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Dent disease is a rare X-linked tubulopathy that is characterized by low-molecular-weight (LMW) proteinuria associated with hypercalciuria, which may lead to nephrolithiasis, nephrocalcinosis, and kidney failure between the 3rd and the 5th decades of life in 30-80% of affected males. The disease is most often associated with various manifestations of proximal tubular dysfunction. Affected individuals may present nephrotic range proteinuria which may be misinterpreted and cause diagnostic delay. Due to its rarity, there is limited evidence to guide diagnosis and management. This clinical practice recommendations summarize the current knowledge on Dent disease and provide guidance for diagnosis and management. The recommendations are based on a systematic search of the literature and were endorsed by a Delphi procedure among stakeholders in the field as well as the respective ERA and ESPN working groups., (© The Author(s) 2025. Published by Oxford University Press on behalf of the ERA.)

Over the past two decades there has been increased interest in orphan drug development for rare diseases. However, hurdles to clinical trial design for these disorders remain. This phase 1a/1b study addressed several challenges, while evaluating the safety and tolerability of the novel oral molecule KL1333 in healthy volunteers and subjects with primary mitochondrial disease. KL1333 aims to normalize the NAD+:NADH ratio that is critical for ATP production. The trial incorporated innovative design elements with potential translatability to other rare diseases including patient involvement, adaptive design and exploratory objectives, all of which have subsequently informed the protocol of an ongoing phase 2, pivotal efficacy study of KL1333. Results indicate KL1333 is safe and well tolerated, with dose-dependent gastrointestinal side effects, and validate potential novel outcome measures in primary mitochondrial disease including the 30-s Sit to Stand, and the patient-reported fatigue scales. Importantly, the data from the trial support efficacy of KL1333 based on improvements in fatigue and functional strength and endurance. Furthermore, the study highlights the value in using phase 1 studies to capture data that helps optimize later phase efficacy trial design., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: The concept of cognitive reserve may explain inter-individual differences in susceptibility to neuropathological changes. Studies suggest that experiences over a lifetime impact on cognitive reserve, and it is hypothesised that following a dementia diagnosis, greater reserve levels are linked to accelerated disease progression., Objective: To investigate the longitudinal impact of cognitive reserve on cognitive and functional abilities, physical activity and quality of life in people with dementia., Design: Longitudinal cohort design., Setting and Participants: Participants were 1537 people with mild-to-moderate dementia at baseline, 1183 at 12 months follow-up and 851 at 24 months follow-up, from the IDEAL study., Methods: A comprehensive latent measure of cognitive reserve incorporated domains from all stages of life: education, occupational attainment and later-life engagement in leisure activities. The impact of cognitive reserve on cognition, functional abilities, physical activity and quality of life at baseline and over time was investigated using latent growth curve modelling., Results: Higher cognitive reserve was associated with better cognition, fewer functional difficulties, more physical activity and better quality of life at baseline but was associated with accelerated cognitive decline and greater dependence over time. After 2 years, those with higher initial reserve were estimated to still have better cognition than those with low reserve., Conclusions: Cognitive reserve may be important in initially delaying dementia progression but is linked with accelerated deterioration once dementia becomes clinically evident, likely because of the more advanced neuropathological stage of the condition. Engagement in leisure activities is a potentially modifiable domain of cognitive reserve warranting further investigation., (© The Author(s) 2025. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Background: As populations age, low- and middle-income countries (LMICs) are rapidly adapting hospital services to meet the needs of older populations. This systematic review aimed to establish the prevalence of frailty and pre-frailty amongst older people admitted to hospital in LMICs, and to compare levels with existing estimates for high-income settings., Methods: Databases Medline, Embase, CINAHL and PsychInfo were searched, and results were manually screened by two researchers. Included studies were cross-sectional or cohort design and reported data from hospital inpatients, aged ≥60 years, in LMICs, using validated methods for identifying frailty. Risk of bias was assessed by two researchers using the Joanna Briggs Institute checklist. Where possible, results were synthesised using meta-analysis., Results: Twenty-nine studies were included, all reporting data from middle-income countries. Physical frailty tools were the most common, with Fried's phenotype and the FRAIL Scale being the most often used methods of assessment. The pooled estimate of the prevalence of frailty was 39.1% [95% confidence interval (CI) 31.9-46.6%] comprising data from 23 311 older inpatients. For pre-frailty, prevalence was 40.0% (95% CI 25.1-51.4%) from 6954 individuals., Discussion: Due to the paucity of eligible studies and their geographical distribution, these pooled estimates are only representative of the burden of frailty in select middle-income settings (particularly China). Future research should seek to establish the prevalence of frailty in hospitals in low-income countries, and to assess clinical outcomes by frailty status, in order to develop bespoke clinical tools and to aid the planning of future geriatric services., (© The Author(s) 2025. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Acquired angioedema due to C1-inhibitor deficiency (AAE-C1-INH) is very rare compared to its prototype, hereditary angioedema. An updated characterisation of the AAE-C1-INH cohort in UK is required to inform management., Objectives: To describe the disease burden of AAE-C1-INH, long-term prophylaxis (LTP) and the clinical, immunochemical and treatment profiles of AAE-associated diseases in UK., Method: Retrospective data on 117 AAE-C1-INH patients were collected using a national survey proforma across 25/34 Adult Clinical Immunology and Allergy centres in UK. Other European cohorts were compared., Results: Median age at AAE-C1-INH diagnosis was 65 years with 3.4% of patients diagnosed below 40 years. The median delay in diagnosis was one year. Antifibrinolytics and attenuated androgens showed comparable efficacy as LTP 88.9% and 89.5%, respectively. A haematological disorder was identified in 83.8% AAE-C1-INH patients compared to 3.4% autoimmune diseases. The predominant haematological disorders were splenic marginal zone lymphoma (SZL) 34% followed by MGUS 16%. The severity of angioedema did not depend on the associated disease. Anti-C1INH-autoantibodies testing was limited at 23.1%. Rituximab monotherapy was effective in treating 9/9 SZL and 1/2 MGUS-associated AAE-C1-INH. Rituximab efficacy was independent of anti-C1INH-autoantibodies detection with response in 3/3 seronegative and 4/4 seropositive patients., Conclusion: The diagnosis of AAE-C1-INH should not be overlooked below the age of 40 years. The choice of oral LTP should be informed by propensity to side-effects. B-cell depletion could be considered in treating monoclonal B cell disorder-associated-AAE-C1-INH in the absence of haematological indications. Further studies are required to address the clinical utility of anti-C1INH-autoantibodies., (© The Author(s) 2025. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Brain stimulation has, for many decades, been considered as a potential solution for the unmet needs of the many people living with drug-resistant epilepsy. Clinically, there are several different approaches in use, including vagus nerve stimulation (VNS), deep brain stimulation of the thalamus, and responsive neurostimulation (RNS). Across populations of patients, all deliver reductions in seizure load and SUDEP risk, yet do so variably, and the improvements seem incremental rather than transformative. In contrast, within the field of experimental neuroscience, the transformational impact of optogenetic stimulation is evident; by providing a means to control subsets of neurons in isolation, it has revolutionized our ability to dissect out the functional relations within neuronal microcircuits. It is worth asking, therefore, how pre-clinical optogenetics research could advance clinical practice in epilepsy? Here, we review the state of the clinical field, and the recent progress in pre-clinical animal research. We report various breakthrough results, including the development of new models of seizure initiation, its use for seizure prediction, and for fast, closed-loop control of pathological brain rhythms, and what these experiments tell us about epileptic pathophysiology. Finally, we consider how these pre-clinical research advances may be translated into clinical practice., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Nonattendance at colonoscopy is associated with reduced colorectal cancer (CRC) survival., Purpose: The aim of this research was to quantify barriers to colonoscopy and test the effectiveness of behavior change techniques (BCTs) to address them., Methods: Two studies were conducted. In the first study, participants were asked to imagine their next CRC screening result was abnormal, and were presented with the standard abnormal result letter used in the English CRC Screening Programme. Participants then completed a short survey. Multivariate regression tested associations between perceived barriers and intentions. In the second study, participants were randomly presented with a modified version of the abnormal results letter, which incorporated one or more BCTs, designed to target barriers identified in study 1, using a 28 factorial design. Participants then completed the same survey used in study 1. Multivariate regression tested the effectiveness of the BCTs to modify target barriers and intentions., Results: In study 1, 5 items were associated with intentions, namely "Lack of understanding that CRC can be asymptomatic," "Perceived importance of screening," "Transport/travel," "Shared decision making and family influenced participation," and "Fear of pain and discomfort" (all P's < .05). In study 2, the inclusion of a social support message, targeting "shared decision-making and family influenced participation," facilitated independent decision making and increased intentions (both P's < .05). There was no evidence to support the remaining 7 BCTs to modify barriers or intentions (all P's < .05)., Conclusions: Inclusion of a social support message facilitated independent decision-making and improved intentions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Behavioral Medicine.)

