title: Longitudinal SARS-CoV-2 seroprevalence in a rural and urban community household cohort in South Africa, during the first and second waves July 2020-March 2021

abstract:
BackgroundSARS-CoV-2 infections may be underestimated due to limited testing access, particularly in sub-Saharan Africa. South Africa experienced two SARS-CoV-2 waves, the second associated with emergence of variant 501Y.V2. In this study, we report longitudinal SARS-CoV-2 seroprevalence in cohorts in two communities in South Africa.

MethodsWe measured SARS-CoV-2 seroprevalence two monthly in randomly selected household cohorts in a rural and an urban community (July 2020-March 2021). We compared seroprevalence to laboratory-confirmed infections, hospitalisations and deaths reported in the districts to calculate infection-case (ICR), infection-hospitalisation (IHR) and infection-fatality ratio (IFR) in the two waves of infection.

FindingsSeroprevalence after the second wave ranged from 18% (95%CrI 10-26%) and 28% (95%CrI 17-41%) in children <5 years to 37% (95%CrI 28-47%) in adults aged 19-34 years and 59% (95%CrI 49-68%) in adults aged 35-59 years in the rural and urban community respectively. Individuals infected in the second wave were more likely to be from the rural site (aOR 4.7, 95%CI 2.9-7.6), and 5-12 years (aOR 2.1, 95%CI 1.1-4.2) or [≥]60 years (aOR 2.8, 95%CI 1.1-7.0), compared to 35-59 years. The in-hospital IFR in the urban site was significantly increased in the second wave 0.36% (95%CI 0.28-0.57%) compared to the first wave 0.17% (95%CI 0.15-0.20%). ICR ranged from 3.69% (95%CI 2.59-6.40%) in second wave at urban community, to 5.55% (95%CI 3.40-11.23%) in first wave in rural community.

InterpretationThe second wave was associated with a shift in age distribution of cases from individuals aged to 35-59 to individuals at the extremes of age, higher attack rates in the rural community and a higher IFR in the urban community. Approximately 95% of SARS-CoV-2 infections in these two communities were not reported to the national surveillance system, which has implications for contact tracing and infection containment.

FundingUS Centers for Disease Control and Prevention

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSeroprevalence studies provide better estimates of SARS-CoV-2 burden than laboratory-confirmed cases because many infections may be missed due to restricted access to care and testing, or differences in disease severity and health-care seeking behaviour. This underestimation may be amplified in African countries, where testing access may be limited. Seroprevalence data from sub-Saharan Africa are limited, and comparing seroprevalence estimates between countries can be challenging because populations studied and timing of the study relative to country-specific epidemics differs. During the first wave of infections in each country, seroprevalence was estimated at 4% in Kenya and 11% in Zambia. Seroprevalence estimates in South African blood donors is estimated to range between 32% to 63%. South Africa has experienced two waves of infection, with the emergence of the B.1.351/501Y.V2 variant of concern after the first wave. Reported SARS-CoV-2 cases may not be a true reflection of SARS-CoV-2 burden and specifically the differential impact of the first and second waves of infection.

Added value of this studyWe collected longitudinal blood samples from prospectively followed rural and urban communities, randomly selected, household cohorts in South Africa between July 2020 and March 2021. From 668 and 598 individuals included from the rural and urban communities, respectively, seroprevalence was found to be 7% (95%CrI 5-9%) and 27% (95%CrI 23-31%), after the first wave of infection, and 26% (95%CrI 22-29%) and 41% (95%CrI 37-45%) after the second wave, in rural and urban study districts, respectively. After standardising for age, we estimated that only 5% of SARS-CoV-2 infections were laboratory-confirmed and reported. Infection-hospitalisation ratios in the urban community were higher in the first (2.01%, 95%CI 1.57-2.57%) and second (2.29%, 95%CI 1.63-3.94%) wave than the rural community where there was a 0.75% (95%CI 0.49-1.41%) and 0.66% (95%CI 0.50-0.98%) infection-hospitalisation ratio in the first and second wave, respectively.

When comparing the infection fatality ratios for the first and second SARS-CoV-2 waves, at the urban site, the ratios for both in-hospital and excess deaths to cases were significantly higher in the second wave (0.36%, 95%CI 0.28-0.57% in-hospital and 0.51%, 95%CI 0.34-0.93% excess deaths), compared to the first wave in-hospital (0.17%, 95%CI 0.15-0.20%) and excess (0.13%, 95%CI 0.10-0.17%) fatality ratios, p<0.001 and p<0.001, respectively). In the rural community, the point estimates for infection-fatality ratios also increased in the second wave compared to the first wave for in-hospital deaths, 0.13% (95%CI 0.10-0.23%) first wave vs 0.20% (95%CI 0.13%-0.28%) second wave, and excess deaths (0.51%, 95%CI 0.30-1.06% vs 0.70%, 95%CI 0.49-1.12%), although neither change was statistically significant.

Implications of all the available evidenceIn South Africa, the overall prevalence of SARS-CoV-2 infections is substantially underestimated, resulting in many cases being undiagnosed and without the necessary public health action to isolate and trace contacts to prevent further transmission. There were more infections during the first wave in the urban community, and the second wave in the rural community. Although there were less infections during the second wave in the urban community, the infection-fatality ratios were significantly higher compared to the first wave. The lower infection-hospitalisation ratio and higher excess infection-fatality ratio in the rural community likely reflect differences in access to care or prevalence of risk factors for progression to severe disease in these two communities. In-hospital infection-fatality ratios for both communities during the first wave were comparable with what was experienced during the first wave in India (0.15%) for SARS-CoV-2 confirmed deaths. To our knowledge, these are the first longitudinal seroprevalence data from a sub-Saharan Africa cohort, and provide a more accurate understanding of the pandemic, allowing for serial comparisons of antibody responses in relation to reported laboratory-confirmed SARS-CoV-2 infections within diverse communities.

category: public and global health


title: Cellular and humoral immunogenicity of a SARS-CoV-2 mRNA vaccine in patients on hemodialysis

abstract:
BackgroundPatients with chronic renal insufficiency on intermittent hemodialysis face an increased risk of COVID-19 induced mortality and impaired vaccine responses. To date, only few studies addressed SARS-CoV-2 vaccine elicited immunity in this immunocompromised population.

MethodsWe assessed immunogenicity of the mRNA vaccine BNT162b2 in at risk dialysis patients and characterized systemic cellular and humoral immune responses in serum and saliva using interferon {gamma} release assay and multiplex-based cytokine and immunoglobulin measurements. We further compared binding capacity and neutralization efficacy of vaccination-induced immunoglobulins against emerging SARS-CoV-2 variants of concern B.1.1.7, B.1.351, B.1.429 and Cluster 5 by ACE2-RBD competition assay.

FindingsPatients on intermittent hemodialysis exhibit detectable but variable cellular and humoral immune responses against SARS-CoV-2 and variants of concern after a two-dose regimen of BNT162b2. Although vaccination-induced immunoglobulins were detectable in saliva and plasma, both anti-SARS-CoV-2 IgG and neutralization efficacy was reduced compared to controls. Similarly, T-cell mediated interferon {gamma} release after stimulation with SARS-CoV-2 spike peptides was significantly diminished.

InterpretationQuantifiable humoral and cellular immune responses after BNT162b2 vaccination in individuals on intermittent dialysis are encouraging, but urge for longitudinal follow-up to assess longevity of immunity. Diminished virus neutralization and interferon {gamma} responses in face of emerging variants of concern may favor this at risk population for re-vaccination using modified vaccines at the earliest opportunity.

FundingInitiative and Networking Fund of the Helmholtz Association of German Research Centers, EU Horizon 2020 research and innovation program, State Ministry of Baden-Wurttemberg for Economic Affairs, Labor and Tourism.

Research in the contextO_ST_ABSEvidence before this studyC_ST_ABSPatients on dialysis tend to have a reduced immune response to both infection and vaccination. We searched PubMed and MedRxiv for studies including search terms such as "COVID-19", "vaccine", and "dialysis" but no peer-reviewed studies to date assessed both SARS-CoV-2 specific B- and T-cell responses, mucosal immunoglobulins, and considered the impact of SARS-CoV-2 variants of concern in this at risk population.

Added value of the studyWe provide a comprehensive functional characterization of both T- and B-cell responses following a two-dose regimen of BNT162b2 in at risk patients on maintenance hemodialysis. More importantly, to the best of our knowledge, we assess for the first time binding and neutralization capacity of vaccination-induced circulation and mucosal antibodies towards emerging SARS-CoV-2 variants of concern in an immunocompromised population.

Implications of all the available evidencePatients on maintenance hemodialysis develop a substantial cellular and humoral immune response following the BNT162b2 vaccine. These findings should encourage patients on intermittent hemodialysis to receive the vaccine. However, we suggest continuing additional protection measures against variants of concern in this at risk population until longevity of the vaccine response is fully evaluated.

category: allergy and immunology


title: The real-life impact of vaccination on COVID-19 mortality in Europe and Israel

abstract:
OBJECTIVESThis study aimed at estimating the real-life impact of vaccination on COVID-19 mortality, with adjustment for SARS-CoV-2 variants spread and other factors across Europe and Israel.

METHODSTime series analysis of daily number of COVID-19 deaths was performed using non-linear Poisson mixed regression models. Variants frequency, demographic, climate, health and mobility characteristics of thirty-two countries were considered as potentially relevant adjustment factors between January 2020 and April 2021.

RESULTSThe analysis revealed that vaccination efficacy in terms of protection against deaths was equal to 72%, with a lower reduction of number of deaths for B.1.1.7 versus non-B.1.1.7 variants (70% and 78%, respectively). Other factors significantly related to mortality were arrivals at airports, mobility change from the pre-pandemic level and temperature.

CONCLUSIONSOur study confirms a strong effectiveness of COVID-19 vaccination based on real-life public data, although lower than expected from clinical trials. This suggests the absence of indirect protection for non-vaccinated individuals. Results also show that vaccination effectiveness against mortality associated with the B.1.1.7 variant is slightly lower compared with other variants. Lastly, this analysis confirms the role of mobility reduction, within and between countries, as an effective way to reduce COVID-19 mortality and suggests the possibility of seasonal variations in COVID-19 incidence.

category: epidemiology


title: Spatially refined time-varying reproduction numbers of SARS-CoV-2 in Arkansas and Kentucky and their relationship to population size and public health policy, March - November, 2020

abstract:
PurposeTo examine the time-varying reproduction number, Rt, for COVID-19 in Arkansas and Kentucky and investigate the impact of policies and preventative measures on the variability in Rt.

