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In this study we provide a comprehensive assessment of metal contamination in the Amazon River and its main tributaries, with a focus on urban contamination hotspots. A monitoring campaign was conducted across 40 sampling sites, analysing water concentrations of As, Cd, Cu, Cr, Fe, Mn, Pb, Ni, and Zn. Metal concentrations were evaluated against national and international water quality standards and compared between urbanized and less impacted regions to delineate pollution patterns. Additionally, an ecological risk assessment was conducted for individual metals and for metal mixtures using Species Sensitivity Distributions (SSDs). The results of this study show that Fe levels in the Amazon River were exceptionally high, with potential implications for aquatic species distribution across the basin. Exceedances of water quality standards were identified for four metals (Fe, Pb, Mn, Cu), with metal enrichment observed particularly in Manaus, Macapá, and Belém. Acute multi-substance potentially affected fraction (msPAF) of species in the Amazon River and its tributaries indicated insignificant risks, while chronic values ranged from 3% to 33%. In urban areas, acute msPAF values were generally low, with the exception of two samples taken in Manaus that exhibited values of 11% and 16%. Chronic riskvalues, however, were consistently high in these urban locations, reaching up to 72% of species potentially affected and reflecting sustained ecotoxicological stress. Cu, Zn and Mn were identified as the primary contributors to chronic toxicity, with Cu and Zn dominating in Manaus, and Mn in Macapá. These findings underscore the need for stricter industrial discharge regulations and improved wastewater treatment systems to preserve Amazonian freshwater ecosystems.
The transition toward Software-Defined Vehicles has rendered internal networks, particularly the Controller Area Network, vulnerable to sophisticated cyberattacks. Although recent research has prioritized Deep Learning Intrusion Detection Systems for their statistical accuracy, these black-box models often fail to meet the strict latency and explainability constraints of automotive safety standards. This article proposes a Multi-Standard (CAN/CAN-FD) logic extraction framework validated herein on legacy CAN and CAN Flexible Data-rate, that reconciles high-precision detection with the deterministic requirements of embedded systems. By employing an elastic parsing mechanism and a constrained Classification and Regression Tree algorithm, the methodology distills complex attack signatures into compact, interpretable boolean rules. Unlike computationally intensive neural networks, this white-box approach ensures deterministic, bounded, worst-case execution time by design. Experimental validation using diverse datasets, including legacy and high-bandwidth CAN Flexible Data-rate traffic, demonstrates that the extracted boolean logic achieves a deterministic algorithmic inference latency as low as 0.15 microseconds. When benchmarked in an identical hardware environment, this represents a 14× empirical speedup over optimized internal ML baselines (XGBoost), and theoretically eliminates the heavy matrix multiplication overhead typical of state-of-the-art deep learning approaches, while maintaining average detection accuracy above 99.97 percent for the CAN Flexible Data-rate. Furthermore, the generated logic satisfies the interpretability mandates of functional safety standards.
Small community water systems in California's San Joaquin Valley disproportionately fail to provide safe drinking water, with most serving disadvantaged communities and lacking the technical, managerial, and financial capacity to maintain compliance. The State Water Board designates such systems as failing when they have documented violations of drinking water standards or cannot reliably deliver safe water. Physical consolidation, which involves connecting a smaller failing system to a larger provider through new pipeline infrastructure, is the primary long-term solution promoted by state regulators. Here, we assess consolidation feasibility and capital costs across four counties (Kern, Kings, Tulare, and Fresno) via the state's 2024 screening methodology. The methodology identifies smaller failing and at-risk systems as candidates for joining a larger receiving system with sufficient capacity. Among the 210 eligible systems, 114 (54%) matched a receiving system within three miles, with an estimated total capital need of $413.5 million. Nearly all identified pairs met state funding viability thresholds. The remaining 96 systems, including 49 classified as failing, lacked an eligible receiving partner and will require alternative solutions. Physical consolidation is necessary but insufficient for achieving safe drinking water access across the region.
