Phenibut (Regulated)

Temporomandibular disorders (TMDs) are the prevalent causes of orofacial pain and dysfunction of the temporomandibular joint (TMJ) and masticatory muscles. Previous studies have revealed that proinflammatory cytokines play a key role in promoting inflammation, pain, and degeneration within the TMJ. In this context, the present systematic review synthesizes current evidence on various cytokines involved in the pathophysiology of TMDs and evaluates their associations with clinical signs and structural TMJ damage. A PRISMA-guided search (PROSPERO: CRD420251163290) was conducted in PubMed/MEDLINE, Embase, Scopus, and the Cochrane Library to identify human-based, in vivo, and in vitro studies (January 2014 to September 2025) that assessed the roles of proinflammatory cytokines in TMDs. The following data were extracted from the identified studies: cytokine profiles, sampling methods, clinical outcomes, and TMJ structural changes. Study quality and risk of bias were systematically evaluated. A total of 15 studies (clinical, animal, and mechanistic) were included in the review. Tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-17 (IL-17) consistently emerged as the major contributors to synovitis, cartilage degradation, nociceptive sensitization, and bone resorption. Human studies showed that high levels of TNF-α, IL-1β, and IL-6 and chemokines such as C-C motif chemokine ligand 2 (CCL2) and regulated on activation, normal T-cell expressed and secreted (RANTES) were associated with TMJ pain, restricted mandibular motion, crepitus, malocclusion, and erosive changes on imaging. An increased ratio of TNF to soluble TNF receptor in synovial fluid correlated with both pain and condylar damage, suggesting that loss of cytokine control contributes to progressive joint destruction. TMDs, particularly inflammatory and degenerative subtypes, are cytokine-driven pathologies rather than purely mechanical disorders. TNF-α, IL-1β, and IL-6 are the promising candidate biomarkers of local inflammation and structural joint pathology. Standardized longitudinal studies are required to validate cytokine-based diagnostics and develop anti-cy

Orexin-A and orexin-B, originally discovered as hypothalamic neuropeptides, have been detected in extra-hypothalamic tissues together with their receptors (OX1R and OX2R) since the early 2000s. This systematic review is the first to comprehensively synthesize evidence on the autocrine/paracrine effects of locally produced orexin across extra-hypothalamic tissues. Following PRISMA 2020 guidelines, a systematic search was conducted in PubMed, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and Google Scholar. Eligible studies were original, full-text, peer-reviewed articles reporting primary data on prepro-orexin/orexin peptide and/or OX1R/OX2R expression in non-neuronal extra-hypothalamic tissues, with evidence of co-expression within the same cell/tissue or functional effects reasonably attributable to locally produced orexin. From the 10 eligible studies, autocrine orexinergic signaling was functionally demonstrated in the adrenal gland (steroidogenesis via Gq/PLC/IP3/Ca2+), male reproductive tract (testosterone secretion), adipose tissue (lipolysis/thermogenesis), heart (myocardial protection via PI3K/Akt/eNOS), pancreas (glucose-regulated insulin/glucagon modulation), and liver (lipogenesis via ERK1/2). OX1R primarily activates the Gq/PLC/IP3/Ca2+ pathway, resulting in ERK1/2 and p38 MAPK signaling (promoting secretion and proliferation), while OX2R couples to Gs/Gi, modulating cAMP and PI3K/Akt (favoring cytoprotection and anti-apoptosis). Autocrine orexinergic signaling constitutes a legitimate, compartment-autonomous regulatory mechanism in peripheral tissues, enabling rapid, tissue-specific responses insulated from central fluctuations. © 2026 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.

Accumulating evidence supports ferroptosis as a key driver for nanomaterial (NM) exposure-induced toxicity. There is considerable interest in the therapeutic potential of ferroptosis inhibition for cells or animals exposed to NMs before clinical applications. This study aimed to synthesize data from published studies for achieving strong evidence about the effects of ferroptosis inhibitors. Fifty-three studies were included after searching PubMed, EMBASE and Cochrane Library databases up to October, 2025. The meta-analysis of in vitro studies (n = 51) showed treatment with ferroptosis inhibitors ferrostatin-1 (Fer-1; standardized mean difference [SMD] = 3.19; 95% confidence interval [CI] = 2.63-3.75) and deferoxamine (DFO; SMD = 3.40; 95% CI = 2.62-4.18) significantly improved the viability of cells exposed to NMs. The pooled results of in vivo studies (n = 8) demonstrated Fer-1 administration suppressed tissue cell death (SMD = -1.38; 95% CI = -2.39 to -0.37) and alleviated damages on the organ function [respiratory frequency (SMD = -1.33; 95% CI = -2.32 to -0.34); enhanced pause (SMD = -1.85; 95% CI = -2.95 to -0.75)] or the body weight (SMD = 1.28; 95% CI = 0.63-1.92) of animals exposed to NMs. The protective mechanisms of Fer-1 or DFO included iron removal (showing reduced iron levels and down-regulated TFRC), anti-oxidation (manifested as inhibited formation of L-ROS, MDA, restoration of GSH, up-regulation of GPX4, down-regulation of ACSL4 and COX2) or anti-inflammation (lowering IL-6, TNF-α and MCP-1). Accordingly, Fer-1 or DFO may be a potentially effective intervention for populations with NM exposure to prevent tissue damages. © 2026 Wiley Periodicals LLC.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal cancer due to its strong resistance to chemotherapeutic agents that induce apoptosis. As conventional treatments gradually lose their effectiveness over time, necroptosis has become a key therapeutic target worth exploiting. Necroptosis is a regulated cell death independent of caspases. It is driven by the receptor-interacting protein kinase 1/3 (RIPK1/3) and mixed lineage kinase domain-like pseudokinase (MLKL) signaling axis. This systematic review summarizes the complex role of necroptosis in PDAC. We clarify how necroptosis can be triggered or manipulated pharmacologically, and how it can be induced by accumulating reactive oxygen species (ROS). We also critically analyze its tumor-promoting side. Persistent necroptotic signaling reshapes the tumor microenvironment (TME) by releasing damage-associated molecular patterns (DAMPs) and activating inflammatory cascades. We also highlight the growing clinical significance of necroptosis-related genes (NRGs), long non-coding RNAs (lncRNAs), and specific biomarkers such as fermitin family member 1 (FERMT1). Finally, we propose a new, context-dependent therapeutic framework. This framework proposes a combination of strategies for controlling necroptosis induction and immunomodulatory agents, offering a reasonable strategy for PDAC management. © 2026. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

