Therapeutic vaccine in chronically Hiv-1-infected patients

Therapeutic vaccinations aim to re-educate human immunodeficiency virus (HIV)-1specific immune responses to achieve durable control of HIV-1 replication in virally suppressed infected individuals after antiretroviral therapy (ART) is interrupted. In a double blinded, placebocontrolled phase IIa multicenter study, we investigated the safety and immunogenicity of intranodal administration of the HIVACAT T cell Immunogen (HTI)-TriMix vaccine. It consists of naked mRNA based on cytotoxic T lymphocyte (CTL) targets of subdominant and conserved HIV-1 regions (HTI), in combination with mRNAs encoding constitutively active TLR4, the ligand for CD40 and CD70 as adjuvants (TriMix). We recruited HIV-1-infected individuals under stable ART. Study-arms HTI-TriMix, TriMix or Water for Injection were assigned in an 8:3:3 ratio. Participants received three vaccinations at weeks 0, 2, and 4 in an inguinal lymph node. Two weeks after the last vaccination, immunogenicity was evaluated using ELISpot assay. ART was interrupted at week 6 to study the effect of the vaccine on viral rebound. The vaccine was considered safe and well tolerated. Eighteen percent (n = 37) of the AEs were considered definitely related to the study product (grade 1 or 2). Three SAEs occurred: two were unrelated to the study product, and one was possibly related to ART interruption (ATI). ELISpot assays to detect T cell responses using peptides covering the HTI sequence showed no significant differences in immunogenicity between groups. There were no significant differences in viral load rebound dynamics after ATI between groups. The vaccine was safe and well tolerated. We were not able to demonstrate immunogenic effects of the vaccine

Characterization of the HIV-1 transcription profile after romidepsin administration in ART-suppressed individuals

ObjectivesReversing HIV-1 latency has been suggested as a strategy to eradicate HIV-1. We investigated the effect of romidepsin on the HIV transcription profile in participants from the REDUC part B clinical trial.DesignSeventeen participants on suppressive antiretroviral therapy were vaccinated with six doses of the therapeutic vaccine Vacc-4x followed by treatment with three doses of romidepsin. Samples from nine study participants were available for HIV transcription profile analysis.MethodsRead-through, total (TAR), elongated (longLTR), polyadenylated (polyA) and multiply-spliced (Tat-Rev) HIV transcripts and total HIV DNA were quantified at baseline (visit 1) and 4 h after the second (visit 10b) and third (visit 11b) romidepsin infusions.ResultsRead-through, total, elongated, and polyadenylated HIV transcripts increased after romidepsin infusion (P = 0.020, P = 0.0078, P = 0.0039, P = 0.027, respectively), but no changes were observed in multiply-spliced HIV RNA or HIV DNA. No change was observed in the ratio of read-through/total HIV transcripts. The ratio of elongated/total HIV RNA increased after romidepsin (P = 0.016), whereas the ratio of polyadenylated/elongated HIV decreased. Both elongated HIV transcripts and total HIV DNA correlated negatively with the time to viral rebound after interruption of ART.ConclusionsIn these patients, romidepsin increased early events in HIV transcription (initiation and especially elongation), but had less effect on later stages (completion, multiple splicing) that may be required for comprehensive latency reversal and cell killing. Without cell death, increased HIV transcription before or after latency reversal may hasten viral rebound after therapy interruption

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Angular analysis of the rare decay Bs0 {B}_s^0 → ϕμ+^{+}μ−^{−}

International audienceAn angular analysis of the rare decay ${B}_s^0$→ ϕμ$^{+}$μ$^{−}$ is presented, using proton-proton collision data collected by the LHCb experiment at centre-of-mass energies of 7, 8 and 13 TeV, corresponding to an integrated luminosity of 8.4 fb$^{−1}$. The observables describing the angular distributions of the decay ${B}_s^0$→ ϕμ$^{+}$μ$^{−}$ are determined in regions of q$^{2}$, the square of the dimuon invariant mass. The results are consistent with Standard Model predictions.[graphic not available: see fulltext

