搜索结果：affairs

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, and cardiovascular disease remains the leading cause of death in this population. Statins are therefore a cornerstone of therapy in MASLD because of their antiatherosclerotic efficacy. Less attention has been paid to the possibility that part of the hepatic benefit observed in MASLD cohorts-including lower aminotransferase levels, slower fibrosis progression, reduced decompensation and lower hepatocellular carcinoma incidence-may reflect direct hepatic effects beyond LDL reduction. Although the evidence is predominantly observational, the direction and magnitude of the association have remained broadly consistent across independent cohorts. Recent studies have strengthened this signal, including a post hoc analysis of the PROSPER trial showing attenuation of excess mortality in individuals with elevated FIB-4, and a large Veterans Affairs cohort demonstrating a dose-dependent association between cumulative statin exposure and lower primary liver cancer risk in MASLD. This review integrates the preclinical, observational and indirect randomized evidence supporting the biological plausibility of liver-directed effects of statins. Mechanistically, the argument centres on inhibition of the mevalonate pathway as a molecular hub linking lipotoxicity, NLRP3-dependent inflammation, fibrogenesis and carcinogenesis through impaired prenylation of small GTPases. A fifth axis, intrahepatic hemodynamics mediated through KLF2/eNOS signaling, is supported by randomized evidence in compensated cirrhosis. In contrast, the LIVERHOPE-EFFICACY trial showed no benefit in decompensated cirrhosis, helping define the therapeutic window. Within the limitations of the available evidence, we propose a conceptual reframing: in MASLD, statins may act not only as cardiovascular drugs, but also as agents with potentially relevant hepatic effects mediated through a shared molecular substrate.

Small companies face the same regulations as organizations many times their size, but with fewer resources and less specialized departments. This can present challenges for ensuring rigorous data analysis, but also encourage creativity in mapping a pathway to FDA approval of drug products.This presentation explores three topics within Quality and Regulatory Affairs: the Animal Rule, Stability Reports, and implementing electronic quality management systems (eQMS). The Animal Rule is a little known regulatory pathway that highlights one of the ways the United States prepares for public health emergencies, supporting development of medical products that might not otherwise see attention from industry. Stability reports ultimately contribute to module 3 of the common technical document (CTD), and are essential to understanding the expiration dates of drug products and drug substances. Finally, electronic quality management systems (eQMS) support quality activities company-wide, and play a major role in compliance and efficiency in an organization.

Automatically localizing the Anterior Commissure (AC) and Posterior Commissure (PC) is foundational for CT-based algorithmic disease screening, yet robust computational methods for this on CT remain lacking. We developed a registration-guided 3D-UNet framework for CT-based AC-PC localization, demonstrating its utility in computing ventriculomegaly features for Normal Pressure Hydrocephalus (NPH) detection. Framework development and evaluation were on an internal cohort of scans from patients with NPH, Alzheimer's disease, post-traumatic volume loss, and headache (Veterans Affairs [VA]-Cohort, n = 427). External validation was on separate datasets (VA-ExtCohort, University of California, Santa Barbara [UCSB]-ExtCohort). AC-PC reference standard definition, model development, and evaluation were on 1 mm3-resampled scans. On 1-mm3 resampled scans, test-set AC-PC mean radial errors (MREs) were 1.64/1.49 mm on the VA-Cohort, 2.42/1.79 mm on the VA-ExtCohort (n = 40), and 2.31/1.93 mm on the UCSB-ExtCohort (n = 43). Notably, the upper limits of the 95% confidence intervals (CIs) for localization errors across all cohorts were well below 3.2 mm; we empirically determined this to be a clinically relevant threshold beyond which the discriminative power of AC-PC-referenced ventriculomegaly features degrades. Ventriculomegaly features assessed using our framework's predictions successfully distinguished NPH from Alzheimer's disease, post-traumatic volume loss, and headache on a chart-verified VA-Cohort subset (n = 238) with a test-set Area Under the Receiver Operating Characteristic Curve (AUC) of 0.95, closely matching the performance of features assessed using manual AC-PC localization. The proposed registration-guided 3D-UNet framework accurately and automatically localizes the AC-PC on CT despite varied structural degeneration, enabling standardized radiological feature computation. This approach can augment neurodegenerative disease screening on CT, the primary modality for elderly patients evaluated for falls and altered mentation.

