Search Results (6,931)

Cancer nanomedicine has generated extensive preclinical evidence of improved drug delivery, pharmacokinetics, and tolerability, yet its clinical impact has often remained modest. This narrative review examines the interconnected biological, pharmacokinetic, manufacturing, regulatory, and clinical factors underlying this translational paradox. A structured literature search was conducted primarily in PubMed and Google Scholar, focusing on studies published between 2022 and 2026 while retaining seminal earlier reports. Major biological barriers include protein corona formation, mononuclear phagocyte system clearance, heterogeneous enhanced permeability and retention, complex tumor microenvironments, and intratumoral heterogeneity. These factors limit circulation, tumor accumulation, tissue penetration, drug release, and interpatient reproducibility. Translation is further constrained by off-target accumulation, uncertain long-term toxicity, non-standardized experimental methods, batch-to-batch variability, scale-up challenges, and fragmented regulatory pathways. Clinical experience shows that successful products are dominated by relatively established platforms and reformulations of known anticancer agents, whereas many actively targeted or structurally complex systems have failed to demonstrate sufficient efficacy or safety. Future progress will require mechanism-driven design, human-relevant preclinical models, harmonized characterization, quality-by-design manufacturing, early regulatory integration, biomarker-guided patient selection, and adaptive clinical trials. Aligning nanoparticle engineering with biological and clinical realities is essential for achieving meaningful patient benefit. Full article

Small, heterogeneous clinical datasets pose a challenge for whole-cohort prediction because clinically meaningful treatment or response patterns may be diluted across biologically diverse patients. We describe and evaluate NetraAI, an interpretable dynamical-systems framework for selective subgroup discovery that uses finite-iteration contraction-inspired dynamics and long-range memory (LRM) to identify stable, outcome-linked Model-Derived Subgroups (MDS). This system can abstain by assigning No Call when a stable subgroup assignment is not supported. A large language model (LLM) Strategist is outlined only as a possible future extension; it is not evaluated here and contributes nothing to the results reported. Foundation and language models asked to perform subgroup discovery directly did not recover the structure the specialized discovery step recovered. We demonstrate this framework across three retrospective clinical trial datasets: Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia (olanzapine vs. perphenazine comparative treatment-preference benchmark), Canadian Biomarker Integration Network in Depression (CAN-BIND) depression (escitalopram response), and Comprehensive Molecular Characterization of Advanced Pancreatic Ductal Adenocarcinoma for Better Treatment Selection (COMPASS) pancreatic cancer (GnP vs. FOLFIRINOX observational regimen-associated response). The benchmark is not a contest between NetraAI and competing predictors: the same eight downstream methods are evaluated with and without what NetraAI discovered. Given the full feature sets and their own selection procedures, those methods were at or near chance on all three datasets, and blind de novo searches by an independent interaction model and by a pretrained tabular foundation model did not recover an equivalent signature or subpopulation. In internal downstream evaluation, given the discovered variables alone—the same patients, the same classifiers, the full cohort and no abstention of any kind—every one of the eight methods improved on every dataset, 24 of 24 method-dataset comparisons, moving from a raw-feature range of 0.46–0.62 AUC to 0.54–0.78. Restricting further to the subpopulation in which those variables hold improved all eight methods again in CAN-BIND and in COMPASS, 16 of 16 comparisons, reaching 0.66–0.83 and 0.96–1.00, respectively; in CATIE, where the called subgroups are the least outcome-homogeneous of the three, it improved only one of eight. Taking the framework as a whole, 23 of 24 method-dataset combinations improved over the raw-feature baseline. NetraAI abstains on patients without stable subgroup structure, calling 27.7% to 40.4% of each cohort. The contribution demonstrated is therefore subgroup discovery rather than downstream prediction, and its beneficiaries are the conventional methods themselves. In COMPASS, NetraAI identified a three-SNV signature associated with regimen-linked response ranking among called patients; because the cohort was observational and the permutation test was conditional on the selected signature, this finding is exploratory. The two mechanisms are complementary rather than competing: variable discovery establishes which features carry the structure, and abstention establishes in which patients it holds. Neither mechanism replaces conventional modeling. Variable discovery improved every method on every dataset, the pretrained tabular foundation model included; identifying the population in which those variables hold conferred further benefit in two of the three datasets and not in the third. These findings support NetraAI as an exploratory system for generating compact, inspectable subgroup hypotheses that may inform future enrichment strategies after external validation, and indicate that its value lies in what it contributes to other methods rather than in competing with them. Full article

