New and continuing physician-based outpatient mental health care among children and adolescents during the COVID-19 pandemic in Ontario, Canada: a population-based study.

Objective: To assess physician-based mental health care utilization during the COVID-19 pandemic among children and adolescents new to care and those already engaged with mental health services, and to evaluate differences by sociodemographic factors. Study design: We performed a population-based repeated cross-sectional study using linked health and administrative databases in Ontario, Canada among all children and adolescents 3-17 years. We examined outpatient visit rates per 1,000 population for mental health concerns for those new to care (no physician-based mental healthcare for ≥1 year) and those with continuing care needs (any physician-based mental healthcare <1 year) following onset of the pandemic. Results: Among ~2.5 million children and adolescents (48.7% female, mean age 10.1 ± 4.3 years), expected monthly mental health outpatient visits were 1.5/1,000 for those new to mental health care and 5.4/1,000 for those already engaged in care. Following onset of the pandemic, visit rates for both groups were above expected [adjusted rate ratio (aRR) 1.22, 95% CI 1.17, 1.27; aRR 1.10, 95% CI 1.07, 1.12] for new and continuing care, respectively. The greatest increase above expected was among females (new: aRR 1.33, 95% CI 1.25, 1.42; continuing: aRR 1.22 95% CI 1.17, 1.26) and adolescents ages 13-17 years (new: aRR 1.31, 95% CI 1.27, 1.34; continuing: aRR 1.15 95% CI 1.13, 1.17). Mood and anxiety concerns were prominent among those new to care. Conclusion: In the 18 months following onset of the pandemic, outpatient mental health care utilization increased for those with new and continuing care needs, especially among females and adolescents.

Mental health treatment programs for children and young people in secure settings: A systematic review.

BACKGROUND: While there are mental health treatment programs for children and young people in secure settings (i.e., secure treatment programs) in many countries, there is a lack of transparency and consistency across these that causes confusion for stakeholders and challenges for the design and delivery of high-quality, evidence-based programs. This systematic review addresses two questions: What do mental health treatment programs for children and young people in secure community settings look like across jurisdictions? What is the evidence underlying the various components of these programs? METHODS: Twelve databases were searched in November 2021: CINAHL, EMBASE, MEDLINE, PsycINFO, PubMed, Scopus, Science Direct, Academic Search Complete, Psychology and Behavioral Sciences Collection, Google Scholar, OpenDOAR, and GreyLit.org. To be included, publications had to be empirical literature or a report on mental health treatment within a secure setting for people under the age of 25; contain pre-identified keywords; be based on a research or evaluation study conducted since 2000; and be assessed as low risk of bias using an adaptation of the Critical Appraisal Skills Programme qualitative research checklist. The systematic review included 63 publications. Data were collected and analyzed in NVivo qualitative software using a coding framework. RESULTS: There are secure treatment programs in Australia, Belgium, Canada, New Zealand, the Netherlands, England and Wales, Scotland, and the United States. Although there are inconsistencies across programs in terms of the systems in which they are embedded, client profiles, treatments provided, and lengths of stays, most share commonalities in their governance, definitions, designs, and intended outcomes. CONCLUSIONS: The commonalities across secure treatment programs appear to stem from them being designed around a need for treatment that includes a mental disorder, symptom severity and salience involving significant risk of harm to self and/or others, and a proportionality of the risks and benefits of treatment. Most share a common logic; however, the evidence suggested that this logic may not to lead to sustained outcomes. Policymakers, service providers, and researchers could use the offered recommendations to ensure the provision of high-quality secure treatment programming to children and young people with serious and complex mental health needs.

Meeting the service needs of youth with and without a self-reported mental health diagnosis during COVID-19.

