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Background Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can manifest with varying disease severity and mortality. Genetic predisposition influences the clinical course of infectious diseases. We investigated whether genetic polymorphisms in candidate genes ACE2, TIRAP, and factor X are associated with clinical outcomes in COVID-19. Methods We conducted a single-centre retrospective cohort study. All patients who visited the emergency department with SARS-CoV-2 infection proven by polymerase chain reaction were included. Single nucleotide polymorphisms in ACE2 (rs2285666), TIRAP (rs8177374) and factor X (rs3211783) were assessed. The outcomes were mortality, respiratory failure and venous thromboembolism. Respiratory failure was defined as the necessity of >5 litres/minute oxygen, high flow nasal oxygen suppletion or mechanical ventilation. Results Between March and April 2020, 116 patients (35% female, median age 65 [inter quartile range 55–75] years) were included and treated according to the then applicable guidelines. Sixteen patients (14%) died, 44 patients (38%) had respiratory failure of whom 23 required endotracheal intubation for mechanical ventilation, and 20 patients (17%) developed venous thromboembolism. The percentage of TIRAP polymorphism carriers in the survivor group was 28% as compared to 0% in the non-survivor group (p = 0.01, Bonferroni corrected p = 0.02). Genotype distribution of ACE2 and factor X did not differ between survivors and non-survivors. Conclusion This study shows that carriage of TIRAP polymorphism rs8177374 could be associated with a significantly lower mortality in COVID-19. This TIRAP polymorphism may be an important predictor in the outcome of COVID-19.

The potential occurrence of disease outbreaks during the hajj season is of great concern due to extreme congestion in a confined space. This promotes the acquisition, spread and transmission of pathogenic microorganisms and pneumococcal disease are one of the most frequent infections among Hajj pilgrims. This study aimed to assess the cost-effectiveness and budget impact of introducing the PPV23 to Malaysian Hajj pilgrims. A decision tree framework with a 1-year cycle length was adapted to evaluate the cost-effectiveness of a PPV23 vaccination program with no vaccination. The cost information was retrieved from the Lembaga Tabung Haji Malaysia (LTH) database. Vaccine effectiveness was based on the locally published data and the disease incidence specifically related to Streptococcus pneumoniae was based on a literature search. Analyses were conducted from the perspective of the provider: Ministry of Health and LTH Malaysia. The incremental cost-effectiveness ratios (ICER), cases averted, and net cost savings were estimated. Findings from this study showed that PPV23 vaccination for Malaysian Hajj pilgrims was cost-effective. The PPV23 vaccination programme has an ICER of MYR -449.3 (US$-110.95) per case averted. Based on the national threshold value of US$6,200-US$8,900 per capita, the base-case result shows that introduction of the PPV23 vaccine for Malaysian Hajj pilgrims is very cost-effective. Sensitivity analysis revealed parameters related to annual incidence and hospitalised cost of septicemia and disease without vaccination as the key drivers of the model outputs. Compared with no vaccination, the inclusion of PPV23 vaccination for Malaysian Hajj pilgrims was projected to result in a net cost saving of MYR59.6 million and 109,996 cases averted over 5 years period. The PPV23 vaccination program could substantially offer additional benefits in reducing the pneumococcal disease burden and healthcare cost. This could be of help for policymakers to consider the implementation of PPV23 vaccination for Malaysian performing hajj.

Background Both physical inactivity and sedentary behavior are considered modifiable risk factors for chronic diseases and all-cause mortality. Adult office-workers spend most of their working day in sedentary behaviors, so they are particularly at high risk of developed chronic diseases (e.g., cardiovascular diseases, metabolic disorders like diabetes mellitus, …). It seems important to promote behavioral changes that could prevent or delay metabolic disease development. Evidence supports the use of exercise programs, however, to date there are several knowledge gaps and inconsistencies in the literature regarding the effects of Combined Training (i.e., aerobic plus resistance training) in sedentary healthy adults. This paper outlines an RCT designed to evaluate the effects of a 16-week combined training program on biochemical and immune markers of metabolic disease, lung function, salivary stress hormones and subjective quality of life (primary outcomes), as well as on body composition and physical fitness (secondary outcomes) in sedentary middle-aged office-workers. Furthermore, we aimed to assess the associations between the changes promoted by the exercise program and the different variables studied. Methods and design This is a single-blinded two-arm RCT with parallel groups. A minimum of healthy 40 office-workers aged 40–64 years will be recruited to engage in a 16-week intervention study. After baseline assessments, participants will be randomized to one of the two groups: (1) combined training group or (2) control group. Baseline assessments will be repeated after 8 weeks of intervention (mid-testing) and upon completion of the intervention (post-testing). Discussion This RCT involves a multi-disciplinary approach and seems to be a relevant contribution to understanding the potential role of combined training in improving the metabolic profile, lung function, stress, and quality of life in adults. The results can provide important insights for clinical recommendations and for the optimization of strategies to prevent metabolic disorders in adults with sedentary jobs. Trial registration This trial is registered with ClinicalTrials.gov (registration number: NCT04868240; date of registration April 30, 2021).

Objectives We aimed to explore the synergistic combination of a topologically invariant Betti number (BN)-based signature and a biomarker for the accurate prediction of symptomatic (grade ≥2) radiation-induced pneumonitis (RP+) before stereotactic ablative radiotherapy (SABR) for lung cancer. Methods A total of 272 SABR cases with early-stage non-small cell lung cancer were chosen for this study. The occurrence of RP+ was predicted using a support vector machine (SVM) model trained with the combined features of the BN-based signature extracted from planning computed tomography (pCT) images and a pretreatment biomarker, serum Krebs von den Lungen-6 (BN+KL-6 model). In all, 242 (20 RP+ and 222 RP–(grade 1)) and 30 cases (8 RP+ and 22 RP–) were used for training and testing the model, respectively. The BN-based features were extracted from BN maps that characterize topologically invariant heterogeneous traits of potential RP+ lung regions on pCT images by applying histogram- and texture-based feature calculations to the maps. The SVM models were built to predict RP+ patients with a BN signature that was constructed based on the least absolute shrinkage and selection operator logistic regression model. The evaluation of the prediction models was performed based on the area under the receiver operating characteristic curves (AUCs) and accuracy in the test. The performance of the BN+KL-6 model was compared to the performance based on the BN, conventional original pCT, and wavelet decomposition (WD) models. Results The test AUCs obtained for the BN+KL-6, BN, pCT, and WD models were 0.825, 0.807, 0.642, and 0.545, respectively. The accuracies of the BN+KL-6, BN, pCT, and WD models were found to be 0.724, 0.708, 0.591, and 0.534, respectively. Conclusion This study demonstrated the comprehensive performance of the BN+KL-6 model for the prediction of potential RP+ patients before SABR for lung cancer.

The COVID-19 pandemic has been widely spread and affected millions of people and caused hundreds of deaths worldwide, especially in patients with comorbilities and COVID-19. This manuscript aims to present models to predict, firstly, the number of coronavirus cases and secondly, the hospital care demand and mortality based on COVID-19 patients who have been diagnosed with other diseases. For the first part, I present a projection of the spread of coronavirus in Mexico, which is based on a contact tracing model using Bayesian inference. I investigate the health profile of individuals diagnosed with coronavirus to predict their type of patient care (inpatient or outpatient) and survival. Specifically, I analyze the comorbidity associated with coronavirus using Machine Learning. I have implemented two classifiers: I use the first classifier to predict the type of care procedure that a person diagnosed with coronavirus presenting chronic diseases will obtain (i.e. outpatient or hospitalised), in this way I estimate the hospital care demand; I use the second classifier to predict the survival or mortality of the patient (i.e. survived or deceased). I present two techniques to deal with these kinds of unbalanced datasets related to outpatient/hospitalised and survived/deceased cases (which occur in general for these types of coronavirus datasets) to obtain a better performance for the classification.

Comparisons of histopathological features and microbiological findings between decedents with respiratory symptoms due to SARS-CoV-2 infection or other causes, in settings with high prevalence of HIV and Mycobacterium tuberculosis (MTB) infections have not been reported. Deaths associated with a positive ante-mortem SARS-CoV-2 PCR test and/or respiratory disease symptoms at Chris Hani Baragwanath Academic Hospital in Soweto, South Africa from 15th April to 2nd November 2020, during the first wave of the South African COVID-19 epidemic, were investigated. Deceased adult patients had post-mortem minimally-invasive tissue sampling (MITS) performed to investigate for SARS-CoV-2 infection and molecular detection of putative pathogens on blood and lung samples, and histopathology examination of lung, liver and heart tissue. During the study period MITS were done in patients displaying symptoms of respiratory disease including 75 COVID-19-related deaths (COVID+) and 42 non-COVID-19-related deaths (COVID-). The prevalence of HIV-infection was lower in COVID+ (27%) than in the COVID- (64%), MTB detection was also less common among COVID+ (3% vs 13%). Lung histopathology findings showed differences between COVID+ and COVID- in the severity of the morphological appearance of Type-II pneumocytes, alveolar injury and repair initiated by SARS-CoV-2 infection. In the liver necrotising granulomatous inflammation was more common among COVID+. No differences were found in heart analyses. The prevalence of bacterial co-infections was higher in COVID+. Most indicators of respiratory distress syndrome were undifferentiated between COVID+ and COVID- except for Type-II pneumocytes. HIV or MTB infection does not appear in these data to have a meaningful correspondence with COVID-related deaths. Funding Information: This study was supported by the Bill & Melinda Gates Foundation (grant number INV-016202). There was also partial support from the Department of Science and Technology and National Research Foundation: South African Research Chair Initiative in Vaccine Preventable Diseases; and the South African Medical Research Council. Declaration of Interests: All other authors have nothing to disclose. Ethics Approval Statement: The study was approved by the Human Research Ethics Committee at the University of the Witwatersrand (HREC approval number: M200313). Informed consent was obtained from relatives of the deceased.

Conductive olfactory dysfunction (COD) is caused by an obstruction in the nasal cavity and is characterized by changeable olfaction. COD can occur even when the olfactory cleft is anatomically normal, and therefore, the cause in these cases remains unclear. Herein, we used computational fluid dynamics to examine olfactory cleft airflow with a retrospective cohort study utilizing the cone beam computed tomography scan data of COD patients. By measuring nasal–nasopharynx pressure at maximum flow, we established a cut-off value at which nasal breathing can be differentiated from combined mouth breathing in COD patients. We found that increased nasal resistance led to mouth breathing and that the velocity and flow rate in the olfactory cleft at maximum flow were significantly reduced in COD patients with nasal breathing only compared to healthy olfactory subjects. In addition, we performed a detailed analysis of common morphological abnormalities associated with concha bullosa. Our study provides novel insights into the causes of COD, and therefore, it has important implications for surgical planning of COD, sleep apnea research, assessment of adenoid hyperplasia in children, and sports respiratory physiology.

