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Incident cardiac arrhythmias associated with metabolic dysfunction-associated steatotic liver disease: a nationwide histology cohort study

BackgroundPrior studies suggest a link between metabolic dysfunction-associated steatotic liver disease (MASLD) and incident arrhythmias, including atrial fibrillation (AF). However, robust data are lacking from cohorts with liver histology, which remains the gold standard for staging MASLD severity.MethodsThis population-based cohort included all Swedish adults with histologically-confirmed MASLD and without prior cardiac arrhythmias (1966–2016; n = 11,206). MASLD was defined from prospectively-recorded histopathology, and characterized as simple steatosis, non-fibrotic steatohepatitis (MASH), non-cirrhotic fibrosis, or cirrhosis. MASLD patients were matched to ≤ 5 controls without MASLD or arrhythmias, by age, sex, calendar year and county (n = 51,856). Using Cox proportional hazards modeling, we calculated multivariable-adjusted hazard ratios (aHRs) for incident arrhythmias (including AF, bradyarrhythmias, other supraventricular arrhythmias, ventricular arrhythmias/cardiac arrest).ResultsOver a median follow-up of 10.8 years, incident arrhythmias were confirmed in 1351 MASLD patients (10.3/1000 person-years [PY]) and 6493 controls (8.7/1000PY; difference = 1.7/1000PY; aHR = 1.30, 95%CI 1.22–1.38), and MASLD patients had significantly higher rates of incident AF (difference = 0.9/1000PY; aHR = 1.26, 95%CI 1.18–1.35). Rates of both overall arrhythmias and AF were significantly elevated across all MASLD histological groups, particularly cirrhosis (differences, 8.5/1000PY and 5.3/1000PY, respectively). In secondary analyses, MASLD patients also had significantly higher rates of incident ventricular arrhythmias/cardiac arrest (aHR = 1.53, 95%CI 1.30–1.80), bradyarrhythmias (aHR = 1.26, 95%CI 1.06–1.48), and other supraventricular arrhythmias (aHR = 1.27, 95%CI 1.00–1.62), compared to controls.ConclusionsCompared to matched controls, patients with biopsy-confirmed MASLD had modest but significantly higher incidence of cardiac arrhythmias, including AF, bradyarrhythmias, other supraventricular arrhythmias and ventricular arrhythmias/cardiac arrest. Excess risk was observed across all stages of MASLD and was highest with cirrhosis.

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Sex bias in celiac disease: XWAS and monocyte eQTLs in women identify TMEM187 as a functional candidate gene

BackgroundCeliac disease (CeD) is an immune-mediated disorder that develops in genetically predisposed individuals upon gluten consumption. HLA risk alleles explain 40% of the genetic component of CeD, so there have been continuing efforts to uncover non-HLA loci that can explain the remaining heritability. As in most autoimmune disorders, the prevalence of CeD is significantly higher in women. Here, we investigated the possible involvement of the X chromosome on the sex bias of CeD.MethodsWe performed a X chromosome-wide association study (XWAS) and a gene-based association study in women from the CeD Immunochip (7062 cases, 5446 controls). We also constructed a database of X chromosome cis-expression quantitative trait loci (eQTLs) in monocytes from unstimulated (n = 226) and lipopolysaccharide (LPS)-stimulated (n = 130) female donors and performed a Summary-data-based MR (SMR) analysis to integrate XWAS and eQTL information. We interrogated the expression of the potentially causal gene (TMEM187) in peripheral blood mononuclear cells (PBMCs) from celiac patients at onset, on a gluten-free diet, potential celiac patients and non-celiac controls.ResultsThe XWAS and gene-based analyses identified 13 SNPs and 25 genes, respectively, 22 of which had not been previously associated with CeD. The X chromosome cis-eQTL analysis found 18 genes with at least one cis-eQTL in naïve female monocytes and 8 genes in LPS-stimulated female monocytes, 2 of which were common to both situations and 6 were unique to LPS stimulation. SMR identified a potentially causal association of TMEM187 expression in naïve monocytes with CeD in women, regulated by CeD-associated, eQTL-SNPs rs7350355 and rs5945386. The CeD-risk alleles were correlated with lower TMEM187 expression. These results were replicated using eQTLs from LPS-stimulated monocytes. We observed higher levels of TMEM187 expression in PBMCs from female CeD patients at onset compared to female non-celiac controls, but not in male CeD individuals.ConclusionUsing X chromosome genotypes and gene expression data from female monocytes, SMR has identified TMEM187 as a potentially causal candidate in CeD. Further studies are needed to understand the implication of the X chromosome in the higher prevalence of CeD in women.

