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Immunity to pulmonary infection typically requires elicitation of lung-resident T cells that subsequently confer protection against secondary infection. The presence of tissue-resident T cells in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent patients is unknown. Using a sublethal mouse model of coronavirus disease 2019, we determined if SARS-CoV-2 infection potentiated Ag-specific pulmonary resident CD4+ and CD8+ T cell responses and if these cells mediated protection against secondary infection. S protein–specific T cells were present in resident and circulating populations. However, M and N protein–specific T cells were detected only in the resident T cell pool. Using an adoptive transfer strategy, we found that T cells from SARS-CoV-2 immune animals did not protect naive mice. These data indicate that resident T cells are elicited by SARS-CoV-2 infection but are not sufficient for protective immunity.

Cardiometabolic multimorbidity (CM) is the diagnosis of 2 or more cardiometabolic conditions. Multimorbidity and individual cardiometabolic conditions have been associated with activity limitation, a common form of disability, but few studies have investigated the association between CM and activity limitation.To estimate the prevalence of activity limitation among Canadians with CM and to quantify the association between CM and activity limitation.Using data from the Canadian Longitudinal Study on Aging, we conducted a cross-sectional analysis of activity limitation among Canadians aged 45-85 (n = 50,777; weighted n = 13,118,474). CM was defined as the diagnosis of 2 or more of diabetes/prediabetes, myocardial infarction, and stroke, and activity limitation was evaluated using the Older Americans Resources and Services scale. Descriptive statistics and logistic and multinomial logistic regression analyses were conducted to determine the association between CM and activity limitation.The estimated prevalence of activity limitation among participants living with CM was 27.4% compared with 7.5% with no cardiometabolic conditions. Activity limitation increased in prevalence and severity with the number of cardiometabolic conditions. People with CM had increased odds of activity limitation compared with those without any cardiometabolic conditions (adjusted relative risk ratio = 3.99, 95% confidence interval [3.35-4.75]), and the odds increased with each additional condition. Stroke survivors had greater odds of activity limitation than those without a history of stroke and the same number of cardiometabolic conditions.Activity limitation is common among Canadians living with CM. Odds of activity limitation increase with each additional cardiometabolic condition, especially for stroke survivors.Cardiometabolic multimorbidity (CM) is a common pattern of multimorbidity characterized by the diagnosis of 2 or more cardiometabolic conditions, such as stroke, diabetes, and myocardial infarction. Previous research has found that individuals with stroke, diabetes, or myocardial infarction are at an increased risk of activity limitation, defined by the World Health Organization as the “difficulties an individual may have in executing activities.” This study investigated the prevalence, risk, and severity of activity limitation among Canadians with CM and combinations of stroke, diabetes/prediabetes, and myocardial infarction. Using data from the Canadian Longitudinal Study on Aging, the estimated prevalence of activity limitation among those living with CM was 27.4% compared with 7.5% among individuals without any cardiometabolic conditions. Individuals living with CM also had increased odds of activity limitation compared with those with no cardiometabolic conditions. Importantly, the prevalence, severity, and risk of activity limitation increased with each additional condition, especially when the cluster of conditions included stroke, suggesting an additive effect of CM on activity limitation. Based on these findings, special efforts should be made to manage chronic disease risk in individuals with a history of stroke given the increased risk of activity limitation when combined with diabetes/prediabetes and myocardial infarction.

Study Design Participatory design. Objectives Activity-based therapies (ABT) have physical and psychosocial benefits for individuals with spinal cord injury (SCI). A Canadian ABT summit was held to: (1) identify methods used in stroke rehabilitation that may be appropriate for SCI; (2) understand the current state of ABT activities in Canada; and (3) identify priorities for ABT research and care for the next five years. Setting Stakeholder-engaged meeting at a tertiary rehabilitation hospital. Methods Thirty-nine stakeholders, including individuals with SCI, frontline clinicians, healthcare administrators, researchers, funders and health policy experts, attended. Two participants were note-takers. Priority identification occurred through input from stakeholder groups, followed by individual voting. Conventional content analysis was used to synthesize the information in the meeting notes. Results The strengths of ABT in stroke rehabilitation included clear and clinically feasible definitions, measurements and interventions, and recognized requirements for implementation (e.g. behavior change, partnerships). Knowledge gaps concerning ABT activities in Canada were identified for acute and community settings, non-traumatic populations, and the interventions, equipment and standardized measures (i.e. upper limb, activity levels) used. Five priorities for ABT across the continuum of care were identified: (1) Identify current ABT activities; (2) Create a network to facilitate dialog; (3) Track engagement in ABT activities; (4) Develop and implement best practice recommendations; and (5) Study optimal timing, methods, and dose of ABT. Working groups were formed to address priorities 1–3. Conclusions The priorities will guide SCI research and care activities in Canada over the next five years. Sponsorship Praxis Spinal Cord Institute.

Protection is now the modal motivation for gun ownership, and men continue to outnumber women among gun owners. While research has linked economic precarity (e.g., insecurity and anxiety) to gun ownership and attitudes, separating economic well-being from constructions of masculinity is challenging. In response to blocked economic opportunities, some gun owners prioritize armed protection, symbolically replacing the masculine role of “provider” with one associated with “protection.” Thus, understanding both persistently high rates of gun ownership in the United States (in spite of generally declining crime) alongside the gender gap in gun ownership requires deeper investigations into the meaning of guns in the United States and the role of guns in conceptualizations of American masculinity. We use recently collected crowdsourced survey data to test this provider-to-protector shift, exploring how economic precarity may operate as a cultural-level masculinity threat for some, and may intersect with marital/family status to shape gun attitudes and behaviors for both gun owners and nonowners. Results show that investments in stereotypical masculine ideals, rather than economic precarity, are linked to support for discourses associated with protective gun ownership and empowerment.

