Non-Hodgkin lymphoma risk in adults living with HIV across five continents: a multicohort study

OBJECTIVE: To compare non-Hodgkin lymphoma (NHL) incidence rates in adults who started antiretroviral therapy (ART) across the Asia-Pacific, South Africa, Europe, Latin, and North America. METHODS: We included cohort data of adults living with HIV who started ART after 1995 within the framework of the International epidemiology Databases to Evaluate AIDS (IeDEA) and the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE). We used flexible parametric survival models to compare regional NHL rates at 2 years after ART start and to identify risk factors for NHL. RESULTS: We included 210,898 adults with 1.1 million person-years (pys) of follow-up and 1,552 incident NHL cases (raw overall incidence rate 142/100,000 pys). After adjusting for age at ART start, first-line ART regimen, calendar period of ART start, and especially current CD4 cell count, NHL rates were similar across regions for most population groups. However, South African women remained at increased risk of developing NHL compared with their European counterparts (adjusted hazard ratio [aHR] 1.79, 95% CI 1.19-2.70). In Europe, Latin and North America, NHL risk was highest in men who have sex with men (MSM, aHR 1.30, 95% CI 1.14-1.48), followed by heterosexual men (referent), and women (aHR 0.66, 95% CI 0.57-0.78). CONCLUSIONS: The risk of developing NHL is higher in women in South Africa than in Europe and higher in MSM compared with heterosexual men and women. Reasons for these differences remain unclear. Early ART access and regular patient monitoring to avert low CD4 cell counts remain key for NHL prevention

The endoplasmic reticulum membrane protein complex localizes to the mitochondrial - endoplasmic reticulum interface and its subunits modulate phospholipid biosynthesis in Trypanosoma brucei.

The endoplasmic reticulum membrane complex (EMC) is a versatile complex that plays a key role in membrane protein biogenesis in the ER. Deletion of the complex has wide-ranging consequences including ER stress, disturbance in lipid transport and organelle tethering, among others. Here we report the function and organization of the evolutionarily conserved EMC (TbEMC) in the highly diverged eukaryote, Trypanosoma brucei. Using (co-) immunoprecipitation experiments in combination with mass spectrometry and whole cell proteomic analyses of parasites after depletion of select TbEMC subunits, we demonstrate that the TbEMC is composed of 9 subunits that are present in a high molecular mass complex localizing to the mitochondrial-endoplasmic reticulum interface. Knocking out or knocking down of single TbEMC subunits led to growth defects of T. brucei procyclic forms in culture. Interestingly, we found that depletion of individual TbEMC subunits lead to disruption of de novo synthesis of phosphatidylcholine (PC) or phosphatidylethanolamine (PE), the two most abundant phospholipid classes in T. brucei. Downregulation of TbEMC1 or TbEMC3 inhibited formation of PC while depletion of TbEMC8 inhibited PE synthesis, pointing to a role of the TbEMC in phospholipid synthesis. In addition, we found that in TbEMC7 knock-out parasites, TbEMC3 is released from the complex, implying that TbEMC7 is essential for the formation or the maintenance of the TbEMC

Cohort profile: the South African HIV Cancer Match (SAM) study, a national population-based cohort

Purpose The South African HIV Cancer Match (SAM) Study is a national cohort of people living with HIV (PLWH). It was created using probabilistic record linkages of routine laboratory records of PLWH retrieved by National Health Laboratory Services (NHLS) and cancer data from the National Cancer Registry. The SAM Study aims to assess the spectrum and risk of cancer in PLWH in the context of the evolving South African HIV epidemic. The SAM Study's overarching goal is to inform cancer prevention and control programmes in PLWH in the era of antiretroviral treatment in South Africa. Participants PLWH (both adults and children) who accessed HIV care in public sector facilities and had HIV diagnostic or monitoring laboratory tests from NHLS. Findings to date The SAM cohort currently includes 5 248 648 PLWH for the period 2004 to 2014; 69% of these are women. The median age at cohort entry was 33.0 years (IQR: 26.2-40.9). The overall cancer incidence in males and females was 235.9 (95% CI: 231.5 to 240.5) and 183.7 (181.2-186.2) per 100 000 person-years, respectively. Using data from the SAM Study, we examined national cancer incidence in PLWH and the association of different cancers with immunodeficiency. Cancers with the highest incidence rates were Kaposi sarcoma, cervix, breast, non-Hodgkin's lymphoma and eye cancer. Future plans The SAM Study is a unique, evolving resource for research and surveillance of malignancies in PLWH. The SAM Study will be regularly updated. We plan to enrich the SAM Study through record linkages with other laboratory data within the NHLS (eg, tuberculosis, diabetes and lipid profile data), mortality data and socioeconomic data to facilitate comprehensive epidemiological research of comorbidities among PLWH

