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Introduction: Abrupt declines in kidney function often occur in patients with advanced chronic kidney disease and may exacerbate the need to initiate dialysis treatment. It is unclear how frequently such events occur in patients transitioning to chronic dialysis therapy, and what outcomes they are associated with. Methods: We examined a national cohort of 23,349 US veterans with incident end-stage renal disease (ESRD) and with available pre-ESRD estimated glomerular filtration rate (eGFR) to identify abrupt declines in kidney function, defined as an unexpected >50% decrease in eGFR at the time of chronic dialysis transition. Associations with all-cause mortality and with renal recovery were examined in Cox proportional hazard and competing risk regression models. Results: A total of 4804 (21%) patients experienced an abrupt decline in kidney function at dialysis transition. Renal recovery occurred in 586 (12.2%) and 297 (1.6%) patients with and without an abrupt decline, respectively (adjusted subhazard ratio: 4.42; 95% confidence interval [CI]: 3.72–5.27; P < 0.001). In the first 6 months after dialysis transition 1178 patients (24.5%) with abrupt decline died (annualized mortality rate 574/1000 patient-years), compared with 2354 deaths (12.7%) in patients without abrupt decline (274 deaths/1000 patient-years). An abrupt decline was associated with 45% higher mortality after multivariable adjustments (hazard ratio: 1.45; 95% CI: 1.33–1.57). Conclusion: Abrupt declines in kidney function are common in patients transitioning to chronic dialysis, and are associated with higher mortality. Patients with abrupt declines also experience a higher rate of renal recovery; hence, careful attention to residual kidney function is warranted in these patients. Keywords: acute kidney injury, chronic kidney disease, dialysis, end-stage renal disease, kidney function recovery, mortality

Objective To evaluate whether a behavioral weight management program combined with a smoking cessation program delivered via interactive technology could prevent postcessation weight gain. Methods Three hundred and thirty young adult smokers, age 18 to 35 years, were randomized to a smoking cessation program alone (comparison group), which included behavioral counseling and nicotine replacement, or to a behavioral weight management program adapted from the Look AHEAD trial plus the same smoking cessation program (intervention group). Results The Treating Adult Smokers at Risk for Weight Gain with Interactive Technology study randomized 164 participants to the comparison group and 166 participants to the intervention group. On average, the participants gained 0.91 kg after 24 months in the trial (comparison group + 1.45 kg and intervention group + 0.32; P = 0.157). The only variable systematically affecting weight change over time was smoking abstinence, in which those who were abstinent, on average, gained 0.14 kg more per month compared with those who continued to smoke (P

Albuminuria is a robust predictor of CKD progression. However, little is known about the associations of changes in albuminuria with the risk of kidney events outside the settings of clinical trials.In a nationwide cohort of 56,946 United States veterans with an eGFR≥60 ml/min per 1.73 mThe mean age was 64 (SD, 10) years old; 97% were men, and 91% were diabetic. There was a nearly linear association between 1-year fold changes in albuminuria and incident CKD. The multivariable-adjusted hazard ratios (95% confidence intervals) of incident CKD associated with more than twofold decrease, 1.25- to twofold decrease, 1.25- to twofold increase, and more than twofold increase (versus1.25-fold decrease to1.25-fold increase) in albuminuria were 0.82 (95% confidence interval, 0.77 to 0.89), 0.93 (95% confidence interval, 0.86 to 1.00), 1.12 (95% confidence interval, 1.05 to 1.20), and 1.29 (95% confidence interval, 1.21 to 1.38), respectively. Qualitatively similar associations were present for rapid eGFR decline (adjusted odds ratios; 95% confidence intervals for corresponding albuminuria changes: adjusted odds ratio, 0.86; 95% confidence interval, 0.78 to 0.94; adjusted odds ratio, 0.98; 95% confidence interval, 0.89 to 1.07; adjusted odds ratio, 1.18; 95% confidence interval, 1.08 to 1.29; and adjusted odds ratio, 1.67; 95% confidence interval, 1.54 and 1.81, respectively).Relative changes in albuminuria over a 1-year interval were linearly associated with subsequent risk of kidney outcomes. Additional studies are warranted to elucidate the underlying mechanisms of the observed associations and test whether active interventions to lower elevated albuminuria can improve kidney outcomes.

Higher SBP visit-to-visit variability (SBPV) has been associated with increased risk of adverse events in patients with chronic kidney disease, but the association of SBPV in advanced nondialysis-dependent chronic kidney disease with mortality after the transition to end-stage renal disease (ESRD) remains unknown. Among 17 729 US veterans transitioning to dialysis between October 2007 and September 2011, we assessed SBPV calculated from the SD of at least three intraindividual outpatient SBP values during the last year prior to dialysis transition (prelude period). Outcomes included factors associated with higher prelude SBPV and post-transition all-cause, cardiovascular, and infection-related mortality, assessed using multivariable linear regression and Cox and competing risk regressions, respectively, adjusted for demographics, comorbidities, medications, cardiovascular medication adherence, SBP, BMI, estimated glomerular filtration rate, and type of vascular access. Modifiable clinical factors associated with higher prelude SBPV included higher SBP, use of antihypertensive medications and erythropoiesis-stimulating agents, inadequate cardiovascular medication adherence, and catheter use. After multivariable adjustment, higher prelude SBPV was significantly associated with higher post-ESRD all-cause and infection-related mortality, but not cardiovascular mortality [hazard/subhazard ratios (95% confidence interval) for the highest (vs. lowest) quartile of SBPV, 1.08 (1.01–1.16), 1.02 (0.89–1.15), and 1.41 (1.10–1.80) for all-cause, cardiovascular, and infection-related mortality, respectively]. High pre-ESRD SBPV is potentially modifiable and associated with higher all-cause and infection-related mortality following dialysis initiation. Further studies are needed to test whether modification of pre-ESRD SBPV can improve clinical outcomes in incident ESRD patients. http://links.lww.com/HJH/A772

Mortality is extremely high immediately after the transition to dialysis therapy, but the association of blood pressure (BP) before dialysis therapy initiation with mortality after dialysis therapy initiation remains unknown.Observational study.17,729 US veterans transitioning to dialysis therapy in October 2007 to September 2011, with a median follow-up of 2.0 years.Systolic (SBP) and diastolic BP (DBP) averaged over the last 1-year predialysis transition period as 6 (120 to ≥160mmHg in 10-mmHg increments) and 5 (60 to ≥90mmHg in 10-mmHg increments) categories, respectively, and as continuous measures.Postdialysis all-cause mortality, assessed over different follow-up periods (ie, 3, 3-6, 6-12, and ≥12 months after dialysis therapy initiation) using Cox regressions adjusted for demographics, comorbid conditions, medications, cardiovascular medication adherence, body mass index, estimated glomerular filtration rate, and type of vascular access.Mean predialysis SBP and DBP were 141.2±16.1 (SD) and 73.7±10.6mmHg, respectively. There was a reverse J-shaped association of SBP with all-cause mortality, with significantly higher mortality seen with SBP140mmHg. Mortality risks associated with lower SBP were greatest in the first 3 months after dialysis therapy initiation, with multivariable-adjusted HRs of 2.40 (95% CI, 1.96-2.93), 1.99 (95% CI, 1.66-2.40), 1.35 (95% CI, 1.13-1.62), 0.98 (95% CI, 0.78-1.22), and 0.76 (95% CI, 0.57-1.00) for SBP 120, 120 to 130, 130 to 140, 150 to 160, and ≥160 (vs 140-150) mmHg, respectively. No consistent association was observed between predialysis DBP and postdialysis mortality.Results cannot be inferred to show causality and may not be generalizable to women or the general US population.Lower predialysis SBP is associated with higher all-cause mortality in the immediate postdialysis period. Predialysis DBP showed no consistent association with postdialysis mortality. Further studies are needed to clarify ideal predialysis SBP levels among incident dialysis patients as a potential means to improve the excessively high early dialysis mortality.

