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Emerging hantavirus risks in mass gatherings: epidemiology, diagnostic challenges, and outbreak preparedness.

Hantaviruses are emerging rodent borne zoonotic pathogens of increasing global public health concern because of their high mortality, expanding ecological distribution, and potential for international dissemination. Although traditionally associated with sporadic rural outbreaks, recent ecological disruption, climate variability, urbanization, and increased global mobility have heightened concerns regarding hantavirus risks in mass gathering settings. This review critically examines the epidemiology, transmission uncertainty, diagnostic and surveillance challenges, and preparedness strategies related to hantavirus infections in the context of mass gatherings, including religious events, refugee settlements, cruise tourism, sporting events, and temporary accommodations. Particular emphasis is placed on the 2026 multinational cruise ship associated outbreak linked to the MV Hondius, which highlighted vulnerabilities related to delayed diagnosis, international passenger dispersal, and uncertainties surrounding possible human to human transmission of Andes virus. Current evidence indicates that hantavirus transmission occurs primarily through inhalation of aerosolized rodent excreta; however, controversies regarding limited interpersonal transmission, environmental persistence, and asymptomatic infections continue to complicate risk assessment and outbreak preparedness. Diagnostic limitations, underreporting, insufficient environmental surveillance, and lack of mass gathering specific preparedness frameworks remain major public health challenges, especially in resource limited settings. Strengthening proactive preparedness through integrated One Health approaches, ecological surveillance, genomic monitoring, AI driven epidemic intelligence, and coordinated international response systems is essential for mitigating future risks. The review emphasizes the urgent need for multidisciplinary research and evidence based policy development to improve global preparedness against emerging hantavirus associated threats in increasingly interconnected mass gathering environments.

Humans

A Systematic Review of Help-Seeking Barriers for Racial-Ethnic Minority Caregivers Accessing Autism Diagnostic and Intervention Services.

Caregivers play an essential role in early help-seeking and intervention for children with Autism Spectrum Disorder (ASD). Caregivers, therefore, provide a crucial role in helping to address the racial and ethnic disparity identified in accessing ASD intervention and diagnostic services (Bejarano-Martín et al., Journal of Autism and Developmental Disorders 50(9), 3380-3394, 2020). Unfortunately, racial-ethnic minority caregivers of children with autism (CCA) are less likely to contact a physician or healthcare professionals about their concerns and more likely to delay their contact to have their child evaluated (Zeleke et al., Journal of Autism and Developmental Disorders 49(10), 4320-4331, 2019). However, little evidence exists to explain why such a gap exists in the help-seeking behaviors between White and racial-ethnic minority CCA. To address this knowledge gap, we conducted a systematic literature review to identify articles that have studied barriers in help-seeking for racial-ethnic minority CCA. A broad literature search across four databases was conducted (i.e., PubMed, PsycINFO, Education Resources Information Center, and Child Development and Adolescent Studies). The coding team identified 17 articles on help-seeking barriers for racial-ethnic minority CCA. A thematic analysis was used to narratively synthesize the help-seeking barriers identified across these 17 studies. Four themes emerged from our findings: logistical barriers, provider competence, ASD literacy, and cultural stigma. We also provided clinical recommendations for healthcare providers working with families with racial-ethnic minority CCA.

Humans

Antagonistic regulation by mango MiSPL9a and MiSPL9b regulates flowering time, drought and salt stress in Arabidopsis.

SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) transcription factors, which are unique to plants, contain a highly conserved SBP domain that regulates gene expression by binding to downstream targets. They play critical roles in various biological processes, especially in the regulation of flowering in plants. In this study, two SPL-like genes (MiSPL9a and MiSPL9b) were identified from mango genomic and transcriptomic data, and their sequence, expression and function were further analyzed. Sequence analysis revealed that MiSPL9a and MiSPL9b have open reading frames of 1173 bp and 1158 bp, respectively, with slight differences in the number of cis-regulatory elements within their promoter regions. Expression analysis under stress conditions revealed distinct patterns: MiSPL9a expression significantly differed under drought stress but did not significantly differ under salt stress, whereas MiSPL9b expression responded significantly to salt stress but changed minimally under drought stress. Phenotypic analysis of the transgenic Arabidopsis lines revealed that MiSPL9a overexpression delayed flowering, whereas MiSPL9b overexpression promoted early flowering. Under stress conditions, compared with wild-type plants, MiSPL9a-overexpressing plants presented increased drought tolerance but did not significantly differ. In contrast, MiSPL9b-overexpressing plants were sensitive to salt stress, with no notable phenotypic differences observed under drought conditions. Physiological assays revealed that under drought stress, MiSPL9a transgenic plants presented significantly reduced levels of malondialdehyde (MDA) and hydrogen peroxide (H2O2) and increased proline (Pro) content and superoxide dismutase (SOD) activity. Under salt stress, MiSPL9b transgenic plants presented opposite trends in terms of these physiological markers. In summary, both MiSPL9a and MiSPL9b are involved in the regulation of plant flowering time and stress responses, but their functions differ.

