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Abstract Geophysical DC resistivity imaging is crucial in subsurface exploration, environmental studies, and resource assessment. However, traditional inversion techniques face challenges in accurately resolving complex subsurface features because of the inherent nonlinearities in geophysical data. To overcome these challenges, we propose a hybrid optimization approach that combines incomprehensible but intelligible-in-time (IbI) logic with the interior point method (IPM). The IbI logic framework leverages complexity and temporal intelligibility, allowing for a dynamic interpretation of subsurface phenomena. By integrating IbI with IPM, our approach benefits from global exploration and local refinement, leading to improved convergence speed and solution quality. The objective function formulated for the inversion process includes data misfit and model regularization terms, which promote accurate and smooth solutions. Our methodology involves the use of the IbI logic algorithm (ILA) for initial global search, which identifies promising regions in the search space. This is followed by the application of IPM for local optimization. This synergy between the two algorithms ensures robustness and efficiency in handling large datasets and complex geological models. We conducted tests using synthetic and real DC resistivity data to validate our approach. The synthetic test demonstrated the accurate reconstruction of subsurface anomalies, whereas the real data test successfully identified fault zones, which is consistent with previous studies. The hybrid optimization algorithm significantly improves the resolution of subsurface structures and enhances geophysical data inversion practices. It balances the exploration and refinement phases effectively, optimizing the computation time and ensuring precise model delineation.

Abstract Background Continuous monitoring of antimicrobial resistance (AMR) in Uganda involves testing bacterial isolates from clinical samples at national and regional hospitals. Although the National Microbiology Reference Laboratory (NMRL) analyzes these isolates for official AMR surveillance data, there's limited integration into public health planning. To enhance the utilization of NMRL data to better inform drug selection and public health strategies in combating antibiotic resistance, we evaluated the trends and spatial distribution of AMR to common antibiotics used in Uganda. Methods We analyzed data from pathogenic bacterial isolates from blood, cerebrospinal, peritoneal, and pleural fluid from AMR surveillance data for 2018–2021. We calculated the proportions of isolates that were resistant to common antimicrobial classes. We used the chi-square test for trends to evaluate changes in AMR resistance over the study period. Results Out of 537 isolates with 15 pathogenic bacteria, 478 (89%) were from blood, 34 (6.3%) were from pleural fluid, 21 (4%) were from cerebrospinal fluid, and 4 (0.7%) were from peritoneal fluid. The most common pathogen was Staphylococcus aureus (20.1%), followed by Salmonella species (18.8%). The overall change in resistance over the four years was 63–84% for sulfonamides, fluoroquinolones macrolides (46–76%), phenicols (48–71%), penicillins (42–97%), β-lactamase inhibitors (20–92%), aminoglycosides (17–53%), cephalosporins (8.3–90%), carbapenems (5.3–26%), and glycopeptides (0–20%). There was a fluctuation in resistance of Staphylococcus aureus to methicillin (60%-45%) (using cefoxitin resistance as a surrogate for oxacillin resistance) Among gram-negative organisms, there were increases in resistance to tetracycline (29–78% p

Type 2 diabetes mellitus (T2DM) represents a major healthcare condition of the 21st century. It is characterised by persistently elevated blood glucose occurring as a result of peripheral insulin resistance and reduced insulin production which may lead to multiple long-term health conditions such as retinopathy, neuropathy, and nephropathy. The estimated number of individuals suffering from diabetes mellitus (DM) is expected to rise to 591 million by the year 2035 with 4.4 million in the United Kingdom (UK) alone, 90% of which is attributed to T2DM. Moreover, a significant proportion of individuals may have undetected diabetes mellitus, especially among those presenting with symptoms of ischaemic heart disease (IHD). This is particularly important in those individuals presenting with acute coronary syndromes (ACS) who are at the highest risk of complications and sudden cardiac death. Identifying abnormal levels of common biochemical markers of diabetes, such as capillary blood glucose or glycated haemoglobin (HbA1c) in these patients is important for early diagnosis, which will then allow for timely intervention to improve outcomes. However, a significant proportion of individuals who meet the criteria for the diagnosis of diabetes remain undiagnosed, representing missed opportunities for early intervention. This may result in a prolonged period of untreated hyperglycaemia, which can result resulting in significant further microvascular and macrovascular complications. There is an increased risk of IHD, heart failure, cerebrovascular accidents (CVA), and peripheral artery disease (PVD). These account accounting for 50% of deaths in patients with T2DM. Cardiovascular diseases in the context of diabetes particular represent a significant cause of morbidity and mortality with a two to three times higher risk of cardiovascular disease in individuals with T2DM than in those without the condition normo-glycaemia. In the United Kingdom UK alone, around 120 amputations, 770 CVA, 590 heart attacks, and more than 2300 presentations with heart failure per week are attributed to diabetes DM. with One 1 in six 6 hospital beds and around 10% of the healthcare budget may be being spent on managing diabetes DM or its complications. Therefore, it represents a significant burden on our healthcare system.

Cognitive changes associated with PASC may not be uniform across populations. We conducted individual-level pooled analyses and meta-analyses of cognitive assessments from eight prospective cohorts, comprising 2,105 patients and 1,432 controls from Argentina, Canada, Chile, Greece, India, Italy, Russia, and the UK. The meta-analysis found no differences by country of origin. The profile and severity of cognitive impairment varied by age, with mild attentional impairment observed in young and middle-aged adults, but memory, language, and executive function impairment in older adults. The risk of moderate to severe impairment doubled in older adults. Moderately severe or severe impairment was significantly associated with infection diagnoses (chi-square = 26.57, p ≤ 0.0001) and the severity of anosmia (chi-square = 31.81, p ≤ 0.0001). We found distinct age-related phenotypes of cognitive impairment in patients recovering from COVID-19. We identified the severity of acute illness and the presence of olfactory dysfunction as the primary predictors of dementia-like impairment in older adults.