Background/Objectives: Postoperative thirst is a common and distressing symptom among surgical patients; however, standardized management guidelines remain limited. Oral care interventions using cold stimulation (e.g., ice chips, popsicles, and menthol-infused products) may relieve postoperative thirst, but variation in intervention protocols and outcome measures has so far precluded clear clinical recommendations. This protocol outlines a systematic review evaluating the effectiveness of cold-stimulation oral care interventions in reducing thirst intensity among adult surgical patients during the immediate postoperative period, defined as the first 6 h after emergence from general anesthesia. Methods: Randomized controlled trials (RCTs) comparing cold-stimulation oral care with standard care will be included; as pre-specified at registration, quasi-randomized trials will be considered only if fewer than three eligible RCTs are identified (appraised with ROBINS-I and reported separately). MEDLINE, Cochrane Library, EMBASE, CINAHL Plus and trial registries were searched. Risk of bias will be assessed using the Cochrane Risk of Bias tool version 2.0. The primary outcome is change in thirst intensity; secondary outcomes are oral dryness, patient satisfaction, and adverse events. Continuous outcomes will be pooled as mean differences, or as standardized mean differences across differing scales, and dichotomous outcomes as risk ratios, with 95% confidence intervals. Random-effects meta-analysis will be performed in R where appropriate, otherwise narrative synthesis, with pre-specified subgroup and sensitivity analyses. Certainty of evidence will be rated using GRADE. Conclusions: This protocol was developed in accordance with PRISMA-P and prospectively registered in PROSPERO (CRD420251139881). The review will clarify the effectiveness and safety of cold-stimulation oral care for postoperative thirst and support perioperative nursing practice. Full article

Background/Objectives: Stress is increasingly recognized as an important modulator of gut microbiome composition and function through the bidirectional microbiota–gut–brain axis. Dietary, psychobiotic, and other lifestyle-oriented interventions have therefore attracted growing interest as potential strategies for simultaneously influencing stress-related outcomes and the gut microbiome. This systematic review aimed to evaluate randomized controlled trials (RCTs) investigating the effects of lifestyle-oriented and psychobiotic interventions on both stress-related outcomes and the gut microbiome in adults. Methods: A systematic literature search was conducted in PubMed, Scopus, and Cochrane CENTRAL for English-language RCTs published between 2016 and April 2026, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Eligible studies included adults (≥18 years), evaluated lifestyle-oriented or psychobiotic interventions, and reported both gut microbiome-related and stress-related psychological or biological outcomes. Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool. Owing to substantial methodological and clinical heterogeneity, findings were synthesized narratively. Results: Twenty-nine RCTs met the eligibility criteria. Interventions included psychobiotic supplementation, dietary interventions and functional foods, and other lifestyle-oriented approaches. Across intervention categories, microbiome responses were heterogeneous, and no single taxonomic or diversity signature consistently characterized trials reporting favorable stress-related outcomes. Nevertheless, recurrent changes involving Bifidobacterium/Bifidobacteriaceae, Lactobacillus/Lactobacillaceae, Faecalibacterium, Roseburia, and members of the Lachnospiraceae/Ruminococcaceae families were identified across several interventions, together with changes in SCFA-related microbial features. Changes in global microbial diversity were inconsistent, and psychological and microbiome responses did not invariably occur in parallel. Overall, the randomized evidence indicates recurrent taxonomic and functional signals rather than a uniform microbiome response across stress-targeting interventions. Substantial heterogeneity in populations, intervention characteristics, study duration, outcome measures, and microbiome assessment methods limited direct comparisons across trials. Conclusions: Current randomized evidence does not identify a uniform microbiome signature associated with successful stress-targeting interventions but suggests partial convergence involving selected bacterial taxa and functional microbial features. The lack of consistent parallel changes in psychological and microbiome outcomes precludes conclusions regarding whether microbiome alterations mediate improvements in stress-related outcomes. Larger, longer-term RCTs incorporating standardized microbiome methodologies and functional microbial analyses are needed to determine the reproducibility and mechanistic relevance of these signals. Full article

