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Abstract Stroke is a leading cause of disability, and Magnetic Resonance Imaging (MRI) is routinely acquired for acute stroke management. Publicly sharing these datasets can aid in the development of machine learning algorithms, particularly for lesion identification, brain health quantification, and prognosis. These algorithms thrive on large amounts of information, but require diverse datasets to avoid overfitting to specific populations or acquisitions. While there are many large public MRI datasets, few of these include acute stroke. We describe clinical MRI using diffusion-weighted, fluid-attenuated and T1-weighted modalities for 1715 individuals admitted in the upstate of South Carolina, of whom 1461 have acute ischemic stroke. Demographic and impairment data are provided for 1106 of the stroke survivors from this cohort. Our validation demonstrates that machine learning can leverage the imaging data to predict stroke severity as measured by the NIH Stroke Scale/Score (NIHSS). We share not only the raw data, but also the scripts for replicating our findings. These tools can aid in education, and provide a benchmark for validating improved methods.

Abstract Metabolic cost greatly impacts trade-offs within a variety of human movements. Standard respiratory measurements only obtain the mean cost of a movement cycle, preventing understanding of the contributions of different phases in, for example, walking. We present a method that estimates the within-stride cost of walking by leveraging measurements under different force perturbations. The method reproduces time series with greater consistency (r = 0.55 and 0.80 in two datasets) than previous model-based estimations (r = 0.29). This perturbation-based method reveals how the cost of push-off (10%) is much smaller than would be expected from positive mechanical work (~ 70%). This work elucidates the costliest phases during walking, offering new targets for assistive devices and rehabilitation strategies.

Abstract Aims Patients with a reduced left ventricular ejection fraction (LVEF) following an acute myocardial infarction (MI) are at risk of progressive adverse cardiac remodelling that can lead to the development of heart failure and death. The early addition of a sodium‐glucose cotransporter 2 (SGLT2) inhibitor to standard treatment may delay or prevent progressive adverse remodelling in these patients. Methods and results EMpagliflozin to PREvent worSening of left ventricular volumes and Systolic function after Myocardial Infarction (EMPRESS‐MI) is a randomized, double‐blind, placebo‐controlled, multi‐centre trial designed to assess the effect of empagliflozin on cardiac remodelling evaluated using cardiovascular magnetic resonance (CMR) in 100 patients with left ventricular systolic dysfunction following MI. Eligible patients were those ≥12 h and ≤14 days following acute MI, with an LVEF

Abstract Impedance-matched Marx generators (IMGs) are considered next generation pulsed-power drivers because of their long lifetime (> 10,000 shots), repetition rate (> 0.1-Hz), fast rise time (~ 100-ns), and high-energy-delivery efficiency (~ 90%). “TITAN” is a 14-stage IMG designed to deliver 1-TW to a 2-Ω matched load. In this paper, design, simulation, and experimental results for six stages of TITAN including its triggering system, air delivery system, and pulse shaping are presented. To achieve efficiency over 85% and maximize the capability of an IMG, synchronized triggering, reduced pre-fire rate, and pulse shaping ability are crucial. In this paper, novel engineering solutions are introduced, tested, and proven to overcome those challenges. 6-stage TITAN, powered by 102 identical bricks and 102 field-distortion-triggered gas switches, could generate ~ 600-kA and ~ 700-kV across a ~ 0.9-Ω matched load when fully charged to ± 100-kV. In these experiments, 6-stage TITAN is tested up to ± 70-kV charge voltage which delivers a peak power of 330-GW to a 1.2-Ω resistive load.

Abstract Background On 20 September 2022, Uganda declared its fifth Sudan virus disease (SVD) outbreak, culminating in 142 confirmed and 22 probable cases. The reproductive rate (R) of this outbreak was 1.25. We described persons who were exposed to the virus, became infected, and they led to the infection of an unusually high number of cases during the outbreak. Methods In this descriptive cross-sectional study, we defined a super-spreader person (SSP) as any person with real-time polymerase chain reaction (RT-PCR) confirmed SVD linked to the infection of ≥ 13 other persons (10-fold the outbreak R). We reviewed illness narratives for SSPs collected through interviews. Whole-genome sequencing was used to support epidemiologic linkages between cases. Results Two SSPs (Patient A, a 33-year-old male, and Patient B, a 26-year-old male) were identified, and linked to the infection of one probable and 50 confirmed secondary cases. Both SSPs lived in the same parish and were likely infected by a single ill healthcare worker in early October while receiving healthcare. Both sought treatment at multiple health facilities, but neither was ever isolated at an Ebola Treatment Unit (ETU). In total, 18 secondary cases (17 confirmed, one probable), including three deaths (17%), were linked to Patient A; 33 secondary cases (all confirmed), including 14 (42%) deaths, were linked to Patient B. Secondary cases linked to Patient A included family members, neighbours, and contacts at health facilities, including healthcare workers. Those linked to Patient B included healthcare workers, friends, and family members who interacted with him throughout his illness, prayed over him while he was nearing death, or exhumed his body. Intensive community engagement and awareness-building were initiated based on narratives collected about patients A and B; 49 (96%) of the secondary cases were isolated in an ETU, a median of three days after onset. Only nine tertiary cases were linked to the 51 secondary cases. Sequencing suggested plausible direct transmission from the SSPs to 37 of 39 secondary cases with sequence data. Conclusion Extended time in the community while ill, social interactions, cross-district travel for treatment, and religious practices contributed to SVD super-spreading. Intensive community engagement and awareness may have reduced the number of tertiary infections. Intensive follow-up of contacts of case-patients may help reduce the impact of super-spreading events.

Extragonadal germ cell tumors (GCTs) are rare, accounting for 1% to 5% of all GCTs, with malignant sacrococcygeal yolk sac tumors (SCYSTs) being part of this uncommon subset. These tumors primarily occur in children and young adults and are known for their aggressive behavior, necessitating early diagnosis and prompt treatment. In this case report, we present the case of an 8-month-old female who presented with mild abdominal distension and a 3-week history of difficulty passing urine. Imaging revealed a pelvic mass originating from the coccyx, compressing the urinary bladder. The mass was surgically excised, and histopathological analysis confirmed a malignant yolk sac tumor with positive margins. The patient received adjuvant chemotherapy postsurgery. Despite treatment, follow-up scans showed residual tumor tissue, leading to a second tumor resection. Surveillance was continued using Alpha Fetoprotein (AFP) levels as a marker, which revealed a relapse of the tumor. Subsequent imaging confirmed a growing tumor, and the patient was scheduled for second-line chemotherapy. Management of SCYSTs is complex and requires a multidisciplinary approach, including surgeons, oncologists, radiologists, and pathologists. While relapse is rare, it poses a significant challenge for treatment, underscoring the need for clear and updated guidelines for managing relapsed cases.

Summary: Background: The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. Methods: Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E] ≤ 4) were used for hierarchical clustering to identify patients with similar signatures. Findings: Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. Interpretation: Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. Funding: CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.

