Vaccination is particularly important for people living with dementia (PLWD), who are at risk for meaningful declines in function and cognition after acute illnesses including vaccine-preventable infections. Even so, vaccine uptake remains suboptimal. Optimal tailoring of messaging relies on awareness in advisory, decision-making, and advocacy settings that PLWD are an important population for immunization. This policy forum paper discusses why vaccination is particularly important for PLWD and whether this is translated into public-facing and policy audience messaging. Jurisdictional scans investigated three questions: the inclusion of geriatrics expertise in a sample of eight National Immunization Technical Advisory Groups (NITAGs; Australia, Canada, France, Germany, Switzerland, the UK, United States, World Health Organization), whether PLWD are included in high-risk groups particularly recommended to receive adult vaccinations, and whether dementia advocacy organizations from these same jurisdictions discuss and recommend vaccination. We conclude that there remain important opportunities for improvement in understanding and communicating the benefits of vaccination for PLWD, and present policy recommendations for NITAGs, dementia advocacy organizations, and clinicians.
Frailty is a geriatric syndrome involving inflammation, oxidative stress, mitochondrial dysfunction, and metabolic disturbances. Metabolomics can systematically elucidate metabolic pathways and identify actionable biomarkers. This study systematically reviews the progress and evolutionary trends of metabolomics applications in frailty research from 2006 to 2025. Based on 1924 publications retrieved from the Web of Science Core Collection, systematic analyses were performed using CiteSpace, VOSviewer, SCImago Graphica, and the R package "bibliometrix", focusing on pathway-level research hotspots and collaboration networks. The United States and China are the leading contributors. Research hotspots have shifted from macro-level biomarkers such as inflammation and protein-energy wasting to specific metabolic pathways including amino acid metabolism, energy metabolism, lipid metabolism, and tryptophan degradation. Key metabolites include sphingomyelin, butyrate, and trimethylamine-N-oxide. Emerging frontiers focus on the association between gut microbiota-derived metabolites and frailty phenotypes, as well as intervention strategies targeting these metabolites. This study provides the first systematic overview of global research progress in metabolomics and frailty, establishes a reproducible evaluation framework integrating physiology, nutrition, geriatrics, and computational biology, and identifies butyrate, trimethylamine-N-oxide, and tryptophan metabolites as potential metabolic targets for early identification and intervention.
ICU survivors frequently develop post-intensive care syndrome (PICS), a cluster of persistent physical, cognitive and psychological impairments that substantially impair recovery and quality of life. Existing rehabilitation approaches are predominantly monomodal and exercise-focused, yielding inconsistent outcomes and failing to address the multidimensional burden of PICS adequately. To evaluate the feasibility and preliminary efficacy of COMBAT-ICU, a home-based Combined Activity and Cognitive Intervention for ICU survivors at risk of PICS. A parallel, three-arm, assessor-blinded pilot randomised controlled trial randomised 36 ICU survivors (1:1:1) to COMBAT-ICU-an 8-week blended program of progressive physical exercise and computerised cognitive training delivered via supervised home visits and online sessions-an exercise-only group or an attention control group. The primary outcomes were feasibility (recruitment, retention and intervention adherence) and safety; secondary exploratory outcomes encompassed PICS severity, physical capacity, cognition, mental health and health-related quality of life (HRQoL). COMBAT-ICU was feasible and safe (36 ICU survivors randomised), with no serious adverse events recorded, retention exceeding 82% at follow-up and session adherence exceeding 90%. COMBAT-ICU produced significantly greater reductions in PICS severity versus attention control at post-intervention (p = 0.014, d = -0.50) and follow-up (p = 0.043, d = -0.45). It also yielded clinically meaningful moderate-to-large effect sizes for walking endurance, global cognition, short-term memory and HRQoL index scores compared with attention control and consistently outperformed exercise-only across cognitive and HRQoL domains. Between-group differences in anxiety and depressive symptoms were small across all active groups. COMBAT-ICU is feasible and shows promising preliminary efficacy in mitigating PICS. Integrating cognitive and physical training within a home-based blended delivery model may confer synergistic benefits beyond exercise alone, providing domain-specific effect size estimates and a compelling rationale for definitive multicentre trials. Multidomain home-based rehabilitation is a viable post-discharge strategy for ICU survivors. COMBAT-ICU offers an evidence-informed, scalable framework to enhance survivorship care, pending confirmation in larger, fully powered trials. The trial was registered at ClinicalTrials.gov (NCT06117761).
