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Link to bioRxiv paper: http://medrxiv.org/cgi/content/short/2023.07.29.23293322v1?rss=1 Authors: Rogier, E., Battle, N., Bakari, C., Seth, M. D., Nace, D., Herman, C., Madebe, R. A., Mandara, C. I., Lyimo, B. M., Giesbrecht, D. J., Popkin-Hall, Z. R., Francis, F., Mbwambo, D., Garimo, I., Aaron, S., Lusasi, A., Molteni, F., Njau, R., Cunningham, J. A., Lazaro, S., Mohamed, A., Juliano, J. J., Bailey, J. A., Udhayakumar, V., Ishengoma, D. S. Abstract: Plasmodium falciparum with the histidine rich protein 2 gene (pfhrp2) deleted from its genome can escape diagnosis by HRP2-based rapid diagnostic tests (HRP2-RDTs). The World Health Organization (WHO) recommends switching to a non-HRP2 RDT for P. falciparum clinical case diagnosis when pfhrp2 deletion prevalence causes greater than or equal to 5% of RDTs to return false negative results. Tanzania is a country of heterogenous P. falciparum transmission, with some regions approaching elimination and others at varying levels of control. In concordance with the current recommended WHO pfhrp2 deletion surveillance strategy, 100 health facilities encompassing 10 regions of Tanzania enrolled malaria-suspected patients between February and July 2021. Of 7,863 persons of all ages enrolled and providing RDT result and blood sample, 3,777 (48.0%) were positive by the national RDT testing for Plasmodium lactate dehydrogenase (pLDH) and/or HRP2. A second RDT testing specifically for the P. falciparum LDH (Pf-pLDH) antigen found 95 persons (2.5% of all RDT positives) were positive, though negative by the national RDT for HRP2, and were selected for pfhrp2 and pfhrp3 (pfhrp2/3) genotyping. Multiplex antigen detection by laboratory bead assay found 135/7,847 (1.7%) of all blood samples positive for Plasmodium antigens but very low or no HRP2, and these were selected for genotyping as well. Of the samples selected for genotyping based on RDT or laboratory multiplex result, 158 were P. falciparum DNA positive, and 140 had sufficient DNA to be genotyped for pfhrp2/3. Most of these (125/140) were found to be pfhrp2+/pfhrp3+, with smaller numbers deleted for only pfhrp2 (n=9) or only pfhrp3 (n=6). No dual pfhrp2/3 deleted parasites were observed. This survey estimated that 0.24% (95% confidence interval: 0.08% to 0.39%) of false-negative HRP2-RDTs for symptomatic persons were due to pfhrp2 deletions in this 2021 Tanzania survey. These data provide evidence for HRP2-based diagnostics as currently accurate for P. falciparum diagnosis in Tanzania. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://medrxiv.org/cgi/content/short/2023.07.28.23293338v1?rss=1 Authors: Mushebenge, A. G.-A., Ugbaja, S. C., Mbatha, N. A., Riziki, M. G., Muzumbukilwa, T. W., Kadima, M. G., Kumalo, H. M. Abstract: COVID-19 is a rapidly spreading infectious disease caused by the SARS-CoV-2 virus. Although several therapeutic interventions have been developed, the mortality rate of the disease remains high, and effective treatment options are urgently needed. Host-directed therapies targeting enzymes involved in the immune response represent a promising strategy for the development of novel therapeutics against COVID-19. This study aims to conduct a systematic review and meta-analysis of the literature to evaluate the potential of drug candidates targeting host enzymes involved in the immune response for the treatment of COVID-19. We will conduct a systematic search of electronic databases including PubMed, Embase, and Cochrane Library, as well as preprint servers and clinical trial registries for relevant studies. We will include randomized controlled trials, observational studies, and preclinical studies evaluating the efficacy of drug candidates targeting host enzymes involved in the immune response in COVID-19. Two reviewers will independently screen articles, extract data, and assess study quality. The primary outcome will be the effect of drug candidates on mortality, while secondary outcomes will include time to recovery, adverse events, and changes in immune markers. A meta-analysis will be performed to estimate pooled effect sizes of the interventions, and a narrative synthesis will be conducted for studies that are not amenable to quantitative analysis. This study will provide a comprehensive evaluation of the potential of host-directed therapies targeting enzymes involved in the immune response for the treatment of COVID-19. The results of this study may guide the development of novel therapeutics against COVID-19 and inform clinical practice. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://medrxiv.org/cgi/content/short/2023.07.28.23293335v1?rss=1 Authors: Yang, J., Andersen, K. M., Rai, K. K., Tritton, T., Mugwagwa, T., Tsang, C., Reimbaeva, M., McGrath, L., Payne, P., Backhouse, B. E., Mendes, D., Butfield, R., Wood, R., Nguyen, J. L. Abstract: Background Although COVID-19 morbidity is significantly lower in pediatrics than in adults, the risk of severe COVID-19 may still pose substantial healthcare resource burden. This study aimed to describe healthcare resource utilization (HCRU) and costs associated with COVID-19 in pediatrics aged 1-17 years in England. Methods A population-based retrospective cohort study of pediatrics with COVID-19 using Clinical Practice Research Datalink (CPRD Aurum) primary care data and, where available, linked Hospital Episode Statistics Admitted Patient Care (HES APC) secondary care data. HCRU and associated costs to the National Health Service (NHS) were stratified by age, risk of severe COVID-19, and immunocompromized status, separately for those with and without hospitalization records (hospitalized cohort: COVID-19 diagnosis August 2020-March 2021; primary care cohort: COVID-19 diagnosis August 2020-January 2022). Results This study included 564,644 patients in the primary care cohort and 60 in the hospitalized cohort. Primary care consultations were more common in those aged 1-4 years (face-to-face: 4.3%; telephone: 6.0%) compared to those aged 5-11 (2.0%; 2.1%) and 12-17 years (2.2%; 2.5%). In the hospitalized cohort, mean [SD] length of stay was longer (5.0 [5.8] days) among those aged 12-17 years (n=24) than those aged 1-4 (n=15; 1.8 [0.9] days) and 5-11 years (n=21; 2.8 [2.1] days). Conclusions Most pediatrics diagnosed with COVID-19 were managed in the community. However, hospitalizations were an important driver of HCRU and costs, particularly for those aged 12-17 years. Our results may help optimize the management and resource allocation of COVID-19 in this population. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://medrxiv.org/cgi/content/short/2023.07.31.23293337v1?rss=1 Authors: Hurst, J. H., Mohan, A., Dalapati, T., George, I. A., Aquino, J. N., Lugo, D. J., Pfeiffer, T. S., Rodriguez, J., Rotta, A. T., Turner, N. A., Burke, T. W., McClain, M. T., Henao, R., DeMarco, C. T., Louzao, R., Denny, T. N., Walsh, K. M., Xu, Z., Mejias, A., Ramilo, O., Woods, C. W., Kelly, M. S. Abstract: Age is among the strongest risk factors for severe outcomes from SARS-CoV-2 infection. We sought to evaluate associations between age and both mucosal and systemic host responses to SARS-CoV-2 infection. We profiled the upper respiratory tract (URT) and peripheral blood transcriptomes of 201 participants (age range of 1 week to 83 years), including 137 non-hospitalized individuals with mild SARS-CoV-2 infection and 64 uninfected individuals. Among uninfected children and adolescents, young age was associated with upregulation of innate and adaptive immune pathways within the URT, suggesting that young children are primed to mount robust mucosal immune responses to exogeneous respiratory pathogens. SARS-CoV-2 infection was associated with broad induction of innate and adaptive immune responses within the URT of children and adolescents. Peripheral blood responses among SARS-CoV-2-infected children and adolescents were dominated by interferon pathways, while upregulation of myeloid activation, inflammatory, and coagulation pathways was observed only in adults. Systemic symptoms among SARS-CoV-2-infected subjects were associated with blunted innate and adaptive immune responses in the URT and upregulation of many of these same pathways within peripheral blood. Finally, within individuals, robust URT immune responses were correlated with decreased peripheral immune activation, suggesting that effective immune responses in the URT may promote local viral control and limit systemic immune activation and symptoms. These findings demonstrate that there are differences in immune responses to SARS-CoV-2 across the lifespan, including between young children and adolescents, and suggest that these varied host responses contribute to observed differences in the clinical presentation of SARS-CoV-2 infection by age. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://medrxiv.org/cgi/content/short/2023.07.29.23293373v1?rss=1 Authors: Kanki, P. J., Hamel, D. J., Riedel, S., Dutta, S., Cheng, A., Chang, C. A., Arnaout, R., Kirby, J. E. Abstract: The COVID-19 pandemic has presented unique diagnostic challenges including the need to store and test large number of samples for clinical and research studies. While SARS CoV-2 diagnosis relies on RT-qPCR and antigen testing, live virus culture remains an important surrogate for viral 'infectiousness', as we previously described in 'SARS-CoV-2 Antigen Tests Predict Infectivity Based on Viral Culture: Comparison of Antigen, PCR Viral Load and Viral Culture Testing on a Large Sample Cohort' (Clin Microbiol Infect, 2022, PMC9293398). Live virus isolation and characterization has also been important to the SARS CoV-2 research community, to assess viral fitness, cellular tropism, and live virus neutralization, particularly with the emergence of new variants. Many clinical and research studies make use of samples that are frozen in transport media and investigated at later dates. The effect of freezing on RT-qPCR results is well established. However, the effect of freeze-thaw on viral viability has not been. Here, we therefore examined the effect of freeze-thaw on viral culture isolation from a large number of clinical samples that were split, and then cultured either fresh or after being frozen for 7 or 17-18 days. Samples represented the range of viral loads (genome copies/mL) observed in our patient population. We found that freeze-thaw did not significantly affect viral culture isolation. Therefore, the ability to assess infectiousness of samples previously frozen in transport medium appears to be maintained. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://medrxiv.org/cgi/content/short/2023.08.02.23293478v1?rss=1 Authors: Macesic, N., Dennis, A., Hawkey, J., Vezina, B., Wisniewski, J. A., Cottingham, H., Blakeway, L. V., Harshegyi, T., Pragastis, K., Badoordeen, G. Z., Bass, P., Stewardson, A. J., Dennison, A., Spelman, D. W., Jenney, A. W. J., Peleg, A. Y. Abstract: Objectives: New Delhi metallo-beta-lactamases (NDMs) are major contributors to the spread of carbapenem resistance globally. In Australia, NDMs were previously associated with international travel but from 2019 we noted increasing NDM episodes. We conducted an investigation to determine the clinical and genomic epidemiology of NDM-carriage at a tertiary Australian hospital from 2016-2021. Methods: We identified 49 patients with 84 NDM-carrying isolates in an institutional database and collected clinical data from electronic medical records. Short- and long-read whole genome sequencing was performed on all isolates. Completed genome assemblies were used to assess the genetic setting of blaNDM genes and compare NDM plasmids. Results: Of 49 patients, 38 (78%) were identified in 2019-2021 and only 11/38 (29%) reported prior travel compared with 9/11 (82%) in 2016-2018 (P=0.037). In patients with NDM infection, crude 7-day mortality was 0% and 30-day mortality was 14% (2/14 patients). NDMs were noted in 41 bacterial strains (i.e. species/sequence type combinations). Four NDM variants (blaNDM-1, blaNDM-4, blaNDM-5, blaNDM-7) were detected across 13 plasmid groups. We noted a change from a diverse NDM plasmid repertoire in 2016-2018 to the emergence of conserved blaNDM-1 IncN and blaNDM-7 IncX3 epidemic plasmids with inter-strain spread in 2019-2021. These plasmids were noted in 19/38 (50%) patients and 35/68 (51%) genomes in 2019-2021. Conclusions: Increased NDM case numbers were due to local circulation of two epidemic plasmids with extensive inter-strain transfer. Our study underscores the challenges of outbreak detection when horizontal transmission of plasmids is the primary mode of spread. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://medrxiv.org/cgi/content/short/2023.07.28.23293301v1?rss=1 Authors: Ndzomo, P., Tchatchouang, S., Njih Tabah, E., Njamnshi, T., Noah, M. V. T., Bondi, J. A., Handley, R., Gonzalez Beiras, C., Tchatchueng, J., Muller, C., Luert, S., Knauf, S., Boyomo, O., Harding-Esch, E., Mitja, O., Crucitti, T., Marks, M., Eyangoh, S. Abstract: Epidemics of yaws-like cutaneous ulcers are regularly documented in children in the tropics. They occur mainly in poor and remote communities without access to health facilities. The integration of molecular tools into yaws control efforts has made it possible to describe Haemophilus ducreyi (HD) as a major cause of cutaneous ulcers. The objective of this work was to determine the prevalence of HD as cause of cutaneous ulcers, as asymptomatic carriage and the risk factors associated. A cross-sectional study was conducted in yaws endemic districts of Cameroon. Participants included people presenting yaws-like ulcers and asymptomatic individuals. Swab samples were collected from each participant and tested for HD and Treponema pallidum (TP) using established qPCR method. Additionally, demographic, habitat, proximity, and hygiene characteristics were collected using a structured questionnaire. A total of 443 individuals, including 271 ulcer cases and 172 asymptomatic contacts, were enrolled in this study. The prevalence of HD in ulcers was 30.3% (Confidence Interval (CI) 95% [24.8 - 35.7]) and the prevalence of asymptomatic HD carriage was 8.6% (CI95% [4.5 - 12.9]). TP was also detected in our sample among ulcer cases but in lower proportion (5.2% CI95% [2.5 - 7.8]) compared to HD. The adjusted logistic regression model showed that women were as much at risk of having HD cutaneous ulcer as men regardless of age; physical proximity to a confirmed ulcer case was the major factor favouring HD transmission. HD ulcers were more likely to be present on Bantu individuals compare to Baka as well as HD colonization. Data from this study highlight HD as the most common cause of cutaneous ulcers in yaws-endemic communities in Cameroon. The real issues of HD detection on intact skin are not yet clear. Further studies are needed to elucidate the implications of this carriage in the spread dynamics of the disease. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://medrxiv.org/cgi/content/short/2023.08.01.23293515v1?rss=1 Authors: Chitnis, C. E., Martinez, F. J., White, M., Guillotte-Blisnick, M., Huon, C., Boucharlat, A., Agou, F., England, P., Popovici, J., Hou, M. M., Silk, S. E., Barrett, J. R., Nielsen, C. M., Reimer, J. M., Mukherjee, P., Chauhan, V. S., Minassian, A. M., Draper, S. J. Abstract: The receptor-binding domain, region II, of Plasmodium vivax Duffy binding protein (PvDBPII) binds the Duffy antigen on reticulocytes to mediate invasion. A heterologous vaccine challenge trial recently showed that a delayed dosing regimen with recombinant PvDBPII SalI formulated with adjuvant Matrix-MTM reduced the in vivo parasite multiplication rate (PMR) challenged with the P. vivax Thai isolate PvW1. We describe extensive analysis of the polyfunctional antibody responses elicited by PvDBPII immunization and identify immune correlates for PMR reduction. A classification algorithm identified antibody features that contribute significantly to PMR reduction. These included antibody titre, receptor-binding inhibitory titre, dissociation constant for PvDBPII-antibody interaction, complement C1q and Fc gamma receptor binding and specific IgG subclasses. These data suggest that multiple immune mechanisms elicited by PvDBPII immunization are associated with protection. The identified immune correlates could guide the development of an effective vaccine for P. vivax malaria. Importantly, all the polyfunctional antibody features that correlated with protection cross-reacted with both PvDBPII SalI and PvW1 variants, suggesting that immunization with PvDBPII should protect against diverse P. vivax isolates. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://medrxiv.org/cgi/content/short/2023.07.31.23293441v1?rss=1 Authors: Li, Y., Choudhary, M. C., Regan, J., Boucau, J., Nathan, A., Speidel, T., Liew, M. Y., Edelstein, G. E., Kawano, Y., Uddin, R., Deo, R., Marino, C., Getz, M. A., Reynold, Z., Barry, M., Gilbert, R. F., Tien, D., Sagar, S., Vyas, T. D., Flynn, J. P., Hammond, S. P., Novack, L. A., Choi, B., Cernadas, M., Wallace, Z. S., Sparks, J. A., Vyas, J. M., Seaman, M. S., Gaiha, G. D., Siedner, M. J., Barczak, A. K., Lemieux, J. E., Li, J. Z. Abstract: Despite vaccination and antiviral therapies, immunocompromised individuals are at risk for prolonged SARS-CoV-2 infection, but the immune defects that predispose to persistent COVID-19 remain incompletely understood. In this study, we performed detailed viro-immunologic analyses of a prospective cohort of participants with COVID-19. The median time to nasal viral RNA and culture clearance in the severe hematologic malignancy/transplant group (S-HT) were 72 and 21 days, respectively, which were significantly longer than clearance rates in the severe autoimmune/B-cell deficient (S-A), non-severe, and non-immunocompromised groups (P less than 0.001). Participants who were severely immunocompromised had greater SARS-CoV-2 evolution and higher risk of developing antiviral treatment resistance. Both S-HT and S-A participants had diminished SARS-CoV-2-specific humoral, while only the S-HT group had reduced T cell-mediated responses. This highlights the varied risk of persistent COVID-19 across immunosuppressive conditions and suggests that suppression of both B and T cell responses results in the highest contributing risk of persistent infection. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://medrxiv.org/cgi/content/short/2023.08.01.23293495v1?rss=1 Authors: Cevirgel, A., Shetty, S. A., Vos, M., Nanlohy, N. M., Beckers, L., Bijvank, E., Rots, N., van Beek, J., Buisman, A.-M., van Baarle, D. Abstract: Effective vaccine-induced immune responses are particularly essential in older adults who face an increased risk of immunosenescence. However, the complexity and variability of the human immune system make predicting vaccine responsiveness challenging. To address this knowledge gap, our study aimed to characterize immune profiles that are predictive of vaccine responsiveness using "immunotypes" as an innovative approach. We analyzed an extensive set of innate and adaptive immune cell subsets in the whole blood of 307 individuals (aged 25-92) pre- and post-influenza vaccination which we associated with day 28 hemagglutination inhibition (HI) antibody titers. Building on our previous work that stratified individuals into nine immunotypes based on immune cell subsets, we identified two pre-vaccination immunotypes associated with weak and one showing robust day 28 antibody response. Notably, the weak responders demonstrated immune regulation (HLA-DR+ T-cells) and activation (CD38+ T-cells) signatures respectively, while the robust responders displayed a high naive-to-memory T-cell ratio and percentage of non-classical monocytes. These specific signatures deepen our understanding of the relationship between the baseline of the immune system and its functional potential. This approach could enhance our ability to identify individuals at risk of immunosenescence. Our findings highlight the potential of pre-vaccination immunotypes as an innovative tool for informing personalized vaccination strategies and improving health outcomes, particularly for aging populations. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://medrxiv.org/cgi/content/short/2023.07.30.23292881v1?rss=1 Authors: Abu-Raya, B., Reicherz, F., Michalski, C., Majdoub, A., Golding, L., Vienta, M., Granoski, M., Stojic, A., Marchant, D., Lavoie, P. M. Abstract: Studies have linked reduced respiratory syncytial virus-specific Fc-mediated phagocytic function and complement deposition to more severe infection. This study shows a loss of these functions during the first year of COVID-19 pandemic. These findings corroborate other data supporting a general waning of RSV antibody functions in absence of viral circulation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://medrxiv.org/cgi/content/short/2023.07.27.23293266v1?rss=1 Authors: Paredes, M. I., Ahmed, N., Figgins, M., Colizza, V., Lemey, P., McCrone, J. T., Müller, N. F., Tran-Kiem, C., Bedford, T. Abstract: The World Health Organization (WHO) declared mpox a public health emergency of international concern in July 2022. It is still unclear to what extent international travel contributed to the explosive spread of mpox and the degree to which national vaccination campaigns were