Measles to the Rescue: A Review of Oncolytic Measles Virus

Oncolytic virotherapeutic agents are likely to become serious contenders in cancer treatment. The vaccine strain of measles virus is an agent with an impressive range of oncolytic activity in pre-clinical trials with increasing evidence of safety and efficacy in early clinical trials. This paramyxovirus vaccine has a proven safety record and is amenable to careful genetic modification in the laboratory. Overexpression of the measles virus (MV) receptor CD46 in many tumour cells may direct the virus to preferentially enter transformed cells and there is increasing awareness of the importance of nectin-4 and signaling lymphocytic activation molecule (SLAM) in oncolysis. Successful attempts to retarget MV by inserting genes for tumour-specific ligands to antigens such as carcinoembryonic antigen (CEA), CD20, CD38, and by engineering the virus to express synthetic microRNA targeting sequences, and "blinding" the virus to the natural viral receptors are exciting measures to increase viral specificity and enhance the oncolytic effect. Sodium iodine symporter (NIS) can also be expressed by MV, which enables in vivo tracking of MV infection. Radiovirotherapy using MV-NIS, chemo-virotherapy to convert prodrugs to their toxic metabolites, and immune-virotherapy including incorporating antibodies against immune checkpoint inhibitors can also increase the oncolytic potential. Anti-viral host immune responses are a recognized barrier to the success of MV, and approaches such as transporting MV to the tumour sites by carrier cells, are showing promise. MV Clinical trials are producing encouraging preliminary results in ovarian cancer, myeloma and cutaneous non-Hodgkin lymphoma, and the outcome of currently open trials in glioblastoma multiforme, mesothelioma and squamous cell carcinoma are eagerly anticipated

Second-line antiretroviral therapy in a workplace and community-based treatment programme in South Africa: determinants of virological outcome.

: Background: As antiretroviral treatment (ART) programmes in resource-limited settings mature, more patients are experiencing virological failure. Without resistance testing, deciding who should switch to second-line ART can be difficult. The consequences for second-line outcomes are unclear. In a workplace- and community-based multi-site programme, with 6-monthly virological monitoring, we describe outcomes and predictors of viral suppression on second-line, protease inhibitor-based ART.Methods: We used prospectively collected clinic data from patients commencing first-line ART between 1/1/03 and 31/12/08 to construct a study cohort of patients switched to second-line ART in the presence of a viral load (VL) ?400 copies/ml. Predictors of VL<400 copies/ml within 15 months of switch were assessed using modified Poisson regression to estimate risk ratios.Results: 205 workplace patients (91.7% male; median age 43 yrs) and 212 community patients (38.7% male; median age 36 yrs) switched regimens. At switch compared to community patients, workplace patients had a longer duration of viraemia, higher VL, lower CD4 count, and higher reported non-adherence on first-line ART. Non-adherence was the reported reason for switching in a higher proportion of workplace patients. Following switch, 48.3% (workplace) and 72.0% (community) achieved VL<400, with non-adherence (17.9% vs. 1.4%) and virological rebound (35.6% vs. 13.2% with available measures) reported more commonly in the workplace programme. In adjusted analysis of the workplace programme, lower switch VL and younger age were associated with VL<400. In the community programme, shorter duration of viraemia, higher CD4 count and transfers into programme on ART were associated with VL<400.Conclusion: High levels of viral suppression on second-line ART can be, but are not always, achieved in multi-site treatment programmes with both individual- and programme-level factors influencing outcomes. Strategies to support both healthcare workers and patients during this switch period need to be evaluated; sub-optimal adherence, particularly in the workplace programme must be addressed

Non-inferiority trials: are they inferior? A systematic review of reporting in major medical journals

