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Uropathogenic Escherichia coli (UPEC) can undergo extensive filamentation in the host during acute urinary tract infections (UTIs). It has been hypothesised that this morphological plasticity allows bacteria to avoid host immune responses such as macrophage engulfment. However, it is still unclear what properties of filaments are important in macrophage-bacteria interactions. The aim of this work was to investigate the contribution of bacterial biophysical parameters, such as cell size and shape, and physiological parameters, such as cell surface and the environment, to macrophage engulfment efficiency. Viable, reversible filaments of known lengths and volumes were produced in the UPEC strain UTI89 using a variety of methods, including exposure to cell-wall targeting antibiotics, genetic manipulation and isolation from an in vitro human bladder cell model. Quantification of the engulfment ability of macrophages using gentamicin-protection assays and fluorescence microscopy demonstrated that the ability of filaments to avoid macrophage engulfment is dependent on a combination of size (length and volume), shape, cell surface and external environmental factors. UTI89 filamentation and macrophage engulfment efficiency was also found to occur independently of the SOS-inducible filamentation genes, sulA and ymfM in both in vivo and in vitro models of infection. Compared to filaments formed via antibiotic inhibition of division, the infection-derived filaments were preferentially targeted by macrophages. With several strains of UPEC now resistant to current antibiotics, our work identifies the importance of bacterial physiological and morphological states during infection. Author summary: Urinary tract infections (UTIs) are one of the most common bacterial infections worldwide with 50% of women suffering from a UTI during their lifetime. Escherichia coli is the primary bacteria responsible for UTIs and is usually found in short rod forms. However, during UTIs E. coli can elongate into extremely long thin shapes called 'filaments'. Filaments are thought to be advantageous during infections because they are too long to be engulfed and killed by immune cells called macrophages. Due to increasing antibiotic resistance in bacteria there is a strong need for the discovery of new ways to treat infections and this is only possible once we thoroughly understand the mechanisms bacteria employ to overcome our immune response. Therefore, we investigated the effect of E. coli filamentation on macrophage engulfment along with other aspects of bacteria reported to influence engulfment. We found that the ability of filaments to avoid macrophage engulfment is dependent on a combination of size (length and volume), shape, surface and external environmental factors. Our research has highlighted the importance of bacterial shape changes during infections and provided a foundational understanding of macrophage engulfment of filaments. Eventually, this knowledge may reveal new targets for treatment of infections. [ABSTRACT FROM AUTHOR]

Neisseria gonorrhoeae (the gonococcus, Gc) causes the sexually transmitted infection gonorrhea. Gc is a prominent threat to human health by causing severe lifelong sequelae, including infertility and chronic pelvic pain, which is amplified by the emergence of "superbug" strains resistant to all current antibiotics. Gc is highly adapted to colonize human mucosal surfaces, where it survives despite initiating a robust inflammatory response and influx of polymorphonuclear leukocytes (PMNs, neutrophils) that typically clear bacteria. Here, dual-species RNA-sequencing was used to define Gc and PMN transcriptional profiles alone and after infection. Core host and bacterial responses were assessed for two strains of Gc and three human donors' PMNs. Comparative analysis of Gc transcripts revealed overlap between Gc responses to PMNs, iron, and hydrogen peroxide; 98 transcripts were differentially expressed across both Gc strains in response to PMN co-culture, including iron-responsive and oxidative stress response genes. We experimentally determined that the iron-dependent TbpB is suppressed by PMN co-culture, and iron-limited Gc have a survival advantage when cultured with PMNs. Analysis of PMN transcripts modulated by Gc infection revealed differential expression of genes driving cell adhesion, migration, inflammatory responses, and inflammation resolution pathways. Production of pro-inflammatory cytokines, including IL1B and IL8, the adhesion factor ICAM1, and prostaglandin PGE2 were induced in PMNs in response to Gc. Together, this study represents a comprehensive and experimentally validated dual-species transcriptomic analysis of two isolates of Gc and primary human PMNs that gives insight into how this bacterium survives innate immune onslaught to cause disease. Author summary: The bacterium Neisseria gonorrhoeae (Gc) is a public health threat with emerging resistance to antibiotics. Gc induces robust mucosal inflammatory responses with abundant influx of white blood cells called polymorphonuclear leukocytes (PMNs, neutrophils). While PMNs are highly antimicrobial, Gc survives amongst PMNs for reasons incompletely understood. Here we detail the transcriptional profiles of PMNs from multiple human donors and Gc strains, to investigate this host-pathogen interaction in a comprehensive, unbiased manner. The core transcriptome across Gc exposed to PMNs overlaps transcriptomes of Gc exposed to stresses imparted by immune pressure, specifically nutrient metal starvation. Additionally, core host pathways induced upon PMN exposure to Gc include surface and secreted factors that enable PMN migration and activation. This study uncovers critical features of the Gc-PMN interface to inform how Gc resists innate immune clearance. [ABSTRACT FROM AUTHOR]

Rift Valley fever virus (RVFV) is an encephalitic bunyavirus that can infect neurons in the brain. There are no approved therapeutics that can protect from RVFV encephalitis. Innate immunity, the first line of defense against infection, canonically antagonizes viruses through interferon signaling. We found that interferons did not efficiently protect primary cortical neurons from RVFV, unlike other cell types. To identify alternative neuronal antiviral pathways, we screened innate immune ligands and discovered that the TLR2 ligand Pam3CSK4 inhibited RVFV infection, and other bunyaviruses. Mechanistically, we found that Pam3CSK4 blocks viral fusion, independent of TLR2. In a mouse model of RVFV encephalitis, Pam3CSK4 treatment protected animals from infection and mortality. Overall, Pam3CSK4 is a bunyavirus fusion inhibitor active in primary neurons and the brain, representing a new approach toward the development of treatments for encephalitic bunyavirus infections. Author summary: Rift Valley fever virus (RVFV) is an emerging mosquito-borne pathogen, which has shown the potential to spread geographically, and which can cause severe disease in humans. One of the most serious complications of RVFV infection is invasion into the brain. There are no approved treatments for RVFV infection, or any other bunyavirus that infects the brain. We found that the classically antiviral interferon pathway was not protective in neurons. This led us to screen for new antivirals, and we identified Pam3CSK4, which inhibited RVFV and related bunyaviruses, but not vesicular stomatitis virus. We found that the antiviral activity of Pam3CSK4 was separate from its previously characterized activity as a TLR2 agonist. Instead, Pam3CSK4 blocked RVFV entry at the step of viral membrane fusion. Importantly, we found that Pam3CSK4 prevented RVFV infection in the mouse brain. This work reveals that Pam3CSK4 prevents encephalitic bunyavirus infection in neurons, a vulnerable cell type, and future research should evaluate the therapeutic potential of Pam3CSK4. [ABSTRACT FROM AUTHOR]

Since SARS-CoV-2 emerged in late 2019, it spread from China to the rest of the world. An initial concern was the potential for vaccine- or antibody-dependent enhancement (ADE) of disease as had been reported with other coronaviruses. To evaluate this, we first developed a ferret model by exposing ferrets to SARS-CoV-2 by either mucosal inoculation (intranasal/oral/ocular) or inhalation using a small particle aerosol. Mucosal inoculation caused a mild fever and weight loss that resolved quickly; inoculation via either route resulted in virus shedding detected in the nares, throat, and rectum for 7–10 days post-infection. To evaluate the potential for ADE, we then inoculated groups of ferrets intravenously with 0.1, 0.5, or 1 mg/kg doses of a human polyclonal anti-SARS-CoV-2 IgG from hyper-immunized transchromosomic bovines (SAB-185). Twelve hours later, ferrets were challenged by mucosal inoculation with SARS-CoV-2. We found no significant differences in fever, weight loss, or viral shedding after infection between the three antibody groups or the controls. Signs of pathology in the lungs were noted in infected ferrets but no differences were found between control and antibody groups. The results of this study indicate that healthy, young adult ferrets of both sexes are a suitable model of mild COVID-19 and that low doses of specific IgG in SAB-185 are unlikely to enhance the disease caused by SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Although cannabis was legalized in Canada in 2018 and is one of the most used substances in Canada, few studies have examined how individuals with different patterns of cannabis use differ in their attempts to decrease or abstain from cannabis. The current study examined how groups of cannabis users, which were formed on the basis of demographic characteristics, substance use patterns, mental health symptoms, and self-reported quality of life differed on their experiences with cannabis cessation. A sample of 147 Canadian adult participants who had attempted to decrease or quit cannabis were recruited from the community (n = 84, 57.14%) and crowdsourcing (n = 63, 42.86%). Four profiles of cannabis users emerged using a Latent Profile Analysis: low-risk (n = 62, 42.18%), rapidly escalating high-risk (n = 40, 27.21%), long-term high severity (n = 35, 23.81%), and long-term lower severity (n = 10, 6.80%). Individuals in the rapidly escalating profile had attempted to decrease their cannabis use more times compared to other profiles. More participants in the long-term high severity group found their use stayed the same or got worse after their last cessation attempt, compared to the low-risk group where more individuals indicated their use stopped. The results of the current study indicate that cannabis users differ in their attempts at reducing or ceasing cannabis use and that they may benefit from different intensity of cannabis interventions. [ABSTRACT FROM AUTHOR]

