Search

A recent work by Hartwig et al. (Science, 2020) details an efficient method to borylate strong primary C(sp3)–H bonds via iridium-catalysed C–H activation. The conditions confer counterintuitive selectivity over more labile C–H bonds, while providing an avenue for a gamut of synthetically valuable late-stage functionalisations through versatile borylate intermediates.

Multitreatment designs were used to evaluate the relative effectiveness of multicomponent Stay, Play, Talk (SPT) interventions on peer social behaviors for two groups of children, each including one Participant With Autism Spectrum Disorder (PWA) and two socially competent peers. Children were trained to use buddy strategies during 5-min free-play sessions in an inclusive preschool classroom. Additional components were systematically introduced, including a self-monitored group contingency and recorded reminders. Dependent variables were the percentage of intervals peers spent staying near and playing with the PWA, as well as the number of verbal social interactions between the peers and the PWA. Functional relations were identified for some behaviors for some participants, with the SPT variation including recorded reminders and the group contingency associated with the most positive outcomes. Further research is needed to determine effects of the group contingency and recorded reminders without peer training.

Introduction Approximately 10% to 15% of people affected by sickle cell disease (SCD) in the United States are Latino, many of whom are primary Spanish speakers. A key tool for self-reported outcome measures, the Pediatric QOL Inventory (PedsQL) SCD module, was not available in Spanish. Here, we assess the linguistic validity of a Spanish translation and compare perception of disease-specific and generic quality of life (QOL) in a sample of Latino and non-Latino children with SCD and their parents. Method Following forward and backward translation, Spanish-speaking child–parent dyads linguistically validated the translated instruments. Disease-specific and generic QOL perception of 28 child–parent dyads who participated in a clinical feasibility trial, HABIT (Hydroxyurea Adherence for Personal Best in Sickle Cell Disease), were compared by ethnicity. Data were analyzed by descriptive statistics, Mann–Whitney U test, absolute score differences, and minimal clinically important differences (MCID). Results The translated questionnaire required no further language changes. QOL scores were higher for Latino children and parents compared with non-Latinos, with score differences exceeding MCIDs for total scores and the majority of subscale scores. Conclusion Spanish language PedsQL SCD instruments allow measurement of QOL in Spanish-speaking Latino children with SCD and their parents. Score differences for Latinos mostly exceeded MCIDs, suggesting that these differences are clinically meaningful. Confirmation of these findings is warranted.

Recent evidence indicates that viral components of the microbiota can contribute to intestinal homeostasis and protection from local inflammatory or infectious insults. However, host-derived mechanisms that regulate the virome remain largely unknown. Here, we used colonization of C57BL6/J mice with the model commensal murine norovirus (MNV CR6) to interrogate host-directed mechanisms of viral regulation, and show that STAT1 is a central coordinator of both viral replication and antiviral T cell responses. In STAT1-sufficient mice MNV CR6 is asymptomatic and restricted to the colon, despite the persistence of high viral loads. However, in the absence of STAT1 viral replication is disseminated and observed in key innate and adaptive immune populations. STAT1-deficient mice develop dysregulated inflammatory CD8+ and CD4+ T cell responses, which coincide with weight loss and severe necrosis of the spleen and liver. Despite these altered T cell responses which resemble those that mediate lethal immunopathology following other model viral infections of STAT1-deficient mice, depletion of adaptive immune cells and their associated effector functions had no effect on CR6-induced disease. In contrast, therapeutic administration of an antiviral compound limited viral replication, preventing viral-induced tissue damage and death despite ongoing inflammatory antiviral T cell responses. Collectively, our data show that STAT1 restricts MNV CR6 replication within the intestinal mucosa. Unlike other model viral infections, CR6 induces disease in STAT1-deficient mice via uncontrolled viral replication rather than the concomitant development of dysregulated antiviral T cell responses. Research in the Osborne lab is supported by the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research, the Canada Research Chair program and scholarships from the University of British Columbia.

Recent global events have highlighted the need to better understand mucosal antiviral immunity. Murine Norovirus (MNV) is small non-enveloped positive sense RNA virus that can be used as a model of intestinal viral infection. In this work we use two highly related MNV strains with distinct biological behaviors; CR6 establishes chronic colonic infection, while CW3 establishes systemic infection initiated in the small intestine and is cleared by day 8, correlating with the peak of cell-mediated adaptive immunity. Using flow cytometry and quantitative immunofluorescent microscopy (QIM) of transgenic P14 CD8 T cells specific to recombinant CR6gp33 and CW3gp33, we characterized CD8 T cell responses to CR6 and CW3 from initiation to clearance of CW3. Our data indicate that initiation of CD8 T cell division in response to CR6 infection is delayed, less robust, and largely limited to the mesenteric lymph nodes (MLNs) with less splenic division compared to CW3 infection. Further, the biogeography of P14 T cell priming differs, as early T cell expansion was restricted to distinct nodes of the MLN complex. These early differences propagate out to the time of CW3 clearance. By day 8, there is differential localization of P14 cells in the GI tract to the site of highest viral load and a larger systemic population of P14 cells following CW3 infection. Infection of MLN-deficient mice revealed a critical role for MLN surveillance in targeting P14 T cells to the GI tract following CR6 infection while the spleen plays a compensatory role in response to CW3. These results show how distinct infectious locations of a continuous mucosal surface influence the responses of antiviral CD8 T cells without confounding effects of antigenicity. This work is supported by the Canadian Institutes for Health Research (CIHR) and a UBC 4 Year Fellowship awarded to Blair K Hardman

People living with multiple sclerosis (MS) experience episodic central nervous system (CNS) white matter lesions instigated by autoreactive T cells. With age, MS patients show evidence of grey matter demyelination and experience devastating non-remitting symptomology. What drives progression is unclear and has been hampered by the lack of suitable animal models. Here we show that passive experimental autoimmune encephalomyelitis (EAE) induced by an adoptive transfer of young Th17 cells induces a non-remitting clinical phenotype that is associated with persistent leptomeningeal inflammation and cortical pathology in old, but not young SJL/J mice. While the quantity and quality of T cells did not differ in the brains of old vs young EAE mice, an increase in neutrophils and a decrease in B cells was observed in the brains of old mice. Neutrophils were also found in the leptomeninges of a subset of progressive MS patient brains that showed evidence of leptomeningeal inflammation and subpial cortical demyelination. Taken together, our data show that while Th17 cells initiate CNS inflammation, subsequent clinical symptoms and grey matter pathology are dictated by age and associated with other immune cells such as neutrophils.