responsible for controlling the epidemic. We built phylogeographic and phylodynamic models to analyze MPXV genomes sampled between March 2022 and January 2023 from five global regions together with air traffic and epidemiological data to analyze the global spread of mpox. Our models reveal community transmission prior to detection by local surveillance, changes in case-reporting throughout the epidemic, and a large degree of transmission heterogeneity. Additionally, we find that viral introductions played a limited role in prolonging spread after initial dissemination, suggesting that travel bans would have had only a minor impact. We find that the time-varying effective reproductive number in North America declines below one before more than 10% of individuals at high risk individuals in the USA had vaccine-induced immunity, suggesting little impact of vaccination in controlling the epidemic. Given that cases quickly declined after detection most likely due to behavioral modifications, our findings highlight the importance of broader routine specimen screening surveillance for emerging infectious diseases. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://medrxiv.org/cgi/content/short/2023.07.31.23293324v1?rss=1 Authors: McCabe, R., Donnelly, C. A. Abstract: Mathematical transmission modelling is a key component of scientific evidence used to inform public health policy and became particularly prominent during the COVID-19 pandemic. As key stakeholders, it is vital that the public perception of this set of tools is better understood. To complement a previously published article on the science-policy interface by the authors of this study, novel data were collected via responses to a survey via two methods: via an online panel ('representative' sample) and via social media ('non-probability' sample). Many identical questions were asked separately for the period 'prior to' compared to 'during' the COVID-19 pandemic. All respondents were increasingly aware of the use of modelling in informing policy during the pandemic, with significantly higher levels of awareness among social media respondents than online panel respondents. Awareness generally stemmed from the news media and social media during the pandemic. Transmission modelling informing public health policy was perceived as more reliable during the pandemic compared to the pre-pandemic period in both samples, with awareness being positively associated with reliability within both samples and time points, except for social media during the pandemic. Trust in government public health advice remained high across samples and time periods overall but was lower in the period of the pandemic compared to the pre-pandemic period. The decay in trust was notably greater among social media respondents. Many respondents from both samples explicitly made the distinction that their trust was reserved for 'scientists' and not 'politicians'. Almost all respondents, regardless of sample, believed governments have responsibility for the communication of modelling to the public. These results provide an important reminder of the potentially skewed conclusions that could be drawn from non-representative samples. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://medrxiv.org/cgi/content/short/2023.07.28.23293104v1?rss=1 Authors: James, L. P., Klaassen, F., Sweeney, S., Furin, J., Franke, M. F., Yaesoubi, R., Chesov, D., Ciobanu, N., Codreanu, A., Crudu, V., Cohen, T., Menzies, N. A. Abstract: Background: Emerging evidence suggests that shortened, simplified treatment regimens for rifampicin-resistant tuberculosis (RR-TB) can achieve comparable end-of-treatment outcomes to longer regimens. We compared a 6-month regimen containing bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) to a standard-of-care strategy using a 9- or 18-month regimen depending on whether fluoroquinolone resistance (FQ-R) is detected on Drug Susceptibility Testing (DST). Methods and Findings: Genomic and associated demographic data were used to parameterize a mathematical model estimating long-term health outcomes and costs (2022 USD) for each treatment strategy for patients 15 years and older diagnosed with pulmonary RR-TB in Moldova, a country with a high burden of TB drug resistance. In this model individuals were followed over their lifetime, simulating the natural history of TB and associated treatment outcomes, as well as the process of acquiring resistance to each of 12 anti-TB drugs. Compared to the standard of care, 6 months of BPaLM was estimated to reduce lifetime costs by $3433 (95% Uncertainty Interval (UI): 1480, 5771) per individual, with a small non-significant reduction in quality adjusted life expectancy of 0.06 QALYs (95% UI: -0.33, 0.45). For those stopping moxifloxacin under the BPaLM regimen, continuing with BPaLC provided more QALYs at lower cost than continuing with BPaL alone. Such a regimen (6 months of BPaLM, where clofazimine is added in the event of moxifloxacin discontinuation) had a 92% chance of being cost-effective. With the exception of pretomanid and delamanid, 6 months of BPaLM either reduced or resulted in no significant change in the cumulative incidence of resistance to each drug. Sensitivity analyses showed 6 months of BPaLM to be cost-effective across a broad range of values for the relative effectiveness of the drug regimens and the proportion of the cohort with FQ-R. Conclusions: Compared to the standard of care, the implementation of short-course regimens like BPaLM could improve the cost-effectiveness of care for individuals diagnosed with RR-TB, particularly in settings where current long-course regimens are challenging to implement and afford. Further research may be warranted to explore the suitability of 6 months of BPaLM in specific national settings, including locations where DST capacity is limited. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://medrxiv.org/cgi/content/short/2023.07.31.23293412v1?rss=1 Authors: Dayarathna, S., Kuruppu, H., Silva, T., Gomes, L., Shyamali, N. L. A., Jeewandara, C., Ariyaratne, D., Ramu, S. T., Wijewickrama, A., Ogg, G. S., Malavige, G. N. Abstract: Background As many studies have shown conflicting results regarding the extent of viraemia and clinical disease severity, we sought to investigate if viraemia during early dengue illness is associated with subsequent clinical disease severity. Methodology/Principal Findings 424 adult patients, in whom the dengue virus (DENV) serotype could be identified, who presented within the first 4 days of illness, were recruited from a tertiary care hospital from Sri Lanka from September 2016 to September 2022 following informed written consent. To characterize subsequent clinical disease severity, all patients were followed throughout their illness daily and disease severity classified according to WHO 1997 and 2009 disease classification. 315 patients had DF, 109 progressed to develop DHF and of those 17 developed shock (DSS). Although the viral loads were higher in the febrile phase in patients who progressed to develop DHF than in patients with DF this was not significant (p=0.15). Significant differences were observed in viral loads in patients infected with different DENV serotypes (p=0.0001), with patients infected with DENV2 having the lowest viral loads and the highest viral loads in DENV1. Although those infected with DENV2 had lower viral loads, infection with DENV2 was significantly associated with a higher risk of developing DHF (p=0.016, Odds ratio 1.8; 95% CI 1.116 to 2.905). Based on the WHO 2009 disease classification, 268 had dengue with warning signs (DWW), 139 dengue without warning signs (DWoWS), and 17 had severe dengue (SD). No significant difference was observed in the viral loads between those with SD, DWW and DWoWS (p=0.34). Conclusions/Significance Viral loads in the febrile phase do not appear to significantly associate with subsequent clinical disease severity in a large Sri Lankan cohort. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://medrxiv.org/cgi/content/short/2023.07.27.23293208v1?rss=1 Authors: Pavia, A. T., Cohen, D. M., Leber, A. L., Daly, J. A., Jackson, J. T., Selvarangan, R., Kanwar, N., Bender, J. M., Dien Bard, J., Festekjian, A., Duffy, S., Larsen, C., Holmberg, K. M., Bardsley, T., Haaland, B., Bourzac, K. M., Stockmann, C., Chapin, K. C., Leung, D. T. Abstract: Background: Multiplex molecular tests have greatly enhanced detection of gastrointestinal pathogens. However, data on the impact of these tests on clinical and patient centered outcomes are limited. Methods: We conducted a prospective, multicenter, stepped wedge trial to determine the impact of multiplex molecular testing at five academic childrens hospitals in children presenting to the ED with acute gastroenteritis. Caregivers were interviewed on enrollment and again 7 to 10 days after enrollment to determine symptoms, risk factors, subsequent medical visits, and impact on family members. During the preintervention period, diagnostic testing was performed at the discretion of clinicians. During the intervention period, multiplex molecular testing was performed on all children with results available to clinicians. Primary outcome was return visits to a health care provider within 10 days of enrollment. Results: Potential pathogens were identified by clinician ordered tests in 19/571 (3.3%) in the pre-intervention period compared to 434/586 (74%) in the intervention period; clinically relevant pathogens were detected in 2.1% and 15% respectively. In the multivariate model adjusting for potential confounders, the intervention was associated with a 21% reduction in the odds of any return visit (OR 0.79; 95% CI 0.70 to 0.90). Appropriate treatment was prescribed in 11.3% compared to 19.6% during the intervention period (P=0.22). Conclusions: Routine molecular multiplex testing for all children presenting to the ED with AGE detected more clinically relevant pathogens and led to a 21% decrease in return visits. Additional research is needed to define patients most likely to benefit from testing. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://medrxiv.org/cgi/content/short/2023.07.28.23293282v1?rss=1 Authors: MUSHEBENGE, A. G.