Citations

OBJECTIVE In many individuals, type 2 diabetes (T2D) remains poorly controlled despite taking multiple glucose-lowering therapies. Several studies have demonstrated that endogenous hypercortisolism is prevalent among these individuals. We tested whether cortisol-directed therapy improves their glycemic control. RESEARCH DESIGN AND METHODS In this prospective, multicenter, double-blind study, 136 individuals with T2D (hemoglobin A1c [HbA1c] 7.5%–11.5% [58–102 mmol/mol] on multiple medications) and hypercortisolism (by dexamethasone suppression test) were randomized 2:1 to the glucocorticoid receptor antagonist mifepristone (300–900 mg once daily; n = 91) or placebo (n = 45) for 24 weeks, with stratification by presence/absence of an adrenal imaging abnormality. The primary end point was the change in HbA1c. Secondary end points included changes in glucose-lowering medications, weight, and waist circumference and safety. RESULTS Mean baseline HbA1c in the study cohort was 8.55% (69.9 mmol/mol). At 24 weeks, the least squares mean (LSM) difference from placebo in HbA1c was −1.32% (95% CI −1.81 to −0.83; P < 0.001). Participants receiving mifepristone experienced reductions in body weight and waist circumference (placebo-adjusted LSM differences of −5.12 kg [95% CI −8.20 to −2.03] and −5.1 cm [−8.23 to −1.99], respectively). Of participants on mifepristone, 46% discontinued therapy, compared with 18% on placebo. Adverse events with mifepristone (>10% of participants) included hypokalemia, fatigue, nausea, vomiting, headache, peripheral edema, diarrhea, and dizziness, consistent with mifepristone’s known tolerability profile. Increases in blood pressure also occurred. CONCLUSIONS In individuals with inadequately controlled T2D and hypercortisolism, cortisol-directed medical therapy with mifepristone reduced HbA1c, with a manageable tolerability profile.

ABSTRACTBackgroundPancreatic cysts are increasingly discovered on imaging studies performed for unrelated conditions. Currently, surveillance of these lesions poses a substantial burden on patients, and health care recourses. We hypothesized that individuals with small and stable cysts have a diminutive risk of progressing to high‐grade dysplasia (HGD) or pancreatic cancer (PC) that is similar to that in the general population.MethodsThis nested PACYFIC‐study is a collaboration among 44 centers in Europe and Northern‐America, and investigates the risk of HGD and PC for different cyst sizes and growth rates in participants without baseline worrisome features (WF) or high‐risk stigmata (HRS).ResultsOf the 2369 PACYFIC participants, 975 met the inclusion criteria, with a mean age of 67 years (SD 13) and 65% being female. Of these, 438 individuals (45%) had a baseline small cyst size (< 15 mm), and 885 (91%) individuals had a slow growth rate (< 2.5 mm/year). During a median follow‐up of 45 months (IQR 27), 20 individuals (2.1%) developed HGD, or PC. Individuals with small cysts had a 1.5‐fold lower risk of developing WF or HRS (hazard ratio [HR] 0.7 [0.5–1.0], p = 0.03) than those with larger cysts but a similar risk of developing HGD or PC (p > 0.05). Slow growth was protective against the development of WF or HRS (HR 0.4 [0.2–0.6], p < 0.001) and HGD or PC (HR 0.04 [95% CI 0.02–0.12], p < 0.001). Individuals with small, stable sized cysts without baseline WF or HRS did not have a higher risk of HGD or PC than the general population (standardized incidence ratio [SIR] 1.13 [95% CI 0.01–6.30]).ConclusionCyst size < 15 mm and growth rate < 2.5 mm/year appear to be “reassuring” features associated with a negligible risk of developing WF or HRS and HGD or PC. For cysts with these characteristics—and without baseline WF or HRS—less intensive surveillance (than currently recommended) or even cessation may be appropriate.

Abstract In this study, we quantified differences in iris stiffness between female and male subjects in healthy and postlaser peripheral iridotomy (post-LPI) groups using an image-based inverse modeling approach. We analyzed anterior segment optical coherence tomography (AS-OCT) images from 25 participants across four groups. Finite element models were created using **solidworks, **abaqus, and a custom C program, modeling the iris as a neo-Hookean material. We found that post-LPI females had significantly higher normalized elastic modulus (E′=3.81±1.74) than healthy females (E′=0.92±0.31,p=0.004), while no significant difference was observed in males. Post-LPI females also showed significantly higher stiffness than post-LPI males (p=0.003). Here, p denotes the probability value, with p&lt;0.05 considered statistically significant. Our findings suggest that sex-based differences in iris biomechanics may contribute to the higher susceptibility of females to primary angle-closure disease. Despite the small sample size, this preliminary study highlights the need for larger, sex-stratified investigations into glaucoma pathophysiology.

