Association between mosaic loss of chromosome Y and pulmonary fibrosis susceptibility and severity.

Background Pulmonary fibrosis (PF) is a rare lung disease with diverse pathogenesis and multiple interconnected underlying biological mechanisms. Mosaic loss of chromosome Y (mLOY) is one of the most common forms of acquired chromosome abnormality in men, which has been reported to be associated with increased risk of various chronic progressive diseases including fibrotic diseases. However, the exact role of mLOY in the development of PF remains elusive and to be elucidated. Methods: We adopted three complementary approaches to explore the role of mLOY in the pathogenesis of PF. We used copy number on chromosome Y to estimate mLOY comparing patients in PROFILE and gnomAD cohorts and between cases and control patients from the GE100KGP cohort. Correlation of mLOY with demographic and clinical variables was tested using patients from PROFILE cohort. Lung single-cell transcriptomic data were analysed to assess the cell types implicated in mLOY. We performed Mendelian randomisation to examine the causal relationship between mLOY, IPF, and telomere length. Results: The genetic analysis suggests that mLOY is found in PF from both case cohorts but when compared with an age matched population the effect is minimal (P = 0.0032). mLOY is related to age (P = 0.00021) and shorter telomere length (P = 0.0081) rather than PF severity or progression. Single-cell analysis indicates that mLOY appears to be found primarily in immune cells and appears to be related to presence and severity of fibrosis. Mendelian randomisation demonstrates that mLOY is not on the causal pathway for IPF, but partial evidence supports that telomere shortening is on the causal pathway for mLOY. Conclusion: Our study confirms the existence of mLOY in PF patients and suggests that mLOY is not a major driver of IPF. The combined evidence suggests a triangulation model where telomere shortening leads to both IPF and mLOY.

Smoking status predicts anastomotic leak after esophagectomy: a systematic review & meta-analysis.

BACKGROUND: Anastomotic leak after esophagectomy is a major contributor to surgery-related morbidity and mortality. The purpose of this systematic review was to evaluate if positive-smoking status is associated with the incidence of this complication. METHODS: A systematic search of MEDLINE, EMBASE, Scopus, Web of Science and Cochrane Library was performed on April 4th, 2023. Inclusion criteria comprised human participants undergoing esophagectomy, age ≥ 18, n ≥ 5, and identification of smoking status. The primary outcome was incidence of anastomotic leak. Sub-group analysis by ex- or current smoking status was performed. Meta-analysis was performed with RevMan 5.4.1 using a Mantel-Haenszel random-effects model. Publication bias was evaluated visually with funnel plots and through the Egger test. RESULTS: A total of 220 abstracts were screened, of which 69 full-text studies were assessed for eligibility, with 13 studies selected for final inclusion. This included 16,103 patients, of which 4433 were ex- or current smokers, and 9141 were never smokers. Meta-analysis revealed an increased odds of anastomotic leak in patients with a positive-smoking status (current or ex-smokers) compared to never smokers (OR 1.44, 95% CI 1.18-1.76, I2 = 44%, p < 0.001. Meta-analysis of six studies comparing active smokers alone to never smokers identified a significant increased odds of anastomotic leak (OR 1.80, 95% CI 1.25-2.59, p = 0.002, I2 = 0%). Meta-analysis of five studies comparing ex-smokers to never smokers identified a significant increased odds of anastomotic leak (OR 1.36, 95% CI 1.02-1.82, p = 0.04, I2 = 0%). The odds of anastomotic leak decreased among ex-smokers compared to active smokers. CONCLUSION: The findings of this systematic review and meta-analysis support the association between positive-smoking status and the risk of anastomotic leak after esophagectomy. Results further emphasize the importance of preoperative smoking cessation to reduce post-operative morbidity.

The receptor protein tyrosine phosphatase PTPRK promotes intestinal repair and catalysis-independent tumour suppression.