Medical students experience sustained academic, clinical, and psychosocial pressures. Online forums provide an informal space where students seek information, express concerns, and exchange peer support. However, few studies have analyzed these interactions longitudinally based on real-world data from online social platforms. This study aimed to integrate topic modeling, temporal topic analysis, and social network analysis (SNA) to investigate evolving concerns, network positions, and influence structures within the bulletin board system of a medical university over a 7-year period. We collected all posts and comments from the "Medical Center" board of the Peking University bulletin board system forum between 2017 and 2023. After excluding irrelevant posts, nontextual elements, blank content, and noise terms, the textual corpus was segmented and standardized for analysis. Latent Dirichlet allocation (LDA) was used for topic modeling to identify primary discussion topics. The number of topics was selected through 5-fold cross-validation by evaluating candidate models with 5 to 20 topics using perplexity. Annual topic prevalence was calculated to examine temporal changes in student concerns. SNA was also used to construct interaction networks. Users were defined as nodes, and directed edges were established when one user replied to another user's post or comment. Degree centrality, eigenvector centrality, and betweenness centrality were calculated to identify active users, influential hubs, and bridging users. A topic-network coupling analysis further linked topic categories with the centrality measures of users. The corpus included 4639 posts and 58,942 comments. The annual post numbers fluctuated over the years, reaching their lowest point in 2019 and peaking in 2022. Posting activity increased after 8 AM, remained relatively stable from noon to 10 PM, and declined after 10 PM. Seven major topics of concern were identified, with feedback on living facilities (1025/4639, 22.1%) being the most prevalent, followed by information inquiry (1004/4639, 21.6%) and medical education (883/4639, 19.0%). Temporal analysis showed that concerns related to living facilities remained a recurring topic across years, and emotional support remained a low-frequency but persistent topic. The overall network was sparse, with a small subset of users occupying active, influential, or bridging positions. Topic-network coupling showed that high-volume topics were not necessarily network-central: feedback on living facilities had the largest discussion volume but the lowest median centrality values, whereas current affairs had the highest median degree and eigenvector centrality, and psychological and emotional support had the highest median betweenness centrality. Online forums can reveal not only what students discuss but also how concerns persist, change, and circulate through peer interaction networks. Combining topic modeling with network analysis may help educational administrators identify persistent concerns related to the learning environment, time-sensitive issues, and structurally important topics requiring targeted communication or support strategies.

The role of statins in coronavirus disease 2019 (COVID-19) is controversial. We sought to determine the association between statin use and severe/critical/fatal disease in individuals with COVID-19. Using the US Department of Veterans Affairs COVID-19 database, we identified statin users with COVID-19 and inverse probability of treatment-weighted statin non-users. The primary outcome was severe, critical, or fatal disease within 28 days of diagnosis. Among 8394 statin users and 59,412 inverse probability of treatment-weighted non-users, 277 statin users (3.3%) and 1493 non-users (2.5%) developed severe, critical, or fatal disease (absolute risk difference [ARD], -0.02; 95% confidence interval [CI], -0.19 to 0.16). Statin use was associated with more favorable outcomes among individuals aged >60 years (ARD, -0.79; 95% CI, -1.10 to -0.48), White individuals (ARD, -0.30; 95% CI, -0.51 to -0.09), and those with diabetes mellitus (ARD, -1.36; 95% CI, -1.82 to -0.90), coronary artery disease (ARD, -1.10; 95% CI, -1.89 to -0.31), stroke (ARD, -2.10; 95% CI, -3.65 to -0.55), chronic lung disease (ARD, -1.31; 95% CI, -1.94 to -0.68), chronic kidney disease (ARD, -2.46; 95% CI, -3.38 to -1.54), receipt of a booster vaccine dose (ARD, -0.34; 95% CI, -0.57 to -0.10), or no symptoms (ARD, -0.36; 95% CI, -0.59 to -0.14). After individuals with prevalent CVD were excluded, the nonsignificant association shifted toward favoring statin non-users (ARD, 0.62; 95% CI, 0.34-0.90). Statin users with COVID-19 did not experience a reduction in disease severity. In certain subgroups, favorable outcomes appeared to be related to the effects of statins on underlying disease processes.