Background: Acute brain injury, including traumatic brain injury (TBI), stroke, subarachnoid hemorrhage and secondary neurological injury, such as sepsis-associated encephalopathy (SAE) and delirium, is a major cause of morbidity in the intensive care unit (ICU), and few treatments alter its course once it is established. Critical illness, and brain injury in particular, rapidly disrupts the gut microbiome (GM) and the production of its metabolites. This dysbiosis matters most in neurologically injured patients, because microbial metabolites and a leaky intestinal barrier feed neuroinflammation through the gut–brain axis. Feeding timing and fasting affect circadian biology, the daily rhythm of the GM, and host metabolic pathways, such as ketogenesis, insulin signaling and autophagy. This review asks whether time-restricted or fasting-mimicking strategies can preserve these functions and reduce neuroimmune dysregulation after brain injury. Methods: In this narrative review, we searched the literature for randomized trials, crossover pilot studies, mechanistic human research, and guideline statements comparing continuous, cyclic, and intermittent enteral strategies, and evaluated translational pathways for GM-targeted feeding interventions. Results: Available studies showed no consistent difference in mortality between continuous and intermittent gastric feeding in ICU adults on mechanical ventilation, although the largest pooled analyses report more diarrhea, more abdominal distension and longer ICU stay with intermittent schedules, most pronounced in ventilated patients. While intermittent/cyclic regimens were not associated with an improvement of patient-centered outcomes, pilot studies demonstrated that short macronutrient interruptions (e.g., 12 h) reliably induced a metabolic fasting response in patients with a prolonged ICU stay. One randomized controlled trial (RCT) had GM end-points and reported feasible modulation of gut taxa and 58 differentially abundant serum metabolites with sequential (continuous-to-intermittent) feeding. Only five studies enrolled dedicated brain-injured cohorts; none was designed around neurological or gut–brain mechanistic outcomes, and none measured GM or neuroinflammation. Conclusions: Time-restricted, microbiome-protecting approaches are biologically plausible and deserve a phased translational program to test them in clinical trials. Future trials should focus on brain-injured and other neurologically relevant ICU patients, in whom the gut–brain axis is most engaged, and should pair mechanistic endpoints with clinical safety and proper control for confounders. No clinical study has yet tested whether non-continuous feeding alters neuroinflammatory or neurological outcomes after acute brain injury. There is currently no direct evidence supporting the effectiveness of this intervention in this population, and the case made here is mechanistic, not empirical. Full article

This review aims to provide a comprehensive overview of the currently available therapies for primary vitreoretinal lymphoma (PVRL) and to evaluate emerging therapeutic strategies that may improve patient outcomes. A comprehensive literature search was conducted in databases including PubMed/MEDLINE, Embase, and Scopus for studies published up to 2026. Search terms included “primary vitreoretinal lymphoma”, “intravitreal methotrexate”, “rituximab”, “radiotherapy”, “targeted therapy”, and “immunotherapy”. Eligible publications included randomized controlled trials, prospective and retrospective studies, observational studies, systematic reviews, relevant clinical guidelines, case series, and case reports. Studies were independently screened and assessed by two reviewers. Current therapeutic strategies include intravitreal chemotherapy, systemic high-dose methotrexate-based regimens, and radiotherapy, either as monotherapy or in combination. While intravitreal approaches provide effective local disease control, they fail to address occult or subsequent central nervous system (CNS) dissemination, necessitating the use of systemic treatments in selected patients. In recent years, significant progress in the understanding of PVRL pathophysiology, including the role of MYD88 mutations and interleukin-10 signaling, has paved the way for the development of targeted and immunomodulatory therapies. Agents such as Bruton’s tyrosine kinase inhibitors, immunomodulatory drugs, and immune checkpoint inhibitors have demonstrated promising results in early clinical studies, particularly in relapsed or refractory disease. Despite advances in diagnostic techniques, the management of PVRL remains challenging due to its heterogeneous presentation, high relapse rates, and frequent progression to CNS involvement. Full article

