Interleukin-17A Serves a Priming Role in Autoimmunity by Recruiting IL-1ß-Producing Myeloid Cells that Promote Pathogenic T Cells.

Interleukin-17A (IL-17A) is a major mediator of tissue inflammation in many autoimmune diseases. Anti-IL-17A is an effective treatment for psoriasis and is showing promise in clinical trials in multiple sclerosis. In this study, we find that IL-17A-defective mice or mice treated with anti-IL-17A at induction of experimental autoimmune encephalomyelitis (EAE) are resistant to disease and have defective priming of IL-17-secreting γδ T (γδT17) cells and Th17 cells. However, T cells from Il17a-/- mice induce EAE in wild-type mice following in vitro culture with autoantigen, IL-1ß, and IL-23. Furthermore, treatment with IL-1ß or IL-17A at induction of EAE restores disease in Il17a-/- mice. Importantly, mobilization of IL-1ß-producing neutrophils and inflammatory monocytes and activation of γδT17 cells is reduced in Il17a-/- mice. Our findings demonstrate that a key function of IL-17A in central nervous system (CNS) autoimmunity is to recruit IL-1ß-secreting myeloid cells that prime pathogenic γδT17 and Th17 cells.

IL-27 maintains cytotoxic Ly6C+ γδ T cells that arise from immature precursors.

In mice, γδ-T lymphocytes that express the co-stimulatory molecule, CD27, are committed to the IFNγ-producing lineage during thymic development. In the periphery, these cells play a critical role in host defense and anti-tumor immunity. Unlike αß-T cells that rely on MHC-presented peptides to drive their terminal differentiation, it is unclear whether MHC-unrestricted γδ-T cells undergo further functional maturation after exiting the thymus. Here, we provide evidence of phenotypic and functional diversity within peripheral IFNγ-producing γδ T cells. We found that CD27+ Ly6C- cells convert into CD27+Ly6C+ cells, and these CD27+Ly6C+ cells control cancer progression in mice, while the CD27+Ly6C- cells cannot. The gene signatures of these two subsets were highly analogous to human immature and mature γδ-T cells, indicative of conservation across species. We show that IL-27 supports the cytotoxic phenotype and function of mouse CD27+Ly6C+ cells and human Vδ2+ cells, while IL-27 is dispensable for mouse CD27+Ly6C- cell and human Vδ1+ cell functions. These data reveal increased complexity within IFNγ-producing γδ-T cells, comprising immature and terminally differentiated subsets, that offer new insights into unconventional T-cell biology.

SARS-CoV and SARS-CoV-2 display limited neuronal infection and lack the ability to transmit within synaptically connected axons in stem cell-derived human neurons.

Sarbecoviruses such as SARS and SARS-CoV-2 have been responsible for two major outbreaks in humans, the latter resulting in a global pandemic. While sarbecoviruses primarily cause an acute respiratory infection, they have been shown to infect the nervous system. However, mechanisms of sarbecovirus neuroinvasion and neuropathogenesis remain unclear. In this study, we examined the infectivity and trans-synaptic transmission potential of the sarbecoviruses SARS and SARS-CoV-2 in human stem cell-derived neural model systems. We demonstrated limited ability of sarbecoviruses to infect and replicate in human stem cell-derived neurons. Furthermore, we demonstrated an inability of sarbecoviruses to transmit between synaptically connected human stem cell-derived neurons. Finally, we determined an absence of SARS-CoV-2 infection in olfactory neurons in experimentally infected ferrets. Collectively, this study indicates that sarbecoviruses exhibit low potential to infect human stem cell-derived neurons, lack an ability to infect ferret olfactory neurons, and lack an inbuilt molecular mechanism to utilise retrograde axonal trafficking and trans-synaptic transmission to spread within the human nervous system.

Hepatitis C (HCV) prevalence in citizens of the Métis Nation of Ontario.

