title: COVID-19 mortality across selected states in India: the role of age structure.

abstract:
BackgroundMortality rates provide an opportunity to identify and act on the health system intervention for preventing deaths. Hence, it is essential to appreciate the influence of age structure while reporting mortality for a better summary of the magnitude of the epidemic.

ObjectivesWe described and compared the pattern of COVID-19 mortality standardized by age between selected states and India from January to November 2020.

MethodsWe initially estimated the Indian population for 2020 using the decadal growth rate from the previous census (2011). This was followed by estimations of crude and age-adjusted mortality rate per million for India and the selected states. We used this information to perform indirect standardization and derive the age-standardized mortality rates for the states for comparison. In addition, we derived a ratio for age-standardized mortality to compare across age groups within the state. We extracted information regarding COVID-19 deaths from the Integrated Disease Surveillance Programme special surveillance portal up to November 16, 2020.

ResultsThe crude mortality rate of India stands at 88.9 per million population(118,883/1,337,328,910). Age-adjusted mortality rate (per million) was highest for Delhi (300.5) and lowest for Kerala (35.9).The age-standardized mortality rate (per million) for India is (<15 years=1.6, 15-29 years=6.3, 30-44 years=35.9, 45- 59 years=198.8, 60-74 years=571.2, [≥]75 years=931.6). The ratios for age-standardized mortality increase proportionately from 45-59 years age group across all the states.

ConclusionThere is high COVID-19 mortality not only among the elderly ages, but we also identified heavy impact of COVID-19 on the working population. Therefore, we recommend further evaluation of age-adjusted mortality for all States and inclusion of variables like gender, socio-economic status for standardization while identifying at-risk populations and implementing priority public health actions.


title: Heart-centered positioning and tailored beam-shaping filtration for reduced radiation dose in coronary artery calcium imaging: a MESA study

abstract:
PurposeCardiac CT has a clear clinical role in the evaluation of coronary artery disease and assessment of coronary artery calcium (CAC) but the use of ionizing radiation limits clinical use. Beam shaping "bow-tie" filters determine the radiation dose and the effective scan field-of-view diameter (SFOV) by delivering higher X-ray fluence to a region centered at the isocenter. A method for positioning the heart near the isocenter could enable reduced SFOV imaging and reduce dose in cardiac scans. However, a predictive approach to center the heart, the extent to which heart centering can reduce the SFOV, and the associated dose reductions have not been assessed. The purpose of this study is to build a heart-centered patient positioning model, to test whether it reduces the SFOV required for accurate CAC scoring, and to quantify the associated reduction in radiation dose.

MethodsThe location of 38,184 calcium lesions (3,151 studies) in the Multi-Ethnic Study of Atherosclerosis (MESA) were utilized to build a predictive heart-centered positioning model and compare the impact of SFOV on CAC scoring accuracy in heart-centered and conventional body-centered scanning. Then, the positioning model was applied retrospectively to an independent, contemporary cohort of 118 individuals (81 with CAC>0) at our institution to validate the models ability to maintain CAC accuracy while reducing the SFOV. In these patients, the reduction in dose associated with a reduced SFOV beam-shaping filter was quantified.

ResultsHeart centering reduced the SFOV diameter 25.7% relative to body centering while maintaining high CAC scoring accuracy (0.82% risk reclassification rate). In our validation cohort, imaging at this reduced SFOV with heart-centered positioning and tailored beam-shaping filtration led to a 26.9% median dose reduction (25-75th percentile: 21.6 to 29.8%) without any calcium risk reclassification.

ConclusionsHeart-centered patient positioning enables a significant radiation dose reduction while maintaining CAC accuracy.

category: radiology and imaging


title: Association of long-term body weight variability with dementia: a prospective study

abstract:
Introduction

We aimed to investigate whether long-term body weight variability (BWV) is associated with late-life dementia and to further assess their potential temporal relationships.

Methods

In 5,547 participants in Health and Retirement Study (HRS), a population-based prospective cohort, we quantified BWV as coefficient of variation using self-reported body weight from 1992 to 2008 and followed their dementia status from 2008 to 2016.

Results

A total of 427 incident dementia cases were identified. Larger long-term BWV was significantly associated with higher risk of dementia (HR comparing extreme quartiles: 2.01, 95% CI: 1.48-2.72; HR of each SD increment: 1.21, 95% CI,1.10-1.32; p-trend<0.001). This significant association was even observed for BWV estimated approximately 15 years preceding dementia diagnosis (HR of each SD increment: 1.13, 95% CI: 1.03-1.23) and was more pronounced for that closer to diagnosis.

Discussion

Our findings suggested that large BWV could be a novel risk factor for dementia.

category: neurology


title: Humoral and cellular responses after a third dose of BNT162b2 vaccine in patients treated for lymphoid malignancies.

abstract:
BACKGROUNDImmunocompromised patients such as patients with hematological malignancies have impaired immune response to two doses of BNT162b2 (Pfizer / BioNtech) vaccine against SARS-CoV-2. Evaluation of a repeated immune stimulation with a third vaccine dose is needed.

METHODSa vaccine monitoring observatory was conducted in outpatients who were treated for lymphoid malignancies (LM) to monitor both immune and cellular response measured the day of administration of the dose 3 of the mRNA vaccine BNT162b2 and again three to four weeks. Elecsys (R) Anti-SARS-CoV-2 immunoassay was used to asses to the level of SARS-CoV-2 anti-Spike (S) antibodies (Abs) titer and SARS-CoV-2-specific T-cell responses were assessed by a whole blood Interferon-Gamma Release Immuno Assay (IGRA) (QuantiFERON Human IFN-gamma SARS-CoV-2, Qiagen(R)).

RESULTSAmong the 43 assessable patients (suffering from chronic lymphocytic leukemia (CLL) (n=15), indolent and aggressive B cell non-Hodgkin lymphoma (NHL) (n=14), and multiple myeloma (MM) (n=16)), 18 (41,8%) had no anti-S Abs before the dose 3 of BNT162b2 vaccine (n=9 CLL, n=8 NHL, n=1 MM), and they all 18 remained negative after the dose 3. Amongst the 25 patients with positive anti-S titers before dose 3, all patients remained positive and 23 patients increased their anti-S titer after dose 3. Patients with CLL and/or with previous anti-CD20 therapy treated within 12 months of administration of dose 3 had no significant increase of the humoral response. Among 22 available patients, dose 3 of BNT162b2 vaccine significantly increased the median IFN-gamma secretion. On eight (36.4%) patients who were double-negative for both immune and cellular response, five (22.7%) patients remained double-negative after dose 3.

CONCLUSIONSDose 3 of BNT162b2 vaccine stimulated humoral immune response among patients with LM, in particular patients with MM (who had higher anti-S baseline titer after dose 2) and those with no anti-CD20 treatment history within a year. T-cell response was increased among patients in particular with no active chemotherapy regimen. Our data support the use of an early third vaccine dose among immunocompromised patients followed for LM though some of them will still have vaccine failure.

category: oncology


title: Development and validation of a prognostic model for COVID-19: a population-based cohort study in Iceland

abstract:
BackgroundThe severity of SARS-CoV-2 infection varies from asymptomatic state to severe respiratory failure and the clinical course is difficult to predict. The aim of the study was to develop a prognostic model to predict the severity of COVID-19 at the time of diagnosis and determine risk factors for severe disease.

MethodsAll SARS-CoV-2-positive adults in Iceland were prospectively enrolled into a telehealth service at diagnosis. A multivariable proportional-odds logistic regression model was derived from information obtained during the enrollment interview with those diagnosed before May 1, 2020 and validated in those diagnosed between May 1 and December 31, 2020. Outcomes were defined on an ordinal scale; no need for escalation of care during follow-up, need for outpatient visit, hospitalization, and admission to intensive care unit (ICU) or death. Risk factors were summarized as odds ratios (OR) adjusted for confounders identified by a directed acyclic graph.

ResultsThe prognostic model was derived from and validated in 1,625 and 3,131 individuals, respectively. In total, 375 (7.9%) only required outpatient visits, 188 (4.0%) were hospitalized and 50 (1.1%) were either admitted to ICU or died due to complications of COVID-19. The model included age, sex, body mass index (BMI), current smoking, underlying conditions, and symptoms and clinical severity score at enrollment. Discrimination and calibration were excellent for outpatient visit or worse (C-statistic 0.75, calibration intercept 0.04 and slope 0.93) and hospitalization or worse (C-statistic 0.81, calibration intercept 0.16 and slope 1.03). Age was the strongest risk factor for adverse outcomes with OR of 75-compared to 45-year-olds, ranging from 5.29-17.3. Higher BMI consistently increased the risk and chronic obstructive pulmonary disease and chronic kidney disease correlated with worse outcomes.

ConclusionOur prognostic model can accurately predict the outcome of SARS-CoV-2 infection using information that is available at the time of diagnosis.

category: infectious diseases


title: SARS-CoV-2-specific Humoral Immune Responses after A Single Dose of Inactivated Whole-virus SARS-CoV-2 Vaccine in Kidney Transplant Recipients: An Initial Report

abstract: We presented an initial pilot study report focused on immunogenicity and safety following an inactivated whole-virus severe acute respiratory syndrome coronavirus 2 vaccination among kidney transplant (KT) recipients. At four weeks after the first dose of vaccine, the level of anti-receptor-binding domain IgG antibody was not significantly different compared to before vaccination in 30 KT recipients (p = 0.45). Moreover, a significant lower mean (95% CI) anti-receptor-binding domain IgG antibody was observed compared to 30 immunocompetent controls (2.4 [95% CI 1.3-3.5] vs. 173.1 [95% CI 88.3-2,457.9] AU/mL, p < 0.001). Mild adverse events included fever (17%) and localized pain at the injection site (14%) were observed after vaccination.


title: Assessing COVID prevention strategies to permit the safe opening of college campuses in fall 2021

abstract:
BackgroundEffective vaccines, improved testing technologies, and declines in COVID-19 incidence prompt an examination of the choices available to college administrators to safely resume in-person campus activities in fall 2021.

ObjectiveTo develop a decision support tool that assists college administrators in designing and evaluating customized COVID vaccination, screening, and prevention plans.