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SOX2 promotes vasculogenic mimicry by accelerating glycolysis via the lncRNA AC005392.2-GLUT1 axis in colorectal cancer

Vasculogenic mimicry (VM), a new model of angiogenesis, fulfills the metabolic demands of solid tumors and contributes to tumor aggressiveness. Our previous study demonstrated the effect of SOX2 in promoting VM in colorectal cancer (CRC). However, the underlying mechanisms behind this effect remain elusive. Here, we show that SOX2 overexpression enhanced glycolysis and sustained VM formation via the transcriptional activation of lncRNA AC005392.2. Suppression of either glycolysis or AC005392.2 expression curbed SOX2-driven VM formation in vivo and in vitro. Mechanistically, SOX2 combined with the promoter of AC005392.2, which decreased H3K27me3 enrichment and thus increased its transcriptional activity. Overexpression of AC005392.2 increased the stability of GLUT1 protein by enhancing its SUMOylation, leading to a decrease in the ubiquitination and degradation of GLUT1. Accumulation of GLUT1 contributed to SOX2-mediated glycolysis and VM. Additionally, clinical analyses showed that increased levels of AC005392.2, GLUT1, and EPHA2 expression were positively correlated with SOX2 and were also associated with poor prognoses in patients with CRC. Our study conclusively demonstrates that the SOX2-lncRNA AC005392.2-GLUT1 signaling axis regulates VM formation in CRC, offering a foundation for the development of new antiangiogenic drugs or new drug combination regimens.

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Dutch–Flemish translation and validation of the gastrointestinal symptom scales from the patient‑reported outcomes measurement information system (PROMIS)®

PurposeTo translate the eight PROMIS® GastrointestinaI Symptom Scales into Dutch–Flemish and to evaluate their psychometric properties.MethodsThis study consisted of two parts: (1) translation according to the Functional Assessment of Chronic Illness Therapy (FACIT) translation methodology and (2) evaluation of psychometric properties: structural validity, using confirmatory factor analysis; and construct validity using hypothesis testing.ResultsIn the first part of the study, in 19 out of the 77 items (24.7%) translation was challenging. After discussion between the translators, consensus could be achieved. In the cognitive debriefing interview phase, ten minor changes in the wording of items were made. A universal Dutch–Flemish translation for all 77 items was obtained. In de second part of the study a good fit was found for three DF-PROMIS GI Scales: Bowel Incontinence, Gas and Bloating, and Belly Pain. Four scales (Reflux, Disrupted Swallowing, Diarrhea, and Constipation) did not show sufficient fit and fit for the Nausea and Vomiting scale could not be assessed because of skewed responses. Construct validity was considered sufficient for six out of eight DF-PROMIS GI Scales. Less than 75% of hypothesis for de Constipation and Disrupted Swallowing scales could be confirmed.ConclusionThe PROMIS GI Symptom Scales were successfully translated into DutchFlemish. The findings suggest a sufficient structural validity for the PROMIS GI Scales. Bowel Incontinence, Gas and Bloating and Belly Pain. Construct validity was sufficient for the Scales Gas and Bloating, Incontinence, Nausea and Vomiting, Reflux, Belly Pain, and Diarrhea.

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Variables associated with admission rates among cancer patients presenting to emergency departments: a CONCERN group study

