Citations

Nitrate and nitrite are precursors in the endogenous formation of N‐nitroso compounds (NOC), potential human carcinogens. We evaluated the association of nitrate and nitrite ingestion with postmenopausal ovarian cancer risk in the Iowa Women's Health Study. Among 28,555 postmenopausal women, we identified 315 incident epithelial ovarian cancers from 1986 to 2010. Dietary nitrate and nitrite intakes were assessed at baseline using food frequency questionnaire data. Drinking water source at home was obtained in a 1989 follow‐up survey. Nitrate‐nitrogen (NO3‐N) and total trihalomethane (TTHM) levels for Iowa public water utilities were linked to residences and average levels were computed based on each woman's duration at the residence. We computed multivariable‐adjusted hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards regression. We tested interactions of nitrate with TTHMs and dietary factors known to influence NOC formation. Ovarian cancer risk was 2.03 times higher (CI = 1.22–3.38, ptrend = 0.003) in the highest quartile (≥2.98 mg/L) compared with the lowest quartile (≤0.47 mg/L; reference) of NO3‐N in public water, regardless of TTHM levels. Risk among private well users was also elevated (HR = 1.53, CI = 0.93–2.54) compared with the same reference group. Associations were stronger when vitamin C intake was <median (pinteraction = 0.01 and 0.33 for private well and public supplies, respectively). Dietary nitrate was inversely associated with ovarian cancer risk (ptrend = 0.02); whereas, dietary nitrite from processed meats was positively associated with the risk (ptrend = 0.04). Our findings indicate that high nitrate levels in public drinking water and private well use may increase ovarian cancer risk among postmenopausal women.

Abstract Objective To examine the association of serum inflammatory markers (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) and serum lipid measures (low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol) with risk of myocardial infarction (MI) and ischaemic stroke (IS) among rheumatoid arthritis (RA) patients. Methods We conducted a retrospective cohort study using 2005–2010 data from a US commercial health plan. Eligible patients had two or more physician diagnoses of RA during a baseline period of at least 180 days with continuous medical and pharmacy coverage. We computed age-adjusted incidence rates of MI and IS, and used spline regression to assess non-linear associations and Cox-regression to quantify the independent association between the laboratory values and the outcomes. Results We identified 44 418 eligible RA patients (mean age 49 years; 76% women). CRP&gt;10 mg/L compared with &lt;1 mg/L was associated with increased MI risk (HR 2.12; 95% CI 1.02 to 4.38). ESR&gt;42 mm/h compared with &lt;14 mm/h was associated with increased risk of MI (HR 2.53; 95% CI 1.48 to 4.31) and IS (HR 2.51; 95% CI 1.33 to 4.75) risk. HDL-cholesterol ≥60 mg/dL (1.6 mmol/L) compared with &lt;40 mg/dL (1.0 mmol/L) was associated with reduced MI risk (HR 0.37; 0.21 to 0.66). The association between LDL and MI was not linear; the lowest risk was observed among patients with LDL between 70 mg/L (1.8 mmol/L) and 100 mg/L (2.6 mmol/L). We did not observe a significant association between LDL and IS. Conclusions This study provides evidence supporting the hypothesis that RA-related systemic inflammation plays a role in determining cardiovascular risk and a complex relationship between LDL and cardiovascular risk.

