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Abstract We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5+ cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-LGR5-CAR-T cells also showed specific and potent LGR5+ cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that α-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells.

Introduction: Boerhaave syndrome is a rare condition associated with high morbidity and mortality. Prompt intervention greatly improves outcomes, with surgery traditionally being the mainstay of management. Recent advances in therapeutic endoscopy have led to increasing interest in endoluminal vacuum therapy (EVT), a minimally invasive technique, allowing wound debridement and drainage, encouraging granulation tissue formation. EVT has been associated with positive clinical outcomes, including lower mortality rates compared to surgery and stenting for the management of anastomotic leaks, and to a lesser extent, oesophageal perforations. EVT has been adopted into practice across Europe; however, only few cases have been reported from the UK. Case Presentations: We report three cases of Boerhaave syndrome, successfully managed with EVT, using the Eso-SPONGE ® (B.Braun Medical Ltd, Sheffield, UK). EVT involves the placement of a polyurethane sponge into the wound cavity. The cavity is initially assessed, then an overtube is introduced through which the sponge is inserted, and then the overtube is removed. Sponge position is confirmed and adjusted if necessary. The sponge is connected via a trans-nasal drain to continuous negative pressure suction and is changed every 3–5 days. Having been deemed surgically unfit, all 3 patients were referred for EVT. All patients made excellent recovery and were discharged home. Conclusion: EVT is an effective management strategy for surgically unfit Boerhaave syndrome patients. Eso-SPONGE use aided drainage of the septic focus and closure of the defect, leading to complete recovery. Our findings support the existing evidence that EVT is a promising solution for Boerhaave syndrome.

Abstract Background Polygenic risk scores (PRS) and subjective cognitive decline (SCD) are associated with the risk of developing dementia. It remains to examine whether they can improve the established cardiovascular risk factors aging and dementia (CAIDE) model and how their predictive abilities compare. Methods The CAIDE model was applied to a sub-sample of a large, population-based cohort study (n = 5,360; aged 50–75) and evaluated for the outcomes of all-cause dementia, Alzheimer’s disease (AD) and vascular dementia (VD) by calculating Akaike’s information criterion (AIC) and the area under the curve (AUC). The improvement of the CAIDE model by PRS and SCD was further examined using the net reclassification improvement (NRI) method and integrated discrimination improvement (IDI). Results During 17 years of follow-up, 410 participants were diagnosed with dementia, including 139 AD and 152 VD diagnoses. Overall, the CAIDE model showed high discriminative ability for all outcomes, reaching AUCs of 0.785, 0.793, and 0.789 for all-cause dementia, AD, and VD, respectively. Adding information on SCD significantly increased NRI for all-cause dementia (4.4%, p = 0.04) and VD (7.7%, p = 0.01). In contrast, prediction models for AD further improved when PRS was added to the model (NRI, 8.4%, p = 0.03). When APOE ε4 carrier status was included (CAIDE Model 2), AUCs increased, but PRS and SCD did not further improve the prediction. Conclusions Unlike PRS, information on SCD can be assessed more efficiently, and thus, the model including SCD can be more easily transferred to the clinical setting. Nevertheless, the two variables seem negligible if APOE ε4 carrier status is available.

Background The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p

Abstract Elevated intracellular sodium Nai adversely affects mitochondrial metabolism and is a common feature of heart failure. The reversibility of acute Na induced metabolic changes is evaluated in Langendorff perfused rat hearts using the Na/K ATPase inhibitor ouabain and the myosin-uncoupler para-aminoblebbistatin to maintain constant energetic demand. Elevated Nai decreases Gibb’s free energy of ATP hydrolysis, increases the TCA cycle intermediates succinate and fumarate, decreases ETC activity at Complexes I, II and III, and causes a redox shift of CoQ to CoQH2, which are all reversed on lowering Nai to baseline levels. Pseudo hypoxia and stabilization of HIF-1α is observed despite normal tissue oxygenation. Inhibition of mitochondrial Na/Ca-exchange with CGP-37517 or treatment with the mitochondrial ROS scavenger MitoQ prevents the metabolic alterations during Nai elevation. Elevated Nai plays a reversible role in the metabolic and functional changes and is a novel therapeutic target to correct metabolic dysfunction in heart failure.

Abstract Background Glycolytic flux is regulated by the energy demands of the cell. Upregulated glycolysis in cancer cells may therefore result from increased demand for adenosine triphosphate (ATP), however it is unknown what this extra ATP turnover is used for. We hypothesise that an important contribution to the increased glycolytic flux in cancer cells results from the ATP demand of Na+/K+-ATPase (NKA) due to altered sodium ion homeostasis in cancer cells. Methods Live whole-cell measurements of intracellular sodium [Na+]i were performed in three human breast cancer cells (MDA-MB-231, HCC1954, MCF-7), in murine breast cancer cells (4T1), and control human epithelial cells MCF-10A using triple quantum filtered 23Na nuclear magnetic resonance (NMR) spectroscopy. Glycolytic flux was measured by 2H NMR to monitor conversion of [6,6-2H2]d-glucose to [2H]-labelled l-lactate at baseline and in response to NKA inhibition with ouabain. Intracellular [Na+]i was titrated using isotonic buffers with varying [Na+] and [K+] and introducing an artificial Na+ plasma membrane leak using the ionophore gramicidin-A. Experiments were carried out in parallel with cell viability assays, 1H NMR metabolomics of intracellular and extracellular metabolites, extracellular flux analyses and in vivo measurements in a MDA-MB-231 human-xenograft mouse model using 2-deoxy-2-[18F]fluoroglucose (18F-FDG) positron emission tomography (PET). Results Intracellular [Na+]i was elevated in human and murine breast cancer cells compared to control MCF-10A cells. Acute inhibition of NKA by ouabain resulted in elevated [Na+]i and inhibition of glycolytic flux in all three human cancer cells which are ouabain sensitive, but not in the murine cells which are ouabain resistant. Permeabilization of cell membranes with gramicidin-A led to a titratable increase of [Na+]i in MDA-MB-231 and 4T1 cells and a Na+-dependent increase in glycolytic flux. This was attenuated with ouabain in the human cells but not in the murine cells. 18FDG PET imaging in an MDA-MB-231 human-xenograft mouse model recorded lower 18FDG tumour uptake when treated with ouabain while murine tissue uptake was unaffected. Conclusions Glycolytic flux correlates with Na+-driven NKA activity in breast cancer cells, providing evidence for the ‘centrality of the [Na+]i-NKA nexus’ in the mechanistic basis of the Warburg effect.

Abstract An important aspect of Space Situational Awareness is to estimate the intent of objects in space. This paper discusses how discriminating features can be obtained from Inverse Synthetic Aperture Radar images of such objects and how these discriminators can be used to recognise the objects or to estimate their intent. If the object is, for example, a satellite of a known type, the scheme proposed is able to recognise it. The ability of the scheme to detect damage to the object is also discussed. The focus is on imagery obtained in the sub‐terahertz band (typically 300 GHz) because of the greater imaging capability given by the diffuse scattering which is observed at these frequencies. The paper also discusses the importance of being able to use images obtained by electromagnetic simulation to be able to train the subsystem which recognises features of the objects and describes a practical scheme for creating these simulations for large objects at these very short wavelengths.

Abstract With the aim of investigating the existence of an integrable elliptic deformation of strings on AdS3 × S3 × T4, we compute the tree-level worldsheet S-matrix of the elliptically-deformed bosonic sigma model on AdS3 × S3 in uniform light-cone gauge. The resulting tree-level S-matrix is compatible with the integrability of the model and has interesting features, including a hidden U(1) symmetry not manifest in the Lagrangian. We find that it cannot be embedded in the known exact integrable R-matrices describing deformations of the undeformed AdS3 × S3 × T4 light-cone gauge S-matrix including fermions. Therefore, we construct embeddings of the deformed 6-d metric in type II supergravity with constant dilaton and homogeneous fluxes. The simplicity of these solutions suggests they are promising candidates to lead to an integrable string sigma model including fermions.