MethodsArkansas and Kentucky county-level COVID-19 cumulative case count data (March 6-November 7, 2020) were obtained. Rt was estimated using the R package  EpiEstim, by county, region (Delta, non-Delta, Appalachian, non-Appalachian), and policy measures.

ResultsThe Rt was initially high, falling below 1 in May or June depending on the region, before stabilizing around 1 in the later months. The median Rt for Arkansas and Kentucky at the end of the study were 1.15 (95% credible interval [CrI], 1.13, 1.18) and 1.10 (95% CrI, 1.08, 1.12), respectively, and remained above 1 for the non-Appalachian region. Rt decreased when facial coverings were mandated, changing by -10.64% (95% CrI, -10.60%, -10.70%) in Arkansas and -5.93% (95% CrI, -4.31%, -7.65%) in Kentucky. The trends in Rt estimates were mostly associated with the implementation and relaxation of social distancing measures.

ConclusionsArkansas and Kentucky maintained a median Rt above 1 during the entire study period. Changes in Rt estimates allows quantitative estimates of potential impact of policies such as facemask mandate.


title: PUM1 represses CDKN1B translation and contributes to prostate cancer progression

abstract: Posttranscriptional regulation of cancer gene expression programs plays a vital role in carcinogenesis; identifying the critical regulators of tumorigenesis and their molecular targets may provide novel strategies for cancer diagnosis and therapeutics. Highly conserved RNA binding protein PUM1 regulates mouse growth and cell proliferation, propelling us to examine its role in cancer. We found human PUM1 is highly expressed in a diverse group of cancer, including prostate cancer; enhanced PUM1 expression is also correlated with reduced survival among prostate cancer patients. Detailed expression analysis in twenty prostate cancer tissues showed enhanced expression of PUM1 at mRNA and protein levels. Knockdown of PUM1 reduced prostate cancer cell proliferation and colony formation, and subcutaneous injection of PUM1 knockdown cells led to reduced tumor size. Downregulation of PUM1 in prostate cancer cells consistently elevated CDKN1B protein expression through increased translation but did not impact its mRNA level, while overexpression of PUM1 reduced CDKN1B protein level. Our finding established a critical role of PUM1 mediated translational control, particularly the PUM1-CDKN1B axis, in prostate cancer cell growth and tumorigenesis. We proposed that PUM1-CDKN1B regulatory axis may represent a novel mechanism for the loss of CDKN1B protein expression in diverse cancers and could be potential targets for therapeutics development.

category: oncology


title: Trends in medical and surgical admission length of stay by race/ethnicity and socioeconomic status: a time series analysis

abstract: Length of stay, a metric of hospital efficiency, differs by race/ethnicity and socioeconomic status (SES). Longer LOS is associated with adverse health outcomes. We assessed differences in average adjusted length of stay (aALOS) over time by race/ethnicity, and SES stratified by discharge destination (home or non-home). Using the 2009-2014 State Inpatient Datasets from three states, we examined trends in aALOS differences by race/ethnicity, and SES (defined first vs fourth quartile of median income by zip code) controlling for patient, disease and hospital characteristics. For those discharged home, racial/ethnic and SES aALOS differences remained stable. Notably, for those discharged to non-home destinations, Black vs White, and low vs high SES aALOS differences increased significantly from 2009 to 2013, more sharply after Q3 2011, the Affordable Care Acts (ACA) introduction. Further research to understand the ACAs policy impact on hospital efficiencies, and relationship to racial/ethnic and SES differences in LOS is warranted.

category: health systems and quality improvement


title: Immune transcriptomes from hospitalized patients infected with the SARS-CoV-2 variants B.1.1.7 and B.1.1.7 carrying the E484K escape mutation

abstract: Fast-spreading variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) energize the COVID-19 pandemic. B.1.1.7 (VOC-202012/01) has become the predominant variant in many countries and a new lineage (VOC-202102/02) harboring the E484K escape mutation in the B.1.1.7 background emerged in February 20211. This variant is of concern due to reduced neutralizing activity by vaccine-elicited antibodies2,3. However, it is not known whether this single amino acid change leads to an altered immune response. Here, we investigate differences in the immune transcriptome in hospitalized patients infected with either B.1.1.7 (n=28) or B.1.1.7+E484K (n=12). RNA-seq conducted on PBMCs isolated within five days after the onset of COVID symptoms demonstrated elevated activation of specific immune pathways, including JAK-STAT signaling, in B.1.1.7+E484K patients as compared to B.1.1.7. Longitudinal transcriptome studies demonstrated a delayed dampening of interferon-activated pathways in B.1.1.7+E484K patients. Prior vaccination with BNT162b vaccine (n=8 one dose; n=1 two doses) reduced the transcriptome inflammatory response to B.1.1.7+E484K infection relative to unvaccinated patients. Lastly, the immune transcriptome of patients infected with additional variants (B.1.258, B.1.1.163 and B.1.7.7) displayed a reduced activation compared to patients infected with B.1.1.7. Acquisition of the E484K substitution in the B.1.1.7 background elicits an altered immune response, which could impact disease progression.

category: infectious diseases


title: Time scale performance of rapid antigen testing for SARS-COV-2: evaluation of ten rapid antigen assays

abstract: There is a great demand for more rapid tests for SARS-COV-2 detection to reduce waiting time, boost public health strategies for combating disease, decrease costs, and prevent overwhelming laboratory capacities. This study was conducted to assess the performance of 10 lateral flow device viral antigen immunoassays for the detection of SARS-CoV-2 in nasopharyngeal swab specimens. We analyzed 231 nasopharyngeal samples collected from October 2020-December 2020, from suspected COVID-19 cases and contacts of positive cases at Biotechnology Research Center laboratories, Tripoli, Libya. The performance of 10 COVID-19 Antigen (Ag) rapid test devices for the detection of SARS-CoV-2 antigen was compared to RT-qPCR. In this study 161 cases had symptoms consistent with COVID-19. The mean duration from symptom onset was 6.6 {+/-}4.3 days. The median cycle threshold (Ct) of positive samples was 25. Among the 108 positive samples detected by RT-qPCR, the COVID-19 antigen (Ag) tests detected 83 cases correctly. All rapid Ag test devices used in this study showed 100% specificity. While tests from 6 manufacturers had an overall sensitivity range from 75-100%, the remaining 4 tests had sensitivity of 50-71.43%. Sensitivity during the first 6 days of symptoms and in samples with high viral loads (Ct<25), was 100% in all but 2 of the test platforms. False negative samples had a median Ct of 34 and an average duration of onset of symptoms of 11.3 days (range=5-20 days). Antigen test diagnosis has high sensitivity and specificity in early disease when patients present less than 7 days of symptom onset. Patients are encouraged to test as soon as they get COVID-19 related symptoms within 1 week and to seek medical advice within 24 hrs. if they develop disturbed smell/taste. The use of rapid antigen tests is important for controlling COVID-19 pandemic and reducing burden on molecular diagnostic laboratories.


title: Looking for crumbs in the obesity forest: anti-obesity interventions in the Mexican population. History, and systematic review with Meta-Analysis

abstract:
Mexicans and Mexican Americans share culture, genetic background, and predisposition for chronic complications associated with obesity and diabetes making imperative efficacious treatments and prevention. Obesity has been treated for centuries focused-on weight loss while other treatments on associated conditions like gout, diabetes (T2D), and hypertriglyceridemia. To date, there is no systematic review that synthetize the origin of obesity clinics in Mexico and the efforts to investigate treatments for obesity tested by randomized clinical trials (RCT).

We conducted systematic searches in Pubmed, Scopus, and Web of Science to retrieve anti-obesity RCT through 2019 and without inferior temporal limit. The systematic review included RCT of anti-obesity treatments in the Mexican adult population, including alternative medicine, pharmacological, nutritional, behavioral, and surgical interventions reporting biometric outcomes such as BMI, weight, waist circumference, triglycerides, glucose, among others. Studies with at least three months of treatment were included in the meta-analysis.

We found 634 entries, after removal of duplicates and screening the studies based on eligibility criteria, we analyzed 43, and 2 multinational-collaborative studies. Most of the national studies have small sample sizes, and the studied strategies do not have replications in the population. The nutrition/behavioral interventions were difficult to blind, and most studies have medium to high risk of bias. Nutritional/behavioral interventions and medications showed effects on BMI, waist circumference, and blood pressure. Simple measures like plain water instead of sweet beverages decrease triglycerides and systolic blood pressure. Participants with obesity and hypertension can have benefic effects with antioxidants, and treatment with insulin increase weight in those with T2D.

The study of obesity in Mexico has been on-going for more than four decades, but the interest on RCT just increased until this millennium, but with small sample sizes and lack of replication. The interventions affect different metabolic syndrome components, which should be analyzed in detail with the population living on the U.S.-Mexico border; therefore, bi-national collaboration is desirable to disentangle the cultural effects on this populations treatment response.

category: endocrinology


title: Inference of SARS-CoV-2 generation times using UK household data

abstract: The distribution of the generation time (the interval between individuals becoming infected and passing on the virus) characterises changes in the transmission risk during SARS-CoV-2 infections. Inferring the generation time distribution is essential to plan and assess public health measures. We previously developed a mechanistic approach for estimating the generation time, which provided an improved fit to SARS-CoV-2 data from January-March 2020 compared to existing models. However, few estimates of the generation time exist based on data from later in the pandemic. Here, using data from a household study conducted from March-November 2020 in the UK, we provide updated estimates of the generation time. We consider both a commonly used approach in which the transmission risk is assumed to be independent of when symptoms develop, and our mechanistic model in which transmission and symptoms are linked explicitly. Assuming independent transmission and symptoms, we estimated a mean generation time (4.2 days, 95% CrI 3.3-5.3 days) similar to previous estimates from other countries, but with a higher standard deviation (4.9 days, 3.0-8.3 days). Using our mechanistic approach, we estimated a longer mean generation time (6.0 days, 5.2-7.0 days) and a similar standard deviation (4.9 days, 4.0-6.3 days). Both models suggest a shorter mean generation time in September-November 2020 compared to earlier months. Since the SARS-CoV-2 generation time appears to be changing, continued data collection and analysis is necessary to inform future public health policy decisions.


title: Injustices in pandemic vulnerability: A spatial-statistical analysis of the CDC Social Vulnerability Index and COVID-19 outcomes in the U.S.

abstract:
BackgroundThe COVID-19 pandemic has exacerbated health injustices in the U.S. driven by racism and other forms of structural violence. Research has shown the disproportionate impacts of COVID-19 morbidity and mortality in the most marginalized communities.

