LYCHOS is a human hybrid of a plant-like PIN transporter and a GPCR.

Lysosomes have crucial roles in regulating eukaryotic metabolism and cell growth by acting as signalling platforms to sense and respond to changes in nutrient and energy availability1. LYCHOS (GPR155) is a lysosomal transmembrane protein that functions as a cholesterol sensor, facilitating the cholesterol-dependent activation of the master protein kinase mechanistic target of rapamycin complex 1 (mTORC1)2. However, the structural basis of LYCHOS assembly and activity remains unclear. Here we determine several high-resolution cryo-electron microscopy structures of human LYCHOS, revealing a homodimeric transmembrane assembly of a transporter-like domain fused to a G-protein-coupled receptor (GPCR) domain. The class B2-like GPCR domain is captured in the apo state and packs against the surface of the transporter-like domain, providing an unusual example of a GPCR as a domain in a larger transmembrane assembly. Cholesterol sensing is mediated by a conserved cholesterol-binding motif, positioned between the GPCR and transporter domains. We reveal that the LYCHOS transporter-like domain is an orthologue of the plant PIN-FORMED (PIN) auxin transporter family, and has greater structural similarity to plant auxin transporters than to known human transporters. Activity assays support a model in which the LYCHOS transporter and GPCR domains coordinate to sense cholesterol and regulate mTORC1 activation.

Introducing a specified on-line multimodal prehabilitation approach for total knee replacement surgery candidates using data from the COVID-19 pandemic: An exploratory field-based, pre-post, mixed methods implementation pilot study.

RATIONALE: Individuals waiting for total-knee-replacement surgery are at risk of developing morbidities and frailty which may affect their postoperative recovery. Multi-modal prehabilitation could mitigate these unintentional effects. AIMS AND OBJECTIVES: To implement and evaluate a specified online multi-modal prehabilitation intervention in patients waiting for total-knee-replacement surgery in a large urban acute hospital trust. METHOD: A non-randomised, pre/post analysis implementation pilot with a nested qualitative study was conducted and is reported following the standards for implementation studies (StaRI) guidance. Of 35 listed cases, 12 (34%) were eligible, recruited, and completed an 8-week multi-modal online intervention incorporating 5 modalities (i) cardiovascular exercise, (ii) strength/balance function, (iii) smoking cessation, (iv) opioid use, (v) nutritional intake. Interventions were specified using the Rehabilitation Treatment Specification System, where rehabilitation treatment theory accounts for discrete treatment components. Two participated in an online qualitative interview post-intervention. Process evaluation included intervention fidelity, eligibility/recruitment/retention rates, and clinical outcomes included knee function, frailty, gait velocity, anxiety/depression, and quality of life. RESULTS: Five participants (42%) completed the intervention and were retained at follow-up. The intervention was delivered online at specified doses, frequency/durations indicative of high respective adherence, quantity, and exposure fidelity. There was significant improvement in median oxford knee score (p = 0.015), gait velocity (p = 0.040) and anxiety (p = 0.023). The interview revealed 5 themes; surgery preconceptions, motivation, acceptability, postoperative experiences, and future recommendations confirming acceptance of the intervention by virtue of adhering to the treatment exposure delivered as planned. CONCLUSION: The specified multi-modal prehabilitation was acceptable, implementable, and demonstrated evidence of preliminary efficacy. Further experimental pilot work that represents the spectrum of frailty, obesity, quality of life, and comorbidities associated with total-knee-replacement surgery is indicated.

Immunometabolism and mitochondria in inflammatory bowel disease: a role for therapeutic intervention?

Inflammatory bowel diseases (IBDs), incurable conditions characterised by recurrent episodes of immune-mediated gut inflammation and damage of unknown aetiology, are common. Current advanced therapies target key leukocyte-trafficking and cytokine-signalling hubs but are only effective in 50% of patients. With growing evidence of mitochondrial dysfunction in IBD and advances in our understanding of the role of metabolism in inflammation, we provide an overview of novel metabolic approaches to IBD therapy, challenging the current 'therapeutic ceiling', identifying critical pathways for intervention and re-imagining metabolic biomarkers for the 21st century.

