Predialysis systolic BP variability and outcomes in hemodialysis patients.

BP variability (BPV) is an important predictor of outcomes in the general population, but its association with clinical outcomes in hemodialysis patients is not clear. We identified 11,291 patients starting dialysis in 2003-2008 and followed them through December 31, 2008 (median=22 months). Predialysis systolic BPV was assessed over monthly intervals. Outcomes included factors associated with BPV, mortality (all-cause and cardiovascular), and first cardiovascular event (cardiovascular death or hospitalization). Patients' mean age was 62 years, 55% of patients were men, and 58% of patients were white. Modifiable factors associated with higher BPV included obesity, higher calcium-phosphate product levels, and lower hemoglobin concentration; factors associated with lower BPV included greater fluid removal, achievement of prescribed dry weight during dialysis, higher hemoglobin concentration, and antihypertensive regimens without ß-blockers or renin-angiotensin system blocking agents. In total, 3200 deaths occurred, including 1592 cardiovascular deaths. After adjustment for demographics, comorbidities, and clinical factors, higher predialysis BPV was associated with increased risk of all-cause mortality (hazard ratio [HR], 1.18; 95% confidence interval [95% CI] per 1 SD increase in BPV, 1.13 to 1.22), cardiovascular mortality (HR, 1.18; 95% CI, 1.12 to 1.24), and first cardiovascular event (HR, 1.11; 95% CI, 1.07 to 1.15). Results were similar when BPV was categorized in tertiles and patients were stratified by baseline systolic BP. In summary, predialysis systolic BPV is an important, potentially modifiable risk factor for death and cardiovascular outcomes in incident hemodialysis patients. Studies of BP management in dialysis patients should focus on both absolute BP and BPV.

Patterns in blood pressure medication use in US incident dialysis patients over the first 6 months.

BACKGROUND: Several observational studies have evaluated the effect of a single exposure window with blood pressure (BP) medications on outcomes in incident dialysis patients, but whether BP medication prescription patterns remain stable or a single exposure window design is adequate to evaluate effect on outcomes is unclear. METHODS: We described patterns of BP medication prescription over 6 months after dialysis initiation in hemodialysis and peritoneal dialysis patients, stratified by cardiovascular comorbidity, diabetes, and other patient characteristics. The cohort included 13,072 adult patients (12,159 hemodialysis, 913 peritoneal dialysis) who initiated dialysis in Dialysis Clinic, Inc., facilities January 1, 2003-June 30, 2008, and remained on the original modality for at least 6 months. We evaluated monthly patterns in BP medication prescription over 6 months and at 12 and 24 months after initiation. RESULTS: Prescription patterns varied by dialysis modality over the first 6 months; substantial proportions of patients with prescriptions for beta-blockers, renin angiotensin system agents, and dihydropyridine calcium channel blockers in month 6 no longer had prescriptions for these medications by month 24. Prescription of specific medication classes varied by comorbidity, race/ethnicity, and age, but little by sex. The mean number of medications was 2.5 at month 6 in hemodialysis and peritoneal dialysis cohorts. CONCLUSIONS: This study evaluates BP medication patterns in both hemodialysis and peritoneal dialysis patients over the first 6 months of dialysis. Our findings highlight the challenges of assessing comparative effectiveness of a single BP medication class in dialysis patients. Longitudinal designs should be used to account for changes in BP medication management over time, and designs that incorporate common combinations should be considered.

Outcomes of Patients With Large Versus Small Bone Defects in Open Tibia Fractures Treated With an Intramedullary Nail: A Descriptive Analysis of a Multicenter Retrospective Study.

