title: Human Leukocyte Antigen Homozygosity Contributes to Sensitization in Kidney Transplant Candidates

abstract:
BackgroundHomozygosity for human leukocyte antigens (HLA) has been associated with adverse outcomes after viral infection as well as pregnancy-induced HLA sensitization. We sought to assess the relationship between HLA locus homozygosity and the level of HLA antibody sensitization.

MethodsWe measured sensitization using the calculated panel reactive antibody (CPRA) value for a large cohort of 147,461 patients added to the US OPTN/UNOS kidney transplant waitlist between December 2014 and December 2019. We used multinomial logistic modeling to compare 62,510 sensitized patients to 84,955 unsensitized controls.

ResultsWe found that the number of homozygous HLA loci was strongly associated with the level of sensitization. Within highly- or extremely-sensitized candidates, women displayed a higher relative abundance of HLA homozygosity at multiple HLA loci as compared to men, with attenuation of this effect in Black candidates. In multinomial logistic modeling, the number of homozygous HLA loci was an independent predictor of sensitization and interacted with female sex but not with other factors associated with sensitization.

ConclusionsThis study shows that HLA homozygosity is an innate genetic factor that contributes to HLA sensitization, and enhances the effect of pregnancy-related sensitization.

category: transplantation


title: Effects of medical school on mental health and sleep habits

abstract:
BACKGROUND and OBJECTIVESThis study aims to define changes in anxiety and depression among medical students while evaluating the association of sleep habits and other risk factors, including exercise habits and a diagnosis of chronic disease. The effect of the COVID-19 pandemic was also evaluated.

DESIGNA cohort of first- and second-year medical students was evaluated longitudinally using survey methods to quantify changes from pre-medical school and summer break to each semester in medical school throughout years one and two.

METHODSData was analyzed using Generalized Linear Mixed Models (GLMMs) on the numeric responses of General Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and Pittsburg Sleep Quality Index. Additional assessments evaluated exercise habits, chronic disease, and impact of COVID-19 Pandemic.

RESULTSDepression, anxiety, and sleep habits displayed a cyclical change that was associated with the academic cycle. The COVID-19 pandemic was never significant. Medical students who had a chronic disease diagnosis had increased severity. Exercise did not play a role.

CONCLUSIONThe main driver for depression, anxiety, and poor sleep quality was the academic cycle, while the COVID-19 pandemic did not have an impact on mental health.

category: medical education


title: Development of a clinical model to predict vagus nerve stimulation response in pediatric patients with drug-resistant epilepsy

abstract:
IntroductionEpilepsy impacts 470,000 children in the United States, and children with epilepsy are estimated to expend 6 times more on healthcare than those without epilepsy. For patients with antiseizure medication (ASM)-resistant epilepsy and unresectable seizure foci, vagus nerve stimulation (VNS) is a treatment option. Predicting response to VNS has been historically challenging. We aimed to create a clinical prediction score which could be utilized in a routine outpatient clinical setting.

MethodsWe performed an 11-year, single-center retrospective analysis of patients <21 years old with ASM-resistant epilepsy who underwent VNS. The primary outcome was [≥]50% seizure frequency reduction after one year. Univariate and multivariate logistic regressions were performed to assess clinical factors associated with VNS response; 70% and 30% of the sample were used to train and validate the multivariate model, respectively. A prediction score was developed based on the multivariate regression. Sensitivity, specificity, and area under the receiver operating curve (AUC) were calculated.

ResultsThis analysis included 365 patients. Multivariate logistic regression revealed that variables associated with VNS response were: <4 years of epilepsy duration before VNS (p=0.008) and focal motor seizures (p=0.037). The variables included in the clinical prediction score were: epilepsy duration before VNS, age at seizure onset, number of pre-VNS ASMs, if VNS was the patients first therapeutic epilepsy surgery, and predominant seizure semiology. The final AUC was 0.7013 for the "fitted" sample and 0.6159 for the "validation" sample.

ConclusionsWe developed a clinical model to predict VNS response in one of the largest samples of pediatric VNS patients to date. While the presented clinical prediction model demonstrated an acceptable AUC in the training cohort, clinical variables alone likely do not accurately predict VNS response. This score may be useful upon further validation, though its predictive ability underscores the need for more robust biomarkers of treatment response.

category: neurology


title: ExPRSweb - An Online Repository with Polygenic Risk Scores for Common Health-related Exposures

abstract: Complex traits are influenced by genetic risk factors, lifestyle, and environmental variables, so called exposures. Some exposures, e.g., smoking or lipid levels, have common genetic modifiers identified in genome-wide association studies. Since measurements are often unfeasible, Exposure Polygenic Risk Scores (ExPRSs) offer an alternative to study the influence of exposures on various phenotypes. Here, we collected publicly available summary statistics for 28 exposures and applied four common PRS methods to generate ExPRSs in two large biobanks, the Michigan Genomics Initiative and the UK Biobank. We established ExPRS for 27 exposures and demonstrated their applicability in phenome-wide association studies and as predictors for common chronic conditions. Especially, the addition of multiple ExPRSs showed, for several chronic conditions, an improvement compared prediction models that only included traditional, disease-focused PRSs. To facilitate follow-up studies, we share all ExPRS constructs and generated results via an online repository called ExPRSweb.

category: genetic and genomic medicine


title: Evaluation and modelling of the performance of an automated SARS-CoV-2 antigen assay according to sample type, target population and epidemic trends

abstract: The Lumipulse(R) G SARS-CoV-2 Ag assay performance was evaluated on prospectively collected saliva and nasopharyngeal swabs (NPS) of recently ill in- and outpatients and according to the estimated viral load. Performances were calculated using RT-PCR positive NPS from patients with symptoms [≤] 7 days and RT-PCR negative NPS as gold standard. In addition, non-selected positive NPS were analyzed to assess the performances on various viral loads. This assay yielded a sensitivity of 93.1% on NPS and 71.4% on saliva for recently ill patients. For NPS with a viral load > 103 RNA copies/mL, sensitivity was 96.4%. A model established on our daily routine showed fluctuations of the performances depending on the epidemic trends but an overall good negative predictive value. Lumipulse(R) G SARS-CoV-2 assay yielded good performance for an automated antigen detection assay on NPS. Using it for the detection of recently ill patient or to screen high-risk patients could be an interesting alternative to the more expensive RT-PCR.

category: infectious diseases


title: A national survey of early treatment seeking behavior among those with incident SARS-CoV-2 infection

abstract:
BackgroundDespite effective means to treat SARS-CoV-2 infection, the early treatment seeking behavior of those newly diagnosed with infection is not clear.

MethodsWe surveyed users of a national SARS-CoV-2 testing company to assess the frequency and correlates of early treatment seeking behavior for a positive test result. We recruited adults (18 years or older) who had tested positive for SARS-CoV-2 by PCR at a large clinical laboratory. To be eligible, individuals had to have a positive test result within 7 days of enrollment. Surveys were anonymous and voluntary. We collected data on demographic characteristics, general health care access and utilization, awareness of treatment for COVID-19, treatment seeking behavior, and treatments received. Descriptive statistics and odds ratios (OR) with 95% confidence intervals (95% CI) were calculated on StataSE.

ResultsParticipants were surveyed from 3-7 January 2022: among the 15,991 who viewed a survey request, 7,647 individuals were eligible and provided responses. The median age of a respondent was 42 years (interquartile range: 32 to 54), 68.9% of respondents were women, and respondents represented 33 different states, districts, and territories. Among respondents, 23.1% reported they had sought treatment or medical advice for their current COVID-19 diagnosis. Of those who were very aware of treatment for COVID-19, 31.0% sought treatment versus 16.7% who were unaware (p-value< 0.001). The odds of treatment seeking behavior were higher for those that were contacted by a medical professional after their diagnosis (OR: 4.57 [95% CI: 3.89 to 5.37]), those with a primary doctor (OR: 2.94 [95% CI: 2.52 to 3.43]), those who self-measured their oxygen saturation (OR: 2.53 [95% CI: 2.25 to 2.84]), and those over 65 years of age (OR: 2.36 [95% CI: 2.02 to 2.76]). There was no difference in those seeking treatment based on heritage, ethnicity, prior COVID-19 diagnosis, state political affiliation, or vaccination status. The odds of seeking treatment were lower among men (OR: 0.88 [95% CI: 0.78 to 0.99]) and those without insurance (OR: 0.62 [95% CI: 0.52 to 0.72]). The most common treatment locations were clinics and most common treatments were Vitamin C, Vitamin D, Zinc, Tylenol, and NSAIDs.

ConclusionMore public outreach is needed to raise awareness of the benefits of treatment for COVID-19. We found that people who were more aware about treatment for COVID-19 were more likely to seek medical advice or therapy. Efforts to increase awareness might increase early treatment for SARS-CoV-2 infection. Increased outreach with treatment facilitation from medical professionals and/or public health staff to those with newly detected SARS-CoV-2 infections, particularly among those at higher-risk of complications, might also be helpful.


title: HAT-field: a very cheap, robust and quantitative point-of-care serological test for Covid-19.

abstract:
We have recently described a very simple and cheap serological test called HAT to detect antibodies directed against the RBD of the SARS-Cov-2 virus. HAT is based on hemagglutination, triggered by a single reagent (IH4-RBD) comprised of the viral RBD domain fused to a nanobody specific for glycophorin, which is expressed at very high levels at the surface of human red blood cells (RBCs).

One of the main initial goals of this study was to devise a test protocol that would be sensitive and reliable, yet require no specialized laboratory equipment such as adjustable pipets, so that it could be performed in the most remote corners of the world by people with minimal levels of training. Because antibody levels against the viral RBD have been found to correlate closely with sero-neutralisation titers, and thus with protection against reinfection, it has become obvious during the course of this study that making this test reliably quantitative would be a further significant advantage.

Using IH4-RBD based on the original Wuhan sequence, we have found that, in PBN, a buffer which contains BSA and sodium azide, the reagent is stable for over 6 months at room temperature, and that PBN also improves HAT performance compared to using straight PBS. We also show that performing HAT at either 4{degrees}C, room temperature or 37{degrees}C has minimal influence on the results, and that quantitative evaluation of the levels of antibodies directed against the SARS-CoV-2 RBD can be achieved in a single step using titration of the IH4-RBD reagent.

