PLOS ONE: [sortOrder=DATE_NEWEST_FIRST, sort=Date, newest first, q=subject:"Pharmacology"]PLOShttps://journals.plos.org/plosone/webmaster@plos.orgaccelerating the publication of peer-reviewed sciencehttps://journals.plos.org/plosone/search/feed/atom?sortOrder=DATE_NEWEST_FIRST&unformattedQuery=subject:%22Pharmacology%22&sort=Date,+newest+firstAll PLOS articles are Open Access.https://journals.plos.org/plosone/resource/img/favicon.icohttps://journals.plos.org/plosone/resource/img/favicon.ico2024-03-29T00:45:54ZBehind the scenes: Centromere-driven genomic innovations in fungal pathogensAswathy NarayananMd. Hashim RezaKaustuv Sanyal10.1371/journal.ppat.10120802024-03-28T14:00:00Z2024-03-28T14:00:00Z<p>by Aswathy Narayanan, Md. Hashim Reza, Kaustuv Sanyal</p>Etonogestrel-releasing subdermal contraceptive implant: Budget impact analysis based on the Brazilian private healthcare systemAgnaldo Lopes da Silva FilhoRicardo Luis Pereira BuenoYohanna RamiresLara Marina Cruz Lino10.1371/journal.pone.03012072024-03-28T14:00:00Z2024-03-28T14:00:00Z<p>by Agnaldo Lopes da Silva Filho, Ricardo Luis Pereira Bueno, Yohanna Ramires, Lara Marina Cruz Lino</p>
High rates of unplanned pregnancies persist despite pharmacological developments and advancements in contraceptive methods. Here, we demonstrate that the etonogestrel-releasing subdermal contraceptive implant (IMP-ETN) may be an appropriate and cost-effective alternative to levonorgestrel-releasing intrauterine systems (LNG-IUSs) for women in Brazil. For our pharmacoeconomic analysis, we reviewed the literature on IMP-ETN regarding its acceptance, eligibility criteria, choice, relations with age, adverse events and, finally, the unmet need in the fee-for-service private healthcare sector. We considered qualitative observations in combination with quantitative analysis and performed a deterministic sensitivity analysis to investigate whether this technology can be self-sustainable over a period of five years. The target population for this analysis comprised 158,696 women. Compared with the continued use of LNG-IUSs, adopting the IMP-ETN can result in a cost avoidance of $ 7.640.804,02 in the first year and $ 82,455,254.43 in five years. Disseminating information among physicians will promote this change and strengthen the potential cost avoided by private health system payers. These savings can be used to improve other healthcare programs and strategies. Moreover, the principles of care can be promoted by improving and adapting healthcare systems and expanding treatment and follow-up strategies. This would also provide support to women’s reproductive rights and improve their quality of life. Our results suggest that the IMP-ETN has a favorable cost-effectiveness profile. Given all its advantages and negative incremental cost impact over a period of five years, the IMP-ETN may be a more favorable alternative to LNG-IUSs. Therefore, it should be offered to beneficiaries with a private healthcare plan. This analysis overcomes previous barriers to the use of cost-benefit models, and our results may help balance decision-making by policymakers, technical consultants, and researchers.Impact of COVID-19 vaccination on liver transplant recipients. Experience in a reference center in MexicoDaniel Azamar-LlamasJosealberto Sebastiano Arenas-MartinezAntonio Olivas-MartinezJose Victor JimenezEric Kauffman-OrtegaCristian J García-CarreraBruno Papacristofilou-RiebelingFabián E Rivera-LópezIgnacio García-Juárez10.1371/journal.pone.03011982024-03-28T14:00:00Z2024-03-28T14:00:00Z<p>by Daniel Azamar-Llamas, Josealberto Sebastiano Arenas-Martinez, Antonio Olivas-Martinez, Jose Victor Jimenez, Eric Kauffman-Ortega, Cristian J García-Carrera, Bruno Papacristofilou-Riebeling, Fabián E Rivera-López, Ignacio García-Juárez</p>
Background and aims <p>COVID-19 vaccination has proved to be effective to prevent symptomatic infection and severe disease even in immunocompromised patients including liver transplant patients. We aim to assess the impact of COVID-19 vaccination on the mortality and development of severe and critical disease in our center.</p> Methods <p>A retrospective cohort study of LT patients in a reference center between March 2020 and February 2022. Demographic data, cirrhosis etiology, time on liver transplantation, immunosuppressive therapies, and vaccination status were recorded at the time of diagnosis. Primary outcome was death due to COVID-19, and secondary outcomes included the development of severe COVID-19 and intensive care unit (ICU) requirement.