OBJECTIVES To describe patient characteristics of dogs with septic shock, investigate markers of disease severity, and assess treatment impact on outcome. DESIGN Retrospective study. SETTING Single center, university veterinary teaching intensive care unit. ANIMALS Thirty-seven dogs with septic shock. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Mean number of organ dysfunction was 3.24 ± 1.0, and included cardiovascular (100%), respiratory (73%), hematologic (68%), renal (49%), and hepatic (32%) dysfunction. The gastrointestinal tract was the most common source of sepsis. Mean blood pressure prior to resuscitation was 50 ± 8 mm Hg. All dogs were given IV fluids before vasopressor therapy with a mean rate of 12.1 ± 11.0 mL/kg/h. All dogs were given antimicrobials, administered within a mean of 4.3 ± 5.7 hours after diagnosis. Dopamine or norepinephrine was administered IV, respectively in 51.3% and 37.8% of dogs, with a mean duration of hypotension of 2.6 ± 3.0 hours. Mortality rate was 81.1%. Survivors were more likely to have a feeding tube (P = 0.007) and to have gastrointestinal sepsis (P = 0.012), and less likely to have respiratory dysfunction (P

To characterise health seeking behaviour (HSB) and determine its predictors amongst children in Malawi in 2016.We used the 2016 Malawi Integrated Household Survey data set. The outcome of interest was HSB, defined as seeking care at a health facility amongst people who reported one or more of a list of possible symptoms given on the questionnaire in the past two weeks. We fitted a multivariate logistic regression model of HSB using a forward step-wise selection method, with age, sex and symptoms entered as a priori variables.Of 5350 children, 1666 (32%) had symptoms in the past two weeks. Of the 1666, 1008 (61%) sought care at health facility. The children aged 5-14 years were less likely to be taken to health facilities for health care than those aged 0-4 years. Having fever vs. not having fever and having a skin problem vs. not having skin problem were associated with increased likelihood of HSB. Having a headache vs. not having a headache was associated with lower likelihood of accessing care at health facilities (AOR = 0.50, 95% CI: 0.26-0.96, P = 0.04). Children from urban areas were more likely to be taken to health facilities for health care (AOR = 1.81, 95% CI: 1.17-2.85, P = 0.008), as were children from households with a high wealth status (AOR = 1.86, 95% CI: 1.25-2.78, P = 0.02).There is a need to understand and address individual, socio-economic and geographical barriers to health seeking to increase access and use of health care and fast-track progress towards Universal Health Coverage.Caractériser le comportement de recherche de santé (CRS) et déterminer ses prédicteurs chez les enfants du Malawi en 2016. MÉTHODES: Nous avons utilisé l'ensemble de données de l'Enquête intégrée de 2016 auprès des ménages du Malawi. Le résultat d'intérêt était le CRS, défini comme la recherche de soins dans un établissement de santé chez les personnes qui ont déclaré une ou plusieurs symptômes d'une liste de possibilités figurant sur le questionnaire, dans les deux dernières semaines. Nous avons appliqué un modèle de régression logistique multivariée du CRS en utilisant une méthode de sélection par étape, avec l'âge, le sexe et les symptômes entrés comme variables a priori. RÉSULTATS: Sur 5.350 enfants, 1.666 (32%) ont présenté des symptômes au cours des deux dernières semaines. Sur les 1.666, des soins ont été cherché pour 1.008 (61%) dans un établissement de santé. Les enfants âgés de 5 à 14 ans étaient moins susceptibles d'être emmenés dans des établissements de santé pour des soins de santé que ceux âgés de 0 à 4 ans. Avoir de la fièvre par rapport à ne pas en avoir et avoir un problème de peau par rapport à ne pas en avoir étaient associés à une probabilité accrue de CRS. Avoir un mal de tête par rapport à ne pas en avoir était associé à une probabilité plus faible d'accéder aux soins dans les établissements de santé (AOR = 0,50 ; IC95%: 0,26-0,96 ; P= 0,04). Les enfants des zones urbaines étaient plus susceptibles d'être emmenés dans des établissements de santé pour des soins de santé (AOR = 1,81 ; IC95%: 1,17-2,85 ; P= 0,008), tout comme les enfants de ménages ayant une position socioéconomique plus élevée (AOR = 1,96 ; IC95%: 1,13-3,40 ; P= 0,02).Il est nécessaire de comprendre et de surmonter les obstacles individuels, socioéconomiques et géographiques à la recherche de la santé pour accroître l'accès et l'utilisation des soins de santé et accélérer les progrès vers la couverture sanitaire universelle.

