Laisa Bonafim Negri, William Farinelli, Sandeep Korupolu, Ying Wang, Yara Mannaa, Hang Lee, Jie Hui, Pu-Ting Dong, Andrea Slate, Joshua Tam, R Rox Anderson, Seok-Hyun Andy Yun, Jeffrey A Gelfand
We developed a translational prototype antimicrobial blue light (ABL) device for treating skin wounds with ABL. Partial-thickness surgical wounds were created in live swine, an animal whose skin is considered the most like human skin, then heavily contaminated and left untreated for 24 hours with methicillin-resistant Staphylococcus aureus (MRSA). ABL treatment stabilized and reduced MRSA infection by greater than four orders of magnitude (>99.99%; p<0.0001) compared with untreated wounds in the same animal, after only two daily treatments. These data support further development of such devices for controlling infection in skin wounds. ABL, with or without concomitant administration of negative pressure, antimicrobials, or photosensitizers, could play an important role in modern wound care by reducing the amount, duration, and cost of antibiotics needed, helping reduce AMR. No such device for treating human cutaneous wounds currently exists. This deserves further development and study.
{"title":"An antimicrobial blue light prototype device controls infected wounds in a preclinical porcine model","authors":"Laisa Bonafim Negri, William Farinelli, Sandeep Korupolu, Ying Wang, Yara Mannaa, Hang Lee, Jie Hui, Pu-Ting Dong, Andrea Slate, Joshua Tam, R Rox Anderson, Seok-Hyun Andy Yun, Jeffrey A Gelfand","doi":"10.1093/infdis/jiae548","DOIUrl":"https://doi.org/10.1093/infdis/jiae548","url":null,"abstract":"We developed a translational prototype antimicrobial blue light (ABL) device for treating skin wounds with ABL. Partial-thickness surgical wounds were created in live swine, an animal whose skin is considered the most like human skin, then heavily contaminated and left untreated for 24 hours with methicillin-resistant Staphylococcus aureus (MRSA). ABL treatment stabilized and reduced MRSA infection by greater than four orders of magnitude (&gt;99.99%; p&lt;0.0001) compared with untreated wounds in the same animal, after only two daily treatments. These data support further development of such devices for controlling infection in skin wounds. ABL, with or without concomitant administration of negative pressure, antimicrobials, or photosensitizers, could play an important role in modern wound care by reducing the amount, duration, and cost of antibiotics needed, helping reduce AMR. No such device for treating human cutaneous wounds currently exists. This deserves further development and study.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gustaf Ulfhammer, Aylin Yilmaz, Åsa Mellgren, Erika Tyrberg, Erik Sörstedt, Lars Hagberg, Johanna Gostner, Dietmar Fuchs, Henrik Zetterberg, Staffan Nilsson, Kristina Nyström, Arvid Edén, Magnus Gisslén
Background The incidence and clinical relevance of asymptomatic cerebrospinal fluid escape (CSF-E) during antiretroviral therapy (ART) is uncertain. We examined the impact and incidence of asymptomatic CSF-E in a Swedish HIV cohort. Methods Neuroasymptomatic people living with HIV (PLWH) who have been on ART for at least six months with suppressed plasma viral load were followed longitudinally. CSF-E was defined as either increased CSF HIV-1 RNA with concurrent plasma suppression or as CSF HIV-1 RNA exceeding that in plasma when both were quantifiable. Paired CSF and plasma were analyzed for HIV-1 RNA, neopterin, neurofilament light protein (NfL), white blood cell (WBC) count, and albumin ratio. Results Asymptomatic CSF-E (cut-off 50 copies/mL) was found in 4/173 PLWH (2%) and 5/449 samples (1%). The corresponding proportions were 8% of PLWH and 4% for samples using a 20 copies/mL cut-off for CSF HIV-1 RNA. CSF-E samples (cut-off 20 copies/mL) had a 25% higher geometric mean of CSF neopterin (P = .01) and 8% higher albumin ratio (P = .04) compared to samples without CSF-E. No differences were observed in CSF NfL levels (P = .8). The odds ratio for increased CSF WBC (≥ 3 cells/μL) in samples with CSF-E was 3.9 (P = .004), compared to samples without elevated CSF viral load. Conclusion Asymptomatic CSF-E was identified in only four (2%) PLWH, with no cases of continuous CSF-E observed. Increased CSF HIV-1 RNA was associated with biomarkers of CNS immune activation and blood-brain-barrier impairment, but not with biomarkers of neuronal injury.