Parkinson's disease (PD) lacks reliable peripheral biomarkers and disease-modifying therapies. Although peripheral B-cell alterations have been observed in PD, whether genetically predicted B-cell gene expression contributes to PD risk and can nominate candidate therapeutic targets remains unclear. We established a computational framework integrating two-sample Mendelian randomization (MR) based on B-cell subtype-specific sc-eQTLs (OneK1K) and PD GWAS (IPDGC; 33,674 cases/449,056 controls), Bayesian colocalization with DICE and FinnGen replication, exploratory pseudobulk stage-associated analysis (GSE223138), B-cell subpopulation fine-mapping in 10,466 CD19 + cells (GSE194245), CellChat v2 communication inference, and druggability prioritization with molecular docking-based structural plausibility assessment. Multi-layer computational evidence prioritized eight high-confidence MR causal genes: five risk-increasing genes (CD74, HLA-DRB1, IL2RA, BLK, BANK1) and three protective genes (CR1, PTPN22, FCRL3). Exploratory pseudobulk analysis suggested four tentative stage-associated expression patterns, with early-change genes (CD74, HLA-DRB1, IL2RA) showing expression differences detectable as early as PD-Early in a small exploratory cohort. Subpopulation analysis suggested enrichment in Naive B (BLK, BANK1) and Atypical B cells (CD74, HLA-DRB1, IL2RA, CR1), while acknowledging that these fine-grained assignments are not equivalent to MR exposure categories. CellChat analysis predicted that the MIF signaling pathway showed an inferred communication probability increasing from 0.15 in HC to 0.48 in PD-Late. Five-dimensional evidence convergence nominated CD74, IL2RA, and CR1 as candidate targets, with molecular docking suggesting structural plausibility for selected small-molecule interactions, including Dasatinib-BLK (-7.2 kcal/mol) and ISO-1-CD74 (-6.8 kcal/mol). These computational findings suggest that genetically influenced B-cell gene expression may contribute to peripheral immune dysregulation in PD and nominate CD74, IL2RA, and CR1 as candidate targets for future validation. The results should be interpreted as hypothesis-generating and require experimental and clinical confirmation.
Accurate differentiation between malignant and benign thyroid nodules is essential. Although ultrasound serves as the primary diagnostic modality, there is a paucity of longitudinal data concerning nodule progression and limited validation of the Chinese Thyroid Imaging Reporting and Data System (C-TIRADS). This underscores the necessity for evidence-based follow-up strategies. The present study sought to assess the developmental trends of thyroid nodules over an extended follow-up period and to evaluate the diagnostic efficacy of the C-TIRADS. This was a single-center retrospective longitudinal cohort study. We included patients who underwent thyroid ultrasound between 2019 and 2024 with at least one follow-up examination. Exclusions were: (1) prior thyroid malignancy; (2) incomplete baseline data; (3) follow-up <12 months without pathology/cytology. In the primary analysis, the nodule was the statistical unit. Correlation among multiple nodules within the same patient was addressed by clustering at the patient level. A sensitivity analysis at the patient level retained only the largest or most suspicious nodule per patient. Two radiologists (≥5 years' experience) independently graded nodules using C-TIRADS and Kwak Thyroid Imaging Reporting and Data System (Kwak TI-RADS) while blinded to the reference standard. Disagreements were adjudicated by a senior radiologist. Inter-reader agreement was reported using the weighted kappa (κ). The reference standard was surgical histopathology whenever available. For non-surgical cases, cytology Bethesda V/VI was considered malignant; nodules with ≥24 months of stable imaging (no upgrade or suspicious progression) were considered benign. Indeterminate cases were excluded from the primary endpoint analysis. We reported the verification proportion and performed two sensitivity analyses: (1) surgery-only subset; (2) including nodules deemed benign after ≥24-month stable follow-up. For predefined thresholds (e.g., C-TIRADS ≥4B, Kwak ≥4), 2×2 tables were used to derive sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) with 95% CIs. Area Under the Curves (AUCs) were estimated and compared using the DeLong method. Because nodules were clustered within patients, Generalized Estimating Equations (GEE) with an exchangeable correlation structure or cluster-robust standard errors were applied. Temporal changes in sonographic features were assessed with trend tests. Missing data were handled by complete-case analysis. Ultrasonographic data from patients diagnosed with thyroid nodules in 2019 and monitored consistently until 2024 were analyzed to evaluate longitudinal changes in nodule characteristics. A retrospective analysis of 272 surgically confirmed cases (173 malignant and 99 benign) was performed to compare the diagnostic efficacy of the C-TIRADS with the Kwak TI-RADS. 1.Throughout the follow-up period, the nodules identified in the study participants were predominantly multiple and bilaterally distributed across the thyroid lobes, with their prevalence increasing annually. The majority of these nodules were round or oval in shape, with diameters less than 10 mm. However, there was a gradual increase in the proportion of nodules exceeding 10 mm in diameter, as well as those that were oval or irregularly shaped. Ultrasound characteristics such as microcalcifications, border invasion, a taller-than-wide shape (aspect ratio ≥1), and internal vascularity were largely absent in most nodules. Nonetheless, there was an upward trend in the proportion of nodules exhibiting these features. Nodules characterized by internal hypoechogenicity and lacking posterior acoustic attenuation constituted a significant proportion and did not demonstrate a notable trend of change over time. 2. The AUC for the C-TIRADS classification in the diagnosis of nodules was determined to be 0.784. A C-TIRADS category of ≥4B was identified as the optimal cutoff value for the diagnosis of malignant nodules, yielding sensitivity, specificity, PPV, NPV, and accuracy rates of 75.72%, 75.76%, 84.52%, 64.10%, and 75.74%, respectively. Furthermore, no statistically significant difference (P > 0.05) was observed in the diagnostic efficacy between the C-TIRADS classification and the Kwak TI-RADS classification for thyroid nodules. Microcalcifications, irregular margins, a taller-than-wide morphology, and internal vascularity were increasingly observed during follow-up and may be associated with malignancy, warranting closer surveillance. The C-TIRADS demonstrates diagnostic accuracy comparable to that of the Kwak TI-RADS, thereby reinforcing its clinical utility in the management of thyroid nodules.
Hospital-associated deconditioning is a contributor to secondary sarcopenia, which may be driven by prolonged hospital length of stay (LoS). This study investigated the bidirectional association of LoS and sarcopenia indices (lean soft tissue, muscle strength, physical function) in older inpatients, with a focus on age- and sex-specific differences. Using cross-sectional data from the Copenhagen PROTECT study, 1071 older inpatients (aged ≥ 65 years) were included. Appendicular lean soft tissue index (ALSTI), handgrip strength (HGS), gait speed, and 30-second chair stand test (30CST) were assessed within 24 h of admission and sarcopenia was defined per the EWGSOP2 criteria. Linear and logistic regressions examined associations between LoS and sarcopenia indices, stratified by age and sex. In patients ≥ 80 years, longer LoS (based on the cohort's median) was associated with lower gait speed and 30CST in both sexes (p < 0.01), and lower HGS in women (p = 0.03). In men < 80 years, longer LoS correlated with lower HGS and 30CST (p < 0.01), with higher odds of sarcopenia (Low ALSTI and low 30CST; OR = 3.14, p = 0.03). Higher 30CST and HGS were consistently associated with shorter LoS, particularly in men ≥ 80 years and women across both age groups. HGS and 30CST are strongly associated with LoS in older inpatients, with more pronounced effects in those ≥ 80 years. Future longitudinal studies and trials are warranted to confirm causality, that may guide rehabilitation strategies to reduce LoS through targeted interventions.