The developmental period of adolescence is a known transitional life phase with unique risk and protective factors that can affect mental wellbeing outcomes. This, in combination with the pressures and demand of elite sport, make young elite athletes an important population in which positive mental wellbeing can be explored. This study aimed to examine the state of wellbeing, informed by positive psychology and the Positive emotions, Engagement, Relationships, Meaning, Accomplishment (PERMA) model of wellbeing, in a cohort of young athletes aged 16–19 years in the Australian setting as part of a model of continuous improvement. The objectives of these aims were to inform the development of a wellbeing curriculum for implementation in the Australian Rules Football talent pathway and to assess whether wellbeing presents differently in young athletes relative to the general school-attending population of that same age. Participants were 608 young Australian footballers participating in the developmental talent pathway during 2020 and 2021. There were 299 young male footballers, and 309 young women footballers who completed data collection. Wellbeing was assessed using the Engagement, Perseverance, Optimism, Connectedness, Happiness Measure of Adolescent Wellbeing (EPOCH) which corresponds to the PERMA model of wellbeing, and total mean scores were reported. Engagement and connectedness were similar for the young men and women athletes. Young men reported higher perseverance, optimism, happiness, and overall wellbeing relative to young women. Wellbeing among young athletes appears similar to the general population, however perseverance may be higher among young athletes. These findings form an important component of the continuous improvement model adopted in the football program in that the results informed the development of a tailored wellbeing curriculum program that is reflective of the wellbeing needs of the young athletes.

Abstract INTRODUCTION Subjective hearing and memory problems are detectable earlier than objective measures of sensory loss and cognitive decline, which are known to be related to an increased risk of dementia in later life. METHODS Using a population‐representative cohort of 6006 individuals (aged 50–75) we examined whether participants who self‐reported hearing and short‐term memory issues showed greater rates of dementia within 17 years of follow‐up. A sub‐cohort was tested for audiometric threshold and cognition after 14 years. RESULTS Hearing and memory problems were associated with a greater risk of dementia (hazard ratios [HRs] = 1.42 [95% confidence interval: 1.11–1.81], 1.57 [1.30–1.90]), and poorer cognition 14 years later. The risk was greatest in those reporting both problems (HR = 1.99 [1.42–2.80]). At follow‐up, the level of hearing loss was associated with lower cognitive scores. DISCUSSION Self‐reports of hearing and short‐term memory problems are associated with poorer cognitive performance and a greater risk of dementia. Subjective assessments may have predictive power over more than a decade. Highlights In a sample of older adults subjective hearing and memory problems were associated with dementia risk. Cross‐sectionally, the audiometric screening threshold was associated with cognitive test scores. Subjective sensory and memory loss questions are easy to implement and show good predictive power.

Abstract The interaction between multi‐component rare earth element (REE) aqueous solutions and carbonate grains (dolomite, aragonite, and calcite) are studied at hydrothermal conditions (21–210 °C). The effect of ionic radii of five REEs (La, Ce, Pr, Nd, Dy) on solid formation are analyzed using two solution types: equal REE concentrations and concentrations normalized to Post Archean Australian Shale Standard (PAAS). The interaction replaces the host Ca–Mg carbonate grains with a series of REE minerals (lanthanite → kozoite → bastnäsite → cerianite). At 165 °C, equal concentration solutions promote kozoite crystallization, maintaining similar REE ratios in solids and solution. PAAS solutions result in zoned REE‐bearing crystals with heterogeneous elemental distributions and discreet REE phases (e.g., cerianite). Chemical signatures indicate metastable REE‐bearing phases transforming into more stable polymorphs, along with symplectite textures formed by adjacent phase reactions. Overall, experiments highlight the dependence of polymorph selection, crystallization pathway, mineral formation kinetics, and chemical texture on REE concentrations, ionic radii, temperature, time, and host grain solubility.

Background Pre-existing cardiovascular disease (CVD) or cardiovascular risk factors have been associated with an increased risk of complications following hospitalisation with COVID-19, but their impact on the rate of recovery following discharge is not known.Objectives To determine whether the rate of patient-perceived recovery following hospitalisation with COVID-19 was affected by the presence of CVD or cardiovascular risk factors.Methods In a multicentre prospective cohort study, patients were recruited following discharge from the hospital with COVID-19 undertaking two comprehensive assessments at 5 months and 12 months. Patients were stratified by the presence of either CVD or cardiovascular risk factors prior to hospitalisation with COVID-19 and compared with controls with neither. Full recovery was determined by the response to a patient-perceived evaluation of full recovery from COVID-19 in the context of physical, physiological and cognitive determinants of health.Results From a total population of 2545 patients (38.8% women), 472 (18.5%) and 1355 (53.2%) had CVD or cardiovascular risk factors, respectively. Compared with controls (n=718), patients with CVD and cardiovascular risk factors were older and more likely to have had severe COVID-19. Full recovery was significantly lower at 12 months in patients with CVD (adjusted OR (aOR) 0.62, 95% CI 0.43 to 0.89) and cardiovascular risk factors (aOR 0.66, 95% CI 0.50 to 0.86).Conclusion Patients with CVD or cardiovascular risk factors had a delayed recovery at 12 months following hospitalisation with COVID-19. Targeted interventions to reduce the impact of COVID-19 in patients with cardiovascular disease remain an unmet need.Trail registration number ISRCTN10980107.

Abstract Background Depression ranks as the foremost mental health concern among childbearing women. Within low- and middle-income countries (LMICs), between 20 and 25% of women encounter depression during pregnancy or soon after delivery. This condition impacts not only the mothers but also their offspring. Offspring of women suffering from postnatal depression (PND) exhibit suboptimal cognitive development and increased emotional and behavioural issues throughout their growth. This scenario becomes more pronounced in LMICs, where numerous adversities further jeopardise children’s developmental progress. Despite antenatal services providing a pivotal platform to address women’s mental health needs, PND treatment remains inaccessible in many LMICs. The World Health Organization advocates interpersonal psychotherapy (IPT) for treating depression. While research from high-income countries has established the efficacy of IPT and group-IPT (g-IPT) for PND, its effectiveness within the LMIC context and its potential benefits for child development remain uncharted. This study seeks to gauge the potency of g-IPT for women with PND in two LMICs. Methods This multi-site randomised controlled trial is a continuation of two preceding phases—conceptual mapping and a feasibility study executed in Lebanon and Kenya. Insights gleaned from these phases underpin this comprehensive RCT, which contrasts the efficacy and cost-effectiveness of high-quality standard care (HQ-SC) augmented with g-IPT against HQ-SC in isolation. The trial, characterised as an individually randomised superiority assessment, targets women with postnatal depression in Beirut, Lebanon, and Nairobi, Kenya. It aims to determine if culturally tailored g-IPT, administered within community settings in both countries, outperforms HQ-SC in influencing child developmental outcomes, maternal depression, and the quality of the mother–child bond. Discussion The SUMMIT trial, designed with pragmatism, possesses the magnitude to evaluate g-IPT within two LMIC frameworks. It seeks to enlighten policymakers, service commissioners, professionals, and users about g-IPT’s potential to alleviate maternal PND and bolster child developmental outcomes in LMICs. Additionally, the trial will generate valuable data on the clinical and economic merits of high-quality standard care. Trial registration ISRCTN, ISRCTN15154316. Registered on 27 September 2023, https://doi.org/10.1186/ISRCTN15154316

The role of hepatic venous pressure gradient (HVPG) measurement in risk stratification before liver resection is an ongoing area of debate. This study examines the impact of preoperative HVPG levels on overall survival (OS)/time to recurrence (TTR) and postoperative complications after hepatic resection of hepatocellular carcinoma (HCC). Thirty-eight HCC patients undergoing HVPG measurement before liver resection at Cambridge University Hospitals NHS Foundation Trust between January 2014 and April 2022 were retrospectively analysed. Statistical analysis comprised univariable/multivariable Cox/logistic regression to identify risk factors of reduced OS/TTR or 90-day post-resection complications and Kaplan–Meier estimator, log-rank, chi-squared, Fisher's exact, and Mann–Whitney U test, or Student's t-test for survival/subgroup analysis. The median HPVG was 6 (range: 0–14) mmHg. The HVPG was an independent risk factor for poorer TTR in the overall cohort (cut-off: ≥7.5 mmHg (17.18/43.81 months; P = 0.009)). In the subgroup analysis of cirrhotic patients (N = 29 (76%)), HVPG was additionally an independent risk factor for lower OS (cut-off: ≥8.5 mmHg [44.39/76.84 months; P = 0.012]). The HVPG had no impact on OS/TTR in non-cirrhotic patients (N = 9 (24%)), nor was it associated with postoperative complications in any cohort. In conclusion, preoperative HVPG levels are useful predictors for TTR and OS in cirrhotic HCC patients undergoing hepatic resection.

