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Abstract Background Despite new and better treatments for juvenile dermatomyositis (JDM), not all patients with moderate severity disease respond adequately to first-line therapy. Those with refractory disease remain at higher risk for disease and glucocorticoid-related complications. Biologic disease-modifying antirheumatic drugs (DMARDs) have become part of the arsenal of treatments for JDM. However, prospective comparative studies of commonly used biologics are lacking. Methods The Childhood Arthritis and Rheumatology Research Alliance (CARRA) JDM biologics workgroup met in 2019 and produced a survey assessing current treatment escalation practices for JDM, including preferences regarding use of biologic treatments. The cases and questions were developed using a consensus framework, requiring 80% agreement for consensus. The survey was completed online in 2020 by CARRA members interested in JDM. Survey results were analyzed among all respondents and according to years of experience. Chi-square or Fisher’s exact test was used to compare the distribution of responses to each survey question. Results One hundred twenty-one CARRA members responded to the survey (denominators vary for each question). Of the respondents, 88% were pediatric rheumatologists, 85% practiced in the United States, and 43% had over 10 years of experience. For a patient with moderately severe JDM refractory to methotrexate, glucocorticoids, and IVIG, approximately 80% of respondents indicated that they would initiate a biologic after failing 1–2 non-biologic DMARDs. Trials of methotrexate and mycophenolate were considered necessary by 96% and 60% of respondents, respectively, before initiating a biologic. By weighed average, rituximab was the preferred biologic over abatacept, tocilizumab, and infliximab. Over 50% of respondents would start a biologic by 4 months from diagnosis for patients with refractory moderately severe JDM. There were no notable differences in treatment practices between respondents by years of experience. Conclusion Most respondents favored starting a biologic earlier in disease course after trialing up to two conventional DMARDs, specifically including methotrexate. There was a clear preference for rituximab. However, there remains a dearth of prospective data comparing biologics in refractory JDM. These findings underscore the need for biologic consensus treatment plans (CTPs) for refractory JDM, which will ultimately facilitate comparative effectiveness studies and inform treatment practices.

The impact of the COVID-19 pandemic on new diagnoses of recurrent fevers and autoinflammatory diseases is largely unknown. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) PFAPA/AID Working Group aimed to investigate the impact of the COVID-19 pandemic on the number of pediatric patients evaluated for recurrent fevers and autoinflammatory diseases in North America. The absolute number of new outpatient visits and the proportion of these visits attributed to recurrent fever diagnoses during the pre-pandemic period (1 March 2019–29 February 2020) and the first year of the COVID-19 pandemic (1 March 2020–28 February 2021) were examined. Data were collected from 27 sites in the United States and Canada. Our results showed an increase in the absolute number of new visits for recurrent fever evaluations in 21 of 27 sites during the COVID-19 pandemic compared to the pre-pandemic period. The increase was observed across different geographic regions in North America. Additionally, the proportion of new visits to these centers for recurrent fever in relation to all new patient evaluations was significantly higher during the first year of the pandemic, increasing from 7.8% before the pandemic to 10.9% during the pandemic year (p

Abstract Background A standardized set of quality measures for juvenile idiopathic inflammatory myopathies (JIIM) is not in use. Discordance has been shown between the importance ascribed to quality measures between patients and families and physicians. The objective of this study was to assess and compare the importance of various aspects of high quality care to patients with JIIM and their families with healthcare providers, to aid in future development of comprehensive quality measures. Methods Surveys were developed by members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Juvenile Dermatomyositis Workgroup through a consensus process and administered to patients and families through the CureJM Foundation and to healthcare professionals through CARRA. The survey asked respondents to rate the importance of 19 items related to aspects of high quality care, using a Likert scale. Results Patients and families gave generally higher scores for importance to most of the quality measurement themes compared with healthcare professionals, with ratings of 13 of the 19 measures reaching statistical significance (p

The lipid component of the outer leaflet of the outer membrane of Gram-negative bacteria is primarily composed of the glycolipid lipopolysaccharide (LPS), which serves to form a protective barrier against hydrophobic toxins and many antibiotics. LPS is comprised of three regions: the lipid A membrane anchor, the nonrepeating core oligosaccharide, and the repeating O-antigen polysaccharide. The lipid A portion is also referred to as endotoxin as its overstimulation of the toll-like receptor 4 during systemic infection precipitates potentially fatal septic shock. Because of the importance of LPS for the viability and virulence of human pathogens, understanding how LPS is synthesized and transported to the outer leaflet of the outer membrane is important for developing novel antibiotics to combat resistant Gram-negative strains. The following review describes the current state of our understanding of the proteins responsible for the synthesis and transport of LPS with an emphasis on the contribution of protein structures to our understanding of their functions. Because the lipid A portion of LPS is relatively well conserved, a detailed description of the biosynthetic enzymes in the Raetz pathway of lipid A synthesis is provided. Conversely, less well-conserved biosynthetic enzymes later in LPS synthesis are described primarily to demonstrate conserved principles of LPS synthesis. Finally, the conserved LPS transport systems are described in detail.

We report a case of extramedullary hematopoiesis (EMH) in uterine leiomyoma and associated numerous intravascular thrombi. A 29-year-old nulliparous female presented with heavy vaginal bleeding and a hematocrit of 22%. No bone marrow biopsy has been performed. She had a history of uterine leiomyomata and menorrhagia for a year. A transvaginal ultrasound confirmed the presence of a uterine leiomyoma. The patient was treated conservatively with oral contraceptive pills due to desire for fertility. However, she continued to have heavy vaginal bleeding and developed bilateral upper extremity deep vein thrombosis and multiple superficial vein thromboses after two months. An exploratory laparotomy with uterine myomectomy was performed. Gross examination of the specimen revealed a single nodular mass measuring 10.0×9.5×7.5 cm with a white-tan swirling cut surface. Microscopic examination revealed benign smooth muscle consistent with leiomyoma and numerous intravascular thrombi both with areas of EMH. Immunohistochemical stains confirmed the presence of all three benign lineages of hematopoietic cells. Occurrence of EMH in uterine leiomyoma and intravascular thrombi is very rare. It may be related to systemic hematopoietic stimulation due to severe chronic anemia and local presence of hematopoietic growth factors and/or cytokines.

Cognitive deficits have an important role in the neurodevelopment of schizophrenia and other psychotic disorders. However, there is a continuing debate as to whether cognitive impairments in the psychosis prodrome are stable predictors of eventual psychosis or undergo a decline due to the onset of psychosis. In the present study, to determine how cognition changes as illness emerges, we examined baseline neurocognitive performance in a large sample of helping-seeking youth ranging in clinical state from low-risk for psychosis through individuals at clinical high-risk (CHR) for illness to early first-episode patients (EFEP). At baseline, the MATRICS Cognitive Consensus battery was administered to 322 individuals (205 CHRs, 28 EFEPs, and 89 help-seeking controls, HSC) that were part of the larger Early Detection, Intervention and Prevention of Psychosis Program study. CHR individuals were further divided into those who did (CHR-T; n = 12, 6.8%) and did not (CHR-NT, n = 163) convert to psychosis over follow-up (Mean = 99.20 weeks, SD = 21.54). ANCOVAs revealed that there were significant overall group differences (CHR, EFEP, HSC) in processing speed, verbal learning, and overall neurocognition, relative to healthy controls (CNTL). In addition, the CHR-NTs performed similarly to the HSC group, with mild to moderate cognitive deficits relative to the CTRL group. The CHR-Ts mirrored the EFEP group, with large deficits in processing speed, working memory, attention/vigilance, and verbal learning (>1 SD below CNTLs). Interestingly, only verbal learning impairments predicted transition to psychosis, when adjusting for age, education, symptoms, antipsychotic medication, and neurocognitive performance in the other domains. Our findings suggest that large neurocognitive deficits are present prior to illness onset and represent vulnerability markers for psychosis. The results of this study further reinforce that verbal learning should be specifically targeted for preventive intervention for psychosis.

