Minimum distinguishable difference in concentration: a clinically oriented translation of assay precision summaries.

A trend to market-driven health care in many parts of the world is focusing increasing attention on getting maximum value from available resources. Laboratories are not exempted. Well-informed clinical input has a potentially valuable role in any laboratory rationalization process. However, a communication difficulty exists in the sense that, although laboratory workers, commercial developers, regulatory bodies, etc., are thoroughly conditioned to using assay coefficient of variation as a general performance measure (for excellent reasons), this is not necessarily the most intuitive or informative scale from a clinician's perspective. Here we use routine clinical data from an immunoradiometric assay of thyrotropin to illustrate, first, a general approach to estimation and prediction of reproducibility, and second, an alternative summary that expresses the discriminatory power of an assay. This latter measure, our experience suggests, is more suited to the way clinicians perceive assays and assay results. The overall aim is improved clinician/laboratory communication.     

Decreased Bone Mass and Strength in Ovariectomized Cynomolgus Monkeys (Macaca fascicularis)

Agents for prevention or treatment of osteoporosis must now be tested in a large animal species that exhibits bone remodeling. Ovariectomized, nonhuman primates provide one such model, and they consistently develop osteopenia accompanied by high bone turnover rates. The goal of this study was to further characterize this model, and particularly to determine the effect of ovariectomy on bone strength in vertebrae and femoral necks. Longitudinal evaluations of spinal bone mass and serum markers of bone turnover were performed in 19 sham-ovariectomized (SHAM) and 18 ovariectomized (OVX), domestically reared cynomolgus monkeys, aged >9 years. OVX monkeys lost bone relative to both baseline values and SHAM controls. Serum markers of bone turnover were increased by OVX. After 72 weeks, both vertebral bone compressive strength and femoral neck breaking strength were significantly decreased in OVX animals compared with SHAM. Ovariectomized cynomolgus monkeys, like postmenopausal women, develop accelerated bone loss, increased bone turnover, and reduced bone strength, and provide a suitable large animal model for efficacy studies with agents for prevention or treatment of osteoporosis. Received: 24 June 1996 / Accepted: 3 September 1996     

Effects of the long acting beta agonist formoterol on asthma control in asthmatic patients using inhaled corticosteroids. The Netherlands and Canadian Formoterol Study Investigators

BACKGROUND: The long acting beta 2 agonist formoterol has proved to be an effective bronchodilator with a prolonged action of 12-14 hours. However, the precise role of formoterol in the maintenance treatment of asthma is still under debate. A study was performed to investigate the efficacy and safety of treatment with formoterol for six months in subjects with asthma. METHODS: In a multicentre double blind, placebo controlled, parallel group study 239 subjects with mild to moderate asthma were randomly assigned to treatment with either inhaled formoterol 24 micrograms twice daily (n = 125) or placebo (n = 114) during eight months. The study consisted of a four week run in period, a 24 week treatment period, and a four week washout period. All subjects were using regular inhaled corticosteroids (100-3200 micrograms daily) but were still needing at least five inhalations of short acting beta 2 agonist per week for symptom relief. The study was performed in 10 outpatient clinics in Canada, and five outpatient clinics and one coordinating centre for 44 Dutch general practitioners in The Netherlands. Twice daily self-reported peak expiratory flow (PEF) measurements, symptom scores, and rescue beta 2 agonist use during the last 28 treatment days compared with baseline values were used as main outcome measures. Spirometric values were measured at entry, at the start of treatment, after four, 12 and 24 weeks of treatment, and after four weeks washout. RESULTS: One hundred and twenty five subjects received formoterol 24 micrograms twice daily via Turbohaler and 114 received placebo. Baseline FEV1 was 67.1% predicted and mean bronchodilator reversibility was 26%. The mean total asthma symptom score was 3.6 (maximum possible 21). A significant decrease in symptoms in favour of formoterol (difference from placebo -0.64, 95% CI -0.04 to -1.23, p = 0.04) was observed. Compared with placebo, morning PEF increased (difference from placebo 28 l/min, 95% CI 18.3 to 37.7, p = 0.0001) and the use of short acting beta 1 agonists decreased (daytime difference from placebo -1.1 inhalation, 95% CI -1.4 to -0.7, p = 0.0001) in the formoterol group. PEF returned to baseline following discontinuation of formoterol, as did asthma symptom scores. Thirty three patients treated with formoterol and 32 treated with placebo required treatment with prednisolone during the study (58 and 55 courses, respectively). CONCLUSIONS: Adding formoterol 24 micrograms twice daily by Turbohaler to inhaled corticosteroids was effective in improving symptom scores and morning PEF, and decreasing the use of rescue beta 2 agonists. There was no apparent loss of asthma control during 24 weeks of treatment with formoterol.


