Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes.

BACKGROUND: Higher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate (GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease. METHODS: In a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m2 of body-surface area, and evidence of diabetic kidney disease to receive allopurinol or placebo. The primary outcome was the baseline-adjusted GFR, as measured with iohexol, after 3 years plus a 2-month washout period. Secondary outcomes included the decrease in the iohexol-based GFR per year and the urinary albumin excretion rate after washout. Safety was also assessed. RESULTS: A total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m2 in the allopurinol group and 67.3 ml per minute per 1.73 m2 in the placebo group. During the intervention period, the mean serum urate level decreased from 6.1 to 3.9 mg per deciliter with allopurinol and remained at 6.1 mg per deciliter with placebo. After washout, the between-group difference in the mean iohexol-based GFR was 0.001 ml per minute per 1.73 m2 (95% confidence interval [CI], -1.9 to 1.9; P = 0.99). The mean decrease in the iohexol-based GFR was -3.0 ml per minute per 1.73 m2 per year with allopurinol and -2.5 ml per minute per 1.73 m2 per year with placebo (between-group difference, -0.6 ml per minute per 1.73 m2 per year; 95% CI, -1.5 to 0.4). The mean urinary albumin excretion rate after washout was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. The frequency of serious adverse events was similar in the two groups. CONCLUSIONS: We found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.).

Patient Cognitive Status and Physician Recommendations for Cardiovascular Disease Treatment: Results of Two Nationwide, Randomized Survey Studies.

BACKGROUND: Clinical guidelines recommend that older patients (65+) with mild cognitive impairment (MCI) and early-stage dementia receive similar guideline-concordant care after cardiovascular disease (CVD) events as those with normal cognition (NC). However, older patients with MCI and dementia receive less care for CVD and other conditions than those with NC. Whether physician recommendations for guideline-concordant treatments after two common CVD events, acute myocardial infarction (AMI) and acute ischemic stroke (stroke), differ between older patients with NC, MCI, and early-stage dementia is unknown. OBJECTIVE: To test the influence of patient cognitive status (NC, MCI, early-stage dementia) on physicians' recommendations for guideline-concordant treatments for AMI and stroke. DESIGN: We conducted two parallel, randomized survey studies for AMI and stroke in the US using clinical vignettes where the hypothetical patient's cognitive status was randomized between physicians. PARTICIPANTS: The study included cardiologists, neurologists, and generalists who care for most patients hospitalized for AMI and stroke. MAIN MEASURES: The primary outcome was a composite quality score representing the number of five guideline-concordant treatments physicians recommended for a hypothetical patient after AMI or stroke. KEY RESULTS: 1,031 physicians completed the study (58.5% response rate). Of 1,031 respondents, 980 physicians had complete information. After adjusting for physician factors, physicians recommended similar treatments after AMI and stroke in hypothetical patients with pre-existing MCI (adjusted ratio of expected composite quality score, 0.98 [95% CI, 0.94, 1.02]; P = 0.36) as hypothetical patients with NC. Physicians recommended fewer treatments to hypothetical patients with pre-existing early-stage dementia than to hypothetical patients with NC (adjusted ratio of expected composite quality score, 0.90 [0.86, 0.94]; P < 0.001). CONCLUSION: In these randomized survey studies, physicians recommended fewer guideline-concordant AMI and stroke treatments to hypothetical patients with early-stage dementia than those with NC. We did not find evidence that physicians recommend fewer treatments to hypothetical patients with MCI than those with NC.

Results of untargeted analysis using the SOMAscan proteomics platform indicates novel associations of circulating proteins with risk of progression to kidney failure in diabetes.

