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Background: Ethnic differences in cognitive decline have been reported. Whether they can be explained by differences in systolic blood pressure (SBP) is uncertain. Objective: Determine whether cumulative mean SBP levels explain differences in cognitive decline between Hispanic and White individuals. Methods: Pooled cohort study of individual participant data from six cohorts (1971–2017). The present study reports results on SBP and cognition among Hispanic and White individuals. Outcomes were changes in global cognition (GC) (primary), executive function (EF) (secondary), and memory standardized as t-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1 SD difference in cognition. Median follow-up was 7.7 (Q1–Q3, 5.2–20.1) years. Results: We included 24,570 participants free of stroke and dementia: 2,475 Hispanic individuals (median age, cumulative mean SBP at first cognitive assessment, 67 years, 132.5 mmHg; 40.8% men) and 22,095 White individuals (60 years,134 mmHg; 47.3% men). Hispanic individuals had slower declines in GC, EF, and memory than White individuals when all six cohorts were examined. Two cohorts recruited Hispanic individuals by design. In a sensitivity analysis, Hispanic individuals in these cohorts had faster decline in GC, similar decline in EF, and slower decline in memory than White individuals. Higher time-varying cumulative mean SBP was associated with faster declines in GC, EF, and memory in all analyses. After adjusting for time-varying cumulative mean SBP, differences in cognitive slopes between Hispanic and White individuals did not change. Conclusion: We found no evidence that cumulative mean SBP differences explained differences in cognitive decline between Hispanic and White individuals.

Background and ObjectivesThere are disparities in the prevalence of obesity by race, and the relationship between obesity and cognitive decline is unclear. The objective of this study was to determine whether obesity is independently associated with cognitive decline and whether the association between obesity and cognitive decline differs in Black and White adults. We hypothesized that obesity is associated with greater cognitive decline compared with normal weight and that the effect of obesity on cognitive decline is more pronounced in Black adults compared with their White counterparts.MethodsWe pooled data from 28,867 participants free of stroke and dementia (mean, SD: age 61 [10.7] years at the first cognitive assessment, 55% female, 24% Black, and 29% obese) from 6 cohorts. The primary outcome was the annual change in global cognition. We performed linear mixed-effects models with and without time-varying cumulative mean systolic blood pressure (SBP) and fasting plasma glucose (FPG). Global cognition was set to a t-score metric (mean 50, SD 10) at a participant's first cognitive assessment; a 1-point difference represents a 0.1 SD difference in global cognition across the 6 cohorts. The median follow-up was 6.5 years (25th percentile, 75th percentile: 5.03, 20.15).ResultsObese participants had lower baseline global cognition than normal-weight participants (difference in intercepts, −0.36 [95% CI, −0.46 to −0.17];p< 0.001). This difference in baseline global cognition was attenuated but was borderline significant after accounting for SBP and FPG (adjusted differences in intercepts, −0.19 [95% CI, −0.39 to 0.002];p= 0.05). There was no difference in the rate of decline in global cognition between obese and normal-weight participants (difference in slope, 0.009 points/year [95% CI, −0.009 to 0.03];p= 0.32). After accounting for SBP and FPG, obese participants had a slower decline in global cognition (adjusted difference in slope, 0.03 points/year slower [95% CI, 0.01 to 0.05];p< 0.001). There was no evidence that race modified the association between body mass index and global cognitive decline (p= 0.34).DiscussionThese results suggest that obesity is associated with lower initial cognitive scores and may potentially attenuate declines in cognition after accounting for BP and FPG.

ImportanceIncident stroke is associated with accelerated cognitive decline. Whether poststroke vascular risk factor levels are associated with faster cognitive decline is uncertain.ObjectiveTo evaluate associations of poststroke systolic blood pressure (SBP), glucose, and low-density lipoprotein (LDL) cholesterol levels with cognitive decline.Design, Setting, and ParticipantsIndividual participant data meta-analysis of 4 US cohort studies (conducted 1971-2019). Linear mixed-effects models estimated changes in cognition after incident stroke. Median (IQR) follow-up was 4.7 (2.6-7.9) years. Analysis began August 2021 and was completed March 2023.ExposuresTime-dependent cumulative mean poststroke SBP, glucose, and LDL cholesterol levels.Main Outcomes and MeasuresThe primary outcome was change in global cognition. Secondary outcomes were change in executive function and memory. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition.ResultsA total of 1120 eligible dementia-free individuals with incident stroke were identified; 982 (87.7%) had available covariate data and 138 (12.3%) were excluded for missing covariate data. Of the 982, 480 (48.9%) were female individuals, and 289 (29.4%) were Black individuals. The median age at incident stroke was 74.6 (IQR, 69.1-79.8; range, 44.1-96.4) years. Cumulative mean poststroke SBP and LDL cholesterol levels were not associated with any cognitive outcome. However, after accounting for cumulative mean poststroke SBP and LDL cholesterol levels, higher cumulative mean poststroke glucose level was associated with faster decline in global cognition (−0.04 points/y faster per each 10–mg/dL increase [95% CI, −0.08 to −0.001 points/y]; P = .046) but not executive function or memory. After restricting to 798 participants with apolipoprotein E4 (APOE4) data and controlling for APOE4 and APOE4 × time, higher cumulative mean poststroke glucose level was associated with a faster decline in global cognition in models without and with adjustment for cumulative mean poststroke SBP and LDL cholesterol levels (−0.05 points/y faster per 10–mg/dL increase [95% CI, −0.09 to −0.01 points/y]; P = .01; −0.07 points/y faster per 10–mg/dL increase [95% CI, −0.11 to −0.03 points/y]; P = .002) but not executive function or memory declines.Conclusions and RelevanceIn this cohort study, higher poststroke glucose levels were associated with faster global cognitive decline. We found no evidence that poststroke LDL cholesterol and SBP levels were associated with cognitive decline.