DesignDecision analysis linked to a compartmental epidemic model, quantifying the interaction of policy instruments (e.g., vaccination promotion, asymptomatic testing, physical distancing, and other non-pharmaceutical interventions), institutional priorities (e.g., risk tolerance, desire to resume activities), and assumptions about vaccine performance and background epidemic severity.

ParticipantsHypothetical cohort of 5000 individuals (students, faculty, and staff) living and working in the close environs of a residential college campus.

Main Outcome(s) and Measure(s)Cumulative infections over a 120-day semester.

ResultsUnder Base Case assumptions, if 90% coverage with an 85%-effective vaccine can be attained, the model finds that campus activities can be fully resumed while holding cumulative cases below 5% of the population without the need for routine, asymptomatic testing. With 50% population coverage using such a vaccine, a similar "return to normalcy" would require daily asymptomatic testing of unvaccinated individuals. The effectiveness of vaccination in reducing susceptibility to infection is a critical uncertainty.

Conclusions & RelevanceVaccination coverage is the most powerful tool available to college administrators to achieve a safe return to pre-pandemic operations this fall. Given the breadth of potential outcomes in the face of uncontrollable and uncertain factors, even colleges that achieve high vaccination coverage should be prepared to reinstitute testing and distancing policies on short notice.


title: SARS-CoV-2 seroprevalence in the city of Hyderabad, India in early 2021

abstract:
BackgroundCOVID-19 emerged as a global pandemic in 2020, rapidly spreading to most parts of the world. The proportion of infected individuals in a population can be reliably estimated via sero-surveillance, making it a valuable tool for planning control measures. We conducted a serosurvey study to investigate SARS-CoV-2 seroprevalence in the urban population of Hyderabad at the end of the first wave of infections.

MethodsThe cross-sectional survey conducted in January 2021 included males and females aged 10 years and above, selected by multi-stage random sampling. 9363 samples were collected from 30 wards distributed over 6 zones of Hyderabad and tested for antibodies against SARS-CoV-2 nucleocapsid antigen.

ResultsOverall seropositivity was 54.2%, ranging from 50-60% in most wards. Highest exposure appeared to be among 30-39y and 50-59y olds, with women showing greater seropositivity. Seropositivity increased with family size, with only marginal differences among people with varying levels of education. Seroprevalence was significantly lower among smokers. Only 11% of the survey subjects reported any COVID-19 symptoms, while 17% had appeared for Covid testing.

ConclusionOver half the citys population was infected within a year of onset of the pandemic. However, [~]46% people were still susceptible, contributing to subsequent waves of infection.

Highlights National level serosurveys under-estimate localised prevalence in dense urban areas
 SARS-CoV-2 seroprevalence in Hyderabad city was 54.2% after the first wave
 A large proportion of the population remains at risk over a year into the pandemic


title: Anaphylactic events in mRNA vaccines: a reporting case-control study

abstract:
BackgroundmRNA vaccines are a novel method of eliciting immunity, and play a significant role in the global fight against COVID-19. Anaphylactic reactions are a widespread concern driving vaccine hesitancy due to the serious and potentially fatal nature of anaphylaxis. A quantitative estimation of the risk of anaphylactic and ana-phylactoid reactions deriving from mRNA vaccines is of a significant public health importance.

ObjectiveTo estimate the relative Reporting Odds Ratio of anaphylactic and ana-phylactoid reactions following mRNA vaccination vis-a-vis other vaccinations.

DesignReporting case-control study.

SettingPersons reporting adverse events following vaccination to VAERS whose reports were received between 01 January 2000 and 02 July 2021, inclusive.

PatientsEach case of anaphylaxis or anaphylactoid reaction was matched with 2.7 unique controls on average, by gender and age rounded to the nearest integer.

MeasurementsOverall and stratified Reporting Odds Ratios (ROR) were calculated. Stratified contingency tables were tested for homogeneity using the Breslow-Day procedure, and Cochran-Mantel-Haenszel statistics were calculated to test the hypothesis of a ROR of unity.

Results2,665 cases of anaphylaxis or anaphylactoid reactions and 7,125 controls of non-anaphylactic/anaphylactoid reports were compared. The ROR of an anaphylactic or anaphylactoid reaction was 1.325 (95% CI: 1.212 - 1.448, p < 0.001). The matched set of cases and controls revealed an expected inhomogeneity by sex (with women slightly more likely to report anaphylactic presentations) and age band strata (with a bimodal distribution that reflects the common incidence of anaphylactic and allergic pathologies). No significant increase in the risk of anaphylactic adverse events was witnessed among persons who self-reported previous allergic reactions to vaccines. A slightly elevated ROR was observed with patients who reported a history of allergic reactions to NSAIDs and/or fluoroquinolone antibiotics. The precise meaning and relevance of this finding remains to be elucidated.

LimitationsAs a reporting study using data from VAERS, our analysis is subject tunder- and overreporting, the extent of each of which is not known with any degree of precision. Since the Emergency Use Authorizations for both mRNA vaccines mandate reporting of all serious adverse events, reporting bias is likely in favour of non-mRNA vaccines, where such reporting is not mandatory in adults. Consequently, this analysis may exaggerate the ROR of anaphylactic and anaphylactoid events associated with mRNA vaccines, which may in reality be significantly lower.

ConclusionsmRNA vaccination is not associated with a statistically significant higher risk of reporting an anaphylactic adverse event to VAERS. Anaphylaxis is a serious but very rare complication of all immunisations. No significant increase in reporting odds was found in any age group or gender, nor in most cases of previously known allergic adverse events in relation to vaccines. This study contributes to the growing body of evidence proving the safety and tolerability of mRNA vaccines.

category: epidemiology


title: Association between reactogenicity and SARS-CoV-2 antibodies after the second dose of the BNT162b2 COVID-19 vaccine

abstract: High vaccine reactogenicities may reflect stronger immune responses, but the epidemiological evidence for coronavirus disease 2019 (COVID-19) vaccines is sparse and inconsistent. We observed that a fever of [≥]38{square} after two doses of the BNT162b2 vaccine was associated with higher severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike IgG titers.


title: Predicting future ocular Chlamydia trachomatis infection prevalence using serological, clinical, molecular, and geospatial data

abstract: Trachoma is an infectious disease characterized by repeated exposures to Chlamydia trachomatis (Ct) that may ultimately lead to blindness. District-level estimates of clinical disease are currently used to guide control programs. However, clinical trachoma is a subjective indicator. Serological markers present an objective, scalable alternative for monitoring and targeting of more intensive control efforts. We hypothesized that IgG seroprevalence in combination with geospatial layers, machine learning, and model-based geostatistics would be able to accurately predict future community-level ocular Ct infections detected by PCR. Among 40 communities in the hyperendemic Amhara region of Ethiopia, median Ct infection prevalence among children 0-5 years old increased from 6% at enrollment to 29% at month 36. Seroprevalence was the strongest concurrent predictor of infection prevalence at month 36 among children 0-5 years old (cross-validated R2 = 0.75, 95% CI: 0.58-0.85), though predictive performance declined substantially with increasing temporal lag between predictor and outcome measurements. Geospatial variables, a spatial Gaussian process, and stacked ensemble machine learning did not meaningfully improve predictions. Serological markers among children 0-5 years old may be a promising programmatic tool for identifying communities with high levels of active ocular Ct infections, but accurate, future prediction in the context of changing transmission remains a challenge.


title: Re-emergence of respiratory syncytial virus following the COVID-19 pandemic in the United States: a modeling study

abstract:
ImportanceRespiratory syncytial virus (RSV) is a leading cause of hospitalizations in young children. RSV largely disappeared in 2020 due to precautions taken because of the COVID-19 pandemic. Projecting the timing and intensity of the re-emergence of RSV and the age groups affected is crucial for planning for the administration of prophylactic antibodies and anticipating hospital capacity.

ObjectiveTo project the potential timing and intensity of re-emergent RSV epidemics in different age groups.

Design, Setting, ParticipantsMathematical models were used to reproduce the annual RSV epidemics before the COVID-19 pandemic in New York and California. These models were modified to project the trajectory of RSV epidemics in 2020-2025 under different scenarios with varying stringency of mitigation measures for SARS-CoV-2: 1) constant low RSV transmission rate from March 2020 to March 2021; 2) an immediate decrease in RSV transmission in March 2020 followed by a gradual increase in transmission until April 2021; 3) a decrease in non-household contacts from April to July 2020. Simulations also evaluated factors likely to impact the re-emergence of RSV epidemics, including introduction of virus from out-of-state sources and decreased transplacentally-acquired immunity in infants.

Main Outcomes and MeasuresThe primary outcome of this study was defined as the predicted number of RSV hospitalizations each month in the entire population. Secondary outcomes included the age distribution of hospitalizations among children <5 years of age, incidence of any RSV infection, and incidence of RSV lower respiratory tract infection (LRI).

ResultsIn the 2021-2022 RSV season, we expect that the lifting of mitigation measures and build-up of susceptibility will lead to a larger-than-normal RSV outbreak. We predict an earlier-than-usual onset in the upcoming RSV season if there is substantial external introduction of RSV. Among children 1-4 years of age, the incidence of RSV infections could be twice that of a typical RSV season, with infants <6 months of age having the greatest seasonal increase in the incidence of both severe RSV LRIs and hospitalizations.

Conclusions and RelevancePediatric departments, including pediatric intensive care units, should be alert to large RSV outbreaks. Enhanced surveillance is required for both prophylaxis administration and hospital capacity management.


title: Delta variants of SARS-CoV-2 cause significantly increased vaccine breakthrough COVID-19 cases in Houston, Texas

abstract: Genetic variants of SARS-CoV-2 have repeatedly altered the course of the COVID-19 pandemic. Delta variants of concern are now the focus of intense international attention because they are causing widespread COVID-19 disease globally and are associated with vaccine breakthrough cases. We sequenced the genomes of 16,965 SARS-CoV-2 from samples acquired March 15, 2021 through September 20, 2021 in the Houston Methodist hospital system. This sample represents 91% of all Methodist system COVID-19 patients during the study period. Delta variants increased rapidly from late April onward to cause 99.9% of all COVID-19 cases and spread throughout the Houston metroplex. Compared to all other variants combined, Delta caused a significantly higher rate of vaccine breakthrough cases (23.7% for Delta compared to 6.6% for all other variants combined). Importantly, significantly fewer fully vaccinated individuals required hospitalization. Individuals with vaccine breakthrough cases caused by Delta had a low median PCR cycle threshold (Ct) value (a proxy for high virus load). This value was closely similar to the median Ct value for unvaccinated patients with COVID-19 caused by Delta variants, suggesting that fully vaccinated individuals can transmit SARS-CoV-2 to others. Patients infected with Alpha and Delta variants had several significant differences. Our integrated analysis emphasizes that vaccines used in the United States are highly effective in decreasing severe COVID-19 disease, hospitalizations, and deaths.

category: pathology


title: Irremediable psychiatric suffering in the context of physician assisted death: a Delphi-study

abstract:
BackgroundPatients with a psychiatric disorder (PPD) are eligible to request physician assisted death (PAD) in a small but growing number of jurisdictions, including the Netherlands and Belgium. For this request to be granted, most of these jurisdictions demand that the patient is competent in her request, and that the suffering experienced is unbearable and irremediable. Especially the criterion of irremediability is challenging to establish in patients with psychiatric disorders.

