Baseline natural killer and T cell populations correlation with virologic outcome after regimen simplification to atazanavir/ritonavir alone (ACTG 5201)

Objectives: Simplified maintenance therapy with ritonavir-boosted atazanavir (ATV/r) provides an alternative treatment option for HIV-1 infection that spares nucleoside analogs (NRTI) for future use and decreased toxicity. We hypothesized that the level of immune activation (IA) and recovery of lymphocyte populations could influence virologic outcomes after regimen simplification. Methods: Thirty-four participants with virologic suppression ≥48 weeks on antiretroviral therapy (2 NRTI plus protease inhibitor) were switched to ATV/r alone in the context of the ACTG 5201 clinical trial. Flow cytometric analyses were performed on PBMC isolated from 25 patients with available samples, of which 24 had lymphocyte recovery sufficient for this study. Assessments included enumeration of T-cells (CD4/CD8), natural killer (NK) (CD3+CD56 +CD16+) cells and cell-associated markers (HLA-DR, CD's 38/69/94/95/158/279). Results: Eight of the 24 patients had at least one plasma HIV-1 RNA level (VL) <50 copies/mL during the study. NK cell levels below the group median of 7.1% at study entry were associated with development of VL <50 copies/mL following simplification by regression and survival analyses (p = 0.043 and 0.023), with an odds ratio of 10.3 (95% CI: 1.92-55.3). Simplification was associated with transient increases in naïve and CD25+ CD4+ T-cells, and had no impact on IA levels. Conclusions: Lower NK cell levels prior to regimen simplification were predictive of virologic rebound after discontinuation of nucleoside analogs. Regimen simplification did not have a sustained impact on markers of IA or T lymphocyte populations in 48 weeks of clinical monitoring. Trial Registration: ClinicalTrials.gov NCT00084019

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Search for CP violation in D(s)+→h+π0 {D}_{(s)}^{+}\to {h}^{+}{\pi}^0 and D(s)+→h+η {D}_{(s)}^{+}\to {h}^{+}\eta decays

Abstract Searches for CP violation in the two-body decays $${D}_{(s)}^{+}\to {h}^{+}{\pi}^0$$ D s + → h + π 0 and $${D}_{(s)}^{+}\to {h}^{+}\eta$$ D s + → h + η (where h+ denotes a π+ or K+ meson) are performed using pp collision data collected by the LHCb experiment corresponding to either 9 fb−1 or 6 fb−1 of integrated luminosity. The π0 and η mesons are reconstructed using the e+e−γ final state, which can proceed as three-body decays π0→ e+e−γ and η → e+e−γ, or via the two-body decays π0→ γγ and η → γγ followed by a photon conversion. The measurements are made relative to the control modes $${D}_{(s)}^{+}\to {K}_{\mathrm{S}}^0{h}^{+}$$ D s + → K S 0 h + to cancel the production and detection asymmetries. The CP asymmetries are measured to be$${\displaystyle \begin{array}{c}{\mathcal{A}}_{CP}\left({D}^{+}\to {\pi}^{+}{\pi}^0\right)=\left(-1.3\pm 0.9\pm 0.6\right)\%,\\ {}{\mathcal{A}}_{CP}\left({D}^{+}\to {K}^{+}{\pi}^0\right)=\left(-3.2\pm 4.7\pm 2.1\right)\%,\\ {}\begin{array}{c}{\mathcal{A}}_{CP}\left({D}^{+}\to {\pi}^{+}\eta \right)=\left(-0.2\pm 0.8\pm 0.4\right)\%,\\ {}{\mathcal{A}}_{CP}\left({D}^{+}\to {K}^{+}\eta \right)=\left(-6\pm 10\pm 4\right)\%,\\ {}\begin{array}{c}{\mathcal{A}}_{CP}\left({D}_s^{+}\to {K}^{+}{\pi}^0\right)=\left(-0.8\pm 3.9\pm 1.2\right)\%,\\ {}\begin{array}{c}{\mathcal{A}}_{CP}\left({D}_s^{+}\to {\pi}^{+}\eta \right)=\left(0.8\pm 0.7\pm 0.5\right)\%,\\ {}{\mathcal{A}}_{CP}\left({D}_s^{+}\to {K}^{+}\eta \right)=\left(0.9\pm 3.7\pm 1.1\right)\%,\end{array}\end{array}\end{array}\end{array}}$$ A CP D + → π + π 0 = − 1.3 ± 0.9 ± 0.6 % , A CP D + → K + π 0 = − 3.2 ± 4.7 ± 2.1 % , A CP D + → π + η = − 0.2 ± 0.8 ± 0.4 % , A CP D + → K + η = − 6 ± 10 ± 4 % , A CP D s + → K + π 0 = − 0.8 ± 3.9 ± 1.2 % , A CP D s + → π + η = 0.8 ± 0.7 ± 0.5 % , A CP D s + → K + η = 0.9 ± 3.7 ± 1.1 % , where the first uncertainties are statistical and the second systematic. These results are consistent with no CP violation and mostly constitute the most precise measurements of $${\mathcal{A}}_{CP}$$ A CP in these decay modes to date.</jats:p