</p> Results <p>153 of 324 LT recipients developed COVID-19, in whom the main causes of cirrhosis were HCV infection and metabolic-associated fatty liver disease. The vaccines used were BNT162b2 (48.6%), ChAdOx1 nCoV-19 (21.6%), mRNA-1273 vaccine (1.4%), Sputnik V (14.9%), Ad5-nCoV-S (4.1%) and CoronaVac (9.5%). Case fatality and ICU requirement risk were similar among vaccinated and unvaccinated LT patients (adjusted relative case fatality for vaccinated versus unvaccinated of 0.68, 95% CI 0.14–3.24, p = 0.62; adjusted relative risk [aRR] for ICU requirement of 0.45, 95% CI 0.11–1.88, p = 0.27). Nonetheless, vaccination was associated with a lower risk of severe disease (aRR for severe disease of 0.32, 95% CI 0.14–0.71, p = 0.005).</p> Conclusions <p>Vaccination reduces the risk of severe COVID-19 in LT patients, regardless of the scheme used. Vaccination should be encouraged for all.</p>Focused deterrence: A protocol for a realist multisite randomised controlled trial for evaluating a violence prevention intervention in the UKTia SimanovicPaul McFarlaneIain BrennanWilliam GrahamAlex Sutherland10.1371/journal.pone.03010232024-03-28T14:00:00Z2024-03-28T14:00:00Z<p>by Tia Simanovic, Paul McFarlane, Iain Brennan, William Graham, Alex Sutherland</p>
Introduction <p>Focused deterrence (FD) is a frequently cited intervention for preventing violence, particularly against violent urban gangs. The Youth Endowment Fund (YEF) believes it could be effective in the UK, based primarily on research conducted in the US. However, we contend that these studies have inadequate methodological designs, lack of rigorous testing, and small sample sizes. Therefore, the evidence supporting focused deterrence as an effective method, particularly outside the US, is inconclusive. The aim of the protocol is to better understand the potential effects of FD in the context of the UK, using a multisite evaluation experimental design to more closely investigate the evidence of its likely impact.</p> Methods <p>We planned a realist randomised controlled trial. The design is focused on a multisite trial consisting of two-arm randomised experiments in five locations. Each trial location will test their implementation of a core programme specified by the funder. The multisite nature will allow us to understand differential impacts between locations, improving the external validity of the results. Participants will be randomly selected from a wider pool of eligible individuals for the intervention. We estimate a sample size of approximately <i>N</i> = 1,700 individuals is required. Based on this pooled sample size, a relative reduction of 26% would be detectable in 80% of trials. The trial is coupled with a formative process evaluation of delivery and fidelity. The formative evaluation will use a mixed methods design. The qualitative aspect will include semi-structured cross-sectional and longitudinal interviews with programme leads, programme delivery team, and programme participants, as well as observations of the meetings between the programme delivery team (i.e., community navigators/mentors) and programme participants. The quantitative data for the formative evaluation will be gathered by the sites themselves and consist of routine outcome performance monitoring using administrative data. Sampling for interviews and observations will vary, with the researchers aiming for a higher number of individuals included in the first round of cross-sectional interviews and retaining as many as possible for repeat interviews and observations.</p> Discussion <p>This protocol outlines the process and impact evaluation methodology for the most extensive multisite evaluation of focused deterrence to date in the UK. Spanning five distinct sites with seven trials, the evaluation includes a cohort of 2,000 individuals, marking it as the only multisite trial of focused deterrence. Employing an integrated realist evaluation framework, the study uses qualitative and quantitative research methods. The anticipated findings will offer pivotal insights for formulating future violence prevention policies in the UK. They are also expected to contribute significantly to the corpus of literature on violence prevention and intervention evaluation.</p> Trial registration <p>Protocol registration: ISRCTN: 11650008 4<sup>th</sup> June 2023.</p>Saliva sampling method influences oral microbiome composition and taxa distribution associated with oral diseasesCristian RocaAlaa A. AlkhateebBryson K. DeanhardtJade K. MacdonaldDonald L. ChiJeremy R. WangMatthew C. Wolfgang10.1371/journal.pone.03010162024-03-28T14:00:00Z2024-03-28T14:00:00Z<p>by Cristian Roca, Alaa A. Alkhateeb, Bryson K. Deanhardt, Jade K. Macdonald, Donald L. Chi, Jeremy R. Wang, Matthew C. Wolfgang</p>