{"title":"Asymptomatic Cerebrospinal Fluid HIV-1 Escape: Incidence and Consequences","authors":"Gustaf Ulfhammer, Aylin Yilmaz, Åsa Mellgren, Erika Tyrberg, Erik Sörstedt, Lars Hagberg, Johanna Gostner, Dietmar Fuchs, Henrik Zetterberg, Staffan Nilsson, Kristina Nyström, Arvid Edén, Magnus Gisslén","doi":"10.1093/infdis/jiae555","DOIUrl":"https://doi.org/10.1093/infdis/jiae555","url":null,"abstract":"Background The incidence and clinical relevance of asymptomatic cerebrospinal fluid escape (CSF-E) during antiretroviral therapy (ART) is uncertain. We examined the impact and incidence of asymptomatic CSF-E in a Swedish HIV cohort. Methods Neuroasymptomatic people living with HIV (PLWH) who have been on ART for at least six months with suppressed plasma viral load were followed longitudinally. CSF-E was defined as either increased CSF HIV-1 RNA with concurrent plasma suppression or as CSF HIV-1 RNA exceeding that in plasma when both were quantifiable. Paired CSF and plasma were analyzed for HIV-1 RNA, neopterin, neurofilament light protein (NfL), white blood cell (WBC) count, and albumin ratio. Results Asymptomatic CSF-E (cut-off 50 copies/mL) was found in 4/173 PLWH (2%) and 5/449 samples (1%). The corresponding proportions were 8% of PLWH and 4% for samples using a 20 copies/mL cut-off for CSF HIV-1 RNA. CSF-E samples (cut-off 20 copies/mL) had a 25% higher geometric mean of CSF neopterin (P = .01) and 8% higher albumin ratio (P = .04) compared to samples without CSF-E. No differences were observed in CSF NfL levels (P = .8). The odds ratio for increased CSF WBC (≥ 3 cells/μL) in samples with CSF-E was 3.9 (P = .004), compared to samples without elevated CSF viral load. Conclusion Asymptomatic CSF-E was identified in only four (2%) PLWH, with no cases of continuous CSF-E observed. Increased CSF HIV-1 RNA was associated with biomarkers of CNS immune activation and blood-brain-barrier impairment, but not with biomarkers of neuronal injury.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"159 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Josephine Mak, Sana Khan, Amadea Britton, Spencer Rose, Lisa Gwynn, Katherine D Ellingson, Jennifer Meece, Leora Feldstein, Harmony Tyner, Laura Edwards, Matthew S Thiese, Allison Naleway, Manjusha Gaglani, Natasha Solle, Jefferey L Burgess, Julie Mayo Lamberte, Meghan Shea, Taryn Hunt-Smith, Alberto Caban-Martinez, Cynthia Porter, Ryan Wiegand, Ramona Rai, Kurt T Hegmann, James Hollister, Ashley Fowlkes, Meredith Wesley, Andrew L Philips, Patrick Rivers, Robin Bloodworth, Gabriella Newes-Adeyi, Lauren E W Olsho, Sarang K Yoon, Sharon Saydah, Karen Lutrick
Background While there is evidence that COVID-19 vaccination protects against development of post-COVID conditions (PCC) after severe infection data are limited on whether vaccination reduces the risk after cases of less-severe non-hospitalized COVID-19 disease with more recent SARS-CoV-2 variant viruses. This study assessed whether COVID-19 vaccination was protective against subsequent development of PCC in persons with predominantly mild initial infections during both Delta and Omicron variant predominance. Methods This study utilized a case-control design, nested within the HEROES-RECOVER cohort. Participants aged ≥18 years with PCR-confirmed SARS-CoV-2 infection between 6/28/2021 and 9/14/2022 were surveyed for PCC, defined by symptoms lasting >1 month after initial infection Cases were participants self-reporting PCC and controls were participants that did not self-report PCC. The exposure was mRNA COVID-19 vaccination (2 or 3 monovalent doses) versus no COVID-19 vaccination. Logistic regression was used to compare the odds of PCC among vaccinated and unvaccinated persons; additional analyses evaluating PCC subtypes were also performed. Results A total of 936 participants with documented SARS-CoV-2 infection were included; of these 23.6% (221) reported PCC and 83.3% (779) were vaccinated. Participants who received a 3rd COVID-19 monovalent mRNA dose prior to infection had lower odds of PCC-related gastrointestinal, neurological, and other symptoms compared to unvaccinated participants (aOR: 0.37; 95% CI: 0.16-0.85; aOR: 0.56; 95% CI: 0.32-0.97; aOR:0.48; 95% CI: 0.25-0.91). Conclusions COVID-19 vaccination protected against development of PCC among persons with mild infection during both Delta and Omicron variant predominance, supporting vaccination as an important tool for PCC prevention.
