Virological, Immune and Host genetics Markers in the Control of HIV Infection

HIV infection, if left untreated, leads in most cases to the development of wide immune deterioration, opportunistic infections and eventually AIDS and death. The identification of individuals who despite persisting infection show no or few signs of HIV disease progression has spurred hopes that an effective HIV vaccine could be attainable. The design of such a vaccine will greatly depend on the precise definition of disease markers, host genetic and immune characteristics that mediate relative in vivo control of this virus. Accordingly, a number of viral factors and host genetic characteristics have been shown to play a crucial role in the control of HIV disease by delaying progression to AIDS or even preventing infection. There is also an improved understanding of humoral and cellular immune responses in terms of specificity, functional repertoire, longevity and tissue distribution and their ability to contain HIV replication. However, the definition of good immune correlates unequivocally and causally associated with protection or disease progression remains elusive. Here we review work on viral factors, host genetic markers and immunological determinants that have been identified in individuals with superior control of HIV infection or in subjects who remain uninfected despite frequent exposure to the viral pathogen

Quantum approximated cloning-assisted density matrix exponentiation

Classical information loading is an essential task for many processing quantum algorithms, constituting a cornerstone in the field of quantum machine learning. In particular, the embedding techniques based on Hamiltonian simulation techniques enable the loading of matrices into quantum computers. A representative example of these methods is the Lloyd-Mohseni-Rebentrost protocol, which efficiently implements matrix exponentiation when multiple copies of a quantum state are available. However, this is a quite ideal set up, and in a realistic scenario, the copies are limited and the non-cloning theorem prevents from producing more exact copies in order to increase the accuracy of the protocol. Here, we propose a method to circumvent this limitation by introducing imperfect quantum copies that significantly enhance the performance of previous proposals

Definition of the Viral Targets of Protective HIV-1-Specific T Cell Responses

Background: The efficacy of the CTL component of a future HIV-1 vaccine will depend on the induction ofresponses with the most potent antiviral activity and broad HLA class I restriction. However, current HIV vaccinedesigns are largely based on viral sequence alignments only, not incorporating experimental data on T cellfunction and specificity. Methods: Here, 950 untreated HIV-1 clade B or -C infected individuals were tested for responses to sets of 410overlapping peptides (OLP) spanning the entire HIV-1 proteome. For each OLP, a “protective ratio” (PR) wascalculated as the ratio of median viral loads (VL) between OLP non-responders and responders. Results: For both clades, there was a negative relationship between the PR and the entropy of the OLP sequence.There was also a significant additive effect of multiple responses to beneficial OLP. Responses to beneficial OLPwere of significantly higher functional avidity than responses to non-beneficial OLP. They also had superior in-vitroantiviral activities and, importantly, were at least as predictive of individuals’ viral loads than their HLA class Igenotypes. Conclusions: The data thus identify immunogen sequence candidates for HIV and provide an approach for T cellimmunogen design applicable to other viral infections

Human Vault Nanoparticle Targeted Delivery of Antiretroviral Drugs to Inhibit Human Immunodeficiency Virus Type 1 Infection.

"Vaults" are ubiquitously expressed endogenous ribonucleoprotein nanoparticles with potential utility for targeted drug delivery. Here, we show that recombinant human vault nanoparticles are readily engulfed by certain key human peripheral blood mononuclear cells (PBMC), predominately dendritic cells, monocytes/macrophages, and activated T cells. As these cell types are the primary targets for human immunodeficiency virus type 1 (HIV-1) infection, we examined the utility of recombinant human vaults for targeted delivery of antiretroviral drugs. We chemically modified three different antiretroviral drugs, zidovudine, tenofovir, and elvitegravir, for direct conjugation to vaults. Tested in infection assays, drug-conjugated vaults inhibited HIV-1 infection of PBMC with equivalent activity to free drugs, indicating vault delivery and drug release in the cytoplasm of HIV-1-susceptible cells. The ability to deliver functional drugs via vault nanoparticle conjugates suggests their potential utility for targeted drug delivery against HIV-1

Long-term comparative effectiveness of deep brain stimulation in severe obsessive-compulsive disorder

Background: Twenty years after the first use of Deep Brain Stimulation (DBS) in obsessive-compulsive disorder (OCD), our knowledge of the long-term effects of this therapeutic option remains very limited. Objective: Our study aims to assess the long-term effectiveness and tolerability of DBS in OCD patients and to look for possible predictors of long-term response to this treatment. Methods: We studied the course of 25 patients with severe refractory OCD treated with DBS over an average follow-up period of 6.4 years (+/- 3.2) and compared them with a control group of 25 patients with severe OCD who refused DBS and maintained their usual treatment. DBS was implanted at the ventral anterior limb of the internal capsule and nucleus accumbens (vALIC-Nacc) in the first six patients and later at the bed nucleus of stria terminalis (BNST) in the rest of patients. Main outcome was change in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score between the two groups assessed using mixed models. Secondary effectiveness outcomes included Hamilton Depression Rating Scale (HDRS) and Global Assessment of Functioning (GAF) scores. Results: Obsessive symptoms fell by 42.5% (Y-BOCS score) in patients treated with DBS and by 4.8% in the control group. Fifty-six per cent of DBS-treated patients could be considered responders at the end of follow-up and 28% partial responders. Two patients among those who rejected DBS were partial re-sponders (8%), but none of the non-DBS group achieved criteria for complete response. HDRS and GAF scores improved significantly in 39.2% and 43.6% among DBS-treated patients, while did not significantly change in those who rejected DBS (improvement limited to 6.2% in HDRS and 4.2% in GAF scores). No statistically significant predictors of response were found. Mixed models presented very large compar-ative effect sizes for DBS (4.29 for Y-BOCS, 1.15 for HDRS and 2.54 for GAF). Few patients experienced adverse effects and most of these effects were mild and transitory. Conclusions: The long-term comparative effectiveness and safety of DBS confirm it as a valid option for the treatment of severe refractory OCD. (c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Cost-effectiveness analysis of vaccines for COVID-19 according to sex, comorbidity and socioeconomics status: a population study

Background and Objective Coronavirus disease 2019 (COVID-19) vaccines are extremely effective in preventing severe disease, but their real-world cost-effectiveness is still an open question. We present an analysis of the cost-effectiveness and economic impact of the initial phase of the COVID-19 vaccination rollout in the Basque Country, Spain. Methods To calculate costs and quality-adjusted life years for the entire population of the Basque Country, dynamic modelling and a real-world data analysis were combined. Data on COVID-19 infection outcomes (cases, hospitalisations, intensive care unit admissions and deaths) and population characteristics (age, sex, socioeconomic status and comorbidity) during the initial phase of the vaccination rollout, from January to June of 2021, were retrieved from the Basque Health Service database. The outcomes in the alternative scenario (without vaccination) were estimated with the dynamic model used to guide public health authority policies, from February to December 2020. Individual comorbidity-adjusted life expectancy and costs were estimated. Results By averting severe disease-related outcomes, COVID-19 vaccination resulted in monetary savings of €26.44 million for the first semester of 2021. The incremental cost-effectiveness ratio was €707/quality-adjusted life year considering official vaccine prices and dominant real prices. While the analysis by comorbidity showed that vaccines were considerably more cost effective in individuals with pre-existing health conditions, this benefit was lower in the low socioeconomic status group. Conclusions The incremental cost-effectiveness ratio of the vaccination programme justified the policy of prioritising high-comorbidity patients. The initial phase of COVID-19 vaccination was dominant from the perspective of the healthcare payer

Incidence of mental disorders in the general population aged 1–30 years disaggregated by gender and socioeconomic status

Purpose The objective of this study was to estimate the incidence and age of onset of mental disorders diagnosed by gender and socioeconomic status (SES) in children, adolescents, and young adults up to 30 years of age in the whole population of the Basque Country (Spain). Methods All mental health diagnoses documented in Basque Health Service records from 1 January 2003 to 31 December 2018, were classified into eight clusters: anxiety, attention deficit hyperactivity disorder (ADHD), conduct disorders, depression, psychosis/personality disorders, substance use, eating disorders, and self-harm. We calculated incidence and cumulative incidence for each cluster, disaggregated by gender, and socioeconomic status (SES). Poisson regression analyses were performed. Results Overall, 9,486,853 person-years of observation were available for the 609,281 individuals included. ADHD and conduct disorders were diagnosed in the first decade, anxiety and depression disorders in the second and third decades, and psychosis/personality and substance use in the third. The cumulative incidence at 18 years of age for any type of disorder was 15.5%. The group with low SES had a statistically significantly higher incidence of all eight clusters. The incidence of ADHD, conduct disorders, depression, psychosis/personality disorders, and substance use was higher in males and that of anxiety, eating disorders and self-harm was higher in females. Conclusions The incidence of mental disorders is high among children, adolescents, and young adults in the Basque Country underlining the need for preventive interventions. Marked differences by gender and SES highlight mental health inequalities, especially for depression and psychosis in low SES males.This work is included within the UPRIGHT project, which is funded by the European Union Horizon 2020 Research and Innovation programme under grant agreement No. 754919. This paper reflects only the views of the authors, and the European Union is not responsible for any use that may be made of the information it contains. The funding body has had no role in the study design, writing of the protocol or the decision to submit the paper for publication

Definition of the viral targets of protective HIV-1-specific T cell responses

<p>Abstract</p> <p>Background</p> <p>The efficacy of the CTL component of a future HIV-1 vaccine will depend on the induction of responses with the most potent antiviral activity and broad HLA class I restriction. However, current HIV vaccine designs are largely based on viral sequence alignments only, not incorporating experimental data on T cell function and specificity.</p> <p>Methods</p> <p>Here, 950 untreated HIV-1 clade B or -C infected individuals were tested for responses to sets of 410 overlapping peptides (OLP) spanning the entire HIV-1 proteome. For each OLP, a "protective ratio" (PR) was calculated as the ratio of median viral loads (VL) between OLP non-responders and responders.</p> <p>Results</p> <p>For both clades, there was a negative relationship between the PR and the entropy of the OLP sequence. There was also a significant additive effect of multiple responses to beneficial OLP. Responses to beneficial OLP were of significantly higher functional avidity than responses to non-beneficial OLP. They also had superior in-vitro antiviral activities and, importantly, were at least as predictive of individuals' viral loads than their HLA class I genotypes.</p> <p>Conclusions</p> <p>The data thus identify immunogen sequence candidates for HIV and provide an approach for T cell immunogen design applicable to other viral infections.</p