Matrix Metalloproteinase-2 and CKD Progression: The Chronic Renal Insufficiency Cohort (CRIC) Study.

Rationale & Objective: Matrix metalloproteinase 2 (MMP-2) plays an important role in the development of fibrosis, the final common pathway of chronic kidney disease (CKD). This study aimed to assess the relationship between repeated measures of MMP-2 and CKD progression in a large, diverse prospective cohort. Study Design: In a prospective cohort of Chronic Renal Insufficiency Cohort (CRIC) participants (N = 3,827), MMP-2 was measured at baseline. In a case-cohort design, MMP-2 was additionally measured at year 2 in a randomly selected subcohort and cases of estimated glomerular filtration rate (eGFR) halving or kidney replacement therapy (KRT) (N = 1,439). Setting & Participants: CRIC is a multicenter prospective cohort of adults with CKD. Exposure: MMP-2 measured in plasma at baseline and at year 2. Outcomes: A composite kidney endpoint (KRT/eGFR halving). Analytical Approach: Weighted Cox proportional hazards models for case-cohort participants. Results: Participants were followed for a median of 4.6 years from year 2 and 6.9 years from the baseline. Persistently elevated MMP-2 (≥300 ng/mL at both baseline and year 2) increased the hazard of the composite kidney endpoint (HR, 1.61; 95% CI, 1.07-2.42; P = 0.09) after adjusting for covariates. The relationship of persistently elevated MMP-2 was modified by levels of inflammation, with a 2.6 times higher rate of the composite kidney endpoint in those with high-sensitivity C-reactive protein < 2.5 g/dL at study entry. Heterogeneity of effect was found with proteinuria, with a baseline MMP-2 level of ≥300 ng/mL associated with an increased risk of the composite kidney endpoint (HR, 1.30; 95% CI, 1.09-1.54) only with proteinuria ≥ 442 mg/g. Limitations: The observational study design limits causal interpretation. Conclusions: Elevated MMP-2 is associated with CKD progression, particularly among those with low inflammation and those with proteinuria. Future investigations are warranted to confirm the reduction in risk of CKD progression among these subgroups of patients with CKD.

Matrix metalloproteinase 2 (MMP-2) is a matrix-degrading protease involved in fibrosis and elevated in chronic kidney disease (CKD). Longitudinal patterns of MMP-2 have not previously been assessed as a predictor of CKD progression in a large prospective cohort. Here, we found that a higher baseline level and an increasing or persistently elevated 2-year pattern of MMP-2 were associated with CKD progression, independent of all covariates except proteinuria. The association of baseline MMP-2 with CKD progression differed by level of proteinuria, whereas levels of inflammation modified the associations of 2-year MMP-2 patterns with CKD progression.

Cardiovascular Disease Events and Mortality After Myocardial Infarction Among Black and White Adults: REGARDS Study.

BACKGROUND: Despite improvements in prognosis following myocardial infarction (MI), racial disparities persist. The objective of this study was to examine disparities between Black and White adults in cardiovascular disease (CVD), coronary heart disease, stroke, heart failure (HF), and mortality after MI and characteristics that may explain the disparities. METHODS: This prospective cohort study included 1122 REGARDS (Reasons for Geographic and Racial Differences in Stroke) study participants with incident MI between 2003 and 2016. We followed participants for subsequent CVD events (MI, stroke, HF hospitalization, or death from CVD; n=431), coronary heart disease events (MI or death from coronary heart disease; (n=277), stroke (n=68), HF events (HF hospitalization or death from HF; n=191), and all-cause mortality (n=527; 3-year median follow-up after MI). RESULTS: Among 1122 participants with incident MI, 37.5% were Black participants, 45.4% were women, and mean age was 73.2 (SD, 9.5) years. The unadjusted hazard ratio for CVD events comparing Black to White participants was 1.42 (95% CI, 1.17-1.71). Adjusting for sociodemographic characteristics did not attenuate the association (1.41 [95% CI, 1.14-1.73]), but further adjusting for pre-MI health status (1.25 [95% CI, 1.00-1.56]) and characteristics of the MI (1.01 [95% CI, 0.80-1.27]) resulted in substantial attenuation. Similar patterns were observed for the other outcomes, although the number of strokes was small. CONCLUSIONS: Black individuals had a higher risk of CVD events and mortality after MI than White individuals. The disparities were explained by health status before MI and characteristics of the MI. These findings suggest that both primordial prevention of risk factors and improved acute treatment strategies are needed to reduce disparities in post-MI outcomes.

Comparison of Aggregated N-of-1 Trials with Parallel and Crossover Randomized Controlled Trials Using Simulation Studies.

