Review of therapeutic drug monitoring of anticancer drugs part one - Cytotoxics.

Most anticancer drugs are characterised by a steep dose-response relationship and narrow therapeutic window. Inter-individual pharmacokinetic (PK) variability is often substantial. The most relevant PK parameter for cytotoxic drugs is the area under the plasma concentration versus time curve (AUC). Thus it is somewhat surprising that therapeutic drug monitoring (TDM) is still uncommon for the majority of agents. Goals of the review were to assess the rationale for more widely used TDM of cytotoxics in oncology. There are several reasons why TDM has never been fully implemented into daily oncology practice. These include difficulties in establishing appropriate concentration target ranges, common use of combination chemotherapies for many tumour types, analytical challenges with prodrugs, intracellular compounds, the paucity of published data from pharmacological trials and 'Day1=Day21' administration schedules. There are some specific situations for which these limitations are overcome, including high dose methotrexate, 5-fluorouracil infusion, mitotane and some high dose chemotherapy regimens. TDM in paediatric oncology represents an important challenge. Established TDM approaches includes the widely used anticancer agents carboplatin, busulfan and methotrexate, with 13-cis-retinoic acid also recently of interest. Considerable effort should be made to better define concentration-effect relationships and to utilise tools such as population PK/PD models and comparative randomised trials of classic dosing versus pharmacokinetically guided adaptive dosing. There is an important heterogeneity among clinical practices and a strong need to promote TDM guidelines among the oncological community.

Diagnostic accuracy of G-CSF, IL-8, and IL-1ra in critically ill children with suspected infection.

OBJECTIVE: To elucidate the diagnostic accuracy of granulocyte colony-stimulating factor (G-CSF), interleukin-8 (IL-8), and interleukin-1 receptor antagonist (IL-1ra) in identifying patients with sepsis among critically ill pediatric patients with suspected infection. DESIGN AND SETTING: Nested case-control study in a multidisciplinary neonatal and pediatric intensive care unit (PICU) PATIENTS: PICU patients during a 12-month period with suspected infection, and plasma available from the time of clinical suspicion (254 episodes, 190 patients). MEASUREMENTS AND RESULTS: Plasma levels of G-CSF, IL-8, and IL-1ra. Episodes classified on the basis of clinical and bacteriological findings into: culture-confirmed sepsis, probable sepsis, localized infection, viral infection, and no infection. Plasma levels were significantly higher in episodes of culture-confirmed sepsis than in episodes with ruled-out infection. The area under the receiver operating characteristic curve was higher for IL-8 and G-CSF than for IL-1ra. Combining IL-8 and G-CSF improved the diagnostic performance, particularly as to the detection of Gram-negative sepsis. Sensitivity was low (<50%) in detecting Staphylococcus epidermidis bacteremia or localized infections. CONCLUSIONS: In this heterogeneous population of critically ill children with suspected infection, a model combining plasma levels of IL-8 and G-CSF identified patients with sepsis. Negative results do not rule out S. epidermidis bacteremia or locally confined infectious processes. The model requires validation in an independent data-set.

The use of classification and regression trees to predict the likelihood of seasonal influenza.

Background Individual signs and symptoms are of limited value for the diagnosis of influenza. Objective To develop a decision tree for the diagnosis of influenza based on a classification and regression tree (CART) analysis. Methods Data from two previous similar cohort studies were assembled into a single dataset. The data were randomly divided into a development set (70%) and a validation set (30%). We used CART analysis to develop three models that maximize the number of patients who do not require diagnostic testing prior to treatment decisions. The validation set was used to evaluate overfitting of the model to the training set. Results Model 1 has seven terminal nodes based on temperature, the onset of symptoms and the presence of chills, cough and myalgia. Model 2 was a simpler tree with only two splits based on temperature and the presence of chills. Model 3 was developed with temperature as a dichotomous variable (≥38°C) and had only two splits based on the presence of fever and myalgia. The area under the receiver operating characteristic curves (AUROCC) for the development and validation sets, respectively, were 0.82 and 0.80 for Model 1, 0.75 and 0.76 for Model 2 and 0.76 and 0.77 for Model 3. Model 2 classified 67% of patients in the validation group into a high- or low-risk group compared with only 38% for Model 1 and 54% for Model 3. Conclusions A simple decision tree (Model 2) classified two-thirds of patients as low or high risk and had an AUROCC of 0.76. After further validation in an independent population, this CART model could support clinical decision making regarding influenza, with low-risk patients requiring no further evaluation for influenza and high-risk patients being candidates for empiric symptomatic or drug therapy.