Intussusception is uncommon in children older than 3 years, and use of enema reduction in older children is controversial. We sought to determine whether older children are at greater risk of requiring operative intervention and/or having pathology causing lead points, such that enema reduction should not be attempted.The Pediatric Health Information System database was reviewed from January 1, 2009-June 30, 2014. Patients were followed for 6 months from initial presentation or until bowel resection occurred. Successful enema reduction was defined as having radiologic reduction without additional procedures.A total of 7,412 patients were identified: 6,681 were3 years old, 731 patients were3 years old. In those3 years old, 450 (62%) were treated successfully with enema reduction; the rate of patients with a tumor diagnosis was similar in patients3 years old and patients3 years old (5% vs 6%, P = .07). The rate of a Meckel's diagnosis was greater in patients3 years old (2% vs 14%, P .0001). In patients3 years old, duration of stay between patients who underwent primary operative therapy versus those who underwent operative therapy after enema reduction was similar (4 days vs 4 days, P = .06). Older age was not associated with increased risk of recurrent admission for intussusception (P = .45).Pediatric Health Information System data suggest that enema reduction may be safe and effective for a majority of children even if older than 3 years.

We compared the effectiveness of a ‘stepped care’ approach with increasing treatment intensity (‘Step Care’) to one with repeated treatments (‘Recycle’) among cigarette smokers interested in quitting smoking. Step 1 of the Step Care intervention consisted of a single counseling session, nicotine patch for six weeks and telephonic contact. For smokers not achieving tobacco abstinence 6 months after randomization with Step 1, the intensity of the intervention increased to four counseling sessions, bupropion sustained-release, nine telephone calls and three mailings (Step 2). For those not achieving tobacco abstinence 12 months after randomization, smokers received six behavioral counseling sessions, nicotine patch and nicotine gum, nine telephone calls and three mailings (Step 3). The Recycle participants received one session of health behavior counseling, six weeks of the nicotine patch and a telephone call at each step. 270 cigarette smokers were randomized. At 24 months after randomization using an intention to treat analysis, no statistically significant difference was observed in prolonged smoking abstinence between the Step Care and Recycle condition (16.9% versus 9.4%; adjusted OR = 1.88; 95% CI 0.88–4.01; P =0.10). Additional research is needed to explore whether a stepped care intervention increases long-term smoking abstinence rates compared with repeating the same intervention.

Respiration is controlled by central pattern generating circuits in the brain stem, whose activity can be modulated by inputs from other brain areas to adapt respiration to autonomic and behavioral demands. The cerebellum is known to be part of the neuronal circuitry activated during respiratory challenges, such as hunger for air, but has not been found to be involved in the control of spontaneous, unobstructed breathing (eupnea). Here we applied a measure of intrinsic rhythmicity, the CV2, which evaluates the similarity of subsequent intervals and is thus sensitive to changes in rhythmicity at the temporal resolution of individual respiratory intervals. The variability of intrinsic respiratory rhythmicity was reduced in a mouse model of cerebellar ataxia compared to their healthy littermates. Irrespective of that difference, the average respiratory rate and the average coefficient of variation (CV) were comparable between healthy and ataxic mice. We argue that these findings are consistent with a proposed role of the cerebellum in modulating the duration of individual respiratory intervals, which could serve the purpose of coordinating respiration with other rhythmic orofacial movements, such as fluid licking and swallowing., Summary: The cerebellum was believed to have no role in controlling eupneic respiration. Our findings suggest a cerebellar involvement in the coordination of breathing with other orofacial movements, such as swallowing.

INTRODUCTION: Every year, more than 500,000 US Emergency Department visits are associated with cocaine use. People who use cocaine tend to have a lower incidence of true ST-elevation myocardial infarction (STEMI). OBJECTIVE: To identify the factors associated with true STEMI in patients with cocaine-positive (CPos) findings. METHODS: We retrospectively analyzed 1144 consecutive patients with STEMI between 2008 and 2013. True STEMI was defined as having a culprit lesion on coronary angiogram. Multivariate and univariate analyses were used to identify risk factors and create a predictive model. RESULTS: A total of 64 patients with suspected STEMI were CPos (mean age 53.1 ± 11.2 years; male = 80%). True STEMI was diagnosed in 34 patients. Patients with CPos true STEMI were more likely to be uninsured than those with false STEMI (61.8% vs 34.5%, p = 0.03) and have higher peak troponin levels (21.1 ng/mL vs 2.12 ng/mL, p = < 0.01) with no difference in mean age between the 2 groups (p = 0.24). In multivariate analyses, independent predictors of true STEMI in patients with CPos findings included age older than 65 years (odds ratio [OR] = 19.3, 95% confidence iterval [CI] = 1.2–318.3), lack of health insurance (OR = 4.9, 95% CI = 1.2–19.6), and troponin level higher than 0.05 (OR = 24.0, 95% CI = 2.6–216.8) (all p < 0.05). A multivariate risk score created with a C-statistic of 82% (95% CI = 71–93) significantly improved the identification of patients with true STEMI. CONCLUSION: Among those with suspected STEMI, patients with CPos findings had a higher incidence of false STEMI. Older age, lack of health insurance, and troponin levels outside of defined limits were associated with true STEMI in this group.

Trained cardiologists detect atrial fibrillation by visual interpretation of certain segments of electrocardiogram (EKG) lines known as the QRS complex. Similarly, available EKG-software also evaluates anomalies in the signals from the EKG-leads that produce the traces/lines in order to flag for atrial fibrillation. We and others have previously shown that machine learning methods successfully identify patients with paroxysmal atrial fibrillation (PAF) based on their EKG during normal sinus rhythm. In this work, we go beyond the earlier black-box approaches and identify specific patterns in the QRS complex of a normal sinus rhythm that are associated with atrial fibrillation. We implemented frequent pattern mining on discretized waveform raw EKG data to determine patterns that are specific to patients with PAF based on 1-minute Lead 1 EKG recordings sampled at 128 Hz from 25 patients with PAF and 50 healthy subjects from a Physionet data repository. We discretized the down-sampled (16 Hz) EKG traces with seven symbols corresponding to various degrees of local variability within the traces and selected from the existing unique 1,306 4-symbol patterns the 850 patterns occurring at least 5 times (to mitigate sparsity related problems). The resulting 75x850 pattern frequency matrix represented the frequency of each pattern within each of the 75 patients and PAF subjects were distinguished based on a binary Least Absolute Shrinkage and Selection Operator regression with 5-fold cross validation that selected 50 of the patterns (AUC = 0.95; 95% C.I. 0.88-1.00; 94% specificity, 88% sensitivity). These 50 patterns are candidates to elicit the “fingerprint” of PAF within normal sinus rhythm: e.g., one of the selected patterns in Figure 1 was observed in 76% of PAF patients while it was present only in 30% of healthy patients. Our study is a proof of concept that machine learning and artificial intelligence techniques are not restricted to black-box approaches and can be used to derive interpretable insights that could lead to novel biomarkers associated with certain health conditions.

Background and aims Constipation is one of the most frequent symptoms encountered in daily clinical practice and is implicated in the development of atherosclerosis, potentially through altered gut microbiota. However, little is known about its association with incident cardiovascular events. Methods In a nationally representative cohort of 3,359,653 US veterans with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 between October 1, 2004 and September 30, 2006 (baseline period), with follow-up through 2013, we examined the association of constipation status (absence or presence; defined using diagnostic codes and laxative use) and laxative use (none, one, or ≥2 types of laxatives) with all-cause mortality, incident coronary heart disease (CHD), and incident ischemic stroke. Results Among 3,359,653 patients, 237,855 (7.1%) were identified as having constipation. After multivariable adjustments for demographics, prevalent comorbidities, medications, and socioeconomic status, patients with (versus without) constipation had 12% higher all-cause mortality (hazard ratio [HR], 1.12; 95% CI, 1.11–1.13), 11% higher incidence of CHD (HR, 1.11; 95% CI, 1.08–1.14), and 19% higher incidence of ischemic stroke (HR, 1.19; 95% CI, 1.15–1.22). Patients with one and ≥2 (versus none) types of laxatives experienced a similarly higher risk of all-cause mortality (HRs [95% CI], 1.15 [1.13–1.16] and 1.14 [1.12–1.15], respectively), incident CHD (HRs [95% CI], 1.11 [1.07–1.15] and 1.10 [1.05–1.15], respectively) and incident ischemic stroke (HRs [95% CI], 1.19 [1.14–1.23] and 1.21 [1.16–1.26], respectively). Conclusions Constipation status and laxative use are independently associated with higher risk of all-cause mortality and incident CHD and ischemic stroke.