Autonomic dysfunction (AD) is present in nearly all people with Parkinson disease (PD), contributing to tremendous morbidity and mortality. Highly variable presentations including cardiovascular, gastrointestinal, urogenital, and thermoregulatory dysfunction can substantially affect daily function, safety, medication tolerance, and quality of life. Although autonomic symptoms are frequently encountered in neurologic practice, their management frequently extends beyond the traditional scope of neurologic care and may require input from multiple disciplines. Despite the increasing complexity of PD care and the need for coordinated multidisciplinary involvement, there are currently limited practical frameworks to guide specialist collaboration. Consequently, people with PD and their caregivers are often left to navigate fragmented care systems, conflicting recommendations, and uncertainty regarding which clinician should guide management. To help address these gaps, we provide a framework for the possible indications for specialist referrals and the potential roles of different healthcare practitioners in evaluating and treating AD. The manuscript also discusses the intersection between autonomic and neuropsychiatric manifestations in PD and offers practical clinical guidance for addressing this overlap. By providing a framework informed by coauthors in movement disorders, autonomic disorders, cardiology, nephrology, gastroenterology, urogynecology, physical therapy, and psychiatry, we hope to encourage neurologists - who often serve as the central point of contact - to collaborate closely and actively engage multidisciplinary team members in the management of these complex patients.

Arbuscular mycorrhizal symbiosis (AMS) is a universal mutualism in natural ecosystems, governed by a complex transcriptional network. Although ethylene response factors (ERFs) are implicated in regulating AMS, their underlying molecular mechanisms remain poorly understood. This study aims to investigate the molecular mechanism by which ethylene response factor 15 (SlERF15) regulates AMS and phosphate uptake in tomato (Solanum lycopersicum). We used tomato loss‑of‑function mutants (erf15#1 and erf15#3), liquid chromatography-tandem mass spectrometry (LC-MS/MS), RT-qPCR, electrophoretic mobility shift assay, yeast one-hybrid assay, and dual-luciferase assays to unveil the molecular basis of SlERF15-mediated AMS and phosphate uptake in tomato. SlERF15 expression was significantly up-regulated in tomato roots during the initial stage of AMS. Mutants lacking the SlERF15 gene exhibited a substantial reduction in arbuscular mycorrhizal fungi (AMF) colonization, phosphate uptake, and plant growth. Strigolactones (SLs) and abscisic acid (ABA), which serve as positive regulators of AMS establishment, showed reduced accumulation in the mycorrhizal roots of SlERF15 mutants. Mechanistically, SlERF15 acts as a transcription factor that directly binds and activates the promoters of carotenoid cleavage dioxygenases 7 (SlCCD7), carotenoid cleavage dioxygenases 8 (SlCCD8), and 9-cis-epoxy carotenoid dioxygenase (SlNCED1), key genes for SLs and ABA biosynthesis. Moreover, ABA positively regulated the expression of SlERF15 and SLs biosynthesis genes, forming a feedback loop. Our findings demonstrate that SlERF15 functions as a key regulator involved in SLs and ABA signaling to promote AMS in tomato, offering novel insights into the complex phytohormonal regulation network fine-tuning in plant-mycorrhizal fungi interactions.

The perennial grass Elymus nutans, native to the Qinghai-Tibet Plateau, exhibits exceptional cold tolerance. To understand its underlying mechanisms, we integrated physiological, transcriptomic, and proteomic profiling under cold stress. Our results revealed a distinct two-phase response strategy to cold stress. The early phase (0-24 h) featured rapid Ca2+ signaling, redox-related transcriptional reprogramming, and increased membrane permeability. The late phase (36-72 h) shifted toward primary metabolic regulation and the translation of protective proteins. Notably, a prominent time lag (temporal delay) occurred between transcript and protein accumulation. Mechanistically, transcriptomic and proteomic signatures suggested a potential energy trade-off, characterized by the extensive downregulation of photosynthetic components concurrent with the mobilization of photoprotective and carbohydrate metabolic networks. Simultaneously, defense capacity was fortified via enhanced proline, phenylpropanoid, and sustained ascorbate-glutathione pathways. Network analyses identified EnP5CS2 and EnMDHAR4 as key functional candidate genes associated with proline accumulation and redox homeostasis. Heterologous expression in yeast further indicated their basic biochemical competence in enhancing cold tolerance. Collectively, these findings provide multi-omics insights into resource reallocation and adaptive strategies employed by alpine extremophytes in response to cold stress, offering valuable genetic targets for breeding climate-resilient forage and crop.