{"title":"Association of mRNA COVID-19 vaccination and reductions in Post-COVID Conditions following SARS-CoV-2 infection in a US prospective cohort of essential workers","authors":"Josephine Mak, Sana Khan, Amadea Britton, Spencer Rose, Lisa Gwynn, Katherine D Ellingson, Jennifer Meece, Leora Feldstein, Harmony Tyner, Laura Edwards, Matthew S Thiese, Allison Naleway, Manjusha Gaglani, Natasha Solle, Jefferey L Burgess, Julie Mayo Lamberte, Meghan Shea, Taryn Hunt-Smith, Alberto Caban-Martinez, Cynthia Porter, Ryan Wiegand, Ramona Rai, Kurt T Hegmann, James Hollister, Ashley Fowlkes, Meredith Wesley, Andrew L Philips, Patrick Rivers, Robin Bloodworth, Gabriella Newes-Adeyi, Lauren E W Olsho, Sarang K Yoon, Sharon Saydah, Karen Lutrick","doi":"10.1093/infdis/jiae556","DOIUrl":"https://doi.org/10.1093/infdis/jiae556","url":null,"abstract":"Background While there is evidence that COVID-19 vaccination protects against development of post-COVID conditions (PCC) after severe infection data are limited on whether vaccination reduces the risk after cases of less-severe non-hospitalized COVID-19 disease with more recent SARS-CoV-2 variant viruses. This study assessed whether COVID-19 vaccination was protective against subsequent development of PCC in persons with predominantly mild initial infections during both Delta and Omicron variant predominance. Methods This study utilized a case-control design, nested within the HEROES-RECOVER cohort. Participants aged ≥18 years with PCR-confirmed SARS-CoV-2 infection between 6/28/2021 and 9/14/2022 were surveyed for PCC, defined by symptoms lasting &gt;1 month after initial infection Cases were participants self-reporting PCC and controls were participants that did not self-report PCC. The exposure was mRNA COVID-19 vaccination (2 or 3 monovalent doses) versus no COVID-19 vaccination. Logistic regression was used to compare the odds of PCC among vaccinated and unvaccinated persons; additional analyses evaluating PCC subtypes were also performed. Results A total of 936 participants with documented SARS-CoV-2 infection were included; of these 23.6% (221) reported PCC and 83.3% (779) were vaccinated. Participants who received a 3rd COVID-19 monovalent mRNA dose prior to infection had lower odds of PCC-related gastrointestinal, neurological, and other symptoms compared to unvaccinated participants (aOR: 0.37; 95% CI: 0.16-0.85; aOR: 0.56; 95% CI: 0.32-0.97; aOR:0.48; 95% CI: 0.25-0.91). Conclusions COVID-19 vaccination protected against development of PCC among persons with mild infection during both Delta and Omicron variant predominance, supporting vaccination as an important tool for PCC prevention.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"158 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mathilde Hénaut, Julie Carbonneau, Inès Levade, Guy Boivin
The fitness of SARS-CoV-2 Omicron subvariants was determined in human epithelial and continuous cells of the respiratory and gastrointestinal tracts. Competition experiments over 4 days were performed followed by quantification of variant ratios by reverse transcription-droplet digital PCR. These quantitative data were correlated with whole genome sequencing. In competition experiments of two subvariants, the more recent XBB.1 subvariant outcompeted the BA.1.15 subvariant at early time points in the upper respiratory tract epithelium. No difference in replication was observed between the two subvariants in the lower respiratory tract. Furthermore, XBB.1 predominated over BA.1.15 and JN.1.1 subvariants in the gastrointestinal tract.
