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Tuberculosis (TB) remains a major global health challenge. In addition to Mycobacterium tuberculosis (MTB), nontuberculous mycobacteria (NTM) are increasingly recognized as causative agents of mycobacterial infections. However, the limited access to rapid diagnostics often delays appropriate treatment. Accurate and timely differentiation is critical for selecting effective antibiotic regimens. In Indonesia, there is a lack of population-based data comparing MTB and NTM in TB-suspected cases. This study aimed to detect and differentiate MTB and NTM in clinical samples from suspected TB patients in North Sumatra and to assess their drug resistance profiles using a molecular diagnostic approach. We conducted a prospective cohort study using 56 clinical samples (45 smear-positive sputum and 11 fine-needle aspiration biopsies) from suspected TB patients in North Sumatra. DNA was extracted and analyzed using the Genoscholar™ NTM + multidrug-resistant TB (MDR-TB) II line probe assay (LPA) to detect MTB, NTM, and anti-TB drug resistance. Of the 56 samples, 40 (71.4%) were positive for MTB, 2 (3.6%) for Mycobacterium avium, and 5 (8.9%) for other NTM species, while 9 (16.1%) were negative. MDR MTB was detected in 9 (28%) sputum samples and 1 (12.5%) biopsy sample. Both M. avium isolates were susceptible to rifampicin and isoniazid, while resistance profiles for the other NTM species could not be determined. LPA effectively differentiated MTB from NTM and identified drug resistance patterns in clinical samples. Implementation of this rapid diagnostic tool may strengthen TB management in high-burden areas such as North Sumatra, enabling earlier and more targeted treatment. Show less

Apolipoprotein E (APOE) epsilon4 (ε4) is a major genetic risk factor for late-onset Alzheimer's disease (AD), with women exhibiting heightened vulnerability to APOE ε4-associated cognitive impairment. Despite recognition of this sexual dimorphism, the underlying biological mechanisms remain incompletely understood. We performed weighted gene co-expression network analysis (WGCNA) on RNA-seq data from the Mayo Clinic cohort ( Four co-expression modules ( we reveal a female-specific APOE ε4-driven molecular network linking endothelial dysfunction to tau pathology. These hub genes provide potential biomarkers, while vincamine represents a targeted prevention and therapeutic candidate for high-risk APOE ε4-positive women. Show less

In Alzheimer's disease, carriage of the ApoE4 risk allele is linked to faster tau accumulation at lower amyloid-PET levels, thereby accelerating disease progression. However, it remains unclear whether this ApoE4-facilitated transition from amyloidosis to tauopathy is mechanistically promoted by increased secretion of phosphorylated (p)tau, a key intermediate that drives the amyloid-to-tauopathy transition, or alternatively by increased ptau-driven tau aggregation. Therefore, we investigated where along the amyloid-to-tau axis ApoE4 accelerates tau aggregation and assessed i) whether ApoE4 increases ptau secretion or ii) whether ApoE4 increases ptau-associated tau aggregation. To this end, we analysed two large-scale APOE-genotyped cohorts covering the full Alzheimer's disease spectrum (ADNI: n=201) as well as a preclinical cohort (A4-LEARN: n=200), integrating baseline amyloid-PET, plasma ptau217 and CSF ptau181 with longitudinal tau-PET. Using linear regression, we tested whether ApoE4-carriage moderates i) amyloid-PET-associated plasma ptau217 increases or ii) ptau217-associated tau spreading from local epicentres across patient-tailored tau spreading stages. All analyses were independently validated across both cohorts, including an additional replication in an ADNI subset (n=115) with available CSF ptau181 measures as an alternative marker of ptau secretion. Finally, we used logistic regression to determine ApoE4 allele count-stratified plasma ptau217 thresholds marking early pathological tau-PET increases. We found that ApoE4 did not facilitate amyloid-PET-associated ptau increases, suggesting that amyloid-related ptau secretion is not altered by ApoE4-carriage. Contrastingly, we found that plasma ptau217 elevations were linked to faster tau-PET spread from local epicentres across connected brain regions in an ApoE4-allele dose-dependent manner, independent of amyloid (ADNI/A4-LEARN: mean β=0.44/0.56, p<0.001/<0.001). Lastly, we found that a higher ApoE4 allele count was linked to lower ptau217 thresholds marking transition to tauopathy, i.e. early abnormal tau-PET increases, consistently across both samples (ADNI: 0/1/2 ApoE4 alleles=0.62/0.34/0.15pg/ml, representing ∼45% and ∼76% reductions from non-carriers; Fujirebio ptau217 assay; A4/LEARN: 0/1/2 ApoE4 alleles=0.31/0.23/0.18pg/ml, representing ∼26% and ∼42% reductions; Eli Lilly ptau217 assay). These findings suggest that ApoE4, i.e. the key genetic risk factor for sporadic Alzheimer's disease, facilitates amyloid-dependent tau aggregation in an allele dose-dependent manner by enhancing the ptau-driven spread of fibrillar tau, leading to an earlier transition from amyloidosis to tauopathy at lower ptau217 levels. This has implications for plasma ptau-based screening approaches and therapeutic timing of anti-amyloid drugs in ApoE4 carriers: Specifically, ApoE4 carriers may require genotype-adjusted ptau thresholds to detect Alzheimer's disease pathophysiology, as well as anti-amyloid treatment at lower ptau levels to prevent the transition to tauopathy, which ultimately drives neurodegeneration and cognitive decline. Show less