Dietary fibers and their breakdown products have been shown to limit inflammation in multiple disease contexts. However, the term “dietary fiber” encompasses a biochemically diverse family of carbohydrates, and it remains unknown how different fiber sources influence immune cell function. To address this question, we assessed the immunomodulatory capacity of different fiber types in a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). C57BL/6 mice were fed a control diet (5% cellulose) or diets enriched (30%) with resistant starch, inulin, pectin, or guar gum for 2 weeks prior to EAE induction. A diet rich in guar gum uniquely ameliorated the clinical, pathological, and immunological features of EAE. Limited central nervous system (CNS) infiltration of IFNγ+CD4+ T cells (Th1s) in guar gum-fed mice could be attributed to T cell-intrinsic impairment Th1 activation and polarization. Nanostring nCounter transcriptional analyses revealed downregulation of migration-associated markers in CD4+ T cells isolated from guar gum/EAE mice, which was supported by reduced cell-surface expression of integrins involved in migration into the CNS. Functionally, this translated to limited migration of guar gum-derived encephalitogenic Th1s into the CNS upon adoptive transfer into control-fed recipients, which reduced incidence and severity of EAE. However, the 16S rRNA microbiome signature and short chain fatty acid profiles were not unique in comparison to other fiber-supplemented diets, indicating a novel mechanism of action from those previously ascribed in high fiber diet studies. These data confirm the individuality of dietary fibers and identify a novel immunomodulatory function of guar gum. This project was supported by the endMS doctoral studentship program (Multiple Sclerosis Society of Canada) (NMF, JRA), the Canadian Institutes for Health Research (PJT-148909), and the Canada Research Chair program (LCO).

Withdrawal and multitreatment single subject research designs were used to evaluate the effectiveness of stay-play-talk (SPT) interventions on social behaviors of preschool-aged peers to children with disabilities. Each group included at least one socially competent peer and one child with Down syndrome who used an augmentative and alternative communication (AAC) device as a primary mode of communication. Peers were trained to use SPT strategies during free play sessions, and a modified reinforcement system and modified peer arrangement were introduced for one group. For one group, results indicate a functional relation between the original SPT intervention and increased stay and play behaviors. For the other group, results indicate a functional relation between SPT with modified arrangement and increased stay and play behaviors. Future research is needed to determine effectiveness of SPT interventions for children with disabilities who have more sophisticated functional play skills, as well as utility of creating peer dyads compared with peer triads.

Substance use is strongly associated with suicide completions. However, little is known about the patterns of substances used in suicide deaths. The purpose of this analysis is to determine latent classes of toxicology-reported substances among individuals who completed suicide. The sample consists of suicide victims in the National Violent Death Reporting System (NVDRS) during years 2003–2017 (n = 202,838). Toxicology reports were used to construct latent class analyses of substance use among suicide victims. Correlates for latent class membership included sex, race/ethnicity, previous experiences of child abuse, homelessness, and intimate partner violence (IPV) victimization. The majority of suicide victims were male (77.7%), straight/heterosexual (99.5%) and white (88.3%). The final unconditional model yielded a four-class model, including a “No substance/single substance use” class, an “Alcohol and other substance” class, a “Marijuana and other substance” class, and an “Opiate use” class. Compared to the reference class of “No substance/single substance,” females were more likely than males to be classified in the “Alcohol and other substance” class, the “Multi-substance use” class, and the “Opiate use” class. Homelessness was associated with classification in the “Marijuana and other substance” class and the “Opiate use” class compared to the “No substance/single substance” class. IPV was associated with both polysubstance use classes (“Alcohol plus other substance” and “Marijuana plus other substance”) along with the “Opiate use” class compared to the “No substance/single substance” class. These classes highlight profiles of suicide descendants and emphasize the importance of polysubstance use prevention among females, homeless individuals, and those who experience IPV.

Adhesively bonding composite components is a reliable alternative to conventional joining processes that minimizes part weight and reduces fabrication costs. Regarding performance and reliability, of particular interest is developing adherend surface treatments that enhance adhesion of the joint interfaces in aggressive chemical environments. Using fracture mechanics-based adhesion metrologies, critical and subcritical crack growth were evaluated for several peel-ply-treated, adhesively bonded composite joints. Fracture toughness, Gc, and corresponding failure modes were evaluated for specimens constructed using two different bonding processes (co-bonding and secondary bonding) and four different peel ply treatments. Environmentally assisted crack growth was evaluated as a function of time in several environments: humid, high temperature humid, and hydraulic fluid immersion. It is shown that humid environments accelerate crack growth rates, da/dt, relative to the strain energy release rate, G. This effect was amplified at elevated temperatures and further amplified in the presence of hydraulic fluid.

Introduction The introduction of biological and synthetic meshes has revolutionised the practice of implant-based breast reconstruction (IBBR) but evidence for effectiveness is lacking. The iBRA (implant Breast Reconstruction evAluation) study is a national trainee-led project that aims to explore the practice and outcomes of IBBR to inform the design of a future trial. We report the results of the iBRA National Practice Questionnaire (NPQ) which aimed to comprehensively describe the provision and practice of IBBR across the UK. Methods A questionnaire investigating local practice and service provision of IBBR developed by the iBRA Steering Group was completed by trainee and consultant leads at breast and plastic surgical units across the UK. Summary data for each survey item were calculated and variation between centres and overall provision of care examined. Results 81 units within 79 NHS-hospitals completed the questionnaire. Units offered a range of reconstructive techniques, with IBBR accounting for 70% (IQR:50–80%) of participating units' immediate procedures. Units on average were staffed by 2.5 breast surgeons (IQR:2.0–3.0) and 2.0 plastic surgeons (IQR:1.0–3.0) performing 35 IBBR cases per year (IQR:20-50). Variation was demonstrated in the provision of novel different techniques for IBBR especially the use of biological (n = 62) and synthetic (n = 25) meshes and in patient selection for these procedures. Conclusions The iBRA-NPQ has demonstrated marked variation in the provision and practice of IBBR in the UK. The prospective audit phase of the iBRA study will determine the safety and effectiveness of different approaches to IBBR and allow evidence-based best practice to be explored., Highlights • Implant breast reconstruction (IBBR) and the range of techniques is poorly evidence based. • We aimed to explore the current practice of IBBR in the UK to inform the design of a future definitive study. • Significant variation was demonstrated in the availability of techniques and patient selection for IBBR. • There is a need for well-designed studies to establish best practice and improve outcomes for patients considering IBBR.

