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Abstract Background The extent to which type 2 diabetes (T2D) reduces life expectancy depends on the risk of complications. We aimed to characterise the relationship between risk factors for diabetes complications and life expectancy, in individuals with T2D, free from major chronic disease, in a regional database linked with national New Zealand health databases. Methods A prospective cohort study design was employed, analysing data from individuals with T2D drawn from the comprehensive Diabetes Care Support Service database (1994–2018). Participants with known values for all five within-target risk factors (WTRF +) including blood pressure, glycaemia, and LDL cholesterol, alongside being non-smoking with normal renal function at baseline, were included. Life expectancy free from cardiovascular disease (CVD), cancer, and dementia at age 50 years was estimated using multistate life tables, adjusting for demographics and clinical metrics. Results Women and men with no WTRF + at enrolment had a life expectancy free from CVD, cancer, or dementia of 13.1 (95% confidence interval: 9.1–19.0) and 11.2 (6.7–18.6) years, respectively. For the most socioeconomically deprived groups or Māori with no WTRF + at baseline, life expectancies were markedly lower. Life expectancies were 23.7 (18.9–29.7) years for women and 23.2 years (17.2–31.4) years for men with four or five WTRF + at baseline, respectively. While an increasing number of WTRF + at baseline was significantly associated with improved outcomes in men and certain subgroups (e.g. Other ethnicity group), this trend was not statistically significant for women overall or in most subgroups. Conclusions Having multiple WTRF + at baseline is associated with a considerable increase in life expectancy free from major chronic disease among individuals with T2D. This highlights the importance of lifestyle and clinical interventions in the management of T2D and in the prevention and management of associated chronic conditions.

Abstract Background The effect of vaccination on the epigenome remains poorly characterized. In previous research, we identified an association between seroprotection against influenza and DNA methylation at sites associated with the RIG-1 signaling pathway, which recognizes viral double-stranded RNA and leads to a type I interferon response. However, these studies did not fully account for confounding factors including age, gender, and BMI, along with changes in cell-type composition. Results Here, we studied the influenza vaccine response in a longitudinal cohort vaccinated over two consecutive years (2019–2020 and 2020–2021), using peripheral blood mononuclear cells and a targeted DNA methylation approach. To address the effects of multiple factors on the epigenome, we designed a multivariate multiple regression model that included seroprotection levels as quantified by the hemagglutination-inhibition (HAI) assay test. Conclusions Our findings indicate that 179 methylation sites can be combined as potential signatures to predict seroprotection. These sites were not only enriched for genes involved in the regulation of the RIG-I signaling pathway, as found previously, but also enriched for other genes associated with innate immunity to viruses and the transcription factor binding sites of BRD4, which is known to impact T cell memory. We propose a model to suggest that the RIG-I pathway and BRD4 could potentially be modulated to improve immunization strategies.

Abstract Background Immunoglobulin (Ig) glycosylation modulates the immune response and plays a critical role in ageing and diseases. Studies have mainly focused on IgG glycosylation, and little is known about the genetics and epidemiology of IgA glycosylation. Methods We generated, using a novel liquid chromatography-mass spectrometry method, the first large-scale IgA glycomics dataset in serum from 2423 twins, encompassing 71 N- and O-glycan species. Results We showed that, despite the lack of a direct genetic template, glycosylation is highly heritable, and that glycopeptide structures are sex-specific, and undergo substantial changes with ageing. We observe extensive correlations between the IgA and IgG glycomes, and, exploiting the twin design, show that they are predominantly influenced by shared genetic factors. A genome-wide association study identified eight loci associated with both the IgA and IgG glycomes (ST6GAL1, ELL2, B4GALT1, ABCF2, TMEM121, SLC38A10, SMARCB1, and MGAT3) and two novel loci specifically modulating IgA O-glycosylation (C1GALT1 and ST3GAL1). Validation of our findings in an independent cohort of 320 individuals from Qatar showed that the underlying genetic architecture is conserved across ancestries. Conclusions Our study delineates the genetic landscape of IgA glycosylation and provides novel potential functional links with the aetiology of complex immune diseases, including genetic factors involved in IgA nephropathy risk.

Abstract Research suggests that interlocutors manage the timing demands of conversation by preparing what they want to say early. In three experiments, we used a verbal question-answering task to investigate what aspects of their response speakers prepare early. In all three experiments, participants answered more quickly when the critical content (here, barks) necessary for answer preparation occurred early (e.g., Which animal barks and is also a common household pet?) rather than late (e.g., Which animal is a common household pet and also barks?). In the individual experiments, we found no convincing evidence that participants were slower to produce longer answers, consisting of multiple words, than shorter answers, consisting of a single word. There was also no interaction between these two factors. A combined analysis of the first two experiments confirmed this lack of interaction, and demonstrated that participants were faster to answer questions when the critical content was available early rather than late and when the answer was short rather than long. These findings provide tentative evidence for an account in which interlocutors prepare the content of their answer as soon as they can, but sometimes do not prepare its length (and thus form) until they are ready to speak.

Background To study pain, data on pain characteristics, possible triggers and consequences - such as the impact of pain on people’s lives - need to be available. When not collated, described and/or organised in a systematic manner, it can be difficult to assess how useful an existing dataset may be for one’s project. This data note describes and categorises the complex and multi-modal indices of pain available in the Avon Longitudinal Study of Parents and Children (ALSPAC). Methods Data from two generations of the ALSPAC cohort; index child participants (Generation 1, G1), their mothers and fathers/mothers’ partners (Generation 0, G0) were used. Search terms such as ‘pain’, ‘ache’, ‘hurt’, ‘sore’, specific pain conditions, labour pain and methods of pain relief were used to identify pain and pain-related variables. These data were extracted from all waves of data collection. We developed pain categories and subsequently categorised variables in an iterative process. Repeated measurements of the same variables over waves of data collection were also identified. Results We identified 21 categories of pain variables, which were subsequently grouped into themes: pain characteristics, extended pain characteristics and causes, treatment for pain, pain interference and pain-related to specific events. Pain and pain-related data have been collected from G1 participants, G0 mothers, and G0 partners, although there are fewer data for the partners. There were some repeated measurements, most commonly, of pain location. As is typical with longitudinal birth cohort studies, maternal proxy-reports were used during participants’ younger years and self-reports were utilised from adolescence onwards. Conclusions Researchers interested in studying pain can feasibly do so in two generations of a regional UK population who have been followed up over 30 years. ALSPAC can be used to study pain from the early years through to young adulthood and in mothers from the perinatal period onwards.

Introduction A body of research has focused on helping children with disabilities stay physically active. As poor balance has been found as a major limitation in physical activities, a systematic review exploring balance intervention programs is warranted. Methods The primary aim of this is to systematically evaluate evidence for the effect of task-specific training to improve balance outcomes in ambulant children with cerebral palsy. Seven databases were searched for studies involving ambulant children with cerebral palsy (4–15 years old); balance TST; and balance-related outcomes. The quality of the studies was appraised using the JBI Critical Appraisal Checklists for risk of bias, study design, and quality of evidence. Continuous data were transformed and summarised using standardised mean difference and 95%CI. Results Seven randomised controlled trials met the inclusion criteria. The risk of bias was deemed low in most of the studies. Due to heterogeneity of study design and outcome measures, a narrative synthesis was conducted. Positive between-group effects favouring TST were found across the six studies (BBS d = 1.528, 95% CI = 0.7747–2.2813) and follow-up (BBS d = –1.667, 95% CI = –2.459 ÷ –0.874). Despite poor reporting of motor learning strategies, repetitive practice, feedback, and task modulation strategies were used consistently in balance TST. Conclusions TST could be recommended to be a part of an intervention programme to improve balance performance in children with CP. However, more studies with rigorous study design and adequately powered implementation of a more fun task-oriented training programme are needed.

