Interleukin 1-Beta (IL-1) Production by Innate Cells Following TLR Stimulation Correlates With TB Recurrence in ART-Treated HIV-Infected Patients

BACKGROUND: Tuberculosis (TB) remains a major cause of global morbidity and mortality, especially in the context of HIV co-infection, since immunity is not completely restored following antiretroviral therapy (ART). The identification of immune correlates of risk for TB disease could help in the design of host-directed therapies and clinical management. This study aimed to identify innate immune correlates of TB recurrence in HIV+ ART-treated individuals with a history of previous successful TB treatment. METHODS: Twelve participants with a recurrent episode of TB (cases) were matched for age, sex, time on ART, pre-ART CD4 count with 12 participants who did not develop recurrent TB in 60 months of follow-up (controls). Cryopreserved peripheral blood mononuclear cells from time points prior to TB recurrence were stimulated with ligands for Toll like receptors (TLR) including TLR-2, TLR-4, and TLR-7/8. Multi-color flow cytometry and intracellular cytokine staining was used to detect IL-1β, TNF-α, IL-12 and IP10 responses from monocytes and myeloid dendritic cells (mDCs). RESULTS: Elevated production of IL-1β from monocytes following TLR-2, TLR-4 and TLR-7/8 stimulation was associated with reduced odds of TB recurrence. In contrast, production of IL-1β from both monocytes and mDCs following Bacillus Calmette-Guérin (BCG) stimulation was associated with increased odds of TB recurrence (risk of recurrence increased by 30% in monocytes and 42% in mDCs respectively). CONCLUSION: Production of IL-1β by innate immune cells following TLR and BCG stimulations correlated with differential TB recurrence outcomes in ART-treated patients and highlights differences in host response to TB

Adjusting Overall Survival Estimates after Treatment Switching: a Case Study in Metastatic Castration-Resistant Prostate Cancer

Background If patients in oncology trials receive subsequent therapy, standard intention-to-treat (ITT) analyses may inaccurately estimate the overall survival (OS) effect of the investigational product. In this context, a post-hoc analysis of the phase 3 PREVAIL study was performed with the aim to compare enzalutamide with placebo in terms of OS, adjusting for potential confounding from switching to antineoplastic therapies that are not part of standard metastatic castration-resistant prostate cancer (mCRPC) treatment pathways in some jurisdictions. Methods The PREVAIL study, which included 1717 chemotherapy-naïve men with mCRPC randomized to treatment with enzalutamide 160 mg/day or placebo, was stopped after a planned interim survival analysis revealed a benefit in favor of enzalutamide. Data from this cutoff point were confounded by switching from both arms and so were evaluated in terms of OS using two switching adjustment methods: the two-stage accelerated failure time model (two-stage method) and inverse probability of censoring weights (IPCW). Results Following adjustment for switching to nonstandard antineoplastic therapies by 14.8 (129/872 patients) and 21.3% (180/845 patients) of patients initially randomized to enzalutamide and placebo, respectively, the two-stage and IPCW methods both resulted in numerical reductions in the hazard ratio (HR) for OS [HR 0.66, 95% confidence interval (CI) 0.57–0.81 and HR 0.63, 95% CI 0.52–0.75, respectively] for enzalutamide compared to placebo versus the unadjusted ITT analysis (HR 0.71, 95% CI 0.60–0.84). These results suggest a slightly greater effect of enzalutamide on OS than originally reported. Conclusion In the PREVAIL study, switching to nonstandard antineoplastic mCRPC therapies resulted in the ITT analysis of primary data underestimating the benefit of enzalutamide on OS

Automated Classification of Breast Cancer Stroma Maturity from Histological Images

OBJECTIVE: The tumour microenvironment plays a crucial role in regulating tumour progression by a number of different mechanisms, in particular the remodelling of collagen fibres in tumour-associated stroma, which has been reported to be related to patient survival. The underlying motivation of this work is that remodelling of collagen fibres gives rise to observable patterns in Hematoxylin and Eosin (H&E) stained slides from clinical cases of invasive breast carcinoma that the pathologist can label as mature or immature stroma. The aim of this paper is to categorise and automatically classify stromal regions according to their maturity and show that this classification agrees with that of skilled observers, hence providing a repeatable and quantitative measure for prognostic studies. METHODS: We use multi-scale Basic Image Features (BIF) and Local Binary Patterns (LBP), in combination with a random decision trees classifier for classification of breast cancer stroma regions-ofinterest (ROI). RESULTS: We present results from a cohort of 55 patients with analysis of 169 ROI. Our multi-scale approach achieved a classification accuracy of 84%. CONCLUSION: This work demonstrates the ability of texture-based image analysis to differentiate breast cancer stroma maturity in clinically acquired H&E stained slides at least as well as skilled observers

Human genetics and genomics a decade after the release of the draft sequence of the human genome