AimsTo establish what criteria Dutch and Belgian experts agree to be essential in characterising irremediable psychiatric suffering (IPS) in the context of PAD.

MethodA two round Delphi procedure among psychiatrists with relevant experience.

ResultsThirteen consensus-criteria were established: five diagnostic and eight treatment-related criteria. Diagnostically, the participants deem a narrative description and attention to contextual and systemic elements necessary. Also, a mandatory second opinion is required. The criteria concerning treatment show that extensive biopsychosocial treatment is needed, and the suffering must be present for several years. Finally, in the case of treatment refusal, the participants agree that there are limits to the number of diagnostic procedures or treatments a patient must undergo.

ConclusionsConsensus was found among a Dutch and Belgian expert group on essential criteria for establishing IPS in the context of PAD. These criteria can be used in clinical decision making and can inform future procedural demands and research.

category: psychiatry and clinical psychology


title: Effectiveness of Covishield vaccine in preventing Covid-19 -- A test-negative case-control study

abstract:
IntroductionThis study was aimed at assessing the vaccine effectiveness (VE) of Covishield, which is identical to the AstraZeneca vaccine, in preventing laboratory-confirmed Covid-19.

MethodsUsing a test-negative case-control design, information on vaccination status of cases with Covid-19 among healthcare workers in our institution in Puducherry, India, and an equal number of matched controls, i.e., positive and negative for SARS-CoV-2 by RT-PCR, was obtained. The cases and controls were matched for age ({+/-}3 years) and date of testing ({+/-}3 days). The groups were compared using multivariable conditional logistic regression to calculate odds ratios (OR), with adjustment for gender, occupational role, presence of symptoms and presence of a comorbidity condition. Per cent vaccine effectiveness (VE) was calculated as 100 x (1-adjusted odds ratio).

ResultsUsing data from 360 case-control pairs, VE of one dose and of two doses, in providing protection against Covid-19 was 49% (95% CI: 17%-68%) and 54% (27%-71%), respectively. In view of a difference in the proportion of cases and controls who had symptoms, a separate analysis of data from 203 pairs where both the case and the control had symptoms was done, which showed VE of 58% (28%-75%) and 64% (38%-78%) after one dose and two doses, respectively. Among cases with moderately severe disease that required oxygen therapy, VE following any number of vaccine doses was 95% (44%-100%).

ConclusionCovishield vaccine protected significantly against Covid-19, with the protection after two doses being slightly higher than after one dose, and a particularly high protection rate against severe forms of disease.

category: public and global health


title: Exposure to Wildfire Smoke and Particulate Matter among Washington State Construction Workers; Potential Impacts and Implications for Worker Protection

abstract: Driven by climate change, wildfires are increasing in frequency, duration, and intensity across the Western United States. Outdoor workers are being exposed to increasing wildfire-related particulate matter and smoke. Recognizing this emerging risk, Washington adopted an emergency rule and is presently engaged in creating a permanent rule to protect outdoor workers from wildfire smoke exposure. While there are growing bodies of literature on the exposure to and health effects of wildfire smoke in the general public and wildland firefighters, there is a gap in knowledge about wildfire smoke exposure among outdoor workers generally, and construction workers specifically, a large category of outdoor workers in Washington totaling 200,000 people. In this study, several data sources were linked including state-collected employment data and national ambient air quality data to gain insight into the risk of PM2.5 exposure among construction workers and evaluate the impacts of different air quality thresholds that would have triggered a new Washington emergency wildfire smoke rule aimed at protecting workers from high PM2.5 exposure. Results indicate the number of poor air quality days has increased in August and September in recent years. Over the last decade these months with the greatest potential for particulate matter exposure coincided with an annual peak in construction employment that was typically 9.4 to 42.7% larger across Washington counties (one county was 75.8%). Lastly, the "encouraged" threshold of the Washington emergency rule (20.5 g/m3) would have resulted in 5.5 times more days subject to the wildfire rule on average across all Washington counties compared to its "required" threshold (55.5 g/m3), and in 2020 the rule could have created demand for 1.35 million N-95 filtering facepiece respirators among construction workers. These results have important implications for both employers and policy makers as rules are developed. The potential policy implications of wildfire smoke exposure, exposure control strategies, and data gaps that would improve understanding of construction worker exposure to wildfire smoke are also discussed.

category: occupational and environmental health


title: Potential impacts of Washington State's wildfire worker protection rule on construction workers


title: Public Opinion and Sentiment Before and at the Beginning of COVID-19 Vaccinations in Japan: Twitter Analysis

abstract:
BackgroundThe pandemic of COVID-19 is causing a crisis in public health, food systems, and employment. Vaccination is considered as one of the most effective ways for containing the pandemic, but widespread vaccine hesitation on social media may curtail uptake progress. Fully comprehending public sentiment towards the COVID-19 vaccine is critical to building confidence on the vaccines and achieving herd immunity, especially in Japan with inadequate vaccine confidence.

ObjectiveThis study aims to explore the opinion and sentiment towards the COVID-19 vaccine in Japanese tweets, before and at the beginning of large-scale vaccinations.

MethodsWe collected 144,101 Japanese tweets containing COVID-19 vaccine-related keywords between August 1, 2020, and June 30, 2021. We visualized the trend of number of tweets and identified the critical events that triggered a surge and provided high-frequency unigram and bigram tokens. Also, we performed sentiment analysis and calculated the correlation of number of tweets and positive/negative sentiments with infection, death, and vaccinated cases. we also used the latent Dirichlet allocation (LDA) model to identify topics of tweets. In addition, we conducted analysis on three vaccine brands (Pfizer/Moderna/AstraZeneca).

ResultsDaily number of tweets continued growing and the growth accelerated since the large-scale vaccinations in Japan. The sentiment of around 85% tweets were neutral, and the negative sentiment overwhelmed the positive sentiment in the other tweets. Number of tweets strongly correlated (r[≥]0.5) with infection/death/vaccinated cases, and the number of negative tweets correlated strongly with the number of infection/death cases but weakened after the first vaccination in Japan. LDA identified three public-concerned topics: vaccine appointment and distribution strategy; Different vaccines development progress and approval status of countries; Side effects and effectiveness against mutated viruses. Among vaccines of the three manufactures, Pfizer won the most attention and Moderna the least.

ConclusionsOur findings indicated that negative sentiment towards vaccines dominated than positive sentiment in Japan. Changes in number of tweets and sentiments might be driven by critical events related to the COVID-19 vaccine, and negative sentiment continued increasing when numerous adverse accidents occurred at the beginning of large-scale vaccinations. Under the negative sentiment, the concerns of three vaccine brands remains effectiveness and safety with slight differences. The policymakers should provide more evidence about the effectiveness and safety of vaccines and optimize the process of vaccinations.

category: health informatics


title: Vaccine Approvals and the Role of the FDA Vaccine Advisory Committee, 2000-2019

abstract:
BackgroundThe US Food and Drug Administration (FDA) plays a critical role in bolstering public confidence in vaccines and the vaccine review process. An important tool for enhancing transparency and public trust is the FDAs Vaccine and Biological Related Products Advisory Committee (VRBPAC), a group of external experts that advises on scientific issues related to the licensure of vaccines.

ObjectiveTo analyze key features of VRBPAC meetings convened over 20 years; estimate the probability of advisory committee review of newly approved vaccines, focusing on vaccines targeting emerging diseases; and examine the speed of and variance in approval times as a function of VRBPAC review.

MethodsCross-sectional study of VRBPAC meetings convened and new vaccine licensure applications approved between January 1, 2000, and December 31, 2019. We analyzed the frequency of VRBPAC meetings and sessions; the percentage of newly licensed vaccines reviewed by VRBPAC; and the number of days between the submission of the licensure application and the date of FDA approval.

ResultsBetween 2000 and 2019, VRBPAC convened for a mean of 4.1 sessions per year. One-quarter of sessions was devoted to the review of specific vaccine products. During the same period, 44 new vaccine licensures were approved, 20% of which were for vaccines targeting emerging diseases. Almost half (48%) of successful new vaccine applications were reviewed by VRBPAC (n=21), a rate lower than for therapeutic applications. Among new applications targeting emerging diseases, 29% of non-influenza vaccines were reviewed by VRBPAC. There was no difference in the median time to approval as a function of VRBPAC review (364 days with VRBAC review vs. 365 days with no review, p=0.870).

ConclusionThe FDA has convened VRBPAC for reviews of about half of its vaccine products, less frequently for vaccines against non-influenza emerging diseases. There is considerable scope for the FDA to increase VRBPAC engagement in the vaccine review process.

category: health policy


title: Single-dose mRNA vaccine effectiveness against SARS-CoV-2 in healthcare workers extending 16 weeks post-vaccination: a test-negative design from Quebec, Canada

abstract:
IntroductionIn Canada, first and second doses of mRNA vaccines against SARS-CoV-2 were uniquely spaced 16 weeks apart, but the duration of single-dose protection remains uncertain. We estimated one- and two-dose mRNA vaccine effectiveness (VE) among healthcare workers (HCWs) in Quebec, Canada including protection against varying outcome severity, variants of concern (VOC), and the stability of single-dose protection out to 16 weeks post-vaccination.

MethodsA test-negative design compared vaccination among SARS-CoV-2 test-positive and weekly-matched (10:1), randomly-sampled, test-negative HCWs using linked surveillance and immunization databases. Vaccine status was defined by one dose [≥]14 days or two doses [≥]7 days before illness onset or specimen collection. Adjusted VE was estimated by conditional logistic regression.