INTRODUCTION: Time management strategies are critical components of self-regulated learning and a key factor influencing learning outcomes. Although the application of time management strategies to learning behaviors has increased, their outcomes remains a subject of debate. Currently, there is a paucity of reliable, data-driven research conclusions on this topic. This study employed a meta-analytic approach to investigate the primary effect of time management on college students' learning outcomes, as well as five categories of moderating variables. METHODS: A meta-analysis was conducted on 31 studies published in both Chinese and English, utilizing CMA V3 software to analyze 33 aggregated independent samples (derived from 60 original effect sizes) derived from a total sample of 13,506 participants. RESULTS: The results indicate that time management is significantly and moderately positively correlated with college students' learning outcomes (r = 0.250). Moderation analysis revealed that both educational level and the time management measurement significantly moderate the relationship between time management and learning outcomes among college students. Specifically, time management strategies have the most pronounced effect on the learning outcomes of undergraduate students. Additionally, measurement instruments that assess time management abilities and behaviors more accurately capture the influence of time management on learning outcomes. DISCUSSION: These results have practical implications for designing interventions that directly support the growth of students' self-regulation capacities via structured time management training.

BACKGROUND: The complex pathophysiology of ischemic stroke (IS) involves initial injury followed by secondary cascades and endogenous repair. This review systematically explores how electroacupuncture (EA) precisely modulates these processes. METHODS: We systematically searched and summarized all papers related to EA treatment for stroke using the China National Knowledge Infrastructure (CNKI) and PubMed databases. RESULTS: We detail EA's key mechanisms in reducing initial and secondary damage, including the suppression of inflammatory responses (e.g., NF-κB, inflammasomes, gut-brain axis), mitigation of oxidative stress (Nrf2/HO-1), attenuation of excitotoxicity (NMDAR, GLT-1), and inhibition of diverse forms of regulated cell death (apoptosis, pyroptosis, ferroptosis). Critically, EA also actively promotes vital repair mechanisms by enhancing cerebral blood flow, protecting blood-brain barrier integrity, promoting angiogenesis (VEGF, HIF, Notch, Wnt pathways), and fostering extensive neural regeneration and plasticity (neurogenesis, neurotrophic factors, myelination, synaptic changes, network reorganization) at molecular, cellular, and network levels. These well-documented mechanistic actions provide a strong scientific basis for the observed clinical benefits of EA in improving major poststroke sequelae, encompassing motor, cognitive, language, and emotional deficits. CONCLUSIONS: The review highlights the potential for enhanced outcomes through combined therapy approaches and identifies future research avenues leveraging advanced technologies like multi-omics and AI for personalized precision EA. EA stands as a scientifically grounded, multi-target therapy improving stroke recovery. © 2026 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.

BACKGROUND: An increasing number of studies have shown that ferroptosis is related to the initiation and development of small cell lung cancer (SCLC). The systematic review aimed to summarize the characteristics of ferroptosis from its pathogenetic role to translational therapeutic implications in SCLC. METHODS: This systematic review, registered in PROSPERO (CRD420251090058), followed PRISMA 2020 guidelines. Comprehensive research of PubMed, Scopus, and Web of Science was performed for studies published between January 2010 and July 2025 investigating ferroptosis mechanisms, genetic or pharmacological modulation, or molecular profiling in SCLC. Two reviewers independently performed data extraction and quality assessment. RESULTS: Nineteen preclinical studies met the inclusion criteria. Key regulators included solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), and acyl-CoA synthetase long chain family member 4 (ACSL4). The molecular subtypes of SCLC, achaete-scute homolog 1 (ASCL1), neuronal differentiation 1 (NEUROD1), POU class 2 homeobox 3 (POU2F3), and Yes1 associated transcriptional regulator (YAP1) exhibit differential ferroptosis gene expressions, influencing therapeutic responsiveness. Non-neuroendocrine subtypes are more ferroptosis-prone, whereas neuroendocrine variants display enhanced antioxidant defenses. Ferroptosis induction also promotes immune activation through stimulator of interferon genes (STING)-mediated CD8+ T-cell recruitment. CONCLUSIONS: Ferroptosis constitutes a promising therapeutic axis in SCLC. Integrating ferroptosis biomarkers into molecular stratification frameworks could refine patient selection and support precision oncology strategies, warranting further translational and clinical validation. © 2026 The Authors. Published by Tech Science Press.

Conservation Agriculture (CA) is pivotal to achieve sustainable intensification, yet the global efficacy of its core practice, conservation tillage (CT), remains debated regarding the trade-offs between crop productivity and ecosystem services across diverse environmental contexts. Here, we conducted a second-order meta-analysis, synthesizing 69 published meta-analyses, to elucidate the context-dependent drivers regulating the "win-win" outcomes of CT. Globally, CT reduced greenhouse gas (GHG) emissions by 5%, increased soil organic carbon sequestration by 21%, increased soil fertility by 11%, and reduced soil erosion by 12%, all while maintaining crop yields comparable to conventional tillage. However, CT can also emerge as a partial trade-off between crop yields and ecosystem services, notably between crop yield and GHG mitigation. These trade-offs were strongly regulated by climatic and edaphic conditions as well as management intensity. For instance, strong synergies between crop productivity and multiple ecosystem services were more pronounced in (semi-)arid regions characterized by low temperatures and low precipitation, as well as in coarse-textured alkaline soils. Furthermore, integrating CT with residue retention and crop rotations maximized these synergies, mitigating potential yield penalties. Collectively, our synthesis demonstrates that context-specific refinement of CT implementation is essential to reconcile agricultural productivity with ecosystem services, thereby advancing climate-resilient agricultural systems globally. © 2026 John Wiley & Sons Ltd.