Arabidopsis

Triggering modalities to synchronise non-invasive respiratory support in preterm infants: a systematic review and meta-analysis.

BACKGROUND: Increasing evidence suggests that synchronised nasal intermittent positive pressure ventilation (sNIPPV) may be the optimal mode of non-invasive respiratory support. However, no comprehensive review of sNIPPV modes is available. This review aims to describe different synchronisation methods for sNIPPV and compare their effectiveness in clinical, physiological and technical outcomes with other modes of non-invasive respiratory support. METHODS: This review identified all clinical studies in preterm infants that compared sNIPPV to other non-invasive respiratory support modes or compared different trigger modalities between 1990 and 2026. A search was carried out in MEDLINE, Embase and the Cochrane Library. Main outcomes were categorised as clinical (eg, extubation failure (EF)), physiological (eg, breathing effort) and technical (eg, synchronisation rate). RESULTS: 49 studies (2864 infants) were included, with a low to moderate risk of bias. Meta-analysis showed a reduction in EF (risk ratio=0.38; 95% CI 0.17 to 0.85; p=0.03) in favour of sNIPPV compared with nasal continuous positive airway pressure (nCPAP). Physiological outcomes were significantly improved during sNIPPV compared with nCPAP and nasal intermittent positive pressure ventilation (NIPPV), especially breathing effort. When reviewing technical outcomes, non-invasive neurally adjusted ventilatory assist showed lower patient-ventilator asynchrony (PVA) (index ranging from 7% to 50%), a higher synchronisation rate (80%-99%) and a shorter trigger delay (35 ms) compared with other sNIPPV modes. CONCLUSIONS: This review shows that synchronising NIPPV results in consistent physiological (reduced patient effort) and technical benefits (reduced PVA). However, evidence on positive effects on (long-term) major clinical outcomes remains limited and requires further studies. PROSPERO REGISTRATION NUMBER: CRD420251022479.

Humans

An Overview of Red Breast Syndrome: A Qualitative Systematic Review of the Literature and a Single-Center Case Series.

Red breast syndrome (RBS) is an uncommon inflammatory complication that may occur following implant-based breast reconstruction and can clinically mimic surgical-site infection. This qualitative systematic review, based on comprehensive PubMed and Scopus searches, summarizes the existing literature on RBS, focusing on its etiology, clinical presentation, diagnostic characteristics, and therapeutic approaches following breast reconstruction using acellular dermal matrices (ADMs). A management protocol is proposed based on available data, and a single-center case series is presented from our Hospital, including patients who developed RBS after direct-to-implant reconstruction with ADM between January 2022 and December 2024. Twenty-nine studies met the inclusion criteria, comprising case reports, case series, and retrospective or prospective cohort studies. The reported incidence of RBS ranged from 0% to 29.6%. Proposed etiologies include endotoxin contamination, residual cellular debris, delayed hypersensitivity reactions, and lymphatic or vascular impairment of mastectomy flaps. Most reports described localized erythema confined to the area of the ADM, with normal inflammatory markers and negative imaging findings, whereas antibiotic therapy frequently failed to achieve improvement. Corticosteroids represented the most consistently effective treatment, although some cases required ADM removal or replacement. In our institutional case series (n = 8), symptom onset occurred between 4 weeks and 7 months postsurgery. Inflammatory markers remained within normal limits, imaging rarely demonstrated fluid collections, and symptoms resolved within days to weeks with corticosteroid therapy or conservative management. This review consolidates current evidence, proposes a diagnostic-therapeutic algorithm and highlights the need for prospective investigations and manufacturer-level endotoxin testing to elucidate pathogenesis and optimize clinical management. Level of Evidence: 2 (Risk) For image description, please refer to the figure legend and surrounding text.

