Faculty Bibliography

BACKGROUND & AIMS/OBJECTIVE:Primary sclerosing cholangitis (PSC) is a rare, chronic liver disease. Elafibranor, a dual peroxisome proliferator-activated receptor-α/δ agonist, was investigated in the phase II ELMWOOD trial (NCT05627362). METHODS:This 12-week, double-blind trial enrolled adults with PSC and alkaline phosphatase (ALP) ≥1.5× the upper limit of normal. The primary endpoint was elafibranor safety vs. placebo. Additional endpoints included relative mean change from baseline in ALP and enhanced liver fibrosis (ELF) score. RESULTS:A total of 68 participants (male: 54.4%; mean age: 46.3 years; inflammatory bowel disease: 55.9%) were randomized to elafibranor 80 mg (n = 22), elafibranor 120 mg (n = 23), or placebo (n = 23). At baseline, 70.6% were on ursodeoxycholic acid, 48.5% had ELF scores >9.8, and the mean ALP level was 369.5 U/L. At Week 12, rates of treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation in participants on elafibranor 80 mg, 120 mg, and placebo were 68.2%, 78.3%, and 69.6%, and 4.5%, 4.3%, and 8.7%, respectively. Serious TEAEs occurred only in participants on placebo (4.3%). Participants on elafibranor 80 mg and 120 mg had reductions in ALP vs. placebo (least squares mean treatment difference [95% CI]: -35.3% [-49.2, -21.4] and -54.7% [-68.3, -41.0], respectively). ALP normalization occurred only in participants on elafibranor 80 mg (9.1%) and 120 mg (17.4%). The LS mean treatment differences (95% CI) in change from baseline in ELF scores in participants on elafibranor 80 mg and 120 mg vs. placebo were -0.19 (-0.52, +0.15) and -0.28 (-0.62, +0.06), respectively. CONCLUSIONS:Elafibranor was well tolerated in people with PSC and associated with greater biochemical improvements over 12 weeks compared with placebo. A greater magnitude of response was observed with elafibranor 120 mg compared with 80 mg. IMPACT AND IMPLICATIONS/UNASSIGNED:For people with primary sclerosing cholangitis (PSC), there is a need for a well-tolerated and effective treatment that will enhance quality of life, prevent disease progression, and improve long-term outcomes. Here, we present results from the double-blind period of the phase II ELMWOOD trial in PSC, wherein elafibranor, a peroxisome proliferator-activated receptor-α/δ agonist, demonstrated a favorable safety profile, provided greater biochemical improvements over 12 weeks compared with placebo, and appeared to stabilize markers of fibrosis and improve pruritus. These findings support larger and longer term investigations of elafibranor to explore its therapeutic potential as a treatment for people with PSC.

IMPORTANCE/OBJECTIVE:Patients with poor glycaemic control have a high risk for major cardiovascular events. Improving glycaemic monitoring in patients with diabetes can improve morbidity and mortality. OBJECTIVE:To assess the effectiveness of a patient portal message in prompting patients with poorly controlled diabetes without a recent glycated haemoglobin (HbA1c) result to have their HbA1c repeated. DESIGN/METHODS:A pragmatic, randomised clinical trial. SETTING/METHODS:A large academic health system consisting of over 350 ambulatory practices. PARTICIPANTS/METHODS:Patients who had an HbA1c greater than 10% who had not had a repeat HbA1c in the prior 6 months. EXPOSURES/METHODS:A single electronic health record (EHR)-based patient portal message to prompt patients to have a repeat HbA1c test versus usual care. MAIN OUTCOMES/RESULTS:The primary outcome was a follow-up HbA1c test result within 90 days of randomisation. RESULTS:The study included 2573 patients with a mean (SD) HbA1c of 11.2%. Among 1317 patients in the intervention group, 24.2% had follow-up HbA1c tests completed within 90 days, versus 21.1% of 1256 patients in the control group (p=0.07). Patients in the intervention group were more likely to log into the patient portal within 60 days as compared with the control group (61.2% vs 52.3%, p<0.001). CONCLUSIONS:Among patients with poorly controlled diabetes and no recent HbA1c result, a brief patient portal message did not significantly increase follow-up testing but did increase patient engagement with the patient portal. Automated patient messages could be considered as a part of multipronged efforts to involve patients in their diabetes care.

BACKGROUND:Cardiogenic shock (CS) can be complicated by severe valvular heart disease (VHD). We analyzed cardiac intensive care unit (CICU) admissions according to VHD status. METHODS AND RESULTS/RESULTS:The Critical Care Cardiology Trials Network is a multicenter network of tertiary CICUs. Centers contributed data from consecutive admissions during 2-month annual snapshots from 2017-2023. CS admissions were classified as having CS attributed to VHD, CS with noncausative VHD or CS without severe VHD. Demographics and therapies were compared. Unadjusted and adjusted odds ratios for in-hospital mortality were calculated. We analyzed 5242 admissions with CS (4.1% attributed to VHD, 18.8% with noncausative VHD, 77.1% without severe VHD). Mitral regurgitation (32.1%) and aortic stenosis (27.9%) were the most common pathologies in CS attributed to VHD. Admissions with CS attributed to VHD more commonly had LVEF ≥ 40% on admission (present in 62.8%, 22.6% and 15.1%, respectively; P < 0.001). Valve intervention was performed in 32.1% of those with CS attributed to VHD. Unadjusted in-hospital mortality in admissions with CS attributed to VHD was 40.0%, compared to 33.4% and 30.3% in the other groups. CONCLUSIONS:VHD is the underlying cause of CS in a minority of CICU admissions but is associated with high in-hospital mortality rates.

