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The diagnosis of 5α-reductase type 2 deficiency (5α-RD2) is suspected on clinical grounds, typically at birth or during puberty, including pre-pubertal males showing undervirilization and females who virilize at puberty. Isolated micropenis is a relatively rare presentation, and there are limited cases featuring this phenotype. To understand the phenotype and genotype of 5α-RD2 in Taiwan, we performed 5α-reductase type 2(SRD5A2) genetic screening in patients with 46,XY disorders of sex development (DSD). We enrolled 127 Taiwanese patients with 46,XY DSD for clinical and molecular investigation of SRD5A2 and androgen receptor genes. Nine patients in our study carried the SRD5A2 mutation in both alleles. Five patients presented with isolated micropenis, one with severe hypospadias, and three with ambiguous genitalia. Homozygous p.Arg227Gln mutations were detected in six patients (66.7%) five of which had isolated micropenis. One patient who presented with micropenis and severe hypospadias also carried homozygous p.Val89Leu polymorphism. Heterozygous mutations (p.Arg227Gln and p.Arg246Gln) were found in two patients with ambiguous genitalia. A novel homozygous p.Arg94Ser mutation was detected in one patient who presented with ambiguous genitalia. Our study demonstrates different phenotypes and genotypes of 5α-RD2 in Taiwanese patients. Most of the patients presented with isolated micropenis and they were raised as males. The p.Arg227Gln mutation is a hot-spot mutation in Taiwan occurring with an allele frequency of 77.8% (14/18) in all detected mutation loci. The homozygous p.Arg227Gln mutation is assumed to contribute majorly to cases of isolated micropenis in Taiwan.
Taiwan has launched community-based Helicobacter pylori (H. pylori) screening programs in select areas. However, in many parts of Taiwan, the most effective treatment strategies remain unclear. In July 2023, H. pylori stool antigen (HpSA) screening for adults aged 50-69 years was added to the county-wide community-based health promotion program conducted by the Chiayi County Health Bureau. This single-center retrospective analysis included 531 HpSA-positive individuals who were evaluated at Chiayi Chang Gung Memorial Hospital between July 2023 and June 2024. Among the 5749 screened adults aged 50-69 years in Chiayi County, HpSA positivity was 25.6% (95% CI, 24.5-26.7). Of 1470 HpSA-positive individuals identified through screening, 531 (36.1%) were evaluated at the study hospital. Of them, 458 (86.3%) underwent endoscopy, which identified gastric ulcers in 24.5%, duodenal ulcers in 17.0%, and both in 6.6%. Rapid urease test and histological assessment were performed in 316 and 158 patients, respectively, yielding a positivity rate of 87.0% and 86.7% respectively. Among the 441 patients with available follow-up data, eradication rates were 94.7% (216/228) for those receiving 14-day clarithromycin-based triple therapy and 93.1% (149/160) for those receiving pooled 7-14-day concomitant therapy (p = 0.508). Reverse hybrid therapy achieved a 100% eradication rate in 20 patients, without significant difference compared to triple therapy (p = 0.293). Among screened adults aged 50-69 years in Chiayi County, HpSA positivity was approximately 25.6%. Fourteen-day triple therapy, 7-14-day concomitant therapy and reverse hybrid therapy all achieved high eradication rates.
