Bayesian latent class estimation of sensitivity and specificity parameters of diagnostic tests for bovine tuberculosis in chronically infected herds in Northern Ireland

Publication history: Accepted - 26 April 2018; Published online - 1 May 2018.In the European Union, the recommended ante-mortem diagnostic methods for bovine tuberculosis (bTB) include the single intradermal cervical comparative tuberculin (SICCT) test and the interferon-gamma (IFN- g) test as an ancillary test. The SICCT test has a moderate sensitivity (Se) and high specificity (Sp), while the IFN-g test has good Se, but a lower Sp than the SICCT test. A retrospective Bayesian latent class analysis was conducted on 71,185 cattle from 806 herds chronically infected with bTB distributed across Northern Ireland (NI) to estimate the Se and Sp of the common ante-mortem tests and meat inspection. Analyses were also performed on data stratified by farming type and herd location to explore possible differences in test performance given the heterogeneity in the population. The mean estimates in chronically infected herds were: (1) ‘standard’ SICCT: Se 40.5–57.7%, Sp 96.3–99.7%; (2) ‘severe’ SICCT: Se 49.0%–60.6%, Sp 94.4–99.4%; (3) IFN-g(bovine–avian) using a NI optical density (OD) cut-off difference of 0.05: IFN-g(B–A)NI: Se 85.8– 93.0%, Sp 75.6–96.2%; (4) IFN-g(bovine–avian) using a standard ‘commercial’ OD cut-off difference of 0.1: IFN-g(B–A)0.1: Se 83.1–92.1%, Sp 83.1–97.3%; and (5) meat inspection: Se 49.0–57.1% Se, Sp 99.1–100%. Se estimates were lower in cattle from dairy farms than from beef farms. There were no notable differences in estimates by location of herds. Certain population characteristics, such as production type, might influence the ability of bTB tests to disclose truly infected cases.This study is part of a larger project on the evaluation of the performance characteristics of the test in chronic bTB herds in NI from 2004 to 2010. It was financed by DAERA (E&I grant code 11/ 03/10)

Monitoring Mycobacterium bovis in Eurasian badgers ( Meles meles ) killed by vehicles in Northern Ireland between 1998 and 2011

Despite extensive long-term eradication programmes, bovine tuberculosis (bTB) remains endemic in much of the British Isles. The cost of the national eradication programme in Northern Ireland was estimated at £23 million in 2010/2011.1 There is evidence that badgers play a role in the maintenance and spread of Mycobacterium bovis to cattle (as reviewed by Allen and others2). Northern Ireland is a small country (13,843 km2) with an agricultural land that is dominated by grass production, which supports 1.6 million cattle among 20,000 farms.3 The estimated badger population of 34,100 (95 per cent confidence interval (CI) 26,200 to 42,000) is widespread and contained within 7600 social groups (95 per cent CI 6200 to 9000).4 A road traffic accident (RTA) survey began in 1998 in Northern Ireland with the aim of describing the occurrence of M bovis within the badger population

Doenças de bovinos no Sul do Brasil: 6.706 casos

As doenças que acometem bovinos na região Sul do Brasil foram analisadas através de um estudo dos protocolos de necropsia de 6.706 bovinos examinados pelo Laboratório de Patologia Veterinária da Universidade Federal de Santa (LPV-UFSM), Rio Grande do Sul, de 1964-2008. Desses, 20,9% foram necropsias realizadas no LPV-UFSM e 79,1% foram amostras de tecidos submetidos por veterinários de campo. Dos 6.706 exames, 62,9% tinham diagnóstico conclusivo. A autólise ou material insuficiente foram as principais razões para a ocorrência de casos com diagnóstico inconclusivo. A intoxicação por Senecio spp. foi a principal causa de morte de bovinos neste estudo. As plantas tóxicas e as toxiinfecções juntas, responderam por 22,8% dos casos com diagnóstico conclusivo. As doenças inflamatórias e as parasitoses juntas contribuíram com mais de 30% das doenças de bovinos e a tristeza parasitária bovina foi a principal doença nessa categoria. As demais categorias distribuíram-se na seguinte ordem: neoplasmas e lesões tumoriformes (13,87%), doenças causadas por agentes físicos (2,7%), doenças metabólicas e nutricionais (2,46%), distúrbios circulatórios (1,4%), doenças degenerativas (1,1%), distúrbios do desenvolvimento (0,54%), distúrbios iatrogênicos (0,16%), distúrbios imunogênicos (0,19%) e, outros distúrbios (0,21%). A alta prevalência de tumores em bovinos foi atribuída a ingestão crônica de Pteridium aquilinum, uma toxicose comum na região. As principais doenças de bovinos na região estudada estão relacionadas a fatores ambientais resultante do manejo característico de criação predominantemente extensiva adotado na região.The diseases affecting cattle in southern Brazil were studied through a review of the necropsy reports filed at the Laboratório de Patologia Veterinária of the Universidade Federal de Santa Maria (LPV-UFSM), Rio Grande do Sul, and pertaining to the examination of 6.076 cattle during 1964-2008. Of those exams 29.9% were necropsies performed at the LPV-UFSM and 79.1% were mailed-in organ fragments from necropsies performed at the field by veterinary practitioners. Autolysis and non-representative sampling o mailed in organs were the main reasons for non-conclusive diagnosis. Poisoning by Senecio spp. was the main cause of death in cattle in this study and poisonous plants together with toxi-infections accounted for 22.8% of the cases with conclusive diagnosis. Inflammatory diseases together with parasitic diseases accounted for more than 30% of cattle diseases and babesiosis and anaplasmosis were the main diseases in this category. Other categories were distributed in the following order: neoplasms and tumor-like lesions (13.87%), diseases caused by physical agents (2.7%), metabolic and nutritional diseases (2.46%), circulatory disturbances (1.4%), degenerative diseases (1.1%), developmental disorders (0.54%), iatrogenic diseases and sundry lesions. The high prevalence of tumors in cattle in this study was attributed to the chronic ingestion of Pteridium aquilinum, a common toxicosis in the region. The main diseases in cattle from the studied region are related to environmental factors associated to the predominantly husbandry practices adopted in the region