This study applies a large proteomics panel to search for new circulating biomarkers associated with progression to kidney failure in individuals with diabetic kidney disease. Four independent cohorts encompassing 754 individuals with type 1 and type 2 diabetes and early and late diabetic kidney disease were followed to ascertain progression to kidney failure. During ten years of follow-up, 227 of 754 individuals progressed to kidney failure. Using the SOMAscan proteomics platform, we measured baseline concentration of 1129 circulating proteins. In our previous publications, we analyzed 334 of these proteins that were members of specific candidate pathways involved in diabetic kidney disease and found 35 proteins strongly associated with risk of progression to kidney failure. Here, we examined the remaining 795 proteins using an untargeted approach. Of these remaining proteins, 11 were significantly associated with progression to kidney failure. Biological processes previously reported for these proteins were related to neuron development (DLL1, MATN2, NRX1B, KLK8, RTN4R and ROR1) and were implicated in the development of kidney fibrosis (LAYN, DLL1, MAPK11, MATN2, endostatin, and ROR1) in cellular and animal studies. Specific mechanisms that underlie involvement of these proteins in progression of diabetic kidney disease must be further investigated to assess their value as targets for kidney-protective therapies. Using multivariable LASSO regression analysis, five proteins (LAYN, ESAM, DLL1, MAPK11 and endostatin) were found independently associated with risk of progression to kidney failure. Thus, our study identified proteins that may be considered as new candidate prognostic biomarkers to predict risk of progression to kidney failure in diabetic kidney disease. Furthermore, three of these proteins (DLL1, ESAM, and MAPK11) were selected as candidate biomarkers when all SOMAscan results were evaluated.

The Association Between Mild Cognitive Impairment Diagnosis and Patient Treatment Preferences: a Survey of Older Adults.

BACKGROUND: Older patients (65+) with mild cognitive impairment (MCI) receive less guideline-concordant care for cardiovascular disease (CVD) and other conditions than patients with normal cognition (NC). One potential explanation is that patients with MCI want less treatment than patients with NC; however, the treatment preferences of patients with MCI have not been studied. OBJECTIVE: To determine whether patients with MCI have different treatment preferences than patients with NC. DESIGN: Cross-sectional survey conducted at two academic medical centers from February to December 2019 PARTICIPANTS: Dyads of older outpatients with MCI and NC and patient-designated surrogates. MAIN MEASURES: The modified Life-Support Preferences-Predictions Questionnaire score measured patients' preferences for life-sustaining treatment decisions in six health scenarios including stroke and acute myocardial infarction (range, 0-24 treatments rejected with greater scores indicating lower desire for treatment). KEY RESULTS: The survey response rate was 73.4%. Of 136 recruited dyads, 127 (93.4%) completed the survey (66 MCI and 61 NC). The median number of life-sustaining treatments rejected across health scenarios did not differ significantly between patients with MCI and patients with NC (4.5 vs 6.0; P=0.55). Most patients with MCI (80%) and NC (80%) desired life-sustaining treatments in their current health (P=0.99). After adjusting for patient and surrogate factors, the difference in mean counts of rejected treatments between patients with MCI and patients with NC was not statistically significant (adjusted ratio, 1.08, 95% CI, 0.80-1.44; P=0.63). CONCLUSION: We did not find evidence that patients with MCI want less treatment than patients with NC. These findings suggest that other provider and system factors might contribute to patients with MCI getting less guideline-concordant care.

Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 (HSD17B14) with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes.

BACKGROUND: Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage. METHODS: Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort (n=2372/1115 events all cohorts) and replicating in two retrospective case-control studies (n=1072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models. RESULTS: Protein coding variants in the hydroxysteroid 17-ß dehydrogenase 14 gene (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (n=4196; P value=3.3 × 10-7). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies. CONCLUSIONS: HSD17B14 gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.