BACKGROUND: Hepatitis C virus (HCV) infection is a major global concern, with Indigenous Peoples bearing the highest burden. Previous studies exploring HCV prevalence within Indigenous populations have predominantly used a pan-Indigenous approach, consequently resulting in limited availability of Métis-specific HCV data. The Métis are one of the three recognized groups of Indigenous Peoples in Canada with a distinct history and language. The Métis Nation of Ontario (MNO) is the only recognized Métis government in Ontario. This study aims to examine the prevalence of self-reported HCV testing and positive results among citizens of the MNO, as well as to explore the association between sociodemographic variables and HCV testing and positive results. METHODS: A population-based online survey was implemented by the MNO using their citizenship registry between May 6 and June 13, 2022. The survey included questions about hepatitis C testing and results, socio-demographics, and other health related outcomes. Census sampling was used, and 3,206 MNO citizens responded to the hepatitis C-related questions. Descriptive statistics and bivariate analysis were used to analyze the survey data. RESULTS: Among the respondents, 827 (25.8%, CI: 24.3-27.3) reported having undergone HCV testing and 58 indicated testing positive, resulting in a prevalence of 1.8% (CI: 1.3-2.3). Respondents with a strong sense of community belonging, higher education levels, and lower household income were more likely to report having undergone HCV testing. Among those who had undergone testing, older age groups, individuals with lower education levels, and retired individuals were more likely to test positive for HCV. CONCLUSION: This study is the first Métis-led and Métis-specific study to report on HCV prevalence among Métis citizens. This research contributes to the knowledge base for Métis health and will support the MNO's health promotion program and resources for HCV. Future research will examine the actual HCV incidence and prevalence among MNO citizens.

Public Health Dashboards in Overdose Prevention: The Rhode Island Approach to Public Health Data Literacy, Partnerships, and Action.

As the field of public health rises to the demands of real-time surveillance and rapid data-sharing needs in a postpandemic world, it is time to examine our approaches to the dissemination and accessibility of such data. Distinct challenges exist when working to develop a shared public health language and narratives based on data. It requires that we assess our understanding of public health data literacy, revisit our approach to communication and engagement, and continuously evaluate our impact and relevance. Key stakeholders and cocreators are critical to this process and include people with lived experience, community organizations, governmental partners, and research institutions. In this viewpoint paper, we offer an instructive approach to the tools we used, assessed, and adapted across 3 unique overdose data dashboard projects in Rhode Island, United States. We are calling this model the "Rhode Island Approach to Public Health Data Literacy, Partnerships, and Action." This approach reflects the iterative lessons learned about the improvement of data dashboards through collaboration and strong partnerships across community members, state agencies, and an academic research team. We will highlight key tools and approaches that are accessible and engaging and allow developers and stakeholders to self-assess their goals for their data dashboards and evaluate engagement with these tools by their desired audiences and users.

Black and white: how good are clinicians at diagnosing elbow injuries from paediatric elbow radiographs alone?

OBJECTIVES: Paediatric trauma elbow radiographs are difficult to interpret and there is a potential for harm if misdiagnosed. The primary goal of this study was to assess the ability of healthcare professionals internationally to interpret paediatric trauma elbow radiographs from the radiograph alone by formulating the correct diagnosis. METHODS: This prospective international study was conducted online via the Free Open Access Medical Education platform, Don't Forget the Bubbles (DFTB, ISSN 2754-5407). Participants were recruited via the DFTB social media accounts between 17 August and 14 September 2021. Submissions that were incomplete or from participants who do not interpret paediatric elbow radiographs in their clinical practice were excluded. Participants completed an online survey of demographic data followed by interpreting 10 trauma-indicated elbow radiographs, by selecting multiple-choice options. The primary outcome was correct diagnosis. RESULTS: Participant responses from 18 countries were analysed, with most responses from the UK, Australia and Ireland. Participants had backgrounds in emergency medicine (EM), paediatric emergency medicine (PEM), general practice (GP) and paediatrics, with over 70% having 6+ years of postgraduate experience. 3180 radiographs were interpreted by 318 healthcare professionals. Only nine (2.8%) participants correctly diagnosed all 10. The mean number of radiographs correctly interpreted was 5.44 (SD 2.3). The mean number for those with 6+ years of experience was 6.02 (SD 2.2). On reviewing the normal radiograph, 158 (49.7%) overcalled injuries. Participants with EM or PEM background were equally likely to have more correct answers than those from paediatric or GP backgrounds. CONCLUSION: Globally, healthcare professional's success in correctly diagnosing paediatric elbow injuries from radiographs was suboptimal in this non-clinical exercise, despite capturing quite an experienced cohort of clinicians. This study has provided us with detailed baseline data to accurately assess the impact of interventions aimed at improving clinicians' interpretation of paediatric elbow radiographs in future studies.