Competing Interests: Conflicts of interest R.N.M. is chair of the AI Working Party Group at the British Association of Dermatologists and an Associate Editor of the BJD; N.R. is chair of the British Society of Investigative Dermatology. The other authors declare no conflicts of ­interest.

Human induced pluripotent stem cells (iPSCs) provide powerful cellular models of Alzheimer's disease (AD) and offer many advantages over non-human models, including the potential to reflect variation in individual-specific pathophysiology and clinical symptoms. Previous studies have demonstrated that iPSC-neurons from individuals with Alzheimer's disease (AD) reflect clinical markers, including β-amyloid (Aβ) levels and synaptic vulnerability. However, despite neuronal loss being a key hallmark of AD pathology, many risk genes are predominantly expressed in glia, highlighting them as potential therapeutic targets. In this work iPSC-derived astrocytes were generated from a cohort of individuals with high versus low levels of the inflammatory marker YKL-40, in their cerebrospinal fluid (CSF). iPSC-derived astrocytes were treated with exogenous Aβ oligomers and high content imaging demonstrated a correlation between astrocytes that underwent the greatest morphology change from patients with low levels of CSF-YKL-40 and more protective APOE genotypes. This finding was subsequently verified using similarity learning as an unbiased approach. This study shows that iPSC-derived astrocytes from AD patients reflect key aspects of the pathophysiological phenotype of those same patients, thereby offering a novel means of modelling AD, stratifying AD patients and conducting therapeutic screens., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Due to their anatomical locations, optic pathway gliomas (OPGs) can rarely be cured by resection. Given the importance of preserving visual function, we analyzed radiological and visual acuity (VA) outcomes for the type II RAF inhibitor tovorafenib in the OPG subgroup of the phase 2 FIREFLY-1 trial., Methods: FIREFLY-1 investigated the efficacy (arm 1, n=77), safety, and tolerability (arms 1/2) of tovorafenib (420 mg/m2 once weekly; 600 mg maximum) in patients with BRAF-altered relapsed/refractory pediatric low-grade glioma (pLGG). In this post hoc analysis, anti-tumor activity and VA were analyzed in arm 1 patients with OPG. Anti-tumor activity was independently assessed per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG), Response Assessment in Pediatric Neuro-Oncology-LGG (RAPNO) and RANO-LGG criteria. The data cutoff was June 5, 2023., Results: Forty-two of 77 patients had OPGs; 35 of 42 had ≥2 VA assessments. The overall response rate in the OPG subgroup according to RANO-HGG, RAPNO and RANO-LGG criteria were 64%, 50%, and 55%, with clinical benefit rates 95%, 88%, and 90%, respectively. VA per patient was preserved for 80% of patients; 31% demonstrated improved VA; VA per eye was preserved in 87%, with 27% improving. The safety profile in the arm 1 OPG subgroup was similar to the overall FIREFLY-1 safety analysis set., Conclusions: Tovorafenib demonstrated anti-tumor activity in relapsed/refractory BRAF-altered OPG across radiological assessment criteria and was generally well tolerated. Importantly, vision remained stable or improved in most patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Aims: Diabetes mellitus (diabetes) is common amongst patients with non-ST-segment elevation myocardial infarction (NSTEMI). We describe presentation, care, and outcomes of patients admitted with NSTEMI by diabetes status., Methods and Results: Prospective cohort study including 2928 patients (1104 with prior diabetes, 1824 without) admitted to hospital with NSTEMI from 287 centres in 59 countries. Quality of care was evaluated based on 12 guideline-recommended care interventions. Outcomes included in-hospital acute heart failure, cardiogenic shock, repeat myocardial infarction, stroke/transient ischaemic attack (TIA), BARC Type ≥ 3 bleeding and death, as well as 30-day mortality. Patients with diabetes had higher comorbidity burden and more frequently presented with Killip Class II-IV heart failure (10.2% vs. 3.7%, P < 0.001), haemodynamic instability (7.1% vs. 3.7%, P < 0.001), and ongoing chest pain (43.1% vs. 37.0%, P < 0.001), than those without diabetes. Overall, care quality received was similar by diabetes status (60.0% vs. 60.5% received ≥ 80% of eligible care interventions, P = 0.786), but patients with diabetes experienced higher rates of in-hospital acute heart failure (15.3% vs. 6.8% P < 0.001), cardiogenic shock (4.5% vs. 2.5%, P = 0.002), stroke/TIA (2.0% vs. 0.8%, P = 0.006), and death (2.5% vs. 1.4%, P = 0.022), and higher 30-day mortality (3.3% vs. 2.0%, P = 0.025). Of NSTEMI with diabetes, only 1.9% and 9.0% received prescription for glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors, respectively, on discharge, and only 45.9% were referred for cardiac rehabilitation., Conclusion: NSTEMI patients with diabetes, compared with those without, present more clinically unwell and have worse outcomes despite receiving equal quality of care. Prescription of cardiovascular-protective glycaemic agents is an actionable target to reduce risk of further events., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: To develop a suite of quality indicators (QIs) for the evaluation of the care and outcomes for adults undergoing transcatheter aortic valve implantation (TAVI)., Methods and Results: We followed the European Society of Cardiology (ESC) methodology for the development of QIs. Key domains were identified by constructing a conceptual framework for the delivery of TAVI care. A list of candidate QIs was developed by conducting a systematic review of the literature. A modified Delphi method was then used to select the final set of QIs. Finally, we mapped the QIs to the EuroHeart (European Unified Registries on Heart Care Evaluation and Randomized Trials) data standards for TAVI to ascertain the extent to which the EuroHeart TAVI registry captures information to calculate the QIs. We formed an international group of experts in quality improvement and TAVI, including representatives from the European Association of Percutaneous Cardiovascular Interventions, the European Association of Cardiovascular Imaging, and the Association of Cardiovascular Nursing and Allied Professions. In total, 27 QIs were selected across 8 domains of TAVI care, comprising 22 main (81%) and 5 secondary (19%) QIs. Of these, 19/27 (70%) are now being utilized in the EuroHeart TAVI registry., Conclusion: We present the 2023 ESC QIs for TAVI, developed using a standard methodology and in collaboration with ESC Associations. The EuroHeart TAVI registry allows calculation of the majority of the QIs, which may be used for benchmarking care and quality improvement initiatives., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have only been described in six individuals carrying five biallelic predicted loss of function (pLOF) variants. To define the phenotypic effects of RBL2 mutations in detail, we identified and clinically characterized a cohort of 35 patients from 20 families carrying pLOF variants in RBL2, including fifteen new variants that substantially broaden the molecular spectrum. The clinical presentation of affected individuals is characterized by a range of neurological and developmental abnormalities. Global developmental delay and intellectual disability were uniformly observed, ranging from moderate to profound and involving lack of acquisition of key motor and speech milestones in most patients. Disrupted sleep was also evident in some patients. Frequent features included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements, seizures, and non-specific dysmorphic features. Neuroimaging features included cerebral atrophy, white matter volume loss, corpus callosum hypoplasia and cerebellar atrophy. In parallel, we used the fruit fly, Drosophila melanogaster, to investigate how disruption of the conserved RBL2 orthologue Rbf impacts nervous system function and development. We found that Drosophila Rbf LOF mutants recapitulate several features of patients harbouring RBL2 variants, including developmental delay, alterations in head and brain morphology, locomotor defects, and perturbed sleep. Surprisingly, in addition to its known role in controlling tissue growth during development, we found that continued