title: Investigation of the ventilation situation in a lecture room of building 033 at the Universität der Bundeswehr München

abstract: The SARS-CoV-2 pandemic is limiting both the private and public lives of many people around the world. It is now considered certain that SARS-CoV-2 is transmitted via droplets, smear infection, and aerosol particles. While simple masks, spacing, and hand hygiene significantly reduce the risk of infection via the first two routes mentioned, the risk from aerosol particles remains. These small particles move with the air in the room and spread unhindered throughout it. To reduce the risk of infection from viruses present in aerosol particles, the following options exist. First, good respiratory masks can be worn to reduce the viral load in the inhaled air. Another option is to make the viruses harmless (e.g., by UV light). A third option is to reduce the viral load in the room by bringing in virus-free air and moving contaminated air out or cleaning the air in the room. To investigate how well virus load reduction via ventilation works in a real lecture room, measurements were carried out at the Universitat der Bundeswehr Munchen (University of the Federal Armed Forces Munich). The lecture room holds a maximum of approx. 90 people and has a ventilation system as well as 2 windows that can be opened. In the absence of a ventilation system in a comparable room, the effectiveness of a room air cleaner was also investigated.


title: Return to normal: COVID-19 vaccination under mitigation measures

abstract: Vaccination campaigns against COVID-19 are allowing the progressive release of physical distancing restrictions in many countries. However, the global spread of the highly transmissible Delta variant has likely suppressed the residual chances of SARS-CoV-2 elimination through herd immunity alone. Here we assess the impact of the vaccination program in Italy since its start on December 27, 2020 and evaluate possible prospects for reopening the society while at the same time keeping COVID-19 under control. To this aim, we propose a mathematical modeling framework where levels of social activity are adjusted to match the time-series of the net reproduction number as estimated from surveillance data. We compared the estimated level of social contacts, number of deaths, and transmission potential with those of a counterfactual scenario where the same epidemic trajectory is obtained in absence of vaccination. We then evaluate the prospective impact of different scenarios of vaccination coverage and different social activity levels on SARS-CoV-2 reproduction number. We estimate that by June 30, 2021, the COVID-19 vaccination program allowed the resumption of about half the social contacts that were recorded in pre-pandemic times; in absence of vaccination, only about one third could have been resumed to obtain the same number of cases, with the added cost of about 12,100 (95%CI: 6,600-21,000) extra deaths (+27%; 95%CI: 15-47%) between December 27, 2020 and June 30, 2021. We show that the negative effect of the Delta variant diffusion in July was entirely offset by vaccination in the month of July and August 2021. Finally, we estimate that a complete return to the pre-pandemic life could be safely attained only if >90%, including children from 5 years on, will be vaccinated using mRNA vaccines developed in 2020. In any case, increasing the vaccination coverage will allow further margins for societal reopening even in absence of a pediatric vaccine. These results may support the definition of vaccination targets for countries that have already achieved a broad population coverage.

category: infectious diseases


title: Conditions for a return to normal under COVID-19 mitigation measures and vaccinations


title: The effect of COVID-19 vaccination in Italy and perspectives for 'living with the virus'


title: Factors Associated with Intention to Vaccinate against COVID-19 in Puerto Rico

abstract: COVID-19 has been particularly devastating to Black and Latinx communities in the U.S. However, data on acceptability of the COVID-19 vaccines among minority populations are limited. We conducted an online survey among adults in Puerto Rico to identify factors associated with intention to vaccinate against COVID-19. Sociodemographic variables were analyzed independently for association with intention to vaccinate. Significant associations were included in the multivariate logistic regression analysis. A total of 1016 responses were available for analysis. In the bivariate analysis, younger age, higher education, pre-covid employment, male sex, gay/bisexual identity, and single marital status were associated with increased intention to vaccinate. In the multivariate logistic regression, younger, male respondents who had higher educational attainment reported higher intention to vaccinate. Lower-income and living outside the San Juan metro region were associated with lower intention to vaccinate. National and international health organizations were identified as the most reliable sources of information, followed by healthcare professionals. These findings highlight the importance of considering sociodemographic characteristics identified with low intention to vaccinate as well as using trusted sources of information when designing public messaging related to increasing COVID-19 vaccinations.


title: Within-country age-based prioritisation, global allocation, and public health impact of a vaccine against SARS-CoV-2: a mathematical modelling analysis

abstract:
The worldwide endeavour to develop safe and effective COVID-19 vaccines has been extraordinary, and vaccination is now underway in many countries. However, the doses available in 2021 are likely to be limited. We extended a mathematical model of SARS-CoV-2 transmission across different country settings to evaluate the public health impact of potential vaccines using WHO-developed target product profiles. We identified optimal vaccine allocation strategies within- and between-countries to maximise averted deaths under constraints on dose supply. We found that the health impact of SARS-CoV-2 vaccination depends on the cumulative population-level infection incidence when vaccination begins, the duration of natural immunity, the trajectory of the epidemic prior to vaccination, and the level of healthcare available to effectively treat those with disease. Within a country we find that for a limited supply (doses for <20% of the population) the optimal strategy is to target the elderly. However, with a larger supply, if vaccination can occur while other interventions are maintained, the optimal strategy switches to targeting key transmitters to indirectly protect the vulnerable. As supply increases, vaccines that reduce or block infection have a greater impact than those that prevent disease alone due to the indirect protection provided to high-risk groups. Given a 2 billion global dose supply in 2021, we find that a strategy in which doses are allocated to countries proportional to population size is close to optimal in averting deaths and aligns with the ethical principles agreed in pandemic preparedness planning.

HighlightsO_LIThe global dose supply of COVID-19 vaccines will be constrained in 2021
C_LIO_LIWithin a country, prioritising doses to protect those at highest mortality risk is efficient
C_LIO_LIFor a 2 billion dose supply in 2021, allocating to countries according to population size is efficient and equitable
C_LI

category: epidemiology


title: Risk of reinfection after seroconversion to SARS-CoV-2: A population-based propensity-score matched cohort study

abstract:
ImportanceSerological assays detecting specific IgG antibodies generated against the Spike protein following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection are being widely deployed in research studies and clinical practice. However, the duration and the effectiveness of the protection conferred by the immune response against future infection remains to be assessed in a large population.

ObjectiveTo estimate the incidence of newly acquired SARS-CoV-2 infections in seropositive individuals from a population-based sample as compared to seronegative controls.

DesignRetrospective longitudinal propensity-score matched cohort study.

SettingA seroprevalence survey including a population-based representative sample of the population from the canton of Geneva (Switzerland) was conducted between April and June 2020, immediately after the first pandemic wave. Each individual included in the seroprevalence survey was linked to a state centralized registry compiling virologically confirmed SARS-CoV-2 infections since the beginning of the pandemic.

ParticipantsParticipants aged twelve years old and over, who developed anti-spike IgG antibodies were matched one-to-two to seronegative controls, using a propensity-score including age, gender, immunodeficiency, body mass index, smoking status and education level.

ExposureSARS-CoV-2 seropositivity.

Main outcomes and measuresOur primary outcome was virologically confirmed SARS-CoV-2 infections which occurred from serological status assessment in April-June 2020 to the end of the second pandemic wave (January 2021). Additionally, incidence of infections, rate of testing and proportion of positive tests were analysed.

ResultsAmong 8344 serosurvey participants, 498 seropositive individuals were selected and matched with 996 seronegative controls. After a mean follow-up of 35.6 (Standard Deviation, SD: 3.2) weeks, 7 out of 498 (1.4%) seropositive subjects had a positive SARS-CoV-2 test, of which 5 (1.0%) were considered as reinfections. By contrast, infection rate was significantly higher in seronegative individuals (15.5%, 154/996) during a similar mean follow-up of 34.7 (SD 3.2) weeks, corresponding to a 94% (95%CI 86% to 98%, P<0.001) reduction in the hazard of having a positive SARS-CoV-2 test for seropositive subjects.

Conclusions and relevanceSeroconversion after SARS-CoV-2 infection confers protection to successive viral contamination lasting at least 8 months. These findings could help global health authorities establishing priority for vaccine allocation.

Key points

QuestionDo SARS-CoV-2 antibodies confer protection against future infection?

FindingsIn this retrospective matched cohort study nested in a representative sample of the general population of Geneva, Switzerland, we observed a 94% reduction in the hazard of being infected among participants with antibodies against SARS-CoV-2, when compared to seronegative controls, >8 months after initial serology assessment.

MeaningSeroconversion to SARS-CoV-2 is associated with a large and sustained protection against reinfection.


title: Modelling the impact of rapid tests, tracing and distancing in lower-income countries suggest optimal policies varies with rural-urban settings

abstract: Low- and middle-income countries (LMICs) remain of high potential for hotspots for COVID-19 deaths and emerging variants given the inequality of vaccine distribution and their vulnerable healthcare systems. We aim to evaluate containment strategies that are sustainable and effective for LMICs. We constructed synthetic populations with varying contact and household structures to capture LMIC demographic characteristics that vary across communities. Using an agent-based model, we explored the optimal containment strategies for rural and urban communities by designing and simulating setting-specific strategies that deploy rapid diagnostic tests, symptom screening, contact tracing and physical distancing. In low-density rural communities, we found implementing either high quality (sensitivity > 50%) antigen rapid diagnostic tests or moderate physical distancing could contain the transmission. In urban communities, we demonstrated that both physical distancing and case finding are essential for containing COVID-19 (average infection rate < 10%). In high density communities that resemble slums and squatter settlements, physical distancing is less effective compared to rural and urban communities. Lastly, we demonstrated contact tracing is essential for effective containment. Our findings suggested that rapid diagnostic tests could be prioritised for control and monitor COVID-19 transmission and highlighted that contact survey data could guide strategy design to save resources for LMICs. An accompanying open source R package is available for simulating COVID-19 transmission based on contact network models.