Human Papillomavirus (HPV) is a highly prevalent sexually transmitted infection associated with malignancies of the cervix, vulva, and vagina. While prophylactic vaccination with Gardasil^®9 is FDA-approved through age 45, no clinical trials have evaluated its use in older adults who remain sexually active and at risk for HPV-related cancers. We describe the case of a woman who presented with recurrent high-risk HPV and received the three-dose Gardasil^®9 series off-label at the age of 67. Following vaccination, her cervical cytology was negative for HPV and subsequent colposcopy did not demonstrate any evidence of intraepithelial lesion or malignancy. As this is a single case report, this temporal association cannot establish that vaccination caused viral clearance. Nonetheless, this case raises important questions regarding age-based HPV vaccination limits. Immunosenescence in older populations may impair viral clearance and could increase cumulative risk of progression from dysplasia to malignancy. Vaccination may therefore serve both prophylactic and potentially therapeutic roles; however, this must be evaluated in further controlled studies. This case highlights the need for further research into HPV vaccination in patients over the age of 45 years with or without history of HPV infection. Full article

Background/Objectives: Illness coherence has been associated with treatment engagement and adherence, but its relationship with exercise adherence and patient-reported outcomes in chronic spinal pain remains unclear. This study examined whether unsupervised exercise adherence mediates the association between baseline illness coherence and patient-reported outcomes and whether this indirect association differs according to the type of intervention received. Methods: A theory-driven secondary analysis was conducted using data from a randomized controlled trial of adults with chronic spinal pain receiving either exercise-only or combined exercise plus diaphragmatic breathing intervention (initially randomized = 183; n = 57/group). Measures included Revised Illness Perception Questionnaire (IPQ-R), Brief Pain Inventory–Short Form (BPI-SF), Hospital Anxiety and Depression Scale (HADS), World Health Organization Quality of Life Instrument, Brief Version (WHOQOL-BREF), and exercise logs. Moderated mediation analyses examined whether the intervention group moderated the indirect associations between baseline illness coherence and patient-reported outcomes through unsupervised exercise adherence. The parent trial was retrospectively registered at ClinicalTrials.gov (NCT07539116) on 12 April 2026. Results: Mean age was 46.95 ± 14.54 and 46.32 ± 15.97 years, and women comprised 40.4% and 47.4% of the exercise-only and combined groups, respectively. Baseline illness coherence was positively associated with unsupervised exercise adherence in the exercise-only group (b = 71.04, p = 0.018). Significant conditional indirect effects of illness coherence on all patient-reported outcomes through unsupervised exercise adherence were observed in the exercise-only group (b = −1.55 to 1.32, ps < 0.05), but not in the combined intervention group (b = −0.59 to 0.32, ps > 0.05). Indices of moderated mediation were significant across all outcomes (all ps < 0.05). No intervention-related adverse events were reported. Conclusions: Diaphragmatic breathing may reduce the relative contribution of illness-related cognitive representations on patient-reported outcomes by introducing additional self-regulatory pathways through which clinical improvement is achieved. Full article