Molybdenum disulfide (MoS2) field-effect transistors with high-k oxides lag behind silicon standards in stability due to traps causing clockwise hysteresis. While suppressing this effect is mandatory for logic devices, here we show an alternative strategy where initial hysteresis is dynamically overcome by stronger counterclockwise hysteresis coupled with memory-like transient negative differential resistance. We compare back-gated transistors using HfO2 and Al2O3 gate insulators up to 275 °C. At 175 °C, devices with HfO2 exhibit dominant counterclockwise dynamics and transient negative differential resistance. Our compact model suggests this behavior is caused by the drift of mobile oxygen vacancies within HfO2. This mechanism overrides initial hysteresis, revealing a pathway to memory-like functionality enhanced by narrower voltage sweep ranges. In contrast, transistors gated with Al2O3 display only minor counterclockwise dynamics even at 275 °C due to higher vacancy migration barriers, maintaining superior stability. Our results reveal an insulator selection paradigm: Al2O3 is better suited for logic devices, whereas HfO2 counterparts can serve as active layers for memory components.
Anti-amyloid therapies for Alzheimer's disease (AD) require efficient patient selection. The Clinical Dementia Rating (CDR) scale is the reference standard for staging, but it is time-consuming to administer. Simple tools to distinguish early-stage cognitive impairment (CDR 0.5-1) from more advanced stages (CDR 2-3) would therefore be of substantial clinical value. Participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts 1-3 with CDR ≥0.5 were analysed. Three logistic regression models using Mini-Mental State Examination (MMSE), Functional Assessment Questionnaire (FAQ) or the FAQ/MMSE ratio as predictors were developed. Two cut-offs per model were selected to ensure minimum sensitivity and specificity of 0.99, defining rule-out, rule-in and intermediate (uncertain) zones. Performance was assessed using discrimination, calibration and decision curve analysis. Among 1533 ADNI participants with CDR ≥0.5, two-thirds (n=1022) were assigned to the training set and one-third (n=511) to the test set. FAQ/MMSE and FAQ showed excellent discrimination (area under the curve, AUC 0.97-0.98), outperforming MMSE (AUC 0.94-0.95). FAQ/MMSE demonstrated the best overall performance, although differences compared with FAQ were small and not statistically significant. Dual cut-offs for FAQ/MMSE (0.67 and 1.44) and FAQ (12 and 27) enabled clinically meaningful stratification, with 80% and 70% of participants classified into high-confidence zones, respectively. Results were consistent across the training and test sets. The FAQ/MMSE ratio and FAQ score show high accuracy in distinguishing early-stage (CDR 0.5-1) from more advanced cognitive impairment (CDR 2-3). These simple measures may support the clinical preselection of patients for further evaluation in the context of anti-amyloid therapy.
For early colorectal cancer (CRC) following noncurative endoscopic resection, additional curative surgery is the standard of care, but the optimal timing remains unclear. This study investigated the effect of the interval between procedures on surgical complexity, complications, and oncological outcomes. This retrospective study included 112 patients with early CRC who underwent additional laparoscopic surgery after noncurative endoscopic resection between August 2019 and August 2024. Clinical and pathological data were collected, with primary endpoints focused on surgical difficulty (operative duration and intraoperative blood loss). Statistical analyses were performed using multivariate analysis of variance, logistic regression, and receiver operating characteristic curve analysis. The interval between procedures was not significantly associated with surgical difficulty or lymph node metastasis (P>0.05). Multivariate analysis did not identify an optimal timing point for surgery. However, a longer waiting time was independently associated with an increased risk of residual tumor (odds ratio, 1.09; 95% confidence interval, 1.03-1.16; P=0.004). Furthermore, lymphovascular invasion and elevated preoperative carcinoembryonic antigen levels were identified as independent predictors of lymph node metastasis. A higher preoperative lymphocyte ratio was associated with an increased risk of postoperative intra-abdominal infection (r=0.243, P=0.010). In the era of laparoscopic surgery, the timing of additional surgery does not appear to be the primary determinant of surgical difficulty in CRC. Clinical decision-making should prioritize high-risk pathological features, such as lymphovascular invasion, rather than rigid adherence to a predetermined waiting period. Strategically delaying surgery may facilitate the selection of patients without residual disease, thereby helping to avoid unnecessary procedures.