Few studies have explored the direct impact of behavioral parent training programs on child maltreatment behaviors among marginalized, at-risk fathers. This feasibility study examined SafeCare® Dad to Kids (Dad2K), an augmented version of the evidence-based child maltreatment prevention program SafeCare, to determine the acceptability and initial efficacy of the program for improving father parenting skills and reducing maltreatment risk. Ninety-nine fathers were enrolled in the study and randomized to the SafeCare Dad2K Intervention (n=51) or comparison (n=48). Intervention fathers participated in 6 home visiting sessions and comparison fathers received parenting materials via mail. All fathers participating in the study completed a baseline and 8-week assessment (post-intervention) of maltreatment behaviors. In addition, intervention fathers completed feasibility and parenting skill measures. A significant main effect emerged indicating decreases for both groups in psychologically aggressive behaviors. No significant group by time findings emerged for child maltreatment behaviors. Father intervention completers endorsed high satisfaction ratings for the program and demonstrated significant improvements in targeted father-child interaction skills. Based on the high rates of acceptability and initial improvement in positive parenting skills, findings demonstrate the feasibility for involving at-risk fathers in behavioral parent training programs targeting child maltreatment prevention.

An antecedent exercise (AE) intervention was conducted with two young children who demonstrated challenging behaviors during a large group circle time activity in a preschool classroom; outcomes were evaluated in the context of alternating treatments designs. Results from the initial visual analysis suggested no overlap between conditions, with small, consistent effects favoring the AE condition. However, plotting reliability data suggested observer bias was present for one participant. Subsequently (post hoc), a blind observer coded data from all conditions for that participant. Results suggested that no functional relation was present for that participant. Implications include the need for blind data collectors and additional, highly rigorous studies assessing the effectiveness of AE.

Child maltreatment has long-lasting negative impacts, and interventions are needed to improve caregiver's parenting skills to prevent maltreatment. This paper reports on a randomized trial comparing the SafeCare© model to services as usual (SAU) for child-welfare referred caregivers. SafeCare is an 18-session behavioral parenting program that teaches skills in positive parent-child interactions, home safety, and child health. SAU is generally unstructured and includes support, crisis management, referrals for need, and parenting education. Teams of providers at nine sites were randomized to implement SafeCare (19 teams; 119 providers) or continue SAU (17 teams; 118 providers). Two-hundred eighty eight caregivers (193 SafeCare; 95 SAU) with children aged 0–5 who were receiving services agreed to complete a baseline and 6-month assessment. Assessments measured positive parenting behaviors, parenting stress, protective factors, and neglectful behaviors using validated scales. Participants were primarily white (74.6%), female (87.0%), and low-income (68.6%), and had a mean age of 29. Latent change score models (LCSM) using a sandwich estimator consistent with the trial design were used to examine changes in 13 outcomes. Results indicated that SafeCare had small to medium effects for improving several parenting outcomes including supporting positive child behaviors (d = 0.46), proactive parenting (d = 0.25), and two aspects of parenting stress (d = 0.28 and .30). No differential change between groups was found for other indicators, including all indicators of neglect. Parenting programs such as SafeCare offer a promising mode of intervention for child welfare systems. Scale-up of parenting programs can improve parenting, improve child outcomes, and potentially reduce maltreatment. Clinicaltrial.gov registration number NCT02549287

BACKGROUND: We examined the prevalence of and relationships between violence victimization and negative health correlates of Haitian youth exposed to the 2010 earthquake. METHODS: Participants were randomly selected 13–24 year-old youth (1457 females; 1459 males) living in Haiti following the 2010 earthquake. Data collected via Haiti’s 2012 Violence against Children Survey (VACS) were analyzed. RESULTS: Participants reported violence victimization in the past 12 months (females: 49.93%; males: 41.68%), moderate-to-severe mental distress (females: 76.56%; males: 66.41%), and suicidal ideation (females: 26.79%; males: 8.05%). Compared to participants without experiences of violence, victims of violence had significantly higher mean number of sexual partners (females: 1.99, 95% CI: 1.81–2.16, p = .02; males: 4.33, 95% CI: 3.50–5.16, p = .03), mental distress (females: 80.39%, p = .01; males: 72.95%, p = .002), and suicidal ideation (females: 36.09%, p < .0001; males: 12.02%, p < .0001). Male victims of violence were more likely to have sex without a condom (26.02%, p = .01) and female victims of violence were more likely to report histories of STIs (28.04%, p = .01), when compared to participants without history of violence. LIMITATIONS: Data were collected via self-report. Disaster exposure experiences were not assessed. Analysis was correlational and did not control for potential confounding variables. CONCLUSIONS: Disaster-exposed youth endorsed high levels of violence victimization and negative health correlates. Earthquake survivors who experienced violence were more likely to report negative health correlates. Greater attention to downstream sequelae of natural disasters is needed.

Undifferentiated febrile illnesses present diagnostic and treatment challenges in the Firm Base, let alone in the deployed austere environment. We report a series of 14 cases from Operation TRENTON in South Sudan in 2017 that coincided with the rainy season, increased insect numbers and a Relief in Place. The majority of patients had headaches, myalgia, arthralgia and back pain, as well as leucopenia and thrombocytopenia. No diagnoses could be made in theatre, despite a sophisticated deployed laboratory being available, and further testing in the UK, including next-generation sequencing, was unable to establish an aetiology. Such illnesses are very likely to present in tropical environments, where increasing numbers of military personnel are being deployed, and clinicians must be aware of the non-specific presentation and treatment, as well as the availability of Military Infection Reachback services to assist in the management of these cases.