Prevalence of Helicobacter pylori Infection in a Rural Area of the State of Mato Grosso, Brazil

The prevalence of Helicobacter pylori infection was evaluated by ELISA in 40 children and teenagers and in 164 adults from a rural area of the State of Mato Grosso, Brazil. Antibodies to H. pylori were detected in the serum of 31 (77.5%) children and teenagers and in 139 (84.7%) adults. The prevalence of infection increased with age (c2 for trend, p < 0.01) even though no variations occurred in the region in the present century in terms of living conditions or sanitation, economical development and migratory influx supporting the hypothesis that the infection is also acquired during later life in developing countries. An inverse correlation was observed between the prevalence of infection and annual family income (c2 for trend, p < 0.013). There was no correlation between type of system for sewage disposal and prevalence of infection (p = 0.8). In conclusion, the prevalence of H. pylori infection in Nossa Senhora do Livramento, a rural area from Brazil, is very high and similar to that observed in other developing countries. Furthermore, the increase in the prevalence of infection with age observed in this population seems to be due to both, cohort effect and acquisition of the infection during later life

Distribution of Sandflies (Diptera:Psychodidae) on Tree-trunks in a Non-flooded Area of the Ducke Forest Reserve, Manaus, AM, Brazil

Sandflies were collected in the base of tree-trunks in the seasons of high and least rainfall in the Ducke Forest Reserve, near Manaus in the State of Amazonas. Lutzomyia umbratilis was the most abundant sandfly species. Caryocar villosum, Chrysophyllum amazonicum, Dinizia excelsa, Eschweilera atropetiolata and Parkia multijuga were the tree species on which most sandflies were collected and relative abundance were related to trunk characteristics. Seasonal patterns of sandfly distribution in the forest were observed.

Obesity markers and estimated 10-year fatal cardiovascular risk in Switzerland.

BACKGROUND AND AIM: There is an ongoing debate on which obesity marker better predicts cardiovascular disease (CVD). In this study, the relationships between obesity markers and high (>5%) 10-year risk of fatal CVD were assessed. METHODS AND RESULTS: A cross-sectional study was conducted including 3047 women and 2689 men aged 35-75years. Body fat percentage was assessed by tetrapolar bioimpedance. CVD risk was assessed using the SCORE risk function and gender- and age-specific cut points for body fat were derived. The diagnostic accuracy of each obesity marker was evaluated through receiver operating characteristics (ROC) analysis. In men, body fat presented a higher correlation (r=0.31) with 10-year CVD risk than waist/hip ratio (WHR, r=0.22), waist (r=0.22) or BMI (r=0.19); the corresponding values in women were 0.18, 0.15, 0.11 and 0.05, respectively (all p<0.05). In both genders, body fat showed the highest area under the ROC curve (AUC): in men, the AUC (95% confidence interval) were 76.0 (73.8-78.2), 67.3 (64.6-69.9), 65.8 (63.1-68.5) and 60.6 (57.9-63.5) for body fat, WHR, waist and BMI, respectively. In women, the corresponding values were 72.3 (69.2-75.3), 66.6 (63.1-70.2), 64.1 (60.6-67.6) and 58.8 (55.2-62.4). The use of the body fat percentage criterion enabled the capture of three times more subjects with high CVD risk than the BMI criterion, and almost twice as much as the WHR criterion. CONCLUSION: Obesity defined by body fat percentage is more related with 10-year risk of fatal CVD than obesity markers based on WHR, waist or BMI.

Guidance on the transfer of mentally disordered patients detained under the Mental Health (NI) Order 1986 to and from Hospitals in Great Britain - August 2011 (PDF 101 KB)

Guidance on the transfer of mentally disordered patients detained under the Mental Health (NI) Order 1986 to and from Hospitals in Great Britain - August 2011.