Species range shifts due to changing ocean conditions are occurring around the world. As species move, they build new interaction networks as they shift from or into new ecological communities. Typically, species ranges are modeled individually, but biotic interactions have been shown to be important to creating more realistic modeling outputs for species. To understand the importance of consumer interactions in Eastern Pacific kelp forest species distributions, we used a Maxent framework to model a key foundation species, giant kelp (Macrocystis pyrifera), and a dominant herbivore, purple sea urchins (Strongylocentrotus purpuratus). With neither species having previously been modeled in the Eastern Pacific, we found evidence for M. pyrifera expansion in the northern section of its range, with no projected contraction at the southern range edge. Despite its known co-occurrence with M. pyrifera, models of S. purpuratus showed a non-concurrent southern range contraction and a co-occurring northern range expansion. While the co-occurring shifts may lead to increased spatial competition for suitable substrate, this non-concurrent contraction could result in community wide impacts such as herbivore release, tropicalization, or ecosystem restructuring. [ABSTRACT FROM AUTHOR]

Influenza A virus (FLUAV) infects a wide range of hosts and human-to-swine spillover events are frequently reported. However, only a few of these human viruses have become established in pigs and the host barriers and molecular mechanisms driving adaptation to the swine host remain poorly understood. We previously found that infection of pigs with a 2:6 reassortant virus (hVIC/11) containing the hemagglutinin (HA) and neuraminidase (NA) gene segments from the human strain A/Victoria/361/2011 (H3N2) and internal gene segments of an endemic swine strain (sOH/04) resulted in a fixed amino acid substitution in the HA (A138S, mature H3 HA numbering). In silico analysis revealed that S138 became predominant among swine H3N2 virus sequences deposited in public databases, while 138A predominates in human isolates. To understand the role of the HA A138S substitution in the adaptation of a human-origin FLUAV HA to swine, we infected pigs with the hVIC/11A138S mutant and analyzed pathogenesis and transmission compared to hVIC/11 and sOH/04. Our results showed that the hVIC/11A138S virus had an intermediary pathogenesis between hVIC/11 and sOH/04. The hVIC/11A138S infected the upper respiratory tract, right caudal, and both cranial lobes while hVIC/11 was only detected in nose and trachea samples. Viruses induced a distinct expression pattern of various pro-inflammatory cytokines such as IL-8, TNF-α, and IFN-β. Flow cytometric analysis of lung samples revealed a significant reduction of porcine alveolar macrophages (PAMs) in hVIC/11A138S-infected pigs compared to sOH/04 while a MHCIIlowCD163neg population was increased. The hVIC/11A138S showed a higher affinity for PAMs than hVIC/11, noted as an increase of infected PAMs in bronchoalveolar lavage fluid (BALF), and showed no differences in the percentage of HA-positive PAMs compared to sOH/04. This increased infection of PAMs led to an overexpression of granulocyte-monocyte colony-stimulating factor (GM-CSF) stimulation but a reduced expression of peroxisome proliferator-activated receptor gamma (PPARγ) in the sOH/04-infected group. Analysis using the PAM cell line 3D4/21 revealed that the A138S substitution improved replication and apoptosis induction in this cell type compared to hVIC/11 but at lower levels than sOH/04. Overall, our study indicates that adaptation of human viruses to the swine host involves an increased affinity for the lower respiratory tract and alveolar macrophages. Author summary: Human-to-swine FLUAV spillover events are relatively common and have led to the establishment of multiple evolutionarily distinct virus lineages in the swine population worldwide, leading to important economic losses in the pork industry. This also increases the risk of reassortment and emergence of novel FLUAV that may retain the ability to infect and transmit in humans, an event exemplified by the H1N1 pandemic in 2009. However, the molecular mechanisms driving FLUAV adaptation to pigs following the introduction of a human virus are still not fully understood. In this study we found that a point mutation in a human-origin HA improved infection and transmissibility in pigs characterized by an enhanced lung replication and the disruption of lung-resident immune cell populations. This relationship between improved replication and infectivity of lung-resident cells provides insights into host barriers limiting human FLUAV adaptation to pigs and the complexities associated with the host immune response that influenza A viruses must overcome to become established in the swine population. [ABSTRACT FROM AUTHOR]

Background: Poor mental health is associated with obesity, but existing studies are either cross-sectional or have long time periods between measurements of mental health and weight. It is, therefore, unclear how small fluctuations in mental wellbeing within individuals predict bodyweight over short time periods, e.g. within the next month. Studying this could identify modifiable determinants of weight changes and highlight opportunities for early intervention. Methods: 2,133 UK adults from a population-based cohort completed monthly mental health and weight measurements using a mobile app over a period of 6–9 months. We used random intercept regression models to examine longitudinal associations of depressive symptoms, anxiety symptoms and stress with subsequent weight. In sub-group analyses, we included interaction terms of mental health variables with baseline characteristics. Mental health variables were split into "between-individual" measurements (= the participant's median score across all timepoints) and "within-individual" measurements (at each timepoint, the difference between the participant's current score and their median). Results: Within-individual variation in depressive symptoms predicted subsequent weight (0.045kg per unit of depressive symptom severity, 95% CI 0.021–0.069). We found evidence of a moderation effect of baseline BMI on the association between within-individual fluctuation in depressive symptoms and subsequent weight: The association was only apparent in those with overweight/obesity, and it was stronger in those with obesity than those with overweight (BMI<25kg/m2: 0.011kg per unit of depressive symptom severity [95% CI -0.017 to 0.039]; BMI 25–29.9kg/m2: 0.052kg per unit of depressive symptom severity [95%CI 0.010–0.094kg]; BMI≥30kg/m2: 0.071kg per unit of depressive symptom severity [95%CI 0.013–0.129kg]). We found no evidence for other interactions, associations of stress and anxiety with weight, or for a reverse direction of association. Conclusion: In this exploratory study, individuals with overweight or obesity were more vulnerable to weight gain following higher-than-usual (for that individual) depressive symptoms than individuals with a BMI<25kg/m2. [ABSTRACT FROM AUTHOR]

Increased interest in renewable energy has fostered development of wind and solar energy facilities globally. However, energy development sometimes has negative environmental impacts, such as wildlife fatalities. Efforts by regional land managers to balance energy potential while minimizing fatality risk currently rely on datasets that are aggregated at continental, but not regional scales, that focus on single species, or that implement meta-analyses that inappropriately use inferential statistics. We compiled and summarized fatality data from 87 reports for solar and wind facilities in the Mojave and Sonoran Deserts region of southern California within the Desert Renewable Energy Conservation Plan area. Our goal was to evaluate potential temporal and guild-specific patterns in fatalities, especially for priority species of conservation concern. We also aimed to provide a perspective on approaches interpreting these types of data, given inherent limitations in how they were collected. Mourning doves (Zenaida macroura), Chukar (Alectoris chukar) and California Quail (Callipepla californica), and passerines (Passeriformes), accounted for the most commonly reported fatalities. However, our aggregated count data were derived from raw, uncorrected totals, and thus reflect an absolute minimum number of fatalities for the monitored period. Additionally, patterns in the raw data suggested that many species commonly documented as fatalities (e.g., waterbirds and other nocturnal migrants, bats) are rarely counted during typical pre-construction use surveys. This may explain the more commonly observed mismatch between pre-construction risk assessment and actual fatalities. Our work may serve to guide design of future scientific research to address temporal and spatial patterns in fatalities and to apply rigorous guild-specific survey methodologies to estimate populations at risk from renewable energy development. [ABSTRACT FROM AUTHOR]

Sustainable HIV remission after antiretroviral therapy (ART) withdrawal, or post-treatment control (PTC), remains a top priority for HIV treatment. We observed surprising PTC in an MHC-haplomatched cohort of MHC-M3+ SIVmac239+ Mauritian cynomolgus macaques (MCMs) initiated on ART at two weeks post-infection (wpi). None of the MCMs possessed MHC haplotypes previously associated with SIV control. For six months after ART withdrawal, we observed undetectable or transient viremia in seven of the eight MCMs, despite detecting replication competent SIV using quantitative viral outgrowth assays. In vivo depletion of CD8α+ cells induced rebound in all animals, indicating the observed PTC was mediated, at least in part, by CD8α+ cells. With intact proviral DNA assays, we found that MCMs had significantly smaller viral reservoirs two wpi than a cohort of identically infected rhesus macaques, a population that rarely develops PTC. We found a similarly small viral reservoir among six additional SIV+ MCMs in which ART was initiated at eight wpi, some of whom exhibited viral rebound. These results suggest that an unusually small viral reservoir is a hallmark among SIV+ MCMs. By evaluating immunological differences between MCMs that did and did not rebound, we identified that PTC was associated with a reduced frequency of CD4+ and CD8+ lymphocyte subsets expressing exhaustion markers. Together, these results suggest a combination of small reservoirs and immune-mediated virus suppression contribute to PTC in MCMs. Further, defining the immunologic mechanisms that engender PTC in this model may identify therapeutic targets for inducing durable HIV remission in humans. Author summary: The ultimate goal of human immunodeficiency virus (HIV) therapeutic development is to enable HIV+ individuals to stop taking daily lifelong antiretroviral therapeutics (ART) and remain in virological remission, an outcome called post-treatment control. Post-treatment control is challenging to study because it is very rare in humans. Thus, there are currently no therapeutics that lead to post-treatment control. Simian immunodeficiency virus (SIV) in rhesus macaques is the most widely used preclinical model for HIV. However, post-treatment control is also uncommon in rhesus macaques. The mechanisms that govern post-treatment control remain largely unknown because PTC is so rare. Our lab observed surprising post-treatment control in a cohort of Mauritian cynomolgus macaques that were initiated on ART two weeks post-infection. While Mauritian cynomolgus macaques have been used for SIV research, they are not routinely used to study post-treatment control. We found that small viral reservoirs and immune-mediated virus suppression contribute to post-treatment control in Mauritian cynomolgus macaques. Moving forward, this model can be used to further define the mechanisms that engender post-treatment control as well as identify therapeutic targets in humans for inducing durable HIV remission. [ABSTRACT FROM AUTHOR]