Objectives Suicide is the second leading cause of death among adolescents in the United States, and a substantial proportion are committed with a firearm. This study identifies risk patterns among adolescent firearm suicides and examines how demographic factors relate to these patterns. Methods A latent class analysis was conducted using US National Violent Death Reporting System data, years 2007–2017. Adolescent firearm suicide decedents ages 10–17 years were included in the primary analyses (n = 2139). Factors used to identify risk patterns fell under the categories of mental health, relationship or other social problems, and substance use. Demographic factors examined in relation to risk patterns were age, race/ethnicity, and sex. Results Three risk patterns emerged: low problems (i.e., a low probability of all risk factors included in the model; n = 1075; 50.26%); high mental health problems and history of suicidal behavior, ideation, and suicide attempts (n = 742, 34.69%); and high problems at school (n = 322, 15.05%). Compared to White adolescents, Black adolescents had decreased odds of being in the “high mental health and suicidal behavior” class, compared to being in the “low problems” class (AOR, 0.53, 95% CI: 0.36, 0.79). A post hoc analysis identified four risk patterns for non-firearm suicides (n = 3319), with mental health problems featuring more prominently compared to firearm suicide patterns. Conclusions Findings indicate that half of adolescent firearm suicides are characterized by a low probability of having common risk factors for suicide. This emphasizes the importance of universal safe storage practices among firearm-owning parents. Results also indicate a need for more research on the risk factors unique to Black adolescents.

Despite the enduring interest in motion integration, a direct measure of the space–time filter that the brain imposes on a visual scene has been elusive. This is perhaps because of the challenge of estimating a 3D function from perceptual reports in psychophysical tasks. We take a different approach. We exploit the close connection between visual motion estimates and smooth pursuit eye movements to measure stimulus–response correlations across space and time, computing the linear space–time filter for global motion direction in humans and monkeys. Although derived from eye movements, we find that the filter predicts perceptual motion estimates quite well. To distinguish visual from motor contributions to the temporal duration of the pursuit motion filter, we recorded single-unit responses in the monkey middle temporal cortical area (MT). We find that pursuit response delays are consistent with the distribution of cortical neuron latencies and that temporal motion integration for pursuit is consistent with a short integration MT subpopulation. Remarkably, the visual system appears to preferentially weight motion signals across a narrow range of foveal eccentricities rather than uniformly over the whole visual field, with a transiently enhanced contribution from locations along the direction of motion. We find that the visual system is most sensitive to motion falling at approximately one-third the radius of the stimulus aperture. Hypothesizing that the visual drive for pursuit is related to the filtered motion energy in a motion stimulus, we compare measured and predicted eye acceleration across several other target forms.SIGNIFICANCE STATEMENTA compact model of the spatial and temporal processing underlying global motion perception has been elusive. We used visually driven smooth eye movements to find the 3D space–time function that best predicts both eye movements and perception of translating dot patterns. We found that the visual system does not appear to use all available motion signals uniformly, but rather weights motion preferentially in a narrow band at approximately one-third the radius of the stimulus. Although not universal, the filter predicts responses to other types of stimuli, demonstrating a remarkable degree of generalization that may lead to a deeper understanding of visual motion processing.

When engaging with ethnographic research to understand symbols associated with a club and its fan base, researchers need to reflect on the role of the ethnographer and the extent to which we can or...

Tuft cells help contain parasites Trillions of microbes inhabit our guts, including worms and other parasites. Epithelial cells that line the gut orchestrate parasite-targeted immune responses. Howitt et al. now identify a key cellular player in immunity to parasites: tuft cells (see the Perspective by Harris). Tuft cells make up a small fraction of gut epithelial cells but expand when parasites colonize or infect the gut. Parasites cause tuft cells to secrete large amounts of interleukin-25, a key cytokine for parasite clearance that also indirectly feeds back on tuft cells to expand their numbers. Tuft cells express chemosensory signaling machinery: disrupting this blocked parasite-triggered tuft cell expansion and weakened the ability of mice to control a parasitic infection. Science , this issue p. 1329 ; see also p. 1264

— Accounts of obligate nest parasitism (e.g., Brown-headed Cowbird, Molothrus ater) are common in the literature; however, reports of facultative nest parasitism are less frequent. Nest parasitism has been documented only rarely in Wild Turkeys (Meleagris gallopavo). We obtained photographic evidence of a female Wild Turkey parasitizing an artificial ground nest in Lincoln County, Arkansas, in June 2013. A series of photographs show the turkey finding the nest, moving the eggs 0.3 m from the original nest location, returning twice the following day, and parasitizing the nest by laying a single egg. The actual parasitism event occurred 33–55 hrs after the turkey discovered the nest. We are unaware of other published photographs documenting nest parasitism by Wild Turkeys and this series of photographs provides information on the chronology of nest parasitism by Wild Turkeys.

