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OBJECTIVE: The objective of this study was to investigate whether pausing a weight loss program for a defined period of time could enhance weight loss and reduce attrition. METHODS: Five databases and two trial registries were searched from inception to July 2023. Randomized-controlled trials of adults with overweight and/or obesity were included if they compared planned-pause interventions with continuous energy restriction (CER), usual care, or a minimal intervention. To be included, the weight loss intervention must have incorporated a pause of at least 1 week. Pooled mean differences for weight change and risk ratios for attrition were calculated using random-effects meta-analyses. RESULTS: Nine intervention arms (N\u2009=\u2009796 participants, 77% female) were included. Pooled results did not detect a significant difference in weight change between planned pauses and CER interventions at the end of the active intervention at a median 26\u2009weeks (planned pauses vs. CER mean: -7.09 vs. -7.0\u2009kg; mean difference: -0.09\u2009kg; 95% CI: -1.10 to 0.93) or at final follow-up at a median 52\u2009weeks (planned pauses vs. CER mean: -6.91 vs. -6.19\u2009kg; mean difference: -0.72\u2009kg; 95% CI: -2.92 to 1.48). There was no difference in attrition between planned pauses and CER interventions at the end of the active intervention (risk ratio: 1.20, 95% CI: 0.82 to 1.75) or at final follow-up (risk ratio: 1.04, 95% CI: 0.89 to 1.22). CONCLUSIONS: Planned pauses were consistently found to be no more or less effective than CER for weight loss or attrition.
\n \n\n \n \nGenetic signatures have added a molecular dimension to prognostics and therapeutic decision-making. However, tumour heterogeneity in prostate cancer and current sampling methods could confound accurate assessment. Based on previously published spatial transcriptomic data from multifocal prostate cancer, we created virtual biopsy models that mimic conventional biopsy placement and core size. We then analysed the gene expression of different prognostic signatures (OncotypeDx\u00ae, Decipher\u00ae, Prostadiag\u00ae) using a step-wise approach with increasing resolution from pseudo-bulk analysis of the whole biopsy, to differentiation by tissue subtype (benign, stroma, tumour), followed by distinct tumour grade and finally clonal resolution. The gene expression profile of virtual tumour biopsies revealed clear differences between grade groups and tumour clones, compared to a benign control, which were not reflected in bulk analyses. This suggests that bulk analyses of whole biopsies or tumour-only areas, as used in clinical practice, may provide an inaccurate assessment of gene profiles. The type of tissue, the grade of the tumour and the clonal composition all influence the gene expression in a biopsy. Clinical decision making based on biopsy genomics should be made with caution while we await more precise targeting and cost-effective spatial analyses.
\n \n\n \n \nKidney stone disease (nephrolithiasis) is a major clinical and economic health burden1,2 with a heritability of ~45-60%3. To identify genetic variants associated with nephrolithiasis we performed genome-wide association studies (GWAS) and meta-analysis in British and Japanese populations, including 12,123 nephrolithiasis cases and 416,928 controls. Twenty loci associated with nephrolithiasis were identified, ten of which are novel. A novel CYP24A1 locus is predicted to affect vitamin D metabolism and five loci, DGKD, DGKH, WDR72, GPIC1, and BCR, are predicted to influence calcium-sensing receptor (CaSR) signaling. In a validation cohort of nephrolithiasis patients the CYP24A1-associated locus correlated with serum calcium concentration and number of kidney stone episodes, and the DGKD-associated locus correlated with urinary calcium excretion. Moreover, DGKD knockdown impaired CaSR-signal transduction in vitro, an effect that was rectifiable with the calcimimetic cinacalcet. Our findings indicate that genotyping may inform risk of incident kidney stone disease prior to vitamin D supplementation and facilitate precision-medicine approaches, by targeting CaSR-signaling or vitamin D activation pathways in patients with recurrent kidney stones.
\n \n\n \n \nThe next generation of surgical robotics is poised to disrupt healthcare systems worldwide, requiring new frameworks for evaluation. However, evaluation during a surgical robot's development is challenging due to their complex evolving nature, potential for wider system disruption and integration with complementary technologies like artificial intelligence. Comparative clinical studies require attention to intervention context, learning curves and standardized outcomes. Long-term monitoring needs to transition toward collaborative, transparent and inclusive consortiums for real-world data collection. Here, the Idea, Development, Exploration, Assessment and Long-term monitoring (IDEAL) Robotics Colloquium proposes recommendations for evaluation during development, comparative study and clinical monitoring of surgical robots-providing practical recommendations for developers, clinicians, patients and healthcare systems. Multiple perspectives are considered, including economics, surgical training, human factors, ethics, patient perspectives and sustainability. Further work is needed on standardized metrics, health economic assessment models and global applicability of recommendations.
