Clinical and genetic characterisation of a large Indian congenital myasthenic syndrome cohort.

Congenital myasthenic syndromes (CMS) are a rare group of inherited disorders caused by gene defects associated with the neuromuscular junction and potentially treatable with commonly available medications such as acetylcholinesterase inhibitors and ß2 adrenergic receptor agonists. In this study, we identified and genetically characterized the largest cohort of CMS patients from India to date. Genetic testing of clinically suspected patients evaluated in a South Indian hospital during the period 2014-19 was carried out by standard diagnostic gene panel testing or using a two-step method that included hotspot screening followed by whole-exome sequencing. In total, 156 genetically diagnosed patients (141 families) were characterized and the mutational spectrum and genotype-phenotype correlation described. Overall, 87 males and 69 females were evaluated, with the age of onset ranging from congenital to fourth decade (mean 6.6 ± 9.8 years). The mean age at diagnosis was 19 ± 12.8 (1-56 years), with a mean diagnostic delay of 12.5 ± 9.9 (0-49 years). Disease-causing variants in 17 CMS-associated genes were identified in 132 families (93.6%), while in nine families (6.4%), variants in genes not associated with CMS were found. Overall, postsynaptic defects were most common (62.4%), followed by glycosylation defects (21.3%), synaptic basal lamina genes (4.3%) and presynaptic defects (2.8%). Other genes found to cause neuromuscular junction defects (DES, TEFM) in our cohort accounted for 2.8%. Among the individual CMS genes, the most commonly affected gene was CHRNE (39.4%), followed by DOK7 (14.4%), DPAGT1 (9.8%), GFPT1 (7.6%), MUSK (6.1%), GMPPB (5.3%) and COLQ (4.5%). We identified 22 recurrent variants in this study, out of which eight were found to be geographically specific to the Indian subcontinent. Apart from the known common CHRNE variants p.E443Kfs*64 (11.4%) and DOK7 p.A378Sfs*30 (9.3%), we identified seven novel recurrent variants specific to this cohort, including DPAGT1 p.T380I and DES c.1023+5G>A, for which founder haplotypes are suspected. This study highlights the geographic differences in the frequencies of various causative CMS genes and underlines the increasing significance of glycosylation genes (DPAGT1, GFPT1 and GMPPB) as a cause of neuromuscular junction defects. Myopathy and muscular dystrophy genes such as GMPPB and DES, presenting as gradually progressive limb girdle CMS, expand the phenotypic spectrum. The novel genes MACF1 and TEFM identified in this cohort add to the expanding list of genes with new mechanisms causing neuromuscular junction defects.

Frailty and Cardiovascular Outcomes in Adults With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Frailty is common in individuals with chronic kidney disease (CKD) and increases the risk of adverse outcomes in adults with kidney failure requiring dialysis. However, this relationship has not been thoroughly evaluated among those with non-dialysis-dependent CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 2,539 adults in the Chronic Renal Insufficiency Cohort Study. EXPOSURE: Frailty status assessed using 5 criteria: slow gait speed, muscle weakness, low physical activity, exhaustion, and unintentional weight loss. OUTCOME: Atherosclerotic events, incident heart failure, all-cause death, and cardiovascular death. ANALYTICAL APPROACH: Cause-specific hazards models. RESULTS: At study entry, the participants' mean age was 62 years, 46% were female, the mean estimated glomerular filtration rate was 45.4mL/min/1.73m2, and the median urine protein was 0.2mg/day. Frailty status was as follows: 12% frail, 51% prefrail, and 37% nonfrail. Over a median follow-up of 11.4 years, there were 393 atherosclerotic events, 413 heart failure events, 497 deaths, and 132 cardiovascular deaths. In multivariable regression analyses, compared with nonfrailty, both frailty and prefrailty status were each associated with higher risk of an atherosclerotic event (HR, 2.03 [95% CI, 1.41-2.91] and 1.77 [95% CI, 1.35-2.31], respectively) and incident heart failure (HR, 2.22 [95% CI, 1.59-3.10] and 1.39 [95% CI, 1.07-1.82], respectively), as well as higher risk of all-cause death (HR, 2.52 [95% CI, 1.84-3.45] and 1.76 [95% CI, 1.37-2.24], respectively) and cardiovascular death (HR, 3.01 [95% CI, 1.62-5.62] and 1.78 [95% 1.06-2.99], respectively). LIMITATIONS: Self-report of aspects of the frailty assessment and comorbidities, which may have led to bias in some estimates. CONCLUSIONS: In adults with CKD, frailty status was associated with higher risk of cardiovascular events and mortality. Future studies are needed to evaluate the impact of interventions to reduce frailty on cardiovascular outcomes in this population. PLAIN-LANGUAGE SUMMARY: Frailty is common in individuals with chronic kidney disease (CKD) and increases the risk of adverse outcomes. We sought to evaluate the association of frailty status with cardiovascular events and death in adults with CKD. Frailty was assessed according to the 5 phenotypic criteria detailed by Fried and colleagues. Among 2,539 participants in the CRIC Study, we found that 12% were frail, 51% were prefrail, and 37% were nonfrail. Frailty status was associated with an increased risk of atherosclerotic events, incident heart failure, and death.

