Once-daily gentamicin dosing for the preterm and term newborn: proposal for a simple regimen that achieves target levels.

OBJECTIVE: Based on recent safety and efficacy data, combined with the known pharmacokinetic parameters of aminoglycosides in the newborn, once-daily gentamicin should be preferable to the many other dosing regimens currently in use. Although there are growing data to support its use in term newborns, experience with preterm infants is more limited. In our Neonatal Intensive Care Unit, we experienced difficulties regarding complicated dosing regimens, actual dosing errors, and the tendency to check trough and peak levels around the third dose for infants receiving only a 48 hour course. Therefore, we conducted a quality improvement initiative in which we developed and tested a clinical practice guideline for the use of once-daily gentamicin for preterm and term infants that we hoped would yield trough and peak levels in our target range. METHODS: We combined a review of the published English language literature with pharmacokinetic analysis of our own data prior to initiation of this new regimen to design the following dosing regimen: <35 weeks gestation: 3 mg/kg q 24 hours, > or =35 weeks gestation: 4 mg/kg q 24 hours. Our goal serum levels were a trough < or =2 microg/ml and a peak between 6 and 12 microg/ml. We collected and analyzed trough and peak levels from all infants receiving this dosing regimen in the first week of life for at least 72 hours between 3/1/99 and 12/31/00. RESULTS: In total, 214 babies met our inclusion criteria, 75 of whom were <35 weeks gestation. 100% of babies of all gestational ages had a nontoxic trough level. For infants <35 weeks gestation, 79% had a therapeutic peak level, with a mean value of 6.8 microg/ml. For infants of at least 35 weeks gestation, 93% had a therapeutic peak level, with a mean value of 8.4 microg/ml. 92% of nontherapeutic peaks were too low. CONCLUSION: This study of once-daily gentamicin represents the largest sample size of pre-term infants published to date. The proposed regimen is simple and yields a high proportion of desirable levels. We recommend it for use in preterm and term newborns.     

Measurement in clinical trials: A neglected issue for statisticians?

Biostatisticians have frequently uncritically accepted the measurements provided by their medical colleagues engaged in clinical research. Such measures often involve considerable loss of information. Particularly, unfortunate is the widespread use of the so‐called ‘responder analysis’, which may involve not only a loss of information through dichotomization, but also extravagant and unjustified causal inference regarding individual treatment effects at the patient level, and, increasingly, the use of the so‐called number needed to treat scale of measurement. Other problems involve inefficient use of baseline measurements, the use of covariates measured after the start of treatment, the interpretation of titrations and composite response measures. Many of these bad practices are becoming enshrined in the regulatory guidance to the pharmaceutical industry. We consider the losses involved in inappropriate measures and suggest that statisticians should pay more attention to this aspect of their work. Copyright © 2009 John Wiley & Sons, Ltd.     

Autonomy and modernisation: the management of change in an English primary care trust

Recent New Labour policy for the ‘modernisation’ of Government places a good deal of emphasis on decentralisation. This emphasis is particularly marked in relation to the organisation of primary care. However, like hospitals and other National Health Service institutions, primary care trusts (PCTs) are subject to a substantial raft of centrally established performance targets and indicators, including those which contribute to the public award of between zero and three performance ‘stars’. This raises questions about the extent to which employees can exercise autonomy in the context of rigid top‐down directives. This paper presents findings from a study using participant observation and interviews to examine the impact of a training course aimed ostensibly at increasing employee autonomy in an English PCT. The suggestion is that attempts to make employees more autonomous can be seen as a strategy for increasing central control based upon the internalisation by the employees of centrally promulgated values. The attraction of such strategies is that they may be potentially more effective and less costly than alternative strategies of direct control. However, the study suggests that the outcome of attempts by such methods as programmes to increase employee autonomy may be very different from those intended.     