El objetivo del estudio fue evaluar la eficacia del uso de un protocolo terapéutico con Toxina Botulínica tipo A (TB-A) intramuscular en músculos masticatorios y trapecios con dos aplicaciones, con intervalo de 15 días entre cada una para tratar el dolor facial en una muestra de 15 pacientes mediante la Escala Visual Analógica (EVA) registrando el grado de percepción de dolor y disconfort en 8 regiones de la cara, recolectando los datos desde el día de la aplicación de TB-A, a los 7 días , 15 días de la segunda aplicación y a los 30 días. La muestra estudiada estuvo compuesta mayoritariamente por mujeres con edades comprendidas entre 20 a 49 años. Según los datos del interrogatorio clínico, notamos la relación que existe entre el bruxismo, dolor orofacial y el estrés. Las zonas de mayor percepción de dolor registrada inicialmente en la EVA de la muestra estudiada fueron las regiones: mandibular del lado derecho, temporal derecha y trapecios; a los 7 días las regiones que mostraron mayor eficiencia en la percepción de disminución de síntomas fueron: mandíbula del lado derecho, temporal derecha, trapecios y cuello; 15 y 30 días: mandíbula del lado derecho e izquierdo, temporal derecho, trapecios y cuello. La aplicación de TB-A terapéuticamente ofrece una mejoría en la sintomatología dolorosa, disminuyendo el disconfort y aumentando la sensación de bienestar emocional en la muestra estudiada; se recomienda continuar avanzando con investigaciones de este tipo, para así fortalecer su validez como opción terapéutica para el manejo del dolor orofacial.

In transmission lines, wind-induced vibrations, like high-frequency wind vibrations and low-frequency galloping phenomenon, can cause fatigue damage and failure, particularly in aluminum conductors, which have greater flexibility. Wind loads are variable forces applied by the wind to structures, including conductors. These dynamic wind loads vary with weather and altitude where the conductors are located, causing mechanical dissipation energy due to wire friction, particularly in contact zones. To ensure stability and safety, these loads and the damping effect must be taken into account when planning electrical transmission systems. The aim of this study is to investigate the impact of wind loads on the conductor's self-damping characteristics using a new approach to self-damping testing. Indeed, a self-damping test was carried out at the University of Brasilia's fatigue laboratory on 838 MCM AAAC 1120. The test bench was operated at frequencies ranging from 15.25 to 35.55 Hz, with the catenary parameter H/w = 2143 m, representing the ratio between the initial horizontal tensile load (H) and the conductor weight (w) per unit length. The power dissipated per unit length was calculated using the power method. It uses a methodology that allows the dissipation of mechanical energy to be measured accurately. The analysis revealed that higher frequencies lead to greater energy dissipation. Higher normalized amplitude with respect to the conductor diameter (Y/D ratio) lead to greater dissipation at the same frequency. The increase follows a power-law behavior, which is typical of vibration systems where the dissipated energy depends on frequency and amplitude.

Abstract. Objectives:. To develop and validate a prediction model for a deep surgical site infection (SSI) after fixation of a tibial plateau or pilon fracture. Design:. Pooled data from 2 randomized trials (VANCO and OXYGEN). Setting:. Fifty-two US trauma centers. Patients:. In total, 1847 adult patients with operatively treated tibial plateau or pilon fractures who met criteria for a high risk of infection. Intervention:. We considered 13 baseline patient characteristics and developed and externally validated prediction models using 3 approaches (logistic regression, stepwise elimination, and machine learning). Main Outcomes and Measures:. The primary prediction model outcome was a deep SSI requiring operative debridement within 182 days of definitive fixation. Our primary prognostic performance metric for evaluating the models was area under the receiver operating characteristic curve (AUC) with clinical utility set at 0.7. Results:. Deep SSI occurred in 75 VANCO patients (8%) and in 56 OXYGEN patients (6%). The machine learning model for VANCO (AUC = 0.65) and stepwise elimination model for OXYGEN (AUC = 0.62) had the highest internal validation AUCs. However, none of the external validation AUCs exceeded 0.64 (range, 0.58 to 0.64). Conclusions:. The predictive models did not reach the prespecified clinical utility threshold. Our models' inability to distinguish high-risk from low-risk patients is likely due to strict eligibility criteria and, therefore, homogeneous patient populations.

Abstract Background Uganda has a sentinel surveillance system in seven high-risk sites to monitor yellow fever (YF) patterns and detect outbreaks. We evaluated the performance of this system from 2017 to 2022. Methods We evaluated selected attributes, including timeliness (lags between different critical time points), external completeness (proportion of expected sentinel sites reporting ≥ 1 suspect case in the system annually), and internal completeness (proportion of reports with the minimum required data elements filled), using secondary data in the YF surveillance database from January 2017–July 2022. We conducted key informant interviews with stakeholders at health facility and national level to assess usefulness, flexibility, simplicity, and acceptability of the surveillance system. Results In total, 3,073 suspected and 15 confirmed YF cases were reported. The median time lag from sample collection to laboratory shipment was 37 days (IQR:21–54). External completeness was 76%; internal completeness was 65%. Stakeholders felt that the surveillance system was simple and acceptable, but were uncertain about flexibility. Most (71%) YF cases in previous outbreaks were detected through the sentinel surveillance system; data were used to inform interventions such as intensified YF vaccination. Conclusion The YF sentinel surveillance system was useful in detecting outbreaks and informing public health action. Delays in case confirmation and incomplete data compromised its overall effectiveness and efficiency.