Immunotherapeutic cytokines can activate immune cells against cancers and chronic infections. N-803 is an IL-15 superagonist that expands CD8+ T cells and increases their cytotoxicity. N-803 also temporarily reduced viral load in a limited subset of non-human primates infected with simian immunodeficiency virus (SIV), a model of HIV. However, viral suppression has not been observed in all SIV cohorts and may depend on pre-treatment viral load and the corresponding effects on CD8+ T cells. Starting from an existing mechanistic mathematical model of N-803 immunotherapy of SIV, we develop a model that includes activation of SIV-specific and non-SIV-specific CD8+ T cells by antigen, inflammation, and N-803. Also included is a regulatory counter-response that inhibits CD8+ T cell proliferation and function, representing the effects of immune checkpoint molecules and immunosuppressive cells. We simultaneously calibrate the model to two separate SIV cohorts. The first cohort had low viral loads prior to treatment (≈3–4 log viral RNA copy equivalents (CEQ)/mL), and N-803 treatment transiently suppressed viral load. The second had higher pre-treatment viral loads (≈5–7 log CEQ/mL) and saw no consistent virus suppression with N-803. The mathematical model can replicate the viral and CD8+ T cell dynamics of both cohorts based on different pre-treatment viral loads and different levels of regulatory inhibition of CD8+ T cells due to those viral loads (i.e. initial conditions of model). Our predictions are validated by additional data from these and other SIV cohorts. While both cohorts had high numbers of activated SIV-specific CD8+ T cells in simulations, viral suppression was precluded in the high viral load cohort due to elevated inhibition of cytotoxicity. Thus, we mathematically demonstrate how the pre-treatment viral load can influence immunotherapeutic efficacy, highlighting the in vivo conditions and combination therapies that could maximize efficacy and improve treatment outcomes. Author summary: Immunotherapy bolsters and redirects the immune system to fight chronic infections and cancers. However, the effectiveness of some immunotherapies may depend on the level of pre-treatment inflammation and the corresponding presence of regulatory cells and immune checkpoint molecules that normally function to prevent immune overreaction. Here, we consider two previously published cohorts of macaques who were given the immunotherapeutic N-803 to treat Simian Immunodeficiency Virus, an analog of Human Immunodeficiency Virus (HIV). One cohort had low viral loads before treatment, and N-803 temporarily suppressed viral loads. The second cohort had high viral loads that did not consistently decrease with N-803 treatment. In this work, we demonstrate with a mathematical model how these two distinct outcomes can arise due only to the different viral loads and the corresponding immune activation and regulatory response. In the model, we find that the key limiting factor is the direct inhibition of the cytotoxic action of immune cells by immune checkpoint molecules. This model indicates that simultaneous blockade of immune checkpoint molecules may be necessary for effective application of N-803 for the treatment of HIV. This and similar models can inform the design of such combination therapies for cancer and chronic infection. [ABSTRACT FROM AUTHOR]

Background: Antimicrobial Resistance (AMR) is a global problem with large health and economic consequences. Current gaps in quantitative data are a major limitation for creating models intended to simulate the drivers of AMR. As an intermediate step, expert knowledge and opinion could be utilized to fill gaps in knowledge for areas of the system where quantitative data does not yet exist or are hard to quantify. Therefore, the objective of this study was to identify quantifiable data about the current state of the factors that drive AMR and the strengths and directions of relationships between the factors from statements made by a group of experts from the One Health system that drives AMR development and transmission in a European context. Methods: This study builds upon previous work that developed a causal loop diagram of AMR using input from two workshops conducted in 2019 in Sweden with experts within the European food system context. A secondary analysis of the workshop transcripts was conducted to identify semi-quantitative data to parameterize drivers in a model of AMR. Main findings: Participants spoke about AMR by combining their personal experiences with professional expertise within their fields. The analysis of participants' statements provided semi-quantitative data that can help inform a future of AMR emergence and transmission based on a causal loop diagram of AMR in a Swedish One Health system context. Conclusion: Using transcripts of a workshop including participants with diverse expertise across the system that drives AMR, we gained invaluable insight into the past, current, and potential future states of the major drivers of AMR, particularly where quantitative data are lacking. [ABSTRACT FROM AUTHOR]

Sea star wasting syndrome (SSWS) can cause widespread mortality in starfish populations as well as long-lasting changes to benthic community structure and dynamics. SSWS symptoms have been documented in numerous species and locations around the world, but to date there is only one record of SSWS from the Antarctic and this outbreak was associated with volcanically-driven high temperature anomalies. Here we report outbreaks of SSWS-like symptoms that affected ~30% of individuals of Odontaster validus at two different sites in McMurdo Sound, Antarctica in 2019 and 2022. Unlike many SSWS events in other parts of the world, these outbreaks were not associated with anomalously warm temperatures. Instead, we suggest they may have been triggered by high nutrient input events on a local scale. Although the exact cause of these outbreaks is not known, these findings are of great concern because of the keystone role of O. validus and the slow recovery rate of Antarctic benthic ecosystems to environmental stressors. [ABSTRACT FROM AUTHOR]

The 2009 H1N1 pandemic (pdm09) lineage of influenza A virus (IAV) crosses interspecies barriers with frequent human-to-swine spillovers each year. These spillovers reassort and drift within swine populations, leading to genetically and antigenically novel IAV that represent a zoonotic threat. We quantified interspecies transmission of the pdm09 lineage, persistence in swine, and identified how evolution in swine impacted zoonotic risk. Human and swine pdm09 case counts between 2010 and 2020 were correlated and human pdm09 burden and circulation directly impacted the detection of pdm09 in pigs. However, there was a relative absence of pdm09 circulation in humans during the 2020–21 season that was not reflected in swine. During the 2020–21 season, most swine pdm09 detections originated from human-to-swine spillovers from the 2018–19 and 2019–20 seasons that persisted in swine. We identified contemporary swine pdm09 representatives of each persistent spillover and quantified cross-reactivity between human seasonal H1 vaccine strains and the swine strains using a panel of monovalent ferret antisera in hemagglutination inhibition (HI) assays. The swine pdm09s had variable antigenic reactivity to vaccine antisera, but each swine pdm09 clade exhibited significant reduction in cross-reactivity to one or more of the human seasonal vaccine strains. Further supporting zoonotic risk, we showed phylogenetic evidence for 17 swine-to-human transmission events of pdm09 from 2010 to 2021, 11 of which were not previously classified as variants, with each of the zoonotic cases associated with persistent circulation of pdm09 in pigs. These data demonstrate that reverse-zoonoses and evolution of pdm09 in swine results in viruses that are capable of zoonotic transmission and represent a potential pandemic threat. Author summary: The diversity and evolution of influenza A virus (IAV) in pigs is linked to the emergence of IAV with zoonotic potential. Human-to-swine transmission of the 2009 H1N1 pandemic (pdm09) IAV lineage repeatedly occurred across the past decade and has increased genetic diversity in pigs: sporadic swine-to-human cases are associated with these viruses. We measured the frequency of human-to-swine transmission of the H1N1 pandemic IAV lineage between 2009 and 2021 and determined how this affected the diversity of IAV in swine and zoonotic risk. We detected 370 separate human-to-swine spillovers, with the frequency of interspecies transmission increasing when the burden of IAV was highest in the human population. Most spillovers were single events without sustained transmission, but a small subset resulted in the emergence, persistence, and cocirculation of different pdm09 genetic clades in US pigs. Each of the pdm09 representative of different persistent spillovers was genetically and antigenically different from human seasonal vaccine strains. The persistence of pdm09 within pigs resulted in at least five recent swine-to-human transmission events. These data suggest that controlling IAV infection in humans working with swine can minimize spillover into pigs, reduce resulting genetic diversity of IAV in pigs, and proactively reduce the potential for swine-to-human transmission of IAV with zoonotic potential. [ABSTRACT FROM AUTHOR]