Background Family-based behavioral therapy is an efficacious approach to deliver weight management counseling to children and their parents. However, most families do not have access to in-person, evidence-based treatment. We previously developed and tested DRIVE (Developing Relationships that Include Values of Eating and Exercise), a home-based parent training program to maintain body weight among children at risk for obesity, with the intent to eventually disseminate it nationally alongside SafeCare, a parent support program that focuses on parent-child interactions. Currently the DRIVE program has only been tested independently of SafeCare. This study created the “mHealth DRIVE” program by further adapting DRIVE to incorporate digital and mobile health tools, including remotely delivered sessions, a wireless scale that enabled a child-tailored weight graph, and a pedometer. Telehealth delivery via mHealth platforms and other digital tools can improve program cost-effectiveness, deliver long-term care, and directly support both families and care providers. Objective The objective of this study was to examine preliminary acceptability and effectiveness of the mHealth DRIVE program among children and parents who received it and among SafeCare providers who potentially could deliver it. Methods Study 1 was a 13-week pilot study of a remotely delivered mHealth family-based weight management program. Satisfaction surveys were administered, and height and weight were measured pre- and post-study. Study 2 was a feasibility/acceptability survey administered to SafeCare providers. Results Parental and child satisfaction (mean of 4.9/6.0 and 3.8/5.0, respectively) were high, and children’s (N=10) BMI z-scores significantly decreased (mean –0.14, SD 0.17; P=.025). Over 90% of SafeCare providers (N=74) indicated that SafeCare families would benefit from learning how to eat healthily and be more active, and 80% of providers reported that they and the families would benefit from digital tools to support child weight management. Conclusions Pediatric mHealth weight management interventions show promise for effectiveness and acceptability by families and providers. Trial Registration Clinicaltrials.gov NCT03297541, https://clinicaltrials.gov/ct2/show/NCT03297541.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system without a clear cause. Epstein-Barr virus (EBV) is proposed to contribute to the pathogenesis of MS through unknown mechanisms. Evidence for a role of EBV infection in MS comes from both epidemiological and experimental studies, however, due to its narrow host tropism, there are currently few suitable animal models of MS that incorporate EBV infection. Recent advancements in humanized mouse modelling has enabled direct infection for the study of EBV-associated malignancies. We therefore chose to evaluate the role of EBV infection in humanized mice with experimental autoimmune encephalomyelitis (EAE), a widely used model of MS. Immunocompromised mice were engrafted with peripheral blood mononuclear cells (PBMC) derived from individuals with relapsing MS (RRMS) or from matched healthy EBV seropositive or seronegative donors. We observed that HuPBMC mice induced with EAE developed ascending paralysis, weight loss and signs of discomfort consistent with classical EAE models. Further, HuPBMC EAE showed significant T cell infiltration of both the brain and spinal cord, notably of IFN gamma-expressing CD4 and CD8 T cells, resulting in spinal cord and cerebellar demyelination. HuPBMC EAE mice derived from EBV seropositive donors developed earlier disease onset with more severe clinical symptoms compared to EBV seronegative donor-derived mice. We also observed increase disease severity among mice derived from RRMS patients compared to healthy controls. With continued improvement and characterization of this novel humanized EAE model, additional environmental and genetic risk factors can be evaluated in a system with human immune-mediated pathology.

Norovirus is the most common viral cause of gastroenteritis globally. Most infections are either acute, symptomatic, and rapidly cleared or persist asymptomatically. However, the mechanisms underlying these outcomes are unknown. MNV-CW3 and -CR6 are murine noroviruses which demonstrate immune correlates of acute and chronic infection respectively. This research interrogates the mechanisms underlying strain-specific differential antiviral CD8 T cell responses to acute or chronic MNV. At days 3, 4, 5 and 8 post-infection, the phenotype and quantity of adoptively transferred MNV specific CD8 T cells in the spleen, mesenteric lymph node (MLN), and intestines are analyzed by flow cytometry. Concurrently, fluorescent microscopy is used to determine the biogeographical distribution of antiviral CD8 T cells throughout the intestine. Flow cytometry shows activated MNV-specific CD8 T cells first accumulate in the MLN following oral infection with either virus suggesting this is the site of immune activation though CR6 infection results in a delayed, reduced CD8 T cell response as shown by CFSE dilution. Supporting the MLN as a primary initiation site of the antiviral CD8 T cell response, prevention of T cell egress from activation sites by FTY720 treatment enriches activated CD8 T cells in the MLN in CW3 infections with a concurrent decrease in the spleen. Furthermore, by day 8 post-infection CD8 T cell populations are skewed to memory precursors or short-lived effectors in CW3 and CR6, respectively. These data suggest these highly related viral strains may induce activation of distinct populations of, or pathways in, APC populations with long-lasting effects on CD8 T cell function and the outcome of infection.

Environmental factors play an important role in multiple sclerosis (MS) disease progression, but the exact cause remains unknown. The hygiene hypothesis suggests that a lack of exposure to microbes may alter disease susceptibility. Helminths in particular may play a role in preventing autoimmune disease due to the type 2 immune response they typically induce. Trichinella spiralis (Ts) first forms a transient intestinal infection followed by chronic infection where it exerts type 2 and regulatory immune responses, respectively. To evaluate the role of helminth infection in development and progression of MS, C57BL/6J mice were first chronically infected with Ts, then immunized with MOG35–55 to induce experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Ts-infected EAE mice have an altered disease course compared to uninfected controls, demonstrating delayed onset, reduced incidence, and symptom remission. Despite an overall decrease in lymphocyte recruitment to the central nervous system (CNS) in Ts/EAE mice, elevated numbers of infiltrating Th2 cells are maintained through the EAE disease course. In contrast, regulatory T cell expansion is dependent on the presence or absence of EAE symptoms. Histological analysis of cellular infiltration and demyelination in the spinal cord indicate limited demyelination with reduced infiltration into the parenchyma of Ts/EAE mice compared to EAE controls. Further immunophenotyping in the CNS to evaluate the contributions of infiltrating macrophages will be performed, as well as analyses of the cytokine milieu in the CNS. These results suggest that chronic Ts infection limits neuroinflammation, as shown by reduced clinical, immunological, and pathologic signs of EAE.

The diverse commensal ecosystem present in the mammalian intestine requires the host immune system to maintain a tolerogenic environment. The virome is an understudied component of the microbiota which promotes intestinal homeostasis and protection from injury, but the host mechanisms that regulate tolerance to viral commensals are poorly described. The antiviral signal transducer STAT1 has previously been shown to mediate tolerance to systemic viral pathogens by suppressing adaptive immune responses and protecting the host from immunopathology, but we sought to characterize its role in the context of a commensal intestinal viral infection. We used a persistent strain of murine norovirus (MNV CR6) to interrogate host mechanisms of viral tolerance and commensalism, as CR6 has previously been shown to promote intestinal homeostasis. While CR6 infections of wildtype mice were asymptomatic and limited to the colon, STAT1-deficient mice exhibited virus-induced weight loss and mortality accompanied by systemic viral spread, colonic bacterial dysbiosis, CD4+ T cell dysfunction and hyperaccumulation of CD8+ T cells. However, clinical manifestation of virus-induced disease in STAT1-deficient mice was independent of T cells and the bacterial microbiota. Instead, therapeutic control of viral replication was sufficient to prevent virus-induced disease despite ongoing T cell dysregulation. Collectively, our data indicate that STAT1 maintains tolerance to a viral component of the intestinal microbiota by control of viral replication rather than immunopathology, suggesting that STAT1 uses distinct strategies to tolerate pathogenic and commensal viruses.

