Yoga for generalized anxiety disorder: design of a randomized controlled clinical trial.

Generalized anxiety disorder (GAD) is a common disorder associated with significant distress and interference. Although cognitive behavioral therapy (CBT) has been shown to be the most effective form of psychotherapy, few patients receive or have access to this intervention. Yoga therapy offers another promising, yet under-researched, intervention that is gaining increasing popularity in the general public, as an anxiety reduction intervention. The purpose of this innovative clinical trial protocol is to investigate the efficacy of a Kundalini Yoga intervention, relative to CBT and a control condition. Kundalini yoga and CBT are compared with each other in a noninferiority test and both treatments are compared to stress education training, an attention control intervention, in superiority tests. The sample will consist of 230 individuals with a primary DSM-5 diagnosis of GAD. This randomized controlled trial will compare yoga (N=95) to both CBT for GAD (N=95) and stress education (N=40), a commonly used control condition. All three treatments will be administered by two instructors in a group format over 12 weekly sessions with four to six patients per group. Groups will be randomized using permuted block randomization, which will be stratified by site. Treatment outcome will be evaluated bi-weekly and at 6month follow-up. Furthermore, potential mediators of treatment outcome will be investigated. Given the individual and economic burden associated with GAD, identifying accessible alternative behavioral treatments will have substantive public health implications.R01 AT007257 - NCCIH NIH HHS; R01 AT007258 - NCCIH NIH HH

Comparison of methods to predict equilibrated Kt/V in the HEMO Pilot Study

Comparison of methods to predict equilibrated Kt/V in the HEMO Pilot Study. The ongoing HEMO Study, a National Institutes of Health (NIH) sponsored multicenter trial to test the effects of dialysis dosage and membrane flux on morbidity and mortality, was preceded by a Pilot Study (called the MMHD Pilot Study) designed to test the reliability of methods for quantifying hemodialysis. Dialysis dose was defined by the fractional urea clearance per dialysis determined by the predialysis BUN and the equilibrated postdialysis BUN after urea rebound is completed (eKt/V). In the Pilot Study the blood side standard for eKt/V was calculated from the predialysis, postdialysis, and 30-minute postdialysis BUN. Four techniques of approximating eKt/V that eliminated the requirement for the 30-minute postdialysis sample were also evaluated. The first adjusted the single compartment Kt/V using a linear equation with slope based on the relative rate of solute removal (K/V) to predict eKt/V (rate method). The second and third techniques used equations or mathematical curve fitting algorithms to fit data that included one or more samples drawn during dialysis (intradialysis methods). The fourth technique (dialysate-side) predicted eKt/V from an analysis of the time-dependent profile of dialysate urea nitrogen concentrations (BioStat method; Baxter Healthcare, Inc., Round Lake, IL, USA). The Pilot Study demonstrated the feasibility of conventional and high dose targets of about 1.0 and 1.4 for eKt/V. Based on the blood side standard method, the mean ± SD eKt/V for patients randomized to these targets was 1.14 ± 0.11 and 1.52 ± 0.15 (N = 19 and 16 patients, respectively). Single-pool Kt/Vs were about 0.2 Kt/V units higher. Results were similar when eKt/V was based on dialysate side measurements: 1.10 ± 0.11 and 1.50 ± 0.11. The approximations of eKt/V by the three blood side methods that eliminated the delayed 30-minute post-dialysis sample correlated well with eKt/V from the standard blood side method: r = 0.78 and 0.76 for the single-sample (Smye) and multiple-sample intradialysis methods (N = 295 and 229 sessions, respectively) and 0.85 for the rate method (N = 295). The median absolute difference between eKt/V computed using the standard blood side method and eKt/V from the four other methods ranged from 0.064 to 0.097, with the smallest difference (and hence best accuracy) for the rate method. The results suggest that, in a dialysis patient population selected for ability to achieve an equilibrated Kt/V of about 1.45 in less than a 4.5 hour period, use of the pre and postdialysis samples and a kinetically derived rate equation gives reasonably good prediction of equilibrated Kt/V. Addition of one or more intradialytic samples does not appear to increase accuracy of predicting the equilibrated Kt/V in the majority of patients. A method based on dialysate urea analysis and curve-fitting yields results for equilibrated Kt/V that are similar to those obtained using exclusively blood-based techniques of kinetic modeling