Constipation is one of the most prevalent conditions in primary care settings and increases the risk of cardiovascular disease, potentially through processes mediated by altered gut microbiota. However, little is known about the association of constipation with CKD. In a nationwide cohort of 3,504,732 United States veterans with an eGFR ≥60 ml/min per 1.73 m2, we examined the association of constipation status and severity (absent, mild, or moderate/severe), defined using diagnostic codes and laxative use, with incident CKD, incident ESRD, and change in eGFR in Cox models (for time-to-event analyses) and multinomial logistic regression models (for change in eGFR). Among patients, the mean (SD) age was 60.0 (14.1) years old; 93.2% of patients were men, and 24.7% were diabetic. After multivariable adjustments, compared with patients without constipation, patients with constipation had higher incidence rates of CKD (hazard ratio, 1.13; 95% confidence interval [95% CI], 1.11 to 1.14) and ESRD (hazard ratio, 1.09; 95% CI, 1.01 to 1.18) and faster eGFR decline (multinomial odds ratios for eGFR slope

Multiple recruitment strategies are often needed to recruit an adequate number of participants, especially hard to reach groups. Technology-based recruitment methods hold promise as a more robust form of reaching and enrolling historically hard to reach young adults. The TARGIT study is a randomized two-arm clinical trial in young adults using interactive technology testing an efficacious proactive telephone Quitline versus the Quitline plus a behavioral weight management intervention focusing on smoking cessation and weight change. All randomized participants in the TARGIT study were required to be a young adult smoker (18–35 years), who reported smoking at least 10 cigarettes per day, had a BMI

Background: To determine the association of vancomycin with acute kidney injury (AKI) in relation to its serum concentration value and to examine the risk of AKI in patients treated with vancomycin when compared with a matched cohort of patients receiving non-glycopeptide antibiotics (linezolid/daptomycin). Methods: From a cohort of > 3 million US veterans with baseline estimated glomerular filtration rate ≥60 mL/min/1.73 m2, we identified 33,527 patients who received either intravenous vancomycin (n = 22,057) or non-glycopeptide antibiotics (linezolid/daptomycin, n = 11,470). We examined the association of the serum trough vancomycin level recorded within the first 48 h of administration with subsequent AKI in all patients treated with vancomycin and association of vancomycin vs. non-glycopeptide antibiotics use with the risk of incident AKI. Results: The overall multivariable adjusted ORs of AKI stages 1, 2, and 3 in patients on vancomycin vs. non-glycopeptides were 1.1 (1.1–1.2), 1.2 (1–1.4), and 1.4 (1.1–1.7), respectively. When examined in strata divided by vancomycin trough level, the odds of AKI were similar or lower in patients receiving vancomycin compared to non-glycopeptide antibiotics as long as serum vancomycin levels were ≤20 mg/L. However, in patients with serum vancomycin levels > 20 mg/L, the ORs of AKI stages 1, 2, and 3 in patients on vancomycin vs. non-glycopeptide antibiotics were 1.5 (1.4–1.7), 1.9 (1.5–2.3), and 2.7 (2–3.5), respectively. Conclusions: Vancomycin use is associated with a higher risk of AKI when serum levels exceed > 20 mg/L.

A history of posttraumatic stress disorder (PTSD), if uncontrolled, represents a contraindication for kidney transplantation. However, no previous large study has assessed the association between pretransplant history of PTSD and posttransplantation outcomes. We examined 4479 US veterans who had undergone transplantation. The diagnosis of history of PTSD was based on a validated algorithm. Measured covariates were used to create a matched cohort (n = 560). Associations between pretransplant PTSD and death with functioning graft, all-cause death, and graft loss were examined in survival models. Posttransplant medication nonadherence was assessed using proportion of days covered (PDC). From among 4479 veterans, 282 (6.3%) had a history of PTSD. The mean age ± standard deviation (SD) of the cohort at baseline was 61 ± 11 years, 91% were male, and 66% and 28% of patients were white and African American, respectively. Compared to patients without a history of PTSD, patients with a history of PTSD had a similar risk of death with a functioning graft (subhazard ratio [SHR] 0.97, 95% confidence interval [CI] 0.61-1.54), all-cause death (1.05, 0.69-1.58), and graft loss (1.09, 0.53-2.26). Moreover, there was no difference in immunosuppressive drug PDC in patients with and without a history of PTSD (PDC: 98 ± 4% vs 99 ± 3%, P = .733 for tacrolimus; PDC: 99 ± 4% vs 98 ± 7%, P = .369 for mycophenolic acid). A history of PTSD in US veterans with end-stage renal disease should not on its own preclude a veteran from being considered for transplantation.

PURPOSE: Although ~25% of colorectal cancer or polyps (CRC/P) cases show familial aggregation, current germline genetic testing identifies a causal genotype in the 16 major genes associated with high penetrance CRC/P in only 20% of these cases. As there are likely other genes underlying heritable CRC/P, we evaluated the association of variation at novel loci with CRC/P. METHODS: We evaluated 158 a priori selected candidate genes by comparing the number of rare potentially disruptive variants (PDVs) found in 84 CRC/P cases without an identified CRC/P risk associated variant and 2440 controls. We repeated this analysis using an additional 73 CRC/P cases. We also compared the frequency of PDVs in select genes among CRC/P cases with two publicly available data sets. RESULTS: We found a significant enrichment of PDVs in cases versus controls: 20% of cases vs. 11.5% of controls with ≥ 1 PDV (OR=1.9, p=0.01) in the original set of cases. Among the second cohort of CRC/P cases, 18% had a PDV, significantly different from 11.5% (p=0.02). Logistic regression, adjusting for ancestry and multiple testing, indicated association between CRC/P and PDVs in NTHL1 (p=0.0001), BRCA2 (p=0.01) and BRIP1 (p=0.04). However, there was no significant difference in the frequency of PDVs at each of these genes between all 157 CRC/P cases and two publicly available data sets. CONCLUSION: These results suggest an increased presence of PDVs in CRC/P cases and support further investigation of the association of NTHL1, BRCA2 and BRIP1 variation with CRC/P.

Rheumatoid arthritis is associated with reduced kidney function, possibly due to chronic inflammation or the use of nephrotoxic therapies. However, little is known about the effects of using the newer novel non-nephrotoxic biologic agents on the risk of incident chronic kidney disease (CKD). To study this we used a cohort of 20,757 United States veterans diagnosed with rheumatoid arthritiswith an estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73m(2) or more, recruited between October 2004 and September 2006, and followed through 2013. The associations of biologic use with incident CKD (eGFR under 60 with a decrease of at least 25% from baseline, and eGFR under 45 mL/min/1.73m(2)) and change in eGFR (

Objective To better define the prevalence of protein-energy wasting (PEW) in kidney disease is poorly defined. Methods We performed a meta-analysis of PEW prevalence from contemporary studies including more than 50 subjects with kidney disease, published during 2000-2014 and reporting on PEW prevalence by subjective global assessment or malnutrition-inflammation score. Data were reviewed throughout different strata: (1) acute kidney injury (AKI), (2) pediatric chronic kidney disease (CKD), (3) nondialyzed CKD 3-5, (4) maintenance dialysis, and (5) subjects undergoing kidney transplantation (Tx). Sample size, period of publication, reporting quality, methods, dialysis technique, country, geographical region, and gross national income were a priori considered factors influencing between-study variability. Results Two studies including 189 AKI patients reported a PEW prevalence of 60% and 82%. Five studies including 1776 patients with CKD stages 3-5 reported PEW prevalence ranging from 11% to 54%. Finally, 90 studies from 34 countries including 16,434 patients on maintenance dialysis were identified. The 25th-75th percentiles range in PEW prevalence among dialysis studies was 28-54%. Large variation in PEW prevalence across studies remained even when accounting for moderators. Mixed-effects meta-regression identified geographical region as the only significant moderator explaining 23% of the observed data heterogeneity. Finally, two studies including 1067 Tx patients reported a PEW prevalence of 28% and 52%, and no studies recruiting pediatric CKD patients were identified. Conclusion By providing evidence-based ranges of PEW prevalence, we conclude that PEW is a common phenomenon across the spectrum of AKI and CKD. This, together with the well-documented impact of PEW on patient outcomes, justifies the need for increased medical attention.

