Prion diseases, of which Creutzfeldt-Jakob disease is the most common, are fatal neurodegenerative disorders and are often rapidly progressive. They are associated with a significant palliative care burden for patients and families, ranging from prognostic uncertainty to complex symptom management to caregiver distress. Healthcare professionals face unique pressures when caring for these patients, which can include a lack of familiarity with this rare diagnosis and rapidly evolving symptom needs due to accelerated clinical deterioration. We convened a multidisciplinary panel of experts from around the UK, including palliative care doctors, general practitioners, physician and nurse specialists in prion diseases, and a lived experience representative to compile practical, consensus-based recommendations for managing prion diseases, much of which can also be applied to other rapidly progressive dementias. In this article, we examine the available evidence base for managing various aspects of prion diseases. Where evidence is limited, we suggest best practices informed by decades of our collective experiences.

An estimated 60% of autistic adults suffer from insomnia symptoms, which significantly impairs daily functioning and wellbeing. This study evaluated the effectiveness of i-Sleep Autism, a 5-week, guided self-help internet-delivered cognitive behavioral therapy-based intervention (ICBT-I) for insomnia in autistic adults. In co-creation with seven autistic adults with sleeping problems, i-Sleep Autism was adapted from i-Sleep, a pre-existing non-autism specific intervention. A total of 163 adults with autism and insomnia (ISI≥10) was randomly allocated to i-Sleep Autism (n=82) or waitlist control (n=81; receiving psychoeducation and sleep hygiene). Participants were assessed at baseline (T0), mid-intervention (T1; 3-weeks), post-test (T2; 6-weeks), and follow-up (T3; 6 months) on insomnia severity (primary outcome), pre-sleep arousal, anxiety, depression, daily functioning, and quality of life. In the intervention group, 56.1% completed four, and 50% all five modules. Intent-To-Treat analyses revealed a significant reduction in insomnia severity at T1 and T2 (d = 1.02, 95%CI = [0.65, 1.40]), and cognitive- and somatic pre-sleep arousal at post-test, when comparing intervention to control. The intervention group showed significantly higher quality of life at post-test. At T2, 37.8% of the intervention group versus 11.1% of the control group showed clinically meaningful improvement of insomnia. Effects on insomnia severity were maintained at 6-month follow up. No significant effects were found for anxiety, depression, or daily functioning. This is the first RCT to investigate autism-adapted ICBT-I for autistic adults suffering from insomnia. i-Sleep Autism effectively and sustainably improves insomnia. Additional strategies are needed to support dropouts and those who did not benefit.

Learning health systems (LHS) are an approach to translate patient data into actionable clinical insights, empower healthcare teams to drive quality improvement and reduce health inequalities. Here we present a protocol for a realist evaluation to explore what works to implement a learning health system approach in primary care settings in Thailand, for whom does it work, how, why and in what circumstances.

A mixed-methods realist evaluation will run in parallel with an interventional trial [Reg No: NCT06873243] in Northern Thailand which aims to improve the management of hypertension (HTN), type 2 diabetes mellitus (T2DM) and chronic kidney diseases (CKDs) using a data-supported learning health systems approach. As part of the trial, 16 primary care units (PCUs) in Chiang Mai and Lamphun provinces will be randomly selected to receive a learning health system intervention to support quality improvement for care of HTN, T2DM and CKD. Performance will be compared between intervention PCUs and all other PCUs in the region. Participants of the realist evaluation will include clinical and other professional staff involved in the development and implementation of the LHS. This realist evaluation will use both quantitative and qualitative data, including semi-structured interviews, surveys and documents from participating sites. Quantitative and qualitative findings will be systematically integrated to test, refine and validate context-mechanism-outcomes to identify consistencies, contradictions and explanatory mechanisms as part of a final programme theory for the successful implementation of the LHS.

Ethical approval has been granted by all collaborating university Research Ethics Committees (ref: 1090, 0321, 32540). Results will be disseminated to stakeholders, including patients and the public, health providers, the Thai government and WHO office. Our methods and dissemination will be guided by National Institute for Health Research and Guidelines International Network reporting standards for Patient and Public Involvement and Engagement.