{"title":"Fitness of SARS-CoV-2 Omicron subvariants in respiratory and gastrointestinal cell lines as determined by RT-ddPCR and whole genome sequencing","authors":"Mathilde Hénaut, Julie Carbonneau, Inès Levade, Guy Boivin","doi":"10.1093/infdis/jiae554","DOIUrl":"https://doi.org/10.1093/infdis/jiae554","url":null,"abstract":"The fitness of SARS-CoV-2 Omicron subvariants was determined in human epithelial and continuous cells of the respiratory and gastrointestinal tracts. Competition experiments over 4 days were performed followed by quantification of variant ratios by reverse transcription-droplet digital PCR. These quantitative data were correlated with whole genome sequencing. In competition experiments of two subvariants, the more recent XBB.1 subvariant outcompeted the BA.1.15 subvariant at early time points in the upper respiratory tract epithelium. No difference in replication was observed between the two subvariants in the lower respiratory tract. Furthermore, XBB.1 predominated over BA.1.15 and JN.1.1 subvariants in the gastrointestinal tract.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"62 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Johannes Schulte, Andreas Maurer, Lisa-Charlotte Domogalla, Nils Steinacker, Carolin Wadle, Johannes Kinzler, Matthias Eder, Constantin von zur Mühlen, Marvin Krohn-Grimberghe, Ann-Christin Eder
Background To the present day infective endocarditis (IE) represents a life-threatening disease with high mortality rate especially when caused by Staphylococcus aureus (S. aureus), the most common causative pathogen in this disease. Diagnosis of IE is based on clinical manifestations, pathogen detection by blood cultures and echocardiographic or other imaging findings. However, none of the methods used is capable of detecting the causative bacterial cells on the endothelium directly. Modern molecular imaging such as positron emission tomography/computed tomography (PET/CT) is playing an increasingly important role in unclear IE cases. This study focused on 2-[18F]F-p-aminobenzoic acid (2-[18F]F-PABA), a bacteria specific tracer for the diagnosis of IE using PET imaging for direct pathogen detection. Methods In vitro assays were performed to analyze 2-[18F]F-PABA uptake by S. aureus. For proof-of-concept in vivo trials an endocarditis mouse model was used to diagnose IE by PET/Magnetic resonance (MR) imaging. A subcutaneous abscess mouse model was supplemented to create larger bacterial vegetations for PET imaging. Results 2-[18F]F-PABA in vitro uptake by S. aureus was confirmed. Only living bacteria were able to accumulate the tracer while the extent of uptake varied between different S. aureus strains. In the in vivo proof-of-concept, IE was visualized in mice using 2-[18F]F-PABA-PET/MR imaging. Subsequently, 2-[18F]F-PABA specifically located S. aureus vegetations in the subcutaneous abscess model. Conclusions This study highlights the great potential of 2-[18F]F-PABA imaging for the direct detection of IE. Future studies might further investigate the clinical potential of this molecular imaging approach, finally aiming at a clinical implementation.
{"title":"2-[18F]F-p-aminobenzoic acid specifically detects infective endocarditis in positron emission tomography","authors":"Johannes Schulte, Andreas Maurer, Lisa-Charlotte Domogalla, Nils Steinacker, Carolin Wadle, Johannes Kinzler, Matthias Eder, Constantin von zur Mühlen, Marvin Krohn-Grimberghe, Ann-Christin Eder","doi":"10.1093/infdis/jiae547","DOIUrl":"https://doi.org/10.1093/infdis/jiae547","url":null,"abstract":"Background To the present day infective endocarditis (IE) represents a life-threatening disease with high mortality rate especially when caused by Staphylococcus aureus (S. aureus), the most common causative pathogen in this disease. Diagnosis of IE is based on clinical manifestations, pathogen detection by blood cultures and echocardiographic or other imaging findings. However, none of the methods used is capable of detecting the causative bacterial cells on the endothelium directly. Modern molecular imaging such as positron emission tomography/computed tomography (PET/CT) is playing an increasingly important role in unclear IE cases. This study focused on 2-[18F]F-p-aminobenzoic acid (2-[18F]F-PABA), a bacteria specific tracer for the diagnosis of IE using PET imaging for direct pathogen detection. Methods In vitro assays were performed to analyze 2-[18F]F-PABA uptake by S. aureus. For proof-of-concept in vivo trials an endocarditis mouse model was used to diagnose IE by PET/Magnetic resonance (MR) imaging. A subcutaneous abscess mouse model was supplemented to create larger bacterial vegetations for PET imaging. Results 2-[18F]F-PABA in vitro uptake by S. aureus was confirmed. Only living bacteria were able to accumulate the tracer while the extent of uptake varied between different S. aureus strains. In the in vivo proof-of-concept, IE was visualized in mice using 2-[18F]F-PABA-PET/MR imaging. Subsequently, 2-[18F]F-PABA specifically located S. aureus vegetations in the subcutaneous abscess model. Conclusions This study highlights the great potential of 2-[18F]F-PABA imaging for the direct detection of IE. Future studies might further investigate the clinical potential of this molecular imaging approach, finally aiming at a clinical implementation.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"196 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A M A M Winkel, E Kozanli, M E Haverkort, S M Euser, J G C Sluiter-Post, R Mariman, A Vogelzang, J de Bakker, C R Lap, M A van Houten, D Eggink, S F L van Lelyveld
