A meta-analysis of ECG data from healthy male volunteers: diurnal and intra-subject variability, and implications for planning ECG assessments and statistical analysis in clinical pharmacology studies.

OBJECTIVE: To evaluate the innate variability in key electrocardiography (ECG) parameters from clinical pharmacology studies. METHODS: Meta-analysis of ECG data from seven clinical pharmacology studies in healthy male volunteers using model building and stepwise multiple regression analyses. RESULTS: Data from 115 male subjects provided over 2,000 observations for all key ECG parameters from baseline (Day-1) and placebo treatment periods (Day 1). Only heart rate and uncorrected QT showed clear and marked changes over the day. QTcB had greater variability compared to QTcF. 1.4% of QTcB and 0.7% QTcF observations were >430 ms and 0.1% of QTcB and 0% of QTcF observations were >450 ms. We estimated that 8.9% of subjects would have at least one out of eight post-observation QTc value in the range 430-450 ms [assuming QTc mean 385 ms, standard deviation (SD) 20 ms] due to intrinsic variability alone. Time-matched within-subjects observations demonstrated that the SD between measurements taken 1 h apart was less than seen with a longer interval, but there was little increase in variability beyond 1 h. The probability of observing an increase in QTc of 30-60 ms in a subject was estimated as 3.0% and 21.8% for one and eight post-dose observations, respectively. The greater the number of observations used to define baseline the narrower the spread; for QTcF the SD of the baseline value was 17.1 ms for a single assessment, 13.3 ms for the mean of three assessments, and 13.2 ms for the mean of all Day-1 assessments. CONCLUSIONS: The spontaneous variability in QTc measurements must be taken into account when designing studies and interpreting analyses of ECG data. The categorical analysis of QTc change of 30-60 ms is unlikely to be of any additional value to analyses of central tendency. For standard early clinical pharmacology studies, QTcF should be chosen as the primary correction method, while the mean of three measures taken in the afternoon and evening of Day-1 and pre-dose Day 1 should provide a reliable and representative baseline assessment.

Anatomic variance of the coracoclavicular ligaments.

The coracoclavicular ligaments vary widely in morphology and anatomic descriptions. Few authors have adequately described the coracoclavicular ligaments' anatomy, and a number of discrepancies exist in the anatomy literature. This study examines the complex anatomy of the coracoclavicular ligaments and their relationships to clinically important bony landmarks. The geometric dimensions of 24 coracoclavicular ligament specimens from fresh human cadaveric shoulders were examined and quantified with 13 different measurements. Particular attention was given to any inter-specimen anatomic variance. The coracoid insertions of the conoid ligaments displayed high variance, with 33% (8/24) being confluent with the lateral fibers of the superior transverse scapular ligament. A further 15% (3/24) presented an additional lateral fascicle. The distance from the lateral trapezoid ligament to the distal clavicle averaged 15.3 mm. Three distinct and previously unreported conoid ligament variants lend themselves to an anatomic classification (types I, II, and III). A safety margin of 15 mm is suggested for distal clavicle resection in incomplete acromioclavicular joint injuries to preserve the intact coracoclavicular ligament.

Identification of four new translocations involving FGFR1 in myeloid disorders.

The 8p11 myeloproliferative syndrome (EMS) is associated with three translocations, t(8;13)(p11;q12), t(8;9)(p11;q33), and t(6;8)(q27;p11), that fuse unrelated genes (ZNF198, CEP110, and FOP, respectively) to the entire tyrosine kinase domain of FGFR1. In all cases thus far examined (n = 10), the t(8;13) results in an identical mRNA fusion between ZNF198 exon 17 and FGFR1 exon 9. To determine if consistent fusions are also seen in the variant translocations, we performed RT-PCR on four cases and sequenced the products. For two patients with a t(8;9), we found that CEP110 exon 15 was fused to FGFR1 exon 9. For two patients with a t(6;8), we found that FOP exon 5 (n = 1) or exon 7 (n = 1) was fused to FGFR1 exon 9. To determine if FGFR1 might be involved in other myeloid disorders with translocations of 8p, we developed a two-color FISH assay using two differentially labeled PAC clones that flank FGFR1. Disruption of this gene was indicated in a patient with a t(8;17)(p11;q25) and Ph-negative chronic myeloid leukemia in association with systemic malignant mast cell disease, a patient with acute myeloid leukemia with a t(8;11)(p11;p15), and two cases with T-cell lymphoma, myeloproliferative disorder, and marrow eosinophilia with a t(8;12)(p11;q15) and ins(12;8)(p11;p11p21), respectively. For the patient with the t(8;11), the chromosome 11 breakpoint was determined to be in the vicinity of NUP98. We conclude that 1) all mRNA fusions in EMS result in splicing to FGFR1 exon 9 but breakpoints in FOP are variable, 2) two-color FISH can identify patients with EMS, and 3) the t(8;17)(p11;q25), t(8;11)(p11;p15), t(8;12)(p11;q15), and ins(12;8)(p11;p11p21) are novel karyotypic changes that most likely involve FGFR1.