ObjectivesWe examined the associations between COVID-19 cumulative incidence (CI) and case-fatality risk (CFR) and the CDCs Social Vulnerability Index (SVI), a composite score assessing historical marginalization and thus vulnerability to disaster events.

MethodsUsing county-level data from national databases, we used population density, Gini index, percent uninsured, and average annual temperature as covariates, and employed negative binomial regression to evaluate relationships between SVI and COVID-19 outcomes. Optimized hot spot analysis identified hot spots of COVID-19 CI and CFR, which were compared in terms of SVI using logistic regression.

ResultsAs of 2/3/21, 26,452,031 cases of and 448,786 deaths from COVID-19 had been reported in the U.S. Negative binomial regression showed that counties in the top SVI quintile reported 13.7% higher CI (p<0.001) than those in the bottom SVI quintile. Additionally, each unit increase in a countys SVI score was associated with a 0.2% increase in CFR (p<0.001). Logistic regression analysis showed that counties in the lowest SVI quintile had significantly greater odds of being in a CI hot spot than all other counties, yet counties in the highest SVI quintile had 63% greater odds (p=0.008) of being in a CFR hot spot than counties in the lowest SVI quintile.

ConclusionWe demonstrated a significant relationship between SVI and CFR, but the relationship between SVI and CI is complex and warrants further investigation. SVI may help elucidate unequal impacts of COVID-19 and guide prioritization of vaccines to communities most impacted by structural injustices.


title: The rapid reemergence of seasonal respiratory viruses in Houston, Texas, after relaxing COVID-19 restrictions

abstract: Brief abstractImplementation of measures to limit the spread of the SARS-CoV-2 virus at the start of the COVID-19 pandemic resulted in a rapid decrease in all other respiratory pathogens. As COVID-19 containment measures were relaxed, the first non-COVID respiratory viruses to return to prepandemic levels were members of the rhinovirus/enterovirus, followed by the rapid return of seasonal coronaviruses, parainfluenza, and respiratory syncytial virus after the complete removal of COVID-19 precautions at the state level, including an end to mask mandates. Inasmuch as COVID-19 has dominated the landscape of respiratory infections since early 2020, it is important for clinicians to recognize the return of non-COVID respiratory pathogens may be rapid and significant when COVID-19 containment measures are removed.

category: pathology


title: Effect of evidence updates on key determinants of measles vaccination impact: a DynaMICE modelling study in ten high-burden countries

abstract:
BackgroundModel-based estimates of measles burden and the impact of measles-containing vaccine (MCV) are crucial for global health priority setting. Recently, evidence from systematic reviews and database analyses have improved our understanding of key determinants of measles vaccine impact. We explore how updated representations of these determinants affect model-based estimation of MCV impact in ten countries with highest measles burden.

MethodsUsing Dynamic Measles Immunisation Calculation Engine (DynaMICE), an age-structured compartmental model of measles transmission and vaccination, we evaluated the effect of evidence updates for five determinants of MCV impact: case fatality risk, contact patterns, age-dependent vaccine efficacy, the potential of supplementary immunisation activities (SIAs) to reach zero-dose children, and the basic reproduction number. We also evaluated the incremental impact of the first dose (MCV1), second dose (MCV2), and SIA dose of measles vaccines, based on country-specific coverage estimates from the World Health Organization. The MCV impact was assessed by cumulative vaccine-averted cases, deaths, and disability-adjusted life years over 2000-2050.

ResultsIncorporated with the updated data sources, DynaMICE projected 252 million measles cases, 3.7 million deaths and 230 million disability-adjusted life years incurred over 2000-2050 in the ten high-burden countries when MCV1, MCV2, and SIA doses were implemented. Compared to no vaccination, the administration of MCV1 contributed to 66% reduction in cumulative measles burden, while MCV2 and SIAs reduced this further to 89%. With routine and supplementary vaccination, India and countries with high vaccination coverage could maintain measles incidence below 1 per million. Among the updated determinants, shifting from fixed to linearly-varying vaccine efficacy by age and from static to time-varying case fatality risks had the biggest effect on the model projections of MCV impact. While varying the basic reproduction number showed a limited effect on vaccine-averted burden, updates on the other four determinants together led to an overall reduction of MCV impact by 0.87-26.7%.

ConclusionsHigh coverage of measles vaccine through both routine and SIA delivery platforms are essential for achieving and maintaining low incidence in high-measles burden settings. Incorporating updated evidence particularly on vaccine efficacy and case fatality risk reduces estimates of the impact of vaccination slightly, but its overall impact remains considerable.


title: Predicting EGFR mutation status in lung adenocarcinoma presenting as ground-glass opacity: utilizing radiomics model in clinical translation

abstract:
ObjectivesThis study aimed to establish a noninvasive radiomics model based on computed tomography (CT), with favorable sensitivity and specificity to predict EGFR mutation status in GGO-featured lung adenocarcinoma that subsequently guiding the administration of targeted therapy.

MethodClinical-pathological information and preoperative CT-images of 636 lung adenocarcinoma patients (464, 100, and 72 in the training, internal, and external validation sets, respectively) that underwent GGO lesions resection were included. A total of 1476 radiomic features were extracted with gradient boosting decision tree (GBDT).

ResultsThe established radiomics model containing 252 selected features showed an encouraging discrimination performance of EGFR mutation status (mutant or wild-type), and the predictive ability was superior to that of the clinical model (AUC: 0.901 vs. 0.674, 0.813 vs. 0.730, and 0.801 vs. 0.746 the training, internal, and external validation sets, respectively). The combined radiomics plus clinical model showed no additional benefit over the radiomics model in predicting EGFR status (AUC: 0.909 vs. 0.901, 0.803 vs. 0.813, 0.808 vs. 0.801, respectively, in three cohorts). Uniquely, this model was validated in a cohort of lung adenocarcinoma patients who undertaken adjuvant EGFR-TKIs and harbored unresected GGOs, leading to a significantly improved potency of EGFR-TKIs (response rate: 33.9% vs. 62.5%, P =0.04; before- and after-prediction, respectively).

ConclusionThis presented radiomics model can be served as a noninvasive and time-saving approach for predicting the EGFR mutation status in lung adenocarcinoma presenting as GGO.

Key pointsO_LIWe developed a GGO-specific radiomics model containing 252 radiomics features for EGFR mutation status differentiation.
C_LIO_LIAn AUC of 0.813 and 0.801 in the internal and external validation cohort, respectively, were achieved.
C_LIO_LIThe radiomics model was utilized in clinical translation in an adjuvant EGFR-TKIs cohort with unresected GGOs. A significant improvement in the potency of EGFR-TKIs was achieved (response rate: 33.9% vs. 62.5%, P =0.04; before- and after-prediction).
C_LI

category: radiology and imaging


title: Small Airways Disease is a Post-Acute Sequelae of SARS-CoV-2 Infection

abstract:
BackgroundThe sequelae of SARS-CoV-2 infection on pulmonary structure and function remain incompletely characterized.

MethodsAdults with confirmed COVID-19 who remained symptomatic more than thirty days following diagnosis were enrolled and classified as ambulatory, hospitalized or requiring the intensive care unit (ICU) based on the highest level of care received during acute infection. Symptoms, pulmonary function tests and chest computed tomography (CT) findings were compared across groups and to healthy controls. CT images were quantitatively analyzed using supervised machine-learning to measure regional ground glass opacities (GGO) and image-matching to measure regional air trapping. Comparisons were performed using univariate analyses and multivariate linear regression.

ResultsOf the 100 patients enrolled, 67 were in the ambulatory group. All groups commonly reported cough and dyspnea. Pulmonary function testing revealed restrictive physiology in the hospitalized and ICU groups but was normal in the ambulatory group. Among hospitalized and ICU patients, the mean percent of total lung classified as GGO was 13.2% and 28.7%, respectively, and was higher than in ambulatory patients (3.7%, P<0.001). The mean percentage of total lung affected by air trapping was 25.4%, 34.5% and 27.2% in the ambulatory, hospitalized and ICU groups and 7.3% in healthy controls (P<0.001). Air trapping measured by quantitative CT correlated with the residual volume to total lung capacity ratio (RV/TLC; {rho}=0.6, P<0.001).

ConclusionsAir trapping is present in patients with post-acute sequelae of COVID-19 and is independent of initial infection severity, suggesting obstruction at the level of the small airways. The long-term consequences are not known.

category: respiratory medicine


title: How can we increase notification of exposure to STIs between gay and bisexual men?: intervention development using stakeholder engagement, qualitative methods and behavioural science

abstract:
RationaleThe first key step in contact tracing for sexually transmitted infections (STIs) is to notify recent exposed sex partners. Gay and bisexual men and other men who have sex with men (GBMSM) bear a high burden of STIs and one-off partners contribute disproportionately to community transmission, posing a particular challenge to contact tracing. Here we explore and theorise the barriers and facilitators of GBMSM telling their  one-off sexual partners about their exposure to STIs.

DesignUsing focus groups with diverse GBMSM from Leeds, Glasgow, London and on-line (n=28) we used a multi-level approach to intervention development to enhance contact tracing. This framework included initial stakeholder engagement; deductive thematic analysis to identify key barriers and facilitators to contact tracing with one-off partners; the use of the theoretical domains framework (TDF) to theorise these barriers and facilitators and subsequently the use of the behaviour change wheel (BCW), incorporating the behaviour change technique taxonomy (BCTT), to suggest intervention content to enhance the key step of notifying partners; and final stakeholder input to ensure this content was fit for purpose and satisfied the APEASE criteria.

ResultsIn relation to the TDF, the barriers and facilitators primarily related to  beliefs about consequences. Having used the BCW and further stakeholder engagement, our final intervention recommendations related to focussed efforts to change the culture and corresponding norms and social practice of notifying sex partners about the risk of infection in GBMSM communities. This could usefully be achieved through dedicated community engagement and partnership work, through focussed mass and social media interventions twinned with focussed peer-led work to normalise and destigmatise contact tracing.

ConclusionThrough systematically working with key stakeholders, GBMSM communities and using a range of tools from the behavioural sciences, we have developed a suite of evidence-based and theoretically informed intervention content which, if developed further, could enhance GBMSMs willingness to notify sex partners about their risk of infection.

category: sexual and reproductive health


title: Assessment of the Effects of a Sage (Salvia officinalis) Extract on Cognitive Performance in Adolescents and Young Adults

abstract:
BackgroundCognitive health is a major concern for many people, and with potential benefits to academic and professional life, maximising cognitive performance is of interest far beyond the older demographics. Several natural products have been suggested as nootropics, including the herb sage. Previous assessments of various Salvia species have reported a range of effects on cognitive performance and mood in both older adult and younger adult populations. This study was conducted with Sibelius: Sage, an aqueous-ethanol extract of S. officinalis, to assess for the beneficial effects on cognitive performance in adolescents (12-14 year olds) and young adults (18-25 year olds).