Trace metal pollution is globally widespread, largely resulting from human activities. Due to the persistence and high toxicity of trace metals, these pollutants can have serious effects across ecosystems. However, few studies have directly assessed the presence and impact of trace metal pollution across ecosystems, specifically across multiple environmental sources and animal taxa. This study was designed to assess the environmental health impacts of trace metal pollution by assessing its extent and possible transfer into wildlife in the areas surrounding two abandoned metalliferous mine complexes in Wales in the UK. Water, sediment, and soil at the mine sites and in areas downstream had notably elevated concentrations of Pb, Zn, and, to a lesser extent, Cd and Cu, when compared to nearby control sites. These high trace metal concentrations were mirrored in the body burdens of aquatic invertebrates collected in the contaminated streams both at, and downstream of, the mines. Wood mice collected in contaminated areas appeared to be able to regulate their Zn and Cu tissue concentrations, but, when compared to wood mice from a nearby control site, they had significantly elevated concentrations of Cd and, particularly, Pb, detected in their kidney, liver, and bone samples. The Pb concentrations found in these tissues correlated strongly with local soil concentrations (kidney: ρ = 0.690; liver: ρ = 0.668, bone: ρ = 0.649), and were potentially indicative of Pb toxicity in between 10 % and 82 % of the rodents sampled at the mine sites and in areas downstream. The high trace metal concentrations found in the environment and in common prey species (invertebrates and rodents) indicates that trace metal pollution can have far-reaching, ecosystem-wide health impacts long after the polluting activity has ceased, and far beyond the originating site of the pollution.

Introduction Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), currently marketed for type 2 diabetes and obesity, may offer novel mechanisms to delay or prevent neurotoxicity associated with Alzheimer’s disease (AD). The impact of semaglutide in amyloid positivity (ISAP) trial is investigating whether the GLP-1 RA semaglutide reduces accumulation in the brain of cortical tau protein and neuroinflammation in individuals with preclinical/prodromal AD.Methods and analysis ISAP is an investigator-led, randomised, double-blind, superiority trial of oral semaglutide compared with placebo. Up to 88 individuals aged ≥55 years with brain amyloid positivity as assessed by positron emission tomography (PET) or cerebrospinal fluid, and no or mild cognitive impairment, will be randomised. People with the low-affinity binding variant of the rs6971 allele of the Translocator Protein 18 kDa (TSPO) gene, which can interfere with interpreting TSPO PET scans (a measure of neuroinflammation), will be excluded.At baseline, participants undergo tau, TSPO PET and MRI scanning, and provide data on physical activity and cognition. Eligible individuals are randomised in a 1:1 ratio to once-daily oral semaglutide or placebo, starting at 3 mg and up-titrating to 14 mg over 8 weeks. They will attend safety visits and provide blood samples to measure AD biomarkers at weeks 4, 8, 26 and 39. All cognitive assessments are repeated at week 26. The last study visit will be at week 52, when all baseline measurements will be repeated. The primary end point is the 1-year change in tau PET signal.Ethics and dissemination The study was approved by the West Midlands—Edgbaston Research Ethics Committee (22/WM/0013). The results of the study will be disseminated through scientific presentations and peer-reviewed publications.Trial registration number ISRCTN71283871.

Abstract The relevance of KRAS mutation alleles to clinical outcome remains inconclusive in pancreatic adenocarcinoma (PDAC). We conducted a retrospective study of 803 patients with PDAC (42% with metastatic disease) at MD Anderson Cancer Center. Overall survival (OS) analysis demonstrated that KRAS mutation status and subtypes were prognostic (p

We have performed shrinkage restraint force measurements on three shape memory polymers of polyethylene terephthalate (PET), polymethyl methacrylate (PMMA) and a blend of the two at a range of temperatures. Observations are made of the change in stress during temperature rise, hold and cooling. All materials show an increase in stress during rise and hold, but on cooling, the three materials behave differently; the PET shows a drop in stress, the PMMA a rise and the blend a much smaller rise. This behaviour correlates with the reversible thermal dimensional change below the shrinkage threshold temperature; the expansion coefficients are negative for PET, positive for PMMA and positive at a lower order of magnitude for the blend. We model the behaviour by supposing that the shrinkage forces are created by prestressed strains effective at long range within a matrix of shorter chains effective at short range. The total stress is the sum of the shrinkage stress and the thermal stress in the matrix. The drops in stress on cooling are modelled using an elastic analysis based on measured elastic moduli and thermal expansion coefficients. For the blend, downward jumps in temperature produce small transient increases in the total stress, leaving it effectively unchanged. This phenomenon and the results of the elastic model for the stress drops imply that the shrinkage stress from the long-range chain network is largely unaffected by the temperature change and so is not entropic.