Current SARS-CoV-2 serological assays generate discrepant results, and the longitudinal characteristics of antibodies targeting various antigens after asymptomatic to mild COVID-19 are yet to be established. This longitudinal cohort study including 1965 healthcare workers, of which 381 participants exhibited antibodies against the SARS-CoV-2 spike antigen at study inclusion, reveal that these antibodies remain detectable in most participants, 96%, at least four months post infection, despite having had no or mild symptoms. Virus neutralization capacity was confirmed by microneutralization assay in 91% of study participants at least four months post infection. Contrary to antibodies targeting the spike protein, antibodies against the nucleocapsid protein were only detected in 80% of previously anti-nucleocapsid IgG positive healthcare workers. Both anti-spike and anti-nucleocapsid IgG levels were significantly higher in previously hospitalized COVID-19 patients four months post infection than in healthcare workers four months post infection (p = 2*10(-23) and 2*10(-13) respectively). Although the magnitude of humoral response was associated with disease severity, our findings support a durable and functional humoral response after SARS-CoV-2 infection even after no or mild symptoms. We further demonstrate differences in antibody kinetics depending on the antigen, arguing against the use of the nucleocapsid protein as target antigen in population-based SARS-CoV-2 serological surveys.

Background Asthma and nonalcoholic fatty liver disease (NAFLD) are chronic diseases known to be associated with metabolic abnormalities. We aimed to clarify the association between NAFLD and asthma incidence in a large population-based cohort. Methods and findings We selected 160,603 individuals without comorbidities from the National Health Insurance Service-National Sample cohort between 2009 and 2014. NAFLD was defined using a surrogate marker, fatty liver index (FLI). During a median of 5.08 years’ follow-up, 16,377 subjects (10.2%) were newly diagnosed with asthma and categorized into three groups according to FLI. The cumulative incidence of asthma was higher in subjects with higher vs. lower FLIs (FLI < 30, 10.1%; 30 ≤ FLI < 60, 10.8%; FLI ≥ 60, 10.5%). Higher FLI was associated with an increased incidence of asthma (Hazard ratios (HR)highest vs. lowest FLI, 1.25; 95% CI, 1.15–1.36). The results using another definition of NAFLD, as measured by the hepatic steatosis index (HSI), were similar to the primary results. This association was more pronounced in women than in men (HR 1.46; 95% CI, 1.13–1.64 vs. HR 1.07; 95% CI, 0.94–1.20). Conclusions This study demonstrated that NAFLD, as measured by FLI and HSI, may influence the incidence rates of asthma in adults, especially in women.

BackgroundRespiratory failure worsens the outcome of acute pancreatitis (AP) and underlying factors might be early detectable.AimsTo evaluate the prevalence and prognostic relevance of early pleuropulmonary pathologies and pre-existing chronic lung diseases (CLD) in AP patients.MethodsMulticentre retrospective cohort study. Caudal sections of the thorax derived from abdominal contrast enhanced computed tomography (CECT) performed in the early phase of AP were assessed. Independent predictors of severe AP were identified by binary logistic regression analysis. A one-year survival analysis using Kaplan-Meier curves and log rank test was performed.Results358 patients were analysed, finding pleuropulmonary pathologies in 81%. CECTs were performed with a median of 2 days (IQR 1-3) after admission. Multivariable analysis identified moderate to severe or bilateral pleural effusions (PEs) (OR = 4.16, 95%CI 2.05-8.45, pConclusionsIncreasing awareness of the prognostic impact of large and bilateral PEs and pre-existing CLD could facilitate the identification of patients at high risk for severe AP in the early phase and thus improve their prognosis.

Introduction As of February 2021 COVID-19 report in 57 African countries, there were 3,761,512 confirmed cases and 98,088 deaths. Ethiopia reported the highest number of cases in East Africa with a total of 147,092 cases and 2,194 deaths. Over 1.5 billion students from 195 countries across the world separated from school as a consequence of the closure of schools related to the pandemic. This study aimed to determine the level of knowledge, attitude, prevention practices, and determinant factors regarding COVID-19 among preparatory school students in southwest Ethiopia. Methods An institution-based cross-sectional study design was used for 422 samples. Each respondent was selected using simple random sampling. Data were collected using a self-administered questionnaire. The collected data were entered and analyzed using Statistical Package for social science software version 25.0. Multivariable binary logistic regression was used to identify factors that were significantly associated with the practice of COVID-19 prevention. Results The response rate in this study was 96.2%. A higher proportion of the respondents were female (53.9%), Bench (43.6%), and protestant (47.3%). The level of good knowledge, positive attitude, and good practice were 81.8%, 70.9%, and 47.0% respectively. Using social media [AOR: 1.801, 95% CI: 1.005, 3.226], watching television [AOR: 1.884 95% CI: 1.093, 3.247], being knowledgeable [AOR: 5.173 95% CI: 2.276, 11.755], and having a positive attitude [AOR: 4.300 95% CI: 2.351, 7.868] were positively associated with COVID-19 prevention practice. Conclusion Despite the high level of knowledge and a moderate level of positive attitude, the practice of COVID-19 prevention measures was low. Using social media, watching television, being knowledgeable, and having positive attitudes towards COVID-19 increases the tendency to practice COVID-19 prevention measures. School directors and teachers should strictly monitor students for their adherence to COVID-19 prevention measures as directed by the local and national health care departments.

Background Prior studies have established those elderly patients with chronic obstructive pulmonary disease (COPD) are at elevated risk for developing influenza-associated complications such as hospitalization, intensive-care admission, and death. This study sought to determine whether influenza vaccination could improve survival among elderly patients with COPD. Materials/Methods This study included Veterans (age ≥ 65 years) diagnosed with COPD that received care at the United States Veterans Health Administration (VHA) during four influenza seasons, from 2012–2013 to 2015–2016. We linked VHA electronic medical records and Medicare administrative files to Centers for Disease Control and Prevention National Death Index cause of death records as well as influenza surveillance data. A multivariable time-dependent Cox proportional hazards model was used to compare rates of mortality of recipients of influenza vaccination to those who did not have records of influenza vaccination. We estimated hazard ratios (HRs) adjusted for age, gender, race, socioeconomic status, comorbidities, and healthcare utilization. Results Over a span of four influenza seasons, we included 1,856,970 person-seasons of observation where 1,199,275 (65%) had a record of influenza vaccination and 657,695 (35%) did not have a record of influenza vaccination. After adjusting for comorbidities, demographic and socioeconomic characteristics, influenza vaccination was associated with reduced risk of death during the most severe periods of influenza seasons: 75% all-cause (HR = 0.25; 95% CI: 0.24–0.26), 76% respiratory causes (HR = 0.24; 95% CI: 0.21–0.26), and 82% pneumonia/influenza cause (HR = 0.18; 95% CI: 0.13–0.26). A significant part of the effect could be attributed to “healthy vaccinee” bias as reduced risk of mortality was also found during the periods when there was no influenza activity and before patients received vaccination: 30% all-cause (HR = 0.70; 95% CI: 0.65–0.75), 32% respiratory causes (HR = 0.68; 95% CI: 0.60–0.78), and 51% pneumonia/influenza cause (HR = 0.49; 95% CI: 0.31–0.78). However, as a falsification study, we found that influenza vaccination had no impact on hospitalization due to urinary tract infection (HR = 0.97; 95% CI: 0.80–1.18). Conclusions Among elderly patients with COPD, influenza vaccination was associated with reduced risk for all-cause and cause-specific mortality.

BackgroundTo prevent recurrence of medical accidents, the Medical Accident Investigating System was implemented in October 2015 by the Japan Medical Safety Research Organization (Medsafe Japan) to target deaths from medical care that were unforeseen by the administrator. Medsafe Japan analyzed the 10 cases of central venous catheterization-related deaths reported in the system and published recommendations in March 2017. However, the particular emphasis for the prevention of central venous catheterization-related deaths is unclear.MethodsThis study aimed to identify the recommendation points that should be emphasized to prevent recurrence of central venous catheterization-related deaths. We assessed central venous catheterization in 8530 closed-claim cases between January 2002 and December 2016 covered by the medical insurer Sompo-Japan. Moreover, we compared central venous catheterization-related death in closed-claim cases with death in reported cases.ResultsThe background, error type, anatomic insertion site, and fatal complication data were evaluated for 37 closed-claim cases, of which 12 (32.4%) were death cases. Of the 12 closed-claim cases and 10 reported cases, 9 (75.0%) closed-claim cases and 9 (90.0%) reported cases were related to vascular access. Among these, 5 closed-claim cases (41.7%) and 7 reported cases (77.8%) were related to internal jugular vein catheterization (p = 0.28). Coagulopathy was observed in 3 (60.0%) of 5 closed-claim cases and 6 (85.7%) of 7 reported cases.ConclusionsThe risk of internal jugular catheterization in patients with coagulopathy must be carefully considered.

Background Evidence suggests that chronic obstructive pulmonary disease (COPD) is associated with a higher risk of lung carcinoma. Using a territory-wide clinical electronic medical records system, we investigated the association between low-dose aspirin use (≤160 mg) among patients with COPD and incidence of lung carcinoma and the corresponding risk of bleeding. Methods and findings This is a retrospective cohort study conducted utilizing Clinical Data Analysis Reporting System (CDARS), a territory-wide database developed by the Hong Kong Hospital Authority. Inverse probability of treatment weighting (IPTW) was used to balance baseline covariates between aspirin nonusers (35,049 patients) with new aspirin users (7,679 patients) among all eligible COPD patients from 2005 to 2018 attending any public hospitals. The median age of the cohort was 75.7 years (SD = 11.5), and 80.3% were male. Competing risk regression with Cox proportional hazards model were performed to estimate the subdistribution hazard ratio (SHR) of lung carcinoma with low-dose aspirin and the associated bleeding events. Of all eligible patients, 1,779 (4.2%, 1,526 and 253 among nonusers and users) were diagnosed with lung carcinoma over a median follow-up period of 2.6 years (interquartile range [IQR]: 1.4 to 4.8). Aspirin use was associated with a 25% lower risk of lung carcinoma (SHR = 0.75, 95% confidence interval [CI] 0.65 to 0.87, p =, In a cohort study, Si-Yeung Yu and colleagues investigate the association between low-dose aspirin and incidence of lung carcinoma in patients with chronic obstructive pulmonary disease in Hong Kong., Author summary Why was this study done? Lung carcinoma is the most common malignancy worldwide, and chronic obstructive pulmonary disease (COPD), for which no curative treatments exist, is a prevalent risk factor of lung carcinoma. Aspirin is a medication with potential anticancer effects. Its effect on lung cancer, however, remains controversial. To our knowledge, its effect in patients in COPD remains unstudied. Aspirin is also known to cause bleeding. However, its effects in COPD patients, again to our knowledge, also remains unstudied. What did the researchers do and find? Using a territory-wide database, the risk of lung carcinoma was assessed in patients with COPD defined as aspirin nonusers (35,049) and aspirin users (7,679 patients). A mathematical model was used, which balances the 2 cohorts by their comorbidities, drug uses, demographic variables, and proxy variables for their socioeconomic status. Aspirin use was associated with a 25% lower risk of lung carcinoma, implying that within our cohort, every 125 patients treated for 5 years is associated with one fewer case of lung carcinoma. We found, additionally, that aspirin use was associated with an increased risk of coughing up blood, although the overall risk of gastrointestinal bleeding is not increased. What do these findings mean? Aspirin may be implicated as a potential preventative treatment for lung carcinoma in COPD patients, but the increased risk of adverse effects merits further evaluation. The current study design was unable to eliminate the possibility that aspirin users were more likely to seek additional treatment, although this is mitigated through design choices in developing the mathematical model. The observational nature of the study prevents causality from being established. The use of aspirin in COPD should depend on the benefits and harms associated with its usage, when they have been thoroughly studied in randomized trials.