Habitat loss is accelerating at unprecedented rates, leading to the emergence of smaller, more isolated habitat remnants. Habitat isolation adversely affects many ecological processes independently, but little is known about how habitat isolation may interact with ecosystem processes such as top-down (consumer-driven) and bottom-up (resource-driven) effects. To investigate the interactive influence of habitat isolation, resource availability and consumer distribution and impact on community structure, we tested two hypotheses using invertebrate and algal epibionts on temperate seagrasses, an ecosystem of ecological and conservation importance. First, we hypothesized that habitat isolation will change the structure of the seagrass epibiont community, and isolated patches of seagrass will have lower epibiont biomass and different epibiont community composition than contiguous meadows. Second, we hypothesized that habitat isolation would mediate top-down (i.e., herbivory) and bottom-up (i.e., nutrient enrichment) control for algal epibionts. We used observational studies in natural seagrass patches and experimental artificial seagrass to examine three levels of habitat isolation. We further manipulated top-down and bottom-up processes in artificial seagrass through consumer reductions and nutrient additions, respectively. We indeed found that habitat isolation of seagrass patches decreased epibiont biomass and modified epibiont community composition. This pattern was largely due to dispersal limitation of invertebrate epibionts that resulted in a decline in their abundance and richness in isolated patches. Further, habitat isolation reduced consumer abundances, weakening top-down control of algal epibionts in isolated seagrass patches. Nutrient additions, however, reversed this pattern, and allowed a top-down effect on algal richness to emerge in isolated habitats, demonstrating a complex interaction between patch isolation and top-down and bottom-up processes. Habitat isolation may therefore shape the relative importance of central processes in ecosystems, leading to changes in community composition and food web structure in marine habitats. [ABSTRACT FROM AUTHOR]

The Eating Disorders In weight-related Therapy (EDIT) Collaboration brings together data from randomised controlled trials of behavioural weight management interventions to identify individual participant risk factors and intervention strategies that contribute to eating disorder risk. We present a protocol for a systematic review and individual participant data (IPD) meta-analysis which aims to identify participants at risk of developing eating disorders, or related symptoms, during or after weight management interventions conducted in adolescents or adults with overweight or obesity. We systematically searched four databases up to March 2022 and clinical trials registries to May 2022 to identify randomised controlled trials of weight management interventions conducted in adolescents or adults with overweight or obesity that measured eating disorder risk at pre- and post-intervention or follow-up. Authors from eligible trials have been invited to share their deidentified IPD. Two IPD meta-analyses will be conducted. The first IPD meta-analysis aims to examine participant level factors associated with a change in eating disorder scores during and following a weight management intervention. To do this we will examine baseline variables that predict change in eating disorder risk within intervention arms. The second IPD meta-analysis aims to assess whether there are participant level factors that predict whether participation in an intervention is more or less likely than no intervention to lead to a change in eating disorder risk. To do this, we will examine if there are differences in predictors of eating disorder risk between intervention and no-treatment control arms. The primary outcome will be a standardised mean difference in global eating disorder score from baseline to immediately post-intervention and at 6- and 12- months follow-up. Identifying participant level risk factors predicting eating disorder risk will inform screening and monitoring protocols to allow early identification and intervention for those at risk. [ABSTRACT FROM AUTHOR]

X-chromosome inactivation (XCI) silences one X in female cells to balance sex-differences in X-dosage. A subset of X-linked genes escape XCI, but the extent to which this phenomenon occurs and how it varies across tissues and in a population is as yet unclear. To characterize incidence and variability of escape across individuals and tissues, we conducted a transcriptomic study of escape in adipose, skin, lymphoblastoid cell lines and immune cells in 248 healthy individuals exhibiting skewed XCI. We quantify XCI escape from a linear model of genes' allelic fold-change and XIST-based degree of XCI skewing. We identify 62 genes, including 19 lncRNAs, with previously unknown patterns of escape. We find a range of tissue-specificity, with 11% of genes escaping XCI constitutively across tissues and 23% demonstrating tissue-restricted escape, including cell type-specific escape across immune cells of the same individual. We also detect substantial inter-individual variability in escape. Monozygotic twins share more similar escape than dizygotic twins, indicating that genetic factors may underlie inter-individual differences in escape. However, discordant escape also occurs within monozygotic co-twins, suggesting environmental factors also influence escape. Altogether, these data indicate that XCI escape is an under-appreciated source of transcriptional differences, and an intricate phenotype impacting variable trait expressivity in females. Author summary: The difference in the number of X-chromosomes between mammalian males and females is compensated by a process known as X-chromosome inactivation (XCI), which turns off one of a female's X chromosomes. XCI is incomplete: some sections of the silenced X chromosome escape inactivation. The 'escape' is complex, and can vary across tissues and potentially across individuals. Because the X chromosome is enriched of genes with immune and neurological functions, this phenomenon has high biomedical relevance. We studied the extent to which escape occurs and varies across tissues and individuals in a large population of twins. We identify novel candidate escape genes, and genes whose escape is specific to a tissue or immune cell type. There is also substantial variability in escape across individuals. Using data from twins, which enable the assessment of the influence of genetics and environment on a trait, we found that both genetic and environmental factors influence escape. Our results allow detailed characterization of escape, and suggest that escape may influence disease risk and phenotype differences between the sexes, and within females. [ABSTRACT FROM AUTHOR]

I gonorrhoeae i has the remarkable ability to produce outer membrane transporters that serve as receptors for the human metal-sequestering proteins described above, from which the transporters extract and import the cognate metals B (Fig 1) b . I gonorrhoeae i in metal-stripped chemically defined medium; conversely, calprotectin sequesters zinc in metal-replete tissue culture medium such that I N i . I gonorrhoeae i encode the periplasmic metal-binding proteins ZnuA and FbpA, as well as metabolic proteins not previously associated with metal homeostasis [[26]]. [Extracted from the article]

Habitat modification and introduced mammalian predators are linked to global species extinctions and declines, but their relative influences can be uncertain, often making conservation management difficult. Using landscape-scale models, we quantified the relative impacts of habitat modification and mammalian predation on the range contraction of a threatened New Zealand riverine duck. We combined 38 years of whio (Hymenolaimus malacorhynchos) observations with national-scale environmental data to predict relative likelihood of occurrence (RLO) under two scenarios using bootstrapped boosted regression trees (BRT). Our models used training data from contemporary environments to predict the potential contemporary whio distribution across New Zealand riverscapes in the absence of introduced mammalian predators. Then, using estimates of environments prior to human arrival, we used the same models to hindcast potential pre-human whio distribution prior to widespread land clearance. Comparing RLO differences between potential pre-human, potential contemporary and observed contemporary distributions allowed us to assess the relative impacts of the two main drivers of decline; habitat modification and mammalian predation. Whio have undergone widespread catastrophic declines most likely linked to mammalian predation, with smaller declines due to habitat modification (range contractions of 95% and 37%, respectively). We also identified areas of potential contemporary habitat outside their current range that would be suitable for whio conservation if mammalian predator control could be implemented. Our approach presents a practical technique for estimating the relative importance of global change drivers in species declines and extinctions, as well as providing valuable information to improve conservation planning. [ABSTRACT FROM AUTHOR]

In endometrial cancer, occult high-risk subtypes (rooted in histomorphologically low-risk disease) with insensitivity to adjuvant therapies impede improvements in therapeutic efficacy. Therefore, we aimed to assess the ability of molecular high-risk (MHR) and low-risk (MLR) ECPPF (E2F1, CCNA2, POLE, PPP2R1A, FBXW7) stratification to profile recurrence in early, low-risk endometrioid endometrial cancer (EEC) and insensitivity to platinum-based chemotherapy or radiotherapy (or both) in high-risk EEC. Using The Cancer Genome Atlas endometrial cancer database, we identified 192 EEC cases with available DNA sequencing and RNA expression data. Molecular parameters were integrated with clinicopathologic risk factors and adverse surveillance events. MHR was defined as high (-H) CCNA2 or E2F1 log2 expression (≥2.75), PPP2R1A mutations (-mu), or FBXW7mu; MLR was defined as low (-L) CCNA2 and E2F1 log2 expression (<2.75). We assessed 164 cases, plus another 28 with POLEmu for favorable-outcomes comparisons. MHR and MLR had significantly different progression-free survival (PFS) rates (P <.001), independent of traditional risk factors (eg, TP53mu), except for stage IV disease. PFS of CCNA2-L/E2F1-L paralleled that of POLEmu. ECPPF status stratified responses to adjuvant therapy in stage III-IV EEC (P <.01) and profiled stage I, grade 1–2 cases with risk of recurrence (P <.001). MHR was associated with CTNNB1mu-linked treatment failures (P <.001). Expression of homologous recombination repair (HR) and cell cycle genes was significantly elevated in CCNA2-H/E2F1-H compared with CCNA2-L/E2F1-L (P<1.0E-10), suggesting that HR deficiencies may underlie the favorable PFS in MLR. HRmu were detected in 20.7%. No treatment failures were observed in high-grade or advanced EEC with HRmu (P =.02). Favorable PFS in clinically high-risk EEC was associated with HRmu and MLR ECPPF (P <.001). In summary, MLR ECPPF and HRmu were associated with therapeutic efficacy in EEC. MHR ECPPF was associated with low-risk, early-stage recurrences and insensitivity to adjuvant therapies. [ABSTRACT FROM AUTHOR]