PTPRK is a receptor tyrosine phosphatase linked to the regulation of growth factor signalling and tumour suppression. It is stabilized at the plasma membrane by trans homophilic interactions upon cell-cell contact. It regulates cell-cell adhesion, but is also reported to regulate numerous cancer-associated signalling pathways. However, its signalling mechanism remains to be determined. Here, we find that PTPRK regulates cell adhesion signalling, suppresses invasion and promotes collective, directed migration in colorectal cancer cells. In vivo, PTPRK supports recovery from inflammation-induced colitis. In addition, we confirm that PTPRK functions as a tumour suppressor in the mouse colon and in colorectal cancer xenografts. PTPRK regulates growth factor and adhesion signalling, and suppresses epithelial to mesenchymal transition (EMT). Contrary to the prevailing notion that PTPRK directly dephosphorylates EGFR, we find that PTPRK regulation of both EGFR and EMT is independent of its catalytic function. This suggests that additional adaptor and scaffold functions are important features of PTPRK signalling.

Performance Characteristics of the NeuroEXPLORER, a Next-Generation Human Brain PET/CT Imager.

The collaboration of Yale, the University of California, Davis, and United Imaging Healthcare has successfully developed the NeuroEXPLORER, a dedicated human brain PET imager with high spatial resolution, high sensitivity, and a built-in 3-dimensional camera for markerless continuous motion tracking. It has high depth-of-interaction and time-of-flight resolutions, along with a 52.4-cm transverse field of view (FOV) and an extended axial FOV (49.5 cm) to enhance sensitivity. Here, we present the physical characterization, performance evaluation, and first human images of the NeuroEXPLORER. Methods: Measurements of spatial resolution, sensitivity, count rate performance, energy and timing resolution, and image quality were performed adhering to the National Electrical Manufacturers Association (NEMA) NU 2-2018 standard. The system's performance was demonstrated through imaging studies of the Hoffman 3-dimensional brain phantom and the mini-Derenzo phantom. Initial 18F-FDG images from a healthy volunteer are presented. Results: With filtered backprojection reconstruction, the radial and tangential spatial resolutions (full width at half maximum) averaged 1.64, 2.06, and 2.51 mm, with axial resolutions of 2.73, 2.89, and 2.93 mm for radial offsets of 1, 10, and 20 cm, respectively. The average time-of-flight resolution was 236 ps, and the energy resolution was 10.5%. NEMA sensitivities were 46.0 and 47.6 kcps/MBq at the center and 10-cm offset, respectively. A sensitivity of 11.8% was achieved at the FOV center. The peak noise-equivalent count rate was 1.31 Mcps at 58.0 kBq/mL, and the scatter fraction at 5.3 kBq/mL was 36.5%. The maximum count rate error at the peak noise-equivalent count rate was less than 5%. At 3 iterations, the NEMA image-quality contrast recovery coefficients varied from 74.5% (10-mm sphere) to 92.6% (37-mm sphere), and background variability ranged from 3.1% to 1.4% at a contrast of 4.0:1. An example human brain 18F-FDG image exhibited very high resolution, capturing intricate details in the cortex and subcortical structures. Conclusion: The NeuroEXPLORER offers high sensitivity and high spatial resolution. With its long axial length, it also enables high-quality spinal cord imaging and image-derived input functions from the carotid arteries. These performance enhancements will substantially broaden the range of human brain PET paradigms, protocols, and thereby clinical research applications.

From educator to facilitator: Healthcare professionals' experiences of, and views about, delivering a type 1 diabetes structured education programme (DAFNEplus ) informed by behavioural science.

