Faculty Bibliography

BACKGROUND:Clinical cognitive impairment and physical frailty often co-occur. However, it is unclear whether preclinical impairment or decline in cognitive domains are associated with onset of physical frailty. We tested this hypothesis and further hypothesized that preclinical impairment and decline in executive functioning are more strongly associated with frailty onset than memory or general cognitive performance. METHODS:We used 9 years of data from the Women's Health and Aging Study II (six visits) that longitudinally measured psychomotor speed and executive functioning using the Trail Making Test, parts A and B, respectively, and immediate and delayed word-list recall from the Hopkins Verbal Learning Test. We used Cox proportional hazards models to regress time to frailty on indicators for impairment on these cognitive tests and on rates of change of the tests. Models adjusted for depressive symptoms, age, years of education, and race. RESULTS:Of the 331 women initially free of dementia and frailty, 44 (13%) developed frailty. A binary indicator of impaired executive functioning (Trail Making Test, part B [TMT-B]) was most strongly associated with hazard, or risk, of frailty onset (hazard ratio [HR] = 3.3, 95% confidence interval [CI] = 1.4, 7.6) after adjustment for covariates and other tests. Adjusting for baseline cognitive performance, faster deterioration on TMT-B (HR = 0.6, 95% CI = 0.4, 1.0) was additionally associated with hazard of frailty onset. CONCLUSIONS:Findings inform the association of executive functioning with transitions to frailty, suggesting both impairments in and declines in executive functioning are associated with risk of frailty onset. It remains to be determined whether these associations are causal or whether shared aging related or other mechanisms are involved.

BACKGROUND:Patients with end stage renal disease (ESRD), including stage 5 chronic kidney disease (CKD), hemodialysis (HD) and peritoneal dialysis (PD), are at high risk for stroke-related morbidity, mortality and bleeding. The overall risk/benefit balance of warfarin treatment among patients with ESRD and AF remains unclear. METHODS:We systematically reviewed the associations of warfarin use and stroke outcome, bleeding outcome or mortality in patients with ESRD and AF. We conducted a comprehensive literature search in Feb 2016 using key words related to ESRD, AF and warfarin in PubMed, Embase and Cochrane Library without language restriction. We searched for randomized trials and observational studies that compared the use of warfarin with no treatment, aspirin or direct oral anticoagulants (DOACs), and reported quantitative risk estimates on these outcomes. Paired reviewers screened articles, collected data and performed qualitative assessment using the Cochrane Risk of Bias Assessment Tool for Non-randomized Studies of Interventions. We conducted meta-analyses using the random-effects model with the DerSimonian - Laird estimator and the Knapp-Hartung methods as appropriate. RESULTS:We identified 2709 references and included 20 observational cohort studies that examined stroke outcome, bleeding outcome and mortality associated with warfarin use in 56,146 patients with ESRD and AF. The pooled estimates from meta-analysis for the stroke outcome suggested that warfarin use was not associated with all-cause stroke (HR = 0.92, 95 % CI 0.74-1.16) or any stroke (HR = 1.01, 95 % CI 0.81-1.26), or ischemic stroke (HR = 0.80, 95 % CI 0.58-1.11) among patients with ESRD and AF. In contrast, warfarin use was associated with significantly increased risk of all-cause bleeding (HR = 1.21, 95 % CI 1.01-1.44), but not associated with major bleeding (HR = 1.18, 95 % CI 0.82-1.69) or gastrointestinal bleeding (HR = 1.19, 95 % CI 0.81-1.76) or any bleeding (HR = 1.21, 95 % CI 0.99-1.48). There was insufficient evidence to evaluate the association between warfarin use and mortality in this population (pooled risk estimate not calculated due to high heterogeneity). Results on DOACs were inconclusive due to limited relevant studies. CONCLUSIONS:Given the absence of efficacy and an increased bleeding risk, these findings call into question the use of warfarin for AF treatment among patients with ESRD.