Background Oxygen (O2) is a mainstay of treatment in acute severe asthma but how it is administered varies widely. The objectives were to examine whether a trial comparing humidified O2 to standard O2 in children is feasible, and specifically to obtain data on recruitment, tolerability and outcome measure stability. Methods Heated humidified, cold humidified and standard O2 treatments were compared for children (2–16 years) with acute severe asthma in a multi-centre, open, parallel, pilot randomised controlled trial (RCT). Multiple outcomes were assessed. Results Of 258 children screened, 66 were randomised (heated humidified O2 n = 25; cold humidified O2 n = 21; standard O2 n = 20). Median (IQR) length of stay (hours) in hospital was 37.9 (29.1), 52 (35.4) and 49.1 (29.7) for standard, heated humidified and cold humidified respectively and time (hours) on O2 was 15.9 (9.4), 13.6 (14.9) and 13.1 (14.9) for the three groups respectively. The mean (standard deviation) time (hours) taken to step down nebulised to inhaled treatment was 5.6 (14.3), 35.1 (28.2) and 32.7 (20.1). Asthma Severity Score decreased in all three groups similarly, although missing data prevented complete analysis. Humidified O2 was least well tolerated with eight participants discontinuing their randomised treatment early. An important barrier to recruitment was research nurse availability. Conclusion Although, the results of this pilot study should not be extrapolated beyond the study sample and inferential conclusions should not be drawn from the results, this is the first RCT to compare humidified and standard O2 therapy in acute severe asthmatics of any age. These findings and accompanying screening data show that a large RCT of O2 therapy is feasible. However, challenges associated with randomisation and data collection should be addressed in any future trial design.

Introduction Globally, medical students have demonstrated knowledge gaps in emergency care and acute stabilization. In Colombia, new graduates provide care for vulnerable populations. The World Health Organization (WHO) Basic Emergency Care (BEC) course trains frontline providers with limited resources in the management of acute illness and injury. While this course may serve medical students as adjunct to current curriculum, its utility in this learner group has not been investigated. This study performs a baseline assessment of knowledge and confidence in emergency management taught in the BEC amongst medical students in Colombia. Methods A validated, cross-sectional survey assessing knowledge and confidence of emergency care congruent with BEC content was electronically administered to graduating medical students across Colombia. Knowledge was evaluated via 15 multiple choice questions and confidence via 13 questions using 100 mm visual analog scales. Mean knowledge and confidence scores were compared across demographics, geography and prior training using Chi-Squared or one-way ANOVA analyses. Results Data were gathered from 468 graduating medical students at 36 institutions. The mean knowledge score was 59.9% ± 23% (95% CI 57.8–62.0%); the mean confidence score was 59.6 mm ±16.7 mm (95% CI 58.1–61.2). Increasing knowledge and confidence scores were associated with prior completion of emergency management training courses (p Conclusion Knowledge and confidence levels of emergency care management for graduating medical students across Colombia demonstrated room for additional, specialized training. Higher scores were seen in groups that had completed emergency care courses. Implementation of the BEC as an adjunct to current curriculum may serve a valuable addition.

Background Coronavirus disease 2019 (COVID-19) may severely impair pulmonary function and cause hypoxia. However, the association of COVID-19 pneumonia on CT with impaired ventilation remains unexplained. This pilot study aims to demonstrate the relationship between the radiological findings on COVID-19 CT images and ventilation abnormalities simulated in a computational model linked to the patients’ symptoms. Methods Twenty-five patients with COVID-19 and four test-negative healthy controls who underwent a baseline non-enhanced CT scan: 7 dyspneic patients, 9 symptomatic patients without dyspnea, and 9 asymptomatic patients were included. A 2D U-Net-based CT segmentation software was used to quantify radiological futures of COVID-19 pneumonia. The CT image-based full-scale airway network (FAN) flow model was employed to assess regional lung ventilation. Functional and radiological features were compared across groups and correlated with the clinical symptoms. Heterogeneity in ventilation distribution and ventilation defects associated with the pneumonia and the patients’ symptoms were assessed. Results Median percentage ventilation defects were 0.2% for healthy controls, 0.7% for asymptomatic patients, 1.2% for symptomatic patients without dyspnea, and 11.3% for dyspneic patients. The median of percentage pneumonia was 13.2% for dyspneic patients and 0% for the other groups. Ventilation defects preferentially affected the posterior lung and worsened with increasing pneumonia linearly (y = 0.91x + 0.99, R2 = 0.73) except for one of the nine dyspneic patients who had disproportionally large ventilation defects (7.8% of the entire lung) despite mild pneumonia (1.2%). The symptomatic and dyspneic patients showed significantly right-skewed ventilation distributions (symptomatic without dyspnea: 0.86 ± 0.61, dyspnea 0.91 ± 0.79) compared to the patients without symptom (0.45 ± 0.35). The ventilation defect analysis with the FAN model provided a comparable diagnostic accuracy to the percentage pneumonia in identifying dyspneic patients (area under the receiver operating characteristic curve, 0.94 versus 0.96). Conclusions COVID-19 pneumonia segmentations from CT scans are accompanied by impaired pulmonary ventilation preferentially in dyspneic patients. Ventilation analysis with CT image-based computational modelling shows it is able to assess functional impairment in COVID-19 and potentially identify one of the aetiologies of hypoxia in patients with COVID-19 pneumonia.

Background Coronavirus infectious disease 2019 (COVID-19) has had a great impact on global health, but with relatively few confirmed cases in Taiwan. People in Taiwan showed excellent cooperation with the government for disease prevention and faced social and behavioral changes during this period. This study aimed to investigate people’s knowledge of COVID-19, attitudes and practices regarding vaccinations for influenza, pneumococcus and COVID-19. Methods We conducted a community-based, cross-sectional questionnaire survey from September 2020 to October 2020 among adults in northern Taiwan. The four-part questionnaire included questions on sociodemographic characteristics, knowledge, attitude, and practice toward COVID-19. Results Among a total of 410 respondents, 58.5% were categorized as having “good knowledge” responding to COVID-19. Among the total respondents, 86.6% were willing to receive influenza or pneumococcal vaccines, and 76% of them acted to receive COVID-19 immunization once the vaccine became available. Compared with the respondents with poor knowledge of COVID-19, those with good knowledge had a more positive attitude toward receiving influenza or pneumococcal immunization (OR 3.26, 95% CI = 1.74–6.12). Conclusions Participants with good knowledge of COVID-19 had greater intent to receive immunization for influenza or pneumococcal vaccine. The promotion of correct knowledge of both COVID-19 and immunization preparations is necessary.

Drug repurposing can be an interesting strategy for an emergency response to the severe acute respiratory syndrome-coronavirus-2, (SARS-COV-2), the causing agent of the coronavirus disease-19 (COVID-19) pandemic. For this, we applied the Connectivity Map (CMap) bioinformatic resource to identify drugs that generate, in the CMap database, gene expression profiles (GEP) that negatively correlate with a SARS-COV-2 GEP, anticipating that these drugs could antagonize the deleterious effects of the virus at cell, tissue or organism levels. We identified several anti-cancer compounds that target MDM2 in the p53 pathway or signaling proteins: Ras, PKBβ, Nitric Oxide synthase, Rho kinase, all involved in the transmission of proliferative and growth signals. We hypothesized that these drugs could interfere with the high rate of biomass synthesis in infected cells, a feature shared with cancer cells. Other compounds including etomoxir, triacsin-c, PTB1-IN-3, are known to modulate lipid metabolism or to favor catabolic reactions by activating AMPK. Four different anti-inflammatory molecules, including dexamethasone, fluorometholone and cytosporone-b, targeting the glucocorticoid receptor, cyclooxygenase, or NUR77 also came out of the analysis. These results represent a first step in the characterization of potential repositioning strategies to treat SARS-COV-2.

BackgroundThe hospitalization of children during the COVID-19 pandemic has affected their physical and mental health. Pediatric nurses have faced challenges in providing high-quality nursing care for children and their families. However, the pediatric nursing care recommendations for COVID-19 patients in the hospital setting remain unclear. The current scoping review provides recommendations for nursing interventions for pediatric COVID-19 patients in the hospital setting.Methods and findingsThe selected articles containing management and nursing recommendations for COVID-19 that have occurred in pediatric patients ages 0–19 years old. A search strategy was developed and implemented in seven databases. We included peer-reviewed articles that reported observational or interventional studies, as well as policy papers, guides or guidelines, letters and editorials, and web articles. A total of 134 articles and other documents relevant to this review were included. We categorized the results based on The Nursing Intervention Classification (NIC) taxonomy which consists of six domains (e.g., Physiological: Basic); eleven classes (e.g., Nutrition Support); and eighteen intervention themes (e.g., Positioning, Family Presence Facilitation, Family Support, and Discharge Planning).ConclusionApart from the intervention of physical problems, there is a need to promote patient- and family-centered care, play therapy, and discharge planning to help children and families cope with their new situation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has circulated worldwide and causes coronavirus disease 2019 (COVID-19). At the onset of the COVID-19 pandemic, infection control measures were taken, such as hand washing, mask wearing, and behavioral restrictions. However, it is not fully clear how the effects of these non-pharmaceutical interventions changed the prevalence of other pathogens associated with respiratory infections. In this study, we collected 3,508 nasopharyngeal swab samples from 3,249 patients who visited the Yamanashi Central Hospital in Japan from March 1, 2020 to February 28, 2021. We performed multiplex polymerase chain reaction (PCR) using the FilmArray Respiratory Panel and singleplex quantitative reverse transcription PCR targeting SARS-CoV-2 to detect respiratory disease-associated pathogens. At least one pathogen was detected in 246 (7.0%) of the 3,508 samples. Eleven types of pathogens were detected in the samples collected from March–May 2020, during which non-pharmaceutical interventions were not well implemented. In contrast, after non-pharmaceutical interventions were thoroughly implemented, only five types of pathogens were detected, and the majority were SARS-CoV-2, adenoviruses, or human rhinoviruses / enteroviruses. The 0–9 year age group had a higher prevalence of infection with adenoviruses and human rhinoviruses / enteroviruses compared with those 10 years and older, while those 10 years and older had a higher prevalence of infection with SARS-CoV-2 and other pathogens. These results indicated that non-pharmaceutical interventions likely reduced the diversity of circulating pathogens. Moreover, differences in the prevalence of pathogens were observed among the different age groups.