Rbf expression is also required in fully differentiated post-mitotic neurons for normal locomotion in Drosophila, and that adult-stage neuronal re-expression of Rbf is sufficient to rescue Rbf mutant locomotor defects. Taken together, our study provides a clinical and experimental basis to understand genotype-phenotype correlations in an RBL2-linked neurodevelopmental disorder, and suggests that restoring RBL2 expression through gene therapy approaches may ameliorate some symptoms caused by RBL2 pLOF., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Context: Between 10% and 15% of people with hypothyroidism experience persistent symptoms, despite achieving biochemical euthyroidism. The underlying causes are unclear. Type D personality (a vulnerability factor for general psychological distress) is associated with poor health status and symptom burden but has not been studied in people with hypothyroidism., Objective: To investigate type D personality in hypothyroidism and explore associations with other characteristics and patient-reported outcomes., Design: Multinational, cross-sectional survey., Setting: Online., Participants: Individuals with self-reported, treated hypothyroidism., Intervention: Questionnaire., Main Outcome Measures: Type D personality and associations with baseline characteristics, control of the symptoms of hypothyroidism by medication, satisfaction with care and treatment of hypothyroidism, impact of hypothyroidism on everyday living., Results: A total of 3915 responses were received, 3523 of which were valid. The prevalence of type D personality was 54.2%. Statistically significant associations were found between type D personality and several respondent characteristics (age, marital status, ethnicity, household income, comorbidities, type of treatment for hypothyroidism, most recent TSH level), anxiety, depression, somatization, poor control of the symptoms of hypothyroidism by medication, dissatisfaction with care and treatment of hypothyroidism, and a negative impact of hypothyroidism on everyday living)., Discussion: Our study found a high prevalence of type D personality among people with hypothyroidism who responded to the survey. Type D personality may be an important determinant of dissatisfaction with treatment and care among people with hypothyroidism. Our findings require independent confirmation. Close collaboration between the disciplines of thyroidology and psychology is likely to be key in progressing our understanding in this area., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Observational studies have reported that hearing aid (HA) use is associated with a reduced risk of dementia diagnosis, suggesting a possible protective effect. However, extant observational studies do not explicitly model causal effects, while randomised controlled trials on the effect of HA on dementia exhibit short follow-up. Here we used self-report, hearing tests, and healthcare records in UK Biobank to design a hypothetical intervention for the effect of HA use on the risk of dementia diagnosis in people with incident hearing loss (HL). HA users exhibited a higher risk of dementia diagnosis than non-users (RR=1.43, 95%CI=1.08-1.88). Associations between HA use and dementia diagnosis were robust across sensitivity analyses (RRs: 1.34-1.59) but adjustment for primary healthcare utilisation (0.77, 0.44-1.33) or primary and secondary care utilisation (0.68, 0.39-1.18) substantially decreased the observed effect. The decrease in effect estimates upon adjustment for primary (1.30, 0.95-1.78) and primary and secondary healthcare utilisation (1.30, 0.94-1.78) was smaller when participants with relatively early diagnoses of HL were included in the sample compared to when they were not. While the findings are not conclusive, they suggest residual confounding by healthcare utilisation and dating of HL diagnosis in participants without primary care data in UK Biobank., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Background and Aims: Current guidelines recommend 6 h of solid food and 2 h of clear liquid fasting for patients undergoing cardiac procedures with conscious sedation. There are no data to support this practice, and previous single-centre studies support the safety of removing fasting requirements. The objective of this study was to determine the non-inferiority of a no-fasting strategy to fasting prior to cardiac catheterization procedures which require conscious sedation., Methods: This is a multicentre, investigator-initiated, non-inferiority, randomized trial conducted in Australia with a prospective open-label, blinded endpoint design. Patients referred for coronary angiography, percutaneous coronary intervention, or cardiac implantable electronic device (CIED)-related procedures were enrolled. Patients were randomized 1:1 to fasting as normal (6 h solid food and 2 h clear liquid) or no-fasting requirements (encouraged to have regular meals but not mandated to do so). Recruitment occurred from 2022 to 2023. The primary outcome was a composite of aspiration pneumonia, hypotension, hyperglycaemia, and hypoglycaemia assessed with a Bayesian approach. Secondary outcomes included patient satisfaction score, new ventilation requirement (non-invasive and invasive), new intensive care unit admission, 30-day readmission, 30-day mortality, 30-day pneumonia., Results: A total of 716 patients were randomized with 358 in each group. Those in the fasting arm had significantly longer solid food fasting (13.2 vs. 3.0 h, Bayes factor >100, indicating extreme evidence of difference) and clear liquid fasting times (7.0 vs. 2.4 h, Bayes factor >100). The primary composite outcome occurred in 19.1% of patients in the fasting arm and 12.0% of patients in the no-fasting arm. The estimate of the mean posterior difference in proportions with credibility interval (CI) in the primary composite outcome was -5.2% (95% CI -9.6 to -.9), favouring no fasting. This result confirms the non-inferiority (posterior probability >99.5%) and superiority (posterior probability 99.1%) of no fasting for the primary composite outcome. The no-fasting arm had improved patient satisfaction scores with a posterior mean difference of 4.02 points (95% CI 3.36-4.67, Bayes factor >100). Secondary outcome events were observed to be similar., Conclusions: In patients undergoing cardiac catheterization and CIED-related procedures, no fasting was non-inferior and superior to fasting for the primary composite outcome of aspiration pneumonia, hypotension, hyperglycaemia, and hypoglycaemia. Patient satisfaction scores were significantly better with no fasting. This supports removing fasting requirements for patients undergoing cardiac catheterization laboratory procedures that require conscious sedation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Longitudinal studies of thyroid function have demonstrated differing results. It remains unclear whether changes in thyroid function affect the diagnosis of subclinical thyroid dysfunction with ageing., Methods: Survivors of the Whickham cohort study were evaluated on two occasions between the years 2008-2012 and 2016-2019. Serum thyrotropin (TSH), free thyroxine (FT4), free triiodothyronine (FT3) and thyroid peroxidase antibody (TPOAb) were measured on both occasions using the same assay under similar conditions. Individuals with known thyroid disease or on medications affecting thyroid function were excluded. Comorbidities were noted, functional mobility was assessed by the timed up-and-go test and muscle function was evaluated by the hand grip strength test., Results: In 204 individuals (mean age 77.0 [±6.6] years, 114 [56%] female), followed over a median (IQR) of 7.8 (7.3-8.2) years, serum TSH increased by 0.29 mU/L (12.4%), FT3 and TPOAb reduced by 0.1 pmol/L (-2.1%) and 0.6 U/L (-11.2%) and there were no significant changes in FT4 levels. The calculated upper limit of serum TSH increased over the follow-up period from 4.74 mU/L to 6.28 mU/L. The relationship between serum TSH and FT4 at both time points were not significantly different. Utilising standard laboratory reference ranges, the prevalence of subclinical hypothyroidism increased from 3.5% at baseline to 9.0% at follow-up. However, adopting a visit-specific TSH reference range reduced the prevalence of subclinical hypothyroidism at both time points to 2.0%., Discussion: Thyroid function demonstrates subtle but significant changes