\n \n\n \n \nBackground\nThere is debate whether the use of more arterial grafts during coronary artery bypass graft surgery provides advantages to the standard operation using the left internal thoracic artery plus vein grafts. We review data from the Arterial Revascularisation Trial to determine whether there is support for the multiple arterial graft hypothesis.\n\nMethods\nPatients undergoing coronary artery bypass graft for clinical reasons and who provided written informed consent were randomised to standard coronary artery bypass graft using the single internal thoracic artery or use of bilateral internal thoracic arteries. Additional vein grafts could be used. The primary outcome was all-cause mortality at 10 years and exploratory analyses were carried out to test the multiple arterial graft hypothesis.\n\nResults\nA total of 3102 patients were enrolled (1548 bilateral internal thoracic artery and 1554 single internal thoracic artery). Follow-up to 10 years for vital status was 98% complete. In the bilateral group, 14% of patients received a single internal thoracic artery only and use of radial artery grafts occurred in about 20% of patients in both groups. Aspirin was used in 81% of the patients, beta-blockers in 74%, statins in 90% and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in 73%. At 10 years, death rates were 20.3% and 21.2% in the bilateral internal thoracic artery and single internal thoracic artery groups, respectively (hazard ratio 0.96, 95% confidence intervals 0.82 to 1.12; p\u2005=\u20050.62) and composite of all-cause mortality, myocardial infarction or stroke 24.9% and 27.3%, respectively (hazard ratio 0.90, 95% confidence interval 0.79 to 1.03; p\u2005=\u20050.12). Exploratory analyses using the \u2018as-treated\u2019 approach indicate that outcomes were better in patients who received multiple arterial grafts (adding the right internal thoracic and/or radial arteries) compared with a single arterial graft. This effect appeared to be greater in patients with diabetes and those aged 70 years or less. Use of total arterial grafting without vein grafts may provide the best outcomes.\n\nLimitations\nThe elevated cross-over rate between bilateral internal thoracic artery and single internal thoracic artery and the non-randomised use of radial artery grafts may have contributed to a loss of power to detect a difference in mortality between the two groups. Moreover, secondary analyses are prone to bias as they compare non-randomised groups.\n\nConclusions\nThe Arterial Revascularisation Trial is one of the largest long-term studies in cardiac surgery. The primary analysis did not show a mortality benefit for bilateral internal thoracic artery at 10 years, perhaps due to high crossover rates in the bilateral internal thoracic artery group and concomitant use of the radial artery. Secondary analyses suggest a mortality benefit for patients receiving multiple arterial grafts compared with single arterial graft with possible greater effects in patients with diabetes and separately in patients aged 70 years or above. The trial will follow patients to 15 years and the continuing Randomized Comparison of the Clinical Outcome of Single versus Multiple Arterial Grafts trial will further test the multiple arterial graft hypothesis.\n\nTrial registration\nThis trial is registered as ISRCTN46552265.\n\nFunding\nThis project was funded by the British Heart Foundation, the UK. Medical Research Council and the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 7. See the NIHR Journals Library website for further project information.\n
\n \n\n \n \nBACKGROUND: Peroxisomes are central metabolic organelles that have key roles in fatty acid homoeostasis. As prostate cancer (PCa) is particularly reliant on fatty acid metabolism, we explored the contribution of peroxisomal \u03b2-oxidation (perFAO) to PCa viability and therapy response. METHODS: Bioinformatic analysis was performed on clinical transcriptomic datasets to identify the perFAO enzyme, 2,4-dienoyl CoA reductase 2 (DECR2) as a target gene of interest. Impact of DECR2 and perFAO inhibition via thioridazine was examined in vitro, in vivo, and in clinical prostate tumours cultured ex vivo. Transcriptomic and lipidomic profiling was used to determine the functional consequences of DECR2 inhibition in PCa. RESULTS: DECR2 is upregulated in clinical PCa, most notably in metastatic castrate-resistant PCa (CRPC). Depletion of DECR2 significantly suppressed proliferation, migration, and 3D growth of a range of CRPC and therapy-resistant PCa cell lines, and inhibited LNCaP tumour growth and proliferation in vivo. DECR2 influences cell cycle progression and lipid metabolism to support tumour cell proliferation. Further, co-targeting of perFAO and standard-of-care androgen receptor inhibition enhanced suppression of PCa cell proliferation. CONCLUSION: Our findings support a focus on perFAO, specifically DECR2, as a promising therapeutic target for CRPC and as a novel strategy to overcome lethal treatment resistance.
