title: Radius of Gyration as predictor of COVID-19 deaths trend with three-weeks offset

abstract:
Total and perimetral lockdowns were the strongest nonpharmaceutical interventions to fight against Covid-19, as well as the with the strongest socioeconomic collateral effects. Lacking a metric to predict the effect of lockdowns in the spreading of COVID-19, authorities and decision-makers opted for preventive measures that showed either too strong or not strong enough after a period of two to three weeks, once data about hospitalizations and deaths was available. We present here the radius of gyration as a candidate predictor of the trend in deaths by COVID-19 with an offset of three weeks. Indeed, the radius of gyration aggregates the most relevant microscopic aspects of human mobility into a macroscopic value, very sensitive to temporary trends and local effects, such as lockdowns and mobility restrictions. We use mobile phone data of more than 13 million users in Spain during a period of one year (from January 6th 2020 to January 10th 2021) to compute the users daily radius of gyration and compare the median value of the population with the evolution of COVID-19 deaths: we find that for all weeks where the radius of gyration is above a critical value (70% of its pre-pandemic score) the number of weekly deaths increases three weeks after. The reverse also stands: for all weeks where the radius of gyration is below the critical value, the number of weekly deaths decreased after three weeks. This observation leads to two conclusions: i) the radius of gyration can be used as a predictor of COVID-19-related deaths; and ii) partial mobility restrictions are as effective as a total lockdown as far the radius of gyration is below this critical value.

BackgroundAuthorities around the World have used lockdowns and partial mobility restrictions as major nonpharmaceutical interventions to control the expansion of COVID-19. While effective, the efficiency of these measures on the number of COVID-19 cases and deaths is difficult to quantify, severely limiting the feedback that can be used to tune the intensity of these measures. In addition, collateral socioeconomic effects challenge the overall effectiveness of lockdowns in the long term, and the degree by which they are followed can be difficult to estimate. It is desirable to find both a metric to accurately monitor the mobility restrictions and a predictor of their effectiveness.

MethodsWe correlate the median of the daily radius of gyration of more than 13M users in Spain during all of 2020 with the evolution of COVID-19 deaths for the same period. Mobility data is obtained from mobile phone metadata from one of the major operators in the country.

ResultsThe radius of gyration is a predictor of the trend in the number of COVID-19 deaths with 3 weeks offset. When the radius is above/below a critical threshold (70% of the pre-pandemic score), the number of deaths increases/decreases three weeks later.

ConclusionsThe radius of gyration can be used to monitor in real time the effectiveness of the mobility restrictions. The existence of a critical threshold suggest that partial lockdowns can be as efficient as total lockdowns, while reducing their socioeconomic impact. The mechanism behind the critical value is still unknow, and more research is needed.


title: COVID-19 vaccine acceptability and inequity in the United States: Results from a nationally representative survey

abstract:
BackgroundAt the time of this survey, September 1st, there were roughly 6 million COVID-19 cases and 176,771 deaths in the United States and no federally approved vaccine. The objective of this study was to explore the willingness to accept a COVID-19 vaccine in the United States and describe variability in this acceptability by key racial, ethnic and socio-demographic characteristics.

MethodsThis was a cross-sectional digital survey that sampled participants from a nationally-representative panel maintained by a third party, Dynata. Dynata randomly sampled their database and emailed web-based surveys to United States residents ensuring the sample was matched to US Census estimates for age, race, gender, income, and Census region. Participants were asked how willing or unwilling they would be to: 1) receive a COVID-19 vaccine as soon as it was made publicly available, and 2) receive the influenza vaccine for the upcoming influenza season. Participants could respond with extremely willing, willing, unwilling, or extremely unwilling. For those who reported being unwilling to receive a COVID-19 vaccine, reasons for this hesitancy were captured. All participants were asked about where they obtain vaccine-related information, and which sources they trust most. Univariable and multivariable logistic regressions were conducted to examine the association of all demographic characteristics with willingness to receive COVID-19 vaccine.

FindingsFrom September 1st to September 7, 2020, 1592 respondents completed the online survey. Overall, weighted analyses found that only 58.9% of the sample population were either willing or extremely willing to receive a COVID-19 vaccine as soon as it was made publicly available. In comparison, 67.7% of the respondents were willing or extremely willing to take the influenza vaccine. By gender, 66.1% of males and 51.5% of females were willing to receive a COVID-19 vaccine. Males were significantly more willing to receive a COVID-19 vaccine (adjusted odds ratio (OR)=1.98, 95% CI: 1.56, 2.53; p<0.001) than females. Blacks were the least willing racial/ethnic group (48.8%) Blacks, (aOR=0.59, 95%CI: 0.43, 0.80; p<0.001) were significantly less willing, than whites, to receive a COVID-19 vaccine. There were numerous reasons provided for being unwilling to receive a COVID-19 vaccine. The most common reason was concern about the vaccines safety (36.9%), followed by concerns over its efficacy (19.1%).

InterpretationIn conclusion, we found that a substantial proportion (41%) of United States residents are unwilling to receive a COVID-19 vaccine as soon as one is made publicly available. We found that vaccine acceptance differs by sub-populations. In addition to sub-group differences in willingness to receive the vaccine, respondents provided a variety of reasons for being unwilling to receive the vaccine, driven by various sources of vaccine information (and misinformation). This compounds the challenge of delivering a safe and efficacious COVID-19 vaccine at a population level to achieve herd immunity. A multi-pronged and targeted communications and outreach effort is likely needed to achieve a high level of immunization coverage.

category: epidemiology


title: Sustainable targeted interventions to mitigate the COVID-19 pandemic: A big data-driven modeling study in Hong Kong

abstract: Nonpharmaceutical interventions (NPIs) for contact suppression have been widely used worldwide, which impose harmful burdens on the population and the local economy. The evaluation of alternative NPIs is needed to confront the pandemic with less disruption. By harnessing human mobility data, we develop an agent-based model that can evaluate the efficacies of NPIs with individualized mobility simulations. Based on the model, we propose data-driven targeted interventions to mitigate the COVID-19 pandemic in Hong Kong without city-wide NPIs. We develop a data-driven agent-based model for 7.55 million Hong Kong residents to evaluate the efficacies of various NPIs in the first 80 days of the initial outbreak. The entire territory of Hong Kong is split into 4,905 500m x 500m grids. The model can simulate detailed agent interactions based on the demographics data, public facilities and functional buildings, transportation systems, and travel patterns. The general daily human mobility patterns are adopted from Googles Community Mobility Report. The scenario without any NPIs is set as the baseline. By simulating the epidemic progression and human movement at the individual level, we proposed model-driven targeted interventions, which focus on the surgical testing and quarantine of only a small portion of regions instead of enforcing NPIs in the whole city. The efficacious of common NPIs and the proposed targeted interventions are evaluated by extensive 100 simulations. The proposed model can inform targeted interventions, which are able to effectively contain the COVID-19 outbreak with much lower disruption of the city. It represents a promising approach to sustainable NPIs to help us revive the economy of the city and the world.


title: A Logistic Formula in Biology and Its Application to Deaths by the Third Wave of COVID-19 in Japan

abstract: A logistic formulation in biology is applied to analyze deaths by the third wave of COVID-19 in Japan.


title: COVID-19 risk perceptions of social interaction and essential activities and inequity in the United States: Results from a nationally representative survey

abstract:
IntroductionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) related diagnoses, hospitalizations, and deaths have disproportionately affected disadvantaged communities across the United States. Few studies have sought to understand how risk perceptions related to social interaction and essential activities during the COVID-19 pandemic vary by sociodemographic factors, information that could inform targeted interventions to reduce inequities in access to care and information.

MethodsWe conducted a nationally representative online survey of 1,592 adults in the United States to understand risk perceptions related to transmission of COVID-19 for various social and essential activities. We assessed relationships for each activity, after weighting to adjust for the survey design, using bivariate comparisons and multivariable logistic regression modeling, between responses of safe and unsafe, and participant characteristics, including age, gender, race, education, income, and political affiliation.

ResultsHalf of participants were younger than 45 years (n=844, 53.0%), female (n=800, 50.3%), and White/Caucasian (n=685, 43.0%), Black/African American (n=410, 25.8%), or Hispanic/Latino (n=382, 24.0%). Risk perceptions of unsafe for 13 activities ranged from 29.2% to 73.5%. Large gatherings, indoor dining, and visits with elderly relatives had the highest proportion of unsafe responses (>58%) while activities outdoor, visiting the doctor or dentist, and going to the grocery store had the lowest (<36%). Older respondents were more likely to view social gatherings and indoor activities as unsafe, yet more likely to view activities such as going to the grocery store, participating in outdoor activities, visiting elderly relatives, and visiting the doctor or emergency room as safe. Compared to White/Caucasian respondents, Black/African American and Hispanic/Latino respondents were more likely to view activities such as dining and visiting friends outdoor as unsafe. Generally, men vs. women, Republicans vs. Democrats and independents, and individuals with higher vs. lower income were more likely to view activities as safe.

ConclusionsThese findings suggest the importance of sociodemographic differences in risk perception, health behaviors, and access to information and health care when implementing efforts to control the COVID-19 pandemic. Further research should address how evidence-based interventions can be tailored considering these differences with a goal of increased health equity in the pandemic response.

category: public and global health


title: Successful reboot of high-performance sporting activities by Japanese national women's handball team in Tokyo, 2020 during the COVID-19 pandemic: An initiative by Japan Sports-Cyber Physical System (JS-CPS) of Sports Research Innovation Project (SRIP)

abstract:
BackgroundThe COVID-19 pandemic has negatively impacted sporting activities across the world. However, practical training strategies for athletes to reduce the risk of infection during the pandemic has not been definitively studied.

ObjectiveThe purpose of this report was to provide an overview of our challenges encountered during the reboot of high-performance sporting activities of the Japanese national handball team during the 3rd wave of the COVID-19 pandemic in Tokyo, Japan.

MethodsTwenty-nine Japanese national womens handball players and 24 staff participated in the study. To initiate the reboot of their first training camp after COVID-19 stay-home social policy, we conducted: web-based health-monitoring, SARS-CoV-2 screening with polymerase chain reaction (PCR) test, real-time automated quantitative monitoring of social distancing on-court using video-based artificial intelligence (AI) algorithm, physical intensity evaluation with wearable heart rate (HR) and acceleration sensors, and self-reported online questionnaire.