with age. Utilising standard reference ranges tends to increase the diagnosis of subclinical hypothyroidism in older euthyroid individuals. Our data suggest that adopting age-appropriate TSH reference ranges may reduce the risk of diagnosing and (potentially unnecessarily) treating subclinical hypothyroidism., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Subclinical thyroid dysfunction (ScTD) comprising subclinical hypothyroidism (SHypo) and subclinical hyperthyroidism (SHyper) has been associated with increased risk for cardiovascular events., Objective: To assess associations between ScTD and cardiovascular risk factors (cvRFs) according to age and sex., Design and Setting: Pooled individual participant data analysis of large prospective cohort studies from the Thyroid Studies Collaboration., Participants: Aged 18 to 103 years with SHypo (TSH >4.50 mU/l, normal fT4) and SHyper (TSH <0.45 mU/l, normal fT4) vs. euthyroid (TSH 0.45-4.50 mU/l)., Interventions: None as this is an observational study., Main Outcome Measures: cvRFs, i.e. blood pressure, lipid levels, hs-CRP., Results: Of 69,006 participants (mean age 62 years, 55% women, 25% current smokers) from 16 international cohorts, 3,748 (5.4%) had SHypo and 3,428 (5.0%) had SHyper. In both women and men, systolic and diastolic BP were similar regardless of thyroid status. Exceptions were lower diastolic BP in women with SHyper compared to euthyroids (adjusted mean difference [aMD] -1.3 mmHg, 95%CI -2.0 to -0.5), and lower systolic BP in men with SHyper compared to euthyroids (aMD -3.1 mmHg, 95%CI -4.8 to-1.4). In both women and men, lipid levels (total, HDL, LDL cholesterol, triglycerides) and hs-CRP were similar regardless of thyroid status. The only exception were women with SHyper who had a lower LDL cholesterol compared to euthyroids (aMD -0.17 mmol/l, 95%CI -0.29 to -0.05)., Conclusions: Participants with ScTD and euthyroids have similar cvRFs and differences are arguably too small to explain the increased cardiovascular risk in ScTD observed in previous studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Specialized or secondary metabolites are small molecules of biological origin, often showing potent biological activities with applications in agriculture, engineering and medicine. Usually, the biosynthesis of these natural products is governed by sets of co-regulated and physically clustered genes known as biosynthetic gene clusters (BGCs). To share information about BGCs in a standardized and machine-readable way, the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard and repository was initiated in 2015. Since its conception, MIBiG has been regularly updated to expand data coverage and remain up to date with innovations in natural product research. Here, we describe MIBiG version 4.0, an extensive update to the data repository and the underlying data standard. In a massive community annotation effort, 267 contributors performed 8304 edits, creating 557 new entries and modifying 590 existing entries, resulting in a new total of 3059 curated entries in MIBiG. Particular attention was paid to ensuring high data quality, with automated data validation using a newly developed custom submission portal prototype, paired with a novel peer-reviewing model. MIBiG 4.0 also takes steps towards a rolling release model and a broader involvement of the scientific community. MIBiG 4.0 is accessible online at https://mibig.secondarymetabolites.org/., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

EEG slowing is reported in various neurological disorders including Alzheimer's, Parkinson's and Epilepsy. Here, we investigate alpha rhythm slowing in individuals with refractory temporal lobe epilepsy compared with healthy controls, using scalp EEG and magnetoencephalography. We retrospectively analysed data from 17 (46) healthy controls and 22 (24) individuals with temporal lobe epilepsy who underwent scalp EEG and magnetoencephalography recordings as part of presurgical evaluation. Resting-state, eyes-closed recordings were source reconstructed using the standardized low-resolution brain electrographic tomography method. We extracted slow 6-9 Hz and fast 10-11 Hz alpha relative band power and calculated the alpha power ratio by dividing slow alpha by fast alpha. This ratio was computed for all brain regions in all individuals. Alpha oscillations were slower in individuals with temporal lobe epilepsy than controls ( P < 0.05). This effect was present in both the ipsilateral and contralateral hemispheres and across widespread brain regions. Alpha slowing in temporal lobe epilepsy was found in both EEG and magnetoencephalography recordings. We interpret greater slow alpha as greater deviation from health., Competing Interests: No relevant conflicts of interest are reported., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Context & Objective: Sparse large-scale studies have characterized hypoglycemia symptomatology in adults with type 1 diabetes (T1D) who use continuous glucose monitoring (CGM). This research aimed to evaluate the relationship of impaired awareness of hypoglycemia (IAH) with hypoglycemia symptomatology and frequency in this population., Design: A cross-sectional survey was conducted in 2023. HypoA-Q was used to evaluate hypoglycemia frequency, symptomatology, and awareness., Setting & Participants: Registrants who used CGM in the T1D Exchange, a U.S. national T1D registry., Results: Surveys were completed by 1,480 adults with T1D who used CGM (53% female; mean diabetes duration 26 years). Compared to those with intact hypoglycemia awareness, IAH was associated with less frequent hypoglycemia symptom presentation across various glucose levels and lower glucose concentrations for first presenting hypoglycemia symptoms when awake (P<0.05 for all). More than 70% of individuals with IAH did not regularly experience symptoms during episodes with glucose <54 mg/dL. When asleep, those with IAH were less frequently awoken by symptoms, more frequently awoken by others who recognized their hypoglycemia, and more frequently acknowledged hypoglycemia after an episode (P<0.05 for all) despite using CGM. With reduced symptoms, both when awake and asleep, those with IAH experienced more hypoglycemic episodes that they were unable to self-treat than those with intact awareness (P<0.05)., Conclusion: IAH continues to be associated with a significant reduction in detection of hypoglycemia symptoms, both when awake and asleep, in adults using CGM. Current diabetes technologies do not fully protect adults with type 1 diabetes from hypoglycemia., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Objectives: The aim of this work was to evaluate the performance of UK MPharm graduates on the General Pharmaceutical Council's (GPhC) registration assessment, between the years 2011-2024, to explore the factors that impact student performance in this examination., Methods: Student performance in the GPhC registration assessment was contextualized with factors like alma mater, Foundation Training placement, NSS, and HESA data. Relationships between these factors and the weighted average passing rates and raw scores were analysed using a range of statistical methods including correlation analysis, ANOM, Tukey-Kramer, and t-tests., Key Findings: Year on year, students from top performing Schools of Pharmacy consistently perform well and performance becomes less consistent as average passing rate decreases (R2 = 0.89; Prob > F < 0.0001). To best discriminate between MPharm programmes and placement type, students can be grouped by their raw score. We also find that students are more likely to pass in hospital compared to community placements, independent of institution. These relationships hold true for the best- and worst-performing students., Conclusions: Our analysis highlights substantial differences in performance levels between the highest and lowest-performing schools and placement types. While not always the case, it appears that pharmacy students should seek to obtain a pre-registration placement in the hospital environment to maximise their chances of success in the GPhC exam. Moving forward, we advocate for better quality data which could link each individual (and their demographic characteristics) as they move through university right through to their performance on each question in the registration exam., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society.)

