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Long-term real-world data on vedolizumab outcomes remain limited: the LONG-LIVE study evaluates 5-year effectiveness and safety in a large Italian cohort. This is a long-term extension of the multicenter LIVE study involving patients with Crohn's disease (CD) and ulcerative colitis (UC). The primary outcome was the cumulative probability of major adverse clinical outcomes (the composite of IBD-related surgeries, non-surgical hospitalizations, and serious adverse events). Secondary outcomes included cumulative incidences of IBD-related surgery and non-surgical hospitalization, vedolizumab persistence, rates of death, cancer and adverse events of special interest (AESIs), and longitudinal response group transitions; outcomes in elderly patients (≥ 65 years) were compared to non-elderly using inverse probability weighting (IPW). Overall, 782 patients were included (50.4% CD; 49.6% UC; 76.3% anti-tumor necrosis factor (TNF)-experienced; 4324.1 patient-years of follow-up). The 5-year probability of major adverse clinical outcomes was 29.4% (no difference between CD and UC). In CD, penetrating behavior (aHR 1.77) predicted higher risk of the primary endpoint, while colonic location was protective (aHR 0.51). In UC, the primary endpoint was predicted by elderly age (aHR 1.99) and comorbidity burden (aHR 1.27). Five-year cumulative incidences were 23.4% for surgery and 14.3% for non-surgical hospitalization. Patients with CD had higher hospitalization risk than patients with UC (sHR 1.80). Mortality, neoplasm diagnosis, and AESIs occurred at rates of 3.93, 3.93, and 6.27 per 1000 patient-years. Five-year drug persistence was 38.7%. Achieving deep remission within 24 months mediated the relationship between initial clinical response and sustained deep remission at last follow-up. After IPW, elderly patients had a higher risk of major adverse clinical outcomes and non-surgical hospitalization; AESI and cancer rates did not differ. Approximately one in three patients experienced a major adverse clinical outcome over 5 years, driven primarily by disease-related complications rather than adverse events, with a consistent safety profile across age groups. Vedolizumab is a gut-selective biologic therapy approved for Crohn's disease (CD) and ulcerative colitis (UC). While its short-term effectiveness is well established, data on what happens to patients beyond 2 years of treatment remain limited. In this study, we followed 782 patients for up to 7 years across 47 Italian centers to track hard clinical outcomes: surgery, hospitalization, serious adverse events, and death. About one in three patients experienced a major adverse clinical outcome over 5 years—a composite endpoint that includes IBD-related surgeries, non-surgical hospitalizations, and serious adverse events—with no meaningful difference between CD and UC. Surgery occurred in approximately one in five patients, and non-surgical hospitalizations were more frequent in CD. Serious adverse events, including deaths, cancers, and infections, remained uncommon throughout follow-up. Patients who responded early to treatment were more likely to achieve deep remission within 2 years, which was in turn associated with deep remission at last follow-up. Elderly patients faced higher risks of hospitalization and major adverse clinical outcomes, but not of cancer or serious adverse events, suggesting that vedolizumab can be used across different age groups without a disproportionate increase in safety risk.

The authors present a multicenter national prospective cohort of neonatal and adult BPI in Angola from January 2021 to December 2025, focused on clinical data (patient profile and surgical results using the MRC scale) and lessons learned (geographic distribution and logistics) that can be applied to other low- and lower-middle-income countries. This is a national multicenter prospective cohort of neonatal and adult BPI from January 2021 to December 2025. All patients were evaluated prior to surgery using clinical evaluation, always performed by the same nerve surgeon. All adult patients underwent electromyography. Neonatal patients were evaluated using clinical assessment only. All surgeries were performed by the same surgeon, and postoperative clinical follow-up for assessment of surgical results was also performed by the same surgeon. Sixteen neonatal BPI cases were included; 10 were female, and the mean age was 13 months (range, 8-18 months). One patient had a complete injury and underwent reconstruction with grafts; the other 15 had upper trunk injuries and underwent the Oberlin procedure. All pediatric surgeries were performed in Luanda, and all patients were from Luanda. The mean follow-up was 12 months (range, 8-28 months), and an MRC grade of 3 or higher was achieved in 7 patients (43%). Among the 86 adult patients operated on, 76% had complete BPI, and 43% underwent distal transfers with grafts; data regarding type of injury and surgical approach are presented in Tables 2 and 3 The mean time from injury to surgery was 14 months (range, 6-24 months). Almost all patients had neuropathic pain (85 patients, 98%); among these, 78 (90%) showed improvement in pain. This series shows very low rates of functional recovery, which is an expected result given the long interval from injury to surgery in both adult and pediatric patients. The focus of this paper is on the lessons learned, highlighting that a surgical team alone is not sufficient, with the need for a dedicated pediatric team, public-private partnerships, and a team for secondary procedures. These first 100 brachial plexus surgeries represent only a small step in the development of brachial plexus surgery in Angola, and the lessons learned need to be applied to improve patient care.