Risk for Chronic Kidney Disease Progression After Acute Kidney Injury: Findings From the Chronic Renal Insufficiency Cohort Study.

BACKGROUND: Prior studies associating acute kidney injury (AKI) with more rapid subsequent loss of kidney function had methodological limitations, including inadequate control for differences between patients who had AKI and those who did not. OBJECTIVE: To determine whether AKI is independently associated with subsequent kidney function trajectory among patients with chronic kidney disease (CKD). DESIGN: Multicenter prospective cohort study. SETTING: United States. PARTICIPANTS: Patients with CKD (n = 3150). MEASUREMENTS: Hospitalized AKI was defined by a 50% or greater increase in inpatient serum creatinine (SCr) level from nadir to peak. Kidney function trajectory was assessed using estimated glomerular filtration rate (eGFR) based on SCr level (eGFRcr) or cystatin C level (eGFRcys) measured at annual study visits. RESULTS: During a median follow-up of 3.9 years, 433 participants had at least 1 AKI episode. Most episodes (92%) had stage 1 or 2 severity. There were decreases in eGFRcr (-2.30 [95% CI, -3.70 to -0.86] mL/min/1.73 m2) and eGFRcys (-3.61 [CI, -6.39 to -0.82] mL/min/1.73 m2) after AKI. However, in fully adjusted models, the decreases were attenuated to -0.38 (CI, -1.35 to 0.59) mL/min/1.73 m2 for eGFRcr and -0.15 (CI, -2.16 to 1.86) mL/min/1.73 m2 for eGFRcys, and the CI bounds included the possibility of no effect. Estimates of changes in eGFR slope after AKI determined by either SCr level (0.04 [CI, -0.30 to 0.38] mL/min/1.73 m2 per year) or cystatin C level (-0.56 [CI, -1.28 to 0.17] mL/min/1.73 m2 per year) also had CI bounds that included the possibility of no effect. LIMITATIONS: Few cases of severe AKI, no adjudication of AKI cause, and lack of information about nephrotoxic exposures after hospital discharge. CONCLUSION: After pre-AKI eGFR, proteinuria, and other covariables were accounted for, the association between mild to moderate AKI and worsening subsequent kidney function in patients with CKD was small. PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

Association of Proximal Tubular Secretory Clearance with Long-Term Decline in Cognitive Function.

BACKGROUND: People with chronic kidney disease (CKD) are at high risk for cognitive impairment and progressive cognitive decline. Retention of protein-bound organic solutes that are normally removed by tubular secretion is hypothesized to contribute to cognitive impairment in CKD. METHODS: We followed 2362 participants who were initially free of cognitive impairment and stroke in the prospective Chronic Renal Insufficiency Cohort (CRIC) Study. We estimated tubular secretory clearance by the 24-hour kidney clearances of eight endogenous solutes that are primarily eliminated by tubular secretion. CRIC study investigators assessed participants' cognitive function annually using the Modified Mini-Mental State (3MS) Examination. Cognitive decline was defined as a sustained decrease of more than five points in the 3MS score from baseline. Using Cox regression models adjusted for potential confounders, we analyzed associations between secretory solute clearances, serum solute concentrations, and cognitive decline. RESULTS: The median number of follow-up 3MS examinations was six per participant. There were 247 incident cognitive decline events over a median of 9.1 years of follow-up. Lower kidney clearances of five of the eight secretory solutes (cinnamoylglycine, isovalerylglycine, kynurenic acid, pyridoxic acid, and tiglylglycine) were associated with cognitive decline after adjustment for baseline eGFR, proteinuria, and other confounding variables. Effect sizes ranged from a 17% to a 34% higher risk of cognitive decline per 50% lower clearance. In contrast, serum concentrations of the solutes were not associated with cognitive decline. CONCLUSIONS: Lower kidney clearances of secreted solutes are associated with incident global cognitive decline in a prospective study of CKD, independent of eGFR. Further work is needed to determine the domains of cognition most affected by decreased secretory clearance and the mechanisms of these associations.

