Factors in the decline of the African penguin: Are contaminants of emerging concern (CECs) a potential new age stressor?

The African penguin is currently experiencing a significant decline, with just over 10,000 breeding pairs left. A substantial body of research reflects the impacts of contaminants of emerging concern (CECs) on the marine environment, with wastewater treatment plants reported as one of the main sources of CEC release. In South Africa, CECs were identified contaminating the marine environment and bioaccumulating in several marine species. Approximately 70 % of all African penguin colonies breed in close proximity to cities and/or harbors in South Africa. Currently, the impact of CECs as a stressor upon the viability of African penguin populations is unknown. Based on the search results there was a clear lack of information on CECs' bioaccumulation and impact on the African penguin. This narrative review will thus focus on the prevalent sources and types of CECs and examine the reported consequences of constant exposure in seabirds, particularly African penguins.

Vaccination of African penguins (Spheniscus demersus) against high-pathogenicity avian influenza.

BACKGROUND: High-pathogenicity avian influenza (HPAI) has become a conservation threat to wild birds. Therefore, suitable vaccine technology and practical application methods require investigation. METHODS: Twenty-four African penguins (Spheniscus demersus) were vaccinated with either a conventional inactivated clade 2.3.4.4b H5N8 HPAI whole virus or a tobacco leaf-produced H5 haemagglutinin-based virus-like particle (VLP). Six birds received a second dose of the inactivated vaccine. Antibody responses were assessed and compared by employing haemagglutination inhibition tests. RESULTS: A second dose of inactivated vaccine was required to induce antibody titres above the level required to suppress virus shedding, while a single dose of VLP vaccine produced these levels by day 14, and one bird still had antibodies on day 430. LIMITATIONS: Bacterial contamination of the VLP vaccine limited the monitoring period and sample size in that treatment group, and it was not possible to perform a challenge study with field virus. CONCLUSION: VLP vaccines offer a more practical option than inactivated whole viruses, especially in logistically challenging situations involving wild birds.

Is Penguin Circovirus Circulating Only in the Antarctic Circle? Lack of Viral Detection in Namibia.

The known host range of circoviruses is continuously expanding because of more intensive diagnostic activities and advanced sequencing tools. Recently, a new circovirus (penguin circovirus (PenCV)) was identified in the guano and cloacal samples collected from Adélie penguins (Pygoscelis adeliae) and chinstrap penguins (Pygoscelis antarcticus) in Antarctica. Although the virus was detected in several asymptomatic subjects, a potential association with feather disease was speculated. To investigate the occurrence and implications of PenCV in other penguin species located outside of Antarctica, a broad survey was undertaken in African penguins (Spheniscus demersus) on two islands off the southern Namibian coast. For this purpose, specific molecular biology assays were developed and validated. None of the 151 blood samples tested positive for PenCV. Several reasons could explain the lack of PenCV positive samples. African penguins and Pygoscelis species are separated by approximately 6000 km, so there is almost no opportunity for transmission. Similarly, host susceptibility to PenCV might be penguin genus-specific. Overall, the present study found no evidence of PenCV in African penguin colonies in Namibia. Further dedicated studies are required to assess the relevance of PenCV among different penguin species.

Rabies Virus Seroprevalence among Dogs in Limpopo National Park and the Phylogenetic Analyses of Rabies Viruses in Mozambique.