The HAT-field protocol described here requires only very simple disposable equipment and a few microliters of whole blood, such as can be obtained by finger prick. Because it is based on a single soluble reagent, the test can be adapted very simply and rapidly to detect antibodies against variants of the SARS-CoV-2, or conceivably against different pathogens. HAT-field appears well suited to provide quantitative assessments of the serological protection of populations as well as individuals, and given its very low cost, the stability of the IH4-RBD reagent in the adapted buffer, and the simplicity of the procedure, could be deployed pretty much anywhere, including in the poorest countries and the most remote corners of the globe.

Note: This manuscript has been refereed by Review Commons, and modified thanks to the comments and suggestions from three referees. Those comments, and our replies, are provided at the end of the manuscripts pdf, and can also be accessed by clicking on the blue tab found to the right of the MedRXiv window.


title: HAT-field: a cheap, robust and quantitative point-of-care serological test for Covid-19.


title: A digital self-care intervention for Ugandan patients with heart failure and their clinicians: User-centred design and usability study

abstract:
BackgroundThe prevalence of heart failure (HF) is increasing in Uganda. Ugandan patients with HF report receiving limited information about their illness, disease management, or empowerment to engage in self-care behaviors. Interventions targeted at improving HF self-care have been shown to improve patient quality of life and to reduce hospitalizations in high-income countries. However, such interventions remain underutilized in resource-limited settings like Uganda.

ObjectiveTo develop a digital health intervention that enables improved self-care amongst HF patients in Uganda.

MethodsWe implemented a user-centred design process to develop a self-care intervention entitled Medly Uganda. The ideation phase comprised a systematic scoping review and preliminary data collection amongst HF patients and clinicians in Uganda. An iterative design process was then used to advance an initial prototype into a fully-functional digital health intervention. The evaluation phase involved usability testing of the developed intervention amongst Ugandan patients with HF and their clinicians.

ResultsMedly Uganda is a digital health intervention that is fully integrated within a government-operated mobile health platform. The system allows patients to report daily HF symptoms, receive tailored treatment advice, and connect with a clinician when showing signs of decompensation. Medly Uganda harnesses Unstructured Supplementary Service Data technology that is already widely used in Uganda for mobile phone-based financial transactions. Usability testing showed the system to be accepted by patients, caregivers, and clinicians.

ConclusionsMedly Uganda is a fully-functional and well-accepted digital health intervention that enables Ugandan HF patients to better care for themselves. Moving forward, we expect the system to help decongest cardiac clinics and improve self-care efficacy amongst HF patients in Uganda.

category: cardiovascular medicine


title: National-scale surveillance of emerging SARS-CoV-2 variants in wastewater

abstract:
SARS-CoV-2 surveillance is crucial to identify variants with altered epidemiological properties. Wastewater-based epidemiology (WBE) provides an unbiased and complementary approach to sequencing individual cases. Yet, national WBE surveillance programs have not been widely implemented and data analyses remain challenging.

We deep-sequenced 2,093 wastewater samples representing 95 municipal catchments, covering >57% of Austrias population, from December 2020 to September 2021. Our Variant Quantification in Sewage pipeline designed for Robustness (VaQuERo) enabled us to deduce variant abundance from complex wastewater samples and delineate the spatiotemporal dynamics of the dominant Alpha and Delta variants as well as regional clusters of other variants of concern. These results were cross validated by epidemiological records of >130,000 individual cases. Finally, we provide a framework to predict emerging variants de novo and infer variant-specific reproduction numbers from wastewater.

This study demonstrates the power of national-scale WBE to support public health and promises particular value for countries without dense individual monitoring.

Graphical Abstract

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category: epidemiology


title: A Mixed-Methods Feasibility Study of a Novel AI-Enabled, Web-Based, Clinical Decision Support System for the Treatment of Major Depression in Adults

abstract: The objective of this paper is to discuss perceived clinical utility and impact on physician-patient relationship of a novel, artificial-intelligence (AI) enabled clinical decision support system (CDSS) for use in the treatment of adults with major depression. Patients had a baseline appointment, followed by a minimum of two appointments with the CDSS. For both physicians and patients, study exit questionnaires and interviews were conducted to assess perceived clinical utility, impact on patient-physician relationship, and understanding and trust in the CDSS. 17 patients consented to participate in the study, of which 14 completed. 86% of physicians (6/7) felt the information provided by the CDSS provided a more comprehensive understanding of patient situations and 71% (5/7) felt the information was helpful. 86% of physicians (6/7) reported the AI/predictive model was useful when making treatment decisions. 62% of patients (8/13) reported improvement in their care as a result of the tool. 46% of patients (6/13) felt the app significantly or somewhat improved their relationship with their physicians; 54% felt it did not change. 71% of physicians (5/7) and 62% of patients (8/13) rated they trusted the tool. Qualitative results are analyzed and presented. Findings suggest physicians perceived the tool as useful in conducting appointments and used it while making treatment decisions. Physicians and patients generally found the tool trustworthy, and it may have positive effects on physician-patient relationships.

category: psychiatry and clinical psychology


title: Global and National Declines in Life Expectancy: An End-of-2021 Assessment

abstract:
Timely, high-quality mortality data have allowed for assessments of the impact of Covid-19 on life expectancies in upper-middle- and high-income countries. Extant data, though imperfect, suggest that the bulk of the pandemic-induced mortality might have occurred elsewhere. This article reports on changes in life expectancies around the world as far as they can be estimated from the evidence available at the end of 2021.

The global life expectancy appears to have declined by .92 years between 2019 and 2020 and by another .72 years between 2020 and 2021, but the decline seems to have ended during the last quarter of 2021. Uncertainty about its exact size aside, this represents the first decline in global life expectancy since 1950, the first year for which a global estimate is available from the United Nations.

Annual declines in life expectancy (from a 12-month period to the next) appear to have exceeded two years at some point before the end of 2021 in at least 50 countries. Since 1950, annual declines of that magnitude had only been observed in rare occasions, such as Cambodia in the 1970s, Rwanda in the 1990s, and possibly some sub-Saharan African nations at the peak of the HIV/AIDS pandemic.

category: public and global health


title: Two Pools of ATP Detected in the Brains of Pediatric Patients with Myelin Oligodendrocyte Glycoprotein Antibody Disorders (MOGAD) by 3D 31P MR Spectroscopic Imaging (MRSI) at 7T

abstract:
Over the past four decades, ATP, the obligatory energy molecule for keeping all cells alive and functioning, was thought to contribute only one set of 31P MR signals in the human brain. Here we report for the first time the simultaneous detection of two pools of ATP in the human brain by high-resolution 3D 31P MRSI at ultrahigh field 7T. These two ATP pools differ in cytosolic Mg2+ concentration (1:0.5 ratio), with a resonance separation of 0.5 ppm at {beta}-ATP, a well-established imaging marker of intracellular Mg2+ concentration. Mg2+ is a cofactor of ATPase and its deficiency is associated with immune dysfunction, free radical damage, perturbations in Ca2+ homeostasis, and development of atherosclerosis, dyslipidemia and a number of neurological disorders, such as cerebral vasospasm, stroke, migraine, Alzheimers disease, and Parkinsons disease. Our study documents reduced Mg levels in the brain of patients with myelin oligodendrocyte glycoprotein antibody disorders (MOGAD), which is an idiopathic, inflammatory, demyelinating condition of the central nervous system (CNS) more common in pediatric patients. Low-Mg2+ ATP signals were detected mostly in the white matter regions in MOGAD, suggesting an association between Mg2+ deficiency and compromised functions of oligodendrocytes in maintenance and generation of the axonal myelin sheath. This preliminary study demonstrates the utility of the 7T 3D 31P MSRI for probing altered energy metabolism at reduced availability of Mg2+ rather than ATP itself. The potential correlation between [Mg2+] and disease progression over time should be assessed in larger cohorts.

Author ApprovalYes

category: radiology and imaging


title: Novel Application of a Force Sensor during Sit-to-Stands to Measure Dynamic Cerebral Autoregulation Onset

abstract:
PurposeCurrent sit-to-stand methods measuring dynamic cerebral autoregulation (dCA) do not capture the precise onset of the time delay (TD) response. Reduced sit-to-stand reactions in older adults and individuals post-stroke could inadvertently introduce variability, error, and imprecise timing. We applied a force sensor during a sit-to-stand task to more accurately determine how TD before dCA onset may be altered.

MethodsMiddle cerebral artery blood velocity (MCAv) and mean arterial pressure (MAP) were measured during two sit-to-stands separated by 15 minutes. Recordings started with participants sitting on a force-sensitive resistor for 60 seconds, then asked to stand for two minutes. Upon standing, the force sensor voltage immediately dropped and marked the exact moment of arise- and-off (AO). Time from AO until an increase in cerebrovascular conductance (CVC = MCAv/MAP) was calculated as TD.

ResultsWe tested the sensor in 4 healthy young adults, 2 older adults, and 2 individuals post-stroke. Healthy young adults stood quickly and the force sensor detected a small change in TD compared to classically estimated AO, from verbal command to stand. When compared to the estimated AO, older adults had a delayed measured AO and TD decreased up to ~53% while individuals post-stroke had an early AO and TD increased up to ~14%.

ConclusionThe transition reaction speed during the sit to stand has the potential to influence dCA metrics. As observed in the older adults and participants with stroke, this response may drastically vary and influence TD.

New & NoteworthyWe developed a force sensor and are the first to apply it during sit-to-stands measuring the dynamic cerebral autoregulation (dCA) response. Current methodologies estimate the transition reaction speed of the sit-to-stand, which influences the dCA metrics. Compared to estimating the kinetic moment of arise-and-off (AO), our force sensor can detect early or delayed AO in individuals who may present with lower extremity weakness such as older adults and clinical populations such as stroke.

category: rehabilitation medicine and physical therapy


title: Students as Community Vaccinators: Implementation of a Service-Learning COVID-19 Vaccination Program

abstract:
BackgroundService-learning is an integral component of medical education. While the COVID-19 pandemic has caused massive educational disruptions, it has also catalyzed innovation in service-learning as real-time responses to pandemic-related problems. For example, the limited number of qualified providers was a potential barrier to local and national SARS-CoV-2 vaccination efforts. Foreseeing this hurdle, New York State temporarily allowed healthcare professional trainees to vaccinate, enabling medical students to support an overwhelmed healthcare system and contribute to the community. Yet, it was the responsibility of medical schools to interpret these rules and implement the vaccination programs. Here the authors describe a service-learning vaccination program directed towards underserved communities.

MethodsWeill Cornell Medicine (WCM) rapidly developed a faculty-led curriculum to prepare students to communicate with patients about the COVID-19 vaccines and to administer intramuscular injections. Qualified students were deployed to public vaccination clinics located in underserved neighborhoods across New York City in collaboration with an established community partner. The educational value of the program was evaluated with retrospective survey.

