Prevalence and Clinical Significance of Electrocardiographic Complete Right Bundle Branch Block in Young Individuals.

BACKGROUND AND AIMS: There is limited information on the clinical significance of complete right bundle branch block (CRBBB) in young individuals. The aim of this study was to determine the prevalence and significance of CRBBB in a large cohort of young individuals aged 14-35 years old. METHODS: From 2008 to 2018, 104,369 consecutive individuals underwent a cardiovascular assessment with a health questionnaire, electrocardiogram, clinical consultation, and selective echocardiography. Follow-up was obtained via direct telephone consultations. Mean follow-up was 7.3 ± 2.7 years. RESULTS: CRBBB was identified in 154 (0.1%) individuals and was more prevalent in males compared with females (0.20% vs. 0.06%; p<0.05) and in athletes compared with non-athletes (0.25% vs. 0.14%; p<0.05). CRBBB-related cardiac conditions were identified in 7 (5%) individuals (4 with atrial septal defect, 1 with Brugada syndrome, 1 with progressive cardiac conduction disease and 1 with atrial fibrillation). Pathology was more frequently identified in individuals with non-isolated CRBBB compared with individuals with isolated CRBBB (14% vs 1%; p < 0.05) and in individuals with a QRS duration of ≥130 milliseconds (ms) compared with individuals with a QRS of <130ms (10% vs 1%; p<0.05). CONCLUSION: The prevalence of CRBBB in young individuals was 0.1% and was more prevalent in males and athletes. CRBBB-related conditions were identified in 5% of individuals and were more common in individuals with non-isolated CRBBB and more pronounced intraventricular conduction delay (QRS duration of ≥130ms). Secondary evaluation should be considered for young individuals with CRBBB with symptoms, concerning family history, additional electrocardiographic anomalies or significant QRS prolongation (≥130ms).

There is limited information on the clinical significance of complete right bundle branch block (CRBBB) in young people (aged 14 to 35 years old). CRBBB is a rare finding in young individuals and is more common in male and athletic individuals. CRBBB related-conditions are found in 5% of young individuals with this electrocardiogram finding and are more common in those with additional heart symptoms, family history of premature heart disease, other abnormal electrocardiographic (ECG) findings and more pronounced forms of CRBBB (≥ 130 milliseconds). Further investigation, including at least an ultrasound of the heart (echocardiogram), is recommended for all young individuals with CRBBB with concerning symptoms, family history of heart disease, additional ECG anomalies or more pronounced CRBBB (≥130milliseconds).

Use of pediatric thymus to humanize mice for HIV-1 mucosal transmission.

Humanized mice have been used to study human immunodeficiency virus type 1 (HIV-1) transmission, pathogenesis, and treatment. The ability of pediatric thymus tissue implanted either in the leg (Leg PedThy) or under the renal capsule (Renal PedThy) with allogeneic CD34+ hematopoietic cells (HSCs) in NSG mice was evaluated for reconstitution of human immune cells and for rectal transmission of HIV-1. These mice were compared to traditional BLT mice implanted with fetal liver and thymus under the renal capsule and mice injected only with HSCs. Renal PedThy mice had similar immune reconstitution in the blood, spleen and intestine as BLT mice, while Leg PedThy mice had transient detection of immune cells, particularly CD4+ T cells and macrophages, the target cells for HIV-1 infection. Rectal transmission and replication of HIV-1 was efficient in BLT mice but lower and more variable in Renal PedThy mice. HIV-1 was poorly transmitted in HSC mice and not transmitted in Leg PedThy mice, which correlated with the frequencies of target cells in the spleen and intestine. Humanization of NSG mice with pediatric thymus was successful when implanted under the kidney capsule, but led to less efficient HIV-1 rectal transmission and replication compared to BLT mice.

Targeting spike glycans to inhibit SARS-CoV2 viral entry.

SARS-CoV-2 spike harbors glycans which function as ligands for lectins. Therefore, it should be possible to exploit lectins to target SARS-CoV-2 and inhibit cellular entry by binding glycans on the spike protein. Burkholderia oklahomensis agglutinin (BOA) is an antiviral lectin that interacts with viral glycoproteins via N-linked high mannose glycans. Here, we show that BOA binds to the spike protein and is a potent inhibitor of SARS-CoV-2 viral entry at nanomolar concentrations. Using a variety of biophysical approaches, we demonstrate that the interaction is avidity driven and that BOA cross-links the spike protein into soluble aggregates. Furthermore, using virus neutralization assays, we demonstrate that BOA effectively inhibits all tested variants of concern as well as SARS-CoV 2003, establishing that multivalent glycan-targeting molecules have the potential to act as pan-coronavirus inhibitors.

Designing UAV Swarm Experiments: A Simulator Selection and Experiment Design Process.

The rapid advancement and increasing number of applications of Unmanned Aerial Vehicle (UAV) swarm systems have garnered significant attention in recent years. These systems offer a multitude of uses and demonstrate great potential in diverse fields, ranging from surveillance and reconnaissance to search and rescue operations. However, the deployment of UAV swarms in dynamic environments necessitates the development of robust experimental designs to ensure their reliability and effectiveness. This study describes the crucial requirement for comprehensive experimental design of UAV swarm systems before their deployment in real-world scenarios. To achieve this, we begin with a concise review of existing simulation platforms, assessing their suitability for various specific needs. Through this evaluation, we identify the most appropriate tools to facilitate one's research objectives. Subsequently, we present an experimental design process tailored for validating the resilience and performance of UAV swarm systems for accomplishing the desired objectives. Furthermore, we explore strategies to simulate various scenarios and challenges that the swarm may encounter in dynamic environments, ensuring comprehensive testing and analysis. Complex multimodal experiments may require system designs that may not be completely satisfied by a single simulation platform; thus, interoperability between simulation platforms is also examined. Overall, this paper serves as a comprehensive guide for designing swarm experiments, enabling the advancement and optimization of UAV swarm systems through validation in simulated controlled environments.

Manganese cobalt-MOF@carbon nanofiber-based non-enzymatic histamine sensor for the determination of food freshness.

Early detection of histamine in foodstuffs/beverages could be useful in preventing various diseases. In this work, we have prepared a free-standing hybrid mat based on manganese cobalt (2-methylimodazole)-metal organic frameworks (Mn-Co(2-MeIm)MOF) and carbon nanofibers (CNFs) and explored as a non-enzymatic electrochemical sensor for determining the freshness of fish and bananas based on histamine estimation. As-developed hybrid mat possesses high porosity with a large specific surface area and excellent hydrophilicity those allow easy access of analyte molecules to the redox-active metal sites of MOF. Furthermore, the multiple functional groups of the MOF matrix can act as active adsorption sites for catalysis. The Mn-Co(2-MeIm)MOF@CNF mat-modified GC electrode demonstrated excellent electrocatalytic activities toward the oxidation of histamine under acidic conditions (pH = 5.0) with a faster electron transfer kinetics and superior fouling resistance. The Co(2-MeIm)MOF@CNF/GCE sensor exhibited a wide linear range from 10 to 1500 µM with a low limit of detection (LOD) of 89.6 nM and a high sensitivity of 107.3 µA mM-1 cm-2. Importantly, as-developed Nb(BTC)MOF@CNF/GCE sensor is enabled to detect histamine in fish and banana samples stored for different periods of time, which thus indicates its practical viability as analytical histamine detector.

Characteristics of women presenting with hepatitis B at antenatal care services in London, 2008-2018.

BACKGROUND: To support interventions to prevent mother-to-child transmission of hepatitis B and fill gaps in surveillance, the Enhanced Surveillance of Antenatal Hepatitis B (ESAHB) programme was implemented in London from 2008 to 2018 to collect demographic information on women who tested positive for hepatitis B during antenatal screening. We describe the epidemiology of hepatitis B in pregnancy, as reported to ESAHB. METHODS: The characteristics of pregnant women living with hepatitis B were described and rates were calculated by year, local authority and residence deprivation decile (1 being most deprived). Poisson regression tested the association between pregnant women living with hepatitis B and deprivation decile. RESULTS: Between 2008 and 2018, 8879 women living with hepatitis B in London (0.35 per 1000 women) reported 11 193 pregnancies. Annual hepatitis B rates remained stable, but there was strong evidence for an inverse association between rate and deprivation decile (P < 0.001). The majority of women in the cohort presented late to antenatal care, were born outside the UK in a hepatitis B endemic area or required an interpreter for consultations. CONCLUSIONS: ESAHB provided important data to inform service quality improvements for women living with hepatitis B. This analysis highlights the link between deprivation and hepatitis B.

Bayesian approaches to include real-world data in clinical studies.

Randomized clinical trials have been the mainstay of clinical research, but are prohibitively expensive and subject to increasingly difficult patient recruitment. Recently, there is a movement to use real-world data (RWD) from electronic health records, patient registries, claims data and other sources in lieu of or supplementing controlled clinical trials. This process of combining information from diverse sources calls for inference under a Bayesian paradigm. We review some of the currently used methods and a novel non-parametric Bayesian (BNP) method. Carrying out the desired adjustment for differences in patient populations is naturally done with BNP priors that facilitate understanding of and adjustment for population heterogeneities across different data sources. We discuss the particular problem of using RWD to create a synthetic control arm to supplement single-arm treatment only studies. At the core of the proposed approach is the model-based adjustment to achieve equivalent patient populations in the current study and the (adjusted) RWD. This is implemented using common atoms mixture models. The structure of such models greatly simplifies inference. The adjustment for differences in the populations can be reduced to ratios of weights in such mixtures. This article is part of the theme issue 'Bayesian inference: challenges, perspectives, and prospects'.

Evidence of orthohantavirus and leptospira infections in small mammals in an endemic area of Gampaha district in Sri Lanka.

BACKGROUND: Orthohantaviruses and leptospira are emerging zoonotic pathogens of high public health significance. The epidemiology of orthohantavirus infections and leptospirosis is similar and presents related clinical pictures in humans. However, a paucity of data on actual reservoir hosts for orthohantaviruses and leptospira exists. Therefore, this study aimed at determining the occurrence of orthohantaviruses and leptospira in small mammals captured in an endemic region of Sri Lanka. METHODS: Rodents and shrews were morphologically and/or genetically identified using morphological keys and DNA barcoding techniques targeting the cytochrome oxidase b subunit gene (Cytb). Lung tissues and sera were subsequently analyzed for the presence of orthohantavirus RNA using qRT-PCR. Sera of rats were tested for IgG antibodies against orthohantaviruses and leptospira. RESULTS: Forty-three (43) small mammals representing: Rattus (R.) rattus (black rat) or R. tanezumi (Asian rat), Suncus murinus (Asian house shrew), R. norvegicus (brown rat) and Mus musculus (house mouse) were investigated. No orthohantavirus RNA was detected from the lung tissue or serum samples of these animals. Elevated levels of IgG antibodies against Puumala orthohantavirus (PUUV) and/or Seoul orthohantavirus (SEOV) antigens were detected in sera of 28 (72%) out of the 39 rats analysed. Interestingly, 36 (92%) of the 39 rats also showed presence of anti leptospira-IgG antibodies in their serum, representing dual infection or dual exposure in 26/39 (66.7%) of examined rats. CONCLUSIONS: This project targets important public health questions concerning the occupational risk of orthohantavirus infections and/or leptospirosis in an endemic region of Sri Lanka. Most rats (72%) in our study displayed antibodies reacting to orthohantavirus NP antigens, related to PUUV and/or SEOV. No correlation between the orthohantavirus and leptospira IgG antibody levels were noticed. Finally, a combination of both morphological and DNA barcoding approaches revealed that several species of rats may play a role in the maintenance and transmission of orthohantavirus and leptospira in Sri Lanka.