Late-onset Pompe disease (LOPD) is a rare genetic disorder caused by the deficiency of acid alpha-glucosidase leading to progressive cellular dysfunction owing to the accumulation of glycogen in the lysosome. The mechanism of relentless muscle damage (a classic manifestation of the disease) has been studied extensively by analysing the whole-muscle tissue; however, little, if anything, is known about transcriptional heterogeneity among nuclei within the multinucleated skeletal muscle cells. This is the first report of application of single-nucleus RNA sequencing to uncover changes in the gene expression profile in muscle biopsies from eight patients with LOPD and four muscle samples from age- and sex-matched healthy controls. We matched these changes with histological findings using GeoMx spatial transcriptomics to compare the transcriptome of control myofibres from healthy individuals with non-vacuolated (histologically unaffected) and vacuolated (histologically affected) myofibres of LODP patients. We observed an increase in the proportion of slow and regenerative muscle fibres and macrophages in LOPD muscles. The expression of the genes involved in glycolysis was reduced, whereas the expression of the genes involved in the metabolism of lipids and amino acids was increased in non-vacuolated fibres, indicating early metabolic abnormalities. Additionally, we detected upregulation of autophagy genes and downregulation of the genes involved in ribosomal and mitochondrial function leading to defective oxidative phosphorylation. Upregulation of genes associated with inflammation, apoptosis and muscle regeneration was observed only in vacuolated fibres. Notably, enzyme replacement therapy (the only available therapy for the disease) showed a tendency to restore dysregulated metabolism, particularly within slow fibres. A combination of single-nucleus RNA sequencing and spatial transcriptomics revealed the landscape of the normal and diseased muscle and highlighted the early abnormalities associated with disease progression. Thus, the application of these two new cutting-edge technologies provided insight into the molecular pathophysiology of muscle damage in LOPD and identified potential avenues for therapeutic intervention., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: The TRACE (Targeted Research for Addictive and Compulsive Eating) intervention was evaluated in a 3-month randomized controlled trial which demonstrated significant improvement in Yale Food Addiction Scale scores favoring dietitian-led telehealth (active intervention) compared with passive and control groups. This study aimed to determine intervention costs and cost-utility., Methods: Costs of each intervention (2021$AUD) and incremental net monetary benefit (iNMB; incremental benefit, defined as Quality-Adjusted Life Years (QALY) gained, multiplied by willingness to pay threshold minus incremental cost) were calculated to estimate differences between groups., Results: The active intervention (n = 38) cost $294 (95% UI: $266, $316) per person compared to $47 (95% UI: $40, $54) in the passive intervention (n = 24), and $26 in the control group (n = 37). At a cost-effectiveness threshold of $50 000 per QALY score gained, the active intervention iNMB was -$186 (95% UI: -$1137, $834) and the passive group $127 (95% UI: -$1137, $834). Compared to the control group, estimates indicate a 30% chance of the active intervention, and a 60% chance of the passive intervention being cost effective., Conclusion: Although the overall cost of the active intervention was low, this was not considered cost-effective in comparison to the passive intervention, given small QALY score gains., Trial Registration: Australia New Zealand Clinical Trial Registry ACTRN12621001079831., (© The Author(s) 2024. Published by Oxford University Press on behalf of Faculty of Public Health.)

Objective: Systematically review and critically appraise the evidence for the association between delirium and falls in community-dwelling adults aged ≥60 years., Methods: We searched EMBASE, MEDLINE, PsycINFO, Cochrane Database of Systematic Reviews, CINAHL and Evidence-Based Medicine Reviews databases in April 2023. Standard methods were used to screen, extract data, assess risk of bias (using Newcastle-Ottawa scale), provide a narrative synthesis and, where appropriate, conduct meta-analysis., Results: We included 8 studies, with at least 3505 unique participants. Five found limited evidence for an association between delirium and subsequent falls: one adjusted study showed an increase in falls (risk ratio 6.66; 95% confidence interval (CI) 2.16-20.53), but the evidence was low certainty. Four non-adjusted studies found no clear effect. Three studies (one with two subgroups treated separately) found some evidence for an association between falls and subsequent delirium: meta-analysis of three adjusted studies showed an increase in delirium (pooled odds ratio 2.01; 95% CI 1.52-2.66); one subgroup of non-adjusted data found no clear effect. Number of falls and fallers were reported in the studies. Four studies and one subgroup were at high risk of bias and one study had some concerns., Conclusions: We found limited evidence for the association between delirium and falls. More methodologically rigorous research is needed to understand the complex relationship and establish how and why this operates bidirectionally. Studies must consider confounding factors such as dementia, frailty and comorbidity in their design, to identify potential modifying factors involved. Clinicians should be aware of the potential relationship between these common presentations., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Objective: Outcomes are poor for patients with congenital adrenal hyperplasia (CAH), in part due to the supraphysiological glucocorticoid doses required to control adrenal androgen excess. Hydrocortisone (ie, cortisol) is the recommended glucocorticoid for treatment of CAH. However, the other endogenous glucocorticoid in humans, corticosterone, is actively transported out of metabolic tissues such as adipose tissue and muscle, so we hypothesized that corticosterone could control adrenal androgens while causing fewer metabolic adverse effects than hydrocortisone., Methods: Thirteen patients (8 female, 5 male) with CAH due to 21-hydroxylase deficiency completed a randomized placebo-controlled crossover study comparing 5 h intravenous infusions of either hydrocortisone, corticosterone or placebo. 6-6[2H]2-glucose and 1,1,2,3,3-[2H]5-glycerol were infused to measure glucose and glycerol kinetics, and blood samples were collected throughout. Subcutaneous abdominal adipose tissue biopsies were obtained at the end of each infusion., Results: During the infusion, corticosterone and hydrocortisone similarly reduced ACTH, 17α-hydroxyprogesterone, androstenedione, and testosterone (in females only) compared with placebo. Despite achieving circulating corticosterone concentrations ∼2.5-fold higher than hydrocortisone, by T + 300 min hydrocortisone but not corticosterone increased glucose and insulin concentrations and reduced 6-6-[2H]2-glucose clearance compared with placebo. Hydrocortisone increased mRNA levels of the glucocorticoid regulated transcript PER1 in adipose to a greater extent than corticosterone., Conclusions: Corticosterone acutely controls biochemical markers of androgen excess similarly to hydrocortisone but without inducing markers of glucocorticoid "toxicity" in CAH. These data demonstrate proof of concept that corticosterone may be a safer glucocorticoid replacement than current medications, although further research is required to assess the longer-term effects of corticosterone replacement., Competing Interests: Conflict of interest: None of the authors have any conflicts to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Educators and researchers are reliant upon access to data to drive teaching methods, curricular improvements, and progress in medical education research. However, data are not always accessible, due to resource constraints, institutional policies, and privacy concerns. Researchers have attempted to access novel data sources through surveys, semistructured interviews, and databases; however, these methodologies are limited. To improve access to data, Freedom of Information (FOI) Acts grant researchers the ability to formally request data that any public institute holds. Researchers have been reluctant to use this tool due to negative perceptions, despite its unique benefits. To increase awareness of this underutilized methodology, we summarize the process of FOI Act requests, its strengths and weaknesses, and the ways in which health professions education can leverage FOI requests within research. We provide examples of the use of FOI requests as a research method within adjacent fields and nascent use within the field of health professions research. In doing so, we hope to highlight how FOI requests can be a useful tool in health professions education researchers and its potential to increase access to unique data sources., (© The Author(s) 2024. Published by Oxford University Press on behalf of Fellowship of Postgraduate Medicine.)