Background: The COVID-19 pandemic catalyzed major changes in how youth mental health (MH) services are delivered. Understanding youth's MH, awareness and use of services since the pandemic, and differences between youth with and without a MH diagnosis, can help us optimize MH services during the pandemic and beyond. Objectives: We investigated youth's MH and service use one year into the pandemic and explored differences between those with and without a self-reported MH diagnosis. Methods: In February 2021, we administered a web-based survey to youth, 12-25 years, in Ontario. Data from 1373 out of 1497 (91.72%) participants were analyzed. We assessed differences in MH and service use between those with (N=623, 45.38%) and without (N=750, 54.62%) a self-reported MH diagnosis. Logistic regressions were used to explore MH diagnosis as a predictor of service use while controlling for confounders. Results: 86.73% of participants reported worse MH since COVID-19, with no between-group differences. Participants with a MH diagnosis had higher rates of MH problems, service awareness and use, compared to those without a diagnosis. MH diagnosis was the strongest predictor of service use. Gender and affordability of basic needs also independently predicted use of distinct services. Conclusion: Various services are required to mitigate the negative effects of the pandemic on youth MH and meet their service needs. Whether youth have a MH diagnosis may be important to understanding what services they are aware of and use. Sustaining pandemic-related service changes require increasing youth's awareness of digital interventions and overcoming other barriers to care.

Contexte: La pandémie de la COVID-19 a catalysé des changements majeurs de la manière dont les services de santé mentale (SM) sont dispensés aux jeunes. Comprendre la SM des jeunes, la connaissance et l'utilisation des services depuis la pandémie, et les différences entre les jeunes avec et sans un diagnostic de SM peut nous aider à optimiser les services de SM durant la pandémie et au-delà. Objectifs: Nous avons investigué la SM et l'utilisation des services des jeunes un an après le début de la pandémie et exploré les différences entre ceux avec et sans un diagnostic de SM auto-rapporté. Méthodes: En février 2021, nous avons administré un sondage en ligne à des jeunes de 12 à 25 ans en Ontario. Les données de 1373 participants sur 1497 (91,72 %) participants ont été analysées. Nous avons évalué les différences de SM et d'utilisation des services entre ceux avec (N = 623, 45,38 %) et sans (N = 750, 54,62 %) un diagnostic de SM auto-rapporté. Les régressions logistiques ont servi à explorer le diagnostic de SM comme prédicteur de l'utilisation de services tout en contrôlant les confusions. Résultats: 86,73 % des participants ont rapporté une SM pire depuis la COVID-19, sans différences entre les groupes. Les participants ayant un diagnostic de SM avaient des taux plus élevés de problèmes de SM, de connaissance et d'utilisation des services comparé à ceux sans diagnostic. Le diagnostic de SM était le prédicteur le plus fort de l'utilisation de services. Le sexe et l'abordabilité des besoins de base prédisaient aussi indépendamment l'utilisation de services distincts. Conclusion: Divers services sont nécessaires pour atténuer les effets négatifs de la pandémie sur la SM des jeunes et répondre à leurs besoins de service. Savoir si les jeunes ont un diagnostic de SM peut être important pour comprendre quels services ils connaissent et utilisent. Soutenir les changements de services liés à la pandémie exige d'accroître la connaissance des jeunes des interventions numériques et de surmonter d'autres obstacles des soins.

Sociodemographic Differences in Physician-Based Mental Health and Virtual Care Utilization and Uptake of Virtual Care Among Children and Adolescents During the COVID-19 Pandemic in Ontario, Canada: A Population-Based Study.

OBJECTIVE: We sought to evaluate the relationship between social determinants of health and physician-based mental healthcare utilization and virtual care use among children and adolescents in Ontario, Canada, during the COVID-19 pandemic. METHODS: This population-based repeated cross-sectional study of children and adolescents (3-17 years; N = 2.5 million) used linked health and demographic administrative data in Ontario, Canada (2017-2021). Multivariable Poisson regressions with generalized estimating equations compared rates of outpatient physician-based mental healthcare use during the first year of the COVID-19 pandemic with expected rates based on pre-COVID patterns. Analyses were conducted by socioeconomic status (material deprivation quintiles of the Ontario Marginalization index), urban/rural region of residence, and immigration status. RESULTS: Overall, pediatric physician-based mental healthcare visits were 5% lower than expected (rate ratio [RR] = 0.95, 95% confidence interval [CI], 0.92 to 0.98) among those living in the most deprived areas in the first year of the pandemic, compared with the least deprived with 4% higher than expected rates (RR = 1.04, 95% CI, 1.02 to 1.06). There were no differences in overall observed and expected visit rates by region of residence. Immigrants had 14% to 26% higher visit rates compared with expected from July 2020 to February 2021, whereas refugees had similarly observed and expected rates. Virtual care use was approximately 65% among refugees, compared with 70% for all strata. CONCLUSION: During the first year of the pandemic, pediatric physician-based mental healthcare utilization was higher among immigrants and lower than expected among those with lower socioeconomic status. Refugees had the lowest use of virtual care. Further work is needed to understand whether these differences reflect issues in access to care or the need to help inform ongoing pandemic recovery planning.

