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Background: Type 2 diabetes mellitus (T2DM) is a known risk factor for cardiovascular disease including coronary heart disease (CHD), stroke, and peripheral vascular disease (PVD). However, the genetic underpinnings of cardiovascular disease in those with T2DM is not well understood. Methods: Using 15 studies from dbGaP and the UK Biobank, we conducted the largest to date genome-wide association studies (GWAS) for CHD, stroke and PVD in up to 61,880 individuals with T2DM including 47,140 of European, 8,891 of African, 2,622 of Hispanic, 2,120 of South Asian and 1,107 of East Asian ancestry. GWAS were combined via ancestry-specific and transethnic meta-analyses with fixed-effects. Additional transethnic analysis with MR-MEGA was conducted to account for heterogeneity in allelic effects correlated with ancestry. Results: We replicated previously reported CHD associated loci at genome-wide significance (GW, p≤5×10-8) including 9p21, LPA, and PSRC1. Combining our results with those of prior CHD GWAS in T2DM revealed additional GW significant signals in known CHD loci: PHACTR1, ADAMTS7, HHIPL1, and LPL. European ancestry specific analysis confirmed prior GW significant associations between LPA and PHACTR1 loci and PVD. MR-MEGA analysis of PVD identified novel GW significant loci in CNST and AVPI1. We found a significant genetic correlation of 0.74 (SE= .27) between CHD and PVD. Transethnic analysis of stroke GWAS yielded no GW significant loci. However, African ancestry specific analysis yielded two novel GW signals in the NKAIN2 and BRF1 loci. A significant association between interleukin-6 signaling and stroke was identified using pathway analysis. Conclusions: Ancestry-specific and transethnic analysis of cardiovascular disease in T2DM confirmed prior CHD GWAS findings and revealed novel associations with PVD and stroke that warrant further investigation. Disclosure E. L. Richard: None. S. Cao: None. A. Shadyab: None. R. Salem: None. Funding National Institutes of Health

Background: Diabetic kidney disease (DKD) is a microvascular complication of type 2 diabetes (T2D) with significant variability in disease onset and progression. The objective of this study is to evaluate the role of genetic propensity to insulin resistance with kidney disease (KD) in individuals with and without T2D. Methods: A total of 373,487 unrelated European subjects (5.7% T2D) were selected from the UK Biobank. An insulin resistance polygenic risk score (IR-PRS) was constructed using 18 genome-wide significant SNPs from the latest GWAS for insulin resistance. A T2D-PRS was derived using 277 SNPs. Each PRS was categorized into high (>90thpercentile), mid (10th-90th), and low (< 10th) genetic risk groups. Ten KD phenotypes were constructed using eGFR and/or urine albumin cutoffs. T2D-stratified logistic regression models were run for IR-PRS and KD outcomes, adjusting for principal components, age, sex, education, Townsend Deprivation Index, BMI, hypertension, and statin use; similar models were run for T2D-PRS. Results: Among T2D, higher IR-PRS was associated with higher odds of DKD (Mid PRS: OR=5.20, 95% CI: 1.28-21.09; High PRS: OR = 4.17, 95% CI: 0.94-18.52; overall p=0.007) and macroalbuminuria (Mid PRS: OR = 2.05, 95% CI:1.12-3.77; High PRS: OR = 1.62, 95% CI: 0.80-3.27; overall p=0.02). Among nondiabetics, higher IR-PRS was associated with higher odds of microalbuminuria (Mid PRS: OR = 1.08, 95% CI: 1.02-1.15; High Risk: OR = 1.15, 95% CI: 1.06-1.25; overall p=0.006) and albuminuria groups (Mid Risk, OR=1.08, 95% CI: 1.01-1.14; High Risk, OR = 1.15, 95% CI: 1.06-1.24; overall p=0.004). No associations were observed with T2D-PRS. Conclusion: Genetic propensity for insulin resistance is associated with KD or its predisposition among subjects with and without T2D. In contrast, genetic risk of T2D is not associated with KD. Future work will focus on the replication of these results in independent cohorts. Disclosure A. C. Garduno: None. E. L. Richard: None. S. Cao: None. V. Thaker: None. R. Salem: None. Funding National Heart, Lung, and Blood Institute (1R00HL122515)

Introduction Previous studies have shown that veterans with lower limb amputation have a higher risk for cardiovascular disease (CVD) compared with population-based controls. American veterans who have served in Iraq and Afghanistan with lower limb amputation may be at a similarly higher risk. Patients and methods The Navel Health Research Center (NHRC) maintains the Expeditionary Medical Encounter Database (EMED) of military personnel who have sustained combat limb amputation or serious limb injury during the conflicts in Iraq and Afghanistan. Department of Veterans Affairs data from 2003 to April 2015 was used to analyze CVD risk factors in this cohort. Veterans with either unilateral (n=442) or bilateral (n=146) lower limb amputation were compared to those with serious lower limb trauma without amputation (n=184). Multivariate regression was used to measure associations between lower limb amputation and CVD risk factors over an average of 8 years of follow-up. Outcomes included mean arterial pressure (MAP), low-density lipoprotein, high-density lipoprotein (HDL), and serum triglycerides (TG). Results Compared with the limb injury group, those with unilateral lower limb amputation had significantly lower HDL (p