Preexisting Mild Cognitive Impairment, Dementia, and Receipt of Treatments for Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Differences in acute ischemic stroke (AIS) treatment by cognitive status are unclear, but some studies have found patients with preexisting dementia get less treatment. We compared AIS care by preexisting cognitive status. METHODS: Cross-sectional analysis of prospectively obtained data on 836 adults ≥45 with AIS from the population-based Brain Attack Surveillance in Corpus Christi project from 2008 to 2013. We compared receipt of a composite quality measure representing the percentage of 7 treatments/procedures received (ordinal scale; values, <0.75, 0.75-0.99, and 1.0), a binary defect-free quality score, and individual treatments after AIS between patients with preexisting dementia (Informant Questionnaire on Cognitive Decline in the Elderly score ≥3.44), mild cognitive impairment (MCI, score 3.1-3.43), and normal cognition (score ≤3). RESULTS: Among patients with AIS, 42% had normal cognition (47% women; median age [interquartile range], 65 [56-76]), 32% had MCI (54% women; median age, 70 [60-78]), 26% had dementia (56% women; median age, 78 [64-85]). After AIS, 44% of patients with preexisting dementia and 55% of patients with preexisting MCI or normal cognition received defect-free care. Compared with cognitively normal patients, patients with preexisting MCI had similar cumulative odds (unadjusted cumulative odds ratio =0.99, P=0.92), and patients with preexisting dementia had 36% lower cumulative odds of receiving the composite quality measure (unadjusted cumulative odds ratio [OR]=0.64, P=0.005). However, the dementia-quality association became nonsignificant after adjusting for patient factors, namely sex, comorbidity, and body mass index (adjusted cumulative OR [acOR]=0.79, P=0.19). Independent of patient factors, preexisting MCI was negatively associated with receipt of IV tPA (intravenous tissue-type plasminogen activator; acOR=0.36, P=0.04), rehabilitation assessment (acOR=0.28, P=0.016), and echocardiogram (acOR=0.48, P<0.001). Preexisting dementia was negatively associated with receipt of antithrombotic by day 2 (acOR=0.39, P=0.04) and echocardiogram (acOR=0.42, P<0.001). CONCLUSIONS: Patients with preexisting MCI and dementia, compared with cognitively normal patients, may receive less frequently some treatments and procedures, but not the composite quality measure, after AIS.

Mild Cognitive Impairment and Receipt of Treatments for Acute Myocardial Infarction in Older Adults.

BACKGROUND: Older adults with mild cognitive impairment (MCI) should receive evidence-based treatments when indicated. Providers and patients may overestimate the risk of dementia in patients with MCI leading to potential under-treatment. However, the association between pre-existing MCI and receipt of evidence-based treatments is uncertain. OBJECTIVE: To compare receipt of treatments for acute myocardial infarction (AMI) between older adults with pre-existing MCI and cognitively normal patients. DESIGN: Prospective study using data from the nationally representative Health and Retirement Study, Medicare, and American Hospital Association. PARTICIPANTS: Six hundred nine adults aged 65 or older hospitalized for AMI between 2000 and 2011 and followed through 2012 with pre-existing MCI (defined as modified Telephone Interview for Cognitive Status score of 7-11) and normal cognition (score of 12-27). MAIN MEASURES: Receipt of cardiac catheterization and coronary revascularization within 30 days and cardiac rehabilitation within 1 year of AMI hospitalization. KEY RESULTS: Among the survivors of AMI, 19.2% had pre-existing MCI (55.6% were women and 44.4% were male, with a mean [SD] age of 82.3 [7.5] years), and 80.8% had normal cognition (45.7% were women and 54.3% were male, with a mean age of 77.1 [7.1] years). Survivors of AMI with pre-existing MCI were significantly less likely than those with normal cognition to receive cardiac catheterization (50% vs 77%; P < 0.001), coronary revascularization (29% vs 63%; P < 0.001), and cardiac rehabilitation (9% vs 22%; P = 0.001) after AMI. After adjusting for patient and hospital factors, pre-existing MCI remained associated with lower use of cardiac catheterization (adjusted hazard ratio (aHR), 0.65; 95% CI, 0.48-0.89; P = 0.007) and coronary revascularization (aHR, 0.55; 95% CI, 0.37-0.81; P = .003), but not cardiac rehabilitation (aHR, 1.01; 95% CI, 0.49-2.07; P = 0.98). CONCLUSIONS: Pre-existing MCI is associated with lower use of cardiac catheterization and coronary revascularization but not cardiac rehabilitation after AMI.

Mild cognitive impairment and receipt of procedures for acute ischemic stroke in older adults.