Humans

The Role of Artificial Intelligence for Intimate Partner Violence Prevention: A Systematic Review.

INTRODUCTION: Intimate partner violence (IPV), encompassing physical, sexual, emotional and economic abuse, remains a pervasive global health concern. Traditional prevention efforts face obstacles such as underreporting, delayed detection and limited personalised support. Emerging artificial intelligence (AI) approaches offer new opportunities to enhance IPV prevention. AIM: This systematic review maps and synthesises evidence on AI-driven tools in IPV prevention based on studies published between 2004 and 2024. METHODS: Following PRISMA 2020 guidelines and PROSPERO registration, we searched PubMed, Embase, CINAHL, PsycINFO, IEEE Xplore and Web of Science. Eligible studies explicitly evaluated AI technologies targeting IPV prediction, screening, intervention or support delivery. Study quality was appraised using the Mixed Methods Appraisal Tool (MMAT). RESULTS: Of 1304 records initially identified, 41 studies met eligibility criteria. AI applications ranged from machine learning (ML) for risk prediction and natural language processing (NLP) for IPV detection in clinical and social media data, to image analysis for forensic evaluation and chatbot-based support. Predictive modelling demonstrated strong discriminative performance, while NLP-based screening detected IPV with notable sensitivity. Chatbots showed feasibility and user acceptability, but evidence of their direct impact on reducing IPV incidence was limited, with one randomised controlled trial showing a modest reduction. Key challenges identified included algorithmic bias, data privacy risks and barriers to integration across health and social care systems. DISCUSSION: AI-informed interventions show promise for improving IPV detection, risk assessment, and scalable support, but questions remain about long-term effectiveness, ethical fairness, transparency and equitable implementation. Future interdisciplinary research should address these concerns to responsibly deploy AI in IPV prevention. RELEVANCE TO CLINICAL PRACTICE: The findings highlight the importance of trauma-informed, culturally responsive care and provider training in AI applications. Nurse-led innovation and policy advocacy will be crucial for safe, equitable integration of AI in IPV prevention.

Artificial Intelligence

Evolutionary conservation of heat shock proteins in Blattodea and their roles in wing morphogenesis and ovarian development of Blattella germanica.

Heat shock proteins (Hsps) are essential molecular chaperones for protein homeostasis and stress responses. However, the Hsp repertoires and functions in Blattodea remain underexplored. Our genome-scale survey of nine Blattodea species revealed 37-46 conserved Hsp90, Hsp70, and DNAJ (Hsp40) genes, with DNAJ the most abundant and Hsp90 the least. Phylogenetic analysis confirmed the evolutionary conservation of three Hsp90, seven Hsp70, and 29 DNAJ subclades in Blattodea. Selection pressure analysis revealed predominant purifying selection (dN/dS ≪ 1) across lineages, strongest in DNAJ and highest in Hsp90 conservation. In Blattella germanica, expression of six representative BgHsp genes progressively increased during development, peaking in fifth-instar nymphs. Tissue expression profiling revealed that BgHspA1-2/3/4 were predominantly expressed in legs, BgDNAJB5 and BgHsp90AB1-2 were enriched in the fat body, and BgHsp90AB1 was highly expressed in the head. dsRNA injection targeting conserved Hsp gene regions achieved 61.9-94.1% knockdown of all six target genes. RNAi knockdown of six BgHsp genes disrupted wing morphogenesis, causing distinct phenotypes: wing whitening (56.7%, dsBgHspA1-4), unequal length (66.7%, dsBgHspA1-3; 76.7%, dsBgDNAJB5), and wing wrinkling (70%, dsBgHspA1-2; 63.3%, dsBgHsp90AB1; 76.7%, dsBgHsp90AB1-2). During ovarian formation, the developmental delay was most severe in the dsBgHsp90AB1 group, moderate in the dsBgHsp90AB1-2 and dsBgHspA1-2/3/4 groups, and weakest in the dsBgDNAJB5 group. Besides, knockdown significantly downregulated key developmental genes (apterous-a, nubbin, scalloped, ultrabithorax, wingless, and vitellogenin). These findings provide a reference for understanding the evolutionary patterns of Hsps in Blattodea, and offer mechanistic insights into the developmental regulation mediated by Hsps in this important public-health pest.