This study develops a high-resolution Geo-AI framework to quantify the impact of future climate change on PM2.5 concentrations using Taiwan as a subtropical, monsoon-influenced island case. The model integrates long-term ground-based monitoring data (1994-2019), multi-scale geo-environmental predictors, and statistically downscaled CMIP6 meteorology, implemented using a Gradient Boosting Machine. The resulting model demonstrates strong predictive performance (R2 = 0.81 and RMSE = 8.69 μg/m3) and effectively captures PM2.5 dynamics within complex islands and coastal environments. By explicitly coupling a Geo-AI model with Intergovernmental Panel on Climate Change (IPCC) Sixth Assessment Report (AR6) climate scenarios, this study extends data-driven PM2.5 modeling from historical estimation to climate-conditioned future projection, addressing a key methodological gap in existing air-quality research. SHAP-based interpretability analysis identifies temperature and precipitation as dominant predictors, underscoring their central role in shaping future aerosol variability. The SHAP results further indicate that both temperature and precipitation exhibit nonlinear relationships across different temporal and regional scales and overall inverse associations with PM2.5 concentrations, clarifying the climate-driven effects of warming and hydrological change on PM2.5 dynamics under humid subtropical conditions. Across four Shared Socioeconomic Pathway scenarios, projected PM2.5 concentrations consistently decline in the near and midterm (between -1.25 and -1.5 μg/m3), followed by increasing spatial heterogeneity in the long term, with localized PM2.5 hotspots emerging under severe warming conditions. These findings suggest that climate change may generate uneven air-quality responses across space, highlighting the limitations of regional mean assessments and the need for high-resolution, climate-informed mitigation and adaptation strategies. The proposed framework provides a transferable tool for climate-responsive air-quality planning in humid subtropical, monsoon-influenced, and densely populated regions worldwide.
Metabolic syndrome (MetS) is a multifactorial condition characterized by obesity, hypertension, hyperglycemia, and dyslipidemia, often resulting from unhealthy lifestyle and behavioral patterns. This study aimed to develop and validate a Healthy Lifestyle and Behavioral Scale (HLBS) that reflects the combined influence of key pillars of lifestyle medicine and to examine its longitudinal association with MetS risk in a large Taiwanese cohort. Data were drawn from 201,123 participants of the Mei Jau Health Management Institution between 2000 and 2023. Item selection followed a rigorous construct validation process and selection criteria, including exploratory and confirmatory factor analyses, item response theory modeling, and reliability testing. We then combined the HLBS components such as diet, physical activity, sleep, and substance use, and performed a log binomial generalized estimating equation model to assess its risk association with MetS development. The HLBS demonstrated acceptable model fit and strong internal consistency. Moderate (RR = 1.12; 95% CI = 1.09-1.16) and low (RR = 1.46; 95% CI = 1.41-1.50) adherence to healthy lifestyle behaviors were associated with an increased risk of developing MetS compared with high adherence, and each HLBS component independently contributed to elevate MetS risk. Stratified analyses showed consistent linear associations across all age and sex groups, with stronger effects observed among adults and the elderly. The HLBS provides a reliable, culturally adapted tool for assessing lifestyle behaviors and identifying populations at risk for metabolic disorders. These findings emphasize the importance of promoting comprehensive lifestyle interventions to reduce MetS risk in the general population.
Two new species of the duckbill eel genus Facciolella are described based on specimens collected off Taiwan, representing the first record of the genus in the western Pacific Ocean. Facciolella bicolor sp. nov., based on three types, is most similar to F. smithi in having a bicoloured body and trunk, and can be distinguished by more preanal lateral-line pores and preanal vertebrae and a combination of characters. Facciolella punctatus sp. nov., based on six type specimens, is distinct in having a pale body and scattered black dots, and a combination of characters. The DNA barcoding analysis also supports the establishment of both new species. Detailed descriptions and figures are provided. The leptocephali found in the Pacific Ocean are also discussed.