Summary Background COVID-19 has the potential to cause substantial disruptions to health services, due to cases overburdening the health system or response measures limiting usual programmatic activities. We aimed to quantify the extent to which disruptions to services for HIV, tuberculosis, and malaria in low-income and middle-income countries with high burdens of these diseases could lead to additional loss of life over the next 5 years. Methods Assuming a basic reproduction number of 3·0, we constructed four scenarios for possible responses to the COVID-19 pandemic: no action, mitigation for 6 months, suppression for 2 months, or suppression for 1 year. We used established transmission models of HIV, tuberculosis, and malaria to estimate the additional impact on health that could be caused in selected settings, either due to COVID-19 interventions limiting activities, or due to the high demand on the health system due to the COVID-19 pandemic. Findings In high-burden settings, deaths due to HIV, tuberculosis, and malaria over 5 years could increase by up to 10%, 20%, and 36%, respectively, compared with if there was no COVID-19 pandemic. The greatest impact on HIV was estimated to be from interruption to antiretroviral therapy, which could occur during a period of high health system demand. For tuberculosis, the greatest impact would be from reductions in timely diagnosis and treatment of new cases, which could result from any prolonged period of COVID-19 suppression interventions. The greatest impact on malaria burden could be as a result of interruption of planned net campaigns. These disruptions could lead to a loss of life-years over 5 years that is of the same order of magnitude as the direct impact from COVID-19 in places with a high burden of malaria and large HIV and tuberculosis epidemics. Interpretation Maintaining the most critical prevention activities and health-care services for HIV, tuberculosis, and malaria could substantially reduce the overall impact of the COVID-19 pandemic. Funding Bill & Melinda Gates Foundation, Wellcome Trust, UK Department for International Development, and Medical Research Council.

Background and Purpose: We investigated the effect of higher therapeutic exercise doses on walking during inpatient rehabilitation, typically commencing 1 to 4 weeks poststroke. Methods: This phase II, blinded-assessor, randomized controlled trial recruited from 6 Canadian inpatient rehabilitation units, between 2014 and 2018. Subjects (n=75; 25/group) were randomized into: control (usual care) physical therapy: typically, 1 hour, 5 days/week; Determining Optimal Post-Stroke Exercise (DOSE1): 1 hour, 5 days/week, more than double the intensity of Control (based on aerobic minutes and walking steps); and DOSE2: 2 hours, 5 days/week, more than quadruple the intensity of Control, each for 4 weeks duration. The primary outcome, walking endurance at completion of the 4-week intervention (post-evaluation), was compared across these groups using linear regression. Secondary outcomes at post-evaluation, and longitudinal outcomes at 6 and 12-month evaluations, were also analyzed. Results: Both DOSE1 (mean change 61 m [95% CI, 9–113], P =0.02) and DOSE2 (mean change 58 m, 6–110, P =0.03) demonstrated greater walking endurance compared with Control at the post-evaluation. Significant improvements were also observed with DOSE2 in gait speed (5-m walk), and both DOSE groups in quality of life (EQ-5D-5 L) compared with Control. Longitudinal analyses revealed that improvements in walking endurance from the DOSE intervention were retained during the 1-year follow-up period over usual care. Conclusions: This study provides the first preliminary evidence that patients with stroke can improve their walking recovery and quality of life with higher doses of aerobic and stepping activity within a critical time period for neurological recovery. Furthermore, walking endurance benefits achieved from a 4-week intervention are retained over the first-year poststroke. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01915368.

Purpose Fellows in Pediatric Surgery need to learn to manage a variety of gynecologic conditions. We completed a needs assessment of Pediatric Surgery training programs to inform development of a standardized gynecology curriculum. Methods A survey was sent to Program Directors of Canadian Pediatric Surgery training programs with 27 questions that focused on the fellowship program, surgical practice, and trainee exposure to pediatric gynecology, and how the envision a standardized gynecology curriculum. Results Six of eight Program Directors responded. All respondents had treated ovarian-related conditions and genital injuries in the past 5 years, and most felt trainees received adequate training in managing these conditions. Most respondents felt trainees had minimal or inadequate training in imperforate hymens, Mullerian anomalies, vulvar abscesses, vaginal foreign bodies, and labial adhesions. Program Directors currently allot an average of 3.5 h to delivering the gynecology objectives. All Program Directors expressed interest in a formal gynecology curriculum delivered through some combination of case-based teaching and/or simulation. Conclusion There is a need for a standardized gynecology curriculum for Pediatric Surgery trainees. Most Pediatric Surgeons will manage gynecological conditions as part of their practice and current Program Directors feel that training is inadequate for a number of gynecological conditions. Type of Study Observational Cross-Sectional Study. Level of Evidence Level IV.

Introduction In 2016, the WHO published recommendations increasing the number of recommended antenatal care (ANC) visits per pregnancy from four to eight. Prior to the implementation of this policy, coverage of four ANC visits has been suboptimal in many low-income settings. In this study we explore socio-demographic factors associated with early initiation of first ANC contact and attending at least four ANC visits (“ANC4+”) in Malawi using the Malawi Demographic and Health Survey (MDHS) data collected between 2004 and 2016, prior to the implementation of new recommendations. Methods We combined data from the 2004–5, 2010 and 2015–16 MDHS using Stata version 16. Participants included all women surveyed between the ages of 15–49 who had given birth in the five years preceding the survey. We conducted weighted univariate, bivariate and multivariable logistic regression analysis of the effects of each of the predictor variables on the binary endpoint of the woman attending at least four ANC visits and having the first ANC attendance within or before the four months of pregnancy (ANC4+). To determine whether a factor was included in the model, the likelihood ratio test was used with a statistical significance of P< 0.05 as the threshold. Results We evaluated data collected in surveys in 2004/5, 2010 and 2015/6 from 26386 women who had given birth in the five years before being surveyed. The median gestational age, in months, at the time of presenting for the first ANC visit was 5 (inter quartile range: 4–6). The proportion of women initiating ANC4+ increased from 21.3% in 2004–5 to 38.8% in 2015–16. From multivariate analysis, there was increasing trend in ANC4+ from women aged 20–24 years (adjusted odds ratio (aOR) = 1.27, 95%CI:1.05–1.53, P = 0.01) to women aged 45–49 years (aOR = 1.91, 95%CI:1.18–3.09, P = 0.008) compared to those aged 15–19 years. Women from richest socio-economic position ((aOR = 1.32, 95%CI:1.12–1.58, P Conclusion The proportion of women reporting ANC4+ and of key ANC interventions in Malawi have increased significantly since 2004. However, we found that most women did not access the recommended number of ANC visits in Malawi, prior to the 2016 WHO policy change which may mean that women are less likely to undertake the 2016 WHO recommendation of 8 contacts per pregnancy. Additionally, our results highlighted significant variation in coverage according to key socio-demographic variables which should be considered when devising national strategies to ensure that all women access the appropriate frequency of ANC visits during their pregnancy.

Summary Bicuspid aortic valve (BAV) with ∼1%–2% prevalence is the most common congenital heart defect (CHD). It frequently results in valve disease and aorta dilation and is a major cause of adult cardiac surgery. BAV is genetically linked to rare left-heart obstructions (left ventricular outflow tract obstructions [LVOTOs]), including hypoplastic left heart syndrome (HLHS) and coarctation of the aorta (CoA). Mouse and human studies indicate LVOTO is genetically heterogeneous with a complex genetic etiology. Homozygous mutation in the Pcdha protocadherin gene cluster in mice can cause BAV, and also HLHS and other LVOTO phenotypes when accompanied by a second mutation. Here we show two common deletion copy number variants (delCNVs) within the PCDHA gene cluster are associated with LVOTO. Analysis of 1,218 white individuals with LVOTO versus 463 disease-free local control individuals yielded odds ratios (ORs) at 1.47 (95% confidence interval [CI], 1.13–1.92; p = 4.2 × 10−3) for LVOTO, 1.47 (95% CI, 1.10–1.97; p = 0.01) for BAV, 6.13 (95% CI, 2.75–13.7; p = 9.7 × 10−6) for CoA, and 1.49 (95% CI, 1.07–2.08; p = 0.019) for HLHS. Increased OR was observed for all LVOTO phenotypes in homozygous or compound heterozygous PCDHA delCNV genotype comparison versus wild type. Analysis of an independent white cohort (381 affected individuals, 1,352 control individuals) replicated the PCDHA delCNV association with LVOTO. Generalizability of these findings is suggested by similar observations in Black and Chinese individuals with LVOTO. Analysis of Pcdha mutant mice showed reduced PCDHA expression at regions of cell-cell contact in aortic smooth muscle and cushion mesenchyme, suggesting potential mechanisms for BAV pathogenesis and aortopathy. Together, these findings indicate common variants causing PCDHA deficiency play a significant role in the genetic etiology of common and rare LVOTO-CHD.

Background Despite increasing evidence regarding the benefit of intensive task-specific practice and aerobic exercise in stroke rehabilitation, implementation remains difficult. The factors influencing implementation have been explored from therapists’ perspectives; however, despite an increased emphasis on patient involvement in research, patients’ perceptions have not yet been investigated. Objective The study aimed to investigate factors influencing implementation of higher intensity activity in people with stroke and to compare this with therapists’ perspectives. Design The design was a cross-sectional qualitative study. Methods The study used semistructured interviews with people with stroke who were part of a randomized clinical trial, the Determining Optimal post-Stroke Exercise study, which delivered a higher intensity intervention. An interview guide was developed and data analyzed using implementation frameworks. Factors emerging from interviews with people with stroke were compared and contrasted with factors perceived by rehabilitation therapists. Results Ten people with stroke were interviewed before data saturation was reached. Participants had a positive attitude regarding working hard and were satisfied with the graded exercise test, high intensity intervention, and the feedback-monitoring devices. Therapists and patients had contrasting perceptions about their beliefs regarding intensive exercise and the content of the intervention, with therapists more focused on the methods and patients more focused on the personal interactions stemming from the therapeutic relationship. Conclusions People with stroke perceived no barriers regarding the implementation of higher intensity rehabilitation in practice and were positive towards working at more intense levels. Contrastingly, from the therapists’ perspective, therapists’ beliefs about quality of movement and issues around staffing and resources were perceived to be barriers. In addition, therapists and people with stroke perceived the contents of the intervention differently, highlighting the importance of involving patients and clinicians in the development and evaluation of rehabilitation interventions.

OBJECTIVE To characterize the clinical features of dogs with precursor-targeted immune-mediated anemia (PIMA). ANIMALS 66 dogs with PIMA. PROCEDURES Electronic record databases of a teaching hospital were searched to identify dogs with a diagnosis of nonregenerative anemia between 2004 and 2013. Inclusion criteria included persistent nonregenerative anemia (Hct ≤ 30% and reticulocyte count < 76,000 reticulocytes/μL), cytologic findings supportive of ineffective bone marrow erythropoiesis, and absence of underlying disease. Information regarding clinical signs, clinicopathologic findings, treatment, and outcome was extracted from records of eligible dogs. A regenerative response was defined as a reticulocyte count > 76,000 reticulocytes/μL or sustained increase in Hct of > 5%. Remission was defined as a stable Hct ≥ 35%. RESULTS The median Hct was 13%, and reticulocyte count was 17,900 reticulocytes/μL. Rubriphagocytosis was identified in bone marrow aspirate samples from 61 of 66 dogs. Collagen myelofibrosis was detected in bone marrow biopsy specimens obtained from 31 of 63 dogs. Immune-mediated targeting of mature erythrocytes was uncommon. All dogs received immunosuppressive therapy. Fifty-five dogs developed a regenerative response at a median of 29 days, and 40 of those dogs went into remission at a median of 59 days after PIMA diagnosis. Thromboembolic events were confirmed for 9 dogs and were associated with a decreased survival time. Median survival time was 913 days for all dogs. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that most dogs with PIMA responded to prolonged immunosuppressive therapy. Studies to determine optimal immunosuppressive and thromboprophylactic protocols for dogs with PIMA are warranted.