OBJECTIVES: To compare outcomes in patients with open tibia shaft fractures based on defect size. DESIGN: Retrospective review. SETTING: Eighteen trauma centers. POPULATION: The study included 132 patients with diaphyseal tibia bone defects >1 cm and ≥50% cortical loss treated with intramedullary nail. OUTCOMES: The primary outcome was number of secondary surgeries to promote healing (bone graft, revision fixation, or bone transport). Additional outcomes included occurrence of secondary surgeries (bone graft, infection, amputation, and flap failure) and proportion healed at one year. Results are compared by "radiographic apparent bone gap" of <2.5 or ≥2.5 cm. RESULTS: The estimated conditional probability of bone grafting within one year given graft-free at 90 days was 44% and 47% in the <2.5 cm and ≥2.5 cm groups, respectively. An estimated infection risk of 14% was observed in both groups [adjusted hazard ratio (HR) 0.98, 95% confidence interval (CI): 0.33-2.92], estimated amputation risk was 9% (<2.5 cm) and 4% (≥2.5 cm) (unadjusted HR 0.66, 95% CI: 0.13-3.29), and estimated flap failure risk (among those with flaps) was 10% and 13%, respectively (unadjusted HR 1.71, 95% CI: 0.24-12.25). There was no appreciable difference in the proportion healed at one year between defect sizes [adjusted HR: 1.07 (95% CI, 0.63-1.82)]. CONCLUSIONS: Larger size bone defects were not associated with higher number of secondary procedures to promote healing or a lower overall one-year healing rate. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Association of CASP8 D302H polymorphism with reduced risk of aggressive prostate carcinoma.

BACKGROUND: Because of the dramatically different clinical course of aggressive and indolent prostate carcinoma (PCa), markers that distinguish between these phenotypes are of critical importance. Apoptosis is an important protective mechanism for unrestrained cellular growth and metastasis. Therefore, dysfunction in this pathway is a key step in cancer progression. As such, genetic variants in apoptosis genes are potential markers of aggressive PCa. Recent work in breast carcinoma has implicated the histidine variant of CASP8 D302H (rs1045485) as a protective risk allele. METHODS: We tested the hypothesis that the H variant was protective for aggressive PCa in a pooled analysis of 796 aggressive cases and 2,060 controls. RESULTS: The H allele was associated with a reduced risk of aggressive PCa (OR(per allele) = 0.67, 95% CI: 0.54-0.83, P(trend) = 0.0003). The results were similar for European-Americans (OR(per allele) = 0.68; 95% CI: 0.54-0.86) and African-Americans (OR(per allele) = 0.61; 95% CI: 0.34-1.10). We further determined from the full series of 1,160 cases and 1,166 controls in the Prostate, Lung, Colorectal, Ovarian (PLCO) population that the protective effect of the H allele tended to be limited to high-grade and advanced PCa (all cases OR(per allele) = 0.94; 95% CI: 0.79-1.11; localized, low-grade disease OR(per allele) = 0.98; 95% CI: 0.79-1.23; and aggressive disease OR(per allele) = 0.73; 95% CI: 0.50-1.07). CONCLUSION: These results suggest that histidine variant of CASP8 D302H is a protective allele for aggressive PCa with potential utility for identification of patients at differential risk for this clinically significant phenotype.

Risk of urinary incontinence following prostatectomy: the role of physical activity and obesity.

PURPOSE: Urinary incontinence is one of the most commonly reported and distressing side effects of radical prostatectomy for prostate carcinoma. Several studies have suggested that symptoms may be worse in obese men but to our knowledge no research has addressed the joint effects of obesity and a sedentary lifestyle. We evaluated the association of obesity and lack of physical activity with urinary incontinence in a sample of men who had undergone radical prostatectomy. MATERIALS AND METHODS: Height and weight were abstracted from charts, and obesity was defined as body mass index 30 kg/m(2) or greater. Men completed a questionnaire before surgery that included self-report of vigorous physical activity. Men who reported 1 hour or more per week of vigorous activities were considered physically active. Men reported their incontinence to the surgeon at their urology visits. Information on incontinence was abstracted from charts at 6 and 58 weeks after surgery. RESULTS: At 6 weeks after surgery 59% (405) of men were incontinent, defined as any pad use. At 58 weeks after surgery 22% (165) of men were incontinent. At 58 weeks incontinence was more prevalent in men who were obese and physically inactive (59% incontinent). Physical activity may offset some of the negative consequences of being obese because the prevalence of incontinence at 58 weeks was similar in the obese and active (25% incontinent), and nonbese and inactive (24% incontinent) men. The best outcomes were in men who were nonobese and physically active (16% incontinent). Men who were not obese and were active were 26% less likely to be incontinent than men who were obese and inactive (RR 0.74, 95% CI 0.52-1.06). CONCLUSIONS: Pre-prostatectomy physical activity and obesity may be important factors in post-prostatectomy continence levels. Interventions aimed at increasing physical activity and decreasing weight in patients with prostate cancer may improve quality of life by offsetting the negative side effects of treatment.