ResultsThe training camp was conducted successfully with no COVID-19 infections. The web-based health monitoring and the frequent PCR testing with short turnaround times contributed remarkably in early detection of athletes health problems and risk screening. During handball, the AI based on-court social-distancing monitoring revealed key time-dependent spatial metrics to define player-to-player proximity. This information facilitated positive team members on and off-game distancing behavior. Athletes regularly achieved around 80% of maximum HR during training, indicating anticipated improvements in achieving their physical intensities. Self-reported questionnaires related to the COVID management in the training camp revealed a sense of security among the athletes allowing them to focus singularly on their training.

ConclusionThe current challenge provided us considerable know-how to create and manage a safe environment for high-performing athletes in the COVID-19 pandemic via the Japan Sports-Cyber Physical System (JS-CPS) of SRIP (Japan Sports Agency, Tokyo, Japan). This report is envisioned to provide informed decisions to coaches, trainers, policymakers from the sports federations in creating targeted, infection-free, sporting and training environments.

category: sports medicine


title: Genetic determination of regional connectivity in modelling the spread of COVID-19 outbreak for improved mitigation strategies

abstract:
Covid-19 has resulted in the death of more than 1,500,000 individuals. Due to the pandemics severity, thousands of genomes have been sequenced and publicly stored with extensive records, an unprecedented amount of data for an outbreak in a single year. Simultaneously, prediction models offered region-specific and often contradicting results, while states or countries implemented mitigation strategies with little information on success, precision, or agreement with neighboring regions. Even though viral transmissions have been already documented in a historical and geographical context, few studies aimed to model geographic and temporal flow from viral sequence information. Here, using a case study of 7 states, we model the flow of the Covid-19 outbreak with respect to phylogenetic information, viral migration, inter- and intra- regional connectivity, epidemiologic and demographic characteristics. By assessing regional connectivity from genomic variants, we can significantly improve predictions in modeling the viral spread and intensity.

Contrary to previous results, our study shows that the vast majority of the first outbreak can be traced to very few lineages, despite the existence of multiple worldwide transmissions. Moreover, our results show that while the distance from hotspots is initially important, connectivity becomes increasingly significant as the virus establishes itself. Similarly, isolated local strategies-such as relying on herd immunity-can negatively impact neighboring states. Our work suggests that we can achieve more efficient unified mitigation strategies with selective interventions.

category: health informatics


title: High proportion of genome-wide homology and increased basal pvcrt levels in Plasmodium vivax late recurrences: a chloroquine therapeutic efficacy study

abstract: Chloroquine (CQ) is the first-line treatment for Plasmodium vivax malaria in most endemic countries. Monitoring P.vivax CQ resistance (CQR) is critical but remains challenged by the difficulty to distinguish real treatment failure from reinfection or liver relapse. Therapeutic efficacy of CQ against uncomplicated P.vivax malaria was evaluated in Gia Lai province, Vietnam. Sixty-seven patients were enrolled and followed-up for 42 days using microscopy and (RT)qPCR. Adequate clinical and parasitological response (ACPR) was 100% (66/66) on Day 28, but 75.4% (49/65) on Day 42. Eighteen recurrences (27.7%) were detected with a median time-to-recurrence of 42 days (IQR 35, 42) and blood CQ concentration <100ng/ml. Parasite genotyping by microsatellites, SNP-barcoding and whole-genome sequencing (WGS) identified a majority of homologous recurrences, with 80% (8/10) showing >98% identity-by-descent to paired Day 0 samples. Primary infections leading to recurrence occurred in younger individuals (median age for ACPR=25 years [IQR 20, 28]; recurrences=18 [16, 21]; p=0.002), had a longer parasite clearance time (PCT for ACPR=47.5h [IQR 36.2, 59.8]; recurrences=54.2h [48.4, 62.0]; p=0.035) and higher pvcrt gene expression (median relative expression ratio for ACPR=0.09 [IQR 0.05, 0.22]; recurrences=0.20 [0.15, 0.56]; p=0.002), but there was no difference in ex vivo CQ sensitivity. This study shows that CQ remained largely efficacious to treat P.vivax in Gia Lai, i.e. recurrences occurred late (>Day 28) and in the presence of low blood CQ concentrations. However, the combination of WGS and gene expression analysis (pvcrt) with clinical data (PCT) allowed to identify potential emergence of low-grade CQR that should be closely monitored.

category: infectious diseases


title: IN-HOSPITAL CONTINUATION WITH ANGIOTENSIN RECEPTOR BLOCKERS IS ASSOCIATED WITH A LOWER MORTALITY RATE THAN CONTINUATION WITH ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN COVID-19 PATIENTS A RETROSPECTIVE COHORT STUDY

abstract:
BackgroundSeveral studies have reported a reduced risk of death associated with the inpatient use of angiotensin receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) in COVID-19 patients, but have been criticized for incurring in several types of bias. Also, most studies have pooled ACEIs and ARBs as if they were a unique group, overlooking their pharmacological differences. We aimed to assess whether the in-hospital continuation of ARBs and ACEIs, in regular users of these drugs, was associated with a reduced risk of death as compared to their discontinuation and also to compare head-to-head ARBs with ACEIs.

MethodsAdult patients with a PCR-confirmed diagnosis of COVID-19 requiring admission during March, 2020 were consecutively selected from 7 hospitals in Madrid, Spain. Among them, we identified outpatient users of ACEIs/ARBs and divided them in two cohorts depending on treatment discontinuation/continuation at admission. Then, they were followed-up until discharge or in-hospital death. An intention-to-treat survival analysis was carried out and hazard ratios (HRs) and their 95%CI were computed through a Cox regression model adjusted for propensity scores of discontinuation and controlled by potential mediators.

ResultsOut of 625 ACEI/ARB users, 340(54.4%) discontinued treatment. The in-hospital mortality rates were 27.6% and 27.7% in discontinuation and continuation cohorts, respectively (HR=1.01; 95%CI:0.70-1.46). No difference in mortality was observed between ARB and ACEI discontinuation (28.6% vs. 27.1%, respectively), while a significantly lower mortality rate was found among patients who continued with ARBs (20.8%,N=125) as compared to those who continued with ACEIs (33.1%,N=136; p=0.03). The head-to-head comparison (ARB vs. ACEI continuation) yielded an adjusted HR of 0.52 (95%CI:0.29-0.93), being especially notorious among males (HR=0.34; 95%CI:0.12-0.93), subjects older than 74 years (HR=0.46; 95%CI:0.25-0.85), and patients with obesity (HR=0.22; 95%CI:0.05-0.94), diabetes (HR=0.36; 95%CI:0.13-0.97) and heart failure (HR=0.12; 95%CI:0.03-0.97).

ConclusionsAmong regular users of ARBs admitted for COVID-19, the in-hospital continuation with them was associated with an improved survival, while this was not observed with ACEIs. Regular users of ARBs should continue with this treatment if admitted for COVID-19, unless medically contraindicated. In admitted ACEI users, a switching to ARBs should be considered, especially among high-risk patients.

GRAPHICAL ABSTRACT

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category: pharmacology and therapeutics


title: Stay Home and Stay Active? The impact of stay-at-home restrictions on physical activity routines in the UK during the COVID-19 pandemic

abstract: Government restrictions applied during the COVID-19 pandemic in the UK led to the disruption of many peoples physical activity routines, with sports and leisure facilities closed and outdoor exercise only permitted once per day. In this study we investigated which population groups were impacted most in terms of reduced physical activity levels during these periods, and which groups benefitted in terms of increasing their usual level of physical activity. We surveyed UK residents, sampled through users of a rewards-for-exercise app (Sweatcoin; n=749) and an online panel (Prolific; n=907). Of the app users, n=487 further provided daily step-count data collected by the app, prior to, and during the periods of restrictions between March and June 2020. Regression models were applied to investigate factors associated with subjective change (perceived change in physical activity) and objective change (log-percentage change in daily step-count) in physical activity during the periods of restrictions. ANOVAs were used to further investigate the significant factors identified. Key factors associated with a substantial subjective reduction in physical activity included those classed as obese, gym users and people living in urban areas. All participants had a reduced step count during restrictions, with Black, Asian and minority ethnic (BAME) groups, students and urban dwellers showing the largest reductions. Therefore, targeted interventions are required to ensure that the physical and mental health impacts of sedentary behaviour are not exacerbated over the long-term by significant reductions in physical activity identified in these groups, particularly those who are also more vulnerable to the COVID-19 virus.


title: Returning to a normal life via COVID-19 vaccines in the USA: a large-scale agent-based simulation study

abstract:
BackgroundIn 2020, COVID-19 has claimed more than 300,000 deaths in the US alone. While non-pharmaceutical interventions were implemented by federal and state governments in the USA, these efforts have failed to contain the virus. Following the FDA approval of two COVID-19 vaccines, however, the hope for the return to normalcy is renewed. This hope rests on an unprecedented nation-wide vaccine campaign, which faces many logistical challenges and is also contingent on several factors whose values are currently unknown.

ObjectiveWe study the effectiveness of a nation-wide vaccine campaign in response to different vaccine efficacies, the willingness of the population to be vaccinated, and the daily vaccine capacity under two different federal plans. To characterize the possible outcomes most accurately, we also account for the interactions between non-pharmaceutical interventions and vaccines, through six scenarios that capture a range of possible impact from non-pharmaceutical interventions.

MethodsWe use large-scale cloud-based agent-based simulations by implementing the vaccination campaign using Covasim, an open-source ABM for COVID-19 that has been used in several peer-reviewed studies and accounts for individual heterogeneity as well as a multiplicity of contact networks. Several modifications to the parameters and simulation logic were made to better align the model with current evidence. We chose six non-pharmaceutical intervention scenarios and applied the vaccination intervention following both the plan proposed by Operation Warp Speed (former Trump administration) and the plan of one million vaccines per day, proposed by the Biden administration. We accounted for unknowns in vaccine efficacies and levels of population compliance by varying both parameters. For each experiment, the cumulative infection growth is fitted to a logistic growth model, and the carrying capacities and the growth rates are recorded.

