Host genetics and viral load in primary HIV-1 infection: clear evidence for gene by sex interactions

© 2014, The Author(s).Research in the past two decades has generated unequivocal evidence that host genetic variations substantially account for the heterogeneous outcomes following human immunodeficiency virus type 1 (HIV-1) infection. In particular, genes encoding human leukocyte antigens (HLA) have various alleles, haplotypes, or specific motifs that can dictate the set-point (a relatively steady state) of plasma viral load (VL), although rapid viral evolution driven by innate and acquired immune responses can obscure the long-term relationships between HLA genotypes and HIV-1-related outcomes. In our analyses of VL data from 521 recent HIV-1 seroconverters enrolled from eastern and southern Africa, HLA-A*03:01 was strongly and persistently associated with low VL in women (frequency = 11.3 %, P  0.50). In a reduced multivariable model, age, sex, geography (clinical sites), previously identified HLA factors (HLA-B*18, B*45, B*53, and B*57), and the interaction term for female sex and HLA-A*03:01 collectively explained 17.0 % of the overall variance in geometric mean VL over a 3-year follow-up period (P < 0.0001). Multiple sensitivity analyses of longitudinal and cross-sectional VL data yielded consistent results. These findings can serve as a proof of principle that the gap of “missing heritability” in quantitative genetics can be partially bridged by a systematic evaluation of sex-specific associations

Dissolution dominating calcification process in polar pteropods close to the point of aragonite undersaturation

Thecosome pteropods are abundant upper-ocean zooplankton that build aragonite shells. Ocean acidification results in the lowering of aragonite saturation levels in the surface layers, and several incubation studies have shown that rates of calcification in these organisms decrease as a result. This study provides a weight-specific net calcification rate function for thecosome pteropods that includes both rates of dissolution and calcification over a range of plausible future aragonite saturation states (Omega_Ar). We measured gross dissolution in the pteropod Limacina helicina antarctica in the Scotia Sea (Southern Ocean) by incubating living specimens across a range of aragonite saturation states for a maximum of 14 days. Specimens started dissolving almost immediately upon exposure to undersaturated conditions (Omega_Ar,0.8), losing 1.4% of shell mass per day. The observed rate of gross dissolution was different from that predicted by rate law kinetics of aragonite dissolution, in being higher at Var levels slightly above 1 and lower at Omega_Ar levels of between 1 and 0.8. This indicates that shell mass is affected by even transitional levels of saturation, but there is, nevertheless, some partial means of protection for shells when in undersaturated conditions. A function for gross dissolution against Var derived from the present observations was compared to a function for gross calcification derived by a different study, and showed that dissolution became the dominating process even at Omega_Ar levels close to 1, with net shell growth ceasing at an Omega_Ar of 1.03. Gross dissolution increasingly dominated net change in shell mass as saturation levels decreased below 1. As well as influencing their viability, such dissolution of pteropod shells in the surface layers will result in slower sinking velocities and decreased carbon and carbonate fluxes to the deep ocean

Collapse of Amphibian Communities Due to an Introduced Ranavirus

This work was supported by Natural Environment Research Council grant NE/G011885/1, the Systematics and Taxonomy (SynTax) research scheme administered by the Linnean Society of London, the Fundación General CSIC, Banco Santander, and European Research Council grant 260801-BIG-IDE

Comparison of serious inhaler technique errors made by device-naïve patients using three different dry powder inhalers: a randomised, crossover, open-label study