BACKGROUND AND PURPOSE: Older patients with pre-existing mild cognitive impairment (MCI) receive less evidence-based care after acute myocardial infarction, however, whether they receive less care after acute ischemic stroke (AIS) is unknown. We compared receipt of guideline-concordant procedures after AIS between older adults with pre-existing MCI and normal cognition. METHODS: Prospective study of 591 adults ≥65 hospitalized for AIS between 2000 and 2014, and followed through 2015 using data from the nationally representative Health and Retirement Study, Medicare and American Hospital Association. We assessed pre-existing MCI (modified Telephone Interview for Cognitive Status score of 7-11) and normal cognition (score of 12-27). Primary outcome was a composite quality measure representing the number of 4 procedures (carotid imaging, cardiac monitoring, echocardiogram, and rehabilitation assessment) received within 30 days after AIS (ordinal scale with values of 0, 1, 2, 3-4). RESULTS: Among survivors of AIS, 26.9% had pre-existing MCI (62.9% were women, with a mean [SD] age of 82.4 [7.7] years), and 73.1% had normal cognition (51.4% were women, with a mean age of 78.4 [7.2] years). Patients with pre-existing MCI, compared to cognitively normal patients, had 39% lower cumulative odds of receiving the composite quality measure (unadjusted cumulative odds ratio, OR, 0.61 [95% CI, 0.43-0.87]; P=0.006). However, this association became non-significant after adjusting for patient and hospital factors (adjusted cumulative OR, 0.83 [95% CI, 0.56-1.24]; P=0.37). Lower cumulative odds of receiving the composite quality measure were associated with older patient age (adjusted cumulative OR per 1-year older age, 0.97 [95% CI, 0.95-0.99]; P=0.01) and Southern hospitals (adjusted cumulative OR for South vs North, 0.54 [95% CI, 0.31-0.94]; P=0.03). CONCLUSIONS: Differences in receipt of guideline-concordant procedures after AIS exist between patients with pre-existing MCI and normal cognition. These differences were largely explained by patient and regional factors associated with receiving less AIS care.

Association of Blood Pressure and Cognition after Stroke.

BACKGROUND AND AIM: It is unclear whether blood pressure (BP) is associated with cognition after stroke. We examined associations between systolic and diastolic BP (SBP, DBP), pulse pressure (PP), mean arterial pressure (MAP), and cognition, each measured 90 days after stroke. METHODS: Cross-sectional analysis of prospectively obtained data of 432 dementia-free subjects greater than or equal to 45 (median age, 66; 45% female) with stroke (92% ischemic; median NIH stroke score, 3 [IQR, 2-6]) from the population-based Brain Attack Surveillance in Corpus Christi (BASIC) project in 2011-2013. PRIMARY OUTCOME: Modified Mini-Mental Status Examination (3MSE; range, 0-100). SECONDARY OUTCOMES: Animal Fluency Test (AFT; range, 0-10) and Trail Making Tests A and B (number of correct items [range, 0-25]/completion time [Trails A: 0-180 seconds; Trails B: 0-300 second]). Linear or tobit regression adjusted associations for age, education, and race/ethnicity as well as variables significantly associated with BP and cognition. RESULTS: Higher SBP, lower DBP, higher PP, and lower MAP each were associated with worse cognitive performance for all 4 tests (all P < .001). After adjusting for patient factors, no BP measures were associated with any of the 4 tests (all P > .05). Lower cognitive performance was associated with older age, less education, Mexican American ethnicity, diabetes, higher stroke severity, more depressive symptoms, and lower BMI. Among survivors with hypertension, anti-hypertensive medication use 90 days after stroke was significantly associated with higher AFT scores (P = .02) but not other tests (P > .15). CONCLUSIONS: Stroke survivors' BP levels were not associated with cognitive performance at 90 days independent of sociodemographic and clinical factors.

Risk Factors for Poststroke Cognitive Decline: The REGARDS Study (Reasons for Geographic and Racial Differences in Stroke).