AIMS: The DAFNEplus programme incorporates behaviour change techniques into a modified educational intervention and was developed to help address the glycaemic drift observed amongst graduates of standard DAFNE programmes. As the programme's success will be contingent on staff buy-in, we explored healthcare professionals' experiences of, and views about, delivering DAFNEplus during a clinical trial to help inform decision making about rollout post-trial. METHODS: We interviewed n = 18 nurses and dieticians who delivered DAFNEplus during the trial. Data were analysed thematically. RESULTS: While many shared initial reservations, all described how their experiences of DAFNEplus programme delivery had had a positive, transformative impact upon their perceptions and working practices. This transformation was enabled by initial training and supervision sessions, the confidence gained from using scripts to support novel programme content delivery, and experiences of delivering the programme and observing DAFNEplus principles being well received by, and having a positive impact on, attendees. Due to these positive experiences, interviewees described a strongly felt ethical mandate to use some DAFNEplus techniques and curriculum content in routine clinical care. While being supportive of a national rollout, they anticipated a variety of attitudinal and logistical (e.g. workload) challenges. CONCLUSIONS: This study provides a vital dimension to the evaluation of the DAFNEplus programme. Interviewees found the intervention to be acceptable and expressed high levels of buy-in. As well as offering potential endorsement for a national rollout, our findings offer insights which could help inform development and rollout of future behaviour change interventions to support diabetes self-management.

EULAR recommendations for the involvement of patient research partners in rheumatology research: 2023 update.

BACKGROUND: Since the publication of the 2011 European Alliance of Associations for Rheumatology (EULAR) recommendations for patient research partner (PRP) involvement in rheumatology research, the role of PRPs has evolved considerably. Therefore, an update of the 2011 recommendations was deemed necessary. METHODS: In accordance with the EULAR Standardised Operational Procedures, a task force comprising 13 researchers, 2 health professionals and 10 PRPs was convened. The process included an online task force meeting, a systematic literature review and an in-person second task force meeting to formulate overarching principles (OAPs) and recommendations. The level of agreement of task force members was assessed anonymously (0-10 scale). RESULTS: The task force developed five new OAPs, updated seven existing recommendations and formulated three new recommendations. The OAPs address the definition of a PRP, the contribution of PRPs, the role of informal caregivers, the added value of PRPs and the importance of trust and communication in collaborative research efforts. The recommendations address the research type and phases of PRP involvement, the recommended number of PRPs per project, the support necessary for PRPs, training of PRPs and acknowledgement of PRP contributions. New recommendations concern the benefits of support and guidance for researchers, the need for regular evaluation of the patient-researcher collaboration and the role of a designated coordinator to facilitate collaboration. Agreements within the task force were high and ranged between 9.16 and 9.96. CONCLUSION: The updated EULAR recommendations for PRP involvement are more substantially based on evidence. Together with added OAPs, they should serve as a guide for researchers and PRPs and will ultimately strengthen the involvement of PRPs in rheumatology research.

Methylome-wide studies of six metabolic traits.

Exploring the molecular correlates of metabolic health measures may identify the shared and unique biological processes and pathways that they track. Here, we performed epigenome-wide association studies (EWASs) of six metabolic traits: body mass index (BMI), body fat percentage, waist-hip ratio (WHR), and blood-based measures of glucose, high-density lipoprotein (HDL) cholesterol, and total cholesterol. We considered blood-based DNA methylation (DNAm) from >750,000 CpG sites in over 17,000 volunteers from the Generation Scotland (GS) cohort. Linear regression analyses identified between 304 and 11,815 significant CpGs per trait at P<3.6×10-8, with 37 significant CpG sites across all six traits. Further, we performed a Bayesian EWAS that jointly models all CpGs simultaneously and conditionally on each other, as opposed to the marginal linear regression analyses. This identified between 3 and 27 CpGs with a posterior inclusion probability ≥ 0.95 across the six traits. Next, we used elastic net penalised regression to train epigenetic scores (EpiScores) of each trait in GS, which were then tested in the Lothian Birth Cohort 1936 (LBC1936; European ancestry) and Health for Life in Singapore (HELIOS; Indian-, Malay- and Chinese-ancestries). A maximum of 27.1% of the variance in BMI was explained by the BMI EpiScore in the subset of Malay-ancestry Singaporeans. Four metabolic EpiScores were associated with general cognitive function in LBC1936 in models adjusted for vascular risk factors (Standardised ßrange: 0.08 - 0.12, PFDR < 0.05). EpiScores of metabolic health are applicable across ancestries and can reflect differences in brain health.