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Primary central nervous system lymphoma (PCNSL) is a rare, highly aggressive form of non-Hodgkin lymphoma. Although initial responses to the guideline-recommended first-line high-dose methotrexate induction treatment are high, some patients have refractory disease and most experience relapse. Approved therapies for relapsed or refractory (R/R) PCNSL are limited in the US, and there are none in Europe, creating an urgent unmet need for effective treatments. Tirabrutinib is a highly potent and selective second-generation Bruton tyrosine kinase inhibitor approved in Japan, Taiwan, and South Korea for patients with R/R PCNSL. Here, we describe the rationale and design of IGNITE (ONO-4059-17), an ongoing, phase III, multiregional, open-label, randomized study of tirabrutinib vs rituximab and temozolomide combination therapy in R/R PCNSL. The primary endpoint is progression-free survival based on blinded independent review committee (BIRC) per International PCNSL Collaborative Group (IPCG) criteria. Key secondary endpoints are overall response rate based on BIRC per IPCG criteria and overall survival. Safety will be assessed by the incidence and severity of treatment-emergent adverse events.Clinical trial registration: www.clinicaltrials.gov identifier is NCT07104032. Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin lymphoma that mainly affects the brain, spinal cord, fluid around the brain and spine, and sometimes the eyes. The usual first treatment is high-dose chemotherapy, which often works well at first. However, in some patients, the cancer does not respond or responds only for a short time (called refractory disease). Additionally, in many patients, the cancer comes back after a period of recovery (called relapse). Approved treatments for relapsed or refractory (R/R) PCNSL are limited in the US, and there are none in Europe. This shows a strong need for new medicines. The medicine being studied in this trial is called tirabrutinib, and it acts by blocking Bruton tyrosine kinase, an important protein in the development of PCNSL. Tirabrutinib is approved for R/R PCNSL in Japan, Taiwan, and South Korea, and was tested in a phase II trial in the US. This article explains the plan for a phase III trial (called IGNITE) that will compare tirabrutinib with the combination of rituximab and temozolomide in participants with R/R PCNSL. Participants will be randomly assigned to one of two treatment options. The main goal is to determine how long patients live without the cancer getting worse. Other goals include measuring tumor shrinkage and overall survival, as well as monitoring side effects to understand the safety of tirabrutinib.
Motivated by the rising global trend of veterinary Complementary and Alternative Medicine (CAM) usage and a specific data gap in Taiwan, this study investigates the consumption behavior of future pet owners. A cross-sectional survey was conducted among Taiwanese medical university students using a validated online questionnaire. Beyond traditional descriptive statistics, this study employed machine learning techniques to analyze owner demographics, pet characteristics, and determinants of CAM usage. Data analysis revealed a strong correlation between positive owner perceptions-specifically satisfaction, belief in benefits, and understanding-and targeted CAM application. A decision tree model successfully identified "overall satisfaction" as the primary splitting criterion for user segmentation, followed by belief and understanding. Predictive modeling demonstrated high accuracy in identifying usage motivations for joint and digestive health, though predicting "immune system boosting" proved more complex due to behavioral variability. Owner satisfaction is the critical predictor of CAM usage patterns. While the predictive model for specific conditions, such as joint and digestive health, yielded high accuracy (AUC > 0.93), these findings should be interpreted as an exploratory framework given the pilot nature of the study and the limited sample size (n = 41). These findings suggest that veterinarians and industry stakeholders should adopt data-driven communication strategies focusing on transparency and satisfaction.
The assassin bug genus Tapirocoris Miller, 1954 (Hemiptera: Reduviidae: Harpactorinae: Dicrotelini) is distributed in southern China and adjacent regions. However, gradual morphological variation among its members has long complicated species delimitation and obscured the understanding of their phylogenetic relationship and evolutionary history. Here, we apply an integrative taxonomic framework to revise the classification of Tapirocoris and to reconstruct its spatio-temporal diversification history. Based on mitochondrial COI DNA barcode sequences from 94 specimens collected across 26 localities, multiple species-delimitation methods and phylogenetic inference consistently recovered seven well-supported evolutionary lineages, including three previously known species and four newly described species: T. hainanensis Zhao & Cai, sp. nov., T. rufus Zhao & Cai, sp. nov., T. taiwanensis Zhao & Cai, sp. nov., and T. yuensis Zhao & Cai, sp. nov. Geometric morphometric analyses further confirmed that these lineages are morphologically diagnosable. Divergence time estimation may indicate an early Miocene crown origin of Tapirocoris (∼21.48 Ma), and discrete phylogeographic reconstruction is consistent with repeated range shifts between the South China hilly region and the Yunnan-Guizhou Plateau, forming a mainland diversification backbone. Subsequent directional dispersal events likely contributed to the emergence of insular endemic species in Hainan and Taiwan during the Pleistocene. These interpretations are based primarily on mitochondrial COI data and would benefit from further validation using multilocus or nuclear genomic datasets. In addition, we provide an updated key to the species of Tapirocoris and a world catalogue of the tribe Dicrotelini, establishing practical taxonomic resources and a broader systematic framework for future research.