Rift Valley fever (RVF) is a disease of animals and humans associated with abortions in ruminants and late-gestation miscarriages in women. Here, we use a rat model of congenital RVF to identify tropisms, pathologies, and immune responses in the placenta during vertical transmission. Infection of late-gestation pregnant rats resulted in vertical transmission to the placenta and widespread infection throughout the decidua, basal zone, and labyrinth zone. Some pups from infected dams appeared normal while others had gross signs of teratogenicity including death. Histopathological lesions were detected in placenta from pups regardless of teratogenicity, while teratogenic pups had widespread hemorrhage throughout multiple placenta layers. Teratogenic events were associated with significant increases in placental pro-inflammatory cytokines, type I interferons, and chemokines. RVFV displays a high degree of tropism for all placental tissue layers and the degree of hemorrhage and inflammatory mediator production is highest in placenta from pups with adverse outcomes. Given the potential for RVFV to emerge in new locations and the recent evidence of emerging viruses, like Zika and SARS-CoV-2, to undergo vertical transmission, this study provides essential understanding regarding the mechanisms by which RVFV crosses the placenta barrier. Author summary: Rift Valley fever virus (RVFV) infections cause human health and economical burdens given its ability to induce high rates of abortions in ruminants and possible contributions towards late-term miscarriages in women. In this study, we have identified important structures in the placenta targeted by this emerging bunyavirus. Inflammation was associated with more severe fetal outcomes such as death and fetal deformities. The striking similarities between the pathologies of the placenta in this rodent model of congenital RVF and those observed in naturally infected ruminants highlight the utility of this rodent model. These findings may be further translated towards understanding the mechanisms involved in vertical transmission of RVFV in humans. [ABSTRACT FROM AUTHOR]

A surface plasmon polariton (SPP) is an excitation resulting from the coupling of light to a surface charge oscillation at a metal-dielectric interface. The excitation and detection of SPPs is foundational to the operating mechanism of a number of important technologies, most of which require SPP excitation via direct reflectance, commonly achieved via Attenuated Total Reflection (ATR) using the Kretschmann configuration. As a result, the accessible modes are fundamentally high-loss "leaky modes," presenting a critical performance barrier. Recently, our group provided the first demonstration of "forbidden," or guided-wave plasmon polariton modes (GW-PPMs), collective modes of a MIM structure with oscillatory electric field amplitude in the central insulator layer with up to an order of magnitude larger propagation lengths than those of traditional SPPs. However, in that work, GW-PPMs were accessed by indirect reflectance using Otto configuration ATR, making them of limited applied relevance. In this paper, we demonstrate a technique for direct reflectance excitation and detection of GW-PPMs. Specifically, we replace the air gap used in traditional Otto ATR with a low refractive index polymer coupling layer, mirroring a technique previously demonstrated to access Long-Range Surface Plasmon Polariton modes. We fit experimental ATR data using a robust theoretical model to confirm the character of the modes, as well as to explore the potential of this approach to enable advantageous propagation lengths. The ability to excite GW-PPMs using a device configuration that does not require an air gap could potentially enable transformative performance enhancements in a number of critical technologies. [ABSTRACT FROM AUTHOR]

Background Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in 'real-life' settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia. Methods and findings Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5-5.2) years for the total cohort and 6.4 (3.6-8.0) years in Europe, 3.7 (2.0-5.4) years in North America, 2.5 (1.2-4.4) years in South and Southeast Asia, 5.0 (2.7-7.5) years in South America and the Caribbean, and 2.1 (0.9-3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3-2.1) years in North America to 7.1 (5.3-8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4-2.6) years in North America to 7.9 (6.0-9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%-2.8%), 15.6% (15.1%-16.0%), and 11.3% (10.9%-11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%-1.1%]) and highest in South America and the Caribbean (4.4% [3.1%-6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%-6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%-13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria. Conclusion To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses., Author(s): The Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration, Amy L. Slogrove 1, Michael Schomaker 1, Mary-Ann Davies 1, Paige Williams 2, Suna Balkan 3, [...]

Introduction: Abiraterone acetate and enzalutamide are commonly employed in prostate cancer therapy in an interchangeable manner. These drugs are highly efficacious in androgen antagonism to improve patient outcomes, but they also carry noteworthy risk of adverse effects. Common toxicities vary amongst the two drugs and may have differential interactions with patient co-morbidities, but these patterns are unclear as co-morbidities typically serve as exclusion criteria in clinical trials. Hence, there is no existing guidance on how clinicians may tailor treatment based on patient-specific factors. Analysis of differential patient outcomes between these two drugs can inform future systematic reviews, new clinical studies, and clinical decision making. Method and analysis: The framework for this methodology was informed by the Joanna Briggs Institute methodology for scoping reviews. Title and abstract screening will be performed by two independent researchers to create an initial study inventory. This will be followed by full-text screening for study inclusion. Population-based studies describing patient outcomes, common toxicities, and associations with patient co-morbidities following abiraterone or enzalutamide therapy will be included. After data is extracted, it will be summarized for presentation. Ethics and dissemination: The findings of this scoping review will be published in a peer-reviewed journal. The results will be used to inform future studies on patient-specific factors informing treatment choice between abiraterone and enzalutamide for castration-resistant prostate cancer. All data are from published openly accessible sources, and therefore, no ethical clearance is necessary. The protocol is also registered at https://doi.org/10.6084/m9.figshare.19149227. [ABSTRACT FROM AUTHOR]

Background: To investigate changes in sociocultural stressors and protective factors, and mental health in Latina mothers before and after the 2016 Republican presidential nomination. Methods: We examined changes in sociocultural stressors, protective factors, and mental health from two prospective cohorts of Latina mothers from interior and border US cities (Nashville, TN, n = 39 and San Diego, CA, ns range = 78–83; 2013–2020). Results: We identified significant longitudinal increases in depression, anxiety, and perceived stress in the border city, and reductions in protective factors (e.g., optimism, social support, and familism) across sites. Discrimination varied by location, and was associated with higher stress only at baseline in the border city, and with higher anxiety in the interior city at follow-up. Acculturative stress was consistently associated with worse mental health across time points in the border city. Various protective factors were associated with reduced stress and anxiety across time points in both cities. Discussion: We identified decreased mental health at the border city, and reduced protective factors in Latina mothers across both study sites in the years following the 2016 presidential nomination, during a time of shifting sociopolitical climate. We also identify increased acculturative stress and discrimination over time, particularly at the border city. Interventions to maintain and enhance psychosocial protective factors amongst Latina mothers are warranted. [ABSTRACT FROM AUTHOR]

Background: Cerebral palsy (CP) is a complex neuromuscular condition that may negatively influence gross motor function. Children diagnosed with CP often exhibit spasticity, weakness, reduced motor control, contracture, and bony malalignment. Despite many previous association studies, the causal impact of these impairments on motor function is unknown. Aim: In this study, we proposed a causal model which estimated the effects of common impairments on motor function in children with spastic CP as measured by the 66-item Gross Motor Function Measure (GMFM-66). We estimated both direct and total effect sizes of all included variables using linear regression based on covariate adjustment sets implied by the minimally sufficient adjustment sets. In addition, we estimated bivariate effect sizes of all measures for comparison. Method: We retrospectively evaluated 300 consecutive subjects with spastic cerebral palsy who underwent routine clinical gait analysis. Model data included standard information collected during this analysis. Results: The largest causal effect sizes, as measured by standardized regression coefficients, were found for selective voluntary motor control and dynamic motor control, followed by strength, then gait deviations. In contrast, common treatment targets, such as spasticity and orthopedic deformity, had relatively small effects. Effect sizes estimated from bivariate models, which cannot appropriately adjust for other causal factors, substantially overestimated the total effect of spasticity, strength, and orthopedic deformity. Interpretation: Understanding the effects of impairments on gross motor function will allow clinicians to direct treatments at those impairments with the greatest potential to influence gross motor function and provide realistic expectations of the anticipated changes. [ABSTRACT FROM AUTHOR]