In the 2022/2023 training cycle, the VA Prosthetic Orthotic Residency (VAPOR) Program was unable to fill all funded residency positions. Initial debriefing with residency directors revealed a likely cause to be lack of competitiveness of the VAPOR training stipend value, particularly for second-year residents. This demonstrated a need to conduct a training stipend analysis for the VAPOR program. A five-part analysis was conducted including review of the program's stipend history, review of the impact of inflation, and surveys of residency directors and current and former residents. Cumulatively, the analysis revealed that the current stipend was no longer competitive and that the profession was compensating second-year residents more than first-year residents. To effectively compete for top residency candidates, the VA must increase the current training stipend. Ultimately, 4 evidence-based recommendations were derived from the analysis as follows: (1) VAPOR Year 2 (Y2) stipends should be greater than the Year 1 (Y1) stipends; (2) VAPOR Y1 residents should receive a base stipend of $41,620 in addition to a locality adjustment based on the site location; and (3) VAPOR Y2 residents should receive a nonadjusted base stipend valued at 9.3% more than the Y1 stipend or $45,491 to be increased with a locality adjustment based on the site location. A cost-of-living adjustment should be applied to VAPOR program stipends at a minimum of every 3 to 5 years at an increase of 3-5% based on cost-of-living data from other government resources. VA bolstered resident compensation because of these findings.

Glioblastoma (GBM) remains lethal despite maximal therapy. The adult subventricular zone (SVZ), a neural stem-cell niche, has been implicated as a potential site of origin, yet the identity and functional properties of putative GBM origin-like cells (GBM-OCs) within the SVZ remain unclear. An SVZ-restricted somatic mutation mouse model (Cre-induced EGFRvIII expression with Trp53 and Pten disruption) was established and mouse SVZ-derived cells were prospectively isolated for functional and molecular profiling. Self-renewal, multipotency, invasive potential and tumour-initiating capacity were assessed relative to control SVZ cells and matched tumour-derived tumourspheres. Whole-genome and RNA sequencing defined genomic and transcriptional alterations during early progression. Mouse GBM-OCs exhibited self-renewal and multilineage differentiation and initiated tumours only after re-implantation into the SVZ (11/29, 38%), whereas direct striatal implantation failed (0/25, 0%), indicating context-dependent tumorigenic potential associated with the SVZ microenvironment. In contrast, tumour-derived tumourspheres retained tumorigenic capacity upon implantation into both the SVZ and the striatum. During progression from mouse GBM-OCs to tumours, whole-chromosome and arm-level aneuploidies accumulated. In patients with GBM, multi-region single-nucleus RNA sequencing of tumour-free SVZ, matched tumours and tumour-free cortex identified rare neural stem cell-like, astrocyte-like and oligodendrocyte precursor-like SVZ populations transcriptionally aligned with GBM programmes. These cells showed single-nucleus RNA-inferred chromosome 7 gain and/or chromosome 10 loss signals, with concordant low-frequency copy-number alterations in the SVZ detected by exome sequencing and enriched in matched tumours. Together, these findings support the presence of SVZ-resident stem or progenitor-like populations with early GBM-associated features, consistent with putative GBM-OCs, and highlight the SVZ niche as a potential target for early detection and niche-informed therapeutic strategies.

