HIV-1 and the Mycobacterium tuberculosis granuloma: A systematic review and meta-analysis

SummaryInfection with HIV-1 greatly increases the risk of active tuberculosis (TB). Although hypotheses suggest HIV-1 disrupts Mycobacterium tuberculosis (Mtb) granuloma function, few studies have examined this directly. The objective of this study was to determine what evidence exists about the effect HIV-1 co-infection has upon Mtb granulomas. A systematic search of PubMed, Web of Science, and Medline up to 20 March 2015 was conducted, to identify studies comparing Mtb-infected tissue from HIV-1 infected and uninfected persons, or HIV-1 infected persons with stratified peripheral CD4 T cell (pCD4) counts. We summarized findings that focused on how HIV-1 changes granuloma formation, bacterial presence, cellular composition, and cytokine production. Nineteen studies with a combined sample size of 899 persons were included. Although studies frequently were limited by variable or inadequately described definitions of outcomes and analytical methods, HIV-1 was found to be associated with increased bacillary load within Mtb-infected tissue. Reductions in pCD4 counts within co-infected persons associated with both poorer granuloma formation and higher bacterial load. The high degree of heterogeneity among studies combined with experimental limitations made it difficult to conclusively support previously published and prevalent hypotheses about HIV-1/Mtb co-infection granulomas. To elucidate the validity of these hypotheses we have described areas that can be improved in future studies in order to clarify the influence HIV-1 co-infection has upon the Mtb granuloma

Tuberculosis Antigen-Specific T-Cell Responses During the First 6 Months of Antiretroviral Treatment

The reconstitution of Mycobacterium tuberculosis (Mtb)-antigen-specific CD4 T cells in a cohort of HIV-infected persons starting antiretroviral treatment (ART) in high TB endemic area is described. Restoration of the antigen-specific CD4 T cell subsets mirrored the overall CD4 T cell compartment. Activation (assessed by HLA-DR expression) decreased during ART but remained elevated compared to HIV-uninfected persons. Despite known Mtb sensitisation determined by IGRA, 12/23 participants had no Mtb-specific CD4 T cells detectable by flow cytometry, combined with overall elevated T cell activation and memory differentiation, suggesting heightened turnover. Our data suggest early ART initiation to maintain polyfunctional immune memory responses

Evaluating the Role of Prior Experience in Inclusive Design

This thesis investigates the role of prior experience of products and its affect upon interaction. It has been shown within this work that technological experience of products is related to age, and that this has implications for the success of subsequent interaction. This research adds weight to a growing body of literature that has identified age related and generational differences toward product interaction. Implications for intuitive design such as the use of familiar features and icon design are also identified. The adoption of a novel inclusive design approach, framing interaction using an interactional, behavioural model, is proposed as a potential method to identify issues that cause unnecessary interactional complexity. The effect of prior experience and design upon interaction was investigated by performing three main experimental studies that assessed individuals’ performance with products and identified the problems real users’ experience through inadequate product design. The findings reveal that older participants’ ability to learn and transfer knowledge for successful product interaction may be adversely affected by design. Older users recognised fewer features and iconic warning symbols than younger users, and this appears to place them at a disadvantage in terms of learning and intuitive interaction. Technological experience was found to decrease with age, further compromising older users’ ability to draw accurate inference from products. The contribution of this work is to provide the design community with new knowledge and a greater awareness of the diversity of user needs, and particularly the needs and skills of older people. The hope is that the awareness of this knowledge can, in turn, assist toward the community’s development of better design methods. The approach introduced can be applied to new and existing products alike and can aid the development of products that are more accessible and easier to use for a wider proportion of the population

ACE inhibitor and angiotensin receptor-II antagonist prescribing and hospital admissions with acute kidney injury: A longitudinal ecological study

