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Introduction: In anticipation of institutional and community-wide COVID-19 immunization clinics, an educational program for the administration of COVID-19 vaccines was developed, collaborating with the Virginia Department of Health to train doctor of medicine and physician assistant students to serve as vaccinators. Faculty and students also worked with state legislatures to propose and enact a bill that would enable such students to vaccinate patients. Methods: Between January 2021 and August 2022, 263 student volunteers completed 3,685 person-hours, administering 48,279 doses. On the basis of community need, the majority of vaccines were administered at mass vaccination clinics in Chesapeake (47%) and Norfolk (22%) in Virginia. One year after the first COVID-19 immunization clinic, the authors surveyed students who assisted with clinics, utilizing a Likert scale and free-text responses to elicit feedback about the training and volunteer experience. Results: Volunteers ranked the vaccination clinics among the top third of established volunteer experiences offered at Eastern Virginia Medical School, and 75% of respondents believed that this training should be a permanent part of their program curriculum. Conclusions: This paper presents a strategy for preparing students to serve as vaccinators during public health emergencies and show how other institutions of medical education can prepare for and engage student participation in vaccination campaigns and emergent health initiatives.

Abstract Alternate splicing is a critical regulator of gene expression in eukaryotes, however genetic mutations can cause erroneous splicing and disease. Most recorded splicing disorders are caused by mutations of splice donor/acceptor sites, however intronic mutations can affect splicing. Clinical exome analyses largely ignore intronic sequence, limiting the detection of mutations to within coding regions. We describe ‘Trooper’, a novel mouse model of CHARGE syndrome harbouring a pathogenic point mutation in Chd7. The mutation is 18 nucleotides upstream of exon 10 and creates a cryptic acceptor site, causing exon skipping and partial intron retention. This mutation, though detectable in exome sequence, was initially dismissed by computational filtering due to its intronic location. The Trooper strain exhibited many of the previously described CHARGE-like anomalies of CHD7 deficient mouse lines; including hearing impairment, vestibular hypoplasia and growth retardation. However, more common features such as facial asymmetry and circling were rarely observed. Recognition of these characteristic features prompted manual reexamination of Chd7 sequence and subsequent validation of the intronic mutation, highlighting the importance of phenotyping alongside exome analyses. The Trooper mouse serves as a valuable model of atypical CHARGE syndrome and reveals a molecular mechanism that may underpin milder clinical presentation of the syndrome.

We use stochastic simulations to investigate the performance of two recently developed methods for calculating the free energy profiles of ion channels and their electrophysiological properties, such as current–voltage dependence and reversal potential, from molecular dynamics simulations at a single applied voltage. These methods require neither knowledge of the diffusivity nor simulations at multiple voltages, which greatly reduces the computational effort required to probe the electrophysiological properties of ion channels. They can be used to determine the free energy profiles from either forward or backward one-sided properties of ions in the channel, such as ion fluxes, density profiles, committor probabilities, or from their two-sided combination. By generating large sets of stochastic trajectories, which are individually designed to mimic the molecular dynamics crossing statistics of models of channels of trichotoxin, p7 from hepatitis C and a bacterial homolog of the pentameric ligand-gated ion channel, GLIC, we find that the free energy profiles obtained from stochastic simulations corresponding to molecular dynamics simulations of even a modest length are burdened with statistical errors of only 0.3 kcal/mol. Even with many crossing events, applying two-sided formulas substantially reduces statistical errors compared to one-sided formulas. With a properly chosen reference voltage, the current–voltage curves can be reproduced with good accuracy from simulations at a single voltage in a range extending for over 200 mV. If possible, the reference voltages should be chosen not simply to drive a large current in one direction, but to observe crossing events in both directions.

Abstract Low blood flow through the fetal left heart is often conjectured as an etiology for hypoplastic left heart syndrome (HLHS). To investigate if a decrease in left heart flow results in growth failure, we generate left ventricular inflow obstruction (LVIO) in mid-gestation fetal lambs by implanting coils in their left atrium using an ultrasound-guided percutaneous technique. Significant LVIO recapitulates important clinical features of HLHS: decreased antegrade aortic valve flow, compensatory retrograde perfusion of the brain and ascending aorta (AAo) from the arterial duct, severe left heart hypoplasia, a non-apex forming LV, and a thickened endocardial layer. The hypoplastic AAo have miRNA-gene pairs annotating to cell proliferation that are inversely differentially expressed by bulk RNA-seq. Single-nucleus RNA-seq of the hypoplastic LV myocardium shows an increase in fibroblasts with a reciprocal decrease in cardiomyocyte nuclei proportions. Fibroblasts, cardiomyocytes and endothelial cells from hypoplastic myocardium have increased expression of extracellular matrix component or fibrosis genes with dysregulated fibroblast growth factor signaling. Hence, a severe sustained ( ~ 1/3 gestation) reduction in fetal left heart flow is sufficient to cause left heart hypoplasia. This is accompanied by changes in cellular composition and gene expression consistent with a pro-fibrotic environment and aberrant induction of mesenchymal programs.

Abstract Microbes play a key role in human gut homeostasis, metabolic, immunologic and physiopathology of the body. A longitudinal study conducted during 2018–2021 in the Kintampo North Municipality in Ghana demonstrated low hookworm infection cure rates following treatment with a single dose of 400 mg albendazole in some communities. To investigate associations between hookworm infection and the gut microbiome, we examined stool samples from consented participants who were either cured or remained infected after treatment. At each time point, stool was collected prior to and 10–14 days after albendazole treatment. We used 16S rRNA amplicon sequencing of DNA extracted from stool samples to investigate the composition and diversity of the gut microbiota and to identify potential microbial biomarkers associated with treatment outcomes. Hookworm infection was associated with increased species richness (p = 0.0093). Among treated individuals, there was also a significant variation in microbiota composition at 10–14 days following single-dose albendazole treatment. Individuals cured of hookworm infection after treatment showed a significant reduction in microbiota composition when compared to their pre-treatment state (ANOSIM; p = 0.02), whilst individuals who failed to clear the infection showed no change in microbiota composition (ANOSIM; p = 0.35). Uninfected individuals and those who were successfully treated were similar in their microbial composition and structure. We also found that the abundance of Clostridia spp. was increased in infected individuals pre- or post-treatment. Predictive functional profiling revealed the enrichment of two pyruvate ferredoxin oxidoreductase subunit pathways in individuals who remained infected after treatment (p

ABSTRACTHageman factor (FXII) is an essential component in the intrinsic coagulation cascade and a therapeutic target for the prophylactic treatment of hereditary angioedema (HAE). CSL312 (garadacimab) is a novel high-affinity human antibody capable of blocking activated FXII activity that is currently undergoing Phase 3 clinical trials in HAE. Structural studies using hydrogen/deuterium exchange coupled to mass spectrometry revealed evidence of interaction between the antibody and regions surrounding the S1 specificity pocket of FXII, including the 99-loop, 140-loop, 180-loop, and neighboring regions. We propose complementarity-determining regions (CDRs) in heavy-chain CDR2 and CDR3 as potential paratopes on garadacimab, and the 99-loop, 140-loop, 180-loop, and 220-loop as binding sites on the beta chain of activated FXII (β-FXIIa).