OBJECTIVE: To assess the adequacy of reporting of non-inferiority trials alongside the consistency and utility of current recommended analyses and guidelines. DESIGN: Review of randomised clinical trials that used a non-inferiority design published between January 2010 and May 2015 in medical journals that had an impact factor >10 (JAMA Internal Medicine, Archives Internal Medicine, PLOS Medicine, Annals of Internal Medicine, BMJ, JAMA, Lancet and New England Journal of Medicine). DATA SOURCES: Ovid (MEDLINE). METHODS: We searched for non-inferiority trials and assessed the following: choice of non-inferiority margin and justification of margin; power and significance level for sample size; patient population used and how this was defined; any missing data methods used and assumptions declared and any sensitivity analyses used. RESULTS: A total of 168 trial publications were included. Most trials concluded non-inferiority (132; 79%). The non-inferiority margin was reported for 98% (164), but less than half reported any justification for the margin (77; 46%). While most chose two different analyses (91; 54%) the most common being intention-to-treat (ITT) or modified ITT and per-protocol, a large number of articles only chose to conduct and report one analysis (65; 39%), most commonly the ITT analysis. There was lack of clarity or inconsistency between the type I error rate and corresponding CIs for 73 (43%) articles. Missing data were rarely considered with (99; 59%) not declaring whether imputation techniques were used. CONCLUSIONS: Reporting and conduct of non-inferiority trials is inconsistent and does not follow the recommendations in available statistical guidelines, which are not wholly consistent themselves. Authors should clearly describe the methods used and provide clear descriptions of and justifications for their design and primary analysis. Failure to do this risks misleading conclusions being drawn, with consequent effects on clinical practice

Zooplankton Gut Passage Mobilizes Lithogenic Iron for Ocean Productivity

Iron is an essential nutrient for phytoplankton, but low concentrations limit primary production and associated atmospheric carbon drawdown in large parts of the world’s oceans [1 and 2]. Lithogenic particles deriving from aeolian dust deposition, glacial runoff, or river discharges can form an important source if the attached iron becomes dissolved and therefore bioavailable [3, 4 and 5]. Acidic digestion by zooplankton is a potential mechanism for iron mobilization [6], but evidence is lacking. Here we show that Antarctic krill sampled near glacial outlets at the island of South Georgia (Southern Ocean) ingest large amounts of lithogenic particles and contain 3-fold higher iron concentrations in their muscle than specimens from offshore, which confirms mineral dissolution in their guts. About 90% of the lithogenic and biogenic iron ingested by krill is passed into their fecal pellets, which contain ∼5-fold higher proportions of labile (reactive) iron than intact diatoms. The mobilized iron can be released in dissolved form directly from krill or via multiple pathways involving microbes, other zooplankton, and krill predators. This can deliver substantial amounts of bioavailable iron and contribute to the fertilization of coastal waters and the ocean beyond. In line with our findings, phytoplankton blooms downstream of South Georgia are more intensive and longer lasting during years with high krill abundance on-shelf. Thus, krill crop phytoplankton but boost new production via their nutrient supply. Understanding and quantifying iron mobilization by zooplankton is essential to predict ocean productivity in a warming climate where lithogenic iron inputs from deserts, glaciers, and rivers are increasing [7, 8, 9 and 10]

Cost of point-of-care lateral flow urine lipoarabinomannan antigen testing in HIV-positive adults in South Africa

Aaron S. Karat - ORCID 0000-0001-9643-664X https://orcid.org/0000-0001-9643-664XINTRODUCTION: The World Health Organization recommends point-of-care (POC) lateral flow urine lipoarabinomannan (LF-LAM) for tuberculosis (TB) diagnosis in selected human immunodeficiency virus (HIV) positive people. South Africa had 438 000 new TB episodes in 2016, 58.9% of which were contributed by HIV-positive people. LF-LAM is being considered for scale-up in South Africa.METHODS: We estimated the costs of using LF-LAM in HIV-positive adults with CD4 counts 6 150 cells/ll enrolled in the TB Fast Track Trial in South Africa. We also estimated costs of POC haemoglobin (Hb), as this was used in the study algorithm. Data on clinic-level (10 intervention clinics) and above-clinic-level costs were collected.RESULTS: A total of 1307 LF-LAM tests were performed at 10 clinics over 24 months. The mean cliniclevel costs were US$12.80 per patient for LF-LAM and POC Hb; LF-LAM costs were US$11.49 per patient. The mean above-clinic-level unit costs for LF-LAM were US$12.06 for clinic preparation, training, coordination and mentoring. The mean total cost of LF-LAM was US$23.55 per patient.CONCLUSION: At clinic level, the cost of LF-LAM was comparable to other TB diagnostics in South Africa. It is important to consider above-clinic-level costs for POC tests, as these may be required to support roll-out and ensure successful implementation.The trial sponsor was the London School of Hygiene & Tropical Medicine, London, UK. The study was funded by Joint Global Health Trials (UK Medical Research Council, UK Department for International Development, Wellcome Trust). This UK-funded award is part of the EDCTP2 programme supported by the European Union. Alere donated materials for quality control of their LAM assay. The funder and study sponsor had no role in the study design or in the execution of the study, analysis and interpretation of data, or decision to submit results for publication.https://doi.org/10.5588/ijtld.18.004622pubpub