Background: Among older adults, decreased handgrip strength is associated with greater risk of frailty, and loss of physical function, mobility, lean mass, and overall muscular strength and power. Frailty is also associated with sarcopenia, for which handgrip strength measurement has been recommended for diagnostic purposes. Specific cutoff points for diagnosis have been identified, but use of different devices may affect measurement. Therefore to assess validity and reliability, we compared the two most frequently used devices, the Jamar hydraulic and Smedley spring handgrip dynamometers. Methods: Sixty-seven older (76.2 ± 0.9 years) men (n = 34) and women (n = 33) completed two trials of handgrip strength measurement on sequential days (T1, T2) using both devices in random order. Intraclass correlations were used to assess test-retest reliability, and Bland-Altman analysis was used to assess validity as the level of agreement between devices. Results: There were significant (p < 0.001) relationships between devices at T1 (r = 0.94) and T2 (r = 0.94) and strong (p < 0.001) intraclass correlations were observed for both devices (Jamar = 0.98; Smedley = 0.96), indicating excellent reliability. However, there were significant differences between devices. Strength measured with Jamar was greater than Smedley at both T1 (27.4 ± 1.4 vs. 23.4 ± 1.1 kg, p < 0.001) and T2 (25.3 ± 1.4 vs. 21.8 ± 1.2 kg, p < 0.001). Bland-Altman analysis confirmed these differences. Subgroup analysis to evaluate the effect of gender and age indicated that in women and old-old (>75 years) participants, differences between devices were closer to zero for both measurements compared to men and young-old (65–75 years) participants. Conclusions: Our results demonstrate that despite excellent reliability, there is poor agreement between devices, indicating a lack of validity. For use as a diagnostic tool, standardization and device-specific cutoff points for handgrip dynamometry are needed. [ABSTRACT FROM AUTHOR]

Endometriosis affects reproductive-aged females and varies considerably in terms of symptom presentation, morphologic features, and treatment response. Most studies investigating symptom recurrence after an endometriosis-related surgery have been conducted among adults. The Endometriosis pain QUality aftEr Surgical Treatment (EndoQUEST) Study was established to assess characteristics and biomarkers that are associated with pain remediation and improved quality of life after an endometriosis-related surgery among adolescents and young adults. This paper describes the EndoQUEST methodology, summarizes baseline descriptive factors, and compares characteristics by participant retention status. We enrolled 100 surgically-confirmed endometriosis participants aged 12–23 years who provided questionnaire data on reproductive and behavioral factors, pain characteristics and quality of life at three time points; before surgery, 6 weeks to 26 weeks after surgery, and 1 year after surgery. Among these 100 participants, 88 provided blood and/or saliva at all three time points, while 12 provided blood and/or saliva samples only before surgery and 6 to 26 weeks after surgery. There was little evidence of lost to follow-up at 1 year after surgery due to pain symptoms, as pain and quality of life characteristics were similar between participants who completed the questionnaire 1 year after surgery and those who did not. Analyses utilizing these longitudinal data will advance personalized treatment decision making for adolescents and young adults with endometriosis. [ABSTRACT FROM AUTHOR]

Venezuelan equine encephalitis virus (VEEV) is a positively-stranded RNA arbovirus of the genus Alphavirus that causes encephalitis in humans. Cynomolgus macaques are a relevant model of the human disease caused by VEEV and are useful in exploring pathogenic mechanisms and the host response to VEEV infection. Macaques were exposed to small-particle aerosols containing virus derived from an infectious clone of VEEV strain INH-9813, a subtype IC strain isolated from a human infection. VEEV-exposed macaques developed a biphasic fever after infection similar to that seen in humans. Maximum temperature deviation correlated with the inhaled dose, but fever duration did not. Neurological signs, suggestive of virus penetration into the central nervous system (CNS), were predominantly seen in the second febrile period. Electroencephalography data indicated a statistically significant decrease in all power bands and circadian index during the second febrile period that returned to normal after fever resolved. Intracranial pressure increased late in the second febrile period. On day 6 post-infection macaques had high levels of MCP-1 and IP-10 chemokines in the CNS, as well as a marked increase of T lymphocytes and activated microglia. More than four weeks after infection, VEEV genomic RNA was found in the brain, cerebrospinal fluid and cervical lymph nodes. Pro-inflammatory cytokines & chemokines, infiltrating leukocytes and pathological changes were seen in the CNS tissues of macaques euthanized at these times. These data are consistent with persistence of virus replication and/or genomic RNA and potentially, inflammatory sequelae in the central nervous system after resolution of acute VEEV disease. Author summary: Although naturally transmitted by mosquito, Venezuelan equine encephalitis viruses (VEEV) can be highly infectious when aerosolized. In humans, VEEV are only rarely fatal but cause a severe, biphasic fever with neurological symptoms including severe headache, a stiff neck, and photophobia. We report here our efforts to further characterize the disease caused by VEEV in the cynomolgus macaque, using an infectious clone of a human VEEV isolate, to explore the long-term effects of VEEV infection, and the utility of radiotelemetry in continuous monitoring of electroencephalography and intracranial pressure to explore the relationship between fever, virus penetration of the brain, and neurological disease. [ABSTRACT FROM AUTHOR]

Age and gender differences are prominent in the temperament literature, with the former particularly salient in infancy and the latter noted as early as the first year of life. This study represents a meta-analysis utilizing Infant Behavior Questionnaire-Revised (IBQ-R) data collected across multiple laboratories (N = 4438) to overcome limitations of smaller samples in elucidating links among temperament, age, and gender in early childhood. Algorithmic modeling techniques were leveraged to discern the extent to which the 14 IBQ-R subscale scores accurately classified participating children as boys (n = 2,298) and girls (n = 2,093), and into three age groups: youngest (< 24 weeks; n = 1,102), mid-range (24 to 48 weeks; n = 2,557), and oldest (> 48 weeks; n = 779). Additionally, simultaneous classification into age and gender categories was performed, providing an opportunity to consider the extent to which gender differences in temperament are informed by infant age. Results indicated that overall age group classification was more accurate than child gender models, suggesting that age-related changes are more salient than gender differences in early childhood with respect to temperament attributes. However, gender-based classification was superior in the oldest age group, suggesting temperament differences between boys and girls are accentuated with development. Fear emerged as the subscale contributing to accurate classifications most notably overall. This study leads infancy research and meta-analytic investigations more broadly in a new direction as a methodological demonstration, and also provides most optimal comparative data for the IBQ-R based on the largest and most representative dataset to date. [ABSTRACT FROM AUTHOR]

Background: Public health officials have classified smoking as a risk factor for COVID-19 disease severity. Smokers generally have less trust in health experts than do nonsmokers, leading to reduced risk perceptions. This study addresses smokers' trust in information sources about COVID-19 and how trust is associated with perceived COVID-19 susceptibility and severity among smokers. Methods and findings: A nationally representative sample of 1,223 current smokers were surveyed between October and November 2020, indicating their level of trust in COVID-19 information sources, and their perceptions of risk from COVID-19. Multiple differences in trustworthiness emerged; smokers trusted their personal doctor for information about COVID-19 more than other information sources, while news media were generally distrusted. In addition, the FDA was trusted less than the NIH and CDC. Several "trust gaps" were observed, indicating disparities in levels of trust associated with gender, ethnicity, education, and political orientation, which had the strongest association with trust of all factors. Political orientation was also a significant predictor of COVID-19 risk perceptions, but there was no independent effect of political orientation when accounting for trust, which was predictive of all risk perception outcomes. Conclusions: Trusted sources, such as personal doctors, may most effectively convey COVID-19 information across political orientations and sociodemographic groups. News media may be ineffective at informing smokers due to their low credibility. The results suggest that trust may explain the apparent effect of political orientation on COVID-19 risk perceptions. Implications for researchers, communication professionals, and policy makers are discussed. [ABSTRACT FROM AUTHOR]

Background: Parent mental health and wellbeing may have implications for understanding attachment transmission. In this systematic review, we synthesise the published literature to determine the nature of the relationship between parent mental health and wellbeing and the intergenerational transmission of attachment and to provide recommendations for future research, clinical practice and intervention. Method: Using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) approach, five electronic databases were searched for peer-reviewed empirical studies, published in English. Articles were considered for inclusion if data was collected on adult attachment, child attachment, and a domain of parent mental health/wellbeing. No date parameters were applied to the search strategy. The review was registered with PROPSERO (registration number: CRD42020157247). Results: Eleven studies examining the impact on parent mental health and wellbeing on the intergenerational transmission of attachment were identified for inclusion in this review. Our review found preliminary evidence that parent mental health and wellbeing play a role in the intergenerational transmission of attachment. Other key findings from the review were: evidence quality is mixed due to variable measurement of attachment and mental health; studies have mostly included correlational analysis or do not utilise contemporary methodological approaches to testing mediating or moderating relationships; and literature is largely focused on psychopathology and negative factors of mental health. Conclusions: The limited scope of parent mental health and wellbeing constructs examined in the literature, the sparse use of robust statistical analyses, and the lack of literature in general makes it difficult to draw conclusions on how and why parent mental health impacts attachment transmission. Addressing these limitations will further progress attachment-related literature and may have particular implications for attachment-informed interventions with clinical populations. [ABSTRACT FROM AUTHOR]

