Next Generation Sequencing Assay for Detection of Circulating HPV DNA (cHPV-DNA) in Patients Undergoing Radical (Chemo)Radiotherapy in Anal Squamous Cell Carcinoma (ASCC).

Background: Following chemo-radiotherapy (CRT) for human papilloma virus positive (HPV+) anal squamous cell carcinoma (ASCC), detection of residual/recurrent disease is challenging. Patients frequently undergo unnecessary repeated biopsies for abnormal MRI/clinical findings. In a pilot study we assessed the role of circulating HPV-DNA in identifying "true" residual disease. Methods: We prospectively collected plasma samples at baseline (n = 21) and 12 weeks post-CRT (n = 17). Circulating HPV-DNA (cHPV DNA) was measured using a novel next generation sequencing (NGS) assay, panHPV-detect, comprising of two primer pools covering distinct regions of eight high-risk HPV genomes (16, 18, 31, 33, 35, 45, 52, and 58) to detect circulating HPV-DNA (cHPV DNA). cHPV-DNA levels post-CRT were correlated to disease response. Results: In pre-CRT samples, panHPV-detect demonstrated 100% sensitivity and specificity for HPV associated ASCC. PanHPV-detect was able to demonstrate cHPV-DNA in 100% (9/9) patients with T1/T2N0 cancers. cHPV-DNA was detectable 12 weeks post CRT in just 2/17 patients, both of whom relapsed. 1/16 patients who had a clinical complete response (CR) at 3 months post-CRT but relapsed at 9 months and 1/1 patient with a partial response (PR). PanHPV-detect demonstrated 100% sensitivity and specificity in predicting response to CRT. Conclusion: We demonstrate that panHPV-detect, an NSG assay is a highly sensitive and specific test for the identification of cHPV-DNA in plasma at diagnosis. cHPV-DNA post-treatment may predict clinical response to CRT

Toward Enriched Conceptions of Work Learning: Participation, Expansion, and Translation Among Individuals With/In Activity

Despite the long recognition in HRD theory that learning is socially and materially situated in activity and relations, HRD literature indicates a continuing strong emphasis on individualistic theories representing learning as knowledge acquisition or individual development. It is argued here that understandings of work learning within HRD theory can be fruitfully enriched by more fully incorporating practice-based perspectives. Three contemporary theories that analyse learning as a relation of individuals with/in activity have been selected for discussion here: the participational perspective of situated cognition, the notion of expansion from cultural-historical activity theory, and the constructs of translation and mobilization presented by actor-network theory. While these are not particularly new to HRD, the contribution of this discussion is to bring together these theories, along with published empirical workplace research based on them, to highlight selected dynamics that may be useful tools for HRD theory development. One element in particular is read across the three theories: the dialectic of ‘flying’ and ‘grounding’, or lines of discontinuity and continuity characterising work learning. The argument is theory-driven, drawing from HRD literature of work learning and practice-based theories of social activity and knowledge production

Methodological insights from a study using video-ethnography to conduct interdisciplinary research in the study of birth unit design

© eContent Management Pty Ltd. Little is known about how the physical design of a birthing unit can influence the experiences of labour and birth for women, their supporters and midwives. We proposed that an interdisciplinary approach (disciplines of midwifery, architecture, design, communication and public health) was likely to be the most effective way to better understand the complexities and interactions of design, behaviour, communication and experiences. In this methodological paper we aim to provide a roadmap that other researchers may find helpful when considering the use of video as a data collection technique, especially in the study of the powerful and intimate setting of childbirth. The paper also outlines our process for engaging both researchers and participants in reviewing video footage with the aim to contribute multiple perspectives to the analysis process

A gender-sensitised weight loss and healthy living programme for overweight and obese men delivered by Scottish Premier League football clubs (FFIT): a pragmatic randomised controlled trial.

