Antiretroviral Simplification with Darunavir/Ritonavir Monotherapy in Routine Clinical Practice: Safety, Effectiveness, and Impact on Lipid Profile

Simplification of antiretroviral treatment (ART) with darunavir/ritonavir (DRV/r) monotherapy has achieved sustained suppression of plasma viral load (pVL) in clinical trials; however, its effectiveness and safety profile has not been evaluated in routine clinical practice.We performed a retrospective cohort analysis of HIV-1-infected patients who initiated DRV/r monotherapy once daily with a pVL <50 copies/mL under ART and at least 1 subsequent follow-up visit in our clinic. The primary study endpoints were the percentage of patients with virological failure (VF, defined as 2 consecutive pVL>50 copies/mL) at week 48, and time to VF. Other causes of treatment discontinuation and changes in lipid profile were evaluated up to week 48. Ninety-two patients were followed for a median (IQR) of 73 (57-92) weeks. The median baseline and nadir CD4+ T-cell counts were 604 (433-837) and 238 (150-376) cells/mm3, respectively. Patients had previously received a median of 5 (3-9) ART lines and maintained a pVL<50 copies/mL for a median of 76 (32-176) weeks before initiating DRV/r monotherapy. Nine (9.8%) patients developed VF at week 48; time to VF was 47.1 (IQR: 36.1-47.8) weeks among patients with VF. Other reasons for changing ART were gastrointestinal disturbances (n = 3), rash (n = 1), and impaired CD4 recovery (n = 2). Median low-density lipoprotein cholesterol levels increased from 116.1 mg/dL at baseline to 137.3 mg/dL at 48 weeks (p = 0.001).Treatment simplification with DRV/r monotherapy seems safe and effective in routine clinical practice. Further research is needed to elucidate the effect of DRV/r monotherapy on cholesterol levels

Goal and variability modeling for service-oriented system: Integrating i* with decision models

Variability modeling and service-orientation are important approaches that address both the flexibility and adaptability required by stakeholders of today’s software systems. Goal-oriented approaches for modeling service-oriented systems and their variability in an integrated manner are needed to address the needs of heterogeneous stakeholders and to develop and evolve these systems. In this paper we propose an approach that complements the i* modeling framework with decision models from orthogonal variability modeling. We illustrate the approach using an example and present options for tool support.Peer ReviewedPostprint (author's final draft

HIV-1 Gag mutations alone are sufficient to reduce darunavir susceptibility during virological failure to boosted PI therapy

Virological failure (VF) to boosted PIs with a high genetic barrier is not usually linked to the development of resistance-associated mutations in the protease gene. From a cohort of 520 HIV-infected subjects treated with lopinavir/ritonavir or darunavir/ritonavir monotherapy, we retrospectively identified nine patients with VF. We sequenced the HIV-1 Gag-protease region and generated clonal virus from plasma samples. We characterized phenotypically clonal variants in terms of replicative capacity and susceptibility to PIs. Also, we used VESPA to identify signature mutations and 3D molecular modelling information to detect conformational changes in the Gag region. All subjects analysed harboured Gag-associated polymorphisms in the absence of resistance mutations in the protease gene. Most Gag changes occurred outside Gag cleavage sites. VESPA analyses identified K95R and R286K (P < 0.01) as signature mutations in Gag present at VF. In one out of four patients with clonal analysis available, we identified clonal variants with high replicative capacity and 8- to 13-fold reduction in darunavir susceptibility. These clonal variants harboured K95R, R286K and additional mutations in Gag. Low susceptibility to darunavir was dependent on the Gag sequence context. All other clonal variants analysed preserved drug susceptibility and virus replicative capacity. Gag mutations may reduce darunavir susceptibility in the absence of protease mutations while preserving viral fitness. This effect is Gag-sequence context dependent and may occur during boosted PI failure

BCN Rocks: aprendiendo geología urbana a través de una aplicación App interactiva