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

Summary: Background: Traumatic brain injury is conventionally categorised as mild, moderate, or severe on the Glasgow Coma Scale (GCS). Recently developed biomarkers can provide more objective and nuanced measures of the extent of brain injury. Methods: Exposure–response relationships were investigated in 2479 patients aged ≥16 enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. Neurofilament protein-light (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) were assayed from serum sampled in the first 24 h; concentrations were divided into quintiles within GCS severity groups. Relationships with the Glasgow Outcome Scale-Extended were examined using modified Poisson regression including age, sex, major extracranial injury, time to sample, and log biomarker concentration as covariates. Findings: Within severity groups there were associations between biomarkers and outcomes after adjustment for covariates: GCS 13–15 and negative CT imaging (relative risks [RRs] from 1.28 to 3.72), GCS 13–15 and positive CT (1.21–2.81), GCS 9–12 (1.16–2.02), GCS 3–8 (1.09–1.94). RRs were associated with clinically important differences in expectations of prognosis. In patients with GCS 3 (RRs 1.51–1.80) percentages of unfavourable outcome were 37–51% in the lowest quintiles of biomarker levels and reached 90–94% in the highest quintiles. Similarly, for GCS 15 (RRs 1.83–3.79), the percentages were 2–4% and 19–28% in the lowest and highest biomarker quintiles, respectively. Interpretation: Conventional TBI severity classification is inadequate and underestimates heterogeneity of brain injury and associated outcomes. The adoption of circulating biomarkers can add to clinical assessment of injury severity. Funding: European Union 7th Framework program (EC grant 602150), Hannelore Kohl Stiftung, One Mind, Integra LifeSciences, Neuro-Trauma Sciences, NIHR Rosetrees Trust.

Abstract The proto-oncogene MYC encodes a nuclear transcription factor that has an important role in a variety of cellular processes, such as cell cycle progression, proliferation, metabolism, adhesion, apoptosis, and therapeutic resistance. MYC amplification is consistently observed in aggressive forms of several solid malignancies and correlates with poor prognosis and distant metastases. While the tumorigenic effects of MYC in patients with head and neck squamous cell carcinoma (HNSCC) are well known, the molecular mechanisms by which the amplification of this gene may confer treatment resistance, especially to immune checkpoint inhibitors, remains under-investigated. Here we present a unique case of a patient with recurrent/metastatic (R/M) HNSCC who, despite initial response to nivolumab-based treatment, developed rapidly progressive metastatic disease after the acquisition of MYC amplification. We conducted comparative transcriptomic analysis of this patient’s tumor at baseline and upon progression to interrogate potential molecular processes through which MYC may confer resistance to immunotherapy and/or chemoradiation and used TCGA-HNSC dataset and an institutional cohort to further explore clinicopathologic features and key molecular networks associated with MYC amplification in HNSCC. This study highlights MYC amplification as a potential mechanism of immune checkpoint inhibitor resistance and suggest its use as a predictive biomarker and potential therapeutic target in R/M HNSCC.

Summary: Airway epithelial cells represent the first line of defense against respiratory pathogens. Flagellin drives the motility of many mucosal pathogens and has been suggested as an immune enhancing adjunctive therapeutic in infections of the airways. This study leveraged single-cell RNA sequencing to determine cell-specific effects of flagellin in primary human bronchial epithelial cells growing in air-liquid interface. Seven cell clusters were identified, including ciliated cells, ionocytes, and several states of basal and secretory cells, of which only inflammatory basal cells and inflammatory secretory cells demonstrated a proportional increase in response to flagellin. Inflammatory secretory cells showed evidence of metabolic reprogramming toward aerobic glycolysis, while in inflammatory basal cells transcriptome profiles indicated enhanced oxidative phosphorylation. Inhibition of mTOR prevented the shift to glycolysis and reduced inflammatory gene transcription specifically in inflammatory secretory cells. These data demonstrate the functional heterogeneity of the human airway epithelium upon exposure to flagellin.

Aims: To assess the cost-effectiveness of a two-layer compression bandage versus a standard wool and crepe bandage following total knee arthroplasty, using patient-level data from the Knee Replacement Bandage Study (KReBS). Methods: A cost-utility analysis was undertaken alongside KReBS, a pragmatic, two-arm, open label, parallel-group, randomized controlled trial, in terms of the cost per quality-adjusted life year (QALY). Overall, 2,330 participants scheduled for total knee arthroplasty (TKA) were randomized to either a two-layer compression bandage or a standard wool and crepe bandage. Costs were estimated over a 12-month period from the UK NHS perspective, and health outcomes were reported as QALYs based on participants’ EuroQol five-dimesion five-level questionnaire responses. Multiple imputation was used to deal with missing data and sensitivity analyses included a complete case analysis and testing of costing assumptions, with a secondary analysis exploring the inclusion of productivity losses. Results: The base case analysis found participants in the compression bandage group accrued marginally fewer QALYs, on average, compared with those in the standard bandage group (reduction of 0.0050 QALYs (95% confidence interval (CI) -0.0051 to -0.0049)), and accumulated additional mean costs (incremental cost of £52.68 per participant (95% CI 50.56 to 54.80)). Findings remained robust to assumptions tested in sensitivity analyses, although considerable uncertainty surrounded the outcome estimates. Conclusion: Use of a two-layer compression bandage is marginally less effective in terms of health-related quality of life, and more expensive when compared with a standard bandage following TKA, so therefore is unlikely to provide a cost-effective option. Cite this article: Bone Jt Open 2024;5(7):550–559.

Background: Early recognition of neonatal illnesses followedby care-seeking and intervention are key factors in improving neonatal health and survival. Objectives: To assess mothers’ ability to recognize newborn danger signs and actions taken by mothers in the event of neonatal illness. Methods: The study was carried out in three health centres in Yenagoa Metropolis from April to May 2011. A 15 itemed Questionnaire based on the WHO/UNICEF IMCI programme handbook was administered to 146 mothers with infants younger than three months. The mothers were asked to identify danger signs of neonatal illness from a list of symptoms, to indicate which of the listed symptoms their babies experienced, to state what actions were taken in response to the symptoms and reasons for not utilizing orthodox healthcare. Results: None of the listed symptoms was recognized by up to half the mothers as danger signs of neonatal illness, the best being fast breathing by 66 (45.2%) mothers. Eighty two (56.2%) mothers reported that their children experienced some of the neonatal danger signs: the commonest were difficult breathing and convulsions in 8 (9.8%) cases each. Unconsciousness and excessive crying were thought to be caused by evil spirits and consultations sought with faith healers. The major constraint to utilization of health facilities was cost {45(29.8%)}. Conclusion: Mothers’ recognition of danger signs in the newborn was poor. Self-medication and the use of home remedies delayed timely consultation. The commonest reason for non-utilization of health facilities was lack of money.

Background: Effective school health instruction in primary schools is essential in addressing the health risks and needs of school age children and adolescents. This study sought to evaluate the status of school health instruction in public primary schools in Bonny Local Government Area. Method: This is a cross sectional school based study carried out in 20 public primary schools in Bonny Local Government Area, Rivers State, in March 2006. The availability of the various components of the school health instruction programme was evaluated sing an evaluation scale. Components had weighted scores. The minimum acceptable and maximum attainable scores for school health instruction were 31 and 47. Data was analyzed using SPSS version 11. Results: There were a total of 100 teachers in all the schools. The teacher population per school ranged from 2 to 13 with a mean of 5±2.77SD. The pupil population of the schools ranged between 100-1460 with a mean of 352±336SD. Teacher/pupil ratio per school ranged from 1: 30 to 1: 128. Fourteen (70%) schools had teacher/pupil ratio less than 1:40. There was no professional health instructor in all the schools. Four schools (20%) allotted 3 periods per week to health teaching, while the rest (80%) allotted less than 3 periods per week. HIV/AIDS was not in the health education curriculum being used. The only teaching method used by all the schools was the direct teaching method. No school used teaching aids; no school went on field trips. Teachers did not receive in-service training on health education. No school attained the minimum acceptable score of 31 points using the evaluation scale. Conclusion: School health instruction was poorly implemented in the primary schools investigated. Teachers were not adequately prepared for health teaching and the classrooms were overcrowded.

