Efficacy and Safety of a Tetravalent Dengue Vaccine (TAK-003) in Children With Prior Japanese Encephalitis or Yellow Fever Vaccination.

BACKGROUND: We explored the impact of prior Yellow fever (YF) or Japanese encephalitis (JE) vaccination on the efficacy of Takeda's dengue vaccine candidate, TAK-003 (NCT02747927). METHODS: Children 4-16 years of age were randomized 2:1 to receive TAK-003 or placebo and were under active febrile surveillance. Symptomatic dengue was confirmed by serotype-specific RT-PCR. YF and JE vaccination history was recorded. RESULTS: Of the 20,071 children who received TAK-003 or placebo, 21.1% had a YF and 23.9% had a JE vaccination history at randomization. Fifty-seven months after vaccination, vaccine efficacy was 55.7% (95% CI, 39.7%-67.5%) in those with YF vaccination, 77.8% (70.8%-83.1%) for JE vaccination, and 53.5% (45.4%-60.4%) for no prior YF/JE vaccination. Regional differences in serotype distribution confound these results. The apparent higher vaccine efficacy in the JE vaccination subgroup could be largely explained by serotype-specific efficacy of TAK-003. Within 28 days of any vaccination, the proportions of participants with serious adverse events in the YF/JE prior vaccination population were comparable between the TAK-003 and placebo groups. CONCLUSIONS: The available data do not suggest a clinically relevant impact of prior JE or YF vaccination on TAK-003 performance. Overall, TAK-003 was well-tolerated and efficacious in different epidemiological settings.

Low-level fiber-induced radiographic changes caused by Libby vermiculite: a 25-year follow-up study.

RATIONALE: From 1921 to 1990, vermiculite ore from Libby, Montana, was shipped worldwide for commercial and residential use. A 1980 study of a manufacturing facility using Libby vermiculite was the first to demonstrate a small but significant prevalence of pleural chest radiographic changes associated with amphibole fibers contained in the ore. OBJECTIVES: This follow-up study of the original cohort evaluated the extent of radiographic changes and cumulative fiber exposure (CFE) 25 years after cessation of exposure. METHODS: From the original cohort of 513 workers, 431 (84%) were living and available for participation and exposure reconstruction. Of these, 280 (65%) completed both chest radiographs and interviews. Primary outcomes were pleural and/or interstitial changes. MEASUREMENTS AND MAIN RESULTS: Pleural and interstitial changes were demonstrated in 80 (28.7%) and 8 (2.9%) participants, respectively. Of those participants with low lifetime CFE of less than 2.21 fiber/cc-years, 42 (20%) had pleural changes. A significant (P < 0.001) exposure-response relationship of pleural changes with CFE was demonstrated, ranging from 7.1 to 54.3% from the lowest to highest exposure quartile. Removal of individuals with commercial asbestos exposure did not alter this trend. CONCLUSIONS: This study indicates that exposure within an industrial process to Libby vermiculite ore is associated with pleural thickening at low lifetime CFE levels. The propensity of the Libby amphibole fibers to dramatically increase the prevalence of pleural changes 25 years after cessation of exposure at low CFE levels is a concern in view of the wide national distribution of this ore for commercial and residential use.

Statistical analyses of chicken intestinal lesion scores in battery cage studies of anti-coccidial drugs.

Establishing the efficacy of an anti-coccidial drug in poultry begins with conducting multiple battery cage studies, where the target animals are challenged with single and mixed Eimeria species inoculum under controlled laboratory conditions. One of the primary outcomes in a battery cage study is the intestinal lesion score defined on a discrete ordinal scale of 0 to 4. So far, the statistical analysis of lesion scores has routinely employed the linear mixed model (LMM). This present work proposes to apply the generalized linear mixed model (GLMM) with the cumulative logit link to statistically analyze coccidial lesion scores collected from battery cage studies. Upon applying this new approach on 9 datasets generated by challenging battery-cage-housed broilers with various mixtures of Eimeria species, it is observed that the GLMM fitted adequately to the data, produced variance component estimates that agreed with the experimental setup, and, at the 0.05 significance level, generated statistical results in complete concordance with the LMM approach. Advantages of the proposed GLMM over the LMM are discussed from several standpoints. Parallel to the regulatory requirement of a ≥1-unit reduction in the mean lesion score for clinical relevant efficacy under the LMM, the clinical relevancy criterion under the GLMM could be set as a ≥10-fold increase in the odds of having low lesion scores. That is, the effect of an anti-coccidial drug product would be deemed clinically relevant in battery-cage studies when the odds of having low lesion scores with the medication is 10 times or more than the odds without the medication.