Abstract The Antibody Mediated Prevention (AMP) trials (NCT02716675 and NCT02568215) demonstrated that passive administration of the broadly neutralizing monoclonal antibody VRC01 could prevent some HIV-1 acquisition events. Here, we use mathematical modeling in a post hoc analysis to demonstrate that VRC01 influenced viral loads in AMP participants who acquired HIV. Instantaneous inhibitory potential (IIP), which integrates VRC01 serum concentration and VRC01 sensitivity of acquired viruses in terms of both IC50 and IC80, follows a dose-response relationship with first positive viral load (p = 0.03), which is particularly strong above a threshold of IIP = 1.6 (r = -0.6, p = 2e-4). Mathematical modeling reveals that VRC01 activity predicted from in vitro IC80s and serum VRC01 concentrations overestimates in vivo neutralization by 600-fold (95% CI: 300–1200). The trained model projects that even if future therapeutic HIV trials of combination monoclonal antibodies do not always prevent acquisition, reductions in viremia and reservoir size could be expected.

Alzheimer’s disease is the most common cause of dementia in the elderly population (aged 65 years and over), followed by vascular dementia, Lewy body dementia, and rare types of neurodegenerative diseases, including frontotemporal dementia. There is an unmet need to improve diagnosis and prognosis for patients with dementia, as cycles of misdiagnosis and diagnostic delays are challenging scenarios in neurodegenerative diseases. Neuroimaging is routinely used in clinical practice to support the diagnosis of neurodegenerative diseases. Clinical neuroimaging is amenable to errors owing to varying human judgement as the imaging data are complex and multidimensional. Artificial intelligence algorithms (machine learning and deep learning) enable automation of neuroimaging interpretation and may reduce potential bias and ameliorate clinical decision-making. Graph convolutional network-based frameworks implicitly provide multimodal sparse interpretability to support the detection of Alzheimer’s disease and its prodromal stage, mild cognitive impairment. In patients with amyloid-related imaging abnormalities, radiologists had significantly better detection performances with both ARIA-E (sensitivity higher in the assisted/deep learning method [87%] compared to unassisted [71%]) and for ARIA-H signs (sensitivity was higher in assisted [79%] compared to unassisted [69%]). A convolutional neural network method was developed, and external validation predicted final clinical diagnoses of Alzheimer’s disease, dementia with Lewy bodies, mild cognitive impairment due to Alzheimer’s disease, or cognitively normal with FDG-PET. The translation of artificial intelligence to clinical practice is plagued with technical, disease-related, and institutional challenges. The implementation of artificial intelligence methods in clinical practice has the potential to transform the diagnostic and treatment landscape and improve patient health and outcomes.

Increasingly scarce water resources and growing global populations have exacerbated the problems of water quality in river systems and freshwaters in general. New monitoring methodologies and tools to democratize access to water quality information are needed if we are to reach ambitious societal objectives such as the UN Sustainable Development Goals and the European Green Deal. Here we present a cloud-based system for producing publicly accessible real time water quality forecasts coupled to novel biosensor technology. Short term forecasts of water quality impairments, e.g., as cyanobacteria blooms, sediment plumes and toxic pollution incidents are increasingly relevant both to citizens and stakeholders. Here, we present a new cloud based system that utilizes satellite data to produce real time forecasts of flow and water quality using a chain of dynamic catchment-scale models at multiple locations in a river network. We demonstrate this new system using two case studies: the River Thames and the Essex Colne River (United Kingdom). These rivers are key water supply sources for London and South-East England, respectively and are of high interest to recreational water users. We show how the new system can predict and forecast water quality, estimate toxicity and connect to citizen science observations using an App (www.aquascope.com) for information synthesis and delivery.

IntroductionThe adipokines leptin and adiponectin have been associated with atherosclerosis and the risk of cerebral infarcts. Pre-clinical studies, however, suggest a protective role against ischemic brain damage. In this study we analyzed the relationship between serum leptin and adiponectin levels and the onset or progression of brain infarcts in subjects with mild cognitive impairment (MCI) and Alzheimer’s disease (AD).MethodsAll data were extracted from the ADNI database. The final population included 566 subjects, with 58 healthy controls, 396 MCI and 112 AD. All patients with available serum leptin and adiponectin levels at baseline were selected. Demographics, neuropsychological test results, CSF biomarkers, regional brain metabolism with FDG-PET data and the number of brain infarcts on longitudinal MRI scans were extracted.ResultsLeptin levels were significantly lower in patients with MCI than controls at baseline, while adiponectin levels were not different between the groups. Multivariate logistic regression analysis at baseline for the presence of brain infarcts showed a predictive value for leptin but not for adiponectin. Multivariate longitudinal analysis showed that age was the only significant predictor of brain infarcts development at 15-year follow-up, while serum leptin and adiponectin levels did not play a role in this population.DiscussionThe evidence on the pathogenetic or protective role of adipokines on ischemic brain damage is mixed. In this MCI and AD population, serum leptin and adiponectin were not associated with the development of brain infarcts; therefore, these results do not support the use of adipokines as biomarkers of cerebrovascular pathology in this population.