ResultsThroughout the program, which lasted from February to June 2021, 128 WCM students worked at 103 local events, helping to administer 26,889 vaccine doses. Analysis of student evaluations revealed this program taught fundamental clinical skills, increasing comfort giving intramuscular injection from 2% to 100% and increasing comfort talking to patients about the COVID-19 vaccine from 30% to 100%. Qualitatively participants described the program as a transformative service-learning experience.

ConclusionAs new virus variants emerge, nations battle recurrent waves of infection, and vaccine eligibility expands to include children and boosters, the need for effective vaccination plans continues to grow. The program described here offers a novel framework that academic medical centers could adapt to increase vaccine access in their local community and provide students with a uniquely meaningful educational experience.


title: Immunosuppression impaired the immunogenicity of inactivated SARS-CoV-2 vaccine in non-dialysis kidney disease patients

abstract: Patients with chronic kidney disease (CKD) are at higher risk for coronavirus disease 2019 (COVID-19)-related morbidity and mortality. However, a significant portion of CKD patients showed hesitation toward vaccination in telephone survey of our center. Yet no serial data available on humoral response in patients with CKD, especially those on immunosuppression. We conducted a pilot, prospective study to survey the safety and humoral response to inactivated SARS-CoV-2 vaccine in CKD patients receiving a 2-dose immunization of inactivated SARS-CoV-2 vaccine. We found the neutralizing antibody titers in CKD patients was significantly lower than that in healthy controls, hypertension patients, and diabetes patients. Notably, immunosuppressive medication rather than eGFR levels or disease types showed effect on the reduction of immunogenicity. Interestingly, a third dose significantly boosted neutralizing antibody in CKD patients while immunosuppressants impeded the boosting effects. In conclusion, our data demonstrates that CKD patients, even for those on immunosuppression treatment, can benefit from a third vaccination boost by improving their humoral immunity.

category: nephrology


title: Prognostic Value of Serum/Plasma Neurofilament Light Chain for COVID-19 Associated Mortality

abstract:
Given the continued spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), early predictors of coronavirus disease 19 (COVID-19) mortality might improve patients outcomes. Increased levels of circulating neurofilament light chain (NfL), a biomarker of neuro-axonal injury, have been observed in patients with severe COVID-19. We investigated whether NfL provides non-redundant clinical value to previously identified predictors of COVID-19 mortality.

We measured serum or plasma NfL concentrations in a blinded fashion in 3 cohorts totaling 338 COVID-19 patients. In cohort 1, we found significantly elevated NfL levels only in critically ill COVID-19 patients compared to healthy controls. Longitudinal cohort 2 data showed that NfL is elevated late in the course of the disease, following two other prognostic markers of COVID-19: decrease in absolute lymphocyte count (ALC) and increase in lactate dehydrogenase (LDH). Significant correlations between LDH and ALC abnormalities and subsequent rise of NfL implicate multi-organ failure as a likely cause of neuronal injury at the later stages of COVID-19. Addition of NfL to age and gender in cohort 1 significantly improved the accuracy of mortality prediction and these improvements were validated in cohorts 2 and 3.

In conclusion, although substantial increase in serum/plasma NfL reproducibly enhances COVID-19 mortality prediction, NfL has clinically meaningful prognostic value only close to death, which may be too late to alter medical management. When combined with other prognostic biomarkers, rising longitudinal NfL measurements triggered by LDH and ALC abnormalities would identify patients at risk of COVID-19 associated mortality who might still benefit from escalated care.


title: Health and Economic Consequences of Universal Paid Sick Leave Policies During the COVID-19 Pandemic

abstract:
ImportanceUniversal paid sick-leave (PSL) policies have been implemented in jurisdictions to mitigate the spread of SARS-CoV-2. However empirical data regarding health and economic consequences of PSL policies is scarce.

ObjectiveTo estimate effects of a universal PSL policy in Ontario, Canadas most populous province.

DesignAn agent-based model (ABM) to simulate SARS-CoV-2 transmission informed by data from Statistics Canada, health administrative sources, and from the literature.

SettingOntario from January 1st to May 1st, 2021.

ParticipantsA synthetic population (1 million) with occupation and household characteristics representative of Ontario residents (14.5 million).

ExposureA base case of existing employer-based PSL alone versus the addition of a 3-or 10-day universal PSL policy to facilitate testing and self-isolation among workers infected with SARS-CoV-2 themselves or because of infected household members.

Main Outcome(s) and Measure(s)Number of SARS-CoV-2 infections and COVID-19 hospitalizations, worker productivity, lost wages, and presenteeism (going to a workplace while infected).

ResultsIf a 3- and 10-day universal PSL were implemented over the 4-month study period, then compared with the base-case, the PSL policies were estimated to reduce cumulative SARS-CoV-2 cases by 85,531 (95% credible interval, CrI -2,484; 195,318) and 215,302 (81,500; 413,742), COVID-19 hospital admissions by 1,307 (-201; 3,205) and 3,352 (1,223; 6,528), numbers of workers forgoing wages by 558 (-327;1,608) and 7,406 (6,764; 8,072), and numbers of workers engaged in presenteeism by 24,499 (216; 54,170) and 279,863 (262,696; 295,449). Hours of productivity loss were estimated to be 10,854,379 (10,212,304; 11,465,635) in the base case, 17,446,525 (15,934,321; 18,854,683) in the 3-day scenario, and 26,127,165 (20,047,239; 29,875,161) in the 10-day scenario. Lost wages were $5,256,316 ($4,077,280; $6,804,983) and $12,610,962 ($11,463,128; $13,724,664) lower in the 3 day and 10 day scenarios respectively, relative to the base case.

Conclusions and RelevanceExpanded access to PSL is estimated to reduce total numbers of COVID-19 cases, reduce presenteeism of workers with SARS-CoV-2 at workplaces, and mitigate wage loss experienced by workers.

Competing interestsThe authors have no competing interests relevant to this article to disclose.

FundingSupported by COVID-19 Rapid Research Funding (C-291-2431272-SANDER). This research was further supported, in part, by a Canada Research Chair in Economics of Infectious Diseases held by Beate Sander (CRC-950-232429). The study sponsor had no role in the design, collection, analysis, interpretation of the data, manuscript preparation or the decision to submit for publication.

Author ContributionsConceptualization: PP, JDR, BS, DN

Data Curation: PP, JDR, BS, DN

Formal Analysis: PP, JDR, DN

Methodology: PP, JDR, BS, DN

Supervision: PP, DN, BS

Validation: PP, JDR, BS, DN

First Draft: PP, JDR, BS, DN

Review and Edit

PP, JDR, BS, DN

Key pointsO_ST_ABSQuestionC_ST_ABSWhat could be the health and economic consequence of more generous paid sick leave policies in the context of the COVID-19 pandemic?

FindingsMore generous policies are estimated to reduce SARS-CoV-2 infections (and thus COVID-19 hospitalizations), lost wages and presence of individuals with infection at workplaces.

MeaningMore generous paid sick leave can be a valuable addition to other COVID-19 public health interventions.

category: health economics


title: A Computational Framework for Identifying Age Risks in Drug-Adverse Event Pairs

abstract: The identification of associations between drugs and adverse drug events (ADEs) is crucial for drug safety surveil-lance. An increasing number of studies have revealed that children and seniors are susceptible to ADEs at the population level. However, the comprehensive explorations of age risks in drug-ADE pairs are still limited. The FDA Adverse Event Reporting System (FAERS) provides individual case reports, which can be used for quantifying different age risks. In this study, we developed a statistical computational framework to detect age group of patients who are susceptible to some ADEs after taking specific drugs. We adopted different Chi-squared tests and conducted disproportionality analysis to detect drug-ADE pairs with age differences. We analyzed 4,580,113 drug-ADE pairs in FAERS (2004 to 2018Q3) and identified 2,523 pairs with the highest age risk. Furthermore, we conducted a case study on statin-induced ADE in children and youth. The code and results are available at https://github.com/Zhizhen-Zhao/Age-Risk-Identification

category: health informatics


title: Algorithmic Fairness and Bias Mitigation for Clinical Machine Learning: Insights from Rapid COVID-19 Diagnosis by Adversarial Learning

abstract: Machine learning is becoming increasingly prominent in healthcare. Although its benefits are clear, growing attention is being given to how machine learning may exacerbate existing biases and disparities. In this study, we introduce an adversarial training framework that is capable of mitigating biases that may have been acquired through data collection or magnified during model development. For example, if one class is over-presented or errors/inconsistencies in practice are reflected in the training data, then a model can be biased by these. To evaluate our adversarial training framework, we used the statistical definition of equalized odds. We evaluated our model for the task of rapidly predicting COVID-19 for patients presenting to hospital emergency departments, and aimed to mitigate regional (hospital) and ethnic biases present. We trained our framework on a large, real-world COVID-19 dataset and demonstrated that adversarial training demonstrably improves outcome fairness (with respect to equalized odds), while still achieving clinically-effective screening performances (NPV>0.98). We compared our method to the benchmark set by related previous work, and performed prospective and external validation on four independent hospital cohorts. Our method can be generalized to any outcomes, models, and definitions of fairness.


title: Assessing the clinical severity of the Omicron variant in the Western Cape Province, South Africa, using the diagnostic PCR proxy marker of RdRp target delay to distinguish between Omicron and Delta infections: a survival analysis

abstract:
BackgroundEmerging data suggest that SARS-CoV-2 Omicron variant of concern (VOC)is associated with reduced risk of severe disease. The extent to which this reflects a difference in the inherent virulence of Omicron, or just higher levels of population immunity, is currently not clear.

MethodsRdRp target delay (RTD: a difference in cycle threshold value of RdRp - E > 3.5) in the Seegene Allplex 2019-nCoV PCR assay is a proxy marker for the Delta VOC. The absence of this proxy marker in the period of transition to Omicron was used to identify suspected Omicron VOC infections.

Cox regression was performed for the outcome of hospital admission in those who tested positive for SARS-CoV-2 on the Seegene Allplex assay from 1 November to 14 December 2021 in the Western Cape Province, South Africa, public sector. Vaccination status at time of diagnosis, as well as prior diagnosed infection and comorbidities, were adjusted for.