A radiographic artificial intelligence tool to identify candidates suitable for partial knee arthroplasty.

INTRODUCTION: Knee osteoarthritis is a prevalent condition frequently necessitating knee replacement surgery, with demand projected to rise substantially. Partial knee arthroplasty (PKA) offers advantages over total knee arthroplasty (TKA), yet its utilisation remains low despite guidance recommending consideration alongside TKA in shared decision making. Radiographic decision aids exist but are underutilised due to clinician time constraints. MATERIALS AND METHODS: This research develops a novel radiographic artificial intelligence (AI) tool using a dataset of knee radiographs and a panel of expert orthopaedic surgeons' assessments. Six AI models were trained to identify PKA candidacy. RESULTS: 1241 labelled four-view radiograph series were included. Models achieved statistically significant accuracies above random assignment, with EfficientNet-ES demonstrating the highest performance (AUC 95%, F1 score 83% and accuracy 80%). CONCLUSIONS: The AI decision tool shows promise in identifying PKA candidates, potentially addressing underutilisation of this procedure. Its integration into clinical practice could enhance shared decision making and improve patient outcomes. Further validation and implementation studies are warranted to assess real-world utility and impact.

Can ChatGPT make surgical decisions with confidence similar to experienced knee surgeons?

BACKGROUND: Unicompartmental knee replacements (UKRs) have become an increasingly attractive option for end-stage single-compartment knee osteoarthritis (OA). However, there remains controversy in patient selection. Natural language processing (NLP) is a form of artificial intelligence (AI). We aimed to determine whether general-purpose open-source natural language programs can make decisions regarding a patient's suitability for a total knee replacement (TKR) or a UKR and how confident AI NLP programs are in surgical decision making. METHODS: We conducted a case-based cohort study using data from a separate study, where participants (73 surgeons and AI NLP programs) were presented with 32 fictitious clinical case scenarios that simulated patients with predominantly medial knee OA who would require surgery. Using the overall UKR/TKR judgments of the 73 experienced knee surgeons as the gold standard reference, we calculated the sensitivity, specificity, and positive predictive value of AI NLP programs to identify whether a patient should undergo UKR. RESULTS: There was disagreement between the surgeons and ChatGPT in only five scenarios (15.6%). With the 73 surgeons' decision as the gold standard, the sensitivity of ChatGPT in determining whether a patient should undergo UKR was 0.91 (95% confidence interval (CI): 0.71 to 0.98). The positive predictive value for ChatGPT was 0.87 (95% CI: 0.72 to 0.94). ChatGPT was more confident in its UKR decision making (surgeon mean confidence = 1.7, ChatGPT mean confidence = 2.4). CONCLUSIONS: It has been demonstrated that ChatGPT can make surgical decisions, and exceeded the confidence of experienced knee surgeons with substantial inter-rater agreement when deciding whether a patient was most appropriate for a UKR.

Long-term outcomes and predictors of vedolizumab persistence in ulcerative colitis.

Background: Long-term vedolizumab (VDZ) outcomes in real-world cohorts have been largely limited to 1-year follow-up, with few bio-naïve patients or objective markers of inflammation assessed. Objectives: We aimed to assess factors affecting VDZ persistence including clinical, biochemical and faecal biomarker remission at 1, 3 and 5 years. Design: We performed a retrospective, observational, cohort study. Methods: All adult inflammatory bowel disease (IBD) patients who had received VDZ induction for ulcerative colitis (UC)/IBD-unclassified (IBDU) were included. Baseline phenotype and follow-up data were collected via a review of electronic medical records. Results: We included 290 patients [UC n = 271 (93.4%), IBDU n = 19 (6.6%)] with a median time on VDZ of 27.6 months (interquartile range: 14.4-43.2). At the end of follow-up, a total of 157/290 (54.1%) patients remained on VDZ. The median time to discontinuation was 14.1 months (7.0-23.3). Previous exposure to ⩾1 advanced therapy, steroid use at baseline and disease extension (E3 and E2 versus E1) were independent predictors for worse VDZ persistence. Clinical remission (partial Mayo < 2) was 75.7% (171/226), 72.4% (157/217) and 70.2% (127/181) at years 1, 3 and 5, respectively. Steroid use during maintenance VDZ therapy occurred in 31.7% (92/290), hospitalization in 15.5% (45/290) and surgery in 3.4% (10/291). The rate of serious adverse events was 1.2 per 100 patient-years of follow-up. Conclusion: VDZ effectiveness appears enduring with favourable long-term safety profile. VDZ persistence was influenced by previous exposure to biologics/small molecules, disease distribution and steroid use at baseline in our study.

