HIV prevalence and HIV clinical outcomes of transgender and gender-diverse people in England

Objectives: We provide the first estimate of HIV prevalence among trans and gender‐diverse people living in England and compare outcomes of people living with HIV according to gender identity. Methods: We analysed a comprehensive national HIV cohort and a nationally representative self‐reported survey of people accessing HIV care in England (Positive Voices). Gender identity was recorded using a two‐step question co‐designed with community members and civil society. Responses were validated by clinic follow‐up and/or self‐report. Population estimates were obtained from national government offices. Results: In 2017, HIV prevalence among trans and gender‐diverse people was estimated at 0.46–4.78 per 1000, compared with 1.7 (95% credible interval: 1.6–1.7) in the general population. Of 94 885 people living with diagnosed HIV in England, 178 (0.19%) identified as trans or gender‐diverse. Compared with cisgender people, trans and gender‐diverse people were more likely to be London residents (57% vs. 43%), younger (median age 42 vs. 46 years), of white ethnicity (61% vs. 52%), under psychiatric care (11% vs. 4%), to report problems with self‐care (37% vs. 13%), and to have been refused or delayed healthcare (23% vs. 11%). Antiretroviral uptake and viral suppression were high in both groups. Conclusions: HIV prevalence among trans and gender‐diverse people living in England is relatively low compared with international estimates. Furthermore, no inequalities were observed with regard to HIV care. Nevertheless, trans and gender‐diverse people with HIV report poorer mental health and higher levels of discrimination compared with cisgender people

Spleen Tyrosine Kinase (Syk) Regulates Systemic Lupus Erythematosus (SLE) T Cell Signaling

Engagement of the CD3/T cell receptor complex in systemic lupus erythematosus (SLE) T cells involves Syk rather than the zeta-associated protein. Because Syk is being considered as a therapeutic target we asked whether Syk is central to the multiple aberrantly modulated molecules in SLE T cells. Using a gene expression array, we demonstrate that forced expression of Syk in normal T cells reproduces most of the aberrantly expressed molecules whereas silencing of Syk in SLE T cells normalizes the expression of most abnormally expressed molecules. Protein along with gene expression modulation for select molecules was confirmed. Specifically, levels of cytokine IL-21, cell surface receptor CD44, and intracellular molecules PP2A and OAS2 increased following Syk overexpression in normal T cells and decreased after Syk silencing in SLE T cells. Our results demonstrate that levels of Syk affect the expression of a number of enzymes, cytokines and receptors that play a key role in the development of disease pathogenesis in SLE and provide support for therapeutic targeting in SLE patients

DNA sense-and-respond protein modules for mammalian cells

We generated synthetic protein components that can detect specific DNA sequences and subsequently trigger a desired intracellular response. These modular sensors exploit the programmability of zinc-finger DNA recognition to drive the intein-mediated splicing of an artificial trans-activator that signals to a genetic circuit containing a given reporter or response gene. We used the sensors to mediate sequence recognition−induced apoptosis as well as to detect and report a viral infection. This work establishes a synthetic biology framework for endowing mammalian cells with sentinel capabilities, which provides a programmable means to cull infected cells. It may also be used to identify positively transduced or transfected cells, isolate recipients of intentional genomic edits and increase the repertoire of inducible parts in synthetic biology.United States. Defense Advanced Research Projects Agency (DARPA-BAA-11-23)Defense Threat Reduction Agency (DTRA) (HDTRA1-14-1-0006)United States. Air Force Office of Scientific Research (FA9550-14-1-0060

Cell motility: the integrating role of the plasma membrane

The plasma membrane is of central importance in the motility process. It defines the boundary separating the intracellular and extracellular environments, and mediates the interactions between a motile cell and its environment. Furthermore, the membrane serves as a dynamic platform for localization of various components which actively participate in all aspects of the motility process, including force generation, adhesion, signaling, and regulation. Membrane transport between internal membranes and the plasma membrane, and in particular polarized membrane transport, facilitates continuous reorganization of the plasma membrane and is thought to be involved in maintaining polarity and recycling of essential components in some motile cell types. Beyond its biochemical composition, the mechanical characteristics of the plasma membrane and, in particular, membrane tension are of central importance in cell motility; membrane tension affects the rates of all the processes which involve membrane deformation including edge extension, endocytosis, and exocytosis. Most importantly, the mechanical characteristics of the membrane and its biochemical composition are tightly intertwined; membrane tension and local curvature are largely determined by the biochemical composition of the membrane and the biochemical reactions taking place; at the same time, curvature and tension affect the localization of components and reaction rates. This review focuses on this dynamic interplay and the feedbacks between the biochemical and biophysical characteristics of the membrane and their effects on cell movement. New insight on these will be crucial for understanding the motility process

Taking stock of 10 years of published research on the ASHA programme: Examining India’s national community health worker programme from a health systems perspective

Background: As India’s accredited social health activist (ASHA) community health worker (CHW) programme enters its second decade, we take stock of the research undertaken and whether it examines the health systems interfaces required to sustain the programme at scale. Methods: We systematically searched three databases for articles on ASHAs published between 2005 and 2016. Articles that met the inclusion criteria underwent analysis using an inductive CHW–health systems interface framework. Results: A total of 122 academic articles were identified (56 quantitative, 29 mixed methods, 28 qualitative, and 9 commentary or synthesis); 44 articles reported on special interventions and 78 on the routine ASHA program. Findings on special interventions were overwhelmingly positive, with few negative or mixed results. In contrast, 55% of articles on the routine ASHA programme showed mixed findings and 23% negative, with few indicating overall positive findings, reflecting broader system constraints. Over half the articles had a health system perspective, including almost all those on general ASHA work, but only a third of those with a health condition focus. The most extensively researched health systems topics were ASHA performance, training and capacity-building, with very little research done on programme financing and reporting, ASHA grievance redressal or peer communication. Research tended to be descriptive, with fewer influence, explanatory or exploratory articles, and no predictive or emancipatory studies. Indian institutions and authors led and partnered on most of the research, wrote all the critical commentaries, and published more studies with negative results. Conclusion: Published work on ASHAs highlights a range of small-scale innovations, but also showcases the challenges faced by a programme at massive scale, situated in the broader health system. As the programme continues to evolve, critical comparative research that constructively feeds back into programme reforms is needed, particularly related to governance, intersectoral linkages, ASHA solidarity, and community capacity to provide support and oversight

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified