Caring for patients with end-stage kidney disease (ESKD) in the United States is challenging not only because the epidemiology of the disease's progression is complex, but also because treatment delivery occurs within social and environmental contexts that can be difficult to navigate. Chronic kidney disease (CKD) often results from other conditions, such as hypertension and diabetes. In turn, CKD can contribute to a cascade of new chronic conditions, such as anemia and cardiovascular disease. Notably, 83% of US Medicare fee-for-service program enrollees with CKD have three or more comorbid chronic conditions. 1 As CKD progresses toward ESKD, the number of comorbidities increases, care becomes much more complex and the potential for adverse outcomes increases. 2,3 As a result, care for individuals with ESKD typically involves multiple healthcare providers from multiple subspecialties. In the context of a US healthcare delivery system that has been historically siloed by provider specialty, organization, payment system, and administration,
ImportanceOlder adults vary widely in age at diagnosis and duration of type 2 diabetes, but treatment often ignores this heterogeneity.ObjectivesTo investigate the associations of diabetes vs no diabetes, age at diagnosis, and diabetes duration with negative health outcomes in people 50 years and older.Design, Setting, and ParticipantsThis cohort study included participants in the 1995 through 2018 waves of the Health and Retirement Study (HRS), a population-based, biennial longitudinal health interview survey of older adults in the US. The study sample included adults 50 years or older (n = 36 060) without diabetes at entry. Data were analyzed from June 1, 2021, to July 31, 2022.ExposuresThe presence of diabetes, specifically the age at diabetes diagnosis, was the main exposure of the study. Age at diagnosis was defined as the age when the respondent first reported diabetes. Adults who developed diabetes were classified into 3 age-at-diagnosis groups: 50 to 59 years, 60 to 69 years, and 70 years and older.Main Outcomes and MeasuresFor each diabetes age-at-diagnosis group, a propensity score–matched control group of respondents who never developed diabetes was constructed. The association of diabetes with the incidence of key outcomes—including heart disease, stroke, disability, cognitive impairment, and all-cause mortality—was estimated and the association of diabetes vs no diabetes among the age-at-diagnosis case and matched control groups was compared.ResultsA total of 7739 HRS respondents developed diabetes and were included in the analysis (4267 women [55.1%]; mean [SD] age at diagnosis, 67.4 [9.9] years). The age-at-diagnosis groups included 1866 respondents at 50 to 59 years, 2834 at 60 to 69 years, and 3039 at 70 years or older; 28 321 HRS respondents never developed diabetes. Age at diagnosis of 50 to 59 years was significantly associated with incident heart disease (hazard ratio [HR], 1.66 [95% CI, 1.40-1.96]), stroke (HR, 1.64 [95% CI, 1.30-2.07]), disability (HR, 2.08 [95% CI, 1.59-2.72]), cognitive impairment (HR, 1.30 [95% CI, 1.05-1.61]), and mortality (HR, 1.49 [95% CI, 1.29-1.71]) compared with matched controls, even when accounting for diabetes duration. These associations significantly decreased with advancing age at diagnosis. Respondents with diabetes diagnosed at 70 years or older only showed a significant association with the outcome of elevated mortality (HR, 1.08 [95% CI, 1.01-1.17]).Conclusions and RelevanceThe findings of this cohort study suggest that age at diabetes diagnosis was differentially associated with outcomes and that younger age groups were at elevated risk of heart disease, stroke, disability, cognitive impairment, and all-cause mortality. These findings reinforce the clinical heterogeneity of diabetes and highlight the importance of improving diabetes management in adults with earlier diagnosis.
A BS TRACT: Background: Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by the aggregation of α-synuclein in glia and neurons. Sirolimus (rapamycin) is an mTOR inhibitor that promotes α-synuclein autophagy and reduces its associated neurotoxicity in preclinical models. Objective: To investigate the efficacy and safety of sirolimus in patients with MSA using a futility design. We also analyzed 1-year biomarker trajectories in the trial participants. Methods: Randomized, double-blind, parallel group, placebo-controlled clinical trial at the New York University of patients with probable MSA randomly assigned (3:1) to sirolimus (2-6 mg daily) for 48 weeks or placebo. Primary endpoint was change in the Unified MSA Rating Scale (UMSARS) total score from baseline to 48 weeks. (ClinicalTrials.gov NCT03589976). Results: The trial was stopped after a pre-planned interim analysis met futility criteria. Between August 15, 2018 and November 15, 2020, 54 participants were screened, and 47 enrolled and randomly assigned (35 sirolimus, 12 placebo). Of those randomized, 34 were included in the intention-to-treat analysis. There was no difference in change from baseline to week 48 between the sirolimus and placebo in UMSARS total score (mean difference, 2.66; 95% CI, À7.35-6.91; P = 0.648). There was no difference in UMSARS-1 and UMSARS-2 scores either. UMSARS scores changes were similar to those reported in natural history studies. Neuroimaging and blood biomarker results were similar in the sirolimus and placebo groups. Adverse events were more frequent with sirolimus. Analysis of 1-year biomarker trajectories in all participants showed that increases in blood neurofilament light chain (NfL) and reductions in whole brain volume correlated best with UMSARS progression. Conclusions: Sirolimus for 48 weeks was futile to slow the progression of MSA and had no effect on biomarkers compared to placebo. One-year change in blood NfL and whole brain atrophy are promising biomarkers of disease progression for future clinical trials.
Purpose: Adjuvant immunotherapy produces durable benefit for patients with resected melanoma, but many develop recurrence and/or immune-related adverse events (irAE). We investigated whether baseline serum autoantibody (autoAb) signatures predicted recurrence and severe toxicity in patients treated with adjuvant nivolumab, ipilimumab, or ipilimumab plus nivolumab. Experimental Design: This study included 950 patients: 565 from CheckMate 238 (408 ipilimumab versus 157 nivolumab) and 385 from CheckMate 915 (190 nivolumab versus 195 ipilimumab plus nivolumab). Serum autoAbs were profiled using the HuProt Human Proteome Microarray v4.0 (CDI Laboratories, Mayaguez, PR). Analysis of baseline differentially expressed autoAbs was followed by recurrence and severe toxicity signature building for each regimen, testing of the signatures, and additional independent validation for nivolumab using patients from CheckMate 915. Results: In the nivolumab independent validation cohort, high recurrence score predicted significantly worse recurrence-free survival [RFS; adjusted HR (aHR), 3.60; 95% confidence interval (CI), 1.98–6.55], and outperformed a model composed of clinical variables including PD-L1 expression (P < 0.001). Severe toxicity score was a significant predictor of severe irAEs (aHR, 13.53; 95% CI, 2.59–86.65). In the ipilimumab test cohort, high recurrence score was associated with significantly worse RFS (aHR, 3.21; 95% CI, 1.38–7.45) and severe toxicity score significantly predicted severe irAEs (aHR, 11.04; 95% CI, 3.84–37.25). In the ipilimumab plus nivolumab test cohort, high autoAb recurrence score was associated with significantly worse RFS (aHR, 6.45; 95% CI, 1.48–28.02), and high severe toxicity score was significantly associated with severe irAEs (aHR, 23.44; 95% CI, 4.10–212.50). Conclusions: Baseline serum autoAb signatures predicted recurrence and severe toxicity in patients treated with adjuvant immunotherapy. Prospective testing of the signatures that include datasets with longer follow-up and rare but more severe toxicities will help determine their generalizability and potential clinical utility. See related commentary by Hassel and Luke, p. 3914
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