Dominant-Negative Versus Gain-of-Function STAT3 Defects: A Systematic Review on Epidemiological, Clinical, Immunological, and Molecular Aspects

\ua9 2025 American Academy of Allergy, Asthma & Immunology. Background: Germline signal transducer and activator of transcription 3 (STAT3) mutations cause 2 distinct syndromes with predominant infectious or autoimmune phenotype. Objective: The objective of this study is to compile literature reports on gain-of-function (GOF) and dominant-negative (DN) mutations in the STAT3. Methods: We searched 3 main databases including PubMed, Scopus, and Web of Science from 1990 to 2023. All full-text articles and major reviews were manually searched for additional studies. Results: A total of 490 patients were reported in 107 articles including 265 patients with DN-STAT3 and 225 patients with GOF-STAT3 mutations. Major clinical differences between STAT3-DN and STAT3-GOF patients were observed in rates of infectious complication (98.2% vs 85.4%, P <. 001), pneumonia (67.3% vs 52.1%, P =. 006), sinusitis (17.5% vs 2.1%, P <. 001), otitis (27.7% vs 5.2%, P <. 001), abscess (52.7% vs 17.7%, P <. 001), dermatologic manifestation (88.3% vs 58.4%, P <. 001), atopic disorders (66.4% vs 40.2%, P <. 001), interstitial lung disease (0.7% vs 17.7%, P <. 001), dental/gingival disorders (38.5% vs 11.7%, P <. 001), and endocrinopathies (0.9% vs 16.5%, P <. 001), respectively. Most patients had normal counts of lymphocyte subsets, with the exceptions of higher CD3+ T cells and lower natural killer cells in STAT3-DN patients, and lower CD4+ T cells in STAT3-GOF patients. Most STAT3-DN patients had either normal or high serum concentrations of IgG, IgA, and IgM with almost universal raised serum IgE. Most STAT3-GOF patients had a low level of IgG, but normal levels of IgA, IgM, and IgE. Conclusions: Patients with STAT3-DN had recurrent dermatological and pulmonary infections, eczema, elevated IgE, and eosinophilia, whereas patients with STAT3-GOF had early-onset polyautoimmunity and frequently require immunosuppressive therapy

The United Kingdom\u27s experience of controlled donation after circulatory death direct procurement of lungs with concomitant abdominal normothermic regional perfusion with an analysis of short-term outcomes

\ua9 2025 International Society for the Heart and Lung TransplantationBackground: Abdominal Normothermic Regional Perfusion (A-NRP) improves outcomes for transplanted abdominal organs from Donation after Circulatory Death (DCD) donors. Concerns have been raised about the effect of A-NRP on lungs procured during multi-organ donation. We present the UK experience of performing direct procurement (DRP) of lungs from DCD donors with A-NRP. Methods: Retrospective analysis of all 487 UK DCD lung donors between April 1, 2011 and December 31, 2023. Organ transplantation rate and 30-day, 90-day and 1-year survival rates were compared between DRP of DCD lungs, DRP of DCD lungs with A-NRP and donation after brainstem death (DBD) lungs. Primary graft dysfunction (PGD) rates were compared between DCD lungs with and without A-NRP. Results: Three hundred ninety-seven DCD donors resulted in a lung transplant (22 retrieved by DRP with A-NRP). There was no difference in lung transplantation rates between DRP and DRP with A-NRP. Of the 390 first adult-only lung transplants performed from DCD donors, there was no significant difference in 30-day, 90-day and 1-year survival between DRP of DCD lungs and DRP with A-NRP. There was a significant difference in survival between standard DCD donors and DBD donors at 30-days and 90-days, but not 1 year. There was no significant difference in grade 3 PGD rates at 72 hours post-implantation for DCD lungs with or without A-NRP. Conclusion: In the UK experience, use of A-NRP is not detrimental to procurement of DCD lungs. We advocate the use of this technique until further studies can explore the safety and efficacy of thoraco-abdominal NRP for lungs in multi-organ retrieval

Baseline Characteristics of the TOPaZ Study: Randomised Trial of Teriparatide and Zoledronic Acid Compared with Standard Care in Adults with Osteogenesis Imperfecta