Results150 cases with RTD (proxy for Delta) and 1486 cases without RTD (proxy for Omicron) were included. Cases without RTD had a lower hazard of admission (adjusted Hazard Ratio [aHR] of 0.56, 95% confidence interval [CI] 0.34-0.91). Complete vaccination was protective of admission with an aHR of 0.45 (95%CI 0.26-0.77).

ConclusionOmicron has resulted in a lower risk of hospital admission, compared to contemporaneous Delta infection in the Western Cape Province, when using the proxy marker of RTD. Under-ascertainment of reinfections with an immune escape variant like Omicron remains a challenge to accurately assessing variant virulence.


title: The emergence of two distinct SARS-CoV-2 Gamma related variants during the second wave of COVID-19 in Santa Catarina, Southern Brazil and the rapid spread of P.1-like-II SARS-CoV-2 variant transmission and a regionalization in the Western region

abstract: The Western mesoregion, the State of Santa Catarina (SC), Southern Brazil, was heavily affected as a whole by the COVID-19 pandemic in early 2021. This study aimed to evaluate the dynamics of the SARS-CoV-2 virus spreading patterns in the SC state through March 2020 to April 2021 using genomic surveillance. During this period, 23 distinct variants, including Beta and Gamma, among which, the Gamma and related lineages were predominant in the second pandemic wave within SC. A regionalization of P.1-like-II in the Western-SC region was observed, concomitant to the increase in cases, mortality, and case fatality rate (CFR) index. This is the first evidence of the regionalization of the SARS-CoV-2 in SC transmission and highlights the importance of tracking variants, dispersion, and impact of SARS-CoV-2 on the public health systems.


title: Emergence of two distinct SARS-CoV-2 Gamma variants and the rapid spread of P.1-like-II SARS-CoV-2 during the second wave of COVID-19 in Santa Catarina, Southern Brazil


title: The risk of SARS-CoV-2 Omicron variant emergence in low and middle-income countries (LMICs)

abstract: We estimated the probability of undetected emergence of the SARS-CoV-2 Omicron variant in 25 low and middle-income countries (LMICs) prior to December 5, 2021. In nine countries, the risk exceeds 50%; in Turkey, Pakistan and the Philippines, it exceeds 99%. Risks are generally lower in the Americas than Europe or Asia.


title: SARS-CoV-2 Omicron Neutralization After Heterologous Vaccine Boosting

abstract: As part of an ongoing study assessing homologous and heterologous booster vaccines, following primary EUA series, we assessed neutralization of D614G and Omicron variants prior to and 28 days after boost. Subset analysis was done in six combinations (N = 10/group): four homologous primary-booster combinations included mRNA-1273 two-dose priming followed by boosting with 100-g or 50-g mRNA-1273, Ad26.COV2.S single-dose priming followed by Ad26.COV2.S booster and BNT162b2 two-dose priming followed by BNT162b2 boosting; and two heterologous primary-booster combinations: BNT162b2 followed by Ad26.COV2.S and Ad26.COV2.S followed by BNT162b2. Neutralizing antibody (Nab) titers to D614G on the day of boost (baseline) were detected in 85-100% of participants, with geometric mean titers (GMT) of 71-343 in participants who received an mRNA vaccine series versus GMTs of 35-41 in participants primed with Ad26.OV2.S. Baseline NAb titers to Omicron were detected in 50-90% of participants who received an mRNA vaccine series (GMT range 12.8-24.5) versus 20-25% among participants primed with Ad26.COV2.S. The booster dose increased the neutralizing GMT in most combinations to above 1000 for D614G and above 250 for Omicron by Day 29. Homologous prime-boost Ad26.COV2.S had the lowest NAb on Day 29 (D614G GMT 128 and Omicron GMT 45). Results were similar between age groups. Most homologous and heterologous boost combinations examined will increase humoral immunity to the Omicron variant.


title: Identifying the potential role of insomnia on multimorbidity: A Mendelian randomization phenome-wide association study in UK Biobank

abstract:
ObjectivesTo identify the breadth of potential causal effects of insomnia on health outcomes and hence its possible role in multimorbidity.

DesignMendelian randomisation (MR) Phenome-wide association study (MR-PheWAS) with two-sample Mendelian randomisation follow-up.

SettingIndividual data from UK Biobank and summary data from a number of genome-wide association studies.

Participants336,975 unrelated white-British UK Biobank participants.

ExposuresStandardised genetic risk of insomnia for the MR-PheWAS and genetically predicted insomnia for the two-sample MR follow-up, with insomnia instrumented by a genetic risk score (GRS) created from 129 single-nucleotide polymorphisms (SNPs).

Main outcomes measures11,409 outcomes from UK Biobank extracted and processed by an automated pipeline (PHESANT). Potential causal effects (i.e., those passing a Bonferroni-corrected significance threshold) were followed up with two-sample MR in MR-Base, where possible.

Results437 potential causal effects of insomnia were observed for a number of traits, including anxiety, stress, depression, mania, addiction, pain, body composition, immune, respiratory, endocrine, dental, musculoskeletal, cardiovascular and reproductive traits, as well as socioeconomic and behavioural traits. We were able to undertake two-sample MR for 71 of these 437 and found evidence of causal effects (with directionally concordant effect estimates across all analyses) for 25 of these. These included, for example, risk of anxiety disorders (OR=1.55 [95% confidence interval (CI): 1.30, 1.86] per category increase in insomnia), diseases of the oesophagus/stomach/duodenum (OR=1.32 [95% CI: 1.14, 1.53]) and spondylosis (OR=1.57 [95% CI: 1.22, 2.01]).

ConclusionInsomnia potentially causes a wide range of adverse health outcomes and behaviours. This has implications for developing interventions to prevent and treat a number of diseases in order to reduce multimorbidity and associated polypharmacy.

O_TEXTBOXWhat this paper addsO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIInsomnia symptoms are widespread in the population and insomnia is the second most common mental health disorder after anxiety disorders.
C_LIO_LIInsomnia might have broad and numerous effects on health and multimorbidity, but both observational and Mendelian randomisation studies have focused on select hypothesised associations/effects rather than taking a systematic hypothesis-free approach across many health outcomes.
C_LI

What this study addsO_LIThis study uses a hypothesis-free approach to systematically identify causal effects of insomnia on 11,409 health outcomes; it identified 437 potential causal effects and for 71 that could be followed-up with two-sample MR, 25 showed evidence of a causal effect and were directionally consistent across all analyses.
C_LIO_LIThese findings identify potential routes for developing interventions to prevent and treat a number of diseases and reduce multimorbidity and polypharmacy.
C_LI

C_TEXTBOX


title: High-cited favorable studies for COVID-19 treatments ineffective in large trials

abstract:
ImportanceCOVID-19 has resulted in massive production, publication and wide dissemination of clinical studies trying to identify effective treatments. However, several widely touted treatments failed to show effectiveness in large well-done randomized controlled trials (RCTs).

ObjectiveTo evaluate for COVID-19 treatments that showed no benefits in subsequent large RCTs how many of their most-cited clinical studies had declared favorable results for these interventions.

MethodsScopus (last update December 23, 2021) identified articles on lopinavir-ritonavir, hydroxycholoroquine/azithromycin, remdesivir, convalescent plasma, colchicine or interferon (index interventions) that represented clinical trials and that had received >150 citations. Their conclusions were assessed and correlated with study design features. The ten most recent citations for the most-cited article on each index intervention were examined on whether they were critical to the highly-cited study. Altmetric scores were also obtained.

Findings40 articles of clinical studies on these index interventions had received >150 citations (7 exceeded 1,000 citations). 20/40 (50%) had favorable conclusions and 4 were equivocal. Highly-cited articles with favorable conclusions were rarely RCTs while those without favorable conclusions were mostly RCTs (3/20 vs 15/20, p=0.0003). Only 1 RCT with favorable conclusions had sample size >160. Citation counts correlated strongly with Altmetric scores, in particular news items. Only 9 (15%) of 60 recent citations to the most highly-cited studies with favorable or equivocal conclusions were critical to the highly-cited study.

ConclusionMany clinical studies with favorable conclusions for largely ineffective COVID-19 treatments are uncritically heavily cited and disseminated. Early observational studies and small randomized trials may cause spurious claims of effectiveness that get perpetuated.


title: Simple risk scores to predict hospitalization or death in outpatients with COVID-19

abstract:
ImportanceOutpatient physicians need guidance to support their clinical decisions regarding management of patients with COVID-19, in particular whether to hospitalize a patient and if managed as an outpatient, how closely to follow them.

ObjectiveTo develop and prospectively validate a clinical prediction rule to predict the likelihood of hospitalization for outpatients with COVID-19 that does not require laboratory testing or imaging.

DesignDerivation and temporal validation of a clinical prediction rule, and prospective validation of two externally derived clinical prediction rules.

SettingPrimary and Express care clinics in a Pennsylvania health system.

ParticipantsPatients 12 years and older presenting to outpatient clinics who had a positive polymerase chain reaction test for COVID-19.

Main outcomes and measuresClassification accuracy (percentage in each risk group hospitalized) and area under the receiver operating characteristic curve (AUC).

ResultsOverall, 7.4% of outpatients in the early derivation cohort (5843 patients presenting before 3/1/21) and 5.5% in the late validation cohort (3806 patients presenting 3/1/21 or later) were ultimately hospitalized. We developed and temporally validated three risk scores that all included age, dyspnea, and the presence of comorbidities, adding respiratory rate for the second score and oxygen saturation for the third. All had very good overall accuracy (AUC 0.77 to 0.78) and classified over half of patients in the validation cohort as very low risk with a 1.7% or lower likelihood of hospitalization. Two externally derived risk scores identified more low risk patients, but with a higher overall risk of hospitalization (2.8%).

Conclusions and relevanceSimple risk scores applicable to outpatient and telehealth settings can identify patients with very low (1.6% to 1.7%), low (5.2% to 5.9%), moderate (14.7% to 15.6%), and high risk (32.0% to 34.2%) of hospitalization. The Lehigh Outpatient COVID Hospitalization (LOCH) risk score is available online as a free app: https://ebell-projects.shinyapps.io/LehighRiskScore/.

category: primary care research


title: Simple risk scores to predict hospitalization or death in outpatients with COVID-19 including the Omicron variant


title: Network-based integrative analysis of lithium response in bipolar disorder using transcriptomic and GWAS data

abstract: Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA- boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric=1.28E- 09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.


title: The effect of livestock density on Trypanosoma brucei gambiense and T. b. rhodesiense : a causal inference-based approach

abstract:
Domestic and wild animals are important reservoirs of the rhodesiense form of human African trypanosomiasis (rHAT), however quantification of this effect offers utility for deploying non-medical control activities, and anticipating their success when wildlife are excluded. Further, the uncertain role of animal reservoirs--particularly pigs--threatens elimination of transmission (EOT) targets set for the gambiense form (gHAT). Using a new time series of high-resolution cattle and pig density maps, HAT surveillance data collated by the WHO Atlas of HAT, and methods drawn from causal inference and spatial epidemiology, we conducted a retrospective ecological cohort study in Uganda, Malawi, Democratic Republic of Congo (DRC) and South Sudan to estimate the effect of cattle and pig density on HAT risk.