Anthropogenic phosphorus (P) inputs are rapidly altering terrestrial P cycling through plant - soil - microbial interactions; however, global patterns and underlying mechanisms driving these changes remain poorly understood. By performing a global meta-analysis of 1315 observations from 176 studies across diverse natural terrestrial ecosystems, we found that P addition increased P concentrations in foliage, stems, roots, and litter by 62%, 114%, 100% and 63%, respectively. Soil total P, plant-available P, and microbial P concentrations rose by 43%, 221%, and 70%, while leaf P-resorption efficiency and soil phosphatase activity declined by 23% and 15%, respectively. Stem P and soil phosphatase activity exhibited consistent trends across tropical, temperate, and boreal zones, suggesting climate-specific P acquisition strategies. In addition, foliar P responses diverged among ecosystem and plant functional types. These responses were primarily regulated by background soil total P concentration, precipitation, soil pH, and P addition duration and rate. Our findings provide critical insights into the potential consequences of increasing anthropogenic P inputs in natural terrestrial ecosystems, improving our understanding of nutrient cycling and informing future ecosystem management under ongoing global change. © 2026 John Wiley & Sons Ltd.

The polycyclic aromatic hydrocarbons present in vehicle exhaust, including both particulate and gaseous components, constitute a yet inadequately regulated threat to environmental health. However, there has been no systematic review on the emission characteristics and toxicity mechanism of polycyclic aromatic hydrocarbons in vehicle exhaust. Through comprehensive analysis, it was revealed that while high-ring particulate polycyclic aromatic hydrocarbons, especially Benzo[a]pyrene and Dibenz[a,h]anthracene, exhibit greater toxicity, the gaseous fraction of polycyclic aromatic hydrocarbons demonstrates higher emission levels and bioavailability, an aspect frequently underestimated in vehicle exhaust assessments. Meanwhile, engine type, emission standards, fuel type, driving conditions, and temperature largely affect the emission factors and compositional makeup of polycyclic aromatic hydrocarbons. This review, from the dual perspectives of emissions and toxicity, systematically analyzed the emission characteristics and influencing factors of polycyclic aromatic hydrocarbons from vehicle sources, as well as the toxicity mechanism, provided ideas for the formulation of future motor vehicle regulations that balance air quality improvement and public health protection, and also offered support for whether polycyclic aromatic hydrocarbons control should be included in future emission standards.

Background: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) refers to fatty liver disease associated with metabolic syndrome. MASLD causes alterations in lipid metabolism, which can be regulated with a diet rich in polyphenols. The present study aims to evaluate the effects of daily consumption of 400 g of "Navelina" oranges for 4 weeks on serum lipid profiles in a group of 60 patients with MASLD, to identify specific lipid species associated with improvements in hepatic steatosis. Methods: Blood samples were collected from all participants, and biochemical measurements and a serum lipidomic profile were performed. Finally, a Spearman correlation analysis was used to assess the relationships between serum lipidomic fatty acids and biochemical lipid markers. Results: In the experimental treatment arm, serum lipidomic analysis showed a slight decrease in Arachidonic acid (AA) and the Arachidonic acid/Eicosapentaenoic acid ratio (AA/EPA ratio) but no significant interaction between time and treatment was detected. In the same group, Oleic acid, MUFAs and the AA/EPA ratio were significantly and negatively correlated with HDL (r = -0.368, p = 0.046), (r = -0.384, p = 0.036), and (r = -0.522, p = 0.003), respectively. Conversely, EPA and n-3 PUFAs were positively and significantly correlated with HDL (r = 0.447, p = 0.013) and (r = 0.403, p = 0.027) respectively. Conclusions: Furthermore, this study represents one of the first clinical trials to shed a light on the potential association of "Navelina" orange polyphenols on serum fatty acid profiles in patients with MASLD, supporting studies on the nutraceutical effect of oranges on lipid metabolism.

OBJECTIVES: The aim of this randomized clinical trial was to evaluate the 18-month clinical performance of alkasite and glass-hybrid restorations compared with resin composite in Class II restorations. MATERIALS AND METHODS: A total of 50 patients requiring at least three Class II restorations in premolar and molar teeth were recruited. Each patient received three restorations, which were randomly assigned to one of the following materials: an alkasite (Cention N, Ivoclar Vivadent), a glass-hybrid (Equia Forte HT, GC Corp.), or a resin composite (Gradia Direct Posterior, GC Corp.). Alkasite and glass-hybrid served as test groups while resin composite served as the control group. During the 18-month follow-up, restorations were scored at baseline, 6, 12, and 18 months using the FDI criteria. Data were analyzed using the Chi-square and Cochran's Q tests (α = 0.05). RESULTS: No significant differences were detected among the groups for esthetic, functional, or biological criteria over 18 months (p > 0.05). Regarding esthetic properties, the control group showed 100% success for all esthetic criteria at all recall visits, while the alkasite group maintained a 96% success rate at all time points, and glass-hybrid showed 98% success at 6 and 12 months and 92% at 18 months. Minor score-2 changes in color match and gloss were detected in the glass-hybrid and alkasite groups but were not significant (p > 0.05). For functional and biological outcomes, all groups achieved 100% success rates for all evaluated parameters. CONCLUSIONS: Alkasite and glass-hybrid groups exhibited clinical performance comparable to resin composite over the 18-month follow-up in Class II cavities. All materials demonstrated excellent functional and biological stability while achieving clinically acceptable aesthetic results. © 2026. The Author(s).