Background Quality of life and care varies between and within the care homes in which almost half a million older people live and over half a million direct care staff (registered nurses and care assistants) work. The reasons are complex, understudied and sometimes oversimplified, but staff and their work are a significant influence. Objective(s) To explore variations in the care home nursing and support workforce; how resident and relatives’ needs in care homes are linked to care home staffing; how different staffing models impact on care quality, outcomes and costs; how workforce numbers, skill mix and stability meet residents’ needs; the contributions of the care home workforce to enhancing quality of care; staff relationships as a platform for implementation by providers. Design Mixed-method (QUAL-QUANT) parallel design with five work packages. WP1 – two evidence syntheses (one realist); WP2 – cross-sectional survey of routine staffing and rated quality from care home regulator; WP3 – analysis of longitudinal data from a corporate provider of staffing characteristics and quality indicators, including safety; WP4 – secondary analysis of care home regulator reports; WP5 – social network analysis of networks likely to influence quality innovation. We expressed our synthesised findings as a logic model. Setting English care homes, with and without nursing, with various ownership structures, size and location, with varying quality ratings. Participants Managers, residents, families and care home staff. Findings Staffing’s contribution to quality and personalised care requires: managerial and staff stability and consistency; sufficient staff to develop ‘familial’ relationships between staff and residents, and staff–staff reciprocity, ‘knowing’ residents, and skills and competence training beyond induction; supported, well-led staff seeing modelled behaviours from supervisors; autonomy to act. Outcome measures that capture the relationship between staffing and quality include: the extent to which resident needs and preferences are met and culturally appropriate; resident and family satisfaction; extent of residents living with purpose; safe care (including clinical outcomes); staff well-being and job satisfaction were important, but underacknowledged. Limitations Many of our findings stem from self-reported and routine data with known biases – such as under reporting of adverse incidents; our analysis may reflect these biases. COVID-19 required adapting our original protocol to make it feasible. Consequently, the effects of the pandemic are reflected in our research methods and findings. Our findings are based on data from a single care home operator and so may not be generalised to the wider population of care homes. Conclusions Innovative and multiple methods and theory can successfully highlight the nuanced relationship between staffing and quality in care homes. Modifiable characteristics such as visible philosophies of care and high-quality training, reinforced by behavioural and relational role modelling by leaders can make the difference when sufficient amounts of consistent staff are employed. Greater staffing capacity alone is unlikely to enhance quality in a cost-effective manner. Social network analysis can help identify the right people to aid adoption and spread of quality and innovation. Future research should focus on richer, iterative, evaluative testing and development of our logic model using theoretically and empirically defensible – rather than available – inputs and outcomes. Study registration This study is registered as PROSPERO CRD42021241066 and Research Registry registration: 1062. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 15/144/29) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 8. See the NIHR Funding and Awards website for further award information. Plain language summary This study was about the relationship between staffing and quality in care homes. Almost half a million older people live in care homes in England. Why quality of care and quality of life for residents vary so much between and within homes is unknown, but staff and the ways they work are likely to be important. Researching staffing and quality is difficult: quality means different things to different people and a lot of things shape how quality feels to residents, families and staff. In the past, researchers have oversimplified the problem to study it and may have missed important influences. We took a more complex view. In five interlinked work packages, we collected and analysed: (1) research journal articles; (2) national data from different care homes; (3) data from a large care organisation to look at what it is about staffing that influences quality; (4) reports and ratings of homes from the Care Quality Commission; and (5) we looked at the networks between staff in homes that shape how quality improvement techniques might spread. We used theories about how our findings might be linked to plan for this data collection and analysis. The results were combined into something called a ‘logic model’ – a diagram and explanation that make it easier for managers, researchers and people interested in care homes to see how staffing influences quality. Staffing considerations that might improve quality include: not swapping managers too much; having sufficient and consistent staff for family-like relationships in homes and putting residents’ needs first; supporting staff and giving them freedom to act; and key staff leading by example. Research examining care home quality should capture those aspects that mean the most to residents, their families and staff. Scientific summary Background An estimated 425,000 older people in England live in 18,000 care homes: with nursing, without nursing, or dual registered homes. They are some of the oldest and the most vulnerable people in society. Resident dependency levels and care needs are often similar in homes with and without nursing – but their workforces differ significantly. In homes with nursing care, registered nurses (RNs) are employed to provide clinical care and supervise care delivery, mainly from a large workforce of non-registered care assistants. Care homes without nursing comprise only social care staff or care assistants. The NHS provides health care – including nursing care – as required; for example, supporting specialist care for residents at the end of life. Staffing profiles and establishments vary between providers and so studying care homes and their workforce is complex. Conceptually, quality is similarly complex; it is contested, contingent, contextualised, dynamic and often deeply personal. Two dimensions of quality require consideration in care homes: quality of care and quality of life. While care home staff and their work are likely determinants of quality, research into the staffing–quality relationship is comparatively scant. Measuring quality often focuses on clinical outcomes, such as pressure ulcer prevalence, falls or medication errors. Many studies are in North American long-term care and the few English studies’ primary focus has been on staff turnover and quality and working conditions and quality. Our mixed-methods study addresses some of the theoretical gaps and methodological challenges associated with understanding staffing’s relationship to quality. Using established theory we focused on the structures, processes and outcomes of quality. Our aim of investigating workforce models of nursing and care support in care homes that effectively benefit residents, relatives and staff was addressed through six objectives, which were the focus of five linked work packages (WP). Objectives Describe variations in the characteristics of the care home nursing and support workforce (WP1). Identify the dependency and needs of residents and relatives in care homes and their association with care home staffing (WP2, WP3). Examine how different care home staffing models (including new roles) impact on quality of care, resident outcomes and NHS resources (WP1, WP2, WP3). Explain how care home workforce (numbers, skill mix and stability) might meet the dependency and needs of residents (WP1, WP2, WP3, WP4). Explore and understand the contributions of the nursing and support workforce (including innovations in nursing and support roles) in care homes to enhance quality of care (WP1, WP4). Translate methods used for modelling the relationships between staffing and quality to provide a platform for sector-wide implementation (WP5). Methods A mixed-method (QUAL-QUANT) parallel design built around Donabedian’s theoretical framework of structures, processes and outcomes was the basis for our exploration of the relationship between care home staffing and quality. The coronavirus disease 2019 (COVID-19) pandemic meant some deviation from our original protocol was necessary. Work package 1 (WP1) was two evidence reviews: a systematic review synthesising 36 studies of care home staff perceptions of their roles and responsibilities in promoting quality; a realist review (n = 66 studies) then developed evidence and theory-based explanations of how care home staff behaviours promote quality of care and quality of life, why and in what circumstances. Work packages 2 and 3 used routinely collected measures of staffing and examined their relationship to quality. WP2 was a cross-sectional observational study, modelling the relationship between care quality – as measured in Care Quality Commission (CQC) inspection reports – and care home workforce characteristics from the National Minimum Data Set for Social Care (NMDS-SC). WP3 analysed routinely collected longitudinal data measures of workforce, nurse-sensitive indicators of care quality, resident characteristics and home characteristics from a large corporate care home provider over 42 months. A cost analysis from a provider perspective was also undertaken. Work package 4 used documentary analysis of 30 purposively sampled, publicly available, inspection reports from the English national quality regulator (CQC) from homes rated as outstanding or inadequate to examine (1) how staffing structures influenced quality and (2) the care processes that explain the relationship between staffing and quality. In WP5, care homes (n = 11) were purposively sampled and social network analysis (SNA) using questionnaires and roster name generation was used to map the self-reported advice and influence relationships present in care homes. To assess homes’ readiness for innovation and work-related barriers to adoption of our (translated) findings, eight managers completed an adapted version of the Normalisation MeAsure Development questionnaire (NoMAD) questionnaire – an operationalised instrument of Normalisation Process Theory. Public and stakeholder involvement and engagement We worked closely with the public and stakeholders throughout, from question formulation through to synthesis. Two advisory groups were formed: (1) a resident and relative group and (2) a care home manager group. The study steering committee (SSC) contained key stakeholders – including relatives – to provide oversight and guidance. These mechanisms ensured perspectives other than the research team informed and improved research design and implementation and prompted wider conversations and learnRNing that benefited the research. Ethics approval Work package 2 and WP3 were approved (2 August 2017) by the Social Care Research Ethics Committee (17/WM/0232). WP5 was approved (21 June 2019) by the University of Leeds, Faculty of Medicine and Health, Ethics and Governance Committee (HREC 18-028). Findings The five linked WP findings were synthesised using a logic model to explain what is likely to work, why and how, and the interactions between structures, processes and outcomes important for the staffing–quality relationship. Managerial stability was important: care homes with a manager in-post in the 12 months prior to a CQC inspection were more likely to be rated as good or outstanding (WP2). Managers made those workforce decisions necessary for meeting residents’ care and safety needs (WP4). Managers of care homes rated good or outstanding had authority and flexibility to secure the workforce they judged necessary (WP4). Cohesive working relationships between managers and their corporate senior management team or owner helped managers enact their decisions (WP4). Higher staff-to-bed ratios were associated with a greater chance of a good or outstanding CQC inspection score (WP2). More care from RNs was associated with fewer falls with fractures, urinary tract infections (UTIs) and medication errors (WP3). Use of agency nurses to cover for staff sickness or unfilled vacancies was not associated with more falls, infections or pressure ulcers, but was associated with more medication errors (WP3). Simply increasing nursing input is unlikely to be a cost-effective way of reducing adverse incidents in care homes (WP3). WP4 (and WP1ii) identified the importance of having ‘sufficient’ staff to meet residents’ needs and preferences and improve outcomes. But detail of how staffing levels were determined by managers and consistent use of tools to support professional judgement about staffing (WP4) was lacking. Staff stability and minimising agency staff use were perceived as necessary conditions for quality (WP4). Having experienced care staff, that is, staff in post for 5 years, was likely to improve quality, as measured by ratings (WP2). A stable workforce was also associated with skills and competence (WP1i, WP1ii, WP4). Opportunities for staff induction, training and continuing professional development, alongside staff supervision, were extensive in care homes rated as outstanding (WP4). High staff turnover reduced opportunities for developing broader staff skills and competence, narrowing it to staff induction and mandatory training (WP4). Staffing consistency was important for organising care and work (WP1i, WP1ii, WP4). Larger homes were less likely to be rated positively (WP2). Other WPs highlighted the importance of team size (not home size) as a lever for promoting quality (WP1i, WP1ii, WP4). Small groups of linked residents and staff (5–15 residents per staff member based on level of resident dependency) promoted familiarity, communication and a family-like environment for cultivating relationships (WP1ii). Establishing these family-like relationships and ‘knowing’ residents promoted personalisation of resident care (WP1i), encouraging staff to go beyond purely assisting residents with physical tasks, towards addressing wider social and emotional needs (WP1ii). The reviews (WP1i, WP1ii) highlight where the requisite roles and responsibilities of the workforce might help achieve this. Developing relationships based on consultation – with families, professionals outside the home and residents – to support residents was a feature of homes rated as outstanding (WP1i, WP1ii, WP4). These relationships informed care planning and personalisation of care (WP1i). Relationships between staff and families also legitimised family involvement in care to support quality (WP1ii). Unit-level supervisors that role modelled relationship building were important levers for realising team ambitions of relationship-based quality (WP1ii, WP4). Staffing consistency was important for teamworking. In care homes rated outstanding, staff reported working together and supporting each other towards a collective vision of care and support (WP4). Staff that felt supported, valued and – with (managerial) ‘permission’ – able to prioritise residents’ needs, adapted and adopted behaviours promoting residents’ expressing preferences for care (WP1ii, WP4). More autonomy in day-to-day work, with associated accountability, led to greater staff engagement and satisfaction (WP1ii, WP4). Team reciprocity was linked to open communication, information exchange, advice and influence (WP1ii, WP5). Reciprocity encouraged teams to draw on each other’s knowledge and skills to promote individualised care and enhance quality (WP1i, WP1ii, WP4). Combining written and verbal staff communication was a feature in homes rated as outstanding and linked to better resident care (WP4). Visible unit-level supervisors – not always managers – fostered teamworking. They also minimised conflicts, enabling team reciprocity and relationships (WP1ii). Social networks can promote or hinder the behavioural mechanisms influencing quality (WP5). Networks that were interconnected, dense or cohesive, built around strong advice and influence relationships, had higher chances of implementing change associated with innovation around quality (WP5). The care home manager – as opinion leader (i.e. providing most advice and influence and receiving most advice and influence) – was pivotal in implementing innovation-related change (WP5). Leadership and management behaviours promoted resident-centred approaches; ensured effective communication; promoted staff confidence; offered practical and emotional support and recognition to staff; and encouraged diversity (WP1ii). Staff feeling valued was linked to greater staff commitment and contribution to quality (WP4). A managerially endorsed philosophy of care (valuing residents and staff) encouraged the staff behaviours needed for individualised resident care (WP1ii, WP4). Based on our analysis, measuring the following resident outcomes would provide a more meaningful picture of the relationship between staffing and quality: the extent to which resident needs and preferences are met (and culturally appropriate) (WP1i, WP1ii, WP4); resident and family satisfaction (WP1i, WP1ii, WP4); residents living with purpose to promote their quality of life and well-being (WP1i, WP1ii, WP4); and safe care for residents (including clinical outcomes) (WP1i, WP1ii, WP2, WP3, WP4). Staff well-being and job satisfaction were important outcomes which influenced quality as experienced by residents. Conclusions Our study makes a novel and important contribution to understanding the importance of the relationship between staff, their work and behaviours and quality in care homes. We have attempted to shift the debate away from a reductionist picture of numbers of staff and their relationship to clinical indicators, towards a more nuanced recognition of the ways in which staff in the right amounts and with the right behaviours can meet resident’s needs and preferences. Staffing needs to be stable, skilled and competent to realise the benefits of person-focused organisation of care, and enhanced teamworking. Leadership, reward and recognition of staff and a shared philosophy of care provide needed context for the relationships required to improve quality as experienced by residents. Our findings will be useful for people and organisations making policy and delivering services that want to work towards the best ways to deploy and support quality in care homes using their most valuable resource: their staff. Implications for social care Understanding that numbers of staff alone are a necessary but not sufficient condition for care home quality. Quality improves in homes when more care is provided by RNs. Simply introducing ‘more’ staff (particularly RNs) is unlikely to be a cost-effective way of reducing adverse incidents in care homes. Quality relies on the who, what and how of staffing arrangements and organisation of work. Leadership is key, influencing how organisational resources are used to promote the environments and cultures needed for quality-promoting relationships to flourish. Realising and supporting the potential of the staffing resource (clinical, care, social and cultural skills and competence) are essential for quality. Opportunities for learning and development demonstrate an organisation values staff and may support staff retention. A focus on the structures that support staffing consistency (stability, skill and competence) is important for influencing processes (the organisation of care and teamworking) and outcomes for residents and staff. Developing transparent approaches that enable care home managers to effectively judge and make decisions about staffing levels is crucial for safe and appropriate care for residents. Reciprocal relationships, beyond the immediate care team and including residents, their families and health and social care professionals promote quality. Leadership and management behaviours influence staff commitment and thus their contribution to quality. A ‘visible’ unit supervisor and staff who ‘connect’ and influence the team are essential for quality and innovation in care homes. Implications for research Future research should: Unpack the contribution of direct care support workforce (including care assistants, senior care assistants and nursing associates) working at different levels of skills and competence to care home quality. Explore how training for care assistants, senior care assistants and nursing associates contributes to improving quality. Consider differences for temporary (i.e. step-up or step-down care) versus permanent (i.e. long-term placement) care home residents. Explore how resident population levels of dependency are related to quality. Use innovative methods to capture quality in ways that recognise individual stakeholder views, values, expectations and preferences and address both quality of care and quality of life. Develop robust social network interventions to change network structures to enhance reciprocity and advice and influence relationships to embed innovations for enhancing quality. Consider machine learning methods for analysis of routine data because these methods are better able to identify non-linear relationships between staffing and care quality indicators than traditional regression analysis in order to better identify minimum adequate staffing levels. Use methods to promote more accurate modelling of the staffing–quality relationship through data linkage. Further test and develop our logic model. Study registration This study is registered as PROSPERO CRD42021241066 and Research Registry registration: 1062. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 15/144/29) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 8. See the NIHR Funding and Awards website for further award information.