Rabies is considered a neglected disease among many developing Asian and African countries, including Mozambique, where its re-emergence is often attributed to low dog parenteral vaccination coverage. The objectives of this study were two-fold: (1) to assess the level of antibodies against rabies virus in dogs (n = 418) in Limpopo National Park (LNP), and (2) to genetically characterise selected rabies viruses from brain tissue samples collected in 2017 and 2018. To meet the first objective, we used the BioProTM Rabies blocking ELISA antibody kit, and the results were expressed as the percentage of blocking (%PB). Dog sera with PB ≥ 40% were considered positive for antibodies to rabies virus, whereas sera with PB < 40% were negative. Just under ninety percent (89.2%; n = 373) of dogs were seronegative, and the rest (10.8%; n = 45) had detectable levels of rabies virus-specific antibodies. All eight brain tissue samples were positive for rabies virus antigen using a direct fluorescent antibody test and amplified in a quantitative real-time PCR, but only five (n = 4 from dogs and n = 1 from a cat) were amplified in a conventional reverse-transcription PCR targeting partial regions of the nucleoprotein (N) and the glycoprotein (G) genes. All samples were successfully sequenced. Phylogenetically, the rabies viruses were all of dog origin and were very closely related to each other (Africa 1b rabies virus lineage). Furthermore, the sequences had a common progenitor with other rabies viruses from southern Africa, confirming the transboundary nature of rabies and the pivotal role of dogs in maintaining rabies cycles. The study demonstrates the principal application of the BioProTM rabies ELISA antibody for the detection of anti-lyssavirus-specific antibodies in the serum samples of dogs, and most importantly, it highlights the low levels of antibodies against rabies virus in this dog population.

Knowledge, attitudes, practices (KAP) and control of rabies among community households and health practitioners at the human-wildlife interface in Limpopo National Park, Massingir District, Mozambique.

BACKGROUND: Rabies is a viral zoonotic disease that kills more than 26,000 people each year in Africa. In Mozambique, poverty and inadequate surveillance result in gross underreporting and ineffective control of the disease in animals and people. Little is known of the role of human attitudes and behaviour in prevention or control of rabies, thus this study was undertaken to assess the knowledge, attitudes and practices amongst selected households and health practitioners in one affected area, the Limpopo National Park (LNP), Massingir district. METHODOLOGY: A cross-sectional study was conducted among 233 households in eight villages in LNP and among 42 health practitioners from eight health facilities in Massingir district between 2016 and 2018. Consenting household representatives aged 18 years or over were purposively selected. A KAP survey was administered to obtain information on dog ownership and knowledge of rabies, host species affected, modes of transmission, symptoms, recommended treatment and preventive methods. Similar to household study participants, health practitioners were purposively selected and completed the questionnaire during the investigators' visit. The questionnaire sought information on knowledge of rabies, management of bite wounds, vaccination sites and schedules of pre- and post-exposure prophylaxis. Descriptive and inferential data analyses were performed using SPSS software version 18.0. RESULTS: Approximately twenty per cent (18.9%; 95% CI: 14.3-24.3) and 13.3% (95% CI: 9.4-18.1) of households had good knowledge and practices of rabies, respectively. For health practitioners, only 16.7% (95% CI: 7.5-31.9) had good knowledge, whilst 33.3% (95% CI: 20.0-49.7) adopted adequate attitudes/practices towards the disease. CONCLUSIONS/SIGNIFICANCE: In conclusion, both households and health practitioners displayed poor levels of knowledge and adopted bad attitudes and practices towards rabies. The former, had more gaps in their attitudes and practices towards the disease. Village location and education level (P < .05) and similarly, sex and occupation, were found to be statistically associated with good knowledge of rabies among households as compared to HPs. Overall, a lack of community-based education and professional retraining courses contribute significantly to poor awareness of rabies in the LNP of Mozambique. Enhancing public health knowledge should consequently reduce dog-mediated human rabies deaths in this country.

Bovine Brucellosis in Gauteng, South Africa: Seroprevalence amongst Cattle Handlers and Variables Associated with Seropositive Cattle Herds, 2014-2016.