Timing of exposure assessment in studies on Group B streptococcus colonization and preterm birth.

BACKGROUND: Maternal colonization by the bacterium Group B streptococcus (GBS) increases risk of preterm birth, a condition that has an important impact on the health of children. However, research studies that quantify the effect of GBS colonization on preterm birth have reported variable estimates of the effect measure. METHODS: We performed a simulated cohort study of pregnant women to assess how timing of exposure (GBS colonization) assessment might influence results of studies that address this question. We used published data on longitudinal maternal GBS colonization and on the distribution of preterm births by gestational age to inform parameters used in the simulations. RESULTS: Assuming that the probability of preterm birth is higher during weeks when pregnant women are colonized by GBS, our results suggest that studies that assess exposure status early during pregnancy are more likely to estimate an association between GBS colonization and preterm birth that is closer to the null, compared with studies that assess exposure either at birth or during gestational weeks matched to preterm births. In sensitivity analyses assuming different colonization acquisition rates and diagnostic sensitivities, we observed similar results. CONCLUSIONS: Accurate quantification of the effect of maternal GBS colonization on the risk of preterm birth is necessary to understand the full health burden linked to this bacterium. In this study, we investigated one possible explanation, related to the timing of exposure assessment, for the variable findings of previous observational studies. Our findings will inform future research on this question.

Comparing the prevalence and association between anxiety, depression and gastrointestinal symptoms in gastroparesis versus functional dyspepsia: A systematic review and meta-analysis.

OBJECTIVE: To determine the prevalence and associations between anxiety/depression, and gastrointestinal (GI) symptoms across gastroparesis and functional dyspepsia. METHODS: Twenty adult studies were identified through systematic searches of three databases (PubMed, CINAHL and PsycINFO) in September 2023. Meta-analysis was performed to estimate the pooled prevalence rates of anxiety and depression across gastroparesis and functional dyspepsia, and to determine whether the associations of anxiety/depression and gastrointestinal (GI) symptoms differ in gastroparesis versus functional dyspepsia. RESULTS: The overall pooled prevalence rate for anxiety was similar (χ2(1) = 2.45, p = .12) in gastroparesis (49%) and functional dyspepsia (29%). The overall pooled prevalence rate for depression in gastroparesis (39%), and functional dyspepsia (32%) was also similar (χ2(1) = 0.81, p = .37). No significant relationship between anxiety and GI symptoms (r = 0.11) or depression and GI symptoms (r = 0.16) was found in gastroparesis, whilst significant, though weak, positive relationships between anxiety and GI symptoms (r = 0.30) and depression and GI symptoms (r = 0.32) were found in functional dyspepsia. The association between GI symptoms and anxiety, but not depression, across gastroparesis and functional dyspepsia was found to be significant (χ2(1) = 5.22, p = .02). CONCLUSION: Contributing to ongoing debate as to whether gastroparesis and functional dyspepsia are interchangeable syndromes, this review found that anxiety and depression prevalence was similar in both conditions. Psychological assessment and the utilisation of effective and holistic care in both conditions is therefore warranted.

Association between recent exposure to continuous glucose monitoring-recorded hypoglycaemia and counterregulatory and symptom responses to subsequent controlled hypoglycaemia in people with type 1 diabetes.