Cause-specific hazard regression estimation for modified Weibull distribution under a class of non-informative priors.

In time to event analysis, the situation of competing risks arises when the individual (or subject) may experience p mutually exclusive causes of death (failure), where cause-specific hazard function is of great importance in this framework. For instance, in malignancy-related death, colorectal cancer is one of the leading causes of the death in the world and death due to other causes considered as competing causes. We include prognostic variables in the model through parametric Cox proportional hazards model. Mostly, in literature exponential, Weibull, etc. distributions have been used for parametric modelling of cause-specific hazard function but they are incapable to accommodate non-monotone failure rate. Therefore, in this article, we consider a modified Weibull distribution which is capable to model survival data with non-monotonic behaviour of hazard rate. For estimating the cumulative cause-specific hazard function, we utilized maximum likelihood and Bayesian methods. A class of non-informative types of prior (uniform, Jeffrey's and half-t) is introduced for Bayes estimation under squared error (symmetric) as well as LINEX (asymmetric) loss functions. A simulation study is performed for a comprehensive comparison of Bayes and maximum likelihood estimators of cumulative cause-specific hazard function. Real data on colorectal cancer is used to demonstrate the proposed model.

Results of a nationally implemented cardiac screening programme in elite cricket players in England and Wales.

OBJECTIVES: We assessed the diagnostic yield and costs of an electrocardiogram-based national screening programme in elite cricket players and the incremental value of transthoracic echocardiography and periodic evaluation. DESIGN: Cross-sectional study. METHODS: Between 2008 and 2019, 1208 cricketers underwent screening with a health questionnaire, 12-lead electrocardiogram and cardiology consultation. Athletes with concerning findings underwent on-site transthoracic echocardiography and further investigations as necessary. In addition, despite a normal health questionnaire and electrocardiogram, 342 (28.3%) athletes had a transthoracic echocardiogram and 493 (40.8%) underwent repeat evaluations. RESULTS: After initial evaluation, 47 (3.9%) athletes underwent on-site transthoracic echocardiography of whom 35 (2.8%) were referred for further evaluation. Four athletes (0.3%) were diagnosed with major cardiac conditions; hypertrophic cardiomyopathy (n = 1), arrhythmogenic cardiomyopathy (n = 1) and Wolff-Parkinson-White pattern (n = 2). Two athletes were identified with minor valvular abnormalities. Repeat evaluation of 493 athletes identified hypertrophic cardiomyopathy in a 22-year-old athlete, two years after his initial normal screening. During a follow-up of 5.8 ±â€¯2.9 years no additional diagnoses or adverse cardiac events were reported. The cost of the electrocardiogram-based programme was £127,844, translating to £106 per athlete and £25,569 per major cardiac condition identified.Routine transthoracic echocardiography in 342 athletes identified two athletes with major cardiac conditions (bicuspid aortic valve with severe aortopathy and aortic regurgitation and an atrial septal defect associated with right ventricular volume overload) and 10 athletes with minor abnormalities. CONCLUSIONS: An electrocardiogram-based national screening programme identified a major cardiac condition in 0.3% of athletes. Routine transthoracic echocardiography and periodic evaluation increased the diagnostic yield to 0.6%, at an incremental cost.

Targeting Spike Glycans to Inhibit SARS-CoV2 Viral Entry.