Abstract Central nervous system involvement in HIV infection leads to neurobehavioural sequelae. Although apathy is a well-recognised symptom in adults living with HIV linked to alterations in brain structure, there is scarce research examining motivation in children living with HIV (CLWH). We used the Children’s Motivation Scale (CMS; normative mean = 50, SD = 10) to assess motivation levels in 76 CLWH aged 6–16 years (63 on antiretroviral therapy [ART]; 13 ART-naïve slow progressors) in South Africa. Overall, CLWH scored low on the CMS (mean = 35.70 [SD = 5.87]). Motivation levels were significantly reduced in children taking ART compared to ART-naïve slow progressors (p = 0.02), but were not correlated with markers of HIV disease (CD4 + cell count or viral load), or neurocognitive function (p > 0.05). CMS scores were correlated with diffusion tensor imaging metrics of white matter microstructure in specific frontostriatal brain regions (p

Abstract Background Chronic kidney disease (CKD) affects 10% of the global population costing over a hundred billion dollars per annum and leading to increased risk of cardiovascular disease. Many patients with CKD require regular haemodialyses. Synthetic arteriovenous grafts (AVG) are increasingly used to provide rapid vascular connection for dialysis. Initially, they have excellent patency rates but are critically limited by neointimal hyperplasia at the venous anastomosis, which drives subsequent thrombosis, graft failure and death. Methods Here, we describe a system in which electrical impedance spectroscopy sensors are incorporated circumferentially into the wall of a synthetic arteriovenous graft. This is combined with an implantable radiotelemetry system for data transmission outside the patient. The system was tested using monolayers of endothelial and smooth muscle cells as well as swine blood and clots with explanted human carotid artery plaques. Sensor testing was then performed in vitro and the device was implanted in vivo in female swine. Results The device can wirelessly report the accumulation of biological material, both cells and blood. Differences are also detected when comparing controls with pathological atheroma. In swine differences between blockage formation in a graft were remotely obtained and wireless reported. Conclusions Combining electrical impedance spectroscopy and an implantable radiotelemetry system enables graft surveillance. This has the potential to be used for early detection of venous stenosis and blood clot formation in real-time in vivo. In principle, the concept could apply to other cardiovascular diseases and vascular implantable devices.

Introduction: The severity of COVID-19 in the general population ranges from minimally symptomatic disease to critical illness, which may require hospitalization and progress to death. Methods: A retrospective cohort study carried out with all positive cases of COVID-19 reported in the municipality of Foz do Iguaçu (PR) between the period from March 2020 to December 2021. Data were collected from Bank Notifies COVID-19 is the name of the information system that provides notifications by professionals of suspected and confirmed cases of the disease. Data were analyzed using descriptive statistical techniques and calculation of relative risk. Results: 24,647 confirmed cases were identified in the study; among these, 22,211 (90.1%) were not hospitalized and 2436 (9.9%) were hospitalized. Among the 2436 patients hospitalized for COVID-19, 947 (38.9%) died and 1489 (61.1%) recovered. Among the 22,211 outpatients, 93 (0.4%) died and 22,118 (99.6%) recovered. An association between death and the following characteristics was identified among the cases that were hospitalized: male gender, all age groups over 40 years, indigenous race/color, hospital staylength of more than 10 days,hospitalization in a Unified Health System (SUS) bed and in an Intensive Care Unit (ICU). According to the clinical characteristics of symptoms and comorbidities, the following prevailed:ities dyspnea, intercostal retraction, cyanosis, hypertension, diabetes, obesity, cardiovascular disease, smoking, lung disease, kidneydisease, neurological disease, neoplasia, and immunodeficiency. Among the cases that were not hospitalized, death was associated with: malegender, all age groups over 50 years, dyspnea, cyanosis, hypertension, diabetes, obesity, cardiovascular disease, kidney disease, neurological disease, neoplasia, and liver disease. Conclusions: Older adults, male, and Caucasian people are commonly affected by COVID-19 and can evolve with aggravation when they have modifiable risk factors such as obesity and smoking, as well as nonmodifiable risk factors such as: cardiovascular disease, neurological disease, renal, hypertension, diabetes, and immunosuppression.

Abstract External program review is often considered the “gold standard” approach to evaluating academic programs in higher education. Despite the importance of program review, skepticism persists regarding its ability to meaningfully engage faculty and have sustaining impact on program improvement. This paper builds on the academic Program Review Learning Community conceptual model and presents a process for applying a project management facilitation technique that leverages a course structure. The Program Review Course allows for multiple programs to be reviewed concurrently as part of an interdisciplinary cohort. Within the cohort, faculty teams gain access to templates, information sessions, workshops, and discussion forums, with opportunities for engagement both within and across multiple disciplines. Using learning modules, this approach is designed to create efficiency and collaboration in delivering program review tools and customized supports. Utilizing a course structure for program review fits well with a new way to think about program review because successful learning communities are often embedded within institutional structures. Use of this approach is expected to increase clarity and consistency, improve administrative feasibility, provide guidance for those new to program review, promote collegiality within and across programs, and involve team members in the creation of action planning. The authors propose that a course-based approach for conducting program review, with teams of disciplinary faculty joining an interdisciplinary cohort and supported by quality assurance practitioners and educational developers is a novel way to provide structure and academic development while meeting legislative requirements.

Aims Older people (people aged 65 and older) have high rates of suicide, and self-harm is a major risk factor for suicide. While rates of self-harm decrease with age, rates of suicide increase amongst this age group. The aim of this project is to analyse data collected by the National Clinical Programme for Self-Harm and Suicide-related Ideation (NCPSHI) to identify real-life evidence of the characteristics associated with older people who present with self-harm and suicidal ideation to emergency departments (ED) in Ireland. In examining the variables associated with self-harm we may be better able to identify the characteristics of older adults who are at highest risk, including those presenting with high lethality attempts. Methods The NCPSHI collects data on all patients who present with self-harm or suicide-related ideation to EDs in Ireland. We utilised a six-year cohort of anonymised data from the NCPSHI from 2018–2023, representing 5,041 presentations of older people (aged 60 and over); 6.9% of all presentations with self-harm and suicide-related ideation. We examined sociodemographic variables including sex, ethnic background, type of self-harm, lethality of self-harm and substance use contributing to the presentation, in addition to service use variables. Results Older people were less likely to present with self-harm – 45% of older people vs 52% of adults under 60 (p < 0.001). However, those episodes of self-harm were more likely to be categorised as “high lethality” – 20% vs 12% of people under 60 (p < 0.001). Older people were also more likely to have a mental health admission – 25% vs 16% (p < 0.001). Older people were much less likely to present with substance misuse: 30% vs 45% (p < 0.001). There were also significant differences in methods of self-harm. Older people were more likely to attempt drowning (1.5% vs 1.1%) or overdose (21% vs 20%). This was the common method of self-harm across all age groups. Conclusion Our results demonstrate the significant differences in characteristics of older people presenting to Irish emergency departments with self-harm versus younger people, where previously a paucity of data existed. The high lethality of self-harm amongst older people makes it imperative to identify the characteristics of self-harm in this population to understand the factors associated with increased risk and help us to develop treatments and services to meet their needs It also highlights the importance of providing education to staff working with this cohort to appropriately stratify and manage risk.

Aims It is estimated that approximately 15% of adults over 60 years old suffer from a mental disorder. Self-harm and suicidal ideation are associated with a range of mental disorders, and high rates of suicide. The aim of this project is to identify the characteristics of older people who present with self-harm and suicidal ideation to an emergency department (ED) in a university hospital. In examining the variables associated with self-harm we may be better able to identify the characteristics of older adults who are at highest risk. Methods We conducted a cohort study of older adults (aged 65 years+) who presented to the Mater Misericordiae University Hospital with a mental health problem from 2008–2022 (a 15-year cohort). Data were extracted from the Electronic Patient Records including all patients who presented to the ED in that time period with a mental health triage code. We examined this cohort to collect detailed information on the characteristics of those older people presenting with self-harm and suicidal ideation. Results We identified 30,941 ED attendances with a mental health triage code between 2008 and 2022. Of these, 946 (3.1%) were older adults. One-fifth (20%) presented with self-harm, a further 21% reported suicidal ideation. Of these, 8% reported previous self-harm and 32% had previously been reviewed by psychiatry. Over one-third (38%) were admitted. Of those, the majority (78%) were admitted to a medical or surgical ward, 16% to a psychiatric ward and 5% to critical care. Of those presenting with self-harm 37% were admitted to hospital – 32% to a medical or other ward and 5% to psychiatric unit. There was a significant difference in those who were admitted with self-harm versus suicidal ideation (p < 0.001). Conclusion Our results demonstrate key insights into older adults who presented to the ED with self-harm and suicidal ideation. These patients were more likely to be admitted to a medical ward than a psychiatric unit, and those with self-harm were more likely to be admitted medically compared with those with suicidal ideation. Possible reasons for these results include the higher rate of medical co-morbidity in older adults and the potential high lethality of self-harm in this cohort. Another explanation could be the scarcity of acute psychiatric beds necessitating medical admission. There is a need for further exploration of this high-risk population.