Background Limited population-based research has described long-term health outcomes following combat-related upper limb amputation. Objective To compare health outcomes following upper limb amputation with outcomes following serious upper limb injury during the first 5 years postinjury. Design Retrospective cohort. Setting Departments of Defense (DoD) and Veterans Affairs (VA) inpatient and outpatient health care facilities. Participants Three-hundred eighteen U.S. Service Members. Methods Patients sustained an above elbow (AE, n = 51) or below elbow (BE, n = 80) amputation or serious arm injury without amputation (NO AMP, n = 187) in the Iraq or Afghanistan conflicts, 2001 through 2008. Injuries were coded by trauma nurses. Outcomes came from DoD and VA health databases. Main outcome measurements International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes. Results Most patients were injured by blast weaponry causing serious to severe injuries. All groups had a high prevalence of physical and psychological health diagnoses. The prevalence for nearly all wound complications and many physical and psychological disorders decreased substantially after postinjury year 1. The prevalence of posttraumatic stress disorder, however, increased significantly from postinjury year 1 (20%) to 3 (36%). Pain and psychological disorders ranged from 69% to 90% of patients during postinjury year 1 and remained relatively high even postinjury during year 5 (37%-53%). After adjusting for covariates, the AE group had significantly higher odds for some physical and psychological diagnoses (eg, deep vein thrombosis/pulmonary embolism, cervical pain, osteoarthritis, obesity, and mood and adjustment disorders) relative to the BE or NO AMP groups. BE patients had significantly lower odds for osteomyelitis, and AE and BE patients had lower odds for fracture nonunion and joint disorders versus NO AMP. Conclusions The results identify similarities and differences in clinical outcomes following combat-related upper limb amputation versus serious arm injury and can inform medical planning to improve rehabilitation programs and outcomes for these patients. Level of evidence III.

Background physical activity in older age has been associated with better cognitive function, but the role of earlier life physical activity is less well understood. Objective determine associations between physical activity throughout the lifespan and cognitive function in older age. Design cross-sectional study. Setting the Rancho Bernardo Study of Healthy Aging in southern California. Subjects A total of 1,826 community-dwelling men and women (60-99 years) who attended a research visit in 1988-92. Methods participants underwent cognitive testing at older age, and reported physical activity as a teenager, at age 30 years, 50 years and currently. For each time-point, participants were classified as regularly active (3+ times/week) or inactive. Results regular physical activity was associated with better cognitive function, with physical activity at older ages showing the strongest associations. Physical activity in older age was associated with better global cognitive function, executive function and episodic memory, regardless of intensity. Intense physical activity in teenage years was associated with better late-life global cognitive function in women. Teenage physical activity interacted with older age physical activity on executive function; those active at both periods performed better than those active at only one period. Similar patterns of associations were observed after excluding individuals with poor health. Conclusions regular physical activity in older age, regardless of intensity, is associated with better cognitive function. Physical activity in teenage years may enhance cognitive reserve to protect against age-related decline in executive function. Further research is needed to assess the effect of physical activity across the lifespan on healthy brain ageing.

Background: Estimated glomerular filtration rate (eGFR), albuminuria and serum uric acid (SUA) are markers of kidney function that have been associated with cognitive ability. However, whether these associations are causal is unclear. Methods: We performed one-sample Mendelian randomization (MR) to estimate the effects of kidney function markers on cognitive performance using data from 357,590 participants from the UK Biobank. Polygenic scores for serum uric acid (SUA), urine albumin to creatinine ratio (ACR), estimated glomerular filtration rate based on serum creatinine (eGFRcre) and serum cystatin-c (eGFRcys) were used as instruments, and cognitive function outcomes included a test of verbal-numeric reasoning and reaction time. Sensitivity analyses were carried out to address potential pleiotropy using MR-Egger and weighted median regression. Results: We found no evidence of a causal effect of genetically determined SUA, eGFRcre or eGFRcys on either cognitive function outcomes. There was no association between a polygenic score for ACR and verbal-numeric reasoning. However, there was suggestive evidence of a relationship between genetically increased ACR and slower reaction time (β (95% confidence interval [CI])) for 1 standard deviation log ACR = 4.93 (1.60 to 8.26), p=0.004). Pleiotropy adjusted estimates were directionally consistent with those of the principal analysis but overlapped with the null. Conclusions: This MR study does not support causal effects of SUA, eGFRcre or eGFRcys on cognitive performance. Genetically-increased ACR was associated with lower processing speed, but results need confirmation in independent samples.

