Objective: aaWilson’s disease (WD) is a rare genetic disorder of copper metabolism, and longitudinal follow-up studies are limited. We performed a retrospective analysis to determine the clinical characteristics and long-term outcomes in a large WD cohort. Methods: aaMedical records of WD patients diagnosed from 2006–2021 at National Taiwan University Hospital were retrospectively evaluated for clinical presentations, neuroimages, genetic information, and follow-up outcomes. Results: aaThe present study enrolled 123 WD patients (mean follow-up: 11.12 ± 7.41 years), including 74 patients (60.2%) with hepatic features and 49 patients (39.8%) with predominantly neuropsychiatric symptoms. Compared to the hepatic group, the neuropsychiatric group exhibited more Kayser-Fleischer rings (77.6% vs. 41.9%, p < 0.01), lower serum ceruloplasmin levels (4.9 ± 3.9 vs. 6.3 ± 3.9 mg/dL, p < 0.01), smaller total brain and subcortical gray matter volumes (p < 0.0001), and worse functional outcomes during follow-up (p = 0.0003). Among patients with available DNA samples (n = 59), the most common mutations were p.R778L (allelic frequency of 22.03%) followed by p.P992L (11.86%) and p.T935M (9.32%). Patients with at least one allele of p.R778L had a younger onset age (p = 0.04), lower ceruloplasmin levels (p < 0.01), lower serum copper levels (p = 0.03), higher percentage of the hepatic form (p = 0.03), and a better functional outcome during follow-up (p = 0.0012) compared to patients with other genetic variations. Conclusion aaThe distinct clinical characteristics and long-term outcomes of patients in our cohort support the ethnic differences regarding the mutational spectrum and clinical presentations in WD.

Background/Aims: Laryngeal symptoms are largely treated with empiric proton pump inhibitor (PPI) therapy if no apparent pathology shown on ear, nose, and throat evaluation and reflux-related etiologies are suspected. However, treatment response remains unsatisfactory. This study aimed to investigate the clinical and physiological characteristics of patients with PPI-refractory laryngeal symptoms. Methods: Patients with persistent laryngeal symptoms despite PPI treatment for ≥ 8 weeks were recruited. A multidisciplinary evaluationcomprising validated questionnaires for laryngeal symptoms (reflux symptom index [RSI]), gastroesophageal reflux disease symptoms, psychological comorbidity (5-item brief symptom rating scale [BSRS-5]) and sleep disturbance (Pittsburgh sleep quality index [PSQI]), esophagogastroduodenoscopy, ambulatory impedance-pH monitoring, and high-resolution impedance manometry were performed.Healthy asymptomatic individuals were also recruited for comparison of psychological morbidity and sleep disturbances. Results: Ninety-seven adult patients and 48 healthy volunteers were analyzed. The patients had markedly higher prevalence of psychological distress (52.6% vs 2.1%, P < 0.001) and sleep disturbance (82.5% vs 37.5%, P < 0.001) than the healthy volunteers. There were significant correlations between RSI and BSRS-5 scores, and between RSI and PSQI scores (r = 0.26, P = 0.010, and r = 0.29, P = 0.004, respectively). Fifty-eight patients had concurrent gastroesophageal reflux disease symptoms. They had more prominent sleep disturbances (89.7% vs 71.8%, P < 0.001) than those with laryngeal symptoms alone but similar reflux profiles and esophageal motility. Conclusions PPI-refractory laryngeal symptoms are mostly associated with psychological comorbidities and sleep disturbances. Recognition of these psychosocial comorbidities may help optimize management in these patients.

INTRODUCTIONConstipation is a common poststroke complication. This study was designed to document the incidence and clinical course of poststroke constipation in a rehabilitation ward, as well as identify the factors independently associated with the condition.

METHODSThis retrospective study involved patients who were admitted to the rehabilitation ward of our institute due to an acute stroke between 1 August 2010 and 31 July 2011. The main outcome measured was the incidence of poststroke constipation, defined as the use of laxative after stroke, fulfilment of the Rome II diagnostic criteria for functional constipation and/or stool impaction. The variables examined were basic demographic data, presence of impairment, degree of disability (evaluated using the Barthel index), walking ability, medications taken and medical complications.

RESULTSOut of the 155 patients who met the inclusion criteria, 123 (79.4%) had poststroke constipation. All 123 patients used oral laxatives; 56 received additional rectal medications and 13 discontinued their use of laxatives at discharge. Patients with poststroke constipation were more likely to have major medical complications (p = 0.04). Those who used rectal medications had a higher risk of major medical complications than those who used only oral laxatives (p < 0.01). Infratentorial lesions were an independent predictor of poststroke constipation (p = 0.003). More severe disability increased the severity of constipation, as indicated by the use of rectal medication.