ResultsFor both vaccination plans and all non-pharmaceutical intervention scenarios, the presence of the vaccine intervention considerably lowers the total number of infections when life returns to normal, even when the population compliance to vaccines is as low at 20%. We noted an unintended consequence: given the vaccine availability estimates under both federal plans and the focus on vaccinating individuals by age categories, a significant reduction in non-pharmaceutical interventions results in a counterintuitive situation in which higher vaccine compliance then leads to more total infections.

ConclusionsAlthough potent, vaccines alone cannot effectively end the pandemic given the current availability estimates and the adopted vaccination strategy. Non-pharmaceutical interventions need to continue and be enforced to ensure high compliance, so that the rate of immunity established by vaccination outpaces that induced by infections.


title: Effectiveness of Wolbachia-infected mosquito deployments in reducing the incidence of dengue and chikungunya in Niteroi, Brazil: a quasi-experimental study

abstract:
BackgroundThe introduction of the bacterium Wolbachia (wMel strain) into Aedes aegypti mosquitoes reduces their capacity to transmit dengue and other arboviruses. Evidence of a reduction in dengue case incidence following field releases of wMel-infected Ae. aegypti has been reported previously from a cluster randomised controlled trial in Indonesia, and quasi-experimental studies in Indonesia and northern Australia.

MethodsFollowing pilot releases in 2015 - 2016 and a period of intensive community engagement, deployments of adult wMel-infected Ae. aegypti mosquitoes were conducted in Niteroi, Brazil during 2017 - 2019. Deployments were phased across four release zones, with a total area of 83 km2 and a residential population of approximately 373,000. A quasi-experimental design was used to evaluate the effectiveness of wMel deployments in reducing dengue, chikungunya and Zika incidence. An untreated control zone was pre-defined, which was comparable to the intervention area in historical dengue trends. The wMel intervention effect was estimated by controlled interrupted time series analysis of monthly dengue, chikungunya and Zika case notifications to the public health surveillance system before, during and after releases, from release zones and the control zone.

ResultsThree years after commencement of releases, wMel introgression into local Ae. aegypti populations was heterogeneous throughout Niteroi, reaching a high prevalence (>80%) in the earliest release zone, and more moderate levels (prevalence 40 -70%) elsewhere. Despite this spatial heterogeneity in entomological outcomes, the wMel intervention was associated with a 69% reduction in dengue incidence (95% confidence interval 54%, 79%), a 56% reduction in chikungunya incidence (95%CI 16%, 77%) and a 37% reduction in Zika incidence (95%CI 1%, 60%), in the aggregate release area compared with the pre-defined control area. This significant intervention effect on dengue was replicated across all four release zones, and in three of four zones for chikungunya, though not in individual release zones for Zika.

ConclusionsWe demonstrate that wMel Wolbachia can be successfully introgressed into Ae. aegypti populations in a large and complex urban setting, and that a significant public health benefit from reduced incidence of Aedes-borne disease accrues even where the prevalence of wMel in local mosquito populations is moderate and spatially heterogeneous. These findings are consistent with the results of randomised and non-randomised field trials in Indonesia and northern Australia, and are supportive of the Wolbachia biocontrol method as a multivalent intervention against dengue, chikungunya and Zika.


title: Effectiveness of Wolbachia-infected mosquito deployments in reducing the incidence of dengue and other Aedes-borne diseases in Niteroi, Brazil: a quasi-experimental study


title: DPP9 deficiency: an inflammasomopathy which can be rescued by lowering NLRP1/IL-1 signaling

abstract: Dipeptidyl peptidase 9 (DPP9) is a direct inhibitor of NLRP1, but how it impacts inflammasome regulation in vivo is not yet established. Here, we report two families with immune-associated defects, skin pigmentation abnormalities and neurological deficits that segregate with biallelic DPP9 rare variants. Using patient-derived primary cells and biochemical assays, these variants are shown to behave as hypomorphic or loss-of-function alleles that fail to repress NLRP1. Remarkably, the removal in mice, of a single copy of either Nlrp1a/b/c, Asc, Gsdmd, Il-1r, but not Il-18, was sufficient to rescue the lethality of Dpp9 mutant neonates. These experiments suggest that the deleterious consequences of DPP9 deficiency are mostly driven by the aberrant activation of the canonical NLRP1 inflammasome and IL-1{beta} signaling. Collectively, our results delineate a Mendelian disorder of DPP9 deficiency driven by increased NLRP1 activity as demonstrated in patient cells and in a mouse model of the disease.

category: genetic and genomic medicine


title: ESTIMATING THE HEALTH AND ECONOMIC EFFECTS OF THE VOLUNTARY SODIUM REDUCTION TARGETS IN BRAZIL: MICROSIMULATION ANALYSIS

abstract:
ObjectiveTo analyse the potential health and economic impact of the voluntary sodium reduction targets in Brazil, from 2013 to 2032.

DesignModelling study. A microsimulation approach of a close-to-reality synthetic population (IMPACT NCD BR) was used to evaluate the potential health benefits of setting voluntary upper limits for sodium content as part of Brazilian government strategy. The model estimates cardiovascular disease (CVD) deaths and cases prevented or postponed, and disease treatment costs.

Model inputs were informed by the 2013 National Health Survey, the 2008-2009 Household Budget Survey, and high-quality meta-analyses to inform model inputs. Costs included costs of the National Health System on CVD treatment and informal care costs.

SettingSynthetic population with similar characteristics to the community dwelling population of Brazil.

ParticipantsSynthetic people with traits informed by the national surveys of Brazil.

Main outcome measuresCardiovascular disease cases and deaths prevented or postponed by 2032, over a 20-year period (2013-2032), stratified by age and sex.

ResultsApplying the voluntary sodium targets between 2013 and 2032 could prevent or postpone approximately 112,000 CVD cases (95% Uncertainty Intervals UI: 28,000 to 258,000) among men and 70,000 cases among women (95% UI: 16,000 to 167,000), and also prevent or postpone approximately 2,600 CVD deaths (95% UI: -1,000 to 11,000), 55% in men. The policy could also produce a net cost saving of approximately US$ 222 million (95% UI: US$ 53.6-524.4 million) in medical costs to the Brazilian National Health System for the treatment of CHD and stroke, and save approximately US$ 71 million (95% UI: US$ 17.1-166.9 million) in informal costs.

ConclusionsBrazilian voluntary sodium targets could generate substantial health and economic impacts. Further progress in lower, more comprehensive thresholds for sodium in foods and strategies for reducing other sodium sources could maximise the health and economic benefits to the population. This is the first IMPACT NCD microsimulation model adapted to a Latin American country and represents a big step forward for using models to inform policy in the region. The results indicate that sodium reduction targets must go further and faster in order to achieve national and international commitments.

WHAT IS ALREADY KNOWN ON THIS TOPIC- Public-private partnerships (PPPs), including voluntary targets for the reduction of critical nutrients, such as sodium, sugars and fats, through food reformulation, have been promoted as effective strategies for addressing dietary factors for non-communicable disease prevention.
- Salt (sodium chloride) intake is a leading dietary risk factor for cardiovascular disease (CVD) globally. Over 27 thousand deaths from coronary heart disease and stroke are attributable to excessive sodium intake in Brazil every year. About 20% of sodium in the Brazilian diet comes from industrialized foods, and over 70% come from added table salt and salt-based condiments.
- Since 2011, Brazil has implemented a voluntary approach for reducing sodium in processed and ultra-processed foods, including salt-based condiments. Nevertheless, national targets have not matched the targets of other countries in the Region of the Americas and globally, and target compliance has not been achieved across the entire Brazilian food market.

WHAT THIS STUDY ADDS- We estimated the impact of the current sodium reduction targets in Brazil, by analysing individual-level food category consumption and sodium intake.
- Using the first IMPACT NCD microsimulation model adapted to the Latin American context, we estimated that if applied between 2013 and 2032, the voluntary targets could potentially have prevented approximately 180,000 CVD cases and 2,500 CVD deaths. The case reductions might save approximately US$ 220 million in CVD-related medical costs (hospitalizations, outpatient and primary health care and pharmaceutical treatment) and some US$ 70 million in informal costs.
- More impactful sodium reductions in Brazil may not be achieved without more stringent and comprehensive targets; for instance, mandatory rather than voluntary policy formulation, including policies aimed at reducing the consumption of discretionary table salt.

category: health economics


title: Limited specificity of SARS-CoV-2 antigen-detecting rapid diagnostic tests at low temperatures

abstract: SARS-CoV-2 antigen-detecting rapid diagnostic tests (Ag-RDTs) are available within and outside of health care settings to enable increased access to COVID-19 diagnosis. These environments include provisional testing facilities, lacking temperature control; as outside temperatures fall, recommended testing temperatures cannot be guaranteed. We report impaired specificity in two out of six Ag-RDTs when used at 2-4{degrees}C, indicating that testing in cold settings might cause false-positive results potentially entailing unwarranted quarantine assignments and incorrect incidence estimates.


title: Bayesian Calibration of Using CO2 Sensors to Assess Ventilation Conditions and Associated COVID-19 Airborne Aerosol Transmission Risk in Schools

abstract:
Ventilation rate plays a significant role in preventing the airborne transmission of diseases in indoor spaces. Classrooms are a considerable challenge during the COVID-19 pandemic because of large occupancy density and mainly poor ventilation conditions. The indoor CO2 level may be used as an index for estimating the ventilation rate and airborne infection risk. In this work, we analyzed a one-day measurement of CO2 levels in three schools to estimate the ventilation rate and airborne infection risk. Sensitivity analysis and Bayesian calibration methods were applied to identify uncertainties and calibrate key parameters. The outdoor ventilation rate with a 95% confidence was 1.96 {+/-} 0.31ACH for Room 1 with mechanical ventilation and fully open window, 0.40 {+/-} 0.08 ACH for Rooms 2, and 0.79 {+/-} 0.06 ACH for Room 3 with only windows open. A time-averaged CO2 level < 450 ppm is equivalent to a ventilation rate > 10 ACH in all three rooms. We also defined the probability of the COVID-19 airborne infection risk associated with ventilation uncertainties. The outdoor ventilation threshold to prevent classroom COVID-19 aerosol spreading is between 3 - 8 ACH, and the CO2 threshold is around 500 ppm of a school day (< 8 hr) for the three schools.