BACKGROUND: Use of biological or synthetic mesh might improve outcomes of immediate implant-based breast reconstruction-breast reconstruction with implants or expanders at the time of mastectomy-but there is a lack of high-quality evidence to support the safety or effectiveness of the technique. We aimed to establish the short-term safety of immediate implant-based breast reconstruction performed with and without mesh, to inform the feasibility of undertaking a future randomised clinical trial comparing different breast reconstruction techniques.METHODS: In this prospective, multicentre cohort study, we consecutively recruited women aged 16 years or older who had any type of immediate implant-based breast reconstruction for malignancy or risk reduction, with any technique, at 81 participating breast and plastic surgical units in the UK. Data about patient demographics and operative, oncological, and complication details were collected before and after surgery. Outcomes of interest were implant loss (defined as unplanned removal of the expander or implant), infection requiring treatment with antibiotics or surgery, unplanned return to theatre, and unplanned re-admission to hospital for complications of reconstructive surgery, up to 3 months after reconstruction and assessed by clinical review or patient self-report. Follow-up is complete. The study is registered with the ISRCTN Registry, number ISRCTN37664281.FINDINGS: Between Feb 1, 2014, and June 30, 2016, 2108 patients had 2655 mastectomies with immediate implant-based breast reconstruction at 81 units across the UK. 1650 (78%) patients had planned single-stage reconstructions (including 12 patients who had a different technique per breast). 1376 (65%) patients had reconstruction with biological (1133 [54%]) or synthetic (243 [12%]) mesh, 181 (9%) had non-mesh submuscular or subfascial implants, 440 (21%) had dermal sling implants, 42 (2%) had pre-pectoral implants, and 79 (4%) had other or a combination of implants. 3-month outcome data were available for 2081 (99%) patients. Of these patients, 182 (9%, 95% CI 8-10) experienced implant loss, 372 (18%, 16-20) required re-admission to hospital, and 370 (18%, 16-20) required return to theatre for complications within 3 months of their initial surgery. 522 (25%, 95% CI 23-27) patients required treatment for an infection. The rates of all of these complications are higher than those in the National Quality Standards (INTERPRETATION: Complications after immediate implant-based breast reconstruction are higher than recommended by national standards. A randomised clinical trial is needed to establish the optimal approach to immediate implant-based breast reconstruction.FUNDING: National Institute for Health Research, Association of Breast Surgery, and British Association of Plastic, Reconstructive and Aesthetic Surgeons.

Background Human Norovirus infection is the most common viral cause of gastroenteritis globally and the second most reported viral infection in Canada after the common cold. Most infections are acute, symptomatic, and rapidly cleared but some cases persist asymptomatically or induce post-infectious irritable bowel syndrome. Despite the global burden of these infections, no vaccine to prevent disease exists nor is the mechanism for persistence understood. MNV-CW3 and MNV-CR6 are murine noroviruses which demonstrate distinct biological behaviors that correlate with differential quantity and quality of antiviral CD8+ T cell responses. MNV-CW3 causes acute systemic infections initiated in the small intestine and cleared by day 8 due to a robust antiviral CD8+ T cell response. In contrast, MNV-CR6 causes chronic infections localized to the colonic intestinal epithelium and induces fewer antiviral CD8+ T cells with reduced effector molecule expression. Aims This research interrogates the mechanisms underlying strain-specific differential antiviral CD8+ T cell responses. Methods At days 3, 4, 5 and 8 post-infection, the phenotype and quantity of adoptively transferred MNV specific CD8+ T cells in the spleen, mesenteric lymph node (MLN), and the small and large intestine are analyzed by flow cytometry. Concurrently, immunofluorescent microscopy is used to determine whether CD8+ T cells are broadly disseminated throughout the intestines or localize in acute clusters of antiviral response. Combining these complementary techniques provides novel insight into mechanisms governing intestinal antiviral T cell responses. Results Activated MNV-specific CD8 T cells first accumulate in the MLN following oral infection with both MNV-CW3 and CR6, suggesting this is the site of immune activation. Supporting this hypothesis, preliminary data indicates that preventing T cell egress from activation sites by treatment with the S1PR1 agonist FTY720 leads to an enrichment of activated CD8+ T cells in the MLN following CW3 infection. Notably, the earliest stages of CD8+ T cell activation to CR6 infection is delayed compared to that elicited by CW3. Furthermore, at the peak of CD8+ T cell expansion (day 8 post-infection), CR6-elicited CD8+ T cells preferentially develop into short-lived effector populations rather than memory precursor populations. Conclusions These data reveal previously unknown differences in early events in CD8+ T cell activation following infection with two highly related viral strains that correlate with long-lasting effects on T cell differentiation and function. We are currently investigating the hypothesis that MNV-CW3 and CR6 may induce activation of distinct populations of, or pathways in, APC populations that would drive these differences. These results may have broad impacts on our understanding of how non-latent, chronic viral infections persist within a host. Funding Agencies CIHR

Background: Children are a vulnerable population following a natural disaster, due to their age and dependence on adults. The primary presenting problem children report after disasters is posttraumatic stress symptoms (PTSS). Prior research suggests that PTSS is inversely related to social support, which is often disrupted after a disaster. Objective: This study examined the relationship between social support (from parents, teachers, and peers) and PTSS in children affected by Hurricane Katrina. The research contributes to the literature by examining the mechanisms that drive this relationship over time. Methods: In this study, 426 children were followed over four timepoints, beginning 3–7 months after Hurricane Katrina and concluding 25–27 months post-hurricane. Three path models analysed the relationship between social support (from parents, teachers, and peers, measured by the Social Support Scale for Children) and PTSS (measured by the UCLA PTSD Reaction Index). Covariates included child age, minority status, gender, perceived life threat, and actual life threat. Nonsignificant paths were trimmed from the final models. Global fit indices were examined to determine model fit. Results: In the parent and peer social support models, PTSS exhibited statistically significant effects on social support from one wave to the next. In the teacher model, this was only true between Waves 2 and 3. Social support showed a statistically significant effect on PTSS between Wave 2 and Wave 3 in the peer model (standardized estimate = −0.26, p