CONCLUSIONPoststroke constipation is a common complication during inpatient rehabilitation. Healthcare providers should be aware of the incidence of poststroke constipation. Further studies are required to establish standard guidelines for screening and managing bowel function in patients with stroke.

Age Distribution ; Aged ; Aged, 80 and over ; Cohort Studies ; Constipation ; drug therapy ; epidemiology ; etiology ; Female ; Follow-Up Studies ; Humans ; Incidence ; Laxatives ; therapeutic use ; Male ; Middle Aged ; Rehabilitation Centers ; Retrospective Studies ; Risk Assessment ; Severity of Illness Index ; Sex Distribution ; Singapore ; Stroke ; complications ; diagnosis ; Stroke Rehabilitation ; Treatment Outcome

Glycogen synthase kinase-3β (GSK-3β) is an important serine/threonine kinase that implicates in multiple cellular processes and links with the neurodegenerative diseases including Alzheimer’s disease (AD). In this study, structure-based virtual screening was performed to search database for compounds targeting GSK-3β from Enamine’s screening collection. Of the top-ranked compounds, 7 primary hits underwent a luminescent kinase assay and a cell assay using human neuroblastoma SH-SY5Y cells expressing Tau repeat domain (TauRD) with pro-aggregant mutation ΔK280. In the kinase assay for these 7 compounds, residual GSK-3β activities ranged from 36.1% to 90.0% were detected at the IC50 of SB-216763. In the cell assay, only compounds VB-030 and VB-037 reduced Tau aggregation in SH-SY5Y cells expressing ΔK280 TauRD-DsRed folding reporter. In SH-SY5Y cells expressing ΔK280 TauRD, neither VB-030 nor VB-037 increased expression of GSK-3α Ser21 or GSK-3β Ser9. Among extracellular signal-regulated kinase (ERK), AKT serine/threonine kinase 1 (AKT), mitogen-activated protein kinase 14 (P38) and mitogenactivated protein kinase 8 (JNK) which modulate Tau phosphorylation, VB-037 attenuated active phosphorylation of P38 Thr180/ Tyr182, whereas VB-030 had no effect on the phosphorylation status of ERK, AKT, P38 or JNK. However, both VB-030 and VB-037 reduced endogenous Tau phosphorylation at Ser202, Thr231, Ser396 and Ser404 in neuronally differentiated SH-SY5Y expressing ΔK280 TauRD. In addition, VB-030 and VB-037 further improved neuronal survival and/or neurite length and branch in mouse hippocampal primary culture under Tau cytotoxicity. Overall, through inhibiting GSK-3β kinase activity and/or p-P38 (Thr180/Tyr182), both compounds may serve as promising candidates to reduce Tau aggregation/cytotoxicity for AD treatment.

Objective: To quantitatively assess the pulmonary vasculature using non-contrast computed tomography (CT) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) pre- and post-treatment and correlate CT-based parameters with right heart catheterization (RHC) hemodynamic and clinical parameters. Materials and Methods: A total of 30 patients with CTEPH (mean age, 57.9 years; 53% female) who received multimodal treatment, including riociguat for ≥ 16 weeks with or without balloon pulmonary angioplasty and underwent both noncontrast CT for pulmonary vasculature analysis and RHC pre- and post-treatment were included. The radiographic analysis included subpleural perfusion parameters, including blood volume in small vessels with a cross-sectional area ≤ 5 mm 2 (BV5) and total blood vessel volume (TBV) in the lungs. The RHC parameters included mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), and cardiac index (CI). Clinical parameters included the World Health Organization (WHO) functional class and 6-minute walking distance (6MWD). Results: The number, area, and density of the subpleural small vessels increased after treatment by 35.7% (P < 0.001), 13.3% (P = 0.028), and 39.3% (P < 0.001), respectively. The blood volume shifted from larger to smaller vessels, as indicated by an 11.3% increase in the BV5/TBV ratio (P = 0.042). The BV5/TBV ratio was negatively correlated with PVR (r = -0.26; P = 0.035) and positively correlated with CI (r = 0.33; P = 0.009). The percent change across treatment in the BV5/TBV ratio correlated with the percent change in mPAP (r = -0.56; P = 0.001), PVR (r = -0.64; P < 0.001), and CI (r = 0.28; P = 0.049).Furthermore, the BV5/TBV ratio was inversely associated with the WHO functional classes I–IV (P = 0.004) and positively associated with 6MWD (P = 0.013). Conclusion Non-contrast CT measures could quantitatively assess changes in the pulmonary vasculature in response to treatment and were correlated with hemodynamic and clinical parameters.