title: Modelling the impact of rapid tests, tracing and distancing in lower-income countries suggest that optimal policies varies with rural-urban settings


title: Importation, circulation, and emergence of variants of SARS-CoV-2 in the South Indian State of Karnataka

abstract: As the pandemic of COVID-19 caused by the coronavirus SARS-CoV-2 continues, the selection of genomic variants which can influence how the pandemic progresses is of growing concern. Of particular concern, are those variants that carry mutations/amino acid changes conferring higher transmission, more severe disease, re-infection, and immune escape. These can broadly be classified as Variants of Concern (VOCs). VOCs have been reported from several parts of the world- UK (lineage B.1.1.7), South Africa (lineage B.1.351) and, Brazil (lineage P.1/B.1.1.28). The conditions that contribute to the emergence of VOCs are not well understood. International travel remains an important means of spread. To track importation, spread, and the emergence of variants locally; we sequenced whole genomes of SARS-CoV-2 from international travellers (n=75) entering Karnataka, a state in South India, between Dec 22, 2020- Jan 31, 2021, and from positive cases in the city of Bengaluru (n=108), between Nov 22, 2020- Jan 22, 2021. The resulting 176 SARS-CoV-2 genomes could be classified into 34 lineages, that were either imported (73/176) or circulating (103/176) in this time period. The lineage B.1.1.7 (a.k.a the UK variant) was the major lineage imported into the state (24/73, 32.9%), followed by B.1.36 (20/73, 27.4%) and B.1 (14/73, 19.2%). We identified B.1.36 (45/103; 43.7%), B.1 (26/103; 25.2%), B.1.1.74 (5/103; 4.9%) and B.1.468 (4/103; 3.9%) as the major variants circulating in Bengaluru city. A distinct clade within the B.1.36 lineage was associated with a local outbreak. Analysis of the complete genomes predicted multiple amino acid replacements in the Spike protein. In total, we identified nine amino acid changes (singly or in pairs) in the Receptor Binding Domain of the Spike protein. Of these, the amino acid replacement N440K was found in 37/65 (56.92%) sequences in the B.1.36 lineage. The E484K amino acid change which is present in both VOCs, B.1.351 and P.1/B.1.1.28, was found in a single circulating virus in the B.1.36 lineage. This study highlights the introduction of VOCs by travel and the local circulation of viruses with amino acid replacements in the Spike protein. These were spread across lineages, suggesting that multiple paths can lead to the emergence of VOCs, this, in turn, highlights the need to sequence and limit outbreaks of SARS-CoV-2 locally. Our data support the use of concentrated and continued genomic surveillance of SARS-CoV-2 to direct public health measures, suggest revisions to vaccines, and serve as an early warning system to prepare for a surge in COVID-19 cases.

category: public and global health


title: Effect of information about COVID-19 vaccine effectiveness and side effects on behavioural intentions: two online experiments

abstract: The success of mass COVID-19 vaccination campaigns rests on widespread uptake. However, although vaccinations provide good protection, they do not offer full immunity and while they likely reduce transmission of the virus to others, the extent of this remains uncertain. This produces a dilemma for communicators who wish to be transparent about benefits and harms and encourage continued caution in vaccinated individuals but not undermine confidence in an important public health measure. In two large pre-registered experimental studies on quota-sampled UK public participants we investigate the effects of providing transparent communication--including uncertainty--about vaccination effectiveness on decision-making. In Study 1 (n = 2,097) we report that detailed information about COVID-19 vaccines, including results of clinical trials, does not have a significant impact on beliefs about the efficacy of such vaccines, concerns over side effects, or intentions to receive a vaccine. Study 2 (n = 2,217) addressed concerns that highlighting the need to maintain protective behaviours (e.g. social distancing) post-vaccination may lower perceptions of vaccine efficacy and willingness to receive a vaccine. We do not find evidence of this: transparent messages did not significantly reduce perceptions of vaccine efficacy, and in some cases increased perceptions of efficacy. We again report no main effect of messages on intentions to receive a vaccine. The results of both studies suggest that transparently informing people of the limitations of vaccinations does not reduce intentions to be vaccinated but neither does it increase intentions to engage in protective behaviours post-vaccination.


title: Neurological manifestations of patients with mild-to-moderate COVID-19 attending a public hospital in Lima, Peru

abstract:
ObjectiveTo determine the prevalence and characteristics of the most common neurological manifestations in Peruvian patients with mild-to-moderate COVID-19.

MethodsWe conducted a single-center prospective, cross-sectional study at an isolation center functioning as a public acute-care hospital during the COVID-19 pandemic in Lima, the capital city of Peru. This was a convenience sample of patients with acute COVID-19 infection and mild-to-moderate respiratory symptoms who presented for hospital admission between September 25 and November 25, 2020. We interviewed participants and collected demographic, medical history and clinical presentation data; all participants underwent a complete physical and neurological examination. Descriptive statistics and prevalence ratios (PR) with corresponding 95% confidence intervals and p-values were calculated to explore between-groups differences.

ResultsOf 199 patients with mild-to-moderate COVID-19 enrolled in this study, 83% presented with at least one neurological symptom (mean symptom duration 8 +/-6 days). The most common neurological symptoms were headache (72%), hypogeusia or ageusia (41%), hyposmia or anosmia (40%) and dizziness (34%). Only 2.5% of the cohort had an abnormal neurological examination. The majority (42%) had no prior comorbidities. Presence of at least 1 neurological symptom was independently associated with fever, dyspnea, cough, poor appetite, sore throat, chest tightness or diarrhea, but not with comorbid conditions.

ConclusionsThis cross-sectional study found that headaches, and smell and taste dysfunction are common among patients presenting with mild-to-moderate acute COVID-19 in Lima, Peru. International longitudinal studies are needed to determine the long-term neurological sequelae of COVID-19 during the acute and post-infectious period.

category: neurology


title: MRSD: a novel quantitative approach for assessing suitability of RNA-seq in the clinical investigation of mis-splicing in Mendelian disease

abstract:
BackgroundRNA-sequencing of patient biosamples is a promising approach to delineate the impact of genomic variants on splicing, but variable gene expression between tissues complicates selection of appropriate tissues. Relative expression level is often used as a metric to predict RNA-sequencing utility. Here, we describe a gene- and tissue-specific metric to inform the feasibility of RNA-sequencing, overcoming some issues with using expression values alone.

ResultsWe derive a novel metric, Minimum Required Sequencing Depth (MRSD), for all genes across three human biosamples (whole blood, lymphoblastoid cell lines (LCLs) and skeletal muscle). MRSD estimates the depth of sequencing required from RNA-sequencing to achieve user-specified sequencing coverage of a gene, transcript or group of genes of interest. MRSD predicts levels of splice junction coverage with high precision (90.1-98.2%) and overcomes transcript region-specific sequencing biases. Applying MRSD scoring to established disease gene panels shows that LCLs are the optimum source of RNA, of the three investigated biosamples, for 69.3% of gene panels. Our approach demonstrates that up to 59.4% of variants of uncertain significance in ClinVar predicted to impact splicing could be functionally assayed by RNA-sequencing in at least one of the investigated biosamples.

ConclusionsWe demonstrate the power of MRSD as a metric to inform choice of appropriate biosamples for the functional assessment of splicing aberrations. We apply MRSD in the context of Mendelian genetic disorders and illustrate its benefits over expression-based approaches. We anticipate that the integration of MRSD into clinical pipelines will improve variant interpretation and, ultimately, diagnostic yield.

category: genetic and genomic medicine


title: Dental care of patients with dementia: A survey on practice equipment, training, and dental treatment

abstract:
For patients with dementia, dental care can pose a considerable challenge due to cognitive impairment, behavioral, and psychological symptoms, and (often subsequently) limited autonomous oral care. In this study, we aimed to assess the proficiency of dentists in general practice in the outpatient dental care of these patients. A total of 119 dentists from private practices in Lower Saxony, Germany, participated in this study. Concerning treatment of patients with dementia, they provided details about (1) practice equipment/consultation, (2) training/ expertise, and (3) special circumstances of dental treatment.

Participating dentists predominantly reported to use medical aids (e.g., positioning cushions) to improve the treatment situation for patients with dementia. Over two thirds (68.6%) offered consultations in nursing homes, and at the patients homes (47.0%). The training rate was remarkably low in the field of gerodontology for dentists and their practice staff (< 10%), however, 54.5% expressed interest in such training. The majority of dentists reportedly adapted their treatment strategy to the needs of patients with dementia (e.g., communication, inclusion of caregivers, time management). Furthermore, most participants adapted dental treatment adequately (e.g., strict indication for tooth extraction, simple design of dental prostheses).

In summary, even though training in the field of gerodontology must be considered insufficient, most dentists in this study showed an adequate adaptation of their treatment strategy as well as consideration of dental characteristics in patients with dementia, along with interest in trainings. We conclude that dementia-specific training should be expanded in the field of dentistry, preferably already at university level.

category: geriatric medicine


title: Longitudinal assessment of diagnostic test performance over the course of acute SARS-CoV-2 infection

abstract:
What is already known about this topic?Diagnostic tests and sample types for SARS-CoV-2 vary in sensitivity across the infection period.

What is added by this report?We show that both RTqPCR (from nasal swab and saliva) and the Quidel SARS Sofia FIA rapid antigen tests peak in sensitivity during the period in which live virus can be detected in nasal swabs, but that the sensitivity of RTqPCR tests rises more rapidly in the pre-infectious period. We also use empirical data to estimate the sensitivities of RTqPCR and antigen tests as a function of testing frequency.

What are the implications for public health practice?RTqPCR tests will be more effective than rapid antigen tests at identifying infected individuals prior to or early during the infectious period and thus for minimizing forward transmission (provided results reporting is timely). All modalities, including rapid antigen tests, showed >94% sensitivity to detect infection if used at least twice per week. Regular surveillance/screening using rapid antigen tests 2-3 times per week can be an effective strategy to achieve high sensitivity (>95%) for identifying infected individuals.


title: PREDICTIVE IMMUNOLOGICAL, VIROLOGICAL, AND ROUTINE LABORATORY MARKERS FOR CRITICAL COVID-19 ON ADMISSION.Immunocovid study

abstract:
IntroductionEarly identification of COVID-19 patients at risk of critical illness is challenging for clinicians. Immunological, virological, and routine laboratory markers to be used in addition to clinical data are needed.

Aim and methodsBlood tests to measure neutrophil/lymphocyte ratio (NLR), levels of ferritin, CRP, D-dimer, complement components (C3, C4), lymphocyte subsets, and cytokines, and SARS-Cov2 RT-PCR tests were performed in COVID-19 confirmed cases within 48 hours of admission. Cycle threshold (Ct) values were determined by RT-PCR from oral or nasopharyngeal swabs on the day of admission. Severity of symptoms was categorized as mild (grade 1), severe (grade 2), and critical (grade 3).