Wildlife-vehicle collisions are one of the main causes of mortality for wild mammals and birds in the UK. Here, using a dataset of 54,000+ records collated by a citizen science roadkill recording scheme between 2014–2019, we analyse and present temporal patterns of wildlife roadkill of the 19 most commonly reported taxa in the UK (84% of all reported roadkill). Most taxa (13 out of 19) showed significant and consistent seasonal variations in road mortality and fitted one of two seasonal patterns; bimodal or unimodal: only three species (red fox Vulpes vulpes, European polecat Mustela putorius and Reeves' muntjac deer Muntiacus reevesi) showed no significant seasonality. Species that increase movement in spring and autumn potentially have bimodal patterns in roadkill due to the increase in mate-searching and juvenile dispersal during these respective time periods (e.g. European badger Meles meles). Unimodal patterns likely represent increased mortality due to a single short pulse in activity associated with breeding (e.g. birds) or foraging (e.g. grey squirrels Sciurus carolinensis in autumn). Importantly, these patterns also indicate periods of increased risk for drivers, potentially posing a greater threat to human welfare. In addition to behaviour-driven annual patterns, abiotic factors (temperature and rainfall) explained some variance in roadkill. Notably, high rainfall was associated with decreased observations of two bird taxa (gulls and Eurasian magpies Pica pica) and European rabbit Oryctolagus cuniculus. By quantifying seasonal patterns in roadkill, we highlight a significant anthropogenic impact on wild species, which is important in relation to conservation, animal welfare, and human safety. [ABSTRACT FROM AUTHOR]

Objective: To compare the effectiveness and safety of prescribing ibuprofen and oxycodone for at-home management of children's fracture pain. Methods: A prospective observational cohort was conducted at the Stollery Children's Hospital pediatric emergency department (June 2010-July 2014). Children aged 4–16 years with an isolated fracture discharged home with advice to use either ibuprofen or oxycodone were recruited. Results: A cohort of 329 children (n = 217 ibuprofen, n = 112 oxycodone) were included. Mean age was 11.1 years (SD 3.5); 68% (223/329) were male. Fracture distribution included 80.5% (264/329) upper limb with 34.3% (113/329) requiring fracture reduction. The mean reduction in Faces Pain Score-Revised score (maximum pain–post-treatment pain) for Day 1 was 3.6 (SD 1.9) (ibuprofen) and 3.8 (SD 2.1) (oxycodone) (p = 0.50); Day 2 was 3.6 (SD 1.8) (ibuprofen) and 3.7 (SD 1.6) (oxycodone) (p = 0.56); Day 3 was 3.7 (SD 1.7) (ibuprofen) and 3.3 (SD 1.7) (oxycodone) (p = 0.24). Children prescribed ibuprofen (51.2%, 109/213) experienced less adverse events compared to those prescribed oxycodone (70.5% 79/112) on Day 1 (p = 0.001). Children prescribed ibuprofen (71.8%, 150/209) had their function (eat, play, school, sleep) affected less than those prescribed oxycodone (83.0%, 93/112) (p = 0.03) on Day 1. Conclusion: Children prescribed ibuprofen or oxycodone experienced similar analgesic effectiveness for at-home fracture pain. Oxycodone prescribing was associated with more adverse events and negatively impacted function. Oxycodone use does not appear to confer any benefit over ibuprofen for pain relief and has a negative adverse effect profile. Ibuprofen appears to be a safe option for fracture-related pain. [ABSTRACT FROM AUTHOR]

While evidence exists supporting the potential for aerosol transmission of SARS-CoV-2, the infectious dose by inhalation remains unknown. In the present study, the probability of infection following inhalation of SARS-CoV-2 was dose-dependent in a nonhuman primate model of inhalational COVID-19. The median infectious dose, assessed by seroconversion, was 52 TCID50 (95% CI: 23–363 TCID50), and was significantly lower than the median dose for fever (256 TCID50, 95% CI: 102–603 TCID50), resulting in a group of animals that developed an immune response post-exposure but did not develop fever or other clinical signs of infection. In a subset of these animals, virus was detected in nasopharyngeal and/or oropharyngeal swabs, suggesting that infected animals without signs of disease are able to shed virus and may be infectious, which is consistent with reports of asymptomatic spread in human cases of COVID-19. These results suggest that differences in exposure dose may be a factor influencing disease presentation in humans, and reinforce the importance of public health measures that limit exposure dose, such as social distancing, masking, and increased ventilation. The dose-response data provided by this study are important to inform disease transmission and hazard modeling, and, ultimately, mitigation strategies. Additionally, these data will be useful to inform dose selection in future studies examining the efficacy of therapeutics and vaccines against inhalational COVID-19, and as a baseline in healthy, young adult animals for assessment of the importance of other factors, such as age, comorbidities, and viral variant, on the infectious dose and disease presentation. Author summary: SARS-CoV-2 infection and subsequent disease presentation are dependent on exposure dose in a nonhuman primate model of inhalational COVID-19. [ABSTRACT FROM AUTHOR]

Immunomodulatory drugs could contribute to a functional cure for Human Immunodeficiency Virus (HIV). Interleukin-15 (IL-15) promotes expansion and activation of CD8+ T cell and natural killer (NK) cell populations. In one study, an IL-15 superagonist, N-803, suppressed Simian Immunodeficiency Virus (SIV) in non-human primates (NHPs) who had received prior SIV vaccination. However, viral suppression attenuated with continued N-803 treatment, partially returning after long treatment interruption. While there is evidence of concurrent drug tolerance, immune regulation, and viral escape, the relative contributions of these mechanisms to the observed viral dynamics have not been quantified. Here, we utilize mathematical models of N-803 treatment in SIV-infected macaques to estimate contributions of these three key mechanisms to treatment outcomes: 1) drug tolerance, 2) immune regulation, and 3) viral escape. We calibrated our model to viral and lymphocyte responses from the above-mentioned NHP study. Our models track CD8+ T cell and NK cell populations with N-803-dependent proliferation and activation, as well as viral dynamics in response to these immune cell populations. We compared mathematical models with different combinations of the three key mechanisms based on Akaike Information Criterion and important qualitative features of the NHP data. Two minimal models were capable of reproducing the observed SIV response to N-803. In both models, immune regulation strongly reduced cytotoxic cell activation to enable viral rebound. Either long-term drug tolerance or viral escape (or some combination thereof) could account for changes to viral dynamics across long breaks in N-803 treatment. Theoretical explorations with the models showed that less-frequent N-803 dosing and concurrent immune regulation blockade (e.g. PD-L1 inhibition) may improve N-803 efficacy. However, N-803 may need to be combined with other immune therapies to countermand viral escape from the CD8+ T cell response. Our mechanistic model will inform such therapy design and guide future studies. Author summary: Immune therapy may be a critical component in the functional cure for Human Immunodeficiency Virus (HIV). N-803 is an immunotherapeutic drug that activates antigen-specific CD8+ T cells of the immune system. These CD8+ T cells eliminate HIV-infected cells in order to limit the spread of infection in the body. In one study, N-803 reduced plasma viremia in macaques that were infected with Simian Immunodeficiency Virus, an analog of HIV. Here, we used mathematical models to analyze the data from this study to better understand the effects of N-803 therapy on the immune system. Our models indicated that inhibitory signals may be reversing the stimulatory effect of N-803. Results also suggested the possibilities that tolerance to N-803 could build up within the CD8+ T cells themselves and that the treatment may be selecting for virus strains that are not targeted by CD8+ T cells. Our models predict that N-803 therapy may be made more effective if the time between doses is increased or if inhibitory signals are blocked by an additional drug. Also, N-803 may need to be combined with other immune therapies to target virus that would otherwise evade CD8+ T cells. [ABSTRACT FROM AUTHOR]

Objective: Prospective studies on relationships between hedonic hunger and BMI (Body Mass Index) during weight management are lacking. This study examined if hedonic hunger reduced during a behavioural weight management programme, and if hedonic hunger predicted future BMI. Methods: Participants were 594 community-dwelling, UK-based adults(396 female; age 56.43 years, s.d. = 12.50, range 20–83 years); 490 participants (82.5%) had obesity. Participants were randomised to a 12- or 52-week behavioural weight management intervention (WW12 or WW52, respectively) or a brief self-help intervention (BI). Relationships between hedonic hunger and BMI over 24 months (baseline, 3, 12, 24 months) were analysed using an autoregressive cross-lagged model. Results: Hedonic hunger scores decreased from 2.71 (s.d. =.91) at baseline to 2.41 (s.d. =.88) at 3 months (p <.001, CI.22 to.38), remained reduced to 24 months, and were not affected by intervention arm at any time point (p's>.05). Baseline hedonic hunger scores predicted 3-month scores (B =.76, SE =.03, p <.001, CI.71 to.82), 3-month scores predicted 12-month scores (B =.76, SE =.03, p <.001 CI.72 to.80), and 12-month scores predicted 24-month scores (B =.72, SE =.03, p <.001, CI.64 to.77). Higher hedonic hunger at 3 months predicted higher BMI at 12 months (B =.04, SE =.02, p =.03, CI.01 to.07) but not at 24 months (p>.05). BMI at 12 months was lower in WW52 30.87kg/m2, s.d. = 5.02) than WW12 (32.12 kg/m2, s.d. = 5.58, p =.02, CI.16 to 2.34) and BI (32.74 kg/m2, s.d. = 4.15, p =.01, CI.30 to 3.45). BMI was not affected by intervention at any other time point (p's>.05). Conclusion: Hedonic hunger reduced during weight management irrespective of intervention. Early reductions in hedonic hunger appear to be associated with lower BMI in the medium-term. Identifying ways to reduce hedonic hunger during weight loss could aid weight management for some people. [ABSTRACT FROM AUTHOR]