Abstract Background Leishmaniasis is a parasitic disease caused by species of the genus Leishmania, which are transmitted through the bite of infected female sand flies. Since the first reported outbreak of cutaneous leishmaniasis in Ghana, in 1999, there has been limited published information on its vectors and reservoir hosts there. Previous studies have shown strong dominance of the sand fly genus Sergentomyia over the genus Phlebotomus in Ghana. Thus the aim of this study was to determine the possible sand fly vector species in Ghana, as well as their human-feeding behavior, from the time of the first reported outbreak of CL in the country. Methods Sand flies were collected from randomly selected houses in three communities. They were identified and used for blood meal source identification and the detection of Leishmania infection using molecular methods. Results A total of 1051 female sand flies were morphologically identified, of which Sergentomyia africana africana (29%) was the predominant species. Among the 275 female sand flies that had blood-fed, the identified blood meal sources included chicken (33.8%) and goat (12.4%); the percentage of human blood meals was 32%. Single-source and mixed-source blood meals were identified in Sergentomyia africana africana (11.6%), Sergentomyia ingrami (14.9%) and Sergentomyia simillima (20%), with S. simillima having the highest proportion of blood meals that included human blood (14.6%). Using molecular methods, unfed sand flies and identified human-feeding species were examined for the presence of Leishmania DNA. Pool screening analysis revealed three pools of S. ingrami positive for Leishmania major DNA, with an infection rate of 1.27% (95% confidence interval 2.467–3.647). Conclusions The findings suggest that some Sergentomyia species may be involved in the transmission of cutaneous leishmaniasis in Ghana. However, the role of S. ingrami as a vector of leishmaniasis in Ghana needs to be conclusively validated by isolating the parasite from this species and through experimental transmission studies. Graphical abstract

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the transcriptional modulator MECP2. Here, the authors measured transcription rate and mRNA half-life changes in RTT patient-derived neurons to show transcription rate buffered by mRNA half-life changes.

Abstract Introduction The unique evidentiary, economic and ethical challenges associated with health technology assessment (HTA) of precision therapies limit access to novel drugs and therapeutics for children and youth, for whom such challenges are amplified. We elicited citizens' perspectives about values‐based criteria relevant to the assessment of paediatric precision therapies to inform the development of a child‐tailored HTA framework. Methods We held four citizen panels virtually in May–June 2021, informed by a plain‐language citizen brief summarizing global and local evidence about the challenges, policy and programmatic options and implementation strategies related to enhancing access to precision therapies for Canadian children and youth. Panellists were recruited through a nationally representative database, medical/patient networks and social media. We inductively coded and thematically analysed panel transcripts to generate themes and identify priority values. Results The perspectives of panellists (n = 45) coalesced into four overlapping themes, with attendant subthemes, relevant to a child‐tailored HTA framework: (1) Childhood Distinctions: vulnerability, ‘fair innings’, future potential, family impacts; (2) Voice: agency of children and youth; lived versus no lived experience; (3) One versus Many: disease severity, rarity, equity, unmet need and (4) Health System Governance: funding, implementation inequities, effectiveness and safety. Participants broadly agreed that childhood distinctions, particularly family impacts, justify child‐tailored HTA. Dissent arose over whose voice should inform HTA and how such perspectives are best incorporated. Conclusions Citizens can offer unique insights into criteria relevant to the development or revision of HTA frameworks to capture holistic, societally responsive dimensions of value attached to unique contexts or populations, including children. Balancing the hopes and expectations of patients and caregivers for access to expensive but potential life‐altering therapies against the opportunity costs borne by encompassing health systems is a fundamental challenge that will require rigorous methods to elicit, weigh and reconcile varied views. Patient or Public Contribution A patient advocate served on the steering committee of this study and co‐authored this article. Key informants for the Citizen Brief included patient advocates and caregivers; a separate patient advocate reviewed the Brief before dissemination. Qualitative and quantitative data were collected from the general public and caregivers of children, with written consent.

BackgroundEngaging men in psychotherapy is essential in male suicide prevention efforts, yet to date, efforts to upskill mental health practitioners in delivering gender-sensitized therapy for men have been lacking. To address this, we developed Men in Mind, an e-learning training program designed to upskill mental health practitioners in engaging men in therapy. ObjectiveThis study involves an in-depth analysis of the user experience of the Men in Mind intervention, assessed as part of a randomized controlled trial of the efficacy of the intervention. MethodsFollowing completion of the intervention, participants provided qualitative (n=392) and quantitative (n=395) user experience feedback, focused on successes and suggested improvements to the intervention and improvements to their confidence in delivering therapy with specific subpopulations of male clients. We also assessed practitioner learning goals (n=242) and explored the extent to which participants had achieved these goals at follow-up. ResultsParticipants valued the inclusion of video demonstrations of skills in action alongside the range of evidence-based content dedicated to improving their insight into the engagement of men in therapy. Suggested improvements most commonly reflected the desire for more or more diverse content, alongside the necessary adaptations to improve the learning and user experience. Participants also commonly reported improved confidence in assisting men with difficulty articulating their emotions in therapy and suicidal men. ConclusionsThe evidence obtained from this study aids in plans to scale Men in Mind and informs the future development of practitioner training interventions in men’s mental health. International Registered Report Identifier (IRRID)RR2-10.1186/s40359-022-00875-9

Suicide is a major public health concern and leading cause of death among men in Canada. This study reports the feasibility and acceptability of Buddy Up, a peer-based suicide prevention campaign for men. A mixed-methods approach was used to analyze respondent survey questionnaires ( n = 48) and individual participant interviews ( n = 19) collected from campaign users. Survey respondents reported that they enjoyed their involvement in the campaign (92%), were more confident to talk with men about mental health and suicide (95%), and would recommend Buddy Up to others (95%). Qualitative interviews were thematically analyzed to develop three inductively derived themes: (a) Engaging men with relatable masculine content and design: “Buddy Up really spoke to them in their language,” highlighting the importance of understanding and working with gendered practices and motivations to legitimize and motivate involvement in suicide prevention; (b) Leveraging campaign participation to initiate conversations and promote mental health: “It gives men language and license to start asking questions,” revealing ways in which participants utilized Buddy Up to negotiate and norm checking-in to promote men’s mental health; and (c) Driving new masculine cultures: “We start every meeting with a mental health moment,” identifying how participants fostered healthy milieus for disclosing mental health challenges with teamwork and preventive action under the banner of Buddy Up. The study findings support the feasibility of Buddy Up and highlight the acceptability of peer-based approaches to mental health promotion. The findings can also empirically guide future efforts for systematically building men’s peer-based suicide prevention programs.

Female naked mole rats are long lived and show little or no decline in fertility over their lifespan. Here Brieño-Enríquez et al., demonstrate that naked mole-rats establish an exceptionally large ovarian reserve and undergo postnatal oogenesis.

Mesenchymal-epithelial crosstalk plays a key role in gut development and stem cell homeostasis, though underlying mechanisms are still unclear. Here, the authors demonstrate that mesenchymal Polycomb Repressive Complex 2 controls niche signals for gut epithelial fate and growth.

Abstract Background Men account for three-quarters of all suicide deaths in many Western nations including Australia. Whilst extensive research has examined risk factors for suicidal ideation and behaviour in men, protective factors remain underexplored, particularly social support, resilience and coping behaviours. Such factors are important to examine particularly in the context of COVID-19, where enforced isolation (among other negative lifestyle effects) has created widespread risk for the development of suicidal ideation. This mixed-methods study aimed to examine associations of various protective factors with suicidal ideation in men, using data from an online survey conducted during the COVID-19 pandemic. In addition, we aimed to qualitatively investigate men’s self-reported protective strategies when experiencing suicidal thoughts and behaviour. Methods A convenience sample of 700 men (age M = 50.3 years; SD = 15.2 years) responded to an online survey including quantitative measures of suicidal ideation, planning and attempt, alongside employment and relationship status, coping, social support, resilience, and a qualitative free-text item gauging men’s self-reported protective strategies. Multinomial logistic regression was applied to compare odds of sub-categories of suicide risk (ideation; planning) according to protective factors. Qualitative responses were analysed via thematic analysis. Results Men in a relationship, and those lower in emotion-focused and avoidant coping reported lower odds of suicidal ideation. Maintaining employment throughout the pandemic was protective against suicidal ideation and planning; as was greater perceived social support from friends. Greater self-reported resilience was protective against suicidal ideation and planning. Qualitative analyses led to the development of two themes: coping and connecting, reflecting men’s intra- and interpersonal management strategies; and sustaining selflessness, where men’s imaginings of the collateral damage of their suicidal behaviour was protective against action on suicidal thoughts or plans. Conclusions Findings of this study speak to the nuanced roles of interpersonal connections, resilience and coping behaviours in protecting against suicidal ideation and planning in men. In addition, qualitative insights further cement men’s identification with familial protector and/or provider roles as protective against suicidal action.

