Covariate adjustment in randomized controlled trials with dichotomous outcomes increases statistical power and reduces sample size requirements

OBJECTIVE: Randomized controlled trials (RCTs) with dichotomous outcomes may be analyzed with or without adjustment for baseline characteristics (covariates). We studied type I error, power, and potential reduction in sample size with several covariate adjustment strategies. STUDY DESIGN AND SETTING: Logistic regression analysis was applied to simulated data sets (n=360) with different treatment effects, covariate effects, outcome incidences, and covariate prevalences. Treatment effects were estimated with or without adjustment for a single dichotomous covariate. Strategies included always adjusting for the covariate ("prespecified"), or only when the covariate was predictive or imbalanced. RESULTS: We found that the type I error was generally at the nominal level. The power was highest with prespecified adjustment. The potential reduction in sample size was higher with stronger covariate effects (from 3 to 46%, at 50% outcome incidence and covariate prevalence) and independent of the treatment effect. At lower outcome incidences and/or covariate prevalences, the reduction was lower. CONCLUSION: We conclude that adjustment for a predictive baseline characteristic may lead to a potentially important increase in power of analyses of treatment effect. Adjusted analysis should, hence, be considered more often for RCTs with dichotomous outcomes.     

Method for Studying the Processes Maintaining Equilibrium at Rest Standing

According to current concepts, two processes are responsible for the maintenance of body equilibrium: shifts of the reference point caused by changes in the posture and stabilization of oscillations of the center of mass relative to this point. Exact changes in these processes occurring at various forms of locomotor disorders remain unclear. We proposed an original mathematical method allowing separate evaluation of these two processes responsible for the maintenance of body equilibrium.     

Rapid selection of quinolone resistance in Campylobacter jejuni but not in Escherichia coli in individually housed broilers

OBJECTIVE: To determine the within-host population dynamics of Campylobacter jejuni and Escherichia coli in chickens during and after treatment with fluoroquinolones. MATERIALS AND METHODS: Total and resistant faecal counts were determined from cloacal swabs during and after treatment with enrofloxacin. Chickens were housed individually to avoid confounding as a result of interaction between animals, and to be able to focus solely on the within-host dynamics. To determine the molecular basis of resistance, a number of isolates were checked for mutations in gyrA. RESULTS: Treatment with enrofloxacin at doses routinely prescribed (50 ppm) rapidly reduced the faecal counts of E. coli below the detection limit and did not induce resistance. In C. jejuni, on the other hand, treatment with enrofloxacin quickly selected for high frequencies of fluoroquinolone-resistant strains. In all phenotypically resistant isolates, resistance was traced to mutations in the gyrA gene. CONCLUSIONS: (1) A licensed dosage (50 ppm) of enrofloxacin in drinking water of chickens is effective (i.e. markedly reduced faecal counts) and is safe on a short time scale in E. coli (i.e. did not rapidly select for resistance), but is neither safe nor effective in C. jejuni. (2) The rapid emergence of resistance to quinolones in C. jejuni does not necessarily result from horizontal transmission of resistant strains among chickens, but could solely be the result of de novo selection of resistance in individual chickens.     

Short course dexamethasone treatment following injury inhibits bleomycin induced fibrosis in rats

BACKGROUND: Corticosteroids are routinely used in patients with pulmonary fibrosis. The timing for initiation of treatment is likely to be crucial for corticosteroids to exert an antifibrotic effect. Experimental studies in animals have examined the effect of corticosteroid treatment starting before or at the time of lung injury. However, this is not representative of the human condition as treatment only begins after disease has been established. We examined the effect of a short course corticosteroid treatment starting 3 days after bleomycin induced lung injury on the development of pulmonary fibrosis. METHODS: Bleomycin (1.5 mg/kg) was instilled intratracheally into rats to induce pulmonary fibrosis. The effect of a 3-day course of dexamethasone (0.5 mg/kg) initiated 3 days after bleomycin induced lung injury on cell proliferation and collagen deposition was examined by analysing bronchoalveolar lavage (BAL) fluid and lung tissue. RESULTS: Treating bleomycin exposed animals after injury with dexamethasone for 3 days inhibited lung collagen deposition compared with animals exposed to bleomycin without dexamethasone treatment (15.2 (2.2) mg collagen/lung v 22.5 (2.1) mg/lung; p<0.05). Dexamethasone treatment reduced pulmonary parenchymal cell proliferation in bleomycin exposed rats but did not influence BAL fluid mitogenic activity for lung fibroblasts or alter the BAL fluid levels of the fibrogenic mediators transforming growth factor-beta(1), platelet derived growth factor-AB, and thrombin. CONCLUSIONS: A 3 day course of dexamethasone treatment initiated 3 days after bleomycin induced lung injury reduces lung cell proliferation and collagen deposition by mechanisms other than through reduction of transforming growth factor-beta(1), platelet derived growth factor-AB, and thrombin levels in BAL fluid. We propose that an early short course treatment with dexamethasone may be useful in inhibiting pulmonary fibrosis.     