Vedolizumab long-term use in ulcerative colitis What was this study done? • Vedolizumab efficacy and safety in ulcerative colitis have been firmly established by existing evidence. • Long-term data from the GEMINI trial further corroborate the favourable safety profile over an extended duration but there is little data on long-term vedolizumab use over 1 year. What did the researches do? • We performed a retrospective, observational, cohort study. All adult IBD patients who ever received vedolizumab induction from November 2014 to December 2021 for ulcerative colitis/IBDU were included. What did the researchers find? • This real-world study demonstrates that vedolizumab persistence exceeds 80% at 1 year and remains nearly 50% at 5 years with no new safety signals. • Worse vedolizumab persistence is associated with prior exposure to biologics/small molecules, more extensive disease involvement and steroid use at vedolizumab initiation. What do the findings mean? • These findings have important implications for drug positioning and sequencing, as well as for optimizing outcomes when vedolizumab is utilized as first-line therapy. Furthermore, it also emphasizes the long-term safety profile.

British Axial Spondyloarthritis Inception Cohort (BAxSIC): a protocol for a multicentre real-world observational cohort study of early axial spondyloarthritis.

Objectives: Timely diagnosis remains a challenge in axial SpA (axSpA). In addition, data are scarce on the impact of diagnostic delay and disease progression in affected individuals. The British Axial Spondyloarthritis Inception Cohort (BAxSIC) study aims to investigate the impact of newly diagnosed axSpA, the natural history of the disease and the effect of diagnostic delay on disease outcomes. Methods: BAxSIC is a prospective, multicentre, observational study. Eligible participants are adults (≥16 years of age), with a physician-confirmed diagnosis of axSpA in the 6 months prior to study entry, recruited from secondary and tertiary rheumatology centres in the UK. Participants will be followed up for 3 years, with in-person visits at baseline and 24 months. In addition, patient self-reported assessments will be recorded remotely via the online electronic case report form (eCRF) at 6, 12, 18, 30 and 36 months. Results: The first patient was enrolled in BAxSIC in June 2023. Recruitment is currently ongoing and is planned to end in June 2026. Initial results will be available in 2027. Since opening, the trial has undergone two protocol amendments. Conclusion: The BAxSIC study is the first inception cohort designed to investigate the impact of diagnostic delay on clinical presentation and long-term functional outcomes in patients with axSpA in the UK. With an innovative, patient-led virtual longitudinal data collection model, data generated from this study will help inform and improve the care of people newly diagnosed with axSpA. Trial registration: ClinicalTrials.gov (http://clinicaltrials.gov), NCT05676775.

Assessing the Value of Imaging Data in Machine Learning Models to Predict Patient-Reported Outcome Measures in Knee Osteoarthritis Patients.

Knee osteoarthritis (OA) affects over 650 million patients worldwide. Total knee replacement is aimed at end-stage OA to relieve symptoms of pain, stiffness and reduced mobility. However, the role of imaging modalities in monitoring symptomatic disease progression remains unclear. This study aimed to compare machine learning (ML) models, with and without imaging features, in predicting the two-year Western Ontario and McMaster Universities Arthritis Index (WOMAC) score for knee OA patients. We included 2408 patients from the Osteoarthritis Initiative (OAI) database, with 629 patients from the Multicenter Osteoarthritis Study (MOST) database. The clinical dataset included 18 clinical features, while the imaging dataset contained an additional 10 imaging features. Minimal Clinically Important Difference (MCID) was set to 24, reflecting meaningful physical impairment. Clinical and imaging dataset models produced similar area under curve (AUC) scores, highlighting low differences in performance AUC < 0.025). For both clinical and imaging datasets, Gradient Boosting Machine (GBM) models performed the best in the external validation, with a clinically acceptable AUC of 0.734 (95% CI 0.687-0.781) and 0.747 (95% CI 0.701-0.792), respectively. The five features identified included educational background, family history of osteoarthritis, co-morbidities, use of osteoporosis medications and previous knee procedures. This is the first study to demonstrate that ML models achieve comparable performance with and without imaging features.