Strategies to prevent or delay Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) are urgently needed. Blood pressure (BP) management is a promising strategy for AD/ADRD prevention and the key element in the primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD), yet the effects of different population level BP control strategies across the life course on AD/ADRD are not known.Large-scale randomized controlled trials are the least biased approach to identifying the effect of BP control on AD/ADRD, yet trials may be infeasible due to the need for prolonged follow-up and very large sample sizes. Thus, simulation analyses leveraging the best available observational data may be the best and most practical approach to answering these questions.In this manuscript, we describe the design principles, implementation details, and population-level validation of a novel population health microsimulation framework, the MIchigan ChROnic Disease SIMulation (MICROSIM), for The Effect of Lower Blood Pressure over the Life Course on Late-life Cognition in Blacks, Hispanics, and Whites (BP COG) study of the effect of BP levels over the life course on cognitive decline and dementia.MICROSIM was designed by applying computer programming best practices to create a novel simulation model. The initial purpose of this extensible, open-source framework is to explore a series of questions related to the impact of different blood pressure management strategies on late-life cognition and all-cause dementia, as well as the effects on race differences in all-cause dementia incidence. Ultimately, though, the framework is designed to be extensible such that a variety of different clinical conditions could be added to the framework.

Pain, fatigue, and depression frequently co-occur as a symptom cluster. While commonly occurring in those with cancer and autoimmune disease, the cluster is also found in the absence of systemic illness or inflammation. Loneliness is a common psychosocial stressor associated with the cluster cross-sectionally. We investigated whether loneliness predicted the development of pain, fatigue, depression, and the symptom cluster over time.Data from the Health and Retirement Study were used. We included self-respondents ≥50 year-old who had at least two measurements of loneliness and the symptom cluster from 2006-2016 (n = 5974). Time-varying loneliness was used to predict pain, fatigue, depression, and the symptom cluster in the subsequent wave(s) using generalized estimating equations (GEE) and adjusting for sociodemographic covariates, living arrangement, and the presence of the symptom(s) at baseline.Loneliness increased the odds of subsequently reporting pain (aOR 1.22, 95% CI 1.08, 1.37), fatigue (aOR 1.47, 95% CI 1.32, 1.65), depression (aOR 2.33, 95% CI 2.02, 2.68), as well as the symptom cluster (aOR 2.15, 95% CI 1.74, 2.67). The median time between the baseline and final follow-up measurement was 7.6 years (IQR 4.1, 8.2).Loneliness strongly predicts the development of pain, fatigue, and depression as well as the cluster of all three symptoms several years later in a large, nonclinical sample of older American adults. Future studies should examine the multiple pathways through which loneliness may produce this cluster, as well as examine whether other psychosocial stressors also increase risk. It is possible that interventions which address loneliness in older adults may prevent or mitigate the cluster of pain, fatigue, and depression.

BACKGROUND: Ethnic differences in cognitive decline have been reported. Whether they can be explained by differences in systolic blood pressure (SBP) is uncertain. OBJECTIVE: Determine whether cumulative mean SBP levels explain differences in cognitive decline between Hispanic and White individuals. METHODS: Pooled cohort study of individual participant data from six cohorts (1971–2017). The present study reports results on SBP and cognition among Hispanic and White individuals. Outcomes were changes in global cognition (GC) (primary), executive function (EF) (secondary), and memory standardized as t-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1 SD difference in cognition. Median follow-up was 7.7 (Q1–Q3, 5.2–20.1) years. RESULTS: We included 24,570 participants free of stroke and dementia: 2,475 Hispanic individuals (median age, cumulative mean SBP at first cognitive assessment, 67 years, 132.5 mmHg; 40.8% men) and 22,095 White individuals (60 years,134 mmHg; 47.3% men). Hispanic individuals had slower declines in GC, EF, and memory than White individuals when all six cohorts were examined. Two cohorts recruited Hispanic individuals by design. In a sensitivity analysis, Hispanic individuals in these cohorts had faster decline in GC, similar decline in EF, and slower decline in memory than White individuals. Higher time-varying cumulative mean SBP was associated with faster declines in GC, EF, and memory in all analyses. After adjusting for time-varying cumulative mean SBP, differences in cognitive slopes between Hispanic and White individuals did not change. CONCLUSION: We found no evidence that cumulative mean SBP differences explained differences in cognitive decline between Hispanic and White individuals.

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 m(2) 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 m(2) in the allopurinol group and 67.3 ml per minute per 1.73 m(2) 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 m(2) (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 m(2) per year with allopurinol and −2.5 ml per minute per 1.73 m(2) per year with placebo (between-group difference, −0.6 ml per minute per 1.73 m(2) 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.)

Background In people with obesity, β-cell function may adapt to insulin resistance. We describe β-cell function in people with severe obesity and normal fasting glucose (NFG), impaired fasting glucose (IFG), and type 2 diabetes (T2DM), as assessed before, 3 to 6 months after, and 2 years after medical weight loss to describe its effects on insulin sensitivity, insulin secretion, and β-cell function. Methods Fifty-eight participants with body mass index (BMI) ≥ 35 kg/m2 (14 with NFG, 24 with IFG, and 20 with T2DM) and 13 normal weight participants with NFG underwent mixed meal tolerance tests to estimate insulin sensitivity (S[I]), insulin secretion (Φ), and β-cell function assessed as model-based Φ adjusted for S(I). All 58 obese participants were restudied at 3 to 6 months and 27 were restudied at 2 years. Results At 3 to 6 months, after a 20-kg weight loss and a decrease in BMI of 6 kg/m2, S(I) improved in all obese participants, Φ decreased in obese participants with NFG and IFG and tended to decrease in obese participants with T2DM, and β-cell function improved in obese participants with NFG and tended to improve in obese participants with IFG. At 2 years, β-cell function deteriorated in participants with NFG and T2DM but remained significantly better in participants with IFG compared to baseline. Conclusions Short-term weight loss improves β-cell function in participants with NFG and IFG, but β-cell function tends to deteriorate over 2 years. In participants with IFG, weight loss improves longer-term β-cell function relative to baseline and likely relative to no intervention, suggesting that obese people with IFG are a subpopulation whose β-cell function is most likely to benefit from weight loss.