Background: Reduced kidney function has been associated with cognitive decline. Most studies have examined a single marker of kidney function and have limited duration of follow-up. Objective: This study evaluated associations between markers of kidney function (urine albumin, estimated glomerular filtration rate [eGFR], and hyperuricemia) with cognitive performance over time. Methods: This is a longitudinal study of 1,634 community-dwelling adults (mean age = 71.7 years), with kidney function markers and cognitive ability measured at baseline (1992–1996) and at up to five additional time points with a maximum of 23.4 years (mean = 8.1 years) of follow-up. Associations between kidney function and cognitive performance were assessed using linear mixed effects models. Testing for interaction by sex was conducted. Results: Albuminuria (urine albumin-to-creatinine ratio [ACR]≥30 mg/g) was associated with steeper annual declines in global cognitive function (MMSE, β= –0.12, p = 0.003), executive function (Trails B, β= 4.50, p

Background Yoga interventions can improve function and reduce pain in persons with chronic low back pain (cLBP). Objective Using data from a recent trial of yoga for military veterans with cLBP, we analyzed the incremental cost-effectiveness of yoga compared with usual care. Methods Participants (n=150) were randomized to either 2× weekly, 60-minute yoga sessions for 12 weeks, or to delayed treatment (DT). Outcomes were measured at 12 weeks, and 6 months. Quality-adjusted life years (QALYs) were measured using the EQ-5D scale. A 30% improvement on the Roland-Morris Disability Questionnaire (primary outcome) served as an additional effectiveness measure. Intervention costs including personnel, materials, and transportation were tracked during the study. Health care costs were obtained from patient medical records. Health care organization and societal perspectives were examined with a 12-month horizon. Results Incremental QALYs gained by the yoga group over 12 months were 0.043. Intervention costs to deliver yoga were $307/participant. Negligible differences in health care costs were found between groups. From the health care organization perspective, the incremental cost-effectiveness ratio to provide yoga was $4488/QALY. From the societal perspective, yoga was "dominant" providing both health benefit and cost savings. Probabilistic sensitivity analysis indicates an 89% chance of yoga being cost-effective at a willingness-to-pay of $50,000. A scenario comparing the costs of yoga and physical therapy suggest that yoga may produce similar results at a much lower cost. Discussion/conclusions Yoga is a cost-effective treatment for reducing pain and disability among military veterans with cLBP.

Background Hearing impairment is prevalent among older adults and has been identified as a risk factor for cognitive impairment and dementia. We evaluated the association of hearing impairment with long-term cognitive decline among community-dwelling older adults. Methods A population-based longitudinal study of adults not using hearing aids who had hearing acuity and cognitive function assessed in 1992–1996, and were followed for a maximum of 24 years with up to five additional cognitive assessments. Hearing acuity was categorized based on pure-tone average (PTA) thresholds: normal (PTA ≤ 25 dB), mild impairment (PTA > 25–40 dB), moderate/severe impairment (PTA > 40 dB). Results Of 1,164 participants (mean age 73.5 years, 64% women), 580 (49.8%) had mild hearing impairment and 196 (16.8%) had moderate/severe hearing impairment. In fully adjusted models, hearing impairment was associated with steeper decline on the Mini-Mental State Examination (MMSE) (mild impairment β = −0.04, p = .01; moderate/severe impairment β = −0.08, p = .002) and Trails B (mild impairment β = 1.21, p = .003; moderate/severe impairment β = 2.16, p = .003). Associations did not differ by sex or apolipoprotein E (APOE) ϵ4 status and were not influenced by social engagement. The MMSE-hearing association was modified by education: mild hearing impairment was associated with steeper decline on the MMSE among participants without college education but not among those with college education. Moderate/severe hearing impairment was associated with steeper MMSE decline regardless of education level. Conclusions Hearing impairment is associated with accelerated cognitive decline with age, and should be screened for routinely. Higher education may provide sufficient cognitive reserve to counter effects of mild, but not more severe, hearing impairment.

Background and Aims. To evaluate the association of self-reported race with major adverse cardiac events (MACE) and modification of this association by paraoxonase gene (PON1, PON2, and PON3) single nucleotide polymorphisms (SNPs). Methods. Included in this longitudinal study were 12,770 black or white participants from the Atherosclerosis Risk in Communities (ARIC) cohort who completed a baseline visit (1987–1989) with PON genotyping. Demographic, behavioral, and health information was obtained at baseline. MACE was defined as first occurrence of myocardial infarction, stroke, or CHD-related death through 2004. Cox proportional hazards regression was used to evaluate the association between race and MACE after adjustment for age, gender, and other demographic and cardiovascular risk factors such as diabetes and hypertension. Modification of the association between PON SNPs and MACE was also assessed. Results. Blacks comprised 24.6% of the ARIC cohort; overall, 14.0% of participants developed MACE. Compared with whites, blacks had 1.24 times greater hazard of MACE (OR = 1.24,95%CI = 1.10,1.39) than whites after adjusting for age, gender, BMI, cigarette and alcohol use, educational and marital status, and aspirin use. This association became nonsignificant after further adjustment for high cholesterol, diabetes, and hypertension. None of the evaluated SNPs met the significance level (p<0.001) after Bonferroni correction for multiple comparisons. Conclusions. No association between race and MACE was identified after adjusting for high cholesterol, diabetes, and hypertension, suggesting that comorbidities are major determinants of MACE; medical intervention with focus on lifestyle and health management could ameliorate the development of MACE. Further studies are needed to confirm this observation.