Introduction Clinical assessment in emergency departments (EDs) for possible acute myocardial infarction (AMI) requires at least one cardiac troponin (cTn) blood test. The turn-around time from blood draw to posting results in the clinical portal for central laboratory analysers is ~1–2 hours. New generation, high-sensitivity, point-of-care cardiac troponin I (POC-cTnI) assays use whole blood on a bedside (or near bedside) analyser that provides a rapid (8 min) result. This may expedite clinical decision-making and reduce length of stay. Our purpose is to determine if utilisation of a POC-cTnI testing reduces ED length of stay. We also aim to establish an optimised implementation process for the amended clinical pathway.Methods and analysis This quality improvement initiative has a pragmatic multihospital stepped-wedge cross-sectional cluster randomised design. Consecutive patients presenting to the ED with symptoms suggestive of possible AMI and having a cTn test will be included. Clusters (comprising one or two hospitals each) will change from their usual-care pathway to an amended pathway using POC-cTnI—the ‘intervention’. The dates of change will be randomised. Changes occur at 1 month intervals, with a minimum 2 month ‘run-in’ period. The intervention pathway will use a POC-cTnI measurement as an alternate to the laboratory-based cTn measurement. Clinical decision-making steps and logic will otherwise remain unchanged. The POC-cTnI is the Siemens (Erlangen Germany) Atellica VTLi high-sensitivity cTnI assay. The primary outcome is ED length of stay. The safety outcome is cardiac death or AMI within 30 days for patients discharged directly from the ED.Ethics and dissemination Ethics approval has been granted by the New Zealand Southern Health and Disability Ethics Committee, reference 21/STH/9. Results will be published in a peer-reviewed journal. Lay and academic presentations will be made. Māori-specific results will be disseminated to Māori stakeholders.Trial registration number ACTRN12619001189112.

Abstract Background Health assessment tools developed using mainstream or Western concepts have been widely used in clinical practice worldwide. However, even culturally adapted or culturally based tools may not be relevant in other social contexts if they are grounded in Western beliefs and perspectives. The application of mainstream assessment tools, when used in Indigenous populations, can lead to the inappropriate application of normative data and inaccurate or biased diagnosis of conditions as Indigenous concepts of health differ from Western biomedical concepts of health. Thus, considering the need for culturally meaningful, sensitive, safe, and unbiased health assessment approaches and instruments over recent years, tools have been developed or adapted by and with Indigenous populations in Australia, Aotearoa/New Zealand, Canada, and the United States. However, there is no existing systematic or scoping review to identify the methods and approaches used in adapting or developing health assessment tools for use with the Indigenous population in Australia, Aotearoa/New Zealand, Canada, and the United States. Methods In response to these gaps, we are working with a First Nations Community Advisory Group in Northern Ontario, Canada, to undertake a scoping review following the 2020 JBI methodology for scoping reviews. A systematic search will be conducted in PubMed, APA PsychINFO, CINAHL, MEDLINE, Web of Science, Bibliography of Native North Americans, Australian Indigenous Health info data set, and Indigenous Health Portal. Two reviewers will independently screen all abstracts and full-text articles for inclusion using criteria co-developed with an advisory group. We will chart the extracted information and summarize and synthesize the data. The summarized findings will be presented to a Community Advisory Group, including First Nations community partners, an Elder, and community members, and their feedback will be incorporated into the discussion section of the scoping review. Discussion This scoping review involves iterative consultation with the Indigenous and non-Indigenous scholars, First Nations Community Advisory Group, and community partners throughout the research process. This review aims to summarize the evidence on standard ethical approaches and practices used in Indigenous research while adapting or developing health assessment tools. It will inform the larger study focused on developing an Indigenous Functional Assessment tool. Further, it will seek whether the Indigenous ways of knowing and equitable participation of Indigenous people and communities are incorporated in the Indigenous research process. Systematic review registration Open Science Framework https://osf.io/yznwk .

Abstract Domestic pigs are a critical component of the food supply and one of the most commonly raised production animals. Pork consumption has driven the intensification of pig production expanding into environments conducive to increased emergence and spread of infectious diseases, including the spillover of pathogens into human populations. One of these emerging viruses, Reston virus (RESTV), is an enigma among the Orthoebolavirus genus in that its lack of human pathogenicity is in stark contrast to the high virulence associated with most other ebolaviruses. RESTV is, however, associated with outbreaks of highly lethal hemorrhagic disease in non-human primates (NHP), as well as poorly understood clinical manifestations of mixed virulence and lethality in naturally and experimentally infected domestic pigs. Our results show it is possible for RESTV derived from an NHP to infect domestic pigs resulting in a spectrum of disease, from asymptomatic to severe respiratory distress. Further, we report on the first experimental transmission of RESTV between infected pigs and a co-housed, naïve animal, as well as the first report of the successful use of group oral fluids for the detection of RESTV RNA and virus-specific IgA antibodies.

Abstract Influenza virus infection alters the promoter DNA methylation of key immune response-related genes, including type-1 interferons and proinflammatory cytokines. However, less is known about the effect of the influenza vaccine on the epigenome. We utilized a targeted DNA methylation approach to study the longitudinal effects (day 0 pre-vaccination and day 28 post-vaccination) on influenza vaccination responses in peripheral blood mononuclear cells. We found that baseline, pre-vaccination methylation profiles are associated with pre-existing, protective serological immunity. Additionally, we identified 481 sites that were differentially methylated between baseline and day 28 post-vaccination. These were enriched for genes involved in the regulation of the RIG-I signaling pathway, an important regulator of viral responses. Our results suggest that DNA methylation changes to components of the RIG-I pathway are associated with vaccine effectiveness. Therefore, immunization strategies that target this pathway may improve serological responses to influenza vaccination.

IntroductionThe expansive curricular volume of healthcare education makes a necessity the incorporation of innovative methods and immersive media in it. The core challenge in such approaches is the timely development of relevant immersive content such as Virtual, Augmented or Mixed Reality (VR/AR/MR) resources for healthcare topics. There is currently significant interest in the use of co-creative methods for streamlining immersive content development.MethodsA core research pursuit in this translational research field is the formulation of evidence-based, optimized workflows that streamline immersive content creation allowing for rapid expansion of innovative educational approaches in healthcare curricula. The purpose of this paper is to aggregate the perceptions of healthcare technologists and educators who participated in a series of co-creation sessions in order to elicit their best practice insights for design and development of XR educational resources using co-creative methods.ResultsAccording to our thematic analysis, findings of the qualitative study demonstrated that a rigorous organizational approach is required to maintain a constructive exchange of information and to keep the design process alive for both content and technical experts. In addition, rapid prototype and display of co-created features can empower their contributions and help them design more efficiently.DiscussionCo-creative content production can benefit from adaption of existing frameworks and lightweight authoring environments that can facilitate generalized XR content development use cases.

Abstract This paper presents a generalized registration form for systematic reviews that can be used when currently available forms are not adequate. The form is designed to be applicable across disciplines (i.e., psychology, economics, law, physics, or any other field) and across review types (i.e., scoping review, review of qualitative studies, meta-analysis, or any other type of review). That means that the reviewed records may include research reports as well as archive documents, case law, books, poems, etc. Items were selected and formulated to optimize broad applicability instead of specificity, forgoing some benefits afforded by a tighter focus. This PRISMA 2020 compliant form is a fallback for more specialized forms and can be used if no specialized form or registration platform is available. When accessing this form on the Open Science Framework website, users will therefore first be guided to specialized forms when they exist. In addition to this use case, the form can also serve as a starting point for creating registration forms that cater to specific fields or review types.

Abstract The coronavirus 2019 (COVID-19) pandemic has had significant impacts on health systems, population dynamics, public health awareness, and antibiotic stewardship, which could affect antibiotic resistant bacteria (ARB) emergence and transmission. In this study, we aimed to compare knowledge, attitudes, and practices (KAP) of antibiotic use and ARB carriage in Ecuadorian communities before versus after the COVID-19 pandemic began. We leveraged data collected for a repeated measures observational study of third-generation cephalosporin-resistant E. coli (3GCR-EC) carriage among children in semi-rural communities in Quito, Ecuador between July 2018 and September 2021. We included 241 households that participated in surveys and child stool sample collection in 2019, before the pandemic, and in 2021, after the pandemic began. We estimated adjusted Prevalence Ratios (aPR) and 95% Confidence Intervals (CI) using logistic and Poisson regression models. Child antibiotic use in the last 3 months declined from 17% pre-pandemic to 5% in 2021 (aPR: 0.30; 95% CI 0.15, 0.61) and 3GCR-EC carriage among children declined from 40 to 23% (aPR: 0.48; 95% CI 0.32, 0.73). Multi-drug resistance declined from 86 to 70% (aPR: 0.32; 95% CI 0.13; 0.79), the average number of antibiotic resistance genes (ARGs) per 3GCR-EC isolate declined from 9.9 to 7.8 (aPR of 0.79; 95% CI 0.65, 0.96), and the diversity of ARGs was lower in 2021. In the context of Ecuador, where COVID-19 prevention and control measures were strictly enforced after its major cities experienced some of the world’s the highest mortality rates from SARS-CoV-2 infections, antibiotic use and ARB carriage declined in semi-rural communities of Quito from 2019 to 2021.