The Natural Products Atlas is a database of microbially derived natural products that contains structures, producing organism taxonomy, biosynthetic and chemical ontology classifications, grouping by compound classes and cross-links to a suite of other natural product-related data resources. The database is supported by a web server that includes functionality to browse the collection, search the database using both chemical structures and text/numerical terms and visualize the chemical diversity it contains using interactive dashboards. In the current database release, we have curated 1347 papers, increasing the number of compounds to 36 545. In addition, we have initiated a large-scale effort to incorporate data from papers reporting structural reassignments and revisions to previously published structures. This effort led to the incorporation of 590 corrections to existing entries, significantly improving the accuracy of the dataset. The Natural Products Atlas may be accessed at www.npatlas.org., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The "cognitive styles" hypothesis suggests that individual differences in behavior are associated with variation in cognitive performance via underlying speed-accuracy trade-offs. While this is supported, in part, by a growing body of evidence, some studies did not find the expected relationships between behavioral type and cognitive performance. In some cases, this may reflect methodological limitations rather than the absence of a true relationship. The physical design of the testing arena and the number of choices offered in an assay can hinder our ability to detect inter-individual differences in cognitive performance. Here, we re-investigated the cognitive styles hypothesis in threespine stickleback ( Gasterosteus aculeatus ), adapting the maze design of a previous study which found no cost to decision success by faster (bolder) individuals. We used a similar design but increased the size of the maze and incorporated an additional choice in the form of a third maze arm. We found, in accordance with cognitive style expectations, that individuals who were consistently slower to emerge from the start chamber made fewer errors than fish that emerged faster. Activity in an open field test, however, did not show evidence of a relationship with decision success, possibly due to the low number of repeated observations per fish in this separate assay. Our results provide further empirical support for the cognitive styles hypothesis and highlight important methodological aspects to consider in studies of inter-individual differences in cognition., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Society for Behavioral Ecology.)

Galapagos giant tortoises are endemic to the Galapagos Archipelago, where they are found in isolated populations. While these populations are widely considered distinguishable in morphology, behavior, and genetics, the recent divergence of these taxa has made their status as species controversial. Here, we apply multispecies coalescent methods for species delimitation to whole genome resequencing data from 38 tortoises across all 13 extant taxa to assess support for delimiting these taxa as species. In contrast to previous studies based solely on divergence time, we find strong evidence to reject the hypothesis that all Galapagos giant tortoises belong to a single species. Instead, a conservative interpretation of model-based and divergence-based results indicates that these taxa form a species complex consisting of a minimum of 9 species, with most analyses supporting 13 species. There is mixed support for the species status of taxa living on the same island, with some methods delimiting them as separate species and others suggesting multiple populations of a single species per island. These results make clear that Galapagos giant tortoise taxa represent different stages in the process of speciation, with some taxa further along in that evolutionary process than others. Our study provides insight into the complex process of speciation on islands, which is urgently needed given the threatened status of island species around the world. Las tortugas gigantes de las Galápagos son endémicas del Archipiélago de Galápagos, donde se encuentran como poblaciones aisladas. Aunque estas poblaciones se consideran distinguibles en cuanto a morfología, comportamiento y genética, la divergencia reciente de estos taxones hace que su estatus como especies sea controvertido. Aquí aplicamos métodos de coalescencia de especies múltiples con datos de resecuenciación de genomas completos de 38 tortugas de los 13 taxones existentes para evaluar el sustento de la delimitación de estos taxones como especies. En contraste con estudios previos basados únicamente en el tiempo de divergencia, encontramos evidencia sólida para rechazar la hipótesis de que todas las tortugas gigantes de las Galápagos pertenecen a una sola especie. En cambio, una interpretación conservadora de los resultados basados en modelos y divergencia indica que estos taxones forman un complejo de especies que consiste de un mínimo de 9 especies, con la mayoría de los análisis respaldando la existencia de 13 especies. Hay sustento mixto para designar como especies a los taxones que habitan la misma isla, con algunos métodos delimitándolos como especies y otros sugiriendo la existencia de poblaciones múltiples de una sola especie por isla. Estos resultados dejan en claro que los taxones de tortugas gigantes de las Galápagos representan diferentes etapas del proceso de especiación, con algunos taxones más avanzados en ese proceso evolutivo que otros. Nuestro estudio ofrece una perspectiva sobre el complejo proceso de especiación en islas, la cual es urgentemente necesaria dado lo amenazadas que se encuentran las especies insulares en todo el mundo., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Society for the Study of Evolution (SSE).)

Neuromuscular disorders affect almost 20 million people worldwide. Advances in molecular diagnosis have provided valuable insights into neuromuscular disorders, allowing for improved standards of care and targeted therapeutic approaches. Despite this progress, access to genomic diagnosis remains scarce and inconsistent in middle-income countries such as Brazil. The lack of public health policies to enable feasible genetic diagnosis and the shortage of neuromuscular disorders specialists are the main reasons in this process. We report our experience in a transcontinental genomic consortium for neuromuscular disorders highlighting how collaborative efforts have helped overcome various obstacles in diagnosing our patients. We describe several challenging cases categorized into three major themes, underlining significant gaps in genetic diagnosis: (i) reverse phenotyping and variant validation, (ii) deep phenotyping and identifying a bespoke molecular approach, and (iii) exploring the use of genomic tests beyond whole exome sequencing. We applied a qualitative case-based approach to exemplify common pitfalls in genomic diagnosis in a middle-income country. Our experience has shown that establishing a virtual transcontinental partnership is viable, offering effective exchange of scientific experiences, providing both guidance for rational decision-making and specialized training on a local level and access to diverse molecular diagnosis strategies and functional analyses. Collaborative efforts such as these have the potential to overcome local obstacles, strengthen scientific capabilities, foster diverse multi-ethnic cohorts, and ultimately provide improved care for patients., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Aims: Cardiogenic shock (CS) remains the primary cause of in-hospital death after acute coronary syndromes (ACS), with its plateauing mortality rates approaching 50%. To test novel interventions, personalized risk prediction is essential. The ORBI (Observatoire Régional Breton sur l'Infarctus) score represents the first-of-its-kind risk score to predict in-hospital CS in ACS patients undergoing percutaneous coronary intervention (PCI). However, its sex-specific performance remains unknown, and refined risk prediction strategies are warranted., Methods: This multinational study included a total of 53 537 ACS patients without CS on admission undergoing PCI. Following sex-specific evaluation of ORBI, regression and machine-learning models were used for variable selection and risk prediction. By combining best-performing models with highest-ranked predictors, SEX-SHOCK was developed, and internally and externally validated., Results: The ORBI score showed lower discriminative performance for the prediction of CS in females than males in Swiss (area under the receiver operating characteristic curve [95% confidence interval]: 0.78 [0.76-0.81] vs. 0.81 [0.79-0.83]; P =.048) and French ACS patients (0.77 [0.74-0.81] vs. 0.84 [0.81-0.86]; P = .002). The newly developed SEX-SHOCK score, now incorporating ST-segment elevation, creatinine, C-reactive protein, and left ventricular ejection fraction, outperformed ORBI in both sexes (females: 0.81 [0.78-0.83]; males: 0.83 [0.82-0.85]; P < .001), which prevailed following internal and