Associations between major mental disorders (MMDs) and colorectal cancer (CRC) have been reported; however, it remains unknown whether this association extends to an individual's kinship. The aim of this study was to explore the risks of MMDs in first-degree relatives (FDRs) of individuals with CRC. We used data from the Taiwan National Health Insurance Research Database. FDRs of individuals with CRC were identified as the index group, and a demographic-matched group was also included as the controls. The primary outcome was the risk of an MMD. A Poisson regression model with robust error variance was used to estimate the relative risks and 95% confidence intervals. A total of 68,965 FDRs of individuals with CRC (38,024 males and 30,941 females) and 275,860 matched controls were included. After adjustments for potential confounders, the FDR-CRC group had a higher risk of autism spectrum disorder than the controls, especially in the males of fathers with CRC. In addition, individuals who had a son with CRC had a higher risk of bipolar disorder than the controls, especially females. Males whose mother had CRC had higher risks of attention deficit hyperactivity disorder and general anxiety disorder than the controls. With the unique association identified in this study between FDRs of individuals with CRC and the risk of MMDs, genetic studies are encouraged to explore the complicated etiologies behind this association.
Anatomical variability of the mandibular retromolar space (MRS) plays a decisive role in planning mandibular molar distalization; however, available evidence remains fragmented across heterogeneous tomographic studies. To synthesize current evidence derived from computed tomography (CT) and cone-beam computed tomography (CBCT) regarding morphometric factors influencing MRS and their implications for orthodontic distalization. A systematic search was conducted in MEDLINE, LILACS, Scopus, Web of Science, and Google Scholar in accordance with PRISMA guidelines. Observational studies evaluating MRS using CT or CBCT in adult populations were included. Data extraction focused on skeletal classification, vertical facial pattern, sex, age, and third-molar status. Methodological quality was assessed using the Joanna Briggs Institute critical appraisal tools. Fourteen studies met the inclusion criteria, comprising samples from China, South Korea, Egypt, Turkey, India, Japan, and Taiwan, with a mean age of 25.8 years. A skeletal Class III pattern consistently exhibited the greatest MRS, followed by Class I and Class II. Normodivergent individuals demonstrated larger MRS values compared with hyperdivergent or hypodivergent patients. Third-molar position and angulation, rather than mere presence, were identified as key determinants of the effective distalization limit. Sex-related differences were inconsistent across studies, and the influence of age varied. The internal (lingual) cortical plate emerged as the principal anatomical boundary restricting mandibular molar distalization. Mandibular retromolar space is strongly influenced by skeletal classification, vertical growth pattern, and third-molar morphology. Pre-treatment CBCT assessment is essential to identify anatomical constraints, prevent cortical interference, and optimize individualized orthodontic biomechanics. Future multicenter studies employing standardized CBCT protocols are needed to enhance the clinical applicability of these findings across diverse populations.
Accurate identification of cerebrovascular stenosis is essential for early stroke prevention and effective clinical management. Magnetic resonance angiography provides non-invasive 3D visualization of cerebral vessels, but reliable automated stenosis detection remains challenging due to anatomical complexity and imaging variability. This study aims to develop an automated, robust, and clinically useful transformer-based deep learning framework for detecting stenosis in 3D brain MRA scans. We propose a framework designed for cerebrovascular stenosis detection. It first automatically localizes the centerlines of all arteries and veins within the 3D MRA volume. Each resulting vessel-centered 3D region is then analyzed and classified as normal or narrowed using our proposed transformer-based model. The model was trained and validated on a manually curated, expert-annotated dataset from Far Eastern Memorial Hospital, Taiwan, to ensure high-quality ground-truth labels. Our proposed framework demonstrated strong and stable performance across five-fold cross-validation. Specially, under the imbalanced data setting, the model achieved an average accuracy of 0.9339, F1-score of 0.7998, AUC of 0.9488, and Precision-Recall AUC of 0.8313-indicating robust discrimination capability and effective detection. The experimental results underscore the capability of the proposed framework as a dependable tool for automated cerebrovascular evaluation. Its superior performance indicates significant utility in clinical settings, supporting early detection and risk reduction for stroke.