BACKGROUND AND PURPOSE: Poststroke cognitive decline causes disability. Risk factors for poststroke cognitive decline independent of survivors' prestroke cognitive trajectories are uncertain. METHODS: Among 22 875 participants aged ≥45 years without baseline cognitive impairment from the REGARDS cohort (Reasons for Geographic and Racial Differences in Stroke), enrolled from 2003 to 2007 and followed through September 2015, we measured the effect of incident stroke (n=694) on changes in cognitive functions and cognitive impairment (Six-Item Screener score <5) and tested whether patient factors modified the effect. Median follow-up was 8.2 years. RESULTS: Incident stroke was associated with acute declines in global cognition, new learning, verbal memory, and executive function. Acute declines in global cognition after stroke were greater in survivors who were black (P=0.04), men (P=0.04), and had cardioembolic (P=0.001) or large artery stroke (P=0.001). Acute declines in executive function after stroke were greater in survivors who had

Markers of early progressive renal decline in type 2 diabetes suggest different implications for etiological studies and prognostic tests development.

To identify determinants of early progressive renal decline in type 2 diabetes a range of markers was studied in 1032 patients enrolled into the 2nd Joslin Kidney Study. eGFR slopes estimated from serial measurements of serum creatinine during 5-12 years of follow-up were used to define early renal decline. At enrollment, all patients had normal eGFR, 58% had normoalbuminuria and 42% had albuminuria. Early renal decline developed in 6% and in 18% patients, respectively. As determinants, we examined baseline values of clinical characteristics, circulating markers: TNFR1, KIM-1, and FGF23, and urinary markers: albumin, KIM-1, NGAL, MCP-1, EGF (all normalized to urinary creatinine) and the ratio of EGF to MCP-1. In univariate analysis, all plasma and urinary markers were significantly associated with risk of early renal decline. When analyzed together, systolic blood pressure, TNFR1, KIM-1, the albumin to creatinine ratio, and the EGF/MCP-1 ratio remained significant with the latter having the strongest effect. Integration of these markers into a multi-marker prognostic test resulted in a significant improvement of discriminatory performance of risk prediction of early renal decline, compared with the albumin to creatinine ratio and systolic blood pressure alone. However, the positive predictive value was only 50% in albuminuric patients. Thus, markers in plasma and urine indicate that the early progressive renal decline in Type 2 diabetes has multiple determinants with strong evidence for involvement of tubular damage. However, new, more informative markers are needed to develop a better prognostic test for such decline that can be used in a clinical setting.

Improved clinical trial enrollment criterion to identify patients with diabetes at risk of end-stage renal disease.

Design of Phase III trials for diabetic nephropathy currently requires patients at a high risk of progression defined as within three years of a hard end point (end-stage renal disease, 40% loss of estimated glomerular filtration rate, or death). To improve the design of these trials, we used natural history data from the Joslin Kidney Studies of chronic kidney disease in patients with diabetes to develop an improved criterion to identify such patients. This included a training cohort of 279 patients with type 1 diabetes and 134 end points within three years, and a validation cohort of 221 patients with type 2 diabetes and 88 end points. Previous trials selected patients using clinical criteria for baseline urinary albumin-to-creatinine ratio and estimated glomerular filtration rate. Application of these criteria to our cohort data yielded sensitivities (detection of patients at risk) of 70-80% and prognostic values of only 52-63%. We applied classification and regression trees analysis to select from among all clinical characteristics and markers the optimal prognostic criterion that divided patients with type 1 diabetes according to risk. The optimal criterion was a serum tumor necrosis factor receptor 1 level over 4.3 ng/ml alone or 2.9-4.3 ng/ml with an albumin-to-creatinine ratio over 1900 mg/g. Remarkably, this criterion produced similar results in both type 1 and type 2 diabetic patients. Overall, sensitivity and prognostic value were high (72% and 81%, respectively). Thus, application of this criterion to enrollment in future clinical trials could reduce the sample size required to achieve adequate statistical power for detection of treatment benefits.

Does Stroke Contribute to Racial Differences in Cognitive Decline?