Parenting during the COVID-19 pandemic: The sociodemographic and mental health factors associated with maternal caregiver strain.

INTRODUCTION: The COVID-19 pandemic has introduced new stressors for parents ("caregivers") that may affect their own and their child's mental health (MH). We explored self-reported levels of caregiver strain (parents' perceived ability to meet parenting demands), and the MH and sociodemographic factors of caregivers to identify predictors of strain that can be used to guide MH service delivery for families. METHODS: We administered a web-based survey to Ontario caregivers with a child between 4 and 25 years old, between April and June 2020. We analyzed information from 570 maternal caregivers on their sociodemographics, youngest (or only) child's MH, their own MH, and the degree of caregiver strain experienced since the pandemic. We used linear regressions (unadjusted and adjusted models) to explore the relationship between caregiver strain and sociodemographics, child MH and caregiver MH. RESULTS: Over 75% of participants reported "moderate-to-high" caregiver strain. More than 25% of caregivers rated their MH as "poor" and 20% reported moderate-to-severe anxiety. Forty-five percent of the variance in caregiver strain was accounted for by child age, caregiver anxiety, and multiple child and caregiver MH variables. Younger child age and higher caregiver anxiety were the greatest predictors of caregiver strain. CONCLUSION: We found a relationship between child age, child and caregiver MH variables, and caregiver strain. Given the interrelatedness of these factors, supporting caregivers' MH and lessening their role strain becomes critical for family well-being. Evidence-based individual, family, and public health strategies are needed to alleviate pandemic-related strain. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Utilization of Physician-Based Mental Health Care Services Among Children and Adolescents Before and During the COVID-19 Pandemic in Ontario, Canada.

IMPORTANCE: Public health measures to reduce the spread of COVID-19 have heightened distress among children and adolescents and contributed to a shift in delivery of mental health care services. OBJECTIVES: To measure and compare physician-based outpatient mental health care utilization before and during the COVID-19 pandemic and quantify the extent of uptake of virtual care delivery. DESIGN, SETTING, AND PARTICIPANTS: Population-based repeated cross-sectional study using linked health and administrative databases in Ontario, Canada. All individuals aged 3 to 17 years residing in Ontario from January 1, 2017, to February 28, 2021. EXPOSURES: Pre-COVID-19 period from January 1, 2017, to February 29, 2020, and post-COVID-19 onset from March 1, 2020, to February 28, 2021. MAIN OUTCOMES AND MEASURES: Physician-based outpatient weekly visit rates per 1000 population for mental health diagnoses overall and stratified by age group, sex, and mental health diagnostic grouping and proportion of virtual visits. Poisson generalized estimating equations were used to model 3-year pre-COVID-19 trends and forecast expected trends post-COVID-19 onset and estimate the change in visit rates before and after the onset of COVID-19. The weekly proportions of virtual visits were calculated. RESULTS: In a population of almost 2.5 million children and adolescents (48.7% female; mean [SD] age, 10.1 [4.3] years), the weekly rate of mental health outpatient visits was 6.9 per 1000 population. Following the pandemic onset, visit rates declined rapidly to below expected (adjusted relative rate [aRR], 0.81; 95% CI, 0.79-0.82) in April 2020 followed by a growth to above expected (aRR, 1.07; 95% CI, 1.04-1.09) by July 2020 and sustained at 10% to 15% above expected as of February 2021. Adolescent female individuals had the greatest increase in visit rates relative to expected by the end of the study (aRR, 1.26; 95% CI, 1.25-1.28). Virtual care accounted for 5.0 visits per 1000 population (72.5%) of mental health visits over the study period, with a peak of 5.3 visits per 1000 population (90.1%) (April 2020) and leveling off to approximately 70% in the latter months. CONCLUSIONS AND RELEVANCE: Physician-based outpatient mental health care in Ontario increased during the pandemic, accompanied by a large, rapid shift to virtual care. There was a disproportionate increase in use of mental health care services among adolescent female individuals. System-level planning to address the increasing capacity needs and to monitor quality of care with such large shifts is warranted.