\ua9 The Author(s) 2025. Introduction: Osteogenesis imperfecta (OI) is a rare disorder causing multiple fractures throughout life. No treatment has been shown to reduce the risk of fractures in OI. Here, we present the baseline characteristics of participants in the Treatment of Osteogenesis Imperfecta with Parathyroid Hormone and Zoledronic Acid (TOPaZ) trial. The aim of the trial is to determine whether teriparatide and zoledronic acid are superior to standard care in reducing the risk of clinical fractures. Methods: We summarised data on the baseline characteristics of TOPaZ participants, including demographics, genetic diagnosis, clinical features, bone density measurements, previous treatments, and fracture history. Results: We recruited 350 adults with a clinical diagnosis of OI in 27 European referral centres between June 2017 and October 2022. Overall, 266 (76.2%) had type I OI, 55 (15.8%) had type IV, and 19 (5.4%) had type III. The type was unknown in 9 (2.6%). Blue sclera were noted in 80.8%, and 35.8% had dentinogenesis imperfecta. Bisphosphonates had been administered to 28.1% in the 2 years prior to enrolment. Pathogenic variants in COL1A1 or COL1A2 were found in 87.6%. Fractures occurring in the 2 years prior to enrolment were not associated with bone density. Conclusions: The TOPaZ population represents a unique cohort with which to study the genetic epidemiology and outcome of OI in relation to bone density and biochemical markers of bone turnover. When the trial reports, it will also provide new insights into the effect of an anabolic therapy, followed by antiresorptive treatment in the management of OI

Minimally invasive thoracoscopically-guided right minithoracotomy versus conventional sternotomy for mitral valve repair: the UK Mini Mitral multicentre RCT