UGI anastomotic leaks are severe postoperative complications associated with substantial morbidity, mortality, and prolonged hospitalization. EVT is a minimally invasive alternative to conventional approaches, but evidence has not been comprehensively synthesized. This systematic review and meta-analysis was reported in accordance with the PRISMA 2020 statement. Observational studies (January 2015-January 2025) identified in PubMed, Embase, Cochrane, and LILACS. Adults with UGI anastomotic leaks treated with EVT were eligible. Random-effects models pooled proportions using the Freeman-Tukey double-arcsine transformation; sensitivity analyses used a logit transformation. Pre-specified subgroup analyses stratified by surgical indication (oncologic, bariatric, mixed), leak location (intrathoracic vs intra-abdominal), and risk of bias. Risk of bias was appraised using the Joanna Briggs Institute (JBI) critical appraisal checklist for case series and certainty of evidence with GRADE. Thirty-one studies (n = 767) were included. The pooled clinical success was 87% (95% CI, 82-91%) and remained high in sensitivity analyses (84-89%). No material differences were observed across oncologic, bariatric, or mixed series. Intrathoracic leaks showed lower success than intra-abdominal leaks (79 vs 95%). Thirty-day mortality was 7%, primarily in complex clinical contexts. Heterogeneity was substantial, and small-study effects were suspected. Overall certainty of evidence was rated low owing to observational design and risk of bias. Across observational studies, EVT achieved high clinical success for UGI anastomotic leaks with low short-term mortality. Prospective cohorts and randomized trials are needed to refine indications, identify predictors of response, and assess cost-effectiveness.

Lymphangioleiomyomatosis (LAM) is a rare, low-grade neoplasm that causes progressive cystic lung destruction and is often associated with renal angiomyolipomas (AMLs). Given evidence of pleiotropy linking LAM risk to pulmonary traits, we investigated whether glucocorticoid receptor (GR) signalling might influence LAM biology and clinical features. We combined cell-based studies, GR inhibition/activation assays, gene expression and single-cell RNA sequencing analyses, and hormone profiling in retrospective and prospective LAM cohorts. Cellular experiments employed murine Tsc2 -/- embryonic fibroblasts and human TSC2 -/- AML cells. Circulating steroid levels were measured in women with LAM and healthy controls, and associations with clinical variables were evaluated. In LAM/AML models, GR activation by glucocorticoids elicited transcriptional responses, whereas GR inhibition reduced clonogenic potential. GR stimulation was associated with CDKN1C upregulation through enhancer binding, and single-cell profiling suggested a shift towards slower proliferation and differentiation-prone states enriched for a LAM cell signature. Clinically, our analyses suggest that women with LAM may show altered circulating hormone profiles, including elevated adrenocorticotropic hormone (ACTH) and cortisol levels, together with reduced 17-hydroxyprogesterone, compared with controls. In a prospective cohort, ACTH levels were suggestively associated with advanced radiological disease stage. AML cells showed elevated expression of POMC, which encodes the precursor of ACTH, and POMC peptide was detected in LAM lung tissue. Our findings suggest that GR signalling may contribute to aspects of LAM cell behaviour and disease status. Further investigation of this pathway could clarify its role as a disease modifier and potential therapeutic target.