Background: Consumption of alcohol by secondary school students is a major public health concern globally, but its prevalence is not known in secondary schools in Port Harcourt. Objective: To determine the prevalence and factors associated with alcohol use among secondary school students in Port Harcourt. Methods: This was a cross sectional school based study conducted in Port Harcourt in March 2014. A 20 itemed structured, self -administered questionnaire was distributed to 1080 senior secondary 1 to 3 students from 10 public secondary schools selected through Multistage Sampling technique. Questions asked covered drinking of alcohol, frequency of drinking and being drunk in the past 30 days before the survey. Other behaviours sought were smoking of cigarette, use of cocaine and going out in the evening for fun. Sociodemographic was also sought. Data was analyzed using SPSS version 20. Results: 1080 students participated in the study, mean age 16.09±6SD and male to female ratio of 0.9: 1. Prevalence of current drinking of alcohol was 30.6% and 38.1% of current drinkers were also drunk in the past 30 days, with 17.2 % being very frequently drunk. The behaviour which showed a strong association with drinking of alcohol, being drunk and the frequency of being drunk was going out in the evening for fun and recreation. Gender showed a positive association with drinking of alcohol, as more males drank alcohol with in the past 30 days compared to the females (p=0.000). Smoking of cigarette in the past 30 days and truancy were positively associated with being drunk, while academic grades showed an inverse relationship with consumption of alcohol. Majority of those who drank alcohol (42.6%) were experimenting with alcohol, though 5.4% drank due to addiction. Majority (39.3%) bought their drinks from stores and supermarkets. The most Common problems experienced by the drinkers were fatigue, alcohol made them behave in ways they later regretted and it hurt their relationships. Conclusion: Alcoholism is a serious problem with secondary school students in Port Harcourt. It is linked with truancy, poor academic achievement and other substances use. The most serious health and social problem experienced by the drinkers is addiction.

Severe acute respiratory syndrome coronavirus 2-like other viral infections cause temporary immunosuppressive effects. This COVID-19 infection-induced temporary suppression of cellular immunity can predispose to infections like fungal. Furthermore, high-dose corticosteroids used in COVID-19 management can trigger or accelerate fungal infections. This case series presents the clinicomicrobiological profile of a few such admitted cases, as it is very important for all clinicians and clinical microbiologists to keep the new yet recently not-so-uncommon entities in mind while evaluating a patient.

Abstract Background Early detection of outbreaks requires robust surveillance and reporting at both community and health facility levels. Uganda implements Integrated Disease Surveillance and Response (IDSR) for priority diseases and uses the national District Health Information System (DHIS2) for reporting. However, investigations after the first case in the 2022 Uganda Sudan virus outbreak was confirmed on September 20, 2022 revealed many community deaths among persons with Ebola-like symptoms as far back as August. Most had sought care at private facilities. We explored possible gaps in surveillance that may have resulted in late detection of the Sudan virus disease (SVD) outbreak in Uganda. Methods Using a standardized tool, we evaluated core surveillance capacities at public and private health facilities at the hospital level and below in three sub-counties reporting the earliest SVD cases in the outbreak. Key informant interviews (KIIs) were conducted with 12 purposively-selected participants from the district local government. Focus group discussions (FGDs) were conducted with community members from six villages where early probable SVD cases were identified. KIIs and FGDs focused on experiences with SVD and Viral Hemorrhagic Fever (VHF) surveillance in the district. Thematic data analysis was used for qualitative data. Results Forty-six (85%) of 54 health facilities surveyed were privately-owned, among which 42 (91%) did not report to DHIS2 and 39 (85%) had no health worker trained on IDSR; both metrics were 100% in the eight public facilities. Weak community-based surveillance, poor private facility engagement, low suspicion index for VHF among health workers, inability of facilities to analyze and utilize surveillance data, lack of knowledge about to whom to report, funding constraints for surveillance activities, lack of IDSR training, and lack of all-cause mortality surveillance were identified as gaps potentially contributing to delayed outbreak detection. Conclusion Both systemic and knowledge-related gaps in IDSR surveillance in SVD-affected districts contributed to the delayed detection of the 2022 Uganda SVD outbreak. Targeted interventions to address these gaps in both public and private facilities across Uganda could help avert similar situations in the future.

Abstract This paper employs a statistical mechanical model as a framework to investigate how socioeconomic factors of individuals such as gender and place of residence influence their decision when deciding between comprehensive and third-party motor insurance policies in Ghana. Data from a general insurance firm was used for this investigation taking five years’ worth of transactions into account. The methods of partial least squares and the ordinary least squares are, respectively, used to estimate the parameters of the interacting and the non-interacting models in the Multipopulation Currie-Weiss model in a discrete choice framework. The findings showed that both location and gender have discernible influences on how people choose their motor insurance. We encourage insurance companies to intensify their campaign on the importance of motor insurance to all vehicle/car owners, especially those in rural areas in order to reduce the risk and associated losses in vehicular accidents on Ghanaian roads.

Abstract Background Pneumonia is one of the leading causes of infant mortality globally, particularly in sub-Saharan Africa. In Uganda, pneumonia was the fourth leading cause of death in children

Abstract Background Communities affected by Ebola disease (EBOD) may face resulting increases in mental health disorders. We evaluated the prevalence of and factors associated with mental health disorders among persons affected by the 2022 Sudan virus disease (SVD) outbreak in Uganda. Methods We conducted a cross-sectional study among SVD survivors and family members of survivors and fatal cases from 15–31 January 2023. We included only laboratory-confirmed SVD survivors and family members who lived with or cared for confirmed SVD patients during their illness. The Hospital Anxiety and Depression Scale was used to evaluate anxiety and depression. The post-traumatic stress disorder (PTSD) checklist for the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition was used to evaluate PTSD. Modified Poisson regression was used to determine factors associated with each mental health disorder. Results We enrolled 54 survivors and 82 family members; median age was 30 years (range, 15–73) and 54% were female. The prevalence of anxiety (55%) and depression (50%) was higher than PTSD (17%). The prevalence of all mental health disorders was similar between survivors and family members. Household size was associated with both anxiety and PTSD. Number of SVD deaths in the household was associated with depression. Conclusion Approximately two-thirds of SVD survivors and family members of patients in the 2022 outbreak in Uganda had ≥ 1 mental health disorders shortly after the outbreak ended. Strengthening mental health services during and after Ebola virus outbreaks for survivors and family members of patients may enhance the quality of outbreak response.

Abstract In our opinion, the ‘hang-time’ of nitrate-containing products discussed in the letter by Green and Green is an interesting variable that should be considered when nitrate-based treatment or prevention strategies are designed. However, due to direct nitrate recycling after nitrate intake, products with a long ‘hang-time’ (e.g., chewing gum) may not always have an advantage compared to products with a short ‘hang-time’ (e.g., vegetable juices). We argue that extending the ‘hang-time’ is especially relevant and potentially beneficial for different applications, such as using a low nitrate dose to stimulate the oral effects, reaching oral tissues that may otherwise not be exposed to dietary nitrate (e.g., periodontal pockets), and providing a longer nitrate exposure in individuals with an impaired salivary flow. Apart from the ‘hang-time’, other important variables are the nitrate dose and source (e.g., different salts and vegetable extracts), as well as the desired effect (e.g., an oral effect versus systemic effects). Finally, we believe that the alterations in salivary microbiota observed before and after chewing three nitrate-rich gums over a period of ~5 h, as reported by Green and Green, could be considered beneficial. However, the oral microbiota composition is affected by the circadian rhythm and the effect of gum mastication should be evaluated. These results should thus be confirmed by a placebo-controlled study, where these confounding factors can be accounted for.

