Search

Background and aimsENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA).Approach and resultsPatients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( p < 0.0001). ALP normalization occurred in 5.4% ( p =0.08) and 27.3% ( p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 ( p =0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% ( p =0.0008); 10 mg: 16.7% ( p =0.03); placebo: 4%]. There were no serious treatment-related adverse events.ConclusionsPatients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.

Background & Aims: Biochemical response to ursodeoxycholic acid (UDCA) therapy is associated with good prognosis in people living with primary biliary cholangitis (PBC). Biochemical response is typically assessed early in disease and it is not known what proportion of patients lose previously attained biochemical response, nor whether this impacts long-term liver transplant (LT)-free survival. Methods: We identified all UDCA-treated patients with PBC from the Canadian Network for Autoimmune Liver disease with biochemical measurements at 1 year, and evaluated their liver biochemistry over time. Inadequate biochemical response was defined as serum alkaline phosphatase ≥1.67x the upper limit of normal or abnormal serum total bilirubin at 1 year of UDCA therapy and all time points thereafter. Multistate Markov models were used to estimate transition rates between biochemical response states and from each state to LT or death. Results were validated in an external cohort (GLOBAL PBC registry). Results: A total of 823 patients from eight centers were included. Mean age at diagnosis was 53 years, 91% were female, 33% had inadequate biochemical response to UDCA at 1 year (n = 269). Patients who retained initial adequate response had lower rates of LT or death compared to patients who subsequently lost response (relative rate 0.102, 95% CI 0.047-0.223). Patients who regained adequate response had lower rates than patients who did not (0.016, 95% CI 0.001-0.568), and patients who lost response once more (0.010, 95% CI 0.001-0.340). Patients who regained adequate response for a third time also had lower rates than patients who did not (0.151, 95% CI 0.040-0.566). Analyses in the GLOBAL PBC registry (n = 2,237) validated these results. Conclusion: Loss of biochemical response at any time is associated with heightened risks of LT or death in people living with PBC. Achievement of biochemical response is an important goal throughout follow-up, regardless of biochemical response profile early in therapy. Impact and implications:: Early biochemical response to ursodeoxycholic acid is associated with good prognosis in patients with primary biliary cholangitis (PBC). Our work demonstrates that patients with PBC transition between biochemical response states over time, and that these transitions correspond with changes in risk of liver transplantation or death. Clinicians should re-evaluate risk and optimize treatment decisions for patients with PBC throughout follow-up, regardless of early biochemical response to therapy.

Background and aimsPruritus is associated with multiple liver diseases, particularly those with cholestasis, but the mechanism remains incompletely understood. Our aim was to evaluate serum IL-31 as a putative biomarker of pruritus in clinical trials of an farnesoid X receptor (FXR) agonist, cilofexor, in patients with NASH, primary sclerosing cholangitis (PSC), and primary biliary cholangitis (PBC).Approach and resultsSerum IL-31 was measured in clinical studies of cilofexor in NASH, PSC, and PBC. In patients with PSC or PBC, baseline IL-31 was elevated compared to patients with NASH and healthy volunteers (HVs). IL-31 correlated with serum bile acids among patients with NASH, PBC, and PSC. Baseline IL-31 levels in PSC and PBC were positively correlated with Visual Analog Scale for pruritus and 5-D itch scores. In patients with NASH, cilofexor dose-dependently increased IL-31 from Week (W)1 to W24. In patients with NASH receiving cilofexor 100 mg, IL-31 was higher in those with Grade 2-3 pruritus adverse events (AEs) than those with Grade 0-1 pruritus AEs. IL-31 weakly correlated with C4 at baseline in patients with NASH, and among those receiving cilofexor 100 mg, changes in IL-31 and C4 from baseline to W24 were negatively correlated. IL-31 messenger RNA (mRNA) was elevated in hepatocytes from patients with PSC and NASH compared to HVs. In a humanized liver murine model, obeticholic acid increased IL-31 mRNA expression in human hepatocytes and serum levels of human IL-31.ConclusionsIL-31 levels correlate with pruritus in patients with cholestatic disease and NASH, with FXR agonist therapy resulting in higher serum levels in the latter group. IL-31 appears to derive in part from increased hepatocyte expression. These findings have therapeutic implications for patients with liver disease and pruritus.