Results120 patients were included. COVID-19 was mild in 49, severe in 32, and critical in 39. Ferritin >370 ng/mL (OR 16.4, 95% CI 5.3-50.8), D-dimer >440 ng/mL (OR 5.45, 95% CI 2.36-12.61), CRP >7.65 mg/dL (OR 11.54, 95% CI 4.3-30.8), NLR >3.77 (OR 13.4, 95% CI 4.3-41.1), IL-6 >142.5 pg/mL (OR 8.76, 95% CI 3.56-21.54), IL-10 >10.8 pg/mL (OR 16.45, 95% CI 5.32-50.81), sIL-2r (sCD25) >804.5 pg/mL (OR 14.06, 95% CI 4.56-43.28), IL-1Ra >88.4 pg/mL (OR 4.54, 95% CI 2.03-10.17), and IL-18 >144 pg/mL (OR 17.85, 95% CI 6.54-48.78) were associated with critical COVID-19 in the univariate age-adjusted analysis. In the multivariate age-adjusted analysis, this association was confirmed only for ferritin, CRP,NLR, IL-10, sIL-2r, and IL-18. T, B, and NK cells were significantly decreased in critical patients. SARS-CoV-2 was undetected in blood except in 3 patients with indeterminate results. Ct values determined by RT-PCR from oral/nasopharyngeal swabs on admission were not related to symptom severity.

Conclusionlevels of ferritin, D-dimer, CRP, NLR, and cytokines and cytokine receptors IL-6, IL1-Ra, sCD25, IL-18, and IL-10, taken together with clinical data, can contribute to the early identification of critical COVID-19 patients.


title: Modelling addition and replacement mechanisms of plasmid-based beta-lactam resistant E. coli infections

abstract: It is unknown whether antibiotic-resistant bacterial infections occur in addition to antibiotic-susceptible bacterial infections, thereby increasing the infection incidence, or whether they replace such infections, leaving total incidence unaffected. Observational longitudinal studies cannot separate both mechanisms. Using plasmid-based beta-lactam resistant E. coli as example, we applied a mathematical neutral null model to investigate whether biological mechanisms implying either a fitness cost or a benefit due to resistance lead to replacement or addition. Fitness costs cause resistant strains to die out if other strain characteristics are maintained equal. Under the assumptions tested, only increased virulence increases the total number of infections, while other of resistance lead to replacement without changing the total number of infections. As there is no biological evidence that plasmid-based beta-lactam resistance increases virulence, these findings suggest that the burden of disease is determined by attributable effects of resistance rather than by an increase in infections.


title: SGLT2 inhibitors and the risk of diabetic ketoacidosis among adults with Type 2 Diabetes: A systematic review and meta-analysis

abstract:
ImportanceThe risk of diabetic ketoacidosis (DKA) with sodium-glucose cotransporter-2 (SGLT2) inhibitors is unclear.

ObjectiveTo examine the risk of DKA with SGLT2 inhibitors in both observational studies and large clinical trials.

Data SourcesSearches of PubMed, EMBASE and CENTRAL (inception to 15 April 2019) without language restrictions; conference proceedings; and reference lists.

Study SelectionRandomized controlled trials and observational studies that quantified the rate of diabetic ketoacidosis with an SGLT2 inhibitor in comparison to another diabetes medication or placebo.

Data Extraction and SynthesisTwo independent investigators abstracted study data and assessed the quality of evidence. Data were pooled using random effects models with the Hartung-Knapp-Sidik-Jonkman method.

Main Outcome and MeasuresAbsolute event rates and hazard ratios for diabetic ketoacidosis were extracted from each study.

ResultsSeven randomized trials encompassing 42,375 participants and five cohort studies encompassing 318,636 participants were selected. Among the 7 randomized controlled trials, the absolute rate of DKA among patients randomized to an SGLT2 inhibitor ranged from 0.6 to 2.2 events per 1000 person years. Four randomized trials were included in the meta-analysis, and compared to placebo or comparator medication, SGLT2 inhibitors had a 2.4-fold higher risk of DKA (Relative Risk[RR] =2.46 [95% CI, 1.16-5.21]; I2=0%; P= 0.54). Among the 5 observational studies, the absolute rate of DKA associated with SGLT2 inhibitor use ranged from 0.6 to 4.9 per 1000 person years and a 1.7-fold higher rate of DKA compared to another diabetes medication (RR=1.74 [95% CI, 1.01-2.93]; I2=45%; P= 0.12).

Conclusions and RelevanceIn adults with type 2 diabetes, SGLT2 inhibitors increase the risk of DKA in both observational studies and large randomized clinical trials.

RegistrationCRD42019146855

Funding SourceNone

KEY MESSAGES- Case reports and observational studies have suggested that SGLT2 inhibitors may be associated with an increased risk of DKA, but this finding has not been reproduced in older meta-analyses of randomized controlled trials.
- In this systematic review and meta-analysis of randomized trials and observational studies including over 350,000 patients, SGLT2 inhibitors were found to be associated with twice the risk of diabetic ketoacidosis versus placebo or a comparator medication.
- Patients receiving an SGLT2 inhibitors should be counselled on this risk and provided with appropriate sick-day medication management.

category: endocrinology


title: Statistical challenges of investigating a disease with a complex diagnosis

abstract: Given the absence of a disease-specific biomarker, there are more than 20 symptoms-based case definitions of myalgic encephalomyelitis/chronic fatigue syndrome. As a consequence, the diagnosis for a given patient could vary from one case definition to another. In this context, we analyse data from a biobank dedicated to this disease in order to study the agreement between different case definitions, the similarity between symptoms profile among all participants including healthy controls and patients with multiple sclerosis. We also investigate the impact of patients misclassification on a hypothetical association analysis using data simulation.


title: Network-based Modeling of COVID-19 Dynamics: Early Pandemic Spread in India

abstract: Modeling the dynamics of COVID-19 pandemic spread is a challenging and relevant problem. Established models for the epidemic spread such as compartmental epidemiological models e.g. Susceptible-Infected-Recovered (SIR) models and its variants, have been discussed extensively in the literature and utilized to forecast the growth of the pandemic across different hot-spots in the world. The standard formulations of SIR models rely upon summary-level data, which may not be able to fully capture the complete dynamics of the pandemic growth. Since the disease spreads from carriers to susceptible individuals via some form of contact, it inherently relies upon a network of individuals for its growth, with edges established via direct interaction, such as shared physical proximity. Using individual-level COVID-19 data from the early days (January 30 to April 15, 2020) of the pandemic in India, and under a network-based SIR model framework, we performed state-specific forecasting under multiple scenarios characterized by the basic reproduction number of COVID-19 across 34 Indian states and union territories. We validated our short-term projections using observed case counts and the long-term projections using national sero-survey findings. Based on healthcare availability data, we also performed projections to assess the burdens on the infrastructure along the spectrum of the pandemic growth. We have developed an interactive dashboard summarizing our results. Our predictions successfully identified the initial hot-spots of India such as Maharashtra and Delhi, and those that emerged later, such as Madhya Pradesh and Kerala. These models have the potential to inform appropriate policies for isolation and mitigation strategies to contain the pandemic, through a phased approach by appropriate resource prioritization and allocation.


title: Risk-factors Associated with Non-Vaccination in Gambian Children: A Population-Based Cohort Study

abstract:
ObjectiveWe determined the risk-factors associated with children who remain unvaccinated in rural Gambia.

MethodsWe conducted prospective demographic surveillance and recorded immunisations in real-time in the Basse Health and Demographic Surveillance System. Analysis included residents born between January 1, 2012 and December 31, 2016. Demographic data included age, sex, household members and relationships, migrations, births, deaths, ethnicity, residential location, and birth type. Children were defined as unvaccinated at 10-, 15-, and 24-months of age, if they missed all primary series doses (pentavalent, oral polio and pneumococcal conjugate vaccines), secondary series (1st dose measles and yellow-fever vaccines) or both vaccination series, respectively. Multivariate three-level mixed effects logistic regressions measured the strength of association between risk-factors and being unvaccinated at age 10-, 15-, and 24-months.

Findings38,090 infants were born during the study period, while 30,832 survived as residents and 1,567 were unvaccinated at age 10 months. Being unvaccinated at 10-months of age was associated with children not residing with their father (adjusted odds ratio [aOR] 1.38, 95% CI 1.22-1.58) or mother (aOR 2.94, 95% CI 1.33-6.46) or both parents (aOR 2.26, 1.60-3.19), whose parents were not the head of household (aOR 1.29 (1.09-1.52), experiencing external in-migration (aOR 2.78, 95% CI 1.52-5.08) and not of Mandinka ethnicity (aOR varied between 1.57 to 1.85 for three other ethnicities).

ConclusionUnimmunised children in rural Gambia are more likely to not live with their parents and have migrated into the area. These results may inform strategies to increase vaccine coverage.


title: SARS-CoV-2 variants of concern are associated with lower RT-PCR amplification cycles between January and March 2021 in France

abstract: SARS-CoV-2 variants raise concern regarding the mortality caused by COVID-19 epidemics. We analyse 88,375 cycle amplification (Ct) values from variant-specific RT-PCR tests performed between January 26 and March 13, 2021. We estimate that on March 12, nearly 85% of the infections were caused by the V1 variant and that its transmission advantage over wild type strains was between 38 and 44%. We also find that tests positive for V1 and V2/V3 variants exhibit significantly lower cycle threshold (Ct) values.


title: Impact of the COVID-19 pandemic on surgical procedures in Brazil: a descriptive study

abstract:
BackgroundThe COVID-19 pandemic has deeply affected medical practice, and changes in healthcare activities were needed to minimize the overload and avoid healthcare systems collapse. The aim of this study was to evaluate the impact of the pandemic on surgical procedures in Brazil.

Materials and MethodsWe conducted a descriptive study of the number of hospitalizations for surgical procedures in Brazil from 2016 to 2020. Data were collected from the Brazilian Department of Informatics of the Unified Health System (DATASUS). Analyzes were performed according to the type of procedure, geographical region, subgroups of surgical procedures, and the number of surgeries from 2020 were compared with the average from 2016 to 2019.