Practical ImplicationsThe actual outdoor ventilation rate in a room cannot be easily measured, but it can be calculated by measuring the transient indoor CO2 level. Uncertainty in input parameters can result in uncertainty in the calculated ventilation rate. Our three classrooms study shows that the estimated ventilation rate considering various input parameters uncertainties is between {+/-} 8-20 %. As a result, the uncertainty of the ventilation rate contributes to the estimated COVID-19 airborne aerosol infection risks uncertainty up to {+/-} 10 %. Other studies can apply the proposed Bayesian and MCMC method to estimating building ventilation rates and airborne aerosol infection risks based on actual measurement data such as CO2 levels with uncertainties and sensitivity of input parameters identified. The outdoor ventilation rate and CO2 threshold values as functions of exposure times could be used as the baseline models to develop correlations to be implemented by cheap/portable sensors to be applied in similar situations to monitor ventilation conditions and airborne risk levels.


title: Clinical Prediction Models for Primary Prevention of Cardiovascular Disease: Validity in Independent Cohorts

abstract:
BackgroundClinical prediction models (CPMs) are used to inform treatment decisions for the primary prevention of cardiovascular disease. We aimed to assess the performance of such CPMs in fully independent cohorts.

Methods and Results63 models predicting outcomes for patients at risk of cardiovascular disease from the Tufts PACE CPM Registry were selected for external validation on publicly available data from up to 4 broadly inclusive primary prevention clinical trials. For each CPM-trial pair, we assessed model discrimination, calibration, and net benefit. Results were stratified based on the relatedness of derivation and validation cohorts, and net benefit was reassessed after updating model intercept, slope, or complete re-estimation. The median c statistic of the CPMs decreased from 0.77 (IQR 0.72-0.78) in the derivation cohorts to 0.63 (IQR 0.58-0.66) when externally validated. The validation c-statistic was higher when derivation and validation cohorts were considered related than when they were distantly related (0.67 vs 0.60, p < 0.001). The calibration slope was also higher in related cohorts than distantly related cohorts (0.69 vs 0.58, p < 0.001). Net benefit analysis suggested substantial likelihood of harm when models were externally applied, but this likelihood decreased after model updating.

ConclusionsDiscrimination and calibration decrease significantly when CPMs for primary prevention of cardiovascular disease are tested in external populations, particularly when the population is only distantly related to the derivation population. Poorly calibrated predictions lead to poor decision making. Model updating can reduce the likelihood of harmful decision making, and is needed to realize the full potential of risk-based decision making in new settings.

category: cardiovascular medicine


title: Towards a COVID-19 symptom triad: The importance of symptom constellations in the SARS-CoV-2 pandemic

abstract: Pandemic scenarios like SARS-Cov-2 require rapid information aggregation. In the age of eHealth and data-driven medicine, publicly available symptom tracking tools offer efficient and scalable means of collecting and analyzing large amounts of data. As a result, information gains can be communicated to front-line providers. We have developed such an application in less than a month and reached more than 500 thousand users within 48 hours. The dataset contains information on basic epidemiological parameters, symptoms, risk factors and details on previous exposure to a COVID-19 patient. Exploratory Data Analysis revealed different symptoms reported by users with confirmed contacts vs. no confirmed contacts. The symptom combination of anosmia, cough and fatigue was the most important feature to differentiate the groups, while single symptoms such as anosmia, cough or fatigue alone were not sufficient. A linear regression model from the literature using the same symptom combination as features was applied on all data. Predictions matched the regional distribution of confirmed cases closely across Germany, while also indicating that the number of cases in northern federal states might be higher than officially reported. In conclusion, we report that symptom combinations anosmia, fatigue and cough are most likely to indicate an acute SARS-CoV-2 infection.


title: Optimal time to return to normality: parallel use of COVID-19 vaccines and circuit breakers

abstract: By January 2020, the COVID-19 illness has caused over two million deaths. Countries have restricted disease spread through non-pharmaceutical interventions (e.g., social distancing). More severe "lockdowns" have also been required. Although lockdowns keep people safer from the virus, they substantially disrupt economies and individual well-being. Fortunately, vaccines are becoming available. Yet, vaccination programs may take several months to implement, requiring further time for individuals to develop immunity following inoculation. To prevent health services being overwhelmed it may be necessary to implement further lockdowns in conjunction with vaccination. Here, we investigate optimal approaches for vaccination under varying lockdown lengths and/or severities to prevent COVID-19-related deaths exceeding critical thresholds. We find increases in vaccination rate cause a disproportionately larger decrease in lockdowns: with vaccination, severe lockdowns can reduce infections by up to 89%. Notably, we include demographics, modelling three groups: vulnerable, front-line workers, and non-vulnerable. We investigate the sequence of vaccination. One counter-intuitive finding is that even though the vulnerable group is high risk, demographically, this is a small group (per person, vaccination occurs more slowly) so vaccinating this group first achieves limited gains in overall disease control. Better disease control occurs by vaccinating the non-vulnerable group with longer and/or more severe lockdowns.


title: Change in cognition and body mass index in relation to preclinical dementia

abstract:
INTRODUCTIONTo study if declining cognition drives weight loss in preclinical dementia, we examined the longitudinal association between body mass index (BMI) and cognitive abilities in those who did or did not later develop dementia.

METHODSUsing data from individuals spanning age 50-89, we applied dual change score models separately in individuals who remained cognitively intact (n=1,498) and those who were diagnosed with dementia within five years of last assessment (n=459).

RESULTSAmong the cognitively intact, there was a bidirectional association: stable BMI predicted stable cognition and vice versa. Among those subsequently diagnosed with dementia, the association was unidirectional: higher BMI predicted declining cognition, but cognition did not predict change in BMI.

DISCUSSIONWhile BMI and cognition stabilized each other when cognitive functioning was intact, this buffering effect was missing in the preclinical dementia phase. This finding indicates that weight loss in preclinical dementia is not driven by declining cognition.


title: Comparing effect estimates in randomized trials and observational studies from the same population: an application to percutaneous coronary intervention

abstract:
BackgroundThe ability for real world data to deliver similar results as a trial that asks the same question about the risks or benefits of a clinical intervention can be restricted not only by lack of randomization, but also limited information on eligibility criteria and outcomes. To understand when results from observational studies and randomized trials are comparable, we carried out an observational emulation of a target trial designed to ask similar questions as the VALIDATE randomized trial. VALIDATE compared the effect of bivalirudin and heparin during percutaneous coronary intervention on the risk of death, myocardial infarction, and bleeding across Sweden.

MethodsWe specified the protocol of a target trial similar to the VALIDATE trial protocol, then emulated the target trial in the period before the trial took place using data from the SWEDEHEART registry; the same registry in which the trial was undertaken.

ResultsThe target trial emulation and the VALIDATE trial both estimated no difference in the effect of bivalirudin and heparin on the risk of death or myocardial infarction by 180 days: emulation risk ratio for death 1.21 (0.88, 1.54); VALIDATE hazard ratio for death 1.05 (0.78, 1.41). The observational data, however, could not capture less severe cases of bleeding, resulting in an inability to define a bleeding outcome like the trial, and could not account for intractable confounding early in follow-up (risk ratio for death by 14 days 1.85 (0.95, 3.63)).

ConclusionUsing real world data to emulate a target trial can deliver accurate long-term effect estimates. Yet, even with rich observational data, it is not always possible to estimate the short-term effect of interventions, or the effect on outcomes for which data are not routinely collected. If registries included information on reasons for treatment decisions, researchers may be better positioned to identify important confounders.


title: Forskolin-induced swelling of intestinal organoids predicts long-term cystic fibrosis disease progression

abstract: Patient-derived organoids hold great potential as predictive biomarker for disease expression or therapeutic response. Here, we used intestinal organoids to estimate individual cystic fibrosis transmembrane conductance regulator (CFTR) function of people with cystic fibrosis, a monogenic life-shortening disease associated with more than 2000 CFTR mutations and highly variable disease progression. In vitro CFTR function in CF intestinal organoids of 176 individuals with diverse CFTR mutations was quantified by forskolin induced swelling and was strongly associated with longitudinal changes of lung function and development of pancreatic insufficiency, CF-related liver disease and diabetes. This association was not observed when the commonly used biomarker of CFTR function sweat chloride concentration was used. The data strongly exemplifies the value of an organoid-based biomarker in a clinical disease setting and supports the prognostic value of forskolin induced swelling of intestinal organoids, especially for people with CF who have rare CFTR genotypes with unclear clinical consequences.

category: respiratory medicine


title: Differential expression of Angiotensin-Converting Enzyme 2 in Nasal Tissue of Patients with Chronic Rhinosinusitis with Nasal Polyps

abstract: The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became a pandemic and a global health emergency. The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) is highly expressed in nasal epithelial cells and plays a major role in cellular entry leading to infection. High expression of ACE2 has been suggested to be a potential risk factor for virus infection and disease severity. However the profile of ACE2 gene expression in diseases of the upper airways remains poorly understood. We herein investigated ACE2 gene expression in the nasal tissues of a cohort of Swedish patients with chronic rhinosinusitis with nasal polyps (CRSwNPs) using RT-qPCR. ACE2 mRNA expression was significantly reduced in the nasal mucosa of CRSwNP patients compared to that of controls. Moreover, we observed a sex-dependant difference in nasal ACE2 expression, where significantly lower levels of the ACE2 transcript were detected in the nasal mucosa of only female CRSwNP patients. These findings indicate that CRSwNP patients with a decrease in ACE2 gene expression may thereby be less prone to be infected by SARS-CoV-2. These results enhance our understanding on the profile of ACE2 expression in the nasal mucosa of patients with upper airway diseases, and their susceptibility to infection with SARS-CoV-2.


title: Non-invasively measured brain activity and radiological progression in diffuse glioma

abstract: Non-invasively measured brain activity is related to progression-free survival in glioma patients, suggesting its potential as a marker of glioma progression. We therefore assessed the relationship between brain activity and increasing tumor volumes on routine clinical magnetic resonance imaging (MRI) in glioma patients. Postoperative magnetoencephalography (MEG) was recorded in 45 diffuse glioma patients. Brain activity was estimated using three measures (absolute broadband power, offset and slope) calculated at three spatial levels: global average, averaged across the peritumoral areas, and averaged across the homologues of these peritumoral areas in the contralateral hemisphere. Tumors were segmented on MRI. Changes in tumor volume between the two scans surrounding the MEG were calculated and correlated with brain activity. Brain activity was compared between patient groups classified into having increasing or stable tumor volume. Results show that brain activity was significantly increased in the tumor hemisphere in general, and in peritumoral regions specifically. However, none of the measures and spatial levels of brain activity correlated with changes in tumor volume, nor did they differ between patients with increasing versus stable tumor volumes. Longitudinal studies in more homogeneous subgroups of glioma patients are necessary to further explore the clinical potential of non-invasively measured brain activity.