ResultsPrimary analysis included 5,316 cases and 53,160 controls. Single-dose VE was 70% (95%CI: 68-73) against SARS-CoV-2 infection, 73% (95%CI: 71-75) against COVID-19 illness and 97% (95%CI: 92-99) against associated hospitalization. Two-dose VE was 86% (95%CI: 81-90) and 93% (95%CI: 89-95), respectively, with no associated hospitalizations. VE was higher for non-VOC than VOC (73% Alpha) among single-dose (77%, 95%CI: 73-81 versus 63%, 95%CI: 57-67) but not two-dose recipients (87%, 95%CI: 57-96 versus 94%, 95%CI: 89-96). Across 16 weeks, no decline in single-dose VE was observed with appropriate stratification based upon prioritized vaccination determined by higher versus lower likelihood of direct patient contact.

ConclusionOne mRNA vaccine dose provided substantial and sustained protection to HCWs extending at least four months post-vaccination. In circumstances of vaccine shortage, delaying the second dose may be a pertinent public health strategy to consider.


title: The metabolic, virulence and antimicrobial resistance profiles of colonizing Streptococcus pneumoniae shift after pneumococcal vaccine introduction in urban Malawi

abstract: Streptococcus pneumoniae accounts for at least 300,000 deaths from pneumonia, septicaemia and meningitis among children under 5-years-old worldwide. Protein-polysaccharide conjugate vaccines (PCVs) are highly effective at reducing vaccine serotype disease but emergence of non-vaccine serotypes and persistent nasopharyngeal carriage threaten to undermine this success. Here, we address the hypothesis that following vaccine introduction in high disease and carriage burden settings, adapted pneumococcal genotypes emerge with the potential to facilitate vaccine escape. We show that beyond serotype replacement, there are marked changes in S. pneumoniae carriage population genetics amongst 2804 isolates sampled 4-8 years after the 2011 introduction of PCV-13 in urban Malawi. These changes are characterised by metabolic genotypes with distinct virulence and antimicrobial resistance (AMR) profiles. This included exclusive genes responsible for metabolism and carbohydrate transport, and toxin-antitoxin systems located in an integrative-conjugative region suggestive of horizontal gene transfer. These emergent genotypes were found to have differential growth, haemolytic, or epithelial adhesion/invasion traits that may confer advantage in the nasopharyngeal niche. Together these data show that in the context of PCV13 introduction in a high burden population, there has been a shift in the pneumococcal population dynamics with the emergence of genotypes that have undergone multiple adaptations extending beyond simple serotype replacement, a process that could further undermine vaccine control and promote the spread of AMR.


title: SARS-CoV-2 Genomic Surveillance Reveals Little Spread Between a Large University Campus and the Surrounding Community

abstract: COVID-19 has had high incidence at institutions of higher education (IHE) in the United States, but the transmission dynamics in these settings are not well understood. It remains unclear to what extent IHE-associated outbreaks have contributed to transmission in nearby communities. We implemented high-density prospective genomic surveillance to investigate these dynamics at the University of Michigan-Ann Arbor and the surrounding community during the Fall 2020 semester (August 16th -November 24th). We sequenced complete SARS-CoV-2 genomes from 1659 individuals, including 468 students, representing 20% of cases in students and 25% of total confirmed cases in Washtenaw County over the study interval. Phylogenetic analysis identified over 200 introductions into the student population, most of which were not related to other student cases. There were two prolonged transmission clusters among students that spanned across multiple on-campus residences. However, there were very few genetic descendants of student clusters among non-students during a subsequent November wave of infections in the community. We conclude that outbreaks at the University of Michigan did not significantly contribute to the rise in Washtenaw County COVID-19 incidence during November 2020. These results provide valuable insights into the distinct transmission dynamics of SARS-CoV-2 among IHE populations and surrounding communities.


title: Low cost, injection molded, nasopharyngeal swabs for addressing global diagnostic supply shortages

abstract: The SARS-CoV-2 pandemic revealed the fragility of global supply chains, resulting in shortages of essential clinical supplies for the detection and treatment of COVID-19, including nasopharyngeal swabs (NP) commonly used to collect clinical samples for respiratory disease diagnostics. Groups around the world led a response to find alternatives to these shortages. Here, we describe the development of a single-component nasopharyngeal swab (GrooveSwab) composed of medical grade polypropylene that can be mass manufactured using conventional injection molding. The design inspired by cat tongue papillae consists of a non-absorbent stacked ring structure that allows for efficient and comfortable collection of viscous mucus samples and faster release into collection medium compared to traditional absorbent swabs. GroveSwabs were evaluated in 2 clinical studies in the US and Peru and demonstrated 90% or better concordance with commercial swabs. The simplified NP swab offers a reliable, lower cost, and more manufacturable alternative to absorbent swabs to avoid future shortages.


title: Surveillance of SARS-CoV-2 variants in Argentina: detection of Alpha, Gamma, Lambda, Epsilon and Zeta in locally transmitted and imported cases

abstract: Molecular surveillance of SARS-CoV-2 variants was performed on a total of 2,406 samples from the capital city and nine provinces of Argentina, during 30 epidemiological weeks (EW) that covered the end of the first wave and the beginning of the ongoing second wave of the COVID-19 pandemic in the country (EW 44/2020 to EW 20/2021). The surveillance strategy was mainly based on Sanger sequencing of a Spike coding region that allows the simultaneous identification of signature mutations associated with worldwide circulating variants. In addition, whole SARS-CoV-2 genome sequences were obtained from 456 samples. The main variants found were Gamma, Lambda and Alpha, and to a lesser extent, Zeta and Epsilon. Whereas Gamma dominated in different regions of the country, both Gamma and Lambda prevailed in the most populated area, the metropolitan region of Buenos Aires (MABA), although showing a heterogeneous distribution along this region. This cost-effective surveillance protocol allowed for a rapid response in a limited access to resources scenario, added information on the expansion of the Lambda variant in South America and contributed to the implementation of public health measures to control the disease spread in Argentina.


title: RNA viromics of Southern California wastewater and detection of SARS-CoV-2 single nucleotide variants.

abstract:
Municipal wastewater provides an integrated sample of a diversity of human-associated microbes across a sewershed, including viruses. Wastewater-based epidemiology (WBE) is a promising strategy to detect pathogens and may serve as an early-warning system for disease outbreaks. Notably, WBE has garnered substantial interest during the COVID-19 pandemic to track disease burden through analyses of SARS-CoV-2 RNA. Throughout the COVID-19 outbreak, tracking SARS-CoV-2 in wastewater has been an important tool for understanding the spread of the virus. Unlike traditional sequencing of SARS-CoV-2 isolated from clinical samples, which adds testing burden to the healthcare system, in this study, metatranscriptomics was used to sequence virus directly from wastewater.

Here, we present a study in which we explored RNA viral diversity through sequencing 94 wastewater influent samples across seven treatment plants (WTPs), collected August 2020 - January 2021, representing approximately 16 million people in Southern California. Enriched viral libraries identified a wide diversity of RNA viruses that differed between WTPs and over time, with detected viruses including coronaviruses, influenza A, and noroviruses. Furthermore, single nucleotide variants (SNVs) of SARS-CoV-2 were identified in wastewater and we measured proportions of overall virus and SNVs across several months. We detected several SNVs that are markers for clinically-important SARS-CoV-2 variants, along with SNVs of unknown function, prevalence, or epidemiological consequence.

Our study shows the potential of WBE to detect viruses in wastewater and to track the diversity and spread of viral variants in urban and suburban locations, which may aid public health efforts to monitor disease outbreaks.

ImportanceWastewater based epidemiology (WBE) can detect pathogens across sewersheds, which represents the collective waste of human populations. As there is a wide diversity of RNA viruses in wastewater, monitoring the presence of these viruses is useful for public health, industry, and ecological studies. Specific to public health, WBE has proven valuable during the COVID-19 pandemic to track the spread of SARS-CoV-2 without adding burden to healthcare systems. In this study, we used metatranscriptomics and RT-ddPCR to assay RNA viruses across Southern California wastewater from August 2020 - January 2021, representing approximately 16 million people from Los Angeles, Orange, and San Diego counties. We found that SARS-CoV-2 quantification in wastewater correlates well with county-wide COVID-19 case data, and that we can detect SARS-CoV-2 single nucleotide variants through sequencing. Likewise, WTPs harbored different viromes, and we detected other human pathogens such as noroviruses and adenoviruses, furthering our understanding of wastewater viral ecology.


title: Effectiveness of the ChAdOx1 vaccine in the elderly during SARS-CoV-2 Gamma variant transmission in Brazil

abstract:
BackgroundA two-dose regimen of ChAdOx1 coronavirus disease 19 (Covid-19) vaccine with an inter-dose interval of three months has been implemented in many countries with restricted vaccine supply. However, there is limited evidence for the effectiveness of ChAdOx1 by dose in elderly populations in countries with high prevalence of the Gamma variant of severe acute respiratory syndrome 2 (SARS-CoV-2).

MethodsWe conducted a test-negative case-control study to estimate the effectiveness of ChAdOx1 vaccine in adults aged 60 years or older during a Gamma-variant-associated epidemic in Sao Paulo state, Brazil, between 17 January and 2 July 2021. Cases and matched test-negative controls were individuals, identified from surveillance databases, who experienced an acute respiratory illness and underwent SARS-CoV-2 RT-PCR testing. We used conditional logistic regression to estimate the effectiveness by dose against RT-PCR-confirmed Covid-19, Covid-19 hospitalization, and Covid-19-related death.

Results61,164 individuals were selected into matched case-control pairs. Starting [≥]28 days after the first dose, adjusted effectiveness of a single dose of ChAdOx1 was 33.4% (95% CI, 26.4 to 39.7) against Covid-19, 55.1% (95% CI, 46.6 to 62.2) against hospitalization, and 61.8% (95% CI, 48.9 to 71.4) against death. Starting [≥]14 days after the second dose, the adjusted effectiveness of the two-dose schedule was 77.9% (95% CI, 69.2 to 84.2) against Covid-19, 87.6% (95% CI, 78.2 to 92.9) against hospitalization, and 93.6% (95% CI, 81.9 to 97.7) against death.