Background: Diarrheal diseases, are major concerns for Ugandan children; persistent in Obongi District despite high rotavirus vaccination rates (2019–2021). The district recorded the country's highest annual acute watery diarrhea (AWD) incidence from 2017 to 2021. Our study, conducted in April 2022, assessed AWD risk factors among 0–59-month-old children in Obongi. Methods: We conducted a 1:2 (193:386) unmatched case–control study. A case was a child (0–59 months) with ≥ 3 loose/liquid stools/day, negative malaria/pneumonia tests, residing in Itula/Parolinya subcounty from 1 to 30 April 2022. Medical records from 10 facilities were reviewed. Simple random sampling identified cases, who were interviewed, and controls were randomly chosen from non-AWD neighboring households. Child health cards provided vaccination details. We used logistic regression to identify factors associated with AWD. Results: Among 193 cases and 386 controls, 104 (54 %) cases and 183 (47 %) controls were male, 58 (30 %) cases and 127 (33 %) controls were aged 12–23 months, 187 (97 %) cases and 369 (96 %) controls had received at least one dose of rotavirus vaccine, 58 (30 %) cases and 120 (34 %) controls treated drinking water. Comorbidity presence (undernutrition, diabetes, HIV) (AOR = 12; CI: 2.5–53), caregiver's unwashed hands post-toilet (AOR = 3.9; CI: 1.2–13), and borehole vs. piped water (AOR = 4.0; CI: 1.7–9.6) linked to AWD. Conclusion: Modifiable factors, including failure of caregivers to wash their hands with soap after visiting toilets and use of borehole water were associated with AWD, suggesting that community sensitization on handwashing at critical times, using clean water and soap, and expanded use of piped water could reduce AWD incidence in this area.