Background: Older patients (≥65 years) with mild cognitive impairment (MCI) are undertreated for cardiovascular disease (CVD). One reason for this disparity could be that patients with MCI might underestimate the chances of CVD and overestimate dementia. Objective: To compare conceptions of health risk between older patients with MCI and normal cognition (NC) and their care partners. Methods: We conducted a multi-center mixed-methods study of patient-care partner dyads completing written quantitative surveys (73% response rate; 127 dyads: 66 MCI and 61 NC) or semi-structured interviews (20 dyads: 11 MCI, and 9 NC). Surveys assessed two-year patient risks of dementia, heart attack, stroke, and fall. Interviews assessed similar health risks and reasons for risk perceptions. Results: On surveys, a similarly low proportion of MCI and NC patients felt they were at risk of stroke (5% versus 2%; p = 0.62) and heart attack (2% versus 0%; p = 0.99). More MCI than NC patients perceived dementia risk (26% versus 2%; p

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 end stage kidney disease (ESKD) in individuals with type 1 diabetes at advanced kidney disease stage. Methods Gene-based exome array analysis of 15,449 genes in 5 large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time-to-ESKD, testing the top gene in a 6th cohort (N=2,372/1,115 events all cohorts) and replicating in two retrospective case-control studies (N=1,072 cases, 752 controls). Deep resequencing of the top associated gene in 5 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-beta dehydrogenase 14 gene (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (N=4,196; p-value=3.3x10-7). 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 chronic kidney disease-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.

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.

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, 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 P =0.04) and echocardiogram (acOR=0.42, P 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.

OBJECTIVE Higher serum uric acid (SUA) is associated with diabetic kidney disease (DKD). Preventing Early Renal Loss in Diabetes (PERL) evaluates whether lowering SUA with allopurinol slows glomerular filtration rate (GFR) loss in people with type 1 diabetes (T1D) and mild to moderate DKD. We present the PERL rationale, design, and baseline characteristics. RESEARCH DESIGN AND METHODS This double-blind, placebo-controlled, multicenter trial randomized 530 participants with T1D, estimated GFR (eGFR) of 40–99.9 mL/min/1.73 m2, SUA ≥4.5 m/dL, and micro- to macroalbuminuric DKD or normoalbuminuria with declining kidney function (NDKF) (defined as historical eGFR decline ≥3 mL/min/1.73 m2/year) to allopurinol or placebo. The primary outcome is baseline-adjusted iohexol GFR (iGFR) after 3 years of treatment plus a 2-month washout period. RESULTS Participants are 66% male and 84% white. At baseline, median age was 52 years and diabetes duration was 35 years, 93% of participants had hypertension, and 90% were treated with renin-angiotensin system inhibitors (median blood pressure 127/71 mmHg). Median HbA1c was 8%, SUA 5.9 mg/dL, iGFR 68 mL/min/1.73 m2, and historical eGFR slope −3.5 mL/min/1.73 m2/year. Compared with participants with albuminuria (n = 419), those with NDKF (n = 94) were significantly older (56 vs. 52 years), had lower HbA1c (7.7 vs. 8.1%) and SUA (5.4 vs. 6.0 mg/dL), and had higher eGFR (82 vs. 74 mL/min/1.73 m2) and historical eGFR loss (−4.7 vs. −2.5 mL/min/1.73 m2/year). These differences persisted when comparing groups with similar rates of historical eGFR loss. CONCLUSIONS PERL will determine the effect of allopurinol on mild to moderate DKD in T1D, with or without albuminuria. Participants with normoalbuminuria and rapid GFR loss manifested many DKD risk factors of those with albuminuria, but with less severity.

Background: Diabetes-related disability occurs in approximately two-thirds of older adults with diabetes and is associated with loss of independence, increased health care resource utilization, and...

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11606-021-06839-w.

Key Points Question Does the risk of cognitive decline among US adults vary by sex? Findings In this cohort study using pooled data from 26 088 participants, women, compared with men, had higher baseline performance in global cognition, executive function, and memory. Women, compared with men, had significantly faster declines in global cognition and executive function, but not memory. Meaning These findings suggest that women may have greater cognitive reserve but faster cognitive decline than men., This pooled cohort study used data from 5 population-based cohort studies to investigate whether cognitive decline among US adults varies by sex., Importance Sex differences in dementia risk are unclear, but some studies have found greater risk for women. Objective To determine associations between sex and cognitive decline in order to better understand sex differences in dementia risk. Design, Setting, and Participants This cohort study used pooled analysis of individual participant data from 5 cohort studies for years 1971 to 2017: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Linear mixed-effects models were used to estimate changes in each continuous cognitive outcome over time by sex. Data analysis was completed from March 2019 to October 2020. Exposure Sex. Main Outcomes and Measures The primary outcome was change in global cognition. Secondary outcomes were change in memory and executive function. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Results Among 34 349 participants, 26 088 who self-reported Black or White race, were free of stroke and dementia, and had covariate data at or before the first cognitive assessment were included for analysis. Median (interquartile range) follow-up was 7.9 (5.3-20.5) years. There were 11 775 (44.7%) men (median [interquartile range] age, 58 [51-66] years at first cognitive assessment; 2229 [18.9%] Black) and 14 313 women (median [interquartile range] age, 58 [51-67] years at first cognitive assessment; 3636 [25.4%] Black). Women had significantly higher baseline performance than men in global cognition (2.20 points higher; 95% CI, 2.04 to 2.35 points; P

Objective: Pain, fatigue, and depression commonly co-occur as a symptom cluster in pathological inflammatory states. Psychosocial stressors such as loneliness may lead to similar states through shared mechanisms. We investigated the association of loneliness with pain, fatigue, and depression in older adults. Methods: Using Health and Retirement Study data ( N = 11,766), we measured cross-sectional prevalence of frequent, moderate to severe pain; severe fatigue; depressive symptoms; and co-occurrence of symptoms surpassing threshold levels (i.e., symptom cluster). Logistic regression models evaluated associations with loneliness. Results: Pain, fatigue, and depression were reported in 19.2%, 20.0%, and 15.3% of the total sample, respectively. The symptom cluster was seen in 4.9% overall; prevalence in lonely individuals was significantly increased (11.6% vs. 2.3%, p

