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PubMed2026

Reliability, Device Agreement and Validity of Load-Velocity Profiles: A Systematic Review with Meta-analysis.

BACKGROUND: For a valid one-repetition maximum (1RM) prediction via load-velocity (LV) relationships, high reliability and accuracy must be assumed. OBJECTIVE: Since individual study results indicate ambivalent prediction, this systematic review and meta-analysis was designed to provide a updated and comprehensive overview, extending knowledge about the validity and reliability of commercially available velocity sensors in Part I and the validity and reliability of velocity-based 1RM prediction models in Part II. METHODS: A systematic literature search was conducted in PubMed/MEDLINE, Web of Science, and Scopus. Validity and/or reliability studies or velocity-based 1RM prediction evaluations were included. Methodological quality was assessed using adapted COSMIN. The analysis was performed for intraclass correlation coefficient (ICC), Lin's concordance correlation coefficient (CCC), and Pearson's correlation coefficient (r). The review was preregistered in PROSPERO (CRD42025634595). RESULTS: Sixty-three studies were included for sensor validity and reliability and 38 for 1RM prediction models. Part I: Velocity sensors demonstrated good-to-excellent pooled validity and device agreement (ICC = 0.91-0.92 [0.83-0.97]; k = 55 and 439, respectively); intra- and inter-day reliability were classified as good to excellent with ICC = 0.90-0.91 [0.85-0.95] (k = 228 and 608, respectively), with sensor technology moderating the results. However, substantial heterogeneity and wide ranges of study-level estimates indicated considerable variability across moderators, linear position transducer (LPT) generally showing more consistent performance than inertial measurement units (IMU). Part II: Velocity-based 1RM prediction showed ICCs = 0.90 [0.83-0.94] (k = 124) and ICC = 0.91 [0.72-0.98] (k = 9); for reliability and validity, respectively. DISCUSSION: Commercial velocity sensors generally provide high relative validity and reliability. Results varied depending on exercise complexity, intensity, sensor technology, and modeling approach. While velocity-based 1RM prediction demonstrated high average validity, large heterogeneity in lower body exercises significantly biased the results. Furthermore, the dearth of measurement error and agreement analyses prohibits final conclusions. CONCLUSION: Therefore, velocity-based monitoring and 1RM prediction require cautious interpretation, as sensor- and exercise-specific evidence remains limited.

Load–velocity relationship↗

PubMed2026

Identification and functional characterization of a novel antiviral chicken interferon-υ.

Interferons are critical mediators of antiviral immunity in vertebrates. While type IV interferon (IFN-υ) has been identified in fish and amphibians, its existence and function in chickens remained unknown. Through systematic genomic screening, we identified and cloned a novel chicken interferon gene, designated ChIFN-υ. Phylogenetic analysis placed ChIFN-υ within a distinct clade alongside zebrafish and clawed frog IFN-υ, confirming its identity as a type IV interferon, with minimal homology to classical type I, II, or III IFNs. Expression profiling revealed constitutive ChIFN-υ expression in mucosal and immune tissues of healthy chickens, exhibiting a distinct developmental shift: highest in trachea and small intestine in 1-day-old chicks, shifting to spleen and lung in 4-week-old chickens. ChIFN-υ expression was strongly upregulated following H9N2 AIV infection. Functionally, recombinant ChIFN-υ protein activated the interferon-stimulated response element (ISRE) and Mx promoter in a dose-dependent manner and significantly inhibited the replication of both vesicular stomatitis virus (VSV) and H9N2 AIV in DF-1 cells. In vivo, early treatment with exogenous ChIFN-υ significantly reduced pulmonary and tracheal viral loads and decreased oropharyngeal and cloacal virus shedding in H9N2-infected chickens. In conclusion, this study identifies and functionally characterizes the type IV interferon in chickens, elucidating the evolutionary status, regulated expression, and antiviral efficacy of ChIFN-υ. These findings highlight its potential as a candidate for developing interferon-based therapies against avian viral diseases.

Animals↗

PubMed2026

The emerging applications of JAK inhibitors in dermatology - a systematic review.