In South Africa, the prevalence of cattle handler exposure to Brucella on cattle farms is unknown and risk factors and cattle symptoms associated with infected cattle herds are unavailable. To address this gap, a case-control study of cattle herds was conducted in Gauteng province and farm workers and veterinary officials were tested for exposure to Brucella. Seroprevalence amongst farm workers exposed to case herds ranged from 4.0% (BrucellaCapt®) to 16.7% (IgG ELISA®), compared to those exposed to control herds, where seroprevalence ranged from 1.9% (BrucellaCapt®) to 5.7% (IgG ELISA®). Seroprevalence amongst veterinary officials was significantly greater compared to farm workers exposed to case herds for the outcome RBT+ IgM- IgG+ (OR = 11.1, 95% CI: 2.5-49.9, p = 0.002) and RBT- IgM- IgG+ (OR = 6.3, 95% CI: 2.3-17.3, p < 0.001). Risk factors associated with being an infected herd were: being a government-sponsored farm vs. private farm (OR 4.0; 95% CI: 1.4-11.3; p = 0.009), beef vs. dairy herd (OR 7.9; 95% CI: 1.4-44.9; p = 0.020), open vs. closed herd (OR 3.3; 95% CI: 1.1-10.4; p = 0.038) and the presence of antelope on the farm (OR 29.4; 95% CI: 4.0-218.2; p = 0.001). Abortions (OR = 5.1; 95% CI: 2.0-13.3; p < 0.001), weak calves in the herd (OR = 8.0; 95% CI: 2.6-24.4; p < 0.001), reduction in number of calves born (OR = 9.0; 95% CI: 2.1-43.6; p < 0.001), reduction in conception rate (OR = 3.9; 95% CI: 0.8-18.3; p = 0.046), hygromas in cattle (p = 0.011) and farmers reporting brucellosis-like symptoms in their farm workers or in him/herself (OR = 3.4; 95% CI: 1.3-8.7; p = 0.006) were more likely to be associated with Brucella infected herds than control herds. This evidence can be used in strategic planning to protect both human and herd health.

Knowledge of Brucellosis, Health-Seeking Behaviour, and Risk Factors for Brucella Infection amongst Workers on Cattle Farms in Gauteng, South Africa.

Brucellosis in humans is under-detected and underreported in sub-Saharan Africa. Risk factors associated with Brucella infection and health seeking behaviour in response to brucellosis-like symptoms, amongst cattle farm workers and veterinary officials in South Africa, are unknown. Farm workers and veterinary officials (N = 230) were screened for brucellosis using commercial Rose Bengal Test (RBT®), IgM Enzyme-linked Immunoassay (ELISA)®, IgG ELISA® and the BrucellaCapt® test. Knowledge of brucellosis and risk factors for exposure to Brucella were also investigated. Seroprevalence varied according to test used: 10.1% (RBT®), 20.9% (IgG ELISA®) and 6.5% (BrucellaCapt®). Only 22.2% (6/27) of veterinary officials opt to visit a clinic, doctor, or hospital in response to self-experienced brucellosis-like symptoms, compared to 74.9% (152/203) of farm workers (p < 0.001). Of the BrucellaCapt® seropositive participants, 53% (7/15) did not visit a clinic in response to brucellosis-like symptoms. Weak evidence of an association between the handling of afterbirth or placenta and infection of a short evolution (RBT®, IgM ELISA® and IgG ELISA® seropositive) was found (OR = 8.9, 95% CI: 1.0-81.1, p = 0.052), and strong evidence of an association between this outcome and the slaughter of cattle (OR = 5.3, 95% CI: 1.4-19.6, p = 0.013). There was strong evidence of a positive association between inactive/resolved infection and veterinary officials vs. farm workers exposed to seropositive herds (OR = 7.0, 95% CI: 2.4-20.2, p < 0.001), with a simultaneous negative association with the handling of afterbirth or placenta (OR = 3.9, 95% CI: 1.3-11.3, p = 0.012). Findings suggest a proportion of undetected clinical cases of brucellosis amongst workers on cattle farms in Gauteng.

Investigation of Brucella melitensis in Sable Antelope (Hippotragus niger) in South Africa.