Children in Mental Health Crisis: Pediatric Primary Care Providers' Role in Bridging Treatment Following Higher Levels of Care.

The current study examines the role of pediatric PCPs in bridging treatment for youth who have experienced mental health crises and the characteristics of these patients for whom PCPs sought psychiatric consultation and referral support from a child psychiatry access program, Maryland Behavioral Health Integration in Pediatric Primary Care. Psychiatric consultation and referral calls between 2012 and 2021 were included if a) the patient was recently seen in a higher level of care and b) the PCP was bridging treatment following the patient's discharge; 208 calls met criteria. The most common mental health concerns included depressed mood, suicidal thoughts/gestures, and anxiety. Acute concerns of aggression, suicide attempts, and hallucinations were also reported. Over half of the patients had two or more mental health diagnoses. At the time of the call, only one quarter of these patients had outpatient therapy services while about half were receiving medication treatment. Most of these patients were discharged from the higher level of care without a care plan. Pediatric PCPs are managing their patients' complex mental health concerns following receipt of higher levels of care. Improvements in collaboration and care coordination between pediatric PCPs and emergency department providers are needed.

Associations between socioeconomic gradients and racial disparities in preadolescent brain outcomes.

BACKGROUND: The aim of this study was to determine the extent to which socioeconomic characteristics of the home and neighborhood are associated with racial inequalities in brain outcomes. METHODS: We performed a cross-sectional analysis of the baseline dataset (v.2.0.1) from the Adolescent Brain and Cognitive Development (ABCD) Study. Cognitive performance was assessed using the National Institutes of Health Toolbox (NIH-TB) cognitive battery. Standard socioeconomic indicators of the family and neighborhood were derived from census-related statistics. Cortical morphometric measures included MRI-derived thickness, area, and volume. RESULTS: 9638 children were included. Each NIH-TB cognitive measure was negatively associated with household and neighborhood socioeconomic characteristics. Differences in cognitive scores between Black or Hispanic children and other racial groups were mitigated by higher household income. Most children from lowest-income families or residents in impoverished neighborhoods were Black or Hispanic. These disparities were associated with racial differences in NIH-TB measures and mediated by smaller cortical brain volumes. CONCLUSIONS: Neighborhood socioeconomic characteristics are associated with racial differences in preadolescent brain outcomes and mitigated by greater household income. Household income mediates racial differences more strongly than neighborhood-level socioeconomic indicators in brain outcomes. Highlighting these socioeconomic risks may direct focused policy-based interventions such as allocation of community resources to ensure equitable brain outcomes in children. IMPACT: Neighborhood socioeconomic characteristics are associated with racial differences in preadolescent brain outcomes and mitigated by greater household income. Household income mediates racial differences more strongly than neighborhood-level socioeconomic indicators in brain outcomes. Highlighting these disparities related to socioeconomic risks may direct focused policy-based interventions such as allocation of community resources to ensure equitable brain outcomes in children.

Prevalence of Parent Mental Health Problems in an Interdisciplinary Feeding Clinic: Short Communication.

Parents of children with pediatric feeding disorder (PFD) often experience high stress and may be at advanced risk for mental health conditions. We conducted a retrospective chart review of 413 parents who completed intake surveys at an interdisciplinary feeding clinic to determine the prevalence and types of mental health conditions among parents; 41.8% of parents reported a mental health diagnosis among the mother and/or father. Of the parents with mental health conditions, the most prevalent conditions reported were anxiety (71.1% for mothers, 50% for fathers) and mood disorders (62.7% for mothers, 40.9% for fathers). For mothers, 21.1% indicated their mental health disorder had a postpartum onset. Parents of children with birth complications were more likely to have a mental health condition (50.9%) than parents of children without a birth complication (38.7%), and parents reporting mental health conditions had children with significantly more co-occurring medical conditions. Since parent stress and mental health can influence parent-child interactions during mealtime, this study suggests the importance of addressing both parent mental health factors and child factors when treating children for PFD. Future studies are needed to develop novel interventions that support the specific mental health needs of parents of children with PFD.