Summary: Background: Elicitation of broad immune responses is understood to be required for an efficacious preventative HIV vaccine. This Phase 1 randomized controlled trial evaluated whether administration of vaccine antigens separated at multiple injection sites vs combined, fractional delivery at multiple sites affected T-cell breadth compared to standard, single site vaccination. Methods: We randomized 90 participants to receive recombinant adenovirus 5 (rAd5) vector with HIV inserts gag, pol and env via three different strategies. The Standard group received vaccine at a single anatomic site (n = 30) compared to two polytopic (multisite) vaccination groups: Separated (n = 30), where antigens were separately administered to four anatomical sites, and Fractioned (n = 30), where fractions of each vaccine component were combined and administered at four sites. All groups received the same total dose of vaccine. Findings: CD8 T-cell response rates and magnitudes were significantly higher in the Fractioned group than Standard for several antigen pools tested. CD4 T-cell response magnitudes to Pol were higher in the Separated than Standard group. T-cell epitope mapping demonstrated greatest breadth in the Fractioned group (median 8.0 vs 2.5 for Standard, Wilcoxon p = 0.03; not significant after multiplicity adjustment for co-primary endpoints). IgG binding antibody response rates to Env were higher in the Standard and Fractioned groups vs Separated group. Interpretation: This study shows that the number of anatomic sites for which a vaccine is delivered and distribution of its antigenic components influences immune responses in humans. Funding: National Institute of Allergy and Infectious Diseases, NIH.