Nanozymes (primarily peroxidase mimics) coupled with glucose oxidase (GOx) have emerged as an important approach for glucose sensing. However, the widespread application of this strategy is hampered by a critical pH mismatch, as most such nanozymes require an acidic environment for high activity, preventing one-step detection at physiological pH. Here, we report a cascade colorimetric sensing platform based on our previously reported haloperoxidase (HPO) mimic HH-Cu, which exhibits high HPO-like activity exclusively under neutral and alkaline conditions, enabling one-step glucose detection at physiological pH. In this system, GOx catalyzes the oxidation of glucose to generate H2O2, which is utilized by HH-Cu along with externally added Br- to convert phenol red into bromophenol blue (λmax = 590 nm) through its HPO-like activity, resulting in a visible color change from orange to blue. Spectrophotometric analysis yielded a linear detection range of 1-600 μM and a detection limit of 0.99 μM for glucose, with recovery rates of 90.8%-106.6% and relative standard deviations (RSD) below 7% in urine samples. A smartphone-based analysis platform was also developed and showed performance comparable to the spectrophotometric method, with a linear range of 2.5-600 μM, a detection limit of 2.20 μM, and recovery rates of 105.5% in biological samples. Both platforms were also successfully applied to the sensitive detection of H2O2 at physiological pH. This work not only overcomes the key limitation of pH mismatch in conventional enzyme/nanozyme-based colorimetric glucose detection but also broadens the application horizon of HPO mimics in biosensing.
Microarray and RNA-sequencing datasets for recurrent implantation failure (RIF) were retrieved from the Gene Expression Omnibus (GEO) database. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were subsequently integrated with lipid metabolism-related gene sets to identify candidate biomarkers. Cross-analysis of these approaches yielded seven candidate genes, which were then subjected to four machine learning algorithms. This led to the identification of five hub genes: PRKAG2, CPT1A, PPARGC1A, PIK3C2G, and PTGS2. Logistic regression further validated these genes as robust biomarkers, enabling the construction of a diagnostic nomogram. Molecular docking using CB-Dock Tools subsequently demonstrated that peucedanin binds favorably to all five hub gene products. Collectively, these findings highlight PRKAG2, CPT1A, PPARGC1A, PIK3C2G, and PTGS2 as promising diagnostic biomarkers for RIF and offer new perspectives for therapeutic intervention.
Hypomimia is a hallmark of Parkinson's disease (PD), but whether emotional expressions show lateralized abnormalities remains unclear. While asymmetry has been described for posed smiles, no study has examined true spontaneous smile asymmetry in PD. The whistle-smile reflex (WSR), an involuntary smile elicited after voluntary whistling, offers an opportunity to investigate a form of smiling that closely resembles typical spontaneous expressions of joy. In the present study, we aimed to assess the frequency, intensity, and asymmetry of smiling elicited by the WSR in PD compared with healthy controls (HCs) and to explore links between facial and motor asymmetry. Fifty PD patients and 22 age-matched HCs underwent standardized video recording of the WSR. Only participants judged as smiling by ≥ 3/4 raters were included in the chimeric-face analysis. Left-left (LL) and right-right (RR) chimeric images were generated, and seven blinded raters evaluated smile presence and hemiface expressivity. Facial Laterality Index (FLI) and Body Laterality Index (BLI) quantified asymmetries. WSR was less frequent in PD than HCs (video: 44% vs. 72%; mouth-only chimeras: 50% vs. 81%, p < 0.01). PD smiles were more often symmetrical (59% vs. 25%, p = 0.03), with no consistent left-right dominance. Facial and motor asymmetry were unrelated (p > 0.05). Symmetric smilers had higher UPDRS-III scores (p = 0.04). In PD, WSR is reduced and bilaterally flattened, with no lateralized asymmetry, possibly reflecting limbic-subcortical dysfunction. Smile symmetry increases with motor severity, supporting its potential as a simple marker of hypomimia. The WSR and chimeric-smile analysis provide practical tools to assess emotional expressivity in PD.
