Challenges to generating political prioritization for adolescent sexual and reproductive health in Kenya: A qualitative study.

BackgroundDespite the high burden of adverse adolescent sexual and reproductive health (SRH) outcomes, it has remained a low political priority in Kenya. We examined factors that have shaped the lack of current political prioritization of adolescent SRH service provision.MethodsWe used the Shiffman and Smith policy framework consisting of four categories-actor power, ideas, political contexts, and issue characteristics-to analyse factors that have shaped political prioritization of adolescent SRH. We undertook semi-structured interviews with 14 members of adolescent SRH networks between February and April 2019 at the national level and conducted thematic analysis of the interviews.FindingsSeveral factors hinder the attainment of political priority for adolescent SRH in Kenya. On actor power, the adolescent SRH community was diverse and united in adoption of international norms and policies, but lacked policy entrepreneurs to provide strong leadership, and policy windows were often missed. Regarding ideas, community members lacked consensus on a cohesive public positioning of the problem. On issue characteristics, the perception of adolescents as lacking political power made politicians reluctant to act on the existing data on the severity of adolescent SRH. There was also a lack of consensus on the nature of interventions to be implemented. Pertaining to political contexts, sectoral funding by donors and government treasury brought about tension within the different government ministries resulting in siloed approaches, lack of coordination and overall inefficiency. However, the SRH community has several strengths that augur well for future political support. These include the diverse multi-sectoral background of its members, commitment to improving adolescent SRH, and the potential to link with other health priorities such as maternal health and HIV/AIDS.ConclusionIn order to increase political attention to adolescent SRH in Kenya, there is an urgent need for policy actors to: 1) create a more cohesive community of advocates across sectors, 2) develop a clearer public positioning of adolescent SRH, 3) agree on a set of precise approaches that will resonate with the political system, and 4) identify and nurture policy entrepreneurs to facilitate the coupling of adolescent SRH with potential solutions when windows of opportunity arise

Representations of child abuse in contemporary French teenage fiction

Child abuse began to emerge as a central topic depicted in Western children’s and teenage realist fiction from around the 1990s, peaking in prevalence around the turn of the century and into the early years of the twenty-first century. In this thesis I explore the formal expression of abuse and trauma in a corpus of twenty French texts published between 1992 and 2008 for young-adolescent readers aged between 10 and 16 years. The project begins with a Propp-inspired structural model of child-abuse plot features and characters, which identifies a set cast of protagonists across the corpus which serve a specific functional role in the narrative. I then focus on the three main narratological categories of voice, mood and time, using Genette’s Discours du récit as a framework for a close reading of the abuse texts, whilst also drawing upon various trauma theorists, to explore how choice of narrator, focalizing character and temporal perspectives are manipulated to express different aspects of and perspectives on abuse and the psychological impact of abuse in particular. The final chapter is an analysis of the means used by both protagonists within the texts, and the authors of the texts, to communicate and express abuse and trauma on a personal level, to other characters, and to readers. By drawing upon structural and narratological studies as well as trauma theory in my analysis, I show that form and content are inextricably linked across the corpus. Indeed, the protagonists’ traumatic memories and painful experiences are expressed both on a diegetic level via the characters, and also reflected in the formal and structural features of the texts

Comparing alternating pressure mattresses and high-specification foam mattresses to prevent pressure ulcers in high-risk patients: the PRESSURE 2 RCT