SARS-CoV-2 Spike harbors glycans which function as ligands for lectins. Therefore, it should be possible to exploit lectins to target SARS-CoV-2 and inhibit cellular entry by binding glycans on the Spike protein. Burkholderia oklahomensis agglutinin (BOA) is an antiviral lectin that interacts with viral glycoproteins via N-linked high mannose glycans. Here, we show that BOA binds to the Spike protein and is a potent inhibitor of SARS-CoV-2 viral entry at nanomolar concentrations. Using a variety of biophysical tools, we demonstrate that the interaction is avidity driven and that BOA crosslinks the Spike protein into soluble aggregates. Furthermore, using virus neutralization assays, we demonstrate that BOA effectively inhibits all tested variants of concern as well as SARS-CoV 2003, establishing that glycan-targeting molecules have the potential to be pan-coronavirus inhibitors.

CG Dinucleotide Removal in Bioluminescent and Fluorescent Reporters Improves HIV-1 Replication and Reporter Gene Expression for Dual Imaging in Humanized Mice.

Visualizing the transmission and dissemination of human immunodeficiency virus type 1 (HIV-1) in real time in humanized mouse models is a robust tool to investigate viral replication during treatments and in tissue reservoirs. However, the stability and expression of HIV-1 reporter genes are obstacles for long-term serial imaging in vivo. Two replication-competent CCR5-tropic HIV-1 reporter constructs were created that encode either nanoluciferase (nLuc) or a near-infrared fluorescent protein (iRFP) upstream of nef. HIV-1 reporter virus replication and reporter gene expression was measured in cell culture and in humanized mice. While reporter gene expression in vivo correlated initially with plasma viremia, expression decreased after 4 to 5 weeks despite high plasma viremia. The reporter genes were codon optimized to remove cytosine/guanine (CG) dinucleotides, and new CO-nLuc and CO-iRFP viruses were reconstructed. Removal of CG dinucleotides in HIV-1 reporter viruses improved replication in vitro and reporter expression in vivo and ex vivo. Both codon-optimized reporter viruses could be visualized during coinfection and in vivo reporter gene expression during treatment failure preceded detection of plasma viremia. While the dynamic range of CO-iRFP HIV-1 was lower than that of CO-nLuc HIV-1, both viruses could have utility in studying and visualizing HIV-1 infection in humanized mice. IMPORTANCE Animal models are important for studying HIV-1 pathogenesis and treatments. We developed two viruses each encoding a reporter gene that can be expressed in cells after infection. This study shows that HIV-1 infection can be visualized by noninvasive, whole-body imaging in mice with human immune cells over time by reporter expression. We improved reporter expression to reflect HIV-1 replication and showed that two viral variants can be tracked over time in the same animal and can predict failure of antiretroviral therapy to suppress virus.

Whose trait is it anyways? Coevolution of joint phenotypes and genetic architecture in mutualisms.

Evolutionary biologists typically envision a trait's genetic basis and fitness effects occurring within a single species. However, traits can be determined by and have fitness consequences for interacting species, thus evolving in multiple genomes. This is especially likely in mutualisms, where species exchange fitness benefits and can associate over long periods of time. Partners may experience evolutionary conflict over the value of a multi-genomic trait, but such conflicts may be ameliorated by mutualism's positive fitness feedbacks. Here, we develop a simulation model of a host-microbe mutualism to explore the evolution of a multi-genomic trait. Coevolutionary outcomes depend on whether hosts and microbes have similar or different optimal trait values, strengths of selection and fitness feedbacks. We show that genome-wide association studies can map joint traits to loci in multiple genomes and describe how fitness conflict and fitness feedback generate different multi-genomic architectures with distinct signals around segregating loci. Partner fitnesses can be positively correlated even when partners are in conflict over the value of a multi-genomic trait, and conflict can generate strong mutualistic dependency. While fitness alignment facilitates rapid adaptation to a new optimum, conflict maintains genetic variation and evolvability, with implications for applied microbiome science.

Microbial Inoculants: Silver Bullet or Microbial Jurassic Park?