Abstract The risk of pathogen transmission continues to increase significantly in the presence of tick vectors due to the trade of livestock across countries. In Ghana, there is a lack of data on the incidence of tick-borne pathogens that are of zoonotic and veterinary importance. This study, therefore, aimed to determine the prevalence of such pathogens in livestock using molecular approaches. A total of 276 dry blood spots were collected from cattle (100), sheep (95) and goats (81) in the Kassena-Nankana Districts. The samples were analyzed using Polymerase Chain Reaction (qPCR) and conventional assays and Sanger sequencing that targeted pathogens including Rickettsia, Coxiella, Babesia, Theileria, Ehrlichia and Anaplasma. An overall prevalence of 36.96% was recorded from the livestock DBS, with mixed infections seen in 7.97% samples. Furthermore, the prevalence of infections in livestock was recorded to be 19.21% in sheep, 14.13% in cattle, and 3.62% in goats. The pathogens identified were Rickettsia spp. (3.26%), Babesia sp. Lintan (8.70%), Theileria orientalis (2.17%), Theileria parva (0.36%), Anaplasma capra (18.48%), Anaplasma phagocytophilum (1.81%), Anaplasma marginale (3.26%) and Anaplasma ovis (7.25%). This study reports the first molecular identification of the above-mentioned pathogens in livestock in Ghana and highlights the use of dry blood spots in resource-limited settings. In addition, this research provides an update on tick-borne pathogens in Ghana, suggesting risks to livestock production and human health. Further studies will be essential to establish the distribution and epidemiology of these pathogens in Ghana.

A patient in California, USA, with rare and usually fatal Balamuthia mandrillaris granulomatous amebic encephalitis survived after receiving treatment with a regimen that included the repurposed drug nitroxoline. Nitroxoline, which is a quinolone typically used to treat urinary tract infections, was identified in a screen for drugs with amebicidal activity against Balamuthia.

Highlights Male and female mouse pituitary gland gene and miRNA expression was profiled across five postnatal ages spanning pubertal development. Sex differences in pituitary gene expression exist prior to puberty and become more prominent upon puberty. Combining expression data from genes and miRNAs revealed 18 putative sex-biased gene targets of 5 sex-biased miRNAs. Sex differences in the proportions of somatotropes, lactotropes, and gonadotropes are predicted to occur prior to puberty.

Background There has been an increase in the number of policy support organizations (PSOs) that have been created to foster the systematic use of evidence in health system policymaking. Our aim was to identify approaches for establishing a PSO or similar entities by soliciting insights from those with practical experience with developing and operationalizing PSOs in real-world contexts. Methods We used a sequential mixed method approached. We first conducted a survey to identify the views and experiences of those who were directly involved in the establishment of PSOs that have been developed and implemented across a variety of political-, health- and research-system contexts. The survey findings were then used to develop a purposive sample of PSO leaders and refine an interview guide for interviews with them. Results We received 19 completed surveys from leaders of PSOs in countries across the WHO regions and that operate in different settings (eg, as independent organization or within a university or government department) and conducted interviews with 15 senior managers from nine PSOs. Our findings provide in-depth insights about approaches and strategies across four stages for establishing a PSO, which include: (i) building awareness for the PSO; (ii) developing the PSO; (iii) assessing the PSO to identify potential areas for enhancement; and (iv) supporting maturation to build sustainability in the long-term. Our findings provide rich insights about the process of establishing a PSO from leaders who have undertaken the process. Conclusion While all PSOs share the same objective in supporting evidence-informed policy-making (EIPM), there is no single approach that can be considered to be the most successful in establishing a PSO, and each country should identify the approach based on its context.

Abstract Background and Aim Injuries are among the leading causes of mortality worldwide. There exists a paucity of nationally representative injury data from the sub‐Saharan African region on the nature of injuries outside of road traffic contexts. The aim of this study was to estimate the prevalence of nonfatal unintentional injuries that occurred outside of the traffic environment among persons aged 15–54 years in Kenya. Methods We used the 2014 Kenyan Demographic Health Survey data to estimate the prevalence of nonfatal unintentional injuries and their injury mechanisms. Binary logistic regression was used to estimate the odds of unintentional injuries and associated factors. Results Injury prevalence was three times higher among males (27.56%) compared to females (8.25%). The highest prevalence for females and males respectively was among those aged 15–19 years (9.80%) and (31.18%), rural residents (8.45%) and (30.05%) and those who consumed alcohol (18.13%), and (31.39%). For both females and males, the most frequent injuries were cuts (4.95%; 18.15%) and as result of falls (3.29%; 8.92%) respectively. Burns were more prevalent among females (1.65%) compared to males (0.76%). Among males, the demographic and contextual factors associated with nontraffic unintentional injuries were residing in a rural area (OR 1.33, 95% CI 1.14, 1.56), primary education (OR 2.02, 95% CI 1.48, 2.76), a higher wealth index (second quintile OR 1.41, 95% CI 1.19, 1.67) and consuming alcohol (OR 1.49, 95% CI 1.32, 1.69). Females who had completed primary, secondary (OR 2.43, 95% CI 1.92, 3.08) or higher education had higher odds of unintentional injuries. Conclusion The findings mirror prior literature highlighting the clustering of demographic and behavioral factors which underlie predisposition to injuries outside of the traffic environment. Future nationally representative studies would benefit from deeper inquiry into and measurement of injury severity and health care utilization to inform strategic policy‐relevant research.

We developed a novel lentiviral vector, pseudotyped with the F and HN proteins from Sendai virus (rSIV.F/HN), that produces long-lasting, high-efficiency transduction of the respiratory epithelium. Here we addressed whether this platform technology can secrete sufficient levels of a therapeutic protein into the lungs to ameliorate a fatal pulmonary disease as an example of its translational capability. Pulmonary alveolar proteinosis (PAP) results from alveolar granulocyte-macrophage colony-stimulating factor (GM-CSF) insufficiency, resulting in abnormal surfactant homeostasis and consequent ventilatory problems. Lungs of GM-CSF knockout mice were transduced with a single dose of rSIV.F/HN-expressing murine GM-CSF (mGM-CSF; 1e5–92e7 transduction units [TU]/mouse); mGM-CSF expression was dose related and persisted for at least 11 months. PAP disease biomarkers were rapidly and persistently corrected, but we noted a narrow toxicity/efficacy window. rSIV.F/HN may be a useful platform technology to deliver therapeutic proteins for lung diseases requiring long-lasting and stable expression of secreted proteins.