Refractory cancer pain remains difficult to control in older adults, particularly when oral opioid regimens are limited by dysphagia, nausea, bowel dysfunction, or rapidly fluctuating symptom intensity. In this retrospective real-world study conducted in a dedicated geriatric oncology ward, subcutaneous patient-controlled analgesia (PCA) with hydromorphone was evaluated as a routinely implemented rescue strategy for severe opioid-refractory cancer pain. To evaluate the effectiveness and safety of subcutaneous PCA hydromorphone for refractory cancer pain in hospitalized older patients and to identify clinical factors associated with 24-h pain reduction. We reviewed consecutive admissions from January 1 to December 31, 2024. Eligible patients were aged ≥60 years, had pathologically confirmed malignancy, had refractory cancer pain defined as a pre-PCA current NRS score ≥4 recorded within 30 min before pump initiation after prior opioid exposure, and received subcutaneous hydromorphone PCA with at least one follow-up pain assessment. The primary endpoint was change in current NRS score from immediately pre-PCA to 24 h. Secondary endpoints included early analgesic response, responder rates, dosing patterns, and documented adverse events. Complete-case analyses were pre-specified; sensitivity analyses excluded implausible physiologic values and refitted the multivariable model with robust standard errors. Among 499 patients (mean age 68.3 ± 6.9 years; 69% male), 82% had stage IV disease. Mean pre-PCA current NRS decreased from 4.43 ± 1.29 to 2.21 ± 0.73 at 24 h, corresponding to a mean reduction of 2.18 points (95% CI 2.05-2.31; p < 0.001), a magnitude generally regarded as clinically meaningful for severe cancer pain. Response rates at 24 h were 57.3% for ≥30% improvement and 45.2% for ≥50% improvement. Median time to satisfactory analgesia was 0.6 h. Adverse events were ascertained from standardized nursing assessments embedded in routine charting and verified against medication and progress-note documentation; somnolence occurred in 2/499 patients (0.4%) and constipation in 1/499 (0.2%), with no documented respiratory depression. In a specialized geriatric oncology ward, subcutaneous PCA hydromorphone was associated with rapid and clinically meaningful short-term pain improvement and a low rate of documented adverse events. These findings support its use as a pragmatic rescue option for carefully selected older patients with refractory cancer pain, while prospective comparative studies remain necessary before broad implementation can be recommended.
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Chronic periapical periodontitis is a persistent inflammatory disease characterized by progressive bone destruction around the tooth apex. Manual radiographic detection of these lesions is subjective and time-consuming, highlighting the need for automated diagnostic tools. This paper presents a unified deep learning framework for joint tooth segmentation and periapical lesion detection in panoramic radiographs. Our approach employs a joint process: first, a deep learning model identifies and segments individual teeth according to standard dental numbering systems, while a second one detects periapical lesions within the tooth regions obtained from the segmentation outputs in the first stage. The framework incorporates an advanced loss function (Powerful IoU v2) to improve bounding-box regression accuracy and a spatial association mechanism to map detected lesions to specific teeth based on geometric overlap analysis. Our proposed tooth segmentation model achieves an mAP@50 of 97.7% and a mean Dice coefficient of 93.5%, while the periapical lesion detector reaches an mAP@50 of 91.9%. Furthermore, our region-of-interest approach yields a 3.49× computational speedup, averaging 0.1589 s per radiograph when compared to full-image processing. Trained exclusively on open-source datasets, this reproducible framework achieves explicit tooth-to-lesion mapping, providing an efficient and practical tool for periapical lesion screening.