OBJECTIVE Menopause is a risk factor for fracture; thus, menopause age may affect bone mass and fracture rates. We compared bone mineral density (BMD) and fracture rates among healthy postmenopausal women with varying ages at self-reported nonsurgical menopause. METHODS We compared hazard ratios for fractures and differences in BMD among 21,711 postmenopausal women from the Women's Health Initiative Observational Study cohort who had no prior hysterectomy, oophorectomy, or hormone therapy and had varying self-reported ages at menopause (

A higher proportion of military personnel than civilians smoke cigarettes. Few randomized trials of tobacco use interventions have been conducted in the U.S. military. We evaluated the efficacy of a tobacco quitline (QL) in 1298 active duty military personnel, their dependents, reservists, and retirees who smoke cigarettes. Participants were randomized to either a proactive (counselor-initiated) or reactive (participant-initiated) QL intervention for 8 weeks. The proactive condition included up to an 8-week supply of free nicotine replacement therapy, and the reactive condition included a 2-week supply. The primary outcome was 12-month smoking abstinence. The enrolled population was predominantly affiliated with the Air Force and Army. At the end of treatment, proactive treatment was associated with a greater odds of both prolonged (44.22% vs. 24.96%; odds ratio [OR] = 2.4, P < 0.0001) and 7-day point prevalence (49.92% vs. 28.20%; OR = 2.5, P < 0.0001) smoking abstinence, a difference that was maintained for prolonged smoking abstinence at 12 months (22.03% vs. 13.41%; OR = 1.8, P < 0.0001). Our findings provide evidence that a proactive QL with nicotine replacement therapy is highly efficacious among Air Force and Army active duty and TRICARE beneficiaries and would provide an effective telephonic treatment option for this population of smokers.

Kidney and bladder stones (urinary tract stones) and osteoporosis are prevalent, serious conditions for postmenopausal women. Men with kidney stones are at increased risk of osteoporosis; however, the relationship of urinary tract stones to osteoporosis in postmenopausal women has not been established. The purpose of this study was to determine whether urinary tract stones are an independent risk factor for changes in bone mineral density (BMD) and incident fractures in women in the Women's Health Initiative (WHI). Data were obtained from 150,689 women in the Observational Study and Clinical Trials of the WHI with information on urinary tract stones status: 9856 of these women reported urinary tract stones at baseline and/or incident urinary tract stones during follow-up. Cox regression models were used to determine the association of urinary tract stones with incident fractures and linear mixed models were used to investigate the relationship of urinary tract stones with changes in BMD that occurred during WHI. Follow-up was over an average of 8 years. Models were adjusted for demographic and clinical factors, medication use, and dietary histories. In unadjusted models there was a significant association of urinary tract stones with incident total fractures (HR 1.10; 95% CI, 1.04 to 1.17). However, in covariate adjusted analyses, urinary tract stones were not significantly related to changes in BMD at any skeletal site or to incident fractures. In conclusion, urinary tract stones in postmenopausal women are not an independent risk factor for osteoporosis.

Summary Pharmacological mitigation of injuries caused by high-dose ionizing radiation is an unsolved medical problem. A specific nonlipid agonist of the type 2 G protein coupled receptor for lysophosphatidic acid (LPA 2 ) 2-[4-(1,3-dioxo-1 H ,3 H -benzoisoquinolin-2-yl)butylsulfamoyl]benzoic acid (DBIBB) when administered with a postirradiation delay of up to 72 hr reduced mortality of C57BL/6 mice but not LPA 2 knockout mice. DBIBB mitigated the gastrointestinal radiation syndrome, increased intestinal crypt survival and enterocyte proliferation, and reduced apoptosis. DBIBB enhanced DNA repair by augmenting the resolution of γ-H2AX foci, increased clonogenic survival of irradiated IEC-6 cells, attenuated the radiation-induced death of human CD34 + hematopoietic progenitors and enhanced the survival of the granulocyte/macrophage lineage. DBIBB also increased the survival of mice suffering from the hematopoietic acute radiation syndrome after total-body irradiation. DBIBB represents a drug candidate capable of mitigating acute radiation syndrome caused by high-dose γ-radiation to the hematopoietic and gastrointestinal system.

The purpose of this study was to characterize the potential of vitamins to protect the retinal pig-ment epithelium (RPE) from oxidative stress (OS). We have previously shown that OS induces the expression of AP1 transcription factors (FOSB, CFOS and ATF3), but is modulated by pretreatment with vitamin C (200 μM). We propose that OS-induced AP1 expression can be used as a biomarker of OS to test the efficacy of vitamins to limit the impact of OS in the RPE. Here we examined the efficacy of vitamin E or combined vitamin A plus vitamin C to modulate OS-induced AP1 expression in the RPE. We pretreated human ARPE-19 cells with vitamin E (0 - 7.5 μM) or with combined vitamin A (10 or 15 μM) plus vitamin C (50 or 100 μM) for 3 days prior to exposure to 500 μM H2O2 OS for 1 - 4 h. AP1 expression was assessed using qRT-PCR. Pretreatment with ≥2.5 μM vitamin E significantly decreased OS-induced AP1 expression at 1 - 4 h OS, compared to controls. Lower doses of vitamin E were ineffective at modulating OS responses. Pretreatment with 100 μM vitamin C combined with 15 μM vitamin A protected RPE cells from OS-induced AP1 expression. There is an additive and potentially protective effect of 100 μM vitamin C and 15 μM vitamin A on FOSB expression at 4 h, and a potentially protective effect of 100 μM vitamin C and 15 μM vitamin A on CFOS expression at 1 h OS. A protective effect was also seen with 15 μM vitamin A pretreatment alone on ATF3 expression. Thus, “sub-therapeutic” levels of multiple vitamins may protect RPE cells better than higher doses of a single vitamin. This OS-induced AP1 expression biomarker assay may be useful to identify complex antioxidant formulations as therapeutics for degenerative diseases that are thought to be caused by OS, like age-related macular degeneration.

Studies of the associations of sodium and potassium intakes with cardiovascular disease incidence often rely on self-reported dietary data. In the present study, self-reported intakes from postmenopausal women at 40 participating US clinical centers are calibrated using 24-hour urinary excretion measures in cohorts from the Women's Health Initiative, with follow-up from 1993 to 2010. The incidence of hypertension was positively related to (calibrated) sodium intake and to the ratio of sodium to potassium. The sodium-to-potassium ratio was associated with cardiovascular disease incidence during an average follow-up period of 12 years. The estimated hazard ratio for a 20% increase in the sodium-to-potassium ratio was 1.13 (95% confidence interval (CI): 1.04, 1.22) for coronary heart disease, 1.20 (95% CI: 1.01, 1.42) for heart failure, and 1.11 (95% CI: 1.04, 1.19) for a composite cardiovascular disease outcome. The association with total stroke was not significant, but it was positive for ischemic stroke and inverse for hemorrhagic stroke. Aside from hemorrhagic stroke, corresponding associations of cardiovascular disease with sodium and potassium jointly were positive for sodium and inverse for potassium, although some were not statistically significant. Specifically, for coronary heart disease, the hazard ratios for 20% increases were 1.11 (95% CI: 0.95, 1.30) for sodium and 0.85 (95% CI: 0.73, 0.99) for potassium; and corresponding values for heart failure were 1.36 (95% CI: 1.02, 1.82) for sodium and 0.90 (95% CI: 0.69, 1.18) for potassium.