BACKGROUND AND PURPOSE: It is unknown whether blacks' elevated risk of dementia is because of racial differences in acute stroke, the impact of stroke on cognitive health, or other factors. We investigated whether racial differences in cognitive decline are explained by differences in the frequency or impact of incident stroke between blacks and whites, controlling for baseline cognition. METHODS: Among 4908 black and white participants aged ≥65 years free of stroke and cognitive impairment in the nationally representative Health and Retirement Study with linked Medicare data (1998-2010), we examined longitudinal changes in global cognition (modified version of the Telephone Interview for Cognitive Status) by race, before and after adjusting for time-dependent incident stroke followed by a race-by-incident stroke interaction term, using linear mixed-effects models that included fixed effects of participant demographics, clinical factors, and cognition, and random effects for intercept and slope for time. RESULTS: We identified 34 of 453 (7.5%) blacks and 300 of 4455 (6.7%) whites with incident stroke over a mean (SD) of 4.1 (1.9) years of follow-up (P=0.53). Blacks had greater cognitive decline than whites (adjusted difference in modified version of the Telephone Interview for Cognitive Status score, 1.47 points; 95% confidence interval, 1.21 to 1.73 points). With further adjustment for cumulative incidence of stroke, the black-white difference in cognitive decline persisted. Incident stroke was associated with a decrease in global cognition (1.21 points; P<0.001) corresponding to ≈7.9 years of cognitive aging. The effect of incident stroke on cognition did not statistically differ by race (P=0.52). CONCLUSIONS: In this population-based cohort of older adults, incident stroke did not explain black-white differences in cognitive decline or impact cognition differently by race.

Clostridium difficile ribotype 027: relationship to age, detectability of toxins A or B in stool with rapid testing, severe infection, and mortality.

BACKGROUND: Clostridium difficile infection (CDI) can cause severe disease and death, especially in older adults. A better understanding of risk factors for adverse outcomes is needed. This study tests the hypotheses that infection with specific ribotypes and presence of stool toxins independently associate with severity and constructs predictive models of adverse outcomes. METHODS: Cases of non-recurrent CDI were prospectively included after positive stool tests for toxins A and/or B by enzyme immunoassay (EIA) or tcdB by polymerase chain reaction. Outcomes included severe CDI (intensive care unit admission, colectomy, or death attributable to CDI within 30 days of diagnosis) and 30-day all-cause mortality. Adjusted models were developed to test hypotheses and predict outcomes. RESULTS: In total, 1144 cases were included. The toxin EIA was positive in 37.2% and 35.6% of patients were of age >65 years. One of the 137 unique ribotypes was ribotype 027 (16.2%). Detectable stool toxin did not associate with outcomes. Adjusting for covariates, including age, Ribotype 027 was a significant predictor of severe CDI (90 cases; odds ratio [OR], 1.73; 95% confidence interval [CI], 1.03-2.89; P = .037) and mortality (89 cases; OR, 2.02; 95% CI, 1.19-3.43; P = .009). Concurrent antibiotic use associated with both outcomes. Both multivariable predictive models had excellent performance (area under the curve >0.8). CONCLUSIONS: Detection of stool toxin A and/or B by EIA does not predict severe CDI or mortality. Infection with ribotype 027 independently predicts severe CDI and mortality. Use of concurrent antibiotics is a potentially modifiable risk factor for severe CDI.

Dissection of complex adult traits in a mouse synthetic population.

Finding the causative genetic variations that underlie complex adult traits is a significant experimental challenge. The unbiased search strategy of genome-wide association (GWAS) has been used extensively in recent human population studies. These efforts, however, typically find only a minor fraction of the genetic loci that are predicted to affect variation. As an experimental model for the analysis of adult polygenic traits, we measured a mouse population for multiple phenotypes and conducted a genome-wide search for effector loci. Complex adult phenotypes, related to body size and bone structure, were measured as component phenotypes, and each subphenotype was associated with a genomic spectrum of candidate effector loci. The strategy successfully detected several loci for the phenotypes, at genome-wide significance, using a single, modest-sized population (N = 505). The effector loci each explain 2%-10% of the measured trait variation and, taken together, the loci can account for over 25% of a trait's total population variation. A replicate population (N = 378) was used to confirm initially observed loci for one trait (femur length), and, when the two groups were merged, the combined population demonstrated increased power to detect loci. In contrast to human population studies, our mouse genome-wide searches find loci that individually explain a larger fraction of the observed variation. Also, the additive effects of our detected mouse loci more closely match the predicted genetic component of variation. The genetic loci discovered are logical candidates for components of the genetic networks having evolutionary conservation with human biology.