Background/Objectives: Vietnamese evidence on transarterial chemoembolization (TACE) plus lenvatinib for unresectable hepatocellular carcinoma (HCC) remains limited. We examined recorded early imaging responses and uncertainty from missing outcomes, exposure classification, and confounding. Methods: This single-center secondary cohort included all eligible available records during a shared post-approval period (21 February 2024–19 August 2025). The endpoint was a documented complete or partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) at the first recorded post-index computed tomography (CT) or magnetic resonance imaging (MRI), an ascertainment-dependent surrogate rather than a standardized clinical-trial objective response rate. We reported risk differences (RDs), risk ratios (RRs), odds ratios (ORs), 95% confidence intervals (CIs), nonparametric bounds, tipping-point analysis, sequential models, and a comparator co-therapy audit. Results: Among 108 patients (23 combination; 85 comparator), recorded responses occurred in 17/23 (73.9%) and 30/85 (35.3%): RD, 38.6 percentage points (95% CI, 18.0–59.2); RR, 2.09 (95% CI, 1.44–3.05); and OR, 5.19 (95% CI, 1.85–14.57). With 6 and 34 undocumented outcomes, response-difference bounds ranged from −1.4 to 64.7 percentage points. Reclassifying 12 undocumented comparator outcomes as responses made Fisher’s p-value exceed 0.05; reclassifying 33 eliminated the point-estimate advantage when all six undocumented combination outcomes were nonresponses. The expanded complete-case estimate was attenuated (adjusted OR, 1.97; 95% CI, 0.45–8.60). Excluding five comparator records with explicit systemic co-therapy yielded an adjusted OR of 5.49 (95% CI, 1.93–15.61). Safety incidence and survival were not estimable. Conclusions: Recorded responses differed between strategies, but missingness, imaging ascertainment, treatment-selection confounding, and incompletely characterized comparator exposure prevented identification of a comparative treatment effect. This study identifies registry and implementation gaps and generates a hypothesis for prospective modified RECIST (mRECIST)-based evaluation. Full article

Recurrent vulvovaginal candidiasis (RVVC), commonly defined as ≥3 symptomatic episodes per year, affects an estimated 138 million women worldwide. This structured narrative review (PubMed/MEDLINE and open-indexed sources, January 2020–July 2026, as well as selected pre-2020 landmark studies) synthesizes epidemiological and metabolic risk factors (including SGLT2-inhibitor-associated susceptibility), host immunogenetic and vaginal microbiome mechanisms, emerging preventive pharmacotherapies, and patient-reported outcomes within a unified clinical framework. RVVC arises from interacting host, microbial, metabolic, behavioral, and iatrogenic domains—diabetes-related hyperglycemia, innate immune polymorphisms (MBL2, TLR2), altered bacterial–fungal vaginal communities, and non-albicans Candida in difficult-to-treat cases. Fluconazole maintenance remains a guideline-supported suppressive option but relapse after discontinuation is common; oteseconazole and ibrexafungerp expand prevention choices, while probiotics show inconsistent, low-certainty benefit. RVVC consistently impairs health-related quality of life, sexual function, and mental health and imposes substantial economic burden; regional data from Southeastern Europe underscore diagnostic and access gaps. We propose a multifactorial host–pathogen–microbiome model that favors individualized, diagnosis-driven management and routine incorporation of validated patient-reported outcomes. Research priorities include harmonized case definitions, head-to-head trials of new agents, validated quality-of-life instruments, longer post-treatment follow-up, and real-world cost-effectiveness evaluations. Implementation research, equitable access strategies, clinician education, and national health policy are essential to translate evidence into improved patient outcomes globally. Full article