Abstract Hookworm infection remains a significant public health concern, particularly in low- and middle-income countries, where mass drug administration has not stopped reinfection. Developing a vaccine is crucial to complement current control measures, which necessitates a thorough understanding of host immune responses. By leveraging controlled human infection models and high-dimensional immunophenotyping, here we investigated the immune remodeling following infection with 50 Necator americanus L3 hookworm larvae in four naïve volunteers over two years of follow-up and compared the profiles with naturally infected populations in endemic areas. Increased plasmacytoid dendritic cell frequency and diminished responsiveness to Toll-like receptor 7/8 ligand were observed in both controlled and natural infection settings. Despite the increased CD45RA+ regulatory T cell (Tregs) frequencies in both settings, markers of Tregs function, including inducible T-cell costimulatory (ICOS), tumor necrosis factor receptor 2 (TNFR2), and latency-associated peptide (LAP), as well as in vitro Tregs suppressive capacity were higher in natural infections. Taken together, this study provides unique insights into the immunological trajectories following a first-in-life hookworm infection compared to natural infections.

Abstract It has been widely reported that isoprene emissions from the Arctic ecosystem have a strong temperature response. Here we identify sedges (Carex spp. and Eriophorum spp.) as key contributors to this high sensitivity using plant chamber experiments. We observe that sedges exhibit a markedly stronger temperature response compared to that of other isoprene emitters and predictions by the widely accepted isoprene emission model, the Model of Emissions of Gases and Aerosols from Nature (MEGAN). MEGAN is able to reproduce eddy-covariance flux observations at three high-latitude sites by integrating our findings. Furthermore, the omission of the strong temperature responses of Arctic isoprene emitters causes a 20% underestimation of isoprene emissions for the high-latitude regions of the Northern Hemisphere during 2000-2009 in the Community Land Model with the MEGAN scheme. We also find that the existing model had underestimated the long-term trend of isoprene emissions from 1960 to 2009 by 55% for the high-latitude regions.

Abstract Background Aboriginal and Torres Strait Islander peoples are disproportionately impacted by type 2 diabetes. Continuous glucose monitoring (CGM) technology (such as Abbott Freestyle Libre 2, previously referred to as Flash Glucose Monitoring) offers real-time glucose monitoring that is convenient and easy to use compared to self-monitoring of blood glucose (SMBG). However, this technology’s use is neither widespread nor subsidised for Aboriginal and Torres Strait Islander peoples with type 2 diabetes. Building on existing collaborations with a national network of Aboriginal and Torres Strait Islander communities, this randomised controlled trial aims to assess the effect of CGM compared to SMBG on (i) haemoglobin A1c (HbA1c), (ii) achieving blood glucose targets, (iii) reducing hypoglycaemic episodes and (iv) cost-effective healthcare in an Aboriginal and Torres Strait Islander people health setting. Methods This is a non-masked, parallel-group, two-arm, individually randomised, controlled trial (ACTRN12621000753853). Aboriginal and Torres Strait Islander adults with type 2 diabetes on injectable therapy and HbA1c ≥ 7.5% (n = 350) will be randomised (1:1) to CGM or SMBG for 6 months. The primary outcome is change in HbA1c level from baseline to 6 months. Secondary outcomes include (i) CGM-derived metrics, (ii) frequency of hypoglycaemic episodes, (iii) health-related quality of life and (iv) incremental cost per quality-adjusted life year gained associated with the CGM compared to SMBG. Clinical trial sites include Aboriginal Community Controlled Organisations, Aboriginal Medical Services, primary care centres and tertiary hospitals across urban, rural, regional and remote Australia. Discussion The trial will assess the effect of CGM compared to SMBG on HbA1c for Aboriginal and Torres Strait Islander people with type 2 diabetes in Australia. This trial could have long-term benefits in improving diabetes management and providing evidence for funding of CGM in this population. Trial registration Australian and New Zealand Clinical Trials Registry ACTRN12621000753853. Registered on 15th June 2021.

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.

Abstract Background There has been growing interest in using unstable devices in training protocols. This study aimed to assess the effectiveness of two multimodal exercise interventions (i.e., on stable and unstable surfaces) on dynamic balance control and lower limb strength in older adults. Methods Sixty-two older adults were randomly assigned to two intervention groups (N = 20, stable group; N = 19, unstable group), and to a control group (N = 18). In this single-blinded randomized controlled study, the two intervention groups underwent a 12-week training program twice a week for 45 min, consisting of strength and balance exercises. The stable (ST) group performed the training program over stable surfaces, while the unstable (UNST) group over unstable surfaces. Dynamic balance was assessed by computing the center of pressure (CoP) trajectory while a driven movable platform induced an unexpected perturbation of the base of support. Specifically, we considered the following CoP-related parameters within a 2.5-s temporal window from the beginning of the perturbation: displacement (Area95), mean velocity (Unit Path), anterior–posterior first peak (FP), post perturbation variability (PPV), and maximal oscillations (ΔCoPMax). The dominant quadriceps strength was measured through an isometric maximal voluntary contraction on an instrumented chair. Results Four out of five CoP-related parameters (i.e., Area95, Unit Path, ΔCoPMax, and PPV) significantly improved in the UNST group from a minimum of 14.28% (d = 0.44) to a maximum of 52.82% (d = 0.58). The ST group significantly improved only in two (i.e., ΔCoPMax, and PPV) out of five CoP-related parameters with an enhancement of 12.48% (d = 0.68) and 19.10% (d = 1.06). Both intervention groups increased the maximal isometric quadriceps strength (UNST:17.27%, d = 0.69; ST:22.29%, d = 0.98). The control group did not show changes in any of the parameters considered. Conclusions Stable surfaces promoted faster increments of muscular strength. Unstable surfaces were more effective in enhancing dynamic balance efficiency. These findings suggested the employment of multimodal training on unstable rather than stable surfaces to potentially lower the incidence of falls in older adults. Trial registration NCT 05769361, retrospectively registered 13 March 2023, https://clinicaltrials.gov/study/NCT05769361?lat=45.3661864&lng=11.8209139&locStr=Padova,%20Italy&distance=50&page=11&rank=107 .

Abstract In East Africa, community-based conservation models (CBCMs) have been established to support the conservation of wildlife in fragmented landscapes like the Tarangire Ecosystem, Tanzania. To assess how different management approaches maintained large herbivore populations, we conducted line distance surveys and estimated seasonal densities of elephant, giraffe, zebra, and wildebeest in six management units, including three CBCMs, two national parks (positive controls), and one area with little conservation interventions (negative control). Using a Monte-Carlo approach to propagate uncertainties from the density estimates and trend analysis, we analyzed the resulting time series (2011–2019). Densities of the target species were consistently low in the site with little conservation interventions. In contrast, densities of zebra and wildebeest in CBCMs were similar to national parks, providing evidence that CBCMs contributed to the stabilization of these migratory populations in the central part of the ecosystem. CBCMs also supported giraffe and elephant densities similar to those found in national parks. In contrast, the functional connectivity of Lake Manyara National Park has not been augmented by CBCMs. Our analysis suggests that CBCMs can effectively conserve large herbivores, and that maintaining connectivity through CBCMs should be prioritized.