Abstract Sepsis is a leading cause of mortality and early identification improves survival. With increasing digitalization of health care data automated sepsis prediction models hold promise to aid in prompt recognition. Most previous studies have focused on the intensive care unit (ICU) setting. Yet only a small proportion of sepsis develops in the ICU and there is an apparent clinical benefit to identify patients earlier in the disease trajectory. In this cohort of 82,852 hospital admissions and 8038 sepsis episodes classified according to the Sepsis-3 criteria, we demonstrate that a machine learned score can predict sepsis onset within 48 h using sparse routine electronic health record data outside the ICU. Our score was based on a causal probabilistic network model—SepsisFinder—which has similarities with clinical reasoning. A prediction was generated hourly on all admissions, providing a new variable was registered. Compared to the National Early Warning Score (NEWS2), which is an established method to identify sepsis, the SepsisFinder triggered earlier and had a higher area under receiver operating characteristic curve (AUROC) (0.950 vs. 0.872), as well as area under precision-recall curve (APR) (0.189 vs. 0.149). A machine learning comparator based on a gradient-boosting decision tree model had similar AUROC (0.949) and higher APR (0.239) than SepsisFinder but triggered later than both NEWS2 and SepsisFinder. The precision of SepsisFinder increased if screening was restricted to the earlier admission period and in episodes with bloodstream infection. Furthermore, the SepsisFinder signaled median 5.5 h prior to antibiotic administration. Identifying a high-risk population with this method could be used to tailor clinical interventions and improve patient care.

Abstract Reliable estimates of subnational vaccination coverage are critical to track progress towards global immunisation targets and ensure equitable health outcomes for all children. However, conflict can limit the reliability of coverage estimates from traditional household-based surveys due to an inability to sample in unsafe and insecure areas and increased uncertainty in underlying population estimates. In these situations, model-based geostatistical (MBG) approaches offer alternative coverage estimates for administrative units affected by conflict. We estimated first- and third-dose diphtheria-tetanus-pertussis vaccine coverage in Borno state, Nigeria, using a spatiotemporal MBG modelling approach, then compared these to estimates from recent conflict-affected, household-based surveys. We compared sampling cluster locations from recent household-based surveys to geolocated data on conflict locations and modelled spatial coverage estimates, while also investigating the importance of reliable population estimates when assessing coverage in conflict settings. These results demonstrate that geospatially-modelled coverage estimates can be a valuable additional tool to understand coverage in locations where conflict prevents representative sampling.

BackgroundBacterial pneumonia and sepsis are both common causes of end-organ dysfunction, especially in immunocompromised and critically ill patients. Pre-clinical data demonstrate that bacterial pneumonia and sepsis elicit the production of cytotoxic tau and amyloids from pulmonary endothelial cells, which cause lung and brain injury in naïve animal subjects, independent of the primary infection. The contribution of infection-elicited cytotoxic tau and amyloids to end-organ dysfunction has not been examined in the clinical setting. We hypothesized that cytotoxic tau and amyloids are present in the bronchoalveolar lavage fluid of critically ill patients with bacterial pneumonia and that these tau/amyloids are associated with end-organ dysfunction.MethodsBacterial culture-positive and culture-negative mechanically ventilated patients were recruited into a prospective, exploratory observational study. Levels of tau and Aβ42 in, and cytotoxicity of, the bronchoalveolar lavage fluid were measured. Cytotoxic tau and amyloid concentrations were examined in comparison with patient clinical characteristics, including measures of end-organ dysfunction.ResultsTau and Aβ42 were increased in culture-positive patients (n = 49) compared to culture-negative patients (n = 50), independent of the causative bacterial organism. The mean age of patients was 52.1 ± 16.72 years old in the culture-positive group and 52.78 ± 18.18 years old in the culture-negative group. Males comprised 65.3% of the culture-positive group and 56% of the culture-negative group. Caucasian culture-positive patients had increased tau, boiled tau, and Aβ42 compared to both Caucasian and minority culture-negative patients. The increase in cytotoxins was most evident in males of all ages, and their presence was associated with end-organ dysfunction.ConclusionsBacterial infection promotes the generation of cytotoxic tau and Aβ42 within the lung, and these cytotoxins contribute to end-organ dysfunction among critically ill patients. This work illuminates an unappreciated mechanism of injury in critical illness.

Abstract Molecular clocks estimate that diatom microalgae, one of Earth’s foremost primary producers, originated near the Triassic–Jurassic boundary (200 Ma), which is close in age to the earliest, generally accepted diatom fossils of the genus Pyxidicula. During an extensive search for Jurassic diatoms from twenty-five sites worldwide, three sites yielded microfossils initially recognized as diatoms. After applying stringent safeguards and evaluation criteria, however, the fossils found at each of the three sites were rejected as new diatom records. This led us to systematically reexamine published evidence in support of Lower- and Middle-Jurassic Pyxidicula fossils. Although Pyxidicula resembles some extant radial centric diatoms and has character states that may have been similar to those of ancestral diatoms, we describe numerous sources of uncertainty regarding the reliability of these records. We conclude that the Lower Jurassic Pyxidicula fossils were most likely calcareous nannofossils, whereas the Middle Jurassic Pyxidicula species has been reassigned to the Lower Cretaceous and is likely a testate amoeba, not a diatom. Excluding the Pyxidicula fossils widens the gap between the estimated time of origin and the oldest abundant fossil diatom record to 75 million years. This study underscores the difficulties in discovering and validating ancient microfossils.

The use of effective vaccines is among the most important strategies for the prevention and progressive control of transboundary infectious animal diseases. However, the use of vaccine is often impeded by the cost, a lack of cold chains and other factors. In resource-limited countries in Africa, one approach to improve coverage and reduce cost is to vaccinate against multiple diseases using combined vaccines. Therefore, the objective of this study was to evaluate a combined vaccine for the prevention and control of Lumpy Skin Disease (LSD), Contagious Bovine Pleuropneumonia (CBPP) and Rift Valley fever (RVF). The LSD and CBPP were formulated as a combined vaccine, and the RVF was formulated separately as live attenuated vaccines. These consisted of a Mycoplasma MmmSC T1/44 strain that was propagated in Hayflick-modified medium, RVF virus vaccine, C13T strain prepared in African green monkey cells (Vero), and the LSDV Neethling vaccine strain prepared in primary testis cells. The vaccines were tested for safety via the subcutaneous route in both young calves and pregnant heifers with no side effect, abortion or teratogenicity. The vaccination of calves induced seroconversions for all three vaccines starting from day 7 post-vaccination (PV), with rates of 50% for LSD, 70% for CBPP and 100% for RVF, or rates similar to those obtained with monovalent vaccines. The challenge of cattle vaccinated with the LSD/CBPP and the RVF vaccine afforded full protection against virulent strains of LSDV and RVFV. A satisfactory level of protection against a CBPP challenge was observed, with 50% of protection at 6 months and 81% at 13 months PV. A mass vaccination trial was performed in four regions of Burkina Faso that confirmed safety and specific antibody responses induced by the vaccines. The multivalent LSD/CBPP+RVF vaccine provides a novel and beneficial approach to the control of the three diseases through one intervention and, therefore, reduces the cost and improves vaccination coverage.

BackgroundThe spread of antibiotic-resistant bacteria may be driven by human-animal-environment interactions, especially in regions with limited restrictions on antibiotic use, widespread food animal production, and free-roaming domestic animals. In this study, we aimed to identify risk factors related to commercial food animal production, small-scale or "backyard" food animal production, domestic animal ownership, and practices related to animal handling, waste disposal, and antibiotic use in Ecuadorian communities.Methods and findingsWe conducted a repeated measures study from 2018 to 2021 in 7 semirural parishes of Quito, Ecuador to identify determinants of third-generation cephalosporin-resistant E. coli (3GCR-EC) and extended-spectrum beta-lactamase E. coli (ESBL-EC) in children. We collected 1,699 fecal samples from 600 children and 1,871 domestic animal fecal samples from 376 of the same households at up to 5 time points per household over the 3-year study period. We used multivariable log-binomial regression models to estimate relative risks (RR) of 3GCR-EC and ESBL-EC carriage, adjusting for child sex and age, caregiver education, household wealth, and recent child antibiotic use. Risk factors for 3GCR-EC included living within 5 km of more than 5 commercial food animal operations (RR: 1.26; 95% confidence interval (CI): 1.10, 1.45; p-value: 0.001), household pig ownership (RR: 1.23; 95% CI: 1.02, 1.48; p-value: 0.030) and child pet contact (RR: 1.23; 95% CI: 1.09, 1.39; p-value: 0.001). Risk factors for ESBL-EC were dog ownership (RR: 1.35; 95% CI: 1.00, 1.83; p-value: 0.053), child pet contact (RR: 1.54; 95% CI: 1.10, 2.16; p-value: 0.012), and placing animal feces on household land/crops (RR: 1.63; 95% CI: 1.09, 2.46; p-value: 0.019). The primary limitations of this study are the use of proxy and self-reported exposure measures and the use of a single beta-lactamase drug (ceftazidime with clavulanic acid) in combination disk diffusion tests for ESBL confirmation, potentially underestimating phenotypic ESBL production among cephalosporin-resistant E. coli isolates. To improve ESBL determination, it is recommended to use 2 combination disk diffusion tests (ceftazidime with clavulanic acid and cefotaxime with clavulanic acid) for ESBL confirmatory testing. Future studies should also characterize transmission pathways by assessing antibiotic resistance in commercial food animals and environmental reservoirs.ConclusionsIn this study, we observed an increase in enteric colonization of antibiotic-resistant bacteria among children with exposures to domestic animals and their waste in the household environment and children living in areas with a higher density of commercial food animal production operations.