BACKGROUND: Janus kinase (JAK) inhibitors are established treatments for selected dermatologic conditions, but their off-label use has expanded across refractory skin diseases. METHODS: We systematically searched MEDLINE, Embase, and Web of Science from inception to October 1, 2025, for studies reporting off-label JAK inhibitor use in dermatologic disorders beyond approved or late-phase trial indications. RESULTS: Of 9,182 records screened, 277 studies met the inclusion criteria, comprising 210 case reports, 55 case series, and 12 retrospective studies involving 764 patients. Owing to substantial clinical heterogeneity, findings were narratively synthesized using a structured disease-family framework. Off-label use most commonly involved lichenoid, neutrophilic, and granulomatous dermatoses. Overall, 725/764 (94.88%) patients experienced clinical benefit, including complete or near-complete response in 209/764 (27.35%) and significant or partial improvement in 516/764 (67.53%). Thirty-five patients (4.58%) showed no clinical change, and four (0.52%) experienced disease worsening. A total of 154 adverse events were reported, most commonly with tofacitinib; most were mild to moderate, although six were serious and 25 resulted in treatment discontinuation. CONCLUSION: JAK inhibitors demonstrate promising therapeutic potential across a broad spectrum of refractory dermatological diseases. The predominance of uncontrolled case-based evidence, heterogeneous dosing, and frequent combination therapy limits attribution of efficacy and safety to JAK inhibitor monotherapy. Prospective controlled studies are needed to better define their therapeutic role.

Humans↗

PubMed2026

Effect of Semaglutide on the Inflammatory Biomarker High-Sensitivity CRP in Patients With Established Cardiovascular Disease and Overweight or Obesity in SELECT: A Prespecified Secondary Analysis.

BACKGROUND: In SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity), among 17 604 patients with known atherosclerotic cardiovascular disease and overweight or obesity, but not diabetes, randomization to the glucagon-like peptide-1 receptor agonist semaglutide significantly reduced the primary outcome of major adverse cardiovascular events (MACE; cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) compared with placebo (mean follow-up, 39.8 months). Inflammation, as indicated by plasma hsCRP (high-sensitivity C-reactive protein) level, is implicated as a biomarker predicting cardiovascular risk in obesity and atherosclerotic cardiovascular disease. SELECT provides a unique opportunity to study the relationship among hsCRP, obesity, weight loss, and MACE outcomes in semaglutide versus placebo groups. METHODS: In this prespecified SELECT substudy, we evaluated whether baseline hsCRP levels predicted MACE risk and examined the relationships between changes in hsCRP levels and time to first MACE, baseline body weight, weight loss, and other clinical measures among treatment groups over time (104, 208 weeks) using multiple approaches, including Cox modeling. RESULTS: Baseline hsCRP level, which was similar in the semaglutide (geometric mean 1.96 mg/L) and placebo (geometric mean 1.91 mg/L) groups, was prognostic of future MACE. The risk of MACE increased across baseline hsCRP level <2, 2-<10, and ≥10 mg/L subgroups, including significant associations with cardiovascular and all-cause death. Semaglutide reduced hsCRP levels (-37.8% [104 weeks]) and risk of MACE across all hsCRP subgroups. Greater reductions in ratio-to-baseline hsCRP with semaglutide were associated with greater weight loss, but preceded major weight loss, evident by 4 and 8 weeks, and occurred among those without weight loss. Semaglutide-associated changes in hsCRP were independent of low-density lipoprotein cholesterol levels, statin use, and atherosclerotic cardiovascular disease entry criteria. hsCRP reductions were found to be prognostic of decreased risk of MACE. Modeling suggests decreased inflammation as contributing in part to the benefits seen with semaglutide in SELECT. CONCLUSIONS: In SELECT, hsCRP data at baseline and in response to treatment with semaglutide support inflammation as a potential prognostic factor associated with cardiovascular risk in these generally well-treated patients with atherosclerotic cardiovascular disease and overweight or obesity but not diabetes. These findings suggest that the MACE reduction observed with semaglutide versus placebo in SELECT may have partially involved a decrease in inflammation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03574597.

Humans↗

PubMed2026

Eltrombopag Added to Standard Immunosuppressive Treatment as Front-Line Therapy for Severe Aplastic Anemia: Long-Term Outcomes of the Phase-3 Randomized Superiority EBMT-SAAWP RACE Study.