Understanding the barriers to accessing symptom-specific cognitive behavior therapy (CBT) for distressing voices: reflecting on and extending the lessons learnt from the CBT for psychosis literature

The experience of hearing voices ('auditory hallucinations') can cause significant distress and disruption to quality of life for people with a psychosis diagnosis. Psychological therapy in the form of Cognitive Behavior Therapy for psychosis is recommended for the treatment of positive symptoms, including distressing voices, but is rarely available to patients in the UK. Cognitive Behavior Therapy for psychosis has recently evolved with the development of symptom-specific therapies that focus upon only one symptom of psychosis at a time. Preliminary findings from randomized controlled trials suggest that these symptom-specific therapies can be more effective for distressing voices than the use of broad CBT protocols, and have the potential to target voices trans-diagnostically. Whilst this literature is evolving, consideration must be given to the potential for a symptom-specific approach to overcome some of the barriers to delivery of evidence-based psychological therapies within clinical services. These barriers are discussed in relation to the UK mental health services, and we offer suggestions for future research to enhance our understanding of these barriers

‘I don't think I can catch it’: women, confidence and responsibility in football coach education

Whilst women’s participation in sport continues to increase, their presence remains ideologically challenging given the significance of sport for the construction of gendered identities. As a hegmonically masculine institution, leadership roles across sport remain male-dominated and the entry of women into positions of authority (such as coaching) routinely contested. But in powerful male-typed sports, like football, women’s participation remains particularly challenging. Consequently, constructions of gender inequity in coaching were explored at a regional division of the English Football Association through unstructured interviews and coaching course observation. Using critical discourse analysis we identified the consistent re/production of women as unconfident in their own skills and abilities, and the framing of women themselves as responsible for the gendered inequities in football coaching. Women were thereby strategically positioned as deservedly on the periphery of the football category,whilst the organization was positioned as progressive and liberal

Modelling fish habitat preference with a genetic algorithm-optimized Takagi-Sugeno model based on pairwise comparisons

Species-environment relationships are used for evaluating the current status of target species and the potential impact of natural or anthropogenic changes of their habitat. Recent researches reported that the results are strongly affected by the quality of a data set used. The present study attempted to apply pairwise comparisons to modelling fish habitat preference with Takagi-Sugeno-type fuzzy habitat preference models (FHPMs) optimized by a genetic algorithm (GA). The model was compared with the result obtained from the FHPM optimized based on mean squared error (MSE). Three independent data sets were used for training and testing of these models. The FHPMs based on pairwise comparison produced variable habitat preference curves from 20 different initial conditions in the GA. This could be partially ascribed to the optimization process and the regulations assigned. This case study demonstrates applicability and limitations of pairwise comparison-based optimization in an FHPM. Future research should focus on a more flexible learning process to make a good use of the advantages of pairwise comparisons

Rapid Urine-Based Screening for Tuberculosis to Reduce AIDS-Related Mortality in Hospitalized Patients in Africa (STAMP) Trial Protocol

Trial protocol for the STAMP trial- a multi-country (Malawi and South Africa) individually randomised clinical trial to determine the impact on early mortality of the addition of rapid, urine-based TB screening to the standard of care TB screening in HIV-infected patients requiring admission to medical wards in hospitals in southern Africa