Principal components analysis of drug expenditure and utilisation trends for major therapeutic classes in US Medicaid programmes.

OBJECTIVE: Drug expenditures have been increasing much faster than spending on other medical services and have become burdensome for state Medicaid programmes. The purpose of this study was to analyse these trends across major therapeutic classes and to identify their similarities and differences. METHODS: Using national claims data from the Centers for Medicare & Medicaid Services for 1991 quarter 1 through to 2004 quarter 4, expenditures and prescriptions were aggregated across all drugs in 64 different therapeutic classes, providing 128 (64 x 2) different time series, most of length 56 quarters. Principal components analysis (PCA) was then applied to the data. RESULTS: PCA revealed three principal components that accounted for 90% (92%) of total variation in Medicaid drug expenditure (utilisation) patterns. The first principal component (PC1), explaining 66% (67%) of the variation, is an exponential-like upward trend; PC2, explaining 17% (14%) of the variation, represents an increasing-then-decreasing pattern; and PC3, explaining 7% (11%) of the variation, represents an up-and-down cyclical pattern. Highly correlated with PC1 are antiretrovirals, antiseizure agents and corticoid steroids, among other drug classes. CONCLUSION: Most drug therapeutic classes exhibited exponential-like upward expenditure (and utilisation) trends, clearly illustrating the overall rising expenditure burden for Medicaid.

Diagnostic performances of two rapid tests for detection of feline leukemia virus antigen in sera of experimentally feline leukemia virus-infected cats.

OBJECTIVES: The objective of this study was to compare the diagnostic sensitivities and specificities of WITNESS FeLV-FIV (Zoetis) and SNAP FIV/FeLV Combo Test (IDEXX) for the detection of FeLV p27 antigen in the sera of experimentally feline leukemia virus (FeLV)-infected cats. METHODS: Diagnostic sensitivities of WITNESS and SNAP were determined through testing of 47 serum samples collected from cats day 56 post-experimental infection with a virulent FeLV Rickard strain. Successful experimental infection was confirmed based on observation of FeLV antigen and proviral DNA in anti-coagulated (EDTA) whole-blood samples by immunofluorescent antibody (IFA) test and PCR, respectively. Diagnostic specificities of both tests were determined through testing of sera of 92 laboratory-housed, non-FeLV-exposed specific pathogen-free (SPF) cats. RESULTS: Forty-one of 47 blood samples were IFA positive, whereas all 47 samples were PCR positive. All 92 non-FeLV-infected SPF cats were IFA and PCR negative. In comparison to IFA as the reference method, both WITNESS and SNAP tests yielded equivalent sensitivities and specificities of 100% and 97.8%, respectively. In comparison to PCR as the reference method, both WITNESS and SNAP tests likewise performed equivalently, with sensitivities and specificities of 91.5% and 100%, respectively. CONCLUSIONS AND RELEVANCE: Sensitivity and specificity of WITNESS FeLV-FIV for identifying FeLV p27 antigen in the sera of these experimentally FeLV-infected and non-FeLV-exposed SPF cats equaled those of the SNAP FIV/FeLV Combo Test. However, all positive results, regardless of the point-of-care test used, should be confirmed before making clinical decisions such as segregation from other cats or euthanasia.

Microfilarial reduction following ProHeart® 6 and ProHeart® SR-12 treatment in dogs experimentally inoculated with a resistant isolate of Dirofilaria immitis.