Saliva is a readily accessible and inexpensive biological specimen that enables investigation of the oral microbiome, which can serve as a biomarker of oral and systemic health. There are two routine approaches to collect saliva, stimulated and unstimulated; however, there is no consensus on how sampling method influences oral microbiome metrics. In this study, we analyzed paired saliva samples (unstimulated and stimulated) from 88 individuals, aged 7–18 years. Using 16S rRNA gene sequencing, we investigated the differences in bacterial microbiome composition between sample types and determined how sampling method affects the distribution of taxa associated with untreated dental caries and gingivitis. Our analyses indicated significant differences in microbiome composition between the sample types. Both sampling methods were able to detect significant differences in microbiome composition between healthy subjects and subjects with untreated caries. However, only stimulated saliva revealed a significant association between microbiome diversity and composition in individuals with diagnosed gingivitis. Furthermore, taxa previously associated with dental caries and gingivitis were preferentially enriched in individuals with each respective disease only in stimulated saliva. Our study suggests that stimulated saliva provides a more nuanced readout of microbiome composition and taxa distribution associated with untreated dental caries and gingivitis compared to unstimulated saliva.Effects of the Momentum project on postpartum family planning norms and behaviors among married and unmarried adolescent and young first-time mothers in Kinshasa: A quasi-experimental studyAnastasia J. GageFrancine E. WoodRianne GayPierre Akilimali10.1371/journal.pone.03003422024-03-28T14:00:00Z2024-03-28T14:00:00Z<p>by Anastasia J. Gage, Francine E. Wood, Rianne Gay, Pierre Akilimali</p>
This study evaluated the effect of Momentum–an integrated family planning, maternal and newborn health, and nutrition intervention–on postpartum family planning norms and behaviors among ever married and never-married first-time mothers age 15–24 in Kinshasa, Democratic Republic of the Congo. Using data collected in 2018 and 2020, we conducted an intent-to-treat analysis among 1,927 first-time mothers who were about six-months pregnant at enrollment. Difference-in-differences models were run for panel data and treatment effects models with inverse-probability weighting for endline-only outcomes. Average treatment effects (ATE) were estimated. Momentum had positive effects on partner discussion of family planning in the early postpartum period (ever married 15–19: ATE = 0.179, 95% CI = 0.098, 0.261; never married 15–19: ATE = 0.131, 95% CI = 0.029, 0.232; ever married 20–24: ATE = 0.233, 95% CI = 0.164, 0.302; never married 20–24: ATE = 0.241, 95% CI = 0.121, 0.362) and discussion with a health worker, and on obtaining a contraceptive method in the early postpartum period, except among never married adolescents. Among adolescents, intervention effects on modern contraceptive use within 12 months of childbirth/pregnancy loss were larger for the never married (ATE = 0.251, 95% CI = 0.122, 0.380) than the ever married (ATE = 0.114, 95% CI = 0.020, 0.208). Full intervention exposure had consistently larger effects on contraceptive behaviors than partial exposure, except among ever married adolescents. Momentum had no effect on normative expectations about postpartum family planning use among adolescents, and on descriptive norms and personal agency among those who were never married. Results for normative outcomes and personal agency underscored the intersectionality between young maternal age and marital status. Future programs should improve personal agency and foster normative change in support of postpartum family planning uptake and tailor interventions to different age and marital status subsets of first-time mothers.Characterization of a hemolytic and antibiotic-resistant <i>Pseudomonas aeruginosa</i> strain S3 pathogenic to fish isolated from Mahananda River in IndiaDipanwita GhoshPreeti MangarAbhinandan ChoudhuryAnoop KumarAniruddha SahaProtip BasuDipanwita Saha10.1371/journal.pone.03001342024-03-28T14:00:00Z2024-03-28T14:00:00Z<p>by Dipanwita Ghosh, Preeti Mangar, Abhinandan Choudhury, Anoop Kumar, Aniruddha Saha, Protip Basu, Dipanwita Saha</p>