Background The Carotid Revascularization Endarterectomy Versus Stenting Trial ( CREST ) is a multicenter randomized trial of stenting versus endarterectomy in patients with symptomatic and asymptomatic carotid disease. This study assesses management of vascular risk factors. Methods and Results Management was provided by the patient's physician, with biannual monitoring results collected by the local site. Therapeutic targets were low‐density lipoprotein, cholesterol <100 mg/dL, systolic blood pressure <140 mm Hg, fasting blood glucose <126 mg/dL, and nonsmoking status. Optimal control was defined as achieving all 4 goals concurrently. Generalized estimating equations were used to compare risk factors at baseline with those observed in scheduled follow‐up visits for up to 48 months. In the analysis cohort of 2210, significant improvements in risk‐factor control were observed across risk factors for all follow‐up visits compared with baseline. At 48 months, achievement of the low‐density lipoprotein cholesterol goal improved from 59.1% to 73.6% ( P <0.001), achievement of the systolic blood pressure goal improved from 51.6% to 65.1% ( P <0.001), achievement of the glucose goal improved from 74.9% to 80.7% ( P =0.0101), and nonsmoking improved from 74.4% to 80.9% ( P <0.0001). The percentage with optimal risk‐factor control also improved significantly, from 16.7% to 36.2% ( P <0.001), but nearly 2 of 3 study participants did not achieve optimal control during the study. Conclusions Site‐based risk‐factor control improved significantly in the first 6 months and over the long term in CREST but was often suboptimal. Intensive medical management should be considered for future trials of carotid revascularization. Clinical Trial Registration URL: ClinicalTrials.gov. Unique identifier: NCT00004732.

Abstract Eosinophils are versatile cells that regulate innate and adaptive immunity, influence metabolism and tissue repair, and contribute to allergic lung disease. Within the context of immunity to parasitic worm infections, eosinophils are prominent yet highly varied in function. We have shown previously that when mice undergo primary infection with the parasitic nematode Trichinella spiralis, eosinophils play an important immune regulatory role that promotes larval growth and survival in skeletal muscle. In this study, we aimed to address the function of eosinophils in secondary infection with T. spiralis. By infecting eosinophil-ablated mice, we found that eosinophils are dispensable for immunity that clears adult worms or controls fecundity in secondary infection. In contrast, eosinophil ablation had a pronounced effect on secondary infection of skeletal muscle by migratory newborn larvae. Restoring eosinophils to previously infected, ablated mice caused them to limit muscle larvae burdens. Passive immunization of naive, ablated mice with sera or Ig from infected donors, together with transfer of eosinophils, served to limit the number of newborn larvae that migrated in tissue and colonized skeletal muscle. Results from these in vivo studies are consistent with earlier findings that eosinophils bind to larvae in the presence of Abs in vitro. Although our previous findings showed that eosinophils protect the parasite in primary infection, these new data show that eosinophils protect the host in secondary infection.

Arrhythmogenic Substrate of Ventricular Arrhythmias at the AMCIntroductionCatheter ablation of ventricular arrhythmia (VA) at the fibrous aortic mitral continuity (AMC) has been described, yet the nature of the arrhythmogenic substrate remains unknown.MethodsProcedural records of 528 consecutive patients undergoing ablation of VA at Mayo Clinic, Rochester, MN, were reviewed. The electrocardiographic and electrophysiologic characteristics of patients with successful ablation at the AMC were analyzed to characterize the underlying arrhythmogenic substrate.ResultsOf the 21 patients (mean age 53.2 ± 13.4 years, 47.6% male) who underwent ablation of VA at the AMC with acute success, prepotentials (PPs) were found at the ablation sites preceding the ventricular electrogram (VEGM) during arrhythmias in 13 (61.9%) patients and during sinus rhythm in 7 (53.8%) patients. VAs with PPs were associated with a significantly higher burden of premature ventricular complexes (PVCs; 26.1 ± 10.9% vs. 14.9 ± 10.1%, P = 0.03), shorter VEGM to QRS intervals (9.0 ± 28.5 milliseconds vs. 33.1 ± 8.8 milliseconds, P = 0.03), lower pace map scores (8.7 ± 1.6 vs. 11.4 ± 0.8, P = 0.001), and a trend toward shorter V‐H intervals during VA (32.1 ± 38.6 milliseconds vs. 76.3 ± 11.1 milliseconds, P = 0.06) as compared to those without PP. A strong and positive correlation was found between V‐H interval and QRS duration during arrhythmia in those with PPs (B = 2.11, R2 = 0.97, t = 13.7, P < 0.001) but not in those without PPs.ConclusionLocal EGM characteristics and relative activation time of the His bundle suggest the possibility of conduction tissue as the origin for VA arising from the fibrous AMC. Specific identification and targeting of PPs when ablating VAs at this location may improve procedural success.