In this study, Brucella melitensis infection in sable antelope (Hippotragus niger) was investigated on two wildlife ranches in South Africa over a 12-year period in order to determine the origin of the outbreaks and the role of livestock in maintaining the disease. Retrospective data were obtained from farm records and interviews as well as samples tested from different disease scenarios and clinical settings. On one ranch, 10 of 74 sable tested seropositive for B. melitensis in 2004 but were certified clear of infection after no further brucellosis cases were detected following repeated serological tests and culling over a five-year period. Recrudescence occurred in 2013 (7 of 187 brucellosis positives) and in 2014 (one positive), with persistent, latent infection being the most reasonable explanation. In a second case study, linked to the first one through a common vendor, 15 of 80 sable tested positive in 2016, some five years after the acquisition of the animals from a putative source. Brucella melitensis biovar 1 and/or 3 were isolated from each outbreak on both ranches. Both outbreaks resulted in substantial losses for the owners, arising from testing and culling and significant resource expenditure by the state. The study identified the diagnostic challenges for identifying and resolving disease outbreaks in wildlife, the persistence of B. melitensis in sable, the risks associated with animal movements, and the need for a wildlife-sensitive disease control scheme. Although the actual source of infection could not be identified, the investigation points away from local livestock as a source of ongoing infection while the persistent infection is consistent with the disease circulating within small, ranched populations and being spread through the keeping and trading of high-value animals. The implications of the study findings to disease control in wildlife are discussed.

Drug Burden Index and Its Association With Hip Fracture Among Older Adults: A National Population-Based Study.

BACKGROUND: The Drug Burden Index (DBI) calculates the total sedative and anticholinergic load of prescribed medications and is associated with functional decline and hip fractures in older adults. However, it is unknown if confounding factors influence the relationship between the DBI and hip fractures. The objective of this study was to evaluate the association between the DBI and hip fractures, after correcting for mortality and multiple potential confounding factors. METHODS: A competing-risks regression analysis conducted on a prospectively recruited New Zealand community-dwelling older population who had a standardized (International Resident Assessment Instrument) assessment between September 1, 2012, and October 31, 2015, the study's end date. Outcome measures were survival status and hip fracture, with time-varying DBI exposure derived from 90-day time intervals. The multivariable competing-risks regression model was adjusted for a large number of medical comorbidities and activities of daily living. RESULTS: Among 70,553 adults assessed, 2,249 (3.2%) experienced at least one hip fracture, 20,194 (28.6%) died without experiencing a fracture, and 48,110 (68.2%) survived without a fracture. The mean follow-up time was 14.9 months (range: 1 day, 37.9 months). The overall DBI distribution was highly skewed, with median time-varying DBI exposure ranging from 0.93 (Q1 = 0.0, Q3 = 1.84) to 0.96 (Q1 = 0.0, Q3 = 1.90). DBI was significantly related to fracture incidence in unadjusted (p < .001) and adjusted (p < .001) analyses. The estimated subhazard ratio was 1.52 (95% confidence interval: 1.28-1.81) for those with DBI > 3 compared with those with DBI = 0 in the adjusted analysis. CONCLUSIONS: In this study, increasing DBI was associated with a higher likelihood of fractures after accounting for the competing risk of mortality and adjusting for confounders. The results of this unique study are important in validating the DBI as a guide for medication management and it could help reduce the risk of hip fractures in older adults.

Pharmacotherapy in Older Adults with Cardiovascular Disease: Report from an American College of Cardiology, American Geriatrics Society, and National Institute on Aging Workshop.

