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Key Clinical Message Acute Coxiella burnetti (Q fever) infection is known to activate the autoimmune inflammatory response. We report a rare case of glomerulonephritis associated with the Coxiella infection. An elderly male first presented with recurrent fevers of unknown origin and was subsequently diagnosed with Q fever infection and treated with doxycycline. He represented 2 months later with an acute kidney injury and active urinary sediment. Renal biopsy demonstrated a mesangiopathic pattern with staining for both C1q and IgM, raising possibilities of infection‐related glomerulonephritis, C1q nephropathy and lupus nephritis. This case demonstrates glomerulonephritis as a complication of Q fever infection and the differential diagnosis and workup up that needs to be considered in cases of chronic Q fever.

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (

BackgroundDiagnostic errors are an underappreciated cause of preventable mortality in hospitals and pose a risk for severe patient harm and increase hospital length of stay. ObjectiveThis study aims to explore the potential of machine learning and natural language processing techniques in improving diagnostic safety surveillance. We conducted a rigorous evaluation of the feasibility and potential to use electronic health records clinical notes and existing case review data. MethodsSafety Learning System case review data from 1 large health system composed of 10 hospitals in the mid-Atlantic region of the United States from February 2016 to September 2021 were analyzed. The case review outcome included opportunities for improvement including diagnostic opportunities for improvement. To supplement case review data, electronic health record clinical notes were extracted and analyzed. A simple logistic regression model along with 3 forms of logistic regression models (ie, Least Absolute Shrinkage and Selection Operator, Ridge, and Elastic Net) with regularization functions was trained on this data to compare classification performances in classifying patients who experienced diagnostic errors during hospitalization. Further, statistical tests were conducted to find significant differences between female and male patients who experienced diagnostic errors. ResultsIn total, 126 (7.4%) patients (of 1704) had been identified by case reviewers as having experienced at least 1 diagnostic error. Patients who had experienced diagnostic error were grouped by sex: 59 (7.1%) of the 830 women and 67 (7.7%) of the 874 men. Among the patients who experienced a diagnostic error, female patients were older (median 72, IQR 66-80 vs median 67, IQR 57-76; P=.02), had higher rates of being admitted through general or internal medicine (69.5% vs 47.8%; P=.01), lower rates of cardiovascular-related admitted diagnosis (11.9% vs 28.4%; P=.02), and lower rates of being admitted through neurology department (2.3% vs 13.4%; P=.04). The Ridge model achieved the highest area under the receiver operating characteristic curve (0.885), specificity (0.797), positive predictive value (PPV; 0.24), and F1-score (0.369) in classifying patients who were at higher risk of diagnostic errors among hospitalized patients. ConclusionsOur findings demonstrate that natural language processing can be a potential solution to more effectively identifying and selecting potential diagnostic error cases for review and therefore reducing the case review burden.

The Omicron strains of SARS-CoV-2 pose a significant challenge to the development of effective antibody-based treatments as immune evasion has compromised most available immune therapeutics. Therefore, in the ‘arms race’ with the virus, there is a continuing need to identify new biologics for the prevention or treatment of SARS-CoV-2 infections. Here, we report the isolation of nanobodies that bind to the Omicron BA.1 spike protein by screening nanobody phage display libraries previously generated from llamas immunized with either the Wuhan or Beta spike proteins. The structure and binding properties of three of these nanobodies (A8, H6 and B5-5) have been characterized in detail providing insight into their binding epitopes on the Omicron spike protein. Trimeric versions of H6 and B5-5 neutralized the SARS-CoV-2 variant of concern BA.5 both in vitro and in the hamster model of COVID-19 following nasal administration. Thus, either alone or in combination could serve as starting points for the development of new anti-viral immunotherapeutics.

BackgroundThe incidence of stroke in children is low, and pediatric stroke rehabilitation services are less developed than adult ones. Survivors of pediatric stroke have a long poststroke life expectancy and therefore have the potential to experience impairments from their stroke for many years. However, there are relatively few studies characterizing these impairments and what factors facilitate or counteract recovery. ObjectiveThis study aims to characterize the main barriers to and facilitators of recovery from pediatric stroke. A secondary aim was to explore whether these factors last into adulthood, whether they change, or if new factors impacting recovery emerge in adulthood. MethodsWe performed a qualitative thematic analysis based on posts from a population of participants from a UK-based online stroke community, active between 2004 and 2011. The analysis focused on users who talked about their experiences with pediatric stroke, as identified by a previous study. The posts were read by 3 authors, and factors influencing recovery from pediatric stroke were mapped into 4 areas: medical, physical, emotional, and social. Factors influencing recovery were divided into short-term and long-term factors. ResultsThere were 425 posts relating to 52 survivors of pediatric stroke. Some survivors of stroke posted for themselves, while others were talked about by a third party (mostly parents; 31/35, 89% mothers). In total, 79% (41/52) of survivors of stroke were aged ≤18 years and 21% (11/52) were aged >18 years at the time of posting. Medical factors included comorbidities as a barrier to recovery. Medical interventions, such as speech and language therapy and physiotherapy, were also deemed useful. Exercise, particularly swimming, was deemed a facilitator. Among physical factors, fatigue and chronic pain could persist decades after a stroke, with both reported as a barrier to feeling fully recovered. Tiredness could worsen existing stroke-related impairments. Other long-standing impairments were memory loss, confusion, and dizziness. Among emotional factors, fear and uncertainty were short-term barriers, while positivity was a major facilitator in both short- and long-term recovery. Anxiety, grief, and behavioral problems hindered recovery. The social barriers were loneliness, exclusion, and hidden disabilities not being acknowledged by third parties. A good support network and third-party support facilitated recovery. Educational services were important in reintegrating survivors into society. Participants reported that worrying about losing financial support, such as disability allowances, and difficulties in obtaining travel insurance and driving licenses impacted recovery. ConclusionsThe lived experience of survivors of pediatric stroke includes long-term hidden disabilities and barriers to rehabilitation. These are present in different settings, such as health care, schools, workplaces, and driving centers. Greater awareness of these issues by relevant professional groups may help ameliorate them.

Abstract Background Understanding perceptions of telehealth implementation from patients and providers can improve the utility and sustainability of these programs, particularly in under-resourced rural settings. The purpose of this study was to evaluate both patient and provider perceptions of telehealth visits in a large rural healthcare system during the COVID-19 pandemic. To promote sustainability of telehealth approaches, we also assessed whether the percentage of missed appointments differed between in-person and telehealth visits. Methods Using anonymous surveys, we evaluated patient preferences and satisfaction with telehealth visits from November 2020 -March 2021 and assessed perceptions of telehealth efficiency and value among rural providers from September–October 2020. We examined whether telehealth perceptions differed according to patients’ age, educational attainment, insurance status, and distance to clinical site and providers’ age and length of time practicing medicine using ANOVA test. We also examined whether the percentage of missed appointments differed between in-person and telehealth visits at a family practice clinic within the rural healthcare system from April to September 2020 using a Chi-square test. Results Over 73% of rural patients had favorable perceptions of telehealth visits, and satisfaction was generally higher among younger patients. Patients reported difficulty with scheduling follow-up appointments, lack of personal contact and technology challenges as common barriers. Over 80% of the 219 providers responding to the survey reported that telehealth added value to their practice, while 36.6% agreed that telehealth visits are more efficient than in-person visits. Perception of telehealth value and efficiency did not differ by provider age (p = 0.67 and p = 0.67, respectively) or time in practice (p = 0.53 and p = 0.44, respectively). Technology challenges for the patient (91.3%) and provider (45.1%) were commonly reported. The percentage of missed appointments was slightly higher for telehealth visits compared to in-person visits, but the difference was not statistically significant (8.7% vs. 8.0%; p = 0.39). Conclusions Telehealth perceptions were generally favorable among rural patients and providers, although satisfaction was lower among older patients and providers. Our findings suggest that telehealth approaches may add value and efficiency to rural clinical practice. However, technology issues for both patients and providers and gaps in care coordination need to be addressed to promote sustainability of telehealth approaches in rural practice.