AIM: Experimental hypoglycaemia blunts the counterregulatory hormone and symptom responses to a subsequent episode of hypoglycaemia. In this study, we aimed to assess the associations between antecedent exposure and continuous glucose monitoring (CGM)-recorded hypoglycaemia during a 1-week period and the counterregulatory responses to subsequent experimental hypoglycaemia in people with type 1 diabetes. MATERIALS AND METHODS: Forty-two people with type 1 diabetes (20 females, mean ± SD glycated haemoglobin 7.8% ± 1.0%, diabetes duration median (interquartile range) 22.0 (10.5-34.9) years, 29 CGM users, and 19 with impaired awareness of hypoglycaemia) wore an open intermittently scanned CGM for 1 week to detect hypoglycaemic exposure before a standardized hyperinsulinaemic-hypoglycaemic [2.8 ± 0.1 mmol/L (50.2 ± 2.3 mg/dl)] glucose clamp. Symptom responses and counterregulatory hormones were measured during the clamp. The study is part of the HypoRESOLVE project. RESULTS: CGM-recorded hypoglycaemia in the week before the clamp was negatively associated with adrenaline response [ß -0.09, 95% CI (-0.16, -0.02) nmol/L, p = .014], after adjusting for CGM use, awareness of hypoglycaemia, glycated haemoglobin and total daily insulin dose. This was driven by level 2 hypoglycaemia [<3.0 mmol/L (54 mg/dl)] [ß -0.21, 95% CI (-0.41, -0.01) nmol/L, p = .034]. CGM-recorded hypoglycaemia was negatively associated with total, autonomic, and neuroglycopenic symptom responses, but these associations were lost after adjusting for potential confounders. CONCLUSIONS: Recent exposure to CGM-detected hypoglycaemia was independently associated with an attenuated adrenaline response to experimental hypoglycaemia in people with type 1 diabetes.

Incorporating solvent effects in DFT: insights from cation exchange in faujasites.

Zeolites are versatile materials renowned for their extra-framework cation exchange capabilities, with applications spanning diverse fields, including nuclear waste treatment. While detailed experimental characterization offers valuable insight, density functional theory (DFT) proves particularly adept at investigating ion exchange in zeolites, owing to its atomic and electronic resolution. However, the prevalent occurrence of zeolitic ion exchange in aqueous environments poses a challenge to conventional DFT modeling, traditionally conducted in a vacuum. This study seeks to enhance zeolite modeling by systematically evaluating predictive differences across varying degrees of aqueous solvent inclusion. Specifically focusing on monovalent cation exchange in Na-X zeolites, we explore diverse modeling approaches. These range from simple dehydrated systems (representing bare reference states in vacuum) to more sophisticated models that incorporate aqueous solvent effects through explicit water molecules and/or a dielectric medium. Through comparative analysis of DFT and semi-empirical DFT approaches, along with their validation against experimental results, our findings underscore the necessity to concurrently consider explicit and implicit solvent effects for accurate prediction of zeolitic ionic exchange.

Anaesthetic and perioperative considerations for extrapleural pneumonectomy and extended pleurectomy/decortication: a scoping review protocol.

INTRODUCTION: Extrapleural pneumonectomy (EPP) and extended pleurectomy/decortication (ePD) are surgical cytoreductive techniques aimed at achieving macroscopic resection in malignant pleural tumours such as pleural mesothelioma, non-mesothelioma pleural malignancies such as thymoma and sarcoma, and rarely for pleural tuberculosis, in a more limited fashion. Despite extensive studies on both surgical techniques and consequences, a significant knowledge gap remains regarding how best to approach the perioperative anaesthesia challenges for EPP and ePD.It is unknown if the risk stratification processes for such surgeries are standardised or what types of functional and dynamic cardiac and pulmonary tests are employed preoperatively to assist in the perioperative risk stratification. Further, it is unknown whether the types of anaesthesia and analgesia techniques employed, and the types of haemodynamic monitoring tools used, impact on outcomes. It is also unknown whether individualised haemodynamic protocols are used to guide the rational use of fluids, vasoactive drugs and inotropes.Finally, there is a dearth of evidence regarding how best to monitor these patients postoperatively or what the most effective enhanced recovery protocols are to best mitigate postoperative complications and accelerate hospital discharge. To increase our knowledge of the perioperative and anaesthetic treatment for patients undergoing EPP/ePD, this scoping review attempts to synthesise the literature and identify these knowledge gaps. METHODS AND ANALYSIS: This scoping review will be conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Extension for Scoping Review Protocols methodology. Electronic databases, OVID Medline, EMBASE and the Cochrane Library, will be systematically searched for relevant literature corresponding to EPP or ePD and perioperative or anaesthetic management. Data will be analysed and summarised descriptively and organised according to the three perioperative stages: preoperative, intraoperative and postoperative factors in clinical care. ETHICS AND DISSEMINATION: Ethics approval was not required. The findings will be disseminated through professional networks, conference presentations and publications in scientific journals.