Recent reports indicate that respiratory infectious diseases were suppressed during the novel coronavirus disease-2019 (COVID-19) pandemic. COVID-19 led to behavioral changes aimed to control droplet transmission or contact transmission. In this study, we examined the incidence of common infectious diseases in Japan during the COVID-19 pandemic. COVID-19 data were extracted from the national data based on the National Epidemiological Surveillance of Infectious Diseases (NESID). Common infectious diseases were selected from notifiable infectious diseases under the NESID. The epidemic activity of the diseases during 2015–2020 was evaluated based on the Infectious Disease Weekly Reports published by the National Institute of Infectious Diseases. Each disease was then categorized according to the route of transmission. Many Japanese people had adopted hygienic activities, such as wearing masks and hand washing, even before the COVID-19 pandemic. We examined the correlation between the time-series of disease counts of common infectious diseases and COVID-19 over time using cross-correlation analysis. The weekly number of cases of measles, rotavirus, and several infections transmitted by droplet spread, was negatively correlated with the weekly number of cases of COVID-19 for up to 20 weeks in the past. According to the difference-in-differences analysis, the activity of influenza and rubella was significantly lower starting from the second week in 2020 than that in 2015–2019. Only legionellosis was more frequent throughout the year than in 2015–2019. Lower activity was also observed in some contact transmitted, airborne-transmitted, and fecal-oral transmitted diseases. However, carbapenem-resistant Enterobacteriaceae, exanthema subitum, showed the same trend as that over the previous 5 years. In conclusion, our study shows that public health interventions for the COVID-19 pandemic may have effectively prevented the transmission of most droplet-transmitted diseases and those transmitted through other routes.

Background Bacillus Calmette-Guérin (BCG) vaccination has recently been found to have beneficial effects among children infected other than Mycobacterium tuberculosis. Due to the paucity of data on the outcomes of children who had successful BCG vaccination following Expanded Programme on Immunization (EPI) schedule, we aimed to investigate the characteristics of such children and their outcomes who were hospitalized for severe malnutrition. Methods A prospective observational study was conducted to determine the viral etiology of pneumonia in severely malnourished children those were admitted to the Dhaka Hospital of International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) between April 2015 and December 2017, constituted the study population. Using a case-control design for the analysis, children having BCG vaccination prior hospital admission were treated as cases (n = 611) and those without vaccination, constituted as controls (n = 83). Bi-variate analysis was conducted using socio-demographic, clinical, laboratory, and treatment characteristics on admission and outcomes during hospitalization. Finally, log-linear binomial regression analysis was done to identify independent impact of BCG vaccination. Results The cases more often presented with older age, have had lower proportion of maternal illiteracy, higher rate of breastfeeding, severe wasting and lower rate of hypoglycemia, compared to the controls. The cases were also found to have lower risk of severe sepsis and deaths, compared to the controls (for all, p Conclusion BCG vaccination and breastfeeding were found to be protective for the development of severe sepsis in hospitalized severely malnourished under-five children which underscores the importance of continuation of BCG vaccination at birth and breastfeeding up to two years of age.

Objective To describe the impact of different doses of corticosteroids on the evolution of patients with COVID-19 pneumonia, based on the potential benefit of the non-genomic mechanism of these drugs at higher doses. Methods Observational study using data collected from the SEMI-COVID-19 Registry. We evaluated the epidemiological, radiological and analytical scenario between patients treated with megadoses therapy of corticosteroids vs low-dose of corticosteroids and the development of complications. The primary endpoint was all-cause in-hospital mortality according to use of corticosteroids megadoses. Results Of a total of 14,921 patients, corticosteroids were used in 5,262 (35.3%). Of them, 2,216 (46%) specifically received megadoses. Age was a factor that differed between those who received megadoses therapy versus those who did not in a significant manner (69 years [IQR 59–79] vs 73 years [IQR 61–83]; p < .001). Radiological and analytical findings showed a higher use of megadoses therapy among patients with an interstitial infiltrate and elevated inflammatory markers associated with COVID-19. In the univariate study it appears that steroid use is associated with increased mortality (OR 2.07 95% CI 1.91–2.24 p < .001) and megadose use with increased survival (OR 0.84 95% CI 0.75–0.96, p 0.011), but when adjusting for possible confounding factors, it is observed that the use of megadoses is also associated with higher mortality (OR 1.54, 95% CI 1.32–1.80; p < .001). There is no difference between megadoses and low-dose (p .298). Although, there are differences in the use of megadoses versus low-dose in terms of complications, mainly infectious, with fewer pneumonias and sepsis in the megadoses group (OR 0.82 95% CI 0.71–0.95; p < .001 and OR 0.80 95% CI 0.65–0.97; p < .001) respectively. Conclusion There is no difference in mortality with megadoses versus low-dose, but there is a lower incidence of infectious complications with glucocorticoid megadoses.

Introduction Diabetes mellitus (DM), hypertension and pulmonary tuberculosis (PTB) are catastrophic illnesses that collectively lead to increased mortality and premature death. However, the size of the problem and the appropriate approach to deal with the burden is still unclear. We aimed to evaluate the yield, number needed to screen (NNS) to prevent one death or adverse event for screening DM and hypertension and assess the prevalence and contributors to DM and/or hypertension. Methods Based on PTB contact tracing, a cross-sectional study was conducted among 801 PTB index cases and 972 household contacts from April 2019 to October 2020 in Guizhou, China. All the participants were screened for DM and hypertension. The yield was calculated as the proportion of newly detected cases among the study subjects, excluding known cases. The NNS was computed by dividing the number needed to treat for risk factors by the prevalence of the unrecognized diseases. The univariate and multivariate logistic regression analyses were applied to determine the independent predictors of DM and/or hypertension. Results Of the 1,773 participants, the prevalence of DM and hypertension was 8.7% (70/801) and 15.2% (122/801) in the PTB patients, 3.2% (31/972) and 14.0% (136/972) in the contacts, respectively. The prevalence of DM and/or hypertension was 21.2% (170/801) among the PTB patients and 15.4% (150/972) among their contacts. The screening yields to detect new cases of DM and hypertension among PTB patients were 1.9% and 5.2%, and that in the contacts were 0.8% and 4.8%, respectively. The NNS for DM was 359 for the PTB cases and 977 for the contacts, 299 for PTB cases and 325 for hypertension, respectively. Older age, under or overweight and obesity, family history hypertension and earlier diagnosis of other chronic conditions were the independent predictors for DM and/or hypertension among both PTB cases and their contacts. Conclusion Screening for DM and hypertension should be mandated in PTB patients and their household contacts to disclose undetected cases of these two conditions during TB contact tracing, which might reduce the potential cardiovascular disease deaths.

Background Persistent respiratory symptoms and radiographic abnormalities are common among individuals previously treated for tuberculosis (TB) and may contribute to misdiagnosis and incorrect treatment when they seek care. We sought to determine if clinical and radiographic characteristics differed among previously treated, presumptive TB patients according to their current TB disease status. Methods Adults (>18 years of age) seeking care at a public health facility in Lusaka, Zambia were systematically evaluated for active TB using symptom screening and chest X-ray. All patients with presumptive TB submitted a sputum sample for microbiological TB testing. Patients who reported a prior history of TB treatment were included in the present analysis. ‘Confirmed TB’ was defined by the detection of TB using Xpert Ultra and/or liquid culture, while ‘possible TB’ was defined by the receipt of TB treatment without a positive Xpert Ultra or culture result. We evaluated the positive predictive value (PPV) of clinical symptoms and radiographic features for active TB alone and in combination. Results Of 740 presumptive TB patients, 144 (19%) had been previously treated for active TB. Of these, 19 (13%) patients had confirmed TB, 14 (10%) had possible TB, and 111 (77%) had no pulmonary TB. Overall, 119 (83%) patients had ≥1 current respiratory symptom—this did not differ according to current TB disease classification (95%, 93%, 79%; p = 0.23). Sixty-one patients (56%) had radiographic abnormalities suggestive of active TB and such findings were more common among patients with confirmed or possible TB compared to those without TB (93%, 71%, vs. 47%; p = 0.002). Most patients (n = 91, 83%) had at least one radiographic abnormality—no difference by current TB classification was observed (93%, 100%, 79%; p = 0.08). The PPV of any current respiratory symptom, active TB radiographic finding, or any radiographic abnormality for TB was 13% (95%CI: 7–21%), 21% (95%CI: 12–34) and 14% (95%CI: 9–23), respectively; combining clinical and radiographic characteristics did not significantly improve the PPV for active TB. Conclusions Among presumptive TB patients previously treated for TB, respiratory symptoms and radiographic abnormalities were common and poorly differentiated those with current active TB from those without current active TB. Reliance on clinical and radiographic characteristics alone in this patient population may result in substantial overtreatment and therefore, microbiological investigations should be used to inform TB treatment decisions whenever possible.

Background Only one recommendation currently exists for the treatment of Lassa fever (LF), which is ribavirin administered in conjunction with supportive care. This recommendation is primarily based on evidence generated from a single clinical trial that was conducted more than 30 years ago–the methodology and results of which have recently come under scrutiny. The requirement for novel therapeutics and reassessment of ribavirin is therefore urgent. However, a significant amount of work now needs to be undertaken to ensure that future trials for LF can be conducted consistently and reliably to facilitate the efficient generation of evidence. Methodology We convened a consultation group to establish the position of clinicians and researchers on the core components of future trials. A Core Eligibility Criteria (CEC), Core Case Definition (CCD), Core Outcome Set (COS) and Core Data Variables (CDV) were developed through the process of a multi-stakeholder consultation that took place using a modified-Delphi methodology. Results A consensus position was achieved for each aspect of the framework, which accounts for the inclusion of pregnant women and children in future LF clinical trials. The framework consists of 8 core criteria, as well as additional considerations for trial protocols. Conclusions This project represents the first step towards delineating the clinical development pathway for new Lassa fever therapeutics, following a period of 40 years without advancement. Future planned projects will bolster the work initiated here to continue the advancement of LF clinical research through a regionally-centred, collaborative methodology, with the aim of delineating a clear pathway through which LF clinical trials can progress efficiently and ensure sustainable investments are made in research capacity at a regional level., Author summary Lassa fever (LF) is an acute viral haemorrhagic fever endemic to West Africa, causing an estimated 500,000 new infections and 10,000 deaths per year. At present, no treatment has been developed to specifically treat LF and only one prospective clinical trial has been conducted to evaluate the current treatment recommendation. Before a new era of LF clinical trials can begin, it is important to develop standardised methods and tools to ensure that trials are conducted in a consistent way and can generate reliable, comparable data. The aim of this project was initiate the first step to improve the comparability of LF studies by developing a standardised Phase III clinical trial methodology for LF therapeutics that could be applied in low-resource settings. Through multi-stakeholder consultation, we established a consensus position of clinicians and researchers on the core components of future Phase III clinical trials: Core Eligibility Criteria (CEC), Core Case Definition (CCD), Core Outcome Set (COS) and Core Data Variables (CDV).