Objectives To analyse glucocorticoid (GC) use and trajectories in a real-life cohort of rheumatoid arthritis (RA).Methods Patients with RA included in the longitudinal RCVRIC cohort for initiating or changing biological disease-modifying antirheumatic drugs, were compared for the use of GCs at baseline. Among the GC users, the GC dose was analysed over 2 years of follow-up by group-based trajectory models. Characteristics and outcomes were compared between the trajectories.Results Among the 184 patients (RA duration 4.2 years (1.3; 12.6), Disease Activity Scores (DAS)28-C reactive protein (CRP) 4.24±2.14), 81 (44%) were on GCs. The GC users were significantly older, had higher CRP and Health Assessment Questionnaire (HAQ), more hypertension and lower lumbar T-score, but similar activity and erosive scores. Among the GC users, two trajectories were identified: trajectory 1 (n=20, 25%) with GC discontinuation in the first year and trajectory 2 (n=61, 75%) with maintenance of low-dose GCs at 2 years. Trajectory 2 was significantly associated with higher HAQ, a longer GC duration and a less frequent methotrexate association. After adjustment for HAQ, GC duration and MTX use, good EULAR responses were less frequent at 6 months and 1 year in the GC maintenance trajectory (38.3% vs 81.3%, p=0.03; 42.0% vs 82.4%, p=0.02). Diabetes, fractures and increased body mass index were noted in trajectory 2.Conclusion GCs were used in almost half of patients with established RA in real-world practice. For the majority of GC users, a long-term low dose of GCs is maintained over 2 years. These results highlight the difficulties with stopping GCs, the lack of consensus for the efficacy–safety balance of GCs, and the need to individualise the best GC tapering.

Introduction In Liberia, emergency care is still in its early development. In 2019, two emergency care and triage education sessions were done at J. J. Dossen Hospital in Southeastern Liberia. The observational study objectives evaluated key process outcomes before and after the educational interventions.Methods Emergency department paper records from 1 February 2019 to 31 December 2019 were retrospectively reviewed. Simple descriptive statistics were used to describe patient demographics and χ2 analyses were used to test for significance. ORs were calculated for key predetermined process measures.Results There were 8222 patient visits recorded that were included in our analysis. Patients in the post-intervention 1 group had higher odds of having a documented full set of vital signs compared with the baseline group (16% vs 3.5%, OR: 5.4 (95% CI: 4.3 to 6.7)). After triage implementation, patients who were triaged were 16 times more likely to have a full set of vitals compared with those who were not triaged. Similarly, compared with the baseline group, patients in the post-intervention 1 group had higher odds of having a glucose documented if they presented with altered mental status or a neurologic complaint (37% vs 30%, OR: 1.7 (95% CI: 1.3 to 2.2)), documented antibiotic administration if they had a presumed bacterial infection (87% vs 35%, OR: 12.8 (95% CI: 8.8 to 17.1)), documented malaria test if presenting with fever (76% vs 61%, OR: 2.05 (95% CI: 1.37 to 3.08)) or documented repeat set of vitals if presenting with shock (25% vs 6.6%, OR: 8.85 (95% CI: 1.67 to 14.06)). There was no significant difference in the above process outcomes between the education interventions.Conclusion This study showed improvement in most process measures between the baseline and post-intervention 1 groups, benefits that persisted post-intervention 2, thus supporting the importance of short-course education interventions to durably improve facility-based care.

Objectives Emergency care services are rapidly expanding in Africa; however, development must focus on quality. The African Federation of Emergency Medicine consensus conference (AFEM-CC)-based quality indicators were published in 2018. This study sought to increase knowledge of quality through identifying all publications from Africa containing data relevant to the AFEM-CC process clinical and outcome quality indicators.Design We conducted searches for general quality of emergency care in Africa and for each of 28 AFEM-CC process clinical and five outcome clinical quality indicators individually in the medical and grey literature.Data sources PubMed (1964—2 January 2022), Embase (1947—2 January 2022) and CINAHL (1982—3 January 2022) and various forms of grey literature were queried.Eligibility criteria Studies published in English, addressing the African emergency care population as a whole or large subsegment of this population (eg, trauma, paediatrics), and matching AFEM-CC process quality indicator parameters exactly were included. Studies with similar, but not exact match, data were collected separately as ‘AFEM-CC quality indicators near match’.Data extraction and synthesis Document screening was done in duplicate by two authors, using Covidence, and conflicts were adjudicated by a third. Simple descriptive statistics were calculated.Results One thousand three hundred and fourteen documents were reviewed, 314 in full text. 41 studies met a priori criteria and were included, yielding 59 unique quality indicator data points. Documentation and assessment quality indicators accounted for 64% of data points identified, clinical care for 25% and outcomes for 10%. An additional 53 ‘AFEM-CC quality indicators near match’ publications were identified (38 new publications and 15 previously identified studies that contained additional ‘near match’ data), yielding 87 data points.Conclusions Data relevant to African emergency care facility-based quality indicators are highly limited. Future publications on emergency care in Africa should be aware of, and conform with, AFEM-CC quality indicators to strengthen understanding of quality.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a generalist virus, infecting and evolving in numerous mammals, including captive and companion animals, free-ranging wildlife, and humans. Transmission among non-human species poses a risk for the establishment of SARS-CoV-2 reservoirs, makes eradication difficult, and provides the virus with opportunities for new evolutionary trajectories, including the selection of adaptive mutations and the emergence of new variant lineages. Here, we use publicly available viral genome sequences and phylogenetic analysis to systematically investigate the transmission of SARS-CoV-2 between human and non-human species and to identify mutations associated with each species. We found the highest frequency of animal-to-human transmission from mink, compared with lower transmission from other sampled species (cat, dog, and deer). Although inferred transmission events could be limited by sampling biases, our results provide a useful baseline for further studies. Using genome-wide association studies, no single nucleotide variants (SNVs) were significantly associated with cats and dogs, potentially due to small sample sizes. However, we identified three SNVs statistically associated with mink and 26 with deer. Of these SNVs, ~⅔ were plausibly introduced into these animal species from local human populations, while the remaining ~⅓ were more likely derived in animal populations and are thus top candidates for experimental studies of species-specific adaptation. Together, our results highlight the importance of studying animal-associated SARS-CoV-2 mutations to assess their potential impact on human and animal health.