A Comparative Study of Serum Phosphate and Related Parameters in Chronic Kidney Disease between the USA and Japan.

INTRODUCTION: Recent studies have suggested a higher incidence of cardiovascular disease (CVD) among patients with chronic kidney disease (CKD) in the USA than in Japan. Hyperphosphatemia, a possible risk for CVD, may explain this difference; however, international differences in phosphate parameters in CKD have not been well elaborated. METHODS: By using the baseline data from the USA and the Japanese nation-wide, multicenter, CKD cohort studies; the Chronic Renal Insufficiency Cohort Study (CRIC, N = 3,870) and the Chronic Kidney Disease-Japan Cohort Study (CKD-JAC, N = 2,632), we harmonized the measures and compared clinical parameters regarding phosphate metabolism or serum phosphate, fibroblast growth factor-23 (FGF23), and parathyroid hormone (PTH), in the cross-sectional model. RESULTS: Multivariable linear regression analyses revealed that serum phosphate levels were significantly higher in CRIC across all levels of estimated glomerular filtration rate (eGFR) with the greatest difference being observed at lower levels of eGFR. Serum FGF23 and 25-hydroxy vitamin D (25OHD) levels were higher in CRIC, while PTH levels were higher in CKD-JAC at all levels of eGFR. Adjustments for demographics, 25OHD, medications, dietary intake or urinary excretion of phosphate, PTH, and FGF23 did not eliminate the difference in serum phosphate levels between the cohorts (0.43, 0.46, 0.54, 0.64, and 0.78 mg/dL higher in CRIC within eGFR strata of >50, 41-50, 31-40, 21-30, and ≤20 mL/min/1.73 m2, respectively). These findings were consistent when only Asian CRIC participants (N = 105) were included in the analysis. CONCLUSION: Serum phosphate levels in CRIC were significantly higher than those of CKD-JAC across all stages of CKD, which may shed light on the international variations in phosphate parameters and thus in cardiovascular risk among CKD patients. The key mechanisms for the substantial differences in phosphate parameters need to be elucidated.

High-Throughput Metabolomics and Diabetic Kidney Disease Progression: Evidence from the Chronic Renal Insufficiency (CRIC) Study.

INTRODUCTION: Metabolomics could offer novel prognostic biomarkers and elucidate mechanisms of diabetic kidney disease (DKD) progression. Via metabolomic analysis of urine samples from 995 CRIC participants with diabetes and state-of-the-art statistical modeling, we aimed to identify metabolites prognostic to DKD progression. METHODS: Urine samples (N = 995) were assayed for relative metabolite abundance by untargeted flow-injection mass spectrometry, and stringent statistical criteria were used to eliminate noisy compounds, resulting in 698 annotated metabolite ions. Utilizing the 698 metabolites' ion abundance along with clinical data (demographics, blood pressure, HbA1c, eGFR, and albuminuria), we developed univariate and multivariate models for the eGFR slope using penalized (lasso) and random forest models. Final models were tested on time-to-ESKD (end-stage kidney disease) via cross-validated C-statistics. We also conducted pathway enrichment analysis and a targeted analysis of a subset of metabolites. RESULTS: Six eGFR slope models selected 9-30 variables. In the adjusted ESKD model with highest C-statistic, valine (or betaine) and 3-(4-methyl-3-pentenyl)thiophene were associated (p < 0.05) with 44% and 65% higher hazard of ESKD per doubling of metabolite abundance, respectively. Also, 13 (of 15) prognostic amino acids, including valine and betaine, were confirmed in the targeted analysis. Enrichment analysis revealed pathways implicated in kidney and cardiometabolic disease. CONCLUSIONS: Using the diverse CRIC sample, a high-throughput untargeted assay, followed by targeted analysis, and rigorous statistical analysis to reduce false discovery, we identified several novel metabolites implicated in DKD progression. If replicated in independent cohorts, our findings could inform risk stratification and treatment strategies for patients with DKD.