Combinatorial immunotherapy induces tumor-infiltrating CD8+ T cells with distinct functional, migratory, and stem-like properties.

BACKGROUND: Programmed death (ligand) 1 (PD-(L)1) blockade and OX40/4-1BB costimulation have been separately evaluated in the clinic to elicit potent antitumor T cell responses. The precise mechanisms underlying single agent activity are incompletely understood. It also remains unclear if combining individual therapies leads to synergism, elicits novel immune mechanisms, or invokes additive effects. METHODS: We performed high-dimensional flow cytometry and single-cell RNA sequencing-based immunoprofiling of murine tumor-infiltrating lymphocytes (TILs) isolated from hosts bearing B16 or MC38 syngeneic tumors. This baseline infiltrate was compared to TILs after treatment with either anti-PD-(L)1, anti-OX40, or anti-4-1BB as single agents or as double and triple combinatorial therapies. Fingolimod treatment and CXCR3 blockade were used to evaluate the contribution of intratumoral versus peripheral CD8+ T cells to therapeutic efficacy. RESULTS: We identified CD8+ T cell subtypes with distinct functional and migratory signatures highly predictive of tumor rejection upon treatment with single agent versus combination therapies. Rather than reinvigorating terminally exhausted CD8+ T cells, OX40/4-1BB agonism expanded a stem-like PD-1loKLRG-1+Ki-67+CD8+ T cell subpopulation, which PD-(L)1 blockade alone did not. However, PD-(L)1 blockade synergized with OX40/4-1BB costimulation by dramatically enhancing stem-like TIL presence via a CXCR3-dependent mechanism. CONCLUSIONS: Our findings provide new mechanistic insights into the interplay between components of combinatorial immunotherapy, where agonism of select costimulatory pathways seeds a pool of stem-like CD8+ T cells more responsive to immune checkpoint blockade (ICB).

Intra-Tumoral Activation of Endosomal TLR Pathways Reveals a Distinct Role for TLR3 Agonist Dependent Type-1 Interferons in Shaping the Tumor Immune Microenvironment.

Toll-like receptor (TLR) agonists have received considerable attention as therapeutic targets for cancer immunotherapy owing to their ability to convert immunosuppressive tumor microenvironments towards a more T-cell inflamed phenotype. However, TLRs differ in their cell expression profiles and intracellular signaling pathways, raising the possibility that distinct TLRs differentially influence the tumor immune microenvironment. Using single-cell RNA-sequencing, we address this by comparing the tumor immune composition of B16F10 melanoma following treatment with agonists of TLR3, TLR7, and TLR9. Marked differences are observed between treatments, including decreased tumor-associated macrophages upon TLR7 agonist treatment. A biased type-1 interferon signature is elicited upon TLR3 agonist treatment as opposed to a type-2 interferon signature with TLR9 agonists. TLR3 stimulation was associated with increased macrophage antigen presentation gene expression and decreased expression of PD-L1 and the inhibitory receptors Pirb and Pilra on infiltrating monocytes. Furthermore, in contrast to TLR7 and TLR9 agonists, TLR3 stimulation ablated FoxP3 positive CD4 T cells and elicited a distinct CD8 T cell activation phenotype highlighting the potential for distinct synergies between TLR agonists and combination therapy agents.