Agricultural or gardening activity (also known as hobby farming) is a simple strategy that may be effective for maintaining health and preventing lifestyle-related diseases. However, its preventive effect on the development of conditions associated with neurovascular aging (e.g., stroke and dementia) remains unclear. To comprehensively investigate the preventive role of regular agricultural or gardening physical activity (AGPA) in neurovascular aging and its underlying mechanisms using two approaches. We conducted an experimental study in which we assessed arterial stiffness, cognitive performance (Flanker and Stroop tests), and circulating biomarkers (e.g., plasmin-α2-plasmin inhibitor complexes, nitric oxide, brain-derived neurotrophic factor) in 12 male students (average age: 22 ± 1 years) before and after three 40-min interventions (resting, cycling, and simulated AGPA) under controlled conditions. We also conducted a cross-sectional study, in which we recruited 161 (79 in the AGPA group and 82 in the control group) hospital-based older individuals (average age: 78 ± 5 years) and assessed their history of stroke, cognitive function, and brain magnetic resonance imaging (MRI) findings. In the experimental study, simulated AGPA reduced arterial stiffness, improved executive cognitive function, and elevated circulating plasmin-α2-plasmin inhibitor complexes, nitric oxide, and brain-derived neurotrophic factor. Brain MRI-assessed cerebral white matter hyperintensities caused by reduced blood flow to brain tissue and stroke prevalence were lower, and cognitive scores (as assessed by the Hasegawa Dementia Scale-Revised) were higher in the AGPA group than in the control group. Our findings suggest that regular AGPA is associated with markers of slower neurovascular aging in older individuals. AGPA induces a combination of general physical activity-related and specific AGPA-related effects; moreover, it may offer similar or even greater benefits than physical activity alone. Therefore, habitual AGPA may serve as an effective preventive strategy for neurovascular aging. Show less

Patients with Alzheimer's Disease (AD) frequently suffer from comorbidities such as type 2 diabetes mellitus (T2DM), accompanied by shared common pathologies such as increased inflammation and impaired glucose homeostasis. Beta-secretase 1 (BACE1), the rate limiting enzyme in AD associated beta-amyloid (Aβ) production, is also implicated in metabolic dysfunction and can increase central and peripheral protein levels of protein tyrosine phosphatase 1B (PTP1B). PTP1B is a validated target in diabetes and obesity, and is a neuroinflammatory regulator involved in degenerative processes. This study investigated the effects of the PTP1B inhibitor, trodusquemine (MSI-1436) on the cognitive and metabolic phenotypes of the neuronal human BACE1 knock-in (PLB4) mouse, a co-morbidity model of AD and T2DM, and their wild-type (PLB Five-month-old male PLB4 and PLB Inhibition of PTP1B improved motor learning alongside glucose tolerance in PLB4 mice, without affecting body weight/adiposity. MSI-1436 treatment led to lower protein levels of amyloid precursor protein (APP), reduced astrogliosis and restoration of the endoplasmic chaperone immunoglobulin heavy chain binding protein (BIP) in the brain, alongside decreased insulin receptor substrate-1 (IRS1) and dipeptidyl peptidase-4 (DPP4) proteins in the liver. We provide evidence that neuronal BACE1 contributes to neuroinflammation and hyperglycaemia in PLB4 mice, and this can be partially rescued by PTP1B inhibition. Targeting PTP1B may therefore offer an attractive therapeutic approach to ameliorate co-morbidity associated pathologies in AD and T2DM. Show less

Coronary artery disease (CAD) is increasingly recognized as a chronic inflammatory condition. Interleukin-27 (IL-27), a cytokine from the IL-12 and IL-6 families, plays a dual role in CAD pathogenesis. It exacerbates disease by interacting with IL-1β and activating the NLRP3 inflammasome, promoting inflammation and tissue damage. Conversely, IL-27 can delay disease progression by engaging STAT1/3 signalling, suppressing inflammation, and promoting tissue repair. Future research should focus on elucidating IL-27's specific biological functions, interactions with molecular targets, and clinical implications in CAD. This will enhance understanding of CAD and support the development of improved diagnostic and therapeutic strategies. Show less