Multi-drug resistant (MDR) Acinetobacter baumannii (Ab) and Acinetobacter spp. present monumental global health challenges. These organisms represent model Gram-negative pathogens with known antibiotic resistance and biofilm-forming properties. Herein, a novel, nontoxic biocide, AB569, consisting of acidified nitrite (A-NO2-) and ethylenediaminetetraacetic acid (EDTA), demonstrated bactericidal activity against all Ab and Acinetobacter spp. strains, respectively. Average fractional inhibitory concentrations (FICs) of 0.25 mM EDTA plus 4 mM A-NO2- were observed across several clinical reference and multiple combat wound isolates from the Iraq/Afghanistan wars. Importantly, toxicity testing on human dermal fibroblasts (HDFa) revealed an upper toxicity limit of 3 mM EDTA plus 64 mM A-NO2-, and thus are in the therapeutic range for effective Ab and Acinetobacter spp. treatment. Following treatment of Ab strain ATCC 19606 with AB569, quantitative PCR analysis of selected genes products to be responsive to AB569 revealed up-regulation of iron regulated genes involved in siderophore production, siderophore biosynthesis non-ribosomal peptide synthetase module (SBNRPSM), and siderophore biosynthesis protein monooxygenase (SBPM) when compared to untreated organisms. Taken together, treating Ab infections with AB569 at inhibitory concentrations reveals the potential clinical application of preventing Ab from gaining an early growth advantage during infection followed by extensive bactericidal activity upon subsequent exposures. [ABSTRACT FROM AUTHOR]

Aerosol exposure to eastern equine encephalitis virus (EEEV) can trigger a lethal viral encephalitis in cynomolgus macaques which resembles severe human disease. Biomarkers indicative of central nervous system (CNS) infection by the virus and lethal outcome of disease would be useful in evaluating potential medical countermeasures, especially for therapeutic compounds. To meet requirements of the Animal Rule, a better understanding of the pathophysiology of EEEV-mediated disease in cynomolgus macaques is needed. In this study, macaques given a lethal dose of clone-derived EEEV strain V105 developed a fever between 2–3 days post infection (dpi) and succumbed to the disease by 6 dpi. At the peak of the febrile phase, there was a significant increase in the delta electroencephalography (EEG) power band associated with deep sleep as well as a sharp rise in intracranial pressure (ICP). Viremia peaked early after infection and was largely absent by the onset of fever. Granulocytosis and elevated plasma levels of IP-10 were found early after infection. At necropsy, there was a one hundred- to one thousand-fold increase in expression of traumatic brain injury genes (LIF, MMP-9) as well as inflammatory cytokines and chemokines (IFN-γ, IP-10, MCP-1, IL-8, IL-6) in the brain tissues. Phenotypic analysis of leukocytes entering the brain identified cells as primarily lymphoid (T, B, NK cells) with lower levels of infiltrating macrophages and activated microglia. Massive amounts of infectious virus were found in the brains of lethally-infected macaques. While no infectious virus was found in surviving macaques, quantitative PCR did find evidence of viral genomes in the brains of several survivors. These data are consistent with an overwhelming viral infection in the CNS coupled with a tremendous inflammatory response to the infection that may contribute to the disease outcome. Physiological monitoring of EEG and ICP represent novel methods for assessing efficacy of vaccines or therapeutics in the cynomolgus macaque model of EEEV encephalitis. Author summary: Eastern equine encephalitis virus (EEEV) is a mosquito-transmitted virus that can cause highly lethal encephalitis in a subset of infected humans. Due to being highly virulent and infectious by aerosol, a need exists to develop vaccines or therapeutics to prevent lethal disease, and FDA approval of such an intervention would likely require use of the FDA's Animal Rule. To further characterize the cynomolgus macaque model of EEEV after aerosol exposure, we conducted a detailed analysis of the pathological progression of encephalitis in these animals. Physiological condition of the animals was assessed after infection using electroencephalography (EEG) and intracranial pressure (ICP) along with immunological characterization of the inflammatory cells in the brain. We found overwhelming virus infection of the CNS in fatal infections coupled with a strong CNS inflammatory response. Novel findings by EEG and ICP will guide comprehensive studies evaluating the efficacy of medical countermeasures. [ABSTRACT FROM AUTHOR]

The experimental objective was to characterize the impact of insoluble corn-based fiber, xylanase, and an arabinoxylan-oligosaccharide on ileal digesta and mucosa microbiome of pigs. Three replicates of 20 gilts were blocked by initial body weight, individually-housed, and assigned to 1 of 4 dietary treatments: a low-fiber control (LF), a 30% corn bran high-fiber control (HF), HF+100 mg/kg xylanase (HF+XY), and HF+50 mg/kg arabinoxylan oligosaccharide (HF+AX). Gilts were fed their respective treatments for 46 days. On day 46, pigs were euthanized and ileal digesta and mucosa were collected. The V4 region of the 16S rRNA was amplified and sequenced, generating a total of 2,413,572 and 1,739,013 high-quality sequences from the digesta and mucosa, respectively. Sequences were classified into 1,538 mucosa and 2,495 digesta operational taxonomic units (OTU). Hidden-state predictions of 25 enzymes were made using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2 (PICRUST2). Compared to LF, HF increased Erysipelotrichaceae_UCG-002, and Turicibacter in the digesta, Lachnospiraceae_unclassified in the mucosa, and decreased Actinobacillus in both (Q<0.05). Relative to HF, HF+XY increased 19 and 14 of the 100 most abundant OTUs characterized from digesta and mucosa, respectively (Q<0.05). Notably, HF+XY increased the OTU_23_Faecalibacterium by nearly 6 log2-fold change, compared to HF. Relative to HF, HF+XY increased genera Bifidobacterium, and Lactobacillus, and decreased Streptococcus and Turicibacter in digesta (Q<0.05), and increased Bifidobacterium and decreased Escherichia-Shigella in the mucosa (Q<0.05). Compared to HF, HF+AX increased 5 and 6 of the 100 most abundant OTUs characterized from digesta and mucosa, respectively, (Q<0.05), but HF+AX did not modulate similar taxa as HF+XY. The PICRUST2 predictions revealed HF+XY increased gene-predictions for enzymes associated with arabinoxylan degradation and xylose metabolism in the digesta, and increased enzymes related to short-chain fatty acid production in the mucosa. Collectively, these data suggest xylanase elicits a stimbiotic and prebiotic mechanism. [ABSTRACT FROM AUTHOR]

Dis3L2 is a highly conserved 3'-5' exoribonuclease which is mutated in the human overgrowth disorders Perlman syndrome and Wilms' tumour of the kidney. Using Drosophila melanogaster as a model system, we have generated a new dis3L2 null mutant together with wild-type and nuclease-dead genetic lines in Drosophila to demonstrate that the catalytic activity of Dis3L2 is required to control cell proliferation. To understand the cellular pathways regulated by Dis3L2 to control proliferation, we used RNA-seq on dis3L2 mutant wing discs to show that the imaginal disc growth factor Idgf2 is responsible for driving the wing overgrowth. IDGFs are conserved proteins homologous to human chitinase-like proteins such as CHI3L1/YKL-40 which are implicated in tissue regeneration as well as cancers including colon cancer and non-small cell lung cancer. We also demonstrate that loss of DIS3L2 in human kidney HEK-293T cells results in cell proliferation, illustrating the conservation of this important cell proliferation pathway. Using these human cells, we show that loss of DIS3L2 results in an increase in the PI3-Kinase/AKT signalling pathway, which we subsequently show to contribute towards the proliferation phenotype in Drosophila. Our work therefore provides the first mechanistic explanation for DIS3L2-induced overgrowth in humans and flies and identifies an ancient proliferation pathway controlled by Dis3L2 to regulate cell proliferation and tissue growth. Author summary: Regulation of cell proliferation is not only important during development but also required for repair of damaged tissues and during wound healing. Using human kidney cells as well as the fruit fly Drosophila we have recently discovered that cell proliferation can be regulated by a protein named Dis3L2. Depletion or removal of this protein results in excess proliferation. These results are relevant to human disease as DIS3L2 has been shown to be mutated in an overgrowth syndrome (Perlman syndrome) where affected children have abnormal enlargement of organs (e.g. kidneys) and susceptibility to Wilms' tumour (a kidney cancer). Dis3L2 is an enzyme known to "chew up" mRNA molecules which instruct the cell to make particular proteins. Using state-of-the-art molecular methods in Drosophila, we have discovered that Dis3L2 targets a small subset of mRNAs, including an mRNA encoding a growth factor named 'imaginal disc growth factor 2' (idgf2). For human kidney cells in culture, we have found that depletion of DIS3L2 results in enhanced proliferation, and that this involves a well-known cellular pathway. Our results mean that we have discovered a new way of controlling cell proliferation, which could, in the future, be used in human therapies. [ABSTRACT FROM AUTHOR]