Bias in treatment assignment in controlled clinical trials

Controlled clinical trials of the treatment of acute myocardial infarction offer a unique opportunity for the study of the potential influence on outcome of bias in treatment assignment. A group of 145 papers was divided into those in which the randomization process was blinded (57 papers), those in which it may have been unblinded (45 papers), and those in which the controls were selected by a nonrandom process (43 papers). At least one prognostic variable was maldistributed (P less than 0.05) in 14.0 per cent of the blinded-randomization studies, in 26.7 per cent of the unblinded-randomization studies, and in 58.1 per cent of the nonrandomized studies. Differences in case-fatality rates between treatment and control groups (P less than 0.05) were found in 8.8 per cent of the blinded-randomization studies, 24.4 per cent of the unblinded-randomization studies, and 58.1 per cent of the nonrandomized studies. These data emphasize the importance of keeping those who recruit patients for clinical trials from suspecting which treatment will be assigned to the patient under consideration.     

Clinical trials of hepatitis B immune globulin. Development of policies and materials for the 1972-1975 studies sponsored by the National Heart and Lung Institute.

Plasma from persons with high titers of hepatitis B antibody (anti-HBs) was used to manufacture one lot of hepatitis B "immune" globulin sufficient for four interlocking clinical trials of prevention or modification of hepatitis B infections. The trials were carried out in renal dialysis units, in medical personnel with accidental exposures to hepatitis B, in transfused patients, and in patients with fulminant hepatitis. A single policy board developed protocols that allowed comparisons among the four studies while respecting the unique requirements of each.     

Routine mortality monitoring for detecting mass murder in UK general practice: test of effectiveness using modelling.

BACKGROUND: The Shipman Inquiry recommended mortality rate monitoring if it could be 'shown to be workable' in detecting a future mass murderer in general practice. AIM: To examine the effectiveness of cumulative sum (CUSUM) charts, cross-sectional Shewhart charts, and exponentially-weighted, moving-average control charts in mortality monitoring at practice level. DESIGN OF STUDY: Analysis of Scottish routine general practice data combined with estimation of control chart effectiveness in detecting a 'murderer' in a simulated dataset. METHOD: Practice stability was calculated from routine data to determine feasible lengths of monitoring. A simulated dataset of 405,000 'patients' was created, registered with 75 'practices' whose underlying mortality rates varied with the same distribution as case-mix-adjusted mortality in all Scottish practices. The sensitivity of each chart to detect five and 10 excess deaths was examined in repeated simulations. The sensitivity of control charts to excess deaths in simulated data, and the number of alarm signals when control charts were applied to routine data were estimated. RESULTS: Practice instability limited the length of monitoring and modelling was consequently restricted to a 3-year period. Monitoring mortality over 3 years, CUSUM charts were most sensitive but only reliably achieved >50% successful detection for 10 excess deaths per year and generated multiple false alarms (>15%). CONCLUSION: At best, mortality monitoring can act as a backstop to detect a particularly prolific serial killer when other means of detection have failed. Policy should focus on changes likely to improve detection of individual murders, such as reform of death certification and the coroner system.     

Simultaneous demonstration of phenylethanolamine N-methyltransferase immunofluorescent and catecholamine fluorescent nerve cell bodies in the rat medulla oblongata

The distribution of phenylethanolamine N-methlytransferase-immunoreactive nerve cell bodies was investigated in the rat medulla using an antiserum to bovine phenylethanolamine N-methyltransferase raised in rabbits. A procedure that combines immunohistochemistry and catecholamine fluorescence histochemistry was developed with a formaldehyde/glutaraldehyde mixture as a fixative. Three groups of immunoreactive nerve cell bodies were found in the medulla: a ventrolateral group, C1, a dorsal group, C2, in the nucleus of the tractus solitarius and a smaller medial group of cells, C3, scattered in the medial longitudinal fasciculus. Most of the phenylethanolamine N-methyltransferase positive nerve cells did not show catecholamine fluorescence and did not correspond to the catecholamine cell groups A1 and A2. Both groups C1 and C2 of immunoreactive nerve cells extended further rostrally than A1 and A2. Group C3 has not previously been described as a distinct group of catecholamine fluorescent nerve cell bodies.Inhibition of phenylethanolamineN-methyltransferase and monoamine oxidase results in the appearance of catecholamine fluorescence in the immunoreactive cell bodies suggesting that they usually store adrenaline which reacts poorly with the formaldehyde/glutaraldehyde mixture or other aldehydes which induce catecholamine fluorescence and it is for this reason that they are not normally identified in maps of catecholamine fluorescent cells.     

Synaptic connections from large afferents of wrist flexor and extensor muscles to synergistic motoneurones in man

 Short-latency excitatory Ia reflex connections were determined between pairs of human wrist flexor and extensor muscles. Spindle Ia afferents were stimulated by either tendon tap or electrical stimulation. The activity of voluntarily activated single motor units was recorded intramuscularly from pairs of wrist flexor or extensor muscles. Cross-correlation between stimuli and the discharge of the motor units provided a measure of the homonymous or heteronymous excitatory input to a motoneurone. Homonymous motoneurone facilitation was generally stronger than that of the heteronymous motoneurones. The principal wrist flexors, flexor carpi radialis (FCR) and flexor carpi ulnaris (FCU), were tightly connected through a bidirectional short-latency reflex pathway. In contrast, the extensor carpi ulnaris (ECU) and the extensor carpi radialis (ECR) did not have similar connections. ECU motoneurones received no short-latency excitatory Ia input from the ECR. ECR motoneurones did receive excitatory Ia input from ECU Ia afferents; however, its latency was delayed by several milliseconds compared with other heteronymous Ia excitatory effects observed. The wrist and finger extensors were linked through heteronymous Ia excitatory reflexes. The reflex connections observed in humans are largely similar to those observed in the cat, with the exception of heteronymous effects from the ECU to the ECR and from the extensor digitorum communis (EDC) to the ECU, which are present only in humans. The differences in the reflex organization of the wrist flexors versus the extensors probably reflects the importance of grasping. Received: 19 August 1996 / Accepted: 6 March 1997     

Restless red legs: an association of the restless legs syndrome with arborizing telangiectasia of the lower limbs.

Two patients are reported with Ekbom's syndrome of "restless legs" occurring in association with arborizing telangiectasia of the lower limbs. Sensory complaints have previously been reported in this skin condition but not described in detail. The co-existence of the two conditions is discussed in the context of previous explanations of the restless legs syndrome.