Methods and FindingsAn acute, double-blind, placebo-controlled study was conducted with two single doses of Sibelius: Sage (150 mg and 300 mg). Cognitive performance was evaluated using CogTrack, which probes aspects of cognitive performance covering attention, working memory and episodic/declarative memory through a series of computer-based tasks. Consistent with previous study of Sibelius: Sage a significant effect was seen on the Immediate Word Recall task in young adults; suggesting acute treatment benefits to verbal episodic/declarative memory performance. Physiological effects of the treatment on salivary cortisol and oxytocin levels, as well as blood pressure and heart rate were also assessed, with limited evidence of an effect on these factors. No adverse events or side-effects linked to the study product intake was observed. The study was registered at the German Clinical Trials Register (DRKS-ID: DRKS00015716).

ConclusionsA significant improvement due to the Sage extract was shown for a task assessing short-term episodic memory (Immediate Word Recall), supporting beneficial effects on cognitive performance in young adults that are consistent with previous reports in healthy older adults. These findings suggest that further investigation of the effects observed in this study in larger, long-term human volunteer studies could be beneficial to pursue.

category: nutrition


title: Estimates of cases and hospitalizations averted by COVID-19 case investigation and contact tracing in 14 health jurisdictions in the United States

abstract:
ContextThe implementation of case investigation and contact tracing (CICT) for controlling COVID-19 (caused by SARS-Cov-2 virus) has proven challenging due to varying levels of public acceptance and initially constrained resources, especially enough trained staff. Evaluating the impacts of CICT will aid efforts to improve such programs.

ObjectivesEstimate the number of COVID-19 cases and hospitalizations averted by CICT and identify CICT processes that could improve overall effectiveness.

DesignWe used data on proportion of cases interviewed, contacts notified or monitored, and days from testing to contact notification from 14 jurisdictions to model the impact of CICT on cumulative cases counts and hospitalizations over a 60-day period. Using the Centers for Disease Control and Prevention (CDC)s COVIDTracer tool, we estimated a range of impacts by assuming either contacts would quarantine only if monitored or would do so upon notification of potential exposure. We also varied the observed program metrics to assess their relative influence.

ResultsPerformance by jurisdictions varied widely. Jurisdictions isolated between 12 and 86% of cases (including contacts which became cases) within 6 to 10 days after exposure-and-infection. We estimated that CICT-related reductions in transmission ranged from 0.4% to 32%. For every 100 cases prevented by nonpharmaceutical interventions, CICT averted between 4 and 97 additional cases. Reducing time to case isolation by one day increased averted case estimates by up to 15 percentage points. Increasing the proportion of cases interviewed or contacts notified by 20 percentage points each resulted in at most 3 or 6 percentage point improvements in averted cases.

ConclusionsWe estimated that case investigation and contact tracing reduced the number of COVID-19 cases and hospitalizations among all jurisdictions studied. Reducing time to isolation produced the greatest improvements in impact of CICT.

category: health policy


title: CoMix: Changes in social contacts as measured by the contact survey during the 1 COVID-19 pandemic in England between March 2020 and March 2021

abstract:
BackgroundDuring the COVID-19 pandemic, the UK government imposed public health policies in England to reduce social contacts in hopes of curbing virus transmission. We measured contact patterns weekly from March 2020 to March 2021 to estimate the impact of these policies, covering three national lockdowns interspersed by periods of lower restrictions.

MethodsData were collected using online surveys of representative samples of the UK population by age and gender. We calculated the mean daily contacts reported using a (clustered) bootstrap and fitted a censored negative binomial model to estimate age-stratified contact matrices and estimate proportional changes to the basic reproduction number under controlled conditions using the change in contacts as a scaling factor.

ResultsThe survey recorded 101,350 observations from 19,914 participants who reported 466,710 contacts over 53 weeks. Contact patterns changed over time and by participants age, personal risk factors, and perception of risk. The mean of reported contacts among adults have reduced compared to previous surveys with adults aged 18 to 59 reporting a mean of 2.39 (95% CI 2.20 - 2.60) contacts to 4.93 (95% CI 4.65 - 5.19) contacts, and the mean contacts for school-age children was 3.07 (95% CI 2.89 - 3.27) to 15.11 (95% CI 13.87 - 16.41). The use of face coverings outside the home has remained high since the government mandated use in some settings in July 2020.

ConclusionsThe CoMix survey provides a unique longitudinal data set for a full year since the first lockdown for use in statistical analyses and mathematical modelling of COVID-19 and other diseases. Recorded contacts reduced dramatically compared to pre-pandemic levels, with changes correlated to government interventions throughout the pandemic. Despite easing of restrictions in the summer of 2020, mean reported contacts only returned to about half of that observed pre-pandemic.


title: Modeling the impact of COVID-19 vaccination in Lebanon: A call to speed-up vaccine roll out

abstract:
BackgroundAmidst a very difficult economic and political situation, and after a large first SARS-CoV-2 wave near the end of 2020, Lebanon launched its vaccination campaign on 14 February 2021. To date, only 6.7% of the population have received at least one dose of the vaccine, raising serious concerns over the speed of vaccine roll-out and its impact in the event of a future surge.

ObjectiveUsing mathematical modeling, we assessed the short-term impact (by end of 2021) of various vaccine roll-out scenarios on SARS-CoV-2 epidemic course in Lebanon.

ResultsAt current immunity levels in the population, estimated by the model at 40% on 15 April 2021, a large epidemic wave is predicted if all social distancing restrictions are gradually eased and variants of concern are introduced. Reaching 80% vaccine coverage by end of 2021 will flatten the epidemic curve and will result in a 37% and 34% decrease in the peak daily numbers of severe/critical disease cases and deaths, respectively; while reaching intermediate coverage of 40% will result in only 10-11% decrease in each. Reaching 80% coverage by end of 2021 will avert 3 times more hospitalizations and deaths over the course of this year compared with 40% coverage. Impact of vaccination was substantially enhanced with rapid scale-up. Reaching 80% vaccine coverage by August would prevent twice as many severe/critical disease cases and deaths than if it were reached by December. Finally, a longer duration over which restrictions are eased resulted in a more favorable impact of vaccination.

ConclusionFor vaccination to have an impact on the predicted epidemic course and associated disease burden in Lebanon, vaccination has to be rapid and reach high coverage (at least 70%), while sustaining social distancing measures during roll-out. At current vaccination pace, this is unlikely to be achieved. Concerted efforts need to be put to overcome local challenges and substantially scale up vaccination to avoid a surge that the country, with its multiple crises and limited health-care capacity, is largely unprepared for.


title: Effectiveness of the Covid-19 vaccine in preventing infection in dental practitioners: results of a cross-sectional questionnaire based survey

abstract:
India started its vaccination program at the beginning of 2021, the main beneficiaries being health workers and frontline workers including police, paramilitary forces, sanitation workers, and disaster management volunteers in the first phase. By the time, the second wave of Covid-19 impacted India, approximately 14 million healthcare and frontline workers, including dentists had been vaccinated.

AimTo study the effectiveness of vaccination on a subset of high-risk healthcare workers i.e. dentists in preventing Covid-19 during the second wave of the pandemic.

Study designA questionnaire based pan-India online survey was carried out to record the Covid-related experiences of dentists prior to and after vaccination.

ResultThe sample size for this survey was 4493 respondents from across India. During the second wave, 9.18% (n=364) respondents became positive in spite of the vaccine, while 14.69%(n=78) became positive in the unvaccinated group. A chi-square test of independence was performed to examine the relation between vaccination and the Covid positivity rate in all age groups. The relation between these variables was highly significant, [X2 (1, N = 4493) = 15.9809, p=.000064].

ConclusionOur pan-India online survey inferred that vaccination has a definitive role to play in reducing the positivity rate amongst dentists during the second wave of the pandemic across all age groups.

category: dentistry and oral medicine


title: Effectiveness of the Covid-19 vaccines in preventing infection in dental practitioners: results of a cross-sectional questionnaire based survey


title: Monitoring emergence of SARS-CoV-2 B.1.1.7 Variant through the Spanish National SARS-CoV-2 Wastewater Surveillance System (VATar COVID-19) from December 2020 to March 2021

abstract:
BackgroundSince its first identification in the United Kingdom in late 2020, the highly transmissible B.1.1.7 variant of SARS-CoV-2, become dominant in several European countries raising great concern.

AimThe aim of this study was to develop a duplex real-time RT-qPCR assay to detect, discriminate and quantitate SARS-CoV-2 variants containing one of its mutation signatures, the {Delta}HV69/70 deletion, to trace the community circulation of the B.1.1.7 variant in Spain through the Spanish National SARS-CoV-2 Wastewater Surveillance System (VATar COVID-19).

ResultsB.1.1.7 variant was first detected in sewage from the Southern city of Malaga (Andalucia) in week 20_52, and multiple introductions during Christmas holidays were inferred in different parts of the country, earlier than clinical epidemiological reporting by the local authorities. Wastewater-based B.1.1.7 tracking showed a good correlation with clinical data and provided information at the local level. Data from WWTPs which reached B.1.1.7 prevalences higher than 90% for [≥] 2 consecutive weeks showed that 8.1{+/-}1.8 weeks were required for B.1.1.7 to become dominant.