For rHAT, we found a positive effect for cattle (RR 1.61, 95% CI 0.90, 2.99) and pigs (RR 2.07, 95% CI 1.15, 2.75) in Uganda, and a negative effect for cattle (RR 0.88, 95% CI 0.71, 1.10) and pigs (RR 0.42, 95% CI 0.23, 0.67) in Malawi. For gHAT we found a negative effect for cattle in Uganda (RR 0.88, 95% CI 0.50, 1.77) and South Sudan (RR 0.63, 95% CI 0.54, 0.77) but a positive effect in DRC (1.17, 95% CI 1.04, 1.32). For pigs, we found a positive gHAT effect in both Uganda (RR 2.02, 95% CI 0.87, 3.94) and DRC (RR 1.23, 95% CI 1.10, 1.37), and a negative association in South Sudan (RR 0.66, 95% CI 0.50, 0.98).

While ecological bias may drive the findings in South Sudan, estimated E-values and simulation studies suggest unmeasured confounding and underreporting are unlikely to explain our findings in Malawi, Uganda, and DRC. Our results indicate cattle and pigs are important reservoirs of rHAT in Uganda but not Malawi, and that pigs--and possibly cattle-may be gHAT reservoirs.

Author summaryDomestic animals, including cattle and pigs, are known to be important for the transmission of the rhodesiense form of human African trypanosomiasis (rHAT), however the relative importance of these reservoirs compared to wild animals is uncertain and likely focus-specific. For the gambiense form (gHAT) transmission is predominantly human-to-human, however pigs are thought to be a possible reservoir. In this study we used pre-existing data on livestock density and HAT risk to estimate the strength of the effect of cattle and pig density on rHAT risk in Uganda and Malawi, and gHAT risk in Uganda, Democratic Republic of Congo (DRC), and South Sudan. We found evidence that cattle and pigs increase the risk of rHAT in Uganda but not Malawi, that pigs increase the risk of gHAT in Uganda and DRC, and that cattle increase the risk of gHAT in DRC alone. These results indicate that control of both forms of HAT should include domestic animals in a One Health framework, however control of rHAT in Malawi is unlikely to be achieved if measures exclude wild animals.


title: FAMILY SUPPORT-BASED PSYCHOEDUCATION IN CARING SCHIZOPHRENIC PATIENTS: A LITERATURE REVIEW

abstract:
BackgroundThe burden of family in caring a schizophrenia impacts on psychological shock and emotional burden; lack of disease knowledge and care skills; poor patient medication adherence; the difficulty of getting along with patients; conflict in the family or at work; financial burden; and need adequate social support.

AimThis study discussed how family support takes care of people with schizophrenia with a psychoeducational approach in mental health service settings.

MethodA non-systematic literature review was carried out using the PICO (Population, Intervention, Comparison, Outcome) framework utilizing Scopus, CINAHL, and ProQuest databases in the last 5 years, searching with keywords "Family Support AND Schizophrenia OR Family Psychoeducation".

ResultsFamilies with schizophrenia experience the most potent stressors on the burden of care borne, in addition to stigma and the frequency of relapse of sufferers. Community care providers can involve the family in various ways, such as providing psychoeducation, supporting the familys physical, emotional and social needs, and behavioral family assessment or family therapy.

ConclusionMental health services must develop and imply family psychoeducation training.

category: nursing


title: Price elasticity of demand for new and recurring opioid prescriptions

abstract:
ObjectiveSeveral U.S. states have recently enacted excise taxes to curb prescription opioid use and other states are considering similar measures. We assessed the effects of increasing out-of-pocket costs (OPC) on new and recurring opioid fills.

MethodsWe conducted a retrospective cohort study of opioid-naive individuals presenting with acute back pain using data from a nationwide claims repository. We estimated the effect of OPC on the initiation of opioid treatment in logistic regressions, controlling for socio-demographics, medical history, healthcare utilization, insurance type, and region. With the same covariates plus morphine milligram equivalents and days supplied, we estimated the effect of OPC on the number of opioid fills in negative binomial regressions. We report the price elasticity of demand (PED) for prescription opioids, defined as the percentage change in outcome resulting from a two-fold increase in OPC.

ResultsOf 25,531 adults diagnosed with acute back pain in Q1 of 2018, 2,451 (9.6%) filled at least one opioid prescription. In multivariable regression, the association between OPC and initiating opioid treatment was not significant (PED= -1.9%; 95% CI: -5.5%, 1.7%). However, by region, the PED was -10.3% (95% CI: -18.1%, -2.4%) in the coastal states and 1.6% (95% CI: -2.5%, 5.7%) in the central-southern states. The PED for the number of prescription fills was -3.7% (95% CI: -7.3%, -0.1%), which also differed by region. In the coastal states, the PED was -15.2% (95% CI: -24.7%, -5.7%) and in the central-southern states -1.5% (95% CI: -5.4%, 2.4%).

ConclusionsOpioid fills were price sensitive in the coastal states but not in the central-southern states. Policies that would increase OPC might have a restraining effect on opioid consumption in parts, but not all of the U.S.


title: Associations between multiple long-term conditions and mortality in diverse ethnic groups

abstract:
BackgroundMultiple conditions are more prevalent in some minoritised ethnic groups and are associated with higher mortality rate but studies examining differential mortality once conditions are established is US-based. Our study tested whether the association between multiple conditions and mortality varies across ethnic groups in England.

Methods and FindingsA random sample of primary care patients from Clinical Practice Research Datalink (CPRD) was followed from 1st January 2015 until 31st December 2019. Ethnicity, usually self-ascribed, was obtained from primary care records if present or from hospital records. Cox regression models were used to estimate mortality by number of long-term conditions, ethnicity and their interaction, with adjustment for age and sex for 532,059 patients with complete data.

During five years of follow-up, 5.9% of patients died. Each additional long-term condition at baseline was associated with increased mortality. This association differed across ethnic groups. Compared with 50-year-olds of white ethnicity with no conditions, the mortality rate was higher for white 50-year-olds with two conditions (HR 1.77) or four conditions (HR 3.13). Corresponding figures were higher for 50-year-olds of Black Caribbean ethnicity with two conditions (HR=2.22) or four conditions (HR 4.54). The direction of the interaction of number of conditions with ethnicity showed higher mortality associated with long-term conditions in nine out of ten minoritised ethnic groups, attaining statistical significance in four (Pakistani, Black African, Black Caribbean and Black other ethnic groups).

ConclusionsThe raised mortality rate associated with having multiple conditions is greater in minoritised ethnic groups compared with white people. Research is now needed to identify factors that contribute to these inequalities. Within the health care setting, there may be opportunities to target clinical and self-management support for people with multiple conditions from minoritised ethnic groups.


title: A survey assessing antimicrobial prescribing at UNRWA primary health care centers in Jordan

abstract: Antimicrobial resistance (AMR) is a public health emergency. There is insufficient information on AMR in the context of humanitarian settings. An understanding of behavioural and institutional level factors can strengthen antimicrobial stewardship. This study used a semi-structured questionnaire to assess both knowledge, attitudes and practices (KAP) on antimicrobial use, resistance and stewardship, and options to improving prescribing, among prescribers at the Primary Healthcare facilities of the UNRWA Jordan field office. Responses to the KAP questions were evaluated using the Capability, Opportunity, Motivation, Behaviour (COM-B) framework and Blooms cutoffs. For each framework component, Blooms cutoffs and interpretations were: >80%, "good"; 60-79%, "moderate"; and <60% "poor". Fourteen options to improve prescribing were each assessed using 5-point Likert scales from very unhelpful to very helpful, aggregated by helpful and very helpful and ranked as: >90%, best/most acceptable; >80-90%, as acceptable; and, 70-80% as maybe acceptable/good. The questionnaire response rate was 59% (37/63) with a completion rate of 92% (34/37). Aggregate scores for real knowledge on AMR was 97%; opportunity to improve prescribing 88%; and motivation 16% - participants did not believe that there was a connection between their prescribing and AMR or that they had a key role in helping control AMR. Good options (74% aggregate score) to improving prescribing were the availability of guidelines and resistance data. There was good knowledge of AMR and good opportunities, but poor motivation for rational prescribing or behavioral change. There is a clinical need for antimicrobial resistance data to promote rational antibiotic prescribing.


title: Validation of a clinical and genetic model for predicting severe COVID-19

abstract: Using nested case-control data from the Lifelines COVID-19 cohort, we undertook a validation study of a clinical and genetic model to predict the risk of severe COVID-19 in people with confirmed COVID-19 and in people with confirmed or self-reported COVID-19. The model performed well in terms of discrimination of cases and controls for all ages (area under the receiver operating characteristic curve [AUC] = 0.680 for confirmed COVID-19 and AUC = 0.689 for confirmed and self-reported COVID-19) and in the age group in which the model was developed (50 years and older; AUC = 0.658 for confirmed COVID-19 and AUC= 0.651 for confirmed and self-reported COVID-19). There was no evidence of over- or under-dispersion of risk scores but there was evidence of overall over-estimation of risk in all analyses (all P < 0.0001). In the light of large numbers of people worldwide remaining unvaccinated and continuing uncertainty regarding vaccine efficacy over time and against variants of concern, identification of people at high risk of severe COVID-19 may encourage the uptake of vaccinations (including boosters) and the use of non-pharmaceutical inventions.


title: Generation of novel SARS-CoV-2 variants on B.1.1.7 lineage in three patients with advanced HIV disease

abstract: The emergence of new SARS-COV-2 variants is of public health concern in case of vaccine escape. Described are three patients with advanced HIV-1 and chronic SARS-CoV-2 infection in whom there is evidence of selection and persistence of novel mutations which are associated with increased transmissibility and immune escape.


title: Comparison of Antibody Response Durability of mRNA-1273, BNT162b2, and Ad26.COV2.S SARS-CoV-2 Vaccines in Healthcare Workers

abstract:
ImportanceThere is a dearth of comparative immunologic durability data after COVID-19 vaccinations.