ConclusionsCompletion of the ChAdOx1 vaccine schedule afforded significantly increased protection over a single dose against mild and severe Covid-19 outcomes in elderly individuals during widespread Gamma variant transmission.


title: Children with SARS-CoV-2 in the National COVID Cohort Collaborative (N3C)

abstract:
ImportanceSARS-CoV-2

ObjectiveTo determine the characteristics, changes over time, outcomes, and severity risk factors of SARS-CoV-2 affected children within the National COVID Cohort Collaborative (N3C)

DesignProspective cohort study of patient encounters with end dates before May 27th, 2021.

Setting45 N3C institutions

ParticipantsChildren <19-years-old at initial SARS-CoV-2 testing

Main Outcomes and MeasuresCase incidence and severity over time, demographic and comorbidity severity risk factors, vital sign and laboratory trajectories, clinical outcomes, and acute COVID-19 vs MIS-C contrasts for children infected with SARS-CoV-2.

Results728,047 children in the N3C were tested for SARS-CoV-2; of these, 91,865 (12.6%) were positive. Among the 5,213 (6%) hospitalized children, 685 (13%) met criteria for severe disease: mechanical ventilation (7%), vasopressor/inotropic support (7%), ECMO (0.6%), or death/discharge to hospice (1.1%). Male gender, African American race, older age, and several pediatric complex chronic condition (PCCC) subcategories were associated with higher clinical severity (p[≤]0.05). Vital signs (all p[≤]0.002) and many laboratory tests from the first day of hospitalization were predictive of peak disease severity. Children with severe (vs moderate) disease were more likely to receive antimicrobials (71% vs 32%, p<0.001) and immunomodulatory medications (53% vs 16%, p<0.001).

Compared to those with acute COVID-19, children with MIS-C were more likely to be male, Black/African American, 1-to-12-years-old, and less likely to have asthma, diabetes, or a PCCC (p<0.04). MIS-C cases demonstrated a more inflammatory laboratory profile and more severe clinical phenotype with higher rates of invasive ventilation (12% vs 6%) and need for vasoactive-inotropic support (31% vs 6%) compared to acute COVID-19 cases, respectively (p<0.03).

ConclusionsIn the largest U.S. SARS-CoV-2-positive pediatric cohort to date, we observed differences in demographics, pre-existing comorbidities, and initial vital sign and laboratory test values between severity subgroups. Taken together, these results suggest that early identification of children likely to progress to severe disease could be achieved using readily available data elements from the day of admission. Further work is needed to translate this knowledge into improved outcomes.

category: pediatrics


title: IT ambidexterity driven patient agility and hospital patient service performance: a variance approach

abstract: Hospitals are currently exploring digital options to transform their clinical procedures and their overall engagement with patients. This paper investigates how hospital departments can leverage the ability of firms to simultaneously explore new IT resources and practices (IT exploration) as well as exploit their current IT resources and practices (IT exploitation), i.e., IT ambidexterity, to adequately sense and respond to patients needs and demands, i.e., patient agility. This study embraces the dynamic capability view and develops a research model, and tests it accordingly using cross-sectional data from 90 clinical hospital departments from the Netherlands through an online survey. The models hypothesized relationships are tested using Partial Least Squares (PLS) structural equation modeling (SEM). The outcomes demonstrate the significance of IT ambidexterity in developing patient agility, positively influencing patient service performance. The study outcomes support the theorized model can the outcomes shed light on how to transform clinical practice and drive patient agility.

category: health systems and quality improvement


title: Global predictions of short- to medium-term COVID-19 transmission trends : a retrospective assessment

abstract:
BackgroundAs of July 2021, more than 180,000,000 cases of COVID-19 have been reported across the world, with more than 4 million deaths. Mathematical modelling and forecasting efforts have been widely used to inform policy-making and to create situational awareness.

Methods and FindingsFrom 8th March to 29th November 2020, we produced weekly estimates of SARS-CoV-2 transmissibility and forecasts of deaths due to COVID-19 for countries with evidence of sustained transmission. The estimates and forecasts were based on an ensemble model comprising of three models that were calibrated using only the reported number of COVID-19 cases and deaths in each country. We also developed a novel heuristic to combine weekly estimates of transmissibility and potential changes in population immunity due to infection to produce forecasts over a 4-week horizon. We evaluated the robustness of the forecasts using relative error, coverage probability, and comparisons with null models.

ConclusionsDuring the 39-week period covered by this study, we produced short- and medium-term forecasts for 81 countries. Both the short- and medium-term forecasts captured well the epidemic trajectory across different waves of COVID-19 infections with small relative errors over the forecast horizon. The model was well calibrated with 56.3% and 45.6% of the observations lying in the 50% Credible Interval in 1-week and 4-week ahead forecasts respectively. We could accurately characterise the overall phase of the epidemic up to 4-weeks ahead in 84.9% of country-days. The medium-term forecasts can be used in conjunction with the short-term forecasts of COVID-19 mortality as a useful planning tool as countries continue to relax stringent public health measures that were implemented to contain the pandemic.


title: Clinical and Virological Response to a Neutralizing Monoclonal Antibody for Hospitalized Patients with COVID-19

abstract:
BACKGROUNDBamlanivimab, a neutralizing monoclonal antibody given in combination with remdesivir, did not improve outcomes among hospitalized COVID-19 patients based on an early futility assessment. In this final study report, we evaluate an a priori hypothesis that greater benefit of bamlanivimab would be identified in those without detectable endogenous neutralizing antibody levels at study entry, especially if viral levels were high.

METHODSHospitalized COVID-19 patients were randomized to receive bamlanivimab (7000mg) or placebo and followed for 90 days for sustained recovery (home for 14 consecutive days); recovery rate ratios (RRRs) are cited.

RESULTSAmong 314 participants (163 on bamlanivimab and 151 on placebo), the median time to sustained recovery was 19 days and RRR=0.99 (95% CI: 0.79-1.22; p=0.89). At entry, 50% evidenced production of anti-spike neutralizing antibodies; 50% had SARS-CoV-2 nucleocapsid plasma antigen levels [≥] 1,000 ng/L. Among those without and with antibodies at study entry, the RRRs were 1.24 (95% CI: 0.90-1.70) and 0.74 (95% CI: 0.54-1.00) (p=0.02 for interaction). The RRRs were elevated for those with plasma antigen or nasal viral RNA levels above versus below median at entry, and was greatest for those without antibodies and with elevated antigen or viral RNA levels: 1.48 (95% CI: 0.99-2.23), 1.94 (1.25-3.00), respectively (p<0.05 for all interactions). Hazard ratios for safety outcomes also differed by serostatus at entry.

CONCLUSIONSSustained recovery after administration of bamlanivimab versus placebo differed by presence of neutralizing antibodies at study entry, especially if participants had markers of elevated viral replication.

ClinicalTrials.gov number, NCT04501978.


title: Antibody responses to BNT162b2 vaccination in Japan: Monitoring vaccine efficacy by measuring IgG antibodies against the receptor binding domain of SARS-CoV-2

abstract:
BACKGROUNDTo fight severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), mass vaccination has begun in many countries. To investigate the usefulness of a serological assay to predict vaccine efficacy, we analyzed the levels of IgG, IgM, and IgA against the receptor binding domain (RBD) of SARS-CoV-2 in the sera from BNT162b2 vaccinated individuals in Japan.

METHODSThis study included 219 individuals who received two doses of BNT162b2. The levels of IgG, IgM, and IgA against RBD were measured by enzyme-linked immunosorbent assay before and after the first and second vaccination, respectively. The relationship between antibody levels and several factors including age, gender, and hypertension were analyzed. Virus-neutralizing activity in sera was measured to determine the correlation with the levels of antibodies. A chemiluminescent enzyme immunoassay (CLEIA) method to measure IgG against RBD was developed and validated for the clinical setting.

RESULTSThe levels of all antibody isotypes were increased after vaccination. Among them, RBD-IgG was dramatically increased after the second vaccination. The IgG levels in females were significantly higher than in males. There was a negative correlation between age and IgG levels in males. The IgG levels significantly correlated with the neutralizing activity. The CLEIA assay measuring IgG against RBD showed a reliable performance and a high correlation with neutralizing activity.

CONCLUSIONSMonitoring of IgG against RBD is a powerful tool to predict the efficacy of SARS-CoV-2 vaccination and provides useful information in considering a personalized vaccination strategy for COVID-19.


title: Prevalence of SARS CoV-2 infection among Health Care Workers of a hybrid tertiary COVID 19 hospital in Kerala

abstract:
Back ground and objectivesThis study was undertaken to estimate the prevalence of SARS-CoV-2 infection among Health care workers [HCWs] of a hybrid COVID treatment hospital in Kerala.

MethodsThe study was conducted during 3rd week of January 2021. Among 3550 HCWs, 979 subjects were selected by stratified random sampling and grouped into high risk and low risk category based on job setting. Demographic details and clinical information regarding previous history of COVID 19 were collected at the time of SARS-CoV-2 IgG testing.

ResultsFrom 979 subjects, the data with respect to 940 health care workers were analysed. SARS-CoV-2 IgG was detected in 19.1% of HCWs. Seroprevalence among high risk group was 20.3% and that in low risk group was 7.4% [p=0.005]. In high-risk group, seropositivity was noted in 30.54 % of nurses, 19% hospital attenders, 18.9% resident doctors and 6.4% consultant doctors. In those with past history of SARS-CoV-2 infection, seropositivity was 75.4%. In those who were COVID positive during July2020, 33.3% were still IgG reactive.

Interpretation and conclusionThe study reported 19.1% SARS CoV-2 IgG reactivity among health care workers in our hospital. Seropositivity was significantly higher in high risk group compared to low risk group. Antibody decay kinetics in our study is comparable to that in published literature. Infection control challenges in hybrid hospitals account for higher seropositivity in this study compared to overall seroprevalence among HCWs in Kerala.


title: Fairness in Cardiac Magnetic Resonance Imaging: Assessing sex and racial bias in deep learning-based segmentation

abstract:
BackgroundArtificial intelligence (AI) techniques have been proposed for automation of cine CMR segmentation for functional quantification. However, in other applications AI models have been shown to have potential for sex and/or racial bias.

ObjectivesTo perform the first analysis of sex/racial bias in AI-based cine CMR segmentation using a large-scale database.