The appeal of using microbial inoculants to mediate plant traits and productivity in managed ecosystems has increased over the past decade, because microbes represent an alternative to fertilizers, pesticides, and direct genetic modification of plants. Using microbes bypasses many societal and environmental concerns because microbial products are considered a more sustainable and benign technology. In our desire to harness the power of plant-microbial symbioses, are we ignoring the possibility of precipitating microbial invasions, potentially setting ourselves up for a microbial Jurassic Park? Here, we outline potential negative consequences of microbial invasions and describe a set of practices (Testing, Regulation, Engineering, and Eradication, TREE) based on the four stages of invasion to prevent microbial inoculants from becoming invasive. We aim to stimulate discussion about best practices to proactively prevent microbial invasions.

Competing risks survival data under middle censoring-An application to COVID-19 pandemic.

Survival data is being analysed here under the middle censoring scheme, using specifically quantile function modelling under competing risks. The use of middle censoring scheme has been shown to be very appropriate under the COVID-19 pandemic scenario. Cause-specific quantile inference under middle censoring is employed. Such quantile inferences are obtained through cumulative incidence function based on cause-specific proportional hazards model. The baseline lifetime is assumed to follow a very general parametric model namely the Weibull distribution, and is independent of the censoring mechanism. We obtain estimates of the unknown parameters and cause specific quantile functions under classical as well as a Bayesian set-up. A Monte Carlo simulation study assesses the relative performance of the different estimators. Finally, a real life data analysis is given for illustration of the proposed methods.

Association of Hantavirus Infections and Leptospirosis With the Occurrence of Chronic Kidney Disease of Uncertain Etiology in the North Central Province of Sri Lanka: A Prospective Study With Patients and Healthy Persons.

Chronic Kidney disease of uncertain etiology (CKDu) has become a significant disease burden, affecting farming community of Sri Lanka and the exact etiology, which could be multifactorial, is not hitherto established. This study is aimed to determine the association of past hantavirus infection and leptospirosis with the occurrence of CKDu. A cohort (n = 179) of known CKDu patients living in high-CKDu prevalent areas of Anuradhapura district of Sri Lanka was compared with a group of 49 healthy, sex-matched younger blood relatives of CKDu patients (control-1) and another 48 healthy, age, and sex-matched individuals living in low-CKDu prevalent area (control-2) of the same district where same life style and climate conditions prevail. Fifty out of 179 (27.9%) CKDu patients, 16/49 (32.7%) of control-1 and 7/48 (14.6%) of control-2 were found positive for IgG antibodies to Puumala, Hantaan or both strains of hantaviruses. Hantaan strain specificity was found to be predominant in all study groups. Hantavirus IgG sero-prevalence of healthy individuals living in low-CKDu prevalent area was significantly lower compared to CKDu patients and healthy younger blood relatives living in high-CKDu prevalent areas (p = 0.03). Past hantavirus infection possesses a significant risk for the occurrence of CKDu (OR = 4.5; 95% CI-3.1-5.4, p = 0.02). In contrast, IgG seroprevalence to hantaviruses was not significantly different in CKDu patients and healthy younger blood relatives living in high-CKDu prevalent areas indicating past hantavirus infection has no association with the occurrence of CKDu or possibly, younger relatives may develop CKDu in subsequent years. Seroprevalence to leptospirosis showed no significant difference between CKDu patients and healthy controls.

Modeling Stripe Formation on Growing Zebrafish Tailfins.

As zebrafish develop, black and gold stripes form across their skin due to the interactions of brightly colored pigment cells. These characteristic patterns emerge on the growing fish body, as well as on the anal and caudal fins. While wild-type stripes form parallel to a horizontal marker on the body, patterns on the tailfin gradually extend distally outward. Interestingly, several mutations lead to altered body patterns without affecting fin stripes. Through an exploratory modeling approach, our goal is to help better understand these differences between body and fin patterns. By adapting a prior agent-based model of cell interactions on the fish body, we present an in silico study of stripe development on tailfins. Our main result is a demonstration that two cell types can produce stripes on the caudal fin. We highlight several ways that bone rays, growth, and the body-fin interface may be involved in patterning, and we raise questions for future work related to pattern robustness.