OBJECTIVES/OBJECTIVE:To investigate the association between serum potassium, mortality, and kidney outcomes in the general population and whether potassium-altering medications modify these associations. PATIENTS AND METHODS/METHODS:We studied 15,539 adults in the Atherosclerosis Risk in Communities Study. Cox proportional hazard regression was used to investigate the association of serum potassium at baseline (1987-1989), evaluated categorically (hypokalemia, <3.5 mmol/L; normokalemia, ≥3.5 and <5.5 mmol/L; hyperkalemia, ≥5.5 mmol/L) and continuously using linear spline terms (knots at 3.5 and 5.5 mmol/L), with mortality, sudden cardiac death, incident chronic kidney disease, and end-stage renal disease. The end date of follow-up for all outcomes was December 31, 2012. We also evaluated whether classes of potassium-altering medications modified the association between serum potassium and adverse outcomes. RESULTS:Overall, 413 (2.7%) of the participants had hypokalemia and 321 (2.1%) had hyperkalemia. In a fully adjusted model, hyperkalemia was significantly associated with mortality (hazard ratio, 1.24; 95% CI, 1.04-1.49) but not sudden cardiac death, chronic kidney disease, or end-stage renal disease. Hypokalemia as a categorical variable was not associated with any outcome; however, associations of hypokalemia with all-cause mortality and kidney outcomes were observed among those who were not taking potassium-wasting diuretics (all P for interaction, <.001). CONCLUSIONS:Higher values of serum potassium were associated with a higher risk of mortality in the general population. Lower levels of potassium were associated with adverse kidney outcomes and mortality among participants not taking potassium-wasting diuretics.

OBJECTIVE:Anticentromere antibodies (ACAs) define a subset of primary Sjögren's syndrome (SS) with a unique phenotype, including features of limited cutaneous systemic sclerosis and a lower frequency of anti-SSA/SSB antibodies. We sought to determine whether ACAs are associated with more severe exocrine glandular dysfunction in a large cohort of primary SS subjects. METHODS:We performed a cross-sectional analysis of 1,361 subjects with primary SS from the Sjögren's International Collaborative Clinical Alliance Registry, stratified by the presence or absence of ACAs. ACAs were assayed by immunofluorescence staining on HEp-2 cells. RESULTS:ACAs were present in 82 of the 1,361 SS subjects (6%) and were associated with older age, female sex, and lower frequencies of anti-SSA/SSB, rheumatoid factor, and hyperglobulinemia. Among ACA-positive versus ACA-negative subjects, there was a higher frequency of a focus score ≥2 (71% versus 53%; P = 0.002), a higher median focus score (2.8 versus 2.5; P = 0.0440), and greater exocrine gland dysfunction: Schirmer's test value: median 4 versus 5 mm/5 minutes; P = 0.0003, and unstimulated whole saliva (UWS) flow rate: median 0.08 versus 0.37 ml/5 minutes; P < 0.0001. ACA-positive subjects had an increased risk of UWS <0.1 ml/minute (odds ratio [OR] 12.24 [95% confidence interval (95% CI) 4.91-41.02]) and Schirmer's test value <5 mm/5 minutes (OR 2.52 [95% CI 1.50-4.36]) after correcting for age, sex, anti-SSA/SSB, and focus score. Labial gland fibrosis was not different between the 2 groups. CONCLUSION:In a large international registry of SS, ACA had an independent association with more severe exocrine glandular dysfunction. This dysfunction was associated with more pronounced labial salivary glandular inflammation but not fibrosis.

There is an increased risk of acute rejection (AR) in human immunodeficiency virus-positive (HIV+) kidney transplant (KT) recipients. Induction immunosuppression is standard of care for those at high risk of AR; however, use in HIV+ patients is controversial, given fears of increased infection rates. We sought to compare clinical outcomes between HIV+ KT recipients who were treated with (i) anti-thymocyte globulin (ATG), (ii) IL-2 receptor blocker, and (iii) no induction. We studied 830 HIV+ KT recipients between 2000 and 2014, as captured in the Scientific Registry of Transplant Recipients, and compared rates of delayed graft function (DGF), AR, graft loss and death. Infections and hospitalizations were ascertained by International Classification of Diseases, Ninth Revision codes in a subset of 308 patients with Medicare. Compared with no induction, neither induction agent was associated with an increased risk of infection (weighted hazard ratio [wHR] 0.80, 95% confidence interval [CI] 0.55-1.18). HIV+ recipients who received induction spent fewer days in the hospital (weighted relative risk [wRR] 0.70, 95% CI 0.52-0.95), had lower rates of DGF (wRR 0.66, 95% CI 0.51-0.84), less graft loss (wHR 0.47, 95% CI 0.24-0.89) and a trend toward lower mortality (wHR 0.60, 95% CI 0.24-1.28). Those who received induction with ATG had lower rates of AR (wRR 0.59, 95% CI 0.35-0.99). Induction in HIV+ KT recipients was not associated with increased infections; in fact, those receiving ATG, the most potent agent, had the lowest rates. In light of the high risk of AR in this population, induction therapy should be strongly considered.