Background: Serious inhaler technique errors can impair drug delivery to the lungs. This randomised, crossover, open-label study evaluated the proportion of patients making predefined serious errors with Pulmojet compared with Diskus and Turbohaler dry powder inhalers. Methods: Patients ≥18 years old with asthma and/or COPD who were current users of an inhaler but naïve to the study devices were assigned to inhaler technique assessment on Pulmojet and either Diskus or Turbohaler in a randomised order. Patients inhaled through empty devices after reading the patient information leaflet. If serious errors potentially affecting dose delivery were recorded, they repeated the inhalations after watching a training video. Inhaler technique was assessed by a trained nurse observer and an electronic inhalation profile recorder. Results: Baseline patient characteristics were similar between randomisation arms for the Pulmojet-Diskus (n = 277) and Pulmojet-Turbohaler (n = 144) comparisons. Non-inferiority in the proportions of patients recording no nurse-observed serious errors was demonstrated for both Pulmojet versus Diskus, and Pulmojet versus Turbohaler; therefore, superiority was tested. Patients were significantly less likely to make ≥1 nurse-observed serious errors using Pulmojet compared with Diskus (odds ratio, 0.31; 95 % CI, 0.19–0.51) or Pulmojet compared with Turbohaler (0.23; 0.12–0.44) after reading the patient information leaflet with additional video instruction, if required. Conclusions These results suggest Pulmojet is easier to learn to use correctly than the Turbohaler or Diskus for current inhaler users switching to a new dry powder inhaler

BβArg448Lys polymorphism is associated with altered fibrin clot structure and fibrinolysis in type 2 diabetes

Both type 2 diabetes (T2DM) and Bβ448Lys variant of fibrinogen are associated with dense fibrin clots, impaired fibrinolysis and increased cardiovascular risk. It was our objective to investigate whether BβArg448Lys adds to vascular risk by modulating fibrin network structure and/or fibrinolysis in diabetes. The primary aim was to study effects of BβArg448Lys on fibrin network characteristics in T2DM. Secondary aims investigated interactions between gender and BβArg448Lys substitution in relation to fibrin clot properties and vascular disease. Genotyping for BβArg448Lys and dynamic clot studies were carried out on 822 T2DM patients enrolled in the Edinburgh Type 2 Diabetes Study. Turbidimetric assays of individual plasma samples analysed fibrin clot characteristics with additional experiments conducted on clots made from purified fibrinogen, further examined by confocal and electron microscopy. Plasma clot lysis time in Bβ448Lys was longer than Bβ448Arg variant (mean ± SD; 763 ± 322 and 719 ± 351 seconds [s], respectively; p<0.05). Clots made from plasma-purified fibrinogen of individuals with Arg/Arg, Arg/Lys and Lys/Lys genotypes showed differences in fibre thickness (46.75 ± 8.07, 38.40 ± 6.04 and 25 ± 4.99 nm, respectively; p<0.001) and clot lysis time (419 ± 64, 442 ± 87 and 517 ± 65 s, respectively; p=0.02), directly implicating the polymorphism in the observed changes. Women with Bβ448Lys genotype had increased risk of cerebrovascular events and were younger compared with Bβ448Arg variant (67.2 ± 4.0 and 68.2 ± 4.4 years, respectively; p=0.035). In conclusion, fibrinogen Bβ448Lys variant is associated with thrombotic fibrin clots in diabetes independently of traditional risk factors. Prospective studies are warranted to fully understand the role of BβArg448Lys in predisposition to vascular ischaemia in T2DM with the potential to develop individualised antithrombotic management strategies

Determinants of treatment-related paradoxical reactions during anti-tuberculosis therapy: a case control study