This study examined whether heat acclimation (HA), and HA with blood flow restriction (BFR) could attenuate cognition and neuromuscular function impairments in cognitive-motor dual-task (CMDT) during exercise-heat stress. Twenty trained adults were randomly assigned to one of two HA protocols over six sessions (~8 days). Each session consisted of 4 × 8-min self-regulated cycling intervals (5-min "strong effort", 3-min "moderate effort") in temperate conditions (20°C), immediately followed by 40-min hot water immersion (40°C). One group exercised with BFR during the "strong" bouts (50% arterial occlusion pressure; BFRHA), whereas the control group completed without occlusion (CTRLHA). Before and after HA protocols, participants completed an exercise-heat stress test with CMDT (pre- post-HA; 40°C, 40% relative humidity): 1 × 7-min self-regulated cycling ("strong effort") followed by 2 × 7-min fixed-power blocks with an attentional task. Heart rate, rectal temperature, and mental effort were recorded, while neuromuscular function (peripheral, central responses) was assessed post-CMDT during a 1-min sustained maximal contraction. During HA sessions, heart rate and rectal temperature were comparable between groups (p ≥ 0.19), despite a reduced power during BFRHA (-22% ± 6%; p < 0.001). Post-HA, both groups reduced (p ≤ 0.003) peak heart rate (CTRLHA:-5 ± 4 bpm, BFRHA:-7 ± 6 bpm) and rectal temperature (CTRLHA:-0.19 ± 0.15°C, BFRHA:-0.15 ± 0.12°C). Both improved attentional performance (CTRLHA:+10% ± 5%, BFRHA:+9% ± 7%; p < 0.001) with lower mental effort, while reduced force loss was evident only in BFRHA post-HA (+18% ± 12%, p = 0.001), consistent with lower central fatigue (p = 0.028) versus pre-HA. Effective heat adaptations were induced by both HA protocols, despite the lower workload with BFR. Both approaches enhanced sustained attention during an exercise-heat stress with CMDT, while BFR additionally mitigated central fatigue. © 2026 The Author(s). Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.

BACKGROUND: Postoperative nausea and vomiting (PONV) remains a common and distressing side effect of opioid-based patient-controlled analgesia (PCA). Although continuous background infusion stabilizes analgesia, it often induces excessive opioid exposure and related adverse events. This study evaluates a novel smart PCA system featuring feedback-regulated background infusion (FRBI) designed to dynamically adjust opioid delivery based on real-time pain feedback, aiming to reduce PONV without compromising analgesia. METHODS: In this prospective, randomized, controlled, single-center trial, 132 patients undergoing laparoscopic myomectomy were assigned in a 1:1 parallel-group design to either constant-rate background infusion (CRBI) at 2 mL/h (Group A) or FRBI with adjustable rates of 1-4 mL/h (Group B). Both groups received a standardized sufentanil-flurbiprofen solution via PCA. The FRBI algorithm dynamically adjusted the infusion rate: a 20% increase was triggered by ≥2 bolus demands within 30 minutes, and a 20% decrease followed 4 consecutive demand-free hours. The primary outcome was the incidence of PONV (defined as nausea and/or vomiting) within 48 hours postoperatively. Secondary outcomes included pain scores (NRS), total opioid consumption, occurrence of other adverse events, and patient satisfaction. RESULTS: The FRBI group demonstrated a significantly lower incidence of PONV (nausea and/or vomiting) compared to the CRBI group (41.7% vs 62.7%, risk difference: -21.0% [95% CI: -38.1% to -3.9%]; risk ratio: 0.66 [95% CI: 0.46 to 0.96], P = 0.022). Total sufentanil consumption was reduced by approximately 30% in the FRBI group (P < 0.01). Pain scores were comparable between groups at all time points. Patient satisfaction was significantly higher in the FRBI group (P < 0.01). No cases of respiratory depression were observed in either group. CONCLUSION: The feedback-regulated background infusion mode significantly reduces the incidence of PONV and total opioid consumption while maintaining effective analgesia in patients undergoing laparoscopic myomectomy. This strategy suggests a favorable safety profile in this specific surgical population and may represent a

15. Drug Des Devel Ther. 2026 Apr 23;20:597391. doi: 10.2147/DDDT.S597391. eCollection 2026. Feedback-Regulated versus Constant-Rate Sufentanil Patient-Controlled Analgesia for Postoperative Nausea and Vomiting After Laparoscopic Myomectomy: A Randomized Controlled Trial. Ma Q(1), Wang M(1), Zh

BACKGROUND: The exam period is a period full of intense stress and anxiety that deeply affects cognitive and physiological responses for university students. Listening to music has the potential to protect cellular health and alleviate the negative effects of stress by affecting individuals' mood, and cognitive functions. This study aimed to investigate the differential effects of 528 and 432 Hz music frequencies on salivary BDNF, CREB, and GRP78 levels in young adults, along with their association with cognitive performance under exam-related stress. METHODS: A total of 162 healthy university students were randomly assigned to three groups: no music (control), 528 Hz instrumental music, and 432 Hz instrumental music. Participants listened to music for 20 min, after which saliva samples were collected and analyzed for brain-derived neurotrophic factor (BDNF), glucose-regulated protein 78 (GRP78) and cyclic AMP response element-binding protein (CREB) levels using ELISA. Cognitive performance was assessed using the Stroop word-color test administered by medical doctor. RESULTS: Exposure to 528 Hz music significantly increased salivary BDNF (3.84 [2.76-4.13]) and CREB levels (1.5 [1.38-1.59]) compared to control (p < 0.05), whereas GRP78 levels were elevated in the 432 Hz group (0.51 [0.47-0.58]) (p < 0.05). No significant differences were observed between groups in Stroop test performance. CONCLUSION: These findings suggest that specific music frequencies elicit distinct biological responses under exam-related stress, even in the absence of immediate cognitive performance differences. Salivary neurotrophic and stress-related biomarkers may offer valuable non-invasive insights into music's neuromodulatory effects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: AMU-EC-8522. © 2026 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.