BCN Rocks is an application (App) for personal mobile devices (Android and iOS versions) suitable for secondary and high school students as well as people without background in Earth Sciences. The main objective of this App is to learn geology using the city facades and pavements of two emblematic spaces of the city of Barcelona, the Passeig de Gràcia and the Barri Gòtic. The application has three main sections (ELEMENTS, EXPLORE, and LABORATORY) that are intended to satisfy the different needs of users. In the first section, Elements, the user will find all the information about rocks forming the selected buildings as well as a brief explanation about the history and architecture of each edifice. The second section, Explore, aims to arise the curiosity of users. In this sense, several routes are proposed according to different criteria including geographic position and age of the edifices. Finally, the third section, Laboratory, allows all users to investigate several geological aspects by means of interactive experiments.Este trabajo se enmarca en un proyecto financiado por la Fundación Española para la Ciencia y la Tecnología, FECYT (ref. 8524) en el que ha participado la Universitat de Barcelona, el Instituto de Ciencias de la Tierra Jaume Almera del Consejo Superior de Investigaciones Científicas (ICTJA-CSIC) y la empresa FUSTA. AG agradece su contrato Ramón y Cajal (RYC-2012-11024).Peer Reviewe

Determinants of virological failure and antiretroviral drug resistance in Mozambique

Objectives The objective of this study was to inform public health actions to limit first-line ART failure and HIV drug resistance in Mozambique. Methods This was a cross-sectional study. HIV-1-infected adults on first-line ART for at least 1 year attending routine visits in the Manhiça District Hospital, in a semi-rural area in southern Mozambique with no HIV-1 RNA monitoring available, were evaluated for clinical, socio-demographic, therapeutic, immunological and virological characteristics. Factors associated with HIV-1 RNA ≥1000 copies/mL and HIV drug resistance were determined using multivariate logistic regression. Results The study included 334 adults on first-line ART for a median of 3 years, of which 65% (214/332) had suppressed viraemia, 11% (37/332) had low-level viraemia (HIV-1 RNA 150-999 copies/mL) and 24% (81/332) had overt virological failure (HIV-1 RNA ≥1000 copies/mL). HIV drug resistance was detected in 89% of subjects with virological failure, but in none with low-level viraemia. Younger age [OR = 0.97 per additional year (95% CI = 0.94-1.00), P = 0.039], ART initiation at WHO stage III/IV [OR = 2.10 (95% CI = 1.23-3.57), P = 0.003] and low ART adherence [OR = 2.69 (95% CI = 1.39-5.19), P = 0.003] were associated with virological failure. Longer time on ART [OR = 1.55 per additional year (95% CI = 1.00-2.43), P = 0.052] and illiteracy [OR = 0.24 (95% CI = 0.07-0.89), P = 0.033] were associated with HIV drug resistance. Compared with HIV-1 RNA, clinician's judgement of ART failure, based on clinical and immunological outcomes, only achieved 29% sensitivity and misdiagnosed 1 out of every 4.5 subjects. Conclusions Public health programmes in Mozambique should focus on early HIV diagnosis, early ART initiation and adherence support. Virological monitoring drastically improves the diagnosis of ART failure, enabling a better use of resource

The G1/S Specific Cyclin D2 Is a Regulator of HIV-1 Restriction in Non-proliferating Cells

Macrophages are a heterogeneous cell population strongly influenced by differentiation stimuli that become susceptible to HIV-1 infection after inactivation of the restriction factor SAMHD1 by cyclin-dependent kinases (CDK). Here, we have used primary human monocyte-derived macrophages differentiated through different stimuli to evaluate macrophage heterogeneity on cell activation and proliferation and susceptibility to HIV-1 infection. Stimulation of monocytes with GM-CSF induces a non-proliferating macrophage population highly restrictive to HIV-1 infection, characterized by the upregulation of the G1/S-specific cyclin D2, known to control early steps of cell cycle progression. Knockdown of cyclin D2, enhances HIV-1 replication in GM-CSF macrophages through inactivation of SAMHD1 restriction factor by phosphorylation. Co-immunoprecipitation experiments show that cyclin D2 forms a complex with CDK4 and p21, a factor known to restrict HIV-1 replication by affecting the function of the downstream cascade that leads to SAMHD1 deactivation. Thus, we demonstrate that cyclin D2 acts as regulator of cell cycle proteins affecting SAMHD1-mediated HIV-1 restriction in non-proliferating macrophage