Evaluating the sector-wide implementation of virtual child and youth mental health services in response to the COVID-19 pandemic: Perspectives from service providers, agency leaders and clients.

Background: The COVID-19 pandemic prompted an abrupt shift in the delivery of community-based child and youth mental health services as virtual care was rapidly adopted. The objective of this study was to evaluate the sector-wide transition to virtual care across Ontario, with a focus on implementation facilitators and barriers. Methods: We used a multi-level mixed-methods design where agency leaders, service providers, and clients shared their experiences planning, implementing, and accessing virtual care. In total, 97 agency leaders, and 192 youth and family members responded to the surveys; 13 agency leaders, and 11 service providers participated in interviews or focus groups. Results: Most agencies undertook a similar journey to implement virtual care. Stakeholders described common facilitators such as staff engagement, leadership support, and training activities. Barriers included internet connection issues, lack of resources, and privacy concerns. Service providers innovated as they implemented by partnering with agencies to meet clients' needs, using multiple platforms to engage clients, and altering session duration to reduce fatigue. Clients found virtual care easy to use, felt confident using it, and intend to continue accessing virtual care. Conclusion: Implementation of virtual care during the pandemic was complex and the evaluation involved obtaining perspectives at multiple levels. This research provides a blueprint for evaluations of the implementation of virtual mental health services, particularly in a child/youth context. Virtual care is a viable way to deliver mental health services, however, equity, accessibility, and appropriateness need to be addressed to ensure services are effective for children, youth, and their families. Plain language abstract: Academic literature suggests that using technology to deliver child and youth mental health services is a promising way to enhance access to care and improve engagement for many children and youth. Despite this, the provision of virtual child and youth mental health services in Ontario prior to the COVID-19 pandemic was limited. Efforts that did exist were largely focused on providing care to those in rural and remote areas. The COVID-19 pandemic prompted a rapid shift to virtual care, as most in-person mental health services were suspended. This paper presents new insight into how virtual mental health services were quickly established and used across Ontario from the perspectives of senior leaders, service providers, and clients. Results from this evaluation showed that agencies followed similar steps to prepare to use virtual services. Staff engagement, support from leadership, and opportunities for staff training supported the implementation of virtual care while internet connections issues, lack of resources (like computers or phones), and privacy and safety concerns hindered the implementation. Most youth and family members found virtual services easy to use and intend to continue using them. Most agencies intend to continue to offer virtual services post-pandemic but noted that it was not appropriate or accessible for all clients. This study provides a foundation for additional research to examine situations and conditions that are most conducive to virtual care delivery to address child and youth mental health concerns. These results may encourage agencies to rely more confidently on virtual services as another means to meet clients' needs and preferences.

Baseline Frequency of Inflammatory Cxcl9-Expressing Tumor-Associated Macrophages Predicts Response to Avelumab Treatment.

The tumor microenvironment is rich with immune-suppressive macrophages that are associated with cancer progression and resistance to immune checkpoint therapy. Using pre-treatment tumor biopsies complemented with single-cell RNA sequencing (RNA-seq), we characterize intratumoral immune heterogeneity to unveil potential mechanisms of resistance to avelumab (anti-PD-L1). We identify a proinflammatory F480+MHCII+Ly6Clo macrophage population that is associated with response rather than resistance to avelumab. These macrophages are the primary source of the interferon-inducible chemokine Cxcl9, which facilitates the recruitment of protective Cxcr3+ T cells. Consequently, the efficacy of avelumab in mouse tumor models is dependent on Cxcr3 and Cxcl9, and baseline levels of Cxcl9 in patients treated with avelumab are associated with clinical response and overall survival. These data suggest that, within the broadly immune-suppressive macrophage compartment, a pro-inflammatory population exists that promotes responsiveness to PD-L1 blockade.

Strengthening child and youth programs: A look at inter-organizational mentoring strategies.