BackgroundCOVID-19 mitigation strategies have been challenging to implement in resource-limited settings such as Malawi due to the potential for widespread disruption to social and economic well-being. Here we estimate the clinical severity of COVID-19 in Malawi, quantifying the potential impact of intervention strategies and increases in health system capacity.MethodsThe infection fatality ratios (IFR) in Malawi were estimated by adjusting reported IFR for China accounting for demography, the current prevalence of comorbidities and health system capacity. These estimates were input into an age-structured deterministic model, which simulated the epidemic trajectory with non-pharmaceutical interventions. The impact of a novel therapeutic agent and increases in hospital capacity and oxygen availability were explored, given different assumptions on mortality rates.FindingsThe estimated age-specific IFR in Malawi are higher than those reported for China, however the younger average age of the population results in a slightly lower population-weighted IFR (0.48%, 95% uncertainty interval [UI] 0.30% – 0.72% compared with 0.60%, 95% CI 0.4% – 1.3% in China). The current interventions implemented, (i.e. social distancing, workplace closures and public transport restrictions) could potentially avert 3,100 deaths (95% UI 1,500 – 4,500) over the course of the epidemic. Enhanced shielding of people aged ≥ 60 years could avert a further 30,500 deaths (95% UI 17,500 – 45,600) and halve ICU admissions at the peak of the outbreak. Coverage of face coverings of 60% under the assumption of 50% efficacy could be sufficient to control the epidemic. A novel therapeutic agent, which reduces mortality by 0.65 and 0.8 for severe and critical cases respectively, in combination with increasing hospital capacity could reduce projected mortality to 2.55 deaths per 1,000 population (95% UI 1.58 – 3.84).ConclusionThe risks due to COVID-19 vary across settings and are influenced by age, underlying health and health system capacity.Summary BoxWhat is already known?As COVID-19 spreads throughout Sub-Saharan Africa, countries are under increasing pressure to protect the most vulnerable by suppressing spread through, for example, stringent social distancing measures or shielding of those at highest risk away from the general population.There are a number of studies estimating infection fatality ratio due to COVID-19 but none use data from African settings. The estimated IFR varies across settings ranging between 0.28-0.99%, with higher values estimated for Europe (0.77%, 95% CI 0.55 – 0.99%) compared with Asia (0.46%, 95% CI 0.38 – 0.55).The IFR for African settings are still unknown, although several studies have highlighted the potential for increased mortality due to comorbidities such as HIV, TB and malaria.There are a small number of studies looking at the impact of non-pharmaceutical interventions in Africa, particularly South Africa, but none to date have combined this with country-specific estimates of IFR adjusted for comorbidity prevalence and with consideration to the prevailing health system constraints and the impact of these constraints on mortality rates.What are the new findings?After accounting for the health system constraints and differing prevalences of underlying comorbidities, the estimated infection fatality ratio (IFR) for Malawi (0.48%, 95% uncertainty interval 0.30% – 0.72%) is within the ranges reported for the Americas, Asia and Europe (overall IFR 0.70, 95% CI 0.57 – 0.82, range 0.28 – 0.89).Introducing enhanced shielding of people aged ≥ 60 years could avert up to 30,500 deaths (95% UI 17,500 – 45,600) and significantly reduce demand on ICU admissions.Maintaining coverage of face coverings at 60%, under the assumption of 50% efficacy, could be sufficient to control the epidemic.Combining the introduction of a novel therapeutic agent with increases in hospital capacity could reduce projected mortality to 2.55 deaths per 1,000 population (95% UI 1.58 – 3.84).What do the new findings imply?Adjusting estimates of COVID-19 severity to account for underlying health is crucial for predicting health system demands.A multi-pronged approach to controlling transmission, including face coverings, increasing hospital capacity and using new therapeutic agents could significantly reduce deaths to COVID-19, but is not as effective as a theoretical long-lasting lockdown.

PURPOSE: The number of patients who take 5 or more medications—polypharmacy—is increasing. Patients with polypharmacy are at risk for adverse drug events, drug-drug interactions, geriatric-related syndromes, falls, and hospitalizations. METHODS: A retrospective chart review was performed to assess the impact of the VIONE deprescribing tool on polypharmacy and cost avoidance when used by primary care physicians and pharmacists in patient aligned care team primary care clinics at Veteran Affairs Southern Nevada Healthcare System in North Las Vegas. The efficacy of the tool was determined by calculating the total amount of medications deprescribed as well as the estimated annualized costs avoided for the health care system. RESULTS: In a 3-month period, 1060 medications were deprescribed. The total estimated cost avoidance for the facility was $84,030.46. CONCLUSION: The VIONE tool may be useful in improving patient safety through deprescribing and discontinuing potentially inappropriate medications. Use of this deprescribing tool also may reduce the cost of care associated with overprescribing.