category: oncology


title: RAY: CRISPR diagnostic for rapid and accurate detection of SARS-CoV2 variants on a paper strip

abstract: The COVID-19 pandemic originating in the Wuhan province of China in late 2019 has impacted global health, causing increased mortality among elderly patients and individuals with comorbid conditions. During the passage of the virus through affected populations, it has undergone mutations- some of which have recently been linked with increased viral load and prognostic complexities. Interestingly, several of these variants are point mutations that are difficult to diagnose using the gold standard quantitative real-time PCR (qPCR) method. This necessitates widespread sequencing which is expensive, has long turn-around times, and requires high viral load for calling mutations accurately. In this study, we show that the high specificity of Francisella novicida Cas9 (FnCas9) to point mismatches can be successfully adapted for the simultaneous detection of SARS-CoV2 infection as well as for detecting point mutations in the sequence of the virus obtained from patient samples. We report the detection of the mutation N501Y (earlier shown to be present in the British N501Y.V1, South African N501Y.V2, and Brazilian N501Y.V3 variants of SARS-CoV2) within an hour using paper strip chemistry. The results were corroborated using deep sequencing. Our design principle can be rapidly adapted for other mutations, highlighting the advantages of quick optimization and roll-out of CRISPR diagnostics (CRISPRDx) for disease surveillance even beyond COVID-19.


title: Antibody seroprevalence and rate of asymptomatic infections with SARS-CoV-2 in Austrian hospital personnel.

abstract:
ContextOn March 11, the World Health Organization (WHO) announced the current corona virus disease 2019 (COVID-19) outbreak as a pandemic. The first laboratory-confirmed case of COVID-19 in Austria was announced on February 27, 2020. Since then, the incidence of infection followed an exponential increase until a complete lockdown in March 2020. Thereafter easing of restrictions was gradually introduced and until mid-August daily infections remained mostly below 5 per 100.000 population.

ObjectivesThe aims of this study are to determine i) how many employees in Austrian trauma hospitals and rehabilitation facilities have virus specific IgG and IgM, and/or neutralizing antibodies against SARS-CoV-2, ii) how many are active virus carriers (symptomatic and asymptomatic) during the study, iii) the antibody decline in seropositive subjects over a period of around six months, and iv) the utility of rapid antibody tests for outpatient screening.

Study DesignOpen uncontrolled observational cross-sectional study.

Setting/ParticipantsA total of 3301 employees in 11 Austrian trauma hospitals and rehabilitation facilities of the Austrian Social Insurance for Occupational Risks (AUVA) participated in the study.

Study Interventions and MeasuresRapid antibody tests for SARS-CoV-2 specific IgG and IgM antibodies, and RT-PCR tests based on oropharyngeal swab samples, as well as laboratory-based antibody tests using ELISA/PRNT were performed. The tests were conducted twice, with an interval of 42.4{+/-}7.7 (Min=30, Max=64) days. Additionally, participants filled out a questionnaire including questions related to personal health, traveling activities, living situation, as well as inquiries of symptoms and comorbidities. Antibody positive tested participants were re-tested with ELISA/PRNT tests at a third time point on average 188.0{+/-}12.8 days after their initial test.

ResultsIn our study cohort, only 27 out of 3301 participants (0.81%) had a positive antibody test at any time point during the study confirmed via neutralization test. Among participants who had positive test results in either of the antibody tests, 50.4% did not report any symptoms consistent with common manifestations of COVID-19 during the study period or within the preceding six weeks. In the group who tested positive during or prior to study inclusion the most common symptoms of an acute viral illness were rhinitis (21.9%), and loss of taste and olfactory sense (21.9%).

The rapid antibody test was generally more sensitive based on serum (sensitivity=86.6%) as compared to whole blood (sensitivity=65.4). Concerning both ELISA tests overall the Roche test detected 24 (sensitivity=88.9%) and the Diasorin test 22 positive participants (sensitivity=81.5%).

In participants with a positive PRNT, a significant decrease in PRNT concentration from 31.8{+/-}22.9 (Md=32.0) at T1 to 26.1{+/-}17.6 (Md=21.3) at T2 to 21.4{+/-}13.4 (Md=16.0) at T3 ({chi}2=23.848, df=2, p<0.001) was observed ({chi}2=23.848, df=2, p<0.001) - with an average time of 42.4{+/-}7.7 days between T1 and T2 and 146.9{+/-}13.8 days between T2 and T3.

ConclusionsDuring the study period (May 11th - December 21th) only 0.81% were tested positive for antibodies in our study cohort. The antibody concentration decreases significantly over time with 14.8% (4 out of 27) losing detectable antibodies.


title: Diffusion kurtosis imaging of white matter in bipolar disorder

abstract:
ObjectivesWhite matter pathology is thought to contribute to the pathogenesis of bipolar disorder (BD). However, most studies of white matter in BD have used the simple diffusion tensor imaging (DTI) model, which has several limitations. DTI studies have reported heterogenous results, leading to a lack of consensus about the extent and location of white matter alterations. Here, we applied two advanced diffusion magnetic resonance imaging (MRI) techniques to investigate white matter microstructure in BD.

MethodsTwenty-five patients with BD and 24 controls comparable for age and sex were included in the study. Whole-brain voxel-based analysis (VBA) and a network-based connectivity approach using constrained spherical deconvolution (CSD)-tractography were used to assess group differences in diffusion kurtosis imaging (DKI) and DTI metrics.

ResultsVBA showed lower mean kurtosis in the corona radiata and posterior association fibers in BD following threshold-free cluster enhancement. Regional differences in connectivity were indicated by lower mean kurtosis and kurtosis anisotropy in streamlines traversing the temporal and occipital lobes, and lower mean axial kurtosis in the right cerebellar, thalamo-subcortical pathways in BD. Significant differences were not seen in the DTI metrics following FDR- correction.

ConclusionsDifferences between BD and controls were observed in DKI metrics in multiple brain regions, indicating altered connectivity across cortical, subcortical and cerebellar areas. DKI was more sensitive than DTI at detecting these differences, suggesting that DKI is useful for investigating white matter in BD.

category: psychiatry and clinical psychology


title: One Year of Evidence on Mental Health in the COVID-19 Crisis - A Systematic Review and Meta-Analysis

abstract:
This paper provides a systematic review and meta-analysis on the prevalence rate of mental health issues of general population, general and frontline healthcare workers (HCWs) in China over one year of the COVID-19 crisis. We systematically searched PubMed, Embase, Web of Science, and Medrxiv at November 16th, 2020, pooled data using random-effects meta-analyses to estimate the prevalence rates, and ran meta-regression to tease out the heterogeneity. The meta-regression results uncovered several predictors of the prevalence rates, including severity, type of mental issues, population, sampling location, and study quality. Pooled prevalence rates are significantly different from, yet largely between, the findings of previous meta-analyses, suggesting the results of our larger study are consistent with yet more accurate than the findings of the smaller, previous meta-analyses. The prevalence rates of distress and insomnia and those of frontline HCWs are higher suggest future research and interventions should pay more attention to those mental outcomes and populations. Our findings suggest a need to examine the prevalence rates at varying levels of severity. The one-year cumulative evidence on sampling locations (Wuhan vs. non-Wuhan) corroborates the typhoon eye effect theory.

Trial registrationCRD4202022059


title: One Year of Evidence on Mental Health Disorders in China during the COVID-19 Crisis - A Systematic Review and Meta-Analysis


title: A survey of International Health Regulations National Focal Points experiences in carrying out their functions

abstract:
BackgroundThe 2005 International Health Regulations (IHR (2005)) require States Parties to establish National Focal Points (NFPs) responsible for notifying the World Health Organization (WHO) of potential events that might constitute public health emergencies of international concern (PHEICs), such as outbreaks of novel infectious diseases. Given the critical role of NFPs in the global surveillance and response system supported by the IHR, we sought to assess their experiences in carrying out their functions.

MethodsIn collaboration with WHO officials, we administered a voluntary online survey to all 196 States Parties to the IHR (2005) in Africa, Asia, Europe, and South and North America, from October to November 2019. The survey was available in six languages via a secure internet-based system.

ResultsIn total, 121 NFP representatives answered the 56-question survey; 105 in full, and an additional 16 in part, resulting in a response rate of 62% (121 responses to 196 invitations to participate). The majority of NFPs knew how to notify the WHO of a potential PHEIC, and believed they have the content expertise to carry out their functions. Respondents found training workshops organized by WHO Regional Offices helpful on how to report PHEICs. NFPs experienced challenges in four critical areas: 1) insufficient intersectoral collaboration within their countries, including limited access to, or a lack of cooperation from, key relevant ministries; 2) inadequate communications, such as deficient information technology systems in place to carry out their functions in a timely fashion; 3) lack of authority to report potential PHEICs; and 4) inadequacies in some resources made available by the WHO, including a key tool - the NFP Guide. Finally, many NFP representatives expressed concern about how WHO uses the information they receive from NFPs.

ConclusionOur study, conducted just prior to the COVID-19 pandemic, illustrates key challenges experienced by NFPs that can affect States Parties and WHO performance when outbreaks occur. In order for NFPs to be able to rapidly and successfully communicate potential PHEICs such as COVID-19 in the future, continued measures need to be taken by both WHO and States Parties to ensure NFPs have the necessary authority, capacity, training, and resources to effectively carry out their functions as described in the IHR.


title: How lifestyle changes within the COVID-19 global pandemic have affected the pattern and symptoms of the menstrual cycle.

abstract:
BackgroundThe coronavirus 2019 (COVID-19) pandemic has caused significant changes to homes, working life and stress. The purpose of this research was to investigate the implications that the COVID-19 pandemic has had on the menstrual cycle and any contributing factors to these changes.

MethodsA questionnaire was completed by 749 participants, whom ranged from  physically active to elite, in their training status. The questionnaire captured detail on menstrual cycle symptoms and characteristics prior to and during the COVID-19 pandemic lockdown period, as well as lifestyle, stress, exercise and nutrition. Descriptive statistics and frequency distribution were reported and decision tree analysis performed. Statistical significance was assumed at p<0.05.