Hemodialyzer mass transfer-area coefficients for urea increase at high dialysate flow rates

Hemodialyzer mass transfer-area coefficients for urea increase at high dialysate flow rates. The dialyzer mass transfer-area coefficient (KoA) for urea is an important determinant of urea removal during hemodialysis and is considered to be constant for a given dialyzer. We determined urea clearance for 22 different models of commercial hollow fiber dialyzers (N = ~5/model, total N = 107) in vitro at 37°C for three countercurrent blood (Qb) and dialysate (Qd) flow rate combinations. A standard bicarbonate dialysis solution was used in both the blood and dialysate flow pathways, and clearances were calculated from urea concentrations in the input and output flows on both the blood and dialysate sides. Urea KoA values, calculated from the mean of the blood and dialysate side clearances, varied between 520 and 1230ml/min depending on the dialyzer model, but the effect of blood and dialysate flow rate on urea KoA was similar for each. Urea KoA did not change (690 ± 160 vs. 680 ± 140 ml/min, P = NS) when Qb increased from 306 ± 7 to 459 ± 10ml/min at a nominal Qd of 500ml/min. When Qd increased from 504 ± 6 to 819 ± 8ml/min at a nominal Qb of 450ml/min, however, urea KoA increased (P < 0.001) by 14 ± 7% (range 3 to 33%, depending on the dialyzer model) to 780 ± 150ml/min. These data demonstrate that increasing nominal Qd from 500 to 800ml/min alters the mass transfer characteristics of hollow fiber hemodialyzers and results in a larger increase in urea clearance than predicted assuming a constant KoA

CA15-3 and alkaline phosphatase as predictors for breast cancer recurrence: a combined analysis of seven International Breast Cancer Study Group trials

Background: We evaluated the ability of CA15-3 and alkaline phosphatase (ALP) to predict breast cancer recurrence. Patients and methods: Data from seven International Breast Cancer Study Group trials were combined. The primary end point was relapse-free survival (RFS) (time from randomization to first breast cancer recurrence), and analyses included 3953 patients with one or more CA15-3 and ALP measurement during their RFS period. CA15-3 was considered abnormal if >30 U/ml or >50% higher than the first value recorded; ALP was recorded as normal, abnormal, or equivocal. Cox proportional hazards models with a time-varying indicator for abnormal CA15-3 and/or ALP were utilized. Results: Overall, 784 patients (20%) had a recurrence, before which 274 (35%) had one or more abnormal CA15-3 and 35 (4%) had one or more abnormal ALP. Risk of recurrence increased by 30% for patients with abnormal CA15-3 [hazard ratio (HR) = 1.30; P = 0.0005], and by 4% for those with abnormal ALP (HR = 1.04; P = 0.82). Recurrence risk was greatest for patients with either (HR = 2.40; P < 0.0001) and with both (HR = 4.69; P < 0.0001) biomarkers abnormal. ALP better predicted liver recurrence. Conclusions: CA15-3 was better able to predict breast cancer recurrence than ALP, but use of both biomarkers together provided a better early indicator of recurrence. Whether routine use of these biomarkers improves overall survival remains an open questio

Revisiting the association between altitude and mortality in dialysis patients.

It was recently reported that residential altitude is inversely associated with all-cause mortality among incident dialysis patients; however, no adjustment was made for key case-mix and laboratory variables. We re-examined this question in a contemporary patient database with comprehensive clinical and laboratory data. In a contemporary 8-year cohort of 144,892 maintenance dialysis patients from a large dialysis organization, we examined the relationship between residential altitude and all-cause mortality. Using data from the US Geological Survey, the average residential altitudes per approximately 43,000 US zip codes were compiled and linked to the residential zip codes of each patient. Mortality risks for these patients were estimated by Cox proportional hazard ratios. The study population's mean ± standard deviation age was 61 ± 15 years. Forty-five percent of patients were women, and 57% of patients had diabetes. In fully adjusted analysis, those residing in the highest altitude strata (≥ 6000 ft) had a lower all-cause mortality risk in fully adjusted analyses: death hazard ratio: 0.92 (95% confidence interval, 0.86-0.99), as compared with patients in the reference group (&lt;250 ft). Residential altitude is inversely associated in all-cause mortality risk in maintenance dialysis patients notwithstanding the unknown and unmeasured confounders