A US perspective on closing the carbon cycle to defossilize difficult-to-electrify segments of our economy.

Electrification to reduce or eliminate greenhouse gas emissions is essential to mitigate climate change. However, a substantial portion of our manufacturing and transportation infrastructure will be difficult to electrify and/or will continue to use carbon as a key component, including areas in aviation, heavy-duty and marine transportation, and the chemical industry. In this Roadmap, we explore how multidisciplinary approaches will enable us to close the carbon cycle and create a circular economy by defossilizing these difficult-to-electrify areas and those that will continue to need carbon. We discuss two approaches for this: developing carbon alternatives and improving our ability to reuse carbon, enabled by separations. Furthermore, we posit that co-design and use-driven fundamental science are essential to reach aggressive greenhouse gas reduction targets.

Dynamic structural evolution of MgO-supported palladium catalysts: from metal to metal oxide nanoparticles to surface then subsurface atomically dispersed cations.

Supported noble metal catalysts, ubiquitous in chemical technology, often undergo dynamic transformations between reduced and oxidized states-which influence the metal nuclearities, oxidation states, and catalytic properties. In this investigation, we report the results of in situ X-ray absorption spectroscopy, scanning transmission electron microscopy, and other physical characterization techniques, bolstered by density functional theory, to elucidate the structural transformations of a set of MgO-supported palladium catalysts under oxidative treatment conditions. As the calcination temperature increased, the as-synthesized supported metallic palladium nanoparticles underwent oxidation to form palladium oxides (at approximately 400 °C), which, at approximately 500 °C, were oxidatively fragmented to form mixtures of atomically dispersed palladium cations. The data indicate two distinct types of atomically dispersed species: palladium cations located at MgO steps and those embedded in the first subsurface layer of MgO. The former exhibit significantly higher (>500 times) catalytic activity for ethylene hydrogenation than the latter. The results pave the way for designing highly active and stable supported palladium hydrogenation catalysts with optimized metal utilization.

Detonation of fulminating gold produces heterogeneous gold nanoparticles.

Fulminating gold, the first high-explosive compound to be discovered, disintegrates into a mysterious cloud of purple smoke, the nature of which has been speculated upon since its discovery in the 15th century. In this work, we show that the colour of the smoke is due to the presence of gold nanoparticles.

Extracellular modulation of TREK-2 activity with nanobodies provides insight into the mechanisms of K2P channel regulation.

Potassium channels of the Two-Pore Domain (K2P) subfamily, KCNK1-KCNK18, play crucial roles in controlling the electrical activity of many different cell types and represent attractive therapeutic targets. However, the identification of highly selective small molecule drugs against these channels has been challenging due to the high degree of structural and functional conservation that exists not only between K2P channels, but across the whole K+ channel superfamily. To address the issue of selectivity, here we generate camelid antibody fragments (nanobodies) against the TREK-2 (KCNK10) K2P K+ channel and identify selective binders including several that directly modulate channel activity. X-ray crystallography and CryoEM data of these nanobodies in complex with TREK-2 also reveal insights into their mechanisms of activation and inhibition via binding to the extracellular loops and Cap domain, as well as their suitability for immunodetection. These structures facilitate design of a biparatropic inhibitory nanobody with markedly improved sensitivity. Together, these results provide important insights into TREK channel gating and provide an alternative, more selective approach to modulation of K2P channel activity via their extracellular domains.