Community-based non-profit organizations rarely have access to research or evaluation evidence to inform their programs and often lack the capacity to gather or use this information independently. In 2016, Wisdom2Action-a network of knowledge mobilization (KMb) experts, policy makers and service providers across Canada-launched an inter-organizational mentorship program to facilitate the implementation and sharing of best and promising practices within community-based programs for young people. This article outlines the findings from a developmental evaluation of eight mentoring relationships. Drawing on the Promoting Action on Research in Health Sciences (PARiHS) model of KMb, we look at mentoring as a type of facilitation that supports the increased use of evidence and evaluation information by non-profit organizations and identify key themes that support effective organizational mentorship in this sector. Findings reinforce the importance of establishing connected relationships and understanding context in mentoring relationships, creating adaptive and responsive work plans, ensuring consistent communication, and maintaining a focus on capacity-building if knowledge mobilization is to occur.

Epitope Mapping Using Yeast Display and Next Generation Sequencing.

Monoclonal antibodies are the largest class of therapeutic proteins due in part to their ability to bind an antigen with a high degree of affinity and specificity. A precise determination of their epitope is important for gaining insights into their therapeutic mechanism of action and to help differentiate antibodies that bind the same antigen. Here, we describe a method to precisely and efficiently map the epitopes of multiple antibodies in parallel over the course of just several weeks. This approach is based on a combination of rational library design, yeast surface display, and next generation DNA sequencing and provides quantitative insights into the epitope residues most critical for the antibody-antigen interaction. As an example, we will use this method to map the epitopes of several antibodies that neutralize alpha toxin from Staphylococcus aureus.

Towards high-quality, useful practice guidelines for child and youth mental health disorders: protocol for a systematic review and consensus exercise.

INTRODUCTION: The quality of clinical practice guidelines (PGs) has not been evaluated in child and youth mental health (CYMH). To address this gap, we will: (1) conduct a systematic review (SR) to answer the question 'among eligible PGs relevant to the prevention or treatment of CYMH conditions, which PGs meet criteria for minimum and high quality?'; (2) apply nominal group methods to create recommendations for how CYMH PG quality, completeness and usefulness can be strengthened. METHODS AND ANALYSIS: SR: Potentially eligible PGs will be identified in 12 databases using a reproducible search strategy developed by a research librarian. Trained raters will: (1) apply prespecified criteria to identify eligible PGs relevant to depression, anxiety, suicidality, bipolar disorder, behaviour disorder (attention-deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder) and substance use disorder; (2) extract descriptive data and (3) assess PG quality using the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool. Scores on three AGREE II domains (rigour of development, stakeholder involvement, editorial independence) will designate PGs as minimum (≥50%) or high quality (≥70%). Nominal group: Four CYMH PG knowledge user groups (clinicians, mental health service planners, youth and adult family members) will participate in structured exercises derived using nominal group methods to generate recommendations to improve PG quality, completeness and usefulness. ETHICS AND DISSEMINATION: Ethics approval is not required. Study products will be disseminated as follows. A cross-platform website will house eligible CYMH PGs and their quality ratings. Twitter and Facebook tools will promote it to a wide variety of PG users. Data from Google Analytics, Twitonomy and Altmetrics will inform usage evaluation. Complementary educational workshops will be conducted for CYMH professionals. Print materials and journal articles will be produced. PROSPERO REGISTRATION NUMBER: CRD42017060738.

Productive common light chain libraries yield diverse panels of high affinity bispecific antibodies.

The commercial success of bispecific antibodies generally has been hindered by the complexities associated with generating appropriate molecules for both research scale and large scale manufacturing purposes. Bispecific IgG (BsIgG) based on two antibodies that use an identical common light chain can be combined with a minimal set of Fc mutations to drive heavy chain heterodimerization in order to address these challenges. However, the facile generation of common light chain antibodies with properties similar to traditional monoclonal antibodies has not been demonstrated and they have only been used sparingly. Here, we describe the design of a synthetic human antibody library based on common light chains to generate antibodies with biochemical and biophysical properties that are indistinguishable to traditional therapeutic monoclonal antibodies. We used this library to generate diverse panels of well-behaved, high affinity antibodies toward a variety of epitopes across multiple antigens, including mouse 4-1BB, a therapeutically important T cell costimulatory receptor. Over 200 BsIgG toward 4-1BB were generated using an automated purification method we developed that enables milligram-scale production of BsIgG. This approach allowed us to identify antibodies with a wide range of agonistic activity that are being used to further investigate the therapeutic potential of antibodies targeting one or more epitopes of 4-1BB.