This chapter discusses the specific techniques we utilize in foot and ankle rehabilitation for the athlete. We have included our updated techniques. We have also included some new modalities that have become available. We have also kept some of the principles and background from the 2nd edition to help our readers in their understanding of the development of our rehabilitation approaches which have occurred over time. Also, this history helps with understanding the principles we utilize in a rehabilitation approach. In this edition, we also give specific rehabilitation protocols for the Achilles tendon repair, which has undergone such dramatic progression in the last 10–20 years. We also have delineated our postoperative protocol for the difficult and sometimes problematic Lisfranc injury of the midfoot. We have noted a very optimistic recovery if a well-defined and principled approach is undertaken, understanding the balance between stability and motion. Lastly, we present our treatment approach and protocol for both nonoperative and operative for the high ankle sprain and syndesmosis injury, which is a difficult but common problem in the athlete. We hope you enjoy this updated and innervated chapter.

To better understand the association of alcohol intake with cognitively healthy longevity (CHL), we explored the association between amount and frequency of alcohol intake and CHL among 1,344 older community-dwelling adults. Alcohol intake was assessed by questionnaire in 1984-1987. Cognitive function was assessed in approximate four-year intervals between 1988 and 2009. Multinomial logistic regression, adjusting for multiple lifestyle and health factors, was used to examine the association between alcohol consumption and CHL (living to age 85 without cognitive impairment), survival to age 85 with cognitive impairment (MMSE score >1.5 standard deviations below expectation for age, sex, and education), or death before age 85. Most participants (88%) reported some current alcohol intake; 49% reported a moderate amount of alcohol intake, and 48% reported drinking near-daily. Relative to nondrinkers, moderate and heavy drinkers (up to 3 drinks/day for women and for men 65 years and older, up to 4 drinks/day for men under 65 years) had significantly higher adjusted odds of survival to age 85 without cognitive impairment (p's < 0.05). Near-daily drinkers had 2-3 fold higher adjusted odds of CHL versus living to at least age 85 with cognitive impairment (odds ratio (OR) = 2.06; 95% confidence interval (CI): 1.21, 3.49) or death before 85 (OR = 3.24; 95% CI: 1.92, 5.46). Although excessive drinking has negative health consequences, these results suggest that regular, moderate drinking may play a role in cognitively healthy longevity.

INTRODUCTION Little population-based research has described the transition from Department of Defense (DoD) to Department of Veterans Affairs (VA) healthcare following combat related amputations. The objectives were to describe (1) to what extent patients used either DoD only facilities, both DoD and VA facilities, or VA only facilities during the first 5 years postinjury, (2) which specific clinics were used and (3) clinic use among patients with different levels of amputation (upper versus lower), and among patients with early or late amputation. MATERIALS AND METHODS This was a retrospective analysis of health data extracted from the expeditionary medical encounter database (EMED) and national DoD and VA databases. Patients were 649 US service members who sustained a single major limb amputation following injuries in the Iraq and Afghanistan conflicts, 2001-2008. We compared yearly DoD and VA clinic use by patient groups with different levels of amputation (upper limb: above versus below elbow or lower limb: above versus below knee), different timing of amputation (early: within 90 days postinjury versus late: more than 90 days postinjury), military component (Active Duty versus National Guard/Reserve) and race (White versus Black). For all groups, we calculated the percentage of patients using: (1) DoD only, (2) both DoD and VA or 3) VA only clinics during each of postinjury years 1 through 5. We also calculated the percentage of patients who used specific clinics (e.g., social work, prosthetics, mental health) during each postinjury year. RESULTS During postinjury year 1, over 98% of patients used DoD only or both DoD and VA clinics. Most individuals (70% to 78%) used both DoD and VA clinics during postinjury year 1. Use of VA only clinics increased gradually between postinjury year 2 (15% to 30% of patient groups) and year 5 (75% to 88%). This gradual transition to use of VA only clinics was seen consistently across patient groups with different anatomical levels or timing of amputation, military component or race. Patients with lower levels of amputation (versus higher levels) and individuals with early amputations (versus late) transitioned earlier to VA only care. Overall, clinic use was high as 91% to 100% of all patient groups used one or more clinics (DoD or VA) during each of the first 5 years. For specific clinics, most patients used DoD facilities related to rehabilitation (physical therapy, prosthetics) or transitional care (social work) particularly during postinjury year 1. Use of most VA clinics studied (social work, primary care, prosthetics, mental health) showed a modest increase primarily after postinjury year 1 and remained stable through postinjury year 5. The results indicated apparent underuse of psychiatric/mental health and prosthetics between postinjury year 1 and 2. CONCLUSIONS The present study indicated a gradual transition from DoD to VA only healthcare which extended across 5 years following combat related amputations. Patients with lower levels of amputation or early amputation generally transitioned earlier to VA only healthcare. These results can inform medical planning to support a timely and clinically effective transition from DoD to VA healthcare.

