Tyrosine kinase-targeting drugs-associated heart failure.

BACKGROUND: The impact of cancer therapies on cardiac disease in the general adult cancer survivor population is largely unknown. Our objective was to evaluate which tyrosine kinase-targeting drugs are associated with greater risk for new-onset heart failure (HF). METHODS: A nested case-control analysis was conducted within a cohort of 27 992 patients of Clalit Health Services, newly treated with a tyrosine kinase-targeting, and/or chemotherapeutic drug, for a malignant disease, between 1 January 2005 and 31 December 2012. Each new case of HF was matched to up to 30 controls from the cohort on calendar year of cohort entry, age, gender, and duration of follow-up. Main outcome measure was odds ratio (OR) with 95% confidence interval (CI) of new-onset HF. RESULTS: There were 936 incident cases of HF during 71 742 person-years of follow-up. Trastuzumab (OR 1.90, 95% CI 1.46-2.49), cetuximab (OR 1.72, 1.10-2.69), panitumumab (OR 3.01, 1.02-8.85), and sunitinib (OR 3.39, 1.78-6.47) were associated with increased HF risk. Comorbidity independently associated with higher risk in a multivariable conditional regression model was diabetes mellitus, hypertension, chronic renal failure, ischaemic heart disease, valvular heart disease, arrhythmia, and smoking. CONCLUSIONS: Trastuzumab, cetuximab, panitumumab, and sunitinib are associated with increased risk for new-onset HF.

Multiple Sclerosis impact on employment and income in New Zealand.

BACKGROUND AND OBJECTIVES: We investigated the demographic, social and clinical characteristics associated with employment status and income for people with multiple sclerosis (MS) in New Zealand (NZ). METHODS: The NZ National MS Prevalence study included all persons resident in NZ on census day 2006 diagnosed with MS (96.7% coverage). Factors associated with employment and income status among the working age population (25-64 years) were identified by linear regression. RESULTS: Over 90% of working age people with MS (n=1727) had a work history, but 54% were not working. Work loss occurred early in the disease course, and at low disability (P<.001). Advancing age, progressive disease, longer disease duration, higher disability levels, partner loss and lower education were associated with work loss (P<.001). Working age people with MS had lower income than the NZ population (P<.0001). Higher qualifications yielded no additional income for MS females and about half the additional income for MS males (P<.0001). CONCLUSIONS: MS profoundly reduces employment and income early in the disease course, and at low levels of disability, however, unemployment is not entirely accounted for by clinical, social and demographic factors. These findings suggest social supports should be explored early in the disease course to reduce loss of income and unemployment for people with MS.

Assessing the extent and use of risk analysis methodologies in Africa, using data derived from the Performance of Veterinary Services (PVS) Pathway.

African countries that wish to export are increasingly faced with import risk assessments from importing countries concerned about the sources of their imported goods. Other risk analysis methodologies and approaches are also employed, which focus on animal and human health within countries and communities. Based on an analysis of evaluations conducted by the World Organisation for Animal Health (OIE), using the Performance of Veterinary Services Tool, the authors attempt to define current practice in Africa and degrees of compliance with the World Trade Organization Agreement on the Application of Sanitary and Phytosanitary Measures ('SPS Agreement') and OIE standards. To assist in this task, the authors also make use of a review of selected risk assessment reports. Results point to a lack of technical capacity and capability to conduct risk assessments in compliance with OIE standards (except in the case of three countries), ranging from an outright absence of any form of (documented) risk assessment and consecutive risk management decisions (level of advancement 1) to shortcomings in one or several aspects of the risk assessment process. This is confirmed by a number of case studies, half of which have been produced by international consultants. The major recommendations of this paper are i) to strengthen the human resources pool for conducting risk assessments and ii) to establish dedicated risk assessment units, with clear terms of reference, job descriptions and policies, procedures and protocols.