This study presents an enhanced approach for recovering the secret key of the standard classical transposition cryptosystem using a recently introduced metaheuristic, the coati optimization algorithm. To adapt the coati optimization algorithm for cryptanalysis, its core framework is specifically customized for the considered transposition cryptosystem. The performance of the tailored coati optimization algorithm is benchmarked against three established metaheuristics, namely genetic algorithm, cuckoo search and particle swarm optimization based on accuracy, effectiveness, and efficiency. Experimental results demonstrate that the proposed method performs competitively, often surpassing genetic algorithm, cuckoo search, and particle swarm optimization across all evaluation metrics. However, the current experimental evaluation is limited to English-language ciphertexts using English n-gram statistics; therefore, the applicability of the proposed framework to multilingual cryptanalysis remains a direction for future investigation.
Transversus abdominis (TrA) and gluteus medius (GM) play important roles as primary stabilizers of the lumbopelvic-hip complex. Dysfunction of these muscles has been associated with low back pain (LBP), which affects lumbopelvic stability. This study aimed to evaluate the intra-rater and inter-rater reliability of the TrA and GM muscle thickness during standing and single-leg standing, both with and without the abdominal drawing-in maneuver (ADIM). A total of 24 participants, 12 asymptomatic and 12 with non-specific low back pain (NSLBP), were enrolled. Muscle thickness was determined as the average of three consecutive measurements. Intraclass correlation coefficients (ICC) were used to assess reliability, and the standard error of measurement (SEM) and the minimal detectable change (MDC) were calculated. The results demonstrated high intra-rater reliability for the TrA (0.86-0.98) and the GM (0.90-0.99), and high inter-rater reliability for the TrA (0.86-0.95) and the GM (0.91-0.99). The SEM for TrA ranged from 0.12 to 0.39 and the GM ranged from 0.63 to 1.83, while the MDC for TrA ranged from 0.35 to 1.09 and for GM ranged from 1.75 to 5.08 mm. The thickness measurement of the TrA and GM muscles demonstrated high reliability and clinical applicability in both standing and single-leg standing positions.
Vitamin B12 deficiency causes megaloblastic anemia and ineffective hematopoiesis. While intramuscular administration remains standard, intravenous and intranasal alternatives are increasingly used. Rigorous comparative data on hematological efficacy across routes remain limited. We thus aimed to compare intranasal, intramuscular, and intravenous vitamin B12 therapy for hematological recovery in vitamin B12 deficiency anemia, and to identify independent predictors of treatment response. In this prospective randomized controlled trial (IEC/2024/450; CTRI/2024/10/075521), 153 adults with vitamin B12 deficiency were randomized to intranasal (n = 55), intravenous (n = 56), or intramuscular (n = 42) administration. Hemoglobin (Hb), mean corpuscular volume (MCV), reticulocyte count, and lactate dehydrogenase (LDH) were assessed at baseline and on Days 7, 14, and 28. Inter-group comparisons used the Kruskal-Wallis test; covariate-adjusted analyzes employed ANCOVA and multiple linear regression. All three routes produced significant hematological recovery (all within-group p < 0.001). Mean ΔHb was +2.48, +1.80, and +2.18 g/dL for intranasal, intravenous, and intramuscular groups. Although the unadjusted analysis detected an intergroup difference (H = 7.23, p = 0.027), ANCOVA abolished the significance (all p > 0.06). MCV reduction was equivalent (Kruskal-Wallis p = 0.948). LDH normalization was greater with parenteral routes (H = 8.17, p = 0.017); intramuscular therapy produced the most pronounced reticulocytosis (H = 13.93, p = 0.001). In multivariate regression (adj. R2 = 0.575), baseline Hb (β = -0.298, p < 0.001), vegan diet (β = +1.30, p = 0.001), and age (β = -0.013/year, p = 0.039) were independent predictors; route was not. All three routes produce hemoglobin recovery at 28 days with no statistically significant adjusted differences. Intranasal vitamin B12 is a safe, effective, noninvasive alternative suitable for long-term maintenance and resource-limited settings. All conclusions are restricted to short-term hematological outcomes. Trial Registration: CTRI/2024/10/075521.
