Shifting effects in randomised controlled trials of complex interventions: a new kind of performance bias?

OBJECTIVE: Randomised controlled trials (RCTs) aim to provide unbiased estimates of treatment effects. However, the process of implementing trial procedures may have an impact on the performance of complex interventions that rely strongly on the intuition and confidence of therapists. We aimed to examine whether shifting effects over the recruitment period can be observed that might indicate such impact. METHOD: Three RCTs investigating music therapy vs. standard care were included. The intervention was performed by experienced therapists and based on established methods. We examined outcomes of participants graphically, analysed cumulative effects and tested for differences between first vs. later participants. We tested for potential confounding population shifts through multiple regression models. RESULTS: Cumulative differences suggested trends over the recruitment period. Effect sizes tended to be less favourable among the first participants than later participants. In one study, effects even changed direction. Age, gender and baseline severity did not account for these shifting effects. CONCLUSION: Some trials of complex interventions have shifting effects over the recruitment period that cannot be explained by therapist experience or shifting demographics. Replication and further research should aim to find out which interventions and trial designs are most vulnerable to this new kind of performance bias.

Occupational exposure to lead and neuropsychological dysfunction.

OBJECTIVE: To evaluate the neuropsychological effects of current low level and previous higher levels of exposure to lead and evaluate the relation between effects of lead and bone lead. METHODS: A neuropsychological test battery was given to 54 storage battery workers with well documented long term exposure to lead. The effect was studied in two subgroups: those whose blood lead had never exceeded 2.4 mmol/l (the low BPbmax group, n = 26), and those with higher exposure about 10 years earlier (the high BPbmax group, n = 28). In both groups, the recent exposure had been low. Correlations between the test scores and the indices of both long term and recent exposure--including the content of lead in the tibial and calcaneal bone--and covariance analyses were used to assess the exposure-effect relation. Age, sex, and education were controlled in these analyses. RESULTS: Analyses within the low BPbmax group showed a decrement in visuospatial and visuomotor function (block design, memory for design, Santa Ana dexterity), attention (digit symbol, digit span), and verbal comprehension (similarities) associated with exposure to lead and also an increased reporting of subjective symptoms. The performance of the high BPbmax group was worse than that of the low BPbmax group for digit symbol, memory for design, and embedded figures, but there was no reporting of symptoms related to exposure, probably due to selection in this group. No relation was found between the output variables and the tibial lead concentration. The calcaneal lead concentrations were related to the symptoms in the low BPbmax group. CONCLUSIONS: Neuropsychological decrements found in subjects with high past and low present exposure indicate that blood lead concentrations rising to 2.5-4.9 mmol/l cause a risk of long lasting or even permanent impairment of central nervous system function. Milder and narrower effects are associated with lower exposures; their reversibility and time course remain to be investigated. History of blood lead gives a more accurate prediction of the neuropsychological effects of lead than do measurements of bone lead.

Effects of low level exposure to lead on neurophysiological functions among lead battery workers.

OBJECTIVES: Assessment of neurophysiological functions in workers with low level exposure to lead and evaluation of the efficacy of bone lead measurements in the prediction of effects of lead. METHODS: Exposure to lead of 60 workers from a lead battery battery factory was estimated from historical blood lead measurements and analysis of lead in the tibial and calcaneal bones with x ray fluorescence. Peripheral and central nervous system functions were assessed by measuring conduction velocities, sensory distal latencies, sensory amplitudes, and vibration thresholds as well as by quantitative measurement of the absolute and relative powers and mean frequencies of different electroencephalograph (EEG) channels. RESULTS: Sensory amplitudes, and to a smaller degree sensory or motor conduction velocities, showed a negative correlation with long term exposure to lead, most clearly with integrated blood lead concentration and exposure time. Vibration thresholds measured in the arm were related to recent exposure to lead, those measured in the leg to long term exposure. The alpha and beta activities of the EEG were more abundant in subjects with higher long term exposure to lead. Calcaneal lead content reflected short term exposure, tibial lead content reflected long term exposure. Blood lead history showed a closer relation with effects of lead than the tibial or calcaneal lead concentrations. CONCLUSIONS: Vibratory thresholds, quantitative EEG, and to a smaller extent the sensory amplitude, provide sensitive measures of effects of lead in occupationally exposed adults. Most accurate estimates of health risks induced by lead can be obtained from a good history of blood lead measurements. If such a history of blood lead concentrations is not available, analysis of bone lead may be used for the assessment of health risks.