Canagliflozin (Cana) is an FDA-approved diabetes drug that protects against cardiovascular and kidney diseases. It also inhibits the sodium glucose transporter 2 by blocking renal reuptake and intestinal absorption of glucose. In the context of the mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing Cana at 180 ppm at 7 months of age until their death. Cana extended median survival of male mice by 14%. Cana also increased by 9% the age for 90th percentile survival, with parallel effects seen at each of 3 test sites. Neither the distribution of inferred cause of death nor incidental pathology findings at end-of-life necropsies were altered by Cana. Moreover, although no life span benefits were seen in female mice, Cana led to lower fasting glucose and improved glucose tolerance in both sexes, diminishing fat mass in females only. Therefore, the life span benefit of Cana is likely to reflect blunting of peak glucose levels, because similar longevity effects are seen in male mice given acarbose, a diabetes drug that blocks glucose surges through a distinct mechanism, i.e., slowing breakdown of carbohydrate in the intestine. Interventions that control daily peak glucose levels deserve attention as possible preventive medicines to protect from a wide range of late-life neoplastic and degenerative diseases., The SGLT2 inhibitor canagliflozin extends median life span of male mice but does not increase life span of female mice.

To test the hypothesis that glucose variability may impact the progression of kidney disease in type 1 diabetes (T1D), we studied a subgroup of the Preventing Early Renal Loss (PERL) study population with T1D and mild to moderate diabetic kidney disease, using blinded continuous glucose monitoring (CGM) for up to 14 days for each wear period. We studied 175 participants wearing 366 blinded FreeStyle Libre CGMs on one to five occasions between weeks 96 and 164 of the follow-up in the parent study. The mean age of the population was 52.2 ± 10.9 (mean ± SD) years, mean duration of T1D was 36.1 ± 12.2 years. Baseline BMI, A1C, and iothalamate GFR (iGFR) were 29.9 ± 6.3 kg/m2, 8.2 ± 1.2%, and 67.5 ± 17.2 ml/min/1.73m2 respectively. During the study, mean glucose (MG) and coefficient of variation glucose (CV) were 174.5 ± 41.4 mg/dL and 44.5± 8.8% respectively. Mean amplitude of glycemic excursions (MAGE) was 146.0 ± 43.9 mg/dL while time-in-range (TIR) was 50.5 ± 16.1%. A 10% increase in the mean CV was associated with a 1.4 ml/min/1.73m2 decrease in iGFR at the end of the study [95%CI (-3.33, 0.44); p=0.13] while a 10 mg/dL increase in MAGE was associated with a 0.01 ml/min/1.73m2 decrease [95%CI (-0.41, 0.38); p=0.95]. For those with CV >36, iGFR was 2.56 ml/min/1.73m2 lower compared with those with CV Disclosure J.B. McGill: Advisory Panel; Self; Aegerion Pharmaceuticals, Bayer AG, Lilly Diabetes, Novo Nordisk A/S. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Dexcom, Inc. Research Support; Self; Medtronic, Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; Aegerion Pharmaceuticals, Dexcom, Inc., Janssen Pharmaceuticals, Inc. I.B. Hirsch: Consultant; Self; Abbott, Bigfoot Biomedical, Roche Diabetes Care. Research Support; Self; Medtronic, Omnipod. P. Calhoun: Stock/Shareholder; Self; Dexcom, Inc. A. Galecki: None. K. Ruedy: None. C. Wu: None. A. Doria: Research Support; Self; Sanofi. Funding The Leona M. and Harry B. Helmsley Charitable Trust (2018PG-TD1014); National Institute of Diabetes and Digestive and Kidney Diseases (R03DK094484, R34DK097808, UC4DK101108); JDRF (17-2012-377)

Canagliflozin (Cana) is an inhibitor of the sodium glucose transporter 2 (SGLT2), and is thought to act by blocking renal reuptake and intestinal absorption of glucose. Cana is FDA-approved for treatment of diabetes, and affords protection from cardiovascular and kidney diseases. In the context of the mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing 180 ppm Cana at 7 months of age until their death. Cana extended median survival of male mice by 14%, with p < 0.001 by log-rank test. Cana also increased by 9% the age for 90th percentile survival (p < 0.001 by Wang/Allison test), with parallel effects seen at each of three test sites. Cana did not alter the distribution of inferred cause of death, nor of incidental pathology findings at end-of-life necropsies. No benefits were seen in female mice. The lifespan benefit of Cana is likely to reflect blunting of peak glucose levels, because similar longevity effects are seen in mice given acarbose, a diabetes drug that blocks glucose surges through a distinct mechanism, i.e. slowing breakdown of carbohydrate in the intestine. Interventions that control daily peak glucose levels deserve attention as possible preventive medicines to protect from a wide range of late-life neoplastic and degenerative diseases.

ImportanceBlack individuals are more likely than white individuals to develop dementia. Whether higher blood pressure (BP) levels in black individuals explain differences between black and white individuals in dementia risk is uncertain.ObjectiveTo determine whether cumulative BP levels explain racial differences in cognitive decline.Design, Setting, and ParticipantsIndividual participant data from 5 cohorts (January 1971 to December 2017) were pooled from the Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represented a 0.1-SD difference in cognition. The median (interquartile range) follow-up was 12.4 (5.9-21.0) years. Analysis began September 2018.Main Outcomes and MeasuresThe primary outcome was change in global cognition, and secondary outcomes were change in memory and executive function.ExposuresRace (black vs white).ResultsAmong 34 349 participants, 19 378 individuals who were free of stroke and dementia and had longitudinal BP, cognitive, and covariate data were included in the analysis. The mean (SD) age at first cognitive assessment was 59.8 (10.4) years and ranged from 5 to 95 years. Of 19 378 individuals, 10 724 (55.3%) were female and 15 526 (80.1%) were white. Compared with white individuals, black individuals had significantly faster declines in global cognition (−0.03 points per year faster [95% CI, −0.05 to −0.01]; P = .004) and memory (−0.08 points per year faster [95% CI, −0.11 to −0.06]; P P P P P P = .56) and memory (−0.06 points per year [95% CI, −0.08 to −0.03]; P P Conclusions and RelevanceThese results suggest that black individuals’ higher cumulative BP levels may contribute to racial differences in later-life cognitive decline.