Olfactory impairment is common in older age and is a known early feature of several dementia diseases. Blood-based biomarkers of Alzheimer's disease (AD) now offer a scalable method for detecting pathophysiological mechanisms related to olfactory decline in the general population. However, few studies have examined how these biomarkers relate to long-term olfactory trajectories. Most existing work has been limited to cross-sectional settings. In this population-based study, we used biomarker data collected at baseline and followed participants for up to 15 years, enabling us to test whether early biological changes are temporally linked to subsequent olfactory decline. Data came from the ongoing Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal population-based study with baseline assessments from March 21, 2001, through August 30, 2004. We included participants without prevalent neurodegenerative diseases who completed olfactory assessment at baseline. The 15-year follow-up was finished in December 2019. Data were analysed from December 2023 to April 2024. Serum-derived biomarkers of tau phosphorylated at threonine 217 (p-tau217) and at theorine181 (p-tau181), total tau (t-tau), amyloid-β ratio (Aβ42/Aβ40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were obtained at baseline. Linear mixed models examined associations between biomarker quartiles and Sniffin' Sticks odor identification performance over 15 years, adjusting for demographics, health conditions, and semantic knowledge. We included 1868 participants (mean [SD] age 71.3 [9.9] years; 1122 females [60.1%]). In fully adjusted models, higher quartiles of p-tau217, p-tau181, NfL, and GFAP, and lower quartiles of Aβ42/Aβ40, were associated with steeper olfactory decline, with the steepest decline among participants in the highest quartiles (β for Q4 vs Q1: -0.20 [95% CI: -0.26 to -0.15] for p-tau217; -0.19 [95% CI: -0.25 to -0.13] for p-tau181; -0.23 [95% CI: -0.29 to -0.17] for NfL; β = -0.17 [95% CI: -0.23 to -0.11] for GFAP. Participants in the lowest Aβ42/Aβ40 quartile declined more steeply than those in the highest (β = -0.09 [95% CI: -0.14 to -0.04]). Associations appeared stronger in the oldest participants, in APOE ε4 carriers for p-tau181, in non-carriers for NfL and GFAP, and among former smokers for NfL. Blood-based biomarkers of AD were consistently associated with faster olfactory decline in older adults, particularly in the highest biomarker quartiles. These results provide large-scale longitudinal evidence, across up to 15 years of follow-up, that olfactory decline in the general population is linked to AD-related blood biomarkers, supporting the hypothesis that common olfactory losses in ageing partly reflect dementia-related processes. Show less

Inflammatory bowel disease (IBD) with the two predominant endophenotypes-Crohn's disease (CD) and ulcerative colitis (UC)-represents a group of chronic gastrointestinal inflammatory conditions. Since most genetic associations with IBD are often limited to independent subtypes, we reported a genome-wide association study (GWAS) cross-trait analysis combined with CD and UC to enhance statistical power. Initially, we detected 256 association signals at 54 genomic susceptibility loci and further characterized the functionality of variants within these regions. Subsequently, we revealed tissue and cell-specific heritability enrichment, particularly in whole blood, small intestine terminal ileum, spleen, lung, and colon transverse. Leveraging multi-omics datasets, we adopted a two-pronged approach comprising summary data-based Mendelian randomization (SMR) and transcriptome-wide association study (TWAS) to pinpoint likely causal genes and variants. Further, RNA-seq analysis facilitated the evaluation of differential expression and co-expression in intestinal tissues. Through a multi-stage prioritization strategy, compelling evidence for putative targets was nominated; notably highlighting several potential susceptibility genes such as IL27 and SBNO2. Finally, we utilized Mendelian randomization (MR) analysis with diverse datasets to verify the convergence of these two endophenotype-driven genes. Our investigation yields valuable insights to inform genetic mechanisms in IBD and reveal potential causal gene targets. Show less

Residual cardiovascular risk remains substantial despite widespread adoption of intensive lipid-lowering strategies-statins, PCSK9 inhibitors, and RNA-based agents-that achieve very low LDL-C and apoB levels. Over the past three years, converging epidemiologic and mechanistic evidence has highlighted emotional stress-including anger, grief, anxiety, and chronic psychosocial strain-as a biologically active determinant of atherosclerotic disease and a frequent trigger of acute events. We propose the Emotion-Lipid Synergy Model, in which lipid burden establishes the atherothrombotic substrate while emotion-driven autonomic and vascular perturbations amplify endothelial dysfunction, microvascular constriction, inflammation, and thrombogenicity-thereby widening the residual-risk gap even when lipid targets are met. From this perspective, prevention should evolve toward precision psychocardiology: systematically screening for distress and stress reactivity; leveraging wearables to detect high-risk emotional states; and delivering timely, scalable, just-in-time behavioral interventions alongside guideline-directed lipid management. Particular attention is warranted for women and patients with angina and no obstructive coronary disease, who appear disproportionately susceptible to mental-stress ischemia. We outline a research agenda-flagship outcomes trials, mechanistic studies, and multimodal phenotyping-and discuss implementation pathways that integrate emotion metrics into cardiac rehabilitation and routine care. Integrating emotion assessment and modulation with lipid control offers a pragmatic route to reduce residual risk and advance equitable, personalized cardiovascular prevention. Show less