Background In the setting of chronic kidney disease (CKD), altered extra-renal urate handling may be necessary to regulate plasma uric acid. The Remote Sensing and Signaling Hypothesis (Nigam S. What do drug transporters really do? Nat Rev Drug Discov 2015; 14: 29–44) suggests that multispecific solute carrier (SLC) and ATP-binding cassette (ABC) drug transporters in different tissues are part of an inter-organ communication system that maintains levels of urate and other metabolites after organ injury. Methods Data from the Chronic Renal Insufficiency Cohort (CRIC; n = 3598) were used to study associations between serum uric acid and single nucleotide polymorphisms (SNPs) on the following uric acid transporters: ABCG2 (BRCP), SLC22A6 (OAT1), SLC22A8 (OAT3), SLC22A10 (OAT5), SLC22A11 (OAT4), SLC22A12 (URAT1), SLC22A13 (OAT10), SLC17A1-A3 (NPTs), SLC2A9 (GLUT9), ABCC2 (MRP2) and ABCC4 (MRP4). Regression models, controlling for principal components age, gender and renal function, were run separately for those of European (EA) and African ancestry (AA), and P-values corrected for multiple comparisons. A twin cohort with participants of EA and normal renal function was used for comparison. Results Among those of EA in CRIC, statistically significant signals were observed for SNPs in ABCG2 (rs4148157; beta-coefficient = 0.68; P = 4.78E-13) and SNPs in SLC2A9 (rs13125646; beta-coefficient = −0.30; P = 1.06E-5). Among those of AA, the strongest (but not statistically significant) signals were observed for SNPs in SLC2A9, followed by SNPs in ABCG2. In the twin study (normal renal function), only SNPs in SLC2A9 were significant (rs4481233; beta-coefficient=−0.45; P = 7.0E-6). In CRIC, weaker associations were also found for SLC17A3 (NPT4) and gender-specific associations found for SLC22A8 (OAT3), SLC22A11 (OAT4), and ABCC4 (MRP4). Conclusions In patients of EA with CKD (CRIC cohort), we found striking associations between uric acid and SNPs on ABCG2, a key transporter of uric acid by intestine. Compared with ABCG2, SLC2A9 played a much less significant role in this subset of patients with CKD. SNPs in other SLC (e.g. SLC22A8 or OAT3) and ABC (e.g. ABCC4 or MRP4) genes appear to make a weak gender-dependent contribution to uric acid homeostasis in CKD. As renal urate transport is affected in the setting of declining kidney function, extra-renal ABCG2 appears to play a compensatory role—a notion consistent with animal studies and the Remote Sensing and Signaling Hypothesis. Overall, the data indicate how different urate transporters become more or less important depending on renal function, ethnicity and gender. Therapies focused on enhancing ABCG2 urate handling may be helpful in the setting of CKD and hyperuricemia.

Diet may be an important modifiable risk factor for maintenance of cognitive health in later life. This study aimed at examining associations between common dietary indices and dietary patterns defined by factor analysis and cognitive function in older community-dwelling adults. Dietary information for 1499 participants from the Rancho Bernardo Study was collected in 1988&ndash, 1992 and used to calculate the alternate Mediterranean diet score, Alternate Healthy Eating Index (AHEI)-2010 score and factor scores derived from factor analysis of nutrients. Global cognitive function, executive function, verbal fluency and episodic memory were assessed at approximate four-year intervals from 1988&ndash, 2016. Linear mixed models were used to examine associations between dietary patterns and cognitive trajectories. Estimates for the highest vs. lowest tertile in models adjusting for age, sex, education, energy intake, lifestyle variables and retest effect showed greater adherence to the Mediterranean score was associated with better baseline global cognitive function (&beta, (95% CI) = 0.33 (0.11, 0.55)). The AHEI-2010 score was not significantly associated with cognitive performance. Higher loading on a plant polyunsaturated fatty acid (PUFA)/vitamin E factor was associated with better baseline global cognitive function and executive function (&beta, = 0.22 (0.02, 0.42) and &beta, = &minus, 7.85 (&minus, 13.20, &minus, 2.47)). A sugar/low protein factor was associated with poorer baseline cognitive function across multiple domains. Dietary patterns were not associated with cognitive decline over time. Adherence to a healthy diet with foods high in PUFA and vitamin E and a low sugar to protein ratio, as typified by a Mediterranean diet, may be beneficial for cognitive health in late life.