A simple new screening tool for diagnosing imported schistosomiasis

We sought to test the sensitivity and feasibility of a Schistosoma infection screening process consisting of a scored patient consultation questionnaire and a serological diagnostic test. Prospective cross-sectional study. We collected from Schistosoma-exposed individuals a 14-point check list of clinical and laboratory data related to Schistosoma infection, alongside a serological test to detect Schistosoma spp infection. A check list score was created and compared with the risk of infection and clinical recovery through an agreement analysis. Two-hundred and fifty individuals were enrolled, of whom 220 (88%) were male and 30 (12%) female. The median age was 39 (range 18-78). One hundred-fifty (60%, 95% CI 54.9%-65.1%) had a check-list score ≥2. Serology test results were positive for 142 (56.8%, 95% CI 51.6%-62%). Chronic complications compatible with long-term Schistosoma infection were detected in 29 out of these 142 (20.4%, 95% CI 13.8%-27%).,. The median score value was 3, the area under the receiver operating characteristic (ROC) curve against serology results was 0.85 and the estimated intercept check-list questionnaire score value was 1.72 (95%, CI: 1.3-2.2). Participants with a positive serological test had a substantially higher check-list score (Cohen's kappa coefficient: 0.62, 95% CI: 0.54-0.70). Ninety four percent patients empirically treated showed a subsequent improvement in clinical and laboratory parameters. A two-component process consisting of a scored patient consultation questionnaire followed by serological assay can be a suitable strategy for screening populations at high risk of schistosomiasis infection

Factors associated with critical care requirements in diabetic patients treated with dexamethasone for COVID-19 infection in the first wave of the pandemia

Diabetes mellitus (DM) and hyperglycemia are important risk factors for poor outcomes in hospitalized patients with coronavirus disease 2019 (COVID-19). The aim of the present study was to analyze the factors associated with the composite outcome of the necessity of invasive mechanical ventilation (IMV) or admission to the intensive care unit (ICU) in subjects with severe COVID-19 infection treated with dexamethasone comparing patients with DM vs. patients without DM. An observational retrospective cohort study was performed, including hospitalized subjects with a diagnosis of SARS-CoV-2 pneumonia. Inclusion criteria were: age ≥18 years old with severe COVID-19 disease requiring daily intravenous 6 mg dexamethasone treatment for 10 days. Exclusion criteria were: <18 years old, non-severe illness and/or patients in charge of ICU. Variables related to clinical and analytical parameters, glycemic control, acquired-hospital superinfections, mortality, IMV requirement, ICU admission and length of stay were included. Two hundred and nine individuals with COVID-19 disease treated with dexamethasone were included. One hundred twenty-five out of these subjects (59.8%) were patients with DM. Overall, from the 209 subjects, 66 (31.6%) required IMV or were admitted to the ICU, with significant differences between patients with DM (n=50) vs. patients without DM (n=16) (76% vs. 24%, p=0.002). Among the group of subjects with DM (n=125), those who required IMV or were admitted to the ICU showed higher serum concentrations of C-reactive protein, interleukin-6, D-dimer, ferritin and pro-calcitonin and significantly lower serum concentrations of albumin compared to those who did not require IMV or were not admitted to the ICU. Besides, between these two groups of patients with DM, we observed no differences in glycemic parameters, including median capillary blood glucose values, glycosylated hemoglobin, coefficient of variability and hypoglycemic episodes. In the multinomial analysis, factors independently associated with the composite outcome of IMV or admission to the ICU in the insulin-treated group were the National Early Warning Score (NEWS) 2 score (OR 1.55 [1.17-2.17], p=0.005) and the presence of hospital-acquired superinfections (OR 35.21 [5.11-386.99], p=0.001). In our study, parameters related to glycemic control were not associated with IMV requirement nor admission to the ICU in patients with DM and severe COVID-19 disease receiving daily 6 mg of dexamethasone for 10 days. However, hospital-acquired superinfections and disease severity at admission were independent factors associated with this composite outcome

