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HIV screening and retention in care in people who use drugs in Madrid, Spain: a prospective study

Background: The burden of human immunodeficiency virus (HIV) infection in people who use drugs (PWUD) is significant. We aimed to screen HIV infection among PWUD and describe their retention in HIV care. Besides, we also screen for hepatitis C virus (HCV) infection among HIV-seropositive PWUD and describe their linkage to care. Methods: We conducted a prospective study in 529 PWUD who visited the "Cañada Real Galiana" (Madrid, Spain). The study period was from June 1, 2017, to May 31, 2018. HIV diagnosis was performed with a rapid antibody screening test at the point-of-care (POC) and HCV diagnosis with immunoassay and PCR tests on dried blood spot (DBS) in a central laboratory. Positive PWUD were referred to the hospital. We used the Chi-square or Fisher's exact tests, as appropriate, to compare rates between groups. Results: Thirty-five (6.6%) participants were positive HIV antibodies, but 34 reported previous HIV diagnoses, and 27 (76%) had prior antiretroviral therapy. Among patients with a positive HIV antibody test, we also found a higher prevalence of homeless (P < 0.001) and injection drug use (PWID) (P < 0.001), and more decades of drug use (P = 0.002). All participants received HIV test results at the POC. Of the 35 HIV positives, 28 (80%) were retained in HIV medical care at the end of the HIV screening study (2018), and only 22 (62.9%) at the end of 2020. Moreover, 12/35 (34.3%) were positive for the HCV RNA test. Of the latter, 10/12 (83.3%) were contacted to deliver the HCV results test (delivery time of 19 days), 5/12 (41.7%) had an appointment and were attended at the hospital and started HCV therapy, and only 4/12 (33.3%) cleared HCV. Conclusions: We found almost no new HIV-infected PWUD, but their cascade of HIV care was low and remains a challenge in this population at risk. The high frequency of active hepatitis C in HIV-infected PWUD reflects the need for HCV screening and reinforcing the link to care.This work was funded by a research grant from Merck Sharpe & Dohme (Grant Number MISP IIS#54846) and Instituto de Salud Carlos III (ISCII; Grant Numbers PI20CIII/00004, and RD16CIII/0002/0002 to SR). The funders had no role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript.S

School climate and ethnicâ racial identity in school: A longitudinal examination of reciprocal associations

The messages youth receive in schools about how they matter as individuals and as members of ethnicâ racial groups are influential in constructing their developing ethnicâ racial identities (ERI). However, the developing ERI students hold also have a role in shaping their experiences at school. The current study examined the longitudinal and reciprocal association between ERI (exploration and resolution) and school climate (support for cultural pluralism and teacher supportiveness) among 491 Black, Latino, and White middle school youth (Mage = 12.03, SD = 1.05, range: 11â 17) in the Midwest. Crossâ lagged analyses revealed that greater perceptions of support for cultural pluralism within the school predicted greater exploration and resolution at later time points for all students. Moreover, greater exploration and resolution among White students was predictive of greater perceptions of support for cultural pluralism at the school. Higher quality teacherâ student relationships predicted greater engagement in ERI exploration for all youth. The findings highlight the importance of school climate in helping shape ERI among youth attending a culturally diverse school and the role of such youth in shaping the climate at their school.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141725/1/casp2338_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141725/2/casp2338.pd

Modulation of human macrophage responses to mycobacterium tuberculosis by silver nanoparticles of different size and surface modification

Exposure to silver nanoparticles (AgNP) used in consumer products carries potential health risks including increased susceptibility to infectious pathogens. Systematic assessments of antimicrobial macrophage immune responses in the context of AgNP exposure are important because uptake of AgNP by macrophages may lead to alterations of innate immune cell functions. In this study we examined the effects of exposure to AgNP with different particle sizes (20 and 110 nm diameters) and surface chemistry (citrate or polyvinlypyrrolidone capping) on cellular toxicity and innate immune responses against Mycobacterium tuberculosis (M.tb) by human monocyte-derived macrophages (MDM). Exposures of MDM to AgNP significantly reduced cellular viability, increased IL8 and decreased IL10 mRNA expression. Exposure of M.tb-infected MDM to AgNP suppressed M.tb-induced expression of IL1B, IL10, and TNFA mRNA. Furthermore, M.tb-induced IL-1β, a cytokine critical for host resistance to M.tb, was inhibited by AgNP but not by carbon black particles indicating that the observed immunosuppressive effects of AgNP are particle specific. Suppressive effects of AgNP on the M.tb-induced host immune responses were in part due to AgNP-mediated interferences with the TLR signaling pathways that culminate in the activation of the transcription factor NF-κB. AgNP exposure suppressed M.tb-induced expression of a subset of NF-κB mediated genes (CSF2, CSF3, IFNG, IL1A, IL1B, IL6, IL10, TNFA, NFKB1A). In addition, AgNP exposure increased the expression of HSPA1A mRNA and the corresponding stress-induced Hsp72 protein. Up-regulation of Hsp72 by AgNP can suppress M.tb-induced NF-κB activation and host immune responses. The observed ability of AgNP to modulate infectious pathogen-induced immune responses has important public health implications

Detection of active hepatitis C in a single visit and linkage to care among marginalized people using a mobile unit in Madrid, Spain

Background: The burden of hepatitis C virus (HCV) infection among marginalized people in Spain is high, despite the fact that HCV prevalence has decreased in recent years. We aimed to assess the effectiveness of a simplified point-of-care (PoC) model for screening for active HCV infection via a mobile unit and subsequent linkage to care with the assistance of navigators. Methods: We carried out a prospective study on 2001 participants from Madrid, Spain. A nurse and a navigator/educator screened for hepatitis C in a mobile unit, using the OraQuick HCV Rapid Antibody Test and Xpert HCV VL Fingerstick assay. Participants with active HCV were referred to the hospital the same day with a navigator for evaluation and treatment of HCV. Results: Overall, 1621 (81%) participants had not been exposed to HCV, 380 (18.9%) were positive for HCV antibodies, and 136 (6.8%) had active hepatitis C. Among the latter, 134 (98.5%) received the HCV screening results, 133 (97.8%) had an appointment at the hospital, 126 (92.8%) were seen by a physician once they were at the hospital, and 105 (77.2%) started HCV treatment. Being over 50 years old and a person who uses drugs, particularly people who inject drugs (PWID), was directly associated with active hepatitis C (p<0.05). PWID were the only patients with HCV reinfection (4.3% in people without recent injecting drug use and 5.9% in people with recent injecting drug use). Among PWID, no income and daily alcohol intake were also directly associated with active hepatitis C. People with recent injecting drug use showed the lowest rates of attendance at the hospital (91.8%) and starting HCV treatment (70.4%). Conclusion: HCV screening using a two-step PoC-based strategy and its linkage to care was extremely efficient for identifying and treating marginalized people with active hepatitis C, thanks to the use of a mobile unit with personnel and technical equipment, an interdisciplinary team, and collaboration between institutions.This work was funded by a research grant from Gilead Science (IN-ES-987-5391 and GLD20_0144) and Instituto de Salud Carlos III (ISCII; grant numbers PI20CIII/00004 and RD16CIII/0002/0002 to SR). It also received funding from AbbVie, Asociación Española para Estudio del Higado (AEEH), and Madrid Positivo Association.S

Entropic Tension in Crowded Membranes

Unlike their model membrane counterparts, biological membranes are richly decorated with a heterogeneous assembly of membrane proteins. These proteins are so tightly packed that their excluded area interactions can alter the free energy landscape controlling the conformational transitions suffered by such proteins. For membrane channels, this effect can alter the critical membrane tension at which they undergo a transition from a closed to an open state, and therefore influence protein function \emph{in vivo}. Despite their obvious importance, crowding phenomena in membranes are much less well studied than in the cytoplasm. Using statistical mechanics results for hard disk liquids, we show that crowding induces an entropic tension in the membrane, which influences transitions that alter the projected area and circumference of a membrane protein. As a specific case study in this effect, we consider the impact of crowding on the gating properties of bacterial mechanosensitive membrane channels, which are thought to confer osmoprotection when these cells are subjected to osmotic shock. We find that crowding can alter the gating energies by more than $2\;k_BT$ in physiological conditions, a substantial fraction of the total gating energies in some cases. Given the ubiquity of membrane crowding, the nonspecific nature of excluded volume interactions, and the fact that the function of many membrane proteins involve significant conformational changes, this specific case study highlights a general aspect in the function of membrane proteins.Comment: 20 pages (inclduing supporting information), 4 figures, to appear in PLoS Comp. Bio

Erratum: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.

This corrects the article DOI: 10.1038/sdata.2017.179

Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase

Plasmodium falciparum (<i>Pf</i>) prolyl-tRNA synthetase (ProRS) is one of the few chemical-genetically validated drug targets for malaria, yet highly selective inhibitors have not been described. In this paper, approximately 40,000 compounds were screened to identify compounds that selectively inhibit <i>Pf</i>ProRS enzyme activity versus Homo sapiens (<i>Hs</i>) ProRS. X-ray crystallography structures were solved for apo, as well as substrate- and inhibitor-bound forms of <i>Pf</i>ProRS. We identified two new inhibitors of <i>Pf</i>ProRS that bind outside the active site. These two allosteric inhibitors showed >100 times specificity for <i>Pf</i>ProRS compared to <i>Hs</i>ProRS, demonstrating this class of compounds could overcome the toxicity related to <i>Hs</i>ProRS inhibition by halofuginone and its analogues. Initial medicinal chemistry was performed on one of the two compounds, guided by the cocrystallography of the compound with <i>Pf</i>ProRS, and the results can instruct future medicinal chemistry work to optimize these promising new leads for drug development against malaria