OBJECTIVE: To examine the acute effect of a self-regulated dual-task during resistance exercise on muscular endurance, pain intensity and pressure pain threshold (PPT) in patients undergoing carpal tunnel release (CTR). METHODS: Participants were randomly assigned to resistance exercise combined with a self-regulated cognitive task (dual-task) or resistance exercise alone (single-task). Exercise was prescribed using elastic resistance until task failure with a prespecified intensity of 3 on the Borg CR10 scale. The primary outcome measure was muscular endurance (maximum number of repetitions to failure) for wrist flexors and extensors. Secondary outcomes included pain intensity (visual analogue scale) and pressure sensitivity (PPT). Covariates included: catastrophizing, kinesiophobia, self-efficacy and perceived difficulty. RESULTS: Twenty-two participants (63.6% female) with a mean age of 47.8 ± 10.3 years. Participants performed a greater number of repetitions to failure under the dual-task condition compared with the single-task condition, with increases of 9.7 [95% CI: 5.7-13.8] repetitions for wrist flexion and 12.0 [95% CI: 7.7-16.2] repetitions for wrist extension. Pain intensity decreased in both conditions, with no significant condition or time × condition effects. PPTs increased following exercise at the unaffected hand and at the lateral epicondyle, whereas only a trend was observed at the affected hand. No significant time × condition interactions were identified for pain intensity or PPT. Catastrophizing and kinesiophobia were negatively associated with changes in PPT, whereas self-efficacy showed a positive association. CONCLUSION: In patients recovering from CTR surgery, dual-tasking as a cognitive distraction strategy acutely improved exercise capacity by increasing the number of repetitions to failure. TRIAL REGISTRATION: Protocol Registration Number: ClinicalTrials.gov (NCT05592184). © 2026 The Author(s). Musculoskeletal Care published by John Wiley & Sons Ltd.

IMPORTANCE: Familial hypercholesterolemia is a common genetic disorder associated with premature cardiovascular disease. Genetic cascade screening is recommended but remains underused due to privacy laws that prevent clinicians from directly contacting at-risk relatives. OBJECTIVE: To examine whether implementing a web-based communication platform in a patient-mediated genetic cascade screening program for familial hypercholesterolemia increases uptake compared with usual care. DESIGN, SETTING, AND PARTICIPANTS: This open-label, multicenter, implementation randomized clinical trial (CATCH) was conducted between November 1, 2020, and October 31, 2023, at 7 cardiovascular prevention or lipid clinics across Switzerland, representing French-, German-, and Italian-speaking regions. Adults aged 16 years or older with genetically confirmed familial hypercholesterolemia and at least 1 eligible first-degree relative living in Switzerland participated. A total of 87 index patients with 359 eligible first-degree relatives were randomized by family cluster (1:1) to the intervention or usual care arm. INTERVENTION: A secure web-based platform allowing participants to send preprepared electronic messages (email or text) to their relatives, linking them directly to participating centers for genetic testing. MAIN OUTCOMES AND MEASURES: The primary outcome was cascade screening uptake, defined as the proportion of eligible first-degree relatives undergoing genetic testing within 6 months. The secondary outcome was new cases identified. RESULTS: Among 221 adults screened across multiple families, 87 (39.4%) had genetically confirmed familia hypercholesterolemia (median [IQR] age, 49.2 [16.4-83.7] years; 46 [52.9%] female; median [IQR] highest low-density lipoprotein cholesterol, 289.58 [139.00-498.07] mg/dL); 43 were randomized to the usual care arm, and 44 were randomized to the intervention arm. Among the 359 eligible relatives (median family size, 4), 99 (27.6%) underwent genetic testing. Uptake was higher in the intervention arm (30.4%; 95% CI, 22.0%-40.4%) than in usual care arm (16.7%; 95% CI, 10.1%-26.3%), yielding an odds ratio of 2.18 (95% CI, 1.06-4.51; P = .03). New ca

BACKGROUND: Problematic social media use has been linked to reduced well-being and impulse control difficulties. While digital self-control apps show potential for reducing general app usage, they often lack customization, leading to limited effectiveness and increased user resistance. Their impact on problematic social media use remains uncertain. OBJECTIVE: This study evaluates the effectiveness of the Wellspent app, a customizable mobile intervention app designed to promote self-regulated social media use by targeting user-defined problematic app use and offering tailored behavioral nudges. METHODS: In a 3-week randomized controlled trial, 70 iPhone users (mean age 26.2, SD 5.6 years; 47/70, 67% female), regularly using at least 1 social media app, were randomly assigned to an intervention (n=35) or control group (n=35). The intervention group received personalized full-screen reminders with the option to quit or continue social media app use whenever an app session exceeded a self-defined time limit. Participants completed weekly online surveys measuring problematic social media use, problematic smartphone use, self-efficacy, and daily screen time on their most problematic app. Linear mixed models tested intervention effects. RESULTS: While no significant reduction in problematic social media use or increase in self-efficacy was observed, the intervention group showed a significant reduction in daily screen time on their most problematic app by approximately 29 minutes (estimate=-29.35, SE 6.84, 95% CI -42.79 to -15.99; P<.001), and a significant decrease in perceived problematic smartphone use (estimate=-0.46, SE 0.18, 95% CI -0.80 to -0.11; P=.01). CONCLUSIONS: The Wellspent app demonstrated short-term efficacy in reducing problematic smartphone use. By allowing users to tailor interventions to their personal goals, the app shows promise as a self-directed tool to support healthier digital habits. Further research should explore long-term effects and feature-specific impacts. © Lea Mertens, Lina Christin Brockmeier, Christina Roitzheim, Theda Radtke, Tilman Dingler, Jan Keller. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org).