ABSTRACT The detection of emerging infectious diseases (EIDs) within endangered animal populations is increasing rapidly because of many factors, such as anthropogenic influences and climate change. Their impacts can be extensive and may further contribute to the processes risking the threat of extinction of these species. EIDs may be caused by a range of pathogens, including viruses, bacteria, parasites, and fungi. However, detection and diagnosis can be challenging with limited knowledge of existing pathogens in endangered wildlife. The critically endangered orange-bellied parrot (OBP, Neophema chrysogaster), with as few as 70 wild individuals, is a species at risk of extinctions, yet little research has been conducted into their existing viral diversity (virome). To determine the virome in a subset of the captive OBP population, this study characterized the fecal virome using a viral metagenomic approach. Analysis of the generated sequence data sets identified 11 viruses belonging to the families Adenoviridae, Circoviridae, Parvoviridae, and Picornaviridae. Strikingly, eight viruses were detected in the OBPs housed in Aviary 1 compared to only three viruses in OBPs housed at Aviary 2. In addition to detecting six novel viruses, this study also demonstrated ongoing infection with psittacine siadenovirus F. This study highlights the need to broaden this research to other populations of this species. Further virome characterization of co-habiting birds could also identify potential novel viruses and provide insight into their evolutionary relationship. These findings may contribute to strategic management and biosecurity plans for the conservation of endangered parrots. IMPORTANCE The impact of circulating viruses on the critically endangered, orange-bellied parrot (OBP) population can be devastating. The OBP already faces numerous threats to its survival in the wild, including habitat loss, predation, and small population impacts. Conservation of the wild OBP population is heavily reliant on supplementation using OBPs from a managed captive breeding program. These birds may act as a source for introduction of a novel disease agent to the wild population that may affect survival and reproduction. It is, therefore, essential to monitor and assess the health of OBPs and take appropriate measures to prevent and control the spread of viral infections. This requires knowledge of the existing virome to identify novel and emerging viruses and support development of appropriate measures to manage associated risk. By monitoring and protecting these animals from emerging viral diseases, we can help ensure their ongoing survival and preserve the biodiversity of our planet.

Abstract The secondary structure of nucleic acids containing quartets of guanines, termed G-quadruplexes, is known to regulate the transcription of many genes. Several G-quadruplexes can be formed in the HIV-1 long terminal repeat promoter region and their stabilization results in the inhibition of HIV-1 replication. Here, we identified helquat-based compounds as a new class of anti-HIV-1 inhibitors that inhibit HIV-1 replication at the stage of reverse transcription and provirus expression. Using Taq polymerase stop and FRET melting assays, we have demonstrated their ability to stabilize G-quadruplexes in the HIV-1 long-terminal repeat sequence. Moreover, these compounds were not binding to the general G-rich region, but rather to G-quadruplex-forming regions. Finally, docking and molecular dynamics calculations indicate that the structure of the helquat core greatly affects the binding mode to the individual G-quadruplexes. Our findings can provide useful information for the further rational design of inhibitors targeting G-quadruplexes in HIV-1.