolution algorithm. We find significant heterogeneities in the estimation of delay distributions through time and space with delay difference of up to 19 days between epochs at the state level. Further, we find that by changing the spatial scale, estimates of case growth rate can vary by up to 0.13 d-1. Lastly, we find that states with a high variance and/or mean delay in symptom-onset-to-diagnosis also have the largest difference between the rt estimated from raw and deconvolved case counts at the state level. We highlight the importance of high-resolution case based data in understanding biases in disease reporting and how these biases can be avoided by adjusting case numbers based on empirical delay distributions. Code and openly accessible data to reproduce analyses presented here are available. | epidemiology |
10.1101/2022.03.26.22272973 | Strain-stream model of epidemic spread in application to COVID-19 | The recently developed model of the epidemic spread of two virus stains in a closed population is generalized for situation typical for the couple of strains delta and omicron, when there is high probability for omicron infection enough soon after recovering from delta infection. This model can be considered as some kind of weave of SIR and SIS models for the case of competition of two strains of the same virus having different contagiousness in a population.
PACS number(s)02.50.-r, 05.60.-k, 82.39.-k, 87.19.Xx | epidemiology |
10.1101/2022.03.26.22272973 | Strain-stream model of epidemic spread in application to COVID-19 | The recently developed model of the epidemic spread of two virus stains in a closed population is generalized for situation typical for the couple of strains delta and omicron, when there is high probability for omicron infection enough soon after recovering from delta infection. This model can be considered as some kind of weave of SIR and SIS models for the case of competition of two strains of the same virus having different contagiousness in a population.
PACS number(s)02.50.-r, 05.60.-k, 82.39.-k, 87.19.Xx | epidemiology |
10.1101/2022.03.24.22272838 | A Bayesian hierarchical framework to integrate dietary exposure and biomarker measurements into aetiological models | In nutritional epidemiology, self-reported assessments of dietary exposure are prone to measurement errors, which is responsible for bias in the association between dietary factors and risk of disease. In this study, self-reported dietary assessments were complemented by biomarkers of dietary intake. Dietary and serum measurements of folate and vitamin-B6 from two nested case-control studies within the European Prospective Investigation into Cancer and Nutrition (EPIC) study were integrated in a Bayesian model to explore the measurement error structure of the data, and relate dietary exposures to risk of site-specific cancer. A Bayesian hierarchical model was developed, which included: 1) an exposure model, to define the distribution of unknown true exposure (X); 2) a measurement model, to relate observed assessments, in turn, dietary questionnaires (Q), 24-hour recalls (R) and biomarkers (M) to X measurements; 3) a disease model, to estimate exposures/cancer relationships. The marginal posterior distribution of model parameters was obtained from the joint posterior distribution, using Markov Chain Monte Carlo (MCMC) sampling techniques in JAGS. The study included 554 and 882 case/control pairs for kidney and lung cancer, respectively. In the measurement error component, the error correlation between Q measurements of vitamin-B6 and folate was estimated to be equal to 0.82 (95% CI: 0.76, 0.87). After adjustment for age, center, sex, BMI and smoking status, the kidney cancer odds ratios (OR) were 0.55 (0.16, 1.31) and 1.07 (0.33, 3.44) for one standard deviation increase of vitamin-B6 and folate, respectively. For lung cancer ORs were 0.85 (0.27, 2.42) for vitamin-B6 and 0.55 (0.14, 1.39) for folate. Bayesian models offer powerful solutions to handle complex data structures. After accounting for the role of measurement error, folate and vitamin-B6 were not associated to the risk of kidney and lung cancer. | epidemiology |
10.1101/2022.03.31.22273222 | Reducing societal impacts of SARS-CoV-2 interventions through subnational implementation | To curb the initial spread of SARS-CoV-2, many countries relied on nation-wide implementation of non-pharmaceutical interventions, at a high socio-economic cost. Using the first COVID-19 wave in the Netherlands as a case in point, we address how subnational implementations might have achieved similar levels of epidemiological control with fewer societal consequences; e.g., parts of the country could have stayed open for longer. To this end, we develop a high-resolution analysis framework reflecting a demographically stratified population with a spatially explicit, dynamic, individual contact pattern-based epidemiology, exploiting mobility trends extracted from mobile phone signals and Google mobility. The framework is exportable to other countries and settings, and may be used to develop policies on subnational approach as a better strategic choice for controlling future epidemics. | epidemiology |
10.1101/2022.03.30.22273218 | Predicting the time course of replacements of SARS-CoV-2 variants using relative reproduction numbers | The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continuously evolved since its introduction to the human population in 2019. Natural selection selects variants with higher effective reproduction numbers, increasing the overall transmissibility of the circulating viruses. In order to establish effective control measures for a new variant, it is crucial to know its transmissibility and replacement time course in early phases of the variant replacement. In this paper, we conduct retrospective prediction tests of the variant replacement from Alpha to Delta in England. Our method firstly estimated the relative reproduction number, the ratio of the reproduction number of a variant to that of another, from partial observations up to a given time point. Secondly, the replacement time course after the time point was predicted based on the estimates of relative reproduction number. Thirdly, the estimated relative reproduction number and the predicted time course were evaluated by being compared to those estimated using the entire observations. We found that it is possible to estimate the relative reproduction number of Delta with respect to Alpha when the frequency of Delta was more than or equal to 0.25. Using these relative reproduction numbers, predictions targeting on 1st June 2021, the date when the frequency of Delta reached 0.90, had maximum absolute prediction errors of 0.015 for frequencies of Delta and 0.067 for the average relative reproduction number of circulating viruses with respect to Alpha. These results suggest that our method allows us to predict the time course of variant replacement in future from partial datasets observed in early phases of variant replacement. | epidemiology |
10.1101/2022.03.25.22272927 | Changing characteristics over time of individuals receiving COVID-19 vaccines in Denmark: A population-based descriptive study of vaccine uptake | AimsThe Danish authorities implemented a differential rollout of the COVID-19 vaccines where individuals at high risk of COVID-19 were prioritized. We describe the temporal uptake of COVID-19 vaccines and changing characteristics of vaccine recipients in Denmark.
MethodsUsing the Danish national health care registries, we identified all Danish residents [≥]5 years of age who received at least one dose of a COVID-19 vaccine from December 27th, 2020, to January 29th, 2022. We charted the daily number of newly vaccinated individuals and the cumulative vaccine coverage over time, stratified by vaccine type, age groups, and vaccination priority groups. In addition, we described characteristics of vaccine recipients during 2-months-intervals and in vaccination priority groups.
ResultsBy January 29th, 2022, 86%, 84% and 63% of Danish residents [≥]5 years had received a first, second, and third dose, respectively, of a COVID-19 vaccine, most commonly the BNT162b2 vaccine (84% of vaccinated individuals). Vaccine uptake ranged from 48% in 5-11-year-olds up to 98% in 65-74-year-olds. Individuals vaccinated before June 2021 were older (median age 61-70 years vs. 10-35 years in later periods) and had more comorbidities such as hypertension (22-28% vs. 0.77-2.8% in later periods), chronic lung disease (9.4-15% vs. 3.7-4.6% in later periods), and diabetes (9.3-12% vs. 0.91-2.4% in later periods).
ConclusionsThe uptake of the COVID-19 vaccines is high in Denmark. We document substantial changes over time in characteristics of vaccine recipients which should be considered when designing and interpreting studies on the effectiveness and safety of COVID-19 vaccines. | epidemiology |
10.1101/2022.03.31.22273224 | Ethnic inequalities in multiple long-term health conditions in the United Kingdom: a systematic review and narrative synthesis | Indicative evidence suggests that minoritised ethnic groups have higher risk of developing multiple long-term conditions (MLTCs), and do so earlier than the white majority population. While there is evidence on ethnicity and single conditions and comorbidities, no review has attempted to look across these from a MLTCs perspective. As such, we currently have an incomplete understanding of the extent of ethnic inequalities in the prevalence of MLTCs. In this systematic review we aimed to 1) describe the literature that provides evidence of ethnicity and prevalence of MLTCs amongst people living in the UK, and 2) summarise the prevalence estimates of MLTCs across ethnic groups. We registered the protocol on PROSPERO (CRD42020218061). Between October and December 2020, we searched ASSIA, Cochrane Library, EMBASE, MEDLINE, PsycINFO, PubMed, ScienceDirect, Scopus, Web of Science, OpenGrey, and reference lists of key studies/reviews. The main outcome was prevalence estimates for MLTCs for at least one minoritised ethnic group, compared to the majority white population. We included studies conducted in the UK reporting on ethnicity and prevalence of MLTCs. To summarise the prevalence estimates of MLTCs across ethnic groups we included only studies of MLTCs that provided estimates adjusted at least for age. Two reviewers screened and extracted data from a random sample of studies (10%). Data were synthesised using narrative synthesis. Of the 7949 studies identified, 84 met criteria for inclusion. Of these, seven contributed to the evidence of ethnic inequalities in MLTCs. Five of the seven studies point to higher prevalence of MLTCs in at least one minoritised ethnic group compared to their white counterparts. Because the number/types of health conditions varied between studies and some ethnic populations were aggregated, the findings may not accurately reflect the true level of inequality. Thus, our conclusions can only be tentative. Future research should consider key explanatory factors, including those at the macrolevel (e.g. racism, discrimination), as they may play a role in the development of MLTCs in different ethnic groups. | public and global health |
10.1101/2022.03.31.22273238 | Size of societal volunteering predicts COVID-19 mortality | IntroductionDifferent countries responded differently to the COVID-19 pandemic in terms of timing and stringency of measures, and in types of policies adopted. Typically, policy makers tried to balance the capacity of healthcare systems to take care of the ill (as determined by ICU capacity, availability of nurses, etc.), with safeguarding economic output (preventing total lockdown of the labor force, etc.). Later on, also a broader array of considerations such as impact on schooling or the need for social contact were taken into account to varying degrees.