Animals

Lipid metabolism is a key central, systemic and gut microbial feature of the decline in rat hippocampal function during middle age.

Middle age is emerging as a turning point in brain ageing, prognostic of future cognitive health and amenable to intervention. Metabolic and proteomic differences during this period are not yet fully understood and may potentially influence functions of the hippocampus, a brain area that regulates memory and anxiety. While the gut microbiota is implicated in brain ageing, the relationship between the gut microbiota, the metabolic state, and hippocampal proteome in middle age has not been investigated. We hypothesise that peripheral metabolic or protein features are associated with hippocampal vulnerability in middle age. Therefore, young adult and middle-aged rats were assessed for behavioural, proteomic, metabolic, and gut microbiota differences. Proteomic profiling of the hippocampus revealed differential expression of proteins indicative of altered synaptic signalling. Concurrently, adult hippocampal neurogenesis was decreased in middle age. Hippocampal microglia exhibited a lipid rich, inflammatory phenotype in middle age which correlated with poorer memory performance. CSF and serum proteomic and metabolomic analyses identified dysregulated lipid-related pathways potentially contributing to hippocampal vulnerability in middle age. Furthermore, 16S rRNA sequencing revealed reduced abundance of bacteria involved in lipid metabolism regulation. However, faecal microbiota transfer from young to middle aged rats was not sufficient to robustly improve hippocampus-dependent spatial memory. Together, these findings highlight dysfunctional lipid metabolism as a key feature of middle age that may contribute to decline in hippocampal function. Given that the scope for intervention is limited during older age, targeting biomarkers involved in metabolic and lipid homeostasis may be pivotal for the development of pharmacological or lifestyle-based interventions during middle age which could ultimately delay future cognitive ageing.

Animals

Development and Validation of a Predictive Model for Identification of Cognitive Impairment Risk in Older Adults with Subjective Cognitive Decline:A Longitudinal Study.

BACKGROUND: Subjective cognitive decline (SCD) is a transitional state between objective cognitive impairment and cognitively intact mental status, providing a critical window for implementing preventive interventions to delay objective cognitive decline. AIMS: We aimed to develop a predictive model for SCD progression in older adults with mild cognitive impairment (MCI). This model will facilitate the identification of risk factors and establishment of targeted interventions for community-based SCD management. METHODS: Data from the China Health and Retirement Longitudinal Study (CHARLS) was utilized in this study, extracting 18 indicators. Potential predictors selected through univariate Cox regression and LASSO regression analyses were sequentially incorporated into a multivariable Cox regression model. A nomogram was constructed to establish a predictive model. Model validation encompassed Area Under Curve (AUC) metrics for discriminative capacity, complemented by quantitative assessments using calibration curve analysis for precision verification and decision curve analysis (DCA) for clinical utility evaluation. RESULTS: A total of 1099 older adults with SCD were included in the final analysis, of whom 114 (10.3%) developed MCI. Multivariable Cox regression identified residence, marital status, educational level, social participation, gait speed, and baseline cognitive function. The model demonstrated time-dependent AUC values of 0.885, 0.830, 0.839, and 0.836 in the training set when evaluating discriminative capacity at 2-, 4-, 7-, and 9-year, respectively. The predictive model showed excellent predictive ability according to AUC, calibration curve, and DCA. CONCLUSIONS: A predictive model was created to estimate the risk of developing MCI in older individuals with SCD, offering clinician-actionable intervention benchmarks for preventive care.

Humans

A multi-scale fusion model based on multi-phase contrast-enhanced CT for predicting pancreatic cancer resectability.