Les pays africains souhaitant accéder aux marchés d'exportation sont confrontés à la réalisation de plus en plus fréquente d'appréciations du risque à l'importation par les pays importateurs, qui cherchent à vérifier les sources d'approvisionnement des marchandises qu'ils importent. D'autres méthodologies d'analyse du risque sont également pratiquées, axées sur la santé animale et la santé humaine au niveau des pays et des communautés. À partir d'une analyse des évaluations réalisées par l'Organisation mondiale de la santé animale (OIE) au moyen de l'Outil d'évaluation des performances des Services vétérinaires, les auteurs tentent de définir les pratiques actuelles en Afrique ainsi que le niveau de conformité des pays à l'Accord sur l'application des mesures sanitaires et phytosanitaires de l'Organisation mondiale du commerce (« Accord SPS ¼) et aux normes de l'OIE. Pour ce faire, les auteurs s'appuient également sur l'analyse d'une sélection de rapports d'appréciation du risque. Les résultats laissent apparaître l'inadéquation des capacités et des compétences techniques dédiées à l'appréciation du risque par rapport aux normes de l'OIE (à l'exception du cas de trois pays), depuis l'absence totale d'appréciation du risque à partir d'éléments documentés et de décisions relevant de la gestion de ce risque (niveau d'avancement 1), jusqu'à des insuffisances concernant un ou plusieurs aspects du processus d'appréciation du risque. Cette analyse est confirmée par une série d'études de cas, dont la moitié a été produite par des consultants internationaux. Les auteurs recommandent principalement de renforcer les ressources humaines dédiées aux appréciation du risque et de mettre en place des unités dédiées, en déterminant clairement leur mandat, leur fonction, ainsi que les politiques à mener, les procédures applicables et les protocoles à suivre.

Cada vez más, los países africanos que desean exportar son sometidos a determinaciones del riesgo de importación por parte de los países importadores, preocupados por la procedencia de las mercancías que importan. A veces también se emplean otros métodos y planteamientos de análisis del riesgo, centrados en determinados aspectos zoosanitarios y sanitarios de los países o comunidades de origen. Basándose en un análisis de las evaluaciones realizadas por la Organización Mundial de Sanidad Animal (OIE) con la Herramienta PVS, los autores tratan de aprehender los usos actualmente vigentes en África, así como los niveles de cumplimiento del Acuerdo sobre la Aplicación de Medidas Sanitarias y Fitosanitarias (Acuerdo MSF) de la Organización Mundial del Comercio (OMC) y las normas de la OIE, ayudándose también para ello del estudio de una serie de informes de determinación de riesgos. Los resultados ponen de relieve la falta de competencias y capacidades técnicas para llevar a cabo determinaciones de riesgos con arreglo a las normas de la OIE (salvo en el caso de tres países), con situaciones que van desde la ausencia absoluta de toda forma de determinación (documentada) de los riesgos y, a partir de ahí, de toda decisión para gestionarlos (nivel de progreso 1), hasta la existencia de uno o varios aspectos defectuosos en el proceso de determinación de riesgos, observación que confirman una serie de estudios monográficos, la mitad de ellos obra de consultores internacionales. Las principales recomendaciones de los autores apuntan a fortalecer la dotación de recursos humanos para efectuar determinaciones de riesgos y a establecer unidades dedicadas específicamente a esta labor, habiendo definido con toda claridad su mandato, los perfiles que deben integrarlas y sus políticas, procedimientos y protocolos de trabajo.

Latent class regression models for simultaneously estimating test accuracy, true prevalence and risk factors for Brucella abortus.

In 2003/2004 a field trial was conducted in Northern Ireland to assess the diagnostic accuracy of six serological tests for bovine brucellosis caused by Brucella abortus. Whereas between-test comparisons have been used to calculate test performances so far, the present study used a latent class approach to estimate diagnostic test accuracy parameters in the absence of a gold standard for these six tests simultaneously and to estimate the true prevalence, while accounting for clustering in the study population and risk factors for true prevalence. Results obtained in this study with regard to prevalence, sensitivity and specificity were largely in accordance with previous findings. Screening tests (SAT and EDTA) appeared to be the most sensitive; however, at low prevalences the EDTA and CFT showed the highest positive predictive values of all investigated tests. The specificities and negative predictive values of all diagnostic tests were found to be very high. Differences of prevalence between three groups of the study population with different risk of exposure could be attributed to the mode of sampling indicating that a more risk-based sampling will result in a higher prevalence than a cross-sectional sampling mode. Age, dairy status and history of abortion were shown to influence the prediction of the latent true infection status.