INTRODUCTION: The 2008 National Mastectomy and Breast Reconstruction Audit demonstrated marked variation in the practice and outcomes of breast reconstruction in the UK. To standardise practice and improve outcomes for patients, the British professional associations developed best-practice guidelines with specific guidance for newer mesh-assisted implant-based techniques. We explored the degree of uptake of best-practice guidelines within units performing implant-based reconstruction (IBBR) as the first phase of the implant Breast Reconstruction Evaluation (iBRA) study.METHODS: A questionnaire developed by the iBRA Steering Group was completed by trainee and consultant leads at breast and plastic surgical units across the UK. Simple summary statistics were calculated for each survey item to assess compliance with current best-practice guidelines.RESULTS: 81 units from 79 NHS Trusts completed the questionnaire. Marked variation was observed in adherence to guidelines, especially those relating to clinical governance and infection prevention strategies. Less than half (n = 28, 47%) of units obtained local clinical governance board approval prior to offering new mesh-based techniques and prospective audit of the clinical, cosmetic and patient-reported outcomes of surgery was infrequent. Most units screened for methicillin-resistant staphylococcus aureus prior to surgery but fewer than 1 in 3 screened for methicillin-sensitive strains. Laminar-flow theatres (recommended for IBBR) were not widely-available with less than 1 in 5 units having regular access. Peri-operative antibiotics were widely-used, but the type and duration were highly-variable.CONCLUSIONS: The iBRA national practice questionnaire has demonstrated variation in reported practice and adherence to IBBR guidelines. High-quality evidence is urgently required to inform best practice.

BACKGROUND: Globally, >300 million patients have surgery annually, and ≤20% experience adverse postoperative events. We studied the impact of both cardiac and noncardiac adverse events on 1-year disability-free survival after noncardiac surgery. METHODS: We used the study cohort from the Evaluation of Nitrous oxide in Gas Mixture of Anesthesia (ENIGMA-II) trial, an international randomized trial of 6992 noncardiac surgical patients. All were ≥45 years of age and had moderate to high cardiac risk. The primary outcome was mortality within 1 postoperative year. We defined 4 separate types of postoperative adverse events. Major adverse cardiac events (MACEs) included myocardial infarction (MI), cardiac arrest, and myocardial revascularization with or without troponin elevation. MI was defined using the third Universal Definition and was blindly adjudicated. A second cohort consisted of patients with isolated troponin increases who did not meet the definition for MI. We also considered a cohort of patients who experienced major adverse postoperative events (MAPEs), including unplanned admission to intensive care, prolonged mechanical ventilation, wound infection, pulmonary embolism, and stroke. From this cohort, we identified a group without troponin elevation and another with troponin elevation that was not judged to be an MI. Multivariable Cox proportional hazard models for death at 1 year and assessments of proportionality of hazard functions were performed and expressed as an adjusted hazard ratio (aHR) and 95% confidence intervals (CIs). RESULTS: MACEs were observed in 469 patients, and another 754 patients had isolated troponin increases. MAPEs were observed in 631 patients. Compared with control patients, patients with a MACE were at increased risk of mortality (aHR, 3.36 [95% CI, 2.55-4.46]), similar to patients who suffered a MAPE without troponin elevation (n = 501) (aHR, 2.98 [95% CI, 2.26-3.92]). Patients who suffered a MAPE with troponin elevation but without MI had the highest risk of death (n = 116) (aHR, 4.29 [95% CI, 2.89-6.36]). These 4 types of adverse events similarly affected 1-year disability-free survival. CONCLUSIONS: MACEs and MAPEs occur at similar frequencies and affect survival to a similar degree. All 3 types of postoperative troponin elevation in this analysis were associated, to varying degrees, with increased risk of death and disability.

Child Maltreatment (CM) is a public health problem, and experts recommend parent training programs as a prevention method. Few programs target fathers, even though male caregivers are involved as perpetrators in approximately 45% of substantiated CM cases. This study examines the efficacy of an adapted version of SafeCare (Dad2K) with marginalized fathers. Participants include a convenience sample of fathers with children ages 2-5 years. Fathers (n=99) were randomized to an 1) intervention group (SafeCare Dad2K) or to a 2) comparison group (receiving parenting information in the mail). Quantitative data were collected at baseline, post-intervention (7-weeks post-baseline), and 3-months post-intervention. Qualitative data (semi-structured interviews) were collected from 11 intervention father completers following the second quantitative data collection timepoint. Multi-level modeling results indicated no statistically significant time-by-treatment findings for father involvement (b=0.03, 95% confidence interval [CI]: -0.03, 0.08, p=0.38), total corporal punishment (b=-0.03, 95% CI: -0.47, 0.41, p=0.89), or neglect (b=-0.13, 95% CI: -1.93, 1.68, p=0.89). Qualitative findings indicated that Dad2K completers exhibited positive knowledge and behavioral change related to parenting. Study limitations, lessons learned from this formative work, and recommendations for future research are discussed.

Breaches in the skin barrier initiate an inflammatory immune response that is critical for successful wound healing. Innate lymphoid cells (ILCs) are a recently identified population of immune cells that reside at epithelial barrier surfaces such as the skin, lung and gut and promote pro-inflammatory or epithelial repair functions following exposure to allergens, pathogens or chemical irritants. However, the potential role of ILCs in regulating cutaneous wound healing remains undefined. Here, we demonstrate that cutaneous injury promotes an IL-33-dependent group 2 ILC (ILC2) response and that abrogation of this response impairs re-epithelialization and efficient wound closure. Additionally, we provide evidence suggesting that an analogous ILC2 response is operational in acute wounds of human skin. Together, these results indicate that IL-33-responsive ILC2s are an important link between the cutaneous epithelium and the immune system, acting to promote the restoration of skin integrity following injury.