The broad and relatively fast availability of data on healthcare and economic capacity, together with the political estimate that these were the most critical determinants for maintaining societal structure and compliance with the measures taken, in many countries prioritized decision-making. What received far less attention, in part due to the difficulty of obtaining reliable data in a timely manner, was the opposite question: to what extent do societal structures - besides healthcare and economic systems - contribute to a countrys resilience during catastrophes such as the pandemic? While it is commonly understood that the impact of a pandemic goes beyond its death count, perhaps the death count itself is impacted by the way societies are structured.
One example of such societal structure is the contribution of volunteers during the COVID-19 response. Volunteers may contribute to well-functioning societies in different ways, both through practical actions (e.g. knitting face masks) as by strengthening societal cohesion (e.g. encouraging fellow citizens to comply with measures). This paper quantifies the association between COVID-19 mortality and the size of societal volunteering, using the unique context of the COVID-19 crisis with its intensity, sudden onset and global spread. | public and global health |
10.1101/2022.03.26.22272987 | Efficacy of a multiple-component and multifactorial personalized fall prevention program in community-dwelling older adults at moderate-to-high fall risk: The PRE.C.I.S.A. Randomized Controlled Trial | BackgroundThe fall risk in the elderly is a major public health issue due to the immediate injury-related consequences and the risk of associated long-term disability. However, the delivery of effective interventions for fall prevention in usual clinical practice still represents a challenge.
AimTo evaluate the efficacy of a multiple-component intervention combined with a multifactorial personalized intervention in reducing fall rates in community-dwelling older adults at moderate-to-high fall risk compared to usual care.
DesignRandomized Controlled Trial (unique identifier NCT03592420, clinicaltrials.gov).
SettingOutpatients in two Italian centers.
Population403 community-dwelling older adults at moderate-to-high fall risk, including subjects with Parkinsons Disease and stroke.
MethodsSubjects were randomized to the intervention (n=203) or the control group (n=200). A multiple-component and multifactorial personalized interventions were administered to the experimental intervention group. Participants allocated to the control group received usual care and recommendations to minimize the fall risk factors. In addition, each participant was given a diary to record falls and was followed for 12 months with monthly telephone contacts. The primary endpoint was represented by the total number of falls in each group over 12 months. The secondary endpoints were other fall-related indicators (fall rate of subjects with one or more falls, fall rate associated with hospitalization, fall severity, fall probability, and time to the first fall) recorded at the 12-month follow-up. Besides, several clinical scales were used to assess baseline (T1) and 3-month follow-up (T3) functioning.
ResultsA total of 690 falls were reported at 12-month follow-up, 337 (48.8%) in the intervention group and 353 (51.2%) in the control group with 1.66 ({+/-} 3.5) and 1.77 ({+/-} 3.2) mean falls per subject, respectively. The number of subjects with at least one fall was 236 (58.6%), with 119 (58.6%) and 117 falls (58.5%) in the intervention and control groups, respectively. No statistically significant differences were observed between groups regarding the number of falls, the fall probability, and the time to the first fall at 12-month follow-up. Furthermore, according to the subgroup analysis, no significant differences were reported between subgroups (i.e., the four etiological class categories of interest for the study). Finally, considering the two groups at pre-test (T1) and post-test (T3) evaluations, a statistically significant difference was found only for the Fullerton Advanced Balance Scale (p=0.006) and the Mini-BESTest (p=0.004) in favor of the intervention group.
ConclusionsThe proposed intervention was ineffective in reducing the number of falls, the fall probability, and the time to the first fall at 12-month follow-up in community-dwelling older adults at moderate-to-high fall risk. However, a lower number of falls, lower fall rates in multiple fallers, a lower mean number of falls per participant, and a lower rate of fall-related severe injuries were recorded for the intervention group, although not significant. Finally, a significant improvement for two balance-related indicators was recorded in the intervention group between pre and post-test evaluations. Future studies are needed to explore different effects of combined multiple-component and personalized multifactorial interventions to reduce falls and subsequent consequences. Future studies should also be planned with the clear aim of overcoming the limitations highlighted in the PRE.C.I.S.A. study. | rehabilitation medicine and physical therapy |
10.1101/2022.03.26.22272966 | Evaluation of cold pain tolerance in patients with fibromyalgia and opioid use by survival analysis | PurposeCold pain tolerance is traditionally measured using the cold pressor test (CPT), a clinical pain research method in which participants immerse an extremity (i.e., hand or foot) into cold water for as long as tolerable. Prior research studies have investigated cold pain tolerance in patients with chronic pain, yet few have used survival analysis, which allows for proper handling of data censoring and therefore, the optimal statistical method for CPT data analysis. The goal of the present study was to use survival analysis to evaluate cold pain tolerance in patients with fibromyalgia. Furthermore, we aimed to model relationships between psychological and clinical variables as well as opioid medication use and cold pain tolerance.
Patients and MethodsA total of 85 patients with fibromyalgia (42 who were taking opioids) and 47 healthy pain-free controls were involved in two studies that provided CPT and questionnaire data. Survival analysis using Cox regression models evaluated group effects (patients vs. controls) and effects of psychological, clinical, and medication factors on cold pain tolerance.