Ischemic stroke (IS) is a leading cause of death and permanent disability worldwide. Diabetes is a major risk factor for IS and independently increases mortality. This study investigated the neuroprotective effects of Myrtenal (Myrt) in a rat model of IS under both diabetic and non-diabetic conditions. Sprague Dawley rats received Myrt (40 mg/kg, intraperitoneally) for 28 days before undergoing 60-minute middle cerebral artery occlusion followed by 24 h of reperfusion. Neurological outcomes were assessed using behavioral tests, infarct volume was measured by TTC staining, and biochemical analyses evaluated oxidative stress (MDA, SOD, CAT, GSH-Px) and inflammatory markers (NLRP3, TNF-α, IL-6, IL-1β). Western blotting was performed to examine BDNF/TrkB, p-PI3K/p-Akt signaling, and apoptosis-related proteins (Caspase-3, Bcl-2, Bax). IS impaired neurological function and increased infarct size, apoptosis, inflammation, and lipid peroxidation, while reducing antioxidant enzymes and BDNF/TrkB and p-PI3K/p-Akt levels (p < 0.05). These pathological changes were more severe in diabetic rats. Pretreatment with Myrt significantly ameliorated these effects in both diabetic and non-diabetic groups (p < 0.05). These findings suggest that Myrt exerts neuroprotective effects against IS by suppressing inflammation, oxidative stress, and apoptosis, possibly through modulation of BDNF/TrkB and p-PI3K/p-Akt pathways. These findings indicate that Myrt may possess neuroprotective potential in IS under both hyperglycemic and normoglycemic conditions. Show less

Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, has been shown to reduce hunger and weight in patients aged 6 years and older with proopiomelanocortin (POMC) deficiency (including biallelic variants in proprotein convertase subtilisin/kexin type 1 [PCSK1]), leptin receptor (LEPR) deficiency, or Bardet-Biedl syndrome (BBS). No approved therapies for patients younger than 6 years old currently exist. The phase 3, open-label VENTURE trial aimed to evaluate the efficacy and safety of setmelanotide in patients aged 2-5 years with POMC or LEPR deficiency or BBS. This phase 3, open-label, multicentre trial, conducted across six sites in the USA, the UK, Spain, and Australia, enrolled eligible patients aged 2-5 years who had hyperphagia and obesity due to biallelic POMC (including PCSK1) or LEPR variants or genetically confirmed BBS. Open-label subcutaneous setmelanotide was administered once daily for 52 weeks, starting at 0·5 mg with doses increasing every 2 weeks in 0·5 mg increments until reaching the maximum dose based on weight. The co-primary endpoints at week 52 were the percentage of patients reaching a 0·2-point decrease or greater in BMI Z score (a statistical measure used to assess BMI in paediatric patients considering a patient's BMI and comparing it to reference values for the same age and sex) and mean percent change in BMI. Additional endpoints measured safety, hunger, weight-related outcomes, and caregiver burden. The study is registered at ClinicalTrials.gov (NCT04966741) and is complete. Between March 8, 2022, and Sept 18, 2023, 13 patients were screened at the six sites, and 12 patients were enrolled in the study (seven with POMC or LEPR and five with BBS); one patient with BBS was excluded as their BMI was not at the 97th percentile or above. Of the 12 patients enrolled, most were male (seven [58%] vs five [42%] for female) and the mean age was 3·6 years (SD 0·9). 11 patients completed the trial. Ten (83%) of the 12 overall participants reached a 0·2-point reduction or more in BMI Z score per WHO methodology at week 52 (95% CI 58·7-99·8). The mean percent change in BMI from baseline at week 52 was -18% (SD 13) in the overall safety population. Mean percent change in BMI at week 52 was -26% (SD 11) in patients with POMC or LEPR deficiency and -10% (9) in patients with BBS. Mean reductions in secondary endpoints of BMI Z score (3·4 [2·5]) and percent of the BMI 95th percentile (32·5 [22·9]) were seen at Week 52. 91% of caregivers reported that patients were less hungry than at baseline. All adverse events were mild or moderate; skin hyperpigmentation, vomiting, nasopharyngitis, upper respiratory tract infection, and injection site reactions were most common. No serious adverse events or adverse events leading to study discontinuation or death were reported. To our knowledge this is the first trial of setmelanotide in patients younger than 6 years old. These results support the benefit of the drug as an early intervention to manage obesity in this population. Rhythm Pharmaceuticals. Show less