The RACE study (NCT02009747) compared horse antithymocyte globulin (hATG) plus cyclosporine A (CsA) ± eltrombopag as initial immunosuppressive treatment (IST) for severe aplastic anemia. Here we report the final 2-year analysis of this prospective randomized phase III study. One hundred ninety-seven treatment-naive patients were randomized to standard IST (hATG 40 mg/kg × 4 days and CsA 5 mg/kg/day; arm A; n = 101) or standard IST + eltrombopag at the dose of 150 mg/day (arm B; n = 96) from day +14 until 6 months (or 3 months, in case of complete response). The median follow-up was 23.2 months. The 2-year cumulative incidence of complete response was significantly superior in arm B (62.4% vs. 35.3%; p < 0.001). The 2-year overall survival (OS) was 86% in arm A and 91% in arm B (p = 0.081), with hazard ratio (HR), adjusted for age and disease severity, of 0.54 (p = 0.064). The 2-year disease-free survival (DFS) was 56% vs. 37% (adjusted HR = 0.49; p < 0.001), while event-free survival (EFS) was 48% vs. 32% (p < 0.001), with adjusted HR = 0.54 (p < 0.001), both significantly superior for arm B. The cumulative incidence of relapse was comparable in the two arms, while evolution to clinical paroxysmal nocturnal hemoglobinuria was 8% in arm A and 1% in arm B (p = 0.041). The risk of clonal evolution remained negligible, with one patient in arm A and two in arm B developing karyotypic abnormalities. The initial hematological response benefit of eltrombopag added to IST as front-line treatment of AA is associated with better 2-year OS, DFS, and EFS without increased risk of secondary myeloid malignancies.

Humans↗

PubMed2026

Intraspecific variation in Bothrops neuwiedi snake venom: Influence of age and sex.

Snake venom is a complex mixture of molecules and is subject to intraspecific variations due to the influence of abiotic and/or biotic factors, one of which is the animal's ontogeny. Some studies have already shown the influence of age on the composition and properties of snake venom, but these variations are not uniform, and each species may exhibit a specific pattern of variation. Therefore, this study aimed to analyze the influence of age on the venom of Bothrops neuwiedi, using 5 age groups, differentiating between males and females. To this end, we analyzed the protein profile of these venoms (using SDS-PAGE, HPLC, and proteomic analyses); enzymatic activities (PLA2, LAAO, and proteolytic activities); coagulant activity, in vivo assays (MDH; LD50 and ED50), and immunorecognition tests (Western blotting and ELISA). Protein profile analysis showed that males exhibited a gradual increase in SVMP and PLA2 concentrations. Both sexes showed a decrease in CTL concentration and a loss of PLA2 activity, which occurred more gradually in males. Proteolytic activity did not show clear ontogenetic differences, but both sexes showed activity peaks in the 2-year-old and senile groups, with females exhibiting higher proteolytic activity than males. Regarding LAAO activity, it increased in males and decreased in females. Although the LD50 did not show age-dependent differences, the venom from the 1-year-old group took longer to cause death in mice but showed a higher hemorrhagic activity than seniles. Furthermore, more antivenom was needed to neutralize the venom from the 1-year-old group than the venom from the senile group; despite this, immunorecognition tests did not show significant ontogenetic variations. In conclusion, the venom of the snake B. neuwiedi undergoes ontogenetic variations with certain sexual differences, showing some peculiarities that have not been found in ontogenetic analyses of other species of the same genus.

Animals↗

PubMed2026

Evolutionary characterization and expression profiling of ACC and FASN genes in Chinese mitten crab Eriocheir sinensis.

Acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN) are rate-limiting enzymes in the fatty acid biosynthetic pathway, yet their evolutionary relationships, sequence features, and expression profiles remain poorly understood in crustaceans, particularly in the economically important Chinese mitten crab (Eriocheir sinensis). Here, we identified and systematically analyzed ACC and FASN genes in E. sinensis using comparative genomic analyses across 43 species. ACC was highly conserved as a single-copy gene in invertebrates, in contrast to the multiple paralogs observed in vertebrates. Similarly, FASN was generally maintained as a single-copy gene across most taxa but exhibited lineage-specific expansion in certain insect groups. Phylogenetic and structural analysis revealed strong conservation of both genes within crustaceans, supported by multiple conserved motifs and canonical functional domains. Expression profiling showed predominant expression in the hepatopancreas and midgut, suggesting their potential involvement in crustacean lipid metabolism. During the molting cycle, ACC and FASN exhibited higher expression levels during stages C and D, suggesting an increased capacity for fatty acid biosynthesis before molting. In addition, dietary lipid levels experiment revealed that ACC and FASN expression responded dynamically to dietary lipid availability, with increased expression at moderate lipid levels but reduced expression under excessive lipid supplementation, indicating a possible adaptive transcriptional response to lipid status. Collectively, this study provides insights into the evolutionary conservation and expression dynamics of ACC and FASN and improves our understanding of lipid metabolic adaptation in crustaceans.