Abstract Imaging with undetected photons relies upon nonlinear interferometry to extract the spatial image from an infrared probe beam and reveal it in the interference pattern of an easier-to-detect visible beam. Typically, the transmission and phase images are extracted using phase-shifting techniques and combining interferograms from multiple frames. Here we show that off-axis digital holography enables reconstruction of both transmission and phase images at the infrared wavelength from a single interferogram, and hence a single frame, recorded in the visible. This eliminates the need for phase stepping and multiple acquisitions, thereby greatly reducing total measurement time for imaging with long acquisition times at low flux or enabling video-rate imaging at higher flux. With this single-frame acquisition technique, we are able to reconstruct transmission images of an object in the infrared beam with a signal-to-noise ratio of $$3.680\,\pm \,0.004$$ 3.680 ± 0.004 at 10 frames per second, and record a dynamic scene in the infrared beam at 33 frames per second.

Abstract Background Ethnicity is known to be an important correlate of health outcomes, particularly during the COVID-19 pandemic, where some ethnic groups were shown to be at higher risk of infection and adverse outcomes. The recording of patients’ ethnic groups in primary care can support research and efforts to achieve equity in service provision and outcomes; however, the coding of ethnicity is known to present complex challenges. We therefore set out to describe ethnicity coding in detail with a view to supporting the use of this data in a wide range of settings, as part of wider efforts to robustly describe and define methods of using administrative data. Methods We describe the completeness and consistency of primary care ethnicity recording in the OpenSAFELY-TPP database, containing linked primary care and hospital records in > 25 million patients in England. We also compared the ethnic breakdown in OpenSAFELY-TPP with that of the 2021 UK census. Results 78.2% of patients registered in OpenSAFELY-TPP on 1 January 2022 had their ethnicity recorded in primary care records, rising to 92.5% when supplemented with hospital data. The completeness of ethnicity recording was higher for women than for men. The rate of primary care ethnicity recording ranged from 77% in the South East of England to 82.2% in the West Midlands. Ethnicity recording rates were higher in patients with chronic or other serious health conditions. For each of the five broad ethnicity groups, primary care recorded ethnicity was within 2.9 percentage points of the population rate as recorded in the 2021 Census for England as a whole. For patients with multiple ethnicity records, 98.7% of the latest recorded ethnicities matched the most frequently coded ethnicity. Patients whose latest recorded ethnicity was categorised as Other were most likely to have a discordant ethnicity recording (32.2%). Conclusions Primary care ethnicity data in OpenSAFELY is present for over three quarters of all patients, and combined with data from other sources can achieve a high level of completeness. The overall distribution of ethnicities across all English OpenSAFELY-TPP practices was similar to the 2021 Census, with some regional variation. This report identifies the best available codelist for use in OpenSAFELY and similar electronic health record data.

Abstract The tryptophan-metabolizing kynurenine pathway (KP) can be activated by enhanced inflammatory responses and has been implicated in the pathophysiology of schizophrenia. However, there is little evidence for KP dysregulation in the early course of psychotic illness. We aimed to investigate the potential immune-mediated hyperactivity of KP in individuals with first-episode psychosis (FEP) and the relationship with symptom severity and treatment response outcomes. Serum immunoassays were performed to measure peripheral levels of inflammatory cytokines (IL-1β, IL-10, TNF-a), KP rate-limiting enzymes (IDO/TDO), and kynurenic acid (KYNA) metabolite in 104 antipsychotic-naïve patients with FEP and 80 healthy controls (HC). The Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning Scale (GAF) were administered to assess psychopathology and functioning status at admission and following 4-week treatment with antipsychotics. Cytokine and KP components levels were substantially increased in FEP patients compared to HC, before and after antipsychotic treatment. A significant positive correlation between pro-inflammatory IL-1β and KYNA levels was observed among FEP patients, but not in HC. Importantly, within-patient analysis revealed that those with higher baseline KYNA experienced more severe negative symptoms and poorer clinical improvement at follow-up. These findings suggest that KP is upregulated in early psychosis, likely through the induction of IL-1β-dependent pathways, and raised peripheral KYNA might represent a promising indicator of non-response to antipsychotic medication in patients with FEP.

Abstract Kindler syndrome (KS) is a rare genodermatosis resulting from loss-of-function mutations in FERMT1, the gene that encodes Kindlin-1. KS patients have a high propensity to develop aggressive and metastatic cutaneous squamous cell carcinoma (cSCC). Here we show in non-KS-associated patients that elevation of FERMT1 expression is increased in actinic keratoses compared to normal skin, with a further increase in cSCC supporting a pro-tumorigenic role in this population. In contrast, we show that loss of Kindlin-1 leads to increased SCC tumor growth in vivo and in 3D spheroids, which was associated with the development of a hypoxic tumor environment and increased glycolysis. The metalloproteinase Mmp13 was upregulated in Kindlin-1-depleted tumors, and increased expression of MMP13 was responsible for driving increased invasion of the Kindlin-1-depleted SCC cells. These results provide evidence that Kindlin-1 loss in SCC can promote invasion through the upregulation of MMP13, and offer novel insights into how Kindlin-1 loss leads to the development of a hypoxic environment that is permissive for tumor growth.

Abstract Coronary artery bypass surgery can result in endothelial dysfunction due to ischemia/reperfusion (IR) injury. Previous studies have demonstrated that DuraGraft helps maintain endothelial integrity of saphenous vein grafts during ischemic conditions. In this study, we investigated the potential of DuraGraft to mitigate endothelial dysfunction in arterial grafts after IR injury using an aortic transplantation model. Lewis rats (n = 7–9/group) were divided in three groups. Aortic arches from the control group were prepared and rings were immediately placed in organ baths, while the aortic arches of IR and IR + DuraGraft rats were preserved in saline or DuraGraft, respectively, for 1 h before being transplanted heterotopically. After 1 h after reperfusion, the grafts were explanted, rings were prepared, and mounted in organ baths. Our results demonstrated that the maximum endothelium-dependent vasorelaxation to acetylcholine was significantly impaired in the IR group compared to the control group, but DuraGraft improved it (control: 89 ± 2%; IR: 24 ± 1%; IR + DuraGraft: 48 ± 1%, p

Abstract Background The widespread use of physical activity trackers enables the collection of high-resolution health data, such as hourly step counts, to evaluate health promotion programmes. We aim to investigate how participants meet their daily step goals. Methods We used 24-h steps data from the National Steps ChallengeTM Season 3, wherein participants were rewarded with vouchers when achieving specified goals of 5000, 7500, and 10,000 steps per day. We extracted data from 3075 participants’ including a total of 52,346 participant-days. We modelled the hourly step counts using a two-part model, in which the distribution for step counts was allowed to depend on the sum of step counts up to the previous hour and participant demographics. Results Participants have a mean age of 44.2 years (standard deviation = 13.9), and 40.4% are males. We show that on weekdays, the hourly mean step counts among participants aged 60 and above are higher than participants aged 30 to 59 from the start of the day till 6 p.m. We also find that participants who accumulate at least 7000 steps by 7 p.m. are associated with higher success of achieving 10,000 steps. Conclusions We provide recommendations on the hourly targets to achieve daily goals, based on different participants’ characteristics. Future studies could experimentally test if prompts and nudges at the recommended times of day could promote reaching step goals.

Abstract Oropouche and Mayaro viruses are enzootic arboviruses of public health concern throughout Latin America. Recent outbreaks of OROV in northern region and sporadic autochthonous cases in western region of Brazil, suggest a silent circulation of these neglected viruses. Aiming to investigate the exposure of different species of domestic animals to MAYV and OROV in urban and peri-urban areas of West-Central Brazil, we performed a cross-sectional serosurvey by plaque reduction neutralization test (PRNT). Our findings included neutralizing antibodies for both arboviruses in cattle, dogs and horses, suggesting eventual role of domestic animals in enzootic arbovirus surveillance in Brazil.