Long-Acting Rilpivirine (RPV) Preexposure Prophylaxis Does Not Inhibit Vaginal Transmission of RPV-Resistant HIV-1 or Select for High-Frequency Drug Resistance in Humanized Mice.

As a long-acting formulation of the nonnucleoside reverse transcriptase inhibitor rilpivirine (RPV LA) has been proposed for use as preexposure prophylaxis (PrEP) and the prevalence of transmitted RPV-resistant viruses can be relatively high, we evaluated the efficacy of RPV LA to inhibit vaginal transmission of RPV-resistant HIV-1 in humanized mice. Vaginal challenges of wild-type (WT), Y181C, and Y181V HIV-1 were performed in mice left untreated or after RPV PrEP. Plasma viremia was measured for 7 to 10 weeks, and single-genome sequencing was performed on plasma HIV-1 RNA in mice infected during PrEP. RPV LA significantly prevented vaginal transmission of WT HIV-1 and Y181C HIV-1, which is 3-fold resistant to RPV. However, it did not prevent transmission of Y181V HIV-1, which has 30-fold RPV resistance in the viruses used for this study. RPV LA did delay WT HIV-1 dissemination in infected animals until genital and plasma RPV concentrations waned. Animals that became infected despite RPV LA PrEP did not acquire new RPV-resistant mutations above frequencies in untreated mice or untreated people living with HIV-1, and the mutations detected conferred low-level resistance. These data suggest that high, sustained concentrations of RPV were required to inhibit vaginal transmission of HIV-1 with little or no resistance to RPV but could not inhibit virus with high resistance. HIV-1 did not develop high-level or high-frequency RPV resistance in the majority of mice infected after RPV LA treatment. However, the impact of low-frequency RPV resistance on virologic outcome during subsequent antiretroviral therapy still is unclear.IMPORTANCE The antiretroviral drug rilpivirine was developed into a long-acting formulation (RPV LA) to improve adherence for preexposure prophylaxis (PrEP) to prevent HIV-1 transmission. A concern is that RPV LA will not inhibit transmission of drug-resistant HIV-1 and may select for drug-resistant virus. In female humanized mice, we found that RPV LA inhibited vaginal transmission of WT or 3-fold RPV-resistant HIV-1 but not virus with 30-fold RPV resistance. In animals that became infected despite RPV LA PrEP, WT HIV-1 dissemination was delayed until genital and plasma RPV concentrations waned. RPV resistance was detected at similar low frequencies in untreated and PrEP-treated mice that became infected. These results indicate the importance of maintaining RPV at a sustained threshold after virus exposure to prevent dissemination of HIV-1 after vaginal infection and low-frequency resistance mutations conferred low-level resistance, suggesting that RPV resistance is difficult to develop after HIV-1 infection during RPV LA PrEP.

Size and charge correlations in spherical electric double layers: a case study with fully asymmetric mixed electrolytes within the solvent primitive model.

Size and charge correlations in spherical electric double layers are investigated through Monte Carlo simulations and density functional theory, through a solvent primitive model representation. A fully asymmetric mixed electrolyte is used for the small ions, whereas the solvent, apart from being a continuum dielectric, is also treated as an individual component. A partially perturbative density functional theory is adopted here, and for comparison, a standard canonical ensemble Monte Carlo simulation is used. The hard-sphere free energy is treated within a weighted density approach and the residual ionic contribution is estimated through perturbation around the uniform density. The results from both methods corroborate each other quantitatively over a wide range of physical parameters. The importance of structural correlations is envisaged through the size and charge asymmetry of the supporting electrolytes that includes the solvent as a component.