IntroductionPsychological well-being (PWB) is an important component of positive mental health (PMH) and an asset for population health. This study examined correlates of PWB among community-dwelling adults (18+ years) in the 10 Canadian provinces. MethodsUsing data from the 2019 Canadian Community Health Survey Rapid Response on PMH, we conducted linear regression analyses with sociodemographic, mental health, physical health and substance use variables as predictors of PWB. PWB was measured using six questions from the Mental Health Continuum—Short Form, which asked about feelings of self-acceptance, personal growth, environmental mastery, autonomy, positive relations and purpose in life during the past month. ResultsIn unadjusted and adjusted analyses, older age, being married or in a commonlaw relationship and having a BMI in the overweight category (25.00–29.99) were associated with higher PWB, while reporting a mood disorder, anxiety disorder, high perceived life stress, engaging in heavy episodic drinking and frequent cannabis use were associated with lower PWB. Sex, having children living at home, immigrant status, racialized group membership, educational attainment, household income tertile, having a BMI in the obese category (≥30.00), major chronic disease and smoking status were not significantly associated with PWB. ConclusionThis research identifies sociodemographic, mental health, physical health and substance use factors associated with PWB among adults in Canada. These findings highlight groups and characteristics that could be the focus of future research to promote PMH.

IntroductionLe bien-être psychologique est une composante importante de la santé mentale positive et un atout qui favorise la santé de la population. Notre étude a permis d’analyser les corrélats du bien-être psychologique chez les adultes (18 ans et plus) vivant dans la collectivité dans les 10 provinces canadiennes. MéthodologieÀ l’aide des données de l’Enquête sur la santé dans les collectivités canadiennes – Composante de réponse rapide sur la santé mentale positive de 2019, nous avons effectué des analyses de régression linéaire dans lesquelles diverses variables relatives aux caractéristiques sociodémographiques, à la santé mentale, à la santé physique et à la consommation de substances ont été étudiées en tant que prédicteurs du bien-être psychologique. Le bien-être psychologique a été mesuré en fonction de six questions du Continuum de santé mentale – Questionnaire abrégé. Celles-ci évaluaient les perceptions des répondants, pour le mois précédant l’enquête, en lien avec l’acceptation de soi, l’épanouissement personnel, la maîtrise de l’environnement, l’autonomie, les rapports positifs avec les autres et le but dans la vie. RésultatsDans les analyses de régression linéaire simple et de régression linéaire multiple, un âge plus avancé, le fait d’être marié ou de vivre en union libre et le fait d’avoir un IMC correspondant à un excès de poids (25,00 à 29,99) ont été associés à un bienêtre psychologique supérieur, tandis que les facteurs associés à un bien-être psychologique inférieur ont été la présence signalée d’un trouble de l’humeur ou d’un trouble d’anxiété, un haut degré de stress perçu dans la vie, une forte consommation épisodique d’alcool et une consommation fréquente de cannabis. Il n’y a eu aucune association significative entre le bien-être psychologique et le sexe, le fait d’avoir des enfants à la maison, le statut vis-à-vis de l’immigration, l’appartenance à un groupe racisé, le niveau de scolarité, le tertile de revenu du ménage, le fait d’avoir un IMC dans la catégorie de l’obésité (≥ 30,00), les maladies chroniques majeures et le tabagisme. ConclusionCette recherche révèle les caractéristiques sociodémographiques et les facteurs relatifs à la santé mentale, à la santé physique et à la consommation de substances qui sont associés au bien-être psychologique chez les adultes au Canada. Les constats qu’elle a permis de dégager mettent en évidence les groupes et les caractéristiques qui pourraient faire l’objet de recherches futures dans l’objectif de promouvoir le bien-être psychologique.

Abstract Perinatal depression (PND) affects up to 20% of women and is associated with significant impairment and disability in affected women. In addition, perinatal depression is associated with broader public health and multigenerational consequences. Innovative approaches are needed to reduce the burden of perinatal depression through identification, tracking, and treatment of depressive symptoms during the perinatal period. This study is a randomized clinical trial comparing the relative efficacy of a multi-tiered system of care, Screening and Treatment of Anxiety and Depression (STAND) to perinatal care delivered by a reproductive psychiatrist in reducing symptoms of depression and anxiety. A sample of 167 individuals was randomized between week 28 of pregnancy and 6 months postpartum. A secondary aim compares the original online therapy intervention used in the first half of the study to a newer online therapy program used in the second half of the study for individuals assigned to the STAND treatment. The study measures, intervention groups, and analysis methods are described, as well as expected implications. The findings from this study may improve the methods for tracking symptom changes over time, monitoring treatment response, and providing personalized care for individuals with PND. As such, this study may improve the lives of patients with PND and their families and lower the related health care costs to society. Trial registration NCT: 9/24/2021 NCT direct link: https://www.clinicaltrials.gov/study/NCT05056454?term=NCT05056454&rank=1&a=1 .

