Design of the cooperative study on glycemic control and complications in diabetes mellitus type 2: Veterans Affairs Diabetes Trial

INTRODUCTION: Long-term glycemic control trials in type 2 diabetes show as the main clinical benefit a difference in retinal photocoagulation (3/1000 in the UK Prospective Diabetes Study [UKPDS]), but no effect on visual acuity or renal failure. No intensive glycemic control trial has yet affected cardiovascular (CV) events, the main cause of morbidity and mortality. By contrast, modest blood pressure reduction has protective effects on visual acuity, renal function, CV events, and mortality. Optimal glycemic control goals are not established in elderly, obese persons with advanced complications, the most common patients in the Veterans Affairs (VA) system. The earlier feasibility trial in such patients (VA-CSDM) suggested potentially worse CV outcomes with lower attained hemoglobin A1c (HbA1c) levels. OBJECTIVES: The primary objective of the Veterans Affairs Diabetes Trial (VADT) is the assessment of the effect of intensive glycemic treatment on CV events. Other objectives are effects on microangiopathy, quality of life, and cost effectiveness. RESEARCH DESIGN AND METHODS: The VADT, started in December 2000, is enrolling 1700 men and women previously uncontrolled on insulin or maximum doses of oral agents at 20 VA medical centers. Accrual is 2 years and follow-up is 5-7 years, with visits every 1.5 months. The study has a power of 86% to detect a 21% relative reduction in major CV events (CV death, myocardial infarction [MI], cerebrovascular accident [CVA], congestive heart failure [CHF], revascularization and amputation for ischemia). Subjects are randomized to an intensive arm aiming at normal HbA1c levels or to a standard arm with usual, improved glycemic control. An HbA1c separation of >1.5% is to be maintained (expected 2%). Both arms receive step therapy: glimepiride or metformin plus rosiglitazone and addition of insulin or other oral agents to achieve goals. Strict control of blood pressure and dyslipidemia, daily aspirin, diet, and education are identical in both arms. Plasma fibrinogen, plasminogen-activating inhibitor I (PAI-I), lipids, renal function parameters, and ECG are measured throughout. Stereo retinal photographs are obtained at entry and 5 years, eye examinations yearly, and intervention as needed to prevent visual deterioration. Recruitment is proceeding on schedule: the current mean HbA1c at entry is 9.4+/-1.6% and mean duration of diagnosed diabetes 11+/-8 years.     

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.     

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.     

Risk factors for adverse outcomes of bacterial meningitis

Objective : To identify risk factors for adverse outcomes from bacterial meningitis.
Methodology : From a cohort of 166 children with bacterial meningitis who were studied prospectively, 130/158 (82%) survivors underwent neurological, neuropsychological, audiological and behaviour assessments 5–9 years following their illness.
Results : Major adverse outcomes included 8/166 (4.8%) deaths and severe neurological, intellectual or audiological sequelae in 11/130 (8.5%) children followed. Another 24 (18.5%) had cognitive, auditory or behaviour disorders. Bivariate analysis found age ≤12 months, tertiary referral, symptoms >24 h before diagnosis, seizures, focal neurological signs, deteriorating conscious state in hospital, Streptococcus pneumoniae infection and serum sodium concentration < 130 mmol/L were associated with adverse outcomes. Multivariate analysis showed age ≤12 months, symptoms >24 h, seizures after 72 h in hospital and focal neurological signs as independent risk factors. These were present in 18/19 (95%) children with major sequelae, but absent in 9/24 (37.5%) children with minor disabilities.
Conclusions : As minor disabilities following meningitis cannot be predicted, all survivors require assessment during their early school years.     

Making heel pricks less painful

A mechanical lancet, the Autolet, was compared with a manual heel prick in 36 newborn infants undergoing routine blood sampling for the Guthrie test and hypothyroid screening. Each method was equally effective in obtaining satisfactory blood samples but the Autolet was considerably less painful.