Abstract BackgroundSyndromic surveillance represents a potentially inexpensive supplement to test-based COVID-19 surveillance. By strengthening surveillance of COVID-19–like illness (CLI), targeted and rapid interventions can be facilitated that prevent COVID-19 outbreaks without primary reliance on testing. ObjectiveThis study aims to assess the temporal relationship between confirmed SARS-CoV-2 infections and self-reported and health care provider–reported CLI in university and county settings, respectively. MethodsWe collected aggregated COVID-19 testing and symptom reporting surveillance data from Cornell University (2020‐2021) and Tompkins County Health Department (2020‐2022). We used negative binomial and linear regression models to correlate confirmed COVID-19 case counts and positive test rates with CLI rate time series, lagged COVID-19 cases or rates, and day of the week as independent variables. Optimal lag periods were identified using Granger causality and likelihood ratio tests. ResultsIn modeling undergraduate student cases, the CLI rate (PPPP ConclusionsThe real-time correlation between syndromic surveillance and COVID-19 cases on a university campus suggests symptom reporting is a viable alternative or supplement to COVID-19 surveillance testing. At the county level, syndromic surveillance is also a leading indicator of COVID-19 cases, enabling quick action to reduce transmission. Further research should investigate COVID-19 risk using syndromic surveillance in other settings, such as low-resource settings like low- and middle-income countries.

Abstract Many cardiovascular problems stem from blockages that form within the vasculature and often treatment includes fitting a stent through percutaneous coronary intervention. This offers a minimally invasive therapy but re‐occlusion through restenosis or thrombosis formation often occurs post‐deployment. Research is ongoing into the creation of smart stents that can detect the occurrence of further problems. In this study, it is shown that selectively metalizing a non‐conductive stent can create a set of electrodes that are capable of detecting a build‐up of material around the stent. The associated increase in electrical impedance across the electrodes is measured, testing the stent with blood clot to mimic thrombosis. It is shown that the device is capable of sensing different amounts of occlusion. The stent can reproducibly sense the presence of clot showing a 16% +/−3% increase in impedance which is sufficient to reliably detect the clot when surrounded by explanted aorta (one sample t‐test, p = 0.009, n = 9). It is demonstrated that this approach can be extended beyond the 3D printed prototypes by showing that it can be applied to a commercially available stent and it is believed that it can be further utilized by other types of medical implants.

Background Individuals with psychiatric disorders have an increased risk of developing dementia. Most cross-sectional studies suffer from selection bias, underdiagnosis and poor population representation, while there is only limited evidence from longitudinal studies on the role of anxiety, bipolar and psychotic disorders. Electronic health records (EHRs) permit large cohorts to be followed across the lifespan and include a wide range of diagnostic information.Objective To assess the association between four groups of psychiatric disorders (schizophrenia, bipolar disorder/mania, depression and anxiety) with dementia in two large population-based samples with EHR.Methods Using EHR on nearly 1 million adult individuals in Wales, and from 228 937 UK Biobank participants, we studied the relationships between schizophrenia, mania/bipolar disorder, depression, anxiety and subsequent risk of dementia.Findings In Secure Anonymised Information Linkage, there was a steep increase in the incidence of a first diagnosis of psychiatric disorder in the years prior to the diagnosis of dementia, reaching a peak in the year prior to dementia diagnosis for all psychiatric diagnoses. Psychiatric disorders, except anxiety, were highly significantly associated with a subsequent diagnosis of dementia: HRs=2.87, 2.80, 1.63 for schizophrenia, mania/bipolar disorder and depression, respectively. A similar pattern was found in the UK Biobank (HRs=4.46, 3.65, 2.39, respectively) and anxiety was also associated with dementia (HR=1.34). Increased risk of dementia was observed for all ages at onset of psychiatric diagnoses when these were divided into 10-year bins.Conclusions Psychiatric disorders are associated with an increased risk of subsequent dementia, with a greater risk of more severe disorders.Clinical implications A late onset of psychiatric disorders should alert clinicians of possible incipient dementia.

Abstract Electrochemical biosensing represents a highly effective technology for detecting disease biomarkers given its high sensitivity, low and clinically relevant limit of detection, and cost effectiveness. However, in complex media such as urine, blood, sweat or saliva, biosensing performance can be significantly impacted by electrode biofouling by proteins, cells, lipids, and other matrix components. Such biofouling leads to reduced signal from the target analyte coupled with an elevated background signal, resulting in poor signal‐to‐noise ratios (SNRs), reduced sensitivity, and lower specificity. This comprehensive review describes the design of anti‐fouling polymers and peptides as a potential solution to prevent or suppress electrochemical biosensor fouling. Various anti‐fouling polymers and peptides developed for improved biosensing in complex media are summarized in the context of their mechanism(s) of anti‐fouling, methods of deposition, and practical applications. Recent advances and persistent challenges in the field are also reviewed to provide perspectives on new directions toward enhancing anti‐fouling in electrochemical biosensors.

Objectives This study aimed to compare talent development athletes to community-level athletes in Australian Rules Football across various markers of healthy youth development.Methods Survey data were collected from 363 youth athletes (126 women, 232 men, 5 not reported; Mage=18.69 years, SDage=2.62 years, age range 16–25 years) playing Australian Rules Football at a talent development (recruited from Australian Football League Talent Pathway, n=220) or community (n=143) level. Measures included markers of physical health (eg, general health, risk-taking behaviours), psychological and emotional well-being (eg, mental health symptoms, life satisfaction), family and social relationships (eg, social support, relationship status), educational and occupational attainment/engagement (eg, career satisfaction, education), ethical behaviour (eg, moral self-image), civic engagement, life skills (eg, self-mastery, coping), and demographics.Results Based on regression models, relative to community-level athletes, talent development athletes reported better physical health (d=0.51), lower injury rates (OR=0.50) and less problematic drug use (d=−0.46). Talent development athletes also reported better psychological and emotional well-being, evidenced by lower stress (d=−0.30), higher life satisfaction (d=0.47) and less problematic gambling (d=−0.34). Additionally, talent development athletes reported higher family support (d=0.49), lower likelihood of poor educational outcomes (less than expected educational stage; OR=0.37), lower intention to complete less than year 12 education (OR=0.18), higher career satisfaction (d=0.42), higher self-mastery (d=0.37) and higher perfectionistic striving (d=0.59).Conclusion Findings demonstrate markers of healthier development within talent development athletes relative to community athlete peers. Investment in community-level sports may be warranted to improve healthy development. However, further causal evidence is required.

Introduction There is a lack of evidence that the benefits of screening for atrial fibrillation (AF) outweigh the harms. Following the completion of the Screening for Atrial Fibrillation with ECG to Reduce stroke (SAFER) pilot trial, the aim of the main SAFER trial is to establish whether population screening for AF reduces incidence of stroke risk.Methods and analysis Approximately 82 000 people aged 70 years and over and not on oral anticoagulation are being recruited from general practices in England. Patients on the palliative care register or residents in a nursing home are excluded. Eligible people are identified using electronic patient records from general practices and sent an invitation and consent form to participate by post. Consenting participants are randomised at a ratio of 2:1 (control:intervention) with clustering by household. Those randomised to the intervention arm are sent an information leaflet inviting them to participate in screening, which involves use of a handheld single-lead ECG four times a day for 3 weeks. ECG traces identified by an algorithm as possible AF are reviewed by cardiologists. Participants with AF are seen by a general practitioner for consideration of anticoagulation. The primary outcome is stroke. Major secondary outcomes are: death, major bleeding and cardiovascular events. Follow-up will be via electronic health records for an average of 4 years. The primary analysis will be by intention-to-treat using time-to-event modelling. Results from this trial will be combined with follow-up data from the cluster-randomised pilot trial by fixed-effects meta-analysis.Ethics and dissemination The London—Central National Health Service Research Ethics Committee (19/LO/1597) provided ethical approval. Dissemination will include public-friendly summaries, reports and engagement with the UK National Screening Committee.Trial registration number ISRCTN72104369.