Association Between Kidney Clearance of Secretory Solutes and Cardiovascular Events: The Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: The clearance of protein-bound solutes by the proximal tubules is an innate kidney mechanism for removing putative uremic toxins that could exert cardiovascular toxicity in humans. However, potential associations between impaired kidney clearances of secretory solutes and cardiovascular events among patients with chronic kidney disease (CKD) remains uncertain. STUDY DESIGN: A multicenter, prospective, cohort study. SETTING & PARTICIPANTS: We evaluated 3,407 participants from the Chronic Renal Insufficiency Cohort (CRIC) study. EXPOSURES: Baseline kidney clearances of 8 secretory solutes. We measured concentrations of secretory solutes in plasma and paired 24-hour urine specimens using liquid chromatography-tandem mass spectrometry (LC-MS/MS). OUTCOMES: Incident heart failure, myocardial infarction, and stroke events. ANALYTICAL APPROACH: We used Cox regression to evaluate associations of baseline secretory solute clearances with incident study outcomes adjusting for estimated GFR (eGFR) and other confounders. RESULTS: Participants had a mean age of 56 years; 45% were women; 41% were Black; and the median estimated glomerular filtration rate (eGFR) was 43 mL/min/1.73 m2. Lower 24-hour kidney clearance of secretory solutes were associated with incident heart failure and myocardial infarction but not incident stroke over long-term follow-up after controlling for demographics and traditional risk factors. However, these associations were attenuated and not statistically significant after adjustment for eGFR. LIMITATIONS: Exclusion of patients with severely reduced eGFR at baseline; measurement variability in secretory solutes clearances. CONCLUSIONS: In a national cohort study of CKD, no clinically or statistically relevant associations were observed between the kidney clearances of endogenous secretory solutes and incident heart failure, myocardial infarction, or stroke after adjustment for eGFR. These findings suggest that tubular secretory clearance provides little additional information about the development of cardiovascular disease events beyond glomerular measures of GFR and albuminuria among patients with mild-to-moderate CKD.

Differential network enrichment analysis reveals novel lipid pathways in chronic kidney disease.

MOTIVATION: Functional enrichment testing methods can reduce data comprising hundreds of altered biomolecules to smaller sets of altered biological 'concepts' that help generate testable hypotheses. This study leveraged differential network enrichment analysis methodology to identify and validate lipid subnetworks that potentially differentiate chronic kidney disease (CKD) by severity or progression. RESULTS: We built a partial correlation interaction network, identified highly connected network components, applied network-based gene-set analysis to identify differentially enriched subnetworks, and compared the subnetworks in patients with early-stage versus late-stage CKD. We identified two subnetworks 'triacylglycerols' and 'cardiolipins-phosphatidylethanolamines (CL-PE)' characterized by lower connectivity, and a higher abundance of longer polyunsaturated triacylglycerols in patients with severe CKD (stage ≥4) from the Clinical Phenotyping Resource and Biobank Core. These finding were replicated in an independent cohort, the Chronic Renal Insufficiency Cohort. Using an innovative method for elucidating biological alterations in lipid networks, we demonstrated alterations in triacylglycerols and cardiolipins-phosphatidylethanolamines that precede the clinical outcome of end-stage kidney disease by several years. AVAILABILITY AND IMPLEMENTATION: A complete list of NetGSA results in HTML format can be found at http://metscape.ncibi.org/netgsa/12345-022118/cric_cprobe/022118/results_cric_cprobe/main.html. The DNEA is freely available at https://github.com/wiggie/DNEA. Java wrapper leveraging the cytoscape.js framework is available at http://js.cytoscape.org. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Longitudinal Evolution of Markers of Mineral Metabolism in Patients With CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: The pathogenesis of disordered mineral metabolism in chronic kidney disease (CKD) is largely informed by cross-sectional studies of humans and longitudinal animal studies. We sought to characterize the longitudinal evolution of disordered mineral metabolism during the course of CKD. STUDY DESIGN: Retrospective analysis nested in a cohort study. SETTING & PARTICIPANTS: Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study who had up to 5 serial annual measurements of estimated glomerular filtration rate, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), serum phosphate, and serum calcium and who subsequently reached end-stage kidney disease (ESKD) during follow-up (n = 847). EXPOSURE: Years before ESKD. OUTCOMES: Serial FGF-23, PTH, serum phosphate, and serum calcium levels. ANALYTICAL APPROACH: To assess longitudinal dynamics of disordered mineral metabolism in human CKD, we used "ESKD-anchored longitudinal analyses" to express time as years before ESKD, enabling assessments of mineral metabolites spanning 8 years of CKD progression before ESKD. RESULTS: Mean FGF-23 levels increased markedly as time before ESKD decreased, while PTH and phosphate levels increased modestly and calcium levels declined minimally. Compared with other mineral metabolites, FGF-23 levels demonstrated the highest rate of change (velocity: first derivative of the function of concentration over time) and magnitude of acceleration (second derivative). These changes became evident approximately 5 years before ESKD and persisted without deceleration through ESKD onset. Rates of changes in PTH and phosphate levels increased modestly and without marked acceleration around the same time, with modest deceleration immediately before ESKD, when use of active vitamin D and phosphate binders increased. LIMITATIONS: Individuals who entered the CRIC Study at early stages of CKD and who did not progress to ESKD were not studied. CONCLUSIONS: Among patients with progressive CKD, FGF-23 levels begin to increase 5 years before ESKD and continue to rapidly accelerate until transition to ESKD.