ConclusionThe study highlights the applicability of RT-qPCR-based strategies to track specific mutations of variants of concern (VOCs) as soon as they are identified by clinical sequencing, and its integration into existing wastewater surveillance programs, as a cost-effective approach to complement clinical testing during the COVID-19 pandemic.


title: A rapid and simple protocol for concentration of SARS-CoV-2 from sewage

abstract: The aim of this study was to set up a simple protocol to concentrate SARS-CoV-2 from sewage, which can be implemented in laboratories with minimal equipment resources. The method avoids the need for extensive purification steps and reduces the concentration of potential inhibitors of RT-qPCR contained in sewage. The concentration method consists of a single step, in which a small volume of sewage sample is incubated with polyaluminum chloride (PAC). Virus particles adsorbed to the precipitate are collected by low-speed centrifugation, after which the recovered pellet is resuspended with a saline buffer. The PAC concentration method produced an average shift of 4.4-units in Cq values compared to non-concentrated samples, indicating a 25-fold increase in detection sensitivity. The lower detection limit corresponded approximately to 100 copies per ml. Kappa index indicated substantial agreement between PAC and PEG precipitation protocols (k=0.688, CI 0.457-0.919). PAC concentrated samples can be processed immediately for RNA purification and qPCR or sent refrigerated to a diagnosis center, where SARS-CoV-2 detection should be performed in the same way as for clinical samples. This low cost protocol could be useful to aid in the monitoring of community circulation of SARS-CoV-2, especially in low- and middle-income countries, which do not have massive access to support from specialized labs for sewage surveillance.


title: MALDI-ToF Protein Profiling as Potential Rapid Diagnostic Platform for COVID-19

abstract: More than a year after the COVID-19 pandemic has been declared, the need still exists for accurate, rapid, inexpensive and non-invasive diagnostic methods that yield high specificity and sensitivity towards the current and newly emerging SARS-CoV-2 strains. Several studies have since established saliva as a more amenable specimen type for early detection of SARS-CoV-2 as compared to nasopharyngeal swabs. Considering the limitations and high demand for COVID-19 testing, we employed MALDI-ToF mass spectrometry for the analysis of 60 gargle samples from human donors and compared the spectra with their COVID-19 status. Several standards including isolated human serum immunoglobulins and controls such as pre-COVID-19 saliva and heat inactivated SARS-CoV-2 virus were simultaneously analyzed to provide a relative view of the saliva and viral proteome as they would appear in this works methodology. Five potential biomarker peaks were established that demonstrated high concordance with COVID-19 positive individuals. Overall, the agreement of these results with RT-qPCR testing on NP swabs was no less than 90% for the studied cohort, which consisted of young and largely asymptomatic student athletes. From a clinical standpoint, the results from this pilot study are promising and suggest that MALDI-ToF can be used to develop a relatively rapid and inexpensive COVID-19 assay.


title: Visual motion and decision-making in dyslexia: Evidence of reduced accumulation of sensory evidence and related neural dynamics

abstract: Children with and without dyslexia differ in their behavioural responses to visual information, particularly when required to pool dynamic signals over space and time. Importantly, multiple processes contribute to behavioural responses. Here we investigated which processing stages are affected in children with dyslexia when performing visual motion processing tasks, by combining two methods that are sensitive to the dynamic processes leading to responses. We used a diffusion model which decomposes response time and accuracy into distinct cognitive constructs, and high-density EEG. 50 children with dyslexia and 50 typically developing children aged 6 to 14 years judged the direction of motion as quickly and accurately as possible in two global motion tasks, which varied in their requirements for segregating signal-from-noise. Following our pre-registered analyses, we fitted hierarchical Bayesian diffusion models to the data, blinded to group membership. Unblinding revealed reduced evidence accumulation in children with dyslexia compared to typical children for both tasks. We also identified a response-locked EEG component which was maximal over centro-parietal electrodes which indicated a neural correlate of reduced drift-rate in dyslexia, thereby linking brain and behaviour. We suggest that children with dyslexia are slower to extract sensory evidence from global motion displays, regardless of whether they are required to segregate signal-from-noise, thus furthering our understanding of atypical perceptual decision-making processes in dyslexia.

category: psychiatry and clinical psychology


title: Medical brain drain from Western Balkan and Croatia to Germany and Austria: an approach to the digital demography

abstract:
BackgroundIn this paper, we show that the tools of digital demography, such as the Google Trends (GT) can be very useful for determining, estimating, and predicting the migration of healthcare workers as well as for further predictions of the general interest in emigration.

ObjectiveThis paper analyses recent trends in the mobility of health workers in Europe and focuses specifically on the patterns of mobility among medical doctors and nurses from Western Balkans and Croatia to Germany and Austria. It identifies the drivers of this mobility and shows how to predict further migration of this stuff. In the last 10 years, every fourth nurse has emigrated from the Croatian health system -to Germany, while according to projections Croatia will lose as much as 1/3 of all doctors in the next five years.

MethodsA special problem in the analysis of the emigration of healthcare workers from the Western Balkans and Croatia is the fact that there is no system for monitoring this process. Official data up to three years late, and exist only for persons who have deregistered from the state system. The basic methodological concept of our approach is to monitor the digital trace of language searches with the Google Trends analytical tool (trends.google.com). Initially, keywords were chosen by brainstorming possible words that we believed to be predictive, specific, and common enough for use in the forecasting of migration of healthcare professionals. To standardize the data, we requested the data for the period from Dec. 2015 to Dec. 2020 and divided the keyword frequency for each word giving us a search frequency index. Then we have compared searches with official statistics to prove the significations of results and correlations.

ResultsIn Croatia search activities using GT for terms such as   Bewerbung" (job application), "Arbeit" (work), "Krankenschwester, Bewerbung" (nurses, job application) correlate strongly with officially Germans data for emigrants from Croatia. The data collected by this method correlate with official data, which allows reliable forecasts for the future. Austria will soon become one of the most desirable emigration destinations for Croats, especially for healthcare workers. Simultaneously, the emigration of Croatian citizens to Germany will continue.

ConclusionUnderstanding why health care personnel emigrate from Western Balkans and Croatia and which are the consequences of this process are key to enable state agencies and government to develop optimal intervention strategies to retain medical staff. The benefit of this method is reliable estimates that can enable state agencies and the government to prepare and better respond to a possible shortage of healthcare workers and to protect the functioning of the health system.

category: nursing


title: Risk Factors, Clinical Outcomes and Prognostic Factors of Bacterial Keratitis: The Nottingham Infectious Keratitis Study

abstract:
Background/aimTo examine the risk factors, clinical characteristics, outcomes and prognostic factors of bacterial keratitis (BK) in Nottingham, UK.

MethodsThis was a retrospective study of patients who presented to the Queens Medical Centre, Nottingham, with suspected BK during 2015-2019. Relevant data, including the demographic factors, risk factors, clinical outcomes, and potential prognostic factors, were analysed.

ResultsA total of 283 patients (n=283 eyes) were included; mean age was 54.4{+/-}21.0 years and 50.9% were male. Of 283 cases, 128 (45.2%) cases were culture-positive. Relevant risk factors were identified in 96.5% patients, with ocular surface diseases (47.3%), contact lens wear (35.3%) and systemic immunosuppression (18.4%) being the most common factors. Contact lens wear was most commonly associated with P. aeruginosa whereas Staphylococci spp. were most commonly implicated in non-contact lens-related BK cases (p=0.017). At presentation, culture-positive cases were associated with older age, worse presenting corrected-distance-visual-acuity (CDVA), larger epithelial defect and infiltrate, central location and hypopyon (all p<0.01), when compared to culture-negative cases. Hospitalisation was required in 57.2% patients, with a mean length of stay of 8.0{+/-}8.3 days. Surgical intervention was required in 16.3% patients. Significant complications such as threatened/actual corneal perforation (8.8%), loss of perception of light vision (3.9%), and evisceration/enucleation (1.4%) were noted. Poor visual outcome (final corrected-distance-visual-acuity of <0.6 logMAR) and delayed corneal healing (>30 days from initial presentation) were significantly affected by age >50 years, infiltrate size >3mm, and reduced presenting vision (all p<0.05).

ConclusionBK represents a significant ocular morbidity in the UK. Culture positivity is associated with more severe disease at presentation but has no significant influence on the final outcome. Older age, large infiltrate, and poor presenting vision were predictive of poor visual outcome and delayed corneal healing, highlighting the importance of primary prevention and early intervention for BK.

category: ophthalmology


title: A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank

abstract: Genome-first approaches to analyzing rare variants can reveal new insights into human biology and disease. Because pathogenic variants are often rare, new discovery requires aggregating rare coding variants into  gene burdens for sufficient power. However, a major challenge is deciding which variants to include in gene burden tests. Pathogenic variants in MYBPC3 and MYH7 are well-known causes of hypertrophic cardiomyopathy (HCM), and focusing on these  positive control genes in a genome-first approach could help inform variant selection methods and gene burdening strategies for other genes and diseases. Integrating exome sequences with electronic health records among 41,759 participants in the Penn Medicine BioBank, we evaluated the performance of aggregating predicted loss-of-function (pLOF) and/or predicted deleterious missense (pDM) variants in MYBPC3 and MYH7 for gene burden phenome-wide association studies (PheWAS). The approach to grouping rare variants for these two genes produced very different results: pLOFs but not pDM variants in MYBPC3 were strongly associated with HCM, whereas the opposite was true for MYH7. Detailed review of clinical charts revealed that only 38.5% of patients with HCM diagnoses carrying an HCM-associated variant in MYBPC3 or MYH7 had a clinical genetic test result. Additionally, 26.7% of MYBPC3 pLOF carriers without HCM diagnoses had clear evidence of left atrial enlargement and/or septal/LV hypertrophy on echocardiography. Our study shows the importance of evaluating both pLOF and pDM variants for gene burden testing in future studies to uncover novel gene-disease relationships and identify new pathogenic loss-of-function variants across the human genome through genome-first analyses of healthcare-based populations.

category: genetic and genomic medicine


title: Out-of-Pocket Spending for COVID-19 Hospitalizations in 2020

abstract:
IMPORTANCEMany insurers waived cost-sharing for COVID-19 hospitalizations during 2020. Nonetheless, patients may have been billed if their plans did not implement waivers or if waivers did not capture all hospitalization-related care, including clinician services. Assessing out-of-pocket spending for COVID-19 hospitalizations in 2020 could demonstrate the financial burden patients may face if insurers allow waivers to expire, as many chose to do during early 2021.

OBJECTIVETo estimate out-of-pocket spending for COVID-19 hospitalizations in 2020

DESIGNCross-sectional analysis

SETTINGIQVIA PharMetrics(R) Plus for Academics Database, a national claims database

PARTICIPANTSCOVID-19 hospitalizations for privately insured and Medicare Advantage patients during March-September 2020

MAIN OUTCOMES/MEASURESMean total out-of-pocket spending, defined as the sum of out-of-pocket spending for facility services billed by hospitals (e.g., accommodation charges) and for professional/ancillary services billed by clinicians and ancillary providers (e.g., clinician inpatient evaluation and management, ambulance transport)

RESULTSAnalyses included 4,075 hospitalizations. Of the 1,377 hospitalizations for privately insured patients and the 2,698 hospitalizations for Medicare Advantage patients, 981 (71.2%) and 1,324 (49.1%) had out-of-pocket spending for facility services, professional/ancillary services, or both. Among these hospitalizations, mean (SD) total out-of-pocket spending was $788 (1,411) and $277 (363). In contrast, 63 (4.6%) and 36 (1.3%) hospitalizations had out-of-pocket spending for facility services. Among these hospitalizations, mean total out-of-pocket spending was $3,840 (3,186) and $1,536 (1,402). Total out-of-pocket spending exceeded $4,000 for 2.5% of privately insured hospitalizations, compared with 0.2% of Medicare Advantage hospitalizations.