Background Knowledge of SARS-CoV-2 household transmission dynamics guides infection control and vaccination measures. This household cohort study prospectively assessed the impact of both the Omicron BA.2 variant and immunity on household transmission using dense saliva sampling and sequence analysis. Methods Households consisting of a PCR-confirmed index and at least two household members were enrolled in March and April 2022 during the Omicron BA.2 wave in the Netherlands. SARS-CoV-2 PCR was performed on ten consecutive saliva samples. Serum-antibodies were measured at baseline and day 42. Household and per-person Secondary Attack Rate (SAR) were calculated to measure transmission. Whole genome sequencing was performed for phylogenetic analysis, followed by sensitivity analysis, to correct for multiple household introductions and index definition. Results were compared with the identical, early-pandemic, pre-immunisation predecessor study. Results Sixty-seven households were included, consisting of 241 individuals (median age 33.0 years (IQR 12.0-46.0)). Maximum household SAR was 59.7%, per-person SAR 41.5%. Paediatric index cases were more likely to transmit. Transmission was negatively affected by household members’ immunity. Phylogenetic analysis showed multiple introductions in four households. Sensitivity analysis resulted in a minimal household SAR of 51.0% and per-person SAR of 28.5%. Conclusions The Omicron BA.2 variant is highly transmissible within households. However, the transmission rate is lower compared to previous studies with other SARS-CoV-2 variants, highlighting the effect of immunity. Regardless of immune status, children have a crucial role in Omicron household transmission. Intensive sampling and phylogenetic analysis are beneficial for correctly calculating transmission rates, especially during periods of minimal behavioural restrictions.
{"title":"Lower levels of household transmission of SARS-CoV-2 VOC Omicron compared to Wild-type: an interplay between transmissibility and immune status","authors":"A M A M Winkel, E Kozanli, M E Haverkort, S M Euser, J G C Sluiter-Post, R Mariman, A Vogelzang, J de Bakker, C R Lap, M A van Houten, D Eggink, S F L van Lelyveld","doi":"10.1093/infdis/jiae546","DOIUrl":"https://doi.org/10.1093/infdis/jiae546","url":null,"abstract":"Background Knowledge of SARS-CoV-2 household transmission dynamics guides infection control and vaccination measures. This household cohort study prospectively assessed the impact of both the Omicron BA.2 variant and immunity on household transmission using dense saliva sampling and sequence analysis. Methods Households consisting of a PCR-confirmed index and at least two household members were enrolled in March and April 2022 during the Omicron BA.2 wave in the Netherlands. SARS-CoV-2 PCR was performed on ten consecutive saliva samples. Serum-antibodies were measured at baseline and day 42. Household and per-person Secondary Attack Rate (SAR) were calculated to measure transmission. Whole genome sequencing was performed for phylogenetic analysis, followed by sensitivity analysis, to correct for multiple household introductions and index definition. Results were compared with the identical, early-pandemic, pre-immunisation predecessor study. Results Sixty-seven households were included, consisting of 241 individuals (median age 33.0 years (IQR 12.0-46.0)). Maximum household SAR was 59.7%, per-person SAR 41.5%. Paediatric index cases were more likely to transmit. Transmission was negatively affected by household members’ immunity. Phylogenetic analysis showed multiple introductions in four households. Sensitivity analysis resulted in a minimal household SAR of 51.0% and per-person SAR of 28.5%. Conclusions The Omicron BA.2 variant is highly transmissible within households. However, the transmission rate is lower compared to previous studies with other SARS-CoV-2 variants, highlighting the effect of immunity. Regardless of immune status, children have a crucial role in Omicron household transmission. Intensive sampling and phylogenetic analysis are beneficial for correctly calculating transmission rates, especially during periods of minimal behavioural restrictions.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"244 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gesham Magombedze, Elena Vendrame, Devi SenGupta, Romas Geleziunas, Susan Little, Davey Smith, Bruce Walker, Jean-Pierre Routy, Frederick M Hecht, Tae-Wook Chun, Michael Sneller, Jonathan Z Li, Steven G Deeks, Michael J Peluso
Background A key research priority for developing an HIV cure strategy is to define the viral dynamics and biomarkers associated with sustained post-treatment control. The ability to predict the likelihood of sustained post-treatment control or non-control could minimize the time off antiretroviral therapy (ART) for those destined to not control and anticipate longer periods off ART for those destined to control. Methods Mathematical modeling and machine learning were used to characterize virologic predictors of long-term virologic control using viral kinetics data from several studies in which participants interrupted ART. Predictors of post-ART outcomes were characterized using data accumulated from the time of treatment interruption, replicating real-time data collection in a clinical study, and classifying outcomes as either post-treatment control (plasma viremia ≤400 copies/mL at 2 of 3 time points for ≥24 weeks) or non-control. Results Potential predictors of virologic control were the time to rebound, the rate of initial rebound, and the peak plasma viremia. We found that people destined to be non-controllers could be identified within 3 weeks of rebound (prediction scores: accuracy, 80%; sensitivity, 82%; specificity, 71%). Conclusions Given the widespread use of analytic treatment interruption in cure-related trials, these predictors may be useful to increase the safety of analytic treatment interruption through the early identification of people who are unlikely to become post-treatment controllers.