Abstract To promote sustainable aquaculture, the formulation of Atlantic salmon (Salmo salar) feeds has changed in recent decades, focusing on replacing standard marine-based ingredients with plant-based alternatives, increasingly demonstrating successful outcomes in terms of fish performance. However, little is known about how these plant-based diets may impact the gut microbiota at first feeding and onwards. Nutritional programming (NP) is one strategy applied for exposing fish to a plant-based (V) diet at an early stage in life to promote full utilisation of plant-based ingredients and prevent potential adverse impacts of exposure to a plant-rich diet later in life. We investigated the impact of NP on gut microbiota by introducing fish to plant ingredients (V fish) during first feeding for a brief period of two weeks (stimulus phase) and compared those to fish fed a marine-based diet (M fish). Results demonstrated that V fish not only maintained growth performance at 16 (intermediate phase) and 22 (challenge phase) weeks post first feeding (wpff) when compared to M fish but also modulated gut microbiota. PERMANOVA general effects revealed gut microbiota dissimilarity by fish group (V vs. M fish) and phases (stimulus vs. intermediate vs. challenge). However, no interaction effect of both groups and phases was demonstrated, suggesting a sustained impact of V diet (nutritional history) on fish across time points/phases. Moreover, the V diet exerted a significant cumulative modulatory effect on the Atlantic salmon gut microbiota at 16 wpff that was not demonstrated at two wpff, although both fish groups were fed the M diet at 16 wpff. The nutritional history/dietary regime is the main NP influencing factor, whereas environmental and host factors significantly impacted microbiota composition in M fish. Microbial metabolic reactions of amino acid metabolism were higher in M fish when compared to V fish at two wpff suggesting microbiota played a role in digesting the essential amino acids of M feed. The excessive mucin O-degradation revealed in V fish at two wpff was mitigated in later life stages after NP, suggesting physiological adaptability and tolerance to V diet. Future studies are required to explore more fully how the microbiota functionally contributes to the NP.

Abstract Site occupancy models (SOMs) are a common tool for studying the spatial ecology of wildlife. When observational data are collected using passive monitoring field methods, including camera traps or autonomous recorders, detections of animals may be temporally autocorrelated, leading to biased estimates and incorrectly quantified uncertainty. We presently lack clear guidance for understanding and mitigating the consequences of temporal autocorrelation when estimating occupancy models with camera trap data. We use simulations to explore when and how autocorrelation gives rise to biased or overconfident estimates of occupancy. We explore the impact of sampling design and biological conditions on model performance in the presence of autocorrelation, investigate the usefulness of several techniques for identifying and mitigating bias and compare performance of the SOM to a model that explicitly estimates autocorrelation. We also conduct a case study using detections of 22 North American mammals. We show that a join count goodness‐of‐fit test previously proposed for identifying clustered detections is effective for detecting autocorrelation across a range of conditions. We find that strong bias occurs in the estimated occupancy intercept when survey durations are short and detection rates are low. We provide a reference table for assessing the degree of bias to be expected under all conditions. We further find that discretizing data with larger windows decreases the magnitude of bias introduced by autocorrelation. In our case study, we find that detections of most species are autocorrelated and demonstrate how larger detection windows might mitigate the resulting bias. Our findings suggest that autocorrelation is likely widespread in camera trap data and that many previous studies of occupancy based on camera trap data may have systematically underestimated occupancy probabilities. Moving forward, we recommend that ecologists estimating occupancy from camera trap data use the join count goodness‐of‐fit test to determine whether autocorrelation is present in their data. If it is, SOMs should use large detection windows to mitigate bias and more accurately quantify uncertainty in occupancy model parameters. Ecologists should not use gaps between detection periods, which are ineffective at mitigating temporal structure in data and discard useful data.

ABSTRACT: The objective of this study was to assess the potential effect of difructose anhydride III (DFAIII) on calcemia, magnesemia, and milking performance in dairy cows. A total of 66 multiparous Holstein cows in late pregnancy (gestation days, mean ± SD = 253.8 ± 2.13 d) were blocked according to their expected calving date and randomly assigned to either receiving no supplementation (control) or receiving 40 g/d of DFAIII (DFA) between −14 and +7 d relative to calving following a complete randomized block design. Cows in the control group received 640 g/d of a pellet containing no DFAIII, whereas DFA cows received the same pellet but containing 6.25% DFAIII. Pellets of each treatment were top-dressed on a daily basis while cows were dry and were fed via an automatic feeding system twice daily (320 g each feeding) during milking. Dry cows were fed once a day, whereas lactating cows were fed twice daily. Dry matter intake was individually monitored on a daily basis. Cows were milked twice daily and milk production and milk protein and fat contents recorded at every milking. Cows were kept on the study until they reached 21 d postpartum. Cows were weighed at dry-off (∼45 d before study enrollment) and twice daily after calving at the exit of the milking parlor. Cows were blood sampled for subsequent determination of serum Ca and Mg concentrations 3 d before the expected calving date and at 6, 12, 24, and 48 h and 7 and 14 d after calving. We found no differences in DMI before calving, but DFA cows consumed more feed than control cows at ∼15 DIM. All cows lost BW after calving, but DFA cows lost slightly less BW during the first 5 DIM than control cows. Cows on DFAIII produced more milk at ∼10 DIM compared with control cows, and DFAIII cows produced more milk protein than control cows 3 d after calving. Serum Ca concentrations were not affected by DFAIII supplementation; however, serum Mg concentrations at 6, 12, and 24 h after calving were greater in DFA than in control cows. In all, DFAIII did not affect postpartum calcemia but improved magnesemia between 6 and 24 h after calving. Milk production in DFA cows was improved around 10 d after calving and milk protein yield after 3 d postpartum compared with control cows. The mechanism leading to increased Mg availability is not clear and warrants further research.

Abstract Background United States drug overdose deaths are being driven by the increasing prevalence of fentanyl, but whether patients are knowingly using fentanyl is unclear. We examined the analytical confirmation of fentanyl in emergency department (ED) patients with documented heroin overdose. Hypothesis We hypothesized that the proportion of fentanyl and fentanyl analogs would be higher than that of confirmed heroin. Methods This is a subgroup analysis from a prospective multicenter consecutive cohort of ED patients age 18+ with opioid overdose presenting to 10 US sites within the Toxicology Investigators Consortium from 2020 to 2021. Toxicology analysis was performed using liquid chromatography quadrupole time‐of‐flight mass spectrometry. De‐identified toxicology results were paired with the clinical database. The primary outcome was the proportion of patients with fentanyl analytes detected in their serum. Results Of 1006 patients screened, 406 were eligible, and of 168 patients who reported that they had taken heroin or had a documented heroin overdose, 88% (n = 147) were in fact found to have fentanyl and/or a fentanyl analog present on serum analysis (p

A case of a non-fatal crocodile attack on a human was reported on the banks of the Segovia River on the Honduras and Nicaragua border. The 12-year-old girl survived the attack, only with damage to the tibia of her right leg, where she lost part of the muscle tissue due to the bite. It was after the attack that the American crocodile was shot and killed by local people. In this paper, we discuss the possible causes of crocodile attacks.