This study examines whether the mycorrhizal helper bacterium (MHB) Alcaligenes faecalis can enhance the cadmium resistance conferred by the arbuscular mycorrhizal fungus (AMF) Funneliformis mosseae in cucumbers. We evaluated plant growth, nutrient status, and rhizosphere microbiota across four treatments: non-inoculated control (CK), single inoculation of AMF (F), single inoculation of MHB (S), and co-inoculation of AMF and MHB (FS). Compared with the other three treatments, the FS treatment not only significantly increased the contents of N, P, and K in the plants, but also significantly increased the contents of soil nitrate N, available P, and available K. Moreover, the F, S and FS treatments have significantly decreased root Cd concentration and Cd content in the rhizosphere soil compared with the CK treatment. Different inoculation treatments have changed the relative abundance, composition and diversity of cucumber rhizosphere bacterial community. The F, S and FS treatments significantly increased Chao 1, Simpson index and number of OTUs compared with the CK treatment. The relative abundances of soil bacteria such as Ramlibacter, Mitsuaria, Flavisolibacter, Lysobacter, Sphingomonas and Massilia in the FS treatment were significantly higher than those in the other three treatments. Overall, our findings suggest that FS treatment enhances the resistance of cucumber seedlings to Cd stress, and this effect may be associated with changes in the rhizosphere microbial community, activation of soil nutrients, and enhanced plant nutrient uptake.

This study aimed to determine the relationships of happiness status with overweight and obesity risks in Taiwanese older adults. Cross-sectional survey of the 2015-2016 Taiwan National Physical Fitness Survey SETTING: Community PARTICIPANTS: This study includes 20,295 older adults from Taiwan, who were aged 65 years or older MEASUREMENTS: Body mass index was categorized into normal weight, overweight, and obesity. Happiness was assessed using a 10-point scale and classified as happy (scores 8-10) or unhappy (scores 0-7). Although no significant linear association was observed between happiness status and BMI in either men or women, logistic regression analysis indicated that overweight individuals had significantly higher odds of being happy compared with their normal-weight counterparts (adjusted OR = 1.337, p = 0.0002 for men; OR = 1.168, p = 0.018 for women). Obesity, however, was not significantly associated with happiness in either gender. Overweight status was positively linked to happiness among older Taiwanese men, but obesity did not show the same effect.

Compared with white-light cystoscopy (WLC), blue-light cystoscopy (BLC) enhances detection of non-muscle-invasive bladder cancer (NMIBC), especially carcinoma in situ (CIS). However, its effects on health care resource utilization and cost burden have not been fully elucidated. This study assessed the economic implications of BLC vs WLC. We conducted a retrospective cohort analysis with claims data from the Optum Research Database between June 2011 and May 2023. Patients who underwent BLC or WLC were identified, and white-light patients were matched 6:1 to blue-light patients by index year and time between bladder cancer diagnosis and cystoscopy. Inverse probability of treatment weighting was used to adjust for baseline differences. Health care resource utilization and total and bladder cancer-specific costs were calculated on a per-patient-per-month basis. The final cohort included 794 blue-light and 4764 white-light patients. Before weighting, claims coded for CIS were more frequent in blue-light patients (19.6% vs 8.8%; P < .001). Blue-light patients underwent more upper-tract imaging (71.8% vs 57.8%; P < .001), BCG (24.2% vs 15.8%; P < .001), and biomarker testing (65.0% vs 34.9%; P < .001). After weighting, blue-light patients had a higher mean number of bladder cancer-related ambulatory visits per month (1.3 vs 1.0; P = .004). However, neither all-cause health care resource utilization (3.47 vs 3.21; P = .11) nor total cost ($2987.93 vs $2886.16, per patient per month, P = .65) differed significantly between cohorts. BLC is associated with greater health care resource utilization for NMIBC without significantly elevating health care costs, suggesting that enhanced diagnostic strategies can be implemented without added financial burden in real-world practice.