Doppler ultrasound surveillance of recently formed haemodialysis arteriovenous fistula: the SONAR observational cohort study.

Background: Arteriovenous fistulas are considered the best option for haemodialysis provision, but as many as 30% fail to mature or suffer early failure. Objective: To assess the feasibility of performing a randomised controlled trial that examines whether, by informing early and effective salvage intervention of fistulas that would otherwise fail, Doppler ultrasound surveillance of developing arteriovenous fistulas improves longer-term arteriovenous fistula patency. Design: A prospective multicentre observational cohort study (the 'SONAR' study). Setting: Seventeen haemodialysis centres in the UK. Participants: Consenting adults with end-stage renal disease who were scheduled to have an arteriovenous fistula created. Intervention: Participants underwent Doppler ultrasound surveillance of their arteriovenous fistulas at 2, 4, 6 and 10 weeks after creation, with clinical teams blinded to the ultrasound surveillance findings. Main outcome measures: Fistula maturation at week 10 defined according to ultrasound surveillance parameters of representative venous diameter and blood flow (wrist arteriovenous fistulas: ≥ 4 mm and > 400 ml/minute; elbow arteriovenous fistulas: ≥ 5 mm and > 500 ml/minute). Mixed multivariable logistic regression modelling of the early ultrasound scan data was used to predict arteriovenous fistula non-maturation by 10 weeks and fistula failure at 6 months. Results: A total of 333 arteriovenous fistulas were created during the study window (47.7% wrist, 52.3% elbow). By 2 weeks, 37 (11.1%) arteriovenous fistulas had failed (thrombosed), but by 10 weeks, 219 of 333 (65.8%) of created arteriovenous fistulas had reached maturity (60.4% wrist, 67.2% elbow). Persistently lower flow rates and venous diameters were observed in those fistulas that did not mature. Models for arteriovenous fistulas' non-maturation could be optimally constructed using the week 4 scan data, with fistula venous diameter and flow rate the most significant variables in explaining wrist fistula maturity failure (positive predictive value 60.6%, 95% confidence interval 43.9% to 77.3%), whereas resistance index and flow rate were most significant for elbow arteriovenous fistulas (positive predictive value 66.7%, 95% confidence interval 48.9% to 84.4%). In contrast to non-maturation, both models predicted fistula maturation much more reliably [negative predictive values of 95.4% (95% confidence interval 91.0% to 99.8%) and 95.6% (95% confidence interval 91.8% to 99.4%) for wrist and elbow, respectively]. Additional follow-up and modelling on a subset (n = 192) of the original SONAR cohort (the SONAR-12M study) revealed the rates of primary, assisted primary and secondary patency arteriovenous fistulas at 6 months were 76.5, 80.7 and 83.3, respectively. Fistula vein size, flow rate and resistance index could identify primary patency failure at 6 months, with similar predictive power as for 10-week arteriovenous fistula maturity failure, but with wide confidence intervals for wrist (positive predictive value 72.7%, 95% confidence interval 46.4% to 99.0%) and elbow (positive predictive value 57.1%, 95% confidence interval 20.5% to 93.8%). These models, moreover, performed poorly at identifying assisted primary and secondary patency failure, likely because a subset of those arteriovenous fistulas identified on ultrasound surveillance as at risk underwent subsequent successful salvage intervention without recourse to early ultrasound data. Conclusions: Although early ultrasound can predict fistula maturation and longer-term patency very effectively, it was only moderately good at identifying those fistulas likely to remain immature or to fail within 6 months. Allied to the better- than-expected fistula patency rates achieved (that are further improved by successful salvage), we estimate that a randomised controlled trial comparing early ultrasound-guided intervention against standard care would require at least 1300 fistulas and would achieve only minimal patient benefit. Trial Registration: This trial is registered as ISRCTN36033877 and ISRCTN17399438. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR135572) and is published in full in Health Technology Assessment; Vol. 28, No. 24. See the NIHR Funding and Awards website for further award information.