Introduction: Abnormal phosphorus homeostasis develops early in chronic kidney disease (CKD). It is unclear if its correction results in improved clinical outcomes in non–dialysis dependent CKD. Methods: We conducted a randomized controlled, parallel design clinical trial in 120 patients with estimated glomerular filtration rate 15 to 59 ml/min per 1.73 m2 and abnormal phosphorus homeostasis (serum phosphorus >4.6 mg/dl, parathyroid hormone [PTH] >70 pg/ml or tubular reabsorption of phosphorus [TRP]

Purpose Earlier Women’s Health Initiative Dietary Modification trial findings suggested that a low-fat eating pattern may reduce breast cancers with greater mortality. Therefore, as a primary outcome-related analysis from a randomized prevention trial, we examined the long-term influence of this intervention on deaths as a result of and after breast cancer during 8.5 years (median) of dietary intervention and cumulatively for all breast cancers diagnosed during 16.1 years (median) of follow-up. Patients and Methods The trial randomly assigned 48,835 postmenopausal women with normal mammograms and without prior breast cancer from 1993 to 1998 at 40 US clinical centers to a dietary intervention with goals of a reduction of fat intake to 20% of energy and an increased intake of fruits, vegetables, and grains (40%; n = 19,541) or to a usual diet comparison (60%; n = 29,294). Results In the dietary group, fat intake and body weight decreased (all P < .001). During the 8.5-year dietary intervention, with 1,764 incident breast cancers, fewer deaths occurred as a result of breast cancer in the dietary group, which was not statistically significant (27 deaths [0.016% per year] v 61 deaths [0.024% per year]; hazard ratio [HR], 0.67; 95% CI, 0.43 to 1.06; P = .08). During the same period, deaths after breast cancer (n = 134) were significantly reduced (40 deaths [0.025% per year] v 94 deaths [0.038% per year]; HR, 0.65; 95% CI, 0.45 to 0.94; P = .02) by the dietary intervention. During the 16.1-year follow-up, with 3,030 incident breast cancers, deaths after breast cancer also were significantly reduced (234 deaths [0.085% per year] v 443 deaths [0.11% per year]; HR, 0.82; 95% CI, 0.70 to 0.96; P = .01) in the dietary group. Conclusion Compared with a usual diet comparison group, a low-fat dietary pattern led to a lower incidence of deaths after breast cancer.

Author(s): Sumida, Keiichi; Diskin, Charles Dyer; Molnar, Miklos Z; Potukuchi, Praveen K; Thomas, Fridtjof; Lu, Jun Ling; Rhee, Connie M; Streja, Elani; Yamagata, Kunihiro; Kalantar-Zadeh, Kamyar; Kovesdy, Csaba P | Abstract: BackgroundHemoglobin variability (Hb-var) has been associated with increased mortality both in non-dialysis dependent chronic kidney disease (NDD-CKD) and end-stage renal disease (ESRD) patients. However, the impact of Hb-var in advanced NDD-CKD on outcomes after dialysis initiation remains unknown.MethodsAmong 11,872 US veterans with advanced NDD-CKD transitioning to dialysis between October 2007 through September 2011, we assessed Hb-var calculated from the residual SD of at least 3 Hb values during the last 6 months before dialysis initiation (prelude period) using within-subject linear regression models, and stratified into quartiles. Outcomes included post-transition all-cause, cardiovascular, and infection-related mortality, assessed in Cox proportional hazards models and adjusted for demographics, comorbidities, length of hospitalization, medications, estimated glomerular filtration rate (eGFR), type of vascular access, Hb parameters (baseline Hb [i.e., intercept] and change in Hb [i.e., slope]), and number of Hb measurements.ResultsHigher prelude Hb-var was associated with use of iron and antiplatelet agents, tunneled dialysis catheter use, higher levels of baseline Hb, change in Hb, eGFR, and serum ferritin. After multivariable adjustment, higher prelude Hb-var was associated with higher post-ESRD all-cause and infection-related mortality, but not cardiovascular mortality (adjusted hazard ratios [95% CI] for the highest [vs. lowest] quartile of Hb-var, 1.10 [1.02-1.19], 1.28 [0.93-1.75], and 0.93 [0.79-1.10], respectively).ConclusionsHigh pre-ESRD Hb-var is associated with higher mortality, particularly from infectious causes rather than cardiovascular causes. Further research is required to clarify the underlying mechanisms and true causal nature of the observed association.

Background Heart failure (HF) is associated with poor cardiac outcomes and mortality. It is not known whether HF leads to poor renal outcomes in patients with normal kidney function. We hypothesized that HF is associated with worse long-term renal outcomes. Methods and Results Among 3 570 865 US veterans with estimated glomerular filtration rate (eGFR) ≥60 mL min −1 1.73 m −2 during October 1, 2004 to September 30, 2006, we identified 156 743 with an International Classification of Diseases , Ninth Revision , diagnosis of HF. We examined the association of HF with incident chronic kidney disease (CKD), the composite of incident CKD or mortality, and rapid rate of eGFR decline (slopes steeper than −5 mL min −1 1.73 m −2 y −1 ) using Cox proportional hazard analyses and logistic regression. Adjustments were made for various confounders. The mean±standard deviation baseline age and eGFR of HF patients were 68±11 years and 78±14 mL min −1 1.73 m −2 and in patients without HF were 59±14 years and 84±16 mL min −1 1.73 m −2 , respectively. HF patients had higher prevalence of hypertension, diabetes mellitus, cardiac, peripheral vascular and chronic lung diseases, stroke, and dementia. Incidence of CKD was 69.0/1000 patient-years in HF patients versus 14.5/1000 patient-years in patients without HF, and 22% of patients with HF had rapid decline in eGFR compared with 8.5% in patients without HF. HF patients had a 2.12-, 2.06-, and 2.13-fold higher multivariable-adjusted risk of incident CKD, composite of CKD or mortality, and rapid eGFR decline, respectively. Conclusions HF is associated with significantly higher risk of incident CKD, incident CKD or mortality, and rapid eGFR decline. Early diagnosis and management of HF could help reduce the risk of long-term renal complications.

Background and objectives Depression in patients with nondialysis-dependent CKD is often undiagnosed, empirically overlooked, and associated with higher risk of death, progression to ESRD, and hospitalization. However, there is a paucity of evidence on the association between the presence of depression in patients with advanced nondialysis-dependent CKD and post-ESRD mortality, particularly among those in the transition period from late-stage nondialysis-dependent CKD to maintenance dialysis. Design, setting, participants, & measurements From a nation-wide cohort of 45,076 United States veterans who transitioned to ESRD over 4 contemporary years (November of 2007 to September of 2011), we identified 10,454 (23%) patients with a depression diagnosis during the predialysis period. We examined the association of pre-ESRD depression with all-cause mortality after transition to dialysis using Cox proportional hazards models adjusted for sociodemographics, comorbidities, and medications. Results Patients were 72±11 years old (mean±SD) and included 95% men, 66% patients with diabetes, and 23% blacks. The crude mortality rate was similar in patients with depression (289/1000 patient-years; 95% confidence interval, 282 to 297) versus patients without depression (286/1000 patient-years; 95% confidence interval, 282 to 290). Compared with patients without depression, patients with depression had a 6% higher all-cause mortality risk in the adjusted model (hazard ratio, 1.06; 95% confidence interval, 1.03 to 1.09). Similar results were found across all selected subgroups as well as in sensitivity analyses using alternate definitions of depression. Conclusion Pre-ESRD depression has a weak association with post-ESRD mortality in veterans transitioning to dialysis.

Background In ST-elevation myocardial infarction (STEMI), acute kidney injury (AKI) may increase subsequent morbidity and mortality. Still, it remains difficult to predict AKI risk in these patients. We sought to 1) determine the frequency and clinical outcomes of AKI and, 2) develop, validate and compare a web-based tool for predicting AKI. Methods & findings In a racially diverse series of 1144 consecutive STEMI patients, Stage 1 or greater AKI occurred in 12.9% and was severe (Stage 2-3) in 2.9%. AKI was associated with increased mortality (5.7-fold, unadjusted) and hospital stay (2.5-fold). AKI was associated with systolic dysfunction, increased left ventricular end-diastolic pressures, hypotension and intra-aortic balloon counterpulsation. A computational algorithm (UT-AKI) was derived and internally validated. It showed higher sensitivity and improved overall prediction for AKI (area under the curve 0.76) vs. other published indices. Higher UT-AKI scores were associated with more severe AKI, longer hospital stay and greater hospital mortality. Conclusions In a large, racially diverse cohort of STEMI patients, Stage 1 or greater AKI was relatively common and was associated with significant morbidity and mortality. A web-accessible, internally validated tool was developed with improved overall value for predicting AKI. By identifying patients at increased risk, this tool may help physicians tailor post-procedural diagnostic and therapeutic strategies after STEMI to reduce AKI and its associated morbidity and mortality.