Background: SARS-CoV-2 infections have been reported in all age groups including infants, children, and adolescents. However, the role of children in the COVID-19 pandemic is still uncertain. This systematic review of early studies synthesises evidence on the susceptibility of children to SARS-CoV-2 infection, the severity and clinical outcomes in children with SARS-CoV-2 infection, and the transmissibility of SARS-CoV-2 by children in the early phases of the COVID-19 pandemic. Methods and findings: A systematic literature review was conducted in PubMed. Reviewers extracted data from relevant, peer-reviewed studies published up to July 4th 2020 during the first wave of the SARS-CoV-2 outbreak using a standardised form and assessed quality using the NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. For studies included in the meta-analysis, we used a random effects model to calculate pooled estimates of the proportion of children considered asymptomatic or in a severe or critical state. We identified 2,775 potential studies of which 128 studies met our inclusion criteria; data were extracted from 99, which were then quality assessed. Finally, 29 studies were considered for the meta-analysis that included information of symptoms and/or severity, these were further assessed based on patient recruitment. Our pooled estimate of the proportion of test positive children who were asymptomatic was 21.1% (95% CI: 14.0 - 28.1%), based on 13 included studies, and the proportion of children with severe or critical symptoms was 3.8% (95% CI: 1.5 - 6.0%), based on 14 included studies. We did not identify any studies designed to assess transmissibility in children and found that susceptibility to infection in children was highly variable across studies. Conclusions: Children’s susceptibility to infection and onward transmissibility relative to adults is still unclear and varied widely between studies. However, it is evident that most children experience clinically mild disease or remain asymptomatically infected. More comprehensive contact-tracing studies combined with serosurveys are needed to quantify children’s transmissibility relative to adults. With children back in schools, testing regimes and study protocols that will allow us to better understand the role of children in this pandemic are critical.

Enteric viruses infect the mammalian gastrointestinal tract and lead to significant morbidity and mortality worldwide. Data indicate that enteric viruses can utilize intestinal bacteria to promote viral replication and pathogenesis. However, the precise interactions between enteric viruses and bacteria are unknown. Here we examined the interaction between bacteria and Coxsackievirus B3, an enteric virus from the picornavirus family. We found that bacteria enhance the infectivity of Coxsackievirus B3 (CVB3) in vitro. Notably, specific bacteria are required as gram-negative Salmonella enterica, but not Escherichia coli, enhanced CVB3 infectivity and stability. Investigating the cell wall components of both S. enterica and E. coli revealed that structures in the O-antigen or core of lipopolysaccharide, a major component of the gram-negative bacterial cell wall, were required for S. enterica to enhance CVB3. To determine if these requirements were necessary for similar enteric viruses, we investigated if S. enterica and E. coli enhanced infectivity of poliovirus, another enteric virus in the picornavirus family. We found that, in contrast to CVB3, these bacteria enhanced the infectivity of poliovirus in vitro. Overall, these data indicate that distinct bacteria enhance CVB3 infectivity and stability, and specific enteric viruses may have differing requirements for their interactions with specific bacterial species.ImportancePrevious data indicate that several enteric viruses utilize bacteria to promote intestinal infection and viral stability. Here we show that specific bacteria and bacterial cell wall components are required to enhance infectivity and stability of Coxsackievirus B3 in vitro. These requirements are likely enteric virus-specific as the bacteria for CVB3 differs from poliovirus, a closely related virus. Therefore, these data indicate that specific bacteria and their cell wall components dictate the interaction with various enteric viruses in distinct mechanisms.

Introduction Model‐based estimates of key HIV indicators depend on past epidemic trends that are derived based on assumptions about HIV disease progression and mortality in the absence of antiretroviral treatment (ART). Population‐based HIV Impact Assessment (PHIA) household surveys conducted between 2015 and 2018 found substantial numbers of respondents living with untreated HIV infection. CD4 cell counts measured in these individuals provide novel information to estimate HIV disease progression and mortality rates off ART. Methods We used Bayesian multi‐parameter evidence synthesis to combine data on (1) cross‐sectional CD4 cell counts among untreated adults living with HIV from 10 PHIA surveys, (2) survival after HIV seroconversion in East African seroconverter cohorts, (3) post‐seroconversion CD4 counts and (4) mortality rates by CD4 count predominantly from European, North American and Australian seroconverter cohorts. We used incremental mixture importance sampling to estimate HIV natural history and ART uptake parameters used in the Spectrum software. We validated modelled trends in CD4 count at ART initiation against ART initiator cohorts in sub‐Saharan Africa. Results Median untreated HIV survival decreased with increasing age at seroconversion, from 12.5 years [95% credible interval (CrI): 12.1–12.7] at ages 15–24 to 7.2 years (95% CrI: 7.1–7.7) at ages 45–54. Older age was associated with lower initial CD4 counts, faster CD4 count decline and higher HIV‐related mortality rates. Our estimates suggested a weaker association between ART uptake and HIV‐related mortality rates than previously assumed in Spectrum. Modelled CD4 counts in untreated people living with HIV matched recent household survey data well, though some intercountry variation in frequencies of CD4 counts above 500 cells/mm3 was not explained. Trends in CD4 counts at ART initiation were comparable to data from ART initiator cohorts. An alternate model that stratified progression and mortality rates by sex did not improve model fit appreciably. Conclusions Synthesis of multiple data sources results in similar overall survival as previous Spectrum parameter assumptions but implies more rapid progression and longer survival in lower CD4 categories. New natural history parameter values improve consistency of model estimates with recent cross‐sectional CD4 data and trends in CD4 counts at ART initiation.