Background: N-of-1 trials offer an innovative approach to delivering personalized clinical care together with population-level research. While increasingly used, these methods have raised some statistical concerns in the healthcare community. Methods: We discuss concerns of selection bias, carryover effects from treatment, and trial data analysis conceptually, then rigorously evaluate concerns of effect sizes, power, and sample size through simulation study. Four variance structures for patient heterogeneity and model error are considered in a series of 5000 simulated trials with three cycles, which compare N-of-1 trials to parallel randomized controlled trials (RCTs) and crossover trials. Results: N-of-1 trials outperformed both traditional parallel RCTs and crossover designs when trial designs were simulated in terms of power and required sample size to obtain a given power. N-of-1 designs resulted in a higher type-I error probability than parallel RCT and cross over designs when moderate-to-strong carryover or washout effects were not considered or in the presence of modeled selection bias. However, N-of-1 designs allowed better estimation of patient-level random effects. These results reinforce the need to account for these factors when planning N-of-1 trials. Conclusion: N-of-1 trial designs offer a rigorous method for advancing personalized medicine and healthcare with the potential to minimize costs and resources. Interventions can be tested with adequate power with far fewer patients than traditional RCT and crossover designs. Operating characteristics compare favorably to both traditional RCT and crossover designs.

Changing rates in fracture trends are temporally associated with declining testing and treatment: reality or ecologic fallacy?

PURPOSE OF REVIEW: The changing patterns of osteoporosis treatment and fragility fractures have led to what leaders are calling a 'crisis in the osteoporosis.' We address data on changing patterns in fractures, and highlight strengths and limitations of recently published data. RECENT FINDINGS: Declines in hip fracture rates have been shown in studies from around the world. However, recently, using national Medicare data, Michael Lewiecki and colleagues show a plateau in the decline of hip fracture incidence in the United States from 2012 to 2015. Population-based data is integral for evaluating temporal trends; however, researchers must consider the biases associated with them including: age effects, period effects, and cohort effects. Rosengren and colleagues conducted the most comprehensive evaluation of age, period, and birth cohort effects in their study of hip fracture trends from 1987 to 2010 in Denmark and Sweden, in which they identified changes in hip fracture rates based on age, period, and cohort effects. SUMMARY: Recent findings show clear temporal trends in changing fracture rates. Studies, which evaluated these biases largely attribute increased hip fracture rates to various age, period, and cohort effects, highlighting the importance of appropriate screening and treatment.

Gut microbiota diversity is associated with cardiorespiratory fitness in post-primary treatment breast cancer survivors.

NEW FINDINGS: What is the central question of this study? Does the link between cardiorespiratory fitness and gut microbiota diversity persist after adjusting for the potential effects of percentage body fat and activity-related energy expenditure (AEE)? What is the main finding and its importance? This is the first study to examine the link between cardiorespiratory fitness and gut microbiota diversity while accounting for the underlying effects of percentage body fat and free-living AEE. Results from the present work suggest that cardiorespiratory fitness, not physical activity, is a superior correlate of gut microbiota diversity among post-primary treatment, non-metastatic breast cancer survivors. ABSTRACT: Cancer treatment uniquely triggers multiple physiological shifts detrimental to overall health. Although previous research indicates a link between the gut microbiota and cardiorespiratory fitness, it is unclear whether these findings are attributable to potential underlying effects of percentage body fat or free-living activity energy expenditure (AEE). The microbe composition of faecal specimens from 37 breast cancer survivors was determined using 16S microbiome analyses. Individual-sample microbiota diversity (α-diversity) and between-sample community differences (ß-diversity) were examined. Peak oxygen uptake ( V̇O2peak ) was estimated from a graded exercise test consistent with the modified Naughton protocol, in which exercise terminates at 85% of age-predicted maximal heart rate. The AEE was measured over 10 days using doubly labelled water, wherein the percentage body fat was calculated from total body water. Pearson correlations revealed α-diversity indices (Chao1, observed species, PD whole tree and Shannon) to be positively associated with V̇O2peak (r = 0.34-0.51; P < 0.05), whereas the percentage of maximal heart rate during stages 1-4 of the graded exercise test (r = -0.34 to -0.50; P < 0.05) and percentage body fat (r = -0.32 to -0.41; P < 0.05) were negatively associated with the same α-diversity indices. Multiple linear regression models showed that V̇O2peak accounted for 22 and 26% of the variance in taxonomic richness (observed species) and phylogenic diversity after adjustment for percentage body fat and menopausal status. Unweighted UniFrac (ß-diversity) was significant for several outcomes involving cardiorespiratory fitness, and significant taxa comparisons were found. Associations between gut microbiota and free-living AEE were not found. Results from the present work suggest that cardiorespiratory fitness, not physical activity, is a superior correlate of gut microbiota diversity.