\n \n\n \n \nRegulatory T cells (Tregs) are essential to homeostatic immune tolerance. Clinical trials of autologous Treg cell therapy have demonstrated promising preliminary results, but there remain challenges to overcome including the problem of recipient-dependent expansion variability. Enhancing the suppressive function of expanded Tregs to reduce the required Treg dose would present a potential solution to this problem.\nCellular metabolism regulates immune cells through two interacting aspects: bioenergic and biosynthetic activities, and non-canonical activities of metabolic enzymes and intermediates. Early in vitro work has revealed distinct metabolic profiles between mouse conventional T cells (Tconvs) and Tregs. However, it remains unclear how the metabolism of human Tregs is regulated. A better understanding of the contrasting metabolic demands and regulation of function between human Tconvs and Tregs may uncover routes to target Treg-specific metabolic pathways in order to tune their activity as desired.\nIn this work, the immunometabolism of human Treg is investigated and new strategies revealed to harness elements of their metabolism for therapeutic use. In Chapters 3 and 4, I show that Treg display the \u2018Warburg effect\u2019 after T cell receptor stimulation alongside CD28 co-stimulation via the mTOR signalling pathway. Subsequently, I show that only nai\u0308ve and central memory Tregs preferentially utilise glucose; suggesting that human Treg metabolism may differ due to their anatomical location. In contrast, effector memory Tregs and Tconvs have distinct metabolic characteristics: whilst Tconvs negatively alter effector function through limiting glucose metabolism, Tregs positively regulate their suppressive function by limiting mitochondrial energy metabolism. Furthermore, this metabolic regulation allows Tregs to enhance their suppressive activity towards Treg-resistant Tconvs which are characterised by their low mitochondrial mass. In Chapters 5 and 6, I investigate the mechanism of this phenomenon, and show that Tregs generate immunosuppressive extracellular vesicles (exosomes) by mitochondrial ATP synthase inhibition. Metabolomics data suggests that epigenetic alteration in Tregs through a change in mitochondrial metabolism intermediates. The donor-independent function of these small extracellular vesicles suggests a new potential therapeutic strategy in which Treg-derived extracellular vesicles could be used \u2018off-the-shelf\u2019.\nThe immunometabolic experiments presented in this thesis shine new light on the differential metabolic regulation of human Tregs and Tconvs, and reveal novel and potent mode of Treg immunosuppresive action that can be induced by modulating metabolism. By defining these pathways, new therapeutic strategies to immune regulation may be potentially revealed.
\n \n\n \n \nThe last 5 y have seen the development and widespread adoption of high-plex spatial transcriptomic technology. This technique detects and quantifies mRNA transcripts in situ, meaning that transcriptomic signatures can be sampled from specific cells, structures, lesions, or anatomical regions while conserving the physical relationships that exist within complex tissues. These methods now frequently implement next-generation sequencing, enabling the simultaneous measurement of many targets, up to and including the whole mRNA transcriptome. To date, spatial transcriptomics has been foremost used in the fields of neuroscience and oncology, but there is potential for its use in transplantation sciences. Transplantation has a clear dependence on biopsies for diagnosis, monitoring, and research. Transplant patients represent a unique cohort with multiple organs of interest, clinical courses, demographics, and immunosuppressive regimens. Obtaining high complexity data on the disease processes underlying rejection, tolerance, infection, malignancy, and injury could identify new opportunities for therapeutic intervention and biomarker identification. In this review, we discuss currently available spatial transcriptomic technologies and how they can be applied to transplantation.