Background: Cardiovascular disease (CVD) is the leading cause of death among female patients and its likelihood increases following menopause. However, whether estradiol levels are related to CVD remains unknown. We aimed to determine the association between serum estradiol levels and cardiovascular (CV) events in postmenopausal females. Methods: Electronic databases (MEDLINE, Embase) were searched systematically from inception to October 2022. Studies were eligible for inclusion if they included the following: (i) postmenopausal females; (ii) examination of the association between total serum estradiol levels and CV events (CV mortality, CVD, coronary heart disease, myocardial infarction, stroke, venous thromboembolism, heart failure, and CV hospitalization); (iii) original data (randomized controlled trial, quasi-experimental, cohort, case-control, or cross-sectional study). A narrative synthesis was completed because the data were not amenable to meta-analysis. Results: Of the 9026 citations retrieved, 8 articles were included, representing a total of 5635 women. The risk-of-bias was fair, and considerable heterogeneity was present. In those not using menopausal hormone therapy, 3 studies demonstrated mixed results between estradiol levels and risk of coronary heart disease, and 1 study showed that higher estradiol levels were associated with an increased risk of myocardial infarction. No significant associations were present between estradiol levels and the remaining events (ie, CV mortality, heart failure, CVD, and stroke). Conclusions: The association between serum estradiol levels and CV events in postmenopausal females remains unclear. Further studies assessing this association are warranted, given the elevated CVD risk in this population. Résumé: Contexte: Les maladies cardiovasculaires (MCV) sont la principale cause de décès chez les femmes et leur probabilité augmente après la ménopause. Cependant, on ne sait pas encore si le taux d’estradiol est lié aux MCV. Nous avons tenté d’établir le lien entre le taux d’estradiol sérique et les événements cardiovasculaires (CV) chez les femmes post-ménopausées. Méthodologie: Nous avons consulté systématiquement des bases de données électroniques (MEDLINE, Embase) de leur création jusqu’en octobre 2022. Les études admissibles devaient comprendre les éléments suivants : i) femmes post-ménopausées; ii) examen du lien entre le taux total d’estradiol sérique et les événements CV (décès d’origine CV, MCV, coronaropathie, infarctus du myocarde, accident vasculaire cérébral (AVC), thromboembolie veineuse, insuffisance cardiaque et hospitalisation pour une cause CV); iii) données originales (essai contrôlé randomisé; études quasi expérimentales, de cohorte, cas-témoins ou transversales). Une synthèse narrative a été réalisée parce que les données ne se prêtaient pas à une méta-analyse. Résultats: Parmi les 9 026 citations relevées, 8 articles ont été retenus, représentant un total de 5 635 femmes. Le risque de biais était raisonnable, et une très grande hétérogénéité était présente. Chez les femmes qui ne suivaient pas d’hormonothérapie ménopausique, trois études ont affiché des résultats variables quant au lien entre le taux d’estradiol et le risque de coronaropathie, et une étude a montré que des taux élevés d’estradiol étaient associés à un risque accru d’infarctus du myocarde. Aucun lien notable n’a été observé entre le taux d’estradiol et les autres événements (c.-à-d. décès d’origine CV, insuffisance cardiaque, MCV et AVC). Conclusions: Le lien entre le taux d’estradiol sérique et les événements CV chez les femmes post-ménopausées n’a pas été élucidé. D’autres études sont nécessaires pour évaluer ce lien en raison du risque élevé de MCV au sein de cette population.