A novel treatment method, consisting of pea-gravel with a marine coating supplemented with alkyldimethylbenzylammonium chloride (ADBAC or benzalkonium chloride), has been examined for its antimicrobial performance and coating stability in aqueous environments. Initial column studies examining the porous media's ability to reduce bacterial loads in heating, ventilation, and air conditioning (HVAC) water found average reductions of 94% from pre-flush levels (106 colony forming unit (CFU)/mL) when assessed with R2A spread plates and 83% reductions with SimPlates. There was no observed statistical difference between the average of pre- and post-flush waters from four tests of the media without ADBAC. Taxonomic identification, by 16S rRNA gene sequencing, of colonies drawn from pre- and post-ABDAC R2A plates showed similarities with taxa observed in high frequency from prior cultivation-independent surveys of other cooling tower systems. With this proof of concept, two versions of the media were evaluated for potential coating components released during aqueous exposure. Neither released measurable volatile organic compounds (VOC) components, but one did release bisphenol A and ABDAC compounds. Subsequent column tests of the more durable coating were conducted using cultures of interest in industrial water and demonstrated significant reductions in neutralized post-column Enterococcus faecalis samples and near complete loss of Legionella pneumophila in non-neutralized fluids, but lower reductions in Pseudomonas aeruginosa. HIGHLIGHTS Development of antimicrobial treatment based on benzalkonium chloride-amended marine-coated porous media.; Minimal release of ABDAC and coating chemical components from media.; Demonstrated performance in broad reduction bacterial levels in HVAC waters.; Significant reductions in targeted bacteria including Legionella pneumophila.; Greater reduction in bacteria non-neutralized solutions.;

Ultrafine particles (UFPs) are respirable particles with a diameter less than 100 nm, which some studies have associated with adverse effects upon health. UFPs are currently not regulated as the health evidence is insufficient and very few observational data are available in most cities. The 2021 WHO Global Air Quality Guidelines highlighted the pressing issue of UFPs and provided a good practice statement for UFPs, which recommends that more measurement and modelling studies are implemented in future. Particle number concentrations (PNC) are the most common metric for UFPs as this fraction normally dominates the total ambient PNC in urban environments. This study simulates the dispersion of particle number concentrations in the West Midlands (a metropolitan area), UK using the local scale ADMS-Urban model, which is an advanced quasi-Gaussian plume dispersion modelling system. ADMS-Urban implements a physics-based approach to represent the characteristics of the atmospheric boundary layer and has been widely used in the dispersion modelling of air pollutants. It can represent a variety of source types (such as road and grid emissions) occurring in urban environments and requires a range of input data. Particle number was used as a passive scalar, with no inclusion of aerosol microphysics within the model, as a first implementation in the ADMS-Urban model for the West Midlands, UK. Evaluation was conducted by comparing the modelled (from a receptor run) and measured data at the Birmingham Air Quality Supersite. Overall, the model performed well although there was a slight underestimation for PNC. Based on the modelling output from a contour run, PNC maps at a variety of spatial scales (i.e. street scale, ward level and local authority level) and temporal resolutions (i.e. annual, 24-hour, and 1-hour) were generated. PNC mapping could be linked to local population and health data for potential epidemiological studies.

Abstract. Objective:. Human immunodeficiency virus (HIV) infection has been suggested to be associated with an increased risk of the development of nonunion after a fracture. This prospective matched case–control study in South Africa investigated common risk factors, including HIV status, that influence the development of a nonunion after a femur or tibia fracture. Methods:. Adult participants (cases) with established nonunions of the femur or tibia shaft were recruited over a 16-month period, between December 2017 and April 2019. They were matched for (1) age; (2) sex; (3) fracture site; and (4) fracture management type, with “control” participants who progressed to fracture union within 6 months of injury. All participants were tested for HIV. Multivariable logistic regression models were constructed to investigate associations between known risk factors for the development of nonunion and impaired fracture healing. Results:. A total of 57 cases were matched with 57 “control” participants (44/57 male, 77.2% vs. 13/57 female, 22.8%, median age 36 years). HIV status was not associated with the development of nonunion after the management of tibia and femur fractures, on both univariate (odds ratio, 0.40; confidence interval, 0.10–1.32; P = 0.151) or multivariable (odds ratio, 0.86; confidence interval, 0.18–3.73; P = 0.831) analysis. No other confounding factors were shown to have any statistically significant impact on the odds of developing nonunion in this study cohort. Conclusion:. This study demonstrates that HIV does not seem to increase the risk of the development of nonunion and HIV-positive individuals who sustain a fracture can be managed in the same manner as those who are HIV negative.

Intestinal stem cells are responsible for replenishing cells within the high-turnover intestinal epithelium. Here they show that ribosome dynamics affect intestinal stem cell identity through a mechanism that is triggered by changes in nutrient availability.

Tradução do Artigo de William James: A Suggestion about mysticism. Texto publicado originalmente em 17 de fevereiro de 1910 no Volume VII N°4 em The journal of philosophy psychology and scientific methods p. 85 a 92. Artigo de domínio público de acordo com a Convenção de Berna.

Abstract Background Electronic health record (EHR) prediction models may be easier to use in busy clinical settings since EHR data can be auto-populated into models. This study assessed whether adding functional status and/or Medicare claims data (which are often not available in EHRs) improves the accuracy of a previously developed Veterans Affairs (VA) EHR-based mortality index. Methods This was a retrospective cohort study of veterans aged 75 years and older enrolled in VA primary care clinics followed from January 2014 to April 2020 (n = 62,014). We randomly split participants into development (n = 49,612) and validation (n = 12,402) cohorts. The primary outcome was all-cause mortality. We performed logistic regression with backward stepwise selection to develop a 100-predictor base model using 854 EHR candidate variables, including demographics, laboratory values, medications, healthcare utilization, diagnosis codes, and vitals. We incorporated functional measures in a base + function model by adding activities of daily living (range 0-5) and instrumental activities of daily living (range 0-7) scores. Medicare data, including healthcare utilization (e.g., emergency department visits, hospitalizations) and diagnosis codes, were incorporated in a base + Medicare model. A base + function + Medicare model included all data elements. We assessed model performance with the c-statistic, reclassification metrics, fraction of new information provided, and calibration plots. Results In the overall cohort, mean age was 82.6 years and 98.6% were male. At the end of follow-up, 30,263 participants (48.8%) had died. The base model c-statistic was 0.809 (95% CI 0.805-0.812) in the development cohort and 0.804 (95% CI 0.796-0.812) in the validation cohort. Validation cohort c-statistics for the base + function, base + Medicare, and base + function + Medicare models were 0.809 (95% CI 0.801-0.816), 0.811 (95% CI 0.803-0.818), and 0.814 (95% CI 0.807-0.822), respectively. Adding functional status and Medicare data resulted in similarly small improvements among other model performance measures. All models showed excellent calibration. Conclusions Incorporation of functional status and Medicare data into a VA EHR-based mortality index led to small but likely clinically insignificant improvements in model performance.