Cervical cancer screening cascade for women living with HIV: a cohort study from Zimbabwe

Countries with high HIV prevalence, predominantly in sub-Sahahran Africa, have the highest cervical cancer rates globally. HIV care cascades successfully facilitated the scale-up of antiretroviral therapy. A cascade approach could similarly succeed to scale-up cervical cancer screening, supporting WHO's goal to eliminate cervical cancer. We defined a Cervical Cancer Screening Cascade for women living with HIV (WLHIV), evaluating the continuum of cervical cancer screening integrated into an HIV clinic in Zimbabwe. We included WLHIV aged ≥18 years enrolled at Newlands Clinic in Harare from June 2012-2017 and followed them until June 2018. We used a cascade approach to evaluate the full continuum of secondary prevention from screening to treatment of pre-cancer and follow-up. We report percentages, median time to reach cascade stages, and cumulative incidence at two years with 95% confidence intervals (CI). We used univariable Cox proportional hazard regressions to calculate cause-specific hazard ratios with 95% CIs for factors associated with completing the cascade stages. We included 1624 WLHIV in the study. The cumulative incidence of cervical screening was 85.4% (95% CI 83.5-87.1) at two years. Among the 396 WLHIV who received screen-positive tests in the study, the cumulative incidence of treatment after a positive screening test was 79.5% (95% CI 75.1-83.2) at two years. The cumulative incidence of testing negative at re-screening after treatment was 36.1% (95% CI 31.2-40.7) at two years. Using a cascade approach to evaluate the full continuum of cervical cancer screening, we found less-than 80% of WLHIV received treatment after screen-positive tests and less-than 40% were screen-negative at follow-up. Interventions to improve linkage to treatment for screen-positive WLHIV and studies to understand the clinical significance of screen-positive tests at follow-up among WLHIV are needed. These gaps in the continuum of care must be addressed in order to prevent cervical cancer

Major Surface Glycoproteins of Insect Forms of Trypanosoma brucei Are Not Essential for Cyclical Transmission by Tsetse

Procyclic forms of Trypanosoma brucei reside in the midgut of tsetse flies where they are covered by several million copies of glycosylphosphatidylinositol-anchored proteins known as procyclins. It has been proposed that procyclins protect parasites against proteases and/or participate in tropism, directing them from the midgut to the salivary glands. There are four different procyclin genes, each subject to elaborate levels of regulation. To determine if procyclins are essential for survival and transmission of T. brucei, all four genes were deleted and parasite fitness was compared in vitro and in vivo. When co-cultured in vitro, the null mutant and wild type trypanosomes (tagged with cyan fluorescent protein) maintained a near-constant equilibrium. In contrast, when flies were infected with the same mixture, the null mutant was rapidly overgrown in the midgut, reflecting a reduction in fitness in vivo. Although the null mutant is patently defective in competition with procyclin-positive parasites, on its own it can complete the life cycle and generate infectious metacyclic forms. The procyclic form of T. brucei thus differs strikingly from the bloodstream form, which does not tolerate any perturbation of its variant surface glycoprotein coat, and from other parasites such as Plasmodium berghei, which requires the circumsporozoite protein for successful transmission to a new host

Comparison of codes assessing galactic cosmic radiation exposure of aircraft crew

The assessment of the exposure to cosmic radiation onboard aircraft is one of the preoccupations of bodies responsible for radiation protection. Cosmic particle flux is significantly higher onboard aircraft than at ground level and its intensity depends on the solar activity. The dose is usually estimated using codes validated by the experimental data. In this paper, a comparison of various codes is presented, some of them are used routinely, to assess the dose received by the aircraft crew caused by the galactic cosmic radiation. Results are provided for periods close to solar maximum and minimum and for selected flights covering major commercial routes in the world. The overall agreement between the codes, particularly for those routinely used for aircraft crew dosimetry, was better than ±20 % from the median in all but two cases. The agreement within the codes is considered to be fully satisfactory for radiation protection purpose

PSSA-2, a Membrane-Spanning Phosphoprotein of Trypanosoma brucei, Is Required for Efficient Maturation of Infection