Cardiovascular disease is the leading cause of death in women, and women with chronic kidney disease (CKD) experience especially elevated risk. This study examined the association between testosterone and vascular function in 61 reproductive-aged females with CKD. Testosterone levels and measures of vascular function were assessed, including pulse wave velocity, aortic augmentation, flow-mediated dilation (FMD), and velocity time integral. Multivariable linear regression analyses assessed the relationship between testosterone and each measure of vascular function. No associations were observed between testosterone and vascular function outcomes, although a significant positive association between testosterone-to-estradiol ratio and FMD was demonstrated. Although testosterone levels were not independently predictive of vascular function, the level of testosterone relative to estradiol was associated with FMD and may therefore influence endothelial function in the high-risk population of reproductive-aged female patients with CKD. Résumé: Alors que les maladies cardiovasculaires sont la cause principale de décès chez les femmes, les femmes atteintes d’une maladie rénale chronique (MRC) sont exposées à un risque particulièrement élevé. La présente étude vise à examiner l’association entre la testostérone et la fonction vasculaire de 61 femmes en âge de procréer atteintes d’une MCV. Nous avons évalué les concentrations de testostérone et les mesures de la fonction vasculaire, soit la vélocité de l’onde de pouls, l’augmentation de l’aorte, la dilatation médiée par le flux (DMF) et l’intégrale temps-vitesse. Les analyses multivariées de régression linéaire ont permis d’évaluer la relation entre la testostérone et chacune des mesures de la fonction vasculaire. Aucune association n’a été observée entre la testostérone et les résultats de la fonction vasculaire, bien qu’une association positive significative entre le ratio testostérone/œstradiol et la DMF ait été démontrée. Bien que les concentrations de testostérone n’étaient pas indépendamment prédictives de la fonction vasculaire, les concentrations de la testostérone relativement à l’œstradiol ont été associées à la DMF et peuvent par conséquent influencer la fonction endothéliale au sein de la population exposée à un risque élevé composée de patientes en âge de procréer atteintes d’une MRC.

Abstract Background Understanding the epidemiology of ophthalmic presentations to emergency departments can help guide resource allocation, medical education programs, and optimize the patient experience. The purpose of this investigation was to summarize and assess the urgency of ophthalmic presentations in emergency departments (EDs) in Ontario, Canada over a 5-year period. Methods This was a multicentered retrospective review of all patient presentations to EDs in Ontario between January 1st, 2012, to December 31st, 2017. Presentations were included if patients had an ophthalmic related ICD-10 code as their primary problem prompting ED presentation. Results A total of 774,057 patients patient presentations were included across the pediatric (149,679 patients) and adult (624,378 patients) cohorts. The mean (SD) age at presentation was 47.4 (17.9) years, and 6.54 (5.20) in the adult and pediatric cohorts respectively. Of the total presentations, 256,776 (33.1%) were due to a trauma related presentation. Problems pertaining to Cornea and External disease were the most common reason for presentation (51.0% of cases). Of all presentations, 34.1% were classified as either ‘emergent’ or ‘likely emergent’; the remaining presentations were either ‘non-emergent’ (39.5%) or the urgency ‘could not be determined’ (26.4%). The three most frequent presentations were due to conjunctivitis (121,175 cases or 15.7%), ocular foreign bodies (104,322 cases or 13.5%), and corneal / conjunctival abrasions (94,554 cases of 12.2%). Conclusions This investigation summarizes all ophthalmic presentations to EDs in Ontario, Canada over a 5-year period. The results of this investigation can help guide ophthalmic related knowledge translation. Additionally, these results highlight that in Canadian EDs, a significant proportion of ophthalmic presentations are nonurgent; systems level efforts to improve access for eye-related complaints to healthcare professionals outside of the ED can help facilitate improved resource allocation. As we emerge from the COVID-19 pandemic, optimising the structure of patient care access is crucial to help alleviate the pressure from overburdened EDs while effectively meeting patient healthcare needs.

Background Hypertension is the leading modifiable cardiovascular risk factor with recognized sex‐ and gender‐based differences. We assessed the incorporation of sex and gender reporting in the antihypertensive medication literature informing hypertension guidelines. Methods and Results Literature cited in the International Society of Hypertension (2020), European Society of Cardiology/European Society of Hypertension (2018), American College of Cardiology/American Heart Association (2017), Latin American Society of Hypertension (2017), Pan‐African Society of Cardiology (2020), and Hypertension Canada (2020) guidelines was systematically reviewed. Observational studies, randomized controlled trials, and systematic reviews involving antihypertensive medications were included. Studies with participants of a single sex, guidelines, and commentaries were excluded. Data on study participation‐to‐prevalence ratio by sex, analysis of baseline demographics and study outcomes by sex, and stratification of adverse events by sex were extracted. Of 1659 unique citations, 331 studies met inclusion criteria. Of those, 81% reported the sex of participants, and 22% reported a male‐to‐female participation‐to‐prevalence ratio of 0.8 to 1.2. Three percent of studies stratified baseline characteristics by sex, and 20% considered sex during analysis through statistical adjustment or stratification. Although 32% of studies reported adverse events, only 0.6% stratified adverse events by sex. Most (58%) studies reporting sex/gender used sex and gender terms interchangeably. Conclusions Incorporation of sex‐ and gender‐based considerations in study population, analysis, or reporting of results and adverse events is not common in the antihypertensive medication literature informing international hypertension guidelines. Greater attention to sex‐ and gender‐based factors in research is required to optimally inform management of hypertension.