A significant study of the amblypygid fauna of Honduras is lacking. Historically, species were misidentified and data on distribution, natural history and conservation status of the known species are lacking or insufficient. In this contribution, an overview on the amblypygids of Honduras, including taxonomy, distribution, natural history and comments on their conservation are provided. In a review of the literature of the Honduran amblypygids, we examined 21 works, including books, unpublished thesis, articles, the World Amblypygi Catalogue (2023), as well as the website Arácnidos de Centroamérica and the citizen-science websites Alamy, iNaturalist and Flicks. Only the family Phrynidae, with the genera Paraphrynus Moreno, 1940 and Phrynus Lamarck, 1801, is known to occur in Honduras. A total of seven species have been recorded, but only four [Paraphrynus laevifrons (Pocock, 1894), Phrynus palenque Armas, 1996, Ph. similis Armas, Víquez & Trujillo, 2017 and Ph. whitei Gervais, 1842] have been positively identified. No endemic species are known, but available data suggest that some undescribed new species may be restricted to Honduras. In order to understand the amblypygids of Honduras, sampling within the country must be conducted and revisionary studies will be needed. This paper examines our current knowledge of the fauna.

Abstract First-void urine (FVU) samples, containing human papillomavirus (HPV)-specific IgG from female genital tract secretions, provide a non-invasive option for disease monitoring and vaccine impact assessment. This study explores the utility of FVU for IgG quantification, exploring stability and compatibility with DNA preservation methods, alongside various IgG enrichment methods. Healthy female volunteers provided FVU and serum samples. FVU was collected with or without urine conservation medium (UCM) and stored under different conditions before freezing at −80 °C. Four IgG enrichment methods were tested on FVU samples. All samples were analyzed using three total human IgG quantification assays and an in-house HPV16-specific IgG assay. Samples stored with UCM buffer had higher total and HPV16-specific IgG concentrations (p ≤ 0.01) and IgG remained stable for at least 14 days at room temperature. Among IgG enrichment methods, Amicon filtration (AM) and AM combined with Melon Gel purification (AM-MG) provided similar HPV16-IgG concentrations, correlating strongly with serum levels. Protein G magnetic beads methods were incompatible with time-resolved fluorescence-based assays. This study highlights FVU as a reliable and convenient sample for IgG quantification, demonstrating stability for at least 14 days at room temperature and compatibility with UCM DNA preservation. It emphasizes the need to select appropriate IgG enrichment methods and confirms the suitability of both AM and AM-MG methods, with a slightly better performance for AM-MG.

Abstract Background Social isolation and loneliness (SIL) worsens mortality and other outcomes among older adults as much as smoking. We previously tested the impact of the HOW R U? intervention using peer support from similar-aged volunteers and demonstrated reduced SIL among older adults discharged from the emergency department (ED). Generativity, defined as “the interest in establishing and guiding the next generation,” can provide an alternative theoretical basis for reducing SIL via intergenerational programs between members of younger and older generations. The current protocol will examine the impact of younger intergenerational volunteers providing the HOW RU? intervention. Methods In this randomized clinical trial, we will compare the following three arms: (1) the standard same-generation peer support HOW R U? intervention, (2) HOW R U? intervention delivered by intergenerational volunteers, and (3) a common wait-list control group. Outcome assessors will be blinded to the intervention. Trained volunteers will deliver 12 weekly telephone support calls. We will recruit participants ≥ 70 years of age with baseline loneliness (six-item De Jong loneliness score of 2 or greater) from two EDs. Research staff will assess SIL, depression, quality of life, functional status, generativity, and perceived benefit at baseline, at 12 weeks, and 24 weeks post-intervention. Discussion We hypothesize participants receiving the intergenerational intervention will show improved outcomes compared to the control group and peer support HOW R U? intervention. We also hypothesize that participants with higher perceptions of generativity will have greater reductions in SIL than their lower generativity counterparts. Aging is experienced diversely, and social interventions combatting associated SIL should reflect that diversity. As part of a program of research following the Obesity-Related Behavioral Intervention Trials (ORBIT) model, the findings of this RCT will be used to define which intervention characteristics are most effective in reducing SIL. Trial registration ClinicalTrials.gov NCT05998343 Protocol ID:21-0074E. Registered on 24 July 2023.

Abstract Background Acute leukaemias (AL) are life-threatening blood cancers that can be potentially cured with treatment involving myelosuppressive, multiagent, intensive chemotherapy (IC). However, such treatment is associated with a risk of serious infection, in particular invasive fungal infection (IFI) associated with prolonged neutropenia. Current practice guidelines recommend primary antifungal (AF) prophylaxis to be administered to high-risk patients to reduce IFI incidence. AFs are also used empirically to manage prolonged neutropenic fever. Current strategies lead to substantial overuse of AFs. Galactomannan (GM) and β-D-glucan (BG) biomarkers are also used to diagnose IFI. Combining both biomarkers may enhance the predictability of IFI compared to administering each test alone. Currently, no large-scale randomised controlled trial (RCT) has directly compared a biomarker-based diagnostic screening strategy without AF prophylaxis to AF prophylaxis (without systematic biomarker testing). Methods BioDriveAFS is a multicentre, parallel, two-arm RCT of 404 participants from UK NHS Haematology departments. Participants will be allocated on a 1:1 basis to receive either a biomarker-based antifungal stewardship (AFS) strategy, or a prophylactic AF strategy, which includes existing standard of care (SoC). The co-primary outcomes will be AF exposure in the 12-month post randomisation and the patient-reported EQ-5D-5L measured at 12-month post randomisation. Secondary outcomes will include total AF exposure, probable/proven IFI, survival (all-cause mortality and IFI mortality), IFI treatment outcome, AF-associated adverse effects/events/complications, resource use, episodes of neutropenic fever requiring hospital admission or outpatient management, AF resistance in fungi (non-invasive and invasive) and a Desirability of Outcome Ranking. The trial will have an internal pilot phase during the first 9 months. A mixed methods process evaluation will be integrated in parallel to the internal pilot phase and full trial, aiming to robustly assess how the intervention is delivered. Cost-effectiveness analysis will also be performed. Discussion The BioDriveAFS trial aims to further the knowledge of strategies that will safely optimise AF use through comparison of the clinical and cost-effectiveness of a biomarker-led diagnostic strategy versus prophylactic AF to prevent and manage IFI within acute leukaemia. The evidence generated from the study will help inform global clinical practice and approaches within antifungal stewardship. Trial registration ISRCTN11633399. Registered 24/06/2022.

Introduction: Although terlipressin is known to cause bradycardia, this adverse effect is usually described in association with hypertension and is considered a benign compensatory response mediated by arterial baroreceptors. Cardiac monitoring for patients receiving terlipressin is not routinely recommended. Case Presentation: A 77-year-old female patient with no history of coronary artery disease and no other coexisting risk factors for cardiac arrhythmias or conduction disturbances was admitted to intensive care unit with severe cholangitis, complicated by variceal bleeding. She developed severe sinus bradycardia following the use of terlipressin, which was associated with significant hypotension that required the infusion of norepinephrine. The bradycardia occurred again when terlipressin therapy was reattempted. Conclusion: Vasopressin is known to sensitize baroreceptor reflexes by a central mechanism though its actions on V1a receptors in the area postrema, and we speculate that vasopressin analogues such as terlipressin may act in the same manner. That this effect is not widely described in terlipressin safety literature may be due to the overall younger age range of the trial population. This raises the possibility that cardiac monitoring may be warranted for elderly patients receiving terlipressin.