Amyloidosis derived from apolipoprotein C-II (AApoCII) is a recently discovered, rare form of amyloidosis. Data on clinical presentations and natural history are very limited. This study defines the clinicopathologic, proteomic, and outcome characteristics of renal AApoCII. Case series. Twenty-five renal AApoCII cases were identified from the Mayo Clinic Tissue Proteomics Laboratory archives from January 2008 through January 2024. All patients were White, 19 were≥65 years old at diagnosis, and 18 were female. Seven had a family history of chronic kidney disease (CKD). Patients presented with proteinuria (median 3.3g/day) and reduced kidney function (n=16; median creatinine, 1.6mg/dL). No patients had clinical evidence of other organ involvement by amyloidosis or features of monogenic hypertriglyceridemia. Histologically, amyloid deposits were often weakly positive for Congo red and involved glomeruli in all cases (with a nodular pattern in 22), whereas extraglomerular involvement was less common and generally mild. Proteomic analysis revealed abundant spectra for Apo C-II and for all 3 amyloid signature proteins (apolipoprotein E, apolipoprotein A-IV, and serum amyloid P) in all cases and detected an Apo C-II variant in 14 (K19T [p.Lys41Thr] in 12 and E47V [p.Glu69Val] in 2). Among 22 patients with follow-up information available, there were 12 end-stage kidney disease (ESKD) events and 2 deaths without ESKD during an average follow-up period of 75.5±12.5 (SE) months. Retrospective design, small sample size, APOC2 gene sequencing performed in a smaller subset. AApoCII mostly affects the kidney and manifests in the elderly with proteinuria and CKD. A minority of these patients had a family history of kidney disease. Kidney failure occurred in about half, whereas overall survival was more favorable. Amyloidosis derived from apolipoprotein C-II (AApoCII) is very rare, and data on clinicopathologic and outcome characteristics are scant. This study of 25 patients with AApoCII diagnosed by mass spectrometry at the Mayo Clinic Tissue Proteomics Laboratory revealed that most patients were elderly White females who presented with proteinuria and reduced kidney function, without involvement of other organs. A family history of kidney disease was often lacking. Pathologically, most cases exhibited nodular glomerular involvement. Proteomic analysis revealed abundant protein spectra for Apo C-II and amyloid signature proteins, and identified an Apo C-II variant in over half of cases (most commonly the p.Lys41Thr variant). The cumulative incidence of kidney failure was over 50% at 5 years follow-up. Only 4 deaths occurred over an average follow-up period of 76 months. Show less

Metabolic dysfunction-associated steatohepatitis (MASH) is a condition characterized by hepatosteatosis, inflammation, and tissue damage, with steatosis as the initial stage, which involves chronic, excess deposition of lipids in hepatic lipid droplets. Despite the growing prevalence and serious risks it poses, including liver decompensation, the need for transplantation, and increased patient mortality, MASH currently faces no approved pharmacotherapy. Several promising treatment candidates have emerged from recent clinical trials, including analogs of FGF21 and agonists of the associated FGFR1-KLB complex. These agents were well-tolerated in trials and have demonstrated significant improvements in both histological and biochemical markers of liver fat content, inflammation, injury, and fibrosis in patients with MASH. Endocrine FGF21 plays a vital role in maintaining homeostasis of lipid, glucose, and energy metabolism. It achieves this through pathways that target lipids or lipid droplets in adipocytes and hepatocytes. Mechanistically, pharmacological FGF21 acts as a potent catabolic factor to promote lipid or lipid droplet lipolysis, fatty acid oxidation, mitochondrial catabolic flux, and heat-dissipating energy expenditure, leading to effective clearance of hepatic and systemic gluco-lipotoxicity and inflammatory stress, thereby preventing obesity, diabetes, and MASH pathologies. In this review, we aim to provide an update on the outcomes of clinical trials for several FGF21 mimetics. We compare these outcomes with preclinical studies and offer a lipid-centric perspective on the mechanisms underlying the clinical benefits of these agents for MASH. Show less

Extensive research has demonstrated that gut microbiota and its metabolites-including short-chain fatty acids, trimethylamine N-oxide (TMAO), and bile acids-play a crucial role in the pathophysiology of coronary artery disease (CAD).The bidirectional interaction between the gut microbiota and the cardiovascular system significantly influences host metabolic and inflammatory homeostasis. As a result, targeted modulation of the gut microbiota emerges as a promising adjunctive therapeutic strategy for CAD, offering potential benefits with minimal side effects. This study aims to elucidate the therapeutic mechanisms of the clinically validated Chinese medicine formula HJ11 in mitigating coronary heart disease (CHD), with a particular focus on its regulation of the heart-gut axis and associated atherosclerotic processes. This study established an ApoE-/- mouse model of atherosclerosis and treated with HJ11 via gavage.We investigated the effects of HJ11 on the gut microenvironment in these atherosclerotic mice. Gut microbial composition and faecal metabolite profiles were analyzed using 16S rDNA sequencing and metabolomics. Additionally, an in vitro model of atherosclerosis was used to examine whether HJ11 exerts anti-inflammatory effects by modulating the TLR4/MYD88/IκB-α signaling pathway. HJ11 exerted protective effects on coronary atherosclerosis by reducing systemic serum lipid levels and inhibiting plaque formation, vascular inflammation, and collagen deposition, while also alleviating aortic injury. It suppressed endothelial inflammation and inhibited the proliferation of vascular smooth muscle cells. In the gut, HJ11 alleviated intestinal structural damage and enhanced barrier integrity. Notably, it promoted the function of Akkermansia, a beneficial bacterium known to influence TLR4 expression. Finally, in an in vitro atherosclerosis model, HJ11 decoction inhibited cell proliferation and migration by inactivating the TLR4/MYD88/IκB-α signaling pathway-an effect that was abolished by TLR4 overexpression. Show less

