A Stochastic Model of Latently Infected Cell Reactivation and Viral Blip Generation in Treated HIV Patients

Motivated by viral persistence in HIV+ patients on long-term anti-retroviral treatment (ART), we present a stochastic model of HIV viral dynamics in the blood stream. We consider the hypothesis that the residual viremia in patients on ART can be explained principally by the activation of cells latently infected by HIV before the initiation of ART and that viral blips (clinically-observed short periods of detectable viral load) represent large deviations from the mean. We model the system as a continuous-time, multi-type branching process. Deriving equations for the probability generating function we use a novel numerical approach to extract the probability distributions for latent reservoir sizes and viral loads. We find that latent reservoir extinction-time distributions underscore the importance of considering reservoir dynamics beyond simply the half-life. We calculate blip amplitudes and frequencies by computing complete viral load probability distributions, and study the duration of viral blips via direct numerical simulation. We find that our model qualitatively reproduces short small-amplitude blips detected in clinical studies of treated HIV infection. Stochastic models of this type provide insight into treatment-outcome variability that cannot be found from deterministic models

Height and timing of growth spurt during puberty in young people living with vertically acquired HIV in Europe and Thailand.

OBJECTIVE: The aim of this study was to describe growth during puberty in young people with vertically acquired HIV. DESIGN: Pooled data from 12 paediatric HIV cohorts in Europe and Thailand. METHODS: One thousand and ninety-four children initiating a nonnucleoside reverse transcriptase inhibitor or boosted protease inhibitor based regimen aged 1-10 years were included. Super Imposition by Translation And Rotation (SITAR) models described growth from age 8 years using three parameters (average height, timing and shape of the growth spurt), dependent on age and height-for-age z-score (HAZ) (WHO references) at antiretroviral therapy (ART) initiation. Multivariate regression explored characteristics associated with these three parameters. RESULTS: At ART initiation, median age and HAZ was 6.4 [interquartile range (IQR): 2.8, 9.0] years and -1.2 (IQR: -2.3 to -0.2), respectively. Median follow-up was 9.1 (IQR: 6.9, 11.4) years. In girls, older age and lower HAZ at ART initiation were independently associated with a growth spurt which occurred 0.41 (95% confidence interval 0.20-0.62) years later in children starting ART age 6 to 10 years compared with 1 to 2 years and 1.50 (1.21-1.78) years later in those starting with HAZ less than -3 compared with HAZ at least -1. Later growth spurts in girls resulted in continued height growth into later adolescence. In boys starting ART with HAZ less than -1, growth spurts were later in children starting ART in the oldest age group, but for HAZ at least -1, there was no association with age. Girls and boys who initiated ART with HAZ at least -1 maintained a similar height to the WHO reference mean. CONCLUSION: Stunting at ART initiation was associated with later growth spurts in girls. Children with HAZ at least -1 at ART initiation grew in height at the level expected in HIV negative children of a comparable age

A trial of a job-specific workers' health surveillance program for construction workers: study protocol

<p>Abstract</p> <p>Background</p> <p>Dutch construction workers are offered periodic health examinations. This care can be improved by tailoring this workers health surveillance (WHS) to the demands of the job and adjust the preventive actions to the specific health risks of a worker in a particular job. To improve the quality of the WHS for construction workers and stimulate relevant job-specific preventive actions by the occupational physician, we have developed a job-specific WHS. The job-specific WHS consists of modules assessing both physical and psychological requirements. The selected measurement instruments chosen, are based on their appropriateness to measure the workers' capacity and health requirements. They include a questionnaire and biometrical tests, and physical performance tests that measure physical functional capabilities. Furthermore, our job-specific WHS provides occupational physicians with a protocol to increase the worker-behavioural effectiveness of their counselling and to stimulate job-specific preventive actions. The objective of this paper is to describe and clarify our study to evaluate the behavioural effects of this job-specific WHS on workers and occupational physicians.</p> <p>Methods/Design</p> <p>The ongoing study of bricklayers and supervisors is a nonrandomised trial to compare the outcome of an intervention (job-specific WHS) group (n = 206) with that of a control (WHS) group (n = 206). The study includes a three-month follow-up. The primary outcome measure is the proportion of participants who have undertaken one or more of the preventive actions advised by their occupational physician in the three months after attending the WHS. A process evaluation will be carried out to determine context, reach, dose delivered, dose received, fidelity, and satisfaction. The present study is in accordance with the TREND Statement.</p> <p>Discussion</p> <p>This study will allow an evaluation of the behaviour of both the workers and occupational physician regarding the preventive actions undertaken by them within the scope of a job-specific WHS.</p> <p>Trial registration</p> <p><a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3012">NTR3012</a></p

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

Search for R-parity-violating supersymmetry in events with four or more leptons in sqrt(s) =7 TeV pp collisions with the ATLAS detector

A search for new phenomena in final states with four or more leptons (electrons or muons) is presented. The analysis is based on 4.7 fb−1 of $\sqrt{s}=7\;\mathrm{TeV}$ proton-proton collisions delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in two signal regions: one that requires moderate values of missing transverse momentum and another that requires large effective mass. The results are interpreted in a simplified model of R-parity-violating supersymmetry in which a 95% CL exclusion region is set for charged wino masses up to 540 GeV. In an R-parity-violating MSUGRA/CMSSM model, values of m 1/2 up to 820 GeV are excluded for 10 < tan β < 40

Search for high-mass resonances decaying to dilepton final states in pp collisions at s√=7 TeV with the ATLAS detector