Nosema ceranae is an obligate microsporidian parasite that causes nosemosis in honey bees (Apis mellifera). In controlled laboratory cage experiments, newly emerged worker bees were experimentally infected with N. ceranae spores and treated with Bidens pilosa phytogenic extract (BP). Each treatment group consisted of 50 bees per replicate, and experiments were repeated independently. To explore the molecular basis of BP-associated effects, we conducted transcriptome profiling of N. ceranae from infected honey bee midguts at multiple time point. RNA samples from infected bee midguts with BP treatment were collected at 5, 10, and 20 days post-infection (dpi) for transcriptomic analysis. BP treatment significantly improved survival probability and reduced pathogen load compared to infected controls. During the early infection stage (5 dpi), BP treatment was associated with extensive downregulation of parasite genes, including components of the V-type ATPase pathway. Gene Ontology and KEGG analysis suggested suppression of metabolic and ion transport processes. To further evaluate the potential role of V-type ATPase, RNAi-mediated knockdown resulted in reduced gene expression and showed a trend toward decreased pathogen load and modest improvement in host survival. Although the RNAi results do not provide definitive evidence of causality, they support a potential involvement of the V-type ATPase in parasite proliferation. Overall, BP altered the transcriptomic profile of N. ceranae in a stage-dependent manner and may influence parasite development by affecting key metabolic pathways.
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused significant global loss and social disruption. Although large-scale vaccination campaigns and naturally acquired immunity have reduced viral transmission, the rapid evolution of the viral genome-driven by the lack of proofreading during replication-continues to pose a major public health threat. The current SARS-CoV-2 main protease inhibitor (Mpro), Paxlovid, substantially lowers hospitalization rates but is associated with adverse effects and drug-drug interactions with many medications. To discover more effective and safer treatments, we conducted a large-scale virtual screening to identify novel structural scaffolds targeting viral Mpro. This effort yielded a series of spiropyrrolidinoxindole derivative hits with promising low-micromolar inhibitory activity. Through preliminary analysis of the structure-activity relationship and proposed binding conformations, our findings provide a basis for rational structural optimization and may facilitate the development of potent, safer spiropyrrolidinoxindole-based therapeutics against severe COVID-19.
Melatonin (N-acetyl-5-methoxytryptamine, MLT) is an endogenous neurohormone that regulates circadian rhythms, exhibits potent antioxidant activity, and has been implicated in cancer suppression and neuroprotection. In this study, we report the design and development of a highly sensitive optical nanosensor based on nitrogen-doped carbon quantum dots (N-CQDs) for the quantitative detection of MLT in human blood. The N-CQDs were synthesized via a facile pyrolysis route, yielding uniform nanodots that exhibit strong blue photoluminescence. Comprehensive structural, morphological, and optical characterizations were conducted using X-Ray Diffraction (XRD), transmission electron microscopy (TEM), and fluorescence spectroscopy, confirming the successful incorporation of nitrogen functionalities with a photoluminescence quantum yield of 36.6%. The synthesized N-CQDs exhibit a highly selective and sensitive detection towards MLT, and the sensing mechanism is plausibly governed by Förster resonance energy transfer (FRET)-mediated quenching of N-CQD emission upon interaction with MLT. This developed probe of N-CQDs achieved an impressive detection limit of 4.68 nM, demonstrating its potential for biomedical diagnostic applications. Furthermore, the system was successfully integrated into a smartphone-assisted sensing platform for portable and real-time MLT monitoring. Quantitative analysis of spiked human blood samples exhibited excellent recovery values ranging from 96.1% to 104.2%, validating the reliability and applicability of the proposed N-CQD-based sensor for clinical and point-of-care analysis.