BACKGROUND: The prevalence of male obesity is increasing but few men take part in weight loss programmes. We assessed the effect of a weight loss and healthy living programme on weight loss in football (soccer) fans. METHODS: We did a two-group, pragmatic, randomised controlled trial of 747 male football fans aged 35-65 years with a body-mass index (BMI) of 28 kg/m(2) or higher from 13 Scottish professional football clubs. Participants were randomly assigned with SAS (version 9·2, block size 2-9) in a 1:1 ratio, stratified by club, to a weight loss programme delivered by community coaching staff in 12 sessions held every week. The intervention group started a weight loss programme within 3 weeks, and the comparison group were put on a 12 month waiting list. All participants received a weight management booklet. Primary outcome was mean difference in weight loss between groups at 12 months, expressed as absolute weight and a percentage of their baseline weight. Primary outcome assessment was masked. Analyses were based on intention to treat. The trial is registered with Current Controlled Trials, number ISRCTN32677491. FINDINGS: 374 men were allocated to the intervention group and 374 to the comparison group. 333 (89%) of the intervention group and 355 (95%) of the comparison group completed 12 month assessments. At 12 months the mean difference in weight loss between groups, adjusted for baseline weight and club, was 4·94 kg (95% CI 3·95-5·94) and percentage weight loss, similarly adjusted, was 4·36% (3·64-5·08), both in favour of the intervention (p<0·0001). Eight serious adverse events were reported, five in the intervention group (lost consciousness due to drugs for pre-existing angina, gallbladder removal, hospital admission with suspected heart attack, ruptured gut, and ruptured Achilles tendon) and three in the comparison group (transient ischaemic attack, and two deaths). Of these, two adverse events were reported as related to participation in the programme (gallbladder removal and ruptured Achilles tendon). INTERPRETATION: The FFIT programme can help a large proportion of men to lose a clinically important amount of weight; it offers one effective strategy to challenge male obesity. FUNDING: Scottish Government and The UK Football Pools funded delivery of the programme through a grant to the Scottish Premier League Trust. The National Institute for Health Research Public Health Research Programme funded the assessment (09/3010/06)

Glutathione accelerates sodium channel inactivation in excised rat axonal membrane patches

The effects of glutathione were studied on the gating behaviour of sodium channels in membrane patches of rat axons. Depolarizing pulses from –120 to –40 mV elicited sodium currents of up to 500 pA, indicating the simultaneous activation of up to 250 sodium channels. Inactivation of these channels in the excised, inside-out configuration was fitted by two time constants ( h1=0.81 ms; h2= 5.03 ms) and open time histograms at 0 mV revealed a biexponential distribution of channel openings ( short=0.28 ms; long=3.68 ms). Both, the slow time constant of inactivation and the long lasting single channel openings disappeared after addition of the reducing agent glutathione (2–5 mM) to the bathing solution. Sodium channels of excised patches with glutathione present on the cytoplasmatic face of the membrane had inactivation kinetics similar to channels recorded in the cell-attached configuration. These observations indicate that redox processes may contribute to the gating of axonal sodium channels

The relationship between birth unit design and safe, satisfying birth: Developing a hypothetical model

Recent advances in cross-disciplinary studies linking architecture and neuroscience have revealed that much of the built environment for health-care delivery may actually impair rather than improve health outcomes by disrupting effective communication and increasing patient and staff stress. This is also true for maternity care provision, where it is suggested that the design of the environment can also impact on the experiences and outcomes for birthing women.The aim of this paper is to describe the development of a conceptual model based on literature and understandings of design, communication, stress and model of care. The model explores potential relationships among a set of key variables that need to be considered by researchers wishing to determine the characteristics of optimal birth environments in relation to birth outcomes for women and infants. The conceptual model hypothesises that safe satisfying birth is reliant on the level of stress experienced by a woman and the staff around her, stress influences the quality of communication with women and between staff, and this process is mediated by the design of the birth unit and model of care.The conceptual model is offered as a starting point for researchers who have an appreciation of the complexity of birth and the ability to bring together colleagues from a range of disciplines to explore the pre-requisites for safe and effective maternity care in new ways. © 2010 Elsevier Ltd