Background: Malaria remains a major health concern in developing countries with high morbidity and mortality, especially in pregnant women and infants. A major obstacle to the treatment of malaria is a low effectiveness and an increase resistance of the parasite to antimalarial drugs. As a result, there is an ongoing demand for new and potent antimalarial drugs. Medicinal plants remain a potential source for the development of new antimalarial drugs. Amongst them is Dissotis rotundifolia is an ethnomedical important plant used in West Africa to treat malaria. Purpose: This study aimed at identifying new potential antifolates by virtually screening phytochemicals characterized from the whole plant methanolic extract of D. rotundifolia against Plasmodium falciparum Dihydrofolate Reductase (PfDHFR). Methods: LC-ESI-Q-TOF-MS analysis was employed to identify the phytochemicals present in the whole plant methanolic extract of D. rotundifolia. These phytochemicals were docked against the catalytic site of PfDHFR. The docking protocol was evaluated using the Area Under the Curve (AUC) of a Receiver Operating Characteristic (ROC) curve. The binding mechanisms and the drug-likeness of the phytochemicals were characterized. A 100 ns Molecular Dynamics (MD) simulation and Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) calculations were utilized to analyze the stability, the energy decomposition per residue and the binding free energy of the potential leads. Results: Twenty nine phytochemicals were characterized and docked against PfDHFR. Dimethylmatairesinol, flavodic acid, sakuranetin, and sesartemin were identified as potential leads with binding affinities of -8.4, -8.9, -8.6, and -8.9 kcal/mol respectively, greater than a stringent threshold of -8.0 kcal/mol. The potential leads also interacted hydrophobically with critical residue Phe58. A novel critical residue, Leu46 was identified to be crucial in the catalytic activity of PfDHFR. The potential leads were also predicted to be anti-protozoal with a probability of active (Pa) value ranging from 0.319 to 0.537. Conclusion: This study elucidates the potential inhibition of PfDHFR by dimethylmatairesinol, flavodic acid, sakuranetin and sesartemin present in D. rotundifolia. These compounds are druglike, do not violate Lipinski's rule of five, have a high binding affinity to PfDHFR, and interact with crucial residues involved in the catalytic activity PfDHFR. Dimethylmatairesinol, flavodic acid, sakuranetin and sesartemin could therefore be further investigated and developed as new antifolate drugs for malaria.

Personality traits in many taxa correlate with fitness. Several models have been developed to try to explain how variation in these traits is maintained. One model proposes that variation persists because it is linked to trade-offs between current and future adaptive benefits. Tests of this model’s predictions, however, are scant in long-lived species. To test this model, we studied male chimpanzees living in Gombe National Park, Tanzania. We operationalized six personality traits using ratings on 19 items. We used 37 years of behavioral and genetic data to assemble (1) daily rank scores generated from submissive vocalizations and (2) records of male siring success. We tested whether the association between two personality traits, Dominance and Conscientiousness, and either rank or reproductive success, varied over the life course. Higher Dominance and lower Conscientiousness were associated with higher rank, but the size and direction of these relationships did not vary over the life course. In addition, independent of rank at the time of siring, higher Dominance and lower Conscientiousness were related to higher siring success. Again, the size and direction of these relationships did not vary over the life course. The trade-off model, therefore, may not hold in long-lived and/or slowly reproducing species. These findings also demonstrate that ratings are a valid way to measure animal personality; they are related to rank and reproductive success. These traits could therefore be used to test alternative models, including one that posits that personality variation is maintained by environmental heterogeneity, in studies of multiple chimpanzee communities.

Self-testing for COVID-19 may be a preferable strategy for identifying SARS-CoV-2 infection among populations in low- and middle-income settings. To determine South Africans’ values related to COVID-19 self-testing should it become widely available, a cross-sectional survey was administered in Durban, KwaZulu-Natal Province and the King Sabata Dalindyebo sub-district of the Eastern Cape.A 35-question survey was administered to 531 participants (268 female) in one urban and one rural setting of South Africa. Survey participants were randomly selected by household in the rural setting, while in the urban setting participants were approached in randomly selected public places. The survey assessed participants’ likelihood of using and willingness to pay for a COVID-19 self-test and actions they would take following a COVID-19 self-test. The results were analysed using descriptive statistics and bivariate and multivariate regression.Overall, 93.03% of participants supported COVID-19 self-testing, 61.62% of participants were willing to pay for self-testing, and 90.15% indicated they would communicate their results if they tested positive. Rural participants were more positively associated with each of these outcomes compared with urban-based participants. Should they test positive, most participants said they would: go in-person to a health facility for counselling (76.45%), self-isolate (95.85%), notify close contacts (97.74%), and inform their employer (95.14%).COVID-19 self-testing was a preferable option for most participants, although this varied with setting and demographic characteristics. Self-testing may overcome barriers to care for South Africans, but to achieve this, policies for self-testing and delivery methods must not exacerbate individuals’ underlying economic vulnerabilities.

BackgroundIn response to worldwide calls for the need to support evidence-informed policy-making (EIPM), more countries are increasingly interested in enhancing their efforts to use research to inform policy-making. In order to inform the efforts of those asked to lead the support of EIPM, our aim is to develop a conceptual framework to guide the process of establishing a policy support organization (PSO). MethodsWe conducted a critical interpretive synthesis (CIS). We conducted a two steps literature review. In the second step, we systematically searched OVID EMBASE, PsychInfo, HealthStar, CINAHL, Web of Science, Social Science Abstract, Health Systems Evidence, and ProQuest Dissertations and Theses Global databases for documents reporting the establishment of PSOs and the contextual factors influencing the process of establishing these organizations. We assessed the eligibility of the retrieved articles and synthesized the findings iteratively. ResultsWe included 52 documents in the synthesis. Our findings suggest that a PSO establishment process has four interconnected stages: awareness, development, assessment, and maturation. The process of establishing a PSO is iterative and influenced by political, research and health systems contextual factors, which determine the availability of the resources and the trust between researchers and policy-makers. The contextual factors have an impact on each other, and the challenges that arise from one factor can be mitigated by other factors. ConclusionFor those interested in establishing a PSO, our framework provides a road map for identifying the most appropriate starting point and the factors that might influence the establishment process. Leaders of such PSOs can use our findings to expand or refine their scope of work. Given that this framework focuses only on PSOs in the health sector, an important next step for research would be to include other sectors from social systems and identify any additional insight that can enhance our framework.

The role of the microbiota–gut–brain (MGB) axis in mood regulation and depression treatment has gained attention in recent years, as evidenced by the growing number of animal and human studies that have reported the anti-depressive and associated gamma-aminobutyric acid-ergic (GABAergic) effects of probiotics developed from Lactobacillus rhamnosus bacterial strains in the gut microbiome. The depressive states attenuated by these probiotics in patients suffering from clinical depression also characterize the severe and relapse-inducing withdrawal phase of the addiction cycle, which has been found to arise from the intoxication-enabled hyperregulation of the hypothalamic–pituitary–adrenal (HPA) axis, the body’s major stress response system, and a corresponding attenuation of its main inhibitory system, the gamma-aminobutyric acid (GABA) signaling system. Therefore, the use of probiotics in the treatment of general cases of depression provides hope for a novel therapeutic approach to withdrawal depression remediation. This review discusses potential therapeutic avenues by which probiotic application of Lactobacillus rhamnosus strains can be used to restore the central GABAergic activity responsible for attenuating the depression-inducing HPA axis hyperactivity in addiction withdrawal. Also, information is provided on brain GABAergic signaling from other known GABA-producing strains of gut microbiota.

Neuroinvasive infection is the most common cause of meningoencephalitis in people living with human immunodeficiency virus (HIV), but autoimmune etiologies have been reported. We present the case of a 51-year-old man living with HIV infection with steroid-responsive meningoencephalitis whose comprehensive pathogen testing was non-diagnostic. Subsequent tissue-based immunofluorescence with acute-phase cerebrospinal fluid revealed anti-neural antibodies localizing to the axon initial segment (AIS), the node of Ranvier (NoR), and the subpial space. Phage display immunoprecipitation sequencing identified ankyrinG (AnkG) as the leading candidate autoantigen. A synthetic blocking peptide encoding the PhIP-Seq-identified AnkG epitope neutralized CSF IgG binding to the AIS and NoR, thereby confirming a monoepitopic AnkG antibody response. However, subpial immunostaining persisted, indicating the presence of additional autoantibodies. Review of archival tissue-based staining identified candidate AnkG autoantibodies in a 60-year-old woman with metastatic ovarian cancer and seizures that were subsequently validated by cell-based assay. AnkG antibodies were not detected by tissue-based assay and/or PhIP-Seq in control CSF (N = 39), HIV CSF (N = 79), or other suspected and confirmed neuroinflammatory CSF cases (N = 1,236). Therefore, AnkG autoantibodies in CSF are rare but extend the catalog of AIS and NoR autoantibodies associated with neurological autoimmunity.