Background: Catheter ablation is the most effective rhythm-control strategy for symptomatic atrial fibrillation (AF). A fluoroless approach eliminates ionizing radiation exposure for patients, operators, and laboratory staff and removes the ergonomic burden of leaded protective garments. Pulsed field ablation (PFA) is a predominantly non-thermal energy modality with a distinct safety profile, now addressed in dedicated international consensus documents. Several PFA catheters are natively integrated with three-dimensional electroanatomical mapping (3D EAM) platforms and are therefore well suited to fluoroscopy-free workflows. This review is confined to two of them—Sphere-9 (Affera/Medtronic) and VARIPULSE (Biosense Webster)—with which the authors have direct procedural experience. Objective: This study seeks to describe a practical, expert- and experience-based approach to zero-fluoroscopy AF ablation with these two catheters, to review the harms of radiation exposure, and to synthesize the currently available and still limited evidence for fluoroless PFA. The workflow presented is explicitly not an evidence-validated or broadly generalizable algorithm, and each procedural step is labeled according to whether it rests on comparative data, device-specific studies or instructions for use, or institutional practice and expert opinion. Methods: This is a structured narrative review. PubMed/MEDLINE was searched to 30 June 2026 (final search 30 June 2026), with no lower date restriction, using controlled vocabulary and free-text terms for atrial fibrillation, catheter ablation, zero or minimal fluoroscopy, pulsed field ablation, Sphere-9, Affera, and VARIPULSE. English-language randomized trials, cohorts, registries, systematic reviews, and society documents reporting procedural or clinical outcomes were eligible; reference lists were hand-searched. Conference abstracts, preprints, and non-peer-reviewed manufacturer reports were excluded from all numerical statements. Results: Four meta-analyses report comparable acute success, arrhythmia recurrence, and complication rates between zero-fluoroscopy and fluoroscopy-guided AF ablation, with procedural feasibility of 95.1% and a crossover rate of 1.26%. These are pooled observational comparisons without pre-specified non-inferiority designs or margins, and they should not be read as establishing formal non-inferiority. Differences between them reflect ablation technology, imaging strategy, study period, operator experience, and heterogeneous definitions of “zero fluoroscopy”. Randomized evidence comparing PFA with thermal ablation shows comparable 12-month efficacy and major complication rates and shorter procedure duration but no consistent reduction in fluoroscopy time—a finding that bears directly on the present topic. Sheath visualization is the decisive enabler: in a randomized trial of 100 patients, left atrial fluoroscopy time was 0 s (IQR 0–0) with a visualizable steerable sheath. In a nonrandomized subgroup analysis of the AdmIRE trial, 12-month freedom from AF was similar across zero- (72.1%), low- (75.4%) and conventional-fluoroscopy (73.6%) strategies. Conclusions: Integration of PFA with 3D EAM and intracardiac echocardiography makes a fluoroless workflow practical in experienced hands. The supporting evidence remains predominantly observational; no randomized trial has compared zero-fluoroscopy with fluoroscopy-guided PFA, and the approach described here should be regarded as expert practice rather than a standard of care. Patient safety, not the absolute avoidance of fluoroscopy, must remain the governing principle. Full article

Botanical dietary supplements are widely used, and many are marketed for liver support. Yet product-specific prevalence data are limited, and composition, standardisation, authenticity, and safety vary substantially. This focused narrative review integrates clinical, regulatory, product quality, and analytical evidence, using milk thistle, artichoke leaf, turmeric, and green tea as case studies. Unlike ingredient-centred reviews, it links clinical interpretation to product identity, formulation, batch characterisation, and analytical decision-making. Searches updated to 3 August 2026 prioritised controlled human studies, primary regulatory sources, and fit-for-purpose analytical literature. The selected evidence was dominated by small or short trials, heterogeneous formulations, surrogate outcomes, and incomplete lot characterisation. It did not establish disease-modifying efficacy for any reviewed preparation. Bioavailability-enhanced turmeric products and concentrated green tea extracts show that plausible benefits can coexist with liver-injury risk. Product substitution, inaccurate labelling, contamination, undeclared co-ingredients, and microbiological non-conformity can further alter exposure. Because no single method is sufficient, complementary chemical, microbiological, molecular, and palynological analyses are integrated into a staged, qualitative, risk-based workflow, from product definition through confirmatory testing and action. Product- and lot-specific characterisation, transparent trial reporting, adverse-event investigation, and surveillance are required before broad liver-support claims can be sustained. Full article

Background: Mandatory folic acid (FA) fortification prevents neural tube defects but generates unmetabolized folic acid (UMFA) in blood, because hepatic dihydrofolate reductase (DHFR) reduces FA only slowly. Whether UMFA itself, as distinct from high total folate, carries biological consequences is unresolved. Methods: We systematically searched six databases (January 1995–May 2026; PROSPERO CRD420261407616) and included 65 publications describing 61 unique primary studies, yielding 71 analytic contributions (15 mechanistic, 24 observational, 32 interventional). The question of whether equimolar (6S)-5-MTHF substitution alters UMFA, erythrocyte folate, or total homocysteine (tHcy) versus FA was evaluated using random-effects meta-analysis with a DerSimonian–Laird estimator for τ² and Hartung–Knapp–Sidik–Jonkman small-sample confidence intervals and was rated with GRADE. Mechanistic and observational streams were synthesized narratively and classified by exposure metric (UMFA, total folate, FA intake, fortification). Results: 5-MTHF substitution reduced plasma UMFA (SMD +0.99; 95% CI +0.20 to +1.79; I² = 30%; k = 3; GRADE low). The two trials reporting erythrocyte folate were directionally discordant (Hedges’ g +0.40; +0.08 to +0.73 and −0.38; −0.92 to +0.16; I² = 83%) and were not pooled. For tHcy, no pooled estimate could be derived; it is reported qualitatively. Observational UMFA–outcome associations were inconsistent, confounded by total folate, and unreplicated. Conclusions: Substitution of (6S)-5-MTHF for FA appears to reduce circulating UMFA. For erythrocyte folate, the two available trials were directionally discordant but insufficient to establish equivalence or non-inferiority. For tHcy, no between-form difference was detected. With two to three trials per outcome, no prespecified margins, and no trial designed for that purpose, the evidence cannot support an equivalence or non-inferiority claim for either outcome and clinical benefit remains unestablished. Current evidence does not establish that UMFA independently causes harm. Full article