Induction chemotherapy for pediatric Acute Lymphoblastic Leukemia (ALL) is highly curative but accompanied by a severe toxicity profile. Evaluating the genetic susceptibility to these adverse events could inform hypothesis-generating risk stratification. In this exploratory retrospective cohort study (N = 178), we investigated the influence of 14 candidate pharmacogenetic variants on the development of prevalent Adverse Drug Reactions (ADRs, ≥ 10 events). Multiple logistic regression, adjusted for basic demographic and anthropometric covariates (age and body surface area), was utilized across comprehensive inheritance architectures (additive, dominant, recessive, and co-dominant). For clinical translation hypothesis generation, we applied LASSO-penalized logistic regression (α = 1), 10-fold cross-validation to derive parsimonious Pharmacogenetic Risk Scores (PGRS). Model performance was evaluated using the optimism-corrected Area Under the Receiver Operating Characteristic Curve (AUC) via 1000-iteration bootstrap resampling, and calibration was assessed via the Brier score. We observed several complex interactions, notably suggesting an increased risk of severe neutropenia in patients carrying a homozygous variant CYP3A5 rs776746 genotype (nominally significant OR 5.58, p = 0.006) and a potential pleiotropic protective effect from NFATC2 rs6021191 (OR 0.09, p = 0.001). Penalized selection allowed the construction of compact, multi-locus mathematical risk scores that demonstrated promising diagnostic discrimination for Neutropenia (optimism-corrected AUC 0.793, 95% CI 0.72-0.85; Brier score 0.12), while displaying limited to moderate performance for other clinically discriminating toxicities like Infection (AUC 0.650) and Gastrointestinal complications (AUC 0.607). The primary contribution of this study is the prioritization of pharmacogenomic candidate signals rather than the proposal of models ready for clinical intervention. The integration of alternative genotype parameterizations and regularized machine learning highlights pathways for future predictive research. However, given the retrospective nature of the study and inherent risks of internal optimism, these scores serve as biologically informed proof-of-concept models that strictly require robust prospective external validation.

Relapsing polychondritis (RP) is a rare, multisystem inflammatory disease characterized by heterogeneous clinical manifestations and a substantial impact on patients' daily functioning and well-being. Health-related quality of life (HR-QoL) in RP remains insufficiently characterized, and no disease-specific measurement tool is available so far. This study aimed to develop and validate the RP-QoL, a multilingual, patient-reported outcome instrument specifically designed to assess HR-QoL in individuals with RP. The RP-QoL was developed within the European Reference Network ReCONNET using a structured four-step approach: (1) identification of relevant HR-QoL domains through systematic literature review, an international patient survey, and expert consensus; (2) item generation; (3) pilot testing including cognitive debriefing; and (4) comprehensive psychometric validation. Validation analyses included assessment of internal consistency, structural validity, construct validity, convergent validity with the SF-36, and criterion-related validity. Domain identification incorporated input from 274 patients across 22 countries, leading to a 31-item pilot questionnaire with a 28-day recall period and 5-point response scale. Cognitive debriefing confirmed clarity, relevance, and feasibility. Validation in 239 patients from 19 countries (median age 55&#x2009;years; 80% female) demonstrated excellent internal consistency (Cronbach's &#x3b1;&#x2009;=&#x2009;0.96). Exploratory factor analysis supported near-unidimensionality, with the first factor explaining 46.6% of variance. RP-QoL scores correlated strongly with disease impact (&#x3c1;&#x2009;=&#x2009;-0.62, p< 0.0001) and SF-36 physical (&#x3c1;&#x2009;=&#x2009;0.65) and mental (&#x3c1;&#x2009;=&#x2009;0.55, p< 0.0001) components (both p< 0.0001, p< 0.0001). Discriminative ability was high (AUC&#x2009;=&#x2009;0.87). The RP-QoL is the first validated, disease-specific HR-QoL instrument for RP, with robust psychometric performance and applicability in both clinical practice and research.