BACKGROUND: Emerging resistance of heartworms (Dirofilaria immitis) to macrocyclic lactone (ML) preventives is an increasing concern for veterinarians, pet owners and animal health companies that supply heartworm preventives, with recent reports of resistant isolates identified from the Mississippi Delta region of the United States. Products that are effective in eliminating microfilariae (MF) in dogs harboring resistant heartworm infections could be important in reducing the spread of heartworm resistance. The current study was conducted to investigate the potential for ProHeart® 6 (PH 6; Zoetis) and ProHeart® SR-12 (PH 12; Zoetis) to reduce MF in dogs experimentally inoculated with an isolate of D. immitis (ZoeMo-2012) confirmed to be resistant to MLs. METHODS: Twenty-three dogs with preexisting heartworm infections (via surgical transplantation) were randomly allocated to four groups based on pretreatment (Day -14) MF counts. On Day 0, dogs received a subcutaneous injection of either saline (placebo-treated control, 6 dogs), PH 6 (0.17 mg/kg, 6 dogs), PH 12 (0.5 mg/kg, 5 dogs) or a single oral dose of moxidectin powder in a gelatin capsule (0.25 mg/kg, 6 dogs). All dogs were bled for MF counts (modified Knott's test) on Days 0 (pretreatment), 1, 3, 7, 14, 21, 28, 42, 56, and 84. Dogs in control and PH 6 groups were also bled for MF counts on Days 112, 140, and 168. No adverse events associated with treatment were observed for any dog. RESULTS: Average reductions in MF counts compared with controls for PH 6 were 9.7% on Day 1, increasing to 75.0% on Day 7, and further to 86.5% on Day 28. On Day 42, average MF reduction increased to 90.3%. Reductions increased further over the next several months with reductions of 91.3, 96.8, 96.6, and 98.9% on Days 56, 84, 112, and 140, respectively. On Day 168, the reduction was 99.3% (P < 0.0001). Average reductions in MF counts compared with controls for PH 12 were 20.9% on Day 1, increasing to 78.9% on Day 7, and further to 91.2% on Day 28. On Day 84, the reduction was 96.9%. For dogs receiving a single oral moxidectin (0.25 mg/kg) on Day 0, reductions in MF were 86.3% on Day 1 and fluctuated between 74.4 and 83.6% through Day 28. On Days 42 and 56, percentage reductions were 87.1 and 81.8%, respectively, and 92.6% at the final time point (Day 84). CONCLUSION: Both PH 6 and PH 12 were highly effective in reducing the MF levels of a confirmed ML-resistant heartworm isolate following a single dose.

Exposure to potentially dangerous drug-drug interactions involving antipsychotics.

OBJECTIVE: Antipsychotic drug therapy is the cornerstone of treatment of persons with schizophrenia. Because most antipsychotics are metabolized by the hepatic cytochrome P450 system, concomitant use of an antipsychotic and medications that are competitively metabolized by the same system may cause a potentially harmful drug-drug interaction. This study used a large state's Medicaid claims database to examine the proportion of patients exposed to such interactions and the risk factors associated with exposure. METHODS: Claims from January 2000 through December 2003 for adult patients with a diagnosis of schizophrenia and at least one prescription for an antipsychotic (N=27,909) were examined for pairs of medications identified as potentially causing moderate or severe adverse drug effects. Logistic regression models were estimated to determine potential risk factors associated with exposure to the interaction pairs. RESULTS: A total of 6,417 (23%) patients were exposed to 14,213 potentially harmful interactions; 4,725 patients had at least one exposure from the same pharmacy, and 4,032 patients were exposed by the same physician. The greatest number of exposures (N=1,353) to potentially harmful combinations involved olanzapine and haloperidol. Patients prescribed risperidone were most likely to be exposed to an interaction (13.1%), followed by patients prescribed olanzapine (10.3%), quetiapine (3.3%), and clozapine (3.2%). A higher risk of exposure was associated with being female (odds ratio [OR]=.94), being white (OR=1.43), having depression (OR=1.21), or having impulse-control disorder (OR=1.98). CONCLUSIONS: Interventions by physicians and pharmacies to reduce the prescribing and dispensing of potentially harmful pairs of medications to patients with schizophrenia are recommended.