CONCLUSIONSFew COVID-19 hospitalizations in this study had out-of-pocket spending for facility services, suggesting most were covered by insurers with cost-sharing waivers. However, many hospitalizations had out-of-pocket spending for professional/ancillary services. Overall, 7 in 10 privately insured hospitalizations and half of Medicare Advantage hospitalizations had any out-of-pocket spending. Findings suggest insurer cost-sharing waivers may not cover all hospitalization-related care. Moreover, high cost-sharing for some hospitalizations suggests out-of-pocket burden could be substantial if waivers expire, particularly for privately insured patients. Rather than rely on voluntary insurer actions to mitigate this burden, federal policymakers should consider mandating insurers to waive cost-sharing for all COVID-19 hospitalization-related care throughout the pandemic.

KEY POINTSO_ST_ABSQuestionC_ST_ABSHow much were patients billed for COVID-19 hospitalizations in 2020?

FindingsOf 1,377 and 2,698 COVID-19 hospitalizations for privately insured and Medicare Advantage patients, 71.2% and 49.1% had cost-sharing for facility services billed by hospitals, services billed by clinicians or ancillary providers, or both. Among these hospitalizations, mean out-of-pocket spending was $788 and $277. 4.6% and 1.3% had cost-sharing for facility services; among these hospitalizations, mean out-of-pocket spending was $3,840 and $1,536.

MeaningInsurer cost-sharing waivers for COVID-19 hospitalizations may not cover all hospitalization-related care. Patient out-of-pocket burden could be substantial if insurers allow waivers to expire.


title: Use of medicinal plants for COVID-19 prevention and respiratory symptom treatment during the pandemic in Cusco, Peru: A cross-sectional survey

abstract:
BackgroundThe burden of the COVID-19 pandemic in Peru has led to people seeking alternative treatments as preventives and treatment options such as medicinal plants. This study aimed to assess factors associated with the use of medicinal plants as preventive or treatment of respiratory symptom related to COVID-19 during the pandemic in Cusco, Peru.

MethodA web-based cross-sectional study was conducted on general public (20- to 70-year-old) from August 31 to September 20, 2020. Data were collected using a structured questionnaire via Google Forms, it consisted of an 11-item questionnaire that was developed and validated by expert judgment using Aikens V (Aikens V > 0.9). Both descriptive statistics and bivariate followed by multivariable logistic regression analyses were conducted to assess factors associated with the use of medicinal plants for COVID-19 prevention and respiratory symptom treatment during the pandemic. Prevalence ratios (PR) with 95% Confidence Interval (CI), and a P-value of 0.05 was used to determine statistical significance.

ResultsA total of 1,747 respondents participated in the study, 80.2% reported that they used medicinal plants as preventives, while 71% reported that they used them to treat respiratory symptoms. At least, 24% of respondents used medicinal plants when presenting with two or more respiratory symptoms, while at least 11% used plants for malaise. For treatment or prevention, the multivariate analysis showed that most respondents used eucalyptus (p < 0.001 for both), ginger (p < 0.022 for both), spiked pepper (p < 0.003 for both), garlic (p = 0.023 for prevention), and chamomile (p = 0.011 for treatment). The respondents with COVID-19 (p < 0.001), at older ages (p = 0.046), and with a family member or friend who had COVID-19 (p < 0.001) used more plants for prevention. However, the respondents with technical or higher education used less plants for treatment (p < 0.001).

ConclusionThere was a significant use of medicinal plants for both prevention and treatment, which was associated with several population characteristics and whether respondents had COVID-19.


title: Functional and quantitative evaluation of BNT162b2 SARS-CoV-2 vaccine-induced immunity

abstract:
ObjectivesVaccines against severe acute respiratory syndrome coronavirus-2 have been introduced. To investigate whether the vaccine provides protective immunity effectively, the amount and function of vaccine-induced antibodies were evaluated.

MethodsSera from 13-17 days after the second dose of the Pfizer BNT162b2 vaccine were collected from healthcare workers at the University of Toyama (n=740). Antibody levels were quantitatively measured by the anti-receptor binding domain antibody test (anti-RBD test), and neutralising activity against pseudotyped viruses displaying wild-type (WT) and mutant spike proteins (B.1.1.7- and B.1.351-derived variants) were assayed using a high-throughput chemiluminescent reduction neutralising test (htCRNT). Basic clinical characteristics were obtained from questionnaires.

ResultsAntibodies were confirmed in all participants in both the anti-RBD test (median 2112 U/mL, interquartile range [IQR] 1275-3390 U/mL) and the htCRNT against WT (median % inhibition >99.9, IQR >99.9 to >99.9). For randomly selected sera (n=61), 100.0% were positive for htCRNT against the B.1.1.7- and B.1.351-derived variants. Among those who answered the questionnaire (n=237), the values of the anti-RBD test were negatively correlated with age for females (p<0.01; r = -0.31, 95% confidence interval -0.45 to -0.16). Systemic symptoms after vaccination were related to higher values of the anti-RBD test (median 2425, IQR 1450 - 3933 vs. median 1347, IQR 818 - 2125 for no symptoms; p<0.01).

ConclusionsThe BNT162b2 vaccine produced sufficient antibodies in terms of quality and quantity which could neutralise emerging variants. Antibody induction can be affected by age and sex but will still be at a sufficient level.


title: Clinical Evaluation of In House Produced 3D Printed Nasopharyngeal Swabs for COVID-19 Testing

abstract: 3D printed alternatives to standard flocked swabs were rapidly developed to provide a response to the unprecedented and sudden need for an exponentially growing amounts of diagnostic tools to fight the pandemics of COVID-19. In light of the anticipated shortage, an hospital-based 3D printing platform was implemented in our institution for the production of swabs for nasopharyngeal and oropharyngeal sampling based on the freely available open-sourced design made available to the community by University of South Floridas Health Radiology and Northwell Health System teams as replacement for locally used commercial swabs. Validation of our 3D printed swabs was performed by a head-to-head diagnostic accuracy study of the 3D printed "Northwell model" with the cobas PCR Media swabs sample kit. We observed an excellent concordance (total agreement 96.8%, Kappa 0.936) in results obtained with the 3D printed and flocked swabs indicating that the in-house 3D printed swab can be used reliably in a context of shortage of flocked swabs. To our knowledge, this is the first study to report on autonomous hospital-based production and clinical validation of 3D printed swabs.


title: Impact of Sepsis Identification and Treatment Time on In-Hospital Mortality, Length of Stay, and Hours in the Intensive Care Unit

abstract:
ObjectiveThe objective of this study was to examine the impact of timely treatment and identification of sepsis on patient outcomes at Sutter Health, a mixed-payer healthcare system in northern California, US.

MethodsThis observational, retrospective analysis considered electronic health record (EHR) data for individuals who presented with sepsis during 2016-17 at any of Sutter Healths 22 emergency departments (ED). Impacts were assessed for the timing of broad-spectrum antibiotic and intravenous (IV) fluid initiation, first vital signs, sepsis screening, and lactate results. Outcomes were in-hospital mortality, hospital length of stay (LOS) and intensive care unit (ICU) hours for patients discharged alive.

ResultsThe final sample size was 35,847 (N=9,638 severe sepsis, N=5,309 septic shock). Early fluid initiation had the largest estimated impacts: a mortality reduction of 2.85%[2.03%,3.68%] overall and 2.94%[1.44%,4.48%] for severe sepsis (within 1 hour of sepsis presentation), and 14.66%[9.23%,20.07%] for septic shock (within 3 hours); reduced LOS (days) 1.39[1.08,1.71] overall, 2.30[1.31,3.21] severe sepsis, 3.07[1.21,4.94] septic shock; and fewer ICU hours 25.93[16.95,34.66] overall, 35.06[14.7,56.99] severe sepsis, 41.99[15.70,70.68] septic shock (within 3 hours). Sepsis screening within 30 minutes was also associated with mortality reductions (3.88%[2.96%,4.90%] overall, 1.74%[0.08%,3.50%] severe sepsis, 6.78%[3.12%,10.33%] septic shock). The greatest improvement opportunity was estimated for joint initiation of antibiotics and IV fluids, with a modest additional mortality reduction of 0.80%[0.47%,1.17%] overall, 0.77%[0.34%,1.19%] severe sepsis, 2.94%[1.83%,3.97%] septic shock; LOS reduction of 0.37[0.28,0.46] overall, 0.29[0.17,0.43] severe sepsis, 0.25[0.01,0.51] septic shock (within 1 hour); ICU hours reduction of 4.85[3.26,6.57] overall, 5.07[2.55,7.67] severe sepsis, 3.85[1.69,6.24] septic shock (within 3 hours).

category: intensive care and critical care medicine


title: Cohort Design and Natural Language Processing to Reduce Bias in Electronic Health Records Research: The Community Care Cohort Project

abstract:
BackgroundElectronic health records (EHRs) promise to enable broad-ranging discovery with power exceeding that of conventional research cohort studies. However, research using EHR datasets may be subject to selection bias, which can be compounded by missing data, limiting the generalizability of derived insights.

MethodsMass General Brigham (MGB) is a large New England-based healthcare network comprising seven tertiary care and community hospitals with associated outpatient practices. Within an MGB-based EHR warehouse of >3.5 million individuals with at least one ambulatory care visit, we approximated a community-based cohort study by selectively sampling individuals longitudinally attending primary care practices between 2001-2018 (n=520,868), which we named the Community Care Cohort Project (C3PO). We also utilized pre-trained deep natural language processing (NLP) models to recover vital signs (i.e., height, weight, and blood pressure) from unstructured notes in the EHR. We assessed the validity of C3PO by deploying established risk models including the Pooled Cohort Equations (PCE) and the Cohorts for Aging and Genomic Epidemiology Atrial Fibrillation (CHARGE-AF) score, and compared model performance in C3PO to that observed within typical EHR Convenience Samples which included all individuals from the same parent EHR with sufficient data to calculate each score but without a requirement for longitudinal primary care. All analyses were facilitated by the JEDI Extractive Data Infrastructure pipeline which we designed to efficiently aggregate EHR data within a unified framework conducive to regular updates.

