Fluid intake and all-cause mortality, cardiovascular mortality, and kidney function: a population-based longitudinal cohort study

BACKGROUND Drinking eight glasses of fluid or water each day is widely believed to improve health, but evidence is sparse and conflicting. We aimed to investigate the association between fluid consumption and long-term mortality and kidney function. METHODS We conducted a longitudinal analysis within a prospective, population-based cohort study of 3858 men and women aged 49 years or older residing in Australia. Daily fluid intake from food and beverages not including water was measured using a food frequency questionnaire. We did multivariable adjusted Cox proportional hazard models for all-cause and cardiovascular mortality and a boot-strapping procedure for estimated glomerular filtration rate (eGFR). RESULTS Upper and lower quartiles of daily fluid intake corresponded to >3 L and <2 L, respectively. During a median follow-up of 13.1 years (total 43 093 years at risk), 1127 deaths (26.1 per 1000 years at risk) including 580 cardiovascular deaths (13.5 per 1000 years at risk) occurred. Daily fluid intake (per 250 mL increase) was not associated with all-cause [adjusted hazard ratio (HR) 0.99 (95% CI 0.98-1.01)] or cardiovascular mortality [HR 0.98 (95% CI 0.95-1.01)]. Overall, eGFR reduced by 2.2 mL/min per 1.73 m(2) (SD 10.9) in the 1207 (31%) participants who had repeat creatinine measurements and this was not associated with fluid intake [adjusted regression coefficient 0.06 mL/min/1.73 m(2) per 250 mL increase (95% CI -0.03 to 0.14)]. CONCLUSIONS Fluid intake from food and beverages excluding water is not associated with improved kidney function or reduced mortality.

Background Ionizing Radiation and the Risk of Childhood Cancer: A Census-Based Nationwide Cohort Study

BACKGROUND Exposure to medium or high doses of ionizing radiation is a known risk factor for cancer in children. The extent to which low dose radiation from natural sources contributes to the risk of childhood cancer remains unclear. OBJECTIVES In a nationwide census-based cohort study, we investigated whether the incidence of childhood cancer was associated with background radiation from terrestrial gamma and cosmic rays. METHODS Children aged <16 years in the Swiss National Censuses in 1990 and 2000 were included. The follow-up period lasted until 2008 and incident cancer cases were identified from the Swiss Childhood Cancer Registry. A radiation model was used to predict dose rates from terrestrial and cosmic radiation at locations of residence. Cox regression models were used to assess associations between cancer risk and dose rates and cumulative dose since birth. RESULTS Among 2,093,660 children included at census, 1,782 incident cases of cancer were identified including 530 with leukemia, 328 with lymphoma, and 423 with a tumor of the central nervous system (CNS). Hazard ratios for each mSv increase in cumulative dose of external radiation were 1.03 (95% CI: 1.01, 1.05) for any cancer, 1.04 (1.00, 1.08) for leukemia, 1.01 (0.96, 1.05) for lymphoma, and 1.04 (1.00, 1.08) for CNS tumors. Adjustment for a range of potential confounders had little effect on the results. CONCLUSIONS Our study suggests that background radiation may contribute to the risk of cancer in children including leukemia and CNS tumors.

Use of Complementary and Alternative Medicine in patients with organ transplantation in Switzerland

Introduction: The aim was to investigate retrospectively use of Complementary and Alternative Medicine (CAM) in the treatment of patients with organ transplantation in Switzerland. Methods: Members of the Swiss transplant association completed a questionnaire about CAM use retrospectively. Five different stages were differentiated: CAM usage (1) during underlying disease, (2) before transplant, (3) during hospitalisation/ rehabilitation from transplant, (4) for transplant complications and (5) after transplant for other diseases. Results: Of the 267 patients contacted, 124 (46%) completed the questionnaire, and data of 118 (44%) participants could be analyzed: 55 women (47%), mean age 56 years. Overall, 64 (54%) indicated CAM use, with about 30% usage at every stage (except during hospitalization with only 10%). Different methods were most common: during underlying disease classical homeopathy (15% of all participants), before transplant dietary supplements (13%), during hospitalization meditation (3%), for transplantation complications dietary supplements (10%), and after transplant for other diseases massage (11%). Among the 64 CAM-users, the most important reasons for the usage were improvement of general condition (36%) and abatement of adverse effects of conventional treatment (25%). Among the 54 non-CAM-users, most frequent reasons for not choosing CAM were insecurity about interactions with conventional treatment (46%), and ignorance of this option (28%). About 35% of the CAM-users reported an improved general condition, while 30% noticed an abatement of side effects of conventional treatment. Conclusions: To prevent dangerous interactions with conventional treatment, more information on possibilities of CAM in the treatment of patients with transplantations is needed for doctors and patients.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

BACKGROUND Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. METHODS Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). FINDINGS 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. INTERPRETATION Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. FUNDING Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

Five-year follow-up after catheter ablation of persistent atrial fibrillation using the stepwise approach and prognostic factors for success