Key Points Question What is the effect of a multicomponent infection prevention intervention on multidrug-resistant organisms in nursing homes? Findings In this cluster randomized clinical trial of 6 nursing homes, including 245 patients, a multicomponent intervention consisting of enhanced barrier precautions, chlorhexidine bathing, microbial surveillance, and staff engagement statistically significantly reduced the odds of multidrug-resistant organism contamination in patients’ environments. Meaning These findings suggest that multicomponent interventions can be tailored to reduce multidrug-resistant organisms burden and transmission potential in nursing homes., This cluster randomized clinical trial examines the effectiveness of a multicomponent infection prevention intervention for multidrug resistant organisms in nursing homes., Importance Multidrug-resistant organisms (MDROs) can cause significant morbidity and mortality. Preventing MDROs can reduce the risk of subsequent transmission and infection. Objective To determine whether a multicomponent infection prevention intervention can reduce MDRO prevalence in nursing homes (NHs). Design, Setting, and Participants This cluster randomized clinical trial of a multicomponent intervention was conducted in 6 NHs in Michigan from September 2016 to August 2018. Three NHs adopted a multicomponent intervention, while 3 control NHs continued without investigator intervention. Study visits were conducted at baseline; days 7, 14, 21, and 30; and monthly thereafter for up to 6 months or discharge. Visits included clinical data collection and MDRO surveillance culturing of multiple body sites and high-touch surfaces in patient rooms. Any patients who provided informed consent within 14 days of admission to the NH were enrolled in this study. Non-English speakers and patients receiving hospice care were ineligible. Analysis was performed from November 2018 to February 2020. Interventions Intervention NHs adopted a multicomponent intervention that included enhanced barrier precautions, chlorhexidine bathing, MDRO surveillance, environmental cleaning education and feedback, hand hygiene promotion, and health care worker education and feedback. Control nursing homes continued standard care practices. Main Outcomes and Measures The primary outcome, presence of MDROs, was measured longitudinally in the patient and room environment and was evaluated using generalized mixed effect models. The secondary outcome, time to new MDRO acquisition, was assessed using Cox proportional hazard models. Results A total of 6 NHs were included, with 245 patients (mean [SD] age, 72.5 [13.6] years; 134 [54.7%] women) enrolled; 3 NHs with 113 patients (46.1%) were randomized to the intervention group and 3 NHs with 132 patients (53.9%) were randomized to the control group. A total of 132 patients (53.9%) were White, and 235 patients (95.9%) were receiving postacute care. Over 808 study visits, 3654 patient cultures and 5606 environmental cultures were obtained. The intervention reduced the odds of MDRO prevalence in patients’ environment by 43% (aOR, 0.57; 95% CI, 0.35-0.94), but there was no statistically significant difference on the patient level before or after adjustment (aOR, 0.57; 95% CI, 0.29-1.14). There were no significant reductions in time to new acquisition for methicillin-resistant Staphylococcus aureus (hazard ratio [HR], 0.20; 95% CI, 0.04-1.09), vancomycin-resistant enterococci (HR, 0.84; 95% CI, 0.46-1.53), or resistant gram-negative bacilli (HR, 1.14; 95% CI, 0.73-1.78). Conclusions and Relevance This cluster randomized clinical trial found that the multicomponent intervention reduced the prevalence of MDROs in the environment of NH patients. Our findings highlight the potential for multicomponent interventions to directly and indirectly reduce MDRO prevalence in NHs. Trial Registration ClinicalTrials.gov Identifier: NCT02909946

Although the association between high blood pressure (BP), particularly in midlife, and late-life dementia is known, less is known about variations by race and sex. In a prospective national study of 22 164 blacks and whites ≥45 years without baseline cognitive impairment or stroke from the REGARDS cohort study (Reasons for Geographic and Racial Differences in Stroke), enrolled 2003 to 2007 and followed through September 2015, we measured changes in cognition associated with baseline systolic and diastolic BP (SBP and DBP), as well as pulse pressure (PP) and mean arterial pressure, and we tested whether age, race, and sex modified the effects. Outcomes were global cognition (Six-Item Screener; primary outcome), new learning (Word List Learning), verbal memory (Word List Delayed Recall), and executive function (Animal Fluency Test). Median follow-up was 8.1 years. Significantly faster declines in global cognition were associated with higher SBP, lower DBP, and higher PP with increasing age ( P P =0.02) and mean arterial pressure ( P =0.04). Men, compared with women, had faster declines in new learning associated with SBP ( P =0.04). BP was not associated with decline of verbal memory and executive function, after controlling for the effect of age on cognitive trajectories. Significantly faster declines in global cognition over 8 years were associated with higher SBP, lower DBP, and higher PP with increasing age. SBP-related cognitive declines were greater in blacks and men.

Background: High blood pressure (BP), particularly in mid-life, increases the risk for late-life cognitive impairment and dementia (CID). The extent to which Blacks’ and Hispanics’ worse BP control starting in young adulthood contributes to their greater risk of CID compared to Whites is uncertain. Objective: To describe a pooled, multi-ethnic cohort created to determine the associations between BP levels over the life course and CID risk in Blacks, Hispanics, and Whites. Methods: We pooled individual-level data from 35,473 adults (22.6% Blacks, 8.1% Hispanics, 67.3% Whites, 2% Other) with baseline age ≥18 and cognitive assessments across 6 longitudinal cohorts in the United States from 1971 to 2016: Atherosclerosis Risk in Communities Study (ARIC), Coronary Artery Risk Development in Young Adults Study (CARDIA), Cardiovascular Health Study (CHS), Framingham Offspring Study (FOS), Multi-Ethnic Study of Atherosclerosis (MESA), and Northern Manhattan Study (NOMAS). We harmonized cognitive tests across studies into 3 factors representing global cognitive performance, executive function, and memory using statistically appropriate confirmatory factor analysis. Mean (SD) follow up was 17.1 (10.9) years. Results: The mean (SD) baseline age was 54.3 (16.4) years and 19554 (55.1%) participants were female (Table). There were 3193 (9.0%) first incident strokes (2651 ischemic, 348 hemorrhagic, and 117 other or undetermined type) and 15147 (42.7%) deaths. The Table presents mean BPs at the first and last visits by cohort and the pooled sample. From the initial to the last assessment, mean global cognition decreased over time (p Conclusion: This will be the first comprehensive, large investigation of the association of BP levels from young adulthood to late-life and CID risk in Blacks, Hispanics, and Whites.