Background Determining the status of asthma control and identifying risk factors for poor asthma control is a key strategy for curbing the negative health impacts and the financial burden of the disease. Therefore, this review was aimed to determine the rate of asthma control and assess the predictors of uncontrolled asthma in Ethiopia. Methods PubMed, Web of Science, and Google Scholar searches were performed using key terms; “asthma, bronchial asthma, control, controlled, uncontrolled and Ethiopia” up to October 16, 2020. University repositories were also searched to retrieve gray literature. The results were presented as a prevalence rate with a 95% confidence interval (CI). Subgroup analysis and meta-regression were performed to identify the sources of heterogeneity in the outcomes. Results From 1,388 patients, based on the Global Initiative for Asthma (GINA) symptom control, the rate of the uncontrolled asthma was 45.0% (95% CI 34.0% - 56.0%) with a considerable heterogeneity between the studies; (I2: 94.55, p< 0.001). About 19.0% (95% CI 10.0% - 29.0%); (I2: 96.04, p< 0.001) of the asthma patients had a well-controlled asthma. Moreover, 36.0% (95% CI 22.0% - 50.0%), (I2: 97.11, p< 0.001) of patients had a partly controlled asthma. Similarly, based on the asthma control test (ACT), the rate of well-controlled asthma was 22.0% (95% CI 3% - 42.0%), with considerable heterogeneity between the studies; (I2: 97.75, p< 0.001). The most frequent predictors of uncontrolled asthma were incorrect inhalation techniques, frequent SABA use, moderate/severe persistent asthma, history of exacerbations, presence of comorbidities, use of oral corticosteroids, and irregular follow-up. Conclusion The rate of uncontrolled asthma in Ethiopia was high. Several factors are associated with uncontrolled asthma. Comprehensive asthma educations at each follow-up visit should be strengthened to minimize the morbidity and the cost of uncontrolled asthma.

The mechanisms and consequences of genome evolution on viral fitness following host shifts are poorly understood. In addition, viral fitness -the ability of an organism to reproduce and survive- is multifactorial and thus difficult to quantify. Influenza A viruses (IAVs) circulate broadly among wild birds and have jumped into and become endemic in multiple mammalian hosts, including humans, pigs, dogs, seals, and horses. H3N8 equine influenza virus (EIV) is an endemic virus of horses that originated in birds and has been circulating uninterruptedly in equine populations since the early 1960s. Here, we used EIV to quantify changes in infection phenotype associated to viral fitness due to genome-wide changes acquired during long-term adaptation. We performed experimental infections of two mammalian cell lines and equine tracheal explants using the earliest H3N8 EIV isolated (A/equine/Uruguay/63 [EIV/63]), and A/equine/Ohio/2003 (EIV/2003), a monophyletic descendant of EIV/63 isolated 40 years after the emergence of H3N8 EIV. We show that EIV/2003 exhibits increased resistance to interferon, enhanced viral replication, and a more efficient cell-to-cell spread in cells and tissues. Transcriptomics analyses revealed virus-specific responses to each virus, mainly affecting host immunity and inflammation. Image analyses of infected equine respiratory explants showed that despite replicating at higher levels and spreading over larger areas of the respiratory epithelium, EIV/2003 induced milder lesions compared to EIV/63, suggesting that adaptation led to reduced tissue pathogenicity. Our results reveal previously unknown links between virus genotype and the host response to infection, providing new insights on the relationship between virus evolution and fitness., Author summary As viruses are obligate intracellular pathogens, their ability to replicate and spread within their hosts is key for survival, even if it leads to severe disease or death of the host. Understanding the consequences of long-term virus adaptation after viral emergence is key for pandemic preparedness. H3N8 equine influenza virus (EIV) originated in birds and has circulated in horses since 1963, thus providing unique opportunities to study virus adaptation. We compared the replication kinetics of two EIVs of the same lineage but with different evolutionary histories: the earliest virus (EIV/63, isolated in 1963), and EIV/2003, which was isolated after 40 years of continuous circulation in horses. Experimental infections of cell lines (MDCK and E.Derm cells) and equine respiratory explants show that EIV evolved towards enhanced replication and cell-to-cell spread; but reduced tissue damage, confirming that viral fitness is adaptive and does not necessarily result in higher virulence.

Over the past 20 years, 3 highly pathogenic human coronaviruses (HCoVs) have emerged—Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and, most recently, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)—demonstrating that coronaviruses (CoVs) pose a serious threat to human health and highlighting the importance of developing effective therapies against them. Similar to other viruses, CoVs are dependent on host factors for their survival and replication. We hypothesized that evolutionarily distinct CoVs may exploit similar host factors and pathways to support their replication cycles. Herein, we conducted 2 independent genome-wide CRISPR/Cas-9 knockout (KO) screens to identify MERS-CoV and HCoV-229E host dependency factors (HDFs) required for HCoV replication in the human Huh7 cell line. Top scoring genes were further validated and assessed in the context of MERS-CoV and HCoV-229E infection as well as SARS-CoV and SARS-CoV-2 infection. Strikingly, we found that several autophagy-related genes, including TMEM41B, MINAR1, and the immunophilin FKBP8, were common host factors required for pan-CoV replication. Importantly, inhibition of the immunophilin protein family with the compounds cyclosporine A, and the nonimmunosuppressive derivative alisporivir, resulted in dose-dependent inhibition of CoV replication in primary human nasal epithelial cell cultures, which recapitulate the natural site of virus replication. Overall, we identified host factors that are crucial for CoV replication and demonstrated that these factors constitute potential targets for therapeutic intervention by clinically approved drugs., This study identifies essential host dependency factors for human coronavirus replication, showing that these can be directly targeted by clinically approved inhibitors and that treatment leads to effective inhibition of coronavirus replication in primary human nasal epithelial cell cultures.

Ascariasis is one of the most common infections in the world and associated with significant global morbidity. Ascaris larval migration through the host’s lungs is essential for larval development but leads to an exaggerated type-2 host immune response manifesting clinically as acute allergic airway disease. However, whether Ascaris larval migration can subsequently lead to chronic lung diseases remains unknown. Here, we demonstrate that a single episode of Ascaris larval migration through the host lungs induces a chronic pulmonary syndrome of type-2 inflammatory pathology and emphysema accompanied by pulmonary hemorrhage and chronic anemia in a mouse model. Our results reveal that a single episode of Ascaris larval migration through the host lungs leads to permanent lung damage with systemic effects. Remote episodes of ascariasis may drive non-communicable lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), and chronic anemia in parasite endemic regions., Author summary Ascariasis is the most common helminth infection and leads to significant global morbidity. Transient Ascaris larval migration through the host’s lungs is essential for larval development but leads to an exaggerated type-2 host immune response. Our work demonstrates that transient Ascaris spp. larval migration through the lungs has significant long-term consequences including changes in lung structure and function as well as vascular damage causing chronic lung disease and anemia. We propose that Ascaris spp. larval migration through the host lungs is a risk factor for the development of chronic lung disease and anemia in parasite-endemic regions globally.

Epidemiologic data regarding health care acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) from Nepal are negligible. We conducted a prospective observational cohort study in the intensive care unit (ICU) of a major tertiary hospital in Nepal between April 2016 and March 2018, to calculate the incidence of VAP, and to describe clinical variables, microbiological etiology, and outcomes. Four hundred and thirty-eight patients were enrolled in the study. Demographic data, medical history, antimicrobial administration record, chest X-ray, biochemical, microbiological and haematological results, acute physiology and chronic health evaluation II score and the sequential organ failure assessment scores were recorded. Categorical variables were expressed as count and percentage and analyzed using the Fisher’s exact test. Continuous variables were expressed as median and interquartile range and analyzed using Kruskal-Wallis rank sum test and the pairwise Wilcoxon rank—sum test. 46.8% (205/438) of the patients required intubation. Pneumonia was common in both intubated (94.14%; 193/205) and non-intubated (52.36%; 122/233) patients. Pneumonia developed among intubated patients in the ICU had longer days of stay in the ICU (median of 10, IQR 5–15, P< 0.001) when compared to non-intubated patients with pneumonia (median of 4, IQR 3–6, P< 0.001). The incidence rate of VAP was 20% (41/205) and incidence density was 16.45 cases per 1,000ventilator days. Mortality was significantly higher in patients with pneumonia requiring intubation (44.6%, 86/193) than patients with pneumonia not requiring intubation (10.7%, 13/122, pKlebsiella and Acinetobacter species were the dominant organisms from both VAP and non-VAP categories. Multi-drug resistance was highly prevalent in bacterial isolates associated with VAP (90%; 99/110) and non-VAP categories (81.5%; 106/130). HAP including VAP remains to be the most prevalent hospital-acquired infections (HAIs) at Patan hospital. A local study of etiological agents and outcomes of HAP and VAP are required for setting more appropriate guidelines for management of such diseases.

α1-anti-trypsin (A1AT), encoded by SERPINA1, is a neutrophil elastase inhibitor that controls the inflammatory response in the lung. Severe A1AT deficiency increases risk for Chronic Obstructive Pulmonary Disease (COPD), however, the role of A1AT in COPD in non-deficient individuals is not well known. We identify a 2.1-fold increase (p = 2.5x10-6) in the use of a distal poly-adenylation site in primary lung tissue RNA-seq in 82 COPD cases when compared to 64 controls and replicate this in an independent study of 376 COPD and 267 controls. This alternative polyadenylation event involves two sites, a proximal and distal site, 61 and 1683 nucleotides downstream of the A1AT stop codon. To characterize this event, we measured the distal ratio in human primary tissue short read RNA-seq data and corroborated our results with long read RNA-seq data. Integrating these results with 3’ end RNA-seq and nanoluciferase reporter assay experiments we show that use of the distal site yields mRNA transcripts with over 50-fold decreased translation efficiency and A1AT expression. We identified seven RNA binding proteins using enhanced CrossLinking and ImmunoPrecipitation precipitation (eCLIP) with one or more binding sites in the SERPINA1 3’ UTR. We combined these data with measurements of the distal ratio in shRNA knockdown experiments, nuclear and cytoplasmic fractionation, and chemical RNA structure probing. We identify Quaking Homolog (QKI) as a modulator of SERPINA1 mRNA translation and confirm the role of QKI in SERPINA1 translation with luciferase reporter assays. Analysis of single-cell RNA-seq showed differences in the distribution of the SERPINA1 distal ratio among hepatocytes, macrophages, αβ-Tcells and plasma cells in the liver. Alveolar Type 1,2, dendritic cells and macrophages also vary in their distal ratio in the lung. Our work reveals a complex post-transcriptional mechanism that regulates alternative polyadenylation and A1AT expression in COPD., Author summary In certain cases, the molecular mechanism underlying a human genetic disease association occurs at the level of the RNA transcript. The SERPINA1 gene is transcribed into multiple RNA isoforms that differ in their non-coding regions and influence production of the A1AT protein, which is associated with Chronic Obstructive Pulmonary Disease (COPD). Here we report a newly discovered alternative polyadenylation event as an underlying regulatory mechanism that influences A1AT protein expression. In the SERPINA1 mRNA there are two polyadenylation sites in the 3’ untranslated region (3’UTR), resulting in a short and a long transcript. We find that the longer 3’UTR strongly represses protein production, and is expressed at a higher level in individuals with COPD, in two independent studies of lung tissue. The inhibitory mechanism in the long transcript is likely caused by an interaction with the RNA binding protein Quaking, which is also differentially expressed in individuals with COPD. This work demonstrates how post-transcriptional regulation can affect disease and also identifies a potential target in the SERPINA1 3’ UTR for RNA targeted therapeutics.