BACKGROUND/PURPOSE/OBJECTIVE:Intraductal papillary mucinous neoplasms (IPMNs) progress from low-grade dysplasia to high-grade dysplasia (HGD) or invasive carcinoma (IC). High diagnostic accuracy is critical for surgical decision-making. METHODS:We searched Medline, Embase, and Cochrane Library from January 1, 2015, to January 27, 2025. Eligible studies reported on resected IPMNs, assessing diagnostic features for HGD/IC. Two reviewers screened articles, extracted data, and assessed bias using the Newcastle-Ottawa scale. Descriptive statistics summarized outcomes. The performance of worrisome features (WFs) and high-risk stigmata (HRS) based on International Association of Pancreatology guidelines were evaluated. RESULTS:In the 53 studies, 12 953 patients were included. HRS including obstructive jaundice and enhancing mural nodules ≥5mm showed robust specificity for HGD/IC, while main pancreatic duct size ≥10mm showed variable diagnostic accuracy. WFs such as cyst size ≥3 cm performed poorly, while cyst growth rate >3.5 mm/year demonstrated higher sensitivity (88%) and specificity (91%). Although rare, abrupt caliber change with distal atrophy was a robust predictor of malignancy (median odds ratio: 3.01). Acute pancreatitis and lymphadenopathy displayed variable value. Incremental improvement in diagnostic accuracy was observed with additional HRS or WFs. CONCLUSIONS:Current diagnostic markers are valuable but provide limited guidance for surgical decision-making in IPMNs, highlighting the need for further refinement of diagnostic tools.

BACKGROUND:Due to high prevalence of Kaposi Sarcoma (KS)-Associated Herpesvirus (KSHV) among people with HIV, KSHV-associated disease (KAD) may be increased after kidney transplantation from donors with HIV (HIV D+) to recipients with HIV (HIV R+). METHODS:Anti-KSHV antibodies were measured in HIV R+ and donors with and without HIV (HIV D-) using a 30-antigen multiplex assay within three multicenter kidney transplantation studies. KSHV seropositivity was defined as reactivity to conventional KSHV antigens (≥1 ORF73 or K8.1); reactivity to expanded 5-antigen and 30-antigen panels were also reported. Risk factors were identified using modified Poisson regression. Recipients were monitored for post-transplant anti-KSHV antibody changes and KAD. RESULTS:KSHV seroprevalence was 40.6% (143/352) among HIV R+, 25.2% (33/131) among HIV D+, and 7.5% (4/53) among HIV D-. In the multivariable model, only men who have sex with men (MSM) was associated with KSHV seropositivity: relative risk 1.51 (95% confidence interval [CI] 1.07-2.14) in recipients and 2.39 (95%CI 1.03-5.53) in donors. Among 418 HIV R+ (215 HIV D+/R+, 203 HIV D-/R+), there were 5 KAD cases (incidence 0.63 cases/100 person-years, 95%CI 0.26-1.52): 3 skin-only KS, 1 multicentric Castleman disease, 1 allograft KS. The allograft KS occurred in a female HIV D+/R+ and was likely donor-derived. Remaining KAD cases occurred in male HIV D-/R+ and were likely recipient KSHV reactivation or acquisition. CONCLUSIONS:In the United States, KSHV seroprevalence in donors and recipients with HIV was high, particularly among MSM. Reassuringly, KSHV-associated disease was rare, and primarily attributed to recipient rather than donor-derived KSHV.

One of the greatest obstacles to achieving implantable electronics with long-term functionality and minimized inflammatory reactions is the immune-mediated foreign-body response (FBR). Recently, semiconducting polymers with mixed electron-ion conductivity have been demonstrated as promising candidates to achieve direct electrical interfacing on bio-tissues. However, there is limited understanding of their immune compatibility in vivo, and strategies for minimizing the FBR through molecular design remain underexplored. Here we introduce a set of molecular design strategies for enhancing the immune compatibility of semiconducting polymers. Specifically, we show that selenophene, when incorporated in the backbone, can mitigate the FBR by suppressing macrophage activation. In addition, side-chain functionalization with immunomodulatory groups decreases the FBR further by downregulating the expression of inflammatory biomarkers. Together, our synthesized polymers achieve suppression of the FBR by as much as 68% (as indicated by the collagen density). In the meantime, these immune-compatible designs still provide a high charge-carrier mobility of around 1 cm² V^-1 s^-1. We anticipate that such immune-compatible design principles can be translated to a variety of conjugated polymers to suppress the FBR for implantable applications.

Qualitative research methods are frequently described as "compatible" with quantitative epidemiological methods. Instead of simply "compatible," we argue that qualitative methods are epidemiological methods. Especially in social epidemiology, which embraces the relationships between psychosocial, historical, contextual, and intersectional factors and health, qualitative research methods have the potential to provide a more complete picture of the distribution of health and disease within a population and contexts contributing to population health. To this end, this paper compares qualitative research and epidemiological research definitions, outlines epidemiological uses of qualitative data, and addresses common concerns and misconceptions about qualitative research. We emphasize the shared characteristics and champion the use of shared standards across qualitative and quantitative approaches in epidemiology.