Effects of the progesterone receptor modulator VA2914 in a continuous low dose on the hypothalamic-pituitary-ovarian axis and endometrium in normal women: a prospective, randomized, placebo-controlled trial

CONTEXT: Progestin-only pills, the main hormonal alternative to ethinyl estradiol-containing pills in women bearing vascular risk factors, are poorly tolerated due to irregular bleeding. In contrast, progesterone receptor modulators can inhibit ovulation, alter endometrial receptivity, and improve cycle control. OBJECTIVE: We evaluated the effects of a new progesterone receptor modulator, VA2914, administered continuously for 3 months, on ovulation and endometrial maturation. DESIGN, SETTINGS, AND PATIENTS: Forty-six normal women were included in a prospective, placebo-controlled, randomized trial, conducted in four referral centers. INTERVENTION: VA2914 (2.5, 5, or 10 mg/d) was administered continuously for 84 d. Pelvic ultrasound (treatment d 67 and 77), hormonal monitoring (FSH, LH, estradiol, and progesterone on treatment d 59, 63, 67, 70, 74, 77, 80, and 84), and endometrial biopsy (treatment d 77) were performed. MAIN OUTCOME MEASURE: Ovulation inhibition was assessed by the absence of progesterone values above 3 ng/ml at any time during treatment month 3. RESULTS: Anovulation was observed in 81.8% women in the 5-mg group and 80% in the 10-mg group, and amenorrhea occurred in 81.2 and 90% of cases in the 5- and 10-mg groups. We did not detect any cases of endometrial hyperplasia despite estradiol levels that remained in the physiological follicular phase range throughout treatment cycle 3. CONCLUSIONS: Continuous low-dose VA2914 can induce amenorrhea and inhibit ovulation without down-regulating estradiol levels or inducing endometrial hyperplasia in normal women. Long-term studies with a larger population are required to confirm the contraceptive efficacy of this regimen.     

Opioid receptor gene (OPRM1, OPRK1, and OPRD1) variants and response to naltrexone treatment for alcohol dependence: results from the VA Cooperative Study

BACKGROUND: Pharmacotherapy of alcohol dependence (AD) is at an early stage of development; currently available medications have limited efficacy. It would be clinically valuable to identify, before initiation of a course of treatment, those patients who, based on genetic markers, are most likely to respond to a specific pharmacotherapy. A previous report suggested that a functional variant at the genetic locus encoding the mu opioid receptor (Asn40Asp) is such a marker, in short-term (3-month) treatment with the opioid-blocking drug naltrexone (NTX). METHODS: We studied polymorphic variants at each of the 3 opioid receptor genes--OPRM1, OPRD1, and OPRK1, which encode the mu, delta, and kappa opioid receptors, respectively--including the OPRM1 Asn40Asp variant--as predictors of response to NTX or placebo in 215 alcohol-dependent male subjects who participated in Veterans Affairs Cooperative Study 425, "Naltrexone in the Treatment of Alcohol Dependence." RESULTS: At the 3-month time point, treatment condition, age, and the pretreatment number of drinks per drinking day were all significant (p<0.05) predictors of the rate of relapse and time to relapse. Although NTX had no significant effect on relapse to heavy drinking in the overall sample in CSP 425, it significantly reduced relapse in the subgroup that provided DNA for analysis (i.e., the present study sample). There were no significant interactions between any individual single nucleotide polymorphisms studied and NTX treatment response. CONCLUSIONS: These results do not support association of the OPRM1 Asn40Asp polymorphism with NTX treatment response for AD.     

The relationship between posttraumatic stress disorder and smoking outcome expectancies among U.S. military veterans who served since September 11, 2001

Posttraumatic stress disorder (PTSD) is associated with increased rates of smoking although little is known regarding the mechanisms underlying this relationship. The current study examined expectations about smoking outcomes among smokers with and without PTSD. The sample included 96 veterans (mean age of 34 years) and included 17% women and 50% racial minorities. Smoking expectancies were measured with the Smoking Consequences Questionnaire-Adult (Copeland, Brandon, & Quinn, 1995). Consistent with previous work suggesting that smokers with PTSD smoke in an effort to reduce negative affect, unadjusted analyses indicated that smokers with PTSD (n = 38) had higher expectations that smoking reduces negative affect than smokers without PTSD (d = 0.61). Smokers with PTSD also had increased expectancies associated with boredom reduction (d = 0.48), stimulation (d = 0.61), taste/sensorimotor manipulation aspects of smoking (d = 0.73), and social facilitation (d = 0.61). Results of hierarchical linear regression analyses indicated that PTSD symptom severity was uniquely associated with these expectancies beyond the effects of gender and nicotine dependence. More positive beliefs about the consequences of smoking may increase risk of continued smoking among those with PTSD who smoke. Further understanding of smoking expectancies in this group may help in developing interventions tailored for this vulnerable population.     

Evidence-based paediatrics

Evidence-based medicine is practised widely in some specialties and is now part of many undergraduate and graduate medical curricula. However, the extent to which it is used in clinical paediatric practice is not known and its expansion remains a major challenge. Access to technology which facilitates literature searching, and development of journals addressing specific paediatric problems, will encourage the use of evidence-based medicine by the busy paediatrician. Informed practice of evidence-based medicine will ensure that clinical expertise is complemented by a thorough search, evaluation and judicious application of relevant information from the medical literature.     