ResultsFifty-two point six percent of females experienced a change in their menstrual cycle during the lockdown period. Psychosocial symptoms had changed in over half of all participants. Participants who reported increased stress/worry in family and personal health were significantly associated with changes in menstrual symptoms. Similarly, job security stress was associated with increases in bleeding time (p<0.05).

ConclusionsIt is important that females and practitioners become aware of the implications of stressful environments and the possible long-term implications on fertility, particularly given the uncertainty around a second wave of the global pandemic.


title: Exempting low-risk health research from ethics reviews to better serve the interests of the patients and public: a qualitative analysis of survey responses

abstract:
BackgroundWe conducted a survey to identify what types of health research could be exempted from research ethics reviews in Australia.

MethodsWe surveyed active Australian health researchers and members of Human Research Ethics Committees (HREC). We presented the respondents with eight hypothetical research scenarios, involving: N of 1 trials, no treatment studies, linked data sets, surplus samples, audits, surveys, interviews with patients, and professional opinion. We asked whether these scenarios should or should not be exempt from ethics review, and to provide (optional) explanations. We analysed the reasons thematically, to identify Top 3 reasons underlying the decisions.

ResultsMost frequent reasons for requiring ethics reviews, included: the need for independent oversight, privacy/confidentiality issues, review of scientific rigour, and publishing considerations. Most frequent reasons for exempting scenarios from reviews, included: level of risk, study design, privacy/confidentiality issues, and standard clinical practice. Four research scenarios listed the same Top 3 reasons for requiring ethics reviews: need for independent oversight, review of scientific rigour, privacy/confidentiality. Reasons for exempting were less uniform, but low risk was a Top 3 reason for 7 scenarios, and study design for 4 scenarios. Privacy/confidentiality was given as a Top 3 reason for both requiring and exempting from ethics the same two scenarios.

ConclusionsThe most frequently offered reasons in support of requiring ethics reviews for research scenarios are more uniform than those for exempting them. However, considerable disagreement exists about when the risks of research are so minimal that the exemption is appropriate.

category: medical ethics


title: Improving the Prediction of Clinical Success Using Machine Learning

abstract: In pharmaceutical research, assessing drug candidates odds of success as they move through clinical research often relies on crude methods based on historical data. However, the rapid progress of machine learning offers a new tool to identify the more promising projects. To evaluate its usefulness, we trained and validated several machine learning algorithms on a large database of projects. Using various project descriptors as input data we were able to predict the clinical success and failure rates of projects with an average balanced accuracy of 83% to 89%, which compares favorably with the 56% to 70% balanced accuracy of the method based on historical data. We also identified the variables that contributed most to trial success and used the algorithm to predict the success (or failure) of assets currently in the industry pipeline. We conclude by discussing how pharmaceutical companies can use such model to improve the quantity and quality of their new drugs, and how the broad adoption of this technology could reduce the industrys risk profile with important consequences for industry structure, R&D investment, and the cost of innovation


title: A claims-based score for the prediction of bleeding in a contemporary cohort of patients receiving oral anticoagulation for venous thromboembolism

abstract:
BackgroundCurrent scores for bleeding risk assessment in patients with venous thromboembolism (VTE) undergoing oral anticoagulation (OAC) have limited predictive capacity. We developed and internally validated a bleeding prediction model using healthcare claims data.

Methods and ResultsWe selected patients with incident VTE in the 2011-2017 MarketScan databases initiating OAC. Hospitalized bleeding events were identified using validated algorithms in the 180 days after VTE diagnosis. We evaluated demographic factors, comorbidities, and medication use prior to OAC initiation as potential predictors of bleeding using stepwise selection of variables in Cox models ran on 1000 bootstrap samples of the patient population. Variables included in >60% of all models were selected for the final analysis. We internally validated the model using bootstrapping and correcting for optimism. We included 165,434 VTE patients initiating OAC, of which 2,294 had a bleeding event. After undergoing the variable selection process, the final model included 20 terms (15 main effects and 5 interactions). The c-statistic for the final model was 0.68 (95% confidence interval [CI] 0.67-0.69). The internally validated c-statistic corrected for optimism was 0.68 (95%CI 0.67-0.69). For comparison, the c-statistic of the HAS-BLED score in this population was 0.62 (95%CI 0.61-0.63).

ConclusionWe have developed a novel model for bleeding prediction in VTE using large healthcare claims databases. Performance of the model was moderately good, highlighting the urgent need to identify better predictors of bleeding to inform treatment decisions.

category: hematology


title: The effect of mobility restrictions on the SARS-CoV-2 diffusion during the first wave: what are the impacts in Sweden, USA, France and Colombia.

abstract: ResumeCombined with sanitation and social distancing measures, control of human mobility has quickly been targeted as a major leverage to contain the spread of SARS-CoV-2 in a great majority of countries worldwide. The extent to which such measures were successful, however, is uncertain (Gibbs et al. 2020; Kraemer et al. 2020). Very few studies are quantifying the relation between mobility, lockdown strategies and the diffusion of the virus in different countries. Using the anonymised data collected by one of the major social media platforms (Facebook) combined with spatial and temporal Covid-19 data, the objective of this research is to understand how mobility patterns and SARS-CoV-2 diffusion during the first wave are connected in four different countries: the west coast of the USA, Colombia, Sweden and France. Our analyses suggest a relatively modest impact of lockdown on the spread of the virus at the national scale. Despite a varying impact of lockdown on mobility reduction in these countries (83% in France and Colombia, 55% in USA, 10% in Sweden), no country successfully implemented control measures to stem the spread of the virus. As observed in Hubei (Chinazzi et al. 2020), it is likely that the virus had already spread very widely prior to lockdown; the number of affected administrative units in all countries was already very high at the time of lockdown despite the low testing levels. The second conclusion is that the integration of mobility data considerably improved the epidemiological model (as revealed by the QAIC). If inter-individual contact is a fundamental element in the study of the spread of infectious diseases, it is also the case at the level of administrative units. However, this relational dimension is little understood beyond the individual scale mostly due to the lack of mobility data at this scale. Fortunately, these types of data are getting increasingly provided by social media or mobile operators, and they can be used to help administrations to observe changes in movement patterns and/or to better locate where to implement disease control measures such as vaccination (Pollina & Busvine 2020; Pullano et al. 2020; Romm et al. 2020).


title: ABC2-SPH risk score for in-hospital mortality in COVID-19 patients: development, external validation and comparison with other available scores

abstract:
ObjectiveTo develop and validate a rapid scoring system at hospital admission for predicting in-hospital mortality in patients hospitalized with coronavirus disease 19 (COVID-19), and to compare this score with other existing ones.

DesignCohort study

SettingThe Brazilian COVID-19 Registry has been conducted in 36 Brazilian hospitals in 17 cities. Logistic regression analysis was performed to develop a prediction model for in-hospital mortality, based on the 3978 patients that were admitted between March-July, 2020. The model was then validated in the 1054 patients admitted during August-September, as well as in an external cohort of 474 Spanish patients.

ParticipantsConsecutive symptomatic patients ([≥]18 years old) with laboratory confirmed COVID-19 admitted to participating hospitals. Patients who were transferred between hospitals and in whom admission data from the first hospital or the last hospital were not available were excluded, as well those who were admitted for other reasons and developed COVID-19 symptoms during their stay.

Main outcome measuresIn-hospital mortality

ResultsMedian (25th-75th percentile) age of the model-derivation cohort was 60 (48-72) years, 53.8% were men, in-hospital mortality was 20.3%. The validation cohorts had similar age distribution and in-hospital mortality. From 20 potential predictors, seven significant variables were included in the in-hospital mortality risk score: age, blood urea nitrogen, number of comorbidities, C-reactive protein, SpO2/FiO2 ratio, platelet count and heart rate. The model had high discriminatory value (AUROC 0.844, 95% CI 0.829 to 0.859), which was confirmed in the Brazilian (0.859) and Spanish (0.899) validation cohorts. Our ABC2-SPH score showed good calibration in both Brazilian cohorts, but, in the Spanish cohort, mortality was somewhat underestimated in patients with very high (>25%) risk. The ABC2-SPH score is implemented in a freely available online risk calculator (https://abc2sph.com/).

ConclusionsWe designed and validated an easy-to-use rapid scoring system based on characteristics of COVID-19 patients commonly available at hospital presentation, for early stratification for in-hospital mortality risk of patients with COVID-19.

Summary boxesWhat is already known on this topic? O_LIRapid scoring systems may be very useful for fast and effective assessment of COVID-19 patients in the emergency department.
C_LIO_LIThe majority of available scores have high risk of bias and lack benefit to clinical decision making.
C_LIO_LIDerivation and validation studies in low- and middle-income countries, including Latin America, are scarce.
C_LI

What this study adds O_LIABC2-SPH employs seven well defined variables, routinely assessed upon hospital presentation: age, number of comorbidities, blood urea nitrogen, C reactive protein, Spo2/FiO2 ratio, platelets and heart rate.
C_LIO_LIThis easy-to-use risk score identified four categories at increasing risk of death with a high level of accuracy, and displayed better discrimination ability than other existing scores.
C_LIO_LIA free web-based calculator is available and may help healthcare practitioners to estimate the expected risk of mortality for patients at hospital presentation.
C_LI


title: A Rapid Realist Review of the Role of Community Pharmacy in the Public Health Response to COVID-19

abstract:
IntroductionCommunity pharmacists and their teams have remained accessible to the public providing essential services despite immense pressures during the COVID-19 pandemic. They have successfully expanded the influenza vaccination programme and are now supporting the delivery of the COVID-19 vaccination roll-out.

AimThis rapid realist review aims to understand how community pharmacy can most effectively deliver essential and advanced services, with a focus on vaccination, during the pandemic and in the future.

MethodAn embryonic programme theory was generated using four diverse and complementary documents along with the expertise of the project team. Academic databases, preprint services and grey literature were searched and screened for documents meeting our inclusion criteria. The data was extracted from 103 documents to develop and refine a programme theory using a realist logic of analysis. Our analysis generated 13 context-mechanism-outcome configurations explaining when, why and how community pharmacy can support public health vaccination campaigns, maintain essential services during pandemics, and capitalise on opportunities for expanded, sustainable public health service roles. The views of stakeholders including pharmacy users, pharmacists, pharmacy teams and other healthcare professionals were sought throughout to refine the 13 explanatory configurations.