Background/Aims: All hemodialysis (HD) patients are generally recommended to create a fistula first; but to create a mature arteriovenous fistula (AVF) can be challenging in elderly individuals. It is unclear if elderly incident HD patients derive a survival benefit from an AVF over an arteriovenous graft (AVG) or a tunneled central venous catheter (TDC). Methods: We examined the association of vascular access type (AVF, AVG, and TDC with and without a maturing AVF/AVG at dialysis transition) at HD initiation with all-cause, cardiovascular (CV), and infection-related mortality in 46,786 US veterans using Cox models with adjustment for confounders. Effect modification by age was examined by examining associations in pre-specified age subgroups (Results: Patients numbering 8,940 (19%) started HD with an AVF, 1,090 (3%) with an AVG, 8,262 (18%) with a TDC and a maturing AVF/AVG and 28,494 (61%) with a TDC without a maturing AVF/AVG. A total of 13,303 all-cause, 4,392 CV, and 1,058 infection-related deaths were observed in the first year after HD transition. Compared to patients with AVF, those with AVG and TDC with and without maturing AVF/AVG had incrementally higher overall risk of all-cause mortality and CV mortality. Only TDC use was associated with higher infection-associated mortality. These associations were not modified by age. Conclusion: Although most of our patients consisted of male veterans and the results may not be generalized to the general population, the use of TDCs is associated with poor outcomes even in the most elderly incident HD patients.

To evaluate whether a behavioral weight management program combined with a smoking cessation program delivered via interactive technology could prevent postcessation weight gain.Three hundred and thirty young adult smokers, age 18 to 35 years, were randomized to a smoking cessation program alone (comparison group), which included behavioral counseling and nicotine replacement, or to a behavioral weight management program adapted from the Look AHEAD trial plus the same smoking cessation program (intervention group).The Treating Adult Smokers at Risk for Weight Gain with Interactive Technology study randomized 164 participants to the comparison group and 166 participants to the intervention group. On average, the participants gained 0.91 kg after 24 months in the trial (comparison group + 1.45 kg and intervention group + 0.32; P = 0.157). The only variable systematically affecting weight change over time was smoking abstinence, in which those who were abstinent, on average, gained 0.14 kg more per month compared with those who continued to smoke (P 0.001). In exploratory analyses, the intervention participants who were abstinent at 6 months had numerically smaller weight gains compared with abstinent participants in the comparison group, but these differences were not statistically significant.Providing an intensive weight gain prevention program combined with a smoking cessation program via interactive technology was not associated with greater long-term weight gain prevention.

Background: Mortality in the immediate post-hemodialysis transition period is extremely high. Many end-stage renal disease (ESRD) patients in the US start dialysis in an inpatient setting, but the characteristics of patients starting dialysis as inpatients, and the association of inpatient hemodialysis transition with mortality remain unclear. Methods: We examined 48,261 US veterans who transitioned to hemodialysis between October 2007 and September 2011. Associations of inpatient hemodialysis starting with all-cause mortality were examined in Cox proportional hazard models, with adjustments for demographics, comorbidities, vascular access type, pre-dialysis nephrology care and medication use, and last pre-ESRD estimated glomerular filtration rate and hemoglobin. Results: A total of 22,338 (46.3%) patients received the first hemodialysis treatment in an inpatient setting. Inpatient hemodialysis transition was associated with older age, presence of a tunneled catheter, higher comorbidity burden, and lack of pre-dialysis nephrology care. A total of 8,674 patients died (mortality rate 405/1,000 patient-years, 95% CI 397-413) during the first 6 months after transition to hemodialysis. The starting of inpatient vs. outpatient hemodialysis was associated with significantly higher crude all-cause mortality, but this association was attenuated after multivariable adjustments. Conclusions: Transition to hemodialysis in an inpatient setting is more common in older and sicker individuals, and in patients without pre-dialysis nephrology care and those who used a catheter for vascular access. Future studies are needed to determine if a higher proportion of patients could start hemodialysis treatment in outpatient clinics, through interventions targeting modifiable risk factors such as timely vascular access placement or earlier nephrology referrals.

Background: Multiple primary cancers account for approximately 16% of all incident cancers in the United States. Although genome-wide association studies (GWAS) have identified many common genetic variants associated with various cancer sites, no study has examined the association of these genetic variants with risk of multiple primary cancers (MPC). Methods: As part of the National Human Genome Research Institute (NHGRI) Population Architecture using Genomics and Epidemiology (PAGE) study, we used data from the Multiethnic Cohort (MEC) and Women's Health Initiative (WHI). Incident MPC (IMPC) cases (n = 1,385) were defined as participants diagnosed with more than one incident cancer after cohort entry. Participants diagnosed with only one incident cancer after cohort entry with follow-up equal to or longer than IMPC cases served as controls (single-index cancer controls; n = 9,626). Fixed-effects meta-analyses of unconditional logistic regression analyses were used to evaluate the associations between 188 cancer risk variants and IMPC risk. To account for multiple comparisons, we used the false-positive report probability (FPRP) to determine statistical significance. Results: A nicotine dependence–associated and lung cancer variant, CHRNA3 rs578776 [OR, 1.16; 95% confidence interval (CI), 1.05–1.26; P = 0.004], and two breast cancer variants, EMBP1 rs11249433 and TOX3 rs3803662 (OR, 1.16; 95% CI, 1.04–1.28; P = 0.005 and OR, 1.13; 95% CI, 1.03–1.23; P = 0.006), were significantly associated with risk of IMPC. The associations for rs578776 and rs11249433 remained (P < 0.05) after removing subjects who had lung or breast cancers, respectively (P ≤ 0.046). These associations did not show significant heterogeneity by smoking status (Pheterogeneity ≥ 0.53). Conclusions: Our study has identified rs578776 and rs11249433 as risk variants for IMPC. Impact: These findings may help to identify genetic regions associated with IMPC risk. Cancer Epidemiol Biomarkers Prev; 23(11); 2568–78. ©2014 AACR.

Clinically useful predictors of weight gain could be used to reduce the epidemic of post-kidney transplant obesity and resulting co-morbidities. The purpose of this study was to identify predictors of weight gain at 12 months following kidney transplant in a cohort of 96 recipients. Demographic, clinical, and environmental data were obtained at transplant and 12 months. Descriptive, correlational, and Bayesian network analysis were used to identify predictors. For the 52 (55.9%) recipients who gained weight, the average amount gained was 9.18 ± 6.59 kg. From the 15 baseline factors that met inclusion criteria, Bayesian network modeling identified four baseline predictors for weight gain: younger age, higher carbohydrate consumption, higher trunk fat percentage, and higher perception of mental health quality of life. Three are modifiable through either pre- or immediate post-transplant clinical intervention programs.

Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.

Multiple studies show that molecular genetic changes and epigenetic modifications affect the risk of cognitive disability or impairment. However, the role of epigenetic variation in cognitive development of neurotypical young children remains largely unknown. Using data from a prospective, community-based study of mother-infant pairs, we investigated the association of DNA methylation patterns in neonatal umbilical cord blood with cognitive and language development at 1 year of age. No CpG loci achieved genome-wide significance, although a small number of weakly suggestive associations with Bayley-III Receptive Communication scales were noted. While umbilical cord blood is a convenient resource for genetic analyses of birth outcomes, our results do not provide conclusive evidence that its use for DNA methylation profiling yields epigenetic markers that are directly related to postnatal neurocognitive outcomes at 1 year of age.

The unclear relationship of obesity to incident melanoma and nonmelanoma skin cancer (NMSC) risks was evaluated in the large, geographically diverse longitudinal, prospective Women's Health Initiative (WHI) observational study. Risks of melanoma and NMSC in normal weight women were compared with risks in overweight [body mass index (BMI) = 25–29.0 kg/m2] and obese (BMI ≥ 30 kg/m2) women, using Cox proportional hazards models for melanoma and logistic regression for NMSC. Over a mean 9.4 years of follow-up, there were 386 melanoma and 9,870 NSMC cases. Risk of melanoma did not differ across weight categories (P = 0.86), whereas in fully adjusted models, NMSC risk was lower in overweight [OR, 0.93; 95% confidence interval (CI), 0.89–0.99] and obese (OR, 0.85; 95% CI, 0.80–0.91) women (P < 0.001). Excess body weight was not associated with melanoma risk in postmenopausal women but was inversely associated with NMSC risk, possibly due to lower sun exposure in overweight and obese women. This supports previous work demonstrating the relationship between excess body weight and skin cancer risk. Cancer Epidemiol Biomarkers Prev; 22(12); 2412–5. ©2013 AACR.

