Clinical trials comparing two treatment policies: which aspects of the treatment policies make a difference?

We discuss pragmatic clinical trials with survival endpoints in which subjects commonly change treatment during follow-up. Suppose that an intention-to-treat (ITT) analysis shows a significant difference between the randomized groups. We may want to ask questions about the reason for such a difference in outcome between randomized groups: for example, was the difference due to different policies for change to a third more beneficial regime? We address such questions using the semi-parametric accelerated life models of Robins, which exploit the randomization assumption fully and avoid direct comparisons of possibly differently selected subgroups. No assumption is made about the relationship of treatment actually prescribed to prognosis. A sensitivity analysis, using a range of plausible values for the causal effect of a covariate, estimates the contrasts between randomized groups that would have been observed if the covariate had universally been 0. The main technical problem is in dealing with censoring, for the method requires different degrees of recensoring for different values of the causal effect, and this can lead to estimates of low precision. The methods are applied to a randomized comparison of two anti-hypertensive treatments in which approximately half the subjects changed treatment during follow-up. Various time-dependent covariates, representing patterns of side-effects and treatments, are used in the model. We find that the observed difference in cardiovascular deaths between the randomized groups cannot be explained in this way by their different covariate patterns.     

General practitioner attitudes toward mandatory reporting of doctor-patient sexual abuse

AIM: To explore general practitioner attitudes toward mandatory reporting of doctor-patient sexual abuse. METHODS: Anonymous questionnaire mailed to a randomised sample of 217 New Zealand general practitioners. Attitudes toward mandatory reporting of doctor-patient sexual contact, seductive or sexually demeaning behaviour were appraised including an indication of whom the perceived appropriate reporting body should be. RESULTS: Forty-seven per cent of respondents supported the notion of mandatory reporting for doctor-patient sexual contact, 42% for sexually demeaning behaviour and 35% for seductive verbal behaviour. These respondents indicated that the most appropriate body to report to was a Doctor's Health Advisory Service. CONCLUSION: There was a lack of strong consensus on mandatory reporting of doctor-patient sexual abuse.     

Hans von Haberer: a forgotten pioneer in vascular surgery

With AIDS related tuberculosis in the pediatric population on the rise, we review our experience with 14 such children. A brief review of the pertinent literature is also presented.     

Unequal representation of cardinal and oblique contours in ferret visual cortex

We have measured the amount of cortical space activated by differently oriented gratings in 25 adult ferrets by optical imaging of intrinsic signal. On average, 7% more area of the exposed visual cortex was preferentially activated by vertical and horizontal contours than by contours at oblique angles. This anisotropy may reflect the real-world prevalence of contours in the cardinal axes and could explain the greater sensitivity of many animals to vertical and horizontal stimuli.     

Soluble recombinant neutral endopeptidase (CD10) as a potential antiinflammatory agent

The present study assessed fidelity to the behavioral family management (BFM) model for treating bipolar disorder patients and their families. The BFM Therapist Competency/Adherence Scale (BFM-TCAS) was developed to evaluate clinicians' competency and adherence to BFM, as outlined by Miklowitz' (1989) BFM Manual for use with bipolar patients. Therapist competency and treatment adherence was also evaluated with regard to two family characteristics: overall level of family difficulty and family expressed emotion (EE) status. The BFM-TCAS was used to code 78 videotaped sessions of 26 families with a bipolar member, selected from a larger treatment study of bipolar disorder patients. The findings suggest that, overall, clinicians adhered closely to the BFM manual. Specific areas in which there was high competency and treatment adherence were (a) skill in conveying factual information about bipolar illness, (b) establishment of a therapeutic environment, and (c) ability to take command of therapy sessions. The one area in which there was less competency and relatively weak adherence to the manual was the use of between-session homework assignments to assist families in mastering the BFM exercises. Results of this study also suggest that, for the most part, therapist competency and adherence ratings were not related to overall level of difficulty or to family EE status.     

The quality of adolescent friendships: long-term effects?