BACKGROUND: Inflammatory response following initial improvement with anti-tuberculosis (TB) treatment has been termed a paradoxical reaction (PR). HIV co-infection is a recognised risk, yet little is known about other predictors of PR, although some biochemical markers have appeared predictive. We report our findings in an ethnically diverse population of HIV-infected and uninfected adults. METHODS: Prospective and retrospective clinical and laboratory data were collected on TB patients seen between January 1999-December 2008 at four UK centres selected to represent a wide ethnic and socio-economic mix of TB patients. Data on ethnicity and HIV status were obtained for all individuals. The associations between other potential risk factors and PR were assessed in a nested case-control study. All PR cases were matched two-to-one to controls by calendar time and centre. RESULTS: Of 1817 TB patients, 82 (4.5 %, 95 % CI 3.6-5.5 %) were identified as having a PR event. The frequency of PR was 14.4 % (18/125; 95 % CI 8.2-20.6 %) and 3.8 % (64/1692; 2.9-4.7) for HIV-positive and HIV-negative individuals respectively. There were no differences observed in PR frequency according to ethnicity, although the site was more likely to be pulmonary in those of black and white ethnicity, and lymph node disease in those of Asian ethnicity. In multivariate analysis of the case-control cohort, HIV-positive patients had five times the odds of developing PR (aOR = 5.05; 95 % CI 1.28-19.85, p = 0.028), whilst other immunosuppression e.g. diabetes, significantly reduced the odds of PR (aOR = 0.01; 0.00-0.27, p = 0.002). Patients with positive TB culture had higher odds of developing PR (aOR = 6.87; 1.31-36.04, p = 0.045) compared to those with a negative culture or those in whom no material was sent for culture. Peripheral lymph node disease increased the odds of a PR over 60-fold 4(9.60-431.25, p < 0.001). CONCLUSION: HIV was strongly associated with PR. The increased potential for PR in people with culture positive TB suggests that host mycobacterial burden might be relevant. The increased risk with TB lymphadenitis may in part arise from the visibility of clinical signs at this site. Non-HIV immunosuppression may have a protective effect. This study highlights the difficulties in predicting PR using routinely available demographic details, clinical symptoms or biochemical markers

A simple mathematical model of gradual Darwinian evolution: Emergence of a Gaussian trait distribution in adaptation along a fitness gradient

We consider a simple mathematical model of gradual Darwinian evolution in continuous time and continuous trait space, due to intraspecific competition for common resource in an asexually reproducing population in constant environment, while far from evolutionary stable equilibrium. The model admits exact analytical solution. In particular, Gaussian distribution of the trait emerges from generic initial conditions.Comment: 21 pages, 2 figures, as accepted to J Math Biol 2013/03/1

Forest fire management, climate change, and the risk of catastrophic carbon losses

Approaches to management of fireprone forests are undergoing rapid change, driven by recognition that technological attempts to subdue fire at large scales (fire suppression) are ecologically and economically unsustainable. However, our current framework for intervention excludes the full scope of the fire management problem within the broader context of fire−vegetation−climate interactions. Climate change may already be causing unprecedented fire activity, and even if current fires are within the historical range of variability, models predict that current fire management problems will be compounded by more frequent extreme fire-conducive weather conditions (eg Fried et al. 2004)

The hidden burden of adult allergic rhinitis : UK healthcare resource utilisation survey

Funding Funding for this survey was provided by Meda Pharma.Peer reviewedPublisher PD

Self-supervised Depth Estimation to Regularise Semantic Segmentation in Knee Arthroscopy

Intra-operative automatic semantic segmentation of knee joint structures can assist surgeons during knee arthroscopy in terms of situational awareness. However, due to poor imaging conditions (e.g., low texture, overexposure, etc.), automatic semantic segmentation is a challenging scenario, which justifies the scarce literature on this topic. In this paper, we propose a novel self-supervised monocular depth estimation to regularise the training of the semantic segmentation in knee arthroscopy. To further regularise the depth estimation, we propose the use of clean training images captured by the stereo arthroscope of routine objects (presenting none of the poor imaging conditions and with rich texture information) to pre-train the model. We fine-tune such model to produce both the semantic segmentation and self-supervised monocular depth using stereo arthroscopic images taken from inside the knee. Using a data set containing 3868 arthroscopic images captured during cadaveric knee arthroscopy with semantic segmentation annotations, 2000 stereo image pairs of cadaveric knee arthroscopy, and 2150 stereo image pairs of routine objects, we show that our semantic segmentation regularised by self-supervised depth estimation produces a more accurate segmentation than a state-of-the-art semantic segmentation approach modeled exclusively with semantic segmentation annotation.Comment: 10 pages, 6 figure