ResultsC3PO includes 520,868 individuals (mean age 48 years, 61% women, median follow-up 7.2 years, median primary care visits per individual 13). Estimated using reports, C3PO contains over 2.9 million electrocardiograms, 450,000 echocardiograms, 12,000 cardiac magnetic resonance images, and 75 million narrative notes. Using tabular data alone, 286,009 individuals (54.9%) had all vital signs available at baseline, which increased to 358,411 (68.8%) after NLP recovery (31% reduction in missingness). Among individuals with both NLP and tabular data available, NLP-extracted and tabular vital signs obtained on the same day were highly correlated (e.g., Pearson r range 0.95-0.99, p<0.01 for all). Both the PCE models (c-index range 0.724-0.770) and CHARGE-AF (c-index 0.782, 95% 0.777-0.787) demonstrated good discrimination. As compared to the Convenience Samples, AF and MI/stroke incidence rates in C3PO were lower and calibration error was smaller for both PCE (integrated calibration index range 0.012-0.030 vs. 0.028-0.046) and CHARGE-AF (0.028 vs. 0.036).

ConclusionsIntentional sampling of individuals receiving regular ambulatory care and use of NLP to recover missing data have the potential to reduce bias in EHR research and maximize generalizability of insights.

category: epidemiology


title: Corowa-kun: Impact of a COVID-19 vaccine information chatbot on vaccine hesitancy, Japan 2021

abstract:
BackgroundFew studies have assessed how mobile messenger apps affect COVID-19 vaccine hesitancy. We created a COVID-19 vaccine information chatbot in a popular messenger app in Japan to answer commonly asked questions.

MethodsLINE is the most popular messenger app in Japan. Corowa-kun, a free chatbot, was created in LINE on February 6, 2021. Corowa-kun provides instant, automated answers to frequently asked COVID-19 vaccine questions. In addition, a cross-sectional survey assessing COVID-19 vaccine hesitancy was conducted via Corowa-kun during April 5-12, 2021.

ResultsA total of 59,676 persons used Corowa-kun during February-April 2021. Of them, 10,192 users (17%) participated in the survey. Median age was 55 years (range 16-97), and most were female (74%). Intention to receive a COVID-19 vaccine increased from 59% to 80% after using Corowa-kun (p < 0.01). Overall, 20% remained hesitant: 16% (1,675) were unsure, and 4% (364) did not intend to be vaccinated. Factors associated with vaccine hesitancy were: age 16 to 34 (odds ratio [OR] = 3.7, 95% confidential interval [CI]: 3.0-4.6, compared to age [≥]65), female sex (OR = 2.4, Cl: 2.1-2.8), and history of a previous vaccine side-effect (OR = 2.5, Cl: 2.2-2.9). Being a physician (OR = 0.2, Cl: 0.1-0.4) and having received a flu vaccine the prior season (OR = 0.4, Cl: 0.3-0.4) were protective.

ConclusionsCorowa-kun reduced vaccine hesitancy by providing COVID-19 vaccine information in a messenger app. Mobile messenger apps could be leveraged to increase COVID-19 vaccine acceptance.


title: Estimating the SARS-CoV-2 infected population fraction and the infection to-fatality ratio: A data-driven case study based on Swedish time series data

abstract:
AimTo estimate the COVID-19 infection-to-fatality ratio (IFR), infection-to-case ratio (ICR), and infection-to-ICU admission ratio (IIAR) in Sweden; to suggest methods for time series reconstruction and prediction.

MethodsWe optimize a set of simple finite impulse response (FIR) models comprising of a scaling factor and time-delay between officially reported cases, ICU admissions and deaths time series using the least squares method. Combined with randomized PCR study results, we utilize this simple model to estimate the total number of infections in Sweden, and the corresponding IFR.

ResultsThe model class provides a good fit between ICU admissions and deaths throughout 2020. Cases fit consistently from July 2020, by when PCR tests had become broadly available. We observe a diminished IFR in late summer as well as a strong decline during 2021, following the launch of a nation-wide vaccination program. The total number of infections during 2020 is estimated to 1.3 million.

ConclusionsA FIR model with a delta filter function describes the evolution of epidemiological data in Sweden well. The fact that we found IFR, ICR and IIAR constant over large parts of 2020 is in contrast with claims of healthcare adaptation or mutated virus variants importantly affecting these ratios. The model allows us to retrospectively estimate the COVID-19 epidemiological trajectory, and conclude that Sweden was far from herd immunity by the end of 2020.


title: How immunity from and interaction with seasonal coronaviruses can shape SARS-CoV-2 epidemiology

abstract:
We hypothesised that cross-protection from seasonal epidemics of human coronaviruses (HCoVs) could have affected SARS-CoV-2 transmission, including generating reduced susceptibility in children. To determine what the pre-pandemic distribution of immunity to HCoVs was, we fitted a mathematical model to 6 years of seasonal coronavirus surveillance data from England and Wales. We estimated a duration of immunity to seasonal HCoVs of 7.3 years (95%CI 6.8 - 7.9) and show that, while cross-protection between HCoV and SARS-CoV-2 may contribute to the age distribution, it is insufficient to explain the age pattern of SARS-CoV-2 infections in the first wave of the pandemic in England and Wales. Projections from our model illustrate how different strengths of cross-protection between circulating coronaviruses could determine the frequency and magnitude of SARS-CoV-2 epidemics over the coming decade, as well as the potential impact of cross-protection on future seasonal coronavirus transmission.

Significance statementCross-protection from seasonal epidemics of human coronaviruses (HCoVs) has been hypothesised to contribute to the relative sparing of children during the early phase of the pandemic. Testing this relies on understanding the pre-pandemic age-distribution of recent HCoV infections, but little is known about their dynamics. Using England and Wales as a case study, we use a transmission model to estimate the duration of immunity to seasonal coronaviruses, and show how cross-protection could have affected the age distribution of susceptibility during the first wave, and alter SARS-CoV-2 transmission patterns over the coming decade.


title: The isolated effect of age on the risk of COVID-19 severe outcomes: a systematic review with meta-analysis

abstract:
IntroductionIncreased age has been reported to be a factor for COVID-19 severe outcomes. However, many studies do not consider the age-dependency of comorbidities, which influence the course of disease. Protection strategies often target individuals after a certain age, which may not necessarily be evidence-based. The aim of this review was to quantify the isolated effect of age on hospitalization, admission to ICU, mechanical ventilation, and death.

MethodsThis review was based on an umbrella review, in which Pubmed, Embase, and pre-print databases were searched on December 10, 2020 for relevant reviews on COVID-19 disease severity. Two independent reviewers evaluated the primary studies using predefined inclusion and exclusion criteria. The results were extracted, and each study was assessed for risk of bias. The isolated effect of age was estimated by meta-analysis, and the quality of evidence was assessed using GRADE.

ResultsSeventy studies met our inclusion criteria (case mortality n=14, in-hospital mortality n=44, hospitalization n=16, admission to ICU n=12, mechanical ventilation n=7). The risk of in-hospital and case mortality increased per age year by 5.7% and 7.4%, respectively (Effect Size (ES) in-hospital mortality=1.057, 95% CI:1.038-1.054; ES case mortality= 1.074, 95% CI:1.061-1.087), while the risk of hospitalization increased by 3.4% per age year (ES=1.034, 95% CI:1.021-1.048). No increased risk was observed for ICU admission and intubation by age year. There was no evidence of a specific age threshold at which the risk accelerates considerably. The confidence of evidence was high for mortality and hospitalization.

ConclusionsOur results show a best-possible quantification of the increase in COVID-19 disease severity due to age. Rather than implementing age thresholds, prevention programs should consider the continuous increase in risk. There is a need for continuous, high-quality research and "living" reviews to evaluate the evidence throughout the pandemic, as results may change due to varying circumstances.

What is already known?O_LIIncreasing age and comorbidities are risk factors for COVID-19 severe outcomes, such as hospitalization and mortality. However, comorbidities such as diabetes, cardiovascular disease, chronic pulmonary diseases increase with age, and the isolated effect of age on COVID-19 disease severity is not known.
C_LI

What are the new findings?O_LIThe risk of COVID-19 disease severity due to the isolated effect of age increases by age year and no specific age threshold was observed.
C_LIO_LIA best possible quantification of the increase in risk of COVID-19 severe outcomes due to age has been done.
C_LI

What do the new findings imply?O_LIAny workplace restrictions targeting a particular older age group are rather arbitrary, and may contribute to ageism in the society.
C_LIO_LIIf scores are to be built to assess an individuals risk for COVID-19 severe outcomes in workplace settings, these should be based on per-age increases.
C_LI


title: Pharmacological Management of Acute Spinal Cord Injury: A longitudinal multi-cohort observational study

abstract:
BackgroundNearly every individual sustaining traumatic spinal cord injury receives multiple types and classes of medications to manage a litany of secondary complications. Prior clinical studies and evidence from animal models suggest that several of these medications could enhance or impede endogenous neurological recovery. However, there is a knowledge gap surrounding the spectrum of pharmacologic agents typically administered in the routine management of spinal cord injury.

ObjectiveTo systematically determine the types of medications commonly administered, alone or in combination, in the acute to subacute phase of spinal cord injury.

MethodsWe conducted an analysis of two largescale cohorts (the Sygen interventional trial and the SCIRehab observational cohort study) to determine what constitutes " standards of acute pharmacological care" after spinal cord injury. Concomitant medication use, including dosage, timing and reason for administration, was tracked. Descriptive statistics were used to describe the medications administered within the first 60 days after spinal cord injury.

ResultsAcross 2040 individuals with spinal cord injury, 775 unique medications were administered within the two months after injury. On average, patients enrolled in the Sygen trial received 9.9 {+/-} 4.9 (range 0-34), 14.3 {+/-} 6.3 (range 1-40), 18.6 {+/-} 8.2 (range 0-58), and 21.5 {+/-} 9.7 (range 0-59) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Patients enrolled in the SCIRehab cohort study received on average 1.7 {+/-} 1.7 (range 0-11), 3.7 {+/-} 3.7 (range 0-24), 8.5 {+/-} 6.3 (range 0-42), and 13.5 {+/-} 8.3 (range 0-52) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Polypharmacy was commonplace (up to 43 medications per day per patient). Approximately 10% of medications were administered acutely as prophylaxis (e.g., against the development of pain or infections).

ConclusionsTo our knowledge, this was the first time acute pharmacological practices have been comprehensively examined after spinal cord injury. Our study revealed a high degree of polypharmacy in the acute stages of spinal cord injury, with potential to both positively and negatively impact neurological recovery. This data may provide key insight to achieve better understanding of how the acute pharmacological management of spinal cord injury affects long-term recovery. All results can be interactively explored on the RXSCI web site (https://jutzelec.shinyapps.io/RxSCI/) and GitHub repository (https://github.com/jutzca/Acute-Pharmacological-Treatment-in-SCI/).

category: neurology


title: Efficacy of Acceptance and Commitment Therapy in Daily Life (ACT-DL) in early psychosis: Results from the multi-center INTERACT randomized controlled trial

abstract:
ImportanceTreatment in the early stages of psychosis is crucial to prevent poor clinical and social outcomes. Currently, no preventive interventions are available that reduce psychotic distress, or affective and negative symptoms as well as functioning, calling for more and dedicated treatments for these.