Changes and predictors of maternal depressive and anxiety symptoms during the COVID-19 pandemic.

Longitudinal changes in maternal depressive and anxiety symptoms and predictors of symptom variation among a group of middle-to-upper income Canadian women (n = 2152) were examined prior to the pandemic (2017-2019) and at three pandemic timepoints (May-July 2020, March-April 2021, November-December 2021). Mean maternal depression and anxiety scores were elevated throughout the pandemic. Pre-pandemic depressive symptoms were associated with greater increases in depressive symptoms. Coping and relationship quality were protective factors. Supporting the development of coping strategies may mitigate mental health concerns among mothers.

2022 European guideline for the management of balanoposthitis.

BACKGROUND: This guideline is an update to the 2014 edition of the European guideline for the management of balanoposthitis. Balanoposthitis describes inflammation of the glans penis and prepuce and is caused by a range of disparate conditions including infection, dermatoses and premalignancy. OBJECTIVE: The main objectives of this guideline are to aid recognition of the symptoms and signs and complications of penile skin conditions and to offer recommendations on the diagnostic tests and treatment for a selected group of these conditions. METHODS: The previous guideline was updated following a literature review and priority was given to randomized controlled trial and systematic review evidence. RESULTS: The updated guideline includes amended management for infective balanitis to provide clear guidance for Group A streptococcal infections, management of on going Lichen sclerosus (to include circumcision and supportive management to reduce the recurrence of genital herpes and warts), additional regimens for Zoonoid change, use of calcineurin inhibitors in management and risk of premalignancy and change of nomenclaturefrom Premalignant conditions to Penile Intraepithelial neoplasia (PeIN). CONCLUSION: Balanoposthitis has a widerange of causes high quality evidence specific to the management of penile disease is not available for all the conditions described.

An ethics of anthropology-informed community engagement with COVID-19 clinical trials in Africa.

The COVID-19 pandemic has reinforced the critical role of ethics and community engagement in designing and conducting clinical research during infectious disease outbreaks where no vaccine or treatment already exists. In reviewing current practices across Africa, we distinguish between three distinct roles for community engagement in clinical research that are often conflated: 1) the importance of community engagement for identifying and honouring cultural sensitivities; 2) the importance of recognising the socio-political context in which the research is proposed; and 3) the importance of understanding what is in the interest of communities recruited to research according to their own views and values. By making these distinctions, we show that current practice of clinical research could draw on anthropology in ways which are sometimes unnecessary to solicit local cultural values, overlook the importance of socio-political contexts and wider societal structures within which it works, potentially serving to reinforce unjust political or social regimes, and threaten to cast doubt on the trustworthiness of the research. We argue that more discerning anthropological engagement as well as wider collaboration with other social scientists and those working in the humanities is urgently needed to improve the ethics of current biomedical and pharmaceutical research practice in Africa.

Pediatric Tube Weaning: A Meta-Analysis of Factors Contributing to Success.

Approximately 3-10% of children have severe feeding issues, and some require enteral/tube nutrition to grow and thrive. For many children, tube feeding is temporary, making efficacious interventions for tube weaning essential. We conducted a systematic review and meta-analysis of tube weaning treatments. Outcomes included percentage of participants completely weaned from the tube, and mean percentage of kilocalories consumed orally following treatment. Data were extracted from 42 studies, including cohort studies and single-subject research design studies. We evaluated moderators of treatment success, including treatment setting, use of behavioral approaches, use of hunger provocation, and use of a multidisciplinary approach. Results indicated that, after treatment, children received significantly more calories orally, and 67-69% of children were fully weaned. These analyses suggest that current interventions are generally effective; however, variability within treatments exist. Prospective randomized clinical trials are needed to understand effective components of weaning interventions.

Time-critical telephone conversations in the emergency department: lessons learnt from a pilot educational project to improve communication skills over the telephone in response to the COVID-19 global pandemic.