The mortalities and morbidities of leishmaniasis are high and the disease is under reported globally. The absence of vaccines coupled with chemotherapeutic challenges including chemoresistance, scarcity and toxicity have made the fight against leishmaniasis an arduous one. Furthermore, the treatment options currently available for leishmaniasis are long and sometimes require hospitalization. There is therefore the need to explore novel pathways to identify new compounds with alternative mechanisms of action. A pharmacophore-based screening was employed in identifying new potential inhibitors with unique scaffolds targeting Leishmania donovani sterol methyltransferase (LdSMT), a key enzyme for ergosterol biosynthesis. To accomplish this, 22,26-azasterol, a known inhibitor of this target and five other derivatives with IC50 less than 10 μM were used to generate a robust 3D pharmacophore model via LigandScout with a score of 0.9144. The validated model was used as a query to screen a library of 69034 natural products obtained from the InterBioScreen Limited. Compounds with pharmacophore fit scores above 50 were docked against the modelled structure of LdSMT. Altogether, ten molecules with binding energies between −7 and −11 kcal/mol were identified as potential bioactive molecules. The molecular dynamics simulation and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations reinforced the results from the docking studies suggesting the selected hits bind effectively at the active sites of the target protein. The compounds were observed to bind in the S-adenosine-L-homocysteine binding pocket of the modelled LdSMT with Trp208 and Val330 predicted as key residues critical for ligand binding. Prediction of biological activity with probability of activity (Pa) greater than probability of inactivity (Pi) revealed that seven compounds (STOCKIN-54848, STOCKIN-89115, STOCKIN-68720, STOCKIN-44724, STOCKIN-76694, STOCKIN-47277 and STOCKIN-95708) possessed antileishmanial properties. STOCKIN-89115, STOCKIN-68720, STOCKIN-44724, and STOCKIN-47277 were predicted to be membrane permeability inhibitors, while all ten hit compounds possessed antineoplastic activity. The compounds have the propensity of disrupting ergosterol biosynthesis leading to the suppression of growth in Leishmania donovani. The compounds were predicted to have good absorption, distribution, metabolism, excretion and toxicity profiles, hence their potential antileishmanial activity can be exploited upon experimental corroboration.

Hemolysis is associated with many pathologies, including trauma, sepsis, hemorrhagic stroke, malaria, and genetic disorders such as sickle cell disease (SCD). When hemolysis occurs, free-heme drives vascular inflammation, resulting in oxidative tissue damage and cardiometabolic complications. A better understanding of heme clearance and detoxification is essential to preventing sustained tissue damage. Human induced pluripotent stem cell (hiPSC)-derived endothelial cells (hiPSC-ECs) provide a novel source of patient-specific cells and tissues for disease modeling, drug discovery, and regenerative therapeutics. Here we report the use of hiPSC-ECs to elucidate the role of miR-451a and let-7i-5p-loaded extracellular vesicles (EVs, such as exosomes) in the inflammatory response to free-heme as a model for heme-induced inflammation. We provide evidence of a significant correlation between miR-451a and let-7i-5p-loaded circulating exosomes in plasmodium-infected patients with reported clinical benchmarks of malaria-severity (e.g., Hemoglobin (Hb) levels, white blood cell counts). Additionally, we determined that exposure of Plasmodium falciparum (Pf) parasites to EVs, loaded with either miRNA, significantly reduces their counts in vitro. Using hiPSCs derived from individuals with wild-type Hb (HbAA) or homozygous sickle cell mutated Hb (HbSS) genotypes, we demonstrate that heme-treated hiPSC-ECs secreted inflammatory products (cytokines, chemokines and growth factors) into supporting media at concentrations that were similar to that reported in HbAA and HbSS serum. This inflammatory response was attenuated by exposure with miR-451a or let-7i-5p-loaded EVs. We also found a decrease in transcription of ICAM1 and P-Selectin, as well as the secretion of key inflammatory cytokines (e.g., CXCL10, TNF-α, and IFN-γ). Based on these findings, we propose a model in which increased levels of exosomal miR-451a and let-7i-5p in Plasmodium-infected individuals will attenuate inflammatory responses to free-heme and parasite-derived products. As a result, infected erythrocytes will less likely adhere to the endothelium, sequester in brain micro vessels, and reduce vaso-occlusive crises that exacerbate cerebral malaria.

Abstract Cystic Fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The F508del and G542X are the most common mutations found in US patients, accounting for 86.4% and 4.6% of all mutations, respectively. The F508del causes deletion of the phenylalanine residue at position 508 and is associated with impaired CFTR protein folding. The G542X is a nonsense mutation that introduces a stop codon into the mRNA, thus preventing normal CFTR protein synthesis. Here, we describe the generation of CFTRF508del/F508del and CFTRG542X/G542X lambs using CRISPR/Cas9 and somatic cell nuclear transfer (SCNT). First, we introduced either F508del or G542X mutations into sheep fetal fibroblasts that were subsequently used as nuclear donors for SCNT. The newborn CF lambs develop pathology similar to CFTR−/− sheep and CF patients. Moreover, tracheal epithelial cells from the CFTRF508del/F508del lambs responded to a human CFTR (hCFTR) potentiator and correctors, and those from CFTRG542X/G542X lambs showed modest restoration of CFTR function following inhibition of nonsense‐mediated decay (NMD) and aminoglycoside antibiotic treatments. Thus, the phenotype and electrophysiology of these novel models represent an important advance for testing new CF therapeutics and gene therapy to improve the health of patients with this life‐limiting disorder.

Abstract Scoping reviews are an increasingly common approach to evidence synthesis with a growing suite of methodological guidance and resources to assist review authors with their planning, conduct and reporting. The latest guidance for scoping reviews includes the JBI methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses—Extension for Scoping Reviews. This paper provides readers with a brief update regarding ongoing work to enhance and improve the conduct and reporting of scoping reviews as well as information regarding the future steps in scoping review methods development. The purpose of this paper is to provide readers with a concise source of information regarding the difference between scoping reviews and other review types, the reasons for undertaking scoping reviews, and an update on methodological guidance for the conduct and reporting of scoping reviews. Despite available guidance, some publications use the term ‘scoping review’ without clear consideration of available reporting and methodological tools. Selection of the most appropriate review type for the stated research objectives or questions, standardised use of methodological approaches and terminology in scoping reviews, clarity and consistency of reporting and ensuring that the reporting and presentation of the results clearly addresses the review’s objective(s) and question(s) are critical components for improving the rigour of scoping reviews. Rigourous, high-quality scoping reviews should clearly follow up to date methodological guidance and reporting criteria. Stakeholder engagement is one area where further work could occur to enhance integration of consultation with the results of evidence syntheses and to support effective knowledge translation. Scoping review methodology is evolving as a policy and decision-making tool. Ensuring the integrity of scoping reviews by adherence to up-to-date reporting standards is integral to supporting well-informed decision-making.

BackgroundAssistive technology (AT) can contribute to how individuals participate and engage in everyday activities, such as communication and mobility, and facilitates access to the services they require. Navigating Canada’s AT system has been described as fragmented and complex, presenting barriers for individuals who require AT, caregivers, and health service providers. AccessATCanada was developed as a centralized web-based resource to help support access to AT by providing information about the existing jurisdictional funding programs and services. ObjectiveThis study aimed to evaluate the usability of AccessATCanada by gathering feedback about its features, functionality, and areas of strength and opportunity from potential end users. MethodsA usability testing study using a think-aloud approach and semistructured interviews was conducted to measure the effectiveness and efficiency of and user satisfaction with AccessATCanada and to identify issues with the interface during end-user interaction. A qualitative thematic analysis was used to generate insights into and core themes about user experiences. User feedback was used to inform subsequent updates of the database with the goal of enhancing website friendliness and functionality before its official launch. ResultsA total of 10 participants (6 consumers, 1 caregiver, and 3 providers) participated in the usability testing study. The usability performance and scores tended to improve between the 2 testing cycles. Most participants were able to successfully complete all the tasks independently. The efficiency scores tended to improve as the users continued to engage with the interface. The website received an overall System Usability Score of 62.22, which was ranked as “OK/fair to good.” The users provided an overall positive evaluation of the beta version of the web-based resource tested over 2 cycles and helped to identify areas for improvement. They commented on the functionality and added value of the website, discovery of new programs and resources, and design aesthetics. Most usability issues were reported as minor challenges related to presentation, functionality, and language, and feedback was adopted into later iterations of the website. ConclusionsThis study provides reflections on the value of usability testing and elements that are key to the creation of user-centered resources, such as the inclusion of participants with various abilities and considerations regarding website design and accessibility in an increasingly web-based world. AccessATCanada is now part of a growing global response to expand the reach of AT programs and services, improve the equity of access to AT, and reduce the complexity of navigating AT systems.