Background & Aims:A DNA methylation (DNAm) signature derived from 353 CpG sites (the Horvath clock) has been proposed as an epigenetic measure of chronological and biological age. This epigenetic signature is accelerated in diverse tissue types in various disorders, including non-alcoholic steatohepatitis, and is associated with mortality. Here, we assayed whole blood DNAm to explore age acceleration in patients with primary sclerosing cholangitis (PSC). Methods:Using the MethylationEPIC BeadChip (850K) array, DNAm signatures in whole blood were analyzed in 36 patients with PSC enrolled in a 96-week trial of simtuzumab (Ishak F0-1, n = 13; F5-6, n = 23). Age acceleration was calculated as the difference between DNAm age and chronological age. Comparisons between patients with high and low age acceleration (≥ vs. < the median) were made and Cox regression evaluated the association between age acceleration and PSC-related clinical events (e.g. decompensation, cholangitis, transplantation). Results:Age acceleration was significantly higher in patients with PSC compared to a healthy reference cohort (median, 11.1 years, p

Abstract Background Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that can lead to cirrhosis and hepatic decompensation. However, predicting future outcomes in patients with PSC is challenging. Our aim was to extract magnetic resonance imaging (MRI) features that predict the development of hepatic decompensation by applying algebraic topology-based machine learning (ML). Methods We conducted a retrospective multicenter study among adults with large duct PSC who underwent MRI. A topological data analysis-inspired nonlinear framework was used to predict the risk of hepatic decompensation, which was motivated by algebraic topology theory-based ML. The topological representations (persistence images) were employed as input for classification to predict who developed early hepatic decompensation within one year after their baseline MRI. Results We reviewed 590 patients; 298 were excluded due to poor image quality or inadequate liver coverage, leaving 292 potentially eligible subjects, of which 169 subjects were included in the study. We trained our model using contrast-enhanced delayed phase T1-weighted images on a single center derivation cohort consisting of 54 patients (hepatic decompensation, n = 21; no hepatic decompensation, n = 33) and a multicenter independent validation cohort of 115 individuals (hepatic decompensation, n = 31; no hepatic decompensation, n = 84). When our model was applied in the independent validation cohort, it remained predictive of early hepatic decompensation (area under the receiver operating characteristic curve = 0.84). Conclusions Algebraic topology-based ML is a methodological approach that can predict outcomes in patients with PSC and has the potential for application in other chronic liver diseases.

Background:. Liver transplantation (LT) is frequently lifesaving for people living with primary sclerosing cholangitis (PSC). However, patients are waitlisted for LT according to the model for end-stage liver disease-sodium (MELD-Na) score, which may not accurately reflect the burden of living with PSC. We sought to describe and analyze the clinical trajectory for patients with PSC referred for LT, in a mixed deceased donor/living donor transplant program. Methods:. This was a retrospective cohort study from November 2012 to December 2019, including all patients with PSC referred for assessment at the University Health Network Liver Transplant Clinic. Patients who required multiorgan transplant or retransplantation were excluded. Liver symptoms, hepatobiliary malignancy, MELD-Na progression, and death were abstracted from chart review. Competing risk analysis was used for timing of LT, transplant type, and death. Results:. Of 172 PSC patients assessed, 84% (n = 144) were listed of whom 74% were transplanted. Mean age was 47.6 years, and 66% were male. Overall mortality was 18.2% at 2 years. During the follow-up, 16% (n = 23) were removed from the waitlist for infection, clinical deterioration, liver-related mortality or new cancer; 3 had clinical improvement. At listing, 82% (n = 118) had a potential living donor (pLD). Patients with pLD had significantly lower waitlist and liver-related waitlist mortality (HR 0.20, p