MethodsA state-of-the-art deep learning (DL) model was used for automatic segmentation of both ventricles and the myocardium from cine short-axis CMR. The dataset consisted of end-diastole and end-systole short-axis cine CMR images of 5,903 subjects from the UK Biobank database (61.5{+/-}7.1 years, 52% male, 81% white). To assess sex and racial bias, we compared Dice scores and errors in measurements of biventricular volumes and function between patients grouped by race and sex. To investigate whether segmentation bias could be explained by potential confounders, a multivariate linear regression and ANCOVA were performed.

ResultsWe found statistically significant differences in Dice scores (white [~]94% vs minority ethnic groups 86-89%) as well as in absolute/relative errors in volumetric and functional measures, showing that the AI model was biased against minority racial groups, even after correction for possible confounders.

ConclusionsWe have shown that racial bias can exist in DL-based cine CMR segmentation models. We believe that this bias is due to the imbalanced nature of the training data (combined with physiological differences). This is supported by the results which show racial bias but not sex bias when trained using the UK Biobank database, which is sex-balanced but not race-balanced.

Condensed AbstractAI algorithms have the potential to reflect or exacerbate racial/sex disparities in healthcare. We aimed to determine the impact of sex and race on the performance of an AI segmentation model for automatic CMR quantification in a cohort of 5,903 subjects from the UK Biobank database, which is sex-balanced but not race-balanced. We tested the models bias in performance using Dice scores and absolute/relative errors in measurements of biventricular volumes and function. Our study demonstrates that the model had a racial bias but no sex bias, and that subject characteristics and co-morbidities could not explain this bias.

category: cardiovascular medicine


title: SARS-CoV-2 incidence, transmission and reinfection in a rural and an urban setting: results of the PHIRST-C cohort study, South Africa, 2020-2021

abstract:
BackgroundBy August 2021, South Africa experienced three SARS-CoV-2 waves; the second and third associated with emergence of Beta and Delta variants respectively.

MethodsWe conducted a prospective cohort study during July 2020-August 2021 in one rural and one urban community. Mid-turbinate nasal swabs were collected twice-weekly from household members irrespective of symptoms and tested for SARS-CoV-2 using real-time reverse transcription polymerase chain reaction (rRT-PCR). Serum was collected every two months and tested for anti-SARS-CoV-2 antibodies.

ResultsAmong 115,759 nasal specimens from 1,200 members (follow-up rate 93%), 1976 (2%) were SARS-CoV-2-positive. By rRT-PCR and serology combined, 62% (749/1200) of individuals experienced [≥]1 SARS-CoV-2 infection episode, and 12% (87/749) experienced reinfection. Of 662 PCR-confirmed episodes with available data, 15% (n=97) were associated with [≥]1 symptom. Among 222 households, 200 (90%) had [≥]1 SARS-CoV-2-positive individual. Household cumulative infection risk (HCIR) was 25% (213/856). On multivariable analysis, accounting for age and sex, index case lower cycle threshold value (OR 3.9, 95%CI 1.7-8.8), urban community (OR 2.0,95%CI 1.1-3.9), Beta (OR 4.2, 95%CI 1.7-10.1) and Delta (OR 14.6, 95%CI 5.7-37.5) variant infection were associated with increased HCIR. HCIR was similar for symptomatic (21/110, 19%) and asymptomatic (195/775, 25%) index cases (p=0.165). Attack rates were highest in individuals aged 13-18 years and individuals in this age group were more likely to experience repeat infections and to acquire SARS-CoV-2 infection. People living with HIV who were not virally supressed were more likely to develop symptomatic illness, and shed SARS-CoV-2 for longer compared to HIV-uninfected individuals.

ConclusionsIn this study, 85% of SARS-CoV-2 infections were asymptomatic and index case symptom status did not affect HCIR, suggesting a limited role for control measures targeting symptomatic individuals. Increased household transmission of Beta and Delta variants, likely contributed to successive waves, with >60% of individuals infected by the end of follow-up.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPrevious studies have generated wide-ranging estimates of the proportion of SARS-CoV-2 infections which are asymptomatic. A recent systematic review found that 20% (95% CI 3%-67%) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections remained asymptomatic throughout infection and that transmission from asymptomatic individuals was reduced. A systematic review and meta-analysis of 87 household transmission studies of SARS-CoV-2 found an estimated secondary attack rate of 19% (95% CI 16-22). The review also found that household secondary attack rates were increased from symptomatic index cases and that adults were more likely to acquire infection. As of December 2021, South Africa experienced three waves of SARS-CoV-2 infections; the second and third waves were associated with circulation of Beta and Delta variants respectively. SARS-CoV-2 vaccines became available in February 2021, but uptake was low in study sites reaching 5% fully vaccinated at the end of follow up. Studies to quantify the burden of asymptomatic infections, symptomatic fraction, reinfection frequency, duration of shedding and household transmission of SARS-CoV-2 from asymptomatically infected individuals have mostly been conducted as part of outbreak investigations or in specific settings. Comprehensive systematic community studies of SARS-CoV-2 burden and transmission including for the Beta and Delta variants are lacking, especially in low vaccination settings.

Added value of this studyWe conducted a unique detailed COVID-19 household cohort study over a 13 month period in South Africa, with real time reverse transcriptase polymerase chain reaction (rRT-PCR) testing twice a week irrespective of symptoms and bimonthly serology. By the end of the study in August 2021, 749 (62%) of 1200 individuals from 222 randomly sampled households in a rural and an urban community in South Africa had at least one confirmed SARS-CoV-2 infection, detected on rRT-PCR and/or serology, and 12% (87/749) experienced reinfection. Symptom data were analysed for 662 rRT-PCR-confirmed infection episodes that occurred >14 days after the start of follow-up (of a total of 718 rRT-PCR-confirmed episodes), of these, 15% (n=97) were associated with one or more symptoms. Among symptomatic indvidiausl, 9% (n=9) were hospitalised and 2% (n=2) died. Ninety percent (200/222) of included households, had one or more individual infected with SARS-CoV-2 on rRT-PCR and/or serology within the household. SARS-CoV-2 infected index cases transmitted the infection to 25% (213/856) of susceptible household contacts. Index case ribonucleic acid (RNA) viral load proxied by rRT-PCR cycle threshold value was strongly predictive of household transmission. Presence of symptoms in the index case was not associated with household transmission. Household transmission was four times greater from index cases infected with Beta variant and fifteen times greater from index cases infected with Delta variant compared to wild-type infection. Attack rates were highest in individuals aged 13-18 years and individuals in this age group were more likely to experience repeat infections and to acquire SARS-CoV-2 infection within households. People living with HIV (PLHIV) who were not virally supressed were more likely to develop symptomatic illness when infected with SARS-CoV-2, and shed SARS-CoV-2 for longer when compared to HIV-uninfected individuals.

Implications of all the available evidenceWe found a high rate of SARS-CoV-2 infection in households in a rural community and an urban community in South Africa, with the majority of infections being asymptomatic in individuals of all ages. Asymptomatic individuals transmitted SARS-CoV-2 at similar levels to symptomatic individuals suggesting that interventions targeting symptomatic individuals such as symptom-based testing and contact tracing of individuals tested because they report symptoms may have a limited impact as control measures. Increased household transmission of Beta and Delta variants, likely contributed to recurrent waves of COVID-19, with >60% of individuals infected by the end of follow-up. Higher attack rates, reinfection and acquisition in adolescents and prolonged SARS-CoV-2 shedding in PLHIV who were not virally suppressed suggests that prioritised vaccination of individuals in these groups could impact community transmission.


title: Increased transmissibility of emerging SARS-CoV-2 variants is driven either by viral load or probability of infection rather than environmental stability

abstract: Understanding the factors that increase the transmissibility of the recently emerging variants of SARS-CoV-2 (such as the Alpha, Epsilon, and Delta variants) can aid in mitigating their spread. The enhanced transmissibility could be attributed to one or more factors: higher stability on surfaces or within droplet nuclei suspended in air, increased maximal viral load or higher probability of infection. The relative importance of these factors on the transmission was examined using a validated stochastic-jump-continuous hybrid model. The transmissibility was quantified in terms of the household secondary attack rate (hSAR) which is the probability of transmission from an infected individual to a susceptible one in a household. We find that an increase in either the maximal viral load or the probability of infection is consistent with the observed hSAR of the variants. Specifically, in order to reach the relative increase in the hSAR of 40%, 55%, and 87% reported for the Epsilon, Alpha, and Delta variants (respectively), the maximal viral load should increase by 56%, 78%, and 125%, respectively. Alternatively, the probability of infection should increase by 34%, 53%, and 193%, respectively. Contrary to these results, even a dramatic increase in environmental stability increases hSAR by no more than 10%.


title: Performance of a machine learning model in recognition of normal tissue from histological sections

abstract:
IntroductionMachine learning and artificial intelligence (AI) models have been applied in histopathology to solve specific problems like detection of metastasis in lymph nodes and immunohistochemical scoring. We have aimed to develop a machine learning model which can be trained in histopathology from the basics, i.e. identification of normal tissue. We have tried to replicate the process through which a human pathologist learns recognition of normal tissue from histological sections, and evaluate the performance of a machine learning model at this task.

Materials and methodsA total of 658 histologic images were anonymised, microphotographed at 10x magnification, under the same condition of illumination, with a Magnus DC5 integrated microphotography system. The images were split into two subsets, training (386) and validation (272 images). The images belonged to seven classes of tissue: brain, intestine, kidney, liver, lungs, muscle and skin. Archived material of the hospital were used for the study. A machine learning model using convolutional neural network (CNN) was developed on the Keras platform, using the convolution layers of a pretrained VGG16 model. The model was trained with the training set of images over 10 epochs. After training, performance of the model was assessed on the validation set.

ResultsThe model achieved 88.24% accuracy in classifying the images of the validation set. The most frequent errors were met in recognising images of kidney (14 errors, 33.33%). The commonest error was wrongly classifying kidney tissue as liver (07 errors). Analysis of the deeper layers of the neural network revealed specific patterns in images which were wrongly classified.

ConclusionThe results of the present study indicates that a convolutional neural network might be trained in histology similar to a trainee pathologist. The study represents the first step towards developing a machine learning model as a generalised histopathological image classifier.


title: Low uptake of COVID-19 lateral flow testing among university students: a mixed methods evaluation

abstract:
ObjectiveTo evaluate COVID-19 lateral flow testing (LFT) among asymptomatic university students.