Therapeutic resistance in esophageal adenocarcinoma (EAC) remains poorly understood at the level of tumor-stroma interactions. We investigated whether cancer-associated fibroblast (CAF)-derived signaling contributes to chemoradiation resistance and adverse clinical outcomes in EAC, with a focus on the functional role of GDF15 within the CAF-secreted program.

Serum GDF15 levels were analyzed in EAC patients before and after neoadjuvant chemoradiotherapy according to the CROSS regimen, with prognostic relevance validated in an independent cohort and public datasets. Primary EAC CAFs, EAC cell lines, and patient-derived organoids (PDOs) were used to model tumor-stroma crosstalk in 2D and 3D co-culture systems. Compartment-specific transcriptomic and proteomic profiling identified CAF-regulated pathways. Genetic depletion and antibody-mediated neutralization of GDF15 were used to assess its functional contribution, followed by evaluation of chemoradiation sensitivity, mitochondrial function, oxidative phosphorylation dependency, and AKT pathway activation.

Serum GDF15 levels increased significantly following CROSS treatment, and elevated post-treatment GDF15 independently predicted poor overall survival in EAC patients. CAFs enhanced resistance to chemotherapy and radiotherapy in EAC cells and PDOs, accompanied by increased GDF15 secretion. Compartment-specific transcriptomic analysis and ELISA supported CAFs as a major source of inducible GDF15 during tumor-stroma interaction. Genetic depletion of GDF15 reduced treatment resistance, whereas recombinant GDF15 partially restored chemoresistance in GDF15-depleted models. GDF15 neutralization attenuated CAF-associated cisplatin tolerance. Mechanistically, GDF15 contributed to AKT activation and mitochondrial respiratory adaptation, including enhanced oxidative phosphorylation. Pharmacological attenuation of oxidative phosphorylation further sensitized EAC cells to cisplatin, particularly under CAF co-culture conditions.

Our study identifies CAF-derived GDF15 as a clinically relevant and functionally targetable component of a broader CAF-secreted resistance program in EAC. GDF15 contributes to AKT-associated mitochondrial adaptation and tumor cell tolerance to chemoradiation, while elevated post-CROSS serum GDF15 serves as a prognostic biomarker. These findings support further investigation of GDF15-directed and mitochondria-targeted strategies to overcome CAF-associated treatment resistance in esophageal adenocarcinoma.

Blood concentrations of amino acids have been associated with depression, although findings have been inconsistent. We investigated associations between serum amino acid concentrations and genetic liability to depression, assessed by two genetic depression risk scores, in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

The LURIC study enrolled 3,316 participants referred for coronary angiography; serum amino acid measurements were available for 2,143 individuals and were quantified by ion-exchange chromatography. Two weighted genetic depression risk scores, based on 101 and 220 genome-wide significant variants, were calculated. Associations between genetic depression risk scores and amino acid concentrations were assessed using multivariable linear regression models adjusted for age, sex, body mass index, renal function (eGFR), diabetes, hypertension, and coronary artery disease. Clinical depression data were not available; thus, analyses reflect genetic liability rather than manifest depression.

In multivariable-adjusted analyses, higher genetic depression risk (per SD increase) was associated with lower concentrations of α-aminoadipic acid (GDRS₁₀₁: β = -0.097, 95% CI - 0.161 to - 0.033, p = 0.003; GDRS₂₂₀: β = -0.076, 95% CI - 0.141 to - 0.011, p = 0.021), which remained significant after false discovery rate (FDR) correction. α-aminobutyric acid showed inverse associations that did not remain significant after FDR correction. No statistically significant associations for other amino acids remained after multivariable adjustment and correction for multiple testing. Restricted cubic spline analyses suggested predominantly linear relationships, with evidence of non-linearity observed for selected amino acids, particularly homoarginine with respect to GDRS₂₂₀ (p for non-linearity = 0.005).

Genetic liability to depression was associated with differences in serum amino acid concentrations, particularly lower α-aminoadipic acid concentrations in this cardiovascular cohort, whereas associations with other amino acids were not robust after correction for multiple testing. These findings are associative and hypothesis-generating and should be confirmed in cohorts with detailed depression phenotyping and longitudinal follow-up.

Several digestive diseases have been reported as comorbidities of COPD. However, consistent evidence supporting their associations is limited. Our study aims to investigate the associations between prevalent COPD and incident digestive diseases in the Chinese population.