-A., Ugbaja, S. C., Mbatha, N. A., Riziki, M. G., Muzumbukilwa, T. W., Kadima, M. G., Nlooto, M. Z., Kumalo, H. M. Abstract: With the onset of the COVID-19 pandemic caused by the novel coronavirus (SARS-CoV-2), there has been a surge in the pursuit of potential therapeutic interventions for this deadly disease. Given the urgency of the situation, computational drug repurposing methods have emerged as a promising strategy for identifying effective treatments from a pool of approved drugs. This systematic review and meta-analaysis will assess the existing research on the use of computational approaches for drug repurposing in the context of COVID-19. SARS-CoV-2 Main Protease is a critical enzyme that plays a vital role in the replication cycle of the SARS-CoV-2 virus, and its inhibition is a promising strategy for the development of antiviral therapies. Different databases (PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL), MEDLINE via EBSCOhost, Google Scholar, and WILEY online Library) will be utilized to identify and incorporate primary research articles in English and French that employed computational methodologies for drug repurposing in the context of COVID-19 and SARS-CoV-2 Main protease inhibition published between March 2020 to May 2023. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-ScR), we will undertake a comprehensive search of relevant studies. Authors will also search peer-reviewed articles, grey literature sources, and reference lists to identify eligible studies. Title screening will be followed by independent abstract and full-text screening by two reviewers. Any study that focuses on the inhibition of the Mpro using computer aided methods will be included. The analysis of data will be carried out by utilizing two software tools - Review Manager software (version 5.3.5) and R software (version 3.6.1). To determine statistical heterogeneity, a standard chi-square test will be applied with a significance level of P less than 0.10. Potential biases related to study size (such as publication bias) will be examined through the application of several techniques, including funnel plots, Egger's test, Begg's test, as well as Trim and Fill analysis. This study will provide evidence-based information and conduct a comprehensive analysis of the computer-aided drug discovery and repurposing of the SARS-CoV-2 Main protease inhibitors, thereby producing a high-quality synthesis of information. The study will also explore potential innovative therapeutic applications for preventing or treating the novel viral infection by the inhibition of the Main Protease. In addition, the review will highlight research gaps in the treatment of COVID-19 and provide suggestions for future research. The outcomes of this review will be shared through a peer-reviewed publication and presented at relevant conferences while ensuring proper dissemination to reach a wide audience. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://medrxiv.org/cgi/content/short/2023.07.27.23293177v1?rss=1 Authors: Peluso, M. J., Ryder, D. M., Flavell, R., Wang, Y., Levi, J., LaFranchi, B. H., Deveau, T.-M. M., Buck, A. M., Munter, S. E., Asare, K. A., Aslam, M., Koch, W., Szabo, G., Hoh, R., Deswal, M., Rodriguez, A., Buitrago, M., Tai, V., Shrestha, U., Lu, S., Goldberg, S. A., Dalhuisen, T., Durstenfeld, M. S., Hsue, P. Y., Kelly, J. D., Kumar, N., Martin, J. N., Gambhir, A., Somsouk, M., Seo, Y., Deeks, S. G., Laszik, Z. G., VanBrocklin, H. F., Henrich, T. J. Abstract: The etiologic mechanisms of post-acute medical morbidities and unexplained symptoms (Long COVID) following SARS-CoV-2 infection are incompletely understood. There is growing evidence that viral persistence and immune dysregulation may play a major role. We performed whole-body positron emission tomography (PET) imaging in a cohort of 24 participants at time points ranging from 27 to 910 days following acute SARS-CoV-2 infection using a novel radiopharmaceutical agent, [18F]F-AraG, a highly selective tracer that allows for anatomical quantitation of activated T lymphocytes. Tracer uptake in the post-acute COVID group, which included those with and without Long COVID symptoms, was significantly higher compared to pre-pandemic controls in many anatomical regions, including the brain stem, spinal cord, bone marrow, nasopharyngeal and hilar lymphoid tissue, cardiopulmonary tissues, and gut wall. Although T cell activation tended to be higher in participants imaged closer to the time of the acute illness, tracer uptake was increased in participants imaged up to 2.5 years following SARS-CoV-2 infection. We observed that T cell activation in spinal cord and gut wall was associated with the presence of Long COVID symptoms. In addition, tracer uptake in lung tissue was higher in those with persistent pulmonary symptoms. Notably, increased T cell activation in these tissues was also observed in many individuals without Long COVID. Given the high [18F]F-AraG uptake detected in the gut, we obtained colorectal tissue for in situ hybridization SARS-CoV-2 RNA and immunohistochemical studies in a subset of participants with Long COVID symptoms. We identified cellular SARS-CoV-2 RNA in rectosigmoid lamina propria tissue in all these participants, ranging from 158 to 676 days following initial COVID-19 illness, suggesting that tissue viral persistence could be associated with long-term immunological perturbations. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://medrxiv.org/cgi/content/short/2023.07.27.23293219v1?rss=1 Authors: Alkasaby, M., Philip, S., Douba, Z., Tu, H., Eaton, J., Mohammed, M., Essar, M. Y., Kamal, M. A., Adeel Riaz, M. M., Moussallem, M., Bosu, W. K., Walker, I. Abstract: Introduction Infectious disease outbreaks have a substantial impact on people's psychosocial well-being. Yet, mental health and psychosocial support (MHPSS) interventions are not systemically integrated into outbreak and epidemic response. Our review aims to synthesise evidence on the effectiveness of MHPSS interventions in outbreaks and propose a framework for systematically integrating MHPSS into outbreak response. Methods We conducted an umbrella review in accordance with the Joanna Briggs Institute (JBI) methodology for umbrella reviews. Results We identified 23 systematic literature reviews, 6 of which involved meta-analysis, and only 30% (n=7) were of high quality. Most of the available literature was produced during COVID-19 and focused on clinical case management and medical staff well-being, with scarce evidence on the well-being of other outbreak responders and MHPSS in other outbreak response pillars. Conclusion Despite the low quality of the majority of the existing evidence, MHPSS interventions have the potential to improve the psychological well-being of those affected by and those responding to outbreaks. They also can improve the outcomes of the outbreak response activities such as contact tracing, infection prevention and control, and clinical case management. Our proposed framework would facilitate integrating MHPSS into outbreak response and hence mitigate the mental health impact of outbreaks. Review registration PROSPERO CRD42022297138. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://medrxiv.org/cgi/content/short/2023.07.26.23293188v1?rss=1 Authors: Drysdale, M., Galimov, E. R., Yarwood, M. J., Patel, V., Levick, B., Gibbons, D. C., Watkins, J. D., Young, S., Pierce, B. F., Lloyd, E. J., Kerr, W., Birch, H. J., Kamalati, T., Brett, S. J. Abstract: Introduction: There is uncertainty regarding how in vitro antibody neutralisation activity translates to the clinical efficacy of sotrovimab against severe acute respiratory syndrome coronavirus 2, although real-world evidence has demonstrated continued effectiveness during both BA.2 and BA.5 predominance. We previously reported descriptive results from the Discover dataset for patients treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or patients at highest risk per National Health Service (NHS) criteria but who were untreated. This study sought to assess the effectiveness of sotrovimab compared with no early coronavirus disease 2019 (COVID-19) treatment in highest-risk patients with COVID-19. Methods: Retrospective cohort study using the Discover dataset in North West London. Patients had to be non-hospitalised at index, aged greater than or equal to 12 years old and meet greater than or equal to 1 of the NHS highest-risk criteria for receiving early COVID-19 treatment with sotrovimab. The primary objective was to assess the risk of COVID-19-related hospitalisation and/or COVID-19-related death within 28 days of the observed/imputed treatment date between patients treated with sotrovimab and highest-risk patients who received no early COVID-19 treatment. We also performed subgroup analyses for patients aged less than 65 and greater than or equal to 65 years, patients with renal dysfunction, and by Omicron subvariant prevalence period (BA.1/2 emergence: 1 December 2021-12 February 2022 [period 1]; BA.2 reaching and at its peak: 13 February-31 May 2022 [period 2]; BA.2 falling and BA.4/5 emergence: 1 June-31 July 2022 [period 3]). Inverse probability of treatment weighting based on propensity scores was used to adjust for measured known and likely confounders between the cohorts. Cox proportional hazards models with stabilised weights were performed to assess hazard ratios (HRs). Results: A total of 599 highest-risk patients treated with sotrovimab and 5,191 untreated highest-risk patients were included. Compared with untreated patients, sotrovimab treatment reduced the risk of COVID-19 hospitalisation or death by 50% (HR=0.50; 95% confidence interval [CI] 0.24, 1.06); however, statistical significance was not reached (p=0.07). In addition, sotrovimab reduced the risk of COVID-19 hospitalisation by 57% (HR=0.43; 95% CI 0.18, 1.00) compared with the untreated group, although also not statistically significant (p=0.051). Among patients aged greater than or equal to 65 years and patients with renal disease, sotrovimab treatment was associated with a significantly reduced risk of COVID-19 hospitalisation, by 89% (HR=0.11; 95% CI 0.02, 0.82; p=0.03) and 82% (HR=0.18; 95% CI 0.05, 0.62; p=0.007), respectively. In period 1, sotrovimab treatment was associated with a 75% lower risk of COVID-19 hospitalisation or death compared with the untreated group (HR=0.25; 95% CI 0.07, 0.89; p=0.032). In periods 2 and 3, HRs of COVID-19 hospitalisation or death were 0.53 (95% CI 0.14, 2.00; p=0.35) and 0.78 (95% CI 0.23, 2.69; p=0.69), respectively, for the sotrovimab versus untreated groups, but differences were not statistically significant. Conclusions: Sotrovimab treatment was associated with a significant reduction in risk of COVID-19 hospitalisation in patients aged greater than or equal to 65 years and those with renal disease compared with the untreated cohort. For the overall cohort, the risk of hospitalisation following sotrovimab treatment was also lower compared with the untreated group; however, this did not achieve statistical significance (p=0.051). The risk of hospitalisation and/or death was lower for the...