OBJECTIVES: To identify the top priority areas for research to optimize pharmacotherapy in older adults with cardiovascular disease (CVD). DESIGN: Consensus meeting. SETTING: Multidisciplinary workshop supported by the National Institute on Aging, the American College of Cardiology, and the American Geriatrics Society, February 6-7, 2017. PARTICIPANTS: Leaders in the Cardiology and Geriatrics communities, (officers in professional societies, journal editors, clinical trialists, Division chiefs), representatives from the NIA; National Heart, Lung, and Blood Institute; Food and Drug Administration; Centers for Medicare and Medicaid Services, Alliance for Academic Internal Medicine, Patient-Centered Outcomes Research Institute, Agency for Healthcare Research and Quality, pharmaceutical industry, and trainees and early career faculty with interests in geriatric cardiology. MEASUREMENTS: Summary of workshop proceedings and recommendations. RESULTS: To better align older adults' healthcare preferences with their care, research is needed to improve skills in patient engagement and communication. Similarly, to coordinate and meet the needs of older adults with multiple comorbidities encountering multiple healthcare providers and systems, systems and disciplines must be integrated. The lack of data from efficacy trials of CVD medications relevant to the majority of older adults creates uncertainty in determining the risks and benefits of many CVD therapies; thus, developing evidence-based guidelines for older adults with CVD is a top research priority. Polypharmacy and medication nonadherence lead to poor outcomes in older people, making research on appropriate prescribing and deprescribing to reduce polypharmacy and methods to improve adherence to beneficial therapies a priority. CONCLUSION: The needs and circumstances of older adults with CVD differ from those that the current medical system has been designed to meet. Optimizing pharmacotherapy in older adults will require new data from traditional and pragmatic research to determine optimal CVD therapy, reduce polypharmacy, increase adherence, and meet person-centered goals. Better integration of the multiple systems and disciplines involved in the care of older adults will be essential to implement and disseminate best practices. J Am Geriatr Soc 67:371-380, 2019.

ß2-adrenoceptor agonists and antagonists and risk of Parkinson's disease.

BACKGROUND: ß2-adrenoreceptors have recently been identified as regulators of the α-synuclein gene, which is implicated in the pathogenesis of Parkinson's disease. OBJECTIVE: The objectives of this study were to assess the association between use of ß2-agonists and ß-antagonists and the risk of developing PD. METHODS: We conducted a nested case-control study in a cohort of 1,762,164 adults without a diagnosis of PD. They were identified on January, 1, 2004, from the electronic medical records of the largest health care provider in Israel. Participants were followed up until June 30, 2017, for the occurrence of PD. Ten randomly selected controls were matched to each case of PD on age, sex, ethnic group, and duration of follow-up. RESULTS: During follow-up 11,314 patients were newly diagnosed with PD and were matched with 113,140 controls. An increased risk of PD was seen with the use of nonselective ß-antagonists (RR, 2.04 [1.90-2.20]) but not with the use of selective ß1-antagonists (RR, 1.00 [0.95-1.05]). Use of ß2-agonists was associated with reduced risk of PD (RR, 0.89 [0.82-0.96] for short-acting; RR, 0.84 [0.76-0.93] for long-acting; and RR, 0.49 [0.25-0.92] for ultra-long-acting ß2-agonists). In an analysis of individual drugs, propranolol and salbutamol were significantly associated with PD risk, even when these drugs were ascertained 5 years prior to the index date, compared with nonusers (RR, 1.31 [1.08-1.58] and 1.89 {1.53-2.33]) in patients who filled <6 and ≥6 propranolol prescriptions, respectively; the corresponding RRs for salbutamol were 0.95 (0.83-1.08) and 0.65 (0.45-0.94), respectively. CONCLUSIONS: Use of propranolol appears to be associated with an increased risk of PD, whereas use of ß2-agonists is associated with a decreased risk of PD. © 2018 International Parkinson and Movement Disorder Society.

Methodology and preliminary results of a systematic literature review of ante-mortem and post-mortem diagnostic tests for bovine tuberculosis.