Study designMixed methods evaluation of LFT among University of Bristol students.

Methodsi) An analysis of testing uptake and exploration of demographic variations in uptake using logistic regression; ii) an online student survey about views on university testing; and iii) qualitative interviews to explore participants experiences of testing and subsequent behaviour, analysed using a thematic approach.

Results12,391 LFTs were conducted on 8025/36,054 (22.3%) students. Only one in 10 students had the recommended two tests. There were striking demographic disparities in uptake with those from ethnic minority groups having lower uptake (e.g. 3% of Chinese students were tested vs. 30.7% of White students), and variations by level and year of study (ranging from 5.3% to 33.7%), place of residence (29.0% to 35.6%) and faculty (15.2% to 32.8%). Differences persisted in multivariable analyses.

A total of 436 students completed the online survey, and twenty in-depth interviews were conducted. Barriers to engagement with testing included a lack of awareness, knowledge and understanding, and concerns about the accuracy and safety. Students understood limitations of LFTs but requested further information about test accuracy. Tests were used to inform behavioural decisions, often in combination with other information, such as the potential for exposure to the virus and perceptions of vulnerability.

ConclusionsThe low uptake of testing brings into question the role of mass LFT in university settings. Innovative strategies may be needed to increase LFT uptake among students.


title: Why is patient safety a challenge? Insights from the Professionalism Opinions of Medical Students (PoMS) Research

abstract:
IntroductionDespite increased emphasis on education and training for patient safety in medical schools, there is little known about factors influencing decision making regarding patient safety behaviours. This study examined the nature and magnitude of factors which may influence opinions around patient safety related behaviours as a means of providing insights into how Australian doctors and medical students view these issues relative to members of the public.

MethodsA national, multicentre, prospective, on-line cross sectional survey was conducted using responses to hypothetical clinical scenarios. Three cohorts were surveyed - Australian enrolled medical students, medical doctors and members of the public.

Participant responses were compared for the different contextual variables within the scenarios and the participants demographic characteristics - student, doctor, member of the public, gender and age (if public or doctors)/ seniority in the course (if a medical student).

ResultsIn total there were 2602 medical student participants, 809 doctors and 503 members of the Australian public. Medical doctors were more likely than other cohorts to have statistically significant differences in how they viewed the acceptability of patient safety related behaviours; doctors were more tolerant of medical students not reporting concerning behaviours. Medical students opinions frequently demonstrated a  transition effect, bridging between the doctors and publics attitudes, consistent with professional identity formation.

ConclusionsOpinions on the acceptability of medical students patient safety related behaviours were influenced by the demographics of the cohort and the contextual complexity of the scenario. Although the survey used hypothetical scenarios, doctors and medical students opinions appear to be influenced by cognitive dissonances, biases and heuristics which may negatively affect patient safety.

 Opinion is the medium between knowledge and ignorance Plato

category: medical education


title: Personal bias in nutrition advice: A survey of healthcare professionals' recommendations regarding dairy and plant-based dairy alternatives

abstract:
ObjectiveTo examine the relationship between health professionals personal dietary preferences and their professional nutrition advice on dairy and plant-based dairy alternatives.

DesignCross sectional web-based survey. Survey examined health professionals personal dietary preferences, including milk preference, (plant-based or dairy milk), dietary pattern (vegetarian or omnivore), and if they followed a "plant-based" diet, and examined if they would advise patients to consume dairy and/or plant-based dairy alternatives. Logistic regression models examined if health professionals personal dietary preferences were associated with their willingness to recommend either product.

SettingSample of U.S. health professionals.

ParticipantsNon-probability convenience sampling recruited registered dietitian nutritionists, physicians, physician assistants, nurse practitioners, registered nurses, licensed practical nurses, dentists, dental hygienists, and students in any of these degree programs holding Junior standing and above. 331 respondents completed relevant survey questions and were included in analyses.

ResultsMost respondents would recommend dairy (81%) and dairy alternatives (72%) to their patients. Half (49%) reported a preference for plant-based milk, about 40% identified as having a dietary pattern that reduces animal product intake, and about 40% reported following a plant-based dietary pattern. Plant-based milk preference (OR 4.52; 95% CI 2.31 to 8.82, p<0.001) and following a vegetarian dietary pattern (OR 1.91; 95% CI 1.11 to 3.27, p=0.019) were associated with greater odds of recommending dairy alternatives to a patient. Plant-based milk preference (OR 0.16; 95% CI 0.07 to 0.35, p<0.001), following a vegetarian dietary pattern (OR 0.45; 95% CI 0.25 to 0.82, p=0.009), and following a plant-based dietary pattern (OR 0.41; 95% CI 0.22 to 0.76, p=0.005) were associated with lessor odds of recommending dairy to a patient. Dietetics professionals were more likely than all other health professionals to recommend both dairy and dairy alternatives to patients.

ConclusionsHealthcare professionals nutrition recommendations appear to reflect their personal nutrition habits, despite dairy being an important source of essential nutrients for patients who are willing and able to consume it. Improved nutrition training focusing on evidence-based nutrition recommendations, reducing personal bias in practice, and routinely including registered dietitians on interprofessional healthcare teams may improve the quality of nutrition advice given to U.S. consumers.

category: nutrition


title: Monday effect on confirmed cases of COVID-19 in Japan

abstract: We examined the phenomenon of fewer new confirmed cases of COVID-19 on Mondays in Japan, which we refer to as the Monday effect, and reveal the details of this effect. Specifically, we estimated the difference between the number of new positive cases that decreased over the weekend and the number of new confirmed cases that decreased at the beginning of the week. In Japan, prefectures aggregate and announce the number of confirmed daily cases. This analysis allows us to examine whether there is a Monday effect in each prefecture. We show that the Monday effect is due to the decreased number of inspections on the weekend appearing at the beginning of the week due to a time lag. Our results indicate that the administrative system causes delays in some prefectures, and that some prefectures are less likely to conduct screenings on holidays. Our results also suggest that delays generally occur in prefectures with a population of over 2 million. Congestion, Reporting delay, Public health, COVID-19


title: Seroprevalence and Dynamics of anti-SARS-CoV-2 antibody among healthcare workers following ChAdOx1 nCoV-19 vaccination

abstract:
BackgroundThe serological evaluations of IgG, IgM, and IgA to the SARS-CoV-2 proteins are widely used for the epidemiological assessment of COVID-19. The Health Care Workers (HCWs) are presumably exposed to a higher risk of acquiring the disease owing to their regular contact with the patients.

MethodsCOVID-19 prevalence was investigated by classifying 313 HCWs into four groups based on their degree of exposure and estimating the IgG and total antibody. The serological assessment of the anti-SARS-CoV-2 antibody was conducted 21 days post-vaccination of first or both doses of the ChAdOx1 nCoV-19 vaccine among 174 HCWs. The vaccinated HCWs were followed up for 3 months for SARS-CoV-2 infection.

FindingsThe levels of anti-SARS-CoV-2 IgG were comparable among different groups, but the seroprevalence gradually decreased from the most exposed to the less exposed group. The neutralizing antibody was positively correlated with IgG as well as total antibody. IgG was marginally decreased after 2 months followed by a significant drop after 4-6 months post-infection. However, 80% of the HCWs developed a detectable amount of IgG after the first dose of vaccination, the median titer of which was comparable to the seropositive HCWs after natural infection. Almost 100% of the HCWs developed antibodies after the second dose of vaccine with boosting effect among the seropositive HCWs. Although [~]11.5% of the vaccinated HCWs were infected with the SARS-CoV-2, [~]94% of them showed mild symptoms and recovered in home isolation without any O2 support.

InterpretationsThe varying level of seroprevalence among the four groups suggested stratified spread of the disease. One dose of SARS-CoV-2 vaccination was found to be effective in terms of the antibody titer, while the second dose was required to cover the larger population. The effectiveness of the ChAdOx1 nCoV-19 vaccine was noticeable due to the low rate of post-vaccination infection with moderate or severe symptoms.


title: All-cause mortality during SARS-CoV-2 Pandemic in India: Nationally-representative estimates independent of official death registry

abstract: We estimate excess deaths in India during the COVID pandemic using monthly deaths in the sample of a privately-conducted, nationally-representative, large, panel data set. The data set includes roughly 174,000 households (1.2 million members) and spans January 2015 - June 2021. We estimate COVID is associated with 3.36 million (95% CI: 2.08-4.63 million) excess deaths, a 17.3% increase in the all-cause death rate, until April 2021. Excess deaths spike during the peaks of the 2 infection waves in India. The second wave is associated with significantly more excess deaths than the first. The age-pattern of deaths is skewed towards the elderly relative to baseline.


title: Increase in ventilatory ratio indicates progressive alveolar damage and suggests poor prognosis in severe COVID-19: A single-center retrospective observational study.

abstract:
BackgroundThe symptoms of severe COVID-19 are complex and wide-ranging even in intensive care unit (ICU) patients, who may successfully discontinue respiratory support in a short period or conversely require prolonged respiratory support. Damage in the lungs of COVID-19 patients is characterized pathologically as diffuse alveolar damage, the degree of which correlates with the severity of the disease. We hypothesized that the ventilatory ratio (VR), a surrogate parameter for the dead space fraction, might stratify the severity of COVID-19 and predict the successful discontinuation of respiratory support.

MethodsForty COVID-19 patients in our ICU were enrolled in this study. Respiratory variables were collected from 2 hours (day 0) after the initiation of respiratory support. We monitored the longitudinal values of VR and other respiratory parameters for 28 days. Patients successfully discontinued from respiratory support by day 28 of ICU stay were defined as the successfully discontinued group, while those who died or failed to discontinue were defined as the failed to discontinue group. VR and other respiratory parameters were compared between these groups.

ResultsExcept for advanced age, prolonged ventilation period, and higher mortality in the failed to discontinue group, there were no significant differences between the groups in terms of any other background or respiratory parameter at 2 hours (day 0) after initiation of respiratory support. Longitudinal VR monitoring revealed significantly higher VR values in the failed to discontinue group than the successfully discontinued group on day 4 of respiratory support. Upon predicting the failure to discontinue respiratory support, the area under the receiver operating characteristic curve of VR values on day 4 of respiratory support was 0.748. A threshold of 1.56 achieved the highest predictive performance with a sensitivity of 0.667 and a specificity of 0.762. This threshold enabled the prediction of the successfully discontinued outcome at 0.810 of the negative predictive value.