ResultsPatients with fibromyalgia, as compared to healthy controls, exhibited significantly lower CPT survival (HR = 2.17, 95% CI: [1.42, 3.31], p = 0.00035). Cox regression models indicated that the psychological and clinical measures included did not strongly mediate this relationship (p > 0.05). When comparing across patient cohorts (Study 1 vs. Study 2), results were consistent across non-opioid-taking patient and healthy control groups, while differences in CPT survival were observed across the groups of patients taking opioid pain medications.
ConclusionReduced cold pain tolerance in patients with fibromyalgia is identified by survival analysis, an optimal method for time-to-event pain measures. While our selected psychological and clinical measures do not appear to be significantly associated with cold pain tolerance, opioid medication use may impart greater cold pain tolerance among some patients. | pain medicine |
10.1101/2022.03.30.22273201 | A Sex-Specific Genome-Wide Association Study of Depression Phenotypes in UK Biobank | BackgroundThere are marked sex differences in the prevalence, phenotypic presentation and treatment response for major depression. While genome-wide association studies (GWAS) adjust for sex differences, to date no studies seek to identify sex-specific markers and pathways. In this study we performed a sex-stratified genome-wide association analysis for broad depression.
MethodsA genome-wide association study for broad depression was performed in the UK Biobank total participants (N=274,141), including only non-related participants, as well as separately in males (N=127,867) and females (N=146,274). Bioinformatics analyses were performed to characterize common and sex-specific markers and associated processes/pathways.
ResultsWe identified 11 loci passing genome level significance (P < 5* 10-8) in females and one in males. In both males and females, genetic correlations were significant between the broad depression GWA and other psychopathologies, however, correlations with educational attainment and metabolic features including body fat, waist circumference, waist-to-hip ratio and triglycerides were significant only in females. Gene-based analysis showed 147 genes significantly associated with broad depression in the total sample, 64 in the females and 53 in males. Gene-based analysis revealed "Regulation of Gene Expression" as a common biological process, but suggested sex-specific molecular mechanisms. Finally, sex-specific PRSs for broad depression outperformed total and the opposite sex PRSs in the prediction of broad MDD.
ConclusionsThese findings provide evidence for sex-dependent genetic pathways for clinical depression as well as for health conditions comorbid with depression. | genetic and genomic medicine |
10.1101/2022.03.25.22272955 | Novel discoveries and enhanced genomic prediction from modelling genetic risk of cancer age-at-onset | Genome-wide association studies seek to attribute disease risk to DNA regions and facilitate subject-specific prediction and patient stratification. For later-life disease, inference from case-control studies is hampered by the uncertainty that control group subjects might later be diagnosed. Time-to-event analysis treats controls as right-censored, making no additional assumptions about future disease occurrence and representing a more sound conceptual alternative for more accurate inference. Here, using data on 11 common cancers from the UK and Estonian Biobank studies, we provide empirical evidence that discovery and genomic prediction are greatly improved by analysing age-at-diagnosis, compared to a case-control model of association. We replicate previous findings from large-scale case-control studies and find an additional 59 previously unreported independent genomic regions, out of which 16 replicated in independent data (an increase of 18% and 6% over current findings). Our novel discoveries provide new insights into underlying cancer pathways, and our model yields a better understanding of the polygenicity and genetic architecture of the 11 tumours. We find that heritable germline genetic variation plays a vital role in cancer occurrence, with risk attributable to many thousands of underlying genomic regions. Finally, we show that Bayesian modelling strategies utilising time-to-event data increase prediction accuracy. As sample size increases, incorporating time-to-event data should be commonplace, improving case-control studies by using richer information about the disease process. | genetic and genomic medicine |
10.1101/2022.03.27.22273012 | Comparison of procedures performed and costs between an outsourced dental health plan with fee-for-service payment and an evidence-based, in-house dental health service with salaried professionals. | It was evaluated a dental care services provided to almost 4,000 users (employees and their families) of a company (Moinhos de Vento Hospital, Brazil). The analysis was divided into two periods of time: from January 2000 to December 2002, during which time the dental care provided to employees (and families) was outsourced to a dental plan which operates with an accredited network, and from March 2003 to June 2005, when the dental care was provided by an in-house dental care service with preventive and evidence-based dentistry guidelines. Economic data were collected, as well as the type and number of procedures performed.
ConclusionsAn in-house service with evidence-based clinical protocols, as compared with an accredited network, decreased costs and also increased the number of procedures done, changed the profile of care for a less invasive dentistry and one more geared toward the causes of diseases, while still preserving the customers satisfaction. | health economics |
10.1101/2022.03.27.22273006 | The Application of Data Science Techniques and Algorithms in Women Health Research | ObjectiveEvaluate and map data science methods employed to solve health conditions of women, examine the problems tackled and the effectiveness.
Research MethodText analytics, science mapping, and descriptive evaluation of data science methods utilized in women-related health research.