Background and Objectives: Neurogenic rosacea is a clinically useful, but not yet standardized, sensory-weighted presentation within the rosacea spectrum. This narrative review evaluates its clinical features, differential diagnosis, proposed mechanisms, and reported therapeutic approaches while distinguishing direct human evidence from indirect and experimental findings. Materials and Methods: PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar were searched through 30 June 2026 using predefined combinations of terms related to rosacea, facial dysesthesia, neurogenic inflammation, sensory pathways, mast cells, and treatment. English-language clinical and experimental publications were selected by relevance; reference lists were also screened. Evidence was grouped as phenotype-specific human evidence, human evidence from rosacea populations or related conditions, case-based evidence, and animal or cellular evidence. Results: Direct evidence specific to neurogenic rosacea is limited mainly to small observational series and case reports. Human rosacea studies support neurovascular involvement, whereas many TRP-channel, protease, LL-37–MRGPRX2, and mast cell links remain indirect or experimental. No validated diagnostic criteria or phenotype-specific treatment algorithms exist. Conclusions: Neurogenic rosacea is best regarded as a clinically useful but not yet standardized sensory-weighted presentation within the rosacea spectrum, as current evidence does not establish it as an independent phenotype. The clinical features summarized in this review may support recognition of this presentation and its differentiation from relevant mimics, while diagnostic and treatment decisions should remain individualized. Prospective cohorts, validated sensory measures, biomarkers, and controlled phenotype-stratified trials are needed. Full article

Background: Physical activity is relevant for physical and psychosocial development in children and adolescents with Down syndrome. However, evidence regarding the effects of structured physical activity interventions across different motor and psychosocial domains remains limited and heterogeneous. This systematic review aimed to examine the effects of structured physical activity interventions on motor and psychosocial outcomes in this population. Methods: The review was conducted according to PRISMA guidelines and registered in PROSPERO (CRD42025114068). Scopus, PubMed, and Web of Science databases were searched, with the final search conducted on 15 December 2025. Eligible studies were peer-reviewed articles published in English within the previous 10 years that investigated structured physical activity interventions in children and adolescents with Down syndrome and reported motor or psychosocial outcomes. Methodological quality was assessed using a modified Downs and Black Checklist. Due to substantial clinical and methodological heterogeneity across interventions, comparators, and outcome measures, findings were synthesized narratively. The certainty of evidence was assessed using the GRADE approach. Results: Five studies, including 186 participants, were included, of whom 166 had Down syndrome and 20 were typically developing children. The included studies reported improvements in motor skills, balance, coordination, and psychosocial outcomes. Interventions included Pilates, core stability and treadmill training, fundamental movement skills training, adapted football, and traditional Indian dance. Motor outcomes were generally associated with improvements in balance, postural control, coordination, and motor competence. Psychosocial outcomes were assessed in only two studies and showed preliminary improvements, including reductions in aggression, attention problems, anxiety/depression, and social problems. Overall, the certainty of evidence was rated as low across the assessed outcome domains. Conclusions: Structured physical activity interventions may be associated with improvements in motor development, while their effects on psychosocial outcomes appear encouraging but require further investigation. The findings should be interpreted cautiously because of the small number of studies, methodological limitations, and heterogeneity of interventions and outcome measures. Further high-quality randomized controlled trials with larger samples and standardized outcome measures are needed. Full article