ResultsThere were 4,009,116 hospitalizations for surgical procedures in the Brazilian Public Health System in 2020. When comparing it to the average of hospitalizations from 2016-2019, there was a decrease of 14.88% [95%IC (14.82-14.93)]. Decrease rates were 34.82% [95%IC (34.73-34.90)] for elective procedures and 1.11% [95%IC (1.07-1.13)] for urgent procedures. Decrease rates were similar in all the five regions of the country (average 14.17%). Surgical procedure subgroups with the highest decrease rates were endocrine gland surgery (48.03%), breast surgery (40.68%), oral and maxillofacial surgery (37.03%), surgery of the upper airways, face, head and neck (36.06%), and minor surgeries and surgeries of skin, subcutaneous tissue and mucosa (33.16%). Conclusion: The overload of healthcare facilities has demanded a reduction of non-urgent activities to prevent a collapse of healthcare systems, resulting in a decrease in elective surgeries. Recommendations about the performance of surgical procedures were made, and continuous refinements of these recommendations are encouraged.

category: surgery


title: Identifying Patterns of Association and Transition in the Use of Addictive Substances over Five Decades in the United States

abstract:
ObjectivesTo conduct weighted itemset analysis to identify patterns of polysubstance use from National Survey on Drug Use and Health (NSDUH) data.

MethodsWe computed weighted support for every combination of one or more substances, termed as a drugset, used by individuals in the nationally representative NSDUH data over 5 decades (1965-2014). A computational framework for efficient representation and search of patterns of association between drugsets and demographics of user groups over time was developed. A new method for mining rules of transition between pairs of substances used within a time-interval was given.

ResultsWe identified the frequent drugsets from individual substance use data, and determined their representation among different demographic groups at different intervals. An interesting pattern of use of pain relievers and tranquilizers was detected for the age-group of 26-34 years. Transition rules for heroin use in the last decade (2004-2015) of data were mined.

ConclusionsComputation of weighted supports over time for every possible drugset in the data and their association with specific user groups produced a framework for generation and testing new and interesting hypotheses. The framework is useful to explore different combinations of substances used among diverse demographic groups including those that have received less attention in this problem.


title: Isolated fetal neural tube defects associate with increased risk of placental pathology: evidence from the Collaborative Perinatal Project.

abstract:
ObjectiveTo compare placental pathology and fetal growth in pregnancies with an isolated fetal neural tube defect (NTD; cases) to those without congenital anomalies (controls). We hypothesised that cases would be at an increased risk of placental pathology and poorer anthropometric outcomes at birth compared to controls

MethodsWe performed a matched case-cohort study using data from the Collaborative Perinatal Project. Cases (n=74) and controls (n=148) were matched (1:2 ratio) for maternal pre-pregnancy BMI, maternal race, infant sex, gestational age at birth and study site. Primary outcomes were placental characteristics (weight and size measurements, pathology). Secondary outcomes were infant birth outcomes. Subgroup analysis was done by type of NTD (spina bifida, anencephaly or encephalocele), infant sex, and preterm/term delivery. Data were analysed using adjusted generalized linear and nominal logistic regression models. Results are presented as adjusted {beta} or adjusted odds ratio (aOR; 95% confidence interval).

ResultsCases had lower placental weight ({beta}=-22.2 g [-37.8 - -6.6]), surface area ({beta}=-9.6 cm2 [-18.3 - -1.0]) and birth length z-scores ({beta}=-0.4 [-0.7 - -0.001]) compared to controls. Cases were more likely to have a single umbilical artery (vs. two; 6 [8.1%] vs. 1 [0.7%]; aOR=301 [52.6 - 1726]), overall placental hypermaturity (9 [12.2%] vs. 5 [3.4%]; aOR=6.8 [3.1 - 14.7]), and many (vs. few) Hofbauer cells (9 [12.2%] vs. 7 [4.7%]; aOR=3.02 [1.2 - 7.3]), stromal fibrosis (9 [12.2%] vs. 10 [6.8%]; aOR=3.0 [1.4 - 6.3]) and pathological edema (11 [14.9%] vs. 12 [8.1%]; aOR=3.04 [1.4 - 6.7]) in placental terminal villi compared to controls. Placental pathology varied across NTD subtypes, infant sex, and preterms vs. term pregnancies.

ConclusionsFetuses with isolated NTDs may be at increased risk of placental pathology, which could be contributing to poor fetal growth in these pregnancies and subsequent postnatal morbidities.

category: obstetrics and gynecology


title: Homophily in risk and behavior complicate understanding the COVID-19 epidemic curve

abstract: New COVID-19 diagnoses have dropped faster than expected in the United States. Interpretations of the decrease have focused on changing factors (e.g. mask-wearing, vaccines, etc.), but predictive models largely ignore heterogeneity in behaviorally-driven exposure risks among distinct groups. We present a simplified compartmental model with differential mixing in two behaviorally distinct groups. We show how homophily in behavior, risk, and exposure can lead to early peaks and rapid declines that critically do not signal the end of the outbreak. Instead, higher exposure risk groups may more rapidly exhaust available susceptibles while the lower risk group are still in a (slower) growth phase of their outbreak curve. This simplified model demonstrates that complex incidence curves, such as those currently seen in the US, can be generated without changes to fundamental drivers of disease dynamics. Correct interpretation of incidence curves will be critical for policy decisions to effectively manage the pandemic.


title: Monitoring the propagation of SARS CoV2 variants by tracking identified mutation in wastewater using specific RT-qPCR

abstract:
Since the end of 2020, the COVID-19 pandemic has experienced a major turning point with the appearance and rapid spread of new variants, causing a significant increase in the number of new cases requiring hospitalization. These so-called UK, South African or Brazilian variants are characterized by combinations of mutations which allow them to be distinguished from the variants which have circulated since the start of the epidemic. The impact of these variants on the functioning of healthcare systems requires monitoring the spread of these variants, which are more contagious, more lethal and may reinfect people who are already immune to a natural infection or to a vaccination. Monitoring the viral genome in wastewater has shown great value in early detection of the dynamics of virus spreading in populations.

The sequencing of viral genomes is used in humans, but its application and interpretation on wastewater matrices are much more complex due to the diversity of circulating strains. Also this study demonstrates the possibility of following certain mutations found in these new variants by targeted RT-qPCR. This study is the first carried out in France demonstrating the spreading dynamics of the 69-70 deletion in the Spike protein of SARS-CoV-2.


title: Mental health of patients with mental illness during the COVID-19 pandemic lockdown: A questionnaire-based survey weighted for attrition

abstract:
ImportanceIndividuals with pre-existing mental illness may be particularly vulnerable to the negative impact that the coronavirus disease 2019 (COVID-19) pandemic seems to have on mental health. Most prior studies on this topic are limited by non-random sampling, lacking information on non-respondents, and self-reporting of mental illness. In the present study, we aimed to overcome these limitations via random sampling, acquisition of clinical and sociodemographic data on both respondents and non-respondents, and weighting of results informed by attrition.

ObjectiveTo assess whether patients with mental illness experienced deterioration in mental health during the nationwide COVID-19 lockdown of Denmark in the Spring of 2020.

DesignA cross-sectional, questionnaire-based survey coupled with sociodemographic and clinical data from the medical records of all invitees. The latter enabled analysis of attrition and weighting of results.

SettingThe psychiatric services of the Central Denmark Region.

ParticipantsA total of 992 randomly drawn patients diagnosed with mental illness in the psychiatric services of the Central Denmark Region prior to the lockdown responded to the online survey (response rate of 21.6%).

ExposureThe four-week nationwide lockdown during the COVID-19 pandemic (from March 11 to April 15, 2020).

Main Outcomes and MeasuresThe online questionnaire included the 18-item Brief Symptom Inventory (BSI-18), the five-item World Health Organization Well-Being Index (WHO-5), and 14 questions evaluating worsening or improvement in symptoms during the lockdown using the pre-pandemic period as reference. Perceived reasons for deterioration of mental health were also reported.

ResultsThe weighted mean WHO-5 and BSI-18 scores were 38 and 28, respectively. A total of 52% of the respondents reported that their mental health had deteriorated during the lockdown, while 33% reported no change, and 16% reported improvement. The most commonly reported reasons for deterioration were loneliness, disruption of routines, concerns about coronavirus, less frequent contact with family/friends, boredom, and reduced access to psychiatric care.

Conclusion and RelevanceMore than half of the patients with mental illness reported worsening of their mental health during the pandemic lockdown. There should be increased emphasis on ensuring both social and clinical support for individuals with mental illness during pandemics.

KEY POINTSO_ST_ABSQuestionsC_ST_ABSDid patients with mental illness experience worsening of their mental health during the nationwide COVID-19 lockdown of Denmark in the Spring of 2020?

FindingsOf the 925 respondents, 52% reported that their mental health had deteriorated during the lockdown, while 33% reported no change and 16% reported improvement. The most commonly reported reasons for deterioration were loneliness and disruption of routines.

MeaningThese findings suggest that there should be increased emphasis on ensuring both social and clinical support for individuals with mental illness during the ongoing and potential future pandemics.

category: psychiatry and clinical psychology


title: The effect of International Monetary Fund programmes on population health

abstract:
BackgroundAs one of the worlds most powerful international financial organisations, the International Monetary Fund (IMF) is uniquely positioned to shape global developmental trajectories by influencing domestic policy arrangements. However, its role in shaping population health is understudied.

MethodsWe use previously unavailable cross-national time-series data and an instrumental-variables method to examine the causal impact of the IMFs structural adjustment programmes on age-standardised all-cause mortality rates and disability-adjusted life years (DALYs) in 187 countries between 1990 and 2017. For this purpose, we specify two-way fixed-effects regression models.

FindingsAccording to our baseline models, IMF programmes cause 392 excess all-cause deaths (95% CI: 176-608; p = 0.0004) and 4,205 excess DALYs (95% CI: 2,429-5,981; p = 0.000004) per 100,000 population. This aggregate effect appears to be driven by IMF-mandated privatisation reforms, which lead to 562 excess all-cause deaths (95% CI: 267-857; p = 0.0002) and 5,285 excess DALYs (95% CI: 2,749-7,822; p = 0.00004) per 100,000 population.

InterpretationStructural adjustment programmes play a significant role in perpetuating preventable disability and death in developing contexts. The IMFs policy reforms, especially those pertaining to the privatisation of state-owned enterprises, increase excess mortality rates and disease burdens in the worlds most vulnerable regions.