The urban building stock dataset consists of synthetic input and output data for the energy simulation of one million buildings. The dataset consists of four different residential types, namely: terraced, detached, semi-detached, and bungalow. Constructing this buildings dataset requires conversion, categorization, extraction, and analytical processes. The dataset (in .csv) format comprises 19 input parameters, including advanced features such as HVAC system parameters, building fabric (walls, roofs, floors, door, and windows) U-values, and renewable system parameters. The primary output parameter in the dataset is Energy Use Intensity (EUI in kWh/(m2*year)), along with Energy Performance Certificate (EPC) labels categorized on an A to G rating scale. Additionally, the dataset contains end-use demand output parameters for heating and lighting, which are crucial output parameters. jEPlus, a parametric tool, is coupled with EnergyPlus and DesignBuilder templates to facilitate physics-based parametric simulations for generating the dataset. The dataset can be a valuable resource for researchers, practitioners, and policymakers seeking to enhance sustainability and efficiency in urban building environments. Furthermore, dataset holds immense potential for future research in the field of building energy analysis and modeling.

Abstract Introduction While screening uptake is variable, many individuals feel they ‘ought’ to participate in screening programmes to aid the detection of conditions amenable to early treatment. Those not taking part in screening are often presented as either hindered by practical or social barriers or personally at fault. Why some people choose not to participate receives less consideration. Methods We explored screening nonparticipation by examining the accounts of participants who chose not to participate in screening offered by a national research trial of atrial fibrillation (AF) screening in England (SAFER: Screening for Atrial Fibrillation with ECG to Reduce stroke). AF is a heart arrhythmia that increases in prevalence with age and increases the risk of stroke. Systematic screening for AF is not a nationally adopted programme within the United Kingdom; it provides a unique opportunity to explore screening nonparticipation outside of the norms and values attached to existing population‐based screening programmes. We interviewed people aged over 65 (n = 50) who declined an invitation from SAFER and analysed their accounts thematically. Results Beyond practical reasons for nonparticipation, interviewees challenged the utility of identifying and managing AF earlier. Many questioned the benefits of screening at their age. The trial's presentation of the screening as research made it feel voluntary—something they could legitimately decline. Conclusion Nonparticipants were not resistant to engaging in health‐promoting behaviours, uninformed about screening or unsupportive of its potential benefits. Instead, their consideration of the perceived necessity, legitimacy and utility of this screening shaped their decision not to take part. Patient or Public Contribution The SAFER programme is guided by four patient and carer representatives. The representatives are embedded within the team (e.g., one is a co‐applicant, another sits on the programme steering committee) and by participating in regular meetings advise on all aspects of the design, management and delivery of the programme, including engaging with interpreting and disseminating the findings. For the qualitative workstream, we established a supplementary patient and public involvement group with whom we regularly consult about research design questions.

Abstract Background We need to preserve the lessons of the COVID-19 pandemic in caring for the mental health of clinicians, of shared experiences, interdependence, team cohesion and vulnerability, among others. We need reform in the way that clinicians are cared for, and a resistance to the idea of a post-pandemic ‘return to normal’. Main text To build connected and optimally functioning clinical teams, we need to create an inclusive culture in which difficult conversations and caring are the expectation. If we are to be better at solving problems and better at serving our patients, we should be vigilant about creating a psychologically safe medical culture in which colleagues feel safe, seen, heard, and respected. Conclusion Going forward, each of us, regardless of seniority, needs to take responsibility for this culture change. We need to create and participate in weekly collegial peer support sessions that feel nurturing and safe, that allow us to reveal parts of ourselves, to be vulnerable with each other in a way that reduces loneliness, and encourages and maintains social connections and a sense of belonging within clinical teams, improves clinician well-being and reduces the risk of burnout. “Care is a practice of informed responsive actions on behalf of the one cared for and authentically aimed toward their growth and flourishing.” Care Ethics in the Age of Precarity; Maurice Hamington and Michael Flower.

Abstract Direct modulation of cardiac myosin function has emerged as a therapeutic target for both heart disease and heart failure. However, the development of myosin-based therapeutics has been hampered by the lack of targeted in vitro screening assays. In this study we use Artificial Intelligence-based virtual high throughput screening (vHTS) to identify novel small molecule effectors of human β-cardiac myosin. We test the top scoring compounds from vHTS in biochemical counter-screens and identify a novel chemical scaffold called ‘F10’ as a cardiac-specific low-micromolar myosin inhibitor. Biochemical and biophysical characterization in both isolated proteins and muscle fibers show that F10 stabilizes both the biochemical (i.e. super-relaxed state) and structural (i.e. interacting heads motif) OFF state of cardiac myosin, and reduces force and left ventricular pressure development in isolated myofilaments and Langendorff-perfused hearts, respectively. F10 is a tunable scaffold for the further development of a novel class of myosin modulators.

Abstract Background Non-memory-led dementias such as posterior cortical atrophy (PCA), primary progressive aphasia (PPA) and behavioural variant frontotemporal dementia (bvFTD) are low prevalent and often affect individuals under the age of 65. Tailored educational and support resources for caregivers of people living with these dementia phenotypes are scarce and unevenly distributed geographically. Web-based educational programmes are emerging as promising alternatives to improve caregiver self-efficacy and well-being. Here, we present the protocol of a study aiming to assess the feasibility of a co-produced online educational programme for caregivers of people living PCA, PPA and bvFTD: the Better Living with Non-memory-led Dementia programme. Methods A randomised controlled feasibility trial will be conducted on a sample of 30 caregivers of people living with PCA, PPA and bvFTD. Participants will be recruited among members of the support organisation Rare Dementia Support (based at UCL in the UK). The intervention group will be given access to an 8-week co-produced web-based educational programme consisting of 6 modules addressing education about PCA, PPA and bvFTD and support strategies for the person with dementia and for the caregiver. The control group will receive treatment as usual (TAU). Feasibility will be measured through feasibility of recruitment, clinical measurement tools and acceptability. Clinical measures will be used to assess preliminary efficacy and data on completion rates, missing data and variability used to decide on measures to be included in a full-scale trial. Allocation ratio will be 2:1 (intervention:control) stratified by diagnosis. Feasibility of recruitment and acceptability will be assessed. Clinical measures will be administered at baseline and 8-week and 3-month post-randomisation. The control group will be offered access to the intervention at the completion of data collection. Participants will be unblinded, and all measures will be self-reported online. Discussion Online-delivered educational programmes show potential for improving care competency of caregivers and may contribute to overcoming geographical inequalities in local provision of support services. This pilot study will inform a fully powered international trial to determine the effectiveness of Better Living with Non-memory-led Dementia. Trial registration This trial has been registered prospectively on the Clinical Trials Registry on 1st September 2022, registration number NCT05525377.

(1) Background: Tinnitus involves the conscious awareness of a tonal or composite noise for which there is no identifiable corresponding external acoustic source. For many people, tinnitus is a disorder associated with symptoms of emotional distress, cognitive dysfunction, autonomic arousal, behavioural changes, and functional disability. Many symptoms can be addressed effectively using education or cognitive behavioural therapy. However, there is no treatment that effectively reduces or alters tinnitus-related neurophysiological activity and thus the tinnitus percept. In this systematic review, we evaluated the effectiveness of neuromodulation therapies for tinnitus that explicitly target pathological synchronous neural activity. (2) Methods: Multiple databases were searched for randomised controlled trials of neuromodulation interventions for tinnitus in adults, with 24 trials included. The risk of bias was assessed, and where appropriate, meta-analyses were performed. (3) Results: Few trials used acoustic, vagal nerve, or transcranial alternating current stimulation, or bimodal stimulation techniques, with limited evidence of neuromodulation or clinical effectiveness. Multiple trials of transcranial direct current stimulation (tDCS) were identified, and a synthesis demonstrated a significant improvement in tinnitus symptom severity in favour of tDCS versus control, although heterogeneity was high. (4) Discussion: Neuromodulation for tinnitus is an emerging but promising field. Electrical stimulation techniques are particularly interesting, given recent advances in current flow modelling that can be applied to future studies.

Integrable field theories in two dimensions are known to originate as defect theories of 4d Chern-Simons and as symmetry reductions of the 4d anti-self-dual Yang-Mills equations. Based on ideas of Costello, it has been proposed in work of Bittleston and Skinner that these two approaches can be unified starting from holomorphic Chern-Simons in 6 dimensions. We provide the first complete description of this diamond of integrable theories for a family of deformed sigma models, going beyond the Dirichlet boundary conditions that have been considered thus far. Starting from 6d holomorphic Chern-Simons theory on twistor space with a particular meromorphic 3-form $\Omega$, we construct the defect theory to find a novel 4d integrable field theory, whose equations of motion can be recast as the 4d anti-self-dual Yang-Mills equations. Symmetry reducing, we find a multi-parameter 2d integrable model, which specialises to the $\lambda$-deformation at a certain point in parameter space. The same model is recovered by first symmetry reducing, to give 4d Chern-Simons with generalised boundary conditions, and then constructing the defect theory.