ResultsThe 13 context-mechanism-outcome configurations are organised according to decision makers, community pharmacy teams and community pharmacy users as key actors. Review findings include: supporting a clear role for community pharmacies in public health; clarifying pharmacists legal and professional liabilities; involving pharmacy teams in service specification design; providing suitable guidance, adequate compensation and resources; and leveraging accessible, convenient locations of community pharmacy.

DiscussionCommunity pharmacy has been able to offer key services during the pandemic. Decision makers must endorse, articulate and support a clear public health role for community pharmacy. We provide key recommendations for decision makers to optimise such a role during these unprecedented times and in the future.


title: Increased circulating levels of angiotensin-(1-7) in severely ill COVID-19 patients

abstract: The mono-carboxypeptidase Angiotensin-Converting Enzyme 2 (ACE2) is an important "player" of the renin-angiotensin system (RAS). ACE2 is also the receptor for SARS-CoV-2, the new coronavirus that causes COVID-19. It has been hypothesized that following SARS-CoV-2/ACE2 internalization Ang II level would increase in parallel to a decrease of Ang-(1-7) in COVID-19 patients. In this preliminary report, we analyzed the plasma levels of angiotensin peptides in 19 severe COVID-19 patients and 19 non-COVID-19 volunteers, to assess potential outcome associations. Unexpectedly, a significant increase in circulating Ang-(1-7) and lower Ang II plasma level were found in critically ill COVID-19 patients. Accordingly, an increased Ang-(1-7)/ Ang II ratio was observed in COVID-19 suggesting a RAS dysregulation toward an increased formation of Ang-(1-7) in these patients.


title: Estimating the effectiveness of the Pfizer COVID-19 BNT162b2 vaccine after a single dose. A reanalysis of a study of 'real-world' vaccination outcomes from Israel.

abstract: A distinctive feature of the roll out of vaccination against SARS-CoV-2 virus in the UK was the decision to delay the timing of the second injection till 12 weeks after the first. The logic behind this is to protect more people sooner and so reduce the total number of severe infections, hospitalisations, and deaths. This decision caused criticism from some quarters due in part to a belief that a single injection may not give adequate immunity. A recent paper based on Israels experience of vaccination suggested that a single dose may not provide adequate protection. Here we extract the primary data from the Israeli paper and then estimate the incidence per day for each day after the first injection and also estimate vaccine effectiveness for each day from day 13 to day 24. We used a pooled estimate of the daily incidence rate during days 1 to 12 as the counterfactual estimate of incidence without disease and estimated confidence intervals using Monte Carlo modelling. After initial injection case numbers increased to day 8 before declining to low levels by day 21. Estimated vaccine effectiveness was pretty much 0 at day 14 but then rose to about 90% at day 21 before levelling off. The cause of the initial surge in infection risk is unknown but may be related to people being less cautious about maintaining protective behaviours as soon as they have the injection. What our analysis shows is that a single dose of vaccine is highly protective, although it can take up to 21 days to achieve this. The early results coming from Israel support the UK policy of extending the gap between doses by showing that a single dose can give a high level of protection.


title: COVID-19 among bartenders and waiters before and after pub lockdown

abstract:
AimTo study how different bans on serving alcohol in Norwegian bars and restaurants were related to the detection of SARS-CoV-2 in bartenders and waiters.

MethodsIn 24,276 bartenders and waiters and 1,287,970 persons with other occupations (mean [SD] age 41.7 [12.8] years and 51.7% men), we examined the weekly rates of workers tested and detected with SARS-CoV-2, one to five weeks before and one to five weeks after implementation of different degrees of bans on serving alcohol in pubs and restaurants, across 56 Norwegian municipalities with: 1) full blanket ban, 2) partial ban with hourly restrictions (e.g. from 10 pm), or 3) no ban, adjusted for age, sex and testing behavior.

ResultsIn municipalities introducing full ban, COVID-19 among bartenders and waiters had been reduced by 65% by three weeks (from 3.4 [95%CI=2.5-4.3] to 1.2 [95%CI=0.7-1.7] per 1000), i.e. to the same levels as that for persons with other occupations (1.8 [95%CI=1.7-1.9] vs 1.2 [95%CI=1.1-1.3] per 1000). Similarly, in municipalities introducing partial ban, COVID-19 among bartenders and waiters had been reduced by 68% by three weeks (from 2.5 [95%CI=1.4-3.6] to 0.8 [95%CI=0.0-1.5] per 1000). However, there was more uncertainty to the estimated reduction for partial bans.

ConclusionMunicipalities with higher levels of confirmed COVID-19 among bartenders and waiters implemented stricter bans on serving of alcohol than other municipalities. Contraction of COVID-19 among bartenders and waiters declined similarly in municipalities with full and partial bans.


title: Sarilumab treatment of hospitalised patients with severe or critical COVID-19: a multinational, randomised, adaptive, phase 3, double-blind, placebo-controlled trial

abstract:
BackgroundElevated proinflammatory cytokines have been associated with 2019 coronavirus disease (COVID-19) severity. We assessed efficacy and safety of sarilumab, an interleukin-6 receptor inhibitor, in severe (requiring supplemental oxygen by nasal canula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19.

MethodsThis was a 60-day, randomised, double-blind, placebo-controlled, multinational trial in patients hospitalised with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomised 2:2:1 to intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. The primary endpoint was time to [≥]2-point clinical improvement (7-point scale; range: 1 [death] to 7 [not hospitalised]). The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This trial is registered with ClinicalTrials.gov (NCT04327388).

FindingsBetween March 28 and July 3, 2020, 420 patients were randomised; 416 received treatment (placebo, n=84; sarilumab 200 mg, n=159; sarilumab 400 mg, n=173). At day 29, there were no significant differences in median (95% CI) time to [≥]2-point improvement between placebo (12{middle dot}0 [9{middle dot}0-15{middle dot}0] days) and sarilumab groups (200 mg: 10{middle dot}0 [9{middle dot}0-12{middle dot}0] days, p=0.96, log-rank test; 400 mg: 10{middle dot}0 [9{middle dot}0-13{middle dot}0] days, p=0.34) or in proportions of patients alive (placebo, 91{middle dot}7%; sarilumab 200 mg, 89{middle dot}9%, p=0{middle dot}63; sarilumab 400 mg, 91{middle dot}9%, p=0{middle dot}85). At day 29, there were numerical, nonsignificant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +9%, 95% CI -7{middle dot}7 to 25{middle dot}5, p=0{middle dot}25) for critical patients. There were no unexpected safety signals.

InterpretationThis trial did not demonstrate efficacy of sarilumab in patients hospitalised with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19.

FundingSanofi and Regeneron Pharmaceuticals, Inc.


title: A cautionary note on recall vaccination in ex-COVID-19 subjects

abstract: Currently approved COVID-19 vaccines based on mRNA or adenovirus require a first jab followed by recall immunization. There is no indication as to whether individuals who have recovered from COVID-19 should be vaccinated, and if so, if they should receive one or two vaccine doses. Here, we tested the antibody response developed after the first dose of the mRNA based vaccine encoding the SARS-CoV-2 full-length spike protein (BNT162b2) in 124 healthcare professionals of which 57 had a previous history of COVID-19 (ExCOVID). Post-vaccine antibodies in ExCOVID individuals increase exponentially within 7-15 days after the first dose compared to naive subjects (p<0.0001). We developed a multivariate Linear Regression (LR) model with l2 regularization to predict the IgG response for SARS-COV-2 vaccine. We found that the antibody response of ExCOVID patients depends on the IgG pre-vaccine titer and on the symptoms that they developed during the disorder, with anosmia/dysgeusia and gastrointestinal disorders being the most significantly positively correlated in the LR. Thus, one vaccine dose is sufficient to induce a good antibody response in ExCOVID subjects. This poses caution for ExCOVID subjects to receive a second jab both because they may have a overreaction of the inflammatory response and also in light of the current vaccine shortage.

category: allergy and immunology


title: Sex disparities and neutralizing antibody durability to SARS-CoV-2 infection in convalescent individuals

abstract:
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) has now caused over 2 million deaths worldwide and continues to expand. Currently, much is unknown about functionally neutralizing human antibody responses and durability to SARS-CoV-2. Using convalescent sera collected from 101 COVID-19 recovered individuals 21-212 days after symptom onset with forty-eight additional longitudinal samples, we measured functionality and durability of serum antibodies. We also evaluated associations between individual demographic and clinical parameters with functional neutralizing antibody responses to COVID-19. We found robust antibody durability out to six months, as well as significant positive associations with the magnitude of the neutralizing antibody response and male sex. We also show that SARS-CoV-2 convalescent neutralizing antibodies are higher in individuals with cardio-metabolic comorbidities.

