Immunogenicity of personalized dendritic-cell therapy in HIV-1 infected individuals under suppressive antiretroviral treatment:interim analysis from a phase II clinical trial

BACKGROUND: We developed a personalized Monocyte-Derived Dendritic-cell Therapy (MDDCT) for HIV-infected individuals on suppressive antiretroviral treatment and evaluated HIV-specific T-cell responses. METHODS: PBMCs were obtained from 10 HIV(+) individuals enrolled in trial NCT02961829. Monocytes were differentiated into DCs using IFN-α and GM-CSF. After sequencing each patient’s HIV-1 Gag and determining HLA profiles, autologous Gag peptides were selected based on the predicted individual immunogenicity and used to pulse MDDCs. Three doses of the MDDCT were administered every 15 days. To assess immunogenicity, patients’ cells were stimulated in vitro with autologous peptides, and intracellular IL-2, TNF, and interferon-gamma (IFN-γ) production were measured in CD4(+) and CD8(+) T-cells. RESULTS: The protocol of ex-vivo treatment with IFN-α and GM-CSF was able to induce maturation of MDDCs, as well as to preserve their viability for reinfusion. MDDCT administration was associated with increased expression of IL-2 in CD4(+) and CD8(+) T-cells at 15 and/or 30 days after the first MDDCT administration. Moreover, intracellular TNF and IFN-γ expression was significantly increased in CD4(+) T-cells. The number of candidates that increased in vitro the cytokine levels in CD4(+) and CD8(+) T cells upon stimulation with Gag peptides from baseline to day 15 and from baseline to day 30 and day 120 after MDDCT was significant as compared to Gag unstimulated response. This was accompanied by an increasing trend in the frequency of polyfunctional T-cells over time, which was visible when considering both cells expressing two and three out of the three cytokines examined. CONCLUSIONS: MDDC had a mature profile, and this MDDCT promoted in-vitro T-cell immune responses in HIV-infected patients undergoing long-term suppressive antiretroviral treatment. Trial registration NCT02961829: (Multi Interventional Study Exploring HIV-1 Residual Replication: a Step Towards HIV-1 Eradication and Sterilizing Cure, https://www.clinicaltrials.gov/ct2/show/NCT02961829, posted November 11th, 2016) SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12981-021-00426-z

Evaluating risk factor assumptions: a simulation-based approach

<p>Abstract</p> <p>Background</p> <p>Microsimulation models are an important tool for estimating the comparative effectiveness of interventions through prediction of individual-level disease outcomes for a hypothetical population. To estimate the effectiveness of interventions targeted toward high risk groups, the mechanism by which risk factors influence the natural history of disease must be specified. We propose a method for evaluating these risk factor assumptions as part of model-building.</p> <p>Methods</p> <p>We used simulation studies to examine the impact of risk factor assumptions on the relative rate (RR) of colorectal cancer (CRC) incidence and mortality for a cohort with a risk factor compared to a cohort without the risk factor using an extension of the CRC-SPIN model for colorectal cancer. We also compared the impact of changing age at initiation of screening colonoscopy for different risk mechanisms.</p> <p>Results</p> <p>Across CRC-specific risk factor mechanisms, the RR of CRC incidence and mortality decreased (towards one) with increasing age. The rate of change in RRs across age groups depended on both the risk factor mechanism and the strength of the risk factor effect. Increased non-CRC mortality attenuated the effect of CRC-specific risk factors on the RR of CRC when both were present. For each risk factor mechanism, earlier initiation of screening resulted in more life years gained, though the magnitude of life years gained varied across risk mechanisms.</p> <p>Conclusions</p> <p>Simulation studies can provide insight into both the effect of risk factor assumptions on model predictions and the type of data needed to calibrate risk factor models.</p

May Measurement Month 2018: a pragmatic global screening campaign to raise awareness of blood pressure by the International Society of Hypertension