Animals↗

PubMed2026

What do we know about medical invalidation and related concepts? - A scoping review and thematic analysis about the definitions, measurements, causes, consequences and potential solutions for medical invalidation.

BACKGROUND: Medical invalidation, medical gaslighting, and related constructs have gained visibility in public discourse but remain inconsistently defined in scientific literature. Despite growing research-often focused on specific diseases- to date, no single review has comprehensively synthesized their definitions, causes, consequences, or methods of measurement. This scoping review addresses this gap by examining medical invalidation and related constructs. METHODS: Using a preregistered protocol, we systematically searched PubMed, CINAHL, Web of Science, Google Scholar, and ProQuest (dissertations) without year restrictions. Eligible sources included peer-reviewed empirical, theoretical, and conceptual work in English addressing invalidation, gaslighting, or closely related notions within healthcare. A total of 158 studies were identified through database searches and citation tracking. Data extraction followed a standardized schema, and findings were synthesized descriptively and through thematic analysis to clarify terminology, map determinants and outcomes, and identify existing measurement approaches. RESULTS: The results showed substantial inconsistency in how "invalidation," "not being taken seriously," and "gaslighting" were defined. Medical invalidation emerged as a multifactorial phenomenon driven by diagnostic challenges, structural and societal factors, provider and patient characteristics, stigma, misattribution, interactional dynamics, academic knowledge gaps, and disease-related complexity. Invalidation was associated with wide-ranging behavioural, emotional, cognitive, physical, relational, and systemic harms, while validation had consistently beneficial effects. Proposed solutions in the summarized studies included communication improvements, clinician training, patient support, targeted research, and structural and systemic changes. DISCUSSIONS: Medical invalidation represents a complex, systemic issue with significant implications for patient safety. The discussion highlights its multifactorial origins, its potential to cause both psychological and physical harm, and the need for clearer conceptualisation within the field. Advancing research requires validated instruments and longitudinal designs to examine underlying mechanisms and consequences. Addressing medical invalidation will demand multi-level interventions to improve communication, reduce structural barriers, and promote equitable, patient-centred care. OSF PREREGISTRATION: https://doi.org/10.17605/OSF.IO/MPE6U.

Humans↗

PubMed2026

A Systematic Review of Lived Experiences of Receiving a Diagnosis of ADHD in Adulthood.

OBJECTIVE: With rising numbers of adults seeking and receiving ADHD diagnoses, understanding their first-hand experiences of the diagnostic process is key for sensitive support and service design. This systematic review collates, evaluates and synthesises the existing evidence-base on lived experiences of adult ADHD diagnosis. METHOD: Keyword searches of six databases generated 10,357 citations, which were subjected to a systematic screening process that identified 21 relevant studies. Findings were analysed using thematic synthesis. RESULTS: Analysis generated three overarching themes, elaborating how diagnostic experiences are shaped by adults' Relationship with Self, Relationship with Others, and Relationship with Systems. Personally, diagnosis was widely experienced as a pivotal identity event, triggering biographical reflection that could foster greater self-compassion, but also grief, anger and identity confusion. Socially, diagnosis facilitated interpersonal understanding and communication, but also exposed adults to stigma and introduced dilemmas about diagnostic disclosure. Systemically, adults experienced the diagnostic process as beset by barriers and delays, and reported highly variable access to post-diagnosis supports or treatment. CONCLUSION: Results suggest receiving an ADHD diagnosis in adulthood is a complex relational process that can be both validating and destabilising, with variation in experiences resulting from individual biographies, interpersonal resources, stigma climates, and service structures.

Humans↗

PubMed2026

Do vaccinated cases transmit measles? A systematic review and meta-analysis.

INTRODUCTION: We reviewed evidence on whether vaccinated individuals can transmit measles and conducted a meta-analysis to understand transmission characteristics. METHODS: We searched and extracted data from peer-reviewed and gray literature and included studies reporting measles transmission events from vaccinated individuals. We meta-analyzed the data to calculate the median number of transmissions from vaccinated cases by measles burden, number of doses, and time since first and last dose. RESULTS: We identified 11,911 peer-reviewed and 22 gray literature records and included 33 articles in our review. Seventy individuals who had received 1 or more doses of measles-containing vaccine transmitted measles virus, resulting in 237 secondary cases. Vaccinated transmitters in eliminated areas were older (median age of 19 years (IQR: 3, 21)) than those in non-eliminated areas (median age 16 years; IQR 13, 18) (p = 0.12). Additionally, 91% (30/33) of studies provided data on subsequent transmission generations, leading to 812 measles cases traced back to vaccinated individuals, with a median of 4 (IQR: 1, 10) cases per vaccinated transmitter. CONCLUSION: Measles transmissions from vaccinated cases, although relatively uncommon, must be considered in public health investigations, as such transmissions can contribute to outbreaks.