FundingNone.


title: Structural adjustment programmes and communicable disease burdens: causal evidence from 187 countries

abstract: International financial organisations like the International Monetary Fund (IMF) play a central role in shaping the developmental trajectories of fiscally distressed countries through their conditional lending schemes, known as  structural adjustment programmes. These programmes entail wide-ranging domestic policy reforms that influence local health and welfare systems. Using novel panel data from 187 countries between 1990 and 2017 and an instrumental variable technique, we find that IMF programmes lead to over 70 excess deaths from respiratory diseases and tuberculosis per 100,000 population and that IMF-mandated privatisation reforms lead to over 90 excess deaths per 100,000 population. Thus structural adjustment programmes, as currently designed and implemented, are harmful to population health and increase global infectious disease burdens.


title: Structural adjustment programmes and infectious disease mortality


title: Untargeted lipidomics of non-small cell lung carcinoma shows differentially abundant lipid classes in cancer vs non-cancer tissue

abstract:
Lung cancer is the leading cause of cancer death worldwide and non-small cell lung carcinoma (NSCLC) represents 85% of newly diagnosed lung cancers. The high mortality rate of lung cancer is due in part to the lack of effective treatment options for advanced disease. A major limitation in the development of effective treatment options is our incomplete understanding of NSCLC metabolism at a molecular level, especially lipids. Improvements in mass spectrometry combined with our untargeted assignment tool SMIRFE enable the systematic and less biased examination of NSCLC lipid metabolism.

Lipids were extracted from paired tumorous and non-tumorous lung tissue samples from 86 patients with suspected resectable stage I or IIa primary NSCLC and were analyzed using ultra-high resolution Fourier transform mass spectrometry. Pathological examination of the samples revealed that the majority of the samples were primary NSCLC; however, the disease group does include examples of metastases of other cancers and several granulomas. Information-content-informed (ICI) Kendall tau correlation analysis revealed correlation and co-occurrence patterns consistent with significant changes in lipid profiles between disease and non-disease samples. Lipids assigned using the program SMIRFE (Mitchell et al., 2019) were analyzed for differential abundance, followed by machine learning to classify the SMIRFE formula assignments into lipid categories. At the lipid category level, sterol abundances were consistently higher in diseased versus non-diseased lung tissues at statistically significant levels.

The statistically significant increase in sterol abundances in primary NSCLC compared with non-cancerous lung tissue suggests for treatment of primary NSCLC a possible therapeutic role for statins and nitrogenous bisphosphonates, pharmaceuticals that inhibit endogenous sterol biosynthesis. This hypothesis is consistent with previous epidemiological studies that have identified a therapeutic role for statins in the treatment of NSCLC but were unable to identify a molecular mechanism for this effect. Additionally, the majority of the consistently increased sterol abundances belong to the sterol ester subcategory, suggesting increased SCD1 and ACAT1 activity. SCD1 expression is a known negative prognostic indicator for survival in NSCLC. In our study, a large fraction of the NSCLC samples displayed this phenotype; however, SCD1 mutants would be unexpected in all of these samples. This suggests that this metabolic phenotype may be shared across multiple genetic subtypes of NSCLC. Thus, inhibitors of SCD1 and other enzymes involved in the production of this metabolic phenotype could have utility in the treatment of many genetic subtypes of NSCLC.

category: oncology


title: Physiological (TCR-like) regulated lentiviral vectors for the generation of improved CAR-T cells

abstract:
BackgroundChimeric antigen receptor (CAR) T cells directed against CD19 have achieved impressive outcomes for the treatment of relapsed/refractory B lineage lymphoid neoplasms. However, CAR-T therapy still has important limitations due to severe side effects and the lack of efficiency in 40-50% of the patients. Most CARs-T products are generated using retroviral vectors with strong promoters. However, high CAR expression levels can lead to tonic signalling, premature exhaustion and over-stimulation of CAR-T cells, reducing efficacy and increasing side effects. TCR-like expression of the CAR through genome editing resulted in enhanced anti-tumour potency, reducing tonic signalling and improving CAR-T phenotype. In this manuscript, we searched for LVs that mimic the TCR expression pattern as a closer-to-clinic alternative for the generation of improved CAR-T cells.

MethodsDifferent LVs containing viral and human promoters were analysed to select those that closely mimic a TCR-like kinetic profile upon T-cell activation. WAS gene proximal promoter-driven LVs (AW-LVs) were selected to express a second generation 4-1BB aCD19 CAR (ARI-0001) into T cells to generate AWARI CAR-T cells. TCR-like AWARI and EF1-driven ARI CAR T cells were analysed for in vitro and in vivo killing efficiency using leukaemia and lymphoma cellular models. Tonic signalling, exhaustion markers and phenotype were determined by flow cytometry. Large-scale automated manufacturing of AWARI CAR-T cells was performed in a CliniMACs Prodigy bioreactor.

ResultsOur data showed that LVs expressing the transgene through the WAS gene proximal promoter mimic very closely the TCR (CD3) expression pattern kinetic upon TCR stimulation or antigen encounter. Compared to EF1-driven ARI CAR-T cells, AWARI CAR-T cells exhibited a higher proportion of naive/stem cell memory T cells with less exhausted phenotype after efficient killing of CD19+ cells both in vitro and in vivo. AWARI CAR-T cells also showed lower tonic signalling and reduced secretion of pro-inflammatory cytokines and were efficiently manufactured in large-scale GMP-like conditions.

ConclusionsWAS-gene-promoter driven LVs can be used to generate physiological 4-1BB-CAR-T cell products with lower tonic signalling, improved phenotype and a safer profile. We propose the use of TCR-like LVs as an alternative to strong-promoter driven LVs for the generation of CAR-T products.


title: Intensity of COVID-19 in care homes following Hospital Discharge in the early stages of the UK epidemic

abstract:
BackgroundA defining feature of the COVID-19 pandemic in many countries was the tragic extent to which care home residents were affected, and the difficulty preventing introduction and subsequent spread of infection. Management of risk in care homes requires good evidence on the most important transmission pathways. One hypothesised route at the start of the pandemic, prior to widespread testing, was transfer of patients from hospitals, which were experiencing high levels of nosocomial events.

MethodsWe tested the hypothesis that hospital discharge events increased the intensity of care home cases using a national individually linked health record cohort in Wales, UK. We monitored 186,772 hospital discharge events over the period March to July 2020, tracking individuals to 923 care homes and recording the daily case rate in the homes populated by 15,772 residents. We estimated the risk of an increase in cases rates following exposure to a hospital discharge using multi-level hierarchical logistic regression, and a novel stochastic Hawkes process outbreak model.

FindingsIn regression analysis, after adjusting for care home size, we found no significant association between hospital discharge and subsequent increases in care home case numbers (odds ratio: 0.99, 95% CI 0.82, 1.90). Risk factors for increased cases included care home size, care home resident density, and provision of nursing care. Using our outbreak model, we found a significant effect of hospital discharge on the subsequent intensity of cases. However, the effect was small, and considerably less than the effect of care home size, suggesting the highest risk of introduction came from interaction with the community. We estimated approximately 1.8% of hospital discharged patients may have been infected.

InterpretationThere is growing evidence in the UK that the risk of transfer of COVID-19 from the high-risk hospital setting to the high-risk care home setting during the early stages of the pandemic was relatively small. Although access to testing was limited to initial symptomatic cases in each care home at this time, our results suggest that reduced numbers of discharges, selection of patients, and action taken within care homes following transfer all may have contributed to mitigation. The precise key transmission routes from the community remain to be quantified.

category: health informatics


title: Learning from the Experiences of COVID-19 Survivors: A Descriptive Study

abstract:
BackgroundThere are still many unanswered questions about the novel coronavirus, however, a largely underutilized source of knowledge are the millions of people who have recovered after contracting the virus. This includes majority of undocumented cases of the COVID-19 which are classified as mild or moderate and received little to no clinical care during the course of illness.

ObjectiveTo document and glean insights from the experiences of persons with first-hand experience with coronavirus, especially the so-called mild to moderate cases that self-resolved in isolation.

MethodsThis online-based survey study called C19 Insider Scoop recruited adult participants that are 18-years or older who reside in the United States and tested positive for COVID-19 or antibodies. Participants were recruited through various methods including online support groups for COVID-19 survivors, advertisement in local news outlets, and advertisement through professional and other networks. The main outcomes measured include knowledge on contraction/transmission of the virus, symptoms, and personal experiences on road to recovery.

ResultsA total of 72 participants (53 females/19 males, ages 18 - 73 yrs. old, mean = 41-yrs.) from 22 U.S. states participated in this study. We found that the top known source of how people contracted the COVID-19 virus was through a family or household member (n=26 or 35%). This was followed by essential workers contracting the virus through the workplace (n=13 or 18%).

Participants reported up to 27 less-documented symptoms that they experienced during their illness such as brain/memory fog, palpitations, ear pain/discomfort and neurological problems. In addition, 47 out of 72 participants (65%) reported that their symptoms lasted longer than the commonly cited 2-weeks even for mild cases of COVID-19. In our study, the mean recovery time was 4.5-weeks, and exactly one-half of survivors (50%) still experienced lingering symptoms of COVID-19 after an average of 65-days following illness onset. Additionally, 37 participants (51%) reported that they experienced stigma associated with having COVID-19.