Little research has described the long-term health outcomes of patients who had combat-related amputations or leg-threatening injuries. We conducted retrospective analysis of Department of Defense and Department of Veterans Affairs health data for lower extremity combat-injured patients with (1) unilateral amputation within 90 days postinjury (early amputation, n = 440), (2) unilateral amputation more than 90 days postinjury (late amputation, n = 78), or (3) leg-threatening injuries without amputation (limb salvage, n = 107). Patient medical records were analyzed for four years postinjury. After adjusting for group differences, early amputation was generally associated with a lower or similar prevalence for adverse physical and psychological diagnoses (e.g., pain, osteoarthritis, posttraumatic stress disorder) versus late amputation and/or limb salvage. By contrast, early amputation was associated with an increased likelihood of osteoporosis during the first year postinjury. The prevalence of posttraumatic stress disorder increased for all patient groups over four years postinjury, particularly in the second year. The different clinical outcomes among combat extremity injured patients treated with early amputation, late amputation, or limb salvage highlight their different healthcare requirements. These findings can inform and optimize the specific treatment pathways that address the physical and psychological healthcare needs of such patients over time.

Endothelial microparticles (EMPs) are complex vesicular structures that originate from plasma membranes of activated or apoptotic endothelial cells. EMPs play a significant role in vascular function by altering the processes of inflammation, coagulation, and angiogenesis, and they are key players in the pathogenesis of several vascular diseases. Circulating EMPs are increased in many age-related vascular diseases such as coronary artery disease, peripheral vascular disease, cerebral ischemia, and congestive heart failure. Their elevation in plasma has been considered as both a biomarker and bioactive effector of vascular damage and a target for vascular diseases. This review focuses on the pleiotropic roles of EMPs and the mechanisms that trigger their formation, particularly the involvement of decreased estrogen levels, thrombin, and PAI-1 as major factors that induce EMPs in age-related vascular diseases.

It is not known whether serum potassium levels affect blood pressure response to anti-hypertensive medication. The African American trial of Kidney disease and Hypertension (AASK) Genomics Study (N=828) is a subset of the AASK trial that randomized 1,094 African American men and women with hypertensive nephrosclerosis to ramipril, amlodipine or metoprolol. Participants were also randomized to a usual (102–107 mmHg) or low (≤92 mmHg) mean arterial pressure (MAP) treatment goal. Time-to-event analyses were used to determine the relationship between serum potassium prior to randomization and time (days) to reach an MAP of 107 mmHg. Mean baseline serum potassium was 4.22 (standard deviation +/− 0.56 and range 2.8–6.0) mmol/L and the median days to reach target MAP was 32 (interquartile range 8–95) days. The adjusted hazard ratio (HR) for each 1mmol/L increase in serum potassium was 1.31 (95%CI: 1.08–1.59) in the usual MAP group, and 1.21 (95%CI: 1.02–1.44) in the low MAP group. Secondary findings suggested that women in the usual MAP group on amlodipine were more likely to reach target MAP compared to women randomized to ramipril (HR: 2.05, 95%CI: 1.30–3.21). Older subjects in the low MAP group (≥55 years) were also more likely to reach target MAP on amlodipine compared to ramipril (HR: 1.57, 95%CI: 1.03–2.38). Serum potassium appears to be a significant predictor of time to blood pressure response, independent of drug class. Results also suggest a benefit of using amlodipine when more rapid blood pressure control is clinically indicated among women and more aggressively managed older subjects.

Blood pressure is a complex quantitative trait with a strong genetic component. In this study, we leveraged the Veterans Affairs electronic medical record system to explore the relationship between Paraoxonase 1 (PON1)-108 C/T (rs705379) and mean arterial blood pressure (MAP).Outpatient blood pressure data over an approximate 8-year period was collected from the Veterans Affairs Hypertensive Cohort (N = 1,302). Association between genotype and longitudinal MAP was further explored using a random effects model controlling for age, ancestry, renal function, and other determinants of blood pressure. To control for population stratification, principal component groupings based on ancestry informative markers in this dataset were included as covariates (in addition to self-identified ancestry). Data from the African American Study of Kidney Disease and Hypertension (AASK, N = 857) was used to confirm significant findings in an independent cohort.There was a significant interaction between PON1-108 C/T genotype and follow-up age group. At a younger age (50 years), there was an estimated 2.53 mm Hg (95% confidence interval: 1.06, 4.00) increase in MAP with each additional C-allele. At the older age groups, there were no significant associations between PON1-108 C/T genotype and MAP. Using data from the AASK trial, the C-allele at PON1-108 C/T was significantly associated with a higher MAP (P = 0.005) but only among younger participants (54 years).The PON1-108 polymorphism may be associated with MAP in an age-dependent manner.