An implementation evaluation of a sports-based health intervention for underrepresented middle school youth in Philadelphia.

Multicomponent, community-based programs aiming to improve health behaviors in youth are needed but can be challenging to implement. Research is needed to better understand the factors that facilitate and inhibit effective implementation of these programs especially for youth at increased risk of health disparities. This study aimed to identify and explore the implementation determinants and outcomes of a multicomponent health intervention conducted from 2021 to 2022 for middle school students living in underserved communities in Philadelphia, PA, USA. Mixed methods approaches, including self-report surveys and semi-structured qualitative interviews, were administered to 18 members of the implementation staff at the end of the program, including coaches (n = 7), assistant coaches (n = 2), school champions (n = 6), administrative leaders (n = 2), and a school district administrator (n = 1). Survey and interview questions were guided by the Consolidated Framework for Implementation Research (CFIR), and interviews were thematically coded following transcription based on 26 CFIR constructs. Innovation source, evidence strength and quality, cosmopolitanism, and the personal attributes of individuals were key constructs associated with implementation effectiveness. Data revealed three multidimensional themes that highlighted broader challenges influencing implementation: (i) broad consensus, different interpretations, (ii) staffing challenges, and (iii) continuity is key. The need for the program was clearly recognized and overall belief in the purpose of the intervention was strong among key program staff and administration. However, issues including limited engagement with training, staffing turnover, and the rotational programming design hindered implementation. Future projects aiming to implement multicomponent after-school time interventions must ensure a consistent vision among partners and continuity in program delivery.

There is a pressing need for effective interventions to improve health behaviors in youth and schools are ideal settings for this work. The needs are even greater in underresourced school settings where youth have limited access to sports and physical activity. However, implementing multicomponent sports-based programs can be challenging and this leads to inconsistencies in program delivery and effectiveness. Therefore, understanding the factors that support or inhibit program implementation in schools is of great public health importance. This study aimed to evaluate the factors impacting the implementation of an after-school sport-based intervention for youth at five middle schools in Philadelphia, PA, USA. Interviews and surveys were conducted with all programming staff at the end of the program, guided by the Consolidated Framework for Implementation Research (CFIR). Program staff highlighted the need for and importance of the program, but also identified that staffing and training, variability in approaches used, and a lack of consistent support for students were key issues that affected program success. Future programs should focus efforts and resources on hiring and training staff and providing support and consistency for youth to improve the implementation of these important programs in school settings.

Introducing the UK Antimicrobial Registry (UKAR) study: providing real world data on new antimicrobials to support antimicrobial stewardship and tackle antimicrobial resistance.

The UK Antimicrobial Registry (UKAR) has been developed to capture data on real world usage of antimicrobial agents with an initial focus on those used to treat drug-resistant infections. Several industry partners have committed support for the study, which is included in the National Institute for Health and Care Research (NIHR) portfolio in England with similar arrangements in the three devolved UK nations. The two antimicrobials in the National Institute for Health and Care Excellence (NICE) subscription model pilot (cefiderocol and ceftazidime/avibactam) are included in the UKAR and future expansion of work in this area is planned. This model decouples payment from usage by using a fixed annual fee. The study will provide information on the characteristics of patients receiving study drugs, the infections being treated, treatment effectiveness and adverse events. UKAR potentially provides a novel resource of enduring value to support healthcare in the UK and more widely and contribute to AMR National Action Plan goals for optimal use of antimicrobials.

Renal Transplant Outcomes in Plasma Cell Dyscrasias and AL Amyloidosis after Treatment with Daratumumab.