Improved glycemic control and risk of ESRD in patients with type 1 diabetes and proteinuria.

Most patients with type 1 diabetes (T1D) and proteinuria have poor glycemic control and a high risk of ESRD. We investigated whether long-term improvement of glycemic control reduces risk of ESRD in a prospective 7- to 15-year follow-up observation of 349 patients with CKD stages 1-3 enrolled in the Joslin Proteinuria Cohort of adults with T1D. All patients developed proteinuria between 1990 and 2004 and were followed until 2011 to ascertain onset of ESRD and deaths unrelated to ESRD. Furthermore, we analyzed data from 279 patients with ≥3 years of clinic follow-up available to assess the level of glycemic control after enrollment. Average HbA1c during the 5 years before study enrollment (prebaseline) was compared with HbA1c (postbaseline) averaged during the first half of follow-up (median, 5.1 years). Median prebaseline HbA1c was 9.3%, decreasing to 8.7% postbaseline. Cumulative risk of ESRD after 15 years was significantly lower for patients whose HbA1c decreased than for those whose HbA1c increased or remained poor (29% versus 42%; P<0.001). The difference between these groups was not visible at 5 years of follow-up but became visible at 10 and 15 years of follow-up. In multivariate Cox regression analysis of ESRD risk, the hazard ratio corresponding to a 1-percentage point improvement in postbaseline HbA1c was 0.76 (95% confidence interval, 0.63 to 0.91; P=0.003). In conclusion, results of this study suggest that long-term sustained improvement in HbA1c decelerates eGFR loss and delays the onset of ESRD in patients with T1D and proteinuria.

Trajectory of Cognitive Decline After Incident Stroke.

IMPORTANCE: Cognitive decline is a major cause of disability in stroke survivors. The magnitude of survivors' cognitive changes after stroke is uncertain. OBJECTIVE: To measure changes in cognitive function among survivors of incident stroke, controlling for their prestroke cognitive trajectories. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 23,572 participants 45 years or older without baseline cognitive impairment from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, residing in the continental United States, enrolled 2003-2007 and followed up through March 31, 2013. Over a median follow-up of 6.1 years (interquartile range, 5.0-7.1 years), 515 participants survived expert-adjudicated incident stroke and 23,057 remained stroke free. EXPOSURE: Time-dependent incident stroke. MAIN OUTCOMES AND MEASURES: The primary outcome was change in global cognition (Six-Item Screener [SIS], range, 0-6). Secondary outcomes were change in new learning (Consortium to Establish a Registry for Alzheimer Disease Word-List Learning; range, 0-30), verbal memory (Word-List Delayed Recall; range, 0-10), and executive function (Animal Fluency Test; range, ≥0), and cognitive impairment (SIS score <5 [impaired] vs ≥5 [unimpaired]). For all tests, higher scores indicate better performance. RESULTS: Stroke was associated with acute decline in global cognition (0.10 points [95% CI, 0.04 to 0.17]), new learning (1.80 points [95% CI, 0.73 to 2.86]), and verbal memory (0.60 points [95% CI, 0.13 to 1.07]). Participants with stroke, compared with those without stroke, demonstrated faster declines in global cognition (0.06 points per year faster [95% CI, 0.03 to 0.08]) and executive function (0.63 points per year faster [95% CI, 0.12 to 1.15]), but not in new learning and verbal memory, compared with prestroke slopes. Among survivors, the difference in risk of cognitive impairment acutely after stroke, compared with immediately before stroke, was not statistically significant (odds ratio, 1.32 [95% CI, 0.95 to 1.83]; P = .10); however, there was a significantly faster poststroke rate of incident cognitive impairment compared with the prestroke rate (odds ratio, 1.23 per year [95% CI, 1.10 to 1.38]; P < .001). For a 70-year-old black woman with average values for all covariates at baseline, stroke at year 3 was associated with greater incident cognitive impairment: absolute difference of 4.0% (95% CI, -1.2% to 9.2%) at year 3 and 12.4% (95% CI, 7.7% to 17.1%) at year 6. CONCLUSIONS AND RELEVANCE: Incident stroke was associated with an acute decline in cognitive function and also accelerated and persistent cognitive decline over 6 years.