Abstract Background Nucleomorphs are remnants of secondary endosymbiotic events between two eukaryote cells wherein the endosymbiont has retained its eukaryotic nucleus. Nucleomorphs have evolved at least twice independently, in chlorarachniophytes and cryptophytes, yet they have converged on a remarkably similar genomic architecture, characterized by the most extreme compression and miniaturization among all known eukaryotic genomes. Previous computational studies have suggested that nucleomorph chromatin likely exhibits a number of divergent features. Results In this work, we provide the first maps of open chromatin, active transcription, and three-dimensional organization for the nucleomorph genome of the chlorarachniophyte Bigelowiella natans. We find that the B. natans nucleomorph genome exists in a highly accessible state, akin to that of ribosomal DNA in some other eukaryotes, and that it is highly transcribed over its entire length, with few signs of polymerase pausing at transcription start sites (TSSs). At the same time, most nucleomorph TSSs show very strong nucleosome positioning. Chromosome conformation (Hi-C) maps reveal that nucleomorph chromosomes interact with one other at their telomeric regions and show the relative contact frequencies between the multiple genomic compartments of distinct origin that B. natans cells contain. Conclusions We provide the first study of a nucleomorph genome using modern functional genomic tools, and derive numerous novel insights into the physical and functional organization of these unique genomes.

IntroductionFear of clowns or coulrophobia is a little understood phenomenon despite studies indicating that it has a high prevalence in the general population. There have been no previous investigations into the aetiology of this fear, although several plausible hypotheses from the wider literature can be generated; the fear stems from media portrayals of scary clowns, from the unusual physical appearance or the unpredictable behaviour displayed, or it derives from an unpleasant personal experience.MethodsThe current study reviews the literature in this area and also pilots a new questionnaire (Origin of Fear of Clowns Questionnaire; OFCQ) to explore the causes of the fear of clowns in a sample of 528 participants who reported such a fear.ResultsOur findings suggest that uncertainty of harmful intent, media influences and unpredictability of behaviour play an important role in the origins of coulrophobia. There are also multiple features of clown appearance which produce a negative experiential state and a sense of a direct threat.DiscussionWe conclude that the origins of clown fear are multi-factorial and primarily relate to aspects of their facial appearance, their behaviour, and how they have been portrayed in the media. Surprisingly, fear derived from personal experience was not one of our main findings. Further research is focused on looking at associations between the level of fear and each aetiological category.

Abstract While the effect of drought on plant communities and their associated ecosystem functions is well studied, little research has considered how responses are modified by soil depth and depth heterogeneity. We conducted a mesocosm study comprising shallow and deep soils, and variable and uniform soil depths, and two levels of plant community composition, and exposed them to a simulated drought to test for interactive effects of these treatments on the resilience of carbon dioxide fluxes, plant functional traits, and soil chemical properties. We tested the hypotheses that: (a) shallow and variable depth soils lead to increased resistance and resilience of ecosystem functions to drought due to more exploitative plant trait strategies; (b) plant communities associated with intensively managed high fertility soils, will have more exploitative root traits than extensively managed, lower fertility plant communities. These traits will be associated with higher resistance and resilience to drought and may interact with soil depth and depth heterogeneity to amplify the effects on ecosystem functions. Our results showed that while there were strong soil depth/heterogeneity effects on plant‐driven carbon fluxes, it did not affect resistance or resilience to drought, and there were no treatment effects on plant‐available carbon or nitrogen. We did observe a significant increase in exploitative root traits in shallow and variable soils relative to deep and uniform, which may have resulted in a compensation effect which led to the similar drought responses. Plant community compositions representative of intensive management were more drought resilient than more diverse “extensive” communities irrespective of soil depth or soil depth heterogeneity. In intensively managed plant communities, root traits were more representative of exploitative strategies. Taken together, our results suggest that reorganization of root traits in response to soil depth could buffer drought effects on ecosystem functions.

Neutralizing nanobodies (Nb) are of considerable interest as therapeutic agents for COVID-19 treatment. Here, the authors functionally and structurally characterize Nbs that bind with high affinity to the receptor binding domain of the SARS-CoV-2 spike protein and show that an engineered homotrimeric Nb prevents disease progression in a Syrian hamster model of COVID-19 when administered intranasally.

Abstract. Background:. Cervical cancer remains a major public health issue for the Uyghur women and other women living mainly in rural areas of Xinjiang. This study aims to investigate the distribution of human papillomavirus (HPV) infection and cervical cancer in rural areas of Xinjiang, China. Methods:. Cervical cancer screening was performed on rural women aged 35 to 64 years from Xinjiang, China in 2017 through gynecological examination, vaginal discharge smear microscopy, cytology, and HPV testing. If necessary, colposcopy and biopsy were performed on women with suspicious or abnormal screening results. Results:. Of the 216,754 women screened, 15,518 received HPV testing. The HPV-positive rate was 6.75% (1047/15,518). Compared with the age 35–44 years group, the odds ratios (ORs) of HPV positivity in the age 45–54 years and 55–64 years groups were 1.18 (95% confidence interval [CI]: 1.02–1.37) and 1.84 (95% CI: 1.53–2.21), respectively. Compared with women with primary or lower education level, the ORs for HPV infection rates of women with high school and college education or above were 1.37 (95% CI: 1.09–1.72) and 1.62 (95% CI: 1.23–2.12), respectively. Uyghur women were less likely to have HPV infection than Han women, with an OR (95% CI) of 0.78 (0.61–0.99). The most prevalent HPV types among Xinjiang women were HPV 16 (24.00%), HPV 33 (12.70%), and HPV 52 (11.80%). The detection rate of cervical intraepithelial neoplasia (CIN)2+ was 0.14% and the early diagnosis rate of cervical cancer was 85.91%. The detection rates of vaginitis and cervicitis were 19.28% and 21.32%, respectively. Conclusions:. The HPV infection rate in Xinjiang is low, but the detection rate of cervical cancer and precancerous lesions is higher than the national average level. Cervical cancer is a prominent public health problem in Xinjiang, especially in southern Xinjiang.

In this study, Peijun Zhang and colleagues use cryoFIB/SEM volume imaging and soft x-ray cryo-tomography with cryo-electron tomography (cryoET) of cellular periphery, lamellae, and subtomogram averaging to place critical structural events in the SARS-CoV-2 infection cycle in the context of whole-cell images.

After a 20-year-old woman suddenly died, autopsy showed characteristic findings of biventricular arrhythmogenic cardiomyopathy. Screening of her family members revealed the same desmoplakin gene mutation and imaging abnormalities predominantly involving the left ventricle. We describe the variable phenotypic expression in a family that shares a common gene variant. (Level of Difficulty: Advanced.)

Summary: Background: Previous infection with SARS-CoV-2 affects the immune response to the first dose of the SARS-CoV-2 vaccine. We aimed to compare SARS-CoV-2-specific T-cell and antibody responses in health-care workers with and without previous SARS-CoV-2 infection following a single dose of the BNT162b2 (tozinameran; Pfizer–BioNTech) mRNA vaccine. Methods: We sampled health-care workers enrolled in the PITCH study across four hospital sites in the UK (Oxford, Liverpool, Newcastle, and Sheffield). All health-care workers aged 18 years or older consenting to participate in this prospective cohort study were included, with no exclusion criteria applied. Blood samples were collected where possible before vaccination and 28 (±7) days following one or two doses (given 3–4 weeks apart) of the BNT162b2 vaccine. Previous infection was determined by a documented SARS-CoV-2-positive RT-PCR result or the presence of positive anti-SARS-CoV-2 nucleocapsid antibodies. We measured spike-specific IgG antibodies and quantified T-cell responses by interferon-γ enzyme-linked immunospot assay in all participants where samples were available at the time of analysis, comparing SARS-CoV-2-naive individuals to those with previous infection. Findings: Between Dec 9, 2020, and Feb 9, 2021, 119 SARS-CoV-2-naive and 145 previously infected health-care workers received one dose, and 25 SARS-CoV-2-naive health-care workers received two doses, of the BNT162b2 vaccine. In previously infected health-care workers, the median time from previous infection to vaccination was 268 days (IQR 232–285). At 28 days (IQR 27–33) after a single dose, the spike-specific T-cell response measured in fresh peripheral blood mononuclear cells (PBMCs) was higher in previously infected (n=76) than in infection-naive (n=45) health-care workers (median 284 [IQR 150–461] vs 55 [IQR 24–132] spot-forming units [SFUs] per 106 PBMCs; p

Flaviviruses have caused large epidemics and ongoing outbreaks for centuries. They are now distributed in every continent infecting up to millions of people annually and may emerge to cause future epidemics. Some of the viruses from this group cause severe illnesses ranging from hemorrhagic to neurological manifestations. Despite decades of research, there are currently no approved antiviral drugs against flaviviruses, urging for new strategies and antiviral targets. In recent years, integrated omics data-based drug repurposing paired with novel drug validation methodologies and appropriate animal models has substantially aided in the discovery of new antiviral medicines. Here, we aim to review the latest progress in the development of both new and repurposed (i) direct-acting antivirals; (ii) host-targeting antivirals; and (iii) multitarget antivirals against flaviviruses, which have been evaluated both in vitro and in vivo, with an emphasis on their targets and mechanisms. The search yielded 37 compounds that have been evaluated for their efficacy against flaviviruses in animal models; 20 of them are repurposed drugs, and the majority of them exhibit broad-spectrum antiviral activity. The review also highlighted the major limitations and challenges faced in the current in vitro and in vivo evaluations that hamper the development of successful antiviral drugs for flaviviruses. We provided an analysis of what can be learned from some of the approved antiviral drugs as well as drugs that failed clinical trials. Potent in vitro and in vivo antiviral efficacy alone does not warrant successful antiviral drugs; current gaps in studies need to be addressed to improve efficacy and safety in clinical trials.

Background:. In low and middle-income countries (LMICs), individuals suffer from a disproportionately higher number of musculoskeletal (MSK) injuries compared with those living in a high-income setting. However, despite the higher burden of death and disability from MSK injuries in LMICs, there has been little policy, research, and funding invested in addressing this distinctly overlooked problem. Using a consensus-based approach, the aim of this study was to identify research priorities for clinical trials and research in MSK trauma care across sub-Saharan Africa. Methods:. A modified Delphi technique was utilized; it involved an initial scoping survey, a 2-round Delphi process, and, finally, review by an expert panel with members of the Orthopaedic Research Collaboration in Africa. This study was conducted among MSK health-care practitioners treating trauma in sub-Saharan Africa. Results:. Participants from 34 countries across sub-Saharan Africa contributed to the 2 rounds of the Delphi process, and priorities were scored from 1 (low priority) to 5 (high priority). Public health topics related to trauma care ranked higher than those focused on clinical effectiveness, with the top 10 public health research questions scoring higher than the top 10 questions for clinical effectiveness. Ten public health and 10 clinical effectiveness questions related to MSK trauma care were identified; the highest-ranked questions in the respective categories were related to education and training and to the management of femoral fractures. Conclusions:. This consensus-driven research priority study will guide health-care professionals, academics, researchers, and funders to improve the evidence on MSK trauma care across sub-Saharan Africa and inform funders about priority areas of future research.

Zika virus (ZIKV) is a mosquito-borne, single-stranded RNA virus belonging to the genus Flavivirus. Although ZIKV infection is usually known to exhibit mild clinical symptoms, intrauterine ZIKV infections have been associated with severe neurological manifestations, including microcephaly and Guillain Barre syndrome (GBS). Therefore, it is imperative to understand the mechanisms of ZIKV entry into the central nervous system (CNS) and its effect on brain cells. Several routes of neuro-invasion have been identified, among which blood–brain barrier (BBB) disruption is the commonest mode of access. The molecular receptors involved in viral entry remain unknown; with various proposed molecular ZIKV-host interactions including potential non-receptor mediated cellular entry. As ZIKV invade neuronal cells, they trigger neurotoxic mechanisms via cell-autonomous and non-cell autonomous pathways, resulting in neurogenesis dysfunction, viral replication, and cell death, all of which eventually lead to microcephaly. Together, our understanding of the biological mechanisms of ZIKV exposure would aid in the development of anti-ZIKV therapies targeting host cellular and/or viral components to combat ZIKV infection and its neurological manifestations. In this present work, we review the current understanding of ZIKV entry mechanisms into the CNS and its implications on the brain. We also highlight the status of the drug repurposing approach for the development of potential antiviral drugs against ZIKV.

Zika virus (ZIKV), despite being discovered six decades earlier, became a major health concern only after an epidemic in French Polynesia and an increase in the number of microcephaly cases in Brazil. Substantial evidence has been found to support the link between ZIKV and neurological complications in infants. The virus targets various cells in the brain, including radial glial cells, neural progenitor cells (NPCs), astrocytes, microglial and glioblastoma stem cells. It affects the brain cells by exploiting different mechanisms, mainly through apoptosis and cell cycle dysregulation. The modulation of host immune response and the inflammatory process has also been demonstrated to play a critical role in ZIKV induced neurological complications. In addition to that, different ZIKV strains have exhibited specific neurotropism and unique molecular mechanisms. This review provides a comprehensive and up-to-date overview of ZIKV-induced neuroimmunopathogenesis by dissecting its main target cells in the brain, and the underlying cellular and molecular mechanisms. We highlighted the roles of the different ZIKV host factors and how they exploit specific host factors through various mechanisms. Overall, it covers key components for understanding the crosstalk between ZIKV and the brain.

BackgroundDespite a successful antiretroviral therapy (ART), adolescents living with perinatally acquired HIV (PHIV) experience signs of B-cell hyperactivation with expansion of ‘namely’ atypical B-cell phenotypes, including double negative (CD27-IgD-) and termed age associated (ABCs) B-cells (T-bet+CD11c+), which may result in reduced cell functionality, including loss of vaccine-induced immunological memory and higher risk of developing B-cells associated tumors. In this context, perinatally HIV infected children (PHIV) deserve particular attention, given their life-long exposure to chronic immune activation.MethodsWe studied 40 PHIV who started treatment by the 2nd year of life and maintained virological suppression for 13.5 years, with 5/40 patients experiencing transient elevation of the HIV-1 load in the plasma (Spike). We applied a multi-disciplinary approach including immunological B and T cell phenotype, plasma proteomics analysis, and serum level of anti-measles antibodies as functional correlates of vaccine-induced immunity.ResultsPhenotypic signs of B cell hyperactivation were elevated in subjects starting ART later (%DN T-bet+CD11c+ p=0.03; %AM T-bet+CD11c+ p=0.02) and were associated with detectable cell-associated HIV-1 RNA (%AM T-bet+CD11c+ p=0.0003) and transient elevation of the plasma viral load (spike). Furthermore, B-cell hyperactivation appeared to be present in individuals with higher frequency of exhausted T-cells, in particular: %CD4 TIGIT+ were associated with %DN (p=0.008), %DN T-bet+CD11c+ (p=0.0002) and %AM T-bet+CD11c+ (p=0.002) and %CD4 PD-1 were associated with %DN (p=0.048), %DN T-bet+CD11c+ (p=0.039) and %AM T-bet+CD11c+ (p=0.006). The proteomic analysis revealed that subjects with expansion of these atypical B-cells and exhausted T-cells had enrichment of proteins involved in immune inflammation and complement activation pathways. Furthermore, we observed that higher levels of ABCs were associated a reduced capacity to maintain vaccine-induced antibody immunity against measles (%B-cells CD19+CD10- T-bet+, p=0.035).ConclusionWe identified that the levels of hyperactivated B cell subsets were strongly affected by time of ART start and associated with clinical, viral, cellular and plasma soluble markers. Furthermore, the expansion of ABCs also had a direct impact on the capacity to develop antibodies response following routine vaccination.

Abstract To describe the incidence, therapy and outcome of traumatic tracheobronchial injuries (TTBI) in trauma patients with multiple injuries derived from the DGU TraumaRegister. We analyzed the data on all patients listed on the TraumaRegister DGU (TR-DGU) in Germany between 2002 and 2015 aged 16 years or older and with an Injury Severity Score (ISS) of ≥ 9. We analyzed the data on 136,389 trauma patients, 561 of whom had suffered tracheobronchial injuries (0.4%). The majority were male (73.4%) and had a mean age of 43.7 years. In total, 84.0% of all TTBI injuries occurred secondary to blunt trauma, caused mainly by accidents (71.2%). TTBI was accompanied by several concomitant thoracic injuries such as pneumo- (41.2%) and hemothorax (23.2%), lacerations (7.8%) and contusions (32.3%) of the lung, as well as multiple rib fractures (29.6%). The severity of injury was classified via the abbreviated injury scale (AIS): 39.3% with AIS = 3, 51.3% with AIS = 4 and 60% with AIS = 5 patients underwent surgical interventions. The mortality of patients with tracheobronchial injuries was higher: 24.6%, versus 13.7% in all patients (control group). This high percentage reflects their generally severe injury burden through concomitant injuries. The incidence of TTBI in this large cohort of trauma patients is very low. However, its high mortality rate emphasizes its importance. Mortality was associated with higher ISS and AIS scores. Higher rates of concomitant injuries were therefore associated with a higher mortality rate. TTBI injuries revealed a higher rate of progression to surgical management, with 35% undergoing surgery within the first 24 h. This excessive mortality rate demonstrates a high overall injury burden in patients with TTBI and high mortality of associated injuries. A surgical intervention’s impact on mortality cannot be assessed in this study, as it would need to be investigated in a case-matched study.

Bilateral middle cerebral artery occlusion is a very rare and dangerous pathology, accounting for less than 1% of stroke presentations. Unless treated, the natural course of the disease leads to coma or death and thus is extremely important to be detected early and managed appropriately. We present the case of a 69-year-old lady who woke with right-sided weakness and was found to have a left middle cerebral artery stroke on arrival to her local hospital, which progressed to bilateral paresis and dysarthria whilst on transfer to a tertiary hospital for definitive management. The patient underwent emergent mechanical thrombectomy of bilateral middle cerebral artery occlusions and made a complete recovery. This case emphasis the importance of the early recognition of rare bilateral middle cerebral artery occlusions and demonstrates that timely and effective treatment can have favorable outcomes for patients. Keywords: Bilateral MCA Occlusion, CT perfusion, Embolus, Stroke

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new beta coronavirus that emerged at the end of 2019 in the Hubei province of China. SARS-CoV-2 causes coronavirus disease 2019 (COVID-19) and was declared a pandemic by the World Health Organization (WHO) on 11 March 2020. Herd or community immunity has been proposed as a strategy to protect the vulnerable, and can be established through immunity from past infection or vaccination. Whether SARS-CoV-2 infection results in the development of a reservoir of resilient memory cells is under investigation. Vaccines have been developed at an unprecedented rate and 7 408 870 760 vaccine doses have been administered worldwide. Recently emerged SARS-CoV-2 variants are more transmissible with a reduced sensitivity to immune mechanisms. This is due to the presence of amino acid substitutions in the spike protein, which confer a selective advantage. The emergence of variants therefore poses a risk for vaccine effectiveness and long-term immunity, and it is crucial therefore to determine the effectiveness of vaccines against currently circulating variants. Here we review both SARS-CoV-2-induced host immune activation and vaccine-induced immune responses, highlighting the responses of immune memory cells that are key indicators of host immunity. We further discuss how variants emerge and the currently circulating variants of concern (VOC), with particular focus on implications for vaccine effectiveness. Finally, we describe new antibody treatments and future vaccine approaches that will be important as we navigate through the COVID-19 pandemic.

Abstract Combinatorial antibody libraries not only effectively reduce antibody discovery to a numbers game, but enable documentation of the history of antibody responses in an individual. The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic has prompted a wider application of this technology to meet the public health challenge of pandemic threats in the modern era. Herein, a combinatorial human antibody library constructed 20 years before the coronavirus disease 2019 (COVID‐19) pandemic is used to discover three highly potent antibodies that selectively bind SARS‐CoV‐2 spike protein and neutralize authentic SARS‐CoV‐2 virus. Compared to neutralizing antibodies from COVID‐19 patients with generally low somatic hypermutation (SHM), these three antibodies contain over 13–22 SHMs, many of which are involved in specific interactions in their crystal structures with SARS‐CoV‐2 spike receptor binding domain. The identification of these somatically mutated antibodies in a pre‐pandemic library raises intriguing questions about the origin and evolution of these antibodies with respect to their reactivity with SARS‐CoV‐2.

Abstract Millions of people worldwide, and especially schoolchildren, may be infected by geohelminths due to their exposure to a contaminated environment. The aim of this study was to evaluate soil contamination by Ancylostoma spp. and Toxocara spp. eggs in recreation areas at elementary schools in Pelotas, state of Rio Grande do Sul, Brazil. Sand samples were collected from 22 schools and were processed using the centrifugal flotation method. Helminth eggs with zoonotic potential were found in 12 out of the 22 schools (54.5%). Contamination by Ancylostoma spp. and Toxocara spp. was observed in 36.4% (8/22) and 27.3% (6/22) of the soil samples collected at these schools, respectively. These findings of eggs show that the school communities are exposed to risks of zoonotic transmission.

In the final week of March 2020, 2.8 million Canadians were away from their usual places of work and engaging in remote and/or telework to mitigate the spread of COVID-19 (Statistics Canada, 2020). The Government of Canada's Department of National Defence (DND) and the Canadian Armed Forces (CAF) were no exception, with most members from the regular force (Reg F), the primary reserve force (P Res), and the DND public service (DND PS) working from home. The COVID-19 Defence Team Survey was administered from April 29th, 2020, and May 22nd, 2020, to gain insight into work, health, and family-related challenges since the onset of the pandemic and change in work arrangements. Responses from five open-ended questions were qualitatively analyzed to determine general themes of concern regarding work, personal, and family related challenges, stress-management and coping strategies, and recommendations for improving the work situation and personal well-being. Given the different roles and conditions of employment, responses of the different groups or “components” of respondents (Reg F, P Res, DND PS) were compared to identify common and unique challenges to inform targeted organizational responses. A total of 26,207 members (Reg F = 13,668, 52.2%; P Res = 5,052, 19.3%; DND PS = 7,487, 28.6%) responded to the survey's five open-ended questions, which yielded a total of 75,000 open-ended responses. When asked about work-related challenges, respondents' most common challenges included dissatisfaction with technology/software, work arrangements, ergonomics, work-life balance, communication within the organization, and the uncertainties regarding career development. In terms of personal and/or family-related challenges, the most common challenges included social isolation, the impact of the pandemic on mental health, school closures and homeschooling, caring for vulnerable family members, and childcare concerns. The most common stress-management and coping strategies included exercise, spending time outdoors, communicating or spending time with family members, household chores/projects, mind-body wellness exercises, and playing games. The most common recommendations made by respondents to improve their work- or personal-related situations included improving technological capabilities, streamlining communication, providing hardware and software necessary to ensure comfortable ergonomics, the provision of flexibility in terms of telework schedules, return-to-work decisions, and the expansion of benefits and access to childcare services. In terms of differences among the components, DND PS personnel were most likely to report dissatisfaction with technological changes and ergonomics, and to recommend improving these technological limitations to maximize productivity. Reg F members, on the other hand, were most likely to recommend increased support and access to childcare, and both Reg F and P Res members were more likely to mention that increased benefits and entitlements in response to the COVID-19 pandemic would be ameliorative. The results of this study highlight several important facts about the impact of the COVID-19 pandemic on personnel working in large, diverse organizations. For example, advancements in organizational technological capabilities were highlighted herein, and these are likely to grow to maintain productivity should remote work come to be used more extensively in the long-term. This study also highlighted the importance of flexibility and accommodation in relation to individual needs – a trend that was already underway but has taken on greater relevance and urgency in light of the pandemic. This is clearly essential to the organization's role in supporting the well-being of personnel and their families. Clear and streamlined communication regarding organizational changes and support services is also essential to minimize uncertainty and to provide useful supports for coping with this and other stressful situations.

Despite an unprecedented global research effort on SARS-CoV-2, early replication events remain poorly understood. Given the clinical importance of emergent viral variants with increased transmission, there is an urgent need to understand the early stages of viral replication and transcription. We used single-molecule fluorescence in situ hybridisation (smFISH) to quantify positive sense RNA genomes with 95% detection efficiency, while simultaneously visualising negative sense genomes, subgenomic RNAs, and viral proteins. Our absolute quantification of viral RNAs and replication factories revealed that SARS-CoV-2 genomic RNA is long-lived after entry, suggesting that it avoids degradation by cellular nucleases. Moreover, we observed that SARS-CoV-2 replication is highly variable between cells, with only a small cell population displaying high burden of viral RNA. Unexpectedly, the B.1.1.7 variant, first identified in the UK, exhibits significantly slower replication kinetics than the Victoria strain, suggesting a novel mechanism contributing to its higher transmissibility with important clinical implications.

Increased protein synthesis supports the rapid cell proliferation associated with cancer. The Rpl24Bst mutant mouse reduces the expression of the ribosomal protein RPL24 and has been used to suppress translation and limit tumorigenesis in multiple mouse models of cancer. Here, we show that Rpl24Bst also suppresses tumorigenesis and proliferation in a model of colorectal cancer (CRC) with two common patient mutations, Apc and Kras. In contrast to previous reports, Rpl24Bst mutation has no effect on ribosomal subunit abundance but suppresses translation elongation through phosphorylation of eEF2, reducing protein synthesis by 40% in tumour cells. Ablating eEF2 phosphorylation in Rpl24Bst mutant mice by inactivating its kinase, eEF2K, completely restores the rates of elongation and protein synthesis. Furthermore, eEF2K activity is required for the Rpl24Bst mutant to suppress tumorigenesis. This work demonstrates that elevation of eEF2 phosphorylation is an effective means to suppress colorectal tumorigenesis with two driver mutations. This positions translation elongation as a therapeutic target in CRC, as well as in other cancers where the Rpl24Bst mutation has a tumour suppressive effect in mouse models.

Zika virus (ZIKV) received worldwide attention over the past decade when outbreaks of the disease were found to be associated with severe neurological syndromes and congenital abnormalities. Unlike most other flaviviruses, ZIKV can spread through sexual and transplacental transmission, adding to the complexity of Zika pathogenesis and clinical outcomes. In addition, the spread of ZIKV in flavivirus-endemic regions, and the high degree of structural and sequence homology between Zika and its close cousin Dengue have raised questions on the interplay between ZIKV and the pre-existing immunity to other flaviviruses and the potential immunopathogenesis. The Zika epidemic peaked in 2016 and has affected over 80 countries worldwide. The re-emergence of large-scale outbreaks in the future is certainly a possibility. To date, there has been no approved antiviral or vaccine against the ZIKV. Therefore, continuing Zika research and developing an effective antiviral and vaccine is essential to prepare the world for a future Zika epidemic. For this purpose, an in-depth understanding of ZIKV interaction with many different pathways in the human host and how it exploits the host immune response is required. For successful infection, the virus has developed elaborate mechanisms to escape the host response, including blocking host interferon response and shutdown of certain host cell translation. This review provides a summary on the key host factors that facilitate ZIKV entry and replication and the mechanisms by which ZIKV antagonizes antiviral innate immune response and involvement of adaptive immune response leading to immunopathology. We also discuss how ZIKV modulates the host immune response during sexual transmission and pregnancy to induce infection, how the cross-reactive immunity from other flaviviruses impacts ZIKV infection, and provide an update on the current status of ZIKV vaccine development.

Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens in the fluid has important uses in biotechnology, and is integral to many point-of-care SARS-CoV-2 diagnostics. Sandwich enzyme-linked immunosorbent assays (ELISAs) are a sensitive, well-established method of measuring antigens in solutions. They use one ligand to capture and the other ligand to detect the target analyte. Detection is commonly achieved using colorimetric readout obtained upon the reaction of a substrate with HRP-conjugated secondary ligand. Nanobodies, the VHH domain of camelid antibodies, have expanded the repertoire of molecules used in antigen detection. Nanobodies' high affinity for target antigens, their compact structure, their high stability and ease of production has driven research into their use as diagnostic reagents. Guided by a structural understanding of epitopes on the receptor-binding domain of the SARS-CoV-2 Spike protein, we investigated various combinations of engineered nanobodies in a sandwich ELISA to detect the Spike protein of SARS-CoV-2. We have identified an optimal combination of nanobodies. These were selectively functionalized to further improve antigen capture, enabling the measurement of sub-picomolar amounts of SARS-CoV-2 Spike protein in solution. With this combination, the routine detection limit in samples inactivated by heat and detergent corresponded to less than seven focus-forming units of infectious SARS-CoV-2.

In crop improvement programs, hybrid vigour (heterosis) is an important breeding strategy but the molecular mechanisms of hybrid vigour are still unclear. Grain yield declines after F1 generation due to phenotypic segregation. We found that, at the early seedling stage in hybrids derived from the temperate japonica rice varieties ‘Doongara’ and ‘Reiziq’, hybrid vigour was approximately 40% greater than in the better parents. Inbred high-yielding lines (Hybrid Mimics) were developed from the ‘Doongara’ × ‘Reiziq’ F1 by selfing and recurrent selection for F1-like plants in the F2 through to the F5 generation. Grain yields are stable over subsequent generations in the Hybrid Mimic lines. The importance of photosynthesis in early seedling development was demonstrated. Photosynthesis-related genes were expressed in the hybrid earlier than in the parents; physiological evidence using gas exchange indicated the early commencement of photosynthesis. Dark germination experiments supported the requirement for photosynthesis for early vigour in hybrids.

Wine produced by fermentation of Chestnut rose (Rosa roxburghii) hips, known as cili (Chinese-Mandarin), in Guizhou province, and other places in China is becoming popular but there is limited knowledge of suitable yeast strains for its production. In this study, we first investigated the oenological properties of six commercial S. cerevisiae yeast strains (X16, F33, SH12, GV107, S102, RMS2), one commercial Saccharomyces cerevisiae var. bayanus (S103), one commercial, non-Saccharomyces yeast strain, Torulaspora delbrueckii Prelude, and one indigenous S. cerevisiae strain, CZ, for cili wine fermentation. We measured the key traits of each of the yeast strains, viz., sulfite resistance, flocculation, hydrogen sulfide production capacity, fermentation rate, and yeast growth curves. Subsequently, we measured the resultant wine characteristics, viz., pH, alcohol content, residual sugar, titratable acidity, volatile acidity, ascorbic acid content and headspace volatile compounds. The overall suitability of each yeast type was evaluated using a multi-factor, unweighted, scorecard. On that basis, RMS2 was the most suitable, and closely followed by CZ and X16. This study is the first comparative evaluation of yeasts for cili wine production and provides a preliminary guide for their selection.

Summary: COVID-19, caused by the novel coronavirus SARS-CoV-2, is a global health issue with more than 2 million fatalities to date. Viral replication is shaped by the cellular microenvironment, and one important factor to consider is oxygen tension, in which hypoxia inducible factor (HIF) regulates transcriptional responses to hypoxia. SARS-CoV-2 primarily infects cells of the respiratory tract, entering via its spike glycoprotein binding to angiotensin-converting enzyme 2 (ACE2). We demonstrate that hypoxia and the HIF prolyl hydroxylase inhibitor Roxadustat reduce ACE2 expression and inhibit SARS-CoV-2 entry and replication in lung epithelial cells via an HIF-1α-dependent pathway. Hypoxia and Roxadustat inhibit SARS-CoV-2 RNA replication, showing that post-entry steps in the viral life cycle are oxygen sensitive. This study highlights the importance of HIF signaling in regulating multiple aspects of SARS-CoV-2 infection and raises the potential use of HIF prolyl hydroxylase inhibitors in the prevention or treatment of COVID-19.

Serological and plasmablast responses and plasmablast-derived IgG monoclonal antibodies (MAbs) have been analysed in three COVID-19 patients with different clinical severities. Potent humoral responses were detected within 3 weeks of onset of illness in all patients and the serological titre was elicited soon after or concomitantly with peripheral plasmablast response. An average of 13.7% and 3.5% of plasmablast-derived MAbs were reactive with virus spike glycoprotein or nucleocapsid, respectively. A subset of anti-spike (10 of 32) antibodies cross-reacted with other betacoronaviruses tested and harboured extensive somatic mutations, indicative of an expansion of memory B cells upon SARS-CoV-2 infection. Fourteen of 32 anti-spike MAbs, including five anti-receptor-binding domain (RBD), three anti-non-RBD S1 and six anti-S2, neutralised wild-type SARS-CoV-2 in independent assays. Anti-RBD MAbs were further grouped into four cross-inhibiting clusters, of which six antibodies from three separate clusters blocked the binding of RBD to ACE2 and five were neutralising. All ACE2-blocking anti-RBD antibodies were isolated from two recovered patients with prolonged fever, which is compatible with substantial ACE2-blocking response in their sera. Finally, the identification of non-competing pairs of neutralising antibodies would offer potential templates for the development of prophylactic and therapeutic agents against SARS-CoV-2.

Importance Injuries cause 30% more deaths than HIV, TB and malaria combined, and a prospective fracture care registry was established to investigate the fracture burden and treatment in Malawi to inform evidence-based improvements. Objective To use the analysis of prospectively-collected fracture data to develop evidence-based strategies to improve fracture care in Malawi and other similar settings. Design Multicentre prospective registry study. Setting Two large referral centres and two district hospitals in Malawi. Participants All patients with a fracture (confirmed by radiographs)—including patients with multiple fractures—were eligible to be included in the registry. Exposure All fractures that presented to two urban central and two rural district hospitals in Malawi over a 3.5-year period (September 2016 to March 2020). Main outcome(s) and measure(s) Demographics, characteristics of injuries, and treatment outcomes were collected on all eligible participants. Results Between September 2016 and March 2020, 23,734 patients were enrolled with a median age of 15 years (interquartile range: 10–35 years); 68.7% were male. The most common injuries were radius/ulna fractures (n = 8,682, 36.8%), tibia/fibula fractures (n = 4,036, 17.0%), humerus fractures (n = 3,527, 14.9%) and femoral fractures (n = 2,355, 9.9%). The majority of fractures (n = 21,729, 91.6%) were treated by orthopaedic clinical officers; 88% (20,885/2,849) of fractures were treated non-operatively, and 62.7% were treated and sent home on the same day. Open fractures (OR:53.19, CI:39.68–72.09), distal femoral fractures (OR:2.59, CI:1.78–3.78), patella (OR:10.31, CI:7.04–15.07), supracondylar humeral fractures (OR:3.10, CI:2.38–4.05), ankle fractures (OR:2.97, CI:2.26–3.92) and tibial plateau fractures (OR:2.08, CI:1.47–2.95) were more likely to be treated operatively compared to distal radius fractures. Conclusions and relevance The current model of fracture care in Malawi is such that trained orthopaedic surgeons manage fractures operatively in urban referral centres whereas orthopaedic clinical officers mainly manage fractures non-operatively in both district and referral centres. We recommend that orthopaedic surgeons should supervise orthopaedic clinical officers to manage non operative injuries in central and district hospitals. There is need for further studies to assess the clinical and patient reported outcomes of these fracture cases, managed both operatively and non-operatively.