This is the final version. Available from the publisher via the DOI in this record.Background: ACE Inhibitors (ACE-I) and Angiotensin-Receptor Antagonists (ARAs) are commonly prescribed but can cause acute kidney injury (AKI) during intercurrent illness. Rates of hospitalization with AKI are increasing. We aimed to determine whether hospital AKI admission rates are associated with increased ACE-I/ARA prescribing. Methods and Findings: English NHS prescribing data for ACE-I/ARA prescriptions were matched at the level of the general practice to numbers of hospital admissions with a primary diagnosis of AKI. Numbers of prescriptions were weighted for the demographic characteristics of general practices by expressing prescribing as rates where the denominator is Age, Sex, and Temporary Resident Originated Prescribing Units (ASTRO-PUs). We performed a mixed-effect Poisson regression to model the number of admissions for AKI occurring in each practice for each of 4 years from 1/4/2007. From 2007/8-2010/11, crude AKI admission rates increased from 0.38 to 0.57 per 1000 patients (51.6% increase), and national annual ACE-I/ARA prescribing rates increased by 0.032 from 0.202 to 0.234 (15.8% increase). There was strong evidence (p<0.001) that increases in practice-level prescribing of ACE-I/ARA over the study period were associated with an increase in AKI admission rates. The increase in prescribing seen in a typical practice corresponded to an increase in admissions of approximately 5.1% (rate ratio = 1.051 for a 0.03 per ASTRO-PU increase in annual prescribing rate, 95%CI 1.047-1.055). Using the regression model we predict that 1,636 (95%CI 1,540-1,780) AKI admissions would have been avoided if prescribing rates were at the 2007/8 level, equivalent to 14.8% of the total increase in AKI admissions. Conclusion: In this ecological analysis, up to 15% of the increase in AKI admissions in England over a 4-year time period is potentially attributable to increased prescribing of ACE-I and ARAs. However, these findings are limited by the lack of patient level data such as indication for prescribing and patient characteristics. © 2013 Tomlinson et al.Cambridge Biomedical Research InstituteBritish Heart Foundatio

Neutrophil activation and enhanced release of granule products in HIV-TB immune reconstitution inflammatory syndrome

Background: Tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) remains incompletely understood. Neutrophils are implicated in tuberculosis pathology but detailed investigations in TB-IRIS are lacking. We sought to further explore the biology of TB-IRIS and, in particular, the role of neutrophils. Setting: Two observational, prospective cohort studies in HIV/TB coinfected patients starting antiretroviral therapy (ART), 1 to analyze gene expression and subsequently 1 to explore neutrophil biology. Methods: nCounter gene expression analysis was performed in patients with TB-IRIS (n = 17) versus antiretroviral-treated HIV/TB coinfected controls without IRIS (n = 17) in Kampala, Uganda. Flow cytometry was performed in patients with TB-IRIS (n = 18) and controls (n = 11) in Cape Town, South Africa to determine expression of neutrophil surface activation markers, intracellular cytokines, and human neutrophil peptides (HNPs). Plasma neutrophil elastase and HNP1-3 were quantified using enzyme-linked immunosorbent assay. Lymph node immunohistochemistry was performed on 3 further patients with TB-IRIS. Results: There was a significant increase in gene expression of S100A9 (P = 0.002), NLRP12 (P = 0.018), COX-1 (P = 0.025), and IL-10 (P = 0.045) 2 weeks after ART initiation in Ugandan patients with TB-IRIS versus controls, implicating neutrophil recruitment. Patients with IRIS in both cohorts demonstrated increases in blood neutrophil count, plasma HNP and elastase concentrations from ART initiation to week 2. CD62L (L-selectin) expression on neutrophils increased over 4 weeks in South African controls whereas patients with IRIS demonstrated the opposite. Intense staining for the neutrophil marker CD15 and IL-10 was seen in necrotic areas of the lymph nodes of the patients with TB-IRIS. Conclusions: Neutrophils in TB-IRIS are activated, recruited to sites of disease, and release granule contents, contributing to pathology

The accuracy of diagnostic coding for acute kidney injury in England - A single centre study