A systematic review was conducted to identify studies with data for statistical meta-analyses of sensitivity (Se) and specificity (Sp) of ante-mortem and post-mortem diagnostic tests for bovine tuberculosis (bTB) in cattle. Members of a working group (WG) developed and tested search criteria and developed a standardised two-stage review process, to identify primary studies with numerator and denominator data for test performance and an agreed range of covariate data. No limits were applied to year, language, region or type of test in initial searches of electronic databases. In stage 1, titles and available abstracts were reviewed. References that complied with stage 1 selection criteria were reviewed in entirety and agreed data were extracted from references that complied with stage 2 selection criteria. At stage 1, 9782 references were reviewed and 261 (2.6%) passed through to stage 2 where 215 English language references were each randomly allocated to two of 18 WG reviewers and 46 references in other languages were allocated to native speakers. Agreement regarding eligibility between reviewers of the same reference at stage 2 was moderate (Kappa statistic = 0.51) and a resolution procedure was conducted. Only 119 references (published 1934-2009) were identified with eligible performance estimates for one or more of 14 different diagnostic test types; despite a comprehensive search strategy and the global impact of bTB. Searches of electronic databases for diagnostic test performance data were found to be nonspecific with regard to identifying references with diagnostic test Se or Sp data. Guidelines for the content of abstracts to research papers reporting diagnostic test performance are presented. The results of meta-analyses of the sensitivity and specificity of the tests, and of an evaluation of the methodological quality of the source references, are presented in accompanying papers (Nuñez-Garcia et al., 2017; Downs et al., 2017).

Meta-analyses of the sensitivity and specificity of ante-mortem and post-mortem diagnostic tests for bovine tuberculosis in the UK and Ireland.

Bovine Tuberculosis (bTB) in cattle is a global health problem and eradication of the disease requires accurate estimates of diagnostic test performance to optimize their efficiency. The objective of this study was, through statistical meta-analyses, to obtain estimates of sensitivity (Se) and specificity (Sp), for 14 different ante-mortem and post-mortem diagnostic tests for bTB in cattle. Using data from a systematic review of the scientific literature (published 1934-2009) diagnostic Se and Sp were estimated using Bayesian logistic regression models adjusting for confounding factors. Random effect terms were used to account for unexplained heterogeneity. Parameters in the models were implemented using Markov Chain Monte Carlo (MCMC), and posterior distributions for the diagnostic parameters with adjustment for covariates (confounding factors) were obtained using the inverse logit function. Estimates for Se and/or Sp of the tuberculin skin tests and the IFN-γ blood test were compared with estimates published 2010-2015. Median Se for the single intradermal comparative cervical tuberculin skin (SICCT) test (standard interpretation) was 0.50 and Bayesian credible intervals (CrI) were wide (95% CrI 0.26, 0.78). Median Sp for the SICCT test was 1.00 (95% CrI 0.99, 1.00). Estimates for the IFN-γ blood test Bovine Purified Protein Derivative (PPD)-Avian PPD and Early Secreted Antigen target 6 and Culture Filtrate Protein 10 (ESAT-6/CFP10) ESAT6/CFP10 were 0.67 (95% CrI 0.49, 0.82) and 0.78 (95% CrI 0.60, 0.90) respectively for Se, and 0.98 (95% CrI 0.96, 0.99) and 0.99 (95% CrI 0.99, 1.00) for Sp. The study provides an overview of the accuracy of a range of contemporary diagnostic tests for bTB in cattle. Better understanding of diagnostic test performance is essential for the design of effective control strategies and their evaluation.

Drug Burden and its Association with Falls Among Older Adults in New Zealand: A National Population Cross-Sectional Study.

BACKGROUND: Adverse outcomes associated with advanced diseases are often exacerbated by polypharmacy. OBJECTIVES: The current study investigated an association between exposure to anticholinergic and sedative medicines and falls in community-dwelling older people, after controlling for potential confounders. METHODS: We conducted a retrospective cross-sectional study of a continuously recruited national cohort of community-dwelling New Zealanders aged 65 years and over. Participants had an International Resident Assessment Instrument-Home Care (interRAI-HC) assessment between 1 September 2012 and 31 January 2016. InterRAI-HC is a comprehensive, multi-domain, standardised assessment. This study captured 18 variables, including fall frequency, from the interRAI. These data were deterministically matched with the Drug Burden Index (DBI) for each participant, derived from an anonymised national dispensed pharmaceuticals database. DBI groupings were statistically ascertained, and ordinal regression models employed. RESULTS: Overall, there were 71,856 participants, with a mean age of 82.7 years (range 65-106); 43,802 (61.0%) were female, and 63,578 (88.5%) were New Zealand European. In unadjusted and adjusted analyses, DBI groupings were related to falls (p < 0.001). A DBI score > 3 was associated with a 41% increase in falls compared with a DBI score of 0 (p < 0.001). There was a 'dose-response' relationship between DBI levels and falls risk. CONCLUSIONS: DBI was found to be independently and positively associated with a greater risk of falls in this cohort after adjustment for 18 known confounders. We suggest that the DBI could be a valuable tool for clinicians to use alongside electronic prescribing to help reduce falls in older people.