Phage immunoprecipitation sequencing (PhIP-seq) allows for unbiased, proteome-wide autoantibody discovery across a variety of disease settings, with identification of disease-specific autoantigens providing new insight into previously poorly understood forms of immune dysregulation. Despite several successful implementations of PhIP-seq for autoantigen discovery, including our previous work (Vazquez et al., 2020), current protocols are inherently difficult to scale to accommodate large cohorts of cases and importantly, healthy controls. Here, we develop and validate a high throughput extension of PhIP-seq in various etiologies of autoimmune and inflammatory diseases, including APS1, IPEX, RAG1/2 deficiency, Kawasaki disease (KD), multisystem inflammatory syndrome in children (MIS-C), and finally, mild and severe forms of COVID-19. We demonstrate that these scaled datasets enable machine-learning approaches that result in robust prediction of disease status, as well as the ability to detect both known and novel autoantigens, such as prodynorphin (PDYN) in APS1 patients, and intestinally expressed proteins BEST4 and BTNL8 in IPEX patients. Remarkably, BEST4 antibodies were also found in two patients with RAG1/2 deficiency, one of whom had very early onset IBD. Scaled PhIP-seq examination of both MIS-C and KD demonstrated rare, overlapping antigens, including CGNL1, as well as several strongly enriched putative pneumonia-associated antigens in severe COVID-19, including the endosomal protein EEA1. Together, scaled PhIP-seq provides a valuable tool for broadly assessing both rare and common autoantigen overlap between autoimmune diseases of varying origins and etiologies.

Abstract Background Road traffic crashes (RTCs) are a global public health burden whose resulting morbidity and mortality disproportionately impact low‐ and middle‐income countries with stressed health systems. There is a paucity of published studies that evaluate the sociodemographic distribution of RTCs using nationally representative samples from the African region. Aim To examine population‐wide associations between sociodemographic factors and involvement in RTCs in Kenya. Methods Data were obtained from the 2014 Kenyan Demographic Health Survey, representing all 47 counties in Kenya, from May to October of 2014. We estimated the prevalence of RTCs and utilized logistic regression for bivariate and multivariable analyses to determine the sociodemographic factors associated with RTCs. Study variables included age, place of residence, household wealth index, educational attainment, and history of alcohol consumption. We computed odds ratios (ORs) and their corresponding 95% confidence intervals (CIs). Results A higher prevalence was reported among men (8.76%) versus women (3.22%). The risk factors among men included being 20−34 years of age, living in a rural area (OR 1.38, 95% CI 1.09, 1.74), drinking alcohol (OR 1.33, 95% CI 1.11, 1.59), and having not higher than a primary (OR 1.90, 95% CI 1.19, 3.03) or secondary (OR 1.68, 95% CI 1.04, 2.71) education. The strongest risk factors for women included the being aged 45−49 (OR 2.30, 95% CI 1.44, 3.67) and 20−24 years (OR 1.81, 95% 1.17, 2.79) as well as being in the fourth wealth quintile (OR 1.83, 95% CI 1.15, 2.91). Conclusion Men and the most economically productive age groups were more likely to report being involved in RTCs. Strategies to reduce the occurrences of RTCs should prioritize the most vulnerable sociodemographic groups.

Plasmodium falciparum malaria is still an important disease in sub-Saharan Africa (sSA). Great strides have been made in its control spear-headed by artemisinin (ART)-based combination therapies (ACTs). However, concerns about the imminent spread of ART-resistant (ARTr) malaria parasites to sSA threaten gains already made. Attempts to mitigate this risk have highlighted the need to discover novel P. falciparum drug targets. Therefore, studies to deepen our understanding of the biology of P. falciparum are needed. The role of extracellular vesicles (EVs) in the biology of malaria parasites is not fully understood. Recently, the ART resistance-associated transcriptional profile has been reported to involve several biological processes connected to vesicular trafficking, proteotoxic stress, erythrocyte remodelling, and mitochondrial metabolism. We explored a role for EVs in developing the P. falciparum ARTr phenotype using bulk RNA sequencing of unsynchronized parasite cultures under untreated, 0.1% dimethyl sulfoxide and 700nM dihydroartemisinin treated conditions for six hours. As pathway and gene ontology analysis is limited in its curated knowledge repertoire on EVs biogenesis in P. falciparum, we used a modular (gene set) analysis approach to explore whether an EVs biogenesis module is associated with the ARTr phenotype in P. falciparum. We first generated well-defined EVs modules of interest and used statistical tools to determine differences in their expression among the parasite and treatment conditions. Then we used gene set enrichment analysis to determine the strength of the association between each EVs module of interest and the ARTr phenotype. This transcriptome-module phenotype association study (TMPAS) represents a well-powered approach to making meaningful discoveries out of bulk gene expression data. We identified four EVs module of interest and report that one module representing gene sets with correlated expression to PF3D7_1441800 – involved with EVs biogenesis in P. falciparum - is associated with the ARTr phenotype (R539T_DHA_treated versus R539T_untreated: normalized enrichment score (NES) = 1.1830174, FDR q-value < 0.25; C580R_DHA_treated versus C580R_untreated: NES = 1.2457103, FDR q-value < 0.25). PF3D7_1441800 has been reported to reduce EVs production when knocked out in P. falciparum. Altogether, our findings suggest a role for EVs in developing ART resistance and warrant further studies interrogating this association.

Abstract Background and Aim Human hookworm disease caused by Ancylostoma duodenale and Necator americanus is a serious public health problem. Hookworm infection activates eosinophil‐mediated tissue inflammatory responses, involving the production of the eosinophil‐specific chemokine (eotaxin), recruitment of eosinophils, secretion of the cationic protein, and production of antiparasite immunoglobulin E (IgE). We investigated eosinophil‐mediated immune response as markers (CCL11, eosinophil cationic protein [ECP], and IgE) for detecting hookworm infection. Methods This case‐control study was carried out in hookworm endemic areas within the Kintampo North Municipality.Forty hookworm‐positive subjects and 36 apparently healthy individuals were recruited as cases and controls, respectively. Stool samples were collected for hookworm detection by the Kato–Katz technique and speciation by polymerase chain reaction. Approximately, 5 ml of intravenous blood was used to obtain plasma for the immunological assays. Results Of eosinophil‐mediated immune response markers studied, ECP and CCL11 were significantly higher among hookworm patients compared to controls. Increasing CCL11 (β = −0.81, p = 0.015) was associated with a significant decrease hookworm intensity. However, increasing eosinophil count (β = 0.62, p = 0.027) was associated with significant increase in hookworm intensity. In receiver operator characteristics analysis, ECP could significantly detect hookworm infection with a very high area under the curve (AUC) (AUC = 0.97, p