BackgroundPatients with cancer visit the emergency department often and have a high rate of admission compared to other patients. Admission rates by institution may vary widely, even after accounting for patient and hospital-specific characteristics.ObjectivesTo review the variables that affect admission rates among patients with cancer in the emergency department.MethodsWe performed a secondary analysis of a prospective cohort study of patients with cancer at 18 emergency departments between March 1, 2016, and January 30, 2017, to examine differences in patient populations between hospitals with varying admission rates. We calculated the percentage admitted by hospital and used it to categorize hospitals into quartiles. We compared outcomes, patient demographics, and disease characteristics between the admission quartiles using linear or logistic regression.ResultsA total of 1075 patients were included. The median age of our sample was 64, and 51% of patients were female, 84% were white, and 13% were Black. Of the 1075 patients, 615 (57.2%) were admitted as inpatients with a range from 21.2 to 81.7% by hospital. Differences between admission quartiles were found for education, mode of arrival, and recent chemotherapy (p < 0.05). There were no significant differences among quartiles in age, gender, race, or ECOG score. We found significant difference between admission quartiles in 30-day emergency department revisits. Differences in readmission rates and mortality did not appear to be significant between the various quartiles.ConclusionsIn our study, we observed several differences among patients with cancer receiving care at hospitals with different admission rates. These included patients’ education level, mode of arrival, and whether they had received recent chemotherapy. Emergency Severity Index (ESI) score may have also contributed to admission rate variability. Further study into unmeasured factors influencing hospital admissions, such as local culture, resources, and pathways, could identify generalizable findings to reduce avoidable admissions and reduce variation among similar patients in different hospitals.

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Co-design and Consultation Ensure Consumer Needs Are Met: Building an eHealth Platform for Children with Inflammatory Bowel Disease

BackgroundCrohn’s Colitis Care is an adult inflammatory bowel disease eHealth system. Crohn’s Colitis Care required additional pediatric functionality to enable life-long records and mitigate transition inadequacies.AimThis study describes and evaluates a consensus method developed to ensure consumer needs were met.MethodsPediatric-specific functionality and associated resources considered important for inclusion were developed by a clinician consensus group. This group was divided into thematic subgroups and underwent two voting rounds. The content validity index was used to determine items reaching consensus. Children with inflammatory bowel disease and their parents were later shown a descriptive list of non-clinical inclusion topics proposed by the consensus group, and asked to vote on whether topic-related functionality and resources should be included.ResultsThe consensus process consulted 189 people in total (38 clinicians, 32 children with inflammatory bowel disease and 119 parents). There was agreement across all groups to incorporate functionality and resources pertaining to quality of life, mental health, self-management, and transition readiness; however, divergence was seen for general inflammatory bowel disease facts, your inflammatory bowel disease history, and satisfaction. Cost saw the greatest disparity, being less supported by consumers compared to clinicians. Over 75% of consumers agreed it would be okay for appointments to take longer for survey completion, and > 90% thought Crohn’s Colitis Care should allow consumers to ask their treating team questions.ConclusionsWidespread consumer co-design and consultation were important in unveiling differing perspectives to ensure Crohn’s Colitis Care was built to support both consumer and clinician perspectives.Graphical Consumers collaborate to create a list of functionality and resources to be included in software (left), influencing the final product build (right).

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Long-term Efficacy and Safety of Controlled Manual Anal Dilatation in the Treatment of Chronic Anal Fissures: A Single-center Observational Study.

Conventional anal dilatation for anal fissures has long been abandoned because of the high incidence of anal incontinence. However, less invasive and more precise dilation techniques have been developed that have shown high healing and low incontinence rates. This study aimed to evaluate the efficacy and safety of controlled anal dilatation (CAD) using a standardized maximum anal diameter. This study included 523 patients who underwent CAD for chronic anal fissures between January 2010 and December 2014. CAD was performed under sacral epidural anesthesia. The index fingers of both hands were placed in the anus and dilated evenly in various directions. CAD was completed when the anus was dilated to the sixth scale (35 mm in diameter) using a caliber ruler. The mean anal scale size expanded from 3.1 to 5.8 (p<0.001). Non-healing was observed in nine patients (1.7%) at 1 month postoperatively, six of whom underwent additional CAD. The mean maximal anal resting pressure (mmHg) decreased from 90.2 to 79.7 at three months postoperatively (p<0.001). Postoperative complications were observed in 11 (2.1%) patients, of whom three patients with thrombosed hemorrhoids underwent resection. None of the patients complained of anal incontinence during the mean follow-up period of 16.6 months. The cumulative recurrence-free rates at three and five years were 87.9% and 69.2%, respectively. CAD is technically simple and safe and can achieve reasonable long-term outcomes. Thus, CAD appears to be the preferred procedure for patients with chronic anal fissures who do not respond to conservative treatments.

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