Adolescent↗

PubMed2026

The effects of visuomotor training and tDCS stimulation on visuomotor integration and visual processing: an electrophysiological approach.

BACKGROUND: Visuomotor integration coordinates visual and motor cortical activity to produce goal-directed responses and can be indexed by Rolandic Mu-rhythm suppression and visual evoked potential (VEP) P100 parameters. Perceptual-motor training improves visuomotor performance, and transcranial direct current stimulation (tDCS) over primary motor cortex (M1) has been reported to enhance motor learning when paired with training. This study examined whether anodal M1 tDCS augments the effects of Senaptec visuomotor training in healthy adults. METHODS: Sixty participants were randomized to active anodal tDCS (five 10-minute sessions, 1 mA; n = 31) or sham (n = 29) over M1 immediately before each Senaptec training session; 53 completed all sessions and post-testing. Outcomes were Mu-suppression ratios, VEP P100 latency and amplitude, and Senaptec measures of visual sensitivity and visuomotor control. RESULTS: Active tDCS produced no augmentation of any outcome, with no significant group × time interaction for any measure, consistent across composite and task-level analyses. Training alone produced no change in Mu suppression or visuomotor control. By contrast, both groups showed significant training-related gains in visual sensitivity, including near-far quickness and stereopsis, accompanied by shorter P100 latencies and larger amplitudes, indicating more efficient early visual processing. CONCLUSIONS: A clear dissociation emerged: training produced robust improvements in early visual processing, whereas neither tDCS nor training altered sensorimotor (Mu) or visuomotor-control measures. The tDCS results should be interpreted cautiously given the modest dose and limited power to detect small effects, rather than as evidence of inefficacy. Tablet-based perceptual training enhanced visual processing independent of neuromodulation.

Humans↗

PubMed2026

The gut microbiota-obesity axis in the pathogenesis and prognosis of breast cancer.

BACKGROUND: Breast cancer (BC) remains a major global health concern, accounting for 11.7% of all cancer cases and ranking as the second leading cause of female cancer-related deaths worldwide. Increasing evidence highlights the interplay between gut microbiota (GM) dysbiosis and obesity-associated metabolic dysfunction in BC progression. This review aims to elucidate the role of GM in obese patients with BC. METHODS: A systematic literature search was conducted in PubMed and Web of Science databases for publications from July 2015 to January 2025. Search terms combined BC, GM, obesity, dysbiosis, immunity, and microbiome. Article selection prioritized studies investigating microbial alterations in BC patients, mechanistic links between obesity and cancer progression, and GM-targeted interventions. Both original studies and authoritative reviews were included, supplemented by manual reference screening. DISCUSSION: Obesity may trigger systemic inflammation, altered adipokine secretion, and disrupted steroid hormone metabolism via gut-derived β-glucuronidase activity, thereby exacerbating BC occurrence and recurrence. GM dysbiosis-driven metabolites such as branched-chain amino acids (BCAAs) and short-chain fatty acids (SCFAs) can activate oncogenic signaling pathways and immunosuppressive myeloid-derived suppressor cells (MDSCs), fostering tumor immune evasion. Conversely, dietary interventions, probiotics, and fecal microbiota transplantation (FMT) can alleviate dysbiosis, strengthen gut barriers, and restore anti-tumor immunity, improving chemotherapy response and reducing recurrence. However, challenges persist in deciphering BC subtype-related microbial signatures and optimizing microbiota-targeted therapies. CONCLUSION: Future longitudinal studies are needed to clarify causal relationships, validate microbial biomarkers, and translate preclinical findings into clinical applications. Addressing the gut-breast axis may offer transformative potential for precision oncology in obesity-driven BC.

Humans↗

PubMed2026

Efficacy and Safety of iGlarLixi Versus IDegAsp by Baseline Age, Disease Duration and HbA1c in Chinese People With Type 2 Diabetes: Post Hoc Analyses of the Soli-D Study.