Lymphedema is a common and enduring consequence of cancer treatment with substantial physical and psychosocial morbidity, yet research predominantly focuses on physical outcomes. This systematic review examines psychosocial interventions for individuals with lymphedema, describing the intervention characteristics, methodological quality, and strength of the evidence. A systematic literature search was conducted of studies published through November 2025. Empirical interventions with psychosocial components and outcomes for individuals with lymphedema were eligible. Methodological quality was assessed. Strength of the evidence was determined by combining quality with intervention effectiveness. Ten studies met inclusion criteria, including mind-body (n = 3), education and support (n = 3), and physical activity (n = 4) intervention models, and most delivered following completion of decongestive therapy. Psychosocial outcomes included mental health (n = 8) and quality of life (n = 6). Methodological rigor was mixed, with MQRS scores ranging from 5-13 (of 14). Interventions delivered in combined in-clinic and remote settings demonstrated stronger evidence for improving mental health outcomes than either setting alone. Few empirical evaluations exist targeting the psychosocial needs of individuals with lymphedema, particularly during intensive phases of decongestive therapy. Heterogeneity in intervention models, outcome measures, and treatment timing limits cross-study comparisons; however, hybrid delivery approaches show promise for improving psychosocial outcomes. Greater integration of psychosocial care across the lymphatic care continuum, supported by standardized outcome measures, may strengthen supportive care for individuals living with lymphedema.
Highly vascularised neuroendocrine tumours (NETs) are attractive targets for foslinanib (CVM-1118), which disrupts vasculogenic mimicry and induces apoptosis via tumour necrosis factor receptor-associated protein 1. We evaluated the efficacy and safety of CVM-1118 in advanced NETs. Patients with grades 1-2, well-differentiated lung, gastrointestinal, or pancreatic NETs, refractory or intolerant to one or more standard therapies and progressing within 6 months, received CVM-1118 (200-300 mg orally twice daily) in 28-day cycles. Primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Of 43 enroled participants, 35 were efficacy-evaluable; most had grade 2 pancreatic (63%) or gastrointestinal (34%) NETs with two prior therapies. Median PFS was 10.5 months (95% CI, 5.6-22.3). ORR was 3%, DCR was 77%, and median OS was not reached (95% CI, 23.8-NR). Sensitivity analysis in the full analysis set (N = 43) showed a PFS estimate broadly aligned with the primary analysis (median, 8.4 months); patients with prior everolimus, sunitinib, or peptide receptor radionuclide therapy (N = 22; median, 8.3 months) showed similar findings. Treatment-related adverse events occurred in 44%, mostly grades 1-2, with no serious events. CVM-1118 demonstrates favourable efficacy and safety in advanced NETs. ClinicalTrials.gov identifier, NCT03600233.
