Citations

ABSTRACT Background Bile acid (BA) malabsorption (BAM) is a common cause of chronic diarrhoea and may occur in some patients due to abnormalities of the gut microbiota. Effects of probiotics on faecal secretory BAs, particularly the primary BA, chenodeoxycholic acid, are unclear. Aim/Methods We conducted a randomized, double‐blind, placebo‐controlled trial of the De Simone formulation 8‐strain probiotic in 24 patients previously diagnosed with BAM. Patients were randomized to 3 weeks of the probiotic (900 billion bacteria) or placebo (maltose), both administered three times daily. Symptoms, serum 7 α C4, faecal primary BAs, intestinal permeability by 13 C‐mannitol‐lactulose test (0.1 and 1 g of the sugars respectively) over 24 h, faecal short chain fatty acids (SCFA), microbiome, and metabolome were assessed at baseline and post‐intervention. Results Data from 22 patients were included. Probiotic supplementation was associated with a significant decrease in % faecal primary BAs (chenodeoxycholic acid and cholic acid) with median change from baseline −5.7 [IQR −10.3, 0.9]% compared to 9.8 [IQR 0.2, 20.6]% on placebo ( p = 0.012). The faecal microbiome was significantly different in the probiotic group after intervention, driven by probiotic‐specific species. There were no significant differences in symptoms, intestinal permeability, or SCFA. However, there was a numerical difference in the changes from baseline in 0‐2 h 13 C‐mannitol excretion −1.9 [−13.9, 4.2] mg for the probiotic and 1.0 (−0.5, 12.7) mg for placebo ( p = 0.084). Conclusions The De Simone formulation probiotic induced significant microbiome and metabolome changes in patients with BAM, ultimately leading to a decrease in % faecal primary BAs and possible reduction in intestinal permeability. Clinical Trials.gov registration NCT #06609148, January 2, 2025.

Abstract Background Identification of individuals at increased risk for synucleinopathies is becoming more feasible with advances in biomarkers. However, the ethical and practical aspects of communicating disease risk remain unresolved, particularly across diagnostic groups and cultural contexts. Objectives We aimed to evaluate attitudes toward disclosure of future synucleinopathy risk among individuals with isolated/idiopathic REM sleep behavior disorder (iRBD), as well as in individuals who developed Parkinson's disease (PD), or multiple system atrophy (MSA), in a large non‐Western registry. Methods This nationwide survey study included participants from 28 movement disorders and sleep centers across Türkiye. Questionnaires assessing attitudes toward risk disclosure, additional testing, and clinical trial participation were administered face‐to‐face. Responses were analyzed using contingency tables and regression models. Results are reported following the Consensus‐Based Checklist for Reporting of Survey Studies (CROSS) guideline. Results Among 1385 participants (1039 PD, 107 MSA, 239 iRBD), individuals with iRBD showed the highest support for risk disclosure (88.3%), exceeding PD (64.4%) and MSA (51.9%). Approval declined modestly (3–8%) when framed within the absence of disease‐modifying treatment. iRBD participants were more willing for additional testing but less willing to join clinical trials (31.8%) than PD (45.3%) or MSA (48%). MSA patients expressed the greatest concern about psychological impact. Male sex had more favorable views on disclosure and trial participation, while younger and better‐educated participants favored additional testing. Conclusions Attitudes toward risk disclosure differ markedly across the synucleinopathy spectrum and demographic characteristics. Culturally informed and diagnosis‐specific disclosure strategies will be essential for trial recruitment and patient‐centered care.

Abstract Background Upper-airway and respiratory conditions impose a large and growing global burden, yet there is no standardized way to assess whether a nasal microbiome is “healthy”. Currently, monitoring remains reactive, beginning only after symptoms manifest. The nasal cavity is well suited to proactive monitoring: it shapes respiratory health and pathogen colonization resistance, and can be sampled non-invasively and repeatedly. To address this gap, we introduce the Nasal Microbiome Wellness Index (NMWI), a disease-agnostic, continuous score of nasal microbiome health derived from LASSO-penalized logistic regression. Rather than counting taxa, it learns which taxa (and in what balance) characterize a healthy nose and returns the predicted log-odds that a profile resembles a healthy state. The index was trained on 1654 nasal 16S rRNA gene amplicon sequencing samples (589 healthy, 1065 non-healthy) pooled from 27 publicly available studies, uniformly reprocessed through a single computational pipeline. Results The NMWI comprises an interpretable signature of 24 taxa whose combined relative abundances determine the health-associated log-odds. Health-associated genera such as Corynebacterium and Cutibacterium raised the score, while dysbiosis-associated genera such as Pseudomonas and Escherichia – Shigella lowered it. The NMWI substantially outperformed the Shannon, Simpson, and Chao1 diversity indices, which showed negligible, directionally inconsistent separation between healthy and non-healthy samples (|Cliff’s δ | = 0.01–0.20), whereas the NMWI produced large, consistent separation ( δ = 0.65). It achieved a balanced accuracy of 74.37% on the training data (resubstitution estimate), and 73.43% under repeated 10-times 10-fold cross-validation. Performance remained stable at mean balanced accuracy of 73.82% under a leave-one-study-out framework, reflecting cross-study generalizability. In independent external cohorts, the balanced accuracy was 71.49%, and leave-one-disease-out analysis (in which each disease condition was withheld from training) showed a mean balanced accuracy of 63.92% across unseen conditions, consistent with a disease-agnostic design. The index also generalized across heterogeneous datasets spanning multiple 16S rRNA gene hypervariable regions—to our knowledge the first demonstration of such cross-study, cross-region transferability for the nasal cavity. Conclusions The NMWI distills a complex nasal microbial profile into a single interpretable score computed directly from the 16S rRNA gene data that dominate existing nasal research, making it immediately applicable to published and future datasets without re-sequencing. By replacing descriptive, diversity-based comparison with a quantitative standard, it offers a reproducible, open-source foundation for cross-study benchmarking, individual-level phenotyping, and longitudinal respiratory wellness monitoring.