ObjectiveTo compare antibody responses and vaccine effectiveness 8.4 months post-primary COVID-19 vaccination.

DesignSetting and Participants: In this cohort study of 903 healthcare workers who completed surveys about baseline characteristics and COVID-19 vaccine/infection history, 647 had antibody assays completed and were included herein.

ExposureCOVID-19 vaccination with mRNA-1273 (n=387); BNT162b2 (n=212); or Ad26.COV2.S (n=10); unvaccinated (n=10); or boosted (n=28).

Main Outcomes and MeasuresThe primary outcome was IgG anti-spike titer. Secondary/tertiary outcomes included IgG spike receptor-binding domain competitive antibody blocking ELISA pseudoneutralization against the USA-WA1/2020 strain, and vaccine effectiveness against COVID-19 infection. Antibody levels were compared using ANOVA and multiple linear regression.

ResultsMean age was 49.7, 75.3% were female, and mean comorbidities/patient was 0.7. Baseline variables were balanced (p>.05) except for immunosuppression (higher in boosted, p=.047), prior COVID-19 infections (higher with Ad26.COV2.S and unvaccinated, p<.001), and time since primary vaccination (higher with mRNA-1273 and BNT162b2 than Ad26.COV2.S, p<.001).

Unadjusted median (IQR) IgG anti-spike titers (AU/mL) were 1539.5 (876.7-2626.7) for mRNA-1273, 751.2 (422.0-1381.5) for BNT162b2, 451.6 (103.0-2396.7) for Ad26.COV2.S, 113.4 (3.7-194.0) for unvaccinated, and 31898.8 (21347.1-45820.1) for boosted (mRNA-1273 vs. BNT162b2, p<.001; mRNA-1273, BNT162b2, or boosted vs. unvaccinated, p<.006; mRNA-1273, BNT162b2, Ad26.COV2.S, or unvaccinated vs. boosted, p<.001; all other comparisons, p>.05). Unadjusted median (IQR) pseudoneutralization percentages were 90.9% (80.1-95.0) for mRNA-1273, 77.2% (59.1-89.9) for BNT162b2, 57.9% (36.6-95.8) for Ad26.COV2.S, 40.1% (21.7-60.6) for unvaccinated, and 96.4% (96.1-96.6) for boosted (mRNA-1273 vs. BNT162b2, p<.001; mRNA-1273, BNT162b2, or boosted vs. unvaccinated, p<.028; mRNA-1273, BNT162b2, Ad26.COV2.S, or unvaccinated vs. boosted, p<.001; all other comparisons, p>.05). Adjusted anti-spike and pseudoneutralization comparisons of mRNA-1273 and BNT162b2 showed similar patterns (p<.001). Vaccine effectiveness was 87-89% for mRNA-1273, BNT162b2, and boosted, and 33% for Ad26.COV2.S; no group differences were statistically significant.

Conclusions and RelevanceDurability of antibody responses 8.4 months after COVID-19 primary vaccination was significantly higher with mRNA-1273 than with BNT162b2, however, vaccine effectiveness was equivalent. Antibody responses and vaccine effectiveness were lower but not significantly different for Ad26.COV2.S; given statistical uncertainty in the small Ad26.COV2.S group, clinically important effects cannot be excluded.


title: COVID MED - An Early Pandemic Trial of Losartan for Hospitalized COVID-19 Patients

abstract:
BackgroundACEi/ARB medications have been hypothesized to have potential benefit in COVID-19. Despite concern for increased ACE-2 expression in some animal models, preclinical and observational-retrospective and uncontrolled trials suggested possible benefit. Two RCTs of the ARB losartan from University of Minnesota showed no benefit yet safety signals for losartan in outpatient and hospitalized COVID-19 patients. COVID MED, started early in the pandemic, also assessed losartan in a RCT in hospitalized patients with COVID-19.

MethodsCOVID MED was a double-blinded, placebo-controlled, multicenter, platform randomized clinical trial (RCT). Hospitalized COVID-19 patients were randomized to receive standard care and hydroxychloroquine, lopinavir/ritonavir, losartan, or placebo. Hydroxychloroquine and lopinavir/ritonavir arms were discontinued after RCTs showed no benefit. We report data from the losartan arm compared to combined (lopinavir-ritonavir and placebo) and prespecified placebo-only controls. The primary endpoint, the mean COVID-19 Ordinal Severity Score (COSS) slope of change, was compared with the Students t-test. Slow enrollment prompted early termination.

ResultsOf 448 screened patients, 15 (3.5%) were randomized/enrolled, 9 to receive losartan and 6 to receive control (lopinavir/ritonavir [N=2], placebo [N=4]); 1 patient who withdrew prior to study drug was excluded yielding 14 patients for analysis (losartan [N=9] vs. control [N=5] [lopinavir/ritonavir [N=2], placebo [N=3]]). Most baseline parameters were balanced. Treatment with losartan was not associated with a difference in mean COSS slope of change in comparison with combined control (p=0.4) or placebo-only control (p=0.05) (trend favoring placebo). 60-day mortality and overall AE and SAE rates were numerically but not significantly higher with losartan.

ConclusionsIn this small blinded RCT in hospitalized COVID-19 patients, losartan did not improve outcome vs. control comparisons and was associated with adverse safety signals.


title: COVID MED - An Early Pandemic Randomized Clinical Trial of Losartan for Hospitalized COVID-19 Patients


title: The Chinese Assessment of physical literacy: Based on Grounded Theory Paradigm for children in grades 3-6

abstract: The aim of this study is to construct and validate "physical literacy self-assessment questionnaire"(PLAQ)for Chinese students in grades 3-6. This study uses qualitative and quantitative methods to construct evaluation indicators of PL and determine the weights of each indicator. The 60 items of original PLAQ was based on literature review and interviews,and administered to 1179 primary students graded 3-6 in China. Exploratory factor analysis(EFA)and confirmatory factor analysis(CFA) are used to optimize the structure and verify the reliability and validity of the questionnaire. The model of PLAQ is composed of 4 first-level indicators, 10 second-level indicators and 35 third-level indicators. The results of EFA and CFA resulted in a 44-items, 4-factor questionnaire. EFA item loadings ranged from 0.558 to 0.896,and Cronbachs alpha ranged from 0.818 to 0.892. The results of CFA show that the constructed model fits well, and PLAQ has good convergent validity and discriminative validity. The PLAQ appeared to be reliable and valid that can be used as an assessment tool for students in grades 3-6. PLAQ can be used as a guide for the development of PL. Additionally, PLAQ gives us a shared understanding about what PL is and how it can be developed by Chinese children. However, studies on the accuracy and generalizability of the PLAQ should be conducted to improve it in the future.

category: sports medicine


title: A deep learning model for breast ductal carcinoma in situ classification in whole slide images

abstract: The pathological differential diagnosis between breast ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) is of pivotal importance for determining optimum cancer treatment(s) and clinical outcomes. Since conventional diagnosis by pathologists using micro-scopes is limited in terms of human resources, it is necessary to develop new techniques that can rapidly and accurately diagnose large numbers of histopathological specimens. Computational pathology tools which can assist pathologists in detecting and classifying DCIS and IDC from whole slide images (WSIs) would be of great benefit for routine pathological diagnosis. In this paper, we trained deep learning models capable of classifying biopsy and surgical histopathological WSIs into DCIS, IDC, and benign. We evaluated the models on two independent test sets (n=1,382, n=548), achieving ROC areas under the curves (AUCs) up to 0.960 and 0.977 for DCIS and IDC, respectively.

category: pathology


title: Cerebrospinal fluid neurofilament light chain differentiates behavioural variant frontotemporal dementia progressors from phenocopy non-progressors

abstract:
BackgroundDistinguishing behavioural variant frontotemporal dementia (bvFTD) from non-neurodegenerative  non-progressor,  phenocopy mimics of frontal lobe dysfunction, can be one of the most challenging clinical dilemmas. A biomarker of neuronal injury, neurofilament light chain (NfL), could reduce misdiagnosis and delay.

MethodsCerebrospinal fluid (CSF) NfL, amyloid beta 1-42 (AB42), total and phosphorylated tau (T-tau, P-tau) levels were examined in patients with an initial diagnosis of bvFTD. Based on follow up information, patients were categorised as Progressors. Non-Progressors were subtyped in to Phenocopy Non-Progressors (non-neurological/neurodegenerative final diagnosis), and Static Non-Progressors (static deficits, not fully explained by non-neurological/neurodegenerative causes).

ResultsForty-three patients were included: 20 Progressors, 23 Non-Progressors (15 Phenocopy, 8 Static), 20 controls. NfL concentrations were lower in Non-Progressors (Non-Progressors Mean, M=554pg/mL, 95%CI:[461, 675], Phenocopy Non-Progressors M=459pg/mL, 95%CI:[385, 539], Static Non-Progressors M=730pg/mL, 95%CI:[516, 940]), compared to bvFTD Progressors (M=2397pg/mL, 95%CI:[1607, 3332]). NfL distinguished Progressors from Non-Progressors with the highest accuracy (area under the curve 0.92, 90%/87% sensitivity/specificity, 86%/91% positive/negative predictive value, 88% accuracy). Static Non-Progressors tended to have higher T-tau and P-tau levels compared to Phenocopy Non-Progressors.