Primary sclerosing cholangitis (PSC) represents a major unmet medical need. In a phase II double-blind, placebo-controlled study, we tested the safety and efficacy of cilofexor (formerly GS-9674), a nonsteroidal farnesoid X receptor agonist in patients without cirrhosis with large-duct PSC. Patients were randomized to receive cilofexor 100 mg (n = 22), 30 mg (n = 20), or placebo (n = 10) orally once daily for 12 weeks. All patients had serum alkaline phosphatase (ALP) > 1.67 × upper limit of normal and total bilirubin ≤ 2 mg/dL at baseline. Safety, tolerability, pharmacodynamic effects of cilofexor (serum C4 [7α-hydroxy-4-cholesten-3-one] and bile acids), and changes in liver biochemistry and serum fibrosis markers were evaluated. Overall, 52 patients were randomized (median age 43 years, 58% male, 60% with inflammatory bowel disease, 46% on ursodeoxycholic acid). Baseline median serum ALP and bilirubin were 348 U/L (interquartile range 288-439) and 0.7 mg/dL (0.5-1.0), respectively. Dose-dependent reductions in liver biochemistry were observed. At week 12, cilofexor 100 mg led to significant reductions in serum ALP (median reduction -21%; P = 0.029 versus placebo), gamma-glutamyl transferase (-30%; P < 0.001), alanine aminotransferase (ALT) (-49%; P = 0.009), and aspartate aminotransferase (-42%; P = 0.019). Cilofexor reduced serum C4 compared with placebo; reductions in bile acids were greatest with 100 mg. Relative reductions in ALP were similar between ursodeoxycholic acid-treated and untreated patients. At week 12, cilofexor-treated patients with a 25% or more relative reduction in ALP had greater reductions in serum alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, tissue inhibitor of metalloproteinase 1, C-reactive protein, and bile acids than nonresponders. Adverse events were similar between cilofexor and placebo-treated patients. Rates of grade 2 or 3 pruritus were 14% with 100 mg, 20% with 30 mg, and 40% with placebo. Conclusion: In this 12-week, randomized, placebo-controlled study, cilofexor was well tolerated and led to significant improvements in liver biochemistries and markers of cholestasis in patients with PSC.

Background and objective: Transgender and gender-diverse (TGD) persons experience health inequities compared to their cisgender peers, which is in part related to limited evidence informing their care. Thus, we aimed to describe the literature informing care provision of TGD individuals. Data source, eligibility criteria, and synthesis methods: Literature cited by the World Professional Association of Transgender Health Standards of Care Version 8 was reviewed. Original research articles, excluding systematic reviews (n = 74), were assessed (n = 1809). Studies where the population of interest were only caregivers, providers, siblings, partners, or children of TGD individuals were excluded (n = 7). Results were synthesized in a descriptive manner. Results: Of 1809 citations, 696 studies met the inclusion criteria. TGD-only populations were represented in 65% of studies. White (38%) participants and young adults (18 to 29 years old, 64%) were the most well-represented study populations. Almost half of studies (45%) were cross-sectional, and approximately a third were longitudinal in nature (37%). Overall, the median number of TGD participants (median [IQR]: 104 [32, 356]) included in each study was approximately one third of included cisgender participants (271 [47, 15405]). In studies where both TGD and cisgender individuals were included (n = 74), the proportion of TGD to cisgender participants was 1:2 [1:20, 1:1]. Less than a third of studies stratified results by sex (32%) or gender (28%), and even fewer included sex (4%) or gender (3%) as a covariate in the analysis. The proportion of studies with populations including both TGD and cisgender participants increased between 1969 and 2023, while the proportion of studies with study populations of unspecified gender identity decreased over the same time period. Conclusions: While TGD participant-only studies make up most of the literature informing care of this population, longitudinal studies including a diversity of TGD individuals across life stages are required to improve the quality of evidence. [ABSTRACT FROM AUTHOR]

