Citations

Background Female sex hormones used in feminizing hormone therapy (FHT) may influence activation and persistence of HIV pre‐exposure prophylaxis (PrEP) medications. The clinical relevance of this interaction remains unclear, particularly for transgender and cisgender women (TGW and CGW). To address this gap, we examined drug metabolites in HIV susceptible cells isolated from blood and rectal tissues of TGW and CGW. Materials and Methods We enrolled 23 TGW, 13 on FHT and 10 CGW. Participants received five directly observed daily PrEP doses: emtricitabine 200 mg with either tenofovir disoproxil fumarate 300 mg (FTC/TDF) or tenofovir alafenamide 25 mg (FTC/TAF). Blood and rectal tissue samples were obtained. Mononuclear and CD4 + cells were isolated and analysed for intracellular triphosphorylated nucleotides (TFVdp and FTCtp) and total nucleotide pools (pTFV and pFTC) using HPLC‐MS/MS. Serum hormone concentrations were quantified via enzyme immunoassay. Results and Conclusion Total nucleotide pools (pTFV and pFTC) correlated with active metabolites (TFVdp and FTCtp) in blood and rectal CD4 + cells ( r 2 > 0.75, p < .001). No significant differences in pTFV or pFTC concentrations were observed between high and low oestradiol groups in either CGW or TGW ( p > .1). No correlation was observed between serum oestradiol concentrations and nucleotide concentrations. TAF resulted in 6.8‐fold higher median pTFV concentrations in blood CD4 + cells ( p < .001) but eightfold lower median pTFV concentrations in rectal CD4 + cells compared to TDF ( p = .008). These findings suggest that neither endogenous hormonal fluctuations in CGW nor exogenous FHT in TGW adversely impact intracellular PrEP pharmacology in key HIV target cells.

Objective Positive α‐synuclein seed amplification assay (SAA) is a biomarker found in most people with Parkinson's disease (PD). We explored if free‐water (FW) imaging detects microstructural differences in the brains of patients with early PD with SAA+ or SAA– status. Methods We studied patients with PD with baseline diffusion imaging and α‐synuclein SAA data from the Parkinson's Progression Markers Initiative (PPMI). We compared FW, FW corrected fractional anisotropy (FA T ), and clinical characteristics between SAA+ and SAA– groups. We also applied the Automated Imaging Differentiation for Parkinsonism (AIDP) at baseline to classify PD versus atypical parkinsonism, stratified by SAA status. Results Among 462 participants (41 SAA– and 421 SAA+), individuals with SAA+ had hyposmia and shorter motor symptom duration before baseline magnetic resonance imaging (MRI). AIDP identified PD in 92.4% (n = 427, 91.6% had SAA+) and classified 7.6% as atypical parkinsonism (n = 35, 85.7% had SAA+). At baseline, SAA+ individuals had lower FW in the superior cerebellar peduncle, compared to SAA– (pFDR < 0.05). No significant differences in FA T were found between groups. Interpretation Positive α‐synuclein SAA was associated with focal microstructural differences but did not distinguish broader diffusion MRI (dMRI) changes across FW and FA T metrics. These findings indicate that molecular confirmation of synuclein aggregation (via SAA) provides limited stratification of neurodegeneration detected by FW imaging in early PD. ANN NEUROL 2026;100:295–304

Background: Clostridioides difficile infection (CDI) is well-recognised as a cause of flare in inflammatory bowel disease (IBD). Objectives: To prospectively evaluate CDI as a cause of flare in moderate-to-severe ulcerative colitis (UC) and perform a region-specific systematic review to evaluate the role of CDI in IBD patients in South Asia. Design: A single-centre prospective observational study followed by a region-specific systematic review. Data sources and methods: The observational study was conducted between December 2024 and December 2025 and included patients with moderate-to-severe UC flares. Triple testing using Stool glutamate dehydrogenase (GDH), an enzyme immunoassay (EIA) for toxin A/B, and polymerase chain reaction (PCR) testing was performed. A literature search in PubMed, Embase, and Scopus was conducted on 5th December 2025 to identify relevant studies from South Asia. Information on the study population (IBD type, age, gender, disease activity), the testing method, and the outcomes of CDI testing were extracted. The pooled prevalence of CDI was estimated using a random-effects model. The risk of Bias was assessed using Joanna Briggs’ tool. Results: Of the 101 patients with active UC, 59 had acute severe UC. Six patients tested positive for GDH, whereas only one tested positive for EIA and PCR. A total of 13 studies reporting on 1267 patients were included in the systematic review. Pooled prevalence of CDI was 0.06 (0.03–0.11, I 2 = 80.8%). Subgroup analyses were performed by testing method, study type, and region. However, there was persistent statistical heterogeneity. Funnel plot and Egger’s test suggested the presence of publication bias. Conclusion: Our observational study shows a low prevalence of CDI as a cause of UC flares. The findings of the systematic review suggest high variability in the CDI positivity across South Asia. These differences were not fully explained by the method of testing, the type of study, or the geographic location of the study.

ABSTRACT Background Opioids are indicated for pain that occurs with cancer and other disorders that become more prevalent with aging. The most prevalent and persistent adverse effect of opioid therapy is opioid‐induced constipation (OIC). OIC impairs patient quality of life (QoL) and leads to suboptimal pain management due to medication non‐adherence. Unlike other adverse effects, OIC persists and is not associated with pharmacological tolerance, necessitating long‐term management. Objectives The objective of this study is to evaluate current clinical strategies for OIC by comparing recommendations from American, European, and Japanese clinical guidelines. We reviewed the clinical evidence for the peripherally acting μ‐opioid receptor antagonist (PAMORA) naldemedine (the only PAMORA approved in Japan) and the rationale for early intervention in OIC. Methods The clinical guidelines and recent clinical trial data, including the COMPOSE program (phase III clinical trials of naldemedine for OIC in patients with chronic non‐cancer pain), were reviewed to establish an evidence‐based framework for the management of chronic cancer and non‐cancer pain. Results Conventional laxatives frequently provide inadequate relief as they address secondary symptoms rather than the underlying receptor‐mediated cause. PAMORAs (including naldemedine, methyl naltrexone, and naloxegol) antagonize gastrointestinal opioid receptors without compromising central analgesia. Early initiation of PAMORAs stabilizes bowel function and reduces the incidence of treatment‐related diarrhea that occurs when using conventional laxatives to treat OIC. Conclusion The 2023 Japanese guidelines advocate the proactive use of the PAMORA naldemedine as a primary treatment option. This mechanism‐based early intervention model offers a promising framework for optimizing QoL and implementing effective analgesia in an aging global population.

ABSTRACT Background and Objective Despite growing interest in mindfulness‐based interventions for adolescents with chronic pain, the data have not been systematically summarized. We conducted a systematic review and meta‐analyses to estimate the effect of mindfulness‐based interventions on pain intensity, catastrophizing, acceptance and interference; functioning, quality of life, and anxiety and depression in youth with chronic pain. Databases and Data Treatment Electronic databases CINAHL, CCTR, Embase, Medline, PsycINFO, Scopus and Web of Science were systematically searched to January 2, 2025. Studies were included if they were in English, included > 5 patients, were not part of intensive interdisciplinary pain treatment and included pre‐post outcomes from mindfulness‐based interventions delivered to adolescents with chronic pain. Risk of bias was assessed with the Newcastle–Ottawa Scale. Results Fourteen studies including a total of 323 adolescents were identified. There were significant within group improvements in pain intensity, pain catastrophizing, pain acceptance, pain interference, functioning, depression, anxiety, and quality of life, with results maintained or increased at follow‐up effect sizes at follow‐up were moderate to large (e.g., quality of life SMD = 0.33; pain intensity SMD = −0.73; pain interference SMD = −1.44). Heterogeneity of results was generally moderate to high. Compared to standardized long interventions, variable length interventions showed greater pre‐post changes in functioning, pain intensity, and pain catastrophizing. The certainty in the estimates was generally low, due to risk of bias and pre‐post designs. Conclusions Although adolescents with chronic pain report improvements after participating in mindfulness‐based interventions, rigorous RCTs are needed to substantiate these results. Significance Statement Chronic pain in youth is common and difficult to treat. Previous interventions have largely been based on cognitive‐behavioural therapy and not successful for all. This is the first systematic review and meta‐analysis in paediatric chronic pain to focus on mindfulness‐based interventions, highlighting an alternative and potentially effective intervention approach. This study informs clinicians about an effective intervention approach and assists researchers in identifying gaps for further research.

Abstract INTRODUCTION Alzheimer's disease neuropathologic change (ADNC) classification identifies not/low and intermediate/high levels of neuropathology. Our goal was to assess how frequently a positive amyloid positron emission tomography (PET) scan indicates not/low ADNC and whether this autopsy finding can occur >10 years after a positive amyloid PET. METHODS Participants with positive amyloid PET scans were categorized by levels of ADNC at autopsy, grouped by time from initial positive amyloid PET to time of death (<5 years, 5 to <10 years, or 10+ years). RESULTS Among those with a positive amyloid PET scan, the majority had intermediate/high ADNC at autopsy (234/259, 90%). In the group with 10+ years between a positive amyloid PET and death ( n = 39) not/low ADNC occurred in 3/39 (8%). DISCUSSION Not/low ADNC is uncommon among those with positive amyloid PET scans. After 10+ years, it is possible but rare for a positive amyloid PET scan to represent an indolent state of neuropathology.

Abstract INTRODUCTION Prospective studies of blood‐based biomarkers reflecting pathogenic processes, other than Alzheimer‐specific pathologies, that contribute to dementia in diverse cohorts are lacking. METHODS We jointly fitted linear mixed‐effect models and proportional hazards models to examine associations of midlife glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble cluster of differentiation‐14 (sCD14), neurofilament light chain (NfL), total tau (t‐tau), and ubiquitin C‐terminal hydrolase L1 (UCHL1) levels in serum (collected in 1993 to 1995) with cognitive decline and incident dementia (ascertained over 29 years through 2022) in the community‐based Atherosclerosis Risk in Communities Study. sCD14 and YKL‐40 were measured in 3082 participants and the other four biomarkers in 1766 participants. RESULTS Higher serum GFAP, YKL‐40, sCD14, and NfL were associated with faster cognitive decline and elevated dementia rate (e.g., 1 standard deviation [SD] higher log‐base2 YKL‐40 was associated with −0.11SD faster 25‐year cognitive decline (95% confidence interval [CI]: −0.15,−0.07) and 45% higher dementia hazard (hazard ratio [HR]: 1.45 [95% CI: 1.25, 1.68]). Higher t‐tau and UCHL1 were also associated with faster cognitive decline. DISCUSSION Midlife blood biomarkers reflecting glial and neuronal dysfunction and neuroinflammation are associated with early cognitive impairment.