The impact of initiatives in education, self-management training, and computer-assisted self-care on outcomes in diabetes disease management.

The purpose of this work is to elucidate the advantages and disadvantages arising from three distinct diabetes disease management initiatives in a managed care setting. The initiatives included (1) education alone, (2) education with self-management training, and (3) education with computer-assisted self-care. Outcomes of interest were changes in glycated hemoglobin (HbA1c), body weight, and costs of care in each cohort of care recipients. A total of 978 health plan members with diabetes within a mixed model HMO were included in the initiatives for improving blood glucose control. HbA1c was measured at baseline and at 3 and 12 months, body weight at baseline and 12 months, and costs of care over 1 year. Costs were derived from suppliers and the health plan. The design is a longitudinal observation study. With the edu-cation-alone initiative, costs, HbA1c, and body weight were unchanged. When education is supplemented with ongoing self-management training, HbA1c fell 1.1% (p < 0.01), body weight rose by 11 kg (p < 0.01), and costs for care increased by $18 per member per month. When education is supplemented with ongoing computer-assisted self-care, HbA1c also dropped by 1.1% (p < 0.01), body weight was unchanged (p > 0.4), and costs for care were $1.31 per member per month. All initiatives improved glycated hemoglobin. Other outcomes must therefore be considered. Among the initiatives, this study elucidated significant differences in body weight and costs. Therefore, in choosing a diabetes disease management program, it would appear that costs should be the primary consideration and methodologies that control body weight should be a priority.

Structural properties of the intact and the reconstructed coracoclavicular ligament complex.

Numerous procedures have been described for the operative management of acromioclavicular joint injuries, but surprisingly little information is available on the ultimate mechanical behavior of the native coracoclavicular ligament complex or on the various methods of reconstruction. We tested 19 fresh-frozen cadaveric bone-ligament-bone preparations of the coracoclavicular ligament in uniaxial tension at 25 mm/min until failure. Seven specimens were left intact, six had the trapezoid ligament sectioned, and six had the conoid ligament sectioned. Reconstruction of the coracoclavicular ligament was achieved using coracoacromial ligament transfers, woven polyester slings, suture anchors, and Bosworth screws; all reconstructions were also tested to failure. The intact coracoclavicular ligament failed by avulsion or midsubstance tear at 500 (+/-134) N, with a stiffness of 103 (+/-30) N/mm and elongation to failure of 7.7 (+/-1.9) mm. There was no significant difference between the contributions of the conoid or trapezoid ligaments in this loading configuration. Coracoclavicular slings and suture anchors provided strength similar to that of the coracoclavicular ligament, but with significantly greater deformations (14 to 26 mm). Screw fixation resulted in comparable stiffness and superior strength to the coracoclavicular ligament, but only if bicortical purchase was obtained. Coracoacromial ligament transfers were the weakest and least stiff, and augmentation with another form of coracoclavicular fixation is recommended. These results provide a useful baseline for comparison of the initial performance of reconstructive techniques with the performance of the native coracoclavicular ligament.

Topical maxacalcitol for the treatment of psoriasis vulgaris: a placebo-controlled, double-blind, dose-finding study with active comparator.