Alcohol use in the U.S. military is prevalent and associated with alcohol-related incidents (ARIs), an official U.S. Air Force sanction. Military ARIs incur substantial personal and financial costs. We evaluated the impact of the Alcohol Misconduct Prevention Program (AMPP) consisting of a group-based brief alcohol intervention (BAI) conducted jointly with random alcohol breathalyzer testing on ARIs in the U.S. Air Force.A 1-hour, group-based, interactive BAI was conducted, and random alcohol breathalyzer testing was performed among 10,087 Air Force Technical Trainees at Lackland Air Force Base in San Antonio, Texas, in fiscal years 2010 and 2011.The AMPP was associated with a significant reduction in the odds of an ARI over the year of the intervention compared to the previous year (odds ratio 0.555; 95% confidence interval 0.380-0.811; p = 0.0023). Significant reductions in the number of ARIs were observed within all quarters except for the third. The average rate of ARIs per 1,000 trainees per quarter was 7.30 before implementation of the interventions and 4.06 after implementation.An AMPP consisting of an interactive BAI and random alcohol breathalyzer testing may decrease ARIs among military trainees.

Introduction: Statins (HMG CoA reductase inhibitors) are a class of cholesterol lowering drugs that affect many intracellular pathways and have implications for chemopreventive activity against cancer. Epidemiological data on statins and breast cancer risk are conflicting. We analyzed updated data from the Women's Health Initiative (WHI) to assess the relationship between statins and breast cancer risk. Methods: This analysis included 154,587 post-menopausal women ages 50–79 years at baseline, in which 7,430 incident cases of invasive breast cancer were identified over an average of 10.8 (SD 3.3) years of follow-up. All cases of breast cancer were confirmed by review of medical records and pathology reports. Participants were asked to bring all current medications to their baseline visits and information on statin use was recorded. Statins were classified as lipophilic (lovastatin, simvastatin, fluvastatin) or hydrophilic (pravastatin and atorvastatin). Self and interviewer-administered questionnaires were used to collect information on other breast cancer risk factors. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Analyses investigated the association of any statin use as well as, type of statin (lipophilic vs. hydrophilic), statin potency, and duration of use with breast cancer. To evaluate the effect of change in statin use over time, statin use was examined as a time-dependent exposure using updated information on statin use gathered during follow-up visits. Separate analyses were conducted by hormone receptor and HER2neu status, other tumor characteristics and use of postmenopausal hormone therapy. All statistical tests were two-sided. Results: Statins were used at baseline by 11,584 (7.5%) women in the cohort of whom 7,840 used lipophilic statins. The annualized rate of breast cancer was 0.42% among statin users and 0.42% among nonusers. The multivariable adjusted HR of breast cancer for statin users compared with non-users was 0.93 (95% C.I. 0.83–1.05), however for women using lipophilic statins the HR was 0.86 (95% CI, 0.74–1.00). Statin use for < 1 year was associated with a reduction in risk (HR 0.79, 95% C.I. 0.63–0.99) however there was no trend for overall duration of use. In the stratified analysis by tumor size, there was a marginal reduction in risk for tumors between 10 and 30 mm but not in smaller or larger tumors. There were no effect modifications by tumor stage, hormone receptor or HER2neu status, hormone therapy use, family history of breast cancer or body mass index. In the multivariable adjusted time-dependent model, the HR for simvastatin was 0.80 (95% CI, 0.64–0.99). Conclusion: Simvastatin was associated with a reduced risk of invasive breast cancer, and as a class, lipophilic statins were associated with a marginal benefit. This provides further evidence for possible class differences in statins with regard to chemo-preventive effects in breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-09.

Author(s): Sumida, Keiichi; Molnar, Miklos Z; Potukuchi, Praveen K; Thomas, Fridtjof; Lu, Jun Ling; Ravel, Vanessa A; Soohoo, Melissa; Rhee, Connie M; Streja, Elani; Yamagata, Kunihiro; Kalantar-Zadeh, Kamyar; Kovesdy, Csaba P | Abstract: BackgroundPrior studies have suggested that arteriovenous fistula (AVF) or graft (AVG) creation may be associated with slowing of estimated glomerular filtration rate (eGFR) decline. It is unclear if this is attributable to the physiological benefits of a mature access on systemic circulation versus confounding factors.MethodsWe examined a nationwide cohort of 3026 US veterans with advanced chronic kidney disease (CKD) transitioning to dialysis between 2007 and 2011 who had a pre-dialysis AVF/AVG and had at least three outpatient eGFR measurements both before and after AVF/AVG creation. Slopes of eGFR were estimated using mixed-effects models adjusted for fixed and time-dependent confounders, and compared separately for the pre- and post-AVF/AVG period overall and in patients stratified by AVF/AVG maturation. In all, 3514 patients without AVF/AVG who started dialysis with a catheter served as comparators, using an arbitrary 6-month index date before dialysis initiation to assess change in eGFR slopes.ResultsOf the 3026 patients with AVF/AVG (mean age 67 years, 98% male, 75% diabetic), 71% had a mature AVF/AVG at dialysis initiation. eGFR decline accelerated in the last 6 months prior to dialysis in patients with a catheter (median, from -6.0 to -16.3 mL/min/1.73 m2/year, P l 0.001), while a significant deceleration of eGFR decline was seen after vascular access creation in those with AVF/AVG (median, from -5.6 to -4.1 mL/min/1.73 m2/year, P l 0.001). Findings were independent of AVF/AVG maturation status and were robust in adjusted models.ConclusionsThe creation of pre-dialysis AVF/AVG appears to be associated with eGFR slope deceleration and, consequently, may delay the onset of dialysis initiation in advanced CKD patients.

Mitochondrial dysfunction is a prominent hallmark of Alzheimer's disease (AD). Mitochondrial DNA (mtDNA) damage may be a major cause of abnormal reactive oxidative species production in AD or increased neuronal susceptibility to oxidative injury during aging. The purpose of this study was to assess the influence of mtDNA sequence variation on clinically significant cognitive impairment and dementia risk in the population-based Health, Aging, and Body Composition (Health ABC) Study. We first investigated the role of common mtDNA haplogroups and individual variants on dementia risk and 8-year change on the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) among 1,631 participants of European genetic ancestry. Participants were free of dementia at baseline and incidence was determined in 273 cases from hospital and medication records over 10–12 follow-up years. Participants from haplogroup T had a statistically significant increased risk of developing dementia (OR = 1.86, 95% CI = 1.23, 2.82, p = 0.0008) and haplogroup J participants experienced a statistically significant 8-year decline in 3MS (β = −0.14, 95% CI = −0.27, −0.03, p = 0.0006), both compared with common haplogroup H. The m.15244A>G, p.G166G, CytB variant was associated with a significant decline in DSST score (β = −0.58, 95% CI −0.89, −0.28, p = 0.00019) and the m.14178T>C, p.I166V, ND6 variant was associated with a significant decline in 3MS score (β = −0.87, 95% CI −1.31, −3.86, p = 0.00012). Finally, we sequenced the complete ∼16.5 kb mtDNA from 135 Health ABC participants and identified several highly conserved and potentially functional nonsynonymous variants unique to 22 dementia cases and aggregate sequence variation across the hypervariable 2-3 regions that influences 3MS and DSST scores.