In many countries, the COVID-19 pandemic resulted in restricted hospital visiting by relatives.Staff have been forced to deliver unwelcome and bad news over the telephone. There are few training resources around how to do this. We created a bespoke training package consisting of a 15 min eLearning session and a 1-hour facilitated role-play session. Two simulated telephone calls to a professional actor posing as the relative were undertaken on a speakerphone. Following each simulated call, the actor gave feedback to the caller, focusing on the likely experience of a relative during these conversations. Elements specific to telephone conversations included ensuring the safety of the recipient to take the call (eg, not driving a car), ensuring they had adequate local support, and allowing a deliberate silence after delivering the bad news. Silence has a powerful impact, despite being uncomfortable. The opportunity to have written notes before calling and to offer a return call was seen as an opportunity for improving communication. We collated these experiences into a series of phrases found most useful and empathic by the actor and participants. A practical aide- mémoir was created from this learning that could be used to help deliver bad news quickly in the emergency department.

Pilot Study of the MAP Curriculum for Psychotherapy Competencies in Child and Adolescent Psychiatry.

OBJECTIVE: This pilot study aimed to evaluate the relevance, feasibility, acceptability, and instructional efficacy of the Managing and Adapting Practice (MAP) curriculum for enhancing the teaching of psychotherapy to child and adolescent psychiatry (CAP) fellows. MAP is a system of resources and decision models that supports practitioners in selecting and implementing psychotherapeutic interventions for children and adolescents. The MAP curriculum includes modules to guide education about psychotherapeutic procedures (e.g., behavioral activation) common in evidence-based treatments for an array of childhood problems and to support development of competencies in assessment, treatment planning, and reflective practice. METHODS: Curriculum coding was used to examine the relevance of MAP's core components to the skills articulated in the Accreditation Council for Graduate Medical Education (ACGME) CAP milestones. Feasibility, acceptability, and learning outcomes were examined after delivery of the MAP curriculum to 12 CAP fellows at two sites, with instructional features tailored according to faculty preferences and training program structure. RESULTS: Coding suggested that the MAP curriculum was relevant to 95% of the 21 ACGME CAP training subcompetencies. Feasibility was indicated by the successful delivery of 100% of the planned MAP curriculum across the two sites. Acceptability was supported by positive feedback from the CAP fellows, and psychotherapy knowledge increased significantly. Finally, case review scores (mean±SD=2.21±0.15) showed positive posttraining application of MAP to two patients and exceeded scores achieved by other samples of mental health professionals. CONCLUSIONS: This pilot study demonstrated the potential for the MAP curriculum to support CAP education. MAP's versatility as a curriculum supports broader adoption, with continuing rigorous empirical evaluation.

Emerging immunotherapies for metastasis.

Major advances in cancer immunotherapy have dramatically expanded the potential to manipulate immune cells in cancer patients with metastatic disease to counteract cancer spread and extend patient lifespan. One of the most successful types of immunotherapy is the immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1, that keep anti-tumour T cells active. However, not every patient with metastatic disease benefits from this class of drugs and patients often develop resistance to these therapies over time. Tremendous research effort is now underway to uncover new immunotherapeutic targets that can be used in patients who are refractory to anti-CTLA-4 or anti-PD-1 treatment. Here, we discuss results from experimental model systems demonstrating that modulating the immune response can negatively affect metastasis formation. We focus on molecules that boost anti-tumour immune cells and opportunities to block immunosuppression, as well as cell-based therapies with enhanced tumour recognition properties for solid tumours. We also present a list of challenges in treating metastatic disease with immunotherapy that must be considered in order to move laboratory observations into clinical practice and maximise patient benefit.

Chems4EU: chemsex use and its impacts across four European countries in HIV-positive men who have sex with men attending HIV services.

INTRODUCTION: Chemsex in a European context is the use of any of the following drugs to facilitate sex: crystal methamphetamine, mephedrone and gamma-hydroxybutyrate (GHB)/gamma-butyrolactone (GBL) and, to a lesser extent, cocaine and ketamine. This study describes the prevalence of self-reported recreational drug use and chemsex in HIV-positive men who have sex with men (MSM) accessing HIV services in four countries. It also examines the problematic impacts and harms of chemsex and access to chemsex-related services. METHODS: This is a cross-sectional multi-centre questionnaire study of HIV-positive MSM accessing nine HIV services in the UK, Spain, Greece and Italy. RESULTS: In all, 1589 HIV-positive MSM attending HIV services in four countries completed the questionnaire. The median age of participants was 38 years (interquartile range: 32-46 years) and 1525 (96.0%) were taking antiretroviral therapy (ART). In the previous 12 months, 709 (44.6%) had used recreational drugs, 382 (24.0%) reported chemsex and 104 (6.5%) reported injection of chemsex-associated drugs ('slamsex'). Of the 382 engaging in chemsex, 155 (40.6%) reported unwanted side effects as a result of chemsex and 81 (21.2%) as a result of withdrawal from chemsex. The reported negative impacts from chemsex were on work (25.1%, 96), friends/family (24.3%, 93) and relationships (28.3%, 108). Fifty-seven (14.9%) accessed chemsex-related services in the past year, 38 of whom (67%) felt the service met their needs. DISCUSSION: A quarter of participants self-reported chemsex in the past 12 months. There were high rates of harms from chemsex across all countries, including negative impacts on work, friends/family and relationships. Although a minority of those engaging in chemsex accessed support, most found this useful.