Findings(i). The trends in scholarships using data science methods indicate gaps between women and men relating to health burden and access to health. (ii). The coronavirus (SARS-CoV-2) outbreak and the ongoing COVID-19 pandemic tend to widen the identified health gaps, increasing the disease burden for women, while reducing access to health. There are noticeable additional health burdens on pregnant women and those with several health conditions (breast cancer, gynecologic oncology, cardiovascular disease, and more). (iii). Over 95% of studies using data science methods (artificial intelligence, machine learning, novel algorithms, predictive, big data, visual analytics, clinical decision support systems, or a combination of the methods) indicate significant effectiveness. (iv). Mapping of the scientific literature to authors, sources, and countries show an upward trend; 997 (16%), 113 (1.33%), and 57 (2.63%) per article, respectively. About 95% of research utilizing data science methods in womens health studies occurred within the last four (4) years.
ConclusionsThe application of data science methods in tackling different health problems of women is effective and growing, and capable of easing the burden of health in women. The ongoing COVID-19 pandemic tends to compound the health burden for women more than men. Policymakers must do more to improve access to health for women. | health informatics |
10.1101/2022.03.31.22273226 | Cross-talk between red blood cells and plasma influences blood flow and omics phenotypes in severe COVID-19 | Coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and can affect multiple organs, among which is the circulatory system. Inflammation and mortality risk markers were previously detected in COVID-19 plasma and red blood cells (RBCs) metabolic and proteomic profiles. Additionally, biophysical properties, such as deformability, were found to be changed during the infection. Based on such data, we aim to better characterize RBC functions in COVID-19. We evaluate the flow properties of RBCs in severe COVID-19 patients admitted to the intensive care unit by using in vitro microfluidic techniques and automated methods, including artificial neural networks, for an unbiased RBC analysis. We find strong flow and RBC shape impairment in COVID-19 samples and demonstrate that such changes are reversible upon suspension of COVID-19 RBCs in healthy plasma. Vice versa, healthy RBCs immediately resemble COVID-19 RBCs when suspended in COVID-19 plasma. Proteomics and metabolomics analyses allow us to detect the effect of plasma exchanges on both plasma and RBCs and demonstrate a new role of RBCs in maintaining plasma equilibria at the expense of their flow properties. Our findings provide a framework for further investigations of clinical relevance for therapies against COVID-19 and possibly other infectious diseases. | hematology |
10.1101/2022.03.31.22273226 | Cross-talk between red blood cells and plasma influences blood flow and omics phenotypes in severe COVID-19 | Coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and can affect multiple organs, among which is the circulatory system. Inflammation and mortality risk markers were previously detected in COVID-19 plasma and red blood cells (RBCs) metabolic and proteomic profiles. Additionally, biophysical properties, such as deformability, were found to be changed during the infection. Based on such data, we aim to better characterize RBC functions in COVID-19. We evaluate the flow properties of RBCs in severe COVID-19 patients admitted to the intensive care unit by using in vitro microfluidic techniques and automated methods, including artificial neural networks, for an unbiased RBC analysis. We find strong flow and RBC shape impairment in COVID-19 samples and demonstrate that such changes are reversible upon suspension of COVID-19 RBCs in healthy plasma. Vice versa, healthy RBCs immediately resemble COVID-19 RBCs when suspended in COVID-19 plasma. Proteomics and metabolomics analyses allow us to detect the effect of plasma exchanges on both plasma and RBCs and demonstrate a new role of RBCs in maintaining plasma equilibria at the expense of their flow properties. Our findings provide a framework for further investigations of clinical relevance for therapies against COVID-19 and possibly other infectious diseases. | hematology |
10.1101/2022.03.30.22273206 | Remdesivir for the treatment of hospitalised patients with COVID-19: final results from the DisCoVeRy randomised, controlled, open-label trial | BackgroundThe antiviral efficacy of remdesivir is still controversial. We aimed at evaluating its clinical effectiveness in hospitalised patients with COVID-19, with indication of oxygen and/or ventilator support. Following prior publication of preliminary results, here we present the final results after completion of data monitoring.
MethodsIn this European multicentre, open-label, parallel-group, randomised, controlled trial (DisCoVeRy, NCT04315948; EudraCT2020-000936-23), participants were randomly allocated to receive usual standard of care (SoC) alone or in combination with remdesivir, lopinavir/ritonavir, lopinavir/ritonavir and IFN-{beta}-1a, or hydroxychloroquine. Adult patients hospitalised with COVID-19 were eligible if they had clinical evidence of hypoxemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzyme, severe chronic kidney disease, any contra-indication to one of the studied treatments or their use in the 29 days before randomization, or use of ribavirin, as well as pregnancy or breast-feeding. Here, we report results for remdesivir + SoC versus SoC alone. Remdesivir was administered as 200 mg infusion on day 1, followed by once daily infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. Treatment assignation was performed via web-based block randomisation stratified on illness severity and administrative European region. The primary outcome was the clinical status at day 15 measured by the WHO 7-point ordinal scale, assessed in the intention-to-treat population.