Background & Aims: Liver transplantation (LT) for primary sclerosing cholangitis (PSC) is complicated by recurrence of PSC (rPSC) in up to 25% of recipients. Recurrence has been shown to be detrimental for both graft and patient survival. For both PSC and rPSC, a medical cure is not available. To predict and ideally to prevent rPSC, it is imperative to find risk factors for rPSC that can be potentially modified. Therefore, we aimed to identify such factors for rPSC in a large international multicentre study including 6 centres in PSC-prevalent countries. Methods: In this international multicentre, retrospective cohort study, 531 patients who underwent transplantation for PSC were included. In 25% of cases (n = 131), rPSC was diagnosed after a median follow-up of 6.72 (3.29–10.11) years post-LT. Results: In the multivariable competing risk model with time-dependent covariates, we found that factors representing an increased inflammatory state increase the risk for rPSC. Recurrent cholangitis before LT as indication for LT (hazard ratio [HR] 3.6, 95% CI 2.5–5.2), increased activity of inflammatory bowel disease after LT (HR 1.7, 95% CI 1.08–2.75), and multiple acute cellular rejections (HR: non-linear) were significantly and independently associated with an increased risk of rPSC. In contrast to the findings of previous studies, pretransplant colectomy was not found to be independently protective against the development of rPSC. Conclusions: An increased inflammatory state before and after LT may play a causal and modifiable role in the development of rPSC. Pretransplant colectomy did not reduce the risk of rPSC per se. Recurrent cholangitis as indication for LT was associated with an increased risk of rPSC. Impact and implications: Recurrence of PSC (rPSC) negatively affects survival after liver transplant (LT). Modifiable risk factors could guide clinical management and prevention of rPSC. We demonstrate that an increased inflammatory state both before and after LT increases the incidence of rPSC. As these are modifiable factors, they could serve as targets for future studies and therapies. We also added further evidence to the ongoing debate regarding preventive colectomy for rPSC by reporting that in our multicenter study, we could not find an independent association between colectomy and risk of rPSC.

Background: Urinary fistula (UF) is a global health problem but less common in well-resourced countries. Over the past decade there has been a trend toward managing UF in dedicated centres. Most of the evidence for surgical treatment is from individual case series, with few publications that involve high numbers. We describe the repair of recurrent and complex UF cases and outcomes in a tertiary referral setting. Objective: To describe UF aetiology, repair techniques, and outcomes. Design, setting, and participants: This is a retrospective study of a series of patients undergoing UF repair at a specialist unit. Outcome measurements and statistical analysis: We describe the aetiology, cure rate, complications, and postoperative urinary incontinence rates for the series of UF cases. Results and limitations: A consecutive series of 98 patients was identified, all of whom were tertiary referrals. Of these, 31 (31.6%) had at least one prior attempt at repair at another centre. The median age was 48 yr (interquartile range [IQR] 40–60.25). The median time from occurrence to repair was 12 mo (IQR 6–12). UF occurred most commonly following hysterectomy (48.0%), Caesarean section (9.2%), other gynaecological surgery (7.1%), and anti-incontinence surgery (7.1%). Complex fistulae (eg, repeat cases, radiation, ureteric involvement) comprised 41 of the cases (41.8%). Most patients with vesicovaginal fistula underwent repair via a transabdominal approach (70.4%). Tissue interposition was used in 96 cases (98%). There were no Clavien-Dindo grade >3 complications. Two patients (2%) had a persistent UF postoperatively. Two patients (2%) developed recurrence more than 2 yr after their initial repair, and both were successfully repaired at our centre. Twelve patients (12.3%) developed de novo overactive bladder, 22 (22.5%) developed stress urinary incontinence (13 had subsequent incontinence surgery), and two (2%) developed bladder pain (both had a subsequent cystectomy). Conclusions: Despite a high rate of recurrent and complex UF, successful lasting closure was achieved in 96% of our cases. A minority of patients developed other problems such as de novo overactive bladder and stress urinary incontinence that may require further treatment. Patient summary: Urinary fistula is an abnormal opening or connection in the urinary tract and is less common in well-resourced countries. As a consequence, management of this condition is more frequently undertaken at specialist units. Even patients with a complex fistula and those who have had multiple attempts at repair can experience a cure. Urinary leakage is a common complication after the operation but can be successfully managed with surgery.

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC.

Retinal disorders such as retinitis pigmentosa, age-related retinal degeneration, oxygen-induced retinopathy, and ischemia-reperfusion injury cause debilitating and irreversible vision loss. While the exact mechanisms underlying these conditions remain unclear, there has been a growing body of evidence demonstrating the pathological contributions of oxidative stress across different cell types within the eye. Nuclear factor erythroid-2-related factor (Nrf2), a transcriptional activator of antioxidative genes, and its regulator Kelch-like ECH-associated protein 1 (Keap1) have emerged as promising therapeutic targets. The purpose of this review is to understand the protective role of the Nrf2-Keap1 pathway in different retinal tissues and shed light on the complex mechanisms underlying these processes. In the photoreceptors, we highlight that Nrf2 preserves their survival and function by maintaining oxidation homeostasis. In the retinal pigment epithelium, Nrf2 similarly plays a critical role in oxidative stabilization but also maintains mitochondrial motility and autophagy-related lipid metabolic processes. In endothelial cells, Nrf2 seems to promote proper vascularization and revascularization through concurrent activation of antioxidative and angiogenic factors as well as inhibition of inflammatory cytokines. Finally, Nrf2 protects retinal ganglion cells against apoptotic cell death. Importantly, we show that Nrf2-mediated protection of the various retinal tissues corresponds to a preservation of functional vision. Altogether, this review underscores the potential of the Nrf2-Keap1 pathway as a powerful tool against retinal degeneration. Key insights into this elegant oxidative defense mechanism may ultimately pave the path toward a universal therapy for various inherited and environmental retinal disorders.