Introduction Group A Streptococcus (GAS) causes pharyngitis (sore throat) and impetigo (skin sores) GAS pharyngitis triggers rheumatic fever (RF) with epidemiological evidence supporting that GAS impetigo may also trigger RF in Australian Aboriginal children. Understanding the concurrent burden of these superficial GAS infections is critical to RF prevention. This pilot study aimed to trial tools for concurrent surveillance of sore throats and skins sore for contemporary studies of RF pathogenesis including development of a sore throat checklist for Aboriginal families and pharynx photography. Methods Yarning circle conversations and semi-structured interviews were performed with Aboriginal caregivers and used to develop the language and composition of a sore throat checklist. The sore throat story checklist was combined with established methods of GAS pharyngitis and impetigo surveillance (examination, bacteriological culture, rapid antigen detection and serological tests) and new technologies (photography) and used for a pilot cross-sectional surveillance study of Aboriginal children attending their health clinic for a routine appointment. Feasibility, acceptability, and study costs were compiled. Results Ten Aboriginal caregivers participated in the sore-throat yarning circles; a checklist was derived from predominant symptoms and their common descriptors. Over two days, 21 Aboriginal children were approached for the pilot surveillance study, of whom 17 were recruited; median age was 9 years [IQR 5.5–13.5], 65% were female. One child declined throat swabbing and three declined finger pricks; all other surveillance elements were completed by each child indicating high acceptability of surveillance assessments. Mean time for screening assessment was 19 minutes per child. Transport of clinical specimens enabled gold standard microbiological and serological testing for GAS. Retrospective examination of sore throat photography concorded with assessments performed on the day. Conclusion Yarning circle conversations were effective in deriving culturally appropriate sore throat questionnaires for GAS pharyngitis surveillance. New and established tools were feasible, practical and acceptable to participants and enable surveillance to determine the burden of superficial GAS infections in communities at high risk of RF. Surveillance of GAS pharyngitis and impetgio in remote Australia informs primary RF prevention with potential global translation.

Abstract The last decade has seen renewed concern within the scientific community over the reproducibility and transparency of research findings. This paper outlines some of the various responsibilities of stakeholders in addressing the systemic issues that contribute to this concern. In particular, this paper asserts that a united, joined-up approach is needed, in which all stakeholders, including researchers, universities, funders, publishers, and governments, work together to set standards of research integrity and engender scientific progress and innovation. Using two developments as examples: the adoption of Registered Reports as a discrete initiative, and the use of open data as an ongoing norm change, we discuss the importance of collaboration across stakeholders.

Prediction is often used during language comprehension. However, studies of prediction have tended to focus on L1 listeners in quiet conditions. Thus, it is unclear how listeners predict outside the laboratory and in specific communicative settings. Here, we report two eye-tracking studies which used a visual-world paradigm to investigate whether prediction during a consecutive interpreting task differs from prediction during a listening task in L2 listeners, and whether L2 listeners are able to predict in the noisy conditions that might be associated with this communicative setting. In a first study, thirty-six Dutch-English bilinguals either just listened to, or else listened to and then consecutively interpreted, predictable sentences presented on speech-shaped sound. In a second study, another thirty-six Dutch-English bilinguals carried out the same tasks in clear speech. Our results suggest that L2 listeners predict the meaning of upcoming words in noisy conditions. However, we did not find that predictive eye movements depended on task, nor that L2 listeners predicted upcoming word form. We also did not find a difference in predictive patterns when we compared our two studies. Thus, L2 listeners predict in noisy circumstances, supporting theories which posit that prediction regularly takes place in comprehension, but we did not find evidence that a subsequent production task or noise affects semantic prediction.

BackgroundCytomegalovirus (CMV) infection, either de novo or as reactivation after allotransplantation and chronic immunosuppression, is recognized to cause detrimental alloimmune effects, inclusive of higher susceptibility to graft rejection and substantive impact on chronic graft injury and reduced transplant survival. To obtain further insights into the evolution and pathogenesis of CMV infection in an immunocompromised host we evaluated changes in the circulating host proteome serially, before and after transplantation, and during and after CMV DNA replication (DNAemia), as measured by quantitative polymerase chain reaction (QPCR).MethodsLC-MS-based proteomics was conducted on 168 serially banked plasma samples, from 62 propensity score-matched kidney transplant recipients. Patients were stratified by CMV replication status into 31 with CMV DNAemia and 31 without CMV DNAemia. Patients had blood samples drawn at protocol times of 3- and 12-months post-transplant. Additionally, blood samples were also drawn before and 1 week and 1 month after detection of CMV DNAemia. Plasma proteins were analyzed using an LCMS 8060 triple quadrupole mass spectrometer. Further, public transcriptomic data on time matched PBMCs samples from the same patients was utilized to evaluate integrative pathways. Data analysis was conducted using R and Limma.ResultsSamples were segregated based on their proteomic profiles with respect to their CMV Dnaemia status. A subset of 17 plasma proteins was observed to predict the onset of CMV at 3 months post-transplant enriching platelet degranulation (FDR, 4.83E-06), acute inflammatory response (FDR, 0.0018), blood coagulation (FDR, 0.0018) pathways. An increase in many immune complex proteins were observed at CMV infection. Prior to DNAemia the plasma proteome showed changes in the anti-inflammatory adipokine vaspin (SERPINA12), copper binding protein ceruloplasmin (CP), complement activation (FDR = 0.03), and proteins enriched in the humoral (FDR = 0.01) and innate immune responses (FDR = 0.01).ConclusionPlasma proteomic and transcriptional perturbations impacting humoral and innate immune pathways are observed during CMV infection and provide biomarkers for CMV disease prediction and resolution. Further studies to understand the clinical impact of these pathways can help in the formulation of different types and duration of anti-viral therapies for the management of CMV infection in the immunocompromised host.

BackgroundAppropriate medication use is essential in ensuring optimal pharmacotherapeutic outcomes. It is mistakenly assumed that adults can swallow solid oral dosage forms (SODFs, e.g. tablets/capsules colloquially referred to as 'pills'), without difficulty and that children cannot. KidzMed is a 'pill swallowing' training programme designed to teach effective SODF use in patients of all ages. It may be utilised by healthcare professionals to assist patients taking SODFs. E-learning was essential for training during COVID pandemic to reduce viral transmission. The aim of this study was to explore UK student pharmacists views of e-learning to support swallowing solid oral dosage forms.MethodsThis study used pre- and post-intervention online surveys on Microsoft Forms to evaluate self-directed eLearning about pill swallowing on MPharm programmes at three UK Universities using a 13-item survey. A combination of five-point Likert Scales and free-text items were used. The eLearning was available via the virtual learning environment at the University and embedded within existing curriculum. Descriptive statistical analysis was used to explore responses.ResultsIn total, 113 of 340 (33%) students completed the survey. Seventy-eight percent (n = 65) reported the eLearning would enable them to teach adults and children to swallow SODFs successfully. Learners either agreed or strongly agreed that they felt comfortable to teach patients (95%, n = 62/113) and parents or carers (94%, n = 60) to swallow medications having completed the e-learning. Student pharmacists generally found eLearning as an acceptable way to reflect on their own experiences of 'pill' swallowing and how to support patients to swallow SODFs.ConclusionThe KidzMed eLearning was well received by student pharmacists. Further work is needed to explore whether skills translates into real life application in the clinical settings.

COVID-19 necessitated the rapid transition to online learning, challenging the ability of Science, Technology, Engineering, and Math (STEM) professors to offer laboratory experiences to their students. As a result, many instructors sought online alternatives. In addition, recent literature supports the capacity of online curricula to empower students of historically underrepresented identities in STEM fields. Here, we present PARE-Seq, a virtual bioinformatics activity highlighting approaches to antimicrobial resistance (AMR) research. Following curricular development and assessment tool validation, pre- and post-assessments of 101 undergraduates from 4 institutions revealed that students experienced both significant learning gains and increases in STEM identity, but with small effect sizes. Learning gains were marginally modified by gender, race/ethnicity, and number of extracurricular work hours per week. Students with more extracurricular work hours had significantly lower increase in STEM identity score after course completion. Female-identifying students saw greater learning gains than male-identifying, and though not statistically significant, students identifying as an underrepresented minority reported larger increases in STEM identity score. These findings demonstrate that even short course-based interventions have potential to yield learning gains and improve STEM identity. Online curricula like PARE-Seq can equip STEM instructors to utilize research-driven resources that improve outcomes for all students, but support must be prioritized for students working outside of school.

Plain English summary Clinical Trials Units are encouraged to integrate Patient and Public Involvement (PPI) into all aspects of their trials. This research explored the induction and training of PPI Contributors (e.g. patients, carers and members of the public) joining trial oversight committees. These committees regularly review trial progress and ensure participant safety. PPI Contributors sit on the committees to provide important guidance and advice on what the trial is like for a participant taking part. We looked at existing materials and research to find out what is already in use and how useful PPI Contributors felt it may be. We also held a workshop with existing PPI Contributors who had experience of participating in trials and sitting on oversight committees to find out what information they felt would be useful during the induction of a new member. Our research was used to create an induction pack for new PPI Contributors at the Medical Research Council Clinical Trials Unit at University College London (MRC CTU at UCL). We have made this resource available to all researchers and in this report we describe how it was created.