ImportanceEarly detection and intervention of hearing loss may mitigate negative effects on children's development. Children who were admitted to the neonatal intensive care unit (NICU) as babies are particularly susceptible to hearing loss and risk factors are vital for surveillance.Design, setting and participantsThis single-centre retrospective cohort study included data from 142 inborn infants who had been admitted to the NICU in a tertiary regional referral centre. Data were recorded for 71 infants with confirmed permanent congenital hearing loss hearing loss. To determine impact of NICU admission independently of prematurity, babies were individually matched with 71 inborn infants on gestational age, birthweight, and sex.Main outcomes and measuresNeonatal indicators were recorded for all children with permanent congenital hearing loss. Presence of UK and US risk factors for hearing loss were collected on the neonatal population with hearing loss and for the matched controls.ResultsA fifth (21%) of babies with hearing loss had one or more UK risk factors whereas most (86%) had at least one US risk factor. False positives would be evident if US factors were used whereas the matched controls had no UK risk factors. Ten babies who at birth had no UK or US risk factors did not have any significant neonatal indicators identified in their records, one was ventilated for one day and two had a genetic anomaly.Conclusions and relevanceCurrent risk factors for hearing loss we identified for follow-up in this high-risk group are highly specific for congenital hearing loss. UK risk factors were highly specific for hearing loss but not sensitive and conversely, US risk factors are sensitive but not specific so false positives would be recorded. A national study of neonatal indicators could provide the utility to test which combinations of risk factors provide high sensitivity without losing specificity.

Tinnitus Severity and Tinnitus Distress are frequently referenced and conflated constructs in research, measured using established tinnitus patient-reported outcome measures (PROs). Confusion regarding these constructs and their relation to fundamental scientific conceptions of tinnitus represents a threat to the validity of PROs as applied in tinnitus research, the conclusions that are reached when applying them, and subsequent progress of theory and clinical interventions for those experiencing tinnitus. Therefore, we critically review relevant literature, providing the Severity of Symptoms (SoS) and Correlates of Complaint (CoC) framework to link tinnitus theory to these constructs. We provide researchers with an overview of latent variable fundamentals (including distinctions between formative and reflective measures, and psychometric and clinimetric measurement traditions). We then provide a synthesis of the relationship between Tinnitus Severity and Tinnitus Distress, the SoS/CoC framework, and latent variable measurement to elucidate their distinctions. Finally, we take the Tinnitus Handicap Inventory (THI) as an exemplar of established tinnitus PROs and use study data (N = 200) to empirically evaluate the appropriateness of the THI as a reflective measure of Tinnitus Distress. Subsequently, conceptual and criterion mediation tests provide evidence that the THI is not a reflective measure of Tinnitus Distress according to the CoC conception and should be considered as a formative measure. Researchers should therefore consider whether established tinnitus PROs, such as the THI, are congruent with the scientific conceptions and subsequent theories that they aim to evaluate.

IntroductionTinnitus is a common disorder of the auditory system. Questionnaires are essential tools for clinical assessment and research. Whilst many questionnaires are available to measure different aspects of tinnitus complaint in adults, there is currently no self-report questionnaire measure of tinnitus that has been developed for or is suitable for use with children. This study describes the development of the first self-report measure of tinnitus impact for children aged 8–16 years old.MethodsTwo phases of questionnaire development were conducted. In Phase 1 children's tinnitus-related problems were elicited from interviews with children with tinnitus (n = 11; aged 9–16 years old), parents (n = 5), and clinicians (n = 8). Interview transcripts were analyzed using qualitative content analysis. Findings were combined with problems identified by the clinical co-authors, researchers, and clinicians in a conference workshop, and those previously reported in service evaluation of UK National Health Service pediatric tinnitus services and in a scoping review. From this, a conceptual framework of tinnitus impact on health-related quality of life in children was developed. Based on the conceptual framework, a 38-item pilot questionnaire was drafted. In Phase 2, content validity of the pilot questionnaire was assessed in cognitive interviews with six children who had tinnitus (aged 8–15 years old) and an online survey with clinicians working in pediatric tinnitus services (n = 8 services and 28 clinicians). Finally, readability assessments were conducted. Feedback led to iterative revisions to the questionnaire. The final questionnaire was named the Impact of Tinnitus in Children Questionnaire (iTICQ).ResultsThe iTICQ contains three scene setting (non-scoring) items, and 33 scoring items covering six domains of tinnitus impact: Sleep and Feeling Tired, Learning, Emotional Health, Hearing and Listening, Taking Part, and Relationships.ConclusionsThe iTICQ is a new self-report measure of tinnitus impact that can be self-completed by children aged 8–16 years old. It shows good content validity and can be used to measure problem severity across the domains of core relevance to children with tinnitus. Further validation studies and translations of the iTICQ are indicated to determine its psychometric properties in different child populations and to make it widely accessible.

Abstract Background and objectives Policies to support people living with dementia increasingly focus on strengths-based approaches, highlighting the importance of building resilience. This research responds to the lack of a suitable resilience measure for people with dementia. It develops a pool of items to inform a new measure of resilience for this population. Methods A conceptual model and associated data informed the item generation of the draft resilience measure. Regular meetings with professionals (n = 7) discussed response-scale formatting, content and face validity, leading to refinement and item reduction. Cognitive interviews with people living with dementia (n = 11) then examined the face and content validity of items and the suitability of response-scale formatting. These two phases informed subsequent revision and further item reduction of the resilience measure. Results The first item generation exercise led to 140 items. These were independently assessed by the professionals and this refinement reduced the measure to 63 items across 7 domains of the conceptual model (psychological strengths; practical approaches for adapting to life with dementia; continuing with hobbies, interests and activities; strong relationships with family and friends; peer support and education; participating in community activities; the role of professional support services). Cognitive interviews explored the 63 items with people living with dementia. Detailed feedback led to items removed due to difficulty with (a) understanding (N = 7); (b) answering (n = 11); (c) low preference for that item (n = 6); and (d) presence of a preferred item within a cluster of similar questions (n = 4). Items were amended to enhance clarity/conciseness (n = 19) leading to a final 37-item pool. Conclusion Established methods for measurement development included the expertise of people with dementia and led to the generation of a set of items for a new resilience measure that were understandable and acceptable to this target population. This 37-item pool reflects the conceptual understanding of resilience in dementia as being derived across individual, community and societal level resources.

Introduction: Befriending is one of the rehabilitative services embedded in the holistic approach adopted by Spirasi, the Irish National Centre for the Rehabilitation of Survivors of Torture. Their befriending programme offers survivors one-to-one companionship from trained volunteer befrienders. The literature suggests that befriending programmes can improve quality of life, provide emotional support and combat loneliness. However, there is little empirical research of the effectiveness of befriending programmes for torture survivors. Objective: The main objective was to explore, in complementary ways, the impact of the Spirasi befriending programme on befrienders and befriendees and to incorporate their voices into recommendations for optimising the service. Methods: The methodology consisted of five focus groups (two with befriendees, two with befrienders and one with both) and a portrait workshop facilitated by two community artists, where each befriending pair member created a portrait of their partner to express and visually explore the befriending relationship. Data comprised the focus group transcripts and written feedback on the portrait-creation process. Results: The themes identified in both data sets firmly ground the befriending programme in Spirasi’s holistic approach to recovery. For the focus group participants, befriending promotes integration; models trusting, kind and reciprocal relationships; combats loneliness and protects against suicide. They also highlighted the importance of regular befriender training, increasing the programme’s reach and developing a befriender community of practice. The portrait workshop was found to strengthen relationships and provide a context of normality, acceptance and shared humanity through compassionate and creative exchanges. Conclusions: This paper highlights the benefits of the befriending programme within Spirasi’s holistic approach and the importance of collaborative expressive arts activities in building befriending relationships. It provides recommendations for good befriending practice which are relevant to all organisations working with survivors of torture as well as those working with people seeking international protection more broadly.