ConclusionThis study demonstrated strong diagnostic utility of CSF NfL to distinguish bvFTD from phenocopy non-progressor variants, at baseline, with high accuracy, in a real-world clinical setting. This has important clinical implications, to improve outcomes for patients and clinicians facing this challenging clinical dilemma, as well as for healthcare services, and clinical trials. Further research is required to investigate heterogeneity within the non-progressor group and potential diagnostic algorithms, and prospective studies are underway assessing plasma NfL


title: The effect of hand hygiene intervention on the knowledge and skills level of school children: A Literature Review

abstract: BackgroundHand washing is an alternative, effective and inexpensive method that can be used to prevent infectious diseases. Washing hands with soap can improve childrens health. The purpose of this study was to determine the effect of hand hygiene intervention on the level of knowledge and skills of elementary school students. The method used to conduct this research is a critical review, namely by reviewing articles from databases such as Google Scholar, Pubmed, Direct, Medline. The search keywords used were: quantitative studies on delivery, intervention, hand hygiene, skills, children, and primary school. The selected articles are articles that meet the standard writing criteria, which were published between 2017-2021, both in English and Indonesian. Based on these evaluation criteria, 20 (twenty) studies were obtained. From the results of a literature search, several studies on the use of intervention strategies to provide hand hygiene health education found that although there were other intervention strategies to improve hand hygiene, there were significant differences in both knowledge and skills after being given the intervention.


title: Genome-wide Analysis Reflects Novel 5-Hydroxymethylcytosines Implicated in Diabetic Nephropathy

abstract: Long-term complications of type 2 diabetes (T2D) are the major causes for T2D-related disability and mortality. Notably, diabetic nephropathy (DN) has become the most frequent cause of end-stage renal disease (ESRD) in most countries. Understanding epigenetic contributors to DN can provide novel insights into this complex disorder and lay the foundation for more effective monitoring tools and preventive interventions, critical for achieving the ultimate goal of improving patient care and reducing healthcare burden. We have used a selective chemical labeling technique (5hmC-Seal) to profile genome-wide distributions of 5-hydroxymethylcytosines (5hmC), a gene activation mark, in patient-derived circulating cell-free DNA (cfDNA). Differentially modified 5hmC genes were identified across T2D patients with DN (n = 12), T2D patients with non-DN vascular complications (non-DN) (n = 29), and T2D patients with no complications (controls) (n = 14). Specifically, differential 5hmC markers between DN and controls revealed relevant pathways such as NOD-like receptor signaling pathway and tyrosine metabolism. A ten-gene panel was shown to provide differential 5hmC patterns between controls and DN, as well as between controls and non-DN patients using a machine learning approach. The 5hmC profiles in cfDNA reflected novel DN-associated epigenetic modifications relevant to the disease pathogenesis of DN. Importantly, these findings in cfDNA, a convenient liquid biopsy, have the potential to be exploited as a clinically useful tool for predicting DN in high risk T2D patients.


title: Improved prediction of new COVID-19 cases using a simple vector autoregressive model: Evidence from seven New York State counties

abstract: With the rapid spread of COVID-19, there is an urgent need for a framework to accurately predict COVID-19 transmission. Recent epidemiological studies have found that a prominent feature of COVID-19 is its ability to be transmitted before symptoms occur, which is generally not the case for seasonal influenza and SARS. Several COVID-19 predictive epidemiological models have been proposed; however, they share a common drawback--they are unable to capture the unique asymptomatic nature of COVID-19 transmission. Here, we propose vector autoregression (VAR) as an epidemiological county-level prediction model that captures this unique aspect of COVID-19 transmission by introducing newly infected cases in other counties as lagged explanatory variables. Using the number of new COVID-19 cases in seven New York State counties, we predicted new COVID-19 cases in the counties over the next 4 weeks. We then compared our prediction results with those of 11 other state-of-the-art prediction models proposed by leading research institutes and academic groups. The results showed that VAR prediction is superior to other epidemiological prediction models in terms of the root mean square error of prediction. Thus, we strongly recommend the simple VAR model as a framework to accurately predict COVID-19 transmission.


title: Estimating body fat distribution - a driver of cardiometabolic health - from silhouette images

abstract:
BackgroundInter-individual variation in fat distribution is increasingly recognized as clinically important but is not routinely assessed in clinical practice because quantification requires medical imaging.

ObjectivesWe hypothesized that a deep learning model trained on an individuals body shape outline - or "silhouette" - would enable accurate estimation of specific fat depots, including visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) adipose tissue volumes, and VAT/ASAT ratio. We additionally set out to study whether silhouette-estimated VAT/ASAT ratio may stratify risk of cardiometabolic diseases independent of body mass index (BMI) and waist circumference.

MethodsTwo-dimensional coronal and sagittal silhouettes were constructed from whole-body magnetic resonance images in 40,032 participants of the UK Biobank and used to train a convolutional neural network to predict VAT, ASAT, and GFAT volumes, and VAT/ASAT ratio. Logistic and Cox regressions were used to determine the independent association of silhouette-predicted VAT/ASAT ratio with type 2 diabetes and coronary artery disease.

ResultsMean age of the study participants was 65 years and 51% were female. A deep learning model trained on silhouettes enabled accurate estimation of VAT, ASAT, and GFAT volumes (R2: 0.88, 0.93, and 0.93, respectively), outperforming a comparator model combining anthropometric and bioimpedance measures ({Delta}R2 = 0.05-0.13). Next, we studied VAT/ASAT ratio, a nearly BMI- and waist circumference-independent marker of unhealthy fat distribution. While the comparator model poorly predicted VAT/ASAT ratio (R2: 0.17-0.26), a silhouette-based model enabled significant improvement (R2: 0.50-0.55). Silhouette-predicted VAT/ASAT ratio was associated with increased prevalence of type 2 diabetes and coronary artery disease.

ConclusionsBody silhouette images can estimate important measures of fat distribution, laying the scientific foundation for population-based assessment.

category: endocrinology


title: Implementation of a Rapid RT-LAMP Saliva-based SARS-CoV-2 Testing Program in the Workplace

abstract: Rising SARS-CoV-2 cases, testing delays and the risk of pre-symptomatic and asymptomatic transmission provided the impetus for an in-house rapid testing program. Employees and their household contacts were encouraged to self-collect saliva samples which were pooled for routine testing using an established colorimetric reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay. In brief, individual or a maximum of four saliva samples were pooled, heat-inactivated to render microorganisms, especially SARS-CoV-2, non-infectious prior to being added to RT-LAMP assay tubes containing either human sample control gene, RNase P or a region of the SARS-CoV-2 gene, ORF1ab. During the second wave of SARS-CoV-2 infections in November 2020, two samples from an employee and a member of their household tested positive via RT-LAMP within two days of each other. A delayed clinical qRT-PCR test confirmation of both individuals 5 days later underscores the power of routine rapid testing with with-in-the-hour turnaround times. Workplace rapid testing programs using RT-LAMP are flexible in their design, have a reduced cost compared to qRT-PCR, may involve non-invasive self-saliva collection for increased safety for the testing personnel, and can be performed with minimal training.


title: Characterizing the Progression of Pulmonary Edema Severity: Can Pairwise Comparisons in Radiology Reports Help?

abstract: Accurately assessing the severity of pulmonary edema is critical for making treatment decisions in congestive heart failure patients. However, the current scale for quantifying pulmonary edema based on chest radiographs does not have well-characterized severity levels, with substantial inter-radiologist disagreement. In this study, we investigate whether comparisons documented in radiology reports can provide accurate characterizations of pulmonary edema progression. We propose a rules-based natural language processing approach to assess the change in a patients pulmonary edema status (e.g. better, worse, no change) by performing pairwise comparisons of consecutive radiology reports, using regular expressions and heuristics derived from clinical knowledge. Evaluated against ground-truth labels from expert radiologists, our labeler extracts comparisons describing the progression of pulmonary edema with 0.875 precision and 0.891 recall. We also demonstrate the potential utility of comparison labels in providing additional fine-grained information over noisier labels produced by models that directly estimate severity level.


title: Frequency of Hematologic and Solid Malignancies in the Family History of Patients with Myeloid Neoplasms

abstract:
BackgroundStudies demonstrated that there are several germline mutations that lead to a familial predisposition for acute myeloid leukemia and Myelodysplastic syndrome. According to the American Society of Clinical Oncology ,the minimum cancer family history was defined as including first- and second-degree family history, type of primary cancer, and age at diagnosis.

The current study aimed to estimate the frequency of positive family history for hematologic and solid malignancies in patients with Myeloid Neoplasms / Aplastic anemia.

Patients and MethodsA cross section study was carried out at the Center of Blood Diseases, Medical City Campus during the period from March-December 2020. A purposeful sample of all adult patients with Myeloid Neoplasms [Acute Myeloid Leukemia, Myelodysplastic Syndrome, Chronic Myeloid Leukemia and Aplastic Anemia] were included in the study. A data collection form was prepared, based on the Hereditary Hematopoietic Malignancies Screening form adopted by the University of Chicago, and modified by the researchers; The data were collected by direct interview with the patients. Patients with hematologic malignancy and one or more first-degree relatives, or [≥]2 second-degree relatives, with hematologic malignancies and individuals with Myelodysplastic Syndrome or Acute Myeloid Leukemia and two first or second-degree relatives with a diagnosis of solid tumor malignancy were considered potential carriers of such genetic predisposition.

ResultsA total of 153 patients were included; males were nearly equal to females with a male to female ratio of nearly 1:1. Acute Myeloid Leukemia was found in 57.5%, Aplastic Anemia was found in 19%, Chronic Myeloid Leukemia in 17% and only four patients (6.5%) were known cases of Myelodysplastic Syndrome. Nine patients (5.9%) reported family history of hematological malignancies, 29 (19.0%) reported family history of solid malignancies and only one patient reported family history of both hematological and solid malignancies.

Regarding the official medical reports of the patients, no patient had been interviewed properly about this crucial point.

ConclusionPositive family history for hematological and solid malignancies in Iraqi patients with myeloid neoplasms is prevalent. Our current approach to this critical issue in Iraq needs to be re-considered.

category: hematology


title: Resilient T cell responses to B.1.1.529 (Omicron) SARS-CoV-2 variant

abstract: Emergence of the SARS-CoV-2 variant-of-concern (VOC) B.1.1.529 (Omicron) in late 2021 has raised alarm among scientific and health care communities due to a surprisingly large number of mutations in its spike protein. Public health surveillance indicates that the Omicron variant is significantly more contagious than the previously dominant VOC, B.1.617.2 (Delta). Several early reports demonstrated that Omicron exhibits a higher degree ([~]10-30-fold) of escape from antibody neutralization compared to earlier lineage variants. Therefore, it is critical to determine how well the second line of adaptive immunity, T cell memory, performs against Omicron in people following COVID-19 infection and/or vaccination. To that purpose, we analyzed a cohort (n=345 subjects) of two-or three-dose messenger RNA (mRNA) vaccine recipients and COVID-19 post infection subjects (including those receiving 2 doses of mRNA vaccine after infection), recruited to the CDC-sponsored AZ HEROES research study, alongside 32 pre-pandemic control samples. We report that T cell responses against Omicron spike peptides were largely preserved in all cohorts with established immune memory. IFN-{gamma} producing T cell responses remained equivalent to the response against the ancestral strain (WA1/2020), with some (<20%) loss in IL-2 single-or IL-2+IFN{gamma}+ poly-functional responses. Three-dose vaccinated participants had similar responses to Omicron relative to convalescent or convalescent plus two-dose vaccinated groups and exhibited responses significantly higher than those receiving two mRNA vaccine doses. These results provide further evidence that a three-dose vaccine regimen benefits the induction of optimal functional T cell immune memory.


title: Using Mobile Phone-based Text Message to Recruit Representative Samples: Assessment of a Cross-Sectional Survey about the COVID-19 Vaccine Hesitation.

abstract:
BackgroundLimited research has examined mobile phone-based platforms for survey recruitment, especially during the COVID-19 pandemic in Brazil. Our objective was to investigate the feasibility and representativeness of mobile phone-based advertisement during a preliminary study about COVID-19 vaccine hesitation in Brazil. Moreover, we evaluate whether the older population can be reached through mobile phone-based platforms of the survey.