Tuberculosis (TB) and cancer share overlapping clinical features that may worsen outcomes when coexist. We aimed to characterize TB in cancer patients and identify predictors of TB-related mortality in a low TB-prevalence setting. We conducted a 15&#xa0;year retrospective cohort study (2010-2024) across two hospitals in Madrid. Patients with microbiologically confirmed TB during cancer treatment or within the preceding 2&#xa0;years were included. Clinical and demographic variables were analyzed to identify factors associated with adverse outcomes. Eighty-eight cancer patients were diagnosed with TB (median age 62.5 years); 70.5% were male and 17% were immigrants. Immunocompromising conditions were present in 61.3%. Solid tumors predominated (75%), with lung cancer being the most frequent. TB was diagnosed after cancer in 68.1% of cases, and 93.9% of isolates were drug susceptible. Atypical presentations were observed in 68.8% of patients. After excluding six cases of BCGitis, overall and TB-related mortality were 28.0% and 12.1%, respectively. Patients who died had longer diagnostic delays (185.82 vs 69.48 days, p=0.03). Synchronous diagnosis of TB and cancer emerged was the only independent predictor of mortality (p=0.01), whereas no TB-related deaths occurred when TB was incidentally detected during cancer reassessment. Among the 33 patients tested, a positive interferon gamma release assay (IGRA) was associated with better outcomes, potentially reflecting preserved immunity. TB in cancer patients frequently presents atypically and is associated with diagnostic delays and substantial mortality. Proactive and systematic diagnostic strategies are warranted. Negative or indeterminate IGRA results should not exclude active TB.

Cardiovascular outcome trials suggest that glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce major adverse cardiovascular events in individuals with type 2 diabetes (T2DM), but the magnitude of benefit, including recent evidence from the landmark SOUL trial and oral formulations, remains uncertain. We performed a Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 (International Prospective Register of Systematic Reviews ID: CRD420251034652), searching PubMed, Embase, Cochrane CENTRAL, Scopus and ClinicalTrials.gov on 6 May 2025 for randomised controlled trials comparing GLP-1RAs with placebo or usual care in adults with T2DM and established atherosclerotic cardiovascular disease. Seven trials, including 56 191 participants (mean follow-up: 3.5 years), were analysed. GLP-1RAs reduced major adverse cardiovascular events by 11% [hazard ratio: 0.89, 95% confidence interval (CI): 0.83-0.96], all-cause mortality by 11% (hazard ratio: 0.89, 95% CI: 0.82-0.97) and hospitalisation for heart failure by 7% (hazard ratio: 0.93, 95% CI: 0.89-0.98), all with high-certainty evidence. Overall, GLP-1RAs - available in subcutaneous and oral formulations - provide clinically meaningful cardiovascular benefits in high-risk adults with T2DM.

Cognitive and functional decline in older adults poses a growing global health challenge. In the absence of curative pharmacological treatments for dementia, non-pharmacological strategies combining physical and cognitive stimulation are increasingly prioritised. Simultaneous cognitive-motor training is theoretically grounded in the interdependence of motor and cognitive networks and has shown promise in meta-analytic evidence, yet scalable, neuroplasticity-coherent platforms designed from first principles remain scarce. To describe the conceptual architecture, neurophysiological rationale, and neuroplasticity-based design principles of Kinestesia, and to report preliminary feasibility and proof-of-concept data from an uncontrolled pilot study in older adults with and without Mild Cognitive Impairment (MCI). Twenty-two older adults (11 cognitively healthy, 11 MCI) completed 30 sessions (3 &#xd7; /week, 10 weeks) of Kinestesia, a therapeutic videogame platform integrating full-body kinematic interaction with progressive cognitive-motor demands structured around six established neuroplasticity principles. Outcomes included neuropsychological assessment (NEUROPSI Atenci&#xf3;n y Memoria), functional walking capacity (6-Minute Walk Test), balance and gait (Tinetti, TUG), within-platform learning trajectories, and Spearman correlations between game learning indices and clinical change scores. Adherence was 100%, and satisfaction was uniformly high. Both subgroups showed significant pre-to-post improvements in delayed memory, executive functions, and functional walking capacity, with predominantly large effect sizes (d = 0.5-1.4). Within-platform learning was systematic across games (&#x2265;80% of participants improving per game). Spearman correlations revealed that learning in foundational locomotor games (Double Steps, Follow Tiles) predicted clinical cognitive gains most robustly in the combined sample, supporting a cognitive-motor scaffolding hypothesis. Kinestesia demonstrated feasibility and preliminary proof-of-concept as a scalable, affordable, neuroplasticity-grounded cognitive-motor intervention for healthy aging. All findings are hypothesis-generating and require confirmation in adequately powered randomised controlled trials with active comparators.