BACKGROUND In the meantime, catheter ablation is widely used for the treatment of persistent atrial fibrillation (AF). There is a paucity of data about long-term outcomes. This study evaluates (1) 5-year single and multiple procedure success and (2) prognostic factors for arrhythmia recurrences after catheter ablation of persistent AF using the stepwise approach aiming at AF termination. METHODS AND RESULTS A total of 549 patients with persistent AF underwent de novo catheter ablation using the stepwise approach (2007-2009). A total of 493 patients were included (Holter ECGs ≥ every 6 months). Mean follow-up was 59 ± 16 months with 2.1 ± 1.1 procedures per patient. Single and multiple procedure success rates were 20.1% and 55.9%, respectively (80% off antiarrhythmic drug). Antiarrhythmic drug-free multiple procedure success was 46%. Long-term recurrences (n=171) were paroxysmal AF in 48 patients (28%) and persistent AF/atrial tachycardia in 123 patients (72%). Multivariable recurrent event analysis revealed the following factors favoring arrhythmia recurrence: failure to terminate AF during index procedure (hazard ratio [HR], 1.279; 95% confidence interval [CI], 1.093-1.497; P = 0.002), number of procedures (HR, 1.154; 95% CI, 1.051-1.267; P = 0.003), female sex (HR, 1.263; 95% CI, 1.027-1.553; P = 0.027), and the presence of structural heart disease (HR, 1.236; 95% CI, 1.003-1.524; P = 0.047). AF termination was correlated with a higher rate of consecutive procedures because of atrial tachycardia recurrences (P = 0.003; HR, 1.71; 95% CI, 1.20-2.43). CONCLUSIONS Catheter ablation of persistent AF using the stepwise approach provides limited long-term freedom of arrhythmias often requiring multiple procedures. AF termination, the number of procedures, sex, and the presence of structural heart disease correlate with outcome success. AF termination is associated with consecutive atrial tachycardia procedures.

Pharmacokinetics and pharmacodynamics of γ-hydroxybutyrate in healthy subjects.

AIMS γ-Hydroxybutyrate (GHB) is used as a treatment for narcolepsy and alcohol withdrawal and as recreational substance. Nevertheless, there are limited data on the pharmacokinetics and pharmacokinetic-pharmacodynamic relationship of GHB in humans. We characterized the pharmacokinetic profile and exposure-psychotropic effect relationship of GHB in humans. METHODS Two oral doses of GHB (25 and 35 mg/kg) were administered to 32 healthy male subjects (16 for each dose) using a randomized, placebo-controlled, cross-over design. RESULTS Maximal concentrations of GHB were (geometric mean and 95%CI): 218 (176-270) nmol/ml and 453 (374-549) nmol/ml for the 25 and 35 mg/kg GHB doses, respectively. The elimination half-lives (mean ± SD) were 36 ± 9 and 39 ± 7 min and the AUC∞ values (geometric mean and 95%CI) were 15,747 (12,854-19,290) and 40,113 (33,093-48,622) nmol∙min/ml for the 20 and 35 mg/kg GHB doses, respectively. Thus, plasma GHB exposure (AUC0-∞ ) rose disproportionally (+40%) with the higher dose. γ-Hydroxybutyrate produced mixed stimulant-sedative effects, with a dose-dependent increase in sedation and dizziness. It did not alter heart rate or blood pressure. A close relationship between plasma GHB exposure and its psychotropic effects was found, with higher GHB concentrations associated with higher subjective stimulation, sedation, and dizziness. No clockwise hysteresis was observed in the GHB concentration effect plot over time (i.e., no acute pharmacological tolerance). CONCLUSION Evidence was found of a non-linear dose-exposure relationship (i.e., no dose proportionality) at moderate doses of GHB. The effects of GHB on consciousness were closely linked to its plasma exposure and exhibited no acute tolerance. This article is protected by copyright. All rights reserved.

CAD/CAM fabrication accuracy of long- vs. short-span implant-supported FDPs

OBJECTIVE To compare the precision of fit of long-span vs. short-span implant-supported screw-retained fixed dental prostheses (FDPs) made from computer-aided-design/computer-aided-manufactured (CAD/CAM) titanium and veneered with ceramic. The null hypothesis was that there is no difference in the vertical microgap between long-span and short-span FDPs. MATERIALS AND METHODS CAD/CAM titanium frameworks for an implant-supported maxillary FDP on implants with a flat platform were fabricated on one single master cast. Group A consisted of six 10-unit FDPs connected to six implants (FDI positions 15, 13, 11, 21, 23, 25) and group B of six 5-unit FDPs (three implants, FDI positions 21, 23, 25). The CAD/CAM system from Biodenta Swiss AG (Berneck, Switzerland) was used for digitizing (laser scanner) the master cast and anatomical CAD of each framework separately. The frameworks were milled (CAM) from a titanium grade V monobloc and veneered with porcelain. Median vertical distance between implant and FDP platforms from the non-tightened implants (one-screw test on implant 25) was calculated from mesial, buccal, and distal scanning electron microscope measurements. RESULTS All measurements showed values <40 μm. Total median vertical microgaps were 23 μm (range 2-38 μm) for group A and 7 μm (4-24 μm) for group B. The difference between the groups was statistically significant at implant 21 (P = 0.002; 97.5% CI -27.3 to -4.9) and insignificant at implant 23 (P = 0.093; -3.9 to 1.0). CONCLUSIONS CAD/CAM fabrication including laboratory scanning and porcelain firing was highly precise and reproducible for all long- and short-span FDPs. While all FDPs showed clinically acceptable values, the short-span FDPs were statistically more precise at the 5-unit span distance.