     

Executive cognitive deficits in primary dystonia.

Primary dystonia is a disorder of movement for which no consistent pathophysiology has been identified; in the absence of evidence to the contrary, it is assumed to be cognitively benign. We have studied a clinically heterogeneous group of 14 patients with primary dystonia on a battery of neuropsychological tests. Despite well-preserved speed of information processing, language, spatial, memory and general intellectual skills relative to normal controls, we have identified a constellation of attentional-executive cognitive deficits on the Cambridge Neuropsychological Test Automated Battery (CANTAB). Specifically, patients demonstrated significant difficulties negotiating the extra-dimensional set-shifting phase of the IED task. The implications of these findings for the pathophysiology of primary dystonia are discussed. This is, to the best of our knowledge, the first report of a significant cognitive deficit in patients with primary dystonia.     

Patients with schizophrenia previously stabilized on conventional depot antipsychotics experience significant clinical improvements following treatment with long-acting risperidone.

BACKGROUND: Conventional depot antipsychotics can provide constant pharmacologic treatment, eliminating partial compliance and reducing relapse risk. Atypical antipsychotics, have improved clinical profiles but require daily dosing, compromising their overall effectiveness. As oral risperidone provides safety and efficacy benefits over oral haloperidol, improvements may be realized by replacing conventional with atypical agents in long-acting therapy. This report examines 50-weeks of long-acting risperidone therapy in patients previously stabilized with conventional depot antipsychotics. METHODS: A multi-center, open-label study enrolled 725 patients with schizophrenia or schizoaffective disorder, judged clinically stable and maintained on stable antipsychotic doses for > or =4 weeks. Assignment by clinician judgment to receive 25-75 mg of long-acting risperidone every 2 weeks for 50 weeks followed, with performance of standard safety and efficacy assessments. Data are presented on patients receiving conventional depot antipsychotic monotherapy at study entry. RESULTS: In the 188 (25.9%) patients receiving conventional depot antipsychotic monotherapy at entry, mild-to-moderate mean (+/-S.D.) Positive and Negative Syndrome Scale (PANSS)-total scores improved significantly after receiving long-acting risperidone (64.2 +/- 18.9 to 58.2 +/- 20.3; P < 0.001). Clinical improvement of > or =20%, 40%, or 60% reduction in PANSS-total score, occurred in 52%, 34%, and 16% of patients, respectively. ESRS subjective ratings and objective physician ratings (Parkinsonism) decreased significantly (P < 0.001). CONCLUSION: Stable patients with mild, residual symptomatology treated with conventional depot antipsychotics experienced significant improvement in psychiatric and movement disorder symptomatology following 1-year of treatment with long-acting risperidone.     