Virulent strain <i>Pseudomonas aeruginosa</i> isolated from Mahananda River exhibited the highest hemolytic activity and virulence factors and was pathogenic to fish as clinical signs of hemorrhagic spots, loss of scales, and fin erosions were found. S3 was cytotoxic to the human liver cell line (WRL-68) in the trypan blue dye exclusion assay. Genotype characterization using whole genome analysis showed that S3 was similar to <i>P</i>. <i>aeruginosa</i> PAO1. The draft genome sequence had an estimated length of 62,69,783 bp, a GC content of 66.3%, and contained 5916 coding sequences. Eight genes across the genome were predicted to be related to hemolysin action. Antibiotic resistance genes such as class C and class D beta-lactamases, <i>fosA</i>, <i>APH</i>, and <i>catB</i> were detected, along with the strong presence of multiple efflux system genes. This study shows that river water is contaminated by pathogenic <i>P</i>. <i>aeruginosa</i> harboring an array of virulence and antibiotic resistance genes which warrants periodic monitoring to prevent disease outbreaks.Efficacy and safety of biologic agents for IgA nephropathy: A protocol for systematic review and meta-analysisJia MaJianyue XingYupeng ZhangGuangzhen Liu10.1371/journal.pone.02987322024-03-28T14:00:00Z2024-03-28T14:00:00Z<p>by Jia Ma, Jianyue Xing, Yupeng Zhang, Guangzhen Liu</p>
Background <p>IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide and a leading cause of chronic kidney failure. There are currently no definitive therapeutic regimens to treat or prevent the progression of IgAN. However, biologic agents offer novel therapeutic approaches that target immunological mechanisms to slow or halt disease progression. The objective of this study is to evaluate the efficacy and safety of biologic agents in patients with IgA nephropathy.</p> Methods <p>We will systematically search PubMed, EMbase, Web of Science, Cochrane Library, and www.clinicaltrials.gov for randomized controlled trials of biologic agents for the treatment of IgA nephropathy. The search period will span from the establishment of each database until October 2023. The quality assessment of included studies will be performed individually using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2), and meta-analysis will be conducted using Revman 5.4.1 software.</p> Conclusions <p>The results of this study will provide evidence-based medical evidence for the clinical application of biologic agents in patients with IgA nephropathy.</p> Prospero registration number <p>CRD42023400450.</p>Reflected generalized concentration addition and Bayesian hierarchical models to improve chemical mixture predictionDaniel ZilberKyle Messier10.1371/journal.pone.02986872024-03-28T14:00:00Z2024-03-28T14:00:00Z<p>by Daniel Zilber, Kyle Messier</p>
Environmental toxicants overwhelmingly occur together as mixtures. The variety of possible chemical interactions makes it difficult to predict the danger of the mixture. In this work, we propose the novel Reflected Generalized Concentration Addition (RGCA), a piece-wise, geometric technique for sigmoidal dose-responsed inverse functions that extends the use of generalized concentration addition (GCA) for 3+ parameter models. Since experimental tests of all relevant mixtures is costly and intractable, we rely only on the individual chemical dose responses. Additionally, RGCA enhances the classical two-step model for the cumulative effects of mixtures, which assumes a combination of GCA and independent action (IA). We explore how various clustering methods can dramatically improve predictions. We compare our technique to the IA, CA, and GCA models and show in a simulation study that the two-step approach performs well under a variety of true models. We then apply our method to a challenging data set of individual chemical and mixture responses where the target is an androgen receptor (Tox21 AR-luc). Our results show significantly improved predictions for larger mixtures. Our work complements ongoing efforts to predict environmental exposure to various chemicals and offers a starting point for combining different exposure predictions to quantify a total risk to health.Similarity and dissimilarity in alterations of the gene expression profile associated with inhalational anesthesia between sevoflurane and desfluraneTakehiro NogiKousuke UranishiAyumu SuzukiMasataka HirasakiTina NakamuraTomiei KazamaHiroshi NagasakaAkihiko OkudaTsutomu Mieda10.1371/journal.pone.02982642024-03-28T14:00:00Z2024-03-28T14:00:00Z<p>by Takehiro Nogi, Kousuke Uranishi, Ayumu Suzuki, Masataka Hirasaki, Tina Nakamura, Tomiei Kazama, Hiroshi Nagasaka, Akihiko Okuda, Tsutomu Mieda</p>