Background: It is unclear whether blood pressure is associated with cognitive function after stroke. Methods: Cross-sectional analysis of prospectively obtained data of 432 subjects (mean age, 66; 46% female) with stroke (92% ischemic; median NIH stroke score, 3 [IQR, 2-6]) aged 45 or older without dementia from the population-based Brain Attack Surveillance in Corpus Christi project in 2011-2013. We examined associations between systolic and diastolic blood pressure (BP) and cognitive performance each measured 90 days after stroke. BP measured 3 times using standard protocol and averaged. Cognition was assessed using 4 tests: Modified Mini-Mental Status Examination (3MSE), animal fluency test, Trails A and B. Linear or tobit regression adjusted associations for age, education, and race/ethnicity as well as variables that were significantly associated with both BP and cognition. Results: Systolic BP was not significantly associated with cognitive performance (Model 1) unless diastolic BP was included in the model (Model 3)(Table). Both higher systolic BP and lower diastolic BP each were significantly associated with worse cognitive performance for all 4 tests (Model 3). Diastolic BP remained significantly associated with cognitive performance after adjusting for age, education, and race/ethnicity but systolic BP did not (Model 4). With further adjustment for clinical factors, diastolic BP did not remain independently associated with cognition (Model 5). Lower cognitive performance was significantly associated with older age, less education, Mexican American ethnicity, diabetes, higher stroke severity, more depressive symptoms, and lower BMI. Conclusion: Patients with higher systolic BP and lower diastolic BP are more likely to have worse cognitive performance after stroke but sociodemographic and clinical factors may explain these associations.

Background: Mild cognitive impairment (MCI)—measurable cognitive impairment that doesn't severely affect daily functioning—is common, affecting 1 in 5 adults 65 or older. Little is known about the quality of stroke care for patients with pre-existing MCI despite evidence in other diseases that these patients may be under-treated. Methods: Prospective study of 708 patients aged ≥65 hospitalized with acute ischemic stroke between 2000 and 2014 from the Health and Retirement Study with linked Medicare and American Hospital Association data. We compared receipt of process measures after acute ischemic stroke between patients with pre-existing MCI (based on modified Telephone Interview for Cognitive Status [TICS-m] score, 7-11, a valid measure of MCI) and normal cognition (TICS-m score, 12-27). We used Cox regression to estimate the effect of pre-existing MCI on receipt of process measures after adjusting for patient and hospital factors (Table 1). Results: Patients with pre-existing MCI, compared to those with normal cognition, were less likely to receive IV t-PA, carotid revascularization, cardiac monitoring, and rehabilitation assessment, but not carotid imaging (Table 1). Pre-existing MCI was not independently associated with stroke process measures after adjusting for patient and hospital factors such as sex, educational and marriage status, and facility size. Conclusion: Modest differences in use of IV t-PA, carotid revascularization, rehabilitation assessment, cardiac monitoring, and carotid imaging exist in patients with pre-existing MCI and normal cognition after acute ischemic stroke. These differences were largely explained by patients with MCI being more likely to be women, less educated, unmarried, and using smaller hospitals.

OBJECTIVE Patients with type 1 diabetes and diabetic nephropathy are targets for intervention to reduce high risk of end-stage renal disease (ESRD) and deaths. This study compares risks of these outcomes in four international cohorts. RESEARCH DESIGN AND METHODS In the 1990s and early 2000s, Caucasian patients with type 1 diabetes with persistent macroalbuminuria in chronic kidney disease stages 1–3 were identified in the Joslin Clinic (U.S., 432), Finnish Diabetic Nephropathy Study (FinnDiane) (Finland, 486), Steno Diabetes Center Copenhagen (Denmark, 368), and INSERM (France, 232) and were followed for 3–18 years with annual creatinine measurements to ascertain ESRD and deaths unrelated to ESRD. RESULTS During 15,685 patient-years, 505 ESRD cases (rate 32/1,000 patient-years) and 228 deaths unrelated to ESRD (rate 14/1,000 patient-years) occurred. Risk of ESRD was associated with male sex; younger age; lower estimated glomerular filtration rate (eGFR); higher albumin/creatinine ratio, HbA1c, and systolic blood pressure; and smoking. Risk of death unrelated to ESRD was associated with older age, smoking, and higher baseline eGFR. In adjusted analysis, ESRD risk was highest in Joslin versus reference FinnDiane (hazard ratio [HR] 1.44, P = 0.003) and lowest in Steno (HR 0.54, P < 0.001). Differences in eGFR slopes paralleled risk of ESRD. Mortality unrelated to ESRD was lowest in Joslin (HR 0.68, P = 0.003 vs. the other cohorts). Competing risk did not explain international differences in the outcomes. CONCLUSIONS Despite almost universal renoprotective treatment, progression to ESRD and mortality in patients with type 1 diabetes with advanced nephropathy are still very high and differ among countries. Finding causes of these differences may help reduce risk of these outcomes.

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. To compare receipt of treatments for acute myocardial infarction (AMI) between older adults with pre-existing MCI and cognitively normal patients. Prospective study using data from the nationally representative Health and Retirement Study, Medicare, and American Hospital Association. 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). Receipt of cardiac catheterization and coronary revascularization within 30 days and cardiac rehabilitation within 1 year of AMI hospitalization. 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

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.

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 ≥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 P0.05). 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=0.02) but not other tests (P>0.15). CONCLUSION: Stroke survivors’ BP levels were not associated with cognitive performance at 90 days independent of sociodemographic and clinical factors.