Background: The morbidity and mortality from AL amyloidosis has significantly improved with the development of novel treatments. Daratumumab is a highly effective treatment for AL amyloidosis, but end-stage kidney disease is a common complication of this condition. Kidney transplantation is the ideal form of renal replacement therapy but has historically been contraindicated in this group of patients. Methods: Given the improved survival and better treatments of both conditions, we argue that it is time to reconsider transplanting these patients. Results: We report our experience of transplanting four patients with AL amyloidosis who had achieved stable remission through treatment with daratumumab. Conclusions: We highlight the key challenges involved and discuss important clinical issues for patients receiving daratumumab, particularly the difficulties with interpreting the crossmatch in light of daratumumab and immunoglobulin therapy interference. We also discuss the complexities involved in balancing the risks of infection, relapse, rejection, and immunosuppression in such patients.

Femorotibial angle scan-rescan reproducibility: A high-precision calculation on a large cohort.

PURPOSE: Femorotibial angle (FTA) is a convenient measure of coronal knee alignment that can be extracted from a short knee radiograph, avoiding the additional radiation exposure and specialist equipment required for full-leg radiographs. While intra- and inter-reader reproducibility from the same image has been reported, the full scan-rescan reproducibility across images, as calculated in this study, has not. METHODS: In this study, 4589 FTA measurement pairs from 2586 subjects acquired a year apart were used to estimate FTA scan-rescan reproducibility using data from the Osteoarthritis Initiative. Subjects with radiographic progression of osteoarthritis or other conditions that may cause a change in coronal knee alignment were excluded. Measurement pairs were analysed using paired-samples  t $t$ tests to detect differences and compared to symptomatic changes in Western Ontario and McMaster Universities Arthritis Index scores for joint pain, stiffness and physical function to detect correlations. RESULTS: The 95% limit of agreement and the paired-samples correlation were calculated with high precision to be [-1.76°, +1.78°] and 0.938, considerably worse than the corresponding figures for intra- and inter-reader reproducibility, without relation to symptomatic or radiographic changes in knee condition. This error will weakly attenuate R 2 ${R}^{2}$ and r $r$ values from their true values in correlative studies involving FTA. The realistic maximum value for R 2 ${R}^{2}$ is 87% and for Pearson's r $r$ is 93%. CONCLUSION: The scan-rescan reproducibility in FTA is almost double the intra- and inter-reader reliability from a single scan. At almost ±2° accuracy, FTA is inappropriate for surgical use, but it is sufficiently reproducible to produce good correlations in studies predicting disease incidence and progression. LEVEL OF EVIDENCE: Level II, retrospective study.

Ethnicity and Observed Oxygen Saturations, Fraction of Inspired Oxygen, and Clinical Outcomes: A Post-Hoc Analysis of the Oxy-PICU Trial of Conservative Oxygenation.

OBJECTIVES: A conservative oxygenation strategy, targeting peripheral oxygen saturations (Sp o2 ) between 88% and 92% in mechanically ventilated children in PICU, was associated with a shorter duration of organ support and greater survival compared with Sp o2 greater than 94% in our recent Oxy-PICU trial. Sp o2 monitors may overestimate arterial oxygen saturation (Sa o2 ) in patients with higher levels of skin pigmentation compared with those with less skin pigmentation. We investigated if ethnicity was associated with changes in distributions of Sp o2 and F io2 and outcome. DESIGN: Post-hoc analysis of a pragmatic, open-label, multicenter randomized controlled trial. SETTING: Fifteen PICUs across the United Kingdom and Scotland. PATIENTS: Children aged 38 weeks corrected gestational age to 15 years accepted to a participating PICU as an unplanned admission and receiving invasive mechanical ventilation with supplemental oxygen for abnormal gas exchange. METHODS: Hierarchical regression models for Sp o2 and F io2 , and ordinal models for the primary trial outcome of a composite of the duration of organ support at 30 days and death, were used to examine the effects of ethnicity, accounting for baseline Sp o2 , F io2 , and mean airway pressure and trial allocation. MEASUREMENTS AND MAIN RESULTS: Ethnicity data were available for 1577 of 1986 eligible children, 1408 (89.3%) of which were White, Asian, or Black. Sp o2 and F io2 distributions did not vary according to Black or Asian ethnicity compared with White children. The trial primary outcome measure also did not vary significantly with ethnicity. The point estimate for the treatment effect of conservative oxygenation in Black children was 0.64 (95% CI, 0.33-1.25) compared with 0.84 (0.68-1.04) in the overall trial population. CONCLUSIONS: These data do not suggest that the association between improved outcomes and conservative oxygenation strategy in mechanically ventilated children in PICU is modified by ethnicity.