\n \n\n \n \nBACKGROUND: Deep brain stimulation (DBS) has shown promise in effectively treating chronic pain. This study aimed to assess the efficacy of DBS in this context. METHODS: We conducted a systematic literature search using PubMed, Scopus, and Web of Science, following the PRISMA guidelines. A well-constructed search strategy was utilized. Our literature search identified two groups of subjects: one group underwent DBS specifically for chronic pain treatment (DBS-P), while the second group received DBS for other indications (DBS-O), such as Parkinson's disease or dystonia, with pain perception investigated as a secondary outcome in this population. Meta-analysis was performed using R version 4.2.3 software. Heterogeneity was assessed using the tau^2 and I^2 indices, and Cochran's Q-test was conducted. RESULTS: The analysis included 966 patients in 43 original research studies with chronic pain who underwent DBS (340 for DBS-P and 625 for DBS-O). Subgroup analysis revealed that DBS-P exhibited a significant effect on chronic pain relief, with a standardized mean difference (SMD) of 1.65 and a 95% confidence interval (CI) of [1.31; 2.00]. Significant heterogeneity was observed among the studies, with an I^2 value of 85.8%. However, no significant difference was found between DBS-P and DBS-O subgroups. Subgroup analyses based on study design, age, pain diseases, and brain targets demonstrated varying levels of evidence for the effectiveness of DBS across different subgroups. Additionally, meta-regression analyses showed no significant relationship between age or pain duration and DBS effectiveness for chronic pain. CONCLUSION: These findings significantly contribute to the expanding body of knowledge regarding the utility of DBS in the management of chronic pain. The study underscores the importance of conducting further research to enhance treatment outcomes and elucidate patient-specific factors that are associated with treatment response. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=428442, identifier CRD42023428442.
\n \n\n \n \nAIMS/HYPOTHESIS: Diabetes mellitus is associated with impaired insulin secretion, often aggravated by oversecretion of glucagon. Therapeutic interventions should ideally correct both defects. Glucagon-like peptide 1 (GLP-1) has this capability but exactly how it exerts its glucagonostatic effect remains obscure. Following its release GLP-1 is rapidly degraded from GLP-1(7-36) to GLP-1(9-36). We hypothesised that the metabolite GLP-1(9-36) (previously believed to be biologically inactive) exerts a direct inhibitory effect on glucagon secretion and that this mechanism becomes impaired in diabetes. METHODS: We used a combination of glucagon secretion measurements in mouse and human islets (including islets from donors with type 2 diabetes), total internal reflection fluorescence microscopy imaging of secretory granule dynamics, recordings of cytoplasmic Ca2+ and measurements of protein kinase A activity, immunocytochemistry, in vivo physiology and GTP-binding protein dissociation studies to explore how GLP-1 exerts its inhibitory effect on glucagon secretion and the role of the metabolite GLP-1(9-36). RESULTS: GLP-1(7-36) inhibited glucagon secretion in isolated islets with an IC50 of 2.5 pmol/l. The effect was particularly strong at low glucose concentrations. The degradation product GLP-1(9-36) shared this capacity. GLP-1(9-36) retained its glucagonostatic effects after genetic/pharmacological inactivation of the GLP-1 receptor. GLP-1(9-36) also potently inhibited glucagon secretion evoked by \u03b2-adrenergic stimulation, amino acids and membrane depolarisation. In islet alpha cells, GLP-1(9-36) led to inhibition of Ca2+ entry via voltage-gated Ca2+ channels sensitive to \u03c9-agatoxin, with consequential pertussis-toxin-sensitive depletion of the docked pool of secretory granules, effects that were prevented by the glucagon receptor antagonists REMD2.59 and L-168049. The capacity of GLP-1(9-36) to inhibit glucagon secretion and reduce the number of docked granules was lost in alpha cells from human donors with type 2 diabetes. In vivo, high exogenous concentrations of GLP-1(9-36) (>100 pmol/l) resulted in a small (30%) lowering of circulating glucagon during insulin-induced hypoglycaemia. This effect was abolished by REMD2.59, which promptly increased circulating glucagon by >225% (adjusted for the change in plasma glucose) without affecting pancreatic glucagon content. CONCLUSIONS/INTERPRETATION: We conclude that the GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of glucagon secretion. We propose that the increase in circulating glucagon observed following genetic/pharmacological inactivation of glucagon signalling in mice and in people with type 2 diabetes reflects the removal of GLP-1(9-36)'s glucagonostatic action.
\n \n\n \n \nPharmacological studies established a role for AMPARs in the mammalian forebrain in spatial memory performance. Here we generated global GluA1/3 double knockout mice (Gria1/3-/-) and conditional knockouts lacking GluA1 and GluA3 AMPAR subunits specifically from principal cells across the forebrain (Gria1/3\u0394Fb). In both models, loss of GluA1 and GluA3 resulted in reduced hippocampal GluA2 and increased levels of the NMDAR subunit GluN2A. Electrically-evoked AMPAR-mediated EPSPs were greatly diminished, and there was an absence of tetanus-induced LTP. Gria1/3-/- mice showed premature mortality. Gria1/3\u0394Fb mice were viable, and their memory performance could be analyzed. In the Morris water maze (MWM), Gria1/3\u0394Fb mice showed profound long-term memory deficits, in marked contrast to the normal MWM learning previously seen in single Gria1-/- and Gria3-/- knockout mice. Our results suggest a redundancy of function within the pool of available ionotropic glutamate receptors for long-term spatial memory performance.
\n \n\n \n \nDigital health tools, platforms, and artificial intelligence- or machine learning-based clinical decision support systems are increasingly part of health delivery approaches, with an ever-greater degree of system interaction. Critical to the successful deployment of these tools is their functional integration into existing clinical routines and workflows. This depends on system interoperability and on intuitive and safe user interface design. The importance of minimizing emergent workflow stress through human factors research and purposeful design for integration cannot be overstated. Usability of tools in practice is as important as algorithm quality. Regulatory and health technology assessment frameworks recognize the importance of these factors to a certain extent, but their focus remains mainly on the individual product rather than on emergent system and workflow effects. The measurement of performance and user experience has so far been performed in ad hoc, nonstandardized ways by individual actors using their own evaluation approaches. We propose that a standard framework for system-level and holistic evaluation could be built into interacting digital systems to enable systematic and standardized system-wide, multiproduct, postmarket surveillance and technology assessment. Such a system could be made available to developers through regulatory or assessment bodies as an application programming interface and could be a requirement for digital tool certification, just as interoperability is. This would enable health systems and tool developers to collect system-level data directly from real device use cases, enabling the controlled and safe delivery of systematic quality assessment or improvement studies suitable for the complexity and interconnectedness of clinical workflows using developing digital health technologies.
\n \n\n \n \nNormothermic machine perfusion (NMP) enables pretransplant assessment of high-risk donor livers. The VITTAL trial demonstrated that 71% of the currently discarded organs could be transplanted with 100% 90-day patient and graft survivals. Here, we report secondary end points and 5-year outcomes of this prospective, open-label, phase 2 adaptive single-arm study. The patient and graft survivals at 60 months were 82% and 72%, respectively. Four patients lost their graft due to nonanastomotic biliary strictures, one caused by hepatic artery thrombosis in a liver donated following brain death, and 3 in elderly livers donated after circulatory death (DCD), which all clinically manifested within 6 months after transplantation. There were no late graft losses for other reasons. All the 4 patients who died during the study follow-up had functioning grafts. Nonanastomotic biliary strictures developed in donated after circulatory death livers that failed to produce bile with pH >7.65 and bicarbonate levels >25\u00a0mmol/L. Histological assessment in these livers revealed high bile duct injury scores characterized by arterial medial necrosis. The quality of life at 6 months significantly improved in all but 4 patients suffering from nonanastomotic biliary strictures. This first report of long-term outcomes of high-risk livers assessed by normothermic machine perfusion demonstrated excellent 5-year survival without adverse effects in all organs functioning beyond 1 year (ClinicalTrials.gov number NCT02740608).
\n \n\n \n \nINTRODUCTION: This article is part of the Research Topic 'Health Systems Recovery in the Context of COVID-19 and Protracted Conflict'. Children's surgical services are crucial, yet underappreciated, for children's health and must be sufficiently addressed to make and sustain progress toward universal health coverage (UHC). Despite their considerable burden and socioeconomic cost, surgical diseases have been relatively neglected in favor of communicable diseases living up to their inauspicious moniker: 'the neglected stepchild of global health'. This article aims to raise awareness around children's surgical diseases and offers perspectives from two prototypical LMICs on strengthening surgical services in the context of health systems recovery following the COVID-19 experience to make and sustain progress toward UHC. APPROACH: We used a focused literature review supplemented by the perspectives of local experts and the 6-components framework for surgical systems planning to present two case studies of Bangladesh and Zimbabwe. The lived experiences of the authors are used to describe the impact of COVID-19 on respective surgical systems and offer perspectives on building back the health system and recovering essential health services for sustainability and resilience. FINDINGS: We found that limited high-level policy and planning instruments, an overburdened and under-resourced health and allied workforce, underdeveloped surgical infrastructure (from key utilities to essential medical products), lack of locally generated research, and the specter of prohibitively high out-of-pocket costs for children's surgery are common challenges in both countries that have been exacerbated by the COVID-19 pandemic. DISCUSSION: Continued chronic underinvestment and inattention to children's surgical diseases coupled with the devastating effect of the COVID-19 pandemic threaten progress toward key global health objectives. Urgent attention and investment in the context of health systems recovery is needed from policy to practice levels to improve infrastructure; attract, retain and train the surgical and allied health workforce; and improve service delivery access with equity considerations to meet the 2030 Lancet Commission goals, and make and sustain progress toward UHC and the SDGs.
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