Steam explosion (SE) pretreatment effectively enhanced the extraction yield and bioactivity of polysaccharides from Hericium erinaceus (H. erinaceus), demonstrating notable therapeutic potential. In this study, a polysaccharide fraction (Q60E) was isolated from SE-treated H. erinaceus. Structural analysis revealed that Q60E (M w , 8.89&#xa0;&#xd7;&#xa0;104&#xa0;g/mol) was a mannogalactoglucan, featuring a backbone of &#x2192;3)-&#x3b1;-Manp-(1&#x2192;, &#x2192;6)-&#x3b2;-Glcp-(1&#x2192;, &#x2192;3,6)-&#x3b2;-Glcp-(1&#x2192;, &#x2192;3)-&#x3b1;-Glcp-(1&#xa0;&#x2192;&#xa0;and &#x2192;4,6)-&#x3b2;-Galp-(1&#xa0;&#x2192;&#xa0;linkages with side chains of &#x2192;4)-&#x3b1;-Glcp-(1&#xa0;&#x2192;&#xa0;and terminal &#x3b2;-Glcp-(1&#xa0;&#x2192;&#xa0;residues. Based on the shape factor &#x3c1; (1.71) and the Mark-Houwink-Sakurada parameter (exponent &#x3b1;, 0.51), Q60E adopted a random coil conformation in aqueous solution. In vitro fermentation studies demonstrated that Q60E modulated gut microbiota by promoting beneficial genera (Lactobacillus, Lachnospira and Bifidobacterium) while suppressing pathogenic Fusobacterium. Furthermore, Q60E fermentation additionally enhanced the acetic acid and total SCFAs production, underscoring its prebiotic capacity. These findings highlight the potential of the mannogalactoglucan from SE-pretreated H. erinaceus as effective prebiotics for gut health.

The paraventricular nucleus (PVN) of the hypothalamus is a key autonomic and cardiovascular regulatory center that contributes to neuroinflammation-driven sympathetic excitation in heart failure. To define the cellular and transcriptional mechanisms underlying inflammatory signaling during heart failure progression, we performed single-nucleus RNA sequencing of the PVN in rats 2&#x2009;weeks after myocardial infarction (MI). PVN tissues were collected 2&#x2009;weeks post MI for single-nucleus RNA sequencing analysis. Sequencing data were processed through alignment, dimensionality reduction, clustering, and marker-gene identification to define cell populations and gene expression profiles. Gene Set Variation Analysis and transcriptional regulatory network analyses were performed to identify altered signaling pathways and key transcription factors. A total of 16&#x2009;341 nuclei were classified into 5 major cell types: neurons, oligodendrocytes, astrocytes, oligodendrocyte progenitor cells, and microglia. Functional analyses identified microglia as the primary mediators of inflammatory responses in the PVN. Gene Set Variation Analysis revealed substantial pathway alterations across cell types, with microglia exhibiting marked activation of immune-related and cytokine-producing pathways in MI rats. Moreover, IRF5 (interferon regulatory factor 5) was identified as a master transcriptional regulator associated with inflammatory activation and was significantly upregulated in PVN microglia after MI. Increased IRF5 expression in PVN microglia was confirmed by immunofluorescence. Single-nucleus RNA sequencing identified distinct cell-specific gene signatures, regulatory networks, and signaling pathways in the PVN during heart failure, with microglial IRF5 emerging as a central regulator of immune activation and inflammatory processes. Activated IRF5 promotes microglial activation and neuroinflammation, thereby enhancing PVN neuronal activity and driving sympathetic and neurohumoral dysregulation in rats with MI. Targeting IRF5 and its downstream pathways may therefore provide new insights into the central inflammatory mechanisms contributing to cardiac dysfunction during heart failure progression.

This study investigated inhibitory mechanisms of eugenol, the primary bioactive compound in bay leaf, against formation of free and protein-bound heterocyclic aromatic amines (HAAs) in grilled beef. Bay leaf exhibited the strongest inhibitory efficacy among the tested spices, reducing total free (43.10%) and protein-bound (68.88%) HAAs in grilled beef. In chemical models, eugenol mitigated free and bound HAA formation by up to 71.88% and 91.89%, respectively. Density functional theory calculations suggested that eugenol potentially interacted with creatine, phenylacetaldehyde, and 2,5-dimethylpyrazine via hydrogen bonding and van der Waals interactions, which may contribute to the inhibition of free HAA formation. Spectroscopic analyses and molecular dynamics simulations demonstrated that eugenol stably bound to myosin residues, inducing a more compact structure that sterically shielded reactive amino acid sites and inhibited bound HAA formation. These findings offer molecular insights into using natural phenolic compounds for mitigating heat-induced chemical hazards in protein-rich foods.