Abstract Background To analyze the influence of the COVID-19 pandemic on the process of diagnosis and monitoring of drug-resistant pulmonary tuberculosis (TB) cases reported in the state of Paraná, Brazil, from 2015 to 2020. Methods Ecological study with quantitative approach. This study was based on diagnosed cases of pulmonary TB reported in the Notifiable Disease Information System in residents of Paraná; as well as through the number of confirmed cases of COVID-19 in the state epidemiological bulletin for the year 2020. The study data were analyzed using descriptive statistics. Results It was found that, although the number of reported pulmonary TB cases (drug-resistant and general) increased between 2015 and 2019, there was a drop in notification in 2020, the first year of the COVID-19 pandemic. The notification of TB cases was also influenced monthly during the year according to the increase in the number of COVID-19 cases. For cases of drug-resistant pulmonary TB, the provision of diagnostic tests and Directly Observed Treatment decreased by more than half in 2020, especially when compared to 2019. Conclusions In view of these findings, the influence of COVID-19 on the diagnosis and monitoring of drug-resistant and general pulmonary TB cases is evident, showing that the pandemic has compromised the advances of recent decades in achieving the goals established for its eradication by 2035.

Abstract Background Alzheimer’s disease (AD) has been associated with immune dysregulation in biomarker and genome-wide association studies (GWAS). GWAS hits include the genes encoding complement regulators clusterin (CLU) and complement receptor 1 (CR1), recognised as key players in AD pathology, and complement proteins have been proposed as biomarkers. Main body To address whether changes in plasma complement protein levels in AD relate to AD-associated complement gene variants we first measured relevant plasma complement proteins (clusterin, C1q, C1s, CR1, factor H) in a large cohort comprising early onset AD (EOAD; n = 912), late onset AD (LOAD; n = 492) and control (n = 504) donors. Clusterin and C1q were significantly increased (p

Abstract A neoadjuvant immunotherapy platform clinical trial allows for rapid evaluation of treatment-related changes in tumors and identifying targets to optimize treatment responses. We enrolled patients with resectable pancreatic adenocarcinoma into such a platform trial (NCT02451982) to receive pancreatic cancer GVAX vaccine with low-dose cyclophosphamide alone (Arm A; n = 16), with anti-PD-1 antibody nivolumab (Arm B; n = 14), and with both nivolumab and anti-CD137 agonist antibody urelumab (Arm C; n = 10), respectively. The primary endpoint for Arms A/B - treatment-related change in IL17A expression in vaccine-induced lymphoid aggregates - was previously published. Here, we report the primary endpoint for Arms B/C: treatment-related change in intratumoral CD8+ CD137+ cells and the secondary outcomes including safety, disease-free and overall survivals for all Arms. Treatment with GVAX+nivolumab+urelumab meets the primary endpoint by significantly increasing intratumoral CD8+ CD137+ cells (p = 0.003) compared to GVAX+Nivolumab. All treatments are well-tolerated. Median disease-free and overall survivals, respectively, are 13.90/14.98/33.51 and 23.59/27.01/35.55 months for Arms A/B/C. GVAX+nivolumab+urelumab demonstrates numerically-improved disease-free survival (HR = 0.55, p = 0.242; HR = 0.51, p = 0.173) and overall survival (HR = 0.59, p = 0.377; HR = 0.53, p = 0.279) compared to GVAX and GVAX+nivolumab, respectively, although not statistically significant due to small sample size. Therefore, neoadjuvant and adjuvant GVAX with PD-1 blockade and CD137 agonist antibody therapy is safe, increases intratumoral activated, cytotoxic T cells, and demonstrates a potentially promising efficacy signal in resectable pancreatic adenocarcinoma that warrants further study.

Abstract Background The public health measures imposed in many countries to contain the spread of COVID-19 resulted in significant suspensions in the provision of support and care for people with dementia. The negative effects of these measures have been extensively reported. However, little is known about the specific impact on people with young onset, non-memory-led and inherited dementias. This group may have experienced different challenges compared to those with late onset dementia given their non-memory phenotypes and younger age. We explored the impact of the first COVID-19 lockdown on people living with familial Alzheimer’s disease, behavioural variant frontotemporal dementia, familial frontotemporal dementia, dementia with Lewy bodies, posterior cortical atrophy and primary progressive aphasia and their carers in the UK and their self-reported strategies for coping. Methods This was a mixed methods study. An online survey was administered to people with dementia and family carers recruited via Rare Dementia Support. Free-text responses were analysed using framework analysis to identify key issues and themes. Results 184 carers and 24 people with dementia completed the survey. Overall, people with dementia experienced worsening of cognitive symptoms (70%), ability to do things (62%), well-being (57%) and changes to medication (26%) during lockdown. Carers reported a reduction in the support they received (55%) which impacted their own mental health negatively. Qualitative analysis of free-text responses shed light on how the disruption to routines, changes to roles and responsibilities, and widespread disconnection from friends, family and health and social care support varied according to phenotype. These impacts were exacerbated by a more general sense that precious time was being lost, given the progressive nature of dementia. Despite significant challenges, respondents demonstrated resilience and resourcefulness in reporting unexpected positives and strategies for adapting to confinement. Conclusions This study has highlighted the specific impacts of the COVID-19 restrictions on people with young onset, non-memory-led and inherited dementias, including behavioural variant frontotemporal dementia, primary progressive aphasia and posterior cortical atrophy, and their carers. The specific challenges faced according to diagnosis and the self-reported strategies speak to the importance of – and may inform the development of – tailored support for these underrepresented groups more generally. Visual abstract

Abstract Background Metformin, a medication for type 2 diabetes, has been linked to many non-diabetes health benefits including increasing healthy lifespan. Previous work has only examined the benefits of metformin over periods of less than ten years, which may not be long enough to capture the true effect of this medication on longevity. Methods We searched medical records for Wales, UK, using the Secure Anonymised Information Linkage dataset for type 2 diabetes patients treated with metformin (N = 129,140) and sulphonylurea (N = 68,563). Non-diabetic controls were matched on sex, age, smoking, and history of cancer and cardiovascular disease. Survival analysis was performed to examine survival time after first treatment, using a range of simulated study periods. Findings Using the full twenty-year period, we found that type 2 diabetes patients treated with metformin had shorter survival time than matched controls, as did sulphonylurea patients. Metformin patients had better survival than sulphonylurea patients, controlling for age. Within the first three years, metformin therapy showed a benefit over matched controls, but this reversed after five years of treatment. Interpretation While metformin does appear to confer benefits to longevity in the short term, these initial benefits are outweighed by the effects of type 2 diabetes when patients are observed over a period of up to twenty years. Longer study periods are therefore recommended for studying longevity and healthy lifespan. Evidence before this study Work examining the non-diabetes outcomes of metformin therapy has suggested that there metformin has a beneficial effect on longevity and healthy lifespan. Both clinical trials and observational studies broadly support this hypothesis, but tend to be limited in the length of time over which they can study patients or participants. Added value of this study By using medical records we are able to study individuals with Type 2 diabetes over a period of two decades. We are also able to account for the effects of cancer, cardiovascular disease, hypertension, deprivation, and smoking on longevity and survival time following treatment. Implications of all the available evidence We confirm that there is an initial benefit to longevity of metformin therapy, but this benefit does not outweigh the negative effect on longevity of diabetes. Therefore, we suggest that longer study periods are required for inference to be made about longevity in future research.

Abstract Integrable string sigma models on AdS3 backgrounds with 16 supersymmetries have the distinguishing feature that their superisometry group is a direct product. As a result the deformation theory of these models is particularly rich since the two supergroups in the product can be deformed independently. We construct bi-η and bi-λ deformations of two classes of ℤ 4 permutation supercoset sigma models, which describe sectors of the Green-Schwarz and pure-spinor string worldsheet theories on type II AdS3 backgrounds with pure R-R flux. We discuss an important limit of these models when one supergroup is undeformed. The associated deformed supergravity background should preserve 8 supersymmetries and is expected to have better properties than the full bi-deformation. As a step towards investigating the quantum properties of these models, we study the two-loop RG flow of the bosonic truncation of the bi-λ deformation.