This is the final version. Available on open access from BMC via the DOI in this recordBackground: Acute kidney injury (AKI) is an independent risk factor for mortality and is responsible for a significant burden of healthcare expenditure, so accurate measurement of its incidence is important. Administrative coding data has been used for assessing AKI incidence, and shows an increasing proportion of hospital bed days attributable to AKI. However, the accuracy of coding for AKI and changes in coding over time have not been studied in England. Methods. We studied a random sample of admissions from 2005 and 2010 where ICD-10 code N17 (acute renal failure) was recorded in the administrative coding data at one acute NHS Foundation Trust in England. Using the medical notes and computerised records we examined the demographic and clinical details of these admissions. Results: Against a 6.3% (95% CI 4.8-7.9%) increase in all non-elective admissions, we found a 64% increase in acute renal failure admissions (95% CI 41%-92%, p<0.001) in 2010 compared to 2005. Median age was 78 years (IQR 72-87), 11-25% had a relevant pre-admission co-morbidity and 64% (55-73%) were taking drugs known to be associated with AKI. Over both years, 95% (91-99%) of cases examined met the Kidney Disease: Improving Global Outcomes criteria for AKI. Conclusions: Patients with hospital admissions where AKI has been coded are elderly with multiple co-morbidities. Our results demonstrate a high positive predictive value of coding data for a clinical diagnosis of AKI, with no suggestion of marked changes in coding of AKI between 2005 and 2010. © 2013 Tomlinson et al; licensee BioMed Central Ltd.Cambridge Biomedical Research InstituteBritish Heart Foundatio

Too small to succeed: the difficulty of sustaining star formation in low-mass haloes

We present high-resolution simulations of an isolated dwarf spheroidal (dSph) galaxy between redshifts z ∼ 10 and z ∼ 4, the epoch when several Milky Way dSph satellites experienced extended star formation, in order to understand in detail the physical processes which affect a low-mass halo's ability to retain gas. It is well established that supernova feedback is very effective at expelling gas from a 3 × 10$^{7}$ M⊙ halo, the mass of a typical redshift 10 progenitor of a redshift 0 halo with mass ∼10$^{9}$ M⊙. We investigate the conditions under which such a halo is able to retain sufficient high-density gas to support extended star formation. In particular, we explore the effects of: an increased relative concentration of the gas compared to the dark matter; a higher concentration dark matter halo; significantly lower supernova rates; enhanced metal cooling due to enrichment from earlier supernovae. We show that disc-like gas distributions retain more gas than spherical ones, primarily due to the shorter gas cooling times in the disc. However, a significant reduction in the number of supernovae compared to that expected for a standard initial mass function is still needed to allow the retention of high-density gas. We conclude that the progenitors of the observed dSphs would only have retained the gas required to sustain star formation if their mass, concentration and gas morphology were already unusual for those of a dSph-mass halo progenitor by a redshift of 10.CRC and MAB are supported by a Science and Technology facilities council (STFC) PhD studentship. CP acknowledges support from the Australian Research Council (ARC) Future Fellowship FT130100041 and Discovery projects DP130100117 and DP140100198. Figs 4 and 6 were produced using SPLASH (Price 2013). This work used the DiRAC Complexity system, operated by the University of Leicester IT Services, which forms part of the STFC DiRAC HPC Facility (www.dirac.ac.uk). This equipment is funded by BIS National E-Infrastructure capital grant ST/K000373/1 and STFC DiRAC Operations grant ST/K0003259/1. DiRAC is part of the National E-Infrastructure

Fission yeast 26S proteasome mutants are multi-drug resistant due to stabilization of the pap1 transcription factor

