Malignancy and all-cause mortality; incidence in adolescents and young adults living with perinatally acquired HIV.

Background: Adults living with HIV have an increased risk of malignancy yet there is a paucity of data for adolescents and young adults (AYA) with perinatally acquired HIV (PaHIV). Methods: Retrospective cohort analysis of all-cause mortality and malignancies in AYA with PaHIV aged 10-24 years attending a tertiary unit from 01 January 2004 to 31 December 2017, assessing cancer presentation, immunology and comparing mortality and malignancy incidence to age-matched UK general population rates. Results: A total of 290 AYA with PaHIV contributed 2644 person-years of follow up. Six (2.0%) died within the study period at a median age of 17 years (interquartile range [IQR]15-19), 3 of malignancy, 2 with end-stage HIV and 1 with cryptococcal meningitis. Overall mortality rate was 2.3/1000 person-years, with an age-matched general population rate of 0.2/1000 person-years. Eight (2.8%) were diagnosed with a malignancy; 6 with lymphoma (n=3 Hodgkin's, n=1 Burkitt's, n=2 B-cell) and one each with hepatocellular carcinoma and gastrointestinal adenocarcinoma. At cancer diagnosis the median age was 19 years (IQR 14-23), median CD4 T cell count was 453 cells/mm3 (IQR 231-645) and median length of HIV viremia was 15 years (IQR 12-17). The incidence rate of a malignancy was 3.0/1000 person-years in AYA with PaHIV, whilst that in the age-matched general population is 0.2/1000 person-years. Conclusion: AYA living with PaHIV had an increased risk of all-cause mortality and of malignancy compared to their uninfected peers, with the excess in malignancy driven by lymphomas. It is hoped that earlier access to antiretroviral therapy will mitigate some of the AIDS-defining and non-AIDS defining risks for future generations

"The difference that makes a difference": highlighting the role of variable contexts within an HIV Prevention Community Randomised Trial (HPTN 071/PopART) in 21 study communities in Zambia and South Africa.

This paper explores contextual heterogeneity within a community randomised trial HPTN 071 (Population Effects of Antiretroviral Treatment to Reduce HIV Transmission) carried out in 21 study communities (12 Zambian, 9 South African). The trial evaluates the impact of a combination HIV prevention package (including household-based HIV counselling and testing and anti-retroviral treatment (ART) eligibility regardless of CD4-count) on HIV incidence. The selection, matching and randomisation of study communities relied on key epidemiological and demographic variables and community and stakeholder support. In 2013, following the selection of study communities, a "Broad Brush Survey" (BBS) approach was used to rapidly gather qualitative data on each study community, prior to the implementation of the trial intervention. First-year process indicator intervention data (2014-2015) were collected during the household-based intervention by community lay workers. Using an open/closed typology of urban communities (indicating more or less heterogeneity), this qualitative inquiry presents key features of 12 Zambian communities using a list of four meta-indicators (physical features, social organisation, networks and community narratives). These indicators are then compared with four intervention process indicators in a smaller set of four study communities. The process indicators selected for this analysis indicate response to the intervention (uptake) amongst adults. The BBS qualitative data are used to interpret patterns of similarity and variability in the process indicators across four communities. We found that meta-indicators of local context helped to interpret patterns of similarity and variability emerging across and within the four communities. Features especially significant for influencing heterogeneity in process indicators include proportion of middle-class residents, proximity to neighbouring communities and town centre, the scale of the informal economy, livelihood-linked mobility, presence of HIV stakeholders over time and commitment to community action. Future interdisciplinary analysis is needed to explore if these patterns of difference continue to hold up over the full intervention period and all intervention communities

Multiscale nature of hysteretic phenomena: Application to CoPt-type magnets

We suggest a workable approach for the description of multiscale magnetization reversal phenomena in nanoscale magnets and apply it to CoPt-type alloys. We show that their hysteretic properties are governed by two effects originating at different length scales: a peculiar splitting of domain walls and their strong pinning at antiphase boundaries. We emphasize that such multiscale nature of hysteretic phenomena is a generic feature of nanoscale magnetic materials.Comment: 4 pages (revtex 4), 2 color EPS figure

Calculation of coercivity of magnetic nanostructures at finite temperatures

We report a finite temperature micromagnetic method (FTM) that allows for the calculation of the coercive field of arbitrary shaped magnetic nanostructures at time scales of nanoseconds to years. Instead of directly solving the Landau-Lifshitz-Gilbert equation, the coercive field is obtained without any free parameter by solving a non linear equation, which arises from the transition state theory. The method is applicable to magnetic structures where coercivity is determined by one thermally activated reversal or nucleation process. The method shows excellent agreement with experimentally obtained coercive fields of magnetic nanostructures and provides a deeper understanding of the mechanism of coercivity.Comment: submitted to Phys. Rev.

Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival : an updated analysis of KEYNOTE-010 trial

Background: In KEYNOTE-010, pembrolizumab versus docetaxel improved overall survival (OS) in patients with programmed death-1 protein (PD)-L1-positive advanced non-small-cell lung cancer (NSCLC). A prespecified exploratory analysis compared outcomes in patients based on PD-L1 expression in archival versus newly collected tumor samples using recently updated survival data. Patients and methods: PD-L1 was assessed centrally by immunohistochemistry (22C3 antibody) in archival or newly collected tumor samples. Patients received pembrolizumab 2 or 10 mg/kg Q3W or docetaxel 75 mg/m2 Q3W for 24 months or until progression/intolerable toxicity/other reason. Response was assessed by RECIST v1.1 every 9 weeks, survival every 2 months. Primary end points were OS and progression-free survival (PFS) in tumor proportion score (TPS) 50% and 1%; pembrolizumab doses were pooled in this analysis. Results: At date cut-off of 24 March 2017, median follow-up was 31 months (range 23-41) representing 18 additional months of follow-up from the primary analysis. Pembrolizumab versus docetaxel continued to improve OS in patients with previously treated, PD-L1-expressing advanced NSCLC; hazard ratio (HR) was 0.66 [95% confidence interval (CI): 0.57, 0.77]. Of 1033 patients analyzed, 455(44%) were enrolled based on archival samples and 578 (56%) on newly collected tumor samples. Approximately 40% of archival samples and 45% of newly collected tumor samples were PD-L1 TPS 50%. For TPS 50%, the OS HRs were 0.64 (95% CI: 0.45, 0.91) and 0.40 (95% CI: 0.28, 0.56) for archival and newly collected samples, respectively. In patients with TPS 1%, OS HRs were 0.74 (95% CI: 0.59, 0.93) and 0.59 (95% CI: 0.48, 0.73) for archival and newly collected samples, respectively. In TPS 50%, PFS HRs were similar across archival [0.63 (95% CI: 0.45, 0.89)] and newly collected samples [0.53 (95% CI: 0.38, 0.72)]. In patients with TPS 1%, PFS HRs were similar across archival [0.82 (95% CI: 0.66, 1.02)] and newly collected samples [0.83 (95% CI: 0.68, 1.02)]. Conclusion: Pembrolizumab continued to improve OS over docetaxel in intention to treat population and in subsets of patients with newly collected and archival samples

A modified version of the Bayley Scales of Infant Development-II for cognitive matching of infants with and without Down syndrome

Background Many measures of infants' early cognitive development, including the BSID-II (The Bayley Scales of Infant Development), mix together test items that assess a number of different developmental domains including language, attention, motor functioning and social abilities, and some items contribute to the assessment of more than one domain. Consequently, the scales may lead to under- or over-estimates of cognitive abilities in some clinical samples and may not be the best measure to use for matching purposes. Method To address this issue we created a modified form of the BSID-II (the BSID-M) to provide a ‘purer’ assessment of the general cognitive capacities in infants with Down syndrome (DS) from 6 to 18 months of age. We excluded a number of items that implicated language, motor, attentional and social functioning from the original measure. This modified form was administered to 17 infants with Down syndrome when 6, 12 and 18 months old and to 41 typically developing infants at 4, 7 and 10 months old. Results The results suggested that the modified form continued to provide a meaningful and stable measure of cognitive functioning and revealed that DS infants may score marginally higher in terms of general cognitive abilities when using this modified form than they might when using the standard BSID-II scales. Conclusions This modified form may be useful for researchers who need a ‘purer’ measure with which to match infants with DS and other infants with intellectual disabilities on cognitive functioning

Spinning plates: livelihood mobility, household responsibility and anti-retroviral treatment in an urban Zambian community during the HPTN 071 (PopART) study