ConclusionsElevated VR values on day 4 of respiratory support were predictive of successful discontinuation of respiratory support in patients with severe COVID-19. Longitudinal VR values after initiation of respiratory support can be used as a practical index to stratify severe COVID-19.

category: intensive care and critical care medicine


title: Accounting for the Role of Asymptomatic Patients in Understanding the Dynamics of the COVID-19 Pandemic: A Case Studyfrom Singapore

abstract:
ObjectivesTo forecast the true growth of COVID-19 cases in Singapore after accounting for asymptomatic infections, we study and make modifications to the SEIR (Susceptible-Exposed-Infected-Recovered) epidemiological model by incorporating hospitalization dynamics and the presence of asymptomatic cases. We then compare the simulation results of our three epidemiological models of interest against the daily reported COVID-19 case counts across the time period from 23rd January to 6th April 2020. Finally, we compare and evaluate on the performance and accuracy of the aforementioned models simulations.

MethodsThree epidemiological models are used to forecast the true growth of COVID-19 case counts by accounting for asymptomatic infections in Singapore. They are the exponential model, SEIR model with hospitalization dynamics (SEIHRD), and the SEIHRD model with inclusion of asymptomatic cases (SEAIHRD).

ResultsSimulation results of all three models reflect underestimation of COVID-19 cases in Singapore during the early stages of the pandemic. At a 40% asymptomatic proportion, we report basic reproduction number R0 = 3.28 and 3.74 under the SEIHRD and SEAIHRD models respectively. At a 60% asymptomatic proportion, we report R0 = 3.48 and 3.96 under the SEIHRD and SEAIHRD models respectively.

ConclusionsBased on the results of different simulation scenarios, we are highly confident that the number of COVID-19 cases in Singapore was underestimated during the early stages of the pandemic. This is supported by the exponential increase of COVID-19 cases in Singapore as the pandemic developed.


title: mRNA Vaccine Effectiveness against COVID-19 among Symptomatic Outpatients Aged >=16 Years in the United States, February to May 2021

abstract: Evaluations of vaccine effectiveness (VE) are important to monitor as COVID-19 vaccines are introduced in the general population. Research staff enrolled symptomatic participants seeking outpatient medical care for COVID-19-like illness or SARS-CoV-2 testing from a multisite network. VE was evaluated using the test-negative design. Among 236 SARS-CoV-2 nucleic acid amplification test-positive and 576 test-negative participants aged [≥]16 years, VE of mRNA vaccines against COVID-19 was 91% (95% CI: 83-95) for full vaccination and 75% (95% CI: 55-87) for partial vaccination. Vaccination was associated with prevention of most COVID-19 cases among people seeking outpatient medical care.


title: SGLT2-Inhibition reverts urinary peptide changes associated with severe COVID-19: an in-silico proof-of-principle of proteomics-based drug repurposing

abstract:
Severe COVID-19 is reflected by significant changes in multiple urine peptides. Based on this observation, a clinical test based on urinary peptides predicting COVID-19 severity, CoV50, was developed and registered as IVD in Germany. We have hypothesized that molecular changes displayed by CoV50, to a large degree likely reflective of endothelial damage, can be significantly reversed by specific drugs. To test this hypothesis, we have collected urinary peptide data from patients without COVID-19 prior and after drug treatment. The drugs chosen were selected based on availability of sufficient number of participants in the dataset (n>20) and potential value of drug therapies in the treatment of COVID-19 based on reports in the literature. In these participants without COVID-19, while spironolactone did not demonstrate a significant impact on CoV50 scoring, empagliflozin treatment resulted in a significant change in CoV50 scoring, indicative of a potential therapeutic benefit. The results serve as a proof-of-principle for a drug repurposing approach based on human urinary peptide signatures and support the initiation of a randomised control trial testing a potential positive effect of empagliflozin in the treatment of severe COVID-19, possibly via endothelial protective mechanisms.

Significance of the studyCOVID-19 pandemic has imposed a heavy burden on society, health care and economics. Although multiple drugs have been tested in the context of COVID-19, effective treatments for patients experiencing severe disease are still missing, with some drugs demonstrating benefit only at earlier disease stage. Computational drug repurposing emerged as a promising approach to boost drug development, allowing to predict drug efficacy based on the molecular signature of drug impact, mainly using transcriptomics data from cell lines.

Recently we demonstrated that urinary proteomics profiles significantly differ between patients with severe COVID-19 course and those with mild/ moderate disease. This resulted in the development of a molecular signature associated with COVID-19 severity (CoV50), allowing to predict COVID-19 course, and enabling guiding intervention.

Here we report on the first study demonstrating the application of clinical proteomics data (from clinical trial participants) in a drug repurposing approach. We used the CoV50 signature to examine if the molecular changes associated with COVID-19 severity in patients without COVID-19 might be altered by existing drugs. In a study population without COVID-19, empagliflozin demonstrated a partial, yet significant reversion of the CoV50 signature, indicating a potential benefit in the context of severe COVID-19.

category: pharmacology and therapeutics


title: Spread of infection and treatment interruption among Japanese workers during the COVID-19 pandemic: a cross-sectional study

abstract:
ObjectivesThis study aimed to examine the relationship between regional infection level and treatment interruption for chronic diseases.

MethodsA cross-sectional Internet monitoring survey was performed between December 22 and 26, 2020. Data from 9,510 (5,392 males and 4,118 females) participants needing regular treatment or hospital visits were analyzed. We determined the age-sex- and multivariate-adjusted odds ratios (ORs) of treatment interruption associated with various indices of infection level by nesting multilevel logistic models in prefecture of residence. In the multivariate model, sex, age, marital status, job type, equivalent household income, education, self-rated health, and anxiety were adjusted.

ResultsThe ORs of treatment interruption for the lowest versus highest levels of infection were 1.32 (95% CI: 1.09-1.59) for the overall incidence rate (per 1,000 population), 1.34 (95% CI: 1.10-1.63) for the overall number of people infected, 1.28 (95% CI: 1.06-1.54) for the monthly incidence rate (per 1,000 population), and 1.38 (95% CI: 1.14-1.67) for the number of people infected per month. For each index of infection level, higher infection was linked to more workers experiencing treatment interruption.

ConclusionHigher local infection levels were linked to more workers experiencing treatment interruption. Our results suggest that apart from individual characteristics such as socioeconomic and health status, treatment interruptions during the pandemic were also subject to contextual effects related to regional infection levels. Preventing community spread of COVID-19 may thus protect individuals from indirect effects of the pandemic, such as treatment interruption.


title: A Wastewater-based Epidemiology tool for COVID-19 Surveillance in Portugal

abstract: Shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in the feces and urine of infected patients and subsequent presence in wastewater has produced interest on the use of this matrix for sentinel surveillance at a community level and as a complementary approach to syndromic surveillance. With this work, we set the foundations for wastewater-based epidemiology (WBE) in Portugal by monitoring the trends of SARS-CoV-2 RNA circulation in the community, on a nationwide perspective during different epidemiological phases of the pandemic. The Charite assays (E_Sarbecco, RdRP, and N_Sarbecco) were applied to monitor, over 32-weeks (April to December 2020), the dynamics of SARS-CoV-2 RNA at the inlet of five wastewater treatment plants (WWTP), which together serve more than two million people in Portugal. Raw wastewater from three COVID-19 reference hospitals was also analyzed during this period. In total, more than 600 samples were tested. Sampling started late April 2020, during lockdown, and, for the first weeks, detection of SARS-CoV-2 RNA was sporadic, with concentrations varying from 103 to 105 genome copies per liter (GC/L). Prevalence of SARS-CoV-2 RNA increased steeply by the end of May into late June, mainly in Lisboa e Vale do Tejo region (LVT), during the reopening phase. After the summer, with the reopening of schools in mid-September and return to partial face-to-face work, a pronounced increase of SARS-CoV-2 RNA in wastewater was detected. In the LVT area, SARS-CoV-2 RNA load agreed with reported trends in hotspots of infection. Synchrony between trends of SARS-CoV-2 RNA in raw wastewater and daily new COVID-19 cases highlights the value of WBE as a surveillance tool for this virus, particularly after the phasing out of the epidemiological curve and when hotspots of disease re-emerge in the population which might be difficult to spot based solely on syndromic surveillance and contact tracing.


title: Concentration of SARS-CoV-2 from large volumes of raw wastewater is enhanced with the inuvai R180 system

abstract:
Wastewater-based epidemiology (WBE) for severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) is a powerful tool to complement syndromic surveillance: first, as an early-warning system for the spread of the virus in the community, second, to find hotspots of infection, and third, to aid in the early detection and follow-up of circulating virus variants.

Although detection of SARS-CoV-2 in raw wastewater may be prompted with good recoveries during periods of high community prevalence, in the early stages of population outbreaks concentration procedures are required to overcome low viral concentrations. Several methods have become available for the recovery of SARS-CoV-2 from raw wastewater, generally involving filtration. However, these methods are limited to small sample volumes, possibly missing the early stages of virus circulation, and restrained applicability across different water matrices. The aim of this study was thus to evaluate the performance of three methods enabling the concentration of SARS-CoV-2 from large volumes of wastewater: i) hollow fiber filtration using the inuvai R180, with an enhanced elution protocol and polyethylene glycol (PEG) precipitation; ii) PEG precipitation; and iii) skimmed milk flocculation. The performance of the three approaches was evaluated in wastewater from multiple wastewater treatment plants (WWTP) with distinct singularities, according to: i) effective volume; ii) percentage of recovery; iii) extraction efficiency; iv) inhibitory effect; and v) the limits of detection and quantification (The inuvai R180 system had the best performance, with detection of spiked controls across all samples, average recovery percentages of 64% for SARS-CoV-2 control and 68% for porcine epidemic diarrhea virus (PEDV), with low variability.

The inuvai R180 enables the scalability of volumes without negative impact on the costs, time for analysis, and recovery/inhibition. Moreover, hollow fiber filters favor the concentration of different microbial taxonomic groups. Such combined features make this technology attractive for usage in environmental waters monitoring.