FindingsBetween March 22nd, 2020 and January 21st, 2021, 857 participants were randomised to one of the two arms in 5 European countries and 843 participants were included for the evaluation of remdesivir (control, n=423; remdesivir, n=420).
At day 15, the distribution of the WHO ordinal scale was as follow in the remdesivir and control groups, respectively: Not hospitalized, no limitations on activities: 62/420 (14.8%) and 72/423 (17.0%); Not hospitalized, limitation on activities: 126/420 (30%) and 135/423 (31.9%); Hospitalized, not requiring supplemental oxygen: 56/420 (13.3%) and 31/423 (7.3%); Hospitalized, requiring supplemental oxygen: 75/420 (17.9%) and 65/423 (15.4%); Hospitalized, on non-invasive ventilation or high flow oxygen devices: 16/420 (3.8%) and 16/423 (3.8%); Hospitalized, on invasive mechanical ventilation or ECMO: 64/420 (15.2%) and 80/423 (18.9%); Death: 21/420 (5%) and 24/423 (5.7%). The difference between treatment groups was not statistically significant (OR for remdesivir, 1.02, 95% CI, 0.62 to 1.70, P=0.93). There was no significant difference in the occurrence of Serious Adverse Events between treatment groups (remdesivir, n=147/410, 35.9%, versus control, n=138/423, 32.6%, p=0.29).
InterpretationRemdesivir use for the treatment of hospitalised patients with COVID-19 was not associated with clinical improvement at day 15.
FundingEuropean Union Commission, French Ministry of Health, DIM One Health Ile-de-France, REACTing, Fonds Erasme-COVID-ULB; Belgian Health Care Knowledge Centre (KCE), AGMT gGmbH, FEDER "European Regional Development Fund", Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Remdesivir was provided free of charge by Gilead. | infectious diseases |
10.1101/2022.03.30.22273206 | Remdesivir for the treatment of hospitalised patients with COVID-19: final results from the DisCoVeRy randomised, controlled, open-label trial | BackgroundThe antiviral efficacy of remdesivir is still controversial. We aimed at evaluating its clinical effectiveness in hospitalised patients with COVID-19, with indication of oxygen and/or ventilator support. Following prior publication of preliminary results, here we present the final results after completion of data monitoring.
MethodsIn this European multicentre, open-label, parallel-group, randomised, controlled trial (DisCoVeRy, NCT04315948; EudraCT2020-000936-23), participants were randomly allocated to receive usual standard of care (SoC) alone or in combination with remdesivir, lopinavir/ritonavir, lopinavir/ritonavir and IFN-{beta}-1a, or hydroxychloroquine. Adult patients hospitalised with COVID-19 were eligible if they had clinical evidence of hypoxemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzyme, severe chronic kidney disease, any contra-indication to one of the studied treatments or their use in the 29 days before randomization, or use of ribavirin, as well as pregnancy or breast-feeding. Here, we report results for remdesivir + SoC versus SoC alone. Remdesivir was administered as 200 mg infusion on day 1, followed by once daily infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. Treatment assignation was performed via web-based block randomisation stratified on illness severity and administrative European region. The primary outcome was the clinical status at day 15 measured by the WHO 7-point ordinal scale, assessed in the intention-to-treat population.
FindingsBetween March 22nd, 2020 and January 21st, 2021, 857 participants were randomised to one of the two arms in 5 European countries and 843 participants were included for the evaluation of remdesivir (control, n=423; remdesivir, n=420).
At day 15, the distribution of the WHO ordinal scale was as follow in the remdesivir and control groups, respectively: Not hospitalized, no limitations on activities: 62/420 (14.8%) and 72/423 (17.0%); Not hospitalized, limitation on activities: 126/420 (30%) and 135/423 (31.9%); Hospitalized, not requiring supplemental oxygen: 56/420 (13.3%) and 31/423 (7.3%); Hospitalized, requiring supplemental oxygen: 75/420 (17.9%) and 65/423 (15.4%); Hospitalized, on non-invasive ventilation or high flow oxygen devices: 16/420 (3.8%) and 16/423 (3.8%); Hospitalized, on invasive mechanical ventilation or ECMO: 64/420 (15.2%) and 80/423 (18.9%); Death: 21/420 (5%) and 24/423 (5.7%). The difference between treatment groups was not statistically significant (OR for remdesivir, 1.02, 95% CI, 0.62 to 1.70, P=0.93). There was no significant difference in the occurrence of Serious Adverse Events between treatment groups (remdesivir, n=147/410, 35.9%, versus control, n=138/423, 32.6%, p=0.29).
InterpretationRemdesivir use for the treatment of hospitalised patients with COVID-19 was not associated with clinical improvement at day 15.