Mink, on a farm with about 15,000 animals, became infected with SARS-CoV-2. Over 75% of tested animals were positive for SARS-CoV-2 RNA in throat swabs and 100% of tested animals were seropositive. The virus responsible had a deletion of nucleotides encoding residues H69 and V70 within the spike protein gene as well as the A22920T mutation, resulting in the Y453F substitution within this protein, seen previously in mink. The infected mink recovered and after free-testing of 300 mink (a level giving 93% confidence of detecting a 1% prevalence), the animals remained seropositive. During further follow-up studies, after a period of more than 2 months without any virus detection, over 75% of tested animals again scored positive for SARS-CoV-2 RNA. Whole genome sequencing showed that the viruses circulating during this re-infection were most closely related to those identified in the first outbreak on this farm but additional sequence changes had occurred. Animals had much higher levels of anti-SARS-CoV-2 antibodies in serum samples after the second round of infection than at free-testing or during recovery from initial infection, consistent with a boosted immune response. Thus, it was concluded that following recovery from an initial infection, seropositive mink were readily re-infected by SARS-CoV-2., Author summary Early on, in the course of SARS-CoV-2 infections among mink in Denmark, we identified a farm, with about 15,000 mink, that had virus-infected animals. At this time, we found that a very high proportion of the mink had been infected and made antibodies against the virus. In contrast to the three previously infected farms, the mink were allowed to recover (the mink had shown few signs of disease and only low mortality) and our testing demonstrated the absence of circulating virus. Continued screening, in the following weeks, supported the absence of infection in the mink but the maintenance of antibodies against the virus. However, less than 3 months after the initial infection, we again identified the presence of virus in some dead mink from this farm and in many live mink. The viruses responsible for this second wave of infection were slightly different from those found in the first wave but were closer to each other than to the SARS-CoV-2s found on other mink farms. The antibody levels in mink during this second wave of infection were much higher than observed after the initial infection. We concluded that the initial round of infection in mink was insufficient to confer protection against re-infection.

Background Data to better understand and manage the COVID-19 pandemic is urgently needed. However, there are gaps in information stored within even the best routinely-collected electronic health records (EHR) including test results, remote consultations for suspected COVID-19, shielding, physical activity, mental health, and undiagnosed or untested COVID-19 patients. Observational and Pragmatic Research Institute (OPRI) Singapore and Optimum Patient Care (OPC) UK established Platform C19, a research database combining EHR data and bespoke patient questionnaire. We describe the demographics, clinical characteristics, patient behavior, and impact of the COVID-19 pandemic using data within Platform C19. Methods EHR data from Platform C19 were extracted from 14 practices across UK participating in the OPC COVID-19 Quality Improvement program on a continuous, monthly basis. Starting 7th August 2020, consenting patients aged 18–85 years were invited in waves to fill an online questionnaire. Descriptive statistics were summarized using all data available up to 22nd January 2021. Findings From 129,978 invitees, 31,033 responded. Respondents were predominantly female (59.6%), white (93.5%), and current or ex-smokers (52.6%). Testing for COVID-19 was received by 23.8% of respondents, of which 7.9% received positive results. COVID-19 symptoms lasted ≥4 weeks in 19.5% of COVID-19 positive respondents. Up to 39% respondents reported a negative impact on questions regarding their mental health. Most (67%-76%) respondents with asthma, Chronic Obstructive Pulmonary Disease (COPD), diabetes, heart, or kidney disease reported no change in the condition of their diseases. Interpretation Platform C19 will enable research on key questions relating to COVID-19 pandemic not possible using EHR data alone.

The infectivity of a virus sample is measured by the infections it causes, via a plaque or focus forming assay (PFU or FFU) or an endpoint dilution (ED) assay (TCID$_{50}$, CCID$_{50}$, EID$_{50}$, etc., hereafter collectively ID$_{50}$). The counting of plaques or foci at a given dilution intuitively and directly provides the concentration of infectious doses in the undiluted sample. However, it has many technical and experimental limitations. For example, it relies on one's judgement in distinguishing between two merged plaques and a larger one, or between small plaques and staining artifacts. In this regard, ED assays are more robust because one need only determine whether infection occurred. The output of the ED assay, the 50% infectious dose (ID$_{50}$), is calculated using either the Spearman-Karber (SK, 1908,1931) or Reed-Muench (RM, 1938) mathematical approximations. However, these are often miscalculated and their ID$_{50}$ approximation is biased. We propose that the PFU and FFU assays be abandoned, and that the measured output of the ED assay, the ID$_{50}$, be replaced by a more useful measure we coined Specific INfections (SIN). We introduce a free, open-source web-application, midSIN, that computes the SIN concentration in a virus sample from a standard ED assay, requiring no changes to current experimental protocols. We demonstrate that the SIN/mL of a sample reliably corresponds to the number of infections the sample will cause per unit volume, and directly relates to the multiplicity of infection. midSIN estimates are shown to be more accurate and robust than those using the RM and SK approximations. The impact of ED plate design choices (dilution factor, replicates per dilution) on measurement accuracy is also explored. The simplicity of SIN as a measure and the greater accuracy of midSIN make them an easy, superior replacement for the PFU, FFU, and ID$_{50}$ measures., Comment: 22 pages, 8 figures

Background We examined whether key sociodemographic and clinical risk factors for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and mortality changed over time in a population-based cohort study. Methods and findings In a cohort of 9,127,673 persons enrolled in the United States Veterans Affairs (VA) healthcare system, we evaluated the independent associations of sociodemographic and clinical characteristics with SARS-CoV-2 infection (n = 216,046), SARS-CoV-2–related mortality (n = 10,230), and case fatality at monthly intervals between February 1, 2020 and March 31, 2021. VA enrollees had a mean age of 61 years (SD 17.7) and were predominantly male (90.9%) and White (64.5%), with 14.6% of Black race and 6.3% of Hispanic ethnicity. Black (versus White) race was strongly associated with SARS-CoV-2 infection (adjusted odds ratio [AOR] 5.10, [95% CI 4.65 to 5.59], p-value, George Ioannou and co-workers study the distribution of SARS-CoV-2 infections and outcomes among the United States population., Author summary Why was this study done? As the Coronavirus Disease 2019 (COVID-19) pandemic continues to evolve, some risk factors for infection with COVID-19 and death due to COVID-19 that were described early in the pandemic may be changing. Recognizing such changes is important in informing population-based approaches to prevent infection and reduce mortality. What did the researchers do and find? We investigated how the associations of key sociodemographic and clinical factors with COVID-19 infection, mortality, or case fatality changed between February 2020 and March 2021 among a cohort of approximately 9.1 million persons enrolled in the national US Veterans Affairs (VA) healthcare system, including 216,046 who tested positive and 10,230 who died of COVID-19 during the study period. Black (versus White) race was strongly associated with a 5-fold higher risk of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, a 4-fold higher risk of mortality, and a 2.5-fold higher risk of case fatality in February to March 2020, but these associations attenuated over time and were no longer statistically significant by November 2020 for infection and mortality and were reversed for case fatality. American Indian/Alaska Native (AI/AN versus White) race was associated with SARS-CoV-2 infection early in the pandemic, but this association declined over time and reversed by March 2021. Urban (versus rural) residence was associated with 2-fold higher risk of infection, a 2.5-fold higher risk of mortality, and 2.2-fold higher risk of case fatality in February to April 2020, but these associations attenuated over time and reversed by September 2020. Throughout the observation period, high comorbidity burden, younger age, Hispanic ethnicity, and obesity were consistently associated with infection, while high comorbidity burden, older age, Hispanic ethnicity, and male sex were consistently associated with mortality. What do these findings mean? Early in the pandemic, there were strongly positive associations of Black and AI/AN (versus White) race and urban (versus rural) residence with SARS-CoV-2 infection, mortality, and case fatality, but these were ameliorated or even reversed by March 2021. Our results apply directly to VA enrollees who are predominantly male and have access to universal healthcare; they need to be confirmed in other populations.

Respiratory viruses present major public health challenges, as evidenced by the 1918 Spanish Flu, the 1957 H2N2, 1968 H3N2, and 2009 H1N1 influenza pandemics, and the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Severe RNA virus respiratory infections often correlate with high viral load and excessive inflammation. Understanding the dynamics of the innate immune response and its manifestations at the cell and tissue levels is vital to understanding the mechanisms of immunopathology and to developing strain-independent treatments. Here, we present a novel spatialized multicellular computational model of RNA virus infection and the type-I interferon-mediated antiviral response that it induces within lung epithelial cells. The model is built using the CompuCell3D multicellular simulation environment and is parameterized using data from influenza virus-infected cell cultures. Consistent with experimental observations, it exhibits either linear radial growth of viral plaques or arrested plaque growth depending on the local concentration of type I interferons. The model suggests that modifying the activity of signaling molecules in the JAK/STAT pathway or altering the ratio of the diffusion lengths of interferon and virus in the cell culture could lead to plaque growth arrest. The dependence of plaque growth arrest on diffusion lengths highlights the importance of developing validated spatial models of cytokine signaling and the need for in vitro measurement of these diffusion coefficients. Sensitivity analyses under conditions leading to continuous or arrested plaque growth found that plaque growth is more sensitive to variations of most parameters and more likely to have identifiable model parameters when conditions lead to plaque arrest. This result suggests that cytokine assay measurements may be most informative under conditions leading to arrested plaque growth. The model is easy to extend to include SARS-CoV-2-specific mechanisms or to use as a component in models linking epithelial cell signaling to systemic immune models., Author summary Respiratory lung infections form lesions in the lungs, whose number and size correlate with the severity of illness. In some severe cases, respiratory disease triggers a severe inflammatory condition known as a cytokine storm. In order to link molecular signaling at the site of infection to its impact on the overall interferon response and the occurrence of severe inflammation, we created a computational model of the early stages of infection that simulates lung cells infected with RNA viruses, such as those responsible for COVID-19 and flu, to help explore how the disease forms viral plaques, an in vitro analog to lesion growth in the lung. Consistent with experimental observations, our model suggests that the treatment of cells with type-I interferons, which are currently being evaluated for the treatment of COVID-19, may have a protective effect. We found that enhancing certain aspects of the inflammatory response, such as the JAK/STAT pathway, may be able to arrest viral plaque growth, suggesting molecules involved in this pathway as possible drug candidates. Analysis of the model also shows that to better estimate the parameter values needed to model interferon signaling and viral replication, experiments should be performed under conditions that inhibit viral growth, e.g., by pretreating cells with interferon. We present a computational framework built using the CompuCell3D multicellular simulation environment that lays the groundwork for constructing larger models of respiratory-infection-induced immune responses and that can inform experiments to improve our fundamental understanding of the mechanisms regulating the immune response.