external validation in RICO (females: 0.82 [0.79-0.85]; males: 0.88 [0.86-0.89]; P < .001) and SPUM-ACS (females: 0.83 [0.77-0.90], P = .004; males: 0.83 [0.80-0.87], P = .001)., Conclusions: The ORBI score showed modest sex-specific performance. The novel SEX-SHOCK score provides superior performance in females and males across the entire spectrum of ACS, thus providing a basis for future interventional trials and contemporary ACS management., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Alzheimer's disease (AD) is neuropathologically defined by deposits of misfolded hyperphosphorylated tau (HP-tau) and β-amyloid. Lewy body (LB) dementia, which includes dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is characterised pathologically by α-synuclein aggregates. HP-tau and β-amyloid can also occur as copathologies in LB dementia, and a diagnosis mixedAD/DLB can be made if present in sufficient quantities. We hypothesised the spread of these abnormal proteins selectively affects vulnerable areas, resulting in pathologic regional covariance that differentially associates with pre-mortem clinical characteristics. Our aims were to map regional quantitative pathology (HP-tau, β-amyloid, α-synuclein) and investigate the spatial distributions from tissue microarray (TMA) post-mortem samples across healthy aging, AD and LB dementia. The study involved 159 clinico-pathologically diagnosed human post-mortem brains (48 controls, 47 AD, 25 DLB, 20 mixedAD/DLB, 19 PDD). The burden of HP-tau, β-amyloid and α-synuclein was quantitatively assessed in cortical and subcortical areas. Principal components (PC) analysis was applied across all cases to determine the pattern nature of HP-tau, β-amyloid and α-synuclein. Further analyses explored the relationships of these pathological patterns with cognitive and symptom variables. Cortical (tauPC1) and temporolimbic (tauPC2) patterns were observed for HP-tau. For β-amyloid, a cortical-subcortical pattern (amylPC1) was identified. For α-synuclein, four patterns emerged: 'posterior temporal - occipital (synPC1)', 'anterior temporal-frontal (synPC2)', 'parieto-cingulate-insula (synPC3)', and 'frontostriatal-amygdala (synPC4)'. Distinct synPC scores were apparent among DLB, mixedAD/DLB and PDD, and may relate to different spreading patterns of α-synuclein pathology. In dementia, cognitive measures correlated with tauPC1,  tauPC2 and amylPC1 pattern scores (P≤0.02), whereas such variables did not relate to α-synuclein parameters in these or combined LB dementia cases. Mediation analysis then revealed that in the presence of amylPC1, tauPC1 had a direct effect on global cognition in dementia (n=65, P=0.04), while tauPC1 mediated the relationship between amylPC1 and cognition through the indirect pathway (amylPC1→ tauPC1 → global cognition) (P<0.05). Lastly, in synucleinopathies, synPC1 and synPC4 pattern scores were associated with visual hallucinations and motor impairment, respectively (P=0.02). In conclusion, distinct patterns of α-synuclein pathology were apparent in LB dementia, which could explain some of the disease heterogeneity and differing spreading patterns among these conditions. Visual hallucinations and motor severity were associated with specific α-synuclein topographies in LB dementia that may be important to the clinical phenotype, and could, after necessary testing/validation, be integrated into semi-quantitative routine pathological assessment., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Epidemiological evidence suggests the presence of common risk factors for the development and prognosis of both cardio- and cerebrovascular diseases, including stroke, Alzheimer's disease, vascular dementia, heart, and peripheral vascular diseases. Accumulation of harmful blood signals may induce organotypic endothelial dysfunction affecting blood-brain barrier function and vascular health in age-related diseases. Genetic-, age-, lifestyle- or cardiovascular therapy-associated imbalance of amyloid-beta (Aβ) peptide metabolism in the brain and periphery may be the missing link between age-related neurocardiovascular diseases. Genetic polymorphisms of genes related to Aβ metabolism, lifestyle modifications, drugs used in clinical practice, and Aβ-specific treatments may modulate Aβ levels, affecting brain, vascular, and cardiac diseases. This narrative review elaborates on the effects of interventions on Aβ metabolism in the brain, cerebrospinal fluid, blood, and peripheral heart or vascular tissues. Implications for clinical applicability, gaps in knowledge, and future perspectives of Aβ as the link among age-related neurocardiovascular diseases are also discussed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Developments in bioengineering and nanotechnology have ignited the research on biological and molecular communication systems. Despite potential benefits, engineering communication systems to carry data signals using biological messenger molecules and engineered cells is challenging. Diffusing molecules may fall behind their schedule to arrive at the receiver, interfering with symbols of subsequent time slots and distorting the signal. Existing theoretical molecular communication models often focus solely on the characteristics of a communication channel and fail to provide an end-to-end system response since they assume a simple thresholding process for a receiver cell and overlook how the receiver can detect the incoming distorted molecular signal. In this paper, we present a model-based and computational framework called BioRxToolbox for designing diffusion-based and end-to-end molecular communication systems coupled with synthetic genetic circuits. We describe a novel framework to encode information as a sequence of bits, each transmitted from the sender as a burst of molecules, control cellular behavior at the receiver, and minimize cellular signal interference by employing equalization techniques from communication theory. This approach allows the encoding and decoding of data bits efficiently using two different types of molecules that act as the data carrier and the antagonist to cancel out the heavy tail of the former. Here, BioRxToolbox is demonstrated using a biological design and computational simulations for various communication scenarios. This toolbox facilitates automating the choice of communication parameters and identifying the best communication scenarios that can produce efficient cellular signals., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press.)

Mitochondrial disease is a group of rare conditions, with no approved treatment to date, except for Leber hereditary optic neuropathy. Therapeutic options to alleviate the symptoms of mitochondrial disease are urgently needed. Sonlicromanol is a promising candidate, as it positively alters the key metabolic and inflammatory pathways associated with mitochondrial disease. Sonlicromanol is a reductive and oxidative distress modulator, selectively inhibiting microsomal prostaglandin E1 synthase activity. This Phase 2b program, aiming at evaluating sonlicromanol in adults with m.3243A>G mutation and primary mitochondrial disease, consisted of a randomized controlled (RCT) study (dose-selection) followed by a 52-week open-label extension study (EXT, long-term tolerability, safety, and efficacy of sonlicromanol). Patients were randomized (1:1:1) to receive 100- or 50-mg sonlicromanol, or placebo twice daily (bid) for 28 days with ≥2-week wash-out period between treatments. Patients who completed the RCT study entered the EXT study wherein they received 100-mg sonlicromanol bid. Overall, 27 patients were randomized (24 RCT patients completed all periods). 15 patients entered the EXT, and 12 patients were included in the EXT analysis set. All patients reported good tolerability and favourable safety, with pharmacokinetic results comparable to the earlier Phase 2a study. The RCT primary endpoint (change from placebo in the attentional domain of cognition score [IDN: visual identification, Cogstate]) did not reach statistical significance. Using a categorisation of the subject's period baseline a treatment effect over placebo was observed if their baseline was more affected (p=0.0338). Using this approach, there were signals of improvements over placebo in at least one dose in the Beck Depression Inventory (BDI, p=0.0143), Cognitive Failure Questionnaire (CFQ, p=0.0113), and the Depression subscale of the Hospital Anxiety and Depression Scale (p=0.0256). Statistically and/or clinically meaningful improvements were observed in the patient- and clinician-reported outcome measures at the end of the EXT study (Test of attentional performance [TAP] with alarm, p=0.0102; TAP without alarm, p=0.0047; BDI somatic, p=0.0261; BDI Total, p=0.0563; SF12 physical component score, p=0.0008). Seven of nine domains of RAND-Short form-36 like SF-36 pain improved (p=0.0105). Other promising results were observed in Neuro QoL-Fatigue-SF (p=0.0036), MiniBESTest (p=0.0009), McGill Pain Questionnaire (p=0.0105), EQ-5D-5L-VAS (p=0.0213) and EQ-5D-5L-index (p=0.0173). Most patients showed improvement in the 5× sit-to-stand test. Sonlicromanol was well-tolerated and demonstrated a favourable