Abstract Background Plasmodium falciparum and Hookworm infections are prevalent in West Africa and they cause iron deficiency anemia and protein malnutrition in Children. Immune response of these parasites interact and their interactions could have repercussions on vaccine development and efficacy. The current goal of hookworm eradication lies on vaccination. We evaluated the effect of P. falciparum coinfection and albendazole treatment on naturally acquired antibody profile against hookworm L3 stage larvae antigen. Methods In a longitudinal study, 40 individuals infected with Necator americanus only, 63 participants infected with N. americanus and P. falciparum, and 36 nonendemic controls (NECs) were recruited. The study was done in the Kintampo North Metropolis of Ghana. Stool and blood samples were taken for laboratory analyses. Serum samples were obtained before hookworm treatment and 3 weeks after treatment. Results The malaria‐hookworm (N. americanus and P. falciparum) coinfected subjects had significantly higher levels of IgE (β = 0.30, 95% CI = [0.12, 0.48], p = 0.023) and IgG3 (β = 0.15, 95% CI = [0.02, 0.52], p = 0.004) compared to those infected with hookworm only (N. americanus). The N. americanus groups had significantly higher levels of IgG3 (β = 0.39, 95% CI = [0.14–0.62], p = 0.002) compared to the control group. Similarly, N. americanus and P. falciparum coinfected participants had significantly higher levels of IgE (β = 0.35, 95% CI = [0.70–0.39], p = 0.002) and IgG3 (β = 0.54, 95% CI = [0.22–0.76], p = 0.002). Moreover, albendazole treatment led to a significant reduction in IgE, IgA, IgM, and IgG3 antibodies against hookworm L3 stage larvae (p

The therapeutic challenges pertaining to leishmaniasis due to reported chemoresistance and toxicity necessitate the need to explore novel pathways to identify plausible inhibitory molecules. Leishmania donovani 24-sterol methyltransferase (LdSMT) is vital for the synthesis of ergosterols, the main constituents of Leishmania cellular membranes. So far, mammals have not been shown to possess SMT or ergosterols, making the pathway a prime candidate for drug discovery. The structural model of LdSMT was elucidated using homology modeling to identify potential novel 24-SMT inhibitors via virtual screening, scaffold hopping, and de-novo fragment-based design. Altogether, six potential novel inhibitors were identified with binding energies ranging from −7.0 to −8.4 kcal/mol with e-LEA3D using 22,26-azasterol and S1–S4 obtained from scaffold hopping via the ChEMBL, DrugBank, PubChem, ChemSpider, and ZINC15 databases. These ligands showed comparable binding energy to 22,26-azasterol (−7.6 kcal/mol), the main inhibitor of LdSMT. Moreover, all the compounds had plausible ligand efficiency-dependent lipophilicity (LELP) scores above 3. The binding mechanism identified Tyr92 to be critical for binding, and this was corroborated via molecular dynamics simulations and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The ligand A1 was predicted to possess antileishmanial properties with a probability of activity (Pa) of 0.362 and a probability of inactivity (Pi) of 0.066, while A5 and A6 possessed dermatological properties with Pa values of 0.205 and 0.249 and Pi values of 0.162 and 0.120, respectively. Structural similarity search via DrugBank identified vabicaserin, daledalin, zanapezil, imipramine, and cefradine with antileishmanial properties suggesting that the de-novo compounds could be explored as potential antileishmanial agents.

Background: violence among young people, including physical fighting, is a crucial global public health concern. There is a scarcity of evidence directed at understanding the prevalence and associated factors for physical fights among adolescents in Mauritius. This study aimed to examine the prevalence physical fighting in schools and the demographic characteristics that are associated with the phenomenon. Methods: we conducted a cross-sectional analysis of nationally representative data from Mauritius with the aim of examining the 12-month prevalence of physical fighting and frequencies of related individual and social-level characteristics. We further measured the association between physical violence and adolescent parameters using binary logistic regression analyses. Results: the participants were predominantly females (53.49%) with a mean age of 14.91 (1.47) years. Within the preceding twelve months, 15.74% of the participants reported being involved in physical fights. Among other factors, the male gender (OR = 2.6, 95% CI (1.87, 3.62)), food deprivation (OR = 2.46, 95% CI (1.41, 4.32)), bullying victimization (OR = 2.81, 95% CI (2.12, 3.73)), and cigarette use (OR = 2.07, 95% CI (1.34, 3.19)) increased the likelihood of physical fighting. The other associated factors were loneliness (OR = 1.65, 95% CI (1.11, 2.43)), physical activity (OR = 1.52, 95% CI (1.09, 2.12)), early sexual debut (OR = 2.15, 95% CI (1.17, 3.95)), and alcohol use (OR = 1.56, 95% CI (1.11, 2.21)). Conclusions: physical violence is frequent among adolescents in Mauritius; however, a comparison with previous findings in similar sub-Saharan countries suggests a reducing trend. Advocates, policymakers, and other critical stakeholders need to consider the relevant demographic and behavioral factors in formulating strategies and designing public health interventions for the prevention and control of physical violence among adolescents.

Abstract Background Malaria and helminths diseases are co-endemic in most parts of sub-Saharan Africa. Immune responses from each of these pathogens interact, and these interactions may have implications on vaccines. The GMZ2 malaria vaccine candidate is a fusion protein of Plasmodium falciparum merozoite surface protein 3 (MSP3) and glutamate rich protein (GLURP R0). GMZ2 has recently showed modest efficacy in a phase IIb multicenter trial. Here, we assessed the effect of hookworm (Necator americanus) infection and anthelmintic treatment on naturally acquired antibody responses against GMZ2 and constituent antigens. Methods This longitudinal cross-sectional study was conducted in the Kintampo North Municipality of Ghana. Blood and stool samples were taken from 158 individuals (4–88 years old) infected with either P. falciparum alone (n = 59) or both hookworm and P. falciparum (n = 63) and uninfected endemic controls (n = 36). Stool hookworm infection was detected by the Kato-Katz method and PCR. Malaria parasitaemia was detected by RDT, light microscopy and P. falciparum-specific 18S rRNA gene PCR. Serum samples were obtained prior to hookworm treatment with a single dose of albendazole (400 mg) and 3 weeks (21 days) after treatment. Levels of IgG1, IgG3 and IgM against GMZ2, MSP3 and GLURP R0 were measured by ELISA and compared among the groups, before and after treatment. Results Participants with P. falciparum and hookworm co-infection had significantly higher IgG3 levels to GMZ2 than those with only P. falciparum infection and negative control (p

We have previously shown computationally that Mycolactone (MLN), a toxin produced by Mycobacterium ulcerans, strongly binds to Munc18b and other proteins, presumably blocking degranulation and exocytosis of blood platelets and mast cells. We investigated the effect of MLN on endocytosis using similar approaches, and it bound strongly to the N-terminal of the clathrin protein and a novel SARS-CoV-2 fusion protein. Experimentally, we found 100% inhibition up to 60 nM and 84% average inhibition at 30 nM in SARS-CoV-2 live viral assays. MLN was also 10× more potent than remdesivir and molnupiravir. MLN’s toxicity against human alveolar cell line A549, immortalized human fetal renal cell line HEK293, and human hepatoma cell line Huh7.1 were 17.12%, 40.30%, and 36.25%, respectively. The cytotoxicity IC50 breakpoint ratio versus anti-SARS-CoV-2 activity was more than 65-fold. The IC50 values against the alpha, delta, and Omicron variants were all below 0.020 µM, and 134.6 nM of MLN had 100% inhibition in an entry and spread assays. MLN is eclectic in its actions through its binding to Sec61, AT2R, and the novel fusion protein, making it a good drug candidate for treating and preventing COVID-19 and other similarly transmitted enveloped viruses and pathogens.