In vivo measurements of lead in bone at four anatomical sites: long term occupational and consequent endogenous exposure.

Measurements of bone lead concentrations in the tibia, wrist, sternum, and calcaneus were performed in vivo by x ray fluorescence on active and retired lead workers from two acid battery factories, office personnel in the two factories under study, and control subjects. Altogether 171 persons were included. Lead concentrations in the tibia and ulna (representative of cortical bone) appeared to behave similarly with respect to time but the ulnar measurement was much less precise. In an analogous fashion, lead in the calcaneus and sternum (representative of trabecular bone) behaved in the same way, but sternal measurement was less precise. Groups occupationally exposed to lead were well separated from the office workers and the controls on the basis of calculated skeletal lead burdens, whereas the differences in blood lead concentrations were not as great, suggesting that the use of concentrations of lead in blood might seriously underestimate lead body burden. The exposures encountered in the study were modest, however. The mean blood lead value among active lead workers was 1.45 mumol l-1 and the mean tibial lead concentration 21.1 micrograms (g bone mineral)-1. The kinetics of lead in the tibia appeared to be noticeably different from that in the calcaneus. Tibial lead concentration increased consistently both as a function of intensity of exposure and of duration of exposure. Calcaneal lead concentration, by contrast, was strongly dependent on the intensity rather than duration of exposure. This indicated that the biological half life of lead in calcaneus was less than the seven to eight year periods into which the duration of exposure was split. Findings for retired workers clearly showed that endogenous exposure to lead arising from skeletal burdens accumulated over a working lifetime can easily produce the dominant contribution to systemic lead concentrations once occupational exposure has ceased.

Improved method for calculating phase-matching criteria in biaxial nonlinear materials.

We present an analytic method for obtaining phase-matching conditions for general three-wave mixing in biaxial crystals. The method is based on a rarely quoted closed-form solution to the Fresnel equation. Additionally, we show how the method can be used to obtain acceptance angles for both critical and noncritical phase matching and apply the derived formulas to two examples.

Spine deformity subsequent to acquired childhood spinal cord injury.

The cases of forty children who had incurred a spinal cord injury between birth and the age of eighteen years were reviewed at two to 26.8 years (mean, ten years) after injury. In all of the twenty-five patients who were injured prior to the adolescent growth spurt paralytic spinal deformity developed; in twenty-four (96 per cent) of them it was progressive. Scoliosis developed in twenty-three (92 per cent); kyphosis, in sixteen (64 per cent); and excessive lumbar lordosis, in five (20 per cent). Management of the spinal deformities by bracing was difficult, and seventeen patients (68 per cent) required spine fusion, usually to the sacrum. Complications were frequent. All of the fifteen patients who were injured after the onset of the adolescent growth spurt had sustained a spinal fracture or fracture-dislocation. Nine (60 per cent) had an acute angular thoracic or thoracolumbar fracture kyphosis and seven (47 per cent) had progressive fracture kyphosis. A history of a thoracic and thoracolumbar laminectomy always was associated with increased kyphosis progression. Six (40 per cent) of these patients required spinal stabilization, usually for unstable injuries and progressive post-laminectomy deformity. Progressive paralytic spinal deformity was uncommon in the postadolescent patient.

Spine deformities and cystic fibrosis.

Patients with cystic fibrosis have an increased risk for developing kyphosis and scoliosis. The risk for both kyphosis and scoliosis increases with age. The severity of kyphosis did not appear greater in the older age groups. Patients with retarded bone age may be more likely to have a significant spinal deformity. The presence of spine deformity does not correlate with the severity of pulmonary involvement, height, weight, serum protein and albumin in patients with cystic fibrosis.

Annular converging wave resonator: new insights.

A simple theory describing the annular converging wave resonator has been developed. The theory explains results obtained in two recent experiments. Configurations of the converging wave resonator that could be used to extract power from a large-volume annular gain region in a single mode with nonzero azimuthal order are also discussed.