Ozone therapy has been proposed across multiple clinical conditions based on hormetic, antioxidant, and immunomodulatory effects, but its efficacy and safety remain controversial. We conducted an umbrella review to appraise the effectiveness and safety of ozone therapy using evidence from meta-analyses of randomized controlled trials (RCTs). We searched MEDLINE, Web of Science, Embase, and the Cochrane Library from inception to 14 February 2025, with an updated search performed on 9 May 2026. Eligible studies were systematic reviews with meta-analyses comparing ozone therapy with non-active controls, including placebo, sham, saline, or standard care. Methodological quality was evaluated with AMSTAR-2 and certainty of evidence with GRADE. Of 1243 records identified, seven meta-analyses representing four clinical indications (chronic periodontitis, COVID-19, diabetic foot ulcers, and impacted mandibular third-molar surgery) were included. In chronic periodontitis, evidence was mixed: one meta-analysis found no significant adjunctive benefit, whereas a more recent meta-analysis reported improvements in probing depth and gingival index, but not in bleeding on probing, plaque index, or clinical attachment level. For COVID-19, ozone therapy reduced PCR positivity at follow-up (RR 0.07; 95% CI 0.01-0.34), although this was considered a clinically non-important surrogate endpoint, and showed no significant benefit for hospital stay, intensive care unit admission, or mortality. For diabetic foot ulcers, ozone therapy was not superior to control treatment for ulcer healing (RR 1.69; 95% CI 0.90-3.17) or reduction in ulcer area. In third-molar surgery, ozone therapy did not reduce swelling or improve mouth opening, but was associated with improved short-term quality of life and reduced analgesic use. Safety outcomes were inconsistently reported, and available data did not allow firm conclusions regarding adverse events. The certainty of evidence was low or very low for all outcomes. Despite mechanistic plausibility, current meta-analytic evidence from RCTs remains inconsistent, methodologically fragile, and largely based on low- or very low-certainty findings. Routine clinical use is not justified pending adequately powered, blinded RCTs with standardized dosing and delivery, patient-centered endpoints, and rigorous safety monitoring.
Alzheimer's disease (AD) is a heterogeneous syndrome with distinct genetic and clinical profiles between early-onset AD (EOAD) and late-onset AD (LOAD) subtypes. However, specific causal etiologies linking the gut microbiota-immune-metabolic axis to these subtypes remain poorly understood. We employed a comprehensive bidirectional two-sample Mendelian randomization (MR) framework to systematically investigate the causal associations of gut microbiota, immune cell phenotypes, and blood metabolites with EOAD and LOAD. Large-scale genome-wide association study (GWAS) summary statistics were utilized from the MiBioGen consortium, Sardinian cohort, and Canadian Longitudinal Study on Aging, alongside AD outcome data from the FinnGen consortium. Causal estimates were generated using the inverse variance-weighted method, with rigorous sensitivity analyses including false discovery rate (FDR) correction and Steiger directionality tests to ensure robustness. Our analysis revealed divergent multi-omics signatures for AD subtypes. While the genus Veillonella and myeloid dendritic cells emerged as shared protective factors, the risk profiles were distinct. EOAD susceptibility was primarily driven by adaptive immune dysregulation and lipid metabolism disturbances. In contrast, LOAD risk was predominantly associated with innate immune dysfunction and perturbations in amino acid and gut-derived metabolite turnover, such as hippurate. This study provides genetic evidence that EOAD and LOAD are driven by fundamentally different peripheral mechanisms across the gut-immune-metabolic axis. These findings challenge the monolithic view of AD pathogenesis and underscore the critical necessity of stratifying patients by onset age to develop precision therapeutic interventions.
Sepsis-induced myocardial injury (SIMI) is a severe complication with high mortality and limited effective treatments. Although combined aspirin and statin therapy is cardioprotective in coronary artery disease, its impact on SIMI outcomes remains unclear. Using the MIMIC-IV database, we evaluated the association of combined aspirin and statin therapy with 28-day, 90-day, and 1-year mortality in SIMI patients using multivariable Cox regression and Kaplan-Meier analysis. Robustness was assessed via floating absolute risk analysis. External validation was performed in an independent ICU cohort. Among 1,884 SIMI patients, 119 received combination therapy. Compared to those without aspirin or statin, combination therapy was associated with significantly lower mortality at 28 days (11.8% vs. 41.9%; HR = 0.22), 90 days (15.1% vs. 44.8%; HR = 0.23), and 1 year (29.4% vs. 50.9%; HR = 0.38) (all P < 0.001). The combination consistently showed the greatest risk reduction. Subgroup analysis confirmed consistent benefits. External validation (n = 4,002) confirmed a lower 28-day mortality risk with combination therapy (HR = 0.48; P < 0.001). Combined aspirin and statin therapy is associated with reduced mortality and improved outcomes in SIMI patients.