Purpose.Develop a multi-scale fusion model (MSFM) based on multi-phase contrast-enhanced computed tomography (CECT) to predict pancreatic cancer (PC) resectability, thereby assisting expert decision-making.Methods.This retrospective study enrolled 280 patients with PC from four institutions, which were randomly divided into a training cohort (202 patients) and an independent test cohort (78 patients). Three-phase CECT images (arterial, venous, and delayed phases) were used for modeling. The MSFM comprises two sub-networks: (1) a multi-phase fusion network for extracting cross-phase shared fusion features, (2) a phase-specific branch network for capturing phase-specific features; and a post-fusion strategy to generate the final predictive score by integrating the shared fusion features and three groups of phase-specific features. Additionally, a human-machine fusion deep learning model (HMfDL) was constructed by fusing the predictive score of the MSFM with expert assessments.Results.In the independent test, the MSFM achieved an AUC (area under the receiver operating characteristic curve) of 0.8385 (95% CI: 0.7521-0.9249), accuracy of 84.62%, sensitivity of 72.00%, and specificity of 90.57%. This performance outperformed single-phase models (AUC range: 0.7638-0.7781), two-phase models (AUC range: 0.7826-0.7864), and ten states-of-the-art classifiers (AUC range: 0.7404-0.7796). The HMfDL further improved the performance, reaching an AUC of 0.8626 (95% CI: 0.7853-0.9400), accuracy of 91.03%, sensitivity of 80.00%, and specificity of 96.23%. Notably, the HMfDL corrected 58.82% of misdiagnosis made by experts.Conclusions. The MSFM effectively fuses multi-phase CECT to enable highly accurate predictions of PC resectability, and provides valuable support for expert decision-making through HMfDL.

Humans

Meningioma methylation profiling as a complement to WHO grading: a single-center experience.

OBJECTIVE: The methylation profile of meningiomas is a promising predictive tool that may improve risk stratification beyond WHO grading. This study aimed to evaluate the clinical relevance and real-world applicability of routine epigenetic testing in meningioma management. METHODS: The authors retrospectively analyzed patients who underwent meningioma resection between January 2021 and December 2023. Histopathological grading (WHO 2021) and methylation profiling (methylation class [MC]) with the MethylationEPIC v1.0 (850k) chip were performed by an independent neuropathologist. RESULTS: A total of 106 patients were included; 81 tumors (76%) were classified as WHO grade 1, 20 (19%) as grade 2, and 5 (5%) as grade 3. Epigenetically, 55 tumors (52%) were classified as benign, 18 (17%) as intermediate, and 2 (2%) as malignant; 31 (29%) could not be classified. Discordances between WHO grading and methylation profiling were observed in 18 of 74 cases. Tumor board decisions were made after a median of 8 days postoperatively, guided by WHO grading; however, the epigenetic report was only available after a median of 23 days. During follow-up, 20 patients experienced tumor progression. Progression was significantly associated with the MC (r = -0.4, p < 0.001) and tumor volume (r = 0.4, p = 0.0005), but not with WHO grading (r = 0.17, p = 0.084). However, the relatively high rate of unclassified tumors and delayed result availability limited the direct impact of MC profiling on immediate clinical decision-making. Interestingly, progression-free survival in MC-unclassified tumors mirrored that of the intermediate group. CONCLUSIONS: Methylation profiling demonstrates superior predictive accuracy for meningioma progression and complements WHO grading, especially in identifying malignant meningiomas. However, its current clinical utility is constrained by technical and logistical limitations. In real-world practice, epigenetic classification should therefore be considered a complementary tool rather than a replacement for established histopathological assessment.

Humans

Tissue origins of the plasma proteomic response to glucose ingestion in humans.

AIMS/HYPOTHESIS: Circulating proteins act as important hormonal signals of nutrient intake. We aimed to systematically characterise the time-resolved proteomic response to glucose ingestion in humans, and to assess its robustness following prolonged complete caloric restriction. METHODS: We conducted oral glucose tolerance tests (OGTTs) in 11 healthy volunteers before and after 7 days of complete caloric restriction and measured the response of >2900 targets through high-resolution plasma protein profiling. RESULTS: We identified a signature of 44 proteins that changed significantly following glucose ingestion, which was reproducible after 7 days without food, and was strongly (20-fold) enriched for 'stomach-specific' proteins. We report that annexin A10 (ANXA10) shows the most significant post-glucose change observed, similar to the trajectories of secreted hormones. We present observational human evidence from multiple sources suggesting that ANXA10 is secreted upon sensing an increase in gastric pH, with the stomach as the major contributing tissue. Despite a profound metabolic shift after 7 days of complete caloric restriction, characterised by delayed insulin secretion and postprandial hyperglycaemia, only four proteins showed robust evidence for a differential trajectory during both OGTTs. This included plasma levels of tryptophanyl-tRNA synthetase&#xa0;1 (WARS), for which we found a genetic association with glucose homeostasis and coronary artery disease. CONCLUSIONS/INTERPRETATION: Our exploratory study identifies the proteomic response to glucose ingestion and demonstrates its reproducibility despite major shifts in glucose homeostasis. We characterise the gastrointestinal origin of these changes, and hypothesise a hitherto under-recognised role for sensing of changes in gastric pH on the plasma proteome.