INTRODUCTION: Human milk oligosaccharides (HMOs) arise from tightly regulated glycosylation pathways and exert pleiotropic effects on infant immune, microbial, and neurodevelopmental trajectories. Vitamin D influences gene transcription and cellular metabolism, yet its potential role in mammary glycosylation remains unexplored. We examined whether maternal vitamin D status during lactation is associated with HMO composition and whether effects vary by maternal secretor phenotype. METHODS: We performed a post hoc analysis of two clinical studies: the NICHD vitamin D lactation randomized controlled trial (2005-2012) and the Lactation Immune Trial pilot (n = 88). Serum 25-hydroxyvitamin D [25(OH)D, vitamin D status] and 19 HMOs concentrations were measured at 1 and 4 months postpartum. Secretor status was defined by presence of 2'-fucosyllactose. Statistical analyses were conducted using SAS 9.4 with p < 0.05. RESULTS: The cohort comprised 41% White, 7% Black, and 52% Hispanic women. Black and Hispanic mothers exhibited lower 25(OH)D concentrations than White mothers (p < 0.001), and Hispanic mothers were more likely to be secretors (p = 0.006). In secretors, higher 25(OH)D was significantly associated with increased fucosylated and complex HMOs, including lacto-N-fucopentaose II, lacto-N-hexaose, and fucosyl-disialyl-lacto-N-hexaose I at 1 month, with sustained association for the latter at 4 months. In non-secretors, higher 25(OH)D was associated with lower 6'-sialyllactose at 4 months. Distinct HMO patterns were observed by secretor phenotype. CONCLUSION: Vitamin D status is associated with differential HMO profiles during early lactation, supporting a potential role for vitamin D-mediated regulation of mammary glycosylation that is modified by secretor status.

Free-living nitrogen fixation (FLNF), like any enzyme-mediated process, is inherently temperature dependent. As FLNF contributes nearly half of global biological nitrogen fixation in natural ecosystems, its response to warming is crucial for predicting how ecosystems will cope with nutrient limitations under climate warming. However, current model studies on climate change often rely on simplified representations of biological nitrogen fixation based on empirical proxies, overlooking microbial thermal acclimation and community shifts across climate gradients. To address this gap, we quantified FLNF rates and their temperature sensitivity (Q10) along a 1500 m elevational gradient in the eastern Himalayas to evaluate how climate, soil properties and diazotrophic (nitrogen-fixing) microbial communities jointly regulate FLNF. Our results showed that soil FLNF rates at site-specific MAT exhibited a unimodal pattern, peaking at mid-elevations, rather than following the expected monotonic increase with temperature. This pattern was jointly regulated by soil nutrient conditions and shifts in diazotrophic community composition. In contrast, the Q10 of soil FLNF rates increased with the elevation, being more than twofold higher at the coldest sites. This pattern was primarily driven by elevation-induced shifts in diazotrophic community composition, with Q10 closely associated with community structure and positively related to the relative abundance of Thermodesulfobacteriota. Together, these findings reveal a dual regulatory mechanism: soil nutrient availability constrains the baseline of FLNF rates both directly and indirectly via its effects on diazotrophic community composition, whereas community composition predominantly governs the magnitude of temperature sensitivity. The higher Q10 in colder zones also suggests that warming may have a more profound impact on N inputs in nutrient-limited high-elevation and high-latitude ecosystems, although this effect is likely contingent on soil resource availability. We emphasize the importance of incorporating diazotrophic community structure and thermal traits into global biogeochemical models to improve predictions of future n

The present work was designed to investigate the impacts of tartary buckwheat flavonoids (TBF) on the growth performance and physiological metabolism of Liangshan Yanying chickens. A total of 144 healthy 4-week-old Liangshan Yanying chickens of uniform body weight were randomly divided into four groups. Each group consisted of six replicates with six chickens per replicate. The control group was fed a basal diet, whereas the treatment groups received the same basal formulation supplemented with TBF at concentrations of 20, 40, and 60 mg/kg, respectively. The entire feeding trial lasted for 10 consecutive weeks. Growth performance, serum parameters, bone quality, slaughter traits, and hepatic lipid metabolism were determined and statistically analyzed. Results showed that dietary TBF supplementation had no significant impact on the overall growth performance (p > 0.05); however, final body weight and average daily weight gain displayed a positive linear trend in response to increasing TBF levels (0.05 < p < 0.1). For serum parameters, TBF supplementation significantly increased total antioxidant capacity (p < 0.05) and decreased malondialdehyde content (p < 0.05) in a linear manner. Specifically, compared with the control group, the 60 mg/kg TBF group increased T-AOC by approximately 64.6% and reduced MDA by approximately 67.9%, demonstrating a robust antioxidant effect. A linear increase in high-density lipoprotein cholesterol levels approaching significance (p = 0.055) was also observed. A significant quadratic regulatory effect of TBF was observed on serum glucose concentrations (p < 0.05), whereby the 60 mg/kg TBF dose reduced serum glucose by 15.6% relative to the control (p < 0.05), reflecting a robust hypoglycemic effect. Regarding bone quality, supplementation with 20 and 60 mg/kg TBF significantly elevated tibial phosphorus content relative to the 0 mg/kg TBF group (p < 0.05). Regression analysis showed that increasing dietary TBF levels linearly elevated tibial calcium content (p < 0.05) and resulted in linear increasing trends in tibial ash content, tibial phosphorus content, femur ash content, and femur calcium content (0.05 < p < 0.1). Concerning sla

African swine fever (ASF) has become one of the most significant transboundary animal diseases affecting countries worldwide. Wild boars play a major role in virus persistence and in local spread through geographical contiguity, while long-distance and transboundary dissemination is more commonly associated with human-mediated activities, particularly the movement of contaminated pork products and materials. Hunting is frequently considered a central tool for disease control; however, its epidemiological impact remains debated. This review comparatively analyses the approaches adopted by countries of European continent affected by ASF, paying particular attention to the role of hunting within integrated management strategies. The review examines country-specific control measures, including surveillance systems, carcass search and removal, fencing, zoning, and population reduction policies. The analysis shows that successful eradication was associated with early detection, temporary suspension of hunting in infected core areas, rapid spatial containment through fencing, and intensive passive surveillance based on systematic carcass removal. Hunting was reintroduced only after containment, as a regulated depopulation tool under strict biosecurity supervision. In contrast, where the virus was already widespread at detection and containment measures were delayed or fragmented, intensified hunting alone did not prevent endemic persistence. These findings indicate that hunting is neither inherently protective nor detrimental; rather, its effectiveness depends on timing, coordination, and integration within a structured epidemiological framework. Effective control requires combining wildlife management with surveillance, biosecurity, and clear governance.