{"title":"Early Viral Dynamics Predict HIV Post-Treatment Control After Analytic Treatment Interruption","authors":"Gesham Magombedze, Elena Vendrame, Devi SenGupta, Romas Geleziunas, Susan Little, Davey Smith, Bruce Walker, Jean-Pierre Routy, Frederick M Hecht, Tae-Wook Chun, Michael Sneller, Jonathan Z Li, Steven G Deeks, Michael J Peluso","doi":"10.1093/infdis/jiae551","DOIUrl":"https://doi.org/10.1093/infdis/jiae551","url":null,"abstract":"Background A key research priority for developing an HIV cure strategy is to define the viral dynamics and biomarkers associated with sustained post-treatment control. The ability to predict the likelihood of sustained post-treatment control or non-control could minimize the time off antiretroviral therapy (ART) for those destined to not control and anticipate longer periods off ART for those destined to control. Methods Mathematical modeling and machine learning were used to characterize virologic predictors of long-term virologic control using viral kinetics data from several studies in which participants interrupted ART. Predictors of post-ART outcomes were characterized using data accumulated from the time of treatment interruption, replicating real-time data collection in a clinical study, and classifying outcomes as either post-treatment control (plasma viremia ≤400 copies/mL at 2 of 3 time points for ≥24 weeks) or non-control. Results Potential predictors of virologic control were the time to rebound, the rate of initial rebound, and the peak plasma viremia. We found that people destined to be non-controllers could be identified within 3 weeks of rebound (prediction scores: accuracy, 80%; sensitivity, 82%; specificity, 71%). Conclusions Given the widespread use of analytic treatment interruption in cure-related trials, these predictors may be useful to increase the safety of analytic treatment interruption through the early identification of people who are unlikely to become post-treatment controllers.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mary G Slaughter, Samina Bhumbra, Kagan A Mellencamp, Ruth Namazzi, Robert O Opoka, Chandy C John
Background Children with severe malarial anemia (SMA) typically have low in-hospital mortality but have a high risk of post-discharge readmission or death. We hypothesized that the dysregulation of hematopoiesis, vascular growth factors, and endothelial function that occurs in SMA might affect risk of readmission or death. Methods Plasma was obtained from children 18 months to 12 years old with SMA (N=145) in Kampala, Uganda on admission, and outcomes were assessed over 12-month follow-up. Admission plasma levels of ten biomarkers of vascular growth, hematopoiesis, and endothelial function were compared to risk of readmission or death over 12-month follow-up. Results Over 12-month follow-up, 19 of 145 children with SMA were either readmitted or died: 15 children were readmitted (13 with malaria) and 4 children died. In multivariable analyses adjusted for age and sex, elevated plasma levels of platelet-derived growth factor-BB (PDGF-BB) and vascular endothelial growth factor (VEGF) on admission were independently associated with a decreased risk of all-cause readmission or death (adjusted hazard ratios [95% confidence intervals], 0.28 [0.16-0.51] and 0.19 [0.08-0.48], respectively) and a decreased risk of readmission due to severe malaria (0.27 [0.15, 0.51] and 0.16 [0.05, 0.47]) but not with risk of uncomplicated malaria (1.01 [0.53, 1.95] and 2.07 [0.93-4.64]). Conclusions In children with severe malarial anemia, elevated plasma levels of PDGF-BB and VEGF, two factors that promote angiogenesis, are associated with a decreased risk of readmission or death in the year following admission, primarily driven by a decrease in the risk of recurrent severe malaria.
{"title":"Elevated levels of PDGF-BB and VEGF are associated with a decreased risk of readmission or death in children with severe malarial anemia","authors":"Mary G Slaughter, Samina Bhumbra, Kagan A Mellencamp, Ruth Namazzi, Robert O Opoka, Chandy C John","doi":"10.1093/infdis/jiae527","DOIUrl":"https://doi.org/10.1093/infdis/jiae527","url":null,"abstract":"Background Children with severe malarial anemia (SMA) typically have low in-hospital mortality but have a high risk of post-discharge readmission or death. We hypothesized that the dysregulation of hematopoiesis, vascular growth factors, and endothelial function that occurs in SMA might affect risk of readmission or death. Methods Plasma was obtained from children 18 months to 12 years old with SMA (N=145) in Kampala, Uganda on admission, and outcomes were assessed over 12-month follow-up. Admission plasma levels of ten biomarkers of vascular growth, hematopoiesis, and endothelial function were compared to risk of readmission or death over 12-month follow-up. Results Over 12-month follow-up, 19 of 145 children with SMA were either readmitted or died: 15 children were readmitted (13 with malaria) and 4 children died. In multivariable analyses adjusted for age and sex, elevated plasma levels of platelet-derived growth factor-BB (PDGF-BB) and vascular endothelial growth factor (VEGF) on admission were independently associated with a decreased risk of all-cause readmission or death (adjusted hazard ratios [95% confidence intervals], 0.28 [0.16-0.51] and 0.19 [0.08-0.48], respectively) and a decreased risk of readmission due to severe malaria (0.27 [0.15, 0.51] and 0.16 [0.05, 0.47]) but not with risk of uncomplicated malaria (1.01 [0.53, 1.95] and 2.07 [0.93-4.64]). Conclusions In children with severe malarial anemia, elevated plasma levels of PDGF-BB and VEGF, two factors that promote angiogenesis, are associated with a decreased risk of readmission or death in the year following admission, primarily driven by a decrease in the risk of recurrent severe malaria.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jing Bi, Qinglong Guo, Yaqi Gong, Xi Chen, Haojia Wu, Li Song, Yating Xu, Min Ou, Zhaoqin Wang, Jiean Chen, Chenran Jiang, Aimei Liu, Guobao Li, Guoliang Zhang
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb), results in significant morbidity and mortality worldwide. Host-directed therapy (HDT), including conventional drugs, is a promising anti-TB strategy that shows synergistic antibacterial effects when combined with anti-TB drugs. Here, the mycobactericidal effect of three anti-diabetic drugs was examined. Of these, only Troglitazone (Trog) enhanced the antimycobacterial effect in vitro and in vivo. This was due to Trog-mediated autophagy activation. Moreover, a knock-down experiment revealed that Trog activated autophagy and exhibited antimycobacterial activity through the LKB1-AMPK signaling pathway. Molecular docking and co-immunoprecipitation experiments demonstrated that Trog promoted LKB1 phosphorylation and activation by targeting STRADA. Finally, we found that Trog inhibited the intracellular survival of clinical isoniazid (INH)-resistant Mtb, and the combination of Trog and INH showed additive antibacterial effects against Mtb H37Rv. Taken together, anti-diabetic Trog may be repurposed as an HDT candidate and combined with first-line anti-TB drugs.