ObjectiveTo investigate the efficacy of Acceptance and Commitment Therapy in Daily Life (ACT-DL), combining face-to-face therapy with an Ecological Momentary Intervention (EMI), in addition to treatment as usual for psychotic distress, in comparison to treatment as usual only.

DesignThis single-blinded randomized clinical INTERACT trial investigated participants post-intervention and at 6 and 12-month follow-up. Participants were recruited between June 1, 2015 and December 31, 2018. Assessors were blinded to treatment allocation.

SettingINTERACT is a multi-center trial recruiting participants from secondary mental health services in 5 regions in Belgium and The Netherlands.

ParticipantsThe sample was a referral sample of individuals aged 15-65 years with a clinically established UHR or FEP status.

InterventionsIndividuals were randomly assigned (1:1) to ACT-DL, consisting of 8 ACT sessions augmented with an EMI app in addition to treatment as usual, or to treatment as usual only.

Main outcomes and measuresThe primary outcome was a reduction in psychotic distress as assessed with CAARMS at post-intervention, 6-and 12-month follow-up. Secondary outcomes included symptom severity (measured with BPRS and BNNS), functioning (measured with SOFAS and SFS) and momentary psychotic distress (measured with the Experience Sampling Method, a structured diary technique). All analyses were described in the trial protocol and in a postregistration on the open-science framework, prior to accessing the data.

ResultsOf the 196 individuals assessed for eligibility, 148 were randomized to ACT-DL+TAU (n=71) or TAU (n=77) (72 female (49%), average age 25 (SD = 6), 71 FEP (48%)). 115 (78%) provided primary outcome data at least at one follow-up assessment. There was no evidence of a greater reduction in CAARMS distress in ACT-DL+TAU compared to TAU ({chi}2(3)=2.38; p=.50). However, general psychopathology ({chi}2(3)=14.44; p=.002); affective ({chi}2(3)=8.55; p=.04) and negative symptom severity ({chi}2(3)=19.96; p<.001) as measured with the BPRS was reduced, as well as negative symptoms as assessed with BNNS ({chi}2(3)=15.96; p=.001) in. Furthermore, global functioning improved ({chi}2(3)=8.72; p=.033) in ACT-DL+TAU compared to TAU, whereas social functioning failed to reach significance ({chi}2(3)=7.41; p=.060). Finally, a clear and significant reduction was found in momentary psychotic distress ({chi}2(3)=21.56; p<0.001), whereas no effects were found for momentary psychotic experiences ({chi}2(3)=1.02; p=.599), momentary positive ({chi}2(3)=4.17; p=.124) or negative ({chi}2(3)=2.78; p=.249) affect. No serious adverse events directly related to the therapy occurred.

Conclusions and relevanceINTERACT did not support a significant effect on psychotic distress as assessed with the CAARMS. However, significant improvements were found for momentary psychotic distress, global functioning and negative symptomatology. These results are promising given that these latter problems are among the hardest to treat.

Trial RegistrationDutch Trial Register: NTR4252

Key PointsO_ST_ABSQuestionC_ST_ABSCan Acceptance and Commitment Therapy (ACT) in Daily Life, a combined face-to-face ACT intervention with a digital daily life Ecological Momentary Intervention, reduce psychotic distress in the early stages of psychosis?

FindingsThis randomized clinical trial of 148 individuals in the early stages of psychosis (UHR or FEP) found no evidence that ACT-DL improved psychotic distress at post-intervention, 6 or 12-month follow-up over and above treatment as usual. However, significant effects were found for momentary psychotic distress, negative symptoms and functioning.

MeaningWhereas the blended care approach of face-to-face ACT with the ACT-DL EMI did not improve psychotic distress over and above treatment as usual, it provided a promising avenue for the treatment of momentary psychotic distress as well as for negative symptoms and improving functioning, some of the hardest to treat problems in individuals with UHR and FEP.


title: Panic! Rational Risk Avoidance During a Health Pandemic

abstract: During a health pandemic health workers have to balance two competing objectives: their own welfare vs. that of their patients. Intuitively, attending to sick patients during a pandemic poses risks to health workers because some of these patients could be infected. One way to reduce risk is by reducing contact with patients. These changes could be on the extensive margin, e.g., seeing fewer patients; or, more insidiously, on the intensive margin, by reducing the duration/intensity of contact. This paper studies risk avoidance behavior during the Covid-19 pandemic and examines implications for patient welfare. Using primary data on thousands of patient-provider interactions between January 2019 and October 2020 in Nigeria, I present evidence of risk compensation by health workers along the intensive margin. For example, the probability that a patient receives a physical examination has dropped by about a third. I find suggestive evidence of negative effects on health outcomes.

category: health economics


title: Generic Patient-Reported Outcomes and Outcome Measures: A Systematic Review Study Protocol

abstract:
BackgroundPatient-reported outcomes (PROs) are an essential part of health outcome measurement and vital to patient-centricity and valued-based care. Several international consortia have developed core outcome sets and many of them include PROs. PROs are measured by patient-reported outcome measures (PROMs). PROs and PROMs can be generic or specific to certain diseases or conditions. While the characteristics of generic PROs and PROMs are well recognised as widely relevant and applicable across different domains, diseases and conditions, there is a lack of knowledge on the types of PROs measured by generic PROMs. We also do not know in which disease areas generic PROs and PROMs are commonly used. To date, there has been no systematic review solely focusing on generic PROMs, what they measure and their areas of application.

ObjectivesThis systematic review will identify core PROs measured by generic PROMs used in adult populations and the areas in which they are applied.

MethodsWe will conduct a systematic review of reviews. The screening process and the reporting will comply with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) 2020 Statement. We will use four databases, Medline [PubMed], CINHAL [Ebsco], Cochrane [Cochrane Library], and PsycINFO [Ovid], and reports from international consortia. Inclusion criteria are systematic reviews, meta-analysis or patient-reported outcome sets developed by international consortia reporting on generic PROMs in adult populations. Articles primarily focusing on patient-reported experience measures (PREMs), children or adolescents, or those not written in English will be excluded. Risk of bias will be assessed by checking if the included articles comply with established guidelines for systematic reviews such as the PRISMA statement. We will extract generic PROMs and PROs measured by these PROMs, and the areas applied from the selected articles and reports. Extracted data and information will be quantitatively and qualitatively synthesised without statistical interference. The quality of the synthesised evidences will be assessed by clarifying the strengths, limitations and possible biases in our review.

category: health informatics


title: COVID-19 vaccine uptake in United States counties: geospatial vaccination patterns and trajectories towards herd immunity

abstract: Following the COVID-19 pandemic, safe and effective vaccines were developed and authorized for use in the general population. Studying factors that encourage community acceptance of these vaccines is needed to prevent proliferation of SARS-CoV-2 variants, to safely relax local restrictions, and to return to pre-pandemic living conditions. To our knowledge, United States (US) county-level disparities in vaccination are yet to be investigated. Our data span February - May 2021 across 3138 US counties. We consider percentage of residents with at least one dose of an authorized COVID vaccine as the outcome. Spatio-temporal models were used to determine associations of vaccination rates with time-fixed and time-varying covariates. Spatial variability was modelled via Conditional Auto-regressive models; county trajectories over time were specified using random slopes. Greater vaccination rates occur in counties with older residents, high educational attainment, and high proportion of minority residents. Vaccination rates change with COVID risk metrics, suggesting continued slowing of vaccine uptake due to decreasing incidence and infection rates. County effects reveal strong regional patterns in average vaccination rates and trajectories. Although local herd immunity can be expected in August 2021 for counties with typical uptake rates, these counties are clustered in relatively few areas of the country.


title: Estimation of incidence from aggregated current status data without differential mortality

abstract: We use a historical data about breathlessness in British coal miners to compare two methods centered around a differential equation for deriving the age-specific incidence from aggregated current status data with age information, i.e. age-specific prevalence data. Special focus is put on estimating confidence bounds. For this, we derive a maximum likelihood (ML) estimator for estimating the age-specific incidence from the prevalence data and confidence bounds are calculated based on classical ML theory. Second, we construct a Markov-Chain-Monte-Carlo (MCMC) algorithm to estimate confidence bounds, which implements a weighted version of the differential equation into the prior of the MCMC algorithm. The confidence bounds for both methods are compared and it turns out that the MCMC estimates approach the ML estimates if the prior gives strong weight to the differential equation.


title: Risk-Averse Multi-Stage Stochastic Programming to Optimizing Vaccine Allocation and Treatment Logistics for Effective Epidemic Response

abstract: Existing compartmental-logistics models in epidemics control are limited in terms of optimizing the allocation of vaccines and treatment resources under a risk-averse objective. In this paper, we present a data-driven, mean-risk, multi-stage, stochastic epidemics-vaccination-logistics model that evaluates various disease growth scenarios under the Conditional Value-at-Risk (CVaR) risk measure to optimize the distribution of treatment centers, resources, and vaccines, while minimizing the total expected number of infections, deaths, and close contacts of infected people under a limited budget. We integrate a new ring vaccination compartment into a Susceptible-Infected-Treated-Recovered-Funeral-Burial epidemics-logistics model. Our formulation involves uncertainty both in the vaccine supply and the disease transmission rate. Here, we also consider the risk of experiencing scenarios that lead to adverse outcomes in terms of the number of infected and dead people due to the epidemic. Combining the risk-neutral objective with a risk measure allows for a trade-off between the weighted expected impact of the outbreak and the expected risks associated with experiencing extremely disastrous scenarios. We incorporate human mobility into the model and develop a new method to estimate the migration rate between each region when data on migration rates is not available. We apply our multi-stage stochastic mixed-integer programming model to the case of controlling the 2018-2020 Ebola Virus Disease (EVD) in the Democratic Republic of the Congo (DRC) using real data. Our results show that increasing the risk-aversion by emphasizing potentially disastrous outbreak scenarios reduces the expected risk related to adverse scenarios at the price of the increased expected number of infections and deaths over all possible scenarios. We also find that isolating and treating infected individuals are the most efficient ways to slow the transmission of the disease, while vaccination is supplementary to primary interventions on reducing the number of infections. Furthermore, our analysis indicates that vaccine acceptance rates affect the optimal vaccine allocation only at the initial stages of the vaccine rollout under a tight vaccine supply.