BackgroundDiarrhea and acute respiratory infection (ARI) are leading causes of death in children. The WASH Benefits Bangladesh trial implemented a multicomponent sanitation intervention that led to a 39% reduction in the prevalence of diarrhea among children and a 25% reduction for ARI, measured 1 to 2 years after intervention implementation. We measured longer-term intervention effects on these outcomes between 1 to 3.5 years after intervention implementation, including periods with differing intensity of behavioral promotion.Methods and findingsWASH Benefits Bangladesh was a cluster-randomized controlled trial of water, sanitation, hygiene, and nutrition interventions (NCT01590095). The sanitation intervention included provision of or upgrades to improved latrines, sani-scoops for feces removal, children's potties, and in-person behavioral promotion. Promotion was intensive up to 2 years after intervention initiation, decreased in intensity between years 2 to 3, and stopped after 3 years. Access to and reported use of latrines was high in both arms, and latrine quality was significantly improved by the intervention, while use of child feces management tools was low. We enrolled a random subset of households from the sanitation and control arms into a longitudinal substudy, which measured child health with quarterly visits between 1 to 3.5 years after intervention implementation. The study period therefore included approximately 1 year of high-intensity promotion, 1 year of low-intensity promotion, and 6 months with no promotion. We assessed intervention effects on diarrhea and ARI prevalence among children ConclusionsThe observed effect of the WASH Benefits Bangladesh sanitation intervention on diarrhea in children appeared to be sustained for at least 3.5 years after implementation, including 1.5 years after heavy promotion ceased. Existing latrine access was high in the study setting, suggesting that improving on-site latrine quality can deliver health benefits when latrine use practices are in place. Further work is needed to understand how latrine adoption can be achieved and sustained in settings with low existing access and how sanitation programs can adopt transformative approaches of excreta management, including safe disposal of child and animal feces, to generate a hygienic home environment.Trial registrationClinicalTrials.gov; NCT01590095; https://clinicaltrials.gov/ct2/show/NCT01590095.

Abstract The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), calls for prompt and accurate diagnosis and rapid turnaround time for test results to limit transmission. Here, we evaluated two independent molecular assays, the Biomeme SARS-CoV-2 test, and the Precision Biomonitoring TripleLock SARS-CoV-2 test on a field-deployable point-of-care real-time PCR instrument, Franklin three9, in combination with Biomeme M1 Sample Prep Cartridge Kit for RNA 2.0 (M1) manual extraction system for rapid, specific, and sensitive detection of SARS-COV-2 in cell culture, human, and animal clinical samples. The Biomeme SARS-CoV-2 assay, which simultaneously detects two viral targets, the orf1ab and S genes, and the Precision Biomonitoring TripleLock SARS-CoV-2 assay that targets the 5′ untranslated region (5′ UTR) and the envelope (E) gene of SARS-CoV-2 were highly sensitive and detected as low as 15 SARS-CoV-2 genome copies per reaction. In addition, the two assays were specific and showed no cross-reactivity with Middle Eastern respiratory syndrome coronavirus (MERS-CoV), infectious bronchitis virus (IBV), porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis (TGE) virus, and other common human respiratory viruses and bacterial pathogens. Also, both assays were highly reproducible across different operators and instruments. When used to test animal samples, both assays equally detected SARS-CoV-2 genetic materials in the swabs from SARS-CoV-2-infected hamsters. The M1 lysis buffer completely inactivated SARS-CoV-2 within 10 min at room temperature enabling safe handling of clinical samples. Collectively, these results show that the Biomeme and Precision Biomonitoring TripleLock SARS-CoV-2 mobile testing platforms could reliably and promptly detect SARS-CoV-2 in both human and animal clinical samples in approximately an hour and can be used in remote areas or health care settings not traditionally serviced by a microbiology laboratory.

Abstract Background Group A Streptococcus (Strep A) is an important cause of mortality and morbidity globally. This bacterium is responsible for a range of different infections and post-infectious sequelae. Summarising the current knowledge of Strep A transmission to humans will address gaps in the evidence and inform prevention and control strategies. The objective of this study is to evaluate the modes of transmission and attack rates of group A streptococcal infection in human populations. Methods This systematic review protocol was prepared according to the Preferred Reporting Items for Systematic reviews and Meta-analysis Protocols (PRISMA-P) 2015 Statement. Using a comprehensive search strategy to identify any transmission studies that have been published in English since 1980, full-text articles will be identified and considered for inclusion against predefined criteria. We will include all studies reporting on Strep A transmission, who have identified a mode of transmission, and who reported attack rates. Risk of bias will be appraised using an appropriate tool. Our results will be described narratively and where feasible and appropriate, a meta-analysis utilizing the random-effects model will be used to aggregate the incidence proportions (attack rates) for each mode of transmission. In addition, we will also evaluate the emm genotype variants of the M protein causing Strep A infection and the association with transmission routes and attack rates, if any, by setting, socioeconomic background and geographical regions. Discussion We anticipate that this review will contribute to elucidating Strep A modes of transmission which in turn, will serve to inform evidence-based strategies including environmental health activities to reduce the transmission of Strep A in populations at risk of severe disease. Trial registration Systematic review registration: PROSPERO ( CRD42019138472 ).

Abstract This study was aimed to assess the effectiveness of magnesium (Mg)-vitamin B 6 replenishment and its correlation with clinical status in pregnant women (PW), and quality of life in women with hormone-related conditions (HRCW) and hypomagnesemia (HME). Data collected in four observational studies were pooled and analysed. All women received Mg supplementation for 4 weeks. The proportion of women with normalized Mg level, and the correlation between serum Mg dynamics and number of symptoms/complaints (PW) or changes in World Health Organization quality of life questionnaire scores (WHOQOL; HRCW) were evaluated. 869 PW and 957 HRCW were included in the study. Normalization of serum Mg level to ≥ 0.66 mmol/L occurred in 92.1% of PW and 78.4% of HRCW, and to ≥ 0.8 mmol/L in 73.8% and 58.9%, respectively. Mg normalization was accompanied by a median decrease of 1 symptom and 1 complaint in PW. Serum Mg level increase by 0.1 mmol/L was associated to significant changes in the WHOQOL scores in HRCW. Treatment of HME with the Mg for approximately 4 weeks provided a high response rate of Mg serum level, was associated with an improvement in symptom severity and complaints in PW, and WHOQOL score in HRCW. A 0.8 mmol/L cut-off appeared to be more relevant in terms of patient-reported outcomes.

OBJECTIVES/GOALS: The goal of this project is to investigate dementia caregivers’ needs, barriers to access, and current utilization of community-based dementia-care services in Alabama, and how these vary across rural/urban settings and racial groups. METHODS/STUDY POPULATION: We partnered with Marketry Inc. to recruit and conduct interviews among three groups: dementia caregivers, healthcare providers, and aging services representatives. We recruited caregivers from dementia support groups and aging services in 2 rural and 2 urban Alabama counties. Purposive and snowball sampling was used to recruit healthcare providers and aging services representatives. Interviews were conducted by trained Marketry staff, recorded, and transcribed verbatim. Rapid content analysis was conducted by three investigators using the Social Determinants of Health as a coding framework to assess patterns in barriers and facilitators to utilizing community-based dementia resources. RESULTS/ANTICIPATED RESULTS: We interviewed 5 healthcare providers, 32 caregivers, and 15 aging services representatives. Providers thought that the process of memory loss care is not streamlined and they lack key information necessary to fulfill their role. Caregivers expressed a need for more dementia education, social connection, and access to financial resources. Aging services agencies need more funding and volunteers to sustain community-based dementia services. Dementia resources, like memory clinics, were more available in urban than in rural counties. African-American caregivers mentioned a reluctance to accept outside help for taking care of their loved ones with dementia, potentially due to distrust. DISCUSSION/SIGNIFICANCE: There is a need for more accessible dementia services in rural AL and a need to build service trust and familiarity, especially among African-American caregivers. Future research should develop tools for providers and caregivers to start conversations and increase awareness of service availability.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent that causes coronavirus disease, has been shown to infect several species. The role of domestic livestock and associated risks for humans in close contact with food production animals remains unknown for many species. Determining the susceptibility of pigs to SARS-CoV-2 is critical to a One Health approach to manage potential risk for zoonotic transmission. We found that pigs are susceptible to SARS-CoV-2 after oronasal inoculation. Among 16 animals, we detected viral RNA in group oral fluids and in nasal wash from 2 pigs, but live virus was isolated from only 1 pig. Antibodies also were detected in only 2 animals at 11 and 13 days postinoculation but were detected in oral fluid samples at 6 days postinoculation, indicating antibody secretion. These data highlight the need for additional livestock assessment to determine the potential role of domestic animals in the SARS-CoV-2 pandemic.