The triglyceride-glucose-waist-to-height ratio (TyG-WHtR) predicts heart failure, but its association with left ventricular diastolic function (LVDF) in physically fit individuals is unclear. This study aimed to assess whether TyG-WHtR independently associates with echocardiographic LVDF indicators and exercise performance in physically active military personnel. In this cross-sectional analysis, 151 male and 25 female military personnel aged 18 to 44 years underwent biochemistry, echocardiography, and fitness testing (3-km run, push-ups, and sit-ups). Men were dichotomized at the median TyG-WHtR (3.954). Kendall correlations with bootstrap 95% CIs and Benjamini-Hochberg false discovery rate adjustment, plus theory-driven multivariable regression adjusted for age, sex, heart rate, atherogenic lipids, and TyG-WHtR, were used; multiplicative sex interaction was tested. Higher- vs lower-TyG-WHtR men (4.41 [4.13, 4.74] vs 3.62 [3.38, 3.82]) were older (29 [23, 36] vs 25 [21, 30] years), with adverse cardiometabolic profile, lower mitral e' velocity and E/A, and worse exercise performance. TyG-WHtR was age-independently correlated with e' velocity (τ -0.382; 95% CI: -0.462 to -0.297) and E/A (-0.265; -0.367 to -0.165), both Benjamini-Hochberg-adjusted P < 0.001. In regression, TyG-WHtR was the leading e' predictor (standardized β -0.367; -0.491 to -0.242). Sex × TyG-WHtR interaction on e' velocity was statistically detectable (P = 0.012) but underpowered. TyG-WHtR is age-independently associated with subclinical LVDF decline and lower exercise capacity in young, physically active military personnel. Whether insulin resistance reduction could improve diastolic function requires further study.
To investigate the diagnostic utility of augmenting the conventional 3-Hz repetitive nerve stimulation test (RNST) with a 7-Hz protocol in patients with myasthenia gravis (MG). We retrospectively analyzed 11 years of RNST data (2013-2023) from patients at a tertiary medical center. The diagnostic performance (sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV]) of the conventional 3-Hz protocol was compared against a combined 3-Hz plus 7-Hz protocol. Among 311 MG patients (208 generalized MG [gMG]; 103 ocular MG [oMG]), adding 7-Hz stimulation significantly improved the sensitivity for gMG from 69.0% to 82.1% without compromising specificity (91.7%). Multivariable regression confirmed that the combined protocol was independently associated with higher diagnostic yield in gMG (OR = 2.28, p = 0.019). Using a within-group paired analysis, 7-Hz RNST showed superior sensitivity compared to 3-Hz RNST. This increased diagnostic yield was predominantly observed in the gMG subgroup. Notably, 15% of MG patients were positive exclusively at 7 Hz, with the highest rescue rate observed in proximal muscles. Incorporating 7-Hz RNST into standard diagnostic algorithms substantially enhances the detection of gMG, particularly when conventional 3-Hz testing yields negative results in proximal muscles. RNST protocol selection may be tailored by clinical phenotype to maximize sensitivity by adding 7 Hz RNST.
To evaluate the association between diabetic corneal neuropathy and diabetic foot risk by examining corneal nerve features, clinical characteristics, and tear mediators in patients with different diabetic foot risk categories. In this cross-sectional study, 710 participants underwent diabetic foot examination, in vivo confocal microscopy scans, ocular surface assessments, and tear mediators measurements. Ordinal regression analysis was applied to determine the associations between foot risk categories and corneal nerve metrics. ROC curve analysis assessed the ability of corneal nerve parameters to identify high-risk diabetic foot. All diabetic foot risk categories exhibited significantly impaired corneal nerve fibre length, density, fractal dimension, and more swollen width compared with controls (all p < 0.001). These patients also demonstrated significantly shorter tear break-up time, more severe ocular symptoms, elevated tear MMP-9, and reduced tear Substance P levels (all p < 0.05). Patients with high-risk diabetic foot showed significantly more pronounced corneal nerve alterations than those in low and moderate-risk groups (all p < 0.05). The more severe diabetic foot risk category was significantly associated with reduced nerve fibre length, density, fractal dimension, and increased width (all p < 0.05). A predictive model incorporating corneal nerve fibre length, width, and serum creatinine achieved an AUC of 0.80 for identifying high-risk diabetic foot. A CNFL < 5.7 mm/mm2 was associated with 4.37-fold higher odds of having a high-risk diabetic foot. Corneal nerve impairment is evident even in low-risk diabetic foot patients and is associated with foot risk severity. Corneal nerve metrics may serve as early indicators for identifying high-risk diabetic foot.