Malaria affects a significant portion of the global population, with 247 million cases in 2021, primarily in Africa. However, certain hemoglobinopathies, such as sickle cell trait (SCT), have been linked to lower mortality rates in malaria patients. Hemoglobin (Hb) mutations, including HbS and HbC, can cause sickle cell disease (SCD) when both alleles are inherited (HbSS and HbSC). In SCT, one allele is inherited and paired with a normal allele (HbAS, HbAC). The high prevalence of these alleles in Africa may be attributed to their protective effect against malaria. Biomarkers are crucial for SCD and malaria diagnosis and prognosis. Studies indicate that miRNAs, specifically miR-451a and let-7i-5p, are differentially expressed in HbSS and HbAS compared to controls. Our research examined the levels of exosomal miR-451a and let-7i-5p in red blood cells (RBCs) and infected red blood cells (iRBCs) from multiple sickle Hb genotypes and their impact on parasite growth. We assessed exosomal miR-451a and let-7i-5p levels in vitro in RBC and iRBC supernatants. Exosomal miRNAs exhibited distinct expression patterns in iRBCs from individuals with different sickle Hb genotypes. Additionally, we discovered a correlation between let-7i-5p levels and trophozoite count. Exosomal miR-451a and let-7i-5p could modulate SCD and malaria severity and serve as potential biomarkers for malaria vaccines and therapies.

The Ebola virus (EBOV) is still highly infectious and causes severe hemorrhagic fevers in primates. However, there are no regulatorily approved drugs against the Ebola virus disease (EVD). The highly virulent and lethal nature of EVD highlights the need to develop therapeutic agents. Viral protein 40 kDa (VP40), the most abundantly expressed protein during infection, coordinates the assembly, budding, and release of viral particles into the host cell. It also regulates viral transcription and RNA replication. This study sought to identify small molecules that could potentially inhibit the VP40 protein by targeting the N-terminal domain using an in silico approach. The statistical quality of AutoDock Vina’s capacity to discriminate between inhibitors and decoys was determined, and an area under the curve of the receiver operating characteristic (AUC-ROC) curve of 0.791 was obtained. A total of 29,519 natural-product-derived compounds from Chinese and African sources as well as 2738 approved drugs were successfully screened against VP40. Using a threshold of −8 kcal/mol, a total of 7, 11, 163, and 30 compounds from the AfroDb, Northern African Natural Products Database (NANPDB), traditional Chinese medicine (TCM), and approved drugs libraries, respectively, were obtained after molecular docking. A biological activity prediction of the lead compounds suggested their potential antiviral properties. In addition, random-forest- and support-vector-machine-based algorithms predicted the compounds to be anti-Ebola with IC50 values in the micromolar range (less than 25 μM). A total of 42 natural-product-derived compounds were identified as potential EBOV inhibitors with desirable ADMET profiles, comprising 1, 2, and 39 compounds from NANPDB (2-hydroxyseneganolide), AfroDb (ZINC000034518176 and ZINC000095485942), and TCM, respectively. A total of 23 approved drugs, including doramectin, glecaprevir, velpatasvir, ledipasvir, avermectin B1, nafarelin acetate, danoprevir, eltrombopag, lanatoside C, and glycyrrhizin, among others, were also predicted to have potential anti-EBOV activity and can be further explored so that they may be repurposed for EVD treatment. Molecular dynamics simulations coupled with molecular mechanics Poisson–Boltzmann surface area calculations corroborated the stability and good binding affinities of the complexes (−46.97 to −118.9 kJ/mol). The potential lead compounds may have the potential to be developed as anti-EBOV drugs after experimental testing.

During the COVID-19 pandemic, the Summer Food Service Program (SFSP) was allowed to operate in untraditional non-summer months to ensure children did not lose access to free and reduced-priced nutritious meals when schools were mandated to close in the United States. This study assessed the impact of the pandemic on the operations and experiences of Summer Food Service Program (SFSP) sponsors in the state of Maryland during the COVID-19 pandemic in 2020 (Phase I) and 2021 (Phase II). This study used a multiphase explanatory sequential mixed methods design with qualitative prioritization. Maryland SFSP sponsors completed an online survey (Phase I: n = 27, Phase II: n = 30), and semi-structured in-depth interviews were conducted with a subset of sponsors who completed the survey (Phase I: n = 12, Phase II: n = 7). Inductive and deductive analyses were used for qualitative data, and descriptive statistics were used for quantitative data. The COVID-19 pandemic caused SFSP sponsors to change their operations. Sponsors were primarily concerned about staff safety/burnout and decreased participation. Sponsors perceived waivers implemented by the United States Department of Agriculture to be crucial in enabling them to serve meals to children during the pandemic. The findings from our study support advocacy efforts to permanently implement waivers and provide free school meals for all children.

The mutualistic interspecific relationships of trophobiosis between trophobiont planthoppers (Hemiptera, Fulgoromorpha) providing food to the host called xenobiont, are reviewed. The degree of interspecific relationships between these symbionts varies from occasional or short time duration (a few hours to a few days) to longer ones, with trophobionts left free to escape (optobiotic type) by the xenobiont, or maintained enclosed in nests or ant shelters (cryptobiotic type). Of 267 collected cases, 126 are new illustrated observations. Occasional trophobiosis is documented in 13 families of planthoppers and appears to be quite general in Fulgoromorpha, although it is reported for the first time for Dictyopharidae, Eurybrachidae, and Nogodinidae. Xenobionts associated with planthoppers are reported from ants and other Hymenoptera, Lepidoptera, and Blattodea, but also from Mollusca and even small gekkonid vertebrates. Tettigometridae appear to be exclusively tended by ants, while Fulgoridae significantly more often by cockroaches (40%) than by ants (27%). Long-time trophobiosis occurs always with ants, cryptobiotic ones reported in Cixiidae, Delphacidae, Tettigometridae, Meenoplidae, Flatidae and Hypochthonellidae, while optobiotic ones remain restricted to tettigometrids. A particular focus on Tettigometridae attended by ants is provided with new etho-ecological observations of 92 currently described tettigometrids species, 32 different species (35%) are now known to be able to be ant-attended. In Bulgaria, where fourteen species occur, trophobiosis occurs with at least five species of them (36%). In tettigometrids, subsociality, sessility, and underground life appear to be key factors allowing more complex relationships with ants. However, the planthopper size and thus the amount of food (drops of honeydew) is probably also an important factor. This might explain many new observations in large-sized and often isolated fulgorids with cockroaches. Tapping of trophobiont forewings by cockroaches, moths, or of the bark subtrate by geckos has been observed, but antennal palpation behaviours by ants are the most commonly observed with tettigometrids, although not with larger planthoppers. In tettigometrids, specific tegumentary glands secretions (allomones) of the abdomen pleurites might also mediate their long-term mutualistic associations, even possibly completing honeydew kairomones actions mediating planthopper trophobiosis in general.

Abstract Background The fields of implementation science and knowledge translation have evolved somewhat independently from the field of policy implementation research, despite calls for better integration. As a result, implementation theory and empirical work do not often reflect the implementation experience from a policy lens nor benefit from the scholarship in all three fields. This means policymakers, researchers, and practitioners may find it challenging to draw from theory that adequately reflects their implementation efforts. Methods We developed an integrated theoretical framework of the implementation process from a policy perspective by combining findings from these fields using the critical interpretive synthesis method. We began with the compass question: How is policy currently described in implementation theory and processes and what aspects of policy are important for implementation success? We then searched 12 databases as well as gray literature and supplemented these documents with other sources to fill conceptual gaps. Using a grounded and interpretive approach to analysis, we built the framework constructs, drawing largely from the theoretical literature and then tested and refined the framework using empirical literature. Results A total of 11,434 documents were retrieved and assessed for eligibility and 35 additional documents were identified through other sources. Eighty-six unique documents were ultimately included in the analysis. Our findings indicate that policy is described as (1) the context, (2) a focusing lens, (3) the innovation itself, (4) a lever of influence, (5) an enabler/facilitator or barrier, or (6) an outcome. Policy actors were also identified as important participants or leaders of implementation. Our analysis led to the development of a two-part conceptual framework, including process and determinant components. Conclusions This framework begins to bridge the divide between disciplines and provides a new perspective about implementation processes at the systems level. It offers researchers, policymakers, and implementers a new way of thinking about implementation that better integrates policy considerations and can be used for planning or evaluating implementation efforts.