Inter-Rater Reliability of the Modified Radiographic Union Score for Diaphyseal Tibial Fractures With Bone Defects.

OBJECTIVES: To evaluate inter-rater reliability of the modified Radiographic Union Score for Tibial (mRUST) fractures among patients with open, diaphyseal tibia fractures with a bone defect treated with intramedullary nails (IMNs), plates, or definitive external fixation (ex-fix). DESIGN: Retrospective cohort study. SETTING: Fifteen-level one civilian trauma centers; 2 military treatment facilities. PATIENTS/PARTICIPANTS: Patients ≥18 years old with open, diaphyseal tibia fractures with a bone defect ≥1 cm surgically treated between 2007 and 2012. INTERVENTION: Three of 6 orthopedic traumatologists reviewed and applied mRUST scoring criteria to radiographs from the last clinical visit within 13 months of injury. MAIN OUTCOME MEASUREMENTS: Inter-rater reliability was assessed using Krippendorff's alpha (KA) statistic; intraclass correlation coefficient (ICC) is presented for comparison with previous publications. RESULTS: Two hundred thirteen patients met inclusion criteria including 115 IMNs, 24 plates, 29 ex-fixes, and 45 cases that no longer had instrumentation at evaluation. All reviewers agreed on the pattern of scoreable cortices for 90.4% of IMNs, 88.9% of those without instrumentation, 44.8% of rings, and 20.8% of plates. Thirty-one (15%) cases, primarily plates and ex-fixes, did not contribute to KA and ICC estimates because <2 raters scored all cortices. The overall KA for the 85% that could be analyzed was 0.64 (ICC 0.71). For IMNs, plates, ex-fixes, and no instrumentation, KA (ICC) was 0.65 (0.75), 0.88 (0.90), 0.47 (0.62), and 0.48 (0.57), respectively. CONCLUSIONS: In tibia fractures with bone defects, the mRUST seems similarly reliable to previous work in patients treated with IMN but is less reliable in those with plates or ex-fixes, or after removal of instrumentation.

Outcomes After Severe Distal Tibia, Ankle, and/or Foot Trauma: Comparison of Limb Salvage Versus Transtibial Amputation (OUTLET).

Severe foot and ankle injuries are complex and challenging to treat, often requiring multiple operations to salvage the limb contributing to a prolonged healing period. There is some evidence to suggest that early amputation for some patients may result in better long-term outcomes than limb salvage. The challenge is to identify the regional injury burden for an individual that would suggest a better outcome with an amputation. The OUTLET study is a prospective, multicenter observational study comparing 18-month outcomes after limb salvage versus early amputation among patients aged 18-60 years with severe distal tibia, ankle, and foot injuries. This study aims to build upon the previous work of the Lower Extremity Assessment Project by identifying the injury and patient characteristics that help define a subgroup of salvage patients who will have better outcomes had they undergone a transtibial amputation.

Antihypertensive medications and risk of death and hospitalizations in US hemodialysis patients: Evidence from a cohort study to inform hypertension treatment practices.