BackgroundAdequate testing is critically important for control of the SARS-CoV-2 pandemic. Antibody testing is an option for case management and epidemiologic studies, with high specificity and variable sensitivity. However, characteristics of local populations may affect performance of these tests. For this reason, the National Institute of Health (INS) and regulatory agencies in Colombia require verification of diagnostic accuracy of tests introduced to the Colombian market.MethodsWe conducted a validation study of the Abbott SARS-CoV-2 test for qualitative detection of IgG using the Abbott Architect i2000SR. Participants and retrospective samples were included from patients with suspected SARS-CoV-2 infection, age ≥18 years, and ≥8 days elapsed since initiation of symptoms. Pre-pandemic plasma samples (taken before October 2019) were used as controls. We estimated the sensitivity, specificity and agreement (kappa) of the Abbott IgG test compared to the gold standard (RT-PCR).ResultsThe overall sensitivity was 83.1% (95% CI: 75.4–100). Sensitivity among patients with ≥14 days since the start of symptoms was 85.7%, reaching 88% in samples collected from patients with COVID-19 symptoms onset >60 days. Specificity was 100% and the kappa index of agreement was 0.804 (95% CI: 0.642–0.965).ConclusionsOur findings show high sensitivity and specificity of the Abbott IgG test in a Colombian population, which meet the criteria set by the Colombian INS to aid in the diagnosis of COVID-19. Data from our patient groups also suggest that IgG response is detectable in a high proportion of individuals (88.1%) during the first two months following onset of symptoms.

The Coronavirus Disease 2019 (COVID-19) is caused by the betacoronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus that can mediate asymptomatic or fatal infections characterized by pneumonia, acute respiratory distress syndrome (ARDS), and multi-organ failure. Several studies have highlighted the importance of B and T lymphocytes, given that neutralizing antibodies and T cell responses are required for an effective immunity. In addition, other reports have described myeloid cells such as macrophages and monocytes play a major role in the immunity against SARS-CoV-2 as well as dysregulated pro-inflammatory signature that characterizes severe COVID-19. During COVID-19, neutrophils have been defined as a heterogeneous group of cells, functionally linked to severe inflammation and thrombosis triggered by degranulation and NETosis, but also to suppressive phenotypes. The physiological role of suppressive neutrophils during COVID-19 and their implications in severe disease have been poorly studied and is not well understood. Here, we discuss the current evidence regarding the role of neutrophils with suppressive properties such as granulocytic myeloid-derived suppressor cells (G-MDSCs) and their possible role in suppressing CD4+ and CD8+ T lymphocytes expansion and giving rise to lymphopenia in severe COVID-19 infection.

Human parainfluenza viruses (HPIVs) are a leading cause of acute respiratory infection hospitalization in children, yet little is known about how dose, strain, tissue tropism, and individual heterogeneity affects the processes driving growth and clearance kinetics. Longitudinal measurements are possible by using reporter Sendai viruses, the murine counterpart of HPIV 1, that express luciferase, where the insertion location yields a wild-type (rSeV-luc(M-F*)) or attenuated (rSeV-luc(P-M)) phenotype. Bioluminescence from individual animals suggests that there is a rapid increase in expression followed by a peak, biphasic clearance, and resolution. However, these kinetics vary between individuals and with dose, strain, and whether the infection was initiated in the upper and/or lower respiratory tract. To quantify the differences, we translated the bioluminescence measurements from the nasopharynx, trachea, and lung into viral loads and used a mathematical model together a nonlinear mixed effects approach to define the mechanisms distinguishing each scenario. The results confirmed a higher rate of virus production with the rSeV-luc(M-F*) virus compared to its attenuated counterpart, and suggested that low doses result in disproportionately fewer infected cells. The analyses indicated faster infectivity and infected cell clearance rates in the lung and that higher viral doses, and concomitantly higher infected cell numbers, resulted in more rapid clearance. This parameter was also highly variable amongst individuals, which was particularly evident during infection in the lung. These critical differences provide important insight into distinct HPIV dynamics, and show how bioluminescence data can be combined with quantitative analyses to dissect host-, virus-, and dose-dependent effects., Author summary Human parainfluenza viruses (HPIVs) cause acute respiratory infections and can lead to the hospitalization of children. HPIV infection severity may vary due to dose, strain, patient, and whether the infection initiates within the upper or lower respiratory tract. There is a need to determine how the rates of virus spread and clearance change in different infection scenarios in order to better understand varying clinical manifestations. The significance of our research is in identifying the dominant mechanisms driving strain-, dose-, and tissue-specific HPIV infection kinetics, and in pairing bioluminescence data with quantitative analyses to determine how the same virus can yield patient-specific outcomes. This work enhances our understanding of HPIV infection and broadens our knowledge viral dynamics in the upper and lower respiratory tracts.

Background There is limited empiric evidence on the coverage of pneumococcal conjugate vaccines (PCVs) required to generate substantial indirect protection. We investigate the association between population PCV coverage and indirect protection against invasive pneumococcal disease (IPD) and pneumonia hospitalisations among undervaccinated Australian children. Methods and findings Birth and vaccination records, IPD notifications, and hospitalisations were individually linked for children aged, In an observational study, Jocelyn Chan and colleagues investigate associations between pneumococcal conjugate vaccine coverage and incidence of invasive pneumococcal disease and pneumonia among children under 5 years in Australia., Author summary Why was this study done? Pneumococcal conjugate vaccines (PCVs) reduce the burden of pneumococcal disease in vaccinated and unvaccinated populations through both direct and indirect (herd) effects. The indirect effects of a vaccine comprise a substantial component of overall vaccine impact, contributing to the cost-effectiveness of the vaccine, but little is known about what factors contribute to herd protection, including vaccination coverage. In this study, we examined associations between PCV coverage and indirect effects within diverse populations in Australia. What did the researchers do and find? Using a large dataset of 1.3 million children from 2 states in Australia, we quantified the relationship between PCV coverage within small geographical units and indirect protection against pneumococcal disease. We also performed similar analyses for infants too young to be fully vaccinated, urban, rural, and Indigenous populations. There were strong inverse relationships between PCV coverage and the incidence of severe invasive disease due to vaccine types and pneumonia hospitalisations among undervaccinated children, i.e., higher coverage was associated with greater reductions in disease due to indirect effects. We also found substantial indirect effects at relatively low levels of PCV coverage. We estimated that 50% and 90% coverage of 7-valent PCV (PCV7) among children under 5 years of age prevented almost three-quarters (72.5%, 95% confidence interval [CI] 51.6 to 84.4) and almost all (95.2%, 95% CI 89.4 to 97.8) of PCV7-type severe invasive disease, respectively. For pneumonia, we estimated that 50% and 90% coverage was sufficient to prevent one-third (33.3%, 95% CI 27.3 to 38.8) and about half (51.7%, 95% CI 43.7 to 58.6) of all-cause pneumonia hospitalisations among undervaccinated children. These trends were similar for children less than 4 months old, urban, rural, and Indigenous populations, although these effects were smaller for rural and Indigenous populations. There was also a trend towards decreasing incidence of PCV13-type IPD among undervaccinated children as PCV13 coverage increased. What do these findings mean? Our results challenge existing assumptions that high PCV coverage is required to achieve substantial indirect protection. Understanding the determinants of indirect effects are particularly urgent as countries that have controlled vaccine-type pneumococcal disease consider using reducing the number of PCV doses (from 3 to 2). Reduced dose schedules have the potential to significantly lower program costs while maintaining vaccine impact, providing indirect protection is achieved and preserved.

Background Individuals infected with SARS-CoV-2 develop neutralising antibodies. We investigated the proportion of individuals with SARS-CoV-2 neutralising antibodies after infection and how this proportion varies with selected covariates. Methodology/Principal findings This systematic review and meta-analysis examined the proportion of individuals with SARS-CoV-2 neutralising antibodies after infection and how these proportions vary with selected covariates. Three models using the maximum likelihood method assessed these proportions by study group, covariates and individually extracted data (protocol CRD42020208913). A total of 983 reports were identified and 27 were included. The pooled (95%CI) proportion of individuals with neutralising antibodies was 85.3% (83.5–86.9) using the titre cut off >1:20 and 83.9% (82.2–85.6), 70.2% (68.1–72.5) and 54.2% (52.0–56.5) with titres >1:40, >1:80 and >1:160, respectively. These proportions were higher among patients with severe COVID-19 (e.g., titres >1:80, 84.8% [80.0–89.2], >1:160, 74.4% [67.5–79.7]) than those with mild presentation (56.7% [49.9–62.9] and 44.1% [37.3–50.6], respectively) and lowest among asymptomatic infections (28.6% [17.9–39.2] and 10.0% [3.7–20.1], respectively). IgG and neutralising antibody levels correlated poorly. Conclusions/Significance 85% of individuals with proven SARS-CoV-2 infection had detectable neutralising antibodies. This proportion varied with disease severity, study setting, time since infection and the method used to measure antibodies., Author summary Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) elicits adaptive immunological responses, including immunoglobulins A, M, and G and neutralising antibodies. Neutralising antibodies are considered markers of functional immunity and protection. However, not all individuals with proven infections have detectable neutralising antibodies. In this systematic review, we investigated the proportion of individuals with former SARS-CoV-2 infections who develop neutralising antibodies, whether their titres vary with disease severity, and their correlation with Immunoglobulin G. We found that approximately 85% of individuals with SARS-CoV-2 infection have detectable neutralising antibodies. This proportion was higher among patients with severe Coronavirus Disease 19 and lower in asymptomatic infections. The variation across studies reflected the wide range of methods used to measure both immunoglobulins and neutralising antibodies, and highlight the need for an international reference standard to measure SARS-CoV-2 antibodies.

Coronavirus Disease 2019 (COVID-19), caused by a new strain of coronavirus called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), was declared a pandemic by WHO on March 11, 2020. Soon after its emergence in late December 2019, it was noticed that diabetic individuals were at an increased risk of COVID-19–associated complications, ICU admissions, and mortality. Maintaining proper blood glucose levels using insulin and/or other oral antidiabetic drugs (such as Metformin) reduced the detrimental effects of COVID-19. Interestingly, in diabetic COVID-19 patients, while insulin administration was associated with adverse outcomes, Metformin treatment was correlated with a significant reduction in disease severity and mortality rates among affected individuals. Metformin was extensively studied for its antioxidant, anti-inflammatory, immunomodulatory, and antiviral capabilities that would explain its ability to confer cardiopulmonary and vascular protection in COVID-19. Here, we describe the various possible molecular mechanisms that contribute to Metformin therapy’s beneficial effects and lay out the scientific basis of repurposing Metformin for use in COVID-19 patients.