We used data from the China Kadoorie Biobank (CKB), enrolling 512,724 participants aged 30-79 years at baseline from 10 areas in China. COPD was defined by spirometry (without bronchodilator) and self-reported emphysema/chronic bronchitis at baseline. We employed stratified Cox proportional regression models to assess the prospective associations of prevalent COPD and airflow obstruction severity with the risks of incident digestive diseases. A total of 31 digestive diseases were included, including the overall digestive diseases, 15 major disease categories, and 15 specific subtypes nested within the major categories. We further conducted one-sample Mendelian randomization analyses to assess the associations of genetically predicted COPD with digestive diseases.

During a median follow-up of 15.3 years, a total of 131,993 participants experienced at least one hospitalization or death due to the included digestive diseases. For the composite outcome and major categories, prevalent COPD at baseline was significantly associated with a higher risk of overall digestive diseases (hazard ratio and 95% confidence interval: 1.05 [1.03-1.08]), gastrointestinal inflammation (1.11 [1.07-1.15]) and abdominal pain (1.20 [1.12-1.28]). Dose-response associations of airflow obstruction severity with the overall digestive diseases (P value for trend: < 0.001) and six other disease types were identified. In MR analyses, a genetically predicted higher probability of COPD was significantly associated with overall digestive diseases (OR per doubling of genetically-predicted COPD prevalence: 3.21 [1.71-6.03]) and three other disease types.

Prevalent COPD is associated with various digestive diseases in the Chinese population, with MR analyses further supporting a potential causal link. These findings underscore the importance of considering disease severity when managing COPD-related digestive diseases. While COPD was defined based on baseline spirometry in this study, future research incorporating post-bronchodilator assessment could further refine these associations and help distinguish COPD from other reversible airflow limitations.

This study aimed to investigate the incidence and independent risk factors of early elevated intraocular pressure (IOP) after vitrectomy in patients with diabetes and establish a clinical risk prediction model. A retrospective case study was conducted, including 130 patients (130 eyes) who underwent vitrectomy for diabetic retinopathy from June 2022 to June 2024. Patients were divided into 2 groups based on whether early postoperative elevated IOP occurred within 1 week after surgery (defined as IOP ≥25 mm Hg or an increase ≥10 mm Hg compared with preoperative values). Demographic data, systemic conditions, preoperative ocular characteristics, and intraoperative parameters were collected. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors. A risk scoring system was constructed accordingly, and its predictive performance was evaluated using the receiver operating characteristic curve. The incidence of early postoperative elevated IOP was 30.0% (39/130). Multivariate logistic regression analysis showed that higher preoperative glycated hemoglobin (odds ratio [OR] = 1.57, 95% confidence interval [CI]: 1.17-2.11), combined cataract surgery (OR = 3.47, 95% CI: 1.19-10.15), use of intraocular tamponade (expansile gas: OR = 4.96; silicone oil: OR = 10.15), and longer operative time (OR = 1.23) were independent risk factors for early postoperative elevated IOP (all P < .05). The clinical risk scoring system (total score 0-9) based on these factors had an area under the receiver operating characteristic curve of 0.86 (95% CI: 0.79-0.93). With a cutoff value of ≥4 points, the sensitivity was 82.10% and the specificity was 78.00%. According to the score, patients were classified into low-, medium-, and high-risk groups, with actual incidences of elevated IOP of 8.1%, 28.3%, and 63.2%, respectively. The incidence of early postoperative elevated IOP after vitrectomy is high in patients with diabetes. High preoperative glycated hemoglobin, combined cataract surgery, use of silicone oil or gas tamponade, and prolonged operative time are independent risk factors. The clinical risk scoring system established in this study demonstrates good predictive ability and may facilitate early identification of high-risk patients for targeted intervention.