FundingEuropean Union Commission, French Ministry of Health, DIM One Health Ile-de-France, REACTing, Fonds Erasme-COVID-ULB; Belgian Health Care Knowledge Centre (KCE), AGMT gGmbH, FEDER "European Regional Development Fund", Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Remdesivir was provided free of charge by Gilead. | infectious diseases |
10.1101/2022.03.28.22273032 | Effectiveness of Typhoid Conjugate Vaccine in Zimbabwe used in response to an outbreak among children and young adults: a matched case control study | BackgroundZimbabwe suffers from regular outbreaks of typhoid fever (TF), worse since 2017. Most cases were in Harare and a vaccination campaign with Typhoid Conjugate Vaccine (TCV) was conducted in March 2019. The vaccine effectiveness (VE) was assessed against culture-confirmed S. Typhi in children six months to 15 years and in individuals six months to 45 years in Harare.
MethodsA matched case-control study was conducted in three urban suburbs of Harare targeted by the TCV vaccination campaign. Suspected TF cases were enrolled prospectively in four health facilities and were matched to facility (1:1) and community (1:5) controls.
FindingsOf 504 suspected cases from July 2019 to March 2020, 148 laboratory-confirmed TF cases and 153 controls confirmed-negative were identified. One hundred and five (47 aged six months to 15 years) cases were age, sex, and residence matched with 105 facility-based controls while 96 cases were matched 1:5 by age, sex, and immediate-neighbour with 229 community controls.
The adjusted VE against confirmed TF was 75% (95%CI: 1-94, p=0.049) compared to facility controls, and 84% (95%CI: 57-94, p<0.001) compared to community controls in individuals six months to 15 years. The adjusted VE against confirmed TF was 46% (95%CI: 26-77, p=0.153) compared to facility controls, and 67% (95%CI: 35-83, p=0.002) compared to community controls six months to 45 years old.
InterpretationThis study confirms that one vaccine dose of TCV is effective to control TF in children between six months and 15 years old in an African setting. | infectious diseases |
10.1101/2022.03.25.22272932 | Mapping brain endophenotypes associated with idiopathic pulmonary fibrosis genetic risk | BackgroundIdiopathic pulmonary fibrosis (IPF) is a serious disease of the lung parenchyma. It has a known polygenetic risk, with at least seventeen regions of the genome implicated to date. Growing evidence suggests linked multimorbidity of IPF with neurodegenerative or affective disorders. However, no study so far has explicitly explored links between IPF, associated genetic risk profiles, and specific brain features.
MethodsWe exploited imaging and genetic data from more than 32,000 participants available through the UK Biobank population-level resource to explore links between IPF genetic risk and imaging-derived brain endophenotypes. We performed a brain-wide imaging-genetics association study between the 17 known loci of IPF genetic risk and 1,248 multi-modal imaging-derived features, which characterise brain structure and function.
FindingsWe identified strong associations between cortical thickness and white matter microstructure and IPF risk loci in chromosomes 17 (17q21.31) and 8 (DEPTOR). Through co-localisation analysis, we confirmed that the associated neuroimaging features and IPF share a single causal variant at the chromosome 8 locus. Exploratory post-hoc analysis suggested that forced vital capacity may act as a partial mediator in the association between the DEPTOR variant and white matter microstructure, but not between the DEPTOR risk variant and cortical thinning in the anterior cingulate.
InterpretationOur results reveal for the first time associations between IPF genetic risk and differences in brain structure, for both cortex and white matter. Differences in tissue-specific imaging signatures suggest distinct underlying mechanisms with focal cortical thinning in regions with known high DEPTOR expression unrelated to lung function, and more widespread microstructural white matter changes consistent with hypoxia or neuroinflammation with potential mediation by lung function.
FundingThis study was supported by the NIHR-funded Nottingham Biomedical Research Centre and the UK Medical Research Council.
O_TEXTBOXResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSIdiopathic pulmonary fibrosis (IPF) is a condition in which the lungs become scarred (fibrosed). Although IPF primarily affects the lungs, co-occurrence of impaired brain function, such as cognitive decline, increased risk of neurodegenerative disorders, cerebrovascular accidents, depression, and anxiety have been reported. The nature of this association is unclear and no post-mortem or in-vivo investigations have been performed to explore this directly. At the genetic level, 17 regions of the genome have been found to drive the genetic risk for IPF.
Added value of this studyUsing previously identified IPF genetic variants and neuroimaging-derived features from 32,431 participants available through the UK Biobank, we performed the first brain-wide association study for IPF risk variants. We identified brain endophenotypic associations for two IPF risk associated genetic variants, one in chromosome 17 and one in chromosome 8. In particular, increased IPF genetic risk, conferred by a variant near to the DEPTOR gene on chromosome 8, was associated with focal cingulate cortical thinning and more widespread changes in white matter microstructure. The cortical association signature was observed in regions with known DEPTOR expression while the subcortical findings may be mediated by forced vital capacity (measure of impaired lung function), hinting to distinct direct (cingulate) and indirect (subcortical) brain effects of DEPTOR risk alleles.
Implication of all the available evidenceThe reported brain-wide IPF risk association patterns reveal two plausible mechanisms that may explain the known association of IPF and brain disorders: (i) direct and focal, thought to be related to paralimbic mTOR dysregulation and (ii) indirect and widespread, in keeping with secondary effects from impaired lung function such as hypoxia. Taken together, these data support the hypothesis that genetic risk profiles may explain some of the observed comorbidity of IPF and brain disorders.