Although sevoflurane is one of the most commonly used inhalational anesthetic agents, the popularity of desflurane is increasing to a level similar to that of sevoflurane. Inhalational anesthesia generally activates and represses the expression of genes related to xenobiotic metabolism and immune response, respectively. However, there has been no comprehensive comparison of the effects of sevoflurane and desflurane on the expression of these genes. Thus, we used a next-generation sequencing method to compare alterations in the global gene expression profiles in the livers of rats subjected to inhalational anesthesia by sevoflurane or desflurane. Our bioinformatics analyses revealed that sevoflurane and, to a greater extent, desflurane significantly activated genes related to xenobiotic metabolism. Our analyses also revealed that both anesthetic agents, especially sevoflurane, downregulated many genes related to immune response.Safety and efficacy of antioxidant therapy in children and adolescents with attention deficit hyperactivity disorder: A systematic review and network meta-analysisPeike ZhouXiaohui YuTao SongXiaoli Hou10.1371/journal.pone.02969262024-03-28T14:00:00Z2024-03-28T14:00:00Z<p>by Peike Zhou, Xiaohui Yu, Tao Song, Xiaoli Hou</p>
Objective <p>To systematically evaluate the safety and efficacy of antioxidant therapy in children and adolescents with attention deficit hyperactivity disorder (ADHD).</p> Methods <p>Randomized controlled trials and prospective studies on antioxidant therapy in children and adolescents with ADHD were searched in PubMed, Embase, and Cochrane Library from the inception of databases to November 12, 2022. Two investigators independently screened the literature, extracted data, and evaluated the quality of the included studies. Network meta-analysis (PROSPERO registration number CRD 42023382824) was carried out by using R Studio 4.2.1.</p> Results <p>48 studies involving 12 antioxidant drugs (resveratrol, pycnogenol, omega-3, omega-6, quercetin, phosphatidylserine, almond, vitamin D, zinc, folic acid, ginkgo biloba, Acetyl-L-carnitine) were finally included, with 3,650 patients. Network meta-analysis showed that omega-6 (0.18), vitamin D (0.19), and quercetin (0.24) were the top three safest drugs according to SUCRA. The omega-3 (SUCRA 0.35), pycnogenol (SUCRA 0.36), and vitamin D (SUCRA 0.27) were the most effective in improving attention, hyperactivity, and total score of Conners’ parent rating scale (CPRS), respectively. In terms of improving attention, hyperactivity, and total score of Conners’ teacher rating scale (CTRS), pycnogenol (SUCRA 0.32), phosphatidylserine+omega-3 (SUCRA 0.26), and zinc (SUCRA 0.34) were the most effective, respectively. In terms of improving attention, hyperactivity and total score of ADHD Rating Scale-Parent, the optimal agents were phosphatidylserine (SUCRA 0.39), resveratrol+MPH (SUCRA 0.24), and phosphatidylserine (SUCRA 0.34), respectively. In terms of improving attention, hyperactivity and total score of ADHD Rating Scale-Teacher, pycnogenol (SUCRA 0.32), vitamin D (SUCRA 0.31) and vitamin D (SUCRA 0.18) were the optimal agents, respectively. The response rate of omega-3+6 was the highest in CGI (SUCRA 0.95) and CPT (SUCRA 0.42).</p> Conclusion <p>The rankings of safety and efficacy of the 12 antioxidants vary. Due to the low methodological quality of the included studies, the probability ranking cannot fully explain the clinical efficacy, and the results need to be interpreted with caution. More high-quality studies are still needed to verify our findings.</p>Developing medical simulations for opioid overdose response training: A qualitative analysis of narratives from responders to overdosesG. Franklin EdwardsCassandra MierischBrock MutchesonAllison StraussKeel ColemanKimberly HornSarah Henrickson Parker10.1371/journal.pone.02946262024-03-28T14:00:00Z2024-03-28T14:00:00Z<p>by G. Franklin Edwards, Cassandra Mierisch, Brock Mutcheson, Allison Strauss, Keel Coleman, Kimberly Horn, Sarah Henrickson Parker</p>