Retinoic acid (RA) has been implicated in cardiac morphogenesis by its teratogenic effects on the heart, although its role in normal cardiogenesis remains unknown. To define the parameters of RA action in cardiac morphogenesis, we analyzed the patterns of ligand synthesis, response, and inactivation in the developing mouse heart. Activation of a lacZ transgene controlled by an RA response element (RARE) was compared to the localization of the retinaldehyde-oxidizing dehydrogenase RALDH2, the earliest RA synthetic enzyme in the mouse embryo, and to the expression of a gene encoding an RA-degrading enzyme (P450RA). We observed that RALDH2 localization and RA response were virtually superimposable throughout heart development. Initially, both RALDH2 and RARE-LacZ activity were restricted to the sinus venosa in unlooped hearts, but were high in the dorsal mesocardium, while P450RA expression was restricted to the endocardium. Later stages were characterized by a sequential, noncontiguous progression of RALDH2 accumulation and RA response, from the sinus venosa to atria, dorsal-medial conotruncus, aortic arches, and the epicardium. This dynamic pattern of RA response was a direct result of localized RALDH2, since hearts of cultured embryos were uniformly competent to respond to an exogenous RA challenge. These observations support a model in which the influence of endogenous RA on heart development depends upon localized presentation of the ligand, with only limited diffusion from the source of its synthesis.     

Comparison of the efficacy and safety of once-daily versus twice-daily formulations of diltiazem in the treatment of systemic hypertension. The Canadian Multicenter Diltiazem-CD Hypertension Trial Group

The efficacy and safety of optimally titrated once-daily (CD) and twice-daily (SR) diltiazem were compared in 111 patients with mild to moderate systemic hypertension [seated diastolic blood pressure (DBP) > or = 95 mmHg and < or = 114 mmHg] in a multicenter, randomized, double-blind, placebo run-in, parallel-group trial. Following a 4 week washout and placebo-controlled run-in period, patients were randomized to receive diltiazem CD 180 mg and matching placebo (n = 54), or diltiazem SR 90 mg bid (n = 57). Total daily doses were titrated from 180 mg to 360 mg to achieve a goal of seated DBP < 90 mmHg during a 6 week titration period. The patients continued to receive their optimal dose for a 6 week follow-up period. Ninety-six (96) patients (diltiazem CD: 47, diltiazem SR: 49) completed the study protocol, with 60% of the diltiazem CD and 55% of the diltiazem SR patients achieving the goal of seated DBP of < 90 mmHg (p = 0.685). Although significant decreases occurred in seated and standing measurements of diastolic and systolic BP and heart rate with treatment in both groups, there were no significant differences between treatment groups. Both medications were well tolerated, with a similar frequency of adverse effects [diltiazem CD: 24/54 (37%) patients; diltiazem SR: 24/57 (42.1%) patients] with the most frequently reported adverse effects being headache and edema.     

Results of autopsy 7 months after successful endoluminal treatment of an infrarenal abdominal aortic aneurysm

PURPOSE: To report the results of a postmortem examination in a patient who died of unrelated causes 7 months following endoluminal treatment of an infrarenal abdominal aortic aneurysm (AAA). METHODS: As part of an FDA Phase I pilot study, a 73-year-old man underwent successful endoluminal exclusion of an infrarenal AAA using a 9-cm-long endograft (Endovascular Grafting System). Seven months later, he succumbed to complications of a spontaneous esophageal rupture. At autopsy, the aorta was dissected in situ by a vascular surgeon and pathologist before being explanted in order to examine the wound healing characteristics at the aorta-endograft interface. Particular attention was also directed to the hooks composing the attachment system at each end of the endograft. RESULTS: Macroscopic and microscopic examination revealed that the graft had completely excluded the aneurysm sac from the circulation and was incorporated into the aortic wall at the proximal neck and distal cuff. A smooth pannus of endothelial cells covered the proximal end of the endograft at the areas of contact with the aorta, while microscopic examination of the distal end of the graft revealed poorly formed, fibrinous pannus. The neointima deep to the endothelium consisted of a collagenous matrix containing myofibroblasts and histiocytes, providing evidence of healing between the endograft and aorta. Both renal arteries were clear of the proximal end of the endograft, but a previously unrecognized right lower pole renal artery with an extremely caudal origin was excluded from the aortic lumen. Each hook of the attachment system was seen protruding through the adventitia of the aorta. There was no evidence of trauma to the aortic wall or the surrounding tissues caused by these hooks. CONCLUSION: There appears to be evidence that an endoluminally placed aortic graft may be incorporated by the host aortic tissue.