Contemporary Models of Youth Development and Problem Prevention: Toward an Integration of Terms,Concepts, and Models

Over the past several years, increased interest in preventing youth problems and promoting healthy youth development has led youth and family practitioners, policy makers, and researchers to develop a wide range of approaches based on various theoretical frameworks. Although the growth in guiding frameworks has led to more complex models and a greater diversity in the options available to scholars and practitioners, the lack of an integrative conceptual scheme and consistent terminology has led to some confusion in the field. Here, we provide an overview of three approaches to youth development and problem prevention, critically examine their strengths and weaknesses, and offer some elaborations to help clarify, extend, and integrate the models. We conclude by discussing some general implications for researchers, practitioners, and policy makers.     

Comparison of survival by allocation to medical therapy, surgery, or heart transplantation for ischemic advanced heart failure.

BACKGROUND: To ascertain survival of ischemic advanced heart failure patients by treatment allocation, we examined the outcome of transplant assessment patients allocated to medical therapy, high-risk conventional surgery, or transplantation. METHODS: Patients were identified from the Papworth transplant database and excluded if primary etiology was not ischemic. Grouping was undertaken according to treatment allocation at initial assessment, and analysis was performed by intention to treat. Survival was computed from the time of assessment and Cox regression used to stratify patients according risk with the Heart Failure Survival Score. RESULTS: From May 1993 to September 2001, a total of 755 patients were admitted for transplant assessment, with 348 (46.1%) identified as having heart failure of ischemic origin. Variables required for calculation of the Heart Failure Survival Score was available in 273 patients (78.4%), and 20 patients (7.3%) were lost to follow-up. Of the remaining 253 patients, 89 (35.2%) were allocated to medical therapy, 32 (12.6%) to surgery, and 132 (52.2%) to transplantation. The relative risk (95% confidence limit) of death compared with medical therapy was 0.62 (0.28, 1.40) for surgery and 0.38 (0.24, 0.61) for transplantation in medium- to high-risk patients. For low-risk patients, the relative risks for death compared with medical therapy were 1.87 (0.63, 5.60) for surgery and 1.97 (0.79, 4.96) for transplantation. CONCLUSIONS: Transplantation improved survival of medium- and high-risk patients compared with medical therapy. In the low-risk group, this was not evident. However, repeated assessment of risk is required because the hazard for death rises steadily after the third year in these patients.     

Variable impairment of wound healing in the heterozygous collagenase-resistant mouse

Collagen undergoes dramatic reorganization during wound repair. Matrix metalloproteinases degrade and remodel collagen in a tightly controlled process. The collagenase-resistant mouse, Col1a1(tm1Jae), produces type I collagen, which is resistant to degradation by human matrix metalloproteinase 1. These mice grow normally but develop thickened skin with age. We have previously reported that the early wound repair response in homozygous mutant (Col1a1(r/r)) mice is delayed compared to wild type (Col1a1(+/+)). However, the late-stage scar of Col1a1(r/r) wounds was not significantly altered compared to Col1a1(+/+). Here we have investigated the response of heterozygous mice (Col1a1(+/r)) to wounding, not previously reported. Wound reepithelialization was delayed to a similar degree to wounds in the Col1a1(r/r) mice. However, the recovery of impaired wound contraction was faster in Col1a1(+/r) than in Col1a1(r/r) mice, but still slower than in wild-type animals. Analysis of wound protein extracts showed expression of some matrix metalloproteinases was prolonged in both the Col1a1(r/r) and Col1a1(+/r) wounds compared to wild type. We suggest the partial resistance of collagen to collagenase-mediated degradation in the heterozygous animals causes equivalent impairment of keratinocyte migration compared to homozygous collagenase-resistant mice, but that wound contraction during late-stage healing is only partially retarded.     

Pharmacotherapy for cancer pain

The first 150 words of the full text of this article appear below. Key points Cancer pain management services must integrate withpalliative and primary care. Pain is common in cancer and usuallyoccurs in more than one site. Careful assessment and treatmentsaimed at the causes of the pain are essential. Optimal oralpharmacotherapy manages more than 75% of patients with cancerpain. If specific anti-cancer therapy, drugs, physical andpsychological treatments fail, then more invasive therapiesshould be considered early.