The coat of Trypanosoma brucei consists mainly of glycosylphosphatidylinositol-anchored proteins that are present in several million copies and are characteristic of defined stages of the life cycle. While these major components of the coats of bloodstream forms and procyclic (insect midgut) forms are well characterised, very little is known about less abundant stage-regulated surface proteins and their roles in infection and transmission. By creating epitope-tagged versions of procyclic-specific surface antigen 2 (PSSA-2) we demonstrated that it is a membrane-spanning protein that is expressed by several different life cycle stages in tsetse flies, but not by parasites in the mammalian bloodstream. In common with other membrane-spanning proteins in T. brucei, PSSA-2 requires its cytoplasmic domain in order to exit the endoplasmic reticulum. Correct localisation of PSSA-2 requires phosphorylation of a cytoplasmic threonine residue (T305), a modification that depends on the presence of TbMAPK4. Mutation of T305 to alanine (T305A) has no effect on the localisation of the protein in cells that express wild type PSSA-2. In contrast, this protein is largely intracellular when expressed in a null mutant background. A variant with a T305D mutation gives strong surface expression in both the wild type and null mutant, but slows growth of the cells, suggesting that it may function as a dominant negative mutant. The PSSA-2 null mutant exhibits no perceptible phenotype in culture and is fully competent at establishing midgut infections in tsetse, but is defective in colonising the salivary glands and the production of infectious metacyclic forms. Given the protein's structure and the effects of mutation of T305 on proliferation and localisation, we postulate that PSSA-2 might sense and transmit signals that contribute to the parasite's decision to divide, differentiate or migrate

Lowering the radioactivity of the photomultiplier tubes for the XENON1T dark matter experiment

The low-background, VUV-sensitive 3-inch diameter photomultiplier tube R11410 has been developed by Hamamatsu for dark matter direct detection experiments using liquid xenon as the target material. We present the results from the joint effort between the XENON collaboration and the Hamamatsu company to produce a highly radio-pure photosensor (version R11410-21) for the XENON1T dark matter experiment. After introducing the photosensor and its components, we show the methods and results of the radioactive contamination measurements of the individual materials employed in the photomultiplier production. We then discuss the adopted strategies to reduce the radioactivity of the various PMT versions. Finally, we detail the results from screening 216 tubes with ultra-low background germanium detectors, as well as their implications for the expected electronic and nuclear recoil background of the XENON1T experiment.Comment: 10 pages, 5 figure

Search for Event Rate Modulation in XENON100 Electronic Recoil Data

We have searched for periodic variations of the electronic recoil event rate in the (2-6) keV energy range recorded between February 2011 and March 2012 with the XENON100 detector, adding up to 224.6 live days in total. Following a detailed study to establish the stability of the detector and its background contributions during this run, we performed an un-binned profile likelihood analysis to identify any periodicity up to 500 days. We find a global significance of less than 1 sigma for all periods suggesting no statistically significant modulation in the data. While the local significance for an annual modulation is 2.8 sigma, the analysis of a multiple-scatter control sample and the phase of the modulation disfavor a dark matter interpretation. The DAMA/LIBRA annual modulation interpreted as a dark matter signature with axial-vector coupling of WIMPs to electrons is excluded at 4.8 sigma.Comment: 6 pages, 4 figure

Removing krypton from xenon by cryogenic distillation to the ppq level

The XENON1T experiment aims for the direct detection of dark matter in a cryostat filled with 3.3 tons of liquid xenon. In order to achieve the desired sensitivity, the background induced by radioactive decays inside the detector has to be sufficiently low. One major contributor is the $\beta$-emitter $^{85}$Kr which is an intrinsic contamination of the xenon. For the XENON1T experiment a concentration of natural krypton in xenon $\rm{^{nat}}$Kr/Xe < 200 ppq (parts per quadrillion, 1 ppq = 10$^{-15}$ mol/mol) is required. In this work, the design of a novel cryogenic distillation column using the common McCabe-Thiele approach is described. The system demonstrated a krypton reduction factor of 6.4$\cdot$10$^5$ with thermodynamic stability at process speeds above 3 kg/h. The resulting concentration of $\rm{^{nat}}$Kr/Xe < 26 ppq is the lowest ever achieved, almost one order of magnitude below the requirements for XENON1T and even sufficient for future dark matter experiments using liquid xenon, such as XENONnT and DARWIN