AIMS: To compare the efficacy and safety of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) with insulin degludec plus insulin aspart (IDegAsp) by baseline age, Type 2 diabetes (T2D) duration and glycated haemoglobin (HbA1c) in the Soli-D study. MATERIALS AND METHODS: In Soli-D, Chinese adults with T2D suboptimally controlled on oral antidiabetic drugs (OADs) were randomized to iGlarLixi or IDegAsp for 24 weeks. These post hoc analyses evaluated glycaemic efficacy, insulin dose, body weight and hypoglycaemia outcomes in subgroups defined by baseline age (< 65, ≥ 65 years), T2D duration (< 10, ≥ 10 years) and HbA1c (≥ 7% to ≤ 8% [≥ 53 to ≤ 64 mmol/mol], > 8% to ≤ 9% [> 64 to ≤ 75 mmol/mol], > 9% [> 75 mmol/mol]). RESULTS: Among 582 participants (iGlarLixi n = 291; IDegAsp n = 291), baseline age was < 65 years in 442 and ≥ 65 years in 140; T2D duration was < 10 years in 366 and ≥ 10 years in 216; and HbA1c was ≥ 7% to ≤ 8% in 205, > 8% to ≤ 9% in 209 and > 9% in 168. At Week 24, HbA1c reductions were greater with iGlarLixi versus IDegAsp, with no treatment-by-subgroup interactions for baseline age, T2D duration or HbA1c. Change in other glycaemic outcomes, insulin dose and body weight generally showed no interaction across subgroups. Total insulin daily doses during treatment and hypoglycaemia event rates were consistently lower with iGlarLixi versus IDegAsp in all subgroups. CONCLUSIONS: iGlarLixi provides improved glycaemic control at lower insulin doses with reduced risk of hypoglycaemia in Chinese adults with suboptimally controlled T2D on OADs, regardless of baseline age, disease duration or HbA1c.

Humans↗

PubMed2026

Quantification of appetite-regulating hormones in children with hypothalamic and common obesity.

CONTEXT: The pathophysiology of hypothalamic obesity (HyOb) remains incompletely understood with no effective treatments. OBJECTIVE: We examined differences in appetite-regulating hormone concentrations between patients with HyOb, common obesity, and lean controls. DESIGN: Multiway cross-sectional case-control study of patients aged 2 through 19 years. SETTING: Two tertiary pediatric endocrinology centers. PATIENTS: Cases were obese (body mass index [BMI] > +2 SD score [SDS], "HyOb") and lean ("HyLean") patients with congenital (septo-optic dysplasia) or acquired (suprasellar brain tumor) hypothalamic disorders. Controls had common obesity ("Ob") or nonhypothalamic disorders and normal BMI ("Lean"). MAIN OUTCOME MEASURES: Relationships between the Dykens' Hyperphagia Questionnaire Score (DHQS), plasma or serum concentrations of leptin, insulin, α-melanocyte stimulating hormone (αMSH), brain-derived neurotrophic factor, oxytocin, acylated ghrelin, agouti-related peptide and copeptin, and BMI SDS. RESULTS: Dykens' Hyperphagia Questionnaire Score did not differ between HyOb and Ob patients (24 [17-34] vs 24 [18-31]) but correlated with BMI SDS in patients with hypothalamic disorders (P = 0.02). HyOb and Ob patients exhibited similarly increased anorexigens (insulin, leptin) and decreased orexigens (ghrelin, agouti-related peptide) compared to HyLean and Lean patients. The rate of BMI increase was independently associated with lower αMSH (β = -0.23 [-0.36 to -0.11], P = .0007) and ghrelin (β=-0.004 [-0.01 to 0.00], P = .001) concentrations, suggesting that αMSH replacement may be a therapeutic target for HyOb. HyLean patients demonstrated intermediate insulin responses to glucose compared to other subcohorts. CONCLUSION: In our cohort, patients with HyOb appeared indistinguishable from Ob in terms of their appetite and appetite-regulating neuroendocrine circuitry. Higher αMSH concentrations are associated with reduced weight gain and may be a target for therapeutic intervention.

alpha-MSH↗

PubMed2026

Optimized AAV5-RPGR ORF15 Gene Therapy Rescues Photoreceptor Structure and Function in X-Linked Retinitis Pigmentosa Mouse Model.