ConclusionThis study presents preliminary findings which suggests that emphasis on family/household spread of COVID-19 may be lacking and there is a general underestimation of the recovery time even for mild cases of the virus. Although a larger study is needed to validate these results, it is important to note that as more people experience COVID-19, insights from prior survivors can enable a more informed public, pave the way for others who may be affected, and guide further research.


title: A DNA methylome biosignature in alveolar macrophages from TB-exposed individuals predicts exposure to mycobacteria

abstract: Several studies have identified biomarkers for tuberculosis (TB) diagnosis based on blood cell transcriptomics. Here, we instead studied epigenomics in the lung compartment by obtaining induced sputum from subjects included in a TB contact tracing. CD3- and HLA-DR-positive cells were isolated from the collected sputum and DNA methylome analyses performed. Unsupervised cluster analysis revealed that DNA methylomes of cells from TB-exposed individuals and controls appeared as separate clusters and the numerous genes that were differentially methylated were functionally connected. The enriched pathways were strongly correlated to data from published work on protective heterologous immunity to TB. Taken together, our results demonstrate that epigenetic changes related to trained immunity occurs in the pulmonary immune cells of TB-exposed individuals and that a DNA methylation signature can be derived from the DNA methylome. Such a signature can be further developed for clinical use as a marker of TB exposure.


title: Evidence for antibody as a protective correlate for COVID-19 vaccines

abstract: Though eleven novel COVID-19 vaccines have demonstrated efficacy, additional affordable, scalable, and deliverable vaccines are needed to meet unprecedented global demand. With placebo-controlled efficacy trials becoming infeasible due to the roll out of licensed vaccines, a correlate of protection is urgently needed to provide a path for regulatory approval of novel vaccines. To assess whether antibody titers may reasonably predict efficacy, we evaluated the relationship between efficacy and in vitro neutralizing and binding antibodies of 7 vaccines for which sufficient data have been generated. Once calibrated to titers of human convalescent sera reported in each study, a robust correlation was seen between neutralizing titer and efficacy ({rho}= 0.79) and binding antibody titer and efficacy ({rho} = 0.93), despite geographically diverse study populations subject to different forces of infection and circulating variants, and use of different endpoints, assays, convalescent sera panels and manufacturing platforms. This correlation is strengthened by substituting post-hoc analyses for efficacy against the ancestral strain (D614G), where available. Together with an accumulating body of evidence from natural history studies and animal models, these results support the use of post-immunization antibody titers as the basis for establishing a correlate of protection for COVID-19 vaccines.


title: Household transmission of SARS-CoV-2 R.1 lineage with spike E484K mutation in Japan

abstract: We aimed to investigate SARS-CoV-2 emerging lineage harboring variants in receptor binding domain (RBD) of spike protein in Japan. Total nucleic acids were subjected to whole genome sequencing on samples from 133 patients with coronavirus disease (COVID-19). We obtained the SARS-CoV-2 genome sequence from these patients and examined variants in RBD. As a result, three patients were infected with SARS-CoV-2 harboring E484K mutation in January 2021. These three patients were relatives; one was in the 40s, and two were younger than 10 years old. They had no history of staying abroad and were living in Japan. This strains were classified into GR clade (GISAID), 20B clade (Nextstrain) and R.1 lineage (PANGO). As of March 5, 2021, the R.1 lineage have been identified in 305 samples and dominantly observed in the USA (44%, 135 / 305) and Japan (28%, 84 / 305) from the GISAID database. During the period between October 26, 2020 and February 23, 2021, the frequency of the R.1 lineage was 0.97% (84 / 8,629) of the total confirmed data in Japan and 0.15% (135 / 90,450) in the USA. Although SARS-CoV-2 R.1 lineage was not globally predominant as of March 2021, further analysis is needed to determine whether R.1 variant will disappear or expand in the future.


title: DNA methylomes derived from alveolar macrophages display distinct patterns in latent tuberculosis - implication for interferon gamma release assay status determination

abstract:
Host innate immune cells, including alveolar macrophages, have been identified as key players in the early eradication of Mycobacterium tuberculosis and in the maintenance of an anti-mycobacterial immune memory, which is believed to be induced through epigenetic changes. The aim of the study was to elucidate whether exposure to M. tuberculosis induced a different DNA methylation pattern of alveolar macrophages and pulmonary T lymphocytes.

Alveolar macrophages and T lymphocytes were isolated from induced sputum obtained from individuals living in Lima, which is an area high endemic for tuberculosis. To determine the latent tuberculosis infection status of the subjects, an interferon-{gamma} release assay was performed. We evaluated the DNA methylomes of the alveolar macrophages and T lymphocytes using the Illumina Infinium Human Methylation 450K Bead Chip array, revealing a distinct DNA methylation pattern in alveolar macrophages allowing the discrimination of asymptomatic individuals with latent tuberculosis infection from non-infected individuals. Pathway analysis revealed that cell signalling of inflammation and chemokines in alveolar macrophages play a role in latent tuberculosis infection. In conclusion, we demonstrated that DNA methylation in alveolar macrophages can be used to determine the tuberculosis infection status of individuals in a high endemic setting.


title: Epitope-resolved serology test differentiates the clinical outcome of COVID-19 and identifies defects in antibody response in SARS-CoV-2 variants

abstract:
BACKGROUNDThe role of humoral immunity in the coronavirus disease 2019 (COVID-19) is not fully understood owing, in large part, to the complexity of antibodies produced in response to the SARS-CoV-2 infection. There is a pressing need for serology tests to assess patient-specific antibody response and predict clinical outcome.

METHODSUsing SARS-CoV-2 proteome and peptide microarrays, we screened 146 COVID-19 patients plasma samples to identify antigens and epitopes. This enabled us to develop a master epitope array and an epitope-specific agglutination assay to gauge antibody responses systematically and with high resolution.

RESULTSWe identified 54 linear epitopes from the Spike (S) and Nucleocapsid (N) protein and showed that epitopes enabled higher resolution antibody profiling than protein antigens. Specifically, we found that antibody responses to the S(811-825), S(881-895) and N(156-170) epitopes negatively or positively correlated with clinical severity or patient survival. Moreover, we found that the P681H and S235F mutations associated with the coronavirus variant B.1.1.7 altered the specificity of the corresponding epitopes.

CONCLUSIONSEpitope-resolved antibody testing not only offers a high-resolution alternative to conventional immunoassays to delineate the complex humoral immunity to SARS-CoV-2 and differentiate between neutralizing and non-neutralizing antibodies, it may also be used as predictor of clinical outcome. The epitope peptides can be readily modified to detect antibodies against variants in both the peptide array and latex agglutination formats.

FUNDINGOntario Research Fund (ORF)-COVID-19 Rapid Research Fund, the Toronto COVID-19 Action Fund, Western University, the Lawson Health Research Institute, the London Health Sciences Foundation, and the AMOSO Innovation Fund.


title: A Differential DNA Methylome Signature of Pulmonary Immune Cells from Individuals Converting to Latent Tuberculosis Infection

abstract: Tuberculosis (TB), caused by Mycobacterium tuberculosis, spreads via aerosols and the first encounter with the immune system is with the pulmonary resident immune cells. The role of epigenetic regulations through DNA methylation in the immune cells is emerging. We have previously shown that capacity to kill M. tuberculosis is reflected in the DNA methylome. The aim of this study was to investigate epigenetic modifications in the pulmonary immune cells in a cohort of medical students with a previously documented increased risk of TB exposure, longitudinally. Sputum samples containing alveolar macrophages (AMs) and T cells were collected before and after study subjects worked in hospital departments with a high-risk of TB exposure. DNA methylome analysis revealed that a unique DNA methylation profile was present already at inclusion in subjects who developed latent TB during the study. The profile was both reflected in different overall DNA methylation distribution as well as more profound alterations in the methylation status of a unique set of CpG-sites. Over-representation analysis of the DMGs showed enrichment in pathways related to metabolic reprograming of macrophages and T cell migration and IFN-{gamma} production. In conclusion, we identified a unique DNA methylation signature in individuals, while still IGRA-negative and who later developed latent TB. Epigenetic regulation was found in pathways that have previously been reported to be important in TB. Together the study suggests that DNA methylation status of pulmonary immune cells can predict IGRA conversion.


title: Effects of wearing face masks under moderate physical effort

abstract:
Due to the COVID-19 pandemic, face masks have become part of daily life and work. Only few studies have investigated potential negative effects of this measure. It was aim of this study to evaluate whether face masks may affect oygen saturation and heart reate under moderate physical effort. Ten healthy volunteers were asked to climb up four floors (96 steps) with and without a face mask. Oxygen saturation and heart rate were recorded before and after this procedure.

Physical activity lead to a slight decrease of oxygen saturation of 3.0% ({+/-} 3.1) without and 3.7% ({+/-} 3.8) with face masks (p= 0.28). Heart rate increased by 31.0 ({+/-}18.7) and 33.3 ({+/-} 15.9) beats per minute (p= 0.39). Desaturation was more pronounced in individuals > 40 years, however was uncritical in all cases.

This study shows that in healthy adults the use of face masks does not significantly affect oxygen supply nor cause additional cardiac load.

category: cardiovascular medicine


title: Persistence and detection of anti-SARS-CoV-2 antibodies: immunoassay heterogeneity and implications for serosurveillance

abstract: Serologic studies have been critical in tracking the evolution of the COVID-19 pandemic. The reliability of serologic studies for quantifying the proportion of the population that have been infected depends on the extent of antibody decay as well as on assay performance in detecting both recent and older infections. Data on anti-SARS-CoV-2 antibodies persistence remain sparse, especially from infected individuals with few to no symptoms. In a cohort of mostly mild/asymptomatic SARS-CoV-2-infected individuals tested with three widely-used immunoassays, antibodies persisted for at least 8 months after infection, although detection depended on immunoassay choice, with one of them missing up to 40% of past infections. Simulations reveal that without appropriate adjustment for time-varying assay sensitivity, seroprevalence surveys may underestimate infection rates. As the immune landscape becomes more complex with naturally-infected and vaccinated individuals, assay choice and appropriate assay-performance-adjustment will become even more important for the interpretation of serologic studies.


title: The effect of in-person primary and secondary school instruction on county-level SARS-CoV-2 spread in Indiana

abstract:
BackgroundTo determine the county-level effect of in-person primary and secondary school reopening on daily cases of SARS-CoV-2 in Indiana.

MethodsThis is a county-level population-based study using a panel data regression analysis of the proportion of in-person learning to evaluate an association with community-wide daily new SARS-CoV-2 cases. The study period was July 12-October 6, 2020. We included 73 out of 92 (79.3%) Indiana counties in the analysis, accounting for 85.7% of school corporations and 90.6% of student enrollement statewide. The primary exposure was the proportion of students returning to in-person instruction. The primary outcome was the daily new SARS-CoV-2 cases per 100,000 residents at the county level.

ResultsThere is a statistically significant relationship between the proportion of students attending K-12 schools in-person and the county level daily cases of SARS-CoV-2 28 days later. For all ages, the coefficient of interest ({beta}) is estimated at 3.36 (95% CI: 1.91--4.81; p < 0.001). This coefficient represents the effect of a change the proportion of students attending in-person on new daily cases 28 days later. For example, a 10 percentage point increase in K-12 students attending school in-person is associated with a daily increase in SARS-CoV-2 cases in the county equal to 0.336 cases/100,000 residents of all ages.