INTRODUCTION/BACKGROUND:Inflammatory diseases increase risk of venous thromboembolism (VTE). Whether gout, the most common rheumatologic inflammatory arthritis, or its cause, elevated serum uric acid (SUA), is associated with VTE incidence is unknown. MATERIALS AND METHODS/METHODS:The Atherosclerosis Risk in Communities Study measured SUA in 14126 participants aged 45-64, without a history of VTE or gout and not using anticoagulants/gout medications, and obtained information on incident gout between 1987 and 1998 from 10247. We followed them for VTE occurrence from 1987 to 2011. Hazard ratios (HRs) of VTE were estimated using Cox proportional hazards models. RESULTS:We documented 632 incident cases of VTE (236 unprovoked and 396 provoked). Age, sex, and race-adjusted HRs for total VTE were 1, 1.40, 1.43, 1.91, 1.71, and 3.25 (P for trend<0.001) across levels of SUA (range mg/dL: ≤4.9, 5.0-5.9, 6.0-6.9, 7.0-7.5, 7.6-8.7, and ≥8.8). After adjustment for other VTE risk factors, those in the highest level of SUA had HRs [95% confidence interval] of 2.13 (1.47-3.07) for total VTE, 2.07 (1.17-3.67) for unprovoked VTE and 2.16 (1.33-3.50) for provoked VTE. Those with incident gout had a nonsignificantly increased risk of total VTE [HR (95% CI): 1.33 (0.95-1.86)]. CONCLUSIONS:Elevated SUA was associated with an increased risk of VTE, suggesting that SUA might be a novel risk factor or marker for VTE. Further studies are needed to assess the association between gout and VTE.

OBJECTIVE:The effects of carbohydrates on plasma uric acid levels are a subject of controversy. We determined the individual and combined effects of carbohydrate quality (the glycemic index) and quantity (the proportion of total daily energy [percentage of carbohydrates]) on uric acid levels. METHODS:We conducted a randomized, crossover trial of 4 different diets in overweight or obese adults without cardiovascular disease (n = 163). Participants consumed each of 4 diets over a 5-week period, each of which was separated by a 2-week washout period. Body weight was kept constant. The 4 diets were high glycemic index (≥65) with high percentage of carbohydrates (58% kcal), low glycemic index (≤45) with low percentage of carbohydrates (40% kcal), low glycemic index with high percentage of carbohydrates, and high glycemic index with low percentage of carbohydrates. Plasma uric acid levels were measured at baseline and after completion of each 5-week period for comparison between the 4 diets. RESULTS:Of the 163 study participants, 52% were women and 50% were non-Hispanic African American subjects; their mean age was 52.6 years, and their mean ± SD uric acid level was 4.7 ± 1.2 mg/dl. Reducing the glycemic index lowered uric acid levels when the percentage of carbohydrates was low (-0.24 mg/dl; P < 0.001) or high (-0.17 mg/dl; P < 0.001). Reducing the percentage of carbohydrates marginally increased the uric acid level only when the glycemic index was high (P = 0.05). The combined effect of lowering the glycemic index and increasing the percentage of carbohydrates was -0.27 mg/dl (P < 0.001). This effect was observed even after adjustment for concurrent changes in kidney function, insulin sensitivity, and products of glycolysis. CONCLUSION:Reducing the glycemic index lowers uric acid levels. Future studies should examine whether reducing the glycemic index can prevent gout onset or flares.