Antihypertensive medications are commonly prescribed to hemodialysis patients but the optimal regimens to prevent morbidity and mortality are unknown. The goal of our study was to compare the association of routinely prescribed antihypertensive regimens with outcomes in US hemodialysis patients.We used 2 datasets for our analysis. Our primary cohort (US Renal Data System [USRDS]) included adult patients initiating in-center hemodialysis from July 1, 2006 to June 30, 2008 (n = 33,005) with follow-up through December 31, 2009. Our secondary cohort included adult patients from Dialysis Clinic, Inc. (DCI), a national not-for-profit dialysis provider, initiating in-center hemodialysis from January 1, 2003 to June 30, 2008 (n = 11,291) with follow-up through December 31, 2008. We linked the USRDS cohort with Medicare part D prescriptions-fill data and the DCI cohort with USRDS data. Unique aspect of USRDS cohort was pharmacy prescription-fill data and for DCI cohort was detailed clinical data, including blood pressure, weight, and ultrafiltration. We classified prescribed antihypertensives into the following mutually exclusive regimens: ß-blockers, renin-angiotensin system blocking drugs-containing regimens without a ß-blocker (RAS), ß-blocker + RAS, and others. We used marginal structural models accounting for time-updated comorbidities to quantify each regimen's association with mortality (both cohorts) and cardiovascular hospitalization (DCI-Medicare Subcohort).In the USRDS and DCI cohorts there were 9655 (29%) and 3200 (28%) deaths, respectively. In both cohorts, RAS compared to ß-blockers regimens were associated with lower risk of death; (hazard ratio [HR]) (95% confidence interval [CI]) for all-cause mortality, (0.90 [0.82-0.97] in USRDS and 0.87 [0.76-0.98] in DCI) and cardiovascular mortality (0.84 [0.75-0.95] in USRDS and 0.88 [0.71-1.07] in DCI). There was no association between antihypertensive regimens and the risk of cardiovascular hospitalizations.In hemodialysis patients undergoing routine care, renin-angiotensin system blocking drugs-containing regimens were associated with a lower risk of death compared with ß-blockers-containing regimens but there was no association with cardiovascular hospitalizations. Pragmatic clinical trials are needed to specifically examine the effectiveness of these commonly used antihypertensive regimens in dialysis patients.

Comparison of 2004 and 1973 World Health Organization grading systems and their relationship to pathologic staging for predicting long-term prognosis in patients with urothelial carcinoma.

OBJECTIVES: To compare the 1973 and 2004 World Health Organization (WHO) systems for the interval to tumor recurrence (TR), tumor progression (TP), and overall survival (OS) using either the superficial/muscle invasive or strict TMN pathologic staging in patients with urothelial carcinoma with ≥10 years of follow-up. METHODS: A total of 269 tumors from an institutional review board-approved bladder tumor registry were graded using the 1973 and 2004 WHO systems. Kaplan-Meier plots, the log-rank test, the chi-square test, and the Cox proportional hazard model were used to relate the clinical and histologic variables. RESULTS: The Cox model analyses, which were multivariate and included tumor stage (coded as pT1 or less versus pT2 or greater) as a significant covariate to grade, were performed and in all tumor stages were significant. The 2004 WHO grading system was more closely associated with TR (P = .025) and TP (P = .012) than was the 1973 WHO grading system (P = .47, and P = .046, respectively). OS was similar and significant for both. The OS plots for the 1973 WHO system showed a significant overlap between Stage pT1 or less, grade 2 and 3 tumors. For those with high-grade Stage pTa and high-grade Stage pT1 disease, TR and TP were similar; however, OS was significantly longer (P = .05, log-rank test) for those with Stage pTa. The OS was similar for those with high-grade Stage pT1 disease and those with Stage pT2 or greater (P = .069, log-rank test). For those with pTa, the 2004 system predicted TR and TP, but the 1973 system only predicted TP. Neither predicted OS. CONCLUSIONS: The results of our analysis have shown that the 2004 WHO system is superior to the 1973 system for predicting clinical outcomes in patients with urothelial carcinoma, independent of pathologic stage. Its primary usefulness is in those with Stage pTa.