Research of working area development parameters in conditions of deep steep deposit finalizing

Отримано формули розрахунку об’єму запасів корисних копалин в приконтурній та глибинній зоні. Встановлено характер впливу параметрів доробки глибоких крутоспадних родовищ відкритим способом на доцільне положення поточних та проектних контурів кар’єру. Встановлено, що найменший середній коефіцієнт розкриву досягається при мінімальному значенні суми обсягів корисної копалини приконтурної зони лежачого і висячого боків покладу в проектному положенні. Найменший поточний коефіцієнт розкриву досягається при мінімальному значенні суми обсягів корисної копалини приконтурної зони лежачого і висячого боків покладу, а також робочого борту кар'єру в поточному положенні

Mutational processes molding the genomes of 21 breast cancers

All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed "kataegis," was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed

IFN-γ signature enables selection of neoadjuvant treatment in patients with stage III melanoma

Neoadjuvant ipilimumab + nivolumab has demonstrated high pathologic response rates in stage III melanoma. Patients with low intra-tumoral interferon-γ (IFN-γ) signatures are less likely to benefit. We show that domatinostat (a class I histone deacetylase inhibitor) addition to anti-PD-1 + anti-CTLA-4 increased the IFN-γ response and reduced tumor growth in our murine melanoma model, rationalizing evaluation in patients. To stratify patients into IFN-γ high and low cohorts, we developed a baseline IFN-γ signature expression algorithm, which was prospectively tested in the DONIMI trial. Patients with stage III melanoma and high intra-tumoral IFN-γ scores were randomized to neoadjuvant nivolumab or nivolumab + domatinostat, while patients with low IFN-γ scores received nivolumab + domatinostat or ipilimumab + nivolumab + domatinostat. Domatinostat addition to neoadjuvant nivolumab ± ipilimumab did not delay surgery but induced unexpected severe skin toxicity, hampering domatinostat dose escalation. At studied dose levels, domatinostat addition did not increase treatment efficacy. The baseline IFN-γ score adequately differentiated patients who were likely to benefit from nivolumab alone versus patients who require other therapies. Analysis and support of clinical decision makin

Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma

Background: Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) clinical trial of neoadjuvant combination anti-programmed cell death protein 1/anti-cytotoxic T-Iymphocyte-associated protein 4 immunotherapy for stage III melanoma, we sought to determine interobserver reproducibility of INMC histopathological assessment principles, identify specific tumour bed histopathological features of immunotherapeutic response that correlated with recurrence and relapse-free survival (RFS) and evaluate proposed INMC pathological response categories for predicting recurrence and RFS.Patients and methods: Clinicopathological characteristics of lymph node dissection specimens of 83 patients enrolled in the OpACIN-neo clinical trial were evaluated. Two methods of assessing histological features of immunotherapeutic response were evaluated: the previously described immune-related pathologic response (irPR) score and our novel immunotherapeutic response score (ITRS). For a subset of cases (n = 29), cellular composition of the tumour bed was analysed by flow cytometry.Results: There was strong interobserver reproducibility in assessment of pathological response (kappa = 0.879) and percentage residual viable melanoma (intraclass correlation coefficient = 0.965). The immunotherapeutic response subtype with high fibrosis had the strongest association with lack of recurrence (P = 0.008) and prolonged RFS (P = 0.019). Amongst patients with criteria for pathological non-response (pNR, >50% viable tumour), all who recurred had >= 70% viable melanoma. Higher ITRS and irPR scores correlated with lack of recurrence in the entire cohort (P = 0.002 and P = 70% viable melanoma and incorporating additional criteria of <10% fibrosis subtype of response may identify those at highest risk of recurrence, but requires validation.Analysis and support of clinical decision makin

Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma

Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN () and phase 2 OpACIN-neo () studies(1,2). While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-gamma score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-gamma score/high TMB; patients with high IFN-gamma score/low TMB or low IFN-gamma score/high TMB had pRRs of 91% and 88%; while patients with low IFN-gamma score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-gamma score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation