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Tulika Munshi, Antima Gupta, Dimitrios Evangelopoulos, Juan David Guzman, Simon Gibbons, Nicholas H. Keep, Sanjib Bhakta
PLoS One Infectious Diseases, 27.03.2024
Tilføjet 27.03.2024
by Tulika Munshi, Antima Gupta, Dimitrios Evangelopoulos, Juan David Guzman, Simon Gibbons, Nicholas H. Keep, Sanjib Bhakta
Læs mere Tjek på PubMedCrowell, Trevor A.; Ritz, Justin; Zheng, Lu; Naqvi, Asma; Cyktor, Joshua C.; Puleo, Joseph; Clagett, Brian; Lama, Javier R.; Kanyama, Cecilia; Little, Susan J.; Cohn, Susan E.; Riddler, Sharon A.; Collier, Ann C.; Heath, Sonya L.; Tantivitayakul, Pornphen; Grinsztejn, Beatriz; Arduino, Roberto C.; Rooney, James F.; van Zyl, Gert U.; Coombs, Robert W.; Fox, Lawrence; Ananworanich, Jintanat; Eron, Joseph J.; Sieg, Scott F.; Mellors, John W.; Daar, Eric S.; for the AIDS Clinical Trials Group (ACTG) A5354/EARLIER Study Team
AIDS, 23.03.2024
Tilføjet 23.03.2024
Objective: To assess how antiretroviral therapy (ART) initiation during acute or early HIV infection (AEHI) affects the viral reservoir and host immune responses. Design: Single-arm trial of ART initiation during AEHI at 30 sites in the Americas, Africa, and Asia. Methods: HIV DNA was measured at week 48 of ART in 5 million CD4+ T cells by sensitive qPCR assays targeting HIV gag and pol. Peripheral blood mononuclear cells were stimulated with potential HIV T cell epitope peptide pools consisting of env, gag, nef, and pol peptides and stained for expression of CD3, CD4, CD8, and intracellular cytokines/chemokines. Results: From 2017 to 2019, 188 participants initiated ART during Fiebig stages I (n = 6), II (n = 43), III (n = 56), IV (n = 23), and V (n = 60). Median age was 27 years (interquartile range 23–38), 27 (14%) participants were female, and 180 (97%) cisgender. Among 154 virally suppressed participants at week 48, 100% had detectable HIV gag or pol DNA. Participants treated during Fiebig I had the lowest HIV DNA levels (P 0.025). At week 48, the magnitude, but not polyfunctionality, of HIV-specific T cell responses was moderately reduced among participants who initiated ART earliest. Conclusion: Earlier ART initiation during AEHI reduced but did not eliminate the persistence of HIV-infected cells in blood. These findings explain the rapid viral rebound observed after ART cessation in early-treated individuals with undetectable HIV DNA by less sensitive methods. Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.
Læs mere Tjek på PubMedGrzegorz Dudek, Sebastian Sakowski, Olga Brzezińska, Joanna Sarnik, Tomasz Budlewski, Grzegorz Dragan, Marta Poplawska, Tomasz Poplawski, Michał Bijak, Joanna Makowska
PLoS One Infectious Diseases, 22.03.2024
Tilføjet 22.03.2024
by Grzegorz Dudek, Sebastian Sakowski, Olga Brzezińska, Joanna Sarnik, Tomasz Budlewski, Grzegorz Dragan, Marta Poplawska, Tomasz Poplawski, Michał Bijak, Joanna Makowska Machine learning (ML) algorithms can handle complex genomic data and identify predictive patterns that may not be apparent through traditional statistical methods. They become popular tools for medical applications including prediction, diagnosis or treatment of complex diseases like rheumatoid arthritis (RA). RA is an autoimmune disease in which genetic factors play a major role. Among the most important genetic factors predisposing to the development of this disease and serving as genetic markers are HLA-DRB and non-HLA genes single nucleotide polymorphisms (SNPs). Another marker of RA is the presence of anticitrullinated peptide antibodies (ACPA) which is correlated with severity of RA. We use genetic data of SNPs in four non-HLA genes (PTPN22, STAT4, TRAF1, CD40 and PADI4) to predict the occurrence of ACPA positive RA in the Polish population. This work is a comprehensive comparative analysis, wherein we assess and juxtapose various ML classifiers. Our evaluation encompasses a range of models, including logistic regression, k-nearest neighbors, naïve Bayes, decision tree, boosted trees, multilayer perceptron, and support vector machines. The top-performing models demonstrated closely matched levels of accuracy, each distinguished by its particular strengths. Among these, we highly recommend the use of a decision tree as the foremost choice, given its exceptional performance and interpretability. The sensitivity and specificity of the ML models is about 70% that are satisfying. In addition, we introduce a novel feature importance estimation method characterized by its transparent interpretability and global optimality. This method allows us to thoroughly explore all conceivable combinations of polymorphisms, enabling us to pinpoint those possessing the highest predictive power. Taken together, these findings suggest that non-HLA SNPs allow to determine the group of individuals more prone to develop RA rheumatoid arthritis and further implement more precise preventive approach.
Læs mere Tjek på PubMedIsabel M. BarcelóMaria Escobar-SalomGabriel CabotPau Perelló-BauzàElena Jordana-LluchBiel TaltavullGabriel TorrensEstrella Rojo-MolineroLaura ZamoranoAstrid PérezAntonio OliverCarlos Juan1Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain2Microbiology Department, University Hospital Son Espases (HUSE), Palma, Spain3Centro de Investigación Biomédica en Red, Área Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain4Department of Molecular Biology and Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden5National Center for Microbiology, Instituto de Salud Carlos III (ISCIII), Madrid, Spain, Laurent Poirel
Antimicrobial Agents And Chemotherapy, 22.03.2024
Tilføjet 22.03.2024
Clinical Infectious Diseases, 21.03.2024
Tilføjet 21.03.2024
Clinical Infectious Diseases, 21.03.2024
Tilføjet 21.03.2024
Abstract Background Weight gain and associated metabolic complications are increasingly prevalent among people with HIV (PWH). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin-based therapies for diabetes and weight management that have been shown to result in substantial weight loss; however, studies of their effects in PWH are limited.Methods A retrospective single-center cohort study was conducted among PWH who were taking GLP-1RAs at UC San Diego Owen Clinic between 2/1/2021 to 2/1/2023. Baseline clinical data were collected and changes in weight, body mass index (BMI), and hemoglobin A1C (A1C) before starting GLP-1RAs compared to the most recent clinic visit were calculated (with a minimum of 3 months follow-up time required). Logistic regression was performed to identify variables associated with >5% of total body weight loss.Results A total of 225 patients received on average 13 months of GLP-1RA therapy, with 85 (37.8%) achieving the maximum GLP-1RA dose. GLP-1RA therapy resulted, on average, in a loss of 5.4 kg, decrease in BMI by 1.8 kg/m2, and decrease in A1C by 0.6%. In the multivariable analysis, higher baseline BMI [OR 1.10 (1.03-1.16)], treatment duration of GLP-1RA therapy greater than 6 months [OR 3.12 (1.49-6.49], and use of tirzepatide [OR 5.46 (1.44-20.76)] were significantly more likely to be associated with >5% weight loss.Conclusions Use of GLP-1RAs led to declines in weight, BMI, and hemoglobin A1C among PWH and offers an additional strategy to address weight gain and diabetes.
Læs mere Tjek på PubMedClinical Infectious Diseases, 19.03.2024
Tilføjet 19.03.2024
Somayaji, R., Luke, D. R., Lau, A., Guner, R., Tabak, O. F., Hepokoski, M., Gardetto, N., Conrad, S. A., Kumar, S. D., Ghosh, K., Robbins, S. M., Senger, D. L., Sun, D., Lim, R. K. S., Liu, J., Eser, F., Karaali, R., Tremblay, A., Muruve, D.
BMJ Open, 15.03.2024
Tilføjet 15.03.2024
ObjectiveDipeptidase-1 (DPEP-1) is a recently discovered leucocyte adhesion receptor for neutrophils and monocytes in the lungs and kidneys and serves as a potential therapeutic target to attenuate inflammation in moderate-to-severe COVID-19. We aimed to evaluate the safety and efficacy of the DPEP-1 inhibitor, LSALT peptide, to prevent specific organ dysfunction in patients hospitalised with COVID-19. DesignPhase 2a randomised, placebo-controlled, double-blinded, trial. SettingHospitals in Canada, Turkey and the USA. ParticipantsA total of 61 subjects with moderate-to-severe COVID-19. InterventionsRandomisation to LSALT peptide 5 mg intravenously daily or placebo for up to 14 days. Primary and secondary outcome measuresThe primary endpoint was the proportion of subjects alive and free of respiratory failure and/or the need for renal replacement therapy (RRT). Numerous secondary and exploratory endpoints were assessed including ventilation-free days, and changes in kidney function or serum biomarkers. ResultsAt 28 days, 27 (90.3%) and 28 (93.3%) of subjects in the placebo and LSALT groups were free of respiratory failure and the need for RRT (p=0.86). On days 14 and 28, the number of patients still requiring more intensive respiratory support (O2 ≥6 L/minute, non-invasive or invasive mechanical ventilation or extracorporeal membrane oxygenation) was 6 (19.4%) and 3 (9.7%) in the placebo group versus 2 (6.7%) and 2 (6.7%) in the LSALT group, respectively (p=0.14; p=0.67). Unadjusted analysis of ventilation-free days demonstrated 22.8 days for the LSALT group compared with 20.9 in the placebo group (p=0.4). LSALT-treated subjects had a significant reduction in the fold expression from baseline to end of treatment of serum CXCL10 compared with placebo (p=0.02). Treatment-emergent adverse events were similar between groups. ConclusionIn a Phase 2 study, LSALT peptide was demonstrated to be safe and tolerated in patients hospitalised with moderate-to-severe COVID-19. Trial registration numberNCT04402957.
Læs mere Tjek på PubMedSomayaji, R., Luke, D. R., Lau, A., Guner, R., Tabak, O. F., Hepokoski, M., Gardetto, N., Conrad, S. A., Kumar, S. D., Ghosh, K., Robbins, S. M., Senger, D. L., Sun, D., Lim, R. K. S., Liu, J., Eser, F., Karaali, R., Tremblay, A., Muruve, D.
BMJ Open, 15.03.2024
Tilføjet 15.03.2024
ObjectiveDipeptidase-1 (DPEP-1) is a recently discovered leucocyte adhesion receptor for neutrophils and monocytes in the lungs and kidneys and serves as a potential therapeutic target to attenuate inflammation in moderate-to-severe COVID-19. We aimed to evaluate the safety and efficacy of the DPEP-1 inhibitor, LSALT peptide, to prevent specific organ dysfunction in patients hospitalised with COVID-19. DesignPhase 2a randomised, placebo-controlled, double-blinded, trial. SettingHospitals in Canada, Turkey and the USA. ParticipantsA total of 61 subjects with moderate-to-severe COVID-19. InterventionsRandomisation to LSALT peptide 5 mg intravenously daily or placebo for up to 14 days. Primary and secondary outcome measuresThe primary endpoint was the proportion of subjects alive and free of respiratory failure and/or the need for renal replacement therapy (RRT). Numerous secondary and exploratory endpoints were assessed including ventilation-free days, and changes in kidney function or serum biomarkers. ResultsAt 28 days, 27 (90.3%) and 28 (93.3%) of subjects in the placebo and LSALT groups were free of respiratory failure and the need for RRT (p=0.86). On days 14 and 28, the number of patients still requiring more intensive respiratory support (O2 ≥6 L/minute, non-invasive or invasive mechanical ventilation or extracorporeal membrane oxygenation) was 6 (19.4%) and 3 (9.7%) in the placebo group versus 2 (6.7%) and 2 (6.7%) in the LSALT group, respectively (p=0.14; p=0.67). Unadjusted analysis of ventilation-free days demonstrated 22.8 days for the LSALT group compared with 20.9 in the placebo group (p=0.4). LSALT-treated subjects had a significant reduction in the fold expression from baseline to end of treatment of serum CXCL10 compared with placebo (p=0.02). Treatment-emergent adverse events were similar between groups. ConclusionIn a Phase 2 study, LSALT peptide was demonstrated to be safe and tolerated in patients hospitalised with moderate-to-severe COVID-19. Trial registration numberNCT04402957.
Læs mere Tjek på PubMedSomayaji, R., Luke, D. R., Lau, A., Guner, R., Tabak, O. F., Hepokoski, M., Gardetto, N., Conrad, S. A., Kumar, S. D., Ghosh, K., Robbins, S. M., Senger, D. L., Sun, D., Lim, R. K. S., Liu, J., Eser, F., Karaali, R., Tremblay, A., Muruve, D.
BMJ Open, 15.03.2024
Tilføjet 15.03.2024
ObjectiveDipeptidase-1 (DPEP-1) is a recently discovered leucocyte adhesion receptor for neutrophils and monocytes in the lungs and kidneys and serves as a potential therapeutic target to attenuate inflammation in moderate-to-severe COVID-19. We aimed to evaluate the safety and efficacy of the DPEP-1 inhibitor, LSALT peptide, to prevent specific organ dysfunction in patients hospitalised with COVID-19. DesignPhase 2a randomised, placebo-controlled, double-blinded, trial. SettingHospitals in Canada, Turkey and the USA. ParticipantsA total of 61 subjects with moderate-to-severe COVID-19. InterventionsRandomisation to LSALT peptide 5 mg intravenously daily or placebo for up to 14 days. Primary and secondary outcome measuresThe primary endpoint was the proportion of subjects alive and free of respiratory failure and/or the need for renal replacement therapy (RRT). Numerous secondary and exploratory endpoints were assessed including ventilation-free days, and changes in kidney function or serum biomarkers. ResultsAt 28 days, 27 (90.3%) and 28 (93.3%) of subjects in the placebo and LSALT groups were free of respiratory failure and the need for RRT (p=0.86). On days 14 and 28, the number of patients still requiring more intensive respiratory support (O2 ≥6 L/minute, non-invasive or invasive mechanical ventilation or extracorporeal membrane oxygenation) was 6 (19.4%) and 3 (9.7%) in the placebo group versus 2 (6.7%) and 2 (6.7%) in the LSALT group, respectively (p=0.14; p=0.67). Unadjusted analysis of ventilation-free days demonstrated 22.8 days for the LSALT group compared with 20.9 in the placebo group (p=0.4). LSALT-treated subjects had a significant reduction in the fold expression from baseline to end of treatment of serum CXCL10 compared with placebo (p=0.02). Treatment-emergent adverse events were similar between groups. ConclusionIn a Phase 2 study, LSALT peptide was demonstrated to be safe and tolerated in patients hospitalised with moderate-to-severe COVID-19. Trial registration numberNCT04402957.
Læs mere Tjek på PubMedClinical Infectious Diseases, 14.03.2024
Tilføjet 14.03.2024
Abstract Background A next-generation Vero cell rabies vaccine (PVRV-NG2) was developed using the same Pitman–Moore strain as in the licensed purified Vero cell vaccine (PVRV; Verorab®) and the human diploid cell vaccine (HDCV; Imovax Rabies®).Methods This dual-center, modified double-blind, phase III study in France evaluated immunogenic non-inferiority and safety of PVRV-NG2 with and without concomitant intramuscular human rabies immunoglobulin (HRIG), compared with PVRV+HRIG and HDCV+HRIG, in a simulated post-exposure prophylaxis (PEP) regimen. Healthy adults ≥18 years old (N=640) were randomized 3:1:1:1 to receive PVRV-NG2+HRIG, PVRV+HRIG, HDCV+HRIG, or PVRV-NG2 alone (administered as single vaccine injections on days [D] 0, 3, 7, 14, and 28, with HRIG administered on D0 in applicable groups). Rabies virus neutralizing antibodies (RVNA titers) were assessed pre- (D0) and post-vaccination (D14, D28, and D42) using the rapid fluorescent focus inhibition test. Non-inferiority, based on the proportion of participants achieving RVNA titers ≥0.5 IU/mL (primary objective), was demonstrated if the lower limit of the 95% CI of the difference in proportions between PVRV-NG2+HRIG and PVRV+HRIG/HDCV+HRIG was >−5% at D28. Safety was assessed up to 6 months after the last injection.Results The non-inferiority of PVRV-NG2+HRIG, compared with PVRV+HRIG and HDCV+HRIG, was demonstrated. Nearly all participants (99.6%, PVRV-NG2+HRIG; 100%, PVRV+HRIG; 98.7%, HDCV+HRIG; 100%, PVRV-NG2 alone) achieved RVNA titers ≥0.5 IU/mL at D28. Geometric mean titers were similar between groups with concomitant HRIG administration at all time points. Safety profiles were similar between PVRV-NG2 and comparator vaccines.Conclusions In a simulated PEP setting, PVRV-NG2+HRIG showed comparable immunogenicity and safety to current standard-of-care vaccines.Clinical Trials Registration NCT03965962.
Læs mere Tjek på PubMedMalaria Journal, 14.03.2024
Tilføjet 14.03.2024
Abstract Background The Great Mekong Subregion has attained a major decline in malaria cases and fatalities over the last years, but residual transmission hotspots remain, supposedly fueled by forest workers and migrant populations. This study aimed to: (i) characterize the fine-scale mobility of forest-goers and understand links between their daily movement patterns and malaria transmission, using parasites detection via real time polymerase chain reaction (RT PCR) and the individual exposure to Anopheles bites by quantification of anti-Anopheles saliva antibodies via enzyme-linked immunosorbent assay; (ii) assess the concordance of questionnaires and Global Positioning System (GPS) data loggers for measuring mobility. Methods Two 28 day follow-ups during dry and rainy seasons, including a GPS tracking, questionnaires and health examinations, were performed on male forest goers representing the population at highest risk of infection. Their time spent in different land use categories and demographic data were analyzed in order to understand the risk factors driving malaria in the study area. Results Malaria risk varied with village forest cover and at a resolution of only a few kilometers: participants from villages outside the forest had the highest malaria prevalence compared to participants from forest fringe’s villages. The time spent in a specific environment did not modulate the risk of malaria, in particular the time spent in forest was not associated with a higher probability to detect malaria among forest-goers. The levels of antibody response to Anopheles salivary peptide among participants were significantly higher during the rainy season, in accordance with Anopheles mosquito density variation, but was not affected by sociodemographic and mobility factors. The agreement between GPS and self-reported data was only 61.9% in reporting each kind of visited environment. Conclusions In a context of residual malaria transmission which was mainly depicted by P. vivax asymptomatic infections, the implementation of questionnaires, GPS data-loggers and quantification of anti-saliva Anopheles antibodies on the high-risk group were not powerful enough to detect malaria risk factors associated with different mobility behaviours or time spent in various environments. The joint implementation of GPS trackers and questionnaires allowed to highlight the limitations of both methodologies and the benefits of using them together. New detection and follow-up strategies are still called for.
Læs mere Tjek på PubMedJi Woong Kim, Ji Hyun Lee, Hyun Jung Kim, Kyun Heo, Yoonwoo Lee, Hui Jeong Jang, Ho‐Young Lee, Jun Won Park, Yea Bin Cho, Ha Gyeong Shin, Ha Rim Yang, Hee Eon Lee, Jin Young Song, Sukmook Lee
Journal of Medical Virology, 7.03.2024
Tilføjet 7.03.2024
Zhiyi LiaoChaoming WangXiaopeng TangMengli YangZilei DuanLei LiuShuaiyao LuLei MaRuomei ChengGan WangHongqi LiuShuo YangJingwen XuDawit Adisu TadeseJames MwangiPeter Muiruri KamauZhiye ZhangLian YangGuoyang LiaoXudong ZhaoXiaozhong PengRen LaiaEngineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology-Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), and Sino-African Joint Research Center, New Cornerstone Science Laboratory, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming 650201, ChinabKunming College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, ChinacSchool of Basic Medicine, Qingdao University, Qingdao 266071, ChinadInstitute of Medical Biology, Chinese Academy of Medical Sciences, Kunming 650118, ChinaeLaboratory of Animal Tumor Models, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, ChinafKunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China
Proceedings of the National Academy of Sciences, 6.03.2024
Tilføjet 6.03.2024
Proceedings of the National Academy of Sciences, Volume 121, Issue 10, March 2024.
Læs mere Tjek på PubMedJournal of Infectious Diseases, 5.03.2024
Tilføjet 5.03.2024
Abstract We previously described a novel Plasmodium vivax invasion mechanism into human reticulocytes via the PvRBP2a-CD98 receptor-ligand pair. We assessed the PvRBP2a epitopes involved in CD98 binding and recognised by antibodies from infected patients using linear epitope mapping. We identified two epitope clusters mediating PvRBP2a-CD98 interaction. One cluster named cluster B (PvRBP2a431-448, TAALKEKGKLLANLYNKL) was the target of antibody responses in P. vivax-infected humans. Peptides from each cluster were able to prevent live parasite invasion of human reticulocytes. These results provide new insights for development of a malaria blood stage vaccine against P. vivax.
Læs mere Tjek på PubMedWiseman, Robyn L.; Bigos, Kristin L.; Dastgheyb, Raha M.; Barker, Peter B.; Rubin, Leah H.; Slusher, Barbara S.
AIDS, 2.03.2024
Tilføjet 2.03.2024
Objectives : Cognitive impairment persists in virally-suppressed people with HIV (VS-PWH) especially in higher order domains. One cortical circuit, linked to these domains, is regulated by N-acetyl-aspartyl glutamate (NAAG), the endogenous agonist of the metabotropic glutamate receptor 3. The enzyme glutamate carboxypeptidase II (GCPII) catabolizes NAAG and is upregulated in aging and disease. Inhibition of GCPII increases brain NAAG and improves learning and memory in rodent and primate models. Design: As higher-order cognitive impairment is present in VS-PWH, and NAAG has not been investigated in earlier magnetic resonance spectroscopy studies (MRS), we investigated if brain NAAG levels measured by MRS were associated with cognitive function. Methods: We conducted a retrospective analysis of 7-Tesla MRS data from a previously published study on cognition in older VS-PWH. The original study did not separately quantify NAAG, therefore work for this report focused on relationships between regional NAAG levels in frontal white matter (FWM), left hippocampus, left basal ganglia and domain-specific cognitive performance in 40 VS-PWH after adjusting for confounds. Participants were >50 years of age, negative for affective and neurologic disorders, and had no prior 3-month psychoactive-substance use. Results: Higher NAAG levels in FWM were associated with better attention/working memory. Higher left basal ganglia NAAG related to better verbal fluency. There was a positive relationship between hippocampal NAAG and executive function which lost significance after correction for confounds. Conclusions: These data suggest brain NAAG serves as a biomarker of cognition in VS-PWH. Pharmacological modulation of brain NAAG warrants investigation as a therapeutic approach for cognitive deficits in VS-PWH. Conclusions: These data suggest brain NAAG serves as a biomarker of cognition in VS-PWH. Pharmacological modulation of brain NAAG warrants investigation as a therapeutic approach for cognitive deficits in VS-PWH. Graphical_abstract http://links.lww.com/QAD/D137 Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.
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