benefit/risk ratio for up to one year. Sonlicromanol was efficacious in patients when affected at baseline, as seen across a variety of clinically relevant domains. Long-term treatment showed more pronounced changes from baseline., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: This scoping review mapped evidence on physical activity (including structured exercise) and sedentary behaviour interventions (interventions to reduce sedentary behaviour) in people living with both frailty and multiple long-term conditions (MLTCs) and their informal carers., Methods: Ten databases and grey literature were searched from 2000 to October 2023. Two reviewers screened studies and one extracted data. Results were shared with three stakeholder groups (n = 21) in a consultation phase., Results: After screening, 155 papers from 144 studies (1 ongoing) were retained. The majority were randomised controlled trials (86, 55%). Participants' mean age was 73 ± 12 years, and 73% were of White ethnicity. MLTC and frailty measurement varied widely. Most participants were pre-to-moderately frail. Physical health conditions predominated over mental health conditions.Interventions focused on structured exercise (83 studies, 60%) or combined interventions (55 studies, 39%). Two (1%) and one (0.7%) focused solely on habitual physical activity or sedentary behaviour. Adherence was 81% (interquartile range 62%-89%) with goal setting, monitoring and support important to adherence. Carers were only involved in 15 (11%) studies. Most interventions reported positive outcomes, primarily focusing on body functions and structures., Conclusions: A modest volume of evidence exists on multicomponent structured exercise interventions, with less focus on habitual physical activity and sedentary behaviour. Interventions report largely positive effects, but an updated systematic review is required. The field could be advanced by more rigorous characterisation of MLTCs, socioeconomic status and ethnicity, increased informal carer involvement and further evaluation of habitual physical activity and sedentary behaviour interventions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Background: Procalcitonin (PCT) is a blood marker used to help diagnose bacterial infections and guide antibiotic treatment. PCT testing was widely used/adopted during the COVID-19 pandemic in the UK., Objectives: Primary: to measure the difference in length of early (during first 7 days) antibiotic prescribing between patients with COVID-19 who did/did not have baseline PCT testing during the first wave of the pandemic. Secondary: to measure differences in length of hospital/ICU stay, mortality, total days of antibiotic prescribing and resistant bacterial infections between these groups., Methods: Multi-centre, retrospective, observational, cohort study using patient-level clinical data from acute hospital Trusts/Health Boards in England/Wales. Inclusion: patients ≥16 years, admitted to participating Trusts/Health Boards and with a confirmed positive COVID-19 test between 1 February 2020 and 30 June 2020., Results: Data from 5960 patients were analysed: 1548 (26.0%) had a baseline PCT test and 4412 (74.0%) did not. Using propensity-score matching, baseline PCT testing was associated with an average reduction in early antibiotic prescribing of 0.43 days [95% confidence interval (CI): 0.22-0.64 days, P < 0.001) and of 0.72 days (95% CI: 0.06-1.38 days, P = 0.03] in total antibiotic prescribing. Baseline PCT testing was not associated with increased mortality or hospital/ICU length of stay or with the rate of antimicrobial-resistant secondary bacterial infections., Conclusions: Baseline PCT testing appears to have been an effective antimicrobial stewardship tool early in the pandemic: it reduced antibiotic prescribing without evidence of harm. Our study highlights the need for embedded, rapid evaluations of infection diagnostics in the National Health Service so that even in challenging circumstances, introduction into clinical practice is supported by evidence for clinical utility., Study Registration Number: ISRCTN66682918., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: Neurocognition can be severely affected in pediatric brain tumor survivors. We analyzed the association of cognitive functioning with radiotherapy dose, postoperative cerebellar mutism syndrome (pCMS), hydrocephalus, intraventricular methotrexate (MTX) application, tumor localization, and biology in pediatric survivors of a posterior fossa tumor., Methods: Subdomain-specific neurocognitive outcome data from 279 relapse-free survivors of the HIT-2000 trial (241 medulloblastoma and 38 infratentorial ependymoma) using the Neuropsychological Basic Diagnostic tool based on Cattell-Horn-Carroll's model for intelligence were analyzed., Results: Cognitive performance 5.14 years (mean; range = 1.52-13.02) after diagnosis was significantly below normal for all subtests. Processing speed and psychomotor abilities were most affected. Influencing factors were domain-specific: CSI-dose had a strong impact on most subtests. pCMS was associated with psychomotor abilities (β = -0.25 to -0.16) and processing speed (β = -0.32). Postoperative hydrocephalus correlated with crystallized intelligence (β = -0.20) and short-term memory (β = -0.15), age with crystallized intelligence (β = 0.15) and psychomotor abilities (β = -0.16 and β = -0.17). Scores for fluid intelligence (β = -0.23), short-term memory (β = -0.17) and visual processing (β = -0.25) declined, and scores for selective attention improved (β = 0.29) with time after diagnosis., Conclusions: The dose of CSI was strongly associated with neurocognitive outcomes. Low psychomotor abilities and processing speed both in patients treated with and without CSI suggest a strong contribution of the tumor and its surgery on these functions. Future research therefore should analyze strategies to both reduce CSI dose and toxicity caused by other treatment modalities., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Frailty is of increasing interest in trials, either as a target of intervention, as an outcome or as a potential treatment modifier. However, frailty measurement is often highly variable. This scoping review assessed how frailty is quantified in randomised controlled trials (RCTs), in what context and for what purposes., Methods: We searched five electronic databases for RCTs in which frailty was measured among trial participants. We extracted data on intervention type, the frailty measure used and the purpose for which frailty was assessed. We then compared these data according to reasons for frailty assessment., Results: We identified 415 RCTs assessing frailty across a range of interventions. Frailty was used to define the target population (166 trials), as an outcome (156 trials), as an effect modifier examining interaction of frailty on treatment effect (61 trials), as a purely descriptive characteristic (42 trials) or as a prognostic marker examining the impact of frailty on future health outcome (78 trials). The trials used 28 different measures of frailty (plus 29 additional trial-specific measures). The frailty phenotype model was the most common overall (164 trials), for defining the target population (90/166 trials) and as an outcome (81/156 trials). The cumulative deficit model frailty index was also frequently used (102 trials) and was most common among trials assessing treatment effect modification (21/61 trials)., Conclusion: Frailty measurement in RCTs is highly variable. Understanding the properties of respective frailty measures and how these relate to frailty as encountered in clinical practice is a priority to ensure that trial findings can inform healthcare delivery for people living with frailty., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Access to medical and supportive care services is important for the health and quality of life of cancer survivors; however, services are not always available or accessible to all survivors equally. This study aims to explore the experiences of cancer services among cancer survivors in urban and rural settings to inform social work practice. Authors conducted interviews with 25 cancer survivors (colorectal, n = 13; hematological, n = 12) in the West of Ireland, using a narrative inquiry approach. Thematic analysis was used to analyze the data. Authors found variations in the availability of supportive care services for urban and rural cancer survivors. Often, services designed to maximize survivors' individualized choices and needs in community care were limited in rural communities, preventing some survivors from having their physical and psychological needs met. Additionally, access to services proved to be a barrier for rural cancer survivors. Rural survivors stated that traveling to appointments required time and planning, and the implications of travel costs were an increased burden. When rural survivors had good social support, access to services became less of an issue. The study confirms geographical disparities and recommends a review of supports that better meet survivors' needs and informs social work practice., (© 2024 National Association of Social Workers.)