Abstract Background The proportion of infections among young children that are antimicrobial-resistant is increasing across the globe. Newborns may be colonized with enteric antimicrobial-resistant pathogens early in life, which is a risk factor for infection-related morbidity and mortality. Breastfeeding is actively promoted worldwide for its beneficial impacts on newborn health and gut health. However, the role of breastfeeding and human milk components in mitigating young children’s carriage of antimicrobial-resistant pathogens and antibiotic resistance genes has not been comprehensively explored. Main body Here, we review how the act of breastfeeding, early breastfeeding, and/or human milk components, such as the milk microbiota, secretory IgA, human milk oligosaccharides, antimicrobial peptides, and microRNA -bearing extracellular vesicles, could play a role in preventing the establishment of antimicrobial-resistant pathogens in young children’s developing gut microbiomes. We describe findings from recent human studies that support this concept. Conclusion Given the projected rise in global morbidity and mortality that will stem from antimicrobial-resistant infections, identifying behavioral or nutritional interventions that could decrease children’s susceptibility to colonization with antimicrobial-resistant pathogens may be one strategy for protecting their health. We suggest that breastfeeding and human milk supplements deserve greater attention as potential preventive measures in the global effort to combat antimicrobial resistance, particularly in low- and middle-income settings.

Objectives To assess the feasibility and acceptability, and additionally to preliminarily evaluate, the effectiveness and safety of an accelerated diagnostic chest pain pathway in rural general practice using point-of-care troponin to identify patients at low risk of acute myocardial infarction, avoiding unnecessary patient transfer to hospital and enabling early discharge home.Design A prospective observational pilot evaluation.Setting Twelve rural general (family) practices in the Midlands region of New Zealand.Participants Patients aged ≥18 years who presented acutely to rural general practice with suspected ischaemic chest pain for whom the doctor intended transfer to hospital for serial troponin measurement.Outcome measures The proportion of patients managed using the low-risk pathway without transfer to hospital and without 30-day major adverse cardiac event (MACE); pathway adherence; rate of 30-day MACE; patient satisfaction with care; and agreement between point-of-care and laboratory measured troponin concentrations.Results A total of 180 patients were assessed by the pathway. The pathway classified 111 patients (61.7%) as low-risk and all were managed in rural general practice with no 30-day MACE (0%, 95% CI 0.0% to 3.3%). Adherence to the low-risk pathway was 95.5% (106 out of 111). Of the 56 patients classified as non-low-risk and referred to hospital, 9 (16.1%) had a 30-day MACE. A further 13 non-low-risk patients were not transferred to hospital, with no events. The sensitivity of the pathway for 30-day MACE was 100.0% (95% CI 70.1% to 100%). Of low-risk patients, 94% reported good to excellent satisfaction with care. Good concordance was observed between point-of-care and duplicate laboratory measured troponin concentrations.Conclusions The use of an accelerated diagnostic chest pain pathway incorporating point-of-care troponin in a rural general practice setting was feasible and acceptable, with preliminary results suggesting that it may safely and effectively reduce the urgent transfer of low-risk patients to hospital.

Introduction Group A β-haemolytic Streptococcus (GAS), a Gram-positive bacterium, causes skin, mucosal and systemic infections. Repeated GAS infections can lead to autoimmune diseases acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Aboriginal and Torres Strait Islander peoples in Australia have the highest rates of ARF and RHD in the world. Despite this, the contemporaneous prevalence and incidence of GAS pharyngitis and impetigo in remote Australia remains unknown. To address this, we have designed a prospective surveillance study of GAS pharyngitis and impetigo to collect coincident contemporary evidence to inform and enhance primary prevention strategies for ARF.Methods and analysis The Missing Piece Study aims to document the epidemiology of GAS pharyngitis and impetigo through collection of clinical, serological, microbiological and bacterial genomic data among remote-living Australian children. The study comprises two components: (1) screening of all children at school for GAS pharyngitis and impetigo up to three times a year and (2) weekly active surveillance visits to detect new cases of pharyngitis and impetigo. Environmental swabbing in remote schools will be included, to inform environmental health interventions. In addition, the application of new diagnostic technologies, microbiome analysis and bacterial genomic evaluations will enhance primary prevention strategies, having direct bearing on clinical care, vaccine development and surveillance for vaccine clinical trials.Ethics and dissemination Ethical approval has been obtained from the Western Australian Aboriginal Health Ethics Committee (Ref: 892) and Human Research Ethics Committee of the University of Western Australia (Ref: RA/4/20/5101). Study findings will be shared with community members, teachers and children at participating schools, together with academic and medical services. Sharing findings in an appropriate manner is important and will be done in a suitable way which includes plain language summaries and presentations. Finally, findings and updates will also be disseminated to collaborators, researchers and health planners through peer-reviewed journal publications.

Some consider potatoes to be unhealthy vegetables that may contribute to adverse cardiometabolic health outcomes. We evaluated the association between potato consumption (including fried and non-fried types) and three key cardiometabolic outcomes among middle-aged and older adults in the Framingham Offspring Study. We included 2523 subjects ≥30 years of age with available dietary data from 3-d food records. Cox-proportional hazards models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for hypertension, type 2 diabetes or impaired fasting glucose (T2DM/IFG), and elevated triglycerides, adjusting for anthropometric, demographic and lifestyle factors. In the present study, 36 % of potatoes consumed were baked, 28 % fried, 14 % mashed, 9 % boiled and the rest cooked in other ways. Overall, higher total potato intake (≥4 v.

The ability to accurately predict the one-year survival of older adults is challenging for clinicians as they endeavour to provide the most appropriate care. Standardised clinical needs assessments are routine in many countries and some enable application of mortality prediction models. The added value of blood biomarkers to these models is largely unknown. We undertook a proof of concept study to assess if adding biomarkers to needs assessments is of value. Assessment of the incremental value of a blood biomarker, Brain Naturetic Peptide (BNP), to a one year mortality risk prediction model, RiskOP, previously developed from data from the international interRAI-HomeCare (interRAI-HC) needs assessment. Participants were aged ≥65 years and had completed an interRAI-HC assessment between 1 January 2013 and 21 August 2021 in Canterbury, New Zealand. Inclusion criteria was a BNP test within 90 days of the date of interRAI-HC assessment. The primary outcome was one-year mortality. Incremental value was assessed by change in Area Under the Receiver Operating Characteristic Curve (AUC) and Brier Skill, and the calibration of the final model. Of 14,713 individuals with an interRAI-HC assessment 1,537 had a BNP within 90 days preceding the assessment and all data necessary for RiskOP. 553 (36.0%) died within 1-year. The mean age was 82.6 years. Adding BNP improved the overall AUC by 0.015 (95% CI:0.004 to 0.028) and improved predictability by 1.9% (0.26% to 3.4%). In those with no Congestive Heart Failure the improvements were 0.029 (0.004 to 0.057) and 4.0% (0.68% to 7.6%). Adding a biomarker to a risk model based on standardised needs assessment of older people improved prediction of 1-year mortality. BNP added value to a risk prediction model based on the interRAI-HC assessment in those patients without a diagnosis of congestive heart failure.

BackgroundElevations of high-sensitivity cardiac troponin (hs-cTn) concentrations not related to type 1 myocardial infarction are common in chest pain patients presenting to emergency departments. The discrimination of these patients from those with type 1 myocardial infarction (MI) is challenging and resource-consuming. We aimed to investigate whether the hs-cTn I/T ratio might provide diagnostic and prognostic increment in this context.MethodsWe calculated the hs-cTn I/T ratio in 888 chest pain patients having hs-cTnI (Abbott Laboratories) or hs-cTnT (Roche Diagnostics) concentrations above the respective 99th percentile at 2 hours from presentation. All patients were followed for one year regarding mortality.ResultsThe median hs-cTn I/T ratio was 3.45 (25th, 75th percentiles 1.80-6.59) in type 1 MI patients (n = 408 ☯46.0%]), 1.18 (0.81-1.90) in type 2 MI patients (n = 56 ☯6.3%]) and 0.67 (0.39-1.12) in patients without MI. The hs-cTn I/T ratio provided good discrimination of type 1 MI from no type 1 MI (area under the receiver-operator characteristic curve 0.89 ☯95% confidence interval 0.86-0.91]), of type 1 MI from type 2 MI (area under the curve 0.81 ☯95% confidence interval 0.74-0.87]), and was associated with type 1 MI in adjusted analyses. The hs-cTn I/T ratio provided no consistent prognostic value.ConclusionsThe hs-cTn I/T ratio appears to be useful for early diagnosis of type 1 MI and its discrimination from type 2 MI in chest pain patients presenting with elevated hs-cTn. Differences in hs-cTn I/T ratio values may reflect variations in hs-cTn release mechanisms in response to different types of myocardial injury.