Evidence suggests that older adults with mild cognitive impairment (MCI) might not receive evidence-based treatments. We explored the impact of patient MCI on physician decision-making and recommendations for acute ischemic stroke (AIS) and acute myocardial infarction (AMI) in a pilot concurrent mixed-methods study of physicians recruited from one academic center. The mailed survey included a clinical vignette of AIS or AMI where the patient cognitive status was randomized (normal cognition, MCI, or early-stage dementia). The primary outcome was a composite summary measure of the proportion of guideline-concordant treatments recommended. Linear regression compared the primary outcome across patient cognition groups adjusting for physician characteristics. Semi-structured interviews done with 18 physicians (4 cardiologists, 9 neurologists, 5 internists) using a standard guide. Survey response rate was 72% (82/114) (49/61 neurologists; 33/53 cardiologists). As patient cognition worsened, neurologists recommended less guideline-concordant treatments after AIS (Ptrend

Summary Longevity in mammals is influenced by sex, and lifespan extension in response to anti‐aging interventions is often sex‐specific, although the mechanisms underlying these sexual dimorphisms are largely unknown. Treatment of mice with 17‐α estradiol (17aE2) results in sex‐specific lifespan extension, with an increase in median survival in males of 19% and no survival effect in females. Given the links between lifespan extension and metabolism, we performed untargeted metabolomics analysis of liver, skeletal muscle and plasma from male and female mice treated with 17aE2 for eight months. We find that 17aE2 generates distinct sex‐specific changes in the metabolomic profile of liver and plasma. In males, 17aE2 treatment raised the abundance of several amino acids in the liver, and this was further associated with elevations in metabolites involved in urea cycling, suggesting altered amino acid metabolism. In females, amino acids and urea cycling metabolites were unaffected by 17aE2. 17aE2 also results in male‐specific elevations in a second estrogenic steroid—estriol‐3‐sulfate—suggesting different metabolism of this drug in males and females. To understand the underlying endocrine causes for these sexual dimorphisms, we castrated males and ovariectomized females prior to 17aE2 treatment, and found that virtually all the male‐specific metabolite responses to 17aE2 are inhibited or reduced by male castration. These results suggest novel metabolic pathways linked to male‐specific lifespan extension and show that the male‐specific metabolomic response to 17aE2 depends on the production of testicular hormones in adult life.

Background Multimorbidity is common among older adults and strongly associated with physical functioning decline and increased mortality. However, the full spectrum of direct and indirect effects of multimorbidity on physical functioning and survival has not been quantified. We aimed to determine the longitudinal relationship of multimorbidity on physical functioning and quantify the impact of multimorbidity and multimorbidity-attributed changes in physical functioning on mortality risk. Methods The Health and Retirement Study (HRS) is a nationally representative population-based prospective cohort of adults aged 51 or older. In 2000, participants were interviewed about physician-diagnosed chronic conditions, from which their multimorbidity-weighted index (MWI) was computed. Between 2000 and 2011, participants reported their current physical functioning using a modified Short Form-36. With MWI as a time-varying exposure, we jointly modeled its associations with physical functioning and survival. Results The final sample included 74,037 observations from 18,174 participants. At baseline, participants had a weighted mean MWI of 4.6 ± 4.2 (range 0–36.8). During follow-up, physical functioning declined: −1.72 (95% confidence interval [CI] −1.77, −1.67, p < .001) HRS physical functioning units per point MWI in adjusted models. Over follow-up, 6,362 (34%) participants died. Mortality risk increased 8% (hazard ratio 1.08, 95% CI 1.07–1.08, p < .001) per point MWI in adjusted models. Across all population subgroups, MWI was associated with greater physical functioning decline and mortality risk. Conclusions Multimorbidity and its associated decline in physical functioning were significantly associated with increased mortality. These associations can be predicted with an easily interpreted and applied multimorbidity index that can better identify and target adults at increased risk for disability and death.

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.

To use a simple measure of activities of daily living, wounds, and indwelling devices (urinary catheter, feeding tube) to predict prevalent, new, and intermittent multidrug-resistant organism (MDRO) acquisition in nursing home (NH) residents.Secondary analysis, prospective cohort study.Southeast Michigan NHs (n = 15).NH residents (N = 111, mean age 81) with two or more monthly visits (729 total).Monthly microbiological surveillance for MDROs from multiple anatomic sites from enrollment until discharge or 1 year. The Arling scale, previously developed as a measure of NH residents' need (time-intensity) for nursing resources, was used to predict prevalent and time to new or intermittent acquisition (months) of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and antibiotic-resistant gram-negative bacteria (R-GNB) colonization using multiple-failure accelerated time-factor survival analysis, controlling for comorbidity, hospitalization, and antibiotic use in the prior month.One-fifth of participants had a wound, and one-third had a device. There were 60 acquisitions of MRSA, 56 of R-GNB, and 15 of VRE. Expected time to acquisition was less than 1 year for MRSA (median 6.7 months) and R-GNB (median 4.5 months) and more than 1 year for VRE (median 40 months). Arling score was associated with earlier new MRSA and VRE acquisition. A resident with only mild functional impairment and no device or wound would be expected to acquire MRSA in 20 months, versus 5 months for someone needing the most-intense nursing contact.MDRO acquisition is common in community NHs. Need for nursing care predicts new MDRO acquisition in NHs, suggesting potential mechanisms for MDRO acquisition and strategies for future interventions for high-risk individuals (e.g., enhanced barrier precautions).

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.

OBJECTIVE We studied the serum concentration of tumor necrosis factor receptor 2 (TNFR2) and the rate of renal decline, a measure of the intensity of the disease process leading to end-stage renal disease (ESRD). RESEARCH DESIGN AND METHODS A cohort of 349 type 1 diabetic patients with proteinuria was followed for 5–18 years. Serum TNFR2, glycated hemoglobin A1c (HbA1c), and other characteristics were measured at enrollment. We used a novel analytic approach, a joint longitudinal-survival model, fitted to serial estimates of glomerular filtration rate (eGFR) based on serum creatinine (median seven per patient) and time to onset of ESRD (112 patients) to estimate the rate of renal decline (eGFR loss). RESULTS At enrollment, all patients had chronic kidney disease stage 1–3. The mean (±SD) rate of eGFR loss during 5–18 years of follow-up was −5.2 (±4.9) mL/min/1.73 m2/year. Serum TNFR2 was the strongest determinant of renal decline and ESRD risk (C-index 0.79). The rate of eGFR loss became steeper with rising concentration of TNFR2, and elevated HbA1c augmented the strength of this association (P = 0.030 for interaction). In patients with HbA1c ≥10.1% (87 mmol/mol), the difference in the rate of eGFR loss between the first and fourth quartiles of TNFR2 was 5.4 mL/min/1.73 m2/year, whereas it was only 1.9 in those with HbA1c CONCLUSIONS Circulating TNFR2 is a major determinant of renal decline in patients with type 1 diabetes and proteinuria. Elevated HbA1c magnifies its effect. Although the mechanisms of this synergism are unknown, our findings allow us to stratify patients according to risk of ESRD.