Youth homelessness represents a persistent and significant challenge for service sectors with limited best practice guidance. Housing supports, in particular, are widely deployed, with the practice-oriented literature providing little detail regarding service design beyond broad domains such as employment support and life skills coaching. The present multiple case study investigation was designed to develop a preliminary understanding of the guiding principles that attend the development of interventions that support youth exiting homelessness in the Canadian context. These case studies were conducted with a diverse group of five organizations recognized as sector leaders, with findings considered in light of practice standards from the better-established adult housing literature. Key findings with respect to service models included the strategies used to provide flexible, culturally responsive, tailored services with an emphasis on specialist support. Implementation factors included the navigation of strategic partnerships, the use of data in capacity-building, and the benefits and drawbacks of larger, centralized service environments versus smaller, dispersed environments. Youth-specific considerations in housing stabilization models are highlighted. This work contributes to a growing body of literature that seeks to articulate best practices in the effort to address and prevent youth homelessness.

Protecting the rights of people with psychosocial conditions is an important and controversial global aim, particularly in light of multiple calls for reduced coercion catalyzed by General Comment 1 of the United Nations Committee on the Rights of Persons with Disabilities, which stipulates the replacement of substituted care with supported care. Responding to this and other global calls for reduced coercion is complex globally but can entail particular challenges in developing countries, where resource shortages and environmental barriers are sometimes a significant factor in how people with mental conditions experience involuntary care and encounter limitations to their autonomy. To better understand these complexities, our study explored experiences of involuntary care among people with psychosocial conditions in South Africa. Participants described varying degrees of coercion within involuntary care and found that different approaches from professionals when they were in crisis significantly impacted their illness experience, including their ability to make decisions and feel dignified. Participants’ reports include variable feelings and embodied experiences of coercion in different forms and degrees, ambivalence about compliance and resistance while being treated against their will, and gray areas between conventional separations of autonomy and paternalism. On the whole, our analysis troubles binaries about the use or disuse of involuntary care and illustrates the complexity of participants’ experiences and views of coercive intervention, which could hold multiple possibilities for both care and autonomy.

Abstract Modern broiler breeds allow for high feed efficiency and rapid growth, which come at a cost of increased susceptibility to pathogens and disease. Broiler growth rate, feed efficiency, and health are affected by the composition of the gut microbiota, which in turn is influenced by diet. In this study, we therefore assessed how diet composition can affect the broiler jejunal gut microbiota. A total of 96 broiler chickens were divided into four diet groups: control, coated butyrate supplementation, medium-chain fatty acid supplementation, or a high-fibre low-protein content. Diet groups were sub-divided into age groups (4, 12 and 33 days of age) resulting in groups of 8 broilers per diet per age. The jejunum content was used for metagenomic shotgun sequencing to determine the microbiota taxonomic composition at species level. The composed diets resulted in a total of 104 differentially abundant bacterial species. Most notably were the butyrate-induced changes in the jejunal microbiota of broilers 4 days post-hatch, resulting in the reduced relative abundance of mainly Enterococcus faecium (-1.8 l2fc, Padj = 9.9E-05) and the opportunistic pathogen Enterococcus hirae (-2.9 l2fc, Padj = 2.7E-08), when compared to the control diet. This effect takes place during early broiler development, which is critical for broiler health, thus exemplifying the importance of how diet can influence the microbiota composition in relation to broiler health. Future studies should therefore elucidate how diet can be used to promote a beneficial microbiota in the early stages of broiler development.

Abstract Background Gambling and gambling-related harm attract significant researcher and policy attention. The liberalisation of gambling in most western countries is strongly associated with a marked rise in gambling activity and increases in gambling-related harm experienced at the population level. Programs to address gambling-related harm have traditionally focused on individuals who demonstrate problematic gambling behaviour, despite clear evidence of the effectiveness of a public health approach to high-risk activities like gambling. Little is known about the availability or efficacy of programs to address gambling-related harm at a population level. Methods The Victorian Responsible Gambling Foundation commissioned a rapid evidence review of the available evidence on programs designed to reduce gambling-related harm at a population level. The review was conducted using a public health and harm reduction lens. MEDLINE, ProQuest Central and PsychInfo databases were searched systematically. Included studies were published in English between 2017 – 2023 from all countries with gambling policy contexts and public health systems comparable to Australia’s; included primary data; and focused on primary and/or secondary prevention of gambling-related harm or problems. Results One hundred and sixty-seven articles were eligible for inclusion. Themes identified in the literature included: risk and protective factors; primary prevention; secondary prevention; tertiary prevention; target population group; and public health approach. The evidence review revealed a gap in empirical evidence around effective interventions to reduce gambling-related harm at the population level, particularly from a public health perspective. Conclusions Addressing gambling-related harm requires a nuanced, multi-layered approach that acknowledges the complex social, environmental, and commercial nature of gambling and associated harms. Moreover, evidence demonstrates community programs to reduce gambling-related harm are more successful in reducing harm when based on sound theory of co-design and address the social aspects that contribute to harm.

Abstract Radiation therapy (RT) remains a common treatment for cancer patients worldwide, despite the development of targeted biological compounds and immunotherapeutic drugs. The challenge in RT lies in delivering a lethal dose to the cancerous site while sparing the surrounding healthy tissues. Low linear energy transfer (low-LET) and high linear energy transfer (high-LET) radiations have distinct effects on cells. High-LET radiation, such as alpha particles, induces clustered DNA double-strand breaks (DSBs), potentially inducing cell death more effectively. However, due to limited range, alpha-particle therapies have been restricted. In human cancer, mutations in TP53 (encoding for the p53 tumor suppressor) are the most common genetic alteration. It was previously reported that cells carrying wild-type (WT) p53 exhibit accelerated senescence and significant rates of apoptosis in response to RT, whereas cells harboring mutant p53 (mutp53) do not. This study investigated the combination of the alpha-emitting atoms RT based on internal Radium-224 (224Ra) sources and systemic APR-246 (a p53 reactivating compound) to treat tumors with mutant p53. Cellular models of colorectal cancer (CRC) or pancreatic ductal adenocarcinoma (PDAC) harboring mutant p53, were exposed to alpha particles, and tumor xenografts with mutant p53 were treated using 224Ra source and APR-246. Effects on cell survival and tumor growth, were assessed. The spread of alpha emitters in tumors was also evaluated as well as the spatial distribution of apoptosis within the treated tumors. We show that mutant p53 cancer cells exhibit radio-sensitivity to alpha particles in vitro and to alpha-particles-based RT in vivo. APR-246 treatment enhanced sensitivity to alpha radiation, leading to reduced tumor growth and increased rates of tumor eradication. Combining alpha-particles-based RT with p53 restoration via APR-246 triggered cell death, resulting in improved therapeutic outcomes. Further preclinical and clinical studies are needed to provide a promising approach for improving treatment outcomes in patients with mutant p53 tumors.

Abstract Retinal optical coherence tomography has been identified as biomarker for disease progression in relapsing-remitting multiple sclerosis (RRMS), while the dynamics of retinal atrophy in progressive MS are less clear. We investigated retinal layer thickness changes in RRMS, primary and secondary progressive MS (PPMS, SPMS), and their prognostic value for disease activity. Here, we analyzed 2651 OCT measurements of 195 RRMS, 87 SPMS, 125 PPMS patients, and 98 controls from five German MS centers after quality control. Peripapillary and macular retinal nerve fiber layer (pRNFL, mRNFL) thickness predicted future relapses in all MS and RRMS patients while mRNFL and ganglion cell-inner plexiform layer (GCIPL) thickness predicted future MRI activity in RRMS (mRNFL, GCIPL) and PPMS (GCIPL). mRNFL thickness predicted future disability progression in PPMS. However, thickness change rates were subject to considerable amounts of measurement variability. In conclusion, retinal degeneration, most pronounced of pRNFL and GCIPL, occurs in all subtypes. Using the current state of technology, longitudinal assessments of retinal thickness may not be suitable on a single patient level.