ConclusionIn-person primary and secondary school is associated with a statistically significant but proportionally small increase in the spread of SARS-CoV-2 cases.


title: "This is about the coolest thing I've ever seen is that you just showed right up." COVID-19 testing and vaccine acceptability among homeless-experienced adults: Qualitative data from two samples

abstract:
BackgroundHomeless-experienced populations are at increased risk of exposure to SARS CoV-2 due to their living environments and face increased risk of severe COVID-19 disease due to underlying health conditions. Little is known about COVID-19 testing and vaccination acceptability among homeless-experienced populations.

ObjectiveTo understand the facilitators and barriers to COVID-19 testing and vaccine acceptability among homeless-experienced adults.

DesignWe conducted in-depth interviews with participants from July-October 2020. We purposively recruited participants from 1) a longitudinal cohort of homeless-experienced older adults in Oakland, CA (n=37) and 2) a convenience sample of people (n=57) during a mobile outreach COVID-19 testing event in San Francisco.

ParticipantsAdults with current or past experience of homelessness.

ApproachWe asked participants about their experiences with and attitudes towards COVID-19 testing and their perceptions of COVID-19 vaccinations. We used participant observation techniques to document the interactions between testing teams and those approached for testing. We audio-recorded, transcribed and content analyzed all interviews and identified major themes and subthemes.

Key ResultsParticipants found incentivized COVID-19 testing administered in unsheltered settings and supported by community health outreach workers (CHOWs) to be acceptable. The majority of participants expressed positive inclination toward vaccine acceptability, citing a desire to return to routine life and civic responsibility. Those who expressed hesitancy cited a desire to see trial data, concerns that vaccines included infectious materials, and mistrust of the government.

ConclusionsParticipants expressed positive evaluations of the incentivized, mobile COVID-19 testing supported by CHOWs in unsheltered settings. The majority of participants expressed positive inclination toward vaccination. Vaccine hesitancy concerns must be addressed when designing vaccine delivery strategies that overcome access challenges. Based on the successful implementation of COVID-19 testing, we recommend mobile delivery of vaccines using trusted CHOWs to address concerns and facilitate wider access to and uptake of the COVID vaccine.


title: Uncertainty extraction and verification for the Common Conditions Affecting the Hand and Wrist Priority Setting Partnership: A proposed methodology for Priority Setting Partnerships with the James Lind Alliance

abstract:
ObjectiveTo report our recommended methodology for extracting and confirming published research uncertainties during a broad scope Priority Setting Partnership (PSP) with the James Lind Alliance.

SettingThis process was completed in the UK as part of the PSP for "Common Conditions Affecting the Hand and Wrist", comprising of health professionals, patients and carers.

Design and Data ExtractionWe applied best practice in systematic review methodology and reporting, including independent screening and data extraction by multiple researchers and use of a PRISMA flowchart, alongside steering group consensus processes.

Data SourcesCochrane Systematic Reviews and Protocols, NICE (National Institute for Health and Care Excellence) Guidelines, and SIGN (Scottish Intercollegiate Guidelines Network) Guidelines.

Selection CriteriaSelection of research uncertainties was guided by the scope of the Common Conditions Affecting the Hand and Wrist PSP which focused on "common hand conditions routinely treated by hand specialists, including hand surgeons and hand therapists limited to identifying questions concerning the results of intervention, and not the basic science or epidemiology behind disease.

ResultsOf 2358 records identified after duplicate extraction which entered the screening process, 186 records were presented to the PSP steering group for eligibility assessment; 79 were deemed within scope and included for the purpose of research uncertainty extraction (45 full Cochrane Reviews, 18 Cochrane Review protocols, 16 Guidelines). These yielded 89 research uncertainties, which were compared to the stakeholder survey, and added to the longlist where necessary; before derived uncertainties were checked against non-Cochrane published systematic reviews.

ConclusionsIn carrying out this work, beyond reporting on output of the Common Conditions Affecting the Hand and Wrist PSP, we detail the methodology and processes we hope can inform and facilitate the work of future PSPs and other evidence reviews, especially those with a broader scope beyond a single disease or condition.

Strengths and Limitations- This is a novel and rigorous approach to uncertainty extraction and verification in the setting of a James Lind Alliance Priority Setting Partnership.
- The detailed methodology provides transparency regarding the extraction and verification of uncertainties.
- The uncertainty extraction and verification relied upon the HandSRev database - similar resources may not be available for other Priority Setting Partnerships.

category: orthopedics


title: Essential Emergency and Critical Care - a consensus among global clinical experts

abstract:
BackgroundGlobally, critical illness results in millions of deaths every year. Although many of these deaths are potentially preventable, the basic, life-saving care of critically ill patients are often overlooked in health systems. Essential Emergency and Critical Care (EECC) has been devised as the care that should be provided to all critically ill patients in all hospitals in the world. EECC includes the effective care of low cost and low complexity for the identification and timely treatment of critically ill patients across all medical specialities. This study aimed to specify the content of EECC and additionally, given the surge of critical illness in the ongoing pandemic, the essential diagnosis-specific care for critically ill patients with COVID-19.

MethodsA Delphi process was conducted to seek consensus (>90% agreement) in a diverse panel of global clinical experts. The panel was asked to iteratively rate proposed treatments and actions based on previous guidelines and the WHO/ICRCs Basic Emergency Care. The output from the Delphi was adapted iteratively with specialist reviewers into a coherent and feasible EECC package of clinical processes plus a list of hospital resource requirements.

ResultsThe 269 experts in the Delphi panel had clinical experience in different acute medical specialties from 59 countries and from all resource settings. The agreed EECC package contains 40 clinical processes and 67 hospital readiness requirements. The essential diagnosis-specific care of critically ill COVID-19 patients has an additional 7 clinical processes and 9 hospital readiness requirements.

ConclusionThe study has specified the content of the essential emergency and critical care that should be provided to all critically ill patients. Implementation of EECC could be an effective strategy to reduce preventable deaths worldwide. As critically ill patients have high mortality rates, especially where trained staff or resources are limited, even small improvements would have a large impact on survival. EECC has a vital role in the effective scale-up of oxygen and other care for critically ill patients in the COVID-19 pandemic. Policy makers should prioritise EECC, increase its coverage in hospitals, and include EECC as a component of universal health coverage.

category: health systems and quality improvement


title: The Spike-specific IgA in milk commonly-elicited after SARS-Cov-2 infection is concurrent with a robust secretory antibody response, exhibits neutralization potency strongly correlated with IgA binding, and is highly durable over time

abstract: Approximately 10% of infants will experience COVID-19 illness requiring advanced care (1). A potential mechanism to protect this population could be provided by passive immunity through the milk of a previously infected mother. We and others have reported on the presence of SARS-CoV-2-specific antibodies in human milk (2-5). We now report the prevalence of SARS-CoV-2 IgA in the milk of 75 COVID-19-recovered participants, and find that 88% of samples are positive for Spike-specific IgA. In a subset of these samples, 95% exhibited robust IgA activity as determined by endpoint binding titer, with 50% considered high-titer. These IgA positive specimens were also positive for Spike-specific antibodies bearing the secretory component. Levels of IgA antibodies and antibodies bearing secretory component were shown to be strongly positively correlated. The secretory IgA response was dominant among the milk samples tested compared to the IgG response, which was present in 75% of samples and found to be of high-titer in only 13% of cases. Our IgA durability analysis using 28 paired samples, obtained 4-6 weeks and 4-10 months after infection, found that all samples exhibited persistently significant Spike-specific IgA, with 43% of donors exhibiting increasing IgA titers over time. Finally, COVID-19 and pre-pandemic control milk samples were tested for the presence of neutralizing antibodies; 6 of 8 COVID-19 samples exhibited neutralization of Spike-pseudotyped VSV (IC50 range, 2.39 - 89.4ug/mL) compared to 1 of 8 controls. IgA binding and neutralization capacities were found to be strongly positively correlated. These data are highly relevant to public health, not only in terms of the protective capacity of these antibodies for breastfed infants, but also for the potential use of such antibodies as a COVID-19 therapeutic, given that secretory IgA is highly stable not only in milk and the infant mouth and gut, but in all mucosa including the gastrointestinal tract, upper airway, and lungs (6).

category: allergy and immunology


title: Detecting SARS-CoV-2 lineages and mutational load in municipal wastewater; a use-case in the metropolitan area of Thessaloniki, Greece

abstract: The SARS-CoV-2 pandemic represents an unprecedented global crisis necessitating novel approaches for, amongst others, early detection of emerging variants relating to the evolution and spread of the virus. Recently, the detection of SARS-CoV-2 RNA in wastewater has emerged as a useful tool to monitor the prevalence of the virus in the community. Here, we propose a novel methodology, called lineagespot, for the detection of SARS-CoV-2 lineages in wastewater samples using next-generation sequencing. Our proposed method was tested and evaluated using NGS data produced by the sequencing of three wastewater samples from the municipality of Thessaloniki, Greece, covering three distinct time periods. The results showed a clear identification of trends in the presence of SARS-CoV-2 mutations in sewage data, and allowed for a robust inference between the variants evident through our approach and the variants observed in patients from the same area time periods. Lineagespot is an open-source tool, implemented in R, and is freely available on GitHub.


title: The indirect health impacts of COVID19 restrictions: a strong debate informed by weak evidence

abstract:
O_TEXTBOXKEY MESSAGES

O_LIThere has been concern, and much heated debate, on the possible negative effects of restrictions, stay-at-home orders and lockdowns during the COVID-19 pandemic.
C_LIO_LIMost published studies on health impacts of restrictions and lockdowns are low quality and often severely biased.
C_LIO_LIFocusing on the few studies that approximate a change in restrictions alone (i.e. not the impact of the pandemic per se), we see clear adverse impacts of lockdowns on intimate partner violence and physical activity. Regarding diseases, road traffic crashes decrease, and anxiety increases.
C_LIO_LIA discussion driven by science (not politics) is urgently needed on what lockdowns can deliver, their limitations and how to optimally deploy them - along other public health strategies - in the fight against COVID-19.
C_LI

C_TEXTBOX


title: Long lockdowns and rainy days: Modeling the interactive roles of weather, behavior, and restrictions in COVID-19 transmission in the Netherlands

abstract: Extant research on the role of weather in COVID-19 has produced ambiguous results and much methodological debate. Following advice emerging from this methodological debate, we take a step further in modeling effects of weather on COVID-19 spread by including interactions between weather, behavior, baseline cases, and restrictions in our model. Our model was based on secondary infection, hospitalization, restriction, weather, and mobility data per day nested with safety region in the Netherlands. Our findings show significant but inconsistent interactions. The robust effects of weather on COVID-19 spread persisted over and above these interactions, highlighting the need to account for weather with nuance and caution in public policy, communication, and forecasting.