In response to the COVID-19 pandemic, countries have sought to control SARS-CoV-2 transmission by restricting population movement through social distancing interventions, thus reducing the number of contacts. Mobility data represent an important proxy measure of social distancing, and here, we characterise the relationship between transmission and mobility for 52 countries around the world. Transmission significantly decreased with the initial reduction in mobility in 73% of the countries analysed, but we found evidence of decoupling of transmission and mobility following the relaxation of strict control measures for 80% of countries. For the majority of countries, mobility explained a substantial proportion of the variation in transmissibility (median adjusted R-squared: 48%, interquartile range - IQR - across countries [27–77%]). Where a change in the relationship occurred, predictive ability decreased after the relaxation; from a median adjusted R-squared of 74% (IQR across countries [49–91%]) pre-relaxation, to a median adjusted R-squared of 30% (IQR across countries [12–48%]) post-relaxation. In countries with a clear relationship between mobility and transmission both before and after strict control measures were relaxed, mobility was associated with lower transmission rates after control measures were relaxed indicating that the beneficial effects of ongoing social distancing behaviours were substantial., Social distancing policies aiming to reduce COVID-19 transmission have been reflected in reductions in human mobility. Here, the authors show that reduced mobility is correlated with decreased transmission, but that this relationship weakened over time as social distancing measures were relaxed.

BackgroundMass drug administration (MDA) of praziquantel is an intervention used in the treatment and prevention of schistosomiasis. In Malawi, MDA happens annually across high-risk districts and covers around 80% of school aged children and 50% of adults. The current formulation of praziquantel is not approved for use in the preventive chemotherapy for children under 5 years old, known as pre-school aged children (PSAC). However, a new formulation for PSAC will be available by 2022. A comprehensive analysis of the potential additional benefits of including PSAC in the MDA will be critical to guide policy-makers.MethodsWe developed a new individual-based stochastic transmission model of Schistosoma haematobium for the 6 highest prevalence districts of Malawi. The model was used to evaluate the benefits of including PSAC in the MDA campaigns, with respect to the prevalence of high-intensity infections (> 500 eggs per ml of urine) and reaching the elimination target, meaning the prevalence of high-intensity infections under 5% in all sentinel sites. The impact of different MDA frequencies and coverages is quantified by prevalence of high-intensity infection and number of rounds needed to decrease that prevalence below 1%.ResultsIncluding PSAC in the MDA campaigns can reduce the time needed to achieve the elimination target for S. haematobium infections in Malawi by one year. The modelling suggests that in the case of a lower threshold of high-intensity infection, currently set by WHO to 500 eggs per ml of urine, including PSAC in the preventive chemotherapy programmes for 5 years can reduce the number of the high-intensity infection case years for pre-school aged children by up to 9.1 years per 100 children.ConclusionsRegularly treating PSAC in the MDA is likely to lead to overall better health of children as well as a decrease in the severe morbidities caused by persistent schistosomiasis infections and bring forward the date of elimination. Moreover, mass administration of praziquantel to PSAC will decrease the prevalence among the SAC, who are at the most risk of infection.

Background: Cardiometabolic multimorbidity (CM) is the diagnosis of at least two of: diabetes, stroke, or heart disease. CM is a common pattern of multimorbidity, however, the association between CM and activity limitation remains unknown. The objectives of this study were to 1) estimate the prevalence of activity limitations among Canadians with CM; and 2) quantify the association between CM and activity limitations.Methods: Using data from the Canadian Longitudinal Study on Aging (CLSA), we estimated the prevalence of CM in Canadians aged 45 to 85 (n=51,022). Multinomial logistic regression was used to quantify the association between CM and activity limitation, evaluated using the Older American Resources and Services (OARS) scale.Results: The prevalence of people living with CM and reporting any activity limitation was 27.4%, with the greatest proportion (47.9%) observed in participants living with all three cardiometabolic conditions. The multinomial odds ratio (or relative risk ratio (RRR)) of activity limitation was greatest amongst participants with all three CM conditions (any limitation: RRR = 11.229, 95% CI = 5.803 to 21.726). Of the two disease combinations, those that included stroke had the greatest odds of activity limitation (stroke and diabetes: RRR = 6.546, 95% CI = 4.436 – 9.661; stroke and myocardial infarction: RRR = 7.029, 95% CI = 4.168 – 11.853). Conclusion: Activity limitation is common amongst Canadians living with CM, and those with CM have an increased odds of reporting activity limitation relative to those with no CM conditions. The odds increase in dose-response relationship as one accumulates more CM conditions.

Following the detection of cytosolic double-stranded DNA from viral or bacterial infection in mammalian cells, cyclic dinucleotide activation of STING induces interferon β expression to initiate innate immune defenses. STING activation also induces LC3B lipidation, a classical but equivocal marker of autophagy, that promotes a cell-autonomous antiviral response that arose before evolution of the interferon pathway. We report that STING activation induces LC3B lipidation onto single-membrane perinuclear vesicles mediated by ATG16L1 via its WD40 domain, bypassing the requirement of canonical upstream autophagy machinery. This process is blocked by bafilomycin A1 that binds and inhibits the vacuolar ATPase (V-ATPase) and by SopF, a bacterial effector that catalytically modifies the V-ATPase to inhibit LC3B lipidation via ATG16L1. These results indicate that activation of the cGAS-STING pathway induces V-ATPase–dependent LC3B lipidation that may mediate cell-autonomous host defense, an unanticipated mechanism that is distinct from LC3B lipidation onto double-membrane autophagosomes.

Highlight We estimated SARS-CoV-2 infection prevalence in cohorts of repatriated citizens from Wuhan to be 0.44% (95% CI: 0.19%–1.03%). Although not representative of the wider population we believe these estimates are helpful in providing a conservative estimate of infection prevalence in Wuhan City, China, in the absence of large-scale population testing early in the epidemic.