PURPOSE: To develop and evaluate an rAAV5-based gene therapy vector expressing an optimized human RPGR ORF15 transgene (rAAV5-RPGR) for the treatment of X-linked retinitis pigmentosa caused by RPGR mutations, addressing the challenges of cloning the unstable wild-type ORF15 sequence. DESIGN: This was a prospective experimental study. SUBJECTS: This was an animal study. METHODS: An optimized RPGR ORF15 sequence was designed to eliminate problematic secondary structures and cryptic splice sites. In vitro expression was validated in HEK 293T and photoreceptor-like 661 W cells. A complete Rpgr knockout mouse model (Rpgr-knockout [KO]) was generated and characterized phenotypically. Therapeutic efficacy was assessed in Rpgr-KO mice via subretinal injection of rAAV5-RPGR at low (1 × 10⁹ vg/eye), medium (3 × 10⁹ vg/eye), or high (1 × 10¹⁰ vg/eye) doses. Structural and functional outcomes were evaluated at 12- and 14-month postinjection. Short-term safety was assessed in rabbits 1 month after subretinal injection. MAIN OUTCOME MEASURES: Level of RPGR protein expression and Protein isoform profile (elimination of truncated isoforms), Cellular localization of transgene expression and Dose-dependence of expression, outer nuclear layer thickness, and electroretinography parameters. RESULTS: (1) The optimized vector increased RPGR protein expression 3.3-fold in vitro compared to wild-type and eliminated truncated isoforms. (2) Subretinal delivery of rAAV5-RPGR in mice demonstrated dose-dependent transgene expression localized correctly to photoreceptor inner segments. (3) In Rpgr-KO mice, high-dose treatment significantly preserved outer nuclear layer thickness at the injection site (42% greater than controls at 14 months, P < .01) and central retina (P < .05), reduced aberrant rhodopsin mislocalization (P < .01), and partially restored retinal function. ERG showed significantly improved scotopic a-wave (≥100 vs <90 µV in controls at 10 cd·s/m²) and photopic b-wave amplitudes (49-66 vs 31-46 µV at 30 cd·s/m²) in treated mice. (4) No vector-related toxicity was observed in rabbits. CONCLUSIONS: rAAV5-RPGR mediated efficiently, targeted expression of optimized RPGR-ORF15, significantly preserved photoreceptor structure and function in a severe X-linked retinitis pigmentosa mouse model, and demonstrated a favorable safety profile. This study provides preclinical proof-of-concept for RPGR-targeted gene replacement therapy.

Animals↗

PubMed2026

Clinical effectiveness of transversus abdominis plane block versus local anaesthesia wound infiltration for postoperative pain relief after laparoscopic appendicectomy in children: A multicentre, double-blind, randomised, controlled phase III trial.

BACKGROUND: Postoperative pain relief after laparoscopic appendicectomy in children provided by transversus abdominis plane (TAP) block and local anaesthesia wound infiltration (LAWI) of trocar insertion sites has never been compared. OBJECTIVE: To investigate whether TAP block could decrease postoperative opioid requirements after laparoscopic appendicectomy in children compared with LAWI. DESIGN: Multicentre, double-blind, phase III randomised trial. SETTING: Two tertiary paediatric surgery centres. PATIENTS: Children aged 3 to 15 years admitted for laparoscopic appendicectomy. MAIN OUTCOME MEASURES: The primary outcome was the total dose of nalbuphine delivered within 24 h after surgery. Secondary outcomes were the Face Legs Activity Cry Consolability (FLACC) scale values at 1, 2, 6, 12 and 24 h, the time from levobupivacaine injection to the first dose of nalbuphine, and the time from the end of surgery to the first mobilisation. Patients received either ultrasound-guided TAP block (TAP group) or LAWI of trocar insertion sites (infiltration group) with 0.6 ml kg -1 of levobupivacaine 2.5 mg ml -1 , combined with standardised systemic multimodal analgesia including paracetamol, ketoprofen, phloroglucinol and nalbuphine. RESULTS: Forty-six and 50 patients were analysed in the TAP and infiltration groups, respectively [age: 10 [7 to 12] versus 10 [8 to 12] years; females: 16 (35%) versus 25 (50%); duration of surgery: 71 [64 to 90] versus 69 [56 to 89] min]. The primary outcome (total nalbuphine dose) was 0.2 [0.0 to 0.2] and 0.2 [0.0 to 0.2] mg kg -1 in the TAP and infiltration groups, respectively ( P  = 0.95). FLACC scale values did not significantly differ between the two groups ( P  = 0.78). Time to the first dose of nalbuphine or to first mobilisation was not significantly different between groups ( P value for log-rank test = 0.095 and 0.18, respectively). CONCLUSION: TAP block does not appear to provide a greater opioid-sparing effect than LAWI of trocar insertion sites after laparoscopic appendicectomy in children, when combined with systemic multimodal analgesia including nonsteroidal anti-inflammatory drugs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04969133.