BACKGROUND This study focuses on the relationship between β(1)-adrenergic receptor (ADRB1) polymorphisms and blood pressure response to the β-blocker metoprolol among African Americans with early hypertensive nephrosclerosis. METHODS Participants from the African-American Study of Kidney Disease and Hypertension (AASK) trial were genotyped for ADRB1 polymorphisms: Ser49Gly and Arg389Gly. Cox proportional hazards models were used to determine the relationship between ADRB1 polymorphisms and time to reach a mean arterial pressure (MAP) of ≤107 mm Hg in the first year after randomization, adjusted for other predictors of blood pressure response. RESULTS In the Ser49Gly model, Ser49/Gly49 individuals were less responsive compared to Ser49/Ser49 only among the more obese (body mass index (BMI) ≥39 kg/m(2)) participants (P < 0.05 for genotype × BMI interaction). The hazard ratio (HR) with a BMI of 39 kg/m(2) was 0.68 (95% confidence interval (CI) 0.46-0.99). In the Arg389Gly model, participants with Arg389 were less likely to respond to metoprolol: HR: 0.68 (95% CI 0.50-0.93). In addition, women were less responsive to metoprolol compared to men: HR: 0.78 (95% CI 0.60-0.995). CONCLUSIONS Ser49/Gly49 was predictive of blood pressure response to metoprolol only among more obese African Americans with early hypertensive nephrosclerosis. In contrast to other studies suggesting increased short-term responsiveness to β-blockers with Arg389, Arg389 individuals were less responsive in this study analyzing blood pressure over a 1-year period. This may be partly explained by decreased agonist-promoted desensitization with Arg389. However, gender, physiological adaption to stress, interactions between genes and between genes and the environment, as well as study in other patient populations need to be considered.

Purpose: To explore the association between CYP3A4 and CYP3A5 gene polymorphisms and blood pressure response to amlodipine among participants from the African-American Study of Kidney Disease and Hypertension Trial randomized to amlodipine (n = 164). Methods: Cox proportional hazards models were used to determine the risk of reaching a target mean arterial pressure (MAP) of ≤107 mm Hg by CYP3A4 (A–392G and T16090C) and CYP3A5 (A6986G) gene polymorphisms, stratified by MAP randomization group (low or usual) and controlling for other predictors for blood pressure response. Results: Women randomized to a usual MAP goal with an A allele at CYP3A4 A–392G were more likely to reach a target MAP of 107 mm Hg. The adjusted hazard ratio (AA/AG compared to GG) with 95% confidence interval was 3.41 (1.20–9.64; p = 0.020). Among participants randomized to a lower MAP goal, those with the C allele at CYP3A4 T16090C were more likely to reach target MAP: The adjusted hazard ratio was 2.04 (1.17–3.56; p = 0.010). After adjustment for multiple testing using a threshold significance level of p = 0.016, only the CYP3A4 T16090C SNP remained significant. CYP3A5 A6986G was not associated with blood pressure response. Conclusions: Our findings suggest that blood pressure response to amlodipine among high-risk African-Americans appears to be determined by CYP3A4 genotypes, and sex specificity may be an important consideration. Clinical applications of CYP3A4 genotype testing for individualized treatment regimens warrant further study.

AIM/OBJECTIVES/BACKGROUND Hypertension is a risk factor for cardiovascular and kidney disease and is most prevalent in African-American adults. The renin-angiotensin-aldosterone system is integral in blood pressure regulation; angiotensin-converting enzyme inhibitors such as ramipril are first-line treatment options. As decreases in angiotensin result in catecholamine release, β-adrenergic receptor (ADRB) polymorphisms may influence blood pressure response to ramipril. METHODS Associations between ADRB polymorphisms and blood pressure response to ramipril were analyzed in the African American Study of Kidney Disease and Hypertension, a randomized clinical trial. A total of 336 participants were included in this analysis. Six polymorphisms were analyzed here: (a) ADRB1 rs1801252 (Ser49Gly) and rs1801253 (Gly389Arg); and (b) ADRB2 rs2053044, rs1042711, rs1042713 (Arg16Gly), and rs1042714 (Gln27Glu). Time to reach a mean arterial pressure (MAP) of 107 mmHg within the first 60 days after randomization was studied using Kaplan-Meier and Cox proportional hazards modeling for univariate and adjusted analyses. RESULTS Genotypes at rs2053044, upstream from the ADRB2 5' untranslated region, were associated with time to reach target MAP among those randomized to the usual treatment group. Participants with the GG genotype achieved target MAP on average 12.2 days (38.1%) later than in comparison with those with the A allele (P=0.01). After adjusting for covariates, those with the AA/AG genotype had 2.09 greater odds of reaching MAP of 107 mmHg or less within 60 days of treatment in comparison with those with a GG genotype (hazard ratio=2.09, 95% confidence interval=1.21-3.60). CONCLUSION Results suggest that ADRB2 rs2053044 genotypes may be a determinant of blood pressure response to ramipril. Additional studies are needed to clarify the effect of rs2053044 and other 5' untranslated region polymorphisms on gene expression and blood pressure response to angiotensin-converting enzyme inhibitors.