Background We compared AIDS-related mortality rates in people living with HIV (PLHIV) starting antiretroviral therapy (ART) in Brazil during 2006–2015 and examined associated risk factors . Methods Data on ART use in PLHIV and AIDS mortality in Brazil was analysed with piecewise constant exponential models. Mortality rates and hazard ratios were estimated for 0–6, 6–12, 13–24, 25–36 and > 36 months of ART use and adjusted for region, age, sex, baseline CD4 cell count and calendar year of ART initiation. An additional analysis restricted to those with data on risk group was also performed. Results 269,076 individuals were included in the analysis, 165,643 (62%) males and 103,433 (38%) females, with 1,783,305 person-years of follow-up time. 21,749 AIDS deaths were reported and 8898 deaths occurred in the first year of ART. The risk of death in the first six months decreased with early ART initiation; those starting treatment early with CD4 > 500 cells per μL had a hazard ratio of 0.06 (95% CI 0.05–0.07) compared with CD4

Although serum from patients with Parkinson’s disease contains elevated levels of numerous pro-inflammatory cytokines including IL-6, TNF, IL-1β, and IFNγ, whether inflammation contributes to or is a consequence of neuronal loss remains unknown1. Mutations in parkin, an E3 ubiquitin ligase, and PINK1, a ubiquitin kinase, cause early onset Parkinson’s disease2,3. Both PINK1 and parkin function within the same biochemical pathway and remove damaged mitochondria from cells in culture and in animal models via mitophagy, a selective form of autophagy4. The in vivo role of mitophagy, however, is unclear, partly because mice that lack either PINK1 or parkin have no substantial Parkinson’s-disease-relevant phenotypes5–7. Mitochondrial stress can lead to the release of damage-associated molecular patterns (DAMPs) that can activate innate immunity8–12, suggesting that mitophagy may mitigate inflammation. Here we report a strong inflammatory phenotype in both Prkn−/− and Pink1−/− mice following exhaustive exercise and in Prkn−/−;mutator mice, which accumulate mutations in mitochondrial DNA (mtDNA)13,14. Inflammation resulting from either exhaustive exercise or mtDNA mutation is completely rescued by concurrent loss of STING, a central regulator of the type I interferon response to cytosolic DNA15,16. The loss of dopaminergic neurons from the substantia nigra pars compacta and the motor defect observed in aged Prkn−/−;mutator mice are also rescued by loss of STING, suggesting that inflammation facilitates this phenotype. Humans with mono- and biallelic PRKN mutations also display elevated cytokines. These results support a role for PINK1- and parkin-mediated mitophagy in restraining innate immunity. Acute and chronic mitochondrial stress in mice require PINK1 and parkin to restrain STING-mediated innate immunity.

The lung is a complex organ with anatomically distinct pools of T cells that play specific roles in combating infection. Our knowledge regarding the generation and/or maintenance of immunity by parenchymal or circulating T cells has been gathered from either persistent (>60 d) or rapidly cleared (

Rationale A top priority in stroke rehabilitation research is determining the appropriate exercise dose to optimize recovery. Although more intensive rehabilitation very early after stroke may be deleterious to recovery, inpatient rehabilitation, occurring after acute care, may be a more appropriate setting to assess therapeutic dose on neurological recovery. Hypothesis Individuals receiving higher intensity and dose exercise programs will yield greater improvements in walking ability over usual inpatient physical therapy care. Methods and design Seventy-five individuals across seven inpatient rehabilitation sites in Canada will be randomized into one of three treatment programs, each 5 days/week, for four weeks and monitored for exertion (heart rate) and repetitions (step count). Study outcomes The primary outcome measure is the 6 min walk and secondary outcomes include functional independence, cognitive, and quality-of-life measures. Outcome data will be assessed at four time points. Summary This trial will contribute to our knowledge of the therapeutic intensity and dose necessary to maximize functional recovery at a very important stage of rehabilitation and neural recovery poststroke.

PURPOSE OF REVIEW: This paper describes a newly proposed sleep disorder, trauma-associated sleep disorder (TSD). Whether or not this represents a truly unique condition is controversial. In this paper, we describe the overlapping features and differences between TSD, post-traumatic stress disorder (PTSD) and Rapid Eye Movement (REM) sleep behavior disorder (RBD). RECENT FINDINGS: While REM sleep without atonia (RWA) and dream enactment are part of the diagnostic criteria for both RBD and TSD, only TSD features nightmares that occur both in non-REM and REM. A key difference between TSD and PTSD is the presence of symptoms during wakefulness in the latter, though the relationship between the two disorders is, as of yet, unclear. It is unknown whether or not a relationship exists between TSD and neurodegeneration, thus this needs to be explored further. SUMMARY: Additional research, such as application of TSD diagnostic criteria to more diverse population, would help to determine whether or not TSD is a distinct clinical entity, its relationships to PTSD, as well as the association of this condition with the development of neurodegeneration.

Using heme entrapped in recombinant silk films, we have produced 3rd generation biosensors, which allow direct electron transfer from the heme center to an electrode avoiding the need for electron mediators. Here, we demonstrate the use of these heme-silk films for the detection of nitric oxide (NO) at nanomolar levels in the presence and absence of oxygen. The sensor was prepared by drop-casting a silk solution on a glassy carbon electrode modified with multiwalled carbon nanotubes (MWCNT) followed by infusion with heme. The sensor was characterized by cyclic voltammetry and showed well defined and reversible Fe+/ Fe3+ redox couple activity, with NO detection by oxidation at potentials above +0.45V or reduction at potentials below - 0.7V. Evaluation of the effect of pH on the sensor response to NO reduction indicated a maximum response at pH 3. The sensor showed good linearity in the concentration range from 19 to 190nM (R2 = 0.99) with a detection limit of 2nM. The sensor had excellent selectivity towards NO with no or negligible interference from oxygen, nitrite, nitrate, dopamine and ascorbic acid and retained 86% of response after 2 months of operation and storage at room temperature.