Humans

Transcriptomics reveals species-specific adaptive strategies to calorie restriction in two Argopecten scallops with distinct lifespans.

Calorie restriction (CR) is a well-established non-genetic intervention for lifespan extension in multiple model organisms. Seasonal food shortage in cold and temperate seas may mimic CR, inducing in bivalves a response similar to that in vertebrates and thereby prolonging life expectancy. However, the relationship and the mechanism underlying the food availability and lifespan in bivalves remain largely unexplored. Two closely related scallop species the short-lived warm-water Argopecten irradians (lifespan <2&#xa0;years) and the longer-lived cold-water Argopecten purpuratus (7-10&#xa0;years) provide an ideal comparative system to investigate species-specific adaptive strategies. In this study, we subjected both species to CR for 30 and 56&#xa0;days and performed comparative transcriptomic profiling, weighted gene co-expression network analysis (WGCNA), and physiological assays to elucidate their distinct molecular responses. Transcriptomic analysis revealed that A. purpuratus exhibited substantially more DEGs than A. irradians at both time points under CR, with both species showing downregulation of metabolic pathways but to different extents. A. irradians mounted an early nutrient-sensing response at 30&#xa0;days (IGF1R, PIK3R3, INSR suppression), indicating acute sensitivity to limitation; by contrast, A. purpuratus displayed delayed FoxO activation at 56&#xa0;days, along with its downstream effectors NFKBIA, CREB3L4, and SMAD4, suggesting a gradual adaptive program may link to its extended lifespan. WGCNA identified three negatively correlated modules in each species, with coral2 being the most prominent in A. irradians and darkolivegreen in A. purpuratus. The former was dominated by ciliary motility genes, whereas the latter featured coordinated repression of oxidative phosphorylation. Additionally, both species exhibited conserved suppression of mTOR/S6K growth signaling and activation of cellular maintenance programs. Collectively, these findings expand the understanding of CR-mediated longevity regulation in bivalves and provide candidate gene resources for future functional studies and breeding programs.

Pectinidae

Genotype II Live-Attenuated ASFV Vaccine Bearing 24 Genes Deletion in 3 Independent Regions Is Able to Provide Complete Protection Against Homologous Lethal Challenge.

African swine fever (ASF) is an acute, febrile, and highly contagious infectious disease of swine with the etiological agent of African swine fever virus (ASFV). The mortality rate of virulent strains is as high as 100%. Strengthening biosafety is so far the most effective way to prevent and control ASF. Therefore, it is urgent to develop a safe and effective vaccine. In this study, a Genotype II live-attenuated ASF vaccine bearing 24 genes deletion in 3 independent regions was constructed based on the highly virulent Eurasian strain ASFV CN/GS 2018 backbone. The resulting mutant ASFV-&#x394;24 is characterized by complete deletion of 24 genes distributed in 3 genomic positions of 852 to 11&#x2009;468, 19&#x2009;732 to 22&#x2009;929, and 179&#x2009;519 to 180&#x2009;617, among which MGF100 and whole MGF300 families are pioneeringly removed. The ASFV-&#x394;24 displayed a delayed and reduced replication kinetics as well as aberrant icosahedral empty particles devoid of a nucleoid when compared to the parental virus. Animal experiments showed that ASFV-&#x394;24 was completely attenuated in animals as evidenced by stable body temperature and no ASF-compatible clinical signs in vaccinated pigs. The ASFV-&#x394;24 could provide complete homologous protection against lethal challenge, as vaccinated pigs demonstrated boosted antibody response, transient but low levels of viremia in blood and virus titers in organs as well as almost undetectable viral shedding. Gene deletions in multiple regions are helpful for prevention of virulence reversion. These results indicate that ASFV-&#x394;24 can be used as an effective and promising candidate vaccine to control the spread of ASFV.

Animals

Durability and Safety of Imeglimin as an Add-On to DPP-4 Inhibitors in Japanese Type 2 Diabetes: The 104-Week FAMILIAR Trial.

AIMS: To evaluate the long-term efficacy and safety of imeglimin added to dipeptidyl peptidase-4 (DPP-4) inhibitors in Japanese patients with type 2 diabetes, focusing on glycemic durability and safety in elderly patients over 104&#x2009;weeks. MATERIALS AND METHODS: This multicenter, randomized, placebo-controlled trial comprised a 24-week double-blind phase (imeglimin 1000&#x2009;mg or placebo twice daily) followed by an 80-week open-label extension in which all patients received imeglimin. Eligible patients had inadequate glycemic control despite DPP-4 inhibitor monotherapy. The main assessment measured HbA1c changes from baseline to week 104. Secondary assessments included meal tolerance tests (MTT) for evaluating physiological changes in &#x3b2;-cell function and insulin resistance and safety monitoring. RESULTS: Of 117 randomized patients, 81 completed 104&#x2009;weeks. In the early-start group that received imeglimin from week 0, the significant HbA1c reduction observed at week 24 (-0.65%) was maintained through week 104 (-0.55%; p&#x2009;<&#x2009;0.001 vs. baseline). The delayed-start group that switched to imeglimin at week 24 achieved similar glycemic control thereafter. Elderly patients (&#x2265;&#x2009;65&#x2009;years) in the early-start group maintained stable HbA1c reduction (-0.58%) without hypoglycemic events over 2&#x2009;years. MTT analysis in the early-start group showed sustained improvements in glucose AUC and insulin sensitivity without unnecessary insulin secretion over time. CONCLUSIONS: Imeglimin added to DPP-4 inhibitors appeared to improve glycemic control for 104&#x2009;weeks, without clear attenuation. The combination was well-tolerated with a low risk of hypoglycemia even in elderly patients. The long-term effect may be associated with improvements in insulin sensitivity. TRIAL REGISTRATION: jRCTs061210082.

Humans

Mesenchymal Stem Cell-Derived Exosomes Combined With 3-Dimensional Hyaluronan-Based Scaffold Promote Tendon-to-Bone Tunnel Healing.

PURPOSE: Tendon-to-bone healing remains a major clinical challenge due to poor regenerative capacity at the enthesis. This study aimed to evaluate the effects of mesenchymal stem cell-derived exosomes combined with a 3-dimensional hyaluronan-based scaffold on graft healing within bone tunnels. This study was conducted in accordance with the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines. METHODS: A total of 128 tendon-bone models were created in 64 Sprague-Dawley rats, randomized into four groups: control, exosome-only, scaffold-only, and exosome-loaded scaffold. At weeks 4 and 8 postoperatively, samples were analyzed histologically (hematoxylin-eosin, Masson Trichrome), immunohistochemically (fibroblast growth factor 2, bone morphogenetic protein 2), and biomechanically (maximum failure load). RESULTS: At both time points, the exosome-loaded scaffold group demonstrated significantly enhanced vascularization, cellular activity, and collagen fiber continuity and parallelism compared to all other groups (P < .05). Fibroblast growth factor 2 and bone morphogenetic protein 2 expression levels were highest in the exosome-loaded scaffold group, indicating early activation of proregenerative pathways. Biomechanically, this group also exhibited the greatest maximum failure load (15.64 &#xb1; 0.86 N at week 4; 22.97 &#xb1; 2.86 N at week 8), suggesting superior tendon-to-bone integration. The exosome-only group showed delayed but comparable improvements by week 8. CONCLUSIONS: Combining mesenchymal stem cell-derived exosomes with a 3-dimensional hyaluronan-based polycaprolactone/tricalcium phosphate scaffold enhances early and sustained healing at the tendon-bone interface. This cell-free, biocompatible strategy significantly improves vascularization, growth factor expression, collagen organization, and mechanical strength. These findings support its potential as a clinically translatable approach for improving tendon-to-bone healing outcomes. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.