Spectroscopic confirmation of two luminous galaxies at a redshift of 14.

The first observations of the James Webb Space Telescope (JWST) have revolutionized our understanding of the Universe by identifying galaxies at redshift z ≈ 13 (refs. 1-3). In addition, the discovery of many luminous galaxies at Cosmic Dawn (z > 10) has suggested that galaxies developed rapidly, in apparent tension with many standard models4-8. However, most of these galaxies lack spectroscopic confirmation, so their distances and properties are uncertain. Here we present JWST Advanced Deep Extragalactic Survey-Near-Infrared Spectrograph spectroscopic confirmation of two luminous galaxies at z = 14.32 - 0.20 + 0.08 and z = 13.90 ± 0.17. The spectra reveal ultraviolet continua with prominent Lyman-α breaks but no detected emission lines. This discovery proves that luminous galaxies were already in place 300 million years after the Big Bang and are more common than what was expected before JWST. The most distant of the two galaxies is unexpectedly luminous and is spatially resolved with a radius of 260 parsecs. Considering also the very steep ultraviolet slope of the second galaxy, we conclude that both are dominated by stellar continuum emission, showing that the excess of luminous galaxies in the early Universe cannot be entirely explained by accretion onto black holes. Galaxy formation models will need to address the existence of such large and luminous galaxies so early in cosmic history.

Effectiveness of secukinumab in radiographic and non-radiographic axial spondyloarthritis: a European routine-care observational study.

OBJECTIVES: To compare the treatment effectiveness of secukinumab in radiographic (r) versus non-radiographic (nr) axial spondyloarthritis (axSpA) patients treated in routine care across Europe. METHODS: Prospectively collected data on secukinumab-treated axSpA patients with known radiographic status were pooled from nine countries.Remission rates based on patient-reported outcomes (PROs; Numeric Rating Scale (0-10), for example, pain ≤2/Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≤2 and Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease (ID) <1.3 after 6/12/24 months of secukinumab treatment were calculated.Remission and drug retention rates in r-axSpA versus nr-axSpA patients were compared by logistic and Cox regression models (unadjusted/adjusted for age+sex/adjusted for multiple confounders). RESULTS: Overall, 1161 secukinumab-treated patients were included (r-axSpA/nr-axSpA: 922/239). At baseline, r-axSpA patients had longer disease duration and higher C reactive protein, were more often male and HLA-B27 positive and had received fewer prior biological or targeted synthetic disease-modifying antirheumatic drugs compared with nr-axSpA patients, whereas PROs were largely similar.During follow-up, crude PRO remission rates were significantly higher in r-axSpA compared with nr-axSpA patients (6 months: pain≤2: 40%/28%, OR=1.7; BASDAI≤2: 37%/25%, OR=1.8), as were drug retention rates (24 months: 66%/58%, HR 0.73 (ref: r-axSpA)). Proportions of patients achieving ASDAS ID were low for both groups, particularly nr-axSpA (6 months: 11%/8%).However, when adjusting for age+sex, these differences diminished, and after adjusting for multiple confounders, no significant between-group differences remained for either remission or drug retention rates. CONCLUSION: Crude remission/drug retention rates in European secukinumab-treated patients were higher in r-axSpA compared with nr-axSpA patients. In adjusted analyses, secukinumab effectiveness was similar in both groups, suggesting that observed differences were related to factors other than radiographic status.

Understanding P-Rex regulation: structural breakthroughs and emerging perspectives.