To test whether a pneumatic cold-compression system (CC) improves recovery of maximal voluntary contraction (MVC) at 48 h (T4) versus Sham after a standardized hamstring fatigue protocol. Secondary aims were to compare muscle stiffness, microvascular perfusion, pressure pain threshold (PPT), blood lactate, perceived recovery (TQR), and harms across subgroups. This multicenter, randomized, participant- and assessor-blinded, sham-controlled, two-period crossover trial enrolled 80 participants. After fatigue testing, participants received CC (3 °C, 75 mmHg, 10 min twice daily for 3 days) or Sham (15 °C, 15 mmHg). Outcomes were assessed at baseline (T0), post-fatigue (T1), immediately post-first intervention (T2), 24 h (T3), and 48 h (T4). Continuous outcomes were analyzed using mixed-way ANOVA with Population as the between-subject factor and Condition and Time as within-subject factors, followed by Bonferroni-adjusted pairwise comparisons. Paired Cohen's dz was reported for key within-participant contrasts. TQR was analyzed using rank-based factorial ANOVA, and Borg CR10 scores using ordinal logistic regression. Across populations, MVC was higher under CC than Sham from T2 to T4, with the largest between-condition difference at T4 (all p < .001). Muscle stiffness was lower under CC from T2 to T4 (all p < .001). Microvascular perfusion and pressure pain threshold were higher under CC at T2 - T4 overall (all p < .001), with earlier between-condition differences in MMA athletes and young adults and delayed differences in older adults. Blood lactate was lower under CC only immediately after the first intervention session (T2; p < .001). TQR was higher under CC at T2 - T4 in MMA athletes, at T2 - T3 in older adults, and at T3 only in young adults. No adverse events were reported. CC accelerated recovery after hamstring fatigue, improving strength, stiffness, perfusion, pain thresholds, lactate, and perceived recovery across populations, with earlier benefits in athletes and young adults and delayed but comparable improvements in older adults. Registration: ISRCTN49499065.
QacA and QacB are staphylococcal multidrug efflux proteins that share high sequence homology, differing by only six to seven amino acids. While the prevalence of these genes among clinical isolates can exceed 70% in certain regions, and qacA is well-documented to elevate chlorhexidine minimal inhibitory concentrations (MICs), the specific contribution of qacB to chlorhexidine tolerance remains incompletely defined. To investigate these differences, in silico structural analyses were performed using UCSF ChimeraX. Sequence data from NCBI were mapped onto the experimental 3.80 Å cryo-EM structure of QacA (PDB ID: 7Y58) to compare global and local conformational and electrostatic properties. Phenotypically, the pLI50 plasmid carrying either qacA or qacB was electroporated into Staphylococcus aureus strain RN4220. Chlorhexidine MICs were subsequently determined using agar dilution assays. Global in silico modeling demonstrated that the amino acid substitutions distinguishing QacB from QacA did not alter the backbone conformation, hydrogen bond counts, solvent-accessible surface area, or overall Coulombic surface potential. However, local analyses identified distinct microenvironmental perturbations attributable to the physicochemical differences of the substituted residues. Phenotypically, the introduction of qacA into S. aureus RN4220 reproducibly increased chlorhexidine MICs from 1 µg/mL to 4 µg/mL in 96% (48/50) of independent assays (adjusted OR > 999; P < 0.001). Conversely, the presence of qacB significantly increased MICs from 1 µg/mL to 2 µg/mL in 90% (45/50) of analogous assays, demonstrating a distinct but less pronounced elevation in tolerance (adjusted OR = 81.0; P = 0.0013). Both qacA and qacB contribute to increased chlorhexidine MICs in S. aureus RN4220 under the conditions tested. Given the high prevalence of these genes among clinical isolates and the widespread use of chlorhexidine in infection prevention, these findings support continued surveillance and further mechanistic studies to assess clinical and infection-control implications.