Abstract Purpose: High-dose aldesleukin (HD IL2) received FDA approval for the treatment of metastatic renal cell carcinoma (MRCC) in 1992, producing a 14% objective response rate (ORR) and durable remissions. Retrospective studies suggested that clinical and pathologic features could predict for benefit. The Cytokine Working Group conducted this prospective trial to validate proposed predictive markers of response to HD IL2. Experimental Design: Standard HD IL2 was administered to prospectively evaluate whether the ORR of patients with mRCC with “good” predictive pathologic features based on an “integrated selection” model [ISM (e.g., clear-cell histology subclassification and carbonic anhydrase-9 (CA-9) IHC staining] was significantly higher than the ORR of a historical, unselected population. Archived tumor was collected for pathologic analysis including tumor programmed death-ligand 1 (PD-L1) expression. Results: One hundred and twenty eligible patients were enrolled between June 11 and September 7; 70% were Memorial Sloan Kettering Cancer Center (New York, NY) intermediate risk, 96% had clear cell RCC, and 99% had prior nephrectomy. The independently assessed ORR was 25% (30/120, 95% CI, 17.5%–33.7%, P = 0.0014; 3 complete responses, 27 partial responses) and was higher than a historical ORR. Thirteen patients (11%) remained progression free at 3 years and the median overall survival was 42.8 months. ORR was not statistically different by ISM classification (“good-risk” 23% vs. “poor-risk” 30%; P = 0.39). ORR was positively associated with tumor PD-L1 expression (P = 0.01) by IHC. Conclusions: In this prospective, biomarker validation study, HD IL2 produced durable remissions and prolonged survival in both “good” and “poor-risk” patients. The proposed ISM was unable to improve the selection criteria. Novel markers (e.g., tumor PD L1 expression) appeared useful, but require independent validation. Clin Cancer Res; 21(3); 561–8. ©2014 AACR.

Background— Post-percutaneous coronary intervention (PCI) bleeding complications are an important quality metric. We sought to characterize site-level variation in post-PCI bleeding and explore the influence of patient and procedural factors on hospital bleeding performance. Methods and Results— Hospital-level bleeding performance was compared pre- and postadjustment using the newly revised CathPCI Registry ® bleeding risk model (c-index, 0.77) among 1292 National Cardiovascular Data Registry ® hospitals performing >50 PCIs from 7/2009 to 9/2012 (n=1 984 998 procedures). Using random effects models, outlier sites were identified based on 95% confidence intervals around the hospital’s random intercept. Bleeding 72 hours post-PCI was defined as: arterial access site, retroperitoneal, gastrointestinal, or genitourinary bleeding; intracranial hemorrhage; cardiac tamponade; nonbypass surgery–related blood transfusion with preprocedure hemoglobin ≥8 g/dL; or absolute decrease in hemoglobin value ≥3 g/dL with preprocedure hemoglobin ≤16 g/dL. Overall, the median unadjusted post-PCI bleeding rate was 5.2% and varied among hospitals from 2.6% to 10.4% (5th, 95th percentiles). Center-level bleeding variation persisted after case-mix adjustment (2.8%–9.5%; 5th, 95th percentiles). Although hospitals’ observed and risk-adjusted bleeding ranks were correlated (Spearman ρ: 0.88), individual rankings shifted after risk-adjustment (median Δ rank order: ±91.5; interquartile range: 37.0, 185.5). Outlier classification changed postadjustment for 29.3%, 16.1%, and 26.5% of low-, non-, and high-outlier sites, respectively. Hospital use of bleeding avoidance strategies (bivalirudin, radial access, or vascular closure device) was associated with risk-adjusted bleeding rates. Conclusions— Despite adjustment for patient case-mix, there is wide variation in rates of hospital PCI-related bleeding in the United States. Opportunities may exist for best performers to share practices with other sites.