Sexual commitment and stage conversion are two crucial steps in the blood stage cycle of the human malaria parasite, as they mark its initial decision and subsequent differentiation in preparation for transmission to the mosquito vector. Here we present a Protocol Update that allows tracking and quantification of sexual commitment (in the asexual replicative parent, schizont stage) and conversion (in the nonreplicative sexual progeny, gametocyte stage) rates in the human malaria parasite Plasmodium falciparum. For this purpose, we combine three critical tools we recently established and validated. First, we use a standardized minimal medium to efficiently and reproducibly increase sexual commitment. Second, we use Tubulin Tracker Deep Red to label developing gametocytes and quantify the sexual conversion rate in reporter and reporter-free lines. Third, we use a fluorescent transgenic reporter line for consecutive quantification of sexual commitment and stage conversion in the same experimental procedure. These tools enable multiple experimental readouts including flow cytometry, fixed and live cell microscopy (including high content imaging) and other applications such as fluorescence-activated cell sorting. We anticipate that the presented sexual commitment-conversion assay will enable novel screening approaches for the identification of transmission blocking antimalarials and critical knowledge gaps in the Plasmodium transmission cycle to be closed. The Protocol can be completed in 7 d from start to finish.
To determine whether sex differences in marathon pacing strategies and susceptibility to catastrophic deceleration ("hitting the wall") persist in a massive, high-performance dataset, and to quantify this risk across different performance levels. We analyzed 873,334 finishers from the Berlin Marathon (1999-2025). Pacing stability was quantified using the percentage slowdown in the second half relative to the first. "Hitting the wall" was operationally defined as a deceleration of ≥ 20%. A stratified analysis was performed to compare risks between sexes across five performance categories (Competitive to Casual). Multivariable logistic regression adjusted for age and performance category, sensitivity analyses (deduplicated subset; alternative thresholds), and fine-grained pacing metrics from 5 km splits were also conducted. Male runners exhibited significantly greater mean deceleration (10.73% ± 11.41%) compared with female runners (8.34% ± 8.91%, p < 0.001). The prevalence of "hitting the wall" was nearly double in men (17.63%) compared with women (9.66%), corresponding to a crude Odds Ratio of 2.00 (95% CI 1.97 to 2.03); after adjustment for age and performance category, the disparity strengthened (adjusted OR = 3.88, 95% CI 3.81 to 3.94). The risk disparity widened among the fastest runners: in the Competitive (< 3 h) category, male runners were approximately six times more likely to experience catastrophic deceleration than their female counterparts (1.42% vs 0.23%). The gap was stable across the 27-year archive (Mann-Kendall τ = 0.14, p = 0.33). Despite faster finish times, men demonstrate significantly less stable pacing strategies and a twofold higher crude risk of catastrophic deceleration compared with women, with the disparity most pronounced among the fastest runners. These findings are consistent with the hypothesis that behavioral and strategic factors contribute alongside physiological determinants to sex differences in marathon outcomes, and provide a quantitative basis for further investigation of the underlying mechanisms.
Patients with critical illness often exhibit profound biological heterogeneity, complicating the identification of effective interventions. Resolving distinct molecular profiles to enable timely treatment decisions remains challenging, as integrating biomarker-guided care into routine monitoring is often hindered by fragmented, batch-based workflows. These manual operations decouple molecular data from the acute clinical timeline and are a barrier to reliable, real-time, near to patient, multi-center implementation. To address this gap, we developed an integrated microfluidic digital immunoassay system that achieves high analytical fidelity through a fully automated, simple workflow. The system utilizes a monolithic disposable cartridge to automate bead-based analyte capture, oil-phase partitioning, and signal amplification, eliminating the manual handling and emulsion steps that typically compromise digital assay robustness. The platform enables protein measurement within 45 minutes, achieving sub-picogram limit of detection ( < 0.13 pg/mL), a dynamic range spanning three orders of magnitude, and strong analytical reproducibility. We demonstrate the clinical utility of the system by profiling a validated panel of inflammatory biomarkers in plasma from critically ill pediatric patients, using low sample volumes. Results show strong agreement with gold-standard multiplex assays (R2 = 0.925-0.979). By providing a scalable framework for high-fidelity molecular profiling, this system supports the broader goal of accessible, multi-center biomarker validation and the practical implementation of precision medicine in critical care.