Abstract Aims We explored the manifestations of individual weight loss (WL) response to long-term lifestyle interventions on cardiometabolic risk. Methods and results We pooled data from three large long-term lifestyle WL-intervention trials: 24-month DIRECT (ClinicalTrials.gov: NCT00160108; n = 322; 87% adherence), 18-month CENTRAL (ClinicalTrials.gov: NCT01530724; n = 278; 86% adherence), and 18-month DIRECT PLUS (ClinicalTrials.gov: NCT03020186; n = 294; 89% adherence). We analyzed longitudinal changes in cardiometabolic risk markers, including anthropometrics, blood biomarkers, and magnetic-resonance-imaging-assessed fat depots, and measured DNA-methylation, proteomics, and metabolomics. Among trial completers (n = 761, mean age = 50.4 years; 89% men, baseline body-mass-index = 30.1 kg/m2), mean WL was −3.3 kg (−3.5%). We classified participants as Successful-WL (36%) with relative-WL &gt; 5%, WL-Resistant (28%) who did not lose or gained weight, and Moderate-WL (36%) with WL between 0% and 5%. Successful-WL achieved the greatest improvements in multiple health indicators. However, the WL-Resistant also showed some significant improvements, with increased high-density-lipoprotein-cholesterol (HDLc) and decreased leptin and visceral fat (P &lt; 0.05 vs. baseline). Overall, each 1 kg sustained lifestyle-induced WL was associated with improvements in lipid markers and insulin resistance [HDLc (+1.44%), triglycerides (−1.37%), insulin (−2.46%), HOMA-IR (−2.71%), leptin (−2.79%)] and intrahepatic-fat regression (−0.49 absolute-units)] and modest but significant change in systolic and diastolic blood pressures (−0.26% and −0.36%). We identified 12 significant methylation sites that are associated with Successful-WL (FDR &lt; 0.05; AUC = 0.73). Conclusion While only ∼one-third of individuals achieved long-term WL, the Moderate-WL and WL-Resistant individuals could benefit improvements in visceral adiposity and cardiometabolic risk by shifting towards a healthy lifestyle pattern, beyond WL. Site-specific DNA methylation may predict an individual's likelihood of successful WL. Registration NCT00160108, NCT01530724, NCT03020186.

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Summary Background: Precision prevention involves using biological, behavioral, socioeconomic, and epidemiological data to improve health for a particular individual or group. With almost 63% of the global population using social media, these platforms show promise to deliver tailored messaging and personalized interventions to individuals. Objectives: To describe the personalization elements and behavior components used in a sample of precision prevention interventions delivered through social media. Methods: To identify examples of cases, a search was done on clinicaltrials.gov, searching for ‘other terms: prevention’ + ‘Intervention/Treatment: social media intervention’ + ‘study results: With results. The selected cases were described, personalization elements reported, and their adopted intervention components were coded according to the Behavior Change Wheel (BCW) framework. Results: A total of four cases employing personalization in their interventions were identified. Three of these cases targeted women's health. The intervention period varied from two to eight months, with participant commitment ranging from active involvement on five out of seven days to monthly participation. The BCW interventions of persuasion and incentivization, were most frequently utilized, while education and coercion were used sparingly in the selected cases. Notably, none of the four cases reported the use of training, restrictions, or modeling. Conclusions: Social media has the potential to serve as a tool for digital phenotyping and contribute to the advancement of precision prevention. Challenges include the social media platform set-up and ensuring all ethical considerations are met.

Objectives The impact of body mass index (BMI) on cardiovascular risk in rheumatoid arthritis (RA) is unclear. RA characteristics may influence the association between BMI and risk. Disease activity, which predicts cardiovascular risk, is associated with obesity only among anticitrullinated antibody (ACPA)-positive patients. Biologics alter body composition and mitigate cardiovascular risk in RA. We explored the association of BMI with cardiovascular risk and whether this varied across ACPA status and biologic use. Methods We evaluated 3982 patients from an international observational cohort. Outcomes included (a) first major adverse cardiovascular event (MACE) encompassing myocardial infarction, stroke or cardiovascular death; and (b) all events comprising MACE, angina, revascularisation, transient ischaemic attack, peripheral arterial disease and heart failure. Multivariable Cox models stratified by centre risk evaluated the impact of BMI, ACPA, biologics and their two- and three-way interactions on outcomes. Results We recorded 192 MACE and 319 total events. No main effects of BMI, ACPA or biologics were observed. A three-way interaction between them on MACE (p-interaction<0.001) and all events (p-interaction=0.028) was noted. Among ACPA negative patients, BMI was inversely associated with MACE (HR 0.38 (95% CI 0.25 to 0.57)) and all events (HR 0.67 (0.49 to 0.92)) in biologic users but not non-users (p-for-interaction <0.001 and 0.012). Among ACPA-positive patients, BMI was associated with MACE (HR 1.04 [1.01–1.07]) and all events (HR 1.03 (1.00 to 1.06)) independently of biologic use. Conclusions BMI is inversely associated with cardiovascular risk only among ACPA-negative biologic users. In contrast, BMI is associated with cardiovascular risk in ACPA-positive patients independently of biologic use.

Abstract Background and Aims Over 10% of patients with Crohn’s disease require permanent ileostomy. We aimed to summarize the existing data on diagnosis, definitions of recurrence, and management of Crohn’s disease patients with permanent ileostomy. Methods MEDLINE, Embase, and CENTRAL databases were searched from inception to February 6, 2024. Randomized controlled trials, cohort and cross-sectional studies, and case series of more than 5 patients reporting on postoperative recurrence or the need for surgery in patients with Crohn’s disease and permanent ileostomy were included. Search results were independently screened, and full text of all titles meeting eligibility criteria was obtained. Outcomes of interest included diagnostic techniques, recurrence definitions, and management approaches. We estimated pooled rates (with 95% confidence interval [CI]) of recurrence. Results Thirty cohort studies including 2055 Crohn’s patients with permanent ileostomy were included (53% female, median age at the time of ileostomy creation 32 years, the most common reason for ileostomy was refractory disease). The postoperative recurrence rate was 27% (95% CI, 21.3–33.3, 26 studies, 451/1805 patients). Modalities for diagnosis of Crohn’s disease recurrence were symptoms (15 studies), endoscopy (4 studies), histology from endoscopic biopsies (2 studies), imaging (5 studies), and surgery (22 studies). The reported definitions of recurrence for each modality were heterogeneous. Conclusions There is a lack of standardized monitoring tools and criteria for diagnosing recurrence in patients with Crohn’s disease and permanent ileostomy. The results of this systematic review will form the basis of a global expert recommendation exercise focused on developing management standards and trial endpoints for this condition.