The high burden of functional and chronic disability in older adults due to osteoporotic vertebral compression fractures (OVCFs) reflects both fracture characteristics and patient-related factors influencing recovery. The underlying conditions that define frailty and sarcopenia, or the inability of osteoporotic patients to maintain muscle mass, may have an important role in functional recovery after OVCF. In this retrospective cohort study, 120 patients aged ≥60 years who were diagnosed with radiologically confirmed OVCFs and underwent treatment in a tertiary care center from January 2020 to December 2023 were included. Patients were stratified based on sarcopenia and frailty. The primary outcome of interest was functional recovery, as measured by the Barthel Index at discharge; secondary outcomes included length of hospital stay, complications, VAS pain score, and hospital-based complications. Multivariable linear regression of functional recovery on the independent variables was then calculated. The primary endpoint reflects early in-hospital functional recovery and does not capture long-term outcomes. Compared to non-frail patients, frail individuals had lower Barthel Index scores (65.3 ± 12.4 vs. 82.5 ± 10.2, p < 0.001), higher pain (5.1 ± 1.5 vs. 3.8 ± 1.2, p = 0.02), longer length of stay (12.4 ± 4.1 vs. 8.5 ± 3.2 days, p = 0.01), and higher complication rates (27.7% vs. 10.9%, p = 0.03). Similar patterns were observed among patients with sarcopenia. Multivariable regression models showed that frailty (β = -12.45, p < 0.001) and sarcopenia (β = -8.32, p = 0.004) were independently associated with reduced early functional recovery. Frailty and sarcopenia were independently associated with reduced early functional recovery in older adults with osteoporotic vertebral compression fractures. These findings highlight the potential importance of incorporating geriatric and muscle health assessments into clinical evaluation; however, further prospective studies are required to confirm these associations.
To compare racial-sex differences in postoperative mortality by dementia status. Because patients with dementia often find it harder to advocate for themselves, racial-sex differences in postoperative mortality may be greater for patients with dementia versus without dementia. Among Medicare fee-for-service beneficiaries aged 65 to 99 years who underwent one of 12 common surgical procedures in 2016 to 2019, we compared 30-day postoperative mortality (death during the index hospitalization or within 30 days of surgery) across 4 race-sex groups (Black men [reference group], White men, White women, and Black women) stratified by dementia status. Elective and nonelective surgeries were examined separately. Among 888,391 patients undergoing elective surgery, 65,450 (7.4%) had dementia. Postoperative mortality was highest among Black men, both with dementia (adjusted mortality, 3.99%) and without dementia (2.11%). Racial-sex differences were generally greater among patients with dementia. For example, the mortality difference between White women versus Black men was significantly larger among patients with dementia (adjusted difference, -2.38 percentage points [pp]; 95% confidence interval [CI], -3.34 to -1.41) than among those without dementia (-0.75 pp; 95% CI, -0.96 to -0.54) (P-for-interaction = 0.001). In contrast, among 394,554 patients undergoing nonelective surgery, 56,273 (14.3%) had dementia, and we found no evidence that mortality was highest among Black men or that racial-sex differences meaningfully varied by dementia status. Among patients undergoing elective surgery, racial-sex differences in postoperative mortality were greater among patients with dementia than among those without dementia, highlighting the need for targeted strategies to ensure consistent surgical care.
Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer (PCa) that emerges under androgen deprivation and is associated with therapeutic resistance. The contribution of volume-regulated anion channels (VRACs) to this process remains poorly understood. This study identified leucine-rich repeat-containing 8 subunit D (LRRC8D), a VRAC subunit, as the only family member consistently downregulated in NEPC and associated with neuroendocrine (NE)-like features. LRRC8D downregulation was accompanied by suppression of swelling-activated VRAC currents, increased synaptophysin (SYP) expression, decreased cisplatin sensitivity, and neurosecretory remodeling. Conversely, LRRC8D overexpression enhanced cisplatin-induced apoptosis, reduced colony formation, and suppressed tumor growth in xenograft models, including under cisplatin treatment. Consistent alterations in LRRC8D and SYP expression were also observed in enzalutamide-resistant patient-derived organoids. Mechanistically, RE1-silencing transcription factor (REST) promoted LRRC8D transcription. Functional analyses further demonstrated that CAV-1 acted upstream of LRRC8D, and LRRC8D negatively regulated STAT3 activation. Together, these findings indicate that LRRC8D influences PCa phenotype and platinum responsiveness, and implicate a regulatory axis involving LRRC8D and CAV-1/STAT3 signaling in NE-associated features of advanced PCa. Functional analyses further showed that CAV-1 acted upstream of LRRC8D, and LRRC8D negatively regulated STAT3 activation. Together, these findings indicate that LRRC8D influences PCa phenotype and platinum responsiveness and implicate a regulatory axis involving LRRC8D and CAV-1/STAT3 signaling in NE-associated features of advanced PCa.
Hypertension increases the risk for cardiovascular and cerebrovascular diseases and both its preventive and current therapeutics measures require extensive investigations. Despite that Gastrodin, a neuroprotective compound extracted from a Traditional Chinese medicine (TCM), reportedly has preventive and curative potentials in hypertensive patients, its molecular mechanisms in lowering blood pressure still remain obscure. This study was designed to test the hypothesis that gastrodin lowers blood pressure by targeting the PPAR-γ/NF-κB/NLRP3 signaling axis in the hypothalamic paraventricular (PVN). Gastrodin or vehicle (artificial cerebrospinal fluid, aCSF) was directly infused into the PVN through a mini osmotic pump for 28 days to Spontaneous hypertensive rats (SHRs) and Wistar Kyoto (WKY). Four groups of rats were set: WKY + PVN vehicle; WKY + PVN Gastrodin; SHR + PVN vehicle; and SHR + PVN Gastrodin. Blood pressure was monitored and at the conclusion of experiment, plasma and PVN samples were collected and processed for ELISA, PCR, Western blotting and Immunofluorescence analyses. SHRs had elevated blood pressure (BP), heart rate (HR) and plasmatic norepinephrine (NE) validating their hypertensive status. PVN micro-infusion of gastrodin markedly reversed these hypertensive features in SHRs. At molecular level, gastrodin attenuated the local production of reactive oxygen species (ROS), reduced NADPH Oxidases (NOX)2 and NOX4 messenger RNA (mRNA) level and attenuated the activation of PPAR-γ in the PVN. In addition, gastrodin reduced the inflammasome activation and the expression of interleukin-1β (IL-1β). Furthermore, pretreatment with gastrodin reduced the expression of caspase-1 p10 and inflammation (IL-1β and MCP-1), the ratio of phosphorylated kappa B kinase (p-IKK)/IKK, and that of p-p65/p65 in the PVN of SHRs. In conclusion, gastrodin-lowered blood pressure is associated with balanced PPAR-γ/NF-κB/NLRP3 signaling axis within the PVN local highlighting its promising properties in the management of hypertension.
Alzheimer's disease is a neurodegenerative disorder, in which ferroptosis contributes to its pathogenesis and progression. This study explored the precise mechanisms of ferroptosis in the pathological development of Alzheimer's disease. Amyloid beta 1-42 oligomer-treated SH-SY5Y cells were used to simulate Alzheimer's disease in vitro. Ferroptosis was evaluated by detecting the levels of reactive oxygen species (ROS), malonaldehyde, glutathione, Fe2+, and ferroptosis-related proteins. Cell viability was assessed by a Cell Counting Kit-8 assay. Total RNA N6-methyladenosine (m6A) levels were detected using an RNA methylation quantification kit, and peroxiredoxin 6 (PRDX6) m6A levels were analyzed by m6A RNA immunoprecipitation. The binding of methyltransferase-like 14 (METTL14) to PRDX6 was investigated by a dual-luciferase reporter assay. METTL14 levels were decreased in the serum of Alzheimer's disease patients and in an in-vitro model of Alzheimer's disease, and serum levels correlated with the degree of cognitive impairment. METTL14 overexpression significantly inhibited amyloid beta 1-42 oligomer-induced ferroptosis and cytotoxicity in SH-SY5Y cells. Mechanistically, METTL14-mediated m6A modification increased PRDX6 mRNA stability, which inactivated the ROS-apoptosis signal-regulating kinase 1/p38 pathway. Rescue experiments demonstrated that PRDX6 overexpression reversed sh-METTL14-induced ferroptosis and neurotoxicity. METTL14 suppressed neuronal ferroptosis to delay Alzheimer's disease progression through m6A modification of PRDX6 to inactivate the ROS-apoptosis signal-regulating kinase 1/p38 pathway. Our observations provide a potential therapeutic strategy for Alzheimer's disease.