Background/Aims: Ineffective esophageal motility (IEM) is common in patients with gastroesophageal reflux disease (GERD) and can be associated with poor esophageal contraction reserve on multiple rapid swallows. Alterations in the esophageal microbiome have been reported in GERD, but the relationship to presence or absence of contraction reserve in IEM patients has not been evaluated. We aim to investigate whether contraction reserve influences esophageal microbiome alterations in patients with GERD and IEM. Methods: We prospectively enrolled GERD patients with normal endoscopy and evaluated esophageal motility and contraction reserve with multiple rapid swallows during high-resolution manometry. The esophageal mucosa was biopsied for DNA extraction and 16S ribosomal RNA gene V3-V4 (Illumina)/full-length (Pacbio) amplicon sequencing analysis. Results: Among the 56 recruited patients, 20 had normal motility (NM), 19 had IEM with contraction reserve (IEM-R), and 17 had IEM without contraction reserve (IEM-NR). Esophageal microbiome analysis showed a significant decrease in microbial richness in patients with IEM-NR when compared to NM. The beta diversity revealed different microbiome profiles between patients with NM or IEM-R and IEM-NR (P = 0.037). Several esophageal bacterial taxa were characteristic in patients with IEM-NR, including reduced Prevotella spp.and Veillonella dispar, and enriched Fusobacterium nucleatum. In a microbiome-based random forest model for predicting IEM-NR, an area under the receiver operating characteristic curve of 0.81 was yielded. Conclusions In symptomatic GERD patients with normal endoscopic findings, the esophageal microbiome differs based on contraction reserve among IEM. Absent contraction reserve appears to alter the physiology and microbiota of the esophagus.

Background/Aims: Direct‐acting antivirals (DAAs) have been approved for hepatitis C virus (HCV) treatment in patients with end-stage renal disease (ESRD) on hemodialysis. Nevertheless, the complicated comedications and their potential drug-drug interactions (DDIs) with DAAs might limit clinical practice in this special population. Methods: The number, class, and characteristics of comedications and their potential DDIs with five DAA regimens were analyzed among HCV-viremic patients from 23 hemodialysis centers in Taiwan. Results: Of 2,015 hemodialysis patients screened in 2019, 169 patients seropositive for HCV RNA were enrolled (mean age, 65.6 years; median duration of hemodialysis, 5.8 years). All patients received at least one comedication (median number, 6; mean class number, 3.4). The most common comedication classes were ESRD-associated medications (94.1%), cardiovascular drugs (69.8%) and antidiabetic drugs (43.2%). ESRD-associated medications were excluded from DDI analysis. Sofosbuvir/velpatasvir/voxilaprevir had the highest frequency of potential contraindicated DDIs (red, 5.6%), followed by glecaprevir/pibrentasvir (4.0%), sofosbuvir/ledipasvir (1.3%), sofosbuvir/velpatasvir (1.3%), and elbasvir/grazoprevir (0.3%). For potentially significant DDIs (orange, requiring close monitoring or dose adjustments), sofosbuvir/velpatasvir/voxilaprevir had the highest frequency (19.9%), followed by sofosbuvir/ledipasvir (18.2%), glecaprevir/pibrentasvir (12.6%), sofosbuvir/velpatasvir (12.6%), and elbasvir/grazoprevir (7.3%). Overall, lipid-lowering agents were the most common comedication class with red-category DDIs to all DAA regimens (n=62), followed by cardiovascular agents (n=15), and central nervous system agents (n=10). Conclusions HCV-viremic patients on hemodialysis had a very high prevalence of comedications with a broad spectrum, which had varied DDIs with currently available DAA regimens. Elbasvir/grazoprevir had the fewest potential DDIs, and sofosbuvir/velpatasvir/voxilaprevir had the most potential DDIs.

Ulcerative colitis (UC) is a chronic inflammation of the gastrointestinal tract and is characterized by alternating periods of inflammation and remission. Although UC incidence is lower in Taiwan than in Western countries, its impact remains considerable, demanding updated guidelines for addressing local healthcare challenges and patient needs. The revised guidelines employ international standards and recent research, emphasizing practical implementation within the Taiwanese healthcare system. Since the inception of the guidelines in 2017, the Taiwan Society of Inflammatory Bowel Disease has acknowledged the need for ongoing revisions to incorporate emerging therapeutic options and evolving disease management practices. This updated guideline aims to align UC management with local contexts, ensuring comprehensive and context-specific recommendations, thereby raising the standard of care for UC patients in Taiwan. By adapting and optimizing international protocols for local relevance, these efforts seek to enhance health outcomes for patients with UC.