Mammalian lifespan differs by >100 fold, but the mechanisms associated with such longevity differences are not understood. Here, we conducted a study on primary skin fibroblasts isolated from 16 species of mammals and maintained under identical cell culture conditions. We developed a pipeline for obtaining species-specific ortholog sequences, profiled gene expression by RNA-seq and small molecules by metabolite profiling, and identified genes and metabolites correlating with species longevity. Cells from longer lived species up-regulated genes involved in DNA repair and glucose metabolism, down-regulated proteolysis and protein transport, and showed high levels of amino acids but low levels of lysophosphatidylcholine and lysophosphatidylethanolamine. The amino acid patterns were recapitulated by further analyses of primate and bird fibroblasts. The study suggests that fibroblast profiling captures differences in longevity across mammals at the level of global gene expression and metabolite levels and reveals pathways that define these differences. DOI: http://dx.doi.org/10.7554/eLife.19130.001

BACKGROUND: Falls are the leading cause of nonfatal unintentional injuries among hospitalized children with playground equipment accounting for more than 50%. National standards for playground rung and rail design exist, but there a lack of in vivo models available to test these standards. We developed a novel in vivo model to test rung and rail design. We report the feasibility and safety of the model. METHODS: A device was built to simulate children hanging onto a playground bar until their hand slips off. This was defined as breakaway strength. The handle unit was mounted on a vertical cable that was mechanically raised and lowered using a linear actuator controlled by the experimenter. The unit was padded and contained a video camera that recorded the posture of the hand during each trial. Breakaway force and torque were recorded as they held onto the handle by LabView software. In addition, standard anthropometrics and grip strength were recorded. RESULTS: Biomedical engineering approved the device. There were 425 eligible students aged 5 years to 11 years. Of these, 93% (397) participated (212 males and 185 females). Ninety-nine percent (396 of 397) completed all three experimental stations, one declined because of fear. There were no injuries and no falls. Average time to complete the study was 22 ± 0.5 minutes. Ninety-one percent of participants were right handed; the ethnicity was representative of the local area with 79% being white. Mean ± SD height, weight, and body mass index for the 397 participants were 1.28 ± 0.11 m, 28.0 ± 8.12 kg, and 16.31 ± 2.59 kg/m, respectively. Hand size, grip strength, and maximum breakaway force increased with age. CONCLUSION: This model is safe and feasible and maybe a viable method to assess rung and rail design for playgrounds. Language: en

Background and Objectives: Cardiovascular disease (CVD) is the leading cause of death and serious morbidity in older adults with mild cognitive impairment (MCI), many of whom will not progress to dementia. It is unclear whether patients with pre-existing MCI (without dementia) get evidence-based treatments for CVD less often than patients without MCI. We compared treatment for acute ischemic stroke and acute myocardial infarction (AMI) between MCI patients and cognitively normal patients in a nationally representative sample. Methods: Prospective study of patients aged ≥65 years hospitalized with ischemic stroke (n=517) or AMI (n=509) from the Health and Retirement Study and Medicare data from 2000-2011. We compared receipt of CVD process measures (Table) within 12 months of the stroke or AMI hospitalization from Medicare claims between subjects with pre-existing MCI (modified Telephone Interview for Cognitive Status [TICS-m] score, 7-11, a valid measure of MCI) and those with normal cognition (TICS-m score, 12-27), and used logistic regression to adjust associations for age, sex, race, education, number of preexisting functional limitations, and comorbidity. Results: Compared with cognitively normal patients, patients with pre-existing MCI were significantly less likely to receive all 3 AMI process measures, and they got stroke process measures less frequently but results were not statistically significant (Table). MCI patients were less likely than cognitively normal patients to receive any post-MI revascularization (adjusted odds ratio, 0.54; 95% CI, 0.33-0.88), but not the other CVD process measures, after adjustment (Table). Conclusion: Older MCI patients less frequently got process measures for AMI and ischemic stroke compared with cognitively normal patients. Patient factors explain some but not all of this reduced use. We need to better understand decision making for CVD treatment in older MCI patients and reasons for treatment differences.

(See the Editorial Commentary by Barbut and Rupnik, on pages 1669–72.) An increase in the incidence and severity of Clostridium difficile infection (CDI) throughout the United States, Canada, and Europe coincided with the emergence of a previously rare genotype [1]. This genotype, known as polymerase chain reaction (PCR) ribotype 027, North American Pulsed-field type 1 (NAP1), or restriction endonuclease analysis (REA) type BI, was reported to harbor an intrinsic ability to cause more severe disease compared to other pathogenic isolates [1, 2]. At least one other C. difficile lineage, ribotype 078, has been referred to as “hypervirulent” [3]. Laboratory studies identified numerous microbiologic properties to explain the increased virulence of 027 and/or 078 isolates, including antibiotic resistance [4], increased toxin production [5], enhanced ability for toxin B isoforms to bind target cells [6], and increased sporulation ability [7]. More recent data do not support the hypervirulent hypothesis [8–12], although the clinical definition of severe CDI or the methods used for data analysis are not consistent across all studies. Because institutions are often limited to retrospective review of patient records, it is important to define severe CDI using commonly recorded information. Such a definition has been recommended [13] but not universally used. We sought to quantify the prevalence of C. difficile ribotypes at a single institution and to determine whether specific ribotypes were associated with severe disease. In particular, we tested the hypothesis that C. difficile ribotype predicts severe CDI cases even after adjustment for other clinical and laboratory variables. To do so, we developed models using an initial (derivation) data set and then validated our results with the same model fitted to a validation data set.