Morphine and fentanyl are frequently used for analgesia after trauma, but there is debate over the advantages and disadvantages of these opioids. Among combat amputees, intravenous (IV) morphine (vs IV fentanyl) after injury was associated with reduced likelihood of posttraumatic stress disorder (PTSD). The previous results were based on military health diagnoses over 2 yr postinjury. The present study followed psychological diagnoses of patients with amputation for 4 yr using military and Department of Veterans Affairs health data. In-theater combat casualty records (n = 145) documented Glasgow Coma Scale (GCS) scores and/or morphine, fentanyl, or no opioid treatment within hours of injury. We found that (1) GCS scores were not significantly associated with PTSD; (2) longitudinal modeling using four (yearly) time points showed significantly reduced odds of PTSD for patients treated with morphine (vs fentanyl) across years (adjusted odds ratio = 0.40; 95% confidence interval = 0.17–0.94); (3) reduced PTSD prevalence for morphine (vs IV fentanyl; morphine = 25%, fentanyl = 59%, p < 0.05) was significant, specifically among patients with traumatic brain injury during the first 2 yr postinjury; and (4) PTSD prevalence, but not other disorders (e.g., mood), increased between year 1 (PTSD = 18%) and years 2 through 4 postinjury (PTSD range = 30%–32%).

Department of Veterans Affairs (VA) outpatient costs were analyzed for combat Veterans injured in Iraq and Afghanistan from 2001 to 2008. Patients had serious lower-limb injuries (n = 170) or unilateral (n = 460) or bilateral (n = 153) lower-limb amputation(s). Total costs over the follow-up period (2003 to 2012) and annual costs were analyzed. Unadjusted mean costs per year in 2012 U.S. dollars were $7,200, $14,700 and $18,700 for limb injuries and unilateral and bilateral lower-limb amputation(s), respectively (p < 0.001). Multivariate modeling indicated that annual cost declined after the first year in the VA for Veterans with limb injuries (p < 0.001, repeated measures). In contrast, annual costs doubled after 3-5 years with unilateral (p < 0.001) and bilateral amputation(s) (p < 0.001). Among amputees, prosthetics comprised more than 50% of outpatient cost; unadjusted mean cost per year for prosthetics was 7-9 times higher in comparison with Veterans with limb injuries. Amputation status was associated with an adjusted 3.12-fold increase in mean prosthetic cost per year (p < 0.001, generalized linear model). In addition, posttraumatic stress disorder (PTSD) was associated with increased prosthetic cost by amputation status (p < 0.001) and increased psychiatric and pharmacy costs (both p < 0.001). Results indicate relatively high and sustained outpatient costs driven by prosthetics following amputation. Finally, PTSD affected cost for multiple domains of health, highlighting the importance of accurate diagnosis, treatment, and support for PTSD.

Moderate alcohol consumption has been associated with reduced mortality, but the association of alcohol with cognitively healthy longevity has not been well characterized. Here we explored the association between alcohol intake and cognitively healthy longevity among 1353 community-dwelling adults. Frequency and amount of alcohol intake was assessed by questionnaire in 1984–1987. Cognitive function was assessed at approximate 4 year intervals beginning in 1988–1992 through 2007–2009. Multinomial logistic regression was used to examine the association between alcohol intake and a three level outcome: cognitively healthy longevity (living to at least age 85 without cognitive impairment), survival to age 85 with cognitive impairment (defined as an MMSE score > 1.5 standard deviations below expectation for age, sex, and education), or death before age 85, with adjustment for numerous health and lifestyle factors. Only 17% of participants reported no alcohol intake; 48% reported drinking near-daily. Most drinkers (48% of the sample) consumed a moderate amount of alcohol (≤ 1drink/day for women and those over age 65; ≤2 drinks/day for men under age 65). Relative to nondrinkers, those who drank near daily had 2–3 fold higher odds of cognitively healthy longevity versus cognitive impairment (p< .05) or death before 85 (p

[This corrects the article DOI: 10.1371/journal.pone.0170569.].

BACKGROUND African Americans have a disproportionate burden of hypertension and comorbid disease. Pharmacogenetic markers of blood pressure response have yet to be defined clearly. This study explores the association between G-protein-coupled receptor kinase type 4 (GRK4) variants and blood pressure response to metoprolol among African Americans with early hypertensive nephrosclerosis. METHODS Participants from the African American Study of Kidney Disease and Hypertension (AASK) trial were genotyped at three GRK4 polymorphisms: R65L, A142V, and A486V. A Cox proportional hazards model, stratified by gender, was used to determine the relationship between GRK4 variants and time to reach a mean arterial pressure (MAP) of 107 mm Hg, adjusted for other predictors of blood pressure response. Potential interactions between the three polymorphisms were explored by analyzing the effects of gene haplotypes and by stratifying the analysis by neighboring sites. RESULTS The hazard ratio with 95% confidence interval by A142V among men randomized to a usual MAP (102-107 mm Hg) was 1.54 (1.11-2.44; P = 0.0009). The hazard ratio by A142V with R65/L65 or L65/L65 was 2.14 (1.35-3.39; P = 0.001). Haplotype analyses were consistent but inconclusive. There was no association between A142V and blood pressure response among women. CONCLUSIONS Results suggest a sex-specific relationship between GRK4 A142V and blood pressure response among African-American men with early hypertensive nephrosclerosis. Men with a GRK4 A142 were less responsive to metoprolol if they had a GRK4 L65 variant. The effect of GRK4 variants and blood pressure response to metoprolol should be studied in larger clinical trials.