Developing the Active Communities Tool to Implement the Community Guide's Built Environment Recommendation for Increasing Physical Activity.

Physical activity is higher in communities that include supportive features for walking and bicycling. In 2016, the Community Preventive Services Task Force released a systematic review of built environment approaches to increase physical activity. The results of the review recommended approaches that combine interventions to improve pedestrian and bicycle transportation systems with land use and environmental design strategies. Because the recommendation was multifaceted, the Centers for Disease Control and Prevention determined that communities could benefit from an assessment tool to address the breadth of the Task Force recommendations. The purpose of this article is to describe the systematic approach used to develop the Active Communities Tool. First, we created and refined a logic model and community theory of change for tool development. Second, we reviewed existing community-based tools and abstracted key elements (item domains, advantages, disadvantages, updates, costs, permissions to use, and psychometrics) from 42 tools. The review indicated that no tool encompassed the breadth of the Community Guide recommendations for communities. Third, we developed a new tool and pilot tested its use with 9 diverse teams with public health and planning expertise. Final revisions followed from pilot team and expert input. The Active Communities Tool comprises 6 modules addressing all 8 interventions recommended by the Task Force. The tool is designed to help cross-sector teams create an action plan for improving community built environments that promote physical activity and may help to monitor progress toward achieving community conditions known to promote physical activity.

Integrating a Medical Home in an Outpatient Dialysis Setting: Effects on Health-Related Quality of Life.

BACKGROUND: Integrating primary care has been proposed to reduce fragmented care delivery for patients with complex medical needs. Because of their high rates of morbidity, healthcare use, and mortality, patients with end-stage kidney disease (ESKD) may benefit from increased access to a primary care medical home. OBJECTIVE: To evaluate the effect of integrating a primary care medical home on health-related quality of life (HRQOL) for patients with ESKD receiving chronic hemodialysis. DESIGN: Before-after intervention trial with repeated measures at two Chicago dialysis centers. PARTICIPANTS: Patients receiving hemodialysis at either of the two centers. INTERVENTION: To the standard hemodialysis team (nephrologist, nurse, social worker, dietitian), we added a primary care physician, a pharmacist, a nurse coordinator, and a community health worker. The intervention took place from January 2015 through August 2016. MAIN MEASURES: Health-related quality of life, using the Kidney Disease Quality of Life (KDQOL) measures. KEY RESULTS: Of 247 eligible patients, 175 (71%) consented and participated; mean age was 54 years; 55% were men and 97% were African American or Hispanic. In regression analysis adjusted for individual visits with the medical home providers and other factors, there were significant improvements in four of five KDQOL domains: at 12 and 18 months, the Mental Component Score improved from baseline (adjusted mean 49.0) by 2.64 (p = 0.01) and 2.96 (p = 0.007) points, respectively. At 6 and 12 months, the Symptoms domain improved from baseline (adjusted mean = 77.0) by 2.61 (p = 0.02) and 2.35 points (p = 0.05) respectively. The Kidney Disease Effects domain improved from baseline (adjusted mean = 72.7), to 6, 12, and 18 months by 4.36 (p = 0.003), 6.95 (p < 0.0001), and 4.14 (p = 0.02) points respectively. The Physical Component Score improved at 6 months only. CONCLUSIONS: Integrating primary care and enhancing care coordination in two dialysis facilities was associated with improvements in HRQOL among patients with ESKD who required chronic hemodialysis.

