Prospective evaluation of a D-optimal designed population pharmacokinetic study

Recently, methods for computing D-optimal designs for population pharmacokinetic studies have become available. However there are few publications that have prospectively evaluated the benefits of D-optimality in population or single-subject settings. This study compared a population optimal design with an empirical design for estimating the base pharmacokinetic model for enoxaparin in a stratified randomized setting. The population pharmacokinetic D-optimal design for enoxaparin was estimated using the PFIM function (MATLAB version 6.0.0.88). The optimal design was based on a one-compartment model with lognormal between subject variability and proportional residual variability and consisted of a single design with three sampling windows (0-30 min, 1.5-5 hr and 11 - 12 hr post-dose) for all patients. The empirical design consisted of three sample time windows per patient from a total of nine windows that collectively represented the entire dose interval. Each patient was assigned to have one blood sample taken from three different windows. Windows for blood sampling times were also provided for the optimal design. Ninety six patients were recruited into the study who were currently receiving enoxaparin therapy. Patients were randomly assigned to either the optimal or empirical sampling design, stratified for body mass index. The exact times of blood samples and doses were recorded. Analysis was undertaken using NONMEM (version 5). The empirical design supported a one compartment linear model with additive residual error, while the optimal design supported a two compartment linear model with additive residual error as did the model derived from the full data set. A posterior predictive check was performed where the models arising from the empirical and optimal designs were used to predict into the full data set. This revealed the optimal'' design derived model was superior to the empirical design model in terms of precision and was similar to the model developed from the full dataset. This study suggests optimal design techniques may be useful, even when the optimized design was based on a model that was misspecified in terms of the structural and statistical models and when the implementation of the optimal designed study deviated from the nominal design.

Organizational aspects of e-referrals

Three different, well established systems for e-referral were examined. They ranged from a system in a single country handling a large number of cases (60,000 per year) to a global system covering many countries which handled fewer cases (150 per year). Nonetheless, there appeared to be a number of common features. Whether the purpose is e-transfer or e-consultation, the underlying model of the e-referral process is: the referrer initiates an e-request; the organization managing the process receives it, the organization allocates it for reply; the responder replies to the initiator. Various things can go wrong and the organization managing the e-referral process needs to be able to track requests through the system; this requires various performance metrics. E-referral can be conducted using email, or as messages passed either directly between computer systems or via a Web-link to a server. The experience of the three systems studied shows that significant changes in work practice are needed to launch an e-referral service successfully. The use of e-referral between primary and secondary care improves access to services and can be shown to be cost-effective.

A national survey of telehealth activity in Australian hospitals

We conducted a national survey of Australian hospitals to assess their use of telehealth. Information was sought from the 814 hospitals with 10 or more beds, excluding the small number that provided only day surgery and seven for which we could not identify a contact person. A total of 564 replies were received (a 69% response rate). Nationally, nearly half (49%) reported that they were engaged in some telehealth activity. However, there was a significant difference across jurisdictions. Hospitals in the public sector were significantly more likely to report the use of telehealth than those in the private sector (62% vs 14%). Hospital remoteness was measured according to the Accessibility/Remoteness Index of Australia (ARIA). The highest levels of use were reported by hospitals in 'very remote' and 'remote' areas (90% and 88%, respectively), with moderate levels of use in 'moderately accessible' and 'accessible' areas (67% and 52%, respectively) and the lowest level of use in 'highly accessible' areas (35%). This trend was significant.

A review of the first year's experience with an automatic message-routing system for low-cost telemedicine

The Swinfen Charitable Trust has used email for some years as a low-cost telemedicine medium to provide consultant support for doctors in developing countries. A scalable, automatic message-routing system was constructed which automates many of the tasks involved in message handling. During the first 12 months of its use, 1510 messages were processed automatically. There were 128 referrals from 18 hospitals in nine countries. Of these 128 queries, 89 (70%) were replied to within 72 h; the median delay was 1.1 day. The 39 unanswered queries were sent to backup specialists for reply and 36 of them (92%) were replied to within 72 h. In the remaining three cases, a second-line (backup) specialist was required. The referrals were handled by 54 volunteer specialists from a panel of over 70. Two system operators, located 10 time zones apart, managed the system. The median time from receipt of a new referral to its allocation to a specialist was 0.2 days (interquartile range, IQR, 0.1-0.8). The median interval between receipt of a new referral and first reply was 2.6 days (IQR 0.8-5.9). Automatic message handling solves many of the problems of manual email telemedicine systems and represents a potentially scalable way of doing low-cost telemedicine in the developing world.

Self-reported difficulty in conceiving as a measure of infertility

BACKGROUND: This study aimed to explore the meaning and potential use of women's self-reported difficulties in conceiving as a measure of infertility in epidemiological studies, and to compare women's stated reasons for infertility with information in their medical records. METHODS: Data were available from a population-based case-control study of ovarian cancer involving 1638 women. The sensitivity and specificity of women's self-reported infertility were calculated against their estimated fertility status based on detailed reproductive histories. Self-reported reasons for infertility were compared with diagnoses documented in women's medical records. RESULTS: The sensitivity of women's self-reported difficulty in conceiving was 66 and 69% respectively when compared with calendar-derived and self-reported times taken trying to conceive; its specificity was 95%. Forty-one (23%) of the 179 women for whom medical records were available had their self-reported fertility problem confirmed. Self-reported infertility causes could be compared with diagnoses in medical records for only 22 of these women. CONCLUSIONS: Self-reported difficulty conceiving is a useful measure of infertility for quantifying the burden of fertility problems experienced in the community. Validation of reasons for infertility is unlikely to be feasible through examination of medical records. Improved education of the public regarding the availability and success rates of infertility treatments is proposed.