BACKGROUND:It is unclear whether traditional and genetic risk factors in middle age predict the onset of gout in older age. METHODS:We studied the incidence of gout in older adults using the Atherosclerosis Risk in Communities study, a prospective U.S. population-based cohort of middle-aged adults enrolled between 1987 and 1989 with ongoing follow-up. A genetic urate score was formed from common urate-associated single nucleotide polymorphisms for eight genes. The adjusted hazard ratio and 95% confidence interval of incident gout by traditional and genetic risk factors in middle age were estimated using a Cox proportional hazards model. RESULTS:The cumulative incidence from middle age to age 65 was 8.6% in men and 2.5% in women; by age 75 the cumulative incidence was 11.8% and 5.0%. In middle age, increased adiposity, beer intake, protein intake, smoking status, hypertension, diuretic use, and kidney function (but not sex) were associated with an increased gout risk in older age. In addition, a 100 µmol/L increase in genetic urate score was associated with a 3.29-fold (95% confidence interval: 1.63-6.63) increased gout risk in older age. CONCLUSIONS:These findings suggest that traditional and genetic risk factors in middle age may be useful for identifying those at risk of gout in older age.

Married couples might be an appropriate target for obesity prevention interventions. In the present study, we aimed to evaluate whether an individual's risk of obesity is associated with spousal risk of obesity and whether an individual's change in body mass index (BMI; weight in kilograms divided by height in meters squared) is associated with spousal BMI change. We analyzed data from 3,889 spouse pairs in the Atherosclerosis Risk in Communities Study cohort who were sampled at ages 45-65 years from 1986 to 1989 and followed for up to 25 years. We estimated hazard ratios for incident obesity by whether spouses remained nonobese, became obese, remained obese, or became nonobese. We estimated the association of participants' BMI changes with concurrent spousal BMI changes using linear mixed models. Analyses were stratified by sex. At baseline, 22.6% of men and 24.7% of women were obese. Nonobese participants whose spouses became obese were more likely to become obese themselves (for men, hazard ratio = 1.78, 95% confidence interval: 1.30, 2.43; for women, hazard ratio = 1.89, 95% confidence interval: 1.39, 2.57). With each 1-unit increase in spousal BMI change, women's BMI change increased by 0.15 (95% confidence interval: 0.13, 0.18) and men's BMI change increased by 0.10 (95% confidence interval: 0.09, 0.12). Having a spouse become obese nearly doubles one's risk of becoming obese. Future research should consider exploring the efficacy of obesity prevention interventions in couples.

BACKGROUND:Dual-energy computed tomography (DECT) is a new diagnostic tool for gout, but its sensitivity has not been established. Our goal was to assess the sensitivity of DECT for the detection of monosodium urate (MSU) deposits in non-tophaceous and tophaceous gout, both at the level of the patient and that of the individual joint or lesion. METHODS:DECT was performed on 11 patients with crystal-proven non-tophaceous gout and 10 with tophaceous gout and included both the upper and lower extremities in 20/21 patients. DECT images were simultaneously acquired at 80 and 140 kV and then processed on a workstation with proprietary software using a two-material decomposition algorithm. MSU deposits were color coded as green by the software and fused onto grey-scale CT images. The number and location of these deposits was tallied independently by two DECT-trained radiologists blinded to the clinical characteristics of the patient. Sensitivity of DECT was defined as the proportion of patients with a confirmed diagnosis of gout which was correctly identified as such by the imaging technique. All patients provided informed consent to participate in this IRB-approved study. RESULTS:MSU deposits were detected by DECT in ≥1 joint area in 7/11 (64 %) patients with non-tophaceous gout, but were only detected in 3/12 (25 %) joints proven by aspiration to be affected with gout. Inclusion of the upper extremity joints in the scanning protocol did not improve sensitivity. All 10 patients with tophaceous gout had MSU deposits evident by DECT. The sensitivity of DECT for individual gouty erosions was assessed in 3 patients with extensive foot involvement. MSU deposits were detected by DECT within or immediately adjacent to 13/26 (50 %) erosions. CONCLUSIONS:A DECT protocol that includes all lower extremity joints has moderate sensitivity in non-tophaceous and high sensitivity in tophaceous gout. However, DECT has lower sensitivity when restricted to individual crystal-proven gouty joints in non-tophaceous disease or individual erosive lesions in tophaceous gout. The detection of MSU deposits by DECT relates to their size and density and the detection parameters of the DECT scanner and adjustment of the latter might improve sensitivity.