Pharmacological modulation of SAMHD1 activity by CDK4/6 inhibitors improves anticancer therapy

Funding: This research was funded by Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (FIS) PI16/00103, PI17/00624 and CP14/00016 cofinanced by FEDER. EB is a research fellow from ISCIII-FIS (CP14/00016). EGV, MP, LG are research fellows from Generalitat de Catalunya AGAUR. RB is a research fellow from PERIS, Generalitat de Catalunya (PERIS SLT002/16/00059). IE is a research fellow from la Caixa Bank Foundation (LCF/BQ/IN18/11660017) cofunded by the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 713673.Sterile alpha motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1) is a dNTP triphosphohydrolase involved in the regulation of the intracellular dNTP pool, linked to viral restriction, cancer development and autoimmune disorders. SAMHD1 function is regulated by phosphorylation through a mechanism controlled by cyclin-dependent kinases and tightly linked to cell cycle progression. Recently, SAMHD1 has been shown to decrease the efficacy of nucleotide analogs used as chemotherapeutic drugs. Here, we demonstrate that SAMHD1 can enhance or decrease the efficacy of various classes of anticancer drug, including nucleotide analogues, but also anti-folate drugs and CDK inhibitors. Importantly, we show that selective CDK4/6 inhibitors are pharmacological activators of SAMHD1 that act by inhibiting its inactivation by phosphorylation. Combinations of a CDK4/6 inhibitor with nucleoside or folate antimetabolites potently enhanced drug efficacy, resulting in highly synergic drug combinations (CI < 0.04). Mechanistic analyses reveal that cell cycle-controlled modulation of SAMHD1 function is the central process explaining changes in anticancer drug efficacy, therefore providing functional proof of the potential of CDK4/6 inhibitors as a new class of adjuvants to boost chemotherapeutic regimens. The evaluation of SAMHD1 expression in cancer tissues allowed for the identification of cancer types that would benefit from the pharmacological modulation of SAMHD1 function. In conclusion, these results indicate that the modulation of SAMHD1 function may represent a promising strategy for the improvement of current antimetabolite-based treatment

Unraveling the antiviral activity of plitidepsin against SARS-CoV-2 by subcellular and morphological analysis

The pandemic caused by the new coronavirus SARS-CoV-2 has made evident the need for broad-spectrum, efficient antiviral treatments to combat emerging and re-emerging viruses. Plitidepsin is an antitumor agent of marine origin that has also shown a potent pre-clinical efficacy against SARS-CoV-2. Plitidepsin targets the host protein eEF1A (eukaryotic translation elongation factor 1 alpha) and affects viral infection at an early, post-entry step. Because electron microscopy is a valuable tool to study virus-cell interactions and the mechanism of action of antiviral drugs, in this work we have used transmission electron microscopy (TEM) to evaluate the effects of plitidepsin in SARS-CoV-2 infection in cultured Vero E6 cells 24 and 48h post-infection. In the absence of plitidepsin, TEM morphological analysis showed double-membrane vesicles (DMVs), organelles that support coronavirus genome replication, single-membrane vesicles with viral particles, large vacuoles with groups of viruses and numerous extracellular virions attached to the plasma membrane. When treated with plitidepsin, no viral structures were found in SARS-CoV-2-infected Vero E6 cells. Immunogold detection of SARS-CoV-2 nucleocapsid (N) protein and double-stranded RNA (dsRNA) provided clear signals in cells infected in the absence of plitidepsin, but complete absence in cells infected and treated with plitidepsin. The present study shows that plitidepsin blocks the biogenesis of viral replication organelles and the morphogenesis of virus progeny. Electron microscopy morphological analysis coupled to immunogold labeling of SARS-CoV-2 products offers a unique approach to understand how antivirals such as plitidepsin work.info:eu-repo/semantics/publishedVersio