Association between polymorphisms in cell cycle genes and advanced prostate carcinoma.

BACKGROUND: Single nucleotide polymorphisms (SNPs) have been associated with a variety of malignancies including prostate carcinoma (PCa). Since a high percentage of PCa patients have low risk disease, of particular interest is not whether SNPs are associated with localized PCa, but whether they are associated with aggressive, potentially lethal disease. Herein, we explored the role of SNPs in cell cycle genes to determine if they were associated with advanced PCa. METHODS: Nine previously implicated SNPs in six cell cycle genes were evaluated in a European-American cohort of 186 patients with advanced PCa and 222 cancer-free controls. All patients received hormone ablation and had either a PSA>50 ng/ml or documented metastatic disease. Controls were all 75 years of age or older, had a negative DRE and had a PSA<4.0 ng/ml. All genotypes were determined using Pyrosequencing assays. RESULTS: One of nine (CDKN1A c10791t) was statistically different (P<0.05) and an additional two of nine (CCND1 a870g and MDM2 tSNP309g) approached significance (P<0.1). Analysis of genotypes revealed that presence of at least one copy of the t allele of MDM2 tSNP309g was associated with an increased risk of advanced PCa (OR 2.26: 95% CI=1.15-4.46) which was particularly strong in androgen-independent disease (OR 2.28: 95% CI=1.01-5.12) and younger age of diagnosis (OR 2.61: 95% CI=1.05-6.46). CONCLUSION: These results suggest that in a European-American population, SNPs within cell cycle genes are promising markers for aggressive PCa. Larger studies will be needed to confirm these findings.

Prostate-specific antigen density predicts adverse pathology and increased risk of biochemical failure.

OBJECTIVES: To determine whether the prostate-specific antigen (PSA) density (PSAD), measured using either ultrasound (US) or prostatic weight (PW), is an independent predictor of adverse pathologic findings or biochemical-free survival and whether it outperformed PSA. METHODS: The data were obtained prospectively from 1327 patients undergoing radical prostatectomy from 1990 to 2003. The US PSAD was calculated by dividing the preoperative PSA level in nanograms per milliliter by the US measured prostate volume in cubic centimeters. The PW PSAD was calculated by dividing the PSA value in nanograms per milliliter by the measured PW of the prostatectomy specimen in grams. Logistic regression analysis was performed to determine whether the US or PW PSAD was more accurate than the PSA level in predicting for adverse pathologic findings. A proportional hazards model was used to determine whether PSAD more accurately predicted for biochemical failure (PSA level greater 0.2 ng/mL). RESULTS: Multivariate analysis demonstrated that US and PW PSAD were independent predictors of positive margins (odds ratio [OR] 5.00, 95% confidence interval [CI] 2.65 to 9.47 and OR 29.75, 95% CI 10.18 to 86.96, respectively), extracapsular disease (OR 10.89, 95% CI 5.32 to 22.32 and OR 126.62, 95% CI 37.99 to 422.07, respectively), seminal vesical invasion (OR 6.06, 95% CI 2.96 to 12.41 and OR 33.72, 95% CI 9.79 to 116.15, respectively), and biochemical failure (hazard ratio 3.32, 95% CI 2.38 to 4.63 and hazard ratio 8.70, 95% CI 5.21 to 14.52, respectively). The C-index demonstrated that both US and PW PSAD appeared more discriminant for adverse pathologic findings and biochemical failure than did the PSA level. CONCLUSIONS: The US and PW PSAD are strong predictors of advanced pathologic features and biochemical failure after radical prostatectomy. The incorporation of PSAD into the risk assessment could provide additional prognostic information beyond grade, stage, and PSA level; therefore, the inclusion of PSAD into nomograms should be considered.