Restoration of NK Cell Cytotoxic Function With Elotuzumab and Daratumumab Promotes Elimination of Circulating Plasma Cells in Patients With SLE.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by multiple cellular and molecular dysfunctions of the innate and adaptive immunity. Cytotoxic function of NK cells is compromised in patients with SLE. Herein, we characterized the phenotypic alterations of SLE NK cells in a comprehensive manner to further delineate the mechanisms underlying the cytotoxic dysfunction of SLE NK cells and identify novel potential therapeutic targets. Therefore, we examined PBMC from SLE patients and matched healthy controls by single-cell mass cytometry to assess the phenotype of NK cells. In addition, we evaluated the cell function of NK cells (degranulation and cytokine production) and the killing of B cell subpopulations in a B cell-NK cell in vitro co-culture model. We found that SLE NK cells expressed higher levels of CD38 and were not able to adequately upregulate SLAMF1 and SLAMF7 following activation. In addition, ligation of SLAMF7 with elotuzumab or of CD38 with daratumumab on SLE NK cells enhanced degranulation of both healthy and SLE NK cells and primed them to kill circulating plasma cells in an in vitro co-culture system. Overall, our data indicated that dysregulated expression of CD38, SLAMF1 and SLAMF7 on SLE NK cells is associated with an altered interplay between SLE NK cells and plasma cells, thus suggesting their contribution to the accumulation of (auto)antibody producing cells. Accordingly, targeting SLAMF7 and CD38 may represent novel therapeutic approaches in SLE by enhancing NK cell function and promoting elimination of circulating plasma cell

Urogenital schistosomiasis in Cabo Delgado, northern Mozambique: baseline findings from the SCORE study.

BACKGROUND: The results presented here are part of a five-year cluster-randomised intervention trial that was implemented to understand how best to gain and sustain control of schistosomiasis through different preventive chemotherapy strategies. This paper presents baseline data that were collected in ten districts of Cabo Delgado province, northern Mozambique, before treatment. METHODS: A cross-sectional study of 19,039 individuals was sampled from 144 villages from May to September 2011. In each village prevalence and intensity of S. haematobium were investigated in 100 children first-year students (aged 5-8 years), 100 school children aged 9-12 years (from classes 2 to 7) and 50 adults (20-55 years). Prevalence and intensity of S. haematobium infection were evaluated microscopically by two filtrations, each of 10 ml, from a single urine specimen. Given that individual and community perceptions of schistosomiasis influence control efforts, community knowledge and environmental risk factors were collected using a face-to-face interview. Data were entered onto mobile phones using EpiCollect. Data summary was made using descriptive statistics. Chi-square and logistic regression were used to determine the association between dependent and independent variables. RESULTS: The overall prevalence of urogenital schistosomiasis was 60.4% with an arithmetic mean intensity of infection of 55.8 eggs/10 ml of urine. Heavy infections were detected in 17.7%, of which 235 individuals (6.97%) had an egg count of 1000 eggs/10 ml or more. There was a significantly higher likelihood of males being infected than females across all ages (62% vs 58%; P < 0.0005). Adolescents aged 9-12 years had a higher prevalence (66.6%) and mean infection intensity (71.9 eggs/10 ml) than first-year students (63.1%; 58.2 eggs/10 ml). This is the first study in Mozambique looking at infection rates among adults. Although children had higher levels of infection, it was found here that adults had a high average prevalence and intensity of infection (44.5%; 23.9 eggs/10 ml). Awareness of schistosomiasis was relatively high (68.6%); however, correct knowledge of how schistosomiasis is acquired was low (23.2%) among those who had heard of the disease. Schistosomiasis risk behaviour such as washing (91.3%) and bathing (86.7%) in open water sources likely to be infested with host snails was high. CONCLUSIONS: Urogenital schistosomiasis is widespread in Cabo Delgado. In addition, poor community knowledge about the causes of schistosomiasis and how to prevent it increases the significant public health challenge for the national control program. This was the first study in Mozambique that examined infection levels among adults, where results showed that S. haematobium infection was also extremely high. Given that this controlled trial aims to understand the impact of different combinations of schistosomiasis control through treatment of communities, schools, and treatment holidays over a five-year period, these findings highlight the importance of examining the impact of different treatment approaches also in adults. TRIAL REGISTRATION: The trials have been registered with the International Standard Randomised Controlled Trial registry under ISRCT 14117624 Mozambique (14 December 2015)