Prevalence and Factors Associated with De-escalation of Anti-TNFs in Older Adults with Rheumatoid Arthritis: A Medicare Claims-Based Observational Study.

OBJECTIVE: The aim was to evaluate prevalence and factors associated with anti-tumor necrosis factor (anti-TNF) de-escalation in older adults with rheumatoid arthritis (RA). METHODS: We identified adults ≥ 66 years of age with RA on anti-TNF therapy within 6 months after RA diagnosis with at least 6-7 months duration of use (proxy for stable use), using 20% Medicare data from 2008-2017. Patient demographic and clinical characteristics, including concomitant use of glucocorticoid (GC), were collected. Anti-TNF use was categorized as either de-escalation (identified by dosing interval increase, dose reduction, or cessation of use) or continuation. We used (1) an observational cohort design with Cox regression to assess patient characteristics associated with de-escalation and (2) a case-control design with propensity score-adjusted logistic regression to assess the association of de-escalation with different clinical conditions and concomitant medication use. RESULTS: We identified 5106 Medicare beneficiaries with RA on anti-TNF, 65.5% of whom had de-escalation. De-escalation was more likely with older age (hazard ratio [HR] 1.01, 95% confidence interval [CI] 1.01-1.02) or greater comorbidity (HR 1.07, 95% CI 1.05-1.09), but was less likely with low-income subsidy status (HR 0.85, 95% CI 0.78-0.92), adjusting for patient sex and race/ethnicity. Lower odds of de-escalation were associated with serious infection (odds ratio [OR] 0.79, 95% CI 0.66-0.94), new heart failure diagnosis (OR 0.70, 95% CI 0.52-0.95), and long-term GC use (OR 0.84, 95% CI 0.74-0.95), whereas higher odds were associated with concomitant methotrexate use (OR 1.16, 95% CI 1.03-1.31). CONCLUSIONS: Anti-TNFs are de-escalated in two-thirds of older adults with RA in usual care. Further study is needed on RA outcomes after anti-TNF de-escalation.

Poor glycemic control is associated with more rapid kidney function decline after the onset of diabetic kidney disease.

BACKGROUND: The role of glycemic control and its variability on the rate of kidney function decline after the onset of diabetic kidney disease (DKD) remains unclear. METHODS: The association between baseline HbA1c and rates of estimated GFR (eGFR) loss during follow-up was examined by mixed-effects linear regression in 530 individuals with type 1 diabetes and early-to-moderate DKD from the Preventing Early Renal Loss (PERL) trial, and 2,378 individuals with type 2 diabetes and established DKD from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. The benefit of intensive vs. standard glycemic control in slowing eGFR decline was examined in ACCORD. The associations between continuous glucose monitoring-derived short-term glycemic variability indices and rate of GFR decline were also evaluated in PERL. RESULTS: A higher baseline HbA1c was associated with a more negative eGFR slope in both PERL and ACCORD (-0.87 and -0.27 ml/min/1.73m2/year per Hba1c unit increment, p<0.0001 and p=0.0002, respectively). In both studies, the strength of this association progressively increased with increasing levels of albuminuria (p for interaction <0.05). Consistent with this, the benefit of intensive glycemic control on eGFR decline was greater in ACCORD participants with severe than in those with moderate albuminuria (+1.13 vs. +0.26 ml/min/1.73 m2/year, p=0.01). No independent associations were found in PERL between short-term glycemic variability indices and rate of eGFR decline. CONCLUSIONS: In both type 1 and type 2 diabetes, poor glycemic control is associated with a more rapid rate of GFR decline after DKD onset, especially in persons with severe albuminuria.