Predictors of early relapse in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial

Background: Aromatase inhibitors are considered standard adjuvant endocrine treatment of postmenopausal women with hormone receptor-positive breast cancer, but it remains uncertain whether aromatase inhibitors should be given upfront or sequentially with tamoxifen. Awaiting results from ongoing randomized trials, we examined prognostic factors of an early relapse among patients in the BIG 1-98 trial to aid in treatment choices. Patients and methods: Analyses included all 7707 eligible patients treated on BIG 1-98. The median follow-up was 2 years, and the primary end point was breast cancer relapse. Cox proportional hazards regression was used to identify prognostic factors. Results: Two hundred and eighty-five patients (3.7%) had an early relapse (3.1% on letrozole, 4.4% on tamoxifen). Predictive factors for early relapse were node positivity (P < 0.001), absence of both receptors being positive (P < 0.001), high tumor grade (P < 0.001), HER-2 overexpression/amplification (P < 0.001), large tumor size (P = 0.001), treatment with tamoxifen (P = 0.002), and vascular invasion (P = 0.02). There were no significant interactions between treatment and the covariates, though letrozole appeared to provide a greater than average reduction in the risk of early relapse in patients with many involved lymph nodes, large tumors, and vascular invasion present. Conclusion: Upfront letrozole resulted in significantly fewer early relapses than tamoxifen, even after adjusting for significant prognostic factor

Peritoneal dialysis in end-stage renal disease patients with preexisting chronic liver disease and ascites

Hemodialysis in patients with chronic liver disease and ascites may be complicated by intradialytic hypotension, limiting the amount of ultrafiltration and resulting in massive ascites. Successful maintenance peritoneal dialysis (PD) has not been previously reported as an alternative to hemodialysis in this population. Nine patients with chronic renal failure, chronic liver disease, and tense ascites prior to beginning PD are described. All chronic PD catheters were placed percutaneously by the nephrology staff. Seven patients were maintained primarily on continuous ambulatory peritoneal dialysis, whereas two were on intermittent peritoneal dialysis. PD catheters were placed without serious hemorrhage or bowel injury. PD provided adequate clearance and volume maintenance for each patient. Fifteen episodes of peritonitis occurred in 18 patient-years of PD. All episodes of peritonitis were successfully treated with intraperitoneal antibiotics without catheter removal. Only one patient had a decline in the serum albumin level of 0.5 g/dL or more during the course of chronic PD. Three of the nine patients are still alive and on PD for durations of 18 to 24 months. One patient insidiously developed sclerosing peritonitis after 8 years on PD and is now on hemodialysis, and another patient switched to hemodialysis because she was no longer able to care for herself or to manage her PD. Four patients died while maintained on PD; three deaths were due to complications of liver failure within the first 4 months of PD and the fourth was due to empyema after 4 years of PD. PD can be used successfully to treat chronic renal failure in patients with chronic liver disease and ascites when the liver disease itself is not rapidly fatal. PD may be better tolerated than hemodialysis and perhaps should be the renal replacement treatment of choice in these patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29955/1/0000315.pd

Peritoneal dialysis prescription in children: bedside principles for optimal practice

There is no unique optimal peritoneal dialysis prescription for all children, although the goals of ultrafiltration and blood purification are universal. In turn, a better understanding of the physiology of the peritoneal membrane, as a dynamic dialysis membrane with an exchange surface area recruitment capacity and unique permeability characteristics, results in the transition from an empirical prescription process based on clinical experience alone to the potential for a personalized prescription with individually adapted fill volumes and dwell times. In all cases, the prescribed exchange fill volume should be scaled for body surface area (ml/m2), and volume enhancement should be conducted based on clinical tolerance and intraperitoneal pressure measurements (IPP; cmH2O). The exchange dwell times should be determined individually and adapted to the needs of the patient, with particular attention to phosphate clearance and ultrafiltration capacity. The evolution of residual kidney function and the availability of new, more physiologic, peritoneal dialysis fluids (PDFs) also influence the prescription process. An understanding of all of these principles is integral to the provision of clinically optimal PD