Objectives Karoli Lwanga Hospital and Global Emergency Care, a 501(c)(3) nongovernmental organization, operate an Emergency Department (ED) in Uganda’s rural Rukungiri District. Despite available emergency care (EC), preventable death and disability persist due to delayed patient presentations. This study seeks to understand the emergency care seeking behavior of community members utilizing the established ED. Methods We purposefully sampled and interviewed patients and caregivers presenting to the ED more than 12 hours after onset of chief complaint in January-March 2017 to include various ages, genders, and complaints. Semistructured interviews addressing actions taken before seeking EC and delays to presentation once the need for EC was recognized were conducted until a diverse sample and theoretical saturation were obtained. An interdisciplinary and multicultural research team conducted thematic analysis based on descriptive phenomenology. Results The 50 ED patients for whom care was sought (mean age 33) had approximately even distribution of gender, as well as occupation (none, subsistence farmers and small business owner). Interviews were conducted with 13 ED patients and 37 caregivers, on the behalf of patients when unavailable. The median duration of patients’ chief complaint on ED presentation was 5.5 days. On average, participants identified severe symptoms necessitating EC 1 day before presentation. Four themes of treatment delay before and after severity were recognized were identified: 1) Cultural factors and limited knowledge of emergency signs and initial actions to take; 2) Use of local health facilities despite perception of inadequate services; 3) Lack of resources to cover the anticipated cost of obtaining EC; 4) Inadequate transportation options. Conclusions Interventions are warranted to address each of the four major reasons for treatment delay. The next stage of formative research will generate intervention strategies and assess the opportunities and challenges to implementation with community and health system stakeholders.

Passive acoustic monitoring (PAM) has proven a powerful tool for the study of marine mammals, allowing for documentation of biologically relevant factors such as movement patterns or animal behaviors while remaining largely non-invasive and cost effective. From 2008–2019, a set of PAM recordings covering the frequency band of most toothed whale (odontocete) echolocation clicks were collected at sites off the islands of Hawaiʻi, Kauaʻi, and Pearl and Hermes Reef. However, due to the size of this dataset and the complexity of species-level acoustic classification, multi-year, multi-species analyses had not yet been completed. This study shows how a machine learning toolkit can effectively mitigate this problem by detecting and classifying echolocation clicks using a combination of unsupervised clustering methods and human-mediated analyses. Using these methods, it was possible to distill ten unique echolocation click ‘types’ attributable to regional odontocetes at the genus or species level. In one case, auxiliary sightings and recordings were used to attribute a new click type to the rough-toothed dolphin, Steno bredanensis. Types defined by clustering were then used as input classes in a neural-network based classifier, which was trained, tested, and evaluated on 5-minute binned data segments. Network precision was variable, with lower precision occurring most notably for false killer whales, Pseudorca crassidens, across all sites (35–76%). However, accuracy and recall were high (>96% and >75%, respectively) in all cases except for one type of short-finned pilot whale, Globicephala macrorhynchus, call class at Kauaʻi and Pearl and Hermes Reef (recall >66%). These results emphasize the utility of machine learning in analysis of large PAM datasets. The classifier and timeseries developed here will facilitate further analyses of spatiotemporal patterns of included toothed whales. Broader application of these methods may improve the efficiency of global multi-species PAM data processing for echolocation clicks, which is needed as these datasets continue to grow.

Detailed, well-dated palaeoclimate and archaeological records are critical for understanding the impact of environmental change on human evolution. Ga-Mohana Hill, in the southern Kalahari, South Africa, preserves a Pleistocene archaeological sequence. Relict tufas at the site are evidence of past flowing streams, waterfalls, and shallow pools. Here, we use laser ablation screening to target material suitable for uranium-thorium dating. We obtained 33 ages covering the last 110 thousand years (ka) and identify five tufa formation episodes at 114-100 ka, 73-48 ka, 44-32 ka, 15-6 ka, and ~3 ka. Three tufa episodes are coincident with the archaeological units at Ga-Mohana Hill dating to ~105 ka, ~31 ka, and ~15 ka. Based on our data and the coincidence of dated layers from other local records, we argue that in the southern Kalahari, from ~240 ka to ~71 ka wet phases and human occupation are coupled, but by ~20 ka during the Last Glacial Maximum (LGM), they are decoupled.

Pain perception is decreased by shifting attentional focus away from a threatening event. This attentional analgesia engages parallel descending control pathways from anterior cingulate (ACC) to locus coeruleus, and ACC to periaqueductal grey (PAG) – rostral ventromedial medulla (RVM), indicating possible roles for noradrenergic or opioidergic neuromodulators. To determine which pathway modulates nociceptive activity in humans, we used simultaneous whole brain-spinal cord pharmacological-fMRI (N = 39) across three sessions. Noxious thermal forearm stimulation generated somatotopic-activation of dorsal horn (DH) whose activity correlated with pain report and mirrored attentional pain modulation. Activity in an adjacent cluster reported the interaction between task and noxious stimulus. Effective connectivity analysis revealed that ACC interacts with PAG and RVM to modulate spinal cord activity. Blocking endogenous opioids with Naltrexone impairs attentional analgesia and disrupts RVM-spinal and ACC-PAG connectivity. Noradrenergic augmentation with Reboxetine did not alter attentional analgesia. Cognitive pain modulation involves opioidergic ACC-PAG-RVM descending control which suppresses spinal nociceptive activity.

A combination of machine learning and expert analyst review was used to detect odontocete echolocation clicks, identify dominant click types, and classify clicks in 32 years of acoustic data collected at 11 autonomous monitoring sites in the western North Atlantic between 2016 and 2019. Previously-described click types for eight known odontocete species or genera were identified in this data set: Blainville's beaked whales (Mesoplodon densirostris), Cuvier's beaked whales (Ziphius cavirostris), Gervais' beaked whales (Mesoplodon europaeus), Sowerby's beaked whales (Mesoplodon bidens), and True's beaked whales (Mesoplodon mirus), Kogia spp., Risso's dolphin (Grampus griseus), and sperm whales (Physeter macrocephalus). Six novel delphinid echolocation click types were identified and named according to their median peak frequencies. Consideration of the spatiotemporal distribution of these unidentified click types, and comparison to historical sighting data, enabled assignment of the probable species identity to three of the six types, and group identity to a fourth type. UD36, UD26, and UD28 were attributed to Risso's dolphin (G. griseus), short-finned pilot whale (G. macrorhynchus), and short-beaked common dolphin (D. delphis), respectively, based on similar regional distributions and seasonal presence patterns. UD19 was attributed to one or more species in the subfamily Globicephalinae based on spectral content and signal timing. UD47 and UD38 represent distinct types for which no clear spatiotemporal match was apparent. This approach leveraged the power of big acoustic and big visual data to add to the catalog of known species-specific acoustic signals and yield new inferences about odontocete spatiotemporal distribution patterns. The tools and call types described here can be used for efficient analysis of other existing and future passive acoustic data sets from this region.

CMV causes mostly asymptomatic but lifelong infection. Primary infection or reactivation in immunocompromised individuals can be life-threatening. CMV viremia often occurs in solid organ transplant recipients and associates with decreased graft survival and higher mortality. Furthering understanding of impaired immunity that allows CMV reactivation is critical to guiding antiviral therapy and examining the effect of CMV on solid organ transplant outcomes. This study characterized longitudinal immune responses to CMV in 31 kidney transplant recipients with CMV viremia and matched, nonviremic recipients. Recipients were sampled 3 and 12 months after transplant, with additional samples 1 week and 1 month after viremia. PBMCs were stained for NK and T cell markers. PBMC transcriptomes were characterized by RNA-Seq. Plasma proteins were quantified by Luminex. CD8+ T cell transcriptomes were characterized by single-cell RNA-Seq. Before viremia, patients had high levels of IL-15 with concurrent expansion of immature CD56bright NK cells. After viremia, mature CD56dim NK cells and CD28–CD8+ T cells upregulating inhibitory and NK-associated receptors were expanded. Memory NK cells and NK-like CD28–CD8+ T cells were associated with control of viremia. These findings suggest that signatures of innate activation may be prognostic for CMV reactivation after transplant, while CD8+ T cell functionality is critical for effective control of CMV.