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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Application of systems pharmacology to explore mechanisms of hepatotoxicity.

Advances in systems biology have allowed the development of a highly characterized systems pharmacology model to study mechanisms of drug-induced hepatotoxicity. In this issue of CPT, Yang et al. describe a model, DILIsym, used to characterize mechanisms of hepatotoxicity of troglitazone. Their modeling approach has provided new insight into troglitazone-induced hepatotoxicity in humans but is not associated with hepatotoxicity in rats, consistent with preclinical data for this drug.

Bovine tuberculosis in Northern Ireland: risk factors associated with time from post-outbreak test to subsequent herd breakdown.

Compulsory bovine tuberculosis testing has been implemented since 1959 in Northern Ireland. Initial rapid progress in the eradication of the disease was followed by a situation where disease levels tended to fluctuate around a low level. This study explores recrudescence of bovine tuberculosis (bTB) in Northern Ireland herds by assessing risk factors associated with time from the six-month post-outbreak skin test until a further herd breakdown. Bovine herds (n=3377) were recruited in 2002 and 2003 and their survival analysed using Kaplan-Meier survival estimates and a Cox proportional hazards model, with follow-up extending to August 2008. Exclusion criteria applied for study entry were bTB infection in a contiguous herd, changing of post restriction test to one of a higher risk status or chronic infection. Chronic infection was defined as any situation where disclosure preceded the post-outbreak test by two years or more. The application of these exclusion criteria meant that herds recruited to the study were largely cleared of infection and not directly contiguous to other infected herds. Of the 3377 herds, 1402 (41.5%) suffered a further herd breakdown before the end of follow-up. Median survival time was 582 days (interquartile range=336-1002 days). Breakdown severity (defined as the number of Single Intradermal Comparative Tuberculin Test (SICTT) reactors at disclosure test), local bTB prevalence, herd size and type were identified as significant risk factors (p<0.05), as was the purchase of higher numbers (n>27.38 per year) of cattle. Consistent with other studies this work shows bTB confirmation to not be predictive of a future herd breakdown. This work shows bTB history as not being a risk factor for a future breakdown. This result could be reflective of the exclusion criteria used in the study, which may have selected for incidents where historical status was of less importance.

Use of internet search logs to evaluate potential drug adverse events.

Internet search logs provide an abundant source of data that can be explored for purposes such as identifying drug exposure-adverse event relationships. The methodology to rigorously conduct such evaluations is not well characterized, and the utility of such analyses is not well defined. In this issue, White and colleagues propose an approach using Internet search logs for this purpose and compare it to parallel analyses conducted using the US Food and Drug Administration's spontaneous reporting database.

Bovine tuberculosis trends in the UK and the Republic of Ireland, 1995-2010.

Selected demographic features and trends in bovine tuberculosis (BTB) from 1995 to 2010 are described for the countries of the UK and the Republic of Ireland, using standardised definitions and measures. All countries experienced a reduction in the number of cattle and herds and in the proportion of dairy herds, while average herd size increased. In general, the trends indicate a stable situation of very low BTB prevalence in Scotland and, over most of the period, a rising prevalence in England and Wales. The prevalence in the Republic of Ireland declined while Northern Ireland experienced both a rise and fall. Differences in demography, BTB programme structure and test results were noted, particularly between the island of Ireland and Great Britain. Further investigation of these differences may provide valuable insights into risk factors for BTB and optimisation of existing BTB programmes.

Needs for an expanded ontology-based classification of adverse drug reactions and related mechanisms.

The growing significance of bioinformatics and systems biology in drug safety research requires a system of adverse-event classification that goes beyond a simple vocabulary. This opinion piece outlines the need for development of an ontology-based framework of describing adverse drug reactions (ADRs) and describes the potential applications for such a framework.

High-risk prescribing and incidence of frailty among older community-dwelling men.