SignificanceIn this study we found that neutralizing antibody responses in COVID-19 convalescent individuals vary in magnitude but are durable and correlate well with RBD Ig binding antibody levels compared to other SARS-CoV-2 antigen responses. In our cohort, higher neutralizing antibody titers are independently and significantly associated with male sex compared to female sex. We also show for the first time, that higher convalescent antibody titers in male donors are associated with increased age and symptom grade. Furthermore, cardio-metabolic co-morbidities are associated with higher antibody titers independently of sex. Here, we present an in-depth evaluation of serologic, demographic, and clinical correlates of functional antibody responses and durability to SARS-CoV-2.


title: Vaccinating Australia: How long will it take?

abstract: The Australian Governments COVID-19 vaccine rollout strategy is scheduled to commence in late February 2021 and aims to vaccinate the Australian adult population by the end of October 2021. The task of vaccinating some 20 million people within this timeframe presents considerable logistical challenges. Key to meeting this target is the rate of vaccine delivery: the number of vaccine doses that can be administered per day. In the opening phase, high priority groups will receive the Pfizer/BioNTech vaccine through hospital hubs at an initial rate of 80,000 doses per week. However, pending regulatory approval, the currently announced plan appears to be to distribute the AstraZeneca vaccine to the bulk of the popluation through a combination of general practices and community pharmacies. Here, we run a series of projections to estimate how long it will take to vaccinate the Australian population under different assumptions about the rate of vaccine administration as well as the schedule for second doses and prevalence of vaccine hesitancy. Our analysis highlights the ambitious rate of vaccine administration that will be neccessary to meet the Australian Government completion target of October 2021. A rate of 200,000 doses per day would comfortably meet that target; 80,000 doses a day would see roll-out extended until mid-2022. Speed is of the essence when it comes to vaccine rollout: protecting the population quickly will minimise the risk of sporadic and costly lockdowns lockdowns and the potential for small, local clusters getting out of control and sparking new epidemic waves. The government should gather all its resources to maximise the daily vaccination rate, ideally aiming to ramp up administration to at least 200,000 doses per day as quickly as possible. Quickly achieving and maintaining this pace will likely require dedicated large-scale vaccination sites that are capable of delivering thousands of doses a week in addition to the enthusiastic participation of GP practices and community pharmacies around the country. Lessons on the neccessary logistical planning, including coordination of delivery, ultra-cold-chain storage and staffing, can potentially be learned from Israel, where between 7,000 and 20,000 vaccinations per million population have been delivered daily throughout January.


title: Increased hazard of death in community-tested cases of SARS-CoV-2 Variant of Concern 202012/01

abstract: SARS-CoV-2 lineage B.1.1.7, a variant first detected in the United Kingdom in September 20201, has spread to multiple countries worldwide. Several studies have established that B.1.1.7 is more transmissible than preexisting variants, but have not identified whether it leads to any change in disease severity2. We analyse a dataset linking 2,245,263 positive SARS-CoV-2 community tests and 17,452 COVID-19 deaths in England from 1 September 2020 to 14 February 2021. For 1,146,534 (51%) of these tests, the presence or absence of B.1.1.7 can be identified because of mutations in this lineage preventing PCR amplification of the spike gene target (S gene target failure, SGTF1). Based on 4,945 deaths with known SGTF status, we estimate that the hazard of death associated with SGTF is 55% (95% CI 39-72%) higher after adjustment for age, sex, ethnicity, deprivation, care home residence, local authority of residence and test date. This corresponds to the absolute risk of death for a 55-69-year-old male increasing from 0.6% to 0.9% (95% CI 0.8-1.0%) within 28 days after a positive test in the community. Correcting for misclassification of SGTF and missingness in SGTF status, we estimate a 61% (42-82%) higher hazard of death associated with B.1.1.7. Our analysis suggests that B.1.1.7 is not only more transmissible than preexisting SARS-CoV-2 variants, but may also cause more severe illness.


title: Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7


title: Metabolic subgroups and cardiometabolic multimorbidity in the UK Biobank

abstract:
Background

Ischemic heart disease (IHD), diabetes, cancer and dementia share features of age-associated metabolic dysfunction. We hypothesized that metabolic diversity explains the diversity of morbidity later in life.

MethodsWe analyzed data from the UK Biobank (N = 329,908). A self-organizing map (SOM, an artificial neural network) was trained with 51 metabolic traits adjusted for age and sex. The SOM analyses produced six subgroups that summarized the multi-variable metabolic diversity. The subgroup with the lowest adiposity and disease burden was chosen as the reference. Hazard ratios (HR) were modeled by Cox regression (P < 0.0001 unless otherwise indicated). Enrichment of multi-morbidity over random expectation was tested by permutation analysis.

ResultsThe subgroup with the highest sex hormones was not associated with IHD (HR = 1.04, P = 0.14). The subgroup with high urinary excretion without kidney stress (HR = 1.24) and the subgroup with the highest apolipoprotein B and blood pressure (HR = 1.52) were associated with IHD. The subgroup with high adiposity, inflammation and kidney stress was associated with IHD (HR = 2.11), cancer (HR= 1.29), dementia (HR = 1.70) and mortality (HR = 2.12). The subgroup with high triglycerides and liver enzymes was at risk of diabetes (HR = 15.6). Paradoxical enrichment of multimorbidity in young individuals and in favorable subgroups was observed.

ConclusionsThese results support metabolic diversity as an explanation to diverging morbidity and demonstrate the potential value of population-based metabolic subgroups as public health targets for reducing aggregate burden of chronic diseases in ageing populations.

Key messagesO_LIWe introduced six data-driven subgroups of the UK Biobank as a high-dimensional model of metabolic diversity and disease risk within a human population.
C_LIO_LIThree subgroups captured features of the classical cardiometabolic spectrum with stratification along cholesterol and blood pressure, kidney or liver dysfunction and systemic inflammation.
C_LIO_LITwo novel subgroups of high sex hormones and high urinary excretion were observed.
C_LIO_LIWe defined a new concept of multimorbidity enrichment.
C_LIO_LInexpected patterns of multimorbidity indicated that metabolically "healthy" individuals with one cardiometabolic disease may be at a disproportional synergistic risk of co-morbidity.
C_LI


title: Epidemiological and evolutionary considerations of SARS-CoV-2 vaccine dosing regimes

abstract: As the threat of Covid-19 continues and in the face of vaccine dose shortages and logistical challenges, various deployment strategies are being proposed to increase population immunity levels. How timing of delivery of the second dose affects infection burden but also prospects for the evolution of viral immune escape are critical questions. Both hinge on the strength and duration (i.e. robustness) of the immune response elicited by a single dose, compared to natural and two-dose immunity. Building on an existing immuno-epidemiological model, we find that in the short-term, focusing on one dose generally decreases infections, but longer-term outcomes depend on this relative immune robustness. We then explore three scenarios of selection, evaluating how different second dose delays might drive immune escape via a build-up of partially immune individuals. Under certain scenarios, we find that a one-dose policy may increase the potential for antigenic evolution. We highlight the critical need to test viral loads and quantify immune responses after one vaccine dose, and to ramp up vaccination efforts throughout the world.


title: Changes in Characteristics of Opioid Overdose Death Trends during the COVID-19 Pandemic

abstract:
BackgroundReports analyzing drug overdose (OD) mortality data during the COVID-19 pandemic are limited. Outcomes across states are heterogenous, necessitating assessments of associations between COVID-19 and OD deaths on a state-by-state level. This report aims to analyze trends in OD deaths in Massachusetts during COVID-19.

MethodsAnalyzing 3,924 death records, we characterize opioid-, cocaine-, and amphetamine-involved OD mortality and substance co-presence trends from March 24-November 8 in 2020 as compared to 2018 and 2019.

ResultsOD deaths involving amphetamines increased by 85% from 2019 to 2020 (61 vs. 113; P<0.001) but were steady from 2018 to 2019. Heroins presence continued to decrease (341 in 2018, 247 in 2019, 157 in 2020; P<0.001); however, fentanyl was present in more than 85% of all OD deaths across all periods. Among OD deaths, alcohol involvement consistently increased, present in 250 deaths in 2018, 299 in 2019 (P=0.02), and 350 in 2020 (P=0.04). In 2019, 78% of OD decedents were White and 7% were Black, versus 73% and 10% in 2020 (P=0.02).

ConclusionIncreased deaths involving stimulants, alcohol, and fentanyl reflect concerning trends in the era of COVID-19. Rising OD death rates among Black residents underscore that interventions focused on racial equity are necessary.


title: Changes in Characteristics of Drug Overdose Death Trends during the COVID-19 Pandemic


title: Microscopic dynamics modeling unravels the role of asymptomatic virus carriers in SARS-CoV-2 epidemics at the interplay between biological and social factors

abstract: The recent experience of SARS-CoV-2 epidemics spreading revealed the importance of passive forms of infection transmissions. Apart from the virus survival outside the host, the latent infection transmissions caused by asymptomatic and presymptomatic hosts represent major challenges for controlling the epidemics. In this regard, social mixing and various biological factors play their subtle, but often critical, role. For example, a life-threatening condition may result in the infection contracted from an asymptomatic virus carrier. Here, we use a new recently developed microscopic agent-based modelling framework to shed light on the role of asymptomatic hosts and to unravel the interplay between the biological and social factors of these nonlinear stochastic processes. The model accounts for each human actors susceptibility and the virus survival time, as well as traceability along the infection path. These properties enable an efficient dissection of the infection events caused by asymptomatic carriers from those which involve symptomatic hosts before they develop symptoms and become removed to a controlled environment. Consequently, we assess how their relative proportions in the overall infection curve vary with changing model parameters. Our results reveal that these proportions largely depend on biological factors in the process, specifically, the virus transmissibility and the critical threshold for developing symptoms, which can be affected by the virus pathogenicity. Meanwhile, social participation activity is crucial for the overall infection level, further modulated by the virus transmissibility.


title: Multi-modality detection of SARS-CoV-2 in faecal donor samples for transplantation and in asymptomatic emergency surgical admissions

abstract:
IntroductionFaecal transplantation is an evidence based treatment for Clostridiodes difficile. Patients infected with SARS-CoV-2 have been shown to shed the virus in stool for up to 33 days, well beyond the average clearance time for upper respiratory tract shedding. We carried out an analytical and clinical validation of reverse-transcriptase quantitative (RT-qPCR) as well as LAMP, LamPORE and droplet digital PCR in the detection of SARS-CoV-2 RNA in stool from donated samples for FMT, spiked samples and asymptomatic inpatients in an acute surgical unit.

MethodsKilled SARS-CoV-2 viral lysate and extracted RNA was spiked into donor stool & FMT and a linear dilution series from 10-1 to 10-5 and tested via RT-qPCR, LAMP, LamPORE and ddPCR against SARS-CoV-2. Patients admitted to the critical care unit with symptomatic SARS-CoV-2 and sequential asymptomatic patients from acute presentation to an acute surgical unit were also tested.

ResultsIn a linear dilution series, detection of the lowest dilution series was found to be 8 copies per microlitre of sample. Spiked lysate samples down to 10-2 dilution were detected in FMT samples using RTQPCR, LamPORE and ddPCR and down to 10-1 with LAMP. In symptomatic patients 5/12 had detectable SARS-CoV-2 in stool via RT-qPCR and 6/12 via LamPORE, and in 1/97 asymptomatic patients via RT-qPCR.

ConclusionsRT-qPCR can be detected in FMT donor samples using RT-qPCR, LamPORE and ddPCR to low levels using validated pathways. As previously demonstrated, nearly half of symptomatic and less than one percent of asymptomatic patients had detectable SARS-CoV-2 in stool.

category: gastroenterology