Observation of the Bs0 ⁣→D∗+D∗−B^0_s\!\to D^{*+}D^{*-} decay

International audienceThe first observation of the ${B}_s^0$→ D$^{∗+}$D$^{∗−}$ decay and the measurement of its branching ratio relative to the B$^{0}$→ D$^{∗+}$D$^{∗−}$ decay are presented. The data sample used corresponds to an integrated luminosity of 9 fb$^{−1}$ of proton-proton collisions recorded by the LHCb experiment at centre-of-mass energies of 7, 8 and 13 TeV between 2011 and 2018. The decay is observed with more than 10 standard deviations and the time-integrated ratio of branching fractions is determined to be$\frac{\mathcal{B}\left({B}_s^0\to {D}^{\ast +}{D}^{\ast -}\right)}{\mathcal{B}\left({B}^0\to {D}^{\ast +}{D}^{\ast -}\right)}=0.269\pm 0.032\pm 0.011\pm 0.008,$where the first uncertainty is statistical, the second systematic and the third due to the uncertainty of the fragmentation fraction ratio f$_{s}$/f$_{d}$. The ${B}_s^0$→ D$^{*+}$D$^{*−}$ branching fraction is calculated to be$\mathcal{B}\left({B}_s^0\to {D}^{\ast +}{D}^{\ast -}\right)=\left(2.15\pm 0.26\pm 0.09\pm 0.06\pm 0.16\right)\times {10}^{-4},$where the fourth uncertainty is due to the B$^{0}$→ D$^{*+}$D$^{*−}$ branching fraction. These results are calculated using the average ${B}_s^0$ meson lifetime in simulation. Correction factors are reported for scenarios where either a purely heavy or a purely light ${B}_s^0$ eigenstate is considered.[graphic not available: see fulltext

First observation and branching fraction measurement of the Λb0→Ds−p {\Lambda}_b^0\to {D}_s^{-}p decay

International audienceThe first observation of the ${\Lambda}_b^0\to {D}_s^{-}p$ decay is presented using proton-proton collision data collected by the LHCb experiment at a centre-of-mass energy of $\sqrt{s}$ = 13 TeV, corresponding to a total integrated luminosity of 6 fb$^{−1}$. Using the ${\Lambda}_b^0\to {\Lambda}_c^{+}{\pi}^{-}$ decay as the normalisation mode, the branching fraction of the ${\Lambda}_b^0\to {D}_s^{-}p$ decay is measured to be $\mathcal{B}\left({\Lambda}_b^0\to {D}_s^{-}p\right)=\left(12.6\pm 0.5\pm 0.3\pm 1.2\right)\times {10}^{-6}$, where the first uncertainty is statistical, the second systematic and the third due to uncertainties in the branching fractions of the ${\Lambda}_b^0\to {\Lambda}_c^{+}{\pi}^{-}$, ${D}_s^{-}\to {K}^{-}{K}^{+}{\pi}^{-}$ and ${\Lambda}_c^{+}\to p{K}^{-}{\pi}^{+}$ decays.[graphic not available: see fulltext

Test of lepton flavour universality using B0→D∗−τ+ντB^0 \to D^{*-}\tau^+\nu_{\tau} decays with hadronic τ\tau channels

The branching fraction $\mathcal{B}(B^0 \to D^{*-}\tau^+\nu_\tau)$ is measured relative to that of the normalisation mode $B^0 \to D^{*-}\pi^+\pi^-\pi^+$ using hadronic $\tau^+ \to \pi^+\pi^-\pi^+(\pi^0)\bar{\nu}_\tau$ decays in proton-proton collision data at a centre-of-mass energy of 13 TeV collected by the LHCb experiment, corresponding to an integrated luminosity of 2 fb$^{-1}$. The measured ratio is $\mathcal{B}(B^0 \to D^{*-}\tau^+\nu_\tau)/\mathcal{B}(B^0 \to D^{*-}\pi^+\pi^-\pi^+)= 1.70 \pm 0.10^{+0.11}_{-0.10}$, where the first uncertainty is statistical and the second is related to systematic effects. Using established branching fractions for the $B^0 \to D^{*-}\pi^+\pi^-\pi^+$ and $B^0 \to D^{*-} \mu^+\nu_\mu$ modes, the lepton universality test, $\mathcal{R}(D^{*-}) \equiv \mathcal{B}(B^0 \to D^{*-}\tau^+\nu_\tau)/\mathcal{B}(B^0 \to D^{*-} \mu^+\nu_\mu)$ is calculated, $$\mathcal{R}(D^{*-}) = 0.247 \pm 0.015 \pm 0.015 \pm 0.012\, ,$$ where the third uncertainty is due to the uncertainties on the external branching fractions. This result is consistent with the Standard Model prediction and with previous measurements.The branching fraction B(B0→D*-τ+ντ) is measured relative to that of the normalization mode B0→D*-π+π-π+ using hadronic τ+→π+π-π+(π0)ν¯τ decays in proton-proton collision data at a center-of-mass energy of 13 TeV collected by the LHCb experiment, corresponding to an integrated luminosity of 2  fb-1. The measured ratio is B(B0→D*-τ+ντ)/B(B0→D*-π+π-π+)=1.70±0.10-0.10+0.11, where the first uncertainty is statistical and the second is related to systematic effects. Using established branching fractions for the B0→D*-π+π-π+ and B0→D*-μ+νμ modes, the lepton universality test R(D*-)≡B(B0→D*-τ+ντ)/B(B0→D*-μ+νμ) is calculated, R(D*-)=0.247±0.015±0.015±0.012, where the third uncertainty is due to the uncertainties on the external branching fractions. This result is consistent with the Standard Model prediction and with previous measurements.The branching fraction $\mathcal{B}(B^0 \to D^{*-}\tau^+\nu_{\tau})$ is measured relative to that of the normalisation mode $B^0 \to D^{*-}\pi^+\pi^-\pi^+$ using hadronic $\tau^+ \to \pi^+\pi^-\pi^+(\pi^0)\bar{\nu}_{\tau}$ decays in proton-proton collision data at a centre-of-mass energy of 13 TeV collected by the LHCb experiment, corresponding to an integrated luminosity of 2 fb$^{-1}$. The measured ratio is $\mathcal{B}(B^0 \to D^{*-}\tau^+\nu_{\tau})/\mathcal{B}(B^0 \to D^{*-}\pi^+\pi^-\pi^+)= 1.70 \pm 0.10^{+0.11}_{-0.10}$, where the first uncertainty is statistical and the second is related to systematic effects. Using established branching fractions for the $B^0 \to D^{*-}\pi^+\pi^-\pi^+$ and $B^0 \to D^{*-} \mu^+\nu_\mu$ modes, the lepton universality test, $\mathcal{R}(D^{*-}) \equiv \mathcal{B}(B^0 \to D^{*-}\tau^+\nu_{\tau})/\mathcal{B}(B^0 \to D^{*-} \mu^+\nu_\mu)$ is calculated, $$\mathcal{R}(D^{*-}) = 0.247 \pm 0.015 \pm 0.015 \pm 0.012\, ,$$ where the third uncertainty is due to the uncertainties on the external branching fractions. This result is consistent with the Standard Model prediction and with previous measurements