The pathogenesis of lung diseases is highly complex and multifactorial, posing a persistent challenge to global public health, while effective therapeutic options remain limited. Therefore, systematically elucidating the cellular and molecular mechanisms underlying lung injury is a crucial prerequisite for developing novel therapeutic strategies. Accumulating evidence highlights that the endoplasmic reticulum and mitochondria are key organelles driving the progression of lung injury. Notably, mitochondria-associated membranes (MAMs) form a structural and functional bridge between the endoplasmic reticulum and mitochondria, highlighting the essential role of inter-organellar communication in maintaining lung function homeostasis. This review comprehensively summarizes the autonomous mechanisms of the mitochondria and endoplasmic reticulum in lung injury-related diseases, with a further focus on the complex architecture and regulatory mechanisms of MAMs. It emphasizes the molecular mechanisms by which dysfunctional MAMs contribute to the onset and progression of lung injury, including Ca²⁺ signaling, oxidative stress, lipid synthesis and transport, UPRER and UPRmt, mitochondrial homeostasis, and cell death. Finally, incorporating recent research advances, we discuss the current challenges and future prospects in this field, with particular emphasis on intervention strategies targeting Ca²⁺ transport at MAMs, mitochondrial quality control, endoplasmic reticulum stress, and metabolic coupling, as well as their potential for clinical translation. Overall, a deeper understanding of the functional interaction network among mitochondria, the endoplasmic reticulum, and their associated MAMs is expected to provide a robust theoretical foundation and translational insights for elucidating novel molecular mechanisms underlying lung injury and optimizing therapeutic strategies.
Alzheimer's disease is associated with progressive cognitive, functional and social decline. Non-pharmacological interventions that combine cognitive and motor stimulation are increasingly used in long-term care, but less is known about the feasibility and preliminary effects of delivering such programmes in outdoor rather than indoor settings. This exploratory randomized single-blind pilot study compared outdoor and indoor cognitive-motor therapy in institutionalized older women with Alzheimer's disease, focusing on global cognitive performance, selected functional outcomes, attendance and practical implementation. Fifty women aged 66.1-70.2 years with late-onset Alzheimer's disease were randomized to a seven-month outdoor cognitive-motor programme (n = 25) or an indoor cognitive-motor programme (n = 25). Sessions were delivered five times weekly for 45 min. Outcome assessors and data analysts were blinded to group allocation; therapists and participants could not be blinded because of the intervention setting. Global cognition was assessed with the Mini-Mental State Examination (MMSE). Functional outcomes were assessed using modified FIM-based indicators for daily tasks, mobility and social adaptability. Attendance and adverse events were recorded as feasibility outcomes. All randomized participants completed the study. Mean attendance was 91% in the outdoor group and 89% in the indoor group, and no intervention-related adverse events were recorded. Both groups improved on the MMSE, with a median increase of approximately two points. The outdoor group showed statistically significant within-group improvements in all three FIM-based indicators (daily tasks, mobility and social adaptability), whereas the indoor group did not show statistically significant functional change. However, these broader gains were observed in the context of baseline functional imbalance, including lower outdoor-group mobility and social-adaptability scores, and the small female-only sample and partial non-equivalence of intervention content limit between-group causal interpretation. A seven-month cognitive-motor programme was feasible in participating long-term care facilities. The findings suggest that outdoor delivery may be associated with broader functional gains than indoor delivery, but the results should be interpreted as preliminary and in light of the baseline functional imbalance. A fully powered, prospectively registered trial with more equivalent intervention arms, repeated measurement points, standardized functional outcomes and detailed monitoring of comorbidities and medication changes is warranted.