Evaluation of the methodological quality of studies of the performance of diagnostic tests for bovine tuberculosis using QUADAS.

There has been little assessment of the methodological quality of studies measuring the performance (sensitivity and/or specificity) of diagnostic tests for animal diseases. In a systematic review, 190 studies of tests for bovine tuberculosis (bTB) in cattle (published 1934-2009) were assessed by at least one of 18 reviewers using the QUADAS (Quality Assessment of Diagnostic Accuracy Studies) checklist adapted for animal disease tests. VETQUADAS (VQ) included items measuring clarity in reporting (n = 3), internal validity (n = 9) and external validity (n = 2). A similar pattern for compliance was observed in studies of different diagnostic test types. Compliance significantly improved with year of publication for all items measuring clarity in reporting and external validity but only improved in four of the nine items measuring internal validity (p < 0.05). 107 references, of which 83 had performance data eligible for inclusion in a meta-analysis were reviewed by two reviewers. In these references, agreement between reviewers' responses was 71% for compliance, 32% for unsure and 29% for non-compliance. Mean compliance with reporting items was 2, 5.2 for internal validity and 1.5 for external validity. The index test result was described in sufficient detail in 80.1% of studies and was interpreted without knowledge of the reference standard test result in only 33.1%. Loss to follow-up was adequately explained in only 31.1% of studies. The prevalence of deficiencies observed may be due to inadequate reporting but may also reflect lack of attention to methodological issues that could bias the results of diagnostic test performance estimates. QUADAS was a useful tool for assessing and comparing the quality of studies measuring the performance of diagnostic tests but might be improved further by including explicit assessment of population sampling strategy.

Use of Biomedical Ontologies for Integration of Biological Knowledge for Learning and Prediction of Adverse Drug Reactions.

Drug-induced toxicity is a major public health concern that leads to patient morbidity and mortality. To address this problem, the Food and Drug Administration is working on the PredicTox initiative, a pilot research program on tyrosine kinase inhibitors, to build mechanistic and predictive models for drug-induced toxicity. This program involves integrating data acquired during preclinical studies and clinical trials within pharmaceutical company development programs that they have agreed to put in the public domain and in publicly available biological, pharmacological, and chemical databases. The integration process is accommodated by biomedical ontologies, a set of standardized vocabularies that define terms and logical relationships between them in each vocabulary. We describe a few programs that have used ontologies to address biomedical questions. The PredicTox effort is leveraging the experience gathered from these early initiatives to develop an infrastructure that allows evaluation of the hypothesis that having a mechanistic understanding underlying adverse drug reactions will improve the capacity to understand drug-induced clinical adverse drug reactions.

In Vitro-In Vivo Extrapolation of Metabolism- and Transporter-Mediated Drug-Drug Interactions-Overview of Basic Prediction Methods.

Evaluation of drug-drug interaction (DDI) risk is vital to establish benefit-risk profiles of investigational new drugs during drug development. In vitro experiments are routinely conducted as an important first step to assess metabolism- and transporter-mediated DDI potential of investigational new drugs. Results from these experiments are interpreted, often with the aid of in vitro-in vivo extrapolation methods, to determine whether and how DDI should be evaluated clinically to provide the basis for proper DDI management strategies, including dosing recommendations, alternative therapies, or contraindications under various DDI scenarios and in different patient population. This article provides an overview of currently available in vitro experimental systems and basic in vitro-in vivo extrapolation methodologies for metabolism- and transporter-mediated DDIs.