Bladder-sphincter dysfunction in myelomeningocele

 Pediatric urodynamics taught us that detrusor-sphincter dyssynergia creates a bladder outlet obstruction in about 50% of any population of children with myelomeningocele. This functional obstruction causes renal damage due to obstructive uropathy, exactly the same way as a congenital anatomical urethral obstruction does. Pediatric urodynamics also taught us that in children with myelomeningocele pelvic floor activity and detrusor activity can be abnormal (hyperactive or inactive) completely independent from each other. These insights have changed the management of myelomeningocele. Children with overactivity of the pelvic floor can be singled out at infant age, and started on clean intermittent catherization, to prevent obstructive uropathy and preserve renal function. Children with detrusor overactivity can be singled out too at very early age, and treated with anticholinergics, to prevent irreversible structural damage to the detrusor and preserve normal bladder capacity and compliance. Received: 20 July 1999 / Accepted: 24 January 2001     

Higher risk behaviour and rates of sexually transmitted diseases in Mwanza compared to Uganda may help explain HIV prevention trial outcomes

OBJECTIVE: To determine to what extent the higher impact of treatment for sexually transmitted diseases (STD) on HIV incidence in Mwanza, Tanzania than in Rakai and Masaka, Uganda might be explained by baseline differences between the trial populations. DESIGN: A re-analysis of baseline data from the three trial populations comparing demography, sexual risk behaviour and HIV/STD epidemiology. METHODS: Data were compared after age-standardization and adjustments for sample selection where necessary. STD rates were also adjusted for the sensitivities and specificities of the diagnostic techniques used. RESULTS: Demographic patterns were similar across populations, apart from effects of AIDS on fertility and mortality (including widowhood) in Uganda. Higher sexual risk behaviours, including younger age of sexual debut, higher numbers of recent partners and lower frequency of condom use, were apparent in Mwanza compared to Masaka and Rakai. High-titre serological syphilis, gonorrhoea, chlamydia infection and trichomoniasis were all more prevalent in Mwanza, except for chlamydia infection in males. There was little difference between sites in the seroprevalence of Herpes simplex virus type-2. Age patterns in the prevalence of short-duration STD and current risk behaviours were similar across sites but all-titre serological syphilis was more prevalent among older participants in Rakai and Masaka than Mwanza. CONCLUSIONS: Differences between trial populations included higher reported risk behaviour and higher rates of curable STD in Mwanza compared to Rakai and Masaka. These differences probably relate to previous reductions in risk behaviour in Uganda and may explain, at least in part, the contrasting results of these trials.     

Visual Event-Related Potentials in Cirrhotic Patients without Overt Encephalopathy

Ambulant patients with cirrhosis and no clinical evidence of encephalopathy were screened for impaired brain function by neuroelectrophysiological testing dependent on cognitive function. Infrequent large checkerboard visual stimuli were randomly interleaved with frequent small ones to elicit P300 event-related potentials (ERPs). Three ERP components, N200, P3a and P3b, were derived from the electroencephalogram (EEG) by computer averaging. The use of 10% contrast and a minimum of four precisely placed scalp electrodes were found to be necessary for optimal separation of ERPs from sensory evoked potentials. Visual ERPs, onset/offset and pattern-reversal visual evoked potentials (VEPs), the spontaneous EEG and the time taken to complete a standard number connection test (NCT) were obtained from 20 normal adult subjects and 19 age-matched patients with histologically-confirmed cirrhosis and no clinical evidence of encephalopathy. The latencies and amplitudes of evoked potentials and the alpha rhythm of the EEG were determined. In 6 of the 19 patients the latencies of P3a and/or P3b exceeded the corresponding mean for controls+2 standard deviations of that mean. In 4 other patients the NCT was prolonged. In all of the patients the N200, VEPs and alpha rhythm of the EEG were normal. In conclusion: (i) Optimal isolation of ERPs is critically dependent on stimulus contrast and electrode placement; (ii) ERPs appear to be more sensitive than primary sensory evoked potentials or the EEG in detecting impaired brain neuroelectrophysiological function; and (iii) Cirrhotic patients without overt encephalopathy in whom P3a and/or P3b latencies are prolonged may have subclinical hepatic encephalopathy.     

Measuring the impact of antimicrobial stewardship programs

Antimicrobial Stewardship Programs (ASPs) are being implemented worldwide to optimize antimicrobial therapy, and thereby improve patient safety and quality of care. Additionally, this should counteract resistance development. It is, however, vital that correct and timely diagnostics are performed in parallel, and that an institution runs a well-organized infection prevention program. Currently, there is no clear consensus on which interventions an ASP should comprise. Indeed this depends on the institution, the region, and the patient population that is served. Different interventions will lead to different effects. Therefore, adequate evaluations, both clinically and financially, are crucial. Here, we provide a general overview of, and perspective on different intervention strategies and methods to evaluate these ASP programs, covering before mentioned topics. This should lead to a more consistent approach in evaluating these programs, making it easier to compare different interventions and studies with each other and ultimately improve infection and patient management.     

Diagnostic imaging of dopamine receptors in pituitary adenomas

Dopamine D2 receptor scintigraphy of pituitary adenomas is feasible by single-photon emission computed tomography using (123)I-S-(-)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-3-iodo-6-methoxybenzamide ((123)I-IBZM) and (123)I-epidepride. (123)I-epidepride is generally superior to (123)I-IBZM for the visualization of D2 receptors on pituitary macroadenomas. However, (123)I-IBZM and (123)I-epidepride scintigraphy are generally not useful to predict the response to dopaminergic treatment in pituitary tumour patients. These techniques might allow discrimination of non-functioning pituitary macroadenomas from other non-tumour pathologies in the sellar region. Dopamine D2 receptors on pituitary tumours can also be studied using positron emission tomography with (11)C-N-raclopride and (11)C-N-methylspiperone.