MethodsWe conducted a study in December 2021 based on a preliminary survey about the COVID-19 vaccine hesitation in Assis, Brazil, Sao Paulo state. From a list of the adult population hesitant for the second dose of the COVID-19 vaccine, we sent a mobile phone-based advertisement inviting the participants to answer the survey for one week. The respondents data were collected in a Google form platform. The comparison between the target population and the respondents was made using the Chi-squared test and the Welchs test, using a P-value of .05 as significative.

ResultsThe response rate was 9.99% after one week. The mean age of the respondent group was 33.97 (SD 14.99) and 35.05 (SD 14.19) of the population, with a P-value of .192 and a Cohens d coefficient of 0.0754, corresponding to a small effect size between groups. We demonstrate that the mobile phone-based survey is a feasible and representative strategy during the pandemics in Brazil. Moreover, the older population respondent was representative.

ConclusionWe achieved a representative sample of respondents using the mobile phone-based survey in Brazil. Furthermore, it was representative in all sociodemographic and health characteristics assessed. Finally, these findings suggest the method is a highly feasible and economical means of recruiting for survey research.


title: Background incidence rates of adverse events of special interest related to COVID-19 vaccines in Ontario, Canada, 2015 to 2020, to inform COVID-19 vaccine safety surveillance

abstract:
BackgroundBackground incidence rates are critical in pharmacovigilance to facilitate identification of vaccine safety signals. We estimated background incidence rates of nine adverse events of special interest related to COVID-19 vaccines in Ontario, Canada.

MethodsWe conducted a population-based retrospective observational study using linked health administrative databases for hospitalizations and emergency department visits among Ontario residents. We estimated incidence rates of Bells palsy, idiopathic thrombocytopenia, febrile convulsions, acute disseminated encephalomyelitis, myocarditis, pericarditis, Kawasaki disease, Guillain-Barre syndrome, and transverse myelitis during five pre-pandemic years (2015- 2019) and 2020.

ResultsThe average annual population was 14 million across all age groups with 51% female. The pre-pandemic mean annual rates per 100,000 population during 2015-2019 were 43.9 for idiopathic thrombocytopenia, 27.8 for Bells palsy, 25.0 for febrile convulsions, 22.8 for acute disseminated encephalomyelitis, 11.3 for myocarditis/pericarditis, 8.6 for pericarditis, 2.9 for myocarditis, 1.9 for Guillain-Barre syndrome, 1.7 for transverse myelitis, and 1.6 for Kawasaki disease. Females had higher rates of acute disseminated encephalomyelitis and transverse myelitis while males had higher rates of myocarditis, pericarditis, and Guillain-Barre syndrome. Bells palsy, acute disseminated encephalomyelitis, and Guillain-Barre syndrome increased with age. The mean rates of myocarditis and/or pericarditis increased with age up to 79 years; males had higher rates than females: from 12-59 years for myocarditis and [≥]12 years for pericarditis. Febrile convulsions and Kawasaki disease were predominantly childhood diseases and generally decreased with age.

ConclusionsOur estimated background rates will permit estimating numbers of expected events for these conditions and facilitate detection of potential safety signals following COVID-19 vaccination.


title: Prevalence and determinants of oral and cervicogenital HPV infection: baseline analysis of the MHOC cohort study

abstract: We determined baseline oral and cervicogenital human papillomavirus (HPV) prevalence and determinants of infection in the Michigan HPV and Oropharyngeal Cancer (MHOC) study. We enrolled 394 college-age and older-adult participants of both sexes in Ann Arbor, Michigan and the surrounding area. All participants provided an oral sample at baseline, and 130 females provided a cervicogenital sample. Samples were tested for 18 HPV genotypes using polymerase chain reaction (PCR) MassArray. Participants filled out sociodemographic and behavioral questionnaires. Prevalence ratios for HPV oral or cervicogenital prevalence by predictor variables were estimated in univariable log-binomial models. Analysis was conducted 2018-20. In the full cohort, baseline oral HPV prevalence was 10.0% for any detected genotype (among the 338 valid oral tests at baseline) and 6.5% for high-risk types, and cervicogenital prevalence was 20.0% and 10.8%, respectively (among the 130 first valid cervicogenital tests). Oral HPV prevalence did not vary by sex, with 10.5% of women and 9.0% of men having an infection. We found a high prevalence of oral and cervicogenital HPV infection among those reporting no recent sexual partners compared to those with a single recent sexual partner, but prevalence increased with the number of recent partners for most sexual behaviors. We observed an ecological fallacy masking the direction of impact of vaccination on HPV prevalence in the full cohort compared to the college-aged and older-adult populations considered separately. Substance use was not significantly associated with oral or cervicogenital HPV infection. Many studies report substantially higher oral HPV infection prevalence in men than in women. That difference may not be uniform across populations in the US.


title: JOINT CONTRIBUTION OF MARKERS OF NEURODEGENERATION AND HYPERCHOLESTEROLEMIA TO DEMENTIA RISK

abstract:
BackgroundThe examination of markers of neurodegeneration (glial fibrillary acidic protein; GFAP, neurofilament light chain; NfL, phosphorylated tau181; p-tau181) among individuals with high comorbidity of neurodegenerative and cerebrovascular disease and their interplay with vascular risk factors, particularly high cholesterol levels, might contribute to explaining the link between body and brain. The aim of this study was to assess whether the association of GFAP, NfL, and p-tau181 with dementia risk varies depending on levels of total cholesterol (TC) and APOE {varepsilon}4 genotype.

MethodsNested case-control study embedded within a population-based cohort and including 768 older adults (261 dementia cases and 508 randomly selected controls) followed for up to 17 years with regard to clinical diagnosis of various age-related diseases. GFAP, NfL, and p-tau181 were measured in baseline blood samples using the Single-Molecule Array (Simoa) Technology (Quanterix, USA) and categorized into high (quartile 4) versus low (quartiles 1-3). Logistic regression analyses and spline regression models for dose-response analyses were used. ROC curves by cholesterol levels were also calculated.

ResultsThe risk of a dementia diagnosis was significantly increased between participants with high vs. low levels of GFAP and NfL and the risk substantially varied by TC levels. For GFAP and NfL the ORs of a dementia diagnosis were 5.10 (2.45-10.60) and 2.96 (1.43-6.14) in participants with high and 2.44 (1.47-4.07) and 1.15 (0.69-1.92) in those with low TC. APOE {varepsilon}4 genotype further modified the strength of the associations with different patterns, depending on specific marker and type of dementia. No significant association was seen with p-tau181.

ConclusionsThese results suggest that in the general population blood GFAP and NfL are better predictors of dementia than p-tau181 and that their associations with dementia risk are highly amplified by hypercholesterolemia, also depending on APOE {varepsilon}4 genotype.

category: neurology


title: Cell-type-specific transcriptome architecture underlying the establishment and exacerbation of systemic lupus erythematosus

abstract: Systemic lupus erythematosus (SLE) is a complex and heterogeneous autoimmune disease involving multiple immune cells. A major hurdle to the elucidation of SLE pathogenesis is our limited understanding of dysregulated gene expression linked to various clinical statuses with a high cellular resolution. Here, we conducted a large-scale transcriptome study with 6,386 RNA sequencing data covering 27 immune cell types from 159 SLE and 89 healthy donors. We first profiled two distinct cell-type-specific transcriptomic signatures: disease-state and disease-activity signatures, reflecting disease establishment and exacerbation, respectively. We next identified candidate biological processes unique to each signature. This study suggested the clinical value of disease-activity signatures, which were associated with organ involvement and responses to therapeutic agents such as belimumab. However, disease-activity signatures were less enriched around SLE risk variants than disease-state signatures, suggesting that the genetic studies to date may not well capture clinically vital biology in SLE. Together, we identified comprehensive gene signatures of SLE, which will provide essential foundations for future genomic, genetic, and clinical studies.

category: genetic and genomic medicine


title: Forecast of omicron wave time evolution

abstract: Adopting an early doubling time of three days for the rate of new infections with the omicron mutant the temporal evolution of the omicron wave in different countries is predicted. The predictions are based on the susceptible-infectious-recovered/removed (SIR) epidemic compartment model with a constant stationary ratio k = (t)/a(t) between the infection (a(t)) and recovery ((t)) rate. The fixed early doubling time then uniquely relates the initial infection rate a0 to the ratio k, which therefore determines the full temporal evolution of the omicron waves. For each country three scenarios (optimistic, pessimistic, intermediate) are considered and the resulting pandemic parameters are calculated. These include the total number of infected persons, the maximum rate of new infections, the peak time and the maximum 7-day incidence per 100000 persons. Among the considered European countries Denmark has the smallest omicron peak time and the recently observed saturation of the 7-day incidence value at 2478 is in excellent agreement with the prediction in the optimistic scenario. For Germany we predict peak times of the omicron wave ranging from 32 to 38 and 45 days after the start of the omicron wave in the optimistic, intermediate and pessimistic scenario, respectively, with corresponding maximum SDI values of 7090, 13263 and 28911, respectively. Adopting Jan 1st, 2022 as the starting date our predictions implies that the maximum of the omicron wave is reached between Feb 1 and Feb 15, 2022. Rather similar values are predicted for Switzerland. Due to an order of magnitude smaller omicron hospitalization rate, due to the high percentage of vaccinated and boostered population, the German health system can cope with maximum omicron SDI value of 2800 which is about a factor 2.5 smaller than the maximum omicron SDI value 7090 in the optimistic case. By either reducing the duration of intensive care during this period of maximum, and/or by making use of the nonuniform spread of the omicron wave across Germany, it seems that the German health system can barely cope with the omicron wave avoiding triage decisions. The reduced omicron hospitalization rate also causes significantly smaller mortality rates compared to the earlier mutants in Germany. In the optimistic scenario one obtains for the total number of fatalities 7445 and for the maximum death rate 418 per day which are about one order of magnitude smaller than the beta fatality rate and total number.