INTRODUCTION: Qualitative data are lacking on the impact of mobility among people living with HIV (PLHIV) and their decision-making around anti-retroviral treatment (ART). We describe challenges of juggling household responsibility, livelihood mobility and HIV management for six PLHIV in urban Zambia. METHODS: Six PLHIV (three men and three women, aged 21 to 44) were recruited from different geographic zones in one urban community drawn from a qualitative cohort in a social science component of a cluster-randomized trial (HPTN071 PopART). Participants were on ART (n = 2), not on ART (n = 2) and had started and stopped ART (n = 2). At least two in-depth interviews and participant observations, and three drop-in household visits with each were carried out between February and August 2017. Themed and comparative analysis was conducted. RESULTS: The six participants relied on the informal economy to meet basic household needs. Routine livelihood mobility, either within the community and to a nearby town centre, or further afield for longer periods of time, was essential to get by. Although aware of ART benefits, only one of the six participants managed to successfully access and sustain treatment. The other five struggled to find time to access ART alongside other priorities, routine mobility and when daily routines were more chaotic. Difficulty in accessing ART was exacerbated by local health facility factors (congestion, a culture of reprimanding PLHIV who miss appointments, sporadic rationed drug supply), stigma and more limited social capital. CONCLUSIONS: Using a time-space framework illustrated how household responsibility, livelihood mobility and HIV management every day were like spinning plates, each liable to topple and demanding constant attention. If universal lifelong ART is to be delivered, the current service model needs to adjust the limited time that some PLHIV have to access ART because of household responsibilities and the need to earn a living moving around, often away from home. Practical strategies that could facilitate ART access in the context of livelihood mobility include challenging the practice of reprimand, improving drug supply, having ART services more widely distributed, mapped and available at night and weekends, and an effective centralized client health information system

Organization theory and military metaphor: time for a reappraisal?

A ‘conventional’ use of military metaphor would use it to convey attributes such as hierarchical organization, vertical communication and limited autonomy. This is often used in contrast to a looser form of organization based on the metaphor of the network. However, this article argues that military practice is more complex, with examples of considerable autonomy within the constraints of central direction. It is suggested that not only might this be a more useful metaphor for many contemporary organizations, but also that simplistic uses of military metaphor divert our attention away from the functions that management hierarchies play. The discussion is embedded within a critical realist account of metaphor, arguing for both its value and the need for its further development

Perinatal exposure to polychlorinated biphenyls and dioxins through dietary intake

Polychlorinated biphenyls (PCBs) and dioxins (polychlorinated dibenzo p-dioxins and dibenzofurans) are potentially hazardous compounds. Since food is the major source (>90%) for the accumulation of PCBs and dioxins in the human body, food habits in women determine the degree of fetal exposure and levels in human milk. In order to investigate an association between dietary intake and PCB and dioxin levels in human milk and PCB levels in maternal and cord plasma, the food intake of 418 Dutch women during pregnancy was recorded using semi-quantitative food frequency questionnaires. After adjusting for covariates, a weak association was found between the estimated dietary intake of 2,3,7,8-tetrachlorodibenzo p-dioxin (2,3,7,8-TCDD), dioxins, and planar PCBs and their corresponding levels in breast milk. The estimated dietary intake of 2,3,7,8-TCDD, dioxins, and planar PCBs was also related to the PCB levels in maternal and cord plasma. Dairy products accounted for about half and industrial oils for about a quarter of the estimated 2,3,7,8-TCDD, dioxin, and the planar PCB intake. It is concluded that the contribution of a pregnancy related diet to PCB and dioxin levels in human milk and to PCB levels in maternal and cord plasma is relatively low. Decrease of exposure to PCBs and dioxins of the fetus and the neonate probably requires long-term reduction of the intake of these pollutants. Substitution of normal cheese by low-fat cheese and the use of vegetable oils instead of fish oils in the preparation of foodstuffs by the food industry could contribute to a reduced intake of PCBs and dioxins

Therapeutic vaccination following early antiretroviral therapy elicits highly functional T cell responses against conserved HIV-1 regions

'Kick and kill' cure strategies aim to induce HIV protein expression in latently infected cells (kick), and thus trigger their elimination by cytolytic T cells (kill). In the Research in Viral Eradication of HIV Reservoirs trial (NCT02336074), people diagnosed with primary HIV infection received immediate antiretroviral therapy (ART) and were randomised 24 weeks later to either a latency-reversing agent, vorinostat, together with ChAdV63.HIVconsv and MVA.HIVconsv vaccines, or ART alone. This intervention conferred no reduction in HIV-1 reservoir size over ART alone, despite boosting virus-specific CD4+ and CD8+ T cells. The effects of the intervention were examined at the cellular level in the two trial arms using unbiased computational analysis of polyfunctional scores. This showed that the frequency and polyfunctionality of virus-specific CD4+ and CD8+ T cell populations were significantly increased over 12 weeks post-vaccination, compared to the ART-only arm. HIV-specific IL-2-secreting CD8+ T cells also expanded significantly in the intervention arm and were correlated with antiviral activity against heterologous HIV in vitro. Therapeutic vaccination during ART commenced in primary infection can induce functional T cell responses that are phenotypically similar to those of HIV controllers. Analytical therapy interruption may help determine their ability to control HIV in vivo