Rho GTPases are a family of highly conserved G proteins that regulate numerous cellular processes, including cytoskeleton organisation, migration, and proliferation. The 20 canonical Rho GTPases are regulated by ∼85 guanine nucleotide exchange factors (GEFs), with the largest family being the 71 Diffuse B-cell Lymphoma (Dbl) GEFs. Dbl GEFs promote GTPase activity through the highly conserved Dbl homology domain. The specificity of GEF activity, and consequently GTPase activity, lies in the regulation and structures of the GEFs themselves. Dbl GEFs contain various accessory domains that regulate GEF activity by controlling subcellular localisation, protein interactions, and often autoinhibition. This review focuses on the two phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3)-dependent Rac exchangers (P-Rex), particularly the structural basis of P-Rex1 autoinhibition and synergistic activation. First, we discuss structures that highlight the conservation of P-Rex catalytic and phosphoinositide binding activities. We then explore recent breakthroughs in uncovering the structural basis for P-Rex1 autoinhibition and detail the proposed minimal two-step model of how PI(3,4,5)P3 and Gßγ synergistically activate P-Rex1 at the membrane. Additionally, we discuss the further layers of P-Rex regulation provided by phosphorylation and P-Rex2-PTEN coinhibitory complex formation, although these mechanisms remain incompletely understood. Finally, we leverage the available data to infer how cancer-associated mutations in P-Rex2 destabilise autoinhibition and evade PTEN coinhibitory complex formation, leading to increased P-Rex2 GEF activity and driving cancer progression and metastasis.

Thirty years of conservation breeding: Assessing the genetic diversity of captive Livingstone's fruit bats.

Fruit bats (genus Pteropus) are typically island-endemic species important in seed dispersal and reforestation that are vulnerable to increased extinction risk. An effective method of reducing extinction risk in vulnerable species that cannot be conserved in their native habitat is establishing an ex-situ captive breeding programme. Due to anthropogenic threats and low population numbers, in the early 1990s, a captive breeding programme was established at Jersey Zoo, British Isles, for Critically Endangered Livingstone's fruit bats (Pteropus livingstonii). Here we use six polymorphic microsatellite loci to assess genetic diversity in the captive breeding population of Livingstone's fruit bats (P. livingstonii), 30 years after the programme's establishment, investigating change over generations and comparing our findings with published data from the wild population. We found no significant difference between the genetic diversity in the captive and wild populations of Livingstone's fruit bats (P. livingstonii), in both expected heterozygosity and allelic richness. The captive population has retained a comparable level of genetic diversity to that documented in the wild, and there has been no significant decline in genetic diversity over the last 30 years. We advise that a full pedigree of the paternal lineage is created to improve the management of the captive breeding programme and further reduce the possibility of inbreeding. However, it appears that the captive breeding programme is currently effective at maintaining genetic diversity at levels comparable to those seen in the wild population, which suggests reintroductions could be viable if genetic diversity remains stable in captivity.

Surgical management of the diabetic foot: The current evidence.

The prevalence of diabetes mellitus and its associated complications, particularly diabetic foot pathologies, poses significant healthcare challenges and economic burdens globally. This review synthesises current evidence on the surgical management of the diabetic foot, focusing on the interplay between neuropathy, ischemia, and infection that commonly culminates in ulcers, infections, and, in severe cases, amputations. The escalating incidence of diabetes mellitus underscores the urgency for effective management strategies, as diabetic foot complications are a leading cause of hospital admissions among diabetic patients, significantly impacting morbidity and mortality rates. This review explores the pathophysiological mechanisms underlying diabetic foot complications and further examines diabetic foot ulcers, infections, and skeletal pathologies such as Charcot arthropathy, emphasising the critical role of early diagnosis, comprehensive management strategies, and interdisciplinary care in mitigating adverse outcomes. In addressing surgical interventions, this review evaluates conservative surgeries, amputations, and reconstructive procedures, highlighting the importance of tailored approaches based on individual patient profiles and the specific characteristics of foot pathologies. The integration of advanced diagnostic tools, novel surgical techniques, and postoperative care, including offloading and infection control, are discussed in the context of optimising healing and preserving limb function.