Superhydrophobic surfaces are typically achieved through the synergistic integration of appropriate nanostructures and low-surface-energy chemical compositions. This study presents a novel and facile method for constructing a superhydrophobic hierarchical structure directly on a pristine selective laser melting (SLM) titanium surface. The intrinsic partially melted Ti particles, which are inherent to the SLM fabrication process, were strategically utilized as a natural microscale template for the in situ growth of TiO2 nanotubes via electrochemical anodization. Three distinct micro/nano-topographies were successfully fabricated, integrating the spherical microparticles with either conventional TiO2 nanotube arrays or separated nanotube arrays. The results demonstrate that the resulting superhydrophobic behavior can be effectively regulated by two key factors: the liquid-solid contact mode at the microscale and the strength of capillary action within the nanostructures. Notably, these characteristics can be tailored by controlling the nanotube diameter and intertubular spacing. These findings contribute to a deeper understanding of the role of micro-nano hierarchical structures in engineering superhydrophobic surfaces, thereby opening new avenues for advanced applications.

Circulating tumor cells (CTCs) are valuable liquid-biopsy biomarkers, yet their extreme rarity makes high-purity, high-throughput enrichment challenging. In spiral inertial microfluidics, high cell loading induces long-range hydrodynamic interactions that broaden the focused blood-cell stream; consequently, a subpopulation completes the ~0.5 and ~1.0 Dean-cycle migrations with a phase delay, compressing the CTC-blood cell gap and degrading purity. Here we propose a Dean-cycle phase-regulated double-spiral design informed by this phenomenon. This design aims to mitigate the stream-broadening effect by boosting the Dean number during the first half-cycle to promote synchronized blood-cell migration and shifting the CTC equilibrium position near one full cycle to further widen the CTC-blood cell separation. We implement this strategy in a second-generation double-spiral microfluidic chip (SDMC) and scale it to a four-channel parallel array (ASDMC). Under optimized conditions, ASDMC processes diluted whole blood (hematocrit = 4%) without the need for red blood cell (RBC) lysis or antibody labeling, achieving a sample throughput of 1200 μL·min-1. Specifically, it exhibits a mean recovery rate of 98.8% across three spiked tumor cell lines (MCF-7, PC-9, and Mahlavu) and a mean white blood cell (WBC) depletion efficiency of 93.3%. In a pilot clinical testing of 20 patients (NSCLC and HCC), enriched fractions enabled immunofluorescence identification of CK+CD45-DAPI+ CTCs, with an exploratory trend of increasing CTC counts with advanced disease stage (4-34 cells·mL-1). These results describe a scalable, label-free platform, and the observed purification performance aligns with our proposed mechanism: Dean-cycle phase regulation to mitigate blood-cell migration lag. Our findings support further technical validation and clinical assessment in larger cohorts.

Background/Objectives: Onion (Allium cepa) peems are an underutilized by-product rich in polyphenols. This study evaluated the physicochemical profile, and bioactive potential (antidiabetic, antimicrobial, antioxidant, and anticoagulant) of Moroccan red onion peels using integrated in vivo, in vitro, and in silico approaches. Methods: Moisture, pH, ash content, and mineral elements were determined, followed by phytochemical screening and three extractions: decoction E0, aqueous Soxhlet E1, and hydroethanolic Soxhlet E2 (70/30; ethanol/water, v/v). The measurement of polyphenols, flavonoids, and tannins was carried out using colorimetric methods, while the molecular profile was studied by high-performance liquid chromatography coupled to ultraviolet detection and electrospray ionization mass spectrometry (HPLC/UV-ESI-MS). Biological activities were determined using 2,2-diphenyl-1-picrylhydrazyl, ferric reducing antioxidant power, and total antioxidant capacity assays (in vitro antioxidant); microdilution (antimicrobial); prothrombin time and activated partial thromboplastin time (anticoagulant); and α-amylase/α-glucosidase enzymatic inhibition and oral glucose tolerance tests on normoglycemic rats. Also, acute toxicity was evaluated, and molecular interactions between these proteins and ligands (docking, molecular dynamics, and MM-PBSA) were analyzed. Results: Physicochemical analyses showed an acidic pH (3.06) and high ash content (15.21%), with the concentration of regulated elements remaining within FAO/WHO limits. The extractive content was between 6.90% E0 and 19.18% E2. The E1 extract had the maximum amount of total polyphenols (178.95 mg GAE/g); on the other hand, E2 was the richest in flavonoids by 121.43 mg QE/g. The HPLC/ESI-MS analysis of E0 revealed 20 compounds, among which flavonoids (84.93%) were predominant, with isorhamnetin (30.26%), followed by quercetin and its glycosylated forms. E1 showed the most potent antioxidant effects (IC50 DPPH, 22.38 µg/mL, as that of ascorbic acid). The antibacterial activity of E0 was especially potent towards Enterobacter cloacae and Pseudomonas aeruginosa (MIC 75 µg/mL). A mild dose-dependent anticoagulant effect

Background: Cancer patients are highly susceptible to microbial infections due to immune suppression, necessitating therapeutic strategies that integrate anticancer efficacy with effective antimicrobial intervention. Chalcone-derived nitrogen-fused heterocycles represent a promising platform for developing multi-target agents with relevance to antimicrobial drug delivery, particularly for localized infections. Methods: A series of chalcone-based pyrazoline-thiadiazole nitrogen-fused azole hybrids was synthesized via thiosemicarbohydrazide-functionalized intermediates and fully characterized. Antiproliferative activity was evaluated against MCF-7, HepG-2, HeLa, and HCT-116 cell lines, alongside selectivity toward WI-38 normal fibroblasts. Antibacterial, antibiofilm, and in vivo efficacy were assessed against methicillin-resistant Staphylococcus aureus (MRSA USA300) and Acinetobacter baumannii AB5057. Mechanistic investigations included cell-cycle analysis, apoptosis assays, ERK2, RIPK3, p53, BAX/Bcl-2 quantification, DNA gyrase inhibition, molecular docking, molecular dynamics simulations, and density functional theory calculations. Results: Compound 13 exhibited potent cytotoxicity, particularly against MCF-7 (IC50 = 3.87 ± 0.2 µM), outperforming doxorubicin (IC50 = 4.17 ± 0.2 µM), with high selectivity indices (SI = 10.7 for MCF-7). Mechanistically, compound 13 induced G2/M arrest (40.16% vs. 14.15% control), increased apoptosis to 32.89%, up-regulated ERK2 (3.17-fold), RIPK3 (11.97-fold), and p53 (3.54-fold), and markedly increased the BAX/Bcl-2 ratio (~42-fold). Compounds 7 and 13 displayed bactericidal activity against MRSA and A. baumannii (MIC/MBC = 10 mg/mL), potent antibiofilm effects, and significant in vivo efficacy in an MRSA skin infection model. Compound 13 reduced bacterial load by ~5 log units, outperforming vancomycin. DNA gyrase inhibition (IC50 = 17.10 ± 0.17 µM) and computational studies supported target engagement. Conclusions: Pyrazoline-thiadiazole-based nitrogen-fused azole hybrids, particularly compound 13, demonstrated quantifiable anticancer and antimicrobial efficacy with strong in vivo validation, supporting their potential as multi-t