Recognising values and engaging communities across cultures: towards developing a cultural protocol for researchers.

Efforts to build research capacity and capability in low and middle income countries (LMIC) has progressed over the last three decades, yet it confronts many challenges including issues with communicating or even negotiating across different cultures. Implementing global research requires a broader understanding of community engagement and participatory research approaches. There is a considerable amount of guidance available on community engagement in clinical trials, especially for studies for HIV/AIDS, even culturally specific codes for recruiting vulnerable populations such as the San or Maori people. However, the same cannot be said for implementing research in global health. In an effort to build on this work, the Pakistan Institute of Living and Learning and University College London in the UK sought to better understand differences in beliefs, values and norms of local communities in Pakistan. In particular, they have sought to help researchers from high income countries (HIC) understand how their values are perceived and understood by the local indigenous researchers in Pakistan. To achieve this end, a group discussion was organised with indigenous researchers at Pakistan Institute of Living and Learning. The discussion will ultimately help inform the development of a cultural protocol for researchers from HIC engaging with communities in LMIC. This discussion revealed five common themes; (1) religious principles and rules, (2) differing concepts of and moral emphasis on autonomy and privacy, (3) importance of respect and trust; (4) cultural differences (etiquette); (5) custom and tradition (gift giving and hospitality). Based on the above themes, we present a preliminary cultural analysis to raise awareness and to prepare researchers from HIC conducting cross cultural research in Pakistan. This is likely to be particularly relevant in collectivistic cultures where social interconnectedness, family and community is valued above individual autonomy and the self is not considered central to moral thinking. In certain cultures, HIC ideas of individual autonomy, the notion of informed consent may be regarded as a collective family decision. In addition, there may still be acceptance of traditional professional roles such as 'doctor knows best', while respect and privacy may have very different meanings.

Fifteen-minute consultation: Assessing the child with an elbow injury.

This article aims to provide a concise summary of the key considerations when assessing a child with an elbow injury. Elbow injuries are common with acute elbow trauma, accounting for 2%-3% of all visits to the emergency department. This article will cover history, examination and key X-ray findings, along with a brief guide to management. It is hoped this article will help healthcare professionals who assess children with elbow injuries. Our work is applicable to those both in the hospital and community setting.

Telepsychotherapy with Youth at Clinical High Risk for Psychosis: Clinical Issues and Best Practices during the COVID-19 Pandemic.

Early detection and prevention of psychosis has become an international priority. Much of this work has focused on youth presenting with attenuated symptoms of psychosis-those at Clinical High Risk for psychosis (CHR)-given their elevated probability of developing the full disorder in subsequent years. Individuals at CHR may be prone to exacerbated psychological distress during the COVID-19 pandemic and its subsequent physical isolation measures, due to heightened stress sensitivity and comorbid mental health problems. Telepsychotherapy holds promise for reaching this population, especially during the current COVID-19 outbreak. However, there are limited evidence-based guidelines or interventions for use of telepsychotherapy with this population. In this paper, we review common clinical issues for individuals at CHR and how they might be exacerbated by the COVID-19 pandemic; best practices for treatment and adaptations for telepsychotherapy for individuals at CHR; and highlight real clinical issues that we are currently experiencing in a United States-based specialized CHR clinic as we conduct telepsychotherapy via videoconferencing. We conclude with questions for those in the field to contemplate, as well as potential challenges and benefits in using telepsychotherapy with individuals at CHR and their families.