Germline-encoded neutralization of a Staphylococcus aureus virulence factor by the human antibody repertoire.

Staphylococcus aureus is both an important pathogen and a human commensal. To explore this ambivalent relationship between host and microbe, we analysed the memory humoral response against IsdB, a protein involved in iron acquisition, in four healthy donors. Here we show that in all donors a heavily biased use of two immunoglobulin heavy chain germlines generated high affinity (pM) antibodies that neutralize the two IsdB NEAT domains, IGHV4-39 for NEAT1 and IGHV1-69 for NEAT2. In contrast to the typical antibody/antigen interactions, the binding is primarily driven by the germline-encoded hydrophobic CDRH-2 motifs of IGHV1-69 and IGHV4-39, with a binding mechanism nearly identical for each antibody derived from different donors. Our results suggest that IGHV1-69 and IGHV4-39, while part of the adaptive immune system, may have evolved under selection pressure to encode a binding motif innately capable of recognizing and neutralizing a structurally conserved protein domain involved in pathogen iron acquisition.

A Systematic Review of Social Media Use to Discuss and View Deliberate Self-Harm Acts.

OBJECTIVE: To conduct a systematic review of studies of social media platforms used by young people to discuss and view deliberate self-harm. STUDY DESIGN: 11 electronic databases were searched from January 2000 to January 2012 for primary research; in June 2014 an updated search of Medline was conducted. Grey literature sources were also searched. Search results were screened by two reviewers. Data were extracted by one reviewer and verified by another. Methodological quality was assessed using the Mixed Methods Appraisal Tool. RESULTS: Due to heterogeneity in study objectives and outcomes, results were not pooled; a narrative analysis is presented. 26 studies were included. Most were conducted in Canada or the UK (30.8% each), used qualitative designs (42.3%), and evaluated discussion forums (73.1%). Participants were most often aged 19-21 years (69.2%), female (mean 68.6%), and 19.2% had a documented history of depression. The social media platforms evaluated were commonly supportive and provided a sense of community among users. Support included suggestions for formal treatment, advice on stopping self-harming behavior, and encouragement. Harms included normalizing and accepting self-harming behavior; discussion of motivation or triggers, concealment, suicidal ideation or plans; and live depictions of self-harm acts. CONCLUSIONS: Although this evidence is limited by its descriptive nature, studies identify beneficial and detrimental effects for young people using social media to discuss and view deliberate self-harm. The connections users make online may be valuable to explore for therapeutic benefit. Prospective, longitudinal investigations are needed to identify short- and long-term potential harms associated with use.

Prevalence and Effect of Cyberbullying on Children and Young People: A Scoping Review of Social Media Studies.