Periplaneta americana extract can promote wound healing and may play an important role in skin wound healing. In this study, we identified a peptide (DL-13) from Periplaneta americana L. and explored its role and mechanisms in skin wound healing. In vitro, the effects of DL-13 on proliferation, migration, and related gene/protein expression in HaCaT keratinocytes were assessed via qRT-PCR and Western blot. In vivo, rat wound healing assays confirmed its efficacy. Results showed DL-13 accelerated rat wound healing. In in vitro studies, DL-13 activated EGFR and its downstream PI3K/AKT/mTOR, ERK/MAPK, and JAK2/STAT3 pathways, upregulated EMT-related proteins (N-cadherin, MMP-2, p-FAK, β-catenin), partially regulated macrophage cytokine secretion, and promoted HaCaT proliferation/migration, thereby facilitating re-epithelialization at skin injury sites. Overall, DL-13 may enhance the function of HaCaT cells by activating the EGFR signaling pathway and regulate inflammatory factors in macrophages, thereby promoting the healing of skin wounds in rats. The results of this study will lay an experimental and scientific foundation for the discovery of new compounds for wound healing and their application.

Background: Respiratory syncytial virus (RSV) is a leading global pathogen of acute lower respiratory tract infection, posing significant risks to infants, the elderly, and immunocompromised patients. Artemisia argyi Levl.et Vant Extract (AALE) and its active components have a variety of pharmacological effects, but their anti-RSV potential remains unclear. The aim of this study is to investigate the anti-RSV activity of AALE and parthenolide and its underlying mechanisms. Methods: Cell counting kit-8 (CCK-8) assay was used to determine the anti-RSV activities of AALE and parthenolide. Time-of-addition assay and phase of action analysis were used to explore the effect of drugs on the viral replication cycle. Quantitative polymerase chain reaction (qRCR), immunofluorescence (IF) and Western blot (WB) were used to investigate the effects of AALE and parthenolide on RSV-F gene and protein and on RIG-I/TLR-3 pathway related molecules in vitro. In vivo antiviral efficacy was verified by hematoxylin-eosin (HE) staining for lung histopathology, quantitative real-time PCR (qPCR) quantification of RSV-F, RIG-I, TLR-3, IRF3, IL-6, and IFN-β gene expression in lung tissues, and enzyme-linked immunosorbent assay (ELISA) for serum IL-6 and IFN-β levels. Results: AALE exhibited the strongest anti-RSV activity among the extracts (SI = 27.6), while parthenolide was the most potent monomeric compound (SI = 8.19). In vitro, both AALE and parthenolide were effective in the co-treatment and post-treatment models, reducing RSV-F gene and F protein levels in infected cells. Furthermore, they alleviated RSV infection by regulating RIG-I and TLR-3 pathway-related genes and proteins. In vivo, AALE and parthenolide suppressed lung index and RSV proliferation, attenuated lung injury, and down-regulated RIG-I, TLR-3, IRF3, IL-6, and IFN-β expression in the lungs of RSV-infected mice. Conclusions: AALE and its component parthenolide can inhibit the invasion and replication of RSV, making it a potential candidate for the treatment of RSV-related diseases.

Background/Objectives: The purpose of this study was to investigate the association between cardiovascular adverse drug events (ADEs) and the use of COVID-19 medicines. Methods: The analyses were conducted by leveraging pharmacovigilance data from the Food and Drug Authority (FDA) Adverse Event Reporting System (FAERS) and TriNetX electronic health records (EHRs). Transcriptomic data from human embryonic stem cell-derived cardiomyocytes (hESC-CMs) exposed to remdesivir were analyzed to provide supportive biological context for the observed cardiovascular safety signals. Results: Comparative analysis of three approved COVID-19 therapies revealed that COVID-19 patients treated with remdesivir had a higher risk of cardiovascular events than those treated with Paxlovid or REGEN-COV. FAERS analysis further indicated that bradycardia, hypotension, and cardiac arrest were the most frequently reported cardiovascular events associated with remdesivir, which was validated by propensity score-matched EHR data. These findings suggest an association between remdesivir exposure and increased cardiovascular ADEs relative to other COVID-19 therapies. Sex-stratified analysis using FAERS and EHR did not show strong sex-dependent patterns for remdesivir-associated cardiovascular ADEs. Age-stratified analyses of EHR data showed age-associated variation across the three cardiovascular ADEs. Bradycardia displayed a non-uniform pattern with higher prevalence in the youngest and oldest age groups, hypotension showed an overall age-associated increase, and cardiac arrest showed only a weak age-associated effect. Pathway enrichment analysis on transcriptomic data revealed that the "cGMP-PKG signaling pathway", "dilated cardiomyopathy", and "calcium signaling pathway" were enriched among genes up-regulated by remdesivir exposure. Conclusions: In summary, our integrated analysis of pharmacovigilance, EHR, and transcriptomic data provides convergent evidence for associations between remdesivir and cardiovascular ADEs and offers biological context into these associations.