The barrier surfaces of the skin, lung, and intestine are constantly exposed to environmental stimuli that can result in inflammation and tissue damage. Interleukin (IL)-33-dependent group 2 innate lymphoid cells (ILC2s) are enriched at barrier surfaces and have been implicated in promoting inflammation; however, the mechanisms underlying the tissue-protective roles of IL-33 or ILC2s at surfaces such as the intestine remain poorly defined. Here we demonstrate that, following activation with IL-33, expression of the growth factor amphiregulin (AREG) is a dominant functional signature of gut-associated ILC2s. In the context of a murine model of intestinal damage and inflammation, the frequency and number of AREG-expressing ILC2s increases following intestinal injury and genetic disruption of the endogenous AREG-epidermal growth factor receptor (EGFR) pathway exacerbated disease. Administration of exogenous AREG limited intestinal inflammation and decreased disease severity in both lymphocyte-sufficient and lymphocyte-deficient mice, revealing a previously unrecognized innate immune mechanism of intestinal tissue protection. Furthermore, treatment with IL-33 or transfer of ILC2s ameliorated intestinal disease severity in an AREG-dependent manner. Collectively, these data reveal a critical feedback loop in which cytokine cues from damaged epithelia activate innate immune cells to express growth factors essential for ILC-dependent restoration of epithelial barrier function and maintenance of tissue homeostasis.

Group 2 innate lymphoid cells (ILC2s) promote type 2 cytokine-dependent immunity, inflammation, and tissue repair. Although epithelial cell-derived cytokines regulate ILC2 effector functions, the pathways that control the in vivo migration of ILC2s into inflamed tissues remain poorly understood. Here, we provide the first demonstration that expression of the prostaglandin D2 (PGD2) receptor CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) regulates the in vivo accumulation of ILC2s in the lung. Although a significant proportion of ILC2s isolated from healthy human peripheral blood expressed CRTH2, a smaller proportion of ILC2s isolated from nondiseased human lung expressed CRTH2, suggesting that dynamic regulation of CRTH2 expression might be associated with the migration of ILC2s into tissues. Consistent with this, murine ILC2s expressed CRTH2, migrated toward PGD2 in vitro, and accumulated in the lung in response to PGD2 in vivo. Furthermore, mice deficient in CRTH2 exhibited reduced ILC2 responses and inflammation in a murine model of helminth-induced pulmonary type 2 inflammation. Critically, adoptive transfer of CRTH2-sufficient ILC2s restored pulmonary inflammation in CRTH2-deficient mice. Together, these data identify a role for the PGD2-CRTH2 pathway in regulating the in vivo accumulation of ILC2s and the development of type 2 inflammation in the lung.

Knowledge surrounding the trillions of microbes that inhabit the human gut has bloomed exponentially in recent years, and the emerging concept of a gut-brain axis represents a major shift in how we think about neurological health. A recent workshop at the University of British Columbia, Canada brought together multi-disciplinary leaders in the field of microbiomics and brain health and aimed to serve as a springboard for future combined endeavors in these areas. This article provides the motivation for, and overview of, the workshop, and the next steps in establishing a cross-disciplinary initiative on Brain Health and the Microbiome.

The development of coordinated reach-to-grasp movement has been well studied in infants and children. However, the role of motor cortex during this development is unclear because it is difficult to study in humans. We took the approach of using a brain-machine interface (BMI) paradigm in rhesus macaques with prior therapeutic amputations to examine the emergence of novel, coordinated reach to grasp. Previous research has shown that after amputation, the cortical area previously involved in the control of the lost limb undergoes reorganization, but prior BMI work has largely relied on finding neurons that already encode specific movement-related information. In this study, we taught macaques to cortically control a robotic arm and hand through operant conditioning, using neurons that were not explicitly reach or grasp related. Over the course of training, stereotypical patterns emerged and stabilized in the cross-covariance between the reaching and grasping velocity profiles, between pairs of neurons involved in controlling reach and grasp, and to a comparable, but lesser, extent between other stable neurons in the network. In fact, we found evidence of this structured coordination between pairs composed of all combinations of neurons decoding reach or grasp and other stable neurons in the network. The degree of and participation in coordination was highly correlated across all pair types. Our approach provides a unique model for studying the development of novel, coordinated reach-to-grasp movement at the behavioral and cortical levels. NEW & NOTEWORTHY Given that motor cortex undergoes reorganization after amputation, our work focuses on training nonhuman primates with chronic amputations to use neurons that are not reach or grasp related to control a robotic arm to reach to grasp through the use of operant conditioning, mimicking early development. We studied the development of a novel, coordinated behavior at the behavioral and cortical level, and the neural plasticity in M1 associated with learning to use a brain-machine interface.

Summary B cells thwart antigenic aggressions by releasing immunoglobulin M (IgM), IgG, IgA, and IgE, which deploy well-understood effector functions. In contrast, the role of secreted IgD remains mysterious. We found that some B cells generated IgD-secreting plasma cells following early exposure to external soluble antigens such as food proteins. Secreted IgD targeted basophils by interacting with the CD44-binding protein galectin-9. When engaged by antigen, basophil-bound IgD increased basophil secretion of interleukin-4 (IL-4), IL-5, and IL-13, which facilitated the generation of T follicular helper type 2 cells expressing IL-4. These germinal center T cells enhanced IgG1 and IgE but not IgG2a and IgG2b responses to the antigen initially recognized by basophil-bound IgD. In addition, IgD ligation by antigen attenuated allergic basophil degranulation induced by IgE co-ligation. Thus, IgD may link B cells with basophils to optimize humoral T helper type 2-mediated immunity against common environmental soluble antigens.

Type 2 inflammatory responses can be elicited by diverse stimuli, including toxins, venoms, allergens, and infectious agents, and play critical roles in resistance and tolerance associated with infection, wound healing, tissue repair, and tumor development. Emerging data suggest that in addition to characteristic type 2-associated cytokines, the epidermal growth factor (EGF)-like molecule Amphiregulin (AREG) might be a critical component of type 2-mediated resistance and tolerance. Notably, numerous studies demonstrate that in addition to the established role of epithelial- and mesenchymal-derived AREG, multiple leukocyte populations including mast cells, basophils, group 2 innate lymphoid cells (ILC2s), and a subset of tissue-resident regulatory CD4(+) T cells can express AREG. In this review, we discuss recent advances in our understanding of the AREG-EGF receptor pathway and its involvement in infection and inflammation and propose a model for the function of this pathway in the context of resistance and tissue tolerance.