Aims Raised blood pressure (BP) is the biggest contributor to mortality and disease burden worldwide and fewer than half of those with hypertension are aware of it. May Measurement Month (MMM) is a global campaign set up in 2017, to raise awareness of high BP and as a pragmatic solution to a lack of formal screening worldwide. The 2018 campaign was expanded, aiming to include more participants and countries. Methods and results Eighty-nine countries participated in MMM 2018. Volunteers (≥18 years) were recruited through opportunistic sampling at a variety of screening sites. Each participant had three BP measurements and completed a questionnaire on demographic, lifestyle, and environmental factors. Hypertension was defined as a systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, or taking antihypertensive medication. In total, 74.9% of screenees provided three BP readings. Multiple imputation using chained equations was used to impute missing readings. 1 504 963 individuals (mean age 45.3 years; 52.4% female) were screened. After multiple imputation, 502 079 (33.4%) individuals had hypertension, of whom 59.5% were aware of their diagnosis and 55.3% were taking antihypertensive medication. Of those on medication, 60.0% were controlled and of all hypertensives, 33.2% were controlled. We detected 224 285 individuals with untreated hypertension and 111 214 individuals with inadequately treated (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) hypertension. Conclusion May Measurement Month expanded significantly compared with 2017, including more participants in more countries. The campaign identified over 335 000 adults with untreated or inadequately treated hypertension. In the absence of systematic screening programmes, MMM was effective at raising awareness at least among these individuals at risk

Diagnostic guidelines for the histological particle algorithm in the periprosthetic neo-synovial tissue

Background The identification of implant wear particles and non-implant related particles and the characterization of the inflammatory responses in the periprosthetic neo-synovial membrane, bone, and the synovial-like interface membrane (SLIM) play an important role for the evaluation of clinical outcome, correlation with radiological and implant retrieval studies, and understanding of the biological pathways contributing to implant failures in joint arthroplasty. The purpose of this study is to present a comprehensive histological particle algorithm (HPA) as a practical guide to particle identification at routine light microscopy examination. Methods The cases used for particle analysis were selected retrospectively from the archives of two institutions and were representative of the implant wear and non-implant related particle spectrum. All particle categories were described according to their size, shape, colour and properties observed at light microscopy, under polarized light, and after histochemical stains when necessary. A unified range of particle size, defined as a measure of length only, is proposed for the wear particles with five classes for polyethylene (PE) particles and four classes for conventional and corrosion metallic particles and ceramic particles. Results All implant wear and non-implant related particles were described and illustrated in detail by category. A particle scoring system for the periprosthetic tissue/SLIM is proposed as follows: 1) Wear particle identification at light microscopy with a two-step analysis at low (× 25, × 40, and × 100) and high magnification (× 200 and × 400); 2) Identification of the predominant wear particle type with size determination; 3) The presence of non-implant related endogenous and/or foreign particles. A guide for a comprehensive pathology report is also provided with sections for macroscopic and microscopic description, and diagnosis. Conclusions The HPA should be considered a standard for the histological analysis of periprosthetic neo-synovial membrane, bone, and SLIM. It provides a basic, standardized tool for the identification of implant wear and non-implant related particles at routine light microscopy examination and aims at reducing intra-observer and inter-observer variability to provide a common platform for multicentric implant retrieval/radiological/histological studies and valuable data for the risk assessment of implant performance for regional and national implant registries and government agencies

2600 years of stratospheric volcanism reconstruction through sulfate isotopes for Antarctic ice DomeC

We present a 2600 year chronology of stratospheric volcanic events using isotopic signatures (Δ33S and in some cases Δ17O) of ice core sulfate. Five closely-located ice cores from Dome C, Antarctica, are used to reconstruct a record that differs subtly from recent reconstructions calibrated using synchronous volcanic sulfate deposition in Greenland and Antarctica to identify eruptions with global-scale sulfate distribution. Comparing the Dome C stratospheric reconstruction shows good agreement with the recent parts of these bipolar reconstructions, but diverges deeper in the record revealing tropospheric signals for some previously assigned bipolar events. The comparison also reveals several high latitude stratospheric events that are not bipolar. Finally, the Δ17O anomaly of sulfate collapses for the largest volcanic eruptions, showing a further change in atmospheric chemistry induced by large emissions, providing additional levels for climate-volcano connections and supporting the value of adding isotopic information to bipolar volcanic reconstructions