Credit risk contributions under the Vasicek one-factor model: a fast wavelet expansion approximation

To measure the contribution of individual transactions inside the total risk of a credit portfolio is a major issue in financial institutions. VaR Contributions (VaRC) and Expected Shortfall Contributions (ESC) have become two popular ways of quantifying the risks. However, the usual Monte Carlo (MC) approach is known to be a very time consuming method for computing these risk contributions. In this paper we consider the Wavelet Approximation (WA) method for Value at Risk (VaR) computation presented in [Mas10] in order to calculate the Expected Shortfall (ES) and the risk contributions under the Vasicek one-factor model framework. We decompose the VaR and the ES as a sum of sensitivities representing the marginal impact on the total portfolio risk. Moreover, we present technical improvements in the Wavelet Approximation (WA) that considerably reduce the computational effort in the approximation while, at the same time, the accuracy increases.

Joint Communique Under The Auspices of The North South Ministerial Council On Safeguarding Child Protection (PDF 28KB)

This Communication Strategy has been developed by representatives of the statutory sector and Non-Governmental Organisations (NGOs) from the voluntary and community sectors from both Northern Ireland and the Republic of Ireland

Estimation of glomerular filtration rate in hospitalised patients: are we overestimating renal function?

QUESTIONS UNDER STUDY AND PRINCIPLES: Estimating glomerular filtration rate (GFR) in hospitalised patients with chronic kidney disease (CKD) is important for drug prescription but it remains a difficult task. The purpose of this study was to investigate the reliability of selected algorithms based on serum creatinine, cystatin C and beta-trace protein to estimate GFR and the potential added advantage of measuring muscle mass by bioimpedance. In a prospective unselected group of patients hospitalised in a general internal medicine ward with CKD, GFR was evaluated using inulin clearance as the gold standard and the algorithms of Cockcroft, MDRD, Larsson (cystatin C), White (beta-trace) and MacDonald (creatinine and muscle mass by bioimpedance). 69 patients were included in the study. Median age (interquartile range) was 80 years (73-83); weight 74.7 kg (67.0-85.6), appendicular lean mass 19.1 kg (14.9-22.3), serum creatinine 126 μmol/l (100-149), cystatin C 1.45 mg/l (1.19-1.90), beta-trace protein 1.17 mg/l (0.99-1.53) and GFR measured by inulin 30.9 ml/min (22.0-43.3). The errors in the estimation of GFR and the area under the ROC curves (95% confidence interval) relative to inulin were respectively: Cockcroft 14.3 ml/min (5.55-23.2) and 0.68 (0.55-0.81), MDRD 16.3 ml/min (6.4-27.5) and 0.76 (0.64-0.87), Larsson 12.8 ml/min (4.50-25.3) and 0.82 (0.72-0.92), White 17.6 ml/min (11.5-31.5) and 0.75 (0.63-0.87), MacDonald 32.2 ml/min (13.9-45.4) and 0.65 (0.52-0.78). Currently used algorithms overestimate GFR in hospitalised patients with CKD. As a consequence eGFR targeted prescriptions of renal-cleared drugs, might expose patients to overdosing. The best results were obtained with the Larsson algorithm. The determination of muscle mass by bioimpedance did not provide significant contributions.

Simulium cuasiexiguum, a new blackfly species (Diptera: Simuliidae) from the Minaçu area in the State of Goiás, Central Brazil

During studies of Simuliidae at a suspected new focus of human onchocerciasis in central Brazil a new species of Simulium was found. Full descriptions of the adults and pupae of this species, S. cuasiexiguum, are described here, its affinities to closely related species in the subgenus Notolepria are discussed and its distribution in Brazil recorded.

Community Pharmacy Contractor Agreement for Provision of Community Pharmacy Services Under the Health Act 1970

MEMORANDUM OF AGREEMENT BETWEEN THE DEPARTMENT OF HEALTH AND THE IRISH PHARMACEUTICAL UNION IN RESPECT OF THE PROVISION OF COMMUNITY PHARMACY SERVICES UNDER THE HEALTH ACT, 1970 Read the memorandum