Thirty percent of all military personnel smoke cigarettes. Because of the negative health consequences and their impact on physical fitness, overall health, and military readiness, the Department of Defense has identified the reduction of tobacco use as a priority of US military forces. This study aims to evaluate the one-year efficacy of a proactive versus reactive smoking quit line in the US military with adjunctive nicotine replacement therapy (NRT) in both groups. This paper reports on the baseline variables of the first 1000 participants randomized, the design, and proposed analysis of the randomized two-arm clinical trial “Efficacy of a Tobacco Quit Line in the Military”. Participants are adult smokers who are Armed Forces Active Duty personnel, retirees, Reservist, National Guard and family member healthcare beneficiaries. All participants are randomized to either the Counselor Initiated (proactive) group, receiving 6 counseling sessions in addition to an 8-week supply of NRT, or the Self-Paced (reactive) group, in which they may call the quit line themselves to receive the same counseling sessions, in addition to a 2-week supply of NRT. The primary outcome measure of the study is self-reported smoking abstinence at 1-year follow-up. Results from this study will be the first to provide evidence for the efficacy of an intensive Counselor Initiated quit line with provided NRT in military personnel and could lead to dissemination throughout the US Air Force, the armed forces population as a whole and ultimately to civilian personnel that do not have ready access to preventive health services.

Background Case–control studies have reported that exogenous estrogen use is associated with increased risk of skin cancer. The effects of menopausal hormone therapy on incidence of nonmelanoma skin cancer and melanoma were evaluated in post hoc analyses of the Women’s Health Initiative randomized placebo-controlled hormone therapy trials of combined estrogen plus progestin (E + P) and estrogen only (E-alone). Methods Postmenopausal women aged 50–79 years were randomly assigned to conjugated equine estrogen (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo in the E + P trial if they had an intact uterus (N = 16 608) or to conjugated equine estrogen alone or placebo in the E-alone trial if they had a hysterectomy (N =10 739); the mean follow-up was 5.6 and 7.1 years, respectively. Incident nonmelanoma skin cancers (n = 980 [E + P trial]; n = 820 [E-alone trial]) and melanomas (n = 57 [E + P trial]; n =38 [E-alone trial]) were ascertained by self-report. Incident cases of cutaneous malignant melanoma were confirmed by physician review of medical records. Incidences of nonmelanoma skin cancer and melanoma were compared between the two randomization groups within each trial using hazard ratios (HRs), with corresponding 95% confidence intervals (CIs) and Wald statistic P values from Cox proportional hazards models. All statistical tests were two-sided. Results Rates of incident nonmelanoma skin cancer and melanoma were similar between the active hormone (combined analysis of E + P and E-alone) and placebo groups (nonmelanoma skin cancer: HR = 0.98, 95% CI = 0.89 to 1.07; melanoma: HR = 0.92, 95% CI = 0.61 to 1.37). Results were similar for the E + P and E-alone trials when analyzed individually. Conclusions Menopausal hormone therapy did not affect overall incidence of nonmelanoma skin cancer or melanoma. These findings do not support a role of menopausal estrogen, with or without progestin, in the development of skin cancer in postmenopausal women. J Natl Cancer Inst 2011;103:1469–1475

e21631Background: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults with an incidence of 6 cases per million in the US. We sought to describe the characteristics of ou...

Importance Previous studies have suggested an association between cataract surgery and decreased risk for all-cause mortality potentially through a mechanism of improved health status and functional independence, but the association between cataract surgery and cause-specific mortality has not been previously studied and is not well understood. Objective To examine the association between cataract surgery and total and cause-specific mortality in older women with cataract. Design, Setting, and Participants This prospective cohort study included nationwide data collected from the Women’s Health Initiative (WHI) clinical trial and observational study linked with the Medicare claims database. Participants in the present study were 65 years or older with a diagnosis of cataract in the linked Medicare claims database. The WHI data were collected from January 1, 1993, through December 31, 2015. Data were analyzed for the present study from July 1, 2014, through September 1, 2017. Exposures Cataract surgery as determined by Medicare claims codes. Main Outcomes and Measures The outcomes of interest included all-cause mortality and mortality attributed to vascular, cancer, accidental, neurologic, pulmonary, and infectious causes. Mortality rates were compared by cataract surgery status using the log-rank test and Cox regression models with time-varying covariate cataract surgery status adjusting for demographics, systemic and ocular comorbidities, smoking, alcohol use, body mass index, and physical activity. Results A total of 74 044 women with cataract in the WHI included 41 735 who underwent cataract surgery. Mean (SD) age was 70.5 (4.6) years; the most common ethnicity was white (64 430 [87.0%]), followed by black (5293 [7.1%]) and Hispanic (1723 [2.3%]). The mortality rate was 2.56 per 100 person-years in the cataract surgery group and 1.45 per 100 person-years in the cataract diagnosis group. In covariate-adjusted Cox models, cataract surgery was associated with higher all-cause mortality (adjusted hazards ratio [AHR], 1.07; 95% CI, 1.02-1.11) as well as higher mortality specific to vascular (AHR, 1.36; 95% CI, 1.26-1.46), cancer (AHR, 1.27; 95% CI, 1.18-1.38), accidental (AHR, 1.36; 95% CI, 1.05-1.76), pulmonary (AHR, 1.96; 95% CI, 1.62-2.37), and infectious (AHR, 1.37; 95% CI, 1.14-1.65) diseases. Neurologic death causes were not associated with cataract surgery (AHR, 0.98; 95% CI, 0.83-1.17) Conclusions and Relevance In older women with cataract in the WHI, cataract surgery was associated with higher risk for total and cause-specific mortality (except for neurologic causes). Further study of the interplay of cataract surgery, systemic disease, disease-related mortality, and the best timing of when to undergo cataract surgery would be informative for improved patient care.

We discuss Bayesian degradation models that were developed for flexible pavements based on accelerated pavement testing with the heavy vehicle simulator. The models are fitted to data from the Florida Department of Transportation, where rutting performance of three binder types was tested under three temperature settings. The analysis utilizes Bayesian linear mixed-effects models for longitudinal degradation data where the parameter estimates and their posterior marginal distributions are obtained via a Markov chain Monte Carlo (MCMC) technique. The linearity in this model is achieved by utilizing a covariate-dependent Box-Cox transformation of the response variable, where the transformation parameter is estimated as part of the modeling procedure. The paper illustrates the various forms of useful inference that can easily be obtained via the output from the MCMC chains and provides insights regarding the accelerated test experiment at hand. As expected, the results suggest that rut depth development is affected both by the binder type, as well as the test temperature. What is more, the conditional inference made possible by the Bayesian approach utilized here clearly demonstrates the dependence of the inference for the covariate effects on the value of the Box-Cox transformation parameter. Hence the transformation of the response variable is an important step in model building that has to be carefully considered.

ST-elevation myocardial infarction (STEMI) requires emergent diagnostic catheterization and therapeutic percutaneous coronary intervention. These therapies may cause acute kidney injury (AKI), a serious procedural complication that contributes to morbidity and mortality in STEMI patients. Identifying patients at risk for renal complications may save lives and reduce healthcare costs, but there is no validated tool for predicting AKI in STEMI patients. Methods: The UT-Methodist STEMI program is a racially diverse series of 1144 consecutive patients. We derived and validated the UT-AKI score to predict the risk of AKI in patients referred for STEMI (and not currently on dialysis). AKI was categorized by the modified AKI Network and RIFLE indices. The UT-AKI score was derived from logistic regression analysis performed on a randomly selected derivation dataset using variables with significant univariate relationships to AKI and markers of renal function. Receiver operator characteristic (ROC) curves for the UT-AKI were assessed in the derivation and validation datasets. Statistical significance was measured by appropriate parametric and non-parametric tests; a p Results: The incidence of AKI was similar in patients undergoing diagnostic catheterization with or without PCI (12% vs. 14%, p=0.34). ROC curve analysis of the validation data set showed that the UT-AKI score (AUC 0.76 (95% CI 0.70-0.82)) was significantly better at classifying patients at risk for AKI than the ACEF (AUC 0.65 (95% CI: 0.58-0.73)), AGEF (AUC 0.65 (95% CI: 0.58-0.72)), or Mehran (AUC 0.67 (95% CI: 0.59-0.75)). The classification accuracy for the UT-AKI index was comparable for milder and severe forms of AKI. Conclusions: In the largest analysis of STEMI patients to date, we found no significant difference in the risk of AKI from PCI vs. diagnostic catheterization. The validation study indicates that the UT-AKI index was significantly better than other scores at classifying which patients will develop AKI. Accurate prediction of AKI may help physicians to personalize therapies and develop novel strategies to reduce kidney injury in patients with STEMI.