Serum protein signatures detect early radiographic osteoarthritis.

OBJECTIVE: To test the hypothesis that early knee and hand osteoarthritis (OA) development is characterized by detectable changes in serum proteins relevant to inflammation, cell growth, activation, and metabolism several years before OA becomes radiographically evident. METHODS: Using microarray platforms that simultaneously test 169 proteins relevant to inflammation, cell growth, activation and metabolism, we conducted a case-control study nested within the Baltimore Longitudinal Study of Aging (BLSA). Subjects included 22 incident cases of OA and 66 age-, sex- and body mass index (BMI)-matched controls. Serum samples tested were obtained at the time of radiographic classification as either case or control, and up to 10 years earlier at a time when all participants were free of radiographic OA. Proteins with mean signal intensities fourfold higher than background were compared between cases and controls using multivariate techniques. RESULTS: Sixteen proteins were different between OA cases compared to controls. Four of these proteins [matrix metalloproteinase (MMP)-7, interleukin (IL)-15, plasminogen activator inhibitor (PAI)-1 and soluble vascular adhesion protein (sVAP)-1] were already different in samples obtained 10 years before radiographic classification and remained different at the time of diagnosis. Six additional proteins were only associated with subsequent OA development and not with established OA. CONCLUSIONS: Changes in serum proteins implicated in matrix degradation, cell activation, inflammation and bone collagen degradation products accompany early OA development and can precede radiographic detection by several years.

An all-island approach to mapping bovine tuberculosis in Ireland.

This study used techniques in Geographical Information Systems (GIS) to explore the spatial patterns of bovine tuberculosis (TB) in the whole island of Ireland over an 11-year period. This is the first time that data pertaining to TB from the Republic of Ireland and Northern Ireland have been collated and examined in an all-Ireland context. The analyses were based on 198, 156 point locations representing active farms with cattle in Northern Ireland and the Republic of Ireland between the years 1996 and 2006. The results consist of a series of maps giving a visual representation of cattle populations and associated detected bTB levels on the island of Ireland over this time interval.

Risk associated with animals moved from herds infected with brucellosis in Northern Ireland.

The movement of cattle from herds infected with Brucella abortus was investigated in order to assess the control measures for eradication of brucellosis from the cattle population of Northern Ireland. Using recorded cattle movement data, a historical cohort study was designed and carried out to quantify the risk of seropositivity in bovine animals moved from herds infected with brucellosis. The study found that 3.1% of animals, moved in the 6-month period prior to disclosure of infection in the source herd and subsequently tested, were interpreted as seropositive in their destination herds. The odds of seropositivity were approximately 19 (95% confidence interval: 7.8-46.4) times higher in this cohort compared with animals from herds with no history of infection. A multivariate logistic regression model was constructed to examine factors influencing the risk of seropositivity in the exposed cohort of animals, identifying maternal status (whether the dam had been a brucellosis reactor) and age at leaving the infected herd as the main risk factors.

Improving the tools of clinical pharmacology: Goals for 2017 and beyond.

Current trends in pronounced late-stage attrition rates of promising drug candidates are a pressing concern for patients, providers, and other stakeholders across the health care system. Here, we describe six areas in which clinical pharmacology methods and frameworks can help ameliorate these trends in late-stage attrition and increase the efficiency of drug development and evaluation. These recommendations are based, in part, on previous stakeholder engagement and input, as well as a previously published white paper.

Factors that Influence Mycobacterium bovis Infection in Red Deer and Wild Boar in an Epidemiological Risk Area for Tuberculosis of Game Species in Portugal.