Background: The safety, effectiveness and cost-effectiveness of mitral valve repair via thoracoscopically guided minithoracotomy compared with conventional median sternotomy (Sternotomy) in patients with degenerative mitral valve regurgitation is uncertain and widely debated. Objectives: To determine if Mini was more effective than Sternotomy in terms of physical functioning and associated return to usual activities and was cost-effective compared with Sternotomy. Design: A pragmatic, multicentre, expertise-based, superiority, randomised trial. Participants: Adults with degenerative mitral valve regurgitation undergoing mitral valve repair surgery. Setting: Ten tertiary care institutions in the United Kingdom. Intervention: Mini or Sternotomy mitral valve repair performed by an expert surgeon. Blinding: Primary outcome measure [Short Form 36-item Health Survey, version 2 (SF-36v2) physical functioning score] was measured by an independent assessor, blinded to allocation. Echocardiographic findings were measured in a core laboratory, blinded to allocation. Outcome Measures: Primary outcomes were physical functioning and associated return to usual activities measured by change from baseline in SF-36v2 physical function domain at 12 weeks following index surgery. The primary economic measure was incremental cost per quality-adjusted life-year over the year following surgery. Secondary outcomes included recurrent mitral regurgitation grade, physical activity and quality of life measured at time points to 1 year. Safety outcomes included death, repeat mitral valve surgery or heart failure hospitalisation up to 1 year. Results: Between November 2016 and January 2021, 330 participants were randomised; 166 to Mini and 164 to Sternotomy. Of these, 309 underwent surgery and 294 reported the primary outcome. Thirty per cent were female. At 12 weeks, mean difference between groups in the change in SF-36v2 physical function T-scores was 0.68 (95% confidence interval -1.89 to 3.26). Valve repair rates (96%) were similar in both groups. Echocardiography demonstrated mitral regurgitation severity as none or mild for 92% of participants at 1 year in both groups. The composite safety outcome occurred in 5.4% (9/166) of Mini and 6.1% (10/163) of Sternotomy participants at 1 year. On average, Mini was more costly \ua329,424 (95% confidence interval 26,909 to 31,940) versus \ua327,397 (95% confidence interval 25,172 to 29,620) and more effective 0.81 quality-adjusted life-years (95% confidence interval 0.78 to 0.84) versus 0.78 (95% confidence interval 0.75 to 0.81) than Sternotomy. The adjusted incremental cost-effectiveness ratio was \ua374,863 per quality-adjusted life-year for the comparison between Mini and Sternotomy. Mini has a probability of < 50% of being cost-effective at the range of willingness-to-pay values considered. Limitations: To minimise bias, SF-36v2 and all echocardiographic measures were independently assessed by personnel blinded to allocation. Expertise-based randomisation was important to address the limitations of previous studies; however, it is possible that it may have introduced potential confounders. Conclusions: Mini is not superior to Sternotomy in recovery of physical function at 12 weeks. Mini achieves high rates and quality of valve repair and has similar safety outcomes at 1 year to Sternotomy. The balance of probabilities favoured Sternotomy as the preferred surgical procedure in the base-case analysis over the range of willingness-to-pay values society might consider worthwhile for a quality-adjusted life-year. Nevertheless, additional factors such as equity or patient preferences for one procedure over another may need to also be taken into account. Results provide high-quality evidence to inform shared decision-making and treatment guidelines. Future work: Work is ongoing to disseminate findings and influence guidelines; patients have consented to longer-term follow-up. From an economics perspective, the currently available evidence shows that further research into patient preferences is important to inform the choice of surgical procedure. Trial registration: This trial is registered as ISRCTN 13930454. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/192/110) and is published in full in Health Technology Assessment; Vol. 29, No. 55. See the NIHR Funding and Awards website for further award information.Mitral valve regurgitation is a disease where one of the valves in the heart becomes leaky, allowing blood to flow the wrong way. This usually happens with age as the valve becomes floppy, or the muscles around it are weakened. Patients usually become short of breath. When it becomes severe, the best treatment is heart surgery to repair the valve. During surgery, the heart valve can be accessed by cutting through the breastbone (sternotomy) or using keyhole surgery (mini thoracotomy). The UK Mini Mitral Trial compared these two types of surgery. Over 300 UK patients were split into two groups, with each group receiving one type of surgery. Both types of surgery led to patients getting better, with 96% having their valve successfully repaired. After surgery, patients in the keyhole group were discharged from hospital a day earlier than those in the Sternotomy group. To measure recovery, patients completed a questionnaire and wore an activity monitor. Those in the keyhole group did more vigorous exercise early after surgery, such as brisk walking or swimming, and had better sleep than the Sternotomy group. By 12 weeks, both groups had an equally improved activity levels and physical function than before the surgery. Heart scans at 3 months and 1 year showed that almost all patients in both groups had mild or no mitral regurgitation. This tells us that both operations continued to be successful for patients, and their regurgitation has been fixed. Complications were low among both groups. Patients in the keyhole group were less likely to experience a complication early after surgery, and at 1 year after surgery, the results were similar. Mini was on average more costly but had slightly better quality of life over 1 year than sternotomy

Liver Involvement in POLG Disease—a Multicentre Cohort Study of 202 Patients

\ua9 2025 SSIEM. Liver involvement in POLG disease is common and associated with high morbidity and mortality. Detailed, large-scale, systematic studies of liver involvement are lacking. This study aims to describe the onset, clinical course and prognostic implications of liver involvement in POLG disease. We conducted a multinational, retrospective study including clinical, genetic and biochemical data from patients with confirmed POLG disease. Patients were stratified according to age of disease onset: early-onset (< 12 years), juvenile/adult-onset (12–40 years), and late-onset (> 40 years). Of the 202 patients, 110 (54%) had liver involvement. This could present at any time during the lifespan, but occurred more frequently in patients with early-onset disease (76/98, 78%). Median onset age for liver involvement in females was 7 years (range: 1 month to 50 years), and 21 months in males (birth to 71 years). Infection-triggered disease onset carried a significantly higher risk of liver involvement than spontaneous or other disease triggers. Eighty-five percent of those with liver involvement also had epilepsy. Liver involvement was an indicator of poor prognosis and was significantly associated with worse survival. This study provides a comprehensive description of liver involvement in a large cohort of POLG disease patients. Liver involvement is common in this disease and associated with significantly worse survival. POLG disease should be considered in children presenting with liver involvement, and rapid genetic testing may guide management decisions. Our findings emphasize the need for early vigilance in monitoring liver involvement in all patients with confirmed POLG disease, particularly those with early-onset disease and during intercurrent infection

