Dose rationale and pharmacokinetics of dexmedetomidine in mechanically ventilated new-borns: impact of design optimisation

Abstract Purpose There is a need for alternative analgosedatives such as dexmedetomidine in neonates. Given the ethical and practical difficulties, protocol design for clinical trials in neonates should be carefully considered before implementation. Our objective was to identify a protocol design suitable for subsequent evaluation of the dosing requirements for dexmedetomidine in mechanically ventilated neonates. Methods A published paediatric pharmacokinetic model was used to derive the dosing regimen for dexmedetomidine in a firstin-neonate study. Optimality criteria were applied to optimise the blood sampling schedule. The impact of sampling schedule optimisation on model parameter estimation was assessed by simulation and re-estimation procedures for different simulation scenarios. The optimised schedule was then implemented in a neonatal pilot study. Results Parameter estimates were more precise and similarly accurate in the optimised scenarios, as compared to empirical sampling (normalised root mean square error: 1673.1% vs. 13,229.4% and relative error: 46.4% vs. 9.1%). Most importantly, protocol deviations from the optimal design still allowed reasonable parameter estimation. Data analysis from the pilot group (n = 6) confirmed the adequacy of the optimised trial protocol. Dexmedetomidine pharmacokinetics in term neonates was scaled using allometry and maturation, but results showed a 20% higher clearance in this population compared to initial estimates obtained by extrapolation from a slightly older paediatric population. Clearance for a typical neonate, with a post-menstrual age (PMA) of 40 weeks and weight 3.4 kg, was 2.92 L/h. Extension of the study with 11 additional subjects showed a further increased clearance in pre-term subjects with lower PMA. Conclusions The use of optimal design in conjunction with simulation scenarios improved the accuracy and precision of the estimates of the parameters of interest, taking into account protocol deviations, which are often unavoidable in this event-prone population

ETHICS OF MANDATORY PREMARITAL HIV TESTING IN AFRICA: THE CASE OF GOMA, DEMOCRATIC REPUBLIC OF CONGO

Despite decades of prevention efforts, millions of persons worldwide continue to become infected by the human immunodeficiency virus (HIV) every year. This urgent problem of global epidemic control has recently lead to significant changes in HIV testing policies. Provider-initiated approaches to HIV testing have been embraced by the Centers for Disease Control and Prevention and the World Health Organization, such as those that routinely inform persons that they will be tested for HIV unless they explicitly refuse (‘opt out’). While these policies appear to increase uptake of testing, they raise a number of ethical concerns that have been debated in journals and at international AIDS conferences. However, one special form of ‘provider-initiated’ testing is being practiced and promoted in various parts of the world, and has advocates within international health agencies, but has received little attention in the bioethical literature: mandatory premarital HIV testing. This article analyses some of the key ethical issues related to mandatory premarital HIV testing in resource-poor settings with generalized HIV epidemics. We will first briefly mention some mandatory HIV premarital testing proposals, policies and practices worldwide, and offer a number of conceptual and factual distinctions to help distinguish different types of mandatory testing policies. Using premarital testing in Goma (Democratic Republic of Congo) as a point of departure, we will use influential public health ethics principles to evaluate different forms of mandatory testing. We conclude by making concrete recommendations concerning the place of mandatory premarital testing in the struggle against HIV/AIDS

Tuberculosis control in resource-poor countries: alternative approaches in the era of HIV

WHO projections suggest that the annual number of tuberculosis (TB) cases worldwide will reach 10.2 million by the year 2000. HIV plays a dominant role in this increase in many resource-poor countries. The internationally recommended treatment regimens for TB combine some of the six major antituberculosis drugs: isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin, and thiacetazone. WHO treatment guidelines give priority to patients according to the nature of their disease and recommend two regimens of 6-8 months duration, the longer regimen incorporating thiacetazone. Recently, WHO has favored a 6-month treatment regimen given as directly observed therapy (DOT). The disadvantages of the standard approach are the heavy workload of smear examinations, the complexity of some drug regimens, and the low rates of therapy completion. With the increasing TB case load in areas of high HIV infection prevalence, laboratories cannot do initial as well as follow-up smear examinations. In Botswana the proportion of smear-positive TB cases declined to 40% in 1992, but the overall proportion of patients who had smears performed had declined (52% in 1992). The multiple regimens in use cause confusion and nonadherence to guidelines. Nonadherence is the major risk factor for the emergence of drug resistance, and low completion rates are the most obvious signs of inadequate control programs. Alternative approaches mean ensuring high completion rates and using the most effective drugs. Regarding diagnosis, research might show that the number of smears could be reduced depending on the initial reading. There is no reason why a rifampicin-based short-course regimen could not replace the multiple regimens now in use. Rifampicin-containing regimens of 62-78 doses given intermittently have been effective and are suitable for use within a DOT program. For prevention of drug resistance, only pills combining different drugs should be used and rifampicin should be limited to the treatment of TB and leprosy

Patients with coronary stenosis and a fractional flow reserve of ≥0.75 measured in daily practice at the VU University Medical Center

Objectives. The aim of this study was to analyse the rate of major adverse clinical events in patients with coronary artery disease and a fractional flow reserve (FFR) of ≥0.75 and deferred for coronary intervention in daily practice

Estimating HIV Incidence Using a Cross-Sectional Survey: Comparison of Three Approaches in a Hyperendemic Setting, Ndhiwa Subcounty, Kenya, 2012

International audienc

Volkskunde.

Editors: 1888-93, K.M. Pol de Mont, August Gittée.- 1894- K.M. Pol de Mont, Alfons de Cock.Suspended 1915-19, 1921, 1932 and 1939.Mode of access: Internet.1940- "officieel orgaan van de Volkskundecommissie der nederlandsche Akademie van wetenschappen."v. 1-25, 1888-1914

Contribution of reinfection to recurrent tuberculosis in South African gold miners

SETTING: A gold mine in South Africa. OBJECTIVE: To investigate incidence and risk factors for tuberculosis (TB) recurrence and the relative contribution of reinfection and relapse to recurrence. DESIGN: Prospective cohort study. METHODS: Employees cured of a first episode of culture-positive TB were followed up for recurrence, which was classified as reinfection or relapse by restriction fragment length polymorphism using an insertion sequence (IS) 6110 probe. RESULTS: Among 609 patients, 57 experienced recurrence during a median follow-up period of 1.02 years, corresponding to a recurrence rate of 7.89 per 100 person-years (py). The culture positive recurrence rate was 5.79/ 100 py, and was higher in human immunodeficiency virus (HIV) infected patients (8.86/100 py in HIV-infected vs. 3.35/100 py in non-HIV-infected). Among HIV-infected patients, the risk of culture-positive recurrence was higher with decreasing CD4 count (compared with CD4 < 200, hazard ratios for recurrence among individuals with CD4 200-500 and CD4 > 500 were 0.40 [95%CI 0.14-1.09] and 0.14 [95%CI 0.02-1.10], respectively, Ptrend = 0.01). IS6110 genotyping was available on both the initial and subsequent isolate for 16/42 (38%, 14 HIV-infected) patients with culture-positive recurrence, and showed reinfection in 11 (69%). CONCLUSION: HIV-infected gold miners, particularly those who are more immunosuppressed, are at higher risk of TB recurrence. TB control strategies need to take into account reinfection as an important cause of recurrent TB. © 2008 The Union.Articl

Towards rational dosing algorithms for vancomycin in neonates and infants based on population pharmacokinetic modeling

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