Medical simulation offers a controlled environment for studying challenging clinical care situations that are difficult to observe directly. Overdose education and naloxone distribution (OEND) programs aim to train potential rescuers in responding to opioid overdoses, but assessing rescuer performance in real-life situations before emergency medical services arrive is exceedingly complex. There is an opportunity to incorporate individuals with firsthand experience in treating out-of-hospital overdoses into the development of simulation scenarios. Realistic overdose simulations could provide OEND programs with valuable tools to effectively teach hands-on skills and support context-sensitive training regimens. In this research, semi-structured interviews were conducted with 17 individuals experienced in responding to opioid overdoses including emergency department physicians, first responders, OEND program instructors, and peer recovery specialists. Two coders conducted qualitative content analysis using open and axial thematic coding to identify nuances associated with illicit and prescription opioid overdoses. The results are presented as narrative findings complemented by summaries of the frequency of themes across the interviews. Over 20 hours of audio recording were transcribed verbatim and then coded. During the open and axial thematic coding process several primary themes, along with subthemes, were identified, highlighting the distinctions between illicit and prescription opioid overdoses. Distinct contextual details, such as locations, clinical presentations, the environment surrounding the patient, and bystanders’ behavior, were used to create four example simulations of out-of-hospital overdoses. The narrative findings in this qualitative study offer context-sensitive information for developing out-of-hospital overdose scenarios applicable to simulation training. These insights can serve as a valuable resource, aiding instructors and researchers in systematically creating evidence-based scenarios for both training and research purposes.Progress and challenges in achieving tuberculosis elimination in India by 2025: A systematic review and meta-analysisAbhishek PadhiAshwini AgarwalMayuri BhiseAnil ChaudharyKrupal JoshiC. D. S. Katoch10.1371/journal.pone.03010602024-03-27T14:00:00Z2024-03-27T14:00:00Z<p>by Abhishek Padhi, Ashwini Agarwal, Mayuri Bhise, Anil Chaudhary, Krupal Joshi, C. D. S. Katoch</p>
Background <p>Tuberculosis (TB) continues to pose a significant public health challenge in India, which is home to one of the highest TB burdens worldwide. This systematic review and meta-analysis will aim to synthesize the anticipated progress and potential challenges in achieving TB elimination in India by 2025.</p> Methods <p>A comprehensive search will be conducted across multiple databases, including PubMed, Scopus, and Web of Science, to identify relevant studies. The eligibility criteria will encompass individuals diagnosed with TB in India, interventions targeting TB treatment, prevention, or control, and various comparator groups. Outcomes of interest will include incidence reduction, mortality rate, treatment success rate, barriers to TB care, and more. Both quantitative and qualitative data will be synthesized, and the risk of bias will be assessed using established tools.</p> Outcomes <p>The review is expected to provide a holistic understanding of the TB landscape in India, highlighting the effective interventions and potential challenges in the journey towards TB elimination.</p> Conclusions <p>While it is anticipated that significant progress will be made in the fight against TB in India, challenges are likely to persist. This review will offer a comprehensive roadmap for researchers, policymakers, and healthcare professionals, emphasizing the importance of continued efforts, innovative strategies, and a multi-pronged approach in achieving the goal of TB elimination in India by 2025.</p>Study protocol: Identifying transcriptional regulatory alterations of chronic effects of blast and disturbed sleep in United States VeteransMolly J. SullanKelly A. Stearns-YoderZhaoyu WangAndrew J. HoisingtonAdam D. BramowethWalter CarrYongchao GeHanga GalfalvyFatemah HaghighiLisa A. Brenner10.1371/journal.pone.03010262024-03-27T14:00:00Z2024-03-27T14:00:00Z<p>by Molly J. Sullan, Kelly A. Stearns-Yoder, Zhaoyu Wang, Andrew J. Hoisington, Adam D. Bramoweth, Walter Carr, Yongchao Ge, Hanga Galfalvy, Fatemah Haghighi, Lisa A. Brenner</p>