1alpha, 25-Dihydroxy-22-oxacalcitriol (maxacalcitol) is a vitamin D3 analogue which displays approximately 10 times greater efficacy at suppressing keratinocyte proliferation in vitro than calcipotriol and tacalcitol. To determine clinical efficacy, a phase II double-blind, randomized, left vs. right, concentration-response study was performed with once-daily topical maxacalcitol in patients with mild to moderate chronic plaque psoriasis. Primary efficacy parameters were psoriasis severity index (PSI) based on sum of scores for erythema, scaling and induration and investigators' overall assessment of patients' response to therapy at 8 weeks of treatment. One hundred and forty-four patients participated. All concentrations of maxacalcitol ointment (6, 12.5, 25 and 50 microg/g) were significantly more effective at reducing PSI than placebo (P < 0.01), with greatest effect noted for maxacalcitol 25 microg/g. Calcipotriol ointment 50 microg/g once daily as active comparator had a similar effect. Marked improvement or clearance of psoriasis was greatest for maxacalcitol 25 microg/g (55% of subjects) which compared favourably with calcipotriol (46%). Improvement continued throughout the study period, with no plateau at week 8. Investigators' and patients' side preference (secondary efficacy parameters) rated maxacalcitol more effective than placebo and 25 microg/g maxacalcitol better than calcipotriol (P < 0.05 for investigators' assessment). Twelve patients withdrew from the study due to adverse events, of which four were judged to be due to study medication. This study indicates that once-daily maxacalcitol ointment is effective in the management of plaque psoriasis, with greatest effect noted at 25 microg/g. As no response plateau was noted at 8 weeks, these data suggest that further benefit might be obtained if maxacalcitol ointment were applied for longer. Finally, investigators' overall assessment and side preference suggest that maxacalcitol 25 microg/g may be more effective than once-daily calcipotriol.

Diabetes intervention in the information age.

Sustained improvement in blood glucose control is the only treatment outcome which will reduce or eliminate the long term complications of diabetes mellitus. We have designed and evaluated an electronic information system which facilitates this task. The system is voice-interactive, physician directed and affords, to remote patients, 24 h access via touch-tone telephone. Accordingly, patients access the system each day to report self-measured blood glucose levels or hypoglycaemic symptoms together with dietary changes, planned exercise, stress, illness or other lifestyle events. In turn they receive immediate advice with respect to medication dosing changes, and other pertinent feedback. Preliminary system beta-testing for safety and efficacy was performed for one year in an open study of 204 patients derived from two independent, health-care environments. Among the two testing centres, over 60,000 telephone cells were received by the computer systems during the start-up year. Safety and efficacy expectations were met. In addition, prevalence of diabetes related crises (hyperglycaemia or hypoglycaemia) fell approximately 3-fold. Glycated haemoglobin fell significantly (1.0-1.3%) in patients actively using the system. In control groups of patients not actively using the system, there were no improvements in metabolic control while body weights were stable in all groups. The new system was safe and effective in our hands and empowered our health professionals to provide improved diabetes care.

Comparison of CLA with BPT, SPT, and RAST in children with asthma.

Bronchial provocation tests (BPT) with allergen extracts were performed in 82 children with asthma, and the results were compared with the chemiluminescent assay (CLA), the radio-allergo-sorbent-test (RAST) and skin prick test (SPT). It was found that CLA matched BPT with a concordance of 87% (77-93%), RAST with a concordance of 74% (64-83%) and SPT with 80% (70-88%). Most often, CLA and RAST gave similar results, although their classes did not match precisely.

Statistical problems in assessing the true value of new in vitro diagnostic tests, with special reference to the chemiluminescent assay (CLA, MAST).

By virtue of familiarity and usage over many years, diagnostic tests may become established and be regarded as infallible "Gold Standards". In the case of allergic disease no test except perhaps allergen challenge can ever precisely reflect the clinical disease at the actual site of the allergic reaction. Thus when a new test is introduced there are no fixed values available for statistical comparison when directly comparing established tests with more recent additions. This is illustrated by many articles comparing the new multiple allergosorbent test system (CLA, MAST) which is a chemiluminescent assay, to other previously established tests. The major reports on CLA in the diagnosis of allergy are here discussed and summarized. Most trials have compared the accuracy of CLA with clinical history, with the skin prick test (SPT), the universally used in vivo method, or with RAST, the most common in vitro diagnostic method. CLA performed similarly to SPT and most CLA and RAST results matched; nevertheless in statistical analyses the problems of comparing diagnostic methods without a Gold Standard against which to judge become obvious-if two fallible methods disagree, which is correct? These statistical problems are discussed as well as other difficulties, such as the impact of the use of different allergen sources and the differing prevalence of allergies in the various test populations analysed.

Relationships between skin prick test, radioallergosorbent test, and chemiluminescent assays in allergic children.

The results of skin prick tests (SPT), radioallergosorbent tests (RAST), and multiple chemiluminescent tests (DHS-CLA) to grass mix, parietaria, D. farinae, and D. pteronyssinus were evaluated in 43 allergic children. All CLA tests had valid positive and negative control threads. Chemiluminescent assays class 4 matched with RAST class 3 and/or 4 and CLA class 3 with RAST class 2. The D. farinae, D. pteronyssinus, and grass results obtained with CLA, RAST, and SPT were investigated by principal components analysis that showed a good association between different methods of measuring allergenicity. The results of the present study confirm that DHS-CLA is an effective "in vitro" method for the detection of IgE-allergen specific antibody.