The aromatase inhibitor letrozole and inhibitors of insulin-like growth factor I receptor synergistically induce apoptosis in in vitro models of estrogen-dependent breast cancer

INTRODUCTION: Endocrine-dependent, estrogen receptor positive breast cancer cells proliferate in response to estrogens, synthesized by the cytochrome p450 aromatase enzyme. Letrozole is a potent nonsteroidal aromatase inhibitor that is registered for the treatment of postmenopausal women with advanced metastatic breast cancers and in the neoadjuvant, early, and extended adjuvant indications. Because crosstalk exists between estrogen receptor and insulin-like growth factor I receptor (IGF-IR), the effect of combining a selective IGF-IR inhibitor (NVP-AEW541) with letrozole was assessed in two independent in vitro models of estrogen-dependent breast cancer. METHODS: MCF7 and T47D cells stably expressing aromatase (MCF7/Aro and T47D/Aro) were used as in vitro models of aromatase-driven breast cancer. The role of the IGF-IR pathway in breast cancer cells stimulated only by 17ß-estradiol or androstenedione was assessed by proliferation assays. The combination of letrozole and NVP-AEW541 was assessed for synergy in inhibiting cell proliferation using Chou-Talalay derived equations. Finally, combination or single agent effects on proliferation and apoptosis were assessed using proliferation assays, flow cytometry, and immunoblotting. RESULTS: Both MCF7 and T47D cells, as well as MCF7/Aro and T47D/Aro, exhibited sensitivity to inhibition of 17ß-estradiol dependent proliferation by NVP-AEW541. Letrozole combined with NVP-AEW541 synergistically inhibited androstenedione-dependent proliferation in aromatase-expressing cells with combination index values of 0.6 or less. Synergistic combination effects correlated with higher levels of apoptosis as compared with cells treated with the single agent alone. Treatment with either agent also appeared to inhibit IGF-IR signalling via phosphoinositide 3-kinase. Notably, IGF-IR inhibition had limited effect on estrogen-dependent proliferation in the cell lines, but was clearly required for survival, suggesting that the combination of letrozole and IGF-IR inhibition sensitizes cells to apoptosis. CONCLUSION: Inhibition of the IGF-IR pathway and aromatase was synergistic in two independent estrogen-dependent in vitro models of breast cancer. Moreover, synergism of NVP-AEW541 and letrozole correlated with induction of apoptosis, but not cell cycle arrest, in the cell lines tested. Combination of IGF-IR inhibitors and letrozole may hold promise for the treatment of patients with estrogen-dependent breast cancers

Predictors of early relapse in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial

BACKGROUND: Aromatase inhibitors are considered standard adjuvant endocrine treatment of postmenopausal women with hormone receptor-positive breast cancer, but it remains uncertain whether aromatase inhibitors should be given upfront or sequentially with tamoxifen. Awaiting results from ongoing randomized trials, we examined prognostic factors of an early relapse among patients in the BIG 1-98 trial to aid in treatment choices. PATIENTS AND METHODS: Analyses included all 7707 eligible patients treated on BIG 1-98. The median follow-up was 2 years, and the primary end point was breast cancer relapse. Cox proportional hazards regression was used to identify prognostic factors. RESULTS: Two hundred and eighty-five patients (3.7%) had an early relapse (3.1% on letrozole, 4.4% on tamoxifen). Predictive factors for early relapse were node positivity (P < 0.001), absence of both receptors being positive (P < 0.001), high tumor grade (P < 0.001), HER-2 overexpression/amplification (P < 0.001), large tumor size (P = 0.001), treatment with tamoxifen (P = 0.002), and vascular invasion (P = 0.02). There were no significant interactions between treatment and the covariates, though letrozole appeared to provide a greater than average reduction in the risk of early relapse in patients with many involved lymph nodes, large tumors, and vascular invasion present. CONCLUSION: Upfront letrozole resulted in significantly fewer early relapses than tamoxifen, even after adjusting for significant prognostic factors