Background: Laboratory diagnosis of SARS-CoV-2 infection (the cause of COVID-19) uses PCR to detect viral RNA (vRNA) in respiratory samples. SARS-CoV-2 RNA has also been detected in other sample types, but there is limited understanding of the clinical or laboratory significance of its detection in blood. Methods: We undertook a systematic literature review to assimilate the evidence for the frequency of vRNA in blood, and to identify associated clinical characteristics. We performed RT-PCR in serum samples from a UK clinical cohort of acute and convalescent COVID-19 cases (n=212), together with convalescent plasma samples collected by NHS Blood and Transplant (NHSBT) (n=462 additional samples). To determine whether PCR-positive blood samples could pose an infection risk, we attempted virus isolation from a subset of RNA-positive samples. Results: We identified 28 relevant studies, reporting SARS-CoV-2 RNA in 0-76% of blood samples; pooled estimate 10% (95%CI 5-18%). Among serum samples from our clinical cohort, 27/212 (12.7%) had SARS-CoV-2 RNA detected by RT-PCR. RNA detection occurred in samples up to day 20 post symptom onset, and was associated with more severe disease (multivariable odds ratio 7.5). Across all samples collected ≥28 days post symptom onset, 0/494 (0%, 95%CI 0-0.7%) had vRNA detected. Among our PCR-positive samples, cycle threshold (ct) values were high (range 33.5-44.8), suggesting low vRNA copy numbers. PCR-positive sera inoculated into cell culture did not produce any cytopathic effect or yield an increase in detectable SARS-CoV-2 RNA. There was a relationship between RT-PCR negativity and the presence of total SARS-CoV-2 antibody (p=0.02). Conclusions: vRNA was detectable at low viral loads in a minority of serum samples collected in acute infection, but was not associated with infectious SARS-CoV-2 (within the limitations of the assays used). This work helps to inform biosafety precautions for handling blood products from patients with current or previous COVID-19.

Background Obesity is a major risk factor for renal cancer, yet our understanding of its effects on antitumor immunity and immunotherapy outcomes remains incomplete. Deciphering these associations is critical, given the growing clinical use of immune checkpoint inhibitors for metastatic disease and mounting evidence for an obesity paradox in the context of cancer immunotherapies, wherein obese patients with cancer have improved outcomes.Methods We investigated associations between host obesity and anti-programmed cell death (PD-1)-based outcomes in both renal cell carcinoma (RCC) subjects and orthotopic murine renal tumors. Overall survival (OS) and progression-free survival (PFS) were determined for advanced RCC subjects receiving standard of care anti-PD-1 who had ≥6 months of follow-up from treatment initiation (n=73). Renal tumor tissues were collected from treatment-naive subjects categorized as obese (body mass index, ‘BMI’ ≥30 kg/m2) or non-obese (BMI

Background: It is important to distinguish between evaluation as an inherent, automatic, affective process and Program Evaluation (Evaluation, with capitalised ‘E’) as an institution, and equally important to consider what a good understanding of evaluation tells us about Evaluation. Evaluation is an established social institution whose modern roots can be traced back to 16th century France. Since the early 1900s the institution has developed within and across a range of scientific disciplines with interests in perceived social problems and efforts to resolve the said problems. This can be demonstrated objectively by the number and scale of relevant publications within relevant disciplines. This, in turn, helps us understand more about Evaluation as an institution. Set in this context is the question of Evaluation Science: is this simply a fashionable institutional motif or is it a potential new era for Evaluation? Purpose: Commentary on the history and development of Program Evaluation. Setting: Not applicable. Intervention: Not applicable. Research design: Not applicable. Data collection & analysis: Not applicable. Findings: Not applicable. Keywords: program evaluation; evaluation; history; evaluation science.

Immunomodulatory therapies targeting inhibitory checkpoint molecules have revolutionized the treatment of solid tumor malignancies. Concerns about whether systemic administration of an immune checkpoint inhibitor could impact primary brain tumors were answered with the observation of definitive responses in pediatric patients harboring hypermutated gliomas. Although initial clinical results in patients with glioblastoma (GBM) were disappointing, recently published results have demonstrated a potential survival benefit in patients with recurrent GBM treated with neoadjuvant programmed cell death protein 1 blockade. While these findings necessitate verification in subsequent studies, they support the possibility of achieving clinical meaningful immune responses in malignant primary brain tumors including GBM, a disease in dire need of additional therapeutic options. There are several challenges involved in treating glioma with immune checkpoint modulators including the immunosuppressive nature of GBM itself with high inhibitory checkpoint expression, the immunoselective blood brain barrier impairing the ability for peripheral lymphocytes to traffic to the tumor microenvironment and the high prevalence of corticosteroid use which suppress lymphocyte activation. However, by simultaneously targeting multiple costimulatory and inhibitory pathways, it may be possible to achieve an effective antitumoral immune response. To this end, there are now several novel agents targeting more recently uncovered “second generation” checkpoint molecules. Given the multiplicity of drugs being considered for combination regimens, an increased understanding of the mechanisms of action and resistance combined with more robust preclinical and early clinical testing will be needed to be able to adequately test these agents. This review summarizes our current understanding of T lymphocyte-modulating checkpoint molecules as it pertains to glioma with the hope for a renewed focus on the most promising therapeutic strategies.

Abstract The aim of this study was to evaluate environmental contamination by helminth eggs with zoonotic potential that were found in dog feces in the vicinity of elementary schools. Seventy-nine samples of dog feces were collected from 28 municipal schools located in five neighborhoods in Pelotas, Rio Grande do Sul (RS), Brazil. The samples were processed using the Willis-Mollay technique and analyzed using an optical microscope (40X), to identify any parasite eggs present. All neighborhoods were positive and 74.7% of the samples exhibited one or more helminth genera. The agent with the highest prevalence was Ancylostoma spp. (93.2%), followed by Trichuris spp. (18.6%), Toxocara spp. (11.9%) and Toxascaris (1.7%). These data show that there is a need for greater care towards controlling these helminths with zoonotic potential, including responsible pet ownership and daily activities to clean and collect dog feces in the vicinity of schools, because these are places where children play and study.

In the absence of a proven effective vaccine preventing infection by SARS-CoV-2, or a proven drug to treat COVID-19, the positive results of passive immune therapy using convalescent serum provide a strong lead. We have developed a new class of tetravalent, biparatopic therapy, 89C8-ACE2. It combines the specificity of a monoclonal antibody (89C8) that recognizes the relatively conserved N-terminal domain of the viral Spike (S) glycoprotein, and the ectodomain of ACE2, which binds to the receptor-binding domain of S. This molecule shows exceptional performance in vitro, inhibiting the interaction of recombinant S1 to ACE2 and transduction of ACE2-overexpressing cells by S-pseudotyped lentivirus with IC50s substantially below 100 pM, and with potency approximately 100-fold greater than ACE2-Fc itself. Moreover, 89C8-ACE2 was able to neutralize authentic viral infection in a standard 96-h co-incubation assay at low nanomolar concentrations, making this class of molecule a promising lead for therapeutic applications.