The ATLAS detector at the Large Hadron Collider is used to search for high-mass resonances decaying to an electron-positron pair or a muon-antimuon pair. The search is sensitive to heavy neutral Z′ gauge bosons, Randall-Sundrum gravitons, Z * bosons, techni-mesons, Kaluza-Klein Z/γ bosons, and bosons predicted by Torsion models. Results are presented based on an analysis of pp collisions at a center-of-mass energy of 7 TeV corresponding to an integrated luminosity of 4.9 fb−1 in the e + e − channel and 5.0 fb−1 in the μ + μ −channel. A Z ′ boson with Standard Model-like couplings is excluded at 95 % confidence level for masses below 2.22 TeV. A Randall-Sundrum graviton with coupling k/MPl=0.1 is excluded at 95 % confidence level for masses below 2.16 TeV. Limits on the other models are also presented, including Technicolor and Minimal Z′ Models

Increased Liver Uptake and Reduced Hepatic Stellate Cell Activation with a Cell-Specific Conjugate of the Rho-kinase Inhibitor Y27632

Rho-kinase regulates activation of hepatic stellate cells (HSC) during liver fibrosis, but the ubiquitous presence of this kinase may hinder examination of its exact role and the therapeutic use of inhibitors. We therefore coupled the Rho-kinase inhibitor Y27632 to a drug carrier that binds the mannose-6-phosphate insulin-like growth factor II (M6P/IGFII)-receptor which is upregulated on activated HSC. Y27632 was coupled to mannose-6-phosphate human serum albumin (M6PHSA), and in vitro experiments were performed on primary rat HSC. Biodistribution and effect studies were performed in an acute CCl(4) model in mice. Y27-conjugate remained stable in serum, while drug was efficiently released in liver homogenates. Receptor-blocking studies revealed that it was specifically taken up through the M6P/IGFII-receptor on fibroblasts, and it inhibited expression of fibrotic markers in activated HSC. In vivo, liver drug levels were significantly higher after injection of Y27-conjugate as compared to Y27632, and the conjugate accumulated specifically in HSC. After acute CCl(4)-induced liver injury, Y27-conjugate reduced the local activation of HSC, whereas an equimolar dose of free drug did not. We conclude that specific targeting of a Rho-kinase inhibitor to HSC leads to enhanced accumulation of the drug in HSC, reducing early fibrogenesis in the liver

The Evolutionary Origin of Man Can Be Traced in the Layers of Defunct Ancestral Alpha Satellites Flanking the Active Centromeres of Human Chromosomes

Alpha satellite domains that currently function as centromeres of human chromosomes are flanked by layers of older alpha satellite, thought to contain dead centromeres of primate progenitors, which lost their function and the ability to homogenize satellite repeats, upon appearance of a new centromere. Using cladistic analysis of alpha satellite monomers, we elucidated complete layer patterns on chromosomes 8, 17, and X and related them to each other and to primate alpha satellites. We show that discrete and chronologically ordered alpha satellite layers are partially symmetrical around an active centromere and their succession is partially shared in non-homologous chromosomes. The layer structure forms a visual representation of the human evolutionary lineage with layers corresponding to ancestors of living primates and to entirely fossil taxa. Surprisingly, phylogenetic comparisons suggest that alpha satellite arrays went through periods of unusual hypermutability after they became “dead” centromeres. The layer structure supports a model of centromere evolution where new variants of a satellite repeat expanded periodically in the genome by rounds of inter-chromosomal transfer/amplification. Each wave of expansion covered all or many chromosomes and corresponded to a new primate taxon. Complete elucidation of the alpha satellite phylogenetic record would give a unique opportunity to number and locate the positions of major extinct taxa in relation to human ancestors shared with extant primates. If applicable to other satellites in non-primate taxa, analysis of centromeric layers could become an invaluable tool for phylogenetic studies

Perceptions of quality across the maternal care continuum in the context of a health financing intervention: Evidence from a mixed methods study in rural Malawi

Background: In 2013, Malawi with its development partners introduced a Results-Based Financing for Maternal and Newborn Health (RBF4MNH) intervention to improve the quality of maternal and newborn health-care services. Financial incentives are awarded to health facilities conditional on their performance and to women for delivering in the health facility. We assessed the effect of the RBF4MNH on quality of care from women’s perspectives. Methods: We used a mixed-method prospective sequential controlled pre- and post-test design. We conducted 3060 structured client exit interviews, 36 in-depth interviews and 29 focus group discussions (FGDs) with women and 24 in-depth interviews with health service providers between 2013 and 2015. We used difference-in-differences regression models to measure the effect of the RBF4MNH on experiences and perceived quality of care. We used qualitative data to explore the matter more in depth. Results: We did not observe a statistically significant effect of the intervention on women’s perceptions of technical care, quality of amenities and interpersonal relations. However, in the qualitative interviews, most women reported improved health service provision as a result of the intervention. RBF4MNH increased the proportion of women reporting to have received medications/treatment during childbirth. Participants in interviews expressed that drugs, equipment and supplies were readily available due to the RBF4MNH. However, women also reported instances of neglect, disrespect and verbal abuse during the process of care. Providers attributed these negative instances to an increased workload resulting from an increased number of women seeking services at RBF4MNH facilities. Conclusion: Our qualitative findings suggest improvements in the availability of drugs and supplies due to RBF4MNH. Despite the intervention, challenges in the provision of quality care persisted, especially with regard to interpersonal relations. RBF interventions may need to consider including indicators that specifically target the provision of respectful maternity care as a means to foster providers’ positive attitudes towards women in labour. In parallel, governments should consider enhancing staff and infrastructural capacity before implementing RBF