Idiopathicshort stature (ISS) has been used for more than five decades to label children whose height is below -2 SDS without an identified underlying cause. Although originally conceived as a pragmatic diagnosis of exclusion, ISS has gradually been reified as a disease entity and is now embedded in clinical guidelines, regulatory frameworks and indications for recombinant human growth hormone therapy. In parallel, advances in genomic technologies have uncovered a growing spectrum of monogenic and chromosomal variants among children previously classified as ISS, and highlighted the continuous, polygenic architecture of height in the remainder. These developments render the idiopathic construct increasingly misleading and unstable, as every new etiological discovery shrinks - and conceptually undermines - the ISS category. In this article, we review the historical evolution and current use of ISS, summarize the impact of modern genetic testing on the classification of short stature, and argue that most children currently labeled as having ISS are better described as having "Healthy Short Stature". We define Healthy Short Stature as short stature in otherwise healthy children without systemic, syndromic or endocrine disease, in whom short stature represents the lower extreme of normal growth variation. We discuss how adopting Healthy Short Stature can reduce stigma, remain compatible with ongoing genetic investigation, and provide a more robust framework for aligning clinical practice, research and health policy with contemporary knowledge of human growth biology.

The current standard of care for resectable locally advanced colon cancer (LACC) is based on upfront surgery followed by adjuvant chemotherapy (AC). This study aimed to evaluate the safety and efficacy of neoadjuvant chemotherapy (NAC) in this setting. ELECLA is a multicenter, randomized, open-label, phase II controlled trial conducted across 12 hospitals in Spain between March 2017 and June 2024. This report presents the results of a preplanned interim analysis conducted after early termination of recruitment following the loss of clinical equipoise. Patients with radiologically defined LACC (T3 > 5 mm/T4, any N, and M0) and proficient mismatch repair status, were randomly assigned at a 1:1 ratio to receive either NAC (three cycles of CAPOX or five of FOLFOX), surgery, and AC (investigational group) or upfront surgery followed by AC (control group). The primary endpoint was 2-year disease-free survival. A total of 120 patients were included. The NAC completion rate was 94.2%, with a nonsignificant trend toward a reduced surgical complication rate compared with controls (17.3% versus 22.1%; P = 0.52). In the investigational group, a favorable radiologic tumor downstaging was achieved, with a tumor volume reduction of 65.4% (P < 0.001), and a tumor regression grading of 0-2 in 51.2% of assessable patients. An R0 resection was achieved in all patients within the NAC group. A relevant reduction in classical histological adverse prognostic features, including lymphatic invasion (21.5% versus 44.1%; P = 0.009), tumor budding (23.3% versus 58.5%; P = 0.002), and incomplete resections (0% versus 7.4%; P = 0.068) was observed in the NAC group. The 2-year disease-free survival rate was 88.9% [95% confidence interval (CI) 75.2% to 95.2%] in the intervention group and 83.3% (95% CI 70.9% to 90.7%) in the control group (P = 0.34). NAC is safe, feasible, and associated with improved tumor downstaging and favorable pathologic features without increased perioperative morbidity. These findings support the use of NAC as a safe and efficient therapeutic option in patients with LACC.

The treatment of prostate cancer (PCa) requires approaches that eliminate malignant tissue while preserving essential urinary and sexual functions. Irreversible electroporation (IRE) represents a targeted ablative strategy that disrupts cellular membrane integrity through precise electrical pulses, demonstrating the capacity to ablate cancerous foci while sparing adjacent neurovascular bundles and sphincter mechanisms. This structured review examines the mechanistic foundations of IRE technology, evaluates current clinical evidence regarding safety and efficacy, and explores promising applications that may redefine precision urologic care. Existing clinical studies demonstrate encouraging oncological control rates with superior preservation of continence and erectile function compared to whole-gland treatments, though patient selection criteria and long-term durability remain areas requiring further investigation. Emerging applications include salvage therapy following radiation failure, integration with advanced multiparametric imaging for precision targeting, and combination strategies with systemic therapies. The regulatory approval status and economic implications of IRE implementation vary significantly across healthcare systems, creating disparities in patient access and adoption of this technology that must be addressed to ensure equitable availability of focal ablation options. As the technology matures, establishing standardized treatment protocols, refining patient selection algorithms, and conducting robust comparative effectiveness studies will be essential to define the optimal role of IRE within prostate cancer management.