Background: Pressure ulcers (PUs) are a burden to patients, carers and health-care providers. Specialist mattresses minimise the intensity and duration of pressure on vulnerable skin sites in at-risk patients. Primary objective: Time to developing a new PU of category ≥ 2 in patients using an alternating pressure mattress (APM) compared with a high-specification foam mattress (HSFM). Design: A multicentre, Phase III, open, prospective, planned as an adaptive double-triangular group sequential, parallel-group, randomised controlled trial with an a priori sample size of 2954 participants. Randomisation used minimisation (incorporating a random element). Setting: The trial was set in 42 secondary and community inpatient facilities in the UK. Participants: Adult inpatients with evidence of acute illness and at a high risk of PU development. Interventions and follow-up: APM or HSFM – the treatment phase lasted a maximum of 60 days; the final 30 days were post-treatment follow-up. Main outcome measures: Time to event. Results: From August 2013 to November 2016, 2029 participants were randomised to receive either APM (n = 1016) or HSFM (n = 1013). Primary end point – 30-day final follow-up: of the 2029 participants in the intention-to-treat population, 160 (7.9%) developed a new PU of category ≥ 2. There was insufficient evidence of a difference between groups for time to new PU of category ≥ 2 [Fine and Gray model HR 0.76, 95% confidence interval (CI) 0.56 to 1.04; exact p-value of 0.0890 and 2% absolute difference]. Treatment phase sensitivity analysis: 132 (6.5%) participants developed a new PU of category ≥ 2 between randomisation and end of treatment phase. There was a statistically significant difference in the treatment phase time-to-event sensitivity analysis (Fine and Gray model HR 0.66, 95% CI 0.46 to 0.93; p = 0.0176 and 2.6% absolute difference). Secondary end points – 30-day final follow-up: new PUs of category ≥ 1 developed in 350 (17.2%) participants, with no evidence of a difference between mattress groups in time to PU development, (Fine and Gray model HR 0.83, 95% CI 0.67 to 1.02; p-value = 0.0733 and absolute difference 3.1%). New PUs of category ≥ 3 developed in 32 (1.6%) participants with insufficient evidence of a difference between mattress groups in time to PU development (Fine and Gray model HR 0.81, 95% CI 0.40 to 1.62; p = 0.5530 and absolute difference 0.4%). Of the 145 pre-existing PUs of category 2, 89 (61.4%) healed – there was insufficient evidence of a difference in time to healing (Fine and Gray model HR 1.12, 95% CI 0.74 to 1.68; p = 0.6122 and absolute difference 2.9%). Health economics – the within-trial and long-term analysis showed APM to be cost-effective compared with HSFM; however, the difference in costs models are small and the quality-adjusted life-year gains are very small. There were no safety concerns. Blinded photography substudy – the reliability of central blinded review compared with clinical assessment for PUs of category ≥ 2 was ‘very good’ (kappa statistic 0.82, prevalence- and bias-adjusted kappa 0.82). Quality-of-life substudy – the Pressure Ulcer Quality of Life – Prevention (PU-QoL-P) instrument meets the established criteria for reliability, construct validity and responsiveness. Limitations: A lower than anticipated event rate. Conclusions: In acutely ill inpatients who are bedfast/chairfast and/or have a category 1 PU and/or localised skin pain, APMs confer a small treatment phase benefit that is diminished over time. Overall, the APM patient compliance, very low PU incidence rate observed and small differences between mattresses indicate the need for improved indicators for targeting of APMs and individualised decision-making. Decisions should take into account skin status, patient preferences (movement ability and rehabilitation needs) and the presence of factors that may be potentially modifiable through APM allocation, including being completely immobile, having nutritional deficits, lacking capacity and/or having altered skin/category 1 PU. Future work: Explore the relationship between mental capacity, levels of independent movement, repositioning and PU development. Explore ‘what works for whom and in what circumstances’. Trial registration: Current Controlled Trials ISRCTN01151335. Funding: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 52. See the NIHR Journals Library website for further project information

Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling

Adenosine 5′-monophosphate-activated protein kinase (AMPK) is a pivotal regulator of metabolism at cellular and organismal levels. AMPK also suppresses inflammation. We found that pharmacological activation of AMPK rapidly inhibited the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in various cells. In vitro kinase assays revealed that AMPK directly phosphorylated two residues (Ser515 and Ser518) within the Src homology 2 domain of JAK1. Activation of AMPK enhanced the interaction between JAK1 and 14-3-3 proteins in cultured vascular endothelial cells and fibroblasts, an effect that required the presence of Ser515 and Ser518 and was abolished in cells lacking AMPK catalytic subunits. Mutation of Ser515 and Ser518 abolished AMPK-mediated inhibition of JAK-STAT signaling stimulated by either the sIL-6Ra/IL-6 complex or the expression of a constitutively active V658F-mutant JAK1 in human fibrosarcoma cells. Clinically used AMPK activators metformin and salicylate enhanced the inhibitory phosphorylation of endogenous JAK1 and inhibited STAT3 phosphorylation in primary vascular endothelial cells. Therefore, our findings reveal a mechanism by which JAK1 function and inflammatory signaling may be suppressed in response to metabolic stress and provide a mechanistic rationale for the investigation of AMPK activators in a range of diseases associated with enhanced activation of the JAK-STAT pathway. 2016</p

Control of Canalization and Evolvability by Hsp90

Partial reduction of Hsp90 increases expression of morphological novelty in qualitative traits of Drosophila and Arabidopsis, but the extent to which the Hsp90 chaperone also controls smaller and more likely adaptive changes in natural quantitative traits has been unclear. To determine the effect of Hsp90 on quantitative trait variability we deconstructed genetic, stochastic and environmental components of variation in Drosophila wing and bristle traits of genetically matched flies, differing only by Hsp90 loss-of-function or wild-type alleles. Unexpectedly, Hsp90 buffering was remarkably specific to certain normally invariant and highly discrete quantitative traits. Like the qualitative trait phenotypes controlled by Hsp90, highly discrete quantitative traits such as scutellor and thoracic bristle number are threshold traits. When tested across genotypes sampled from a wild population or in laboratory strains, the sensitivity of these traits to many types of variation was coordinately controlled, while continuously variable bristle types and wing size, and critically invariant left-right wing asymmetry, remained relatively unaffected. Although increased environmental variation and developmental noise would impede many types of selection response, in replicate populations in which Hsp90 was specifically impaired, heritability and ‘extrinsic evolvability’, the expected response to selection, were also markedly increased. However, despite the overall buffering effect of Hsp90 on variation in populations, for any particular individual or genotype in which Hsp90 was impaired, the size and direction of its effects were unpredictable. The trait and genetic-background dependence of Hsp90 effects and its remarkable bias toward invariant or canalized traits support the idea that traits evolve independent and trait-specific mechanisms of canalization and evolvability through their evolution of non-linearity and thresholds. Highly non-linear responses would buffer variation in Hsp90-dependent signaling over a wide range, while over a narrow range of signaling near trait thresholds become more variable with increasing probability of triggering all-or-none developmental responses

Activation of AMP-activated protein kinase rapidly suppresses multiple pro-inflammatory pathways in adipocytes including IL-1 receptor-associated kinase-4 phosphorylation

yesInflammation of adipose tissue in obesity is associated with increased IL-1β, IL-6 and TNF-α secretion and proposed to contribute to insulin resistance. AMP-activated protein kinase (AMPK) regulates nutrient metabolism and is reported to have anti-inflammatory actions in adipose tissue, yet the mechanisms underlying this remain poorly characterised. The effect of AMPK activation on cytokine-stimulated proinflammatory signalling was therefore assessed in cultured adipocytes. AMPK activation inhibited IL-1β-stimulated CXCL10 secretion, associated with reduced interleukin-1 receptor associated kinase-4 (IRAK4) phosphorylation and downregulated MKK4/JNK and IKK/IκB/NFκB signalling. AMPK activation inhibited TNF-α-stimulated IKK/IκB/NFκB signalling but had no effect on JNK phosphorylation. The JAK/STAT3 pathway was also suppressed by AMPK after IL-6 stimulation and during adipogenesis. Adipose tissue from AMPKα1−/− mice exhibited increased JNK and STAT3 phosphorylation, supporting suppression of these distinct proinflammatory pathways by AMPK in vivo. The inhibition of multiple pro-inflammatory signalling pathways by AMPK may underlie the reported beneficial effects of AMPK activation in adipose tissue.British Heart Foundatio