IMPORTANCE: Social media has had a profound effect on how children and adolescents interact. While there are many benefits to the use of social media, cyberbullying has emerged as a potential harm, raising questions regarding its influence on mental health. OBJECTIVE: To review existing publications that examine the health-related effects of cyberbullying via social media among children and adolescents. EVIDENCE REVIEW: We searched 11 electronic databases from January 1, 2000, through January 17, 2012 (updated June 24, 2014). Studies were screened by 2 independent reviewers and were included if they reported primary research, described or evaluated the use of a social media tool in the context of cyberbullying, and were conducted with children or adolescents. Data were extracted by 1 reviewer and verified by a second. All studies were assessed by 2 reviewers for methodological quality using the Mixed Methods Appraisal Tool. Results were not pooled owing to heterogeneity in study objectives and outcomes; a narrative analysis is presented. FINDINGS: Thirty-six studies in 34 publications were included. Most were conducted in the United States (21 [58.3%]), sampled middle and high school populations (24 [66.7%]), and included adolescents who were 12 to 18 years of age (35 [97.2%]). The median reported prevalence of cyberbullying was 23.0% (interquartile range, 11.0%-42.6%). Five studies reported inconsistent and/or weak correlations between cyberbullying and anxiety. Ten studies found a statistically significant association between cyberbullying and report of depression. Five studies investigated self-harm or suicidality, with conflicting results. Results indicate that the most common reason for cyberbullying is relationship issues, with girls most often being the recipients. Responses to cyberbullying are most often passive, with a pervasive lack of awareness or confidence that anything can be done. CONCLUSIONS AND RELEVANCE: There is a consistent relationship across studies between cyberbullying and depression among children and adolescents; however, the evidence of the effect of cyberbullying on other mental health conditions is inconsistent. This review provides important information that characterizes cyberbullying within the context of social media, including attributes of the recipients and perpetrators, reasons for and the nature of bullying behaviors, and how recipients react to and manage bullying behaviors. This information is critical to the development of effective prevention and management strategies.

Effect of genome and environment on metabolic and inflammatory profiles.

Twin and family studies have established the contribution of genetic factors to variation in metabolic, hematologic and immunological parameters. The majority of these studies analyzed single or combined traits into pre-defined syndromes. In the present study, we explore an alternative multivariate approach in which a broad range of metabolic, hematologic, and immunological traits are analyzed simultaneously to determine the resemblance of monozygotic (MZ) twin pairs, twin-spouse pairs and unrelated, non-cohabiting individuals. A total of 517 participants from the Netherlands Twin Register, including 210 MZ twin pairs and 64 twin-spouse pairs, took part in the study. Data were collected on body composition, blood pressure, heart rate, and multiple biomarkers assessed in fasting blood samples, including lipid levels, glucose, insulin, liver enzymes, hematological measurements and cytokine levels. For all 51 measured traits, pair-wise Pearson correlations, correcting for family relatedness, were calculated across all the individuals in the cohort. Hierarchical clustering techniques were applied to group the measured traits into sub-clusters based on similarity. Sub-clusters were observed among metabolic traits and among inflammatory markers. We defined a phenotypic profile as the collection of all the traits measured for a given individual. Average within-pair similarity of phenotypic profiles was determined for the groups of MZ twin pairs, spouse pairs and pairs of unrelated individuals. The average similarity across the full phenotypic profile was higher for MZ twin pairs than for spouse pairs, and lowest for pairs of unrelated individuals. Cohabiting MZ twins were more similar in their phenotypic profile compared to MZ twins who no longer lived together. The correspondence in the phenotypic profile is therefore determined to a large degree by familial, mostly genetic, factors, while household factors contribute to a lesser degree to profile similarity.

Precise and efficient antibody epitope determination through library design, yeast display and next-generation sequencing.

The ability of antibodies to bind an antigen with a high degree of affinity and specificity has led them to become the largest and fastest growing class of therapeutic proteins. Clearly identifying the epitope at which they bind their cognate antigen provides insight into their mechanism of action and helps differentiate antibodies that bind the same antigen. Here, we describe a method to precisely and efficiently map the epitopes of a panel of antibodies in parallel over the course of several weeks. This method relies on the combination of rational library design, quantitative yeast surface display and next-generation DNA sequencing and was demonstrated by mapping the epitopes of several antibodies that neutralize alpha toxin from Staphylococcus aureus. The accuracy of this method was confirmed by comparing the results to the co-crystal structure of one antibody and alpha toxin and was further refined by the inclusion of a lower-affinity variant of the antibody. In addition, this method produced quantitative insight into the epitope residues most critical for the antibody-antigen interaction and enabled the relative affinities of each antibody toward alpha toxin variants to be estimated. This affinity estimate serves as a predictor of neutralizing antibody potency and was used to anticipate the ability of each antibody to effectively bind and neutralize naturally occurring alpha toxin variants secreted by strains of S. aureus, including clinically relevant strains. Ultimately this type information can be used to help select the best clinical candidate among a set of antibodies against a given antigen.