The Association between Neighborhood Environments and Physical Activity from Pregnancy to Postpartum: a Prospective Cohort Study.

The objectives of this study were to determine if neighborhood measures were associated with physical activity cross-sectionally during late pregnancy (27-30 weeks' gestation), 3 months postpartum, and 12 months postpartum, and longitudinally with an increase in physical activity from late pregnancy to 12 months postpartum. Data are from the Pregnancy, Infection, and Nutrition (PIN3) and Postpartum Prospective Cohort Study. Dichotomized self-reported recreation and total physical activity hours/week were explored cross-sectionally at three time points, and as an increase over time. Four factors from a neighborhood environmental audit were examined: arterial or thoroughfare, walkable neighborhood, physical incivilities, and decoration. Secondary spatial data included population density, hilliness, intersection density, distance to nearest major road, distance to nearest park, distance to nearest physical activity facility, and distance to nearest bus stop. Multilevel mixed-effects logistic regression models were used to assess the association between environmental variables and physical activity measures. A number of environmental variables were associated with total and recreation physical activity at the three time points in cross-sectional models. For increase in recreation physical activity over time, a moderate distance to nearest major road was significantly associated with increased recreation physical activity from 3 to 12 months postpartum (tertile 2 OR 2.13, 95% CI 1.08, 4.22). Living the furthest distance from the nearest park was inversely associated with an increase in recreation physical activity from pregnancy to 3 months postpartum (tertile 3 OR 0.50, 95% CI 0.29, 0.85). The findings of this study indicate that several aspects of the neighborhood environment, such as walkability, access to transit, distance to recreation facilities, and road networks, are associated with physical activity during different stages of pregnancy and postpartum. Since physical activity may result in long-term health benefits for both the woman and child, environments that support this activity should be encouraged.

Effects of Intensive Blood Pressure Treatment on Acute Kidney Injury Events in the Systolic Blood Pressure Intervention Trial (SPRINT).

BACKGROUND: Treating to a lower blood pressure (BP) may increase acute kidney injury (AKI) events. STUDY DESIGN: Data for AKI resulting in or during hospitalization or emergency department visits were collected as part of the serious adverse events reporting process of the Systolic Blood Pressure Intervention Trial (SPRINT). SETTING & PARTICIPANTS: 9,361 participants 50 years or older with 1 or more risk factors for cardiovascular disease. INTERVENTIONS: Participants were randomly assigned to a systolic BP target of <120 (intensive arm) or <140mmHg (standard arm). OUTCOMES & MEASUREMENTS: Primary outcome was the number of adjudicated AKI events. Secondary outcomes included severity of AKI and degree of recovery of kidney function after an AKI event. Baseline creatinine concentration was defined as the most recent SPRINT outpatient creatinine value before the date of the AKI event. RESULTS: There were 179 participants with AKI events in the intensive arm and 109 in the standard arm (3.8% vs 2.3%; HR, 1.64; 95% CI, 1.30-2.10; P<0.001). Of 288 participants with an AKI event, 248 (86.1%) had a single AKI event during the trial. Based on modified KDIGO (Kidney Disease: Improving Global Outcomes) criteria for severity of AKI, the number of AKI events in the intensive versus standard arm by KDIGO stage was 128 (58.5%) versus 81 (62.8%) for AKI stage 1, 42 (19.2%) versus 18 (14.0%) for AKI stage 2, and 42 (19.2%) versus 25 (19.4%) for AKI stage 3 (P=0.5). For participants with sufficient data, complete or partial resolution of AKI was seen for 169 (90.4%) and 9 (4.8%) of 187 AKI events in the intensive arm and 86 (86.9%) and 4 (4.0%) of 99 AKI events in the standard arm, respectively. LIMITATIONS: Trial results are not generalizable to patients with diabetes mellitus or without risk factors for cardiovascular disease. CONCLUSIONS: More intensive BP lowering resulted in more frequent episodes of AKI. Most cases were mild and most participants had complete recovery of kidney function. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01206062.

Reliability and One-Year Stability of the PIN3 Neighborhood Environmental Audit in Urban and Rural Neighborhoods.

Reliable and stable environmental audit instruments are needed to successfully identify the physical and social attributes that may influence physical activity. This study described the reliability and stability of the PIN3 environmental audit instrument in both urban and rural neighborhoods. Four randomly sampled road segments in and around a one-quarter mile buffer of participants' residences from the Pregnancy, Infection, and Nutrition (PIN3) study were rated twice, approximately 2 weeks apart. One year later, 253 of the year 1 sampled roads were re-audited. The instrument included 43 measures that resulted in 73 item scores for calculation of percent overall agreement, kappa statistics, and log-linear models. For same-day reliability, 81% of items had moderate to outstanding kappa statistics (kappas ≥ 0.4). Two-week reliability was slightly lower, with 77% of items having moderate to outstanding agreement using kappa statistics. One-year stability had 68% of items showing moderate to outstanding agreement using kappa statistics. The reliability of the audit measures was largely consistent when comparing urban to rural locations, with only 8% of items exhibiting significant differences (α < 0.05) by urbanicity. The PIN3 instrument is a reliable and stable audit tool for studies assessing neighborhood attributes in urban and rural environments.

Perceived Social and Built Environment Correlates of Transportation and Recreation-Only Bicycling Among Adults.

INTRODUCTION: Research on perceptions of environmental factors in relation to transportation and recreation bicycling is limited in the United States. We explored the association between perceived social and built environment factors with total, transportation, and recreation bicycling in a sample of adult bicyclists in Austin, Texas, and Birmingham, Alabama. The objective of this study was to examine the relationship between perceived social and built environment factors and domain-specific bicycling in a sample of adult bicyclists. METHODS: Adults aged 18 to 65 who rode a bicycle at least once in the past year completed an internet-based survey that was developed for this study to specifically assess correlates of bicycling; the study was conducted from October 2016 through January 2017. Perceived environmental factors assessed were residential density, traffic safety, destination, connectivity, safety from crime, aesthetics, and bicycle infrastructure. Multivariable logistic regression models were used to estimate the association of each perceived environmental factor (tertile 1, lowest; tertile 3, highest) with recreation-only and transportation bicycling. Effect modification of the relation between environmental factors and bicycling outcomes by sex was also examined. RESULTS: The final analytic sample size was 801 participants. All environmental factors examined, including residential density, traffic safety, destinations, connectivity, aesthetics, bicycle infrastructure, and safety from crime showed significantly direct associations with transportation bicycling. Traffic safety, destinations, aesthetics, and bicycle infrastructure showed significant direct and inverse associations with recreation-only bicycling. Effect modification by sex was identified with residential density; a significant direct association with recreation-only bicycling was seen among women. CONCLUSION: These findings illustrate that bicycling for transportation is associated with different perceived environmental factors than is recreation-only bicycling, with some significant modification by sex. Comprehensive tools that assess the perceived environment for bikeability in the United States are warranted.

Predictors of Impaired Mental Health and Support Seeking in Adults With Inflammatory Bowel Disease: An Online Survey.

This study explored the possible factors associated with psychological distress in adults with inflammatory bowel disease (IBD) and also engagement in mental health services (MHS) in those reporting distress in a large Australian cohort. Participants with IBD completed an online survey assessing perceived IBD activity (Manitoba Index; MI), mental health status (K10), demographic details, and engagement with MHS for IBD-associated issues. Of 336 participants, 76.5% perceived themselves as having active disease over the past 6 months, and on K10 scores, 51.8% had a mental health issue. Of participants with a mental health issue, only 21.3% were currently receiving mental health support. A stepwise logistic regression analysis correctly classified 78.7% of the status of receiving mental health support, with lower income (<$60,000 per annum) the only significant predictor. Paradoxically, the degree of psychological distress did not correlate with seeking mental health support. The data show that in individuals with ongoing symptoms attributed to active IBD, mental health issues are highly prevalent, with older age and higher income being additional drivers of mental health issues. The greater challenge, however, seems not to be identifying mental health issues, but in getting those in need to engage in MHS.

Risks of Adverse Events in Advanced CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: People with advanced chronic kidney disease are at risk for the development of end-stage renal disease (ESRD), but also many other adverse outcomes, including cardiovascular disease (CVD) events and death. Determination of risk factors that explain the variability in prognosis and timing of these adverse outcomes can aid patient counseling and medical decision making. STUDY DESIGN: Prospective research cohort. SETTING & PARTICIPANTS: 1,798 participants with estimated glomerular filtration rates (eGFRs)<30mL/min/1.73m2 in the CRIC Study were followed up for a median of 5.5 years. PREDICTORS: Age, race, sex, eGFR, proteinuria, diabetes mellitus, body mass index, ejection fraction, systolic blood pressure, history of CVD, and smoking history. OUTCOMES: ESRD, CVD (congestive heart failure, stroke, myocardial infarction, and peripheral artery disease), and death. RESULTS: Baseline age of the cohort was 60 years, 46% were women, and 46% were African American. Although 52.3% of participants progressed to ESRD during follow-up, the path by which this occurred was variable. For example, predicted 1-year probabilities for a hypothetical 60-year-old white woman with eGFR of 30mL/min/1.73m2, urine protein excretion of 1.8g/d, and no diabetes or CVD (risk characteristics similar to the average participant) were 3.3%, 4.1%, and 0.3%, for first developing CVD, ESRD, and death, respectively. For a 40-year-old African American man with similar characteristics but higher systolic blood pressure, the corresponding 1-year probabilities were 2.4%, 13.2%, and 0.1%. For all participants, the development of ESRD or CVD increased the risk for subsequent mortality, with no differences by patient race or body mass index. LIMITATIONS: The CRIC population was specifically recruited for kidney disease, and the vast majority had seen a nephrologist. CONCLUSIONS: The prognosis and timing of adverse outcomes in chronic kidney disease vary by patient characteristics. These results may help guide the development of personalized approaches for managing patients with advanced CKD.

Urinary Sodium and Potassium Excretion and CKD Progression.

CKD is a major risk factor for ESRD, cardiovascular disease, and premature death. Whether dietary sodium and potassium intake affect CKD progression remains unclear. We prospectively studied the association of urinary sodium and potassium excretion with CKD progression and all-cause mortality among 3939 patients with CKD in the Chronic Renal Insufficiency Cohort Study. Urinary sodium and potassium excretion were measured using three 24-hour urine specimens, and CKD progression was defined as incident ESRD or halving of eGFR. During follow-up, 939 CKD progression events and 540 deaths occurred. Compared with the lowest quartile of urinary sodium excretion (<116.8 mmol/24 h), hazard ratios (95% confidence intervals) for the highest quartile of urinary sodium excretion (≥194.6 mmol/24 h) were 1.54 (1.23 to 1.92) for CKD progression, 1.45 (1.08 to 1.95) for all-cause mortality, and 1.43 (1.18 to 1.73) for the composite outcome of CKD progression and all-cause mortality after adjusting for multiple covariates, including baseline eGFR. Additionally, compared with the lowest quartile of urinary potassium excretion (<39.4 mmol/24 h), hazard ratios for the highest quartile of urinary potassium excretion (≥67.1 mmol/24 h) were 1.59 (1.25 to 2.03) for CKD progression, 0.98 (0.71 to 1.35) for all-cause mortality, and 1.42 (1.15 to 1.74) for the composite outcome. These data indicate that high urinary sodium and potassium excretion are associated with increased risk of CKD progression. Clinical trials are warranted to test the effect of sodium and potassium reduction on CKD progression.

Freezing and non-freezing cold weather injuries: a systematic review.

INTRODUCTION: The debilitating impact of cold weather on the human body is one of the world's oldest recorded injuries. The severe and life-changing damage which can be caused is now more commonly seen recreationally in extreme outdoor sports rather than in occupational settings such as the military. The diagnosis and treatment of these injuries need to be completed carefully but quickly to reduce the risk of loss of limb and possibly life. Therefore, we have conducted a systematic review of the literature surrounding cold weather injuries (CWIs) to ascertain the epidemiology and current management strategies. SOURCES OF DATA: Medline (PubMED), EMBASE, CINHAL, Cochrane Collaboration Database, Web of Science, Scopus and Google Scholar. AREAS OF AGREEMENT IMMEDIATE FIELD TREATMENT: The risk of freeze thaw freeze injuries. Delayed surgical intervention when possible. Different epidemiology of freezing and non-freezing injuries. AREAS OF CONTROVERSY: Prophylatic use of antibiotics; the use of vasodilators surgical and medical. GROWING POINTS: The use of ilioprost and PFG2a for the treatment of deep frostbite. AREAS TIMELY FOR DEVELOPING RESEARCH: The treatment of non-freezing CWIs with their long-term follow-up.