For people with advanced kidney disease, haemodialysis is best provided by an 'arteriovenous fistula', which is created surgically by joining a vein onto an artery at the wrist or elbow. However, these take about 2 months to develop fully ('mature'), and as many as 3 out of 10 fail to do so. We asked whether we could use early ultrasound scanning of the fistula to identify those that are unlikely to mature. This would allow us to decide whether it would be practical to run a large, randomised trial to find out if using early ultrasound allows us to 'rescue' fistulas that would otherwise fail. We invited adults to undergo serial ultrasound scanning of their fistula in the first few weeks after it was created. We then analysed whether we could use the data from the early scans to identify those fistulas that were not going to mature by week 10. Of the 333 fistulas that were created, about two-thirds reached maturity by week 10. We found that an ultrasound scan 4 weeks after fistula creation could reliably identify those fistulas that were going to mature. However, of those fistulas predicted to fail, about one-third did eventually mature without further intervention, and even without knowing what the early scans showed, another third were successfully rescued by surgery or X-ray-guided treatment at a later stage. Performing an early ultrasound scan on a fistula can provide reassurance that it will mature and deliver trouble-free dialysis. However, because scans are poor at identifying fistulas that are unlikely to mature, we would not recommend their use to justify early surgery or X-ray-guided treatment in the expectation that this will improve outcomes.

Life-course neighbourhood deprivation and brain structure in older adults: the Lothian Birth Cohort 1936.

Neighbourhood disadvantage may be associated with brain health but the importance of exposure at different stages of the life course is poorly understood. Utilising the Lothian Birth Cohort 1936, we explored the relationship between residential neighbourhood deprivation from birth to late adulthood, and global and local neuroimaging measures at age 73. A total of 689 participants had at least one valid brain measures (53% male); to maximise the sample size structural equation models with full information maximum likelihood were conducted. Residing in disadvantaged neighbourhoods in mid- to late adulthood was associated with smaller total brain (ß = -0.06; SE = 0.02; sample size[N] = 658; number of pairwise complete observations[n]=390), grey matter (ß = -0.11; SE = 0.03; N = 658; n = 390), and normal-appearing white matter volumes (ß = -0.07; SE = 0.03; N = 658; n = 390), thinner cortex (ß = -0.14; SE = 0.06; N = 636; n = 379), and lower general white matter fractional anisotropy (ß = -0.19; SE = 0.06; N = 665; n = 388). We also found some evidence on the accumulating impact of neighbourhood deprivation from birth to late adulthood on age 73 total brain (ß = -0.06; SE = 0.02; N = 658; n = 276) and grey matter volumes (ß = -0.10; SE = 0.04; N = 658; n = 276). Local analysis identified affected focal cortical areas and specific white matter tracts. Among individuals belonging to lower social classes, the brain-neighbourhood associations were particularly strong, with the impact of neighbourhood deprivation on total brain and grey matter volumes, and general white matter fractional anisotropy accumulating across the life course. Our findings suggest that living in deprived neighbourhoods across the life course, but especially in mid- to late adulthood, is associated with adverse brain morphologies, with lower social class amplifying the vulnerability.

Emerging Variants of Canine Enteric Coronavirus Associated with Outbreaks of Gastroenteric Disease.

A 2022 canine gastroenteritis outbreak in the United Kingdom was associated with circulation of a new canine enteric coronavirus closely related to a 2020 variant with an additional spike gene recombination. The variants are unrelated to canine enteric coronavirus-like viruses associated with human disease but represent a model for coronavirus population adaptation.