ABSTRACT Beta‐lactam antibiotics (beta‐lactams) are first‐line treatments for most major infectious syndromes in acutely ill patients, with in vitro activity against common pathogens, demonstrated efficacy in trials, and a perceived low risk of adverse effects. The current dosing approach, informed by population‐level data, tends to be simplistically reduced to a “one size fits all” dosing method which only accounts for body weight (i.e., in pediatrics) and end organ function to estimate drug clearance (e.g., estimated glomerular filtration rate); this approach results in substantial variability in observed serum concentrations in acutely ill patients, which can compromise real‐world effectiveness and safety. Beta‐lactam dose individualization, therefore, defined as a dosing regimen for one patient informed by measured concentrations from that patient, has been recommended in international clinical guidelines. Comprehensive guidance on best practices for beta‐lactam dose individualization is lacking. To address this knowledge gap and develop guidance, a multidisciplinary panel of international experts was assembled from the disciplines of infectious diseases, critical care, pharmacometrics, and laboratory medicine, representing both adults and pediatrics. The panel systematically evaluated the literature, using the GRADE approach where feasible, to address broad thematic questions pertaining to whether beta‐lactam dose individualization should be pursued, for what indications beta‐lactam dose individualization is warranted, and the most critical considerations and best practices for implementation of beta‐lactam individualization. The resultant consensus recommendations will equip healthcare professionals caring for acutely ill patients treated with beta‐lactam therapy with the evidence and tools necessary to guide optimal use of beta‐lactam dose individualization.

Abstract Frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD) differ in their clinical features and genetic etiologies but share progressive cognitive decline. Emerging evidence implicates lipid dysregulation in neurodegeneration, but its extent across FTLD subtypes and how it compares to AD are unclear. Here, we performed integrated lipidomic and proteomic analyses of matched frontal (disease-vulnerable) and occipital (relatively spared) post-mortem cortices from individuals with genetic and sporadic FTLD-TDP, FTLD-tau (Pick’s disease, PiD), AD, and controls. FTLD and AD exhibited convergent lipid alterations, including reduced levels of cardiolipins and phosphatidylethanolamines, alongside increased gangliosides, diacylglycerols, cholesterol esters, acylcarnitines, and coenzyme Q, with generally greater changes in FTLD frontal cortex. FTLD displayed additional alterations, including reductions in bis(monoacylglycerol)phosphate, ceramides, phosphatidylserines, phosphatidylinositols, and sulfatides. These lipid changes were accompanied by proteomic alterations involving lysosomal proteins, phospholipases, phospholipid remodeling enzymes, and fatty acid oxidation pathways. Although lipidomic and proteomic signatures were broadly shared across FTLD subtypes, GRN associated FTLD-TDP and PiD showed the most extensive alterations. Triglycerides were selectively reduced in PiD in association with decreased DGAT1 expression, whereas cholesterol esters were elevated across all subtypes except C9orf72 associated FTLD-TDP. These findings identify shared disruptions in lipid homeostasis and lysosomal lipid metabolism across FTLD and AD, highlighting convergent metabolic pathways underlying neurodegeneration.

Background: Influenza-associated encephalopathy, encephalitis, and acute necrotizing encephalopathy (ANE) are rare but potentially life-threatening neurological complications of influenza. Adult cases remain poorly characterized because the available literature is largely limited to isolated case reports and small case series. Methods: A PRISMA-guided scoping review of the MEDLINE database was conducted through 31 May 2026. Published adult cases of influenza-associated encephalopathy, encephalitis, and ANE were identified and analyzed for demographic characteristics, clinical presentation, neuroimaging findings, treatment, and outcomes. Results: Eighty-three adult cases reported between 1958 and 2026 were included. The mean age was 45.6 ± 17.8 years, and 57.8% were male. Two-thirds did not have any underlying comorbidities. Neurological symptoms developed a mean of 4.6 days after influenza onset, with influenza A accounting for 80.7% of infections. Fever (91.6%), altered mental status (86.7%), and seizures (36.1%) were the most common manifestations. Encephalitis was the predominant presentation (44.5%), followed by encephalopathy (31.3%) and ANE (24.1%). MRI most frequently demonstrated cerebral hemispheric lesions (53.0%) and bilateral thalamic involvement (36.4%), while EEG abnormalities were reported in 69.6% of patients. Overall mortality was 22.9%, highest among patients with ANE (45.0%). Among survivors, 28.9% experienced persistent neurological sequelae. Conclusions: Influenza-associated encephalopathy, encephalitis, and ANE are rare in adults but are associated with substantial morbidity and mortality. This review represents the largest adult cohort reported to date and provides important insights into the clinical spectrum, neurodiagnostic findings, and outcomes of these uncommon complications. This review highlights significant gaps in knowledge and the need for collaborative multicenter studies to improve the diagnosis, treatment, and outcome of these severe complications of influenza infection.