Animals

Anti-inflammatory agents after hip and shoulder arthroplasty: A systematic review and meta-analysis.

BACKGROUND: Postoperative inflammation after arthroplasty contributes to pain, delayed mobilization and prolonged hospitalization. Recent randomized trials have evaluated pharmacological anti-inflammatory strategies within contemporary enhanced recovery pathways, but evidence after hip and shoulder arthroplasty remains scattered across different drug classes and perioperative regimens. OBJECTIVES: To synthesize recent randomized controlled trial (RCT) evidence on perioperative anti-inflammatory agents after hip and shoulder arthroplasty. METHODS: PubMed, Embase, Cochrane Library and Web of Science were searched for English-language RCTs published from January 2020 to March 2026. The 2020-2026 window was selected to update evidence generated under modern arthroplasty, anesthesia, multimodal analgesia and enhanced recovery after surgery (ERAS) pathways. Eligible trials included adults undergoing hip or shoulder arthroplasty and compared corticosteroids, cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal anti-inflammatory drug (NSAID)-based/local anti-inflammatory regimens, or related anti-inflammatory interventions with placebo, saline, no treatment, or the same regimen without the target component. Weighted mean differences (WMDs) were pooled using random-effects models. RESULTS: Nine RCTs involving 800 patients were included. Anti-inflammatory interventions significantly reduced postoperative C-reactive protein (CRP) [WMD=-32.18, 95% confidence interval (CI) (-41.16, -23.21), P<0.001], interleukin-6 (IL-6) [WMD=-31.25, 95% CI (-41.79, -20.77), P<0.001], rest pain [WMD=-0.41, 95% CI (-0.58, -0.23), P<0.001], activity pain [WMD=-0.56, 95% CI (-0.83, -0.29), P<0.001] and hospital stay [WMD=-0.54, 95% CI (-0.92, -0.15), P=0.006]. CONCLUSION: Recent RCT evidence suggests that perioperative anti-inflammatory interventions can attenuate early inflammatory responses and improve short-term pain and recovery after hip and shoulder arthroplasty. Because data were limited and clinically heterogeneous, the findings should not be interpreted as evidence favoring a specific drug class, dose, route, or timing.

Humans

Executive function in alcohol use disorder with low psychiatric comorbidity: Comparison with a non-clinical sample and predictive value for treatment outcome.

BACKGROUND: Executive functions (EF) encompass abilities such as planning, decision-making, and inhibitory control, critical for learning, establishing and maintaining behavioral change. The association between alcohol use disorder (AUD) and impairments in EF are well established. However, prior research is dominated by studies on convenience samples including individuals with severe AUD with high levels of psychiatric comorbidity, which limits generalizability. The present study therefore aimed to investigate the degree of impairment and predictive ability of EF, on alcohol consumption, among individuals with moderate AUD with low levels of psychiatric comorbidity. METHODS: Adults with moderate AUD (n&#x2009;=&#x2009;147) were recruited at three specialized addiction outpatient clinics in Stockholm, to a randomized controlled trial investigating the efficacy of two psychological treatments. Participants underwent neuropsychological testing before treatment. Eight tests from the CANTAB&#xae; battery were administered at baseline, assessing mental flexibility, sustained attention, visuospatial working memory, response inhibition, and delay discounting. Assessments of alcohol use and related symptoms were conducted at baseline, the 12- and 26-weeks follow-up. A non-clinical reference sample (n&#x2009;=&#x2009;72) completed corresponding CANTAB&#xae; tests. The two groups were compared regarding EF using descriptive statistics and t-tests, and the predictive value of EF for reduction in alcohol consumption, was investigated using multiple regression models. RESULTS: Individuals with AUD did not perform worse on any of the tests on executive function (CANTAB&#xae;) as compared to the non-clinical reference sample. Measures of EF were not significant predictors for reduction in alcohol use for the 12-week, or the 26-week follow-up. CONCLUSIONS: EFs were not impaired and were not a clinically relevant predictor of treatment outcomes in this population with AUD. Future research on EF as a predictor in AUD treatment, needs to corroborate the present findings, and include other populations, e.g., with different socio-economic backgrounds and by including other methodologies for measuring EF.

Humans