Bovine tuberculosis (bTB) is a worldwide zoonotic disease of domestic and wild animals. Eradication has proved elusive in those countries with intensive national programmes but with ongoing transmission between wildlife and cattle. In Portugal, a high-risk area for bTB was defined and specific measures implemented to assess and minimize the risk from wildlife. Data from the 2011 to 2014 hunting seasons for red deer (Cervus elaphus) and wild boar (Sus scrofa) were analysed with bovine demographic and bTB information to assess factors that determined the occurrence and distribution of bTB in both species. The likelihood of bTB-like lesions in wild boar was positively associated with density of red deer, wild boar and cattle, while for red deer, only their density and age were significant factors. The likelihood of Mycobacterium bovis isolation in wild boar was associated with density of cattle and red deer and also with the anatomical location of lesions, while for red deer, none of the variables tested were statistically significant. Our results suggest that, in the study area, the role of red deer and wild boar may be different from the one previously suggested by other authors for the Iberian Peninsula, as red deer may be the driving force behind M. bovis transmission to wild boar. These findings may assist the official services and game managing bodies for the management of hunting zones, what could also impact the success of the bTB eradication programme.

The Northern Ireland programme for the control and eradication of Mycobacterium bovis.

Bovine tuberculosis is endemic in Northern Ireland and a comprehensive eradication scheme has been in operation since 1959. The current programme involves annual testing, extensive computerized tracing, short-interval testing of herds contiguous to outbreaks and compulsory slaughter of positive cattle. Despite initial reductions in disease prevalence, eradication has proved elusive and potential explanatory factors include high cattle density and potential for between-herd contact, the impact of exotic diseases on resource priorities, and significant levels of bovine tuberculosis in a wildlife reservoir, the European badger (Meles meles). Both the role of the infected bovine and that of the badger in spreading disease have to be addressed to ensure progress towards eradication. Current measures are described and future options for enhancing the programme are outlined.

Epidemiology of bovine brucellosis in Northern Ireland between 1990 and 2000.

Between 1990 and 2000, 317 herds of cattle in Northern Ireland were identified as being seropositive to Brucella abortus, and 68 per cent of them were attributed to transmission from neighbouring herds or to local spread. Of particular significance were three primary outbreaks in 1997, which resulted in significant secondary and tertiary spread. Three spatial clusters were identified, corresponding to two of the primary outbreaks, and the herd density and within-herd spread were highest in the largest cluster. Abortions in an infected herd and the disease-risk status of the disclosure test were positively associated with an increased within-herd prevalence.

Weak promotion of C3H/10T1/2 cell transformation by repeated treatments with formaldehyde.

C3H/10T 1/2 cells were treated with N-methyl-N'-nitro-N-nitrosoguanidine and then repeatedly exposed to formaldehyde (0.1 to 2.0 micrograms/ml). Exposure of N-methyl-N'-nitro-N-nitrosoguanidine-initiated cultures to formaldehyde concentrations of 0.5 or 1.0 micrograms/ml in a variety of treatment regimens resulted in focus formation in up to 9% of the treated dishes. Transformed foci were observed in 2% or less of the cultures treated with N-methyl-N'-nitro-N-nitrosoguanidine or formaldehyde alone. Formaldehyde thus appears to be only a weak tumor promoter for C3H/10T 1/2 cell transformation.

Potential role of treatment artifact in the effect of cell density upon frequencies of C3H/10T1/2 cell transformation.

Reports of unusual increases in transformation frequency in low density cultures of C3H/10T1/2 cells suggest that transformation occurs via an indirect multistage mechanism. The effect of surviving cell density upon subsequent focus production was examined in C3H/10T1/2 cultures treated with acetone, 12-O-tetradecanoylphorbol-13-acetate (TPA), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), MNNG plus TPA, or 3-methylcholanthrene (MCA). Foci developed independent of cell density in 0.5 and 5.9% of all cultures exposed to acetone and TPA (0.25 micrograms/ml), respectively. Transformation after treatment with MNNG (0.5 micrograms/ml) occurred with low frequency (less than or equal to 7 X 10(-4)/surviving cell) and was enhanced by TPA. In MNNG plus TPA treated cultures containing less than or equal to 140 viable cells the fraction of dishes with foci was dependent upon the number of cells present at the time of MNNG treatment. As a result, relatively constant frequencies of focus formation were obtained (less than or equal to 6 X 10(-3) after correction for focus formation in TPA treated solvent controls). Focus frequency declined at cell densities greater than or equal to 350 cells. In contrast, treatment with MCA (1.0 microgram/ml) produced transformed foci with frequencies that varied from 3.3 X 10(-2) at the lowest density (5.5 cells) to 5.4 X 10(-4) at the highest (4400 cells). In low density cultures (5.6-56 cells), the fraction of dishes with foci was independent of the number of cells treated. Thus cell density had differential effects upon the frequency of foci produced by MCA or MNNG plus TPA. However, binding studies demonstrated that 6-7% of the MCA added to cell culture dishes was retained after the termination of carcinogen treatment. This residual MCA possessed biological activity which may be sufficient to elevate transformation frequencies in low density cultures.