Type 2 diabetes presents significant public health challenges. The gut microbiome has emerged as a potential factor influencing glucose metabolism. We performed a randomized, double-blind, single-center trial involving patients with type 2 diabetes and glycated hemoglobin (HbA1c) concentration of 7 % or greater. Patients were randomly assigned to receive 100 billion colony-forming units (CFUs) of probiotic supplementation daily or placebo. The primary efficacy endpoint was the change in HbA1c from baseline to 12 weeks, and secondary endpoints included lipid and inflammatory markers. A total of 130 patients were included. HbA1c was 7.63 ± 0.54 % at baseline and 7.63 ± 0.63 % at 12 weeks in the probiotic group and 7.71 ± 0.74 % and 7.81 ± 0.84 % in the placebo group (p = 0.29 between treatment groups). There were also no significant differences between treatment groups in plasma glucose (p = 0.60) and insulin (p = 0.41), as well as in LDL-cholesterol (p = 0.90) and triglycerides (p = 0.32). The adjusted geometric mean percent change (95 % confidence interval) in high-sensitivity C-reactive protein was 1.59 % (-15.71, 22.44) in the probiotic group and -1.37 % (-18.04, 18.70) in the placebo group (p = 0.82). Gastrointestinal adverse events occurred in 38.5 % and 46.2 % of patients in the probiotic group and placebo group respectively (p = 0.48). Probiotic supplementation for 12 weeks did not improve glycemic control, lipid or inflammatory markers in patients with type 2 diabetes. Further research is needed to determine the potential benefits and underlying mechanisms of probiotics in subsets of patients. gov Identifier no. NCT03239366. Show less

Phosphaturic mesenchymal tumor (PMT) is a rare bone or soft tissue tumor. It exhibits distinctive morphologic features, including bland spindled cells, highly vascularized stroma, "smudgy or grungy" calcified matrix, and osteoclast-like giant cells. It is characterized by paraneoplastic tumor-induced osteomalacia through producing phosphatonins, especially FGF23. Recent findings suggest that its tumorigenesis and FGF23 overproduction depend on the FGFR1 pathways, which may be activated via FN1::FGFR1 or FN1::FGF1 fusion, as well as by α-Klotho overexpression in the majority of fusion-negative PMTs. This review discusses the clinical, histologic, immunohistochemical, and molecular genetic features, along with potential therapies and differentiation from potential mimics. Show less

Lipoprotein (a) (Lp(a)) is a largely genetically determined (70-90%) independent risk factor for cardiovascular disease (CVD). However, clinicians often encounter adults/elder adults with elevated Lp(a), who are otherwise healthy and asymptomatic for atherosclerosis. We aimed to identify additional risk factors and conditions, apart from elevated Lp(a), which lead to atherosclerosis progression and CVD, and whether any protective factors mitigate Lp(a)-related risk. In the STAR (Specialist Care Patients) Lp(a) study, we prospectively enrolled 2,594 consecutive patients aged over 50 years, who had elevated Lp(a), referred to two outpatient cardiology clinics. These patients were either healthy, or had established CVD or three or more cardiovascular risk factors. Lp(a) concentration was measured by enzyme-linked immunosorbent assay. Among adults > 50 years with Lp(a) ≥ 30 mg/dl (75 nmol/l) (mean Lp(a), 65.4 vs. 72.7 mg/dl, In adults > 50 years with elevated Lp(a), Lp(a) - related risk of atherosclerosis progression can be substantially mitigated by addressing modifiable CVD risk factors, such as obesity, diabetes, inflammation, and dyslipidemia, preferably by early preventive measures. In our study cohort, Lp(a) was independently associated with atherosclerosis progression in the patient group only. Show less

This study aims to explore the latent profile characteristics of cognitive function in older adults living with diabetes and analyze the influencing factors, providing theoretical evidence for early intervention. A cross-sectional study design was used to select older adults living with diabetes hospitalized at a tertiary hospital as the study population. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Demographic characteristics, disease-related data (such as duration of diabetes, BMI, and HbA1c levels), and lifestyle factors (such as sleep quality, physical activity, and social support) were collected. Latent profile analysis (LPA) was employed to classify cognitive function, and ordered multinomial logistic regression was performed to analyze the influencing factors of each cognitive profile. A total of 564 patients were included. Latent profile analysis of cognitive impairment identified three categories: complete cognitive impairment (12.82%), partial cognitive impairment (54.74%), and at-risk cognitive impairment (32.44%). Logistic regression analysis revealed that gender, education level, duration of diabetes, HbA1c, diverse intellectual activities, and nutrition were independent factors influencing cognitive impairment (P<0.05). Cognitive impairment in older adults living with diabetes exhibits distinct profile characteristics and is influenced by multiple factors. Interventions should focus on improving blood glucose control, promoting diverse intellectual activities, and enhancing social support to delay the decline in cognitive function. Show less