Here we report the result of a genetic screen for mutants resistant to the microtubule poison methyl benzimidazol-2-yl carbamate (MBC) that were also temperature sensitive for growth. In total the isolated mutants were distributed in ten complementation groups. Cloning experiments revealed that most of the mutants were in essential genes encoding various 26S proteasome subunits. We found that the proteasome mutants are multi-drug resistant due to stabilization of the stress-activated transcription factor Pap1. We show that the ubiquitylation and ultimately the degradation of Pap1 depend on the Rhp6/Ubc2 E2 ubiquitin conjugating enzyme and the Ubr1 E3 ubiquitin-protein ligase. Accordingly, mutants lacking Rhp6 or Ubr1 display drug-resistant phenotypes

Signal intensity enhancement of laser ablated volume holograms

Conventional volume holographic gratings (VHGs) fabricated in photosensitive emulsions such as gelatin containing silver salts enable the facile visualisation of the holographic image in ambient lighting. However, for the fabrication of holographic sensors, which require more defined and chemically-functionalised polymer matrices, laser ablation has been introduced to create the VHGs and thereby broaden their applications, although the replay signal can be challenging to detect in ambient lighting. When traditional photochemical bleaching solutions used to reduce light scattering and modulate refractive index within the VHG are applied to laser ablated volume holographic gratings, these procedures decrease the holographic peak intensity. This is postulated to occur because both light and dark fringes contain a proportion of metal particles, which upon solubilisation are converted immediately to silver iodide, yielding no net refractive index modulation. This research advances a hypothesis that the reduced intensity of holographic replay signals is linked to a gradient of different sized metal particles within the emulsion, which reduces the holographic signal and may explain why traditional bleaching processes result in a reduction in intensity. In this report, a novel experimental protocol is provided, along with simulations based on an effective medium periodic 1D stack, that offers a solution to increase peak signal intensity of holographic sensors by greater than 200%. Nitric acid is used to etch the silver nanoparticles within the polymer matrix and is thought to remove the smaller particles to generate more defined metal fringes containing a soluble metal salt. Once the grating efficiency has been increased, this salt can be converted to a silver halide, to modulate the refractive index and increase the intensity of the holographic signal. This new protocol has been tested in a range of polymer chemistries; those containing functional groups that help to stabilise the metal nanoparticles within the matrix yield more intense holographic signals as the integrity of the fringe is more protected with increasing metal solubility.EPSRC Integrated Photonics and Electronic Systems (Grant number: EP/L015455/1) Centre for Doctoral Training

Child-Abuse-Related-Deaths, Child Mortality (0-4) & Income Inequality in America and Other Developed Nations 1989-91 v 2012-14: Speaking Truth to Power.

The major concern for social work, namely child abuse‐related deaths (CARD), involves parental neglect. Societal neglect, when measured by child mortality rates (CMR), is considered by bodies such as UNICEF to be indicative of how a nation meets the needs of its children. This population‐based study analyses CARD and CMR for children aged from newborn to four years old between 1989–91 and 2013–15 to identify any relative child neglect in the USA and 20 other developed nations (ODN). World Health Organization data were used for CARD, CMR and undetermined deaths (UnD), a possible source of unreported CARD, juxtaposed against World Bank income inequality data. The USA had the highest number of CARD, the highest CMR and the worst income inequality. Five countries reduced their CARD significantly more than the USA, and 14 countries reduced their CMR more than the USA. Income inequality and CMR were correlated. Had the USA matched the CMR of Japan, where income inequality was narrowest, there would have been on average 16 745 fewer child deaths annually. CARD and UnD correlated, suggesting that UnD may contain unreported CARD. US CMR data indicate that services in the USA are less effective than those in ODN, possibly due to income inequality. These results will be unwelcome but child protection services must dare to speak truth to power. ‘This population‐based study analyses CARD and CMR for children aged from newborn to four years old between 1989–91 and 2013–15 to identify any relative child neglect in the USA and 20 other developed nations’ Key Practitioner Messages The richest country in the world, the USA, has the highest rates of child abuse and total child mortality in the Western world. The USA has the highest income inequality in the West, highlighting the statistical link between child mortality and poverty. Children's services should lead the call for the necessary changes and ‘speak truth to power’