This study aimed to investigate the relationship between pulse pressure (PP) and diabetes incidence, with emphasis on gender-specific differences. A retrospective cohort analysis was conducted involving 51,529 diabetes-free participants from Sir Run Run Shaw Hospital Health Promotion Center between 2017 and 2024. Cox models assessed associations between baseline PP and diabetes risk, while latent class trajectory modeling identified PP patterns over time. Among 1117 (2.2%) incident diabetes cases during a median 1.69-year follow-up, elevated baseline PP was significantly associated with diabetes risk only in females (hazard ratio [HR] = 1.014, 95% confidence interval [CI]: 1.004-1.024). Females in the highest PP category had a 42% increased risk (HR = 1.424, 95% CI: 1.038-1.953) compared with the lowest, whereas no significant association was found in males. Three PP trajectories were identified. Compared with the low-stable group, females in the high-stable group had a 1.759-fold higher diabetes risk (95% CI: 1.178-2.628), while males showed no significant increase (HR = 1.297, 95% CI: 0.974-1.726). Higher baseline PP and stable high PP trajectory show significant correlations with elevated diabetes risk among females, but not in males. These findings underscore the importance of gender-specific approaches in diabetes risk assessment and prevention.

Arteriovenous fistula (AVF) intimal hyperplasia (IH) is a major pathological basis of AVF stenosis and dysfunction in patients undergoing maintenance hemodialysis. This single-center retrospective observational cohort study enrolled adult hemodialysis patients with a native AVF at our institution between May 2021 and May 2023. IH was determined primarily by duplex ultrasound (DUS) evidence of pathologic venous intimal thickening and/or hemodynamically significant stenosis attributable to IH, with angiographic confirmation when clinically indicated. Demographic characteristics, hemodialysis vintage, dialysis prescription and adequacy, vascular access profiles, comorbidities, medication exposure, and routine laboratory indices were extracted from electronic medical records, the hemodialysis information platform, and the vascular access imaging database. Comparisons were performed between the IH group (n = 38) and the control group (n = 126), followed by univariate and multivariable logistic regression analyses. Patients with IH were slightly older and had longer hemodialysis vintage and a longer interval from AVF creation to evaluation. The IH group also showed higher rates of diabetes mellitus and recent infection, higher inflammatory burden reflected by C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR), lower albumin, higher d-dimer, and higher serum phosphate. In multivariable analysis, longer time from AVF creation to evaluation, diabetes mellitus, higher CRP, and higher phosphate independently correlated with IH, whereas higher albumin was protective. These findings suggest that cumulative access exposure, metabolic disease, systemic inflammation, nutritional status, and disordered mineral metabolism jointly contribute to IH risk and may inform targeted surveillance and preventive management in routine hemodialysis care.

Diabetes mellitus substantially increases the risk of osteoporosis and fractures, but the mechanisms remain unclear. Dyslipidemia, particularly the role of high-density lipoprotein (HDL), may influence bone mineral density (BMD), yet evidence in diabetic patients is limited. This study aimed to explore the association between HDL and BMD in US adults with diabetes using a nationally representative dataset. We analyzed data from 5 National Health and Nutrition Examination Survey cycles (2005-2018). A total of 5014 diabetic participants with available HDL and dual-energy X-ray absorptiometry (DXA)-measured BMD were included. Weighted multivariable linear regression models, smooth curve fitting, and 2-piecewise linear regression were employed to examine linear and nonlinear associations. Subgroup and sensitivity analyses were also conducted to assess robustness. Among 5014 participants (mean age 40.1 ± 31.2 years; 50.8% male), mean femoral neck and lumbar spine BMD were 0.81 and 1.03 g/cm2, respectively, with a mean HDL of 48.9 mg/dL. Higher HDL levels were inversely associated with BMD at both the femoral neck (β = -0.0011, 95% CI: -0.0015 to -0.0007) and lumbar spine (β = -0.0012, 95% CI: -0.0018 to -0.0007) after full adjustment. Participants in the highest HDL quartile had significantly lower BMD compared with those in the lowest quartile (femoral neck: -0.0294 g/cm2; lumbar spine: -0.0378 g/cm2). Smooth curve fitting indicated nonlinear, negative associations. Subgroup analyses revealed stronger inverse associations in men, participants with hypertension, those <60 years at the femoral neck, and those ≥60 years at the lumbar spine. Sensitivity analyses confirmed the robustness of the results. Higher HDL levels were consistently and independently associated with lower BMD in US adults with diabetes. These findings challenge the traditional view of HDL as universally protective, suggesting that in the diabetic context, elevated HDL may exert detrimental effects on bone health. Further longitudinal and mechanistic studies are warranted to clarify causal pathways and guide osteoporosis prevention strategies in this high-risk population.