Background There is a paucity of information about cardiovascular outcomes related to exercise habit change after a new diagnosis of atrial fibrillation (AF). We investigated the association between exercise habits after a new AF diagnosis and ischemic stroke, heart failure (HF), and all-cause death. Methods and findings This is a nationwide population-based cohort study using data from the Korea National Health Insurance Service. A retrospective analysis was performed for 66,692 patients with newly diagnosed AF between 2010 and 2016 who underwent 2 serial health examinations within 2 years before and after their AF diagnosis. Individuals were divided into 4 categories according to performance of regular exercise, which was investigated by a self-reported questionnaire in each health examination, before and after their AF diagnosis: persistent non-exercisers (30.5%), new exercisers (17.8%), exercise dropouts (17.4%), and exercise maintainers (34.2%). The primary outcomes were incidence of ischemic stroke, HF, and all-cause death. Differences in baseline characteristics among groups were balanced considering demographics, comorbidities, medications, lifestyle behaviors, and income status. The risks of the outcomes were computed by weighted Cox proportional hazards models with inverse probability of treatment weighting (IPTW) during a mean follow-up of 3.4 ± 2.0 years. The new exerciser and exercise maintainer groups were associated with a lower risk of HF compared to the persistent non-exerciser group: the hazard ratios (HRs) (95% CIs) were 0.95 (0.90–0.99) and 0.92 (0.88–0.96), respectively (p < 0.001). Also, performing exercise any time before or after AF diagnosis was associated with a lower risk of mortality compared to persistent non-exercising: the HR (95% CI) was 0.82 (0.73–0.91) for new exercisers, 0.83 (0.74–0.93) for exercise dropouts, and 0.61 (0.55–0.67) for exercise maintainers (p < 0.001). For ischemic stroke, the estimates of HRs were 10%–14% lower in patients of the exercise groups, yet differences were statistically insignificant (p = 0.057). Energy expenditure of 1,000–1,499 MET-min/wk (regular moderate exercise 170–240 min/wk) was consistently associated with a lower risk of each outcome based on a subgroup analysis of the new exerciser group. Study limitations include recall bias introduced due to the nature of the self-reported questionnaire and restricted external generalizability to other ethnic groups. Conclusions Initiating or continuing regular exercise after AF diagnosis was associated with lower risks of HF and mortality. The promotion of exercise might reduce the future risk of adverse outcomes in patients with AF., Using a population-based cohort study, Dr. Choi and colleagues studied patients with atrial fibrillation to determine whether their exercise habits were associated with occurrence of ischemic stroke, heart failure, and all-cause mortality., Author summary Why was this study done? Atrial fibrillation (AF) is associated with an increased risk of stroke, heart failure, and death. As AF and its related healthcare burden are expected to surge, integrated management of AF is advocated as part of holistic care. Exercise has been established to benefit AF-related outcomes, including symptoms, incidence, recurrence, burden, and quality of life. However, there are no current data providing the association between exercise and cardiovascular morbidities in patients with AF. What did the researchers do and find? We performed a retrospective analysis of 66,692 patients with newly diagnosed AF who underwent 2 serial health examinations before and after their AF diagnosis from 2010 to 2016 using data from the Korea National Health Insurance Service. Individuals self-reported exercise status by a questionnaire included in each health examination and were categorized into 4 groups according to their change of exercise status from before to after their AF diagnosis. We investigated and compared the incidences of ischemic stroke, heart failure, and all-cause death across the groups. Initiating or continuing regular exercise after a diagnosis of AF was associated with a 5%–8% lower risk of HF and 17%–39% lower risk of mortality than being a persistent non-exerciser. For ischemic stroke, the estimated hazard ratios were 10%–14% lower in patients in the exercise group, yet statistical significance was undetermined. What do these findings mean? We suggest the potential benefits of exercise as a lifestyle intervention for cardiovascular outcomes in AF patients by demonstrating the association. The promotion of exercise might reduce the future risk of adverse outcomes in patients with AF.

Pseudomonas aeruginosa (PA) is an opportunistic pathogen that causes diverse human infections including chronic airway infection in patients with cystic fibrosis (CF). Comparing the genomes of CF and non-CF PA isolates has great potential to identify the genetic basis of pathogenicity. To gain a deeper understanding of PA adaptation in CF airways, we performed a genome-wide association study (GWAS) on 1,001 PA genomes. Genetic variations identified among CF isolates were categorized into (i) alterations in protein-coding regions, either large- or small-scale, and (ii) polymorphic variation in intergenic regions. We introduced each CF-associated genetic alteration into the genome of PAO1, a prototype PA strain, and validated the outcomes experimentally. Loci readily mutated among CF isolates included genes encoding a probable sulfatase, a probable TonB-dependent receptor (PA2332~PA2336), L-cystine transporter (YecS, PA0313), and a probable transcriptional regulator (PA5438). A promoter region of a heme/hemoglobin uptake outer membrane receptor (PhuR, PA4710) was also different between the CF and non-CF isolate groups. Our analysis highlights ways in which the PA genome evolves to survive and persist within the context of chronic CF infection., Author summary Understanding how human pathogens, such as Pseudomonas aeruginosa (PA), adapt to the host environment during prolonged infections can provide important information for the treatment of disease. In this study, we compared the genome sequences of PA isolates from cystic fibrosis (CF) and non-CF patients and identified genetic variation that was significantly associated with CF disease. CF-associated genetic variations included: (i) the deletion of three amino acids in a transcriptional regulator (PA5438), which leads to decreased antibiotic susceptibility, enhanced virulence expression and sustained biofilm production in the presence of transferrin, and (ii) the insertion of three amino acids in a cystine transporter (PA0313), which results in decreased pyochelin production. Furthermore, single nucleotide replacement in a promoter was identified and shown to upregulate the cellular process for iron acquisition. Our bioinformatics analyses, linked with experimental validation via genetic manipulation and phenotypic investigation of mutants, provides novel insights into the genomic plasticity of PA during chronic CF infection.

Baloxavir is approved in several countries for the treatment of uncomplicated influenza in otherwise-healthy and high-risk patients. Treatment-emergent viruses with reduced susceptibility to baloxavir have been detected in clinical trials, but the likelihood of widespread occurrence depends on replication capacity and onward transmission. We evaluated the fitness of A/H3N2 and A/H1N1pdm09 viruses with the polymerase acidic (PA) I38T-variant conferring reduced susceptibility to baloxavir relative to wild-type (WT) viruses, using a competitive mixture ferret model, recombinant viruses and patient-derived virus isolates. The A/H3N2 PA/I38T virus showed a reduction in within-host fitness but comparable between-host fitness to the WT virus, while the A/H1N1pdm09 PA/I38T virus had broadly similar within-host fitness but substantially lower between-host fitness. Although PA/I38T viruses replicate and transmit between ferrets, our data suggest that viruses with this amino acid substitution have lower fitness relative to WT and this relative fitness cost was greater in A/H1N1pdm09 viruses than in A/H3N2 viruses., Author summary Influenza viruses are associated with considerable disease burden and circulate annually causing seasonal epidemics. Antiviral drugs can be used to treat influenza infections and help reduce the disease burden. Occasionally, treatment can lead to the emergence of viruses with reduced antiviral susceptibility. Normally such viruses have reduced ‘fitness’, meaning they do not tend to spread or transmit widely, however on rare occasions, oseltamivir-resistant variants have become widespread in the community, thereby reducing the utility of the drug for treatment. Baloxavir is an antiviral recently licensed in many parts of the world for the treatment of influenza. Viruses with reduced susceptibility to baloxavir have been observed in clinical trials, but the frequency of such variants in the community has remained low (

Coronavirus disease-19 (COVID-19) emerged in late 2019 in China and rapidly became pandemic. As with other coronaviruses, a preponderance of evidence suggests the virus originated in horseshoe bats (Rhinolophus spp.) and may have infected an intermediate host prior to spillover into humans. A significant concern is that SARS-CoV-2 could become established in secondary reservoir hosts outside of Asia. To assess this potential, we challenged deer mice (Peromyscus maniculatus) with SARS-CoV-2 and found robust virus replication in the upper respiratory tract, lungs and intestines, with detectable viral RNA for up to 21 days in oral swabs and 6 days in lungs. Virus entry into the brain also occurred, likely via gustatory-olfactory-trigeminal pathway with eventual compromise to the blood-brain barrier. Despite this, no conspicuous signs of disease were observed, and no deer mice succumbed to infection. Expression of several innate immune response genes were elevated in the lungs, including IFNα, IFNβ, Cxcl10, Oas2, Tbk1 and Pycard. Elevated CD4 and CD8β expression in the lungs was concomitant with Tbx21, IFNγ and IL-21 expression, suggesting a type I inflammatory immune response. Contact transmission occurred from infected to naive deer mice through two passages, showing sustained natural transmission and localization into the olfactory bulb, recapitulating human neuropathology. In the second deer mouse passage, an insertion of 4 amino acids occurred to fixation in the N-terminal domain of the spike protein that is predicted to form a solvent-accessible loop. Subsequent examination of the source virus from BEI Resources determined the mutation was present at very low levels, demonstrating potent purifying selection for the insert during in vivo passage. Collectively, this work has determined that deer mice are a suitable animal model for the study of SARS-CoV-2 respiratory disease and neuropathogenesis, and that they have the potential to serve as secondary reservoir hosts in North America., Author summary A significant concern is that SARS-CoV-2 could establish in natural wildlife populations that could lead to transmission events to humans. We have determined that deer mice are susceptible to SARS-CoV-2 and that virus can persist for up to 21 days. Moreover, efficient transmission to other deer mice occurred, suggesting the potential for sustained persistence in natural populations of deer mice. The pathology observed in the respiratory tract resembles that which occurs in human COVID-19 patients, including robust inflammation and infiltration of neutrophils and macrophages, and neurological manifestations in the olfactory bulb and tongue that could impact senses of smell and taste, respectively. Collectively, the work suggests deer mice could serve as secondary reservoir hosts of SARS-CoV-2 and as an animal model for COVID-19 disease studies.

We assessed zoonotic tuberculosis (zTB) knowledge and prevention and control practices of 404 cattle handlers via a survey in three dairy-intensive districts of Bangladesh. Most respondents were aged 30–49 (52%) and male (95%). Almost all (99%) recognized the important public health burden of tuberculosis in Bangladesh, however, most (58%) had inadequate knowledge about zTB transmission to humans. Inappropriate practices such as: not using protective equipment (98%); smoking, drinking or eating food whilst working with cattle (69%); and sharing the same premises with animals (83%) were identified. Cattle handlers educated at secondary or higher levels were 2.82- (95% CI: 1.59–5.10) and 5.15 times (95% CI: 1.74–15.20) more likely to have adequate knowledge of control and prevention activities compared to those with no formal education. Those who had reared animals for 1–5 years were 2.67 times (95% CI: 1.44–4.91) more likely to have adequate knowledge, compared to those who reared animals for >15 years. Cattle handlers with a monthly incomes of 10,000–20,000 taka were significantly (Odds Ratio = 0.36, 95% CI: 0.14–0.92) less likely to have adequate knowledge compared to those with monthly incomes 15 years. Overall, education, duration of cattle rearing and monthly income predicted zTB knowledge and practices. There is an urgent need to educate those at high-risk of zTB transmission on issues including the handling of infected animals, and general hygiene. A One Health approach, to support the Sustainable Development Goals and the End TB strategy, appears to be the way forward., Author summary Zoonotic tuberculosis (zTB) is a form of tuberculosis derived mainly from cattle (bovine tuberculosis, bTB) via direct or indirect contact (inhalation), and/or consumption of contaminated animal products or water (ingestion). We evaluated the zTB knowledge and practices among cattle handlers in selected districts of Bangladesh via a questionnaire. It was observed that handlers are moderately aware of tuberculosis as an important public health burden in Bangladesh. However, they have inadequate knowledge on the transmission of zTB from humans and animals. Most of the cattle handlers do not use personal protective equipment. Cattle handlers often smoke, drink or eat whilst working with cattle and some even share the same premise with animals. Education, duration of cattle rearing and cattle handlers’ monthly income significantly influenced cattle handlers’ zTB knowledge and practices. Based on results of this study we recommend implementation of a One Health platform in order to enable health education programs targeting at risk farmers.