10.1186/1479-7364-5-6-577Human Genomics56577-62

Comparing laboratory costs of smear/culture and Xpert(®) MTB/RIF-based tuberculosis diagnostic algorithms

SETTING: Cape Town, South Africa, where Xpert® MTB/RIF was introduced as a screening test for all presumptive tuberculosis (TB) cases. OBJECTIVE: To compare laboratory costs of smear/culture- and Xpert-based tuberculosis (TB) diagnostic algorithms in routine operational conditions. METHODS: Economic costing was undertaken from a laboratory perspective, using an ingredients-based costing approach. Cost allocation was based on reviews of standard operating procedures and laboratory records, timing of test procedures, measurement of laboratory areas and manager interviews. We analysed laboratory test data to assess overall costs and cost per pulmonary TB and multidrug-resistant TB (MDR-TB) case diagnosed. Costs were expressed as 2013 Consumer Price Index-adjusted values. RESULTS: Total TB diagnostic costs increased by 43%, from US$440 967 in the smear/culture-based algorithm (April–June 2011) to US$632 262 in the Xpert-based algorithm (April–June 2013). The cost per TB case diagnosed increased by 157%, from US$48.77 (n = 1601) to US$125.32 (n = 1281). The total cost per MDR-TB case diagnosed was similar, at US$190.14 and US$183.86, with 95 and 107 cases diagnosed in the respective algorithms. CONCLUSION: The introduction of the Xpert-based algorithm resulted in substantial cost increases. This was not matched by the expected increase in TB diagnostic efficacy, calling into question the sustainability of this expensive new technology

Safeguarding children in dentistry: 1. Child protection training, experience and practice of dental professionals with an interest in paediatric dentistry

* Few dental professionals with child protection training have experience of making referrals. * There is a wide gap in practice between recognising signs of child abuse and neglect and responding effectively. * This may indicate missed opportunities to save children from continuing abuse. * There is a need for improved child protection information, support and training for dental professionals. Abstract Following several highly publicised inquiries into the deaths of children from abuse and neglect, there has been much recent interest in the role and responsibility of all health professionals to protect children at risk of maltreatment. The findings of a postal questionnaire, sent in March 2005 to 789 dentists and dental care professionals with an interest in paediatric dentistry working in varied settings in the UK, are presented in a two-part report and discussed in the context of current multi-agency good practice in safeguarding and promoting the welfare of children. This first part explores reported child protection training, experience and practice. There was a significant gap between recognising signs of abuse and responding effectively: 67% of respondents had suspected abuse or neglect of a child patient at some time in their career but only 29% had ever made a child protection referral. The dental profession is alerted to the need to ensure necessary appropriate action to safeguard children is always taken when child abuse or neglect are suspected

Improvements in the South African HIV care cascade: findings on 90-90-90 targets from successive population-representative surveys in North West Province.

IntroductionTo achieve epidemic control of HIV by 2030, countries aim to meet 90-90-90 targets to increase knowledge of HIV-positive status, initiation of antiretroviral therapy (ART) and viral suppression by 2020. We assessed the progress towards these targets from 2014 to 2016 in South Africa as expanded treatment policies were introduced using population-representative surveys.MethodsData were collected in January to March 2014 and August to November 2016 in Dr. Ruth Segomotsi Mompati District, North West Province. Each multi-stage cluster sample included 46 enumeration areas (EA), a target of 36 dwelling units (DU) per EA, and a single resident aged 18 to 49 per DU. Data collection included behavioural surveys, rapid HIV antibody testing and dried blood spot collection. We used weighted general linear regression to evaluate differences in the HIV care continuum over time.ResultsOverall, 1044 and 971 participants enrolled in 2014 and 2016 respectively with approximately 77% undergoing HIV testing. Despite increases in reported testing, known status among people living with HIV (PLHIV) remained similar at 68.7% (95% Confidence Interval (CI) = 60.9-75.6) in 2014 and 72.8% (95% CI = 63.6-80.4) in 2016. Men were consistently less likely than women to know their status. Among those with known status, PLHIV on ART increased significantly from 80.9% (95% CI = 71.9-87.4) to 91.5% (95% CI = 84.4-95.5). Viral suppression (<5000 copies/mL using DBS) among those on ART increased significantly from 55.0% (95% CI = 39.6-70.4) in 2014 to 81.4% (95% CI = 72.0-90.8) in 2016. Among all PLHIV an estimated 72.0% (95% CI = 63.8-80.1) of women and 45.8% (95% CI = 27.0-64.7) of men achieved viral suppression by 2016.ConclusionsOver a period during which fixed-dose combination was introduced, ART eligibility expanded, and efforts to streamline treatment were implemented, major improvements in the second and third 90-90-90 targets were achieved. Achieving the first 90 target will require targeted and improved testing models for men