{"title":"Troglitazone reduces intracellular Mycobacterium tuberculosis survival via macrophage autophagy through LKB1-AMPKα signaling","authors":"Jing Bi, Qinglong Guo, Yaqi Gong, Xi Chen, Haojia Wu, Li Song, Yating Xu, Min Ou, Zhaoqin Wang, Jiean Chen, Chenran Jiang, Aimei Liu, Guobao Li, Guoliang Zhang","doi":"10.1093/infdis/jiae523","DOIUrl":"https://doi.org/10.1093/infdis/jiae523","url":null,"abstract":"Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb), results in significant morbidity and mortality worldwide. Host-directed therapy (HDT), including conventional drugs, is a promising anti-TB strategy that shows synergistic antibacterial effects when combined with anti-TB drugs. Here, the mycobactericidal effect of three anti-diabetic drugs was examined. Of these, only Troglitazone (Trog) enhanced the antimycobacterial effect in vitro and in vivo. This was due to Trog-mediated autophagy activation. Moreover, a knock-down experiment revealed that Trog activated autophagy and exhibited antimycobacterial activity through the LKB1-AMPK signaling pathway. Molecular docking and co-immunoprecipitation experiments demonstrated that Trog promoted LKB1 phosphorylation and activation by targeting STRADA. Finally, we found that Trog inhibited the intracellular survival of clinical isoniazid (INH)-resistant Mtb, and the combination of Trog and INH showed additive antibacterial effects against Mtb H37Rv. Taken together, anti-diabetic Trog may be repurposed as an HDT candidate and combined with first-line anti-TB drugs.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Keon-Woong Yoon, Ki Back Chu, Gi-Deok Eom, Jie Mao, Eun-Kyung Moon, Sung Soo Kim, Fu-Shi Quan
Visceral leishmaniasis (VL) poses a significant public health challenge due to the lack of an approved human vaccine. We attempted to enhance the efficacy of virus-like particle vaccines expressing the Leishmania donovani promastigote surface antigen (LdPSA-VLP) by adjuvanting with CpG oligodeoxynucleotide (CpG-ODN). Here, adjuvanted vaccine-induced immune responses and their efficacies in mice challenged with mCherry-expressing L. donovani promastigotes were evaluated. Adjuvanted LdPSA-VLP vaccination significantly elevated parasite-specific IgG, IgG1, IgG2a, and IgG2b serum antibody levels. Additionally, vaccinated mice exhibited enhanced germinal center B cells and splenic T cell activities, compared to unimmunized mice. Importantly, adjuvanted LdPSA-VLPs reduced the levels of inflammatory cytokines IFN-γ and IL-6 in visceral organs, leading to decreased total parasite burden and protection against L. donovani challenge. Our findings indicate that CpG-ODN enhanced the protection conferred by LdPSA-VLPs, offering a promising step toward effective VL vaccine development.
由于缺乏已获批准的人类疫苗，内脏利什曼病（VL）对公共卫生构成了重大挑战。我们试图通过CpG寡脱氧核苷酸（CpG-ODN）佐剂来提高表达唐氏利什曼原虫表面抗原的病毒样颗粒疫苗（LdPSA-VLP）的效力。在此，我们评估了佐剂疫苗诱导的免疫反应及其在小鼠体内对表达 mCherry 的唐诺瓦尼原鞭毛虫的免疫效果。佐剂 LdPSA-VLP 疫苗接种能显著提高寄生虫特异性 IgG、IgG1、IgG2a 和 IgG2b 血清抗体水平。此外，与未接种疫苗的小鼠相比，接种疫苗的小鼠生殖中心 B 细胞和脾脏 T 细胞活性增强。重要的是，佐剂 LdPSA-VLPs 降低了内脏器官中炎症细胞因子 IFN-γ 和 IL-6 的水平，从而减少了寄生虫的总负荷，保护小鼠免受唐诺瓦尼氏菌的侵袭。我们的研究结果表明，CpG-ODN增强了LdPSA-VLPs的保护作用，为有效开发VL疫苗迈出了充满希望的一步。
{"title":"CpG-adjuvanted virus-like particle vaccine induces protective immunity against Leishmania donovani infection","authors":"Keon-Woong Yoon, Ki Back Chu, Gi-Deok Eom, Jie Mao, Eun-Kyung Moon, Sung Soo Kim, Fu-Shi Quan","doi":"10.1093/infdis/jiae526","DOIUrl":"https://doi.org/10.1093/infdis/jiae526","url":null,"abstract":"Visceral leishmaniasis (VL) poses a significant public health challenge due to the lack of an approved human vaccine. We attempted to enhance the efficacy of virus-like particle vaccines expressing the Leishmania donovani promastigote surface antigen (LdPSA-VLP) by adjuvanting with CpG oligodeoxynucleotide (CpG-ODN). Here, adjuvanted vaccine-induced immune responses and their efficacies in mice challenged with mCherry-expressing L. donovani promastigotes were evaluated. Adjuvanted LdPSA-VLP vaccination significantly elevated parasite-specific IgG, IgG1, IgG2a, and IgG2b serum antibody levels. Additionally, vaccinated mice exhibited enhanced germinal center B cells and splenic T cell activities, compared to unimmunized mice. Importantly, adjuvanted LdPSA-VLPs reduced the levels of inflammatory cytokines IFN-γ and IL-6 in visceral organs, leading to decreased total parasite burden and protection against L. donovani challenge. Our findings indicate that CpG-ODN enhanced the protection conferred by LdPSA-VLPs, offering a promising step toward effective VL vaccine development.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"110 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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