Evidence about the association between treatment with high-risk medicines and frailty in older individuals is limited. We investigated the relationship between high-risk prescribing and frailty at baseline, as well as 2-year incident frailty, in 1,662 men ≥70 years of age. High-risk prescribing was defined as polypharmacy (≥5 medicines), hyperpolypharmacy (≥10 medicines), and by the Drug Burden Index (DBI), a dose-normalized measure of anticholinergic and sedative medicines. At baseline, frail participants had adjusted odds ratios (ORs) of 2.55 (95% confidence interval, CI: 1.69-3.84) for polypharmacy, 5.80 (95% CI: 2.90-11.61) for hyperpolypharmacy, and 2.33 (95% CI: 1.58-3.45) for DBI exposure, as compared with robust participants. Of the 1,242 men who were robust at baseline, 6.2% developed frailty over two years. Adjusted ORs of incident frailty were 2.45 (95% CI: 1.42-4.23) for polypharmacy, 2.50 (95% CI: 0.76-8.26) for hyperpolypharmacy, and 2.14 (95% CI: 1.25-3.64) for DBI exposure. High-risk prescribing may contribute to frailty in community-dwelling older men.

Field trial of six serological tests for bovine brucellosis.

Serum agglutination (SAT), complement fixation (CFT), indirect ELISA (iELISA), competitive ELISA (cELISA), Rose Bengal (RBT) and EDTA-modified agglutination (EDTA) tests were used in parallel on serological samples from 19,935 cattle in 301 herds. The study herds were selected according to putative exposure to Brucellaabortus with cases defined by bacteriological culture or test agreement. No single test identified all infected cattle and, at diagnostic thresholds, relative sensitivity was highest in the iELISA (67.9%) or RBT (78.1%), using bacteriological culture or test agreement, respectively, to define cases. As screening tests, the relative sensitivity of the SAT was highest (75.9% by culture or 84.9% by test agreement), with an optimal threshold of 31 IU. The relative specificity of the diagnostic tests ranged from 99.6% (SAT 31IU) to 100% (iELISA, RBT and CFT). The trial confirmed the value of the SAT as a screening test and the value of parallel testing.

Integration of diverse data sources for prediction of adverse drug events.

The rapid evolution of large biological, pharmacological, and chemical databases has led to optimism that such data resources can be leveraged for prediction of drug action based on molecular descriptors of the drug. Challenges to realize this possibility include organization of each type of database in a manner that allows extraction of information across disparate data sources and the linkage of information across the biological, pharmacological, and chemical domains.

Pharmacological mechanism-based drug safety assessment and prediction.

Advances in cheminformatics, bioinformatics, and pharmacology in the context of biological systems are now at a point that these tools can be applied to mechanism-based drug safety assessment and prediction. The development of such predictive tools at the US Food and Drug Administration (FDA) will complement ongoing efforts in drug safety that are focused on spontaneous adverse event reporting and active surveillance to monitor drug safety. This effort will require the active collaboration of scientists in the pharmaceutical industry, academe, and the National Institutes of Health, as well as those at the FDA, to reach its full potential. Here, we describe the approaches and goals for the mechanism-based drug safety assessment and prediction program.

A comparison of badger activity in two areas of high and low bovine tuberculosis incidence of Northern Ireland.

During 2005, a field survey of badger activity was carried out to evaluate differences between two areas with different levels of bovine tuberculosis (annual herd incidences of 16% and 4%) and to assess the awareness of herd keepers in relation to badgers. A random selection of herd keepers was interviewed and their farm land surveyed for the presence of badgers. The survey end point for each farm was the discovery of an active badger sett. Participation was very high in both areas (>80%). Evidence of badger activity was recorded on a higher proportion of farms in the area with a high tuberculosis herd incidence. However, when the difference in quality of agricultural land within each area was taken into account, a statistically significant association was not demonstrated. This suggests that the quality of agricultural land is a major determinant in the location of active badger setts. Nevertheless, the study did demonstrate the potential for increased exposure of cattle to badgers in the high incidence area. Herd keepers accurately identified the presence of badger setts on their land (positive predictive value=97%) but herd keepers reporting the absence of badger setts/activities on their land were found to be less accurate. Overall, the conclusions from this study tend to reflect the findings observed in other studies.