Injury related to blast exposure dramatically rose during post-911 era military conflicts in Iraq and Afghanistan. Mild traumatic brain injury (mTBI) is among the most common injuries following blast, an exposure that may not result in a definitive physiologic marker (e.g., loss of consciousness). Recent research suggests that exposure to low level blasts and, more specifically repetitive blast exposure (RBE), which may be subconcussive in nature, may also impact long term physiologic and psychological outcomes, though findings have been mixed. For military personnel, blast-related injuries often occur in chaotic settings (e.g., combat), which create challenges in the immediate assessment of related-injuries, as well as acute and post-acute sequelae. As such, alternate means of identifying blast-related injuries are needed. Results from previous work suggest that epigenetic markers, such as DNA methylation, may provide a potential stable biomarker of cumulative blast exposure that can persist over time. However, more research regarding blast exposure and associations with short- and long-term sequelae is needed. Here we present the protocol for an observational study that will be completed in two phases: Phase 1 will address blast exposure among Active Duty Personnel and Phase 2 will focus on long term sequelae and biological signatures among Veterans who served in the recent conflicts and were exposed to repeated blast events as part of their military occupation. Phase 2 will be the focus of this paper. We hypothesize that Veterans will exhibit similar differentially methylated regions (DMRs) associated with changes in sleep and other psychological and physical metrics, as observed with Active Duty Personnel. Additional analyses will be conducted to compare DMRs between Phase 1 and 2 cohorts, as well as self-reported psychological and physical symptoms. This comparison between Service Members and Veterans will allow for exploration regarding the natural history of blast exposure in a quasi-longitudinal manner. Findings from this study are expected to provide additional evidence for repetitive blast-related physiologic changes associated with long-term neurobehavioral symptoms. It is expected that findings will provide foundational data for the development of effective interventions following RBE that could lead to improved long-term physical and psychological health.Caregivers of children with HIV in Botswana prefer monthly IV Broadly Neutralizing Antibodies (bNAbs) to daily oral ARTMaureen Sakoi-MosetlhiGbolahan AjibolaRoxanna HaghighatOganne BatlangKenneth MaswabiMolly Pretorius-HolmeKathleen M. PowisShahin LockmanJoseph MakhemaMathias LitcherfeldDaniel R. KuritzkesRoger Shapiro10.1371/journal.pone.02999422024-03-27T14:00:00Z2024-03-27T14:00:00Z<p>by Maureen Sakoi-Mosetlhi, Gbolahan Ajibola, Roxanna Haghighat, Oganne Batlang, Kenneth Maswabi, Molly Pretorius-Holme, Kathleen M. Powis, Shahin Lockman, Joseph Makhema, Mathias Litcherfeld, Daniel R. Kuritzkes, Roger Shapiro</p>
Introduction <p>Monthly intravenous infusion of broadly neutralizing monoclonal antibodies may be an attractive alternative to daily oral antiretroviral treatment for children living with HIV. However, acceptability among caregivers remains unknown.</p> Methods <p>We evaluated monthly infusion of dual bNAbs (VRCO1LS and 10–1074) as a treatment alternative to ART among children participating in the Tatelo Study in Botswana. Eligible children aged 2–5 years received 8–32 weeks of bNAbs overlapping with ART, and up to 24 weeks of bNAbs alone as monthly intravenous infusion. Using closed-ended questionnaires, we evaluated caregiver acceptability of each treatment strategy prior to the first bNAb administration visit (pre-intervention) and after the completion of the final bNAb administration visit (post-intervention).</p> Results <p>Twenty-five children completed the intervention phase of the study, and acceptability data were available from 24 caregivers at both time points. Responses were provided by the child’s mother at both visits (60%), an extended family member at both visits (28%), or a combination of mother and an extended family member (12%). Caregiver acceptance of monthly bNAb infusions was extremely high both pre-and post-intervention, with 21/24 (87.5%) preferring bNAbs to ART pre-intervention, and 21/25 (84%) preferring bNAbs post-intervention. While no caregiver preferred ART pre-intervention, 2/25 preferred it post-intervention. Pre-intervention, 3 (13%) caregivers had no preference between monthly bNAbs or daily ART, and 2 (8%) had no preference post-intervention. Pre-intervention, the most common reasons for preferring bNAbs over ART were the perception that bNAbs were better at suppressing the virus than ART (n = 10) and the fact that infusions were dosed once monthly compared to daily ART (n = 9). Post-intervention, no dominant reason for preferring bNAbs over ART emerged from caregivers.</p> Conclusions <p>Monthly intravenous bNAb infusions were highly acceptable to caregivers of children with HIV in Botswana and preferred over standard ART by the majority of caregivers.</p> Clinical Trial Number <p>NCT03707977.</p>