title: A Queuing Model for Ventilator Capacity Management during the COVID-19 Pandemic

abstract: We applied a queuing model to inform ventilator capacity planning during the first wave of the COVID-19 epidemic in the province of British Columbia (BC), Canada. The core of our framework is a multiclass Erlang loss model that represents ventilator use by both COVID-19 and non-COVID-19 patients. Input for the model includes COVID-19 case projections, and our analysis incorporates projections with different levels of transmission due to public health measures and social distancing. We incorporated data from the BC Intensive Care Unit Database to calibrate and validate the model. Using discrete event simulation, we projected ventilator access, including when capacity would be reached and how many patients would be unable to access a ventilator. Simulation results were compared with three numerical approximation methods, namely pointwise stationary approximation, modified offered load, and fixed point approximation. Using this comparison, we developed a hybrid optimization approach to efficiently identify required ventilator capacity to meet access targets. Model projections demonstrate that public health measures and social distancing potentially averted up to 50 deaths per day in BC, by ensuring that ventilator capacity was not reached during the first wave of COVID-19. Without these measures, an additional 173 ventilators would have been required to ensure that at least 95% of patients can access a ventilator immediately. Our model provides a tool for policy makers to quantify the interplay between public health measures, necessary critical care resources, and performance indicators for patient access.

category: intensive care and critical care medicine


title: Effect of vaccination on transmission of COVID-19: an observational study in healthcare workers and their households

abstract:
BackgroundThe effect of vaccination for COVID-19 on onward transmission is unknown.

MethodsA national record linkage study determined documented COVID-19 cases and hospitalisations in unvaccinated household members of vaccinated and unvaccinated healthcare workers from 8th December 2020 to 3rd March 2021. The primary endpoint was COVID-19 14 days following the first dose.

ResultsThe cohort comprised of 194,362 household members (mean age 31{middle dot}1 {+/-} 20{middle dot}9 years) and 144,525 healthcare workers (mean age 44{middle dot}4 {+/-} 11{middle dot}4 years). 113,253 (78{middle dot}3%) of healthcare workers received at least one dose of the BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccine and 36,227 (25{middle dot}1%) received a second dose. There were 3,123 and 4,343 documented COVID-19 cases and 175 and 177 COVID-19 hospitalisations in household members of healthcare workers and healthcare workers respectively. Household members of vaccinated healthcare workers had a lower risk of COVID-19 case compared to household members of unvaccinated healthcare worker (rate per 100 person-years 9{middle dot}40 versus 5{middle dot}93; HR 0{middle dot}70, 95% confidence interval [CI] 0{middle dot}63 to 0{middle dot}78). The effect size for COVID-19 hospitalisation was similar, with the confidence interval crossing the null (HR 0{middle dot}77 [95% CI 0{middle dot}53 to 1{middle dot}10]). The rate per 100 person years was lower in vaccinated compared to unvaccinated healthcare workers for documented (20{middle dot}13 versus 8{middle dot}51; HR 0{middle dot}45 [95% CI 0{middle dot}42 to 0{middle dot}49]) and hospitalized COVID-19 (0{middle dot}97 versus 0{middle dot}14; HR 0{middle dot}16 [95% CI 0{middle dot}09 to 0{middle dot}27]). Compared to the period before the first dose, the risk of documented COVID-19 case was lower at [≥] 14 days after the second dose for household members (HR 0{middle dot}46 [95% CI 0{middle dot}30to 0{middle dot}70]) and healthcare workers (HR 0{middle dot}08 [95% CI 0{middle dot}04 to 0{middle dot}17]).

InterpretationVaccination of health care workers was associated with a substantial reduction in COVID-19 cases in household contacts consistent with an effect of vaccination on transmission.


title: Plasma Neurofilament Light Chain predicts cognitive progression in prodromal and clinical dementia with Lewy Bodies

abstract: Plasma neurofilament light chain (NfL) is a marker of neuronal damage in different neurological disorders and might predict disease progression in dementia with Lewy bodies (DLB). The study enrolled 45 controls and 44 DLB patients (including 17 prodromal cases) who underwent an extensive assessment at baseline and at 2 years follow-up. At baseline, plasma NfL levels were higher in both probable DLB and prodromal cases compared to controls. Plasma NfL emerged as the best predictor of cognitive decline compared to age, sex and baseline severity variables. The study supports the role of plasma NfL as a useful prognostic biomarker from the early stages of DLB.


title: Transcriptome-wide association study of risk of recurrence in Black and White breast cancer patients

abstract:
Continuous risk of recurrence scores (CRS) based on tumor gene expression are vital prognostic tools for breast cancer (BC). Studies have shown that Black women (BW) have higher CRS than White women (WW). Although systemic injustices contribute substantially to BC disparities, evidence for biological and germline contributions is emerging. We investigated germline genetic associations with CRS and CRS disparity using approaches modeled after transcriptome-wide association studies (TWAS). In the Carolina Breast Cancer Study, using race-specific predictive models of tumor expression from germline genetics, we performed race-stratified (N=1,043 WW, 1083 BW) linear regressions of three CRS (ROR-S: PAM50 subtype score; Proliferation Score; ROR-P: ROR-S plus Proliferation Score) on imputed Genetically-Regulated tumor eXpression (GReX). Using Bayesian multivariate regression and adaptive shrinkage, we tested GReX-prioritized genes for associations with PAM50 tumor expression and subtype to elucidate patterns of germline regulation underlying GReX-CRS associations. At FDR-adjusted P < 0.10, we detected 7 and 1 GReX-prioritized genes among WW and BW. Among WW, CRS were positively associated with MCM10, FAM64A, CCNB2, and MMP1 GReX and negatively associated with VAV3, PCSK6, and GNG11 GReX. Among BW, higher MMP1 GReX predicted lower Proliferation score and ROR-P. GReX-prioritized gene and PAM50 tumor expression associations highlighted potential mechanisms for GReX-prioritized gene to CRS associations. Among BC patients, we find differential germline associations with CRS by race, underscoring the need for larger, diverse datasets in molecular studies of BC. Our findings also suggest possible germline trans-regulation of PAM50 tumor expression, with potential implications for CRS interpretation in clinical settings.

SIGNIFICANCEWe find race-specific genetic associations with breast cancer risk-of-recurrence scores (CRS). Follow-up analyses suggest mediation of these associations by PAM50 molecular subtype and gene expression, with implications for clinical interpretation of CRS.


title: Gene-level germline contributions to clinical risk of recurrence scores in Black and White breast cancer patients


title: The Impact of Early or Late Lockdowns on the Spread of COVID-19 in US Counties

abstract:
BackgroundCOVID-19 is a highly transmissible infectious disease that has infected over 122 million individuals worldwide. To combat this pandemic, governments around the world have imposed lockdowns. However, the impact of these lockdowns on the rates of COVID-19 transmission in communities is not well known. Here, we used COVID-19 case counts from 3,000+ counties in the United States (US) to determine the relationship between lockdown as well as other county factors and the rate of COVID-19 spread in these communities.

MethodsWe merged county-specific COVID-19 case counts with US census data and the date of lockdown for each of the counties. We then applied a Functional Principal Component (FPC) analysis on this dataset to generate scores that described the trajectory of COVID-19 spread across the counties. We used machine learning methods to identify important factors in the county including the date of lockdown that significantly influenced the FPC scores.

FindingsWe found that the first FPC score accounted for up to 92.81% of the variations in the absolute rates of COVID-19 as well as the topology of COVID-19 spread over time at a county level. The relation between incidence of COVID-19 and time at a county level demonstrated a hockey-stick appearance with an inflection point approximately 7 days prior to the county reporting at least 5 new cases of COVID-19; beyond this inflection point, there was an exponential increase in incidence. Among the risk factors, lockdown and total population were the two most significant features of the county that influenced the rate of COVID-19 infection, while the median family income, median age and within-county move also substantially affect COVID spread.

InterpretationLockdowns are an effective way of controlling the COVID-19 spread in communities. However, significant delays in lockdown cause a dramatic increase in the case counts. Thus, the timing of the lockdown relative to the case count is an important consideration in controlling the pandemic in communities.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed using the term "coronavirus", OR "COVID-19", OR "COVID-19 infection", OR "SARS-CoV-2" combined with "Lockdown" or "sociodemographic factor" or "Vulnerability" for original articles published before March 18, 2021. Similar searches were done in medRxiv, Google Scholar, and Web of Science. Only papers published in English were reviewed. The most similar relevant works to our study were Acharya et al.1 and Karmakar et al.2, which investigated the associations between population-level social factors and COVID-19 incidence and mortality. Unlike our current study, which employed a longitudinal design, both of studies were cross-sectional in nature and thus fixed on a single time point. In addition, neither of these studies investigated the impact of lockdown measures on COVID-19 infection patterns. Another relevant study is Alfano et al.s work3, which focused on the efficacy of lockdown on COVID-19 case rates. However, this study did not evaluate the timing of lockdown on this endpoint.

Added value of this studyTo our knowledge, this is the first study to use functional principal component analysis (FPCA) to investigate COVID-19 infection trajectories (in a longitudinal manner) and their relationships with different sociodemographic factors and lockdown policy at a county level. The FPCA transformed a longitudinal vector with high-dimensions into a "single" surrogate variable, which retained 93% of the information. We used an advanced statistical model (segmented regression) to investigate the effects of lockdown on incidence of COVID-19 across the US. We found that the relationship had a "hockey stick" appearance with an inflection point at [~]7 days prior to a county reporting at least 5 cases of COVID-19. We also applied a machine learning model (i.e., elastic net) to explore joint effects of lockdown and other sociodemographic factors on COVID-19 infection patterns, which estimated the impact of each of factors, adjusted for each other.

Implications of all the available evidenceOur study suggests that lockdown is an effective policy to reduce case counts of COVID-19 in communities; however, significant delays in its implementation result in exponential growth of COVID-19. The inflection point is approximately 7 days prior to a county reporting at least 5 cases of COVID-19. These data will help policy-makers to determine the optimal timing of lockdowns for their communities.