GPS for QSP: A Summary of the ACoP6 Symposium on Quantitative Systems Pharmacology and a Stage for Near-Term Efforts in the Field.

Quantitative Systems Pharmacology (QSP) is experiencing increased application in the drug discovery and development process. Like its older sibling, systems biology, the QSP field is comprised of a mix of established disciplines and methods, from molecular biology to engineering to pharmacometrics. As a result, there exist critical segments of the discipline that differ dramatically in approach and a need to bring these groups together toward a common goal.

Control of Bovine Brucellosis from Persistently Infected Holdings Using RB51 Vaccination with Test-and-Slaughter: A Comparative Case Report from a High Incidence Area in Portugal.

Bovine brucellosis due to Brucella abortus infection causes significant reproductive and production losses in cattle and is a major zoonosis. Eradication of this disease has proved difficult to achieve in Portugal where it still occurs in some regions despite an ongoing national eradication programme. In 2004, the Alentejo region, a major cattle producing area, reported one of the highest levels of bovine brucellosis in the country, especially in one divisional area. In that area, bovine brucellosis was particularly problematic in a holding of ten herds, the largest extensive cattle unit in the country, which remained infected despite an extensive test-and-slaughter programme and depopulation of five herds. A 5-year programme of RB51 vaccination with biannual test-and-slaughter was thus implemented in 2004. The apparent animal seroprevalence decreased from 19% (646/3,400) to 3% (88/2930) on the third herd-level test and remained below 0.8% (27/3324) after the fourth test. After the tenth test, the holding had a prevalence of 0.1% (2/2332) and only one herd remained positive with a within-herd prevalence of 1.1% (2/177). The results were compared to all other herds (n = 10) in the divisional area that were also persistently infected but were subject only to test-and-slaughter before being depopulated. In these herds, the strategy of test-and-slaughter did not reduce the prevalence, which remained significantly higher than the vaccinated group (median = 0.48% and 8.5% in vaccinated versus non-vaccinated herds; Wilcoxon rank sum test; P < 0.01). The success of this pilot programme in continental Portugal provided a valuable case study to the official veterinary services by illustrating the value of RB51 vaccination with parallel testing and improved biosecurity as a comprehensive and sustainable strategy for bovine brucellosis control in persistently infected herds.

Systematic and quantitative assessment of the effect of chronic kidney disease on CYP2D6 and CYP3A4/5.

Recent reviews suggest that chronic kidney disease (CKD) can affect the pharmacokinetics of nonrenally eliminated drugs, but the impact of CKD on individual elimination pathways has not been systematically evaluated. In this study we developed a comprehensive dataset of the effect of CKD on the pharmacokinetics of CYP2D6- and CYP3A4/5-metabolized drugs. Drugs for evaluation were selected based on clinical drug-drug interaction (CYP3A4/5 and CYP2D6) and pharmacogenetic (CYP2D6) studies. Information from dedicated CKD studies was available for 13 and 18 of the CYP2D6 and CYP3A4/5 model drugs, respectively. Analysis of these data suggested that CYP2D6-mediated clearance is generally decreased in parallel with the severity of CKD. There was no apparent relationship between the severity of CKD and CYP3A4/5-mediated clearance. The observed elimination-route dependency in CKD effects between CYP2D6 and CYP3A4/5 may inform the need to conduct clinical CKD studies with nonrenally eliminated drugs for optimal use of drugs in patients with CKD.

Alprazolam kinetics in the elderly. Relation to antipyrine disposition.