Differences in ethical attitudes between registered nurses and medical students

In this study we compared the ethical attitudes of a group of experienced, predominantly female, registered nurses (n = 67) with those of a group of final year, mixed sex, medical students (n = 125). The purpose was to determine the basis of differences in attitudes that could lead to ethical disagreements between these two groups when they came to work together. A questionnaire developed to explore ethical attitudes was administered and the responses of the two groups were compared using t-tests. Because of the preponderance of females among the nurses an analysis of variance of the gender-adjusted scores for each group was also carried out. On comparing the responses, the nurses differed significantly from the medical students in a number of ethical domains. A potential source of conflict between these two groups is that the nurses were inclined to adopt the perspective of patients but the medical students identified with their profession. When corrected for the effects of gender, the differences persisted, indicating that it was discipline that determined the differences. We recommend that students of nursing and medicine receive ethics education together, and that more open dialogue between doctors and nurses with respect to their different ethical viewpoints is needed in the work setting. This article will be of interest to educators of students of medicine and nursing, as well as to doctors and nurses who are eager to improve their professional relations and thereby improve patient care.

Estimating disease likelihood: a case of rubbery figures

In diagnosis and prognosis, we should avoid intuitive “guesstimates” and seek a validated numerical aid

Abolition of valproate-derived choleresis in the Mrp2 transporter-deficient rat

Valproic acid (VPA) is a major therapeutic agent in the treatment of epilepsy and other neurological disorders. It is metabolized in humans and rats primarily along two pathways: direct glucuronidation to yield the acyl glucuronide (VPA-G) and beta-oxidation. We have shown much earlier in the Sprague-Dawley rat that i.v. administration of sodium valproate (NaVPA) caused a marked choleresis ( mean of 3.3 times basal bile flow after doses of 150 mg/kg), ascribed to the passive osmotic flow of bile water following excretion of VPA-G across the canalicular membrane. Active biliary pumping of anionic drug conjugates across the canalicular membrane is now believed to be attributable to transporter proteins, in particular Mrp2, which is deficient in the TR- ( a mutant Wistar) rat. In the present study, normal Wistar and Mrp2-deficient TR- rats were dosed i.v. with NaVPA at 150 mg/kg. In the Wistar rats, there was a peak choleretic effect of about 3.2 times basal bile flow, occurring at about 30 to 45 min postdose ( as seen previously with Sprague-Dawley rats). In TR- rats given the same i.v. dose, there was no evidence of postdose choleresis. The choleresis was correlated with the excretion of VPA-G into bile. In Wistar rats, 62.8 +/- 7.7% of the NaVPA dose was excreted in bile as VPA-G, whereas in TR- rats, only 2.0 +/- 0.6% of the same dose was excreted as VPA-G in bile ( with partial compensatory excretion of VPA-G in urine). This study underlines the functional ( bile flow) consequences of biliary transport of xenobiotic conjugated metabolites.

Assessment of volume depletion in children with malaria

Background The degree of volume depletion in severe malaria is currently unknown, although knowledge of fluid compartment volumes can guide therapy. To assist management of severely ill children, and to test the hypothesis that volume changes in fluid compartments reflect disease severity, we measured body compartment volumes in Gabonese children with malaria. Methods and Findings Total body water volume (TBW) and extracellular water volume (ECW) were estimated in children with severe or moderate malaria and in convalescence by tracer dilution with heavy water and bromide, respectively. Intracellular water volume (ICW) was derived from these parameters. Bioelectrical impedance analysis estimates of TBW and ECW were calibrated and bioelectrical impedance analysis measurements were taken daily against dilution methods, until discharge. Sixteen children had severe and 19 moderate malaria. Severe childhood malaria was associated with depletion of TBW (mean [SD] of 37 [33] ml/kg, or 6.7% [6.0%]) relative to measurement at discharge. This is defined as mild dehydration in other conditions. ECW measurements were normal on admission in children with severe malaria and did not rise in the first few days of admission. Volumes in different compartments (TBW, ECW, and ICW) were not related to hyperlactataemia or other clinical and laboratory markers of disease severity. Moderate malaria was not associated with a depletion of TBW. Conclusions Significant hypovolaemia does not exacerbate complications of severe or moderate malaria. As rapid rehydration of children with malaria may have risks, we suggest that fluid replacement regimens should aim to correct fluid losses over 12-24 h.

Effects of Helicobacter pylori eradication among adults with intellectual disability

Background Compared to the general population, Helicobacter pylori infection is more common among adults with intellectual disability (ID) and is associated with greater levels of disability, maladaptive behaviour, and institutionalization. Little information exists about the effects of eradication therapy in this group, so we aimed to evaluate: (1) success of a standard H. pylori eradication protocol; (2) frequency of side-effects; and (3) impact of eradication on level of functional ability and maladaptive behaviour. Method A cohort of adults with ID underwent assessment of their levels of function and maladaptive behaviour, medical history, physical examination, and H. pylori testing using serology and faecal antigen tests. Some received standard H. pylori eradication therapy. Twelve months later, participants underwent repeat assessment, were grouped by change in H. pylori status and compared. Results Of 168 participants, 117 (70%) were currently infected with H. pylori at baseline, and 96 (82%) of the 117 were given standard H. pylori eradication therapy. The overall eradication rate was 61% but 31% reported side-effects. Institutional status of the participants, their level of behaviour or function, and number of comorbid medical conditions were not associated with failure of eradication. There were no statistically significant differences in level of behaviour or function, ferritin, or weight between the groups in whom H. pylori was eradicated or stayed positive. Conclusion Adults with ID have lower H. pylori eradication and higher side-effect rates than the general population. Levels of maladaptive behaviour and disability did not improve with eradication and thus greater levels of maladaptive behaviour or disability appear to be risk factors for, rather than consequences of, H. pylori infection.