A study of changes in red cell volume and haemoglobin concentration during phlebotomy induced iron deficiency and iron repletion using the Technicon H1.

The recently introduced Technicon H1 analyser uses an improved optical principle to measure the size and haemoglobin concentration of erythrocytes. We have made a serial study of ten patients undergoing phlebotomy to induce mild iron deficiency. The instrument showed the early development of anisohypochromia with subsequent fall in the mean cell haemoglobin concentration (MCHC). Cell volume was preserved until relatively late and during early iron deficient erythropoiesis cell volume would appear to be maintained at the expense of haemoglobin concentration. The Technicon H6000 (conventional technology) used in parallel produced contrasting results indicating anisomicrocytosis with preservation of cell haemoglobin concentration until relatively late. Five cases of severe iron deficiency treated with iron were similarly studied and showed comparable changes on both instruments, with characteristically bimodal cell volume histograms and large increases in red cell distribution width. Our results indicate that the new generation of instruments will generate red cell data of additional clinical value.

Immunotherapy of tree pollen allergy with a modified alginate conjugated birch pollen extract compared to an aluminium adsorbed extract.

The safety and efficacy of two birch pollen extracts, one chemically conjugated to alginate (Anjuvac) the other adsorbed to aluminium hydroxide (Alutard), were investigated in an open multicentre comparative study of 63 birch pollen allergic patients. Both extracts decreased the nasal symptoms during the birch pollen season. The changes in specific IgE and IgG were much the same in both treatment groups. The adverse reactions recorded were mild in both groups, but more frequent in the Anjuvac group, probably because of a more aggressive dose schedule though there were twice as many asthmatics in the Anjuvac group. The two investigated allergen extracts were useful alternatives for immunotherapy.

Translocation t(11;13) and deletion of chromosome 7 in a patient with acute myelomonocytic leukemia.

A translocation between chromosomes 11 and 13, together with a deletion of the long arm of chromosome 7, was found in the bone marrow of a patient with acute myelomonocytic leukemia (AMMOL). All three breakpoints are believed to be associated with a predisposition to malignancy.

Gentamicin and low dose piperacillin in febrile neutropenic patients.

One hundred and twenty-seven febrile neutropenic patients were randomized to receive empirical antibiotic therapy with intravenous gentamicin and 12 g/day or 8 g/day piperacillin. Despite a high incidence of Hickman catheter infections by antibiotic-resistant bacteria, there was an overall response in 56% of patients and no difference in the numbers responding to each antibiotic regimen. In addition, the duration of fever was not significantly different in the two groups of patients. The majority of the unresponsive patients responded to the addition of further antibiotics and there were only two infection related deaths. The results suggest that high dose antibiotics are not essential for the initial empirical therapy in febrile neutropenic patients.

A double-blind study of hyposensitization with an alginate conjugated extract of D. pteronyssinus (Conjuvac) in patients with perennial rhinitis. 1. Clinical aspects.

The efficacy of hyposensitization with a standardised extract of Dermatophagoides pteronyssinus (D. pteronyssinus) conjugated to alginate and containing known amounts of antigen P1 (Conjuvac) was tested in a double blind, placebo controlled, multi-centre study in 66 adult patients with perennial rhinitis. Patients received 11 weekly injections of increasing concentrations of Conjuvac containing from 56 x 10(1) to 448 10(3) IU D. pteronyssinus or placebo injections of the alginate diluent to some of which 5 micrograms of histamine has been randomly added. This was followed by 15 monthly injections of Conjuvac or placebo. The severity of nasal blockage, sneezing and rhinorrhoea was recorded twice daily in a diary and visual analogue assessments (VAS) made at each clinic visit. Nasal provocation testing (NPT) was performed with increasing concentrations of the same extract of D. pteronyssinus as used in the hyposensitization injections, and changes in nasal airways resistance measured by passive anterior rhinomanometry. VAS was recorded and NPT was performed on entry to the study and after the fifth, ninth and final monthly injection. Conjuvac injections were well tolerated. Large local reactions (greater than 5 cm) occurred within 30 min in only 1% of patients but later in 23%. No systemic reactions or anaphylaxis occurred within 30 min of injections, but urticaria or worsening of asthma and rhinitis was reported later in 3% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)