Measurement of the CKM angle γγ with B±→D[K∓π±π±π∓]h± B^\pm \to D[K^\mp π^\pm π^\pm π^\mp] h^\pm decays using a binned phase-space approach

The CKM angle $\gamma$ is determined from $C\!P$-violating observables measured in ${B^\pm \to D[ K^\mp \pi^\pm\pi^\pm\pi^\mp] h^\pm}$, $(h = K,\pi)$ decays, where the measurements are performed in bins of the decay phase-space of the $D$ meson. Using proton-proton collision data collected by the LHCb experiment at centre-of-mass energies of $7, 8$ and $13\,\text{TeV}$, corresponding to a total integrated luminosity of $9\,\text{fb}^{-1}$, $\gamma$ is determined to be \begin{equation*} \gamma = \left( 54.8 \: ^{+\:6.0 }_{-\:5.8} \: ^{+\:0.6}_{-\:0.6} \: ^{+\:6.7}_{-\:4.3} \right)^\circ, \end{equation*} where the first uncertainty is statistical, the second systematic and the third from the external inputs on the coherence factors and strong phases of the $D$-meson decays.The CKM angle γ is determined from CP-violating observables measured in B$^{±}$ → D[K$^{∓}$π$^{±}$π$^{±}$π$^{∓}$]h$^{±}$, (h = K, π) decays, where the measurements are performed in bins of the decay phase-space of the D meson. Using proton-proton collision data collected by the LHCb experiment at centre-of-mass energies of 7, 8 and 13 TeV, corresponding to a total integrated luminosity of 9 fb$^{−1}$, γ is determined to be$\gamma ={\left(54.8\begin{array}{c}+6.0\\ {}-5.8\end{array}\begin{array}{c}+0.6\\ {}-0.6\end{array}\begin{array}{c}+6.7\\ {}-4.3\end{array}\right)}^{\circ },$where the first uncertainty is statistical, the second systematic and the third from the external inputs on the coherence factors and strong phases of the D-meson decays.[graphic not available: see fulltext]The CKM angle $\gamma$ is determined from $C\!P$-violating observables measured in ${B^\pm \to D[ K^\mp \pi^\pm\pi^\pm\pi^\mp] h^\pm}$, $(h = K,\pi)$ decays, where the measurements are performed in bins of the decay phase-space of the $D$ meson. Using proton-proton collision data collected by the LHCb experiment at centre-of-mass energies of $7, 8$ and $13\,\text{TeV}$, corresponding to a total integrated luminosity of $9\,\text{fb}^{-1}$, $\gamma$ is determined to be \begin{equation*} \gamma = \left( 54.8 \: ^{+\:6.0 }_{-\:5.8} \: ^{+\:0.6}_{-\:0.6} \: ^{+\:6.7}_{-\:4.3} \right)^\circ, \end{equation*} where the first uncertainty is statistical, the second systematic and the third from the external inputs on the coherence factors and strong phases of the $D$-meson decays