The Veterans Community Care Program (VCCP) has become essential to how the Veterans Health Administration (VHA) delivers care. Although VCCP expands Veterans' access to community providers, ongoing process inefficiencies create barriers to timely care. Veterans affected by military sexual trauma (MST) are at heightened risk for behavioral health challenges, especially when care is delayed or fragmented. These delays may be particularly harmful for Veterans with MST living in rural communities where structural barriers exacerbate health risks. In this study, the primary author interviewed 38 Veterans with MST (29% rural-dwelling) to understand rural-urban differences in experiences with seeking psychotherapy through VCCP. Three major themes emerged: (1) emotional strain from structural barriers that influenced psychotherapy access, (2) concerns about worsening health and safety, and (3) value of timely and clear processes. While rural and urban Veterans with MST expressed similar frustrations about the VCCP process, rural Veterans raised specific concerns about the impacts of treatment delays on worsening health. By comparison, urban Veterans were emotionally burdened by administrative hurdles (such as miscommunication and billing issues). They also indicated broader concerns about the safety of Veterans facing long wait times without additional support. Study findings highlight opportunities to enhance transparency, streamline administrative procedures, and bolster support for Veterans with MST undergoing the VCCP process. In addition, developing systems to monitor at-risk Veteran groups (such as rural Veterans with MST) during care transitions is necessary to reduce the likelihood of adverse outcomes.

Lactiplantibacillus plantarum (L. plantarum) is a well-characterized probiotic with a long history of safe application, exhibiting prominent potential in improving skeletal muscle function. As the most prevalent and plentiful mRNA modification in eukaryotes, extensive research has highlighted the non-negligible role of N6-methyladenosine (m6A) in regulating various aspects of skeletal muscle biology. However, the underlying mechanisms through which L. plantarum-derived signals regulate host myogenic programs, as well as whether m6A modification is involved in this process, remain unclear. To explore the microbe-host regulatory axis through which L. plantarum promotes skeletal muscle regeneration and whether m6A modification is involved in this process. The cardiotoxin-induced muscle injury mouse model was constructed to investigate the impact of L. plantarum WY2401 on skeletal muscle regeneration. Untargeted metabolomics analysis was used to screen out L. plantarum WY2401-derived key metabolite. The changes in m6A modification were determined using dot blot and MeRIP-qPCR. We identified L. plantarum WY2401 as a pro-myogenic probiotic that promotes skeletal muscle regeneration. Specifically, L. plantarum WY2401 strongly alters circulating metabolomic profiles, particularly elevating the production of microbiota-derived riboflavin. Upregulated riboflavin is transported to skeletal muscle through the bloodstream, where it modulates the expression of the m6A methyltransferase METTL3 in a stage-dependent manner during myogenesis. This modulation promotes myoblast proliferation by enhancing the stability of Cdk2 and Ccnd1 mRNAs through the METTL3-m6A-YTHDF1 pathway. It also facilitates myoblast differentiation by increasing Mef2a mRNA stability through the METTL3-m6A-YTHDF2 pathway. Our findings reveal a novel microbe-host regulatory axis through which L. plantarum WY2401 promotes skeletal muscle regeneration via stage-specific epigenetic modulation of myogenesis. This work highlights the potential of L. plantarum as a functional probiotic supplement for improving skeletal muscle development and provides new insights into probiotic-mediated regulation of muscle regeneration.

Britz et al present an important contribution to the understanding of primary care capacity by identifying all Primary Care Physicians (PCPs) in one state and quantifying their patient panel sizes. Their findings, showing median panels between 1196 and 1290 patients, provide critical insight into how many individuals each PCP can realistically serve amid a national primary care shortage. This commentary explores emerging trends that may reshape how ideal panel size is defined in the future, particularly the increasing integration of non-physician providers, digital health platforms, and artificial intelligence (AI) tools. Technologies such as ambient dictation, automated order entry, and AI-driven patient messaging can reclaim valuable clinician time and help mitigate burnout, potentially allowing physicians to manage larger panels. Likewise, wearable sensors, virtual visits, and non-traditional care outlets such as retail clinics and urgent care centers offer additional opportunities to expand system-wide capacity. However, these efficiencies must be balanced against current capacity issues in primary care, including potential added monitoring workload, increasing complexity of patients, as well as currently over-burdened primary care practices due to administrative burden and high volumes of patient messaging. Future studies are needed to determine whether these innovations truly expand capacity or simply redistribute effort within the evolving ecosystem of primary care.