C_TEXTBOX | neurology |
10.1101/2022.03.27.22272933 | Identification of Global DNA Methylation Signatures in Patients of High Altitude Induced Venous Thrombo-Embolism (HA-VTE) | BackgroundPathophysiology of venous thrombo-embolism (VTE) depends upon several acquired, inherited and environmental risk factors, including high altitude (HA) exposure. The present study aims to gain insights into pathophysiological mechanism(s) of high altitude induced VTE (HA-VTE) by studying global methylation signatures.
MethodologyBlood samples were collected from Indian Army volunteers divided into four study groups; sea level control (SLC), sea level VTE patients (SL-VTE), high altitude control (HAC) and high altitude VTE patients (HA-VTE). Methylation patterns were studied using whole genome bisulfate sequencing. Differentially methylated genes and pathways were identified by comparing percentage methylation.
ResultsHighest DM was observed in SL-VTE (1162 gene) compared to SLC where in hyper methylation was predominant (62.9%) compared to hypo methylation (37.05%). A reverse trend was observed in HA-VTE, where hypo methylation (61.69%) was predominant over hyper methylation (38.30%) in a total of 296 DM genes. Differential hypomethylation of genes involved in cell adhesion/platelet activity (CADM1, PTPRK, PDGFA) and immune response (CXCL12, IL4, IRF4, NLRP1) was observed in HA-VTE whereas genes encoding transcription factors (GSC, RPSKA1), trans membrane receptor (NOTCH2) and growth factor (TGFB2) were hypermethylated in comparison to SL-VTE. Methylation pattern of HA-VTE compared to HAC showed hypomethylation in genes involved in oxidative phosphorylation (CPOX), immune response and stress response (NDRG1), while those involved in signaling mechanisms (KALRN), neurotransmitter release (TMPRSS2) and transcription factor (ELF1) were hyper-methylated.
ConclusionsOur study for the first time reveals genome wide methylation pattern in HA-VTE group where in differential hypo methylation in cell adhesion and inflammation genes was observed. | genetic and genomic medicine |
10.1101/2022.03.28.22273061 | Workload Indicators of Staffing Need (WISN) Method for Midwives Planning and Estimation at Asrade Zewude Memorial Primary Hospital, North west Ethiopia | BackgroundWork force is a crucial component of health services delivery system. Ethiopia faces health workforce challenges with regard to evidence based health work force planning. First the health worker to population ratio was used and later standard staffing schedule for each health facility level was used. Both of these methods did not address the issue of evidence based workload variation between the same levels of facilities at different locations within a country. A workload indicator of staffing need method (WISN) addresses these variations. Therefore this study was assumed for recommendation on use of WISN for health facilities based on WISN results of midwives at Asrade Zewude memorial Hospital.
MethodsCross sectional study using WISN model was used to determine the gaps or excess and workload pressure in midwives at Asrade Zewude Memorial primary hospital, North West Ethiopia.
ResultsThe finding showed that there was five working days with 1030 hrs actual working time per year for midwives. This working time was spent on health service activities (58.4%), additional activities (36.6%) and support activities (5%). WISN calculation showed that a shortage of five midwives with WISN ratio of 0.8 at Asrade Zewude Memorial primary hospital North West Ethiopia.
ConclusionMidwives at the study area were doing their routine work with 20% under staffed by covering the additional five midwives position. With this working condition, it may be hard to achieve universal health coverage goals of the facility. Therefore the hospital should institutionalize WISN method to objectively employ midwifery professionals. | health policy |
10.1101/2022.03.29.22273037 | Human Papillomavirus (HPV) self-testing among un- and under-screened Maori, Pasifika, and Asian women in Aotearoa New Zealand: a preference survey among responders and interviews with clinical-trial non-responders | AimM[a]ori, Pasifika, and Asian women are less likely to attend cervical screening and M[a]ori and Pasifika women are more likely to be diagnosed with later-stage cervical cancer than other women in Aotearoa New Zealand. This study - with under-screened women taking part in a randomised controlled trial comparing self-testing and standard screening - explored the acceptability of an HPV self-test kit and the preferred method for receiving it.
MethodsM[a]ori, Pasifika, and Asian women (N=376) completed a postal questionnaire. Twenty-six women who had not accepted the trial invitation were interviewed to understand their reasons for non-participation.
ResultsMost women found the self-test kit easy and convenient to use and reported that they did not find it painful, uncomfortable, or embarrassing. This was reflected in the preference for a self-test over a future smear test on the same grounds. Most women preferred to receive the kit by mail and take the test themselves, rather than having it done by a doctor or nurse. There was a range of preferences relating to how to return the kit. Phone calls with non-responders revealed that, although most had received the test kit, the reasons for not choosing to be involved included not wanting to, being too busy, or forgetting.
ConclusionsHPV self-testing was acceptable for M[a]ori, Pasifika, and Asian women in Aotearoa New Zealand. HPV self-testing has considerable potential to reduce the inequities in the current screening programme and should be made available with appropriate delivery options as soon as possible. | public and global health |