Background/Objectives: Kidney transplantation (KT) in older recipients remains challenging due to age-related conditions such as frailty and comorbidities, as well as immunological changes related to immunosenescence, which expose older KTRs to a higher risk of infection and infection-related complications. The aim of this study was to evaluate clinical and immunological outcomes in older KTRs, analyzing the incidence of cardiovascular, infective, and neoplastic complications, as well as graft and patient survival and the associated risk factors. Methods: This monocentric study includes 157 KTRs aged over 65 years, followed at the Transplant Ambulatory of Padua University Hospital and transplanted between January 2013 and December 2023. Clinical and immunological outcomes were evaluated, including surgical complications, incidence of delayed graft function (DGF), and renal function at 1, 3, and 5 years after KT. Results: Patient survival rates were 96%, 91.5%, and 71.6% at 1, 3, and 5 years after KT, respectively, while graft survival rates were 94%, 87%, and 68%. Major complications were malignancies (40.1%), cardiovascular disease (33.1%), and bacterial infections (22%). In the multivariate analysis, donor age and history of malignancy were identified as independent risk factors for mortality (p = 0.048 and p = 0.056, respectively). Kaplan-Meier survival analysis confirmed donor age as the only significant risk factor for patient survival. Regarding graft survival, multivariate analysis identified hypertension as an independent risk factor for graft failure (p = 0.009), while Kaplan-Meier analysis showed diabetes (p = 0.040) and single-kidney transplantation (p = 0.003) as significant risk factors. Conclusions: KT in older recipients represents a safe and beneficial therapeutic option, offering favorable patient and graft survival outcomes. However, this epidemiological study highlights the need for personalized follow-up strategies and improved prognostic assessment in older KTRs.
Geriatric distal tibia and fibula fractures are typically treated with open reduction and internal fixation (ORIF) or prolonged cast immobilisation. These methods predispose to wound complications and delayed weight-bearing. Percutaneous fixation can offer a stable construct allowing for early weight-bearing while minimising wound complications. This case series details the management and outcomes of patients over 65 with distal tibia and fibula fractures and poor soft tissue envelope treated with percutaneous fixation. A prospective observational study was conducted at two Victorian orthopaedic units, identifying patients over 65 years of age who underwent percutaneous distal tibia or fibula fracture fixation. Patient selection considered soft tissue quality and overall health. Antegrade tibial intramedullary nails and retrograde percutaneous screws were used. Surgery proceeded without delay for swelling or anticoagulation cessation. Clinical notes and radiographs were analysed for premorbid health, mobility status, injury mechanism and classification, fixation methods, post-operative mobility, and treatment complications. The study identified 13 ankles in 11 patients (average age 82) across two sites. Fractures included 4 trimalleolar, 5 bimalleolar, 1 lateral malleolar, and 3 distal tibia and fibula diaphyseal. Three fractures were open. Median time to operation was 3 days. Six patients were allowed immediate weight-bearing as tolerated. Median post-operative stay was 5 days. One deep infection required removal of a suture-button syndesmosis device and two minor wound breakdowns (distant to surgical site) were managed non-operatively with dressings. Percutaneous distal tibia and fibula fracture fixation appears to be a viable alternative to ORIF in geriatric patients with poor soft tissue envelope, potentially offering reduced complications and earlier mobilisation. Level IV.