Patients with primary biliary cholangitis (PBC) with incomplete response to ursodeoxycholic acid are at risk of disease progression and need additional therapy. Obeticholic acid (OCA) was approved in Canada in May 2017, but its effectiveness in a real‐world setting has not been described. We sought to describe our experience with OCA in a Canadian cohort. OCA‐naive patients treated at two Canadian centers were included. Clinical and biochemical data were collected at OCA initiation and during follow‐up. Primary outcomes were changes in serum alkaline phosphatase (ALP), gamma‐glutamyl transferase (GGT), and total bilirubin (TB) over the duration of therapy. Secondary outcomes were changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), immunoglobulin M (IgM), platelets, and albumin; and achievement of the primary endpoint of the original phase 3 study that led to OCA approval (A Placebo‐Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis [POISE]), dose reductions, discontinuations, and tolerability. Repeated‐measures models were used to assess changes in biochemistry over time. Sixty‐four patients were included; 4 carried a diagnosis of overlap with autoimmune hepatitis. Mean age was 54.6 years, median ALP was 250 U/L, TB was 13 µmol/L, platelet count was 225 × 109/L, and 24% had liver stiffness measurements ≥16.9 kPa. There was a significant reduction in mean ALP of 55 U/L (P

Lassa fever (LF) is an acute viral haemorrhagic illness with various non-specific clinical manifestations. Neurological symptoms are rare at the early stage of the disease, but may be seen in late stages, in severely ill patients.The aim of this study was to describe the epidemiological evolution, socio-demographic profiles, clinical characteristics, and outcomes of patients seen during two Lassa fever outbreaks in Ebonyi State, between December 2017 and December 2018. Routinely collected clinical data from all patients admitted to the Virology Centre of the hospital during the period were analysed retrospectively. Out of a total of 83 cases, 70(84.3%) were RT-PCR confirmed while 13 (15.7%) were probable cases. Sixty-nine (83.1%) patients were seen in outbreak 1 of whom 53.6% were urban residents, while 19%, 15%, and 10% were farmers, students and health workers respectively. There were 14 (16.8%) patients, seen in second outbreak with 92.9% rural residents. There were differences in clinical symptoms, signs and laboratory findings between the two outbreaks. The case fatality rates were 29.9% in outbreak 1 and 85.7% for outbreak 2. Neurological features and abnormal laboratory test results were associated with higher mortality rate, seen in outbreak 2. This study revealed significant differences between the two outbreaks. Of particular concern was the higher case fatality during the outbreak 2 which may be from a more virulent strain of the Lassa virus. This has important public health implications and further molecular studies are needed to better define its characteristics.

Background & Aims: A DNA methylation (DNAm) signature derived from 353 CpG sites (the Horvath clock) has been proposed as an epigenetic measure of chronological and biological age. This epigenetic signature is accelerated in diverse tissue types in various disorders, including non-alcoholic steatohepatitis, and is associated with mortality. Here, we assayed whole blood DNAm to explore age acceleration in patients with primary sclerosing cholangitis (PSC). Methods: Using the MethylationEPIC BeadChip (850K) array, DNAm signatures in whole blood were analyzed in 36 patients with PSC enrolled in a 96-week trial of simtuzumab (Ishak F0-1, n = 13; F5-6, n = 23). Age acceleration was calculated as the difference between DNAm age and chronological age. Comparisons between patients with high and low age acceleration (≥ vs. < the median) were made and Cox regression evaluated the association between age acceleration and PSC-related clinical events (e.g. decompensation, cholangitis, transplantation). Results: Age acceleration was significantly higher in patients with PSC compared to a healthy reference cohort (median, 11.1 years, p