Reliability and validity of a health-related quality of life battery for evaluating outpatient antidepressant treatment

This study was designed to evaluate the reproducibility, validity and responsiveness of a health-related quality of life (HRQOL) battery that was assembled for the evaluation of antidepressant therapy. The Montgomery-Asberg Depression Rating Scale was used to measure severity of depression. The HRQOL battery contained measures of energy and fatigue, social behaviour, cognitive function, home and work role function, and general well-being (i.e., health perceptions, life satisfaction) selected from previously developed and validated instruments. The clinical investigators and research nurses reported on difficulty in using the HRQOL battery. Most patients were able to complete the questionnaire without problems within 10 min. Reproducibility was very good with intraclass correlation coefficients ranging from 0.74 to 0.97. The HRQOL scales showed evidence of good concurrent validity. The scales were moderately correlated with MADRS scores (r=0.30–0.62). The magnitude of these correlations indicate that HRQOL scales are related to depression measures, but they are not alternative measures of depression. Changes in MADRS scores were associated with changes in all scales, except for work behaviour, indicating that improvements in depression ratings also resulted in improvements in health status and well-being. The HRQOL scales included in this study were found to be reliable, reproducible, and valid and no appreciable burden was placed on patients or investigators participating in the study. With the exception of the Work Behaviour scale, the HRQOL scales were very responsive to changes in depression severity. This brief HRQOL instrument can provide a comprehensive assessment of the outcomes of antidepressant treatment.This research was supported by a grant from Pfizer International.     

Prospective randomized controlled trial of urethral versus suprapubic catheterization

Sixty-six patients requiring catheterization in the course of general surgical operations were randomly allocated into two groups. Of the 34 patients catheterized urethrally 16 developed urinary tract infections whereas of the 32 suprapubically catheterized patients only 2 developed an infection (P less than 0.001). Five patients required recatheterization after removal of their urethral catheters. There were no major complications associated with the use of suprapubic catheters. We propose that, when catheterization is required during a general surgical procedure, the suprapubic route is to be preferred.     

3% NaCl and 7.5% NaCl/dextran 70 in the resuscitation of severely injured patients.

Cardiovascular resuscitation of the severely injured patient in the field remains unsatisfactory because large volumes of intravenous fluid are needed to keep up with ongoing blood losses and because only small volumes of fluid can be given. In the first study reported here, small volumes (less than or equal to 12 mL/kg) of 3% NaCl were given to patients who were having surgery for severe injuries. The 3% NaCl restored blood pressure, pH, and urine output with approximately one half of the cumulative fluid requirement of patients who received isotonic fluids (p less than 0.05). In a second study, 7.5% NaCl/dextran 70, 250 mL, was given in a prospective, randomized, and double-blinded trial to injured patients in the field. Blood pressure in the hypertonic/hyperoncotic group increased 49 mmHg during transport (p less than 0.005); blood pressure in patients given lactated Ringer's solution increased 19 mmHg (NS). Survival favored the hypertonic/hyperoncotic group. The 7.5% NaCl/dextran 70 solution appears particularly promising for treatment of injured patients in the field.     

Is perinatal care in southwestern Ontario regionalized?

OBJECTIVE: To determine whether perinatal care in southwestern Ontario is regionalized, to identify trends over time in referral patterns, to quantify trends in perinatal death rates and to identify trends in perinatal death rates that give evidence of regionalization. DESIGN: Cohort study. SETTING: Thirty-two hospitals in southwestern Ontario (1 level III, 1 modified level III and 30 level II or I). PATIENTS: All pregnant women admitted to the hospitals and their infants. MAIN OUTCOME MEASURES: Antenatal and neonatal transfer status, live-born with discharge home alive from hospital of birth, stillborn, and live-born with death before discharge. RESULTS: Between 1982 and 1985 the antenatal transfer rate increased from 2.2% to 2.8% (p less than 0.003). The proportion of births of infants weighing 500 to 1499 g increased from 49% to 69% at the level III hospital. The neonatal transfer rate increased from 26.2% to 47.9% (p less than 0.05) for infants in this birth-weight category and decreased from 10.2% to 7.1% (p less than 0.03) for infants weighing 1500 to 2499 g. The death rate among infants of low birth weight was lowest among those born at the level III centre and decreased at all centres between 1982 and 1985. CONCLUSIONS: Perinatal care in southwestern Ontario is regionalized and not centralized; regionalization in southwestern Ontario increased between 1982 and 1985.