Humans↗

PubMed2026

Risk-Benefit of Phase 2 Monotherapy Trials in Adult Solid Cancers: A Systematic Review and Meta-Analysis.

Phase 2 (and phase 1 dose expansion, which we label phase 2 for the purposes of this study) cancer trials are the first direct tests of a new drug's efficacy. Because efficacy evidence is lacking, the therapeutic status of drug administration during ethical review is uncertain. We compared the efficacy and safety of cancer monotherapies in phase 2 with phase 3, where clinical equipoise underwrites a therapeutic status for drug administration. In this systematic review and meta-analysis, we searched Clinicaltrials.gov for phase 2 and 3 investigational monotherapy drug trials in six solid malignancies, with primary completion dates 2015-2020, inclusive. Two independent reviewers completed data extraction. Effects were estimated using an inverse-variance weighted random-effects model meta-analysis of proportions using the R package meta. We analyzed 130 phase 2 and 52 phase 3 trial arms, enrolling 6665 and 18,694 patients. The pooled objective response rate was 7% (95% CI 5%-11%) in phase 2 versus 24% in phase 3 (95% CI 17%-31%; p < 0.0001). The median PFS and OS were shorter in phase 2 compared to phase 3 (3.23 vs. 5.43 months, p < 0.0001; 9.46 vs. 14.44 months, p = 0.0001). The pooled rate of drug-related grade 3-4 adverse events was 30% (95% CI 23%-37%) in phase 2 and 25% (95% CI 19%-32%) in phase 3. Monotherapies delivered in phase 2 cancer trials present diminished risk-benefit compared with phase 3 and align with historic estimates for phase 1. Though there may be exceptions, risks for drug administration in phase 2 should generally be justified by appeals to research rather than therapeutic value.

Humans↗

PubMed2025

Healthcare transition readiness in an adolescent and young adult urologic population: The ADHERENT study.

INTRODUCTION: There is a paucity of research regarding transition to adult services within pediatric and adolescent urology. Several recent articles have discussed the barriers in transitioning urologic patients from pediatric to adult health care, but empiric data that may drive intervention are lacking. This study proposes to begin to address this gap in literature and to provide information that may lead to improved understanding of how best to support transition in urologic care. OBJECTIVES: 1) to identify modifiable and non-modifiable factors related to transition readiness as measured by Transition Readiness Assessment Questionnaire (TRAQ) scores in a congenital urologic population and 2) to evaluate the relationships between TRAQ scores (a validated questionnaire measuring transition readiness) and scores measuring anxiety levels related to transition (using an adapted, non-validated questionnaire). STUDY DESIGN: This is a cross-sectional study of adolescent and young adult patients with complex congenital urologic diagnoses. Subjects were electronically administered the validated TRAQ and a study-developed ADHERENT survey, which assesses anxiety and worry surrounding transition. Regression models for the outcomes of the TRAQ and ADHERENT scales were developed to assess multivariable associations with variables of clinical importance. RESULTS: The youngest subgroup (14-17 years of age) compared to the oldest subgroup (21-25 years of age) had significantly lower TRAQ scores [regression estimate = 12.3 (95 % CI: 2.9, 21.7), p = 0.010]. Additionally, single participants versus those in a stable relationship had significantly lower TRAQ scores [estimate = 8.7 (95 % CI: 1.9, 15.4), p = 0.012]. The Spearman correlation coefficient between TRAQ and ADHERENT scores was 0.52 (p = <0.001), indicating a positive, moderate relationship between the two measures, suggesting more readiness correlated with less anxiety. DISCUSSION: This study found that age, higher education, and stable relationship status were associated with higher measures of transition readiness. There was a correlation found between more transition readiness and less anxiety surrounding transition. This finding can be used to inform future research and emphasizes the need for multidisciplinary support throughout the transition process. CONCLUSION: Early discussion of transition of care and education around transition readiness are not the only solution to improving transition success. The second phase of ADHERENT seeks to understand the patient experience and to include adolescents and young adults in shaping effective healthcare transition strategies.

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