Background: By 2030, nearly one-quarter of the U.S. population will be over age 65, emphasizing the need to understand factors that promote healthy aging. Vitality is often reduced to physical indicators in clinical frameworks, overlooking its multidimensional nature. Methods: This qualitative descriptive study explored how independently living older adults define and experience vitality, focusing on physical, emotional, cognitive, and social dimensions. Guided by Self-Determination Theory, semi-structured interviews were conducted with 10 participants aged 61–83 years purposively recruited from community and faith-based settings in Northeast Florida. Results: Thematic analysis revealed four interconnected themes: (1) Make Adjustments, Keep Going; (2) Being Mentally Jubilant; (3) Bonds that Keep Me Going; and (4) Thriving Amid Uncertainty. Conclusions: Findings suggest that participants perceived vitality as a dynamic, multidimensional process shaped by adaptation, purpose, and connection rather than physical health alone. These insights underscore the need for holistic approaches to vitality assessment and interventions that support autonomy, competence, and relatedness in later life.

Abstract Aims Randomized trials comparing percutaneous left atrial appendage occlusion (LAAO) with oral anticoagulation (OAC) for stroke prevention in patients with atrial fibrillation have yielded conflicting results across device generations and anticoagulant eras. This Bayesian meta-analysis of randomized trials aimed to compare LAAO vs. OAC for stroke or systemic embolism (SSE) and non-procedural clinically relevant bleeding (CRB). Methods and results We conducted a systematic search across five databases (PubMed, Embase, Scopus, Web of Science, and Cochrane CENTRAL) to identify randomized trials of LAAO vs. OAC. Primary outcomes of stroke or systemic embolism, non-procedural CRB and clinical benefit composite were estimated using a Bayesian hierarchical random effects model and findings confirmed across robust sensitivity and subgroup analyses. Posterior probabilities for superiority, non-inferiority and equivalence were estimated using clinically meaningful margins. Six randomized trials including 7004 participants in the intention-to-treat groups, were analysed. LAAO was not associated with lower SSE vs. OAC (pooled RR, 1.11; 95% CrI, 0.80–1.49), with a 74.6% posterior probability of favouring OAC. The posterior probability of crossing non-inferiority was P(HR < 1.4) of 89%. In contrast, LAAO reduced non-procedural CRB (pooled RR, 0.59; 95% CrI, 0.45–0.78). The net clinical benefit composite, pooling contemporary trials, demonstrated a pooled RR of 0.90 (95% CrI 0.51–1.50), with P(RR < 1) of 76%, with substantial heterogeneity for this outcome. Conclusion This Bayesian meta-analysis found no clear evidence supporting clinically meaningful non-inferiority of LAAO over OAC for stroke prevention. Despite reduced non-procedural bleeding, LAAO did not demonstrate a similar reduction in major bleeding.

ABSTRACT Reliable assessment of infarct severity is essential in experimental stroke research, yet commonly used approaches such as 2,3,5‐triphenyltetrazolium chloride (TTC) staining and magnetic resonance imaging require additional tissue processing, specialized equipment, or substantial time and cost. In this study, we developed and validated a rapid visual Infarct Score to determine infarct volume and evaluate neuroprotective efficacy in rat middle cerebral artery occlusion (MCAO) models. A retrospective analysis was performed using data from 315 male Sprague–Dawley rats, including TTC‐derived infarct volume, visual Infarct Score, neurological deficit scores, and body weight changes. The Infarct Score demonstrated the strongest correlation with infarct volume among individual indicators in both nontreatment (Rho = 0.71) and treatment cohorts (Rho = 0.68). We further developed a Comprehensive Score by integrating the Infarct Score with the Longa 5‐point score at 48 h, which showed the highest overall correlation with infarct volume (Rho = 0.75 in both cohorts) and strong discrimination of infarct severity (AUC = 0.90). Interrater reliability analysis demonstrated excellent agreement among independent raters (intraclass correlation coefficient = 0.89; Kendall's W = 0.83, both p < 0.001). Neuroprotective interventions, including therapeutic hypothermia, nitroglycerin, and remote ischemic conditioning combined with physical exercise, significantly reduced infarct volume, Infarct Score, Comprehensive Score, neurological deficits, and weight loss. These findings indicate that the Infarct Score offers a rapid, practical, and cost‐effective method for infarct assessment, whereas the Comprehensive Score further improves the predictive accuracy and may serve as a useful tool for evaluating stroke severity and treatment outcomes in preclinical studies.