Chronic alcohol drinking increases susceptibility to cognitive impairment; however, the underlying mechanisms remain unclear. In this study, we investigated the effects of chronic alcohol drinking on working and recognition memory in a Marchigian Sardinian alcohol-preferring (msP) rat line. Due to interest in insulin-based medications for alcohol use disorder, we examined insulin/insulin-like growth factor 1 (IGF-1) genes in the prelimbic (PL) and infralimbic (IL) medial prefrontal cortex, a region linked to alcohol dependence and cognition. Male and female msPs received access to alcohol (20% v/v) and water (H Show less

Jiaotaiwan (JTW) is a classic traditional Chinese medicine (TCM) prescription for treating depression, but its potential mechanisms are not fully understood. The aim of this study is to detect the levels of serum Short-chain fatty acids (SCFAs) and cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP-response element binding protein (CREB)-brain derived neurotrophic factor (BDNF) signaling pathway, further revealing the scientific connotation of the antidepressant effect of JTW. In this multicenter, randomized, controlled study, 120 patients with depression were divided into the JTW (16.5 g/d) group, JTW (16.5 g/d) + selective serotonin reuptake inhibitors (SSRIs) group, and SSRIs group. Hamilton depression Scale-24 (HAMD-24) and Self-rating depression scale (SDS) were used for efficacy evaluation. Enzyme linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR) were used to evaluate the expression levels of cAMP-PKA-CREB-BDNF signaling pathway. Serum SCFAs concentrations were analyzed using liquid chromatograph-mass spectrometer (LC-MS) targeted metabolomics. After eight weeks of treatment, HAMD score and SDS score were significantly decreased in the three groups, and HAMD score in JTW + SSRIs group was significantly lower than that in SSRIs group. After treatment, the expression levels of cAMP-PKA-CREB-BDNF signaling pathway were significantly increased in the three group, with the JTW + SSRIs group showing more significant increase. After treatment, the levels of isobutyric, butyric, isovaleric, and valeric acids in the JTW + SSRIs groups were significantly higher than that before treatment, and the levels of isobutyric, and isovaleric acids in the JTW + SSRIs group was significantly higher than that in the JTW group and SSRIs groups. JTW can alleviate symptoms in patients with depression, and its antidepressant mechanism may be related to regulating serum SCFAs and cAMP-PKA-CREB-BDNF signaling pathway. Show less

Coronary artery disease (CAD) is an immune-mediated disorder driven by dysregulated T cell responses. Interleukin-27 (IL-27) has immunoregulatory properties, but its role in CAD remains unclear. This study is the first to investigate the effects of IL-27 on CD4⁺LAP⁺ T cells in CAD and to explore its interaction with interleukin-2 (IL-2) in modulating immune imbalance. CAD severity was quantified by the Gensini score. Plasma IL-27 and oxidized low-density lipoprotein (ox-LDL) were measured by ELISA. Flow cytometry assessed CD4⁺ T cell subsets, while qRT-PCR and Western blot evaluated lineage-specific transcription factors. IL-27 levels were elevated in acute coronary syndrome and correlated with ox-LDL and Gensini scores. Patients with severe CAD showed a Th1/Th17-dominant profile and reductions in Th2, CD4⁺LAP⁺, and Tregs. In vitro, IL-27 promoted Th1 differentiation via T-bet/IFN-γ upregulation and suppressed Th2, Th17, and regulatory subsets, counteracting IL-2-induced expansion of Tregs and CD4⁺LAP⁺ cells. These effects were dose dependent and favored pro-inflammatory responses. IL-27 drives immune imbalance in CAD by reinforcing Th1 polarization and antagonizing IL-2-mediated regulation. Beyond mechanistic insights, these findings identify IL-27 as a potential biomarker for disease severity and a candidate therapeutic target in CAD. Show less

Chronic pain and opioid use disorder (OUD) are highly prevalent and frequently co-occurring conditions that pose complex treatment challenges. While opioids are effective for pain management, prolonged use significantly enhances risk of developing substance dependence. Conversely, addiction-focused therapies often fail to relieve persistent somatic pain. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has emerged as a novel adjunctive treatment with potential to address chronic pain and substance use disorders concurrently. The present investigation examines the role of intravenous ketamine infusions in cases with coexisting chronic pain and OUD. It explores pharmacological mechanisms, therapeutic applications, clinical efficacy, and safety considerations of ketamine. Ketamine primarily acts by blocking NMDA receptors, which are central to glutamatergic signaling. This inhibition reduces neural excitability and promotes neuroplastic changes, including upregulation of brain-derived neurotrophic factor (BDNF), a protein associated with synaptic remodeling and recovery within pain and addiction pathways. These mechanisms are likely to contribute to ketamine mediated dual efficacy in managing nociceptive symptoms and reducing opioid dependence. Clinical studies suggest that ketamine may reduce pain severity, decrease opioid consumption, and alleviate withdrawal symptoms in select populations. While early evidence supports ketamine's use, its side effect profile, including dissociative symptoms, sympathomimetic activity, and potential for misuse, necessitates careful patient selection, monitoring, and oversight. Evidence remains limited by inadequate sample sizes, non-standardized protocols, and short follow-up periods. Despite these limitations, ketamine remains a promising adjunct in multimodal care, especially when conventional therapies are ineffective. Ongoing research is essential to refine protocols and to explore integration with behavioral and pharmacologic addiction interventions. Show less

This study aimed to determine whether a history of childhood abuse (CA) and baseline serum brain-derived neurotrophic factor (sBDNF) levels predict remission at 12 weeks and 12 months in patients with depressive disorders, and to examine potential interactions between these factors. A total of 1,086 patients with depressive disorders, participating in a naturalistic, stepwise antidepressant treatment study, were assessed at baseline. CA was evaluated using the Nemesis Childhood Trauma Interview, and sBDNF levels were measured. Remission was defined as a Hamilton Depression Rating Scale score of ≤ 7. Logistic regression analyses examined the independent and interactive effects of CA and sBDNF on remission outcomes, adjusting for relevant covariates. Low baseline sBDNF independently predicted poorer remission at 12 months (p = 0.045) but not at 12 weeks (p = 0.720). In adjusted analyses, CA alone did not significantly predict remission at either time point (all p > 0.05). However, patients who had both a CA history and low baseline sBDNF showed significantly lower remission rates at 12 weeks (p = 0.018) and 12 months (p = 0.009), indicating a significant interaction between these factors. These findings underscore the importance of integrating psychosocial and biological factors in personalized depression treatment. Routine screening for childhood trauma, combined with assessment of sBDNF levels, may help identify high-risk patients needing targeted interventions. Further prospective research is necessary to validate these findings. Show less

The neuroprotective potential of cannabidiol (CBD) was assessed in a mouse model of acrylamide-induced neurotoxicity. Acrylamide (AA), an environmental and dietary pollutant, is known to cross the blood-brain barrier and induce oxidative stress, inflammation and neurotoxic effects. Male C57BL/6 mice were randomly assigned to four groups: Control (Con), Acrylamide (AA), Cannabidiol (CBD), and a combination treatment (AA + CBD). The AA group received acrylamide (10 mg/kg, i.p.) daily for 5 days. CBD was administered (10 mg/kg, i.p.) for 10 days in the CBD and AA + CBD groups. In the AA + CBD group, acrylamide (10 mg/kg, i.p.) was co-administered during the last 5 days of CBD treatment. Behavioral outcomes were analyzed using the open field test, revealing that CBD mitigated anxiety-like behavior induced by acrylamide, enhancing movement and center exploration. Further, CBD treatment modulated oxidative stress responses, reducing MDA levels and partially restoring antioxidant markers (GSH, SOD, and CAT) in the hippocampus and striatum. Inflammatory markers were also assessed, revealing that acrylamide elevated pro-inflammatory cytokines TNF-α and IL-6. Notably, CBD co-treatment reduced TNF-α levels in the hippocampus and cortex and attenuated IL-6 levels in the cortex and striatum, suggesting an anti-inflammatory effect. Additionally, CBD modulated neuroplasticity by increasing BDNF levels in the hippocampus, counteracting the reduction caused by acrylamide. CBD also influenced cholinergic activity by restoring Ach levels and altering AChE activity across brain regions. Findings suggest that CBD exhibits neuroprotective properties by reducing oxidative stress, inflammation and cholinergic dysregulation, thereby offering a promising therapeutic approach for mitigating pollutant-induced neurotoxicity and potentially treating neurodegenerative disorders. Show less

Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for Alzheimer's disease (AD), with homozygous carriers (ε4/ε4) experiencing accelerated cognitive decline. While its role in amyloid and tau pathology is established, its impact on retinal and cerebral microvasculature remains underexplored. A total of 107 AD (46 non-carriers, 42 heterozygotes, 19 homozygotes) underwent optical coherence tomography angiography (OCTA) to assess retinal microvasculature and magnetic resonance imaging (MRI) -derived peak width of skeletonized mean diffusivity (PSMD) to evaluate cerebral small vessel disease. Plasma biomarkers (Aβ Homozygous APOE ε4 carriers exhibited the most severe reduction in retinal microvascular density and higher PSMD (p < 0.001). Superficial retinal vessels and PSMD partially mediated APOE ε4's association with cognitive impairment. APOE ε4 homozygosity exacerbates retinal and cerebral microvascular dysfunction, which partially mediates cognitive impairment in AD. Apolipoprotein E (APOE) ε4 homozygosity is associated with the most severe reductions in retinal microvascular densities and elevated cerebral small vessel disease (peak width of skeletonized mean diffusivity [PSMD]) in Alzheimer's disease (AD). Vascular dysfunction (retinal and cerebral) correlates with lower Aβ42, higher p-tau217/Aβ Show less