Home-based physical activity intervention (Active-at-Home-HF) improves left atrial function, exercise duration and quality of life in heart failure with preserved ejection fraction

\ua9 2025 Belgian Society of Cardiology. Background: There is limited evidence regarding the effect of physical activity interventions on exercise tolerance, left ventricular (LV) filling pressure, and quality of life (QoL) in patients with heart failure with preserved ejection fraction (HFpEF). This study assessed the acceptability, feasibility, and physiological outcome of a novel, personalised, home-based physical activity intervention in HFpEF. Methods: This was a prospective, feasibility randomised study. Forty HFpEF patients, clinically stable were randomised 2:1 ratio to an intervention group (60\ub16 years, n=25, 12 male) which involved increasing daily physical activity by 2000 steps from baseline (Active-at-Home-HF) or to standard care control group (60\ub17 years, n=15, four male) for 12 weeks. Before and after 12 weeks, patients underwent supervised exercise stress test on treadmill, and assessment of exercise stress echocardiography, QoL (Minnesota Living with Heart Failure questionnaire) and N-terminal prohormone of brain natriuretic peptide (NTproBNP) were also assessed before and after intervention. All patients were monitored weekly via telephone and pedometers. Results: In the intervention group, patients achieved target step count after three weeks (from 4457\ub1653 to 6592\ub1546 steps per day, p<0.001), and maintained throughout the duration of the study. Exercise duration increased significantly in intervention (350\ub1122 vs 463\ub1135 s) but not in control group (399\ub1126 vs 358\ub188 s, p = 0.007 group 7 time interaction) at follow-up. Left ventricular filling pressure (E/E′) improved in intervention group (12.43\ub13.6 vs 9.72\ub11.86) but was not significantly different compared to controls (12.86\ub13.17 vs 12.44\ub12.23) (group 7 time interaction, p=0.08). The left atrial (LA) reservoir strain significantly improved in intervention group (25.5\ub14.4 vs 23.3\ub14.5%) and not in non-intervention group (21.8\ub14.4 vs 21.9\ub14.8%) (p=0.015). There was no change in NTproBNP, LV ejection fraction, LV longitudinal strain, stroke volume, cardiac output, cardiac power output and right ventricular systolic function in the intervention or control group (p>0.05). There were no adverse events. Conclusions: In this study of HFpEF patients, a 12-week personalised home-based physical activity intervention is feasible, acceptable, safe, improves LA function, exercise duration and QoL and may improve LV filling pressures

Modification and validation of the Bluebelle Wound Healing Questionnaire (WHQ) for assessing surgical site infection in wounds healing by secondary intention

\ua9 2025 The Authors. Background: Surgical wounds healing by secondary intention are common. Healing is often complicated by surgical site infection (SSI). SSI assessment is important to guide treatment but existing methods generally require in-person assessment, making them resource intensive. A validated patient-reported SSI outcome measure may be useful to overcome this limitation. Aim: To modify and validate the Bluebelle Wound Healing Questionnaire (WHQ) for wounds healing by secondary intention. Methods: The 18-item Bluebelle WHQ developed for wounds healing by primary intention was modified to make it applicable to secondary healing wounds. Testing was performed as part of the SWHSI-2 randomised trial assessing negative pressure wound dressings versus standard care. Participants completed the WHQ at five timepoints; in-person (baseline, post-healing) and by post (3, 6, 12 months). A reference SSI assessment was performed by a research nurse at the time of wound healing. Acceptability and criterion validity (ability of the Bluebelle WHQ to discriminate between SSI/no SSI) were explored by examining questionnaire return rates, levels of missing data and total score sensitivity/specificity values (receiver operating characteristic curve (ROC)). Results: Baseline in-person questionnaire return rates were highest (672/686; 98 %), with postal return rates of 428/615 (68.5 %), 274/416 (65.9 %) and 186/296 (62.8 %) at follow up points. Overall, low levels of item-missing data were observed with few problems completing the questionnaire reported. Ability to discriminate between SSI/no SSI was good (Area under ROC = 0.796). Conclusion: The modified Bluebelle WHQ is a valuable tool for post-discharge assessment of wounds healing by secondary intention. It is recommended for use in research and clinical practice

Micro-mechanical characterisation of 3D-printed composites via nano-indentation and finite-element homogenization techniques: overcoming challenges in orthotropic property measurement

\ua9 The Author(s) 2025.Mechanical characterisation of 3D-printed composite materials using conventional methods, such as tension and compression tests, faces several challenges, including precise machining of complex geometries, difficulties in testing materials with time-dependent properties, and extensive sample preparation to account for varying build orientations and raster angles. Accurately characterising the mechanical properties of composite constituents is further complicated by their anisotropic nature, visco-plastic behaviour, and phase interactions at the micro-scale. Traditional nano-indentation techniques often suffer from inaccuracies due to pile-up effects and time-dependent deformations in polymer matrices. To overcome these challenges, this study introduces an innovative methodology that integrates nano-indentation and micro-mechanical analysis of a representative volume element (RVE) to determine orthotropic engineering constants. Experimental nano-indentation, coupled with atomic force microscopy, is used to obtain load–displacement curves and residual indentation marks, whilst an inverse finite-element method accounting for neighbouring phase effects and polymer matrix creep properties enhances prediction accuracy. The stiffness properties of composite constituents derived from this method are employed in an RVE-based micro-mechanical model, with effective orthotropic engineering constants validated through experimental tensile and shear tests using the Digital Image Correlation technique. This approach not only enhances micro-mechanical characterisation accuracy but also reduces the need for extensive experimental testing, offering a cost-effective and scalable solution for evaluating 3D-printed composite materials. Additionally, it bridges the gap between microstructural and bulk property measurements, reducing test sample manufacturing costs and minimising the need for repetitive experimental trials

Numerical and experimental investigation of the dynamic responses of an integrated semi-submersible floating wind-wave energy converter

\ua9 2025 Elsevier LtdThis paper introduces an integrated floating wind-wave energy conversion system, with a heave-type WEC attached to a semi-submersible braceless wind turbine\u27s central column. Numerical simulations and a 1/80 scale physical model test were used to evaluate its dynamic responses under combined wind and wave conditions. Free decay tests confirmed the numerical model\u27s accuracy in predicting the platform\u27s natural periods for surge, heave, and pitch motions, with errors under 5 %. In regular waves, numerical and experimental results for motion responses and mooring tensions were highly consistent, with maximum errors not exceeding 15 %. Under irregular waves, the maximum errors in motion responses and mooring tensions were within 19 %. In combined wind-wave conditions, except for pitch motion, the maximum errors in other responses were no more than 20 %. In high wind speed combined wind-wave conditions (23.8 m/s), the pitch error reached 40.52 %. The findings confirm the reliability of the proposed integrated system design and underscore the importance of considering the coupled effects of wind and waves on the system\u27s dynamic response, providing valuable insights for the design and optimization of offshore renewable energy systems

Informing research design through patient and public involvement; patients and carers with lived experience post-hospital discharge and potential roles for general practice pharmacists

\ua9 2025. The Author(s). BACKGROUND: Medication safety across care transitions remains a significant burden on healthcare systems. Patient and Public Involvement (PPI) is useful at the very early stages of intervention development to inform research priorities. The aim of this PPI was to scope patients\u27 and carers\u27 lived experiences of medicines management post-hospital discharge to inform the design of a research proposal. METHODS: A research planning PPI workshop and additional one-to-one discussions were undertaken with patients and informal carers who had experienced a recent discharge from hospital and were prescribed regular repeat medications. RESULTS: The 12 public contributors identified that the priority for patients was not limited to medication management alone but rather a broader care package. Multiple themes as priorities for research emerged: (1) broader holistic and social aspects of care involving various healthcare professionals, (2) practical aspects such as timeliness of follow-up and co-ordination of medication management, and (3) communication with the patient/carer and information transfer between settings. CONCLUSION: Valuable insights from this PPI helped inform future research design priorities and identify the need for a more holistic approach to care. Future work with multi-stakeholder engagement involving different professionals across sectors is needed to explore safer integrated transitions of care, as well as the use of ongoing PPI and co-design, considering populations that are most vulnerable