Summary: Background: Daily methadone maintenance or buprenorphine treatment is the standard-of-care (SoC) medication for opioid use disorder (OUD). Subcutaneously injected, extended-release buprenorphine (BUP-XR) may be more effective—but there has been no superiority evaluation. Methods: This pragmatic, parallel-group, open-label, multi-centre, effectiveness superiority randomised, controlled, phase 3 trial was conducted at five National Health Service community-based treatment clinics in England and Scotland. Participants (adults aged ≥ 18 years; all meeting DSM-5 diagnostic criteria for moderate or severe OUD at admission to their current maintenance treatment episode) were randomly assigned (1:1) to receive continued daily SoC (liquid methadone (usual dose range: 60–120 mg) or sublingual/transmucosal buprenorphine (usual dose range: 8–24 mg) for 24 weeks; or monthly BUP-XR (Sublocade;® two injections of 300 mg, then four maintenance injections of 100 mg or 300 mg, with maintenance dose selected by response and preference) for 24 weeks. In the intent-to-treat population (senior statistician blinded to blinded to treatment group allocation), and with a seven-day grace period after randomisation, the primary endpoint was the count of days abstinent from non-medical opioids between days 8–168 (i.e., weeks 2–24; range: 0–161 days). Safety was reported for the intention-to- treat population. Adopting a broad societal perspective inclusive of criminal justice, NHS and personal social service costs, a trial-based cost-utility analysis estimated the Incremental Cost-effectiveness Ratio (ICER) per quality-adjusted life year (QALY) of BUP-XR versus SoC at the National Institute for Health and Care Excellence threshold. The study was registered EudraCT (2018-004460-63) and ClinicalTrials.gov (NCT05164549), and is completed. Findings: Between Aug 9, 2019 and Nov 2, 2021, 314 participants were randomly allocated to receive SoC (n = 156) or BUP-XR (n = 158). Participants were abstinent from opioids for an adjusted mean of 104.37 days (standard error [SE] 9.89; range: 0–161 days) in the SoC group and an adjusted mean of 123.43 days (SE 4.76; range: 24–161 days) in the BUP-XR group (adjusted incident rate ratio [IRR] 1.18, 95% confidence interval [CI] 1.05–1.33; p-value 0.004). The incidence of any adverse event was higher in the BUP-XR group than the SoC group (128 [81.0%] of 158 participants versus 67 [42.9%] of 156 participants, respectively—most commonly rapidly-resolving (mild–moderate range) pain from drug administration in the BUP-XR group (121 [26.9%] of 450 adverse events). There were 11 serious adverse events (7.0%) in the 158 participants in the BUP-XR group, and 18 serious adverse events (11.5%) in the 156 participants in the SoC group—none judged to be related to study treatment. The BUP-XR treatment group had a mean incremental cost of £1033 (95% central range [CR] −1189 to 3225) and was associated with a mean incremental QALY of 0.02 (95% CR 0.00–0.05), and an ICER of £47,540 (0.37 probability of being cost-effective at the £30,000/QALY gained willingness-to-pay threshold). However, BUP-XR dominated the SoC among participants who were rated more severe at study baseline, and among participants in maintenance treatment for more that 28 days at study enrolment. Interpretation: Evaluated against the daily oral SoC, monthly BUP-XR is clinically superior, delivering greater abstinence from opioids, and with a comparable safety profile. BUP-XR was not cost-effective in a base case cost-utility analysis using the societal perspective, but it was more effective and less costly (dominant) among participants with more severe OUD, or those whose current treatment episode was longer than 28 days. Further trials are needed to evaluate if BUP-XR is associated with better clinical and health economic outcomes over the longer term. Funding: Indivior.

Objective Prehospital rule-out of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) in low-risk patient with a point-of-care troponin measurement reduces healthcare costs with similar safety to standard transfer to the hospital. Risk stratification is performed identical for men and women, despite important differences in clinical presentation, risk factors and age between men and women with NSTE-ACS. Our aim was to compare safety and healthcare costs between men and women in prehospital identified low-risk patients with suspected NSTE-ACS.Methods In the Acute Rule-out of non-ST-segment elevation acute coronary syndrome in the (pre)hospital setting by HEART (History, ECG, Age, Risk factors and Troponin) score assessment and a single poInt of CAre troponin randomised trial, the HEAR (History, ECG, Age and Risk factors) score was assessed by ambulance paramedics in suspected NSTE-ACS patients. Low-risk patients (HEAR score ≤3) were included. In this substudy, men and women were compared. Primary endpoint was 30-day major adverse cardiac events (MACE), secondary endpoints were 30-day healthcare costs and the scores for the HEAR score components.Results A total of 863 patients were included, of which 495 (57.4%) were women. Follow-up was completed in all patients. In the total population, MACE occurred in 6.8% of the men and 1.6% of the women (risk ratio (RR) 4.2 (95% CI 1.9 to 9.2, p

Background Based on 2021 data, Nigeria had the second largest number of zero-dose children globally estimated at over 2.25 million, concentrated in the northern part of the country due to factors some of which are sociocultural. This study analysed the impact of the COVID-19 pandemic and response on childhood vaccination in Northern Nigeria.Methods Using a mixed methods sequential study design in the most populous northern states of Kaduna and Kano, quantitative routine immunisation data for the period 2018–2021 and qualitative data collected through 16 focus group discussions and 40 key informant interviews were used. An adaptation of the socioecological model was used as a conceptual framework. Mean vaccination coverages and test of statistical difference in childhood vaccination data were computed. Qualitative data were coded and analysed thematically.Results Mean Penta 1 coverage declined in Kaduna from 69.88% (SD=21.02) in 2018 to 59.54% (SD=19.14%) by 2021, contrasting with Kano where mean Penta 1 coverage increased from 51.87% (SD=12.61) to 56.32% (SD=17.62%) over the same period. Outreaches and vaccination in urban areas declined for Kaduna state by 10% over the pandemic period in contrast to Kano state where it showed a marginal increase. The two states combined had an estimated 25% of the country’s zero-dose burden in 2021. Lockdowns, lack of transport and no outreaches which varied across the states were some of the factors mentioned by participants to have negatively impacted childhood vaccination. Special vaccination outreaches were among the recommendations for ensuring continued vaccination through a future pandemic.Conclusion While further interrogating the accuracy of denominator estimates for the urban population, incorporating findings into pandemic preparedness and response will ensure uninterrupted childhood vaccination during emergencies. Addressing the identified issues will be critical to achieving and sustaining universal childhood vaccination in Nigeria.

Abstract Introduction Peer support can help navigate the isolation and psychological strain frequently experienced by youth living with chronic illness. Yet, data are lacking on the impact of providing support for youth living with mixed chronic conditions. We assessed the acceptability, feasibility and preliminary mental health impacts of a clinic‐based peer support group for South African youth living with chronic illnesses, including HIV. Methods This mixed‐methods pilot study (September 2021–June 2022) enrolled 58 young patients, ages 13–24, at an urban hospital in Cape Town, South Africa. In‐depth interviews elicited the perspectives of 20 young people in relation to their participation in the Better Together programme, a recurring clinic‐based peer support group for patients with mixed chronic illnesses. Self‐reported resilience, attitudes towards illness, stigma and mental health were captured via established measures. T‐tests and multivariate analysis of variance compared psychosocial outcomes for 20 group participants and 38 control patients, controlling for socio‐demographic characteristics at enrolment. Logistic regression analyses estimated the predicted probability of a positive depression or anxiety screening given peer group participation. Results All interviewees valued being able to compare treatment regimens and disease management habits with peers living with different conditions. Adolescents living with HIV stated that understanding the hardships faced by those with other conditions helped them accept their own illness and lessened feelings of isolation. Compared to patients who did not participate in Better Together, those who attended ≥5 groups had statistically significantly higher individual‐level resilience, a more positive attitude towards their illness(es), lower internalised stigma and a more positive self‐concept. The probability of being screened positive for depression was 23.4 percentage points lower (95% CI: 1.5, 45.3) for Better Together participants compared to controls; the probability of a positive anxiety screening was 45.8 percentage points lower (95% CI: 18.1, 73.6). Conclusions Recurring, clinic‐based peer support groups that integrate youth living with HIV and other chronic diseases are novel. Group sustainability will depend on the commitment of experienced peer leaders and providers, routine scheduling and transportation support. A fully powered randomised trial is needed to test the optimal implementation and causal mental health effects of the Better Together model.

Summary: Liver sinusoidal endothelial cells (LSEC) undergo significant phenotypic change in chronic liver disease (CLD), and yet the factors that drive this process and the impact on their function as a vascular barrier and gatekeeper for immune cell recruitment are poorly understood. Plasmalemma-vesicle-associated protein (PLVAP) has been characterized as a marker of LSEC in CLD; notably we found that PLVAP upregulation strongly correlated with markers of tissue senescence. Furthermore, exposure of human LSEC to the senescence-associated secretory phenotype (SASP) led to a significant upregulation of PLVAP. Flow-based assays demonstrated that SASP-driven leukocyte recruitment was characterized by paracellular transmigration of monocytes while the majority of lymphocytes migrated transcellularly. Knockdown studies confirmed that PLVAP selectively supported monocyte transmigration mediated through PLVAP’s impact on LSEC permeability by regulating phospho-VE-cadherin expression and endothelial gap formation. PLVAP may therefore represent an endothelial target that selectively shapes the senescence-mediated immune microenvironment in liver disease.