Predictors of Health Utility among 60-Day Survivors of Acute Kidney Injury in the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study

Background and objectives: Health-related quality of life (HRQOL) after acute kidney injury (AKI) is an area of great importance to patients. It was hypothesized that HRQOL after AKI would relate to intensity of dialysis during AKI and dialysis dependence at follow-up.Design, setting, participants, & measurements: The Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study was a multicenter, prospective, randomized trial of intensive versus less intensive renal replacement therapy in critically ill patients with AKI. Of 1124 participants, 415 survived at least 60 days and completed the Health Utilities Index (HUI), which measures 8 health attributes and calculates an overall HRQOL score, also called a utility score. How strongly pre–intensive care unit (ICU) health, severity of illness, hospital course, intensity of dialysis, and outcome were associated with 60-day HUI scores was assessed, after adjustment for demographics.Results: The overall HUI score was 0.40 ± 0.37, indicating severely compromised health utility and was associated with only admission from home and hospital and ICU length of stay (LOS). Ambulation was better among those with a shorter hospital and ICU LOS. Better cognition was associated with dialysis independence and with fewer comorbid chronic illnesses. Emotion was associated with only hospital LOS. Pain was associated with ICU LOS.Conclusions: Health utility was low in this cohort of patients after AKI, and intensity of dialysis did not affect subsequent health utility. The effects of a lengthy hospitalization generally outweighed the effects of delayed recovery of kidney function on HRQOL after AKI.A cute kidney injury (AKI) is common among hospitalized patients and is particularly prevalent among patients cared for in the intensive care unit (ICU) setting (1–3). AKI has been associated with increased morbidity, mortality, and costs (1–4). It remains unclear to what extent treatment of or recovery from AKI influences health-related quality of life in survivors of AKI. There have been several reports of health-related quality of life (HRQOL) among survivors of AKI in the ICU (5–10). However, many of these studies are limited by small sample size and low response rate. In addition, follow-up times are variable among and sometimes within studies, ranging from 3 months to several years. Several measures of HRQOL have been used, including the Medical Outcomes Study Short Form 36-item health survey (SF-36) (9), EuroQol (EQ-5D) (5), and Nottingham Health Profile (6,8,10), and also health utilities by time trade-off (7) or visual analog scale (5) and Activities of Daily Living (7,8). Perhaps because of this variability, results are mixed. On balance, limitations in mobility were fairly common, ranging from 29 to 60% (6,8). However, patients generally reported a favorable health status, with 62 to 77% of patients reporting “good” or “excellent” health status (7,10). Health utility on the EQ-5D index was 0.68 compared with an age- and sex-matched norm of 0.86 (5), but in the same study utility by visual analog scale was not different from the general population. Health utility by the time trade-off method was reported by Hamel et al. to be 0.84, but no normative data were presented (7).The availability of HRQOL data in a large cohort of survivors of AKI requiring renal replacement therapy (RRT) provides a unique opportunity to study HRQOL and its potential determinants in this population. The Veterans Affairs/National Institutes of Health (VA/NIH) Acute Renal Failure Trial Network (ATN) study (ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT00076219","term_id":"NCT00076219"}}NCT00076219) was a multicenter randomized trial of intensive versus less intensive renal replacement therapy in critically ill patients with acute kidney injury conducted between November 2003 and July 2007 at 27 VA and university-affiliated medical centers (11,12). Although the major goals of the ATN study were to assess the effects of treatment assignment on 60-day mortality, in-hospital mortality, and recovery of renal function, HRQOL was also assessed at 60 days among survivors with the intention of establishing the effect of dialysis intensity on HRQOL and of assigning health utilities to facilitate performance of cost-effectiveness analysis.We hypothesized that study treatment assignment and ongoing dialysis dependence at 60 days would be potential determinants of HRQOL. Although intensive dialysis did not lead to shorter hospital stays or more rapid recovery of renal function (12), both of which might have contributed to improved HRQOL at 60 days, we postulated that better control of uremia could have direct effects on HRQOL. In addition, given that patients receiving maintenance dialysis routinely report impaired HRQOL (13–15), we also hypothesized that ongoing need for dialysis would be an important determinant of HRQOL at 60 days.     

Prevalence and distinct correlates of anxiety, substance, and combined comorbidity in a multi-site public sector sample with bipolar disorder

BACKGROUND: Recent data indicate high prevalence of both anxiety and substance comorbidity in bipolar disorder. However, few studies have utilized public sector samples, and only one has attempted to separate contributions of each type of comorbidity. METHODS: 328 inpatient veterans with bipolar disorder across 11 sites were assessed using selected Structured Clinical Interview for DSM-IV modules and self-reports. RESULTS: Comorbidity was common (current: 57.3%; lifetime: 78.4%), with multiple current comorbidities in 29.8%. Substance comorbidity rate was comparable to rates typically reported in non-veteran inpatient samples (33.8% current, 72.3% lifetime). Selected anxiety comorbidity rates exceeded those in other inpatient samples and appeared more chronic than episodic/recurrent (38.3% current, 43.3% lifetime). 49% of PTSD was due to non-combat stressors. Major correlates of current substance comorbidity alone were younger age, worse marital status, and higher current employability. Correlates of current anxiety comorbidity alone were early age of onset, greater number of prior-year depressive episodes, higher rates of disability pension receipt, and lower self-reported mental and physical function. Combined comorbidity resembled anxiety comorbidity. LIMITATIONS: This is a cross-sectional analysis of acutely hospitalized veterans. CONCLUSIONS: Distinct patterns of substance and anxiety comorbidity are striking, and may be subserved by distinct neurobiologic mechanisms. The prevalence, chronicity and functional impact of anxiety disorders indicate the need for improved recognition and treatment of this other dual diagnosis group is warranted. Clinical and research interventions should recognize these divergent comorbidity patterns and provide individualized treatment built "from the patient out."