The pharmacokinetics of alprazolam, a triazolobenzodiazepine anxiolytic-antidepressant, were assessed in 32 healthy men and women aged 21 to 78 years after a single 1.0-mg oral dose. Peak alprazolam levels averaged 20.4 ng/mL and were reached a mean of 1.25 hours after dosage. Mean elimination half-life did not differ significantly between elderly and young women, nor did total metabolic clearance. However, half-life was significantly prolonged, and total clearance significantly reduced, in elderly v young men. Antipyrine oxidizing capacity was also evaluated, and half-life for the two drugs was highly correlated, as were their metabolic clearances. Thus, old age is associated with impaired capacity to oxidize alprazolam, but this effect is far more apparent in men than in women. A test of antipyrine half-life and clearance may help identify slow or rapid metabolizers of alprazolam.

On-line coal analysis using fast neutron-induced gamma-rays.

On-line measurement of bulk elemental composition is often best achieved with highly penetrative neutron-gamma techniques. CSIRO has developed and implemented one such technique, neutron inelastic-scattering and thermal-capture analysis (NITA). A distinctive feature of NITA is its use of fast neutron sources to generate inelastic scattering reactions, thus exciting gamma-rays from industrially important elements such as carbon and oxygen. A full-scale prototype for on-line coal quality measurement has been tested under simulated industrial conditions. The effect of sample compositional inhomogeneity and stream thickness will be discussed.

Risk factors for visible lesions or positive laboratory tests in bovine tuberculosis reactor cattle in Northern Ireland.

An observational case-control study was conducted to investigate risk factors for confirmed bovine tuberculosis (bTB) infection in cattle reacting positively to the single intradermal comparative cervical test (SICCT) in Northern Ireland in the years 1998, 2002 and 2006. Macroscopic lesions were detected at slaughter (positive visible lesion (VL) status) in 43.0% of reactor cattle, whilst 45.3% of those sampled were confirmed as bTB positive due to the presence of lesions or positive histopathology/mycobacterial culture (positive bTB status). In 97.5% of the reactors, the VL status and bTB status were either both negative or both positive. Generalized linear mixed model analyses were conducted on data of 24,923 reactor cattle with the variables herd identifier, local veterinary office (DVO) and abattoir being used as random effects within all the models generated at univariable and multivariable level. The other variables within the dataset were used as fixed effects. Significant risk factors associated with VL status and bTB status at multivariable level (p<0.05) included age at death, breed, sex, test year, net increase in skin thickness at bovine tuberculin injection site, epidemiological status of skin test, total number of reactors at the disclosure test, mean herd size and prior response to the skin test. These risk factors are likely related to the time since infection, the strength of the challenge of infection and the susceptibility of the animal. These findings are important as the detection of visible lesions and the confirmation of bTB are an integral part of the overall bTB control programme in Northern Ireland and the veterinary meat inspection and hygiene programme. The visible lesion status and bTB status of an animal can affect the way in which bTB breakdowns are managed, since failure to detect visible lesions and recovery of Mycobacterium bovis can lead to a less stringent follow-up after other risk factors have been taken into account.

Forearm vascular alpha 1-adrenergic blockade by verapamil.

With use of direct brachial artery infusion and measurement of forearm blood flow and vascular resistance by strain gauge plethysmography, the effect of verapamil on phenylephrine-induced vasoconstriction was determined. Seven healthy men (age range, 19 to 47 years; weight range, 68 to 108 kg; mean blood pressure, 74 to 100 mm Hg; five nonsmokers) were systemically beta-blocked with intravenous administrations of 10 mg propranolol. Each subject then received ascending doses of phenylephrine (0.191 to 7.6 micrograms/min) alone and with concurrent verapamil (19.1 micrograms/min) by brachial arterial infusion. Dose-ratio during verapamil infusion compared with control was 8.1 (p less than 0.05). No change in slope of the phenylephrine dose-response curve was noted; however, consistent with the dose ratio, verapamil shifted the curve to the right with a decrease in the y intercept determined by linear regression (60.0 versus 40.3 mm Hg ml/100 ml forearm volume/min; p less than 0.05). Verapamil-induced attenuation of forearm vasoconstriction elicited by phenylephrine indicates that, in humans, in vivo verapamil forearm vasodilating effects are, in part, a result of alpha 1-adrenergic blockade.