Abstract Hypertension remains a leading cause of cardiovascular and kidney diseases. Failure to control blood pressure with ≥ 3 medications or control requiring ≥ 4 medications is classified as resistant hypertension (rHTN) and new therapies are needed to reduce the resulting increased risk of morbidity and mortality. Here, we report genetic evidence that relaxin family peptide receptor 2 (RXFP2) is associated with rHTN in men, but not in women. This study shows that adrenal gland gene expression of RXFP2 is increased in men with hypertension and the RXFP2 natural ligand, INSL3, increases adrenal steroidogenesis and corticosteroid secretion in human adrenal cells. To address the hypothesis that RXFP2 activation is an important mechanism in rHTN, we discovered and characterized small molecule and monoclonal antibody (mAb) blockers of RXFP2. The novel chemical entities and mAbs show potent, selective inhibition of RXFP2 and reduce aldosterone and cortisol synthesis and release. The RXFP2 mAbs have suitable rat pharmacokinetic profiles to evaluate the role of RXFP2 in the development and maintenance of rHTN. Overall, we identified RXFP2 activity as a potential new mechanism in rHTN and discovered RXFP2 antagonists for the future interrogation of RXFP2 in cardiovascular and renal diseases.

Objectives: To describe psychological symptoms in 8-12-year-old children with cerebral palsy; to investigate predictors of these symptoms and their impact on the child and family. Design: A cross-sectional multi-centre survey. Participants: Eight hundred and eighteen children with cerebral palsy, aged 8-12 years, identified from population-based registers of cerebral palsy in eight European regions and from multiple sources in one further region. Main outcome measures: The Strengths and Difficulties Questionnaire (SDQ)[superscript P4-16] and the Total Difficulties Score (TDS) dichotomised into normal/borderline (TDS less than or equal to 16) versus abnormal (TDS greater than 16). Statistical analysis: Multilevel, multivariable logistic regression to relate the presence of psychological symptoms to child and family characteristics. Results: About a quarter of the children had TDS greater than 16 indicating significant psychological symptoms, most commonly in the domain Peer Problems. Better gross motor function, poorer intellect, more pain, having a disabled or ill sibling and living in a town were independently associated with TDS greater than 16. The risk of TDS greater than 16 was odds ratio (OR) = 0.2 (95% CI: 0.1 to 0.3) comparing children with the most and least severe functional limitations; OR = 3.2 (95% CI: 2.1 to 4.8) comparing children with IQ less than 70 and others; OR = 2.7 (95% CI: 1.5 to 4.6) comparing children in severe pain and others; OR = 2.7 (95% CI:1.6 to 4.6) comparing children with another disabled sibling or OR = 1.8 (95% CI: 1.2 to 2.8) no siblings and others; OR = 1.8 (95% CI: 1.1 to 2.8) comparing children resident in a town and others. Among parents who reported their child to have psychological problems, 95% said they had lasted over a year, 37% said they distressed their child and 42% said they burdened the family at least "quite a lot". Conclusions: A significant proportion of children with cerebral palsy have psychological symptoms or social impairment sufficiently severe to warrant referral to specialist services. Care must be taken in the assessment and management of children with cerebral palsy to ensure psychological problems are not overlooked and potentially preventable risk factors like pain are treated effectively. The validity of the SDQ for children with severe disability warrants further assessment.

BackgroundIn the United States, innovation is needed to address the increasing need for mental health care services and widen the patient-to-provider ratio. Despite the benefits of digital mental health interventions (DMHIs), they have not been effective in addressing patients’ behavioral health challenges as stand-alone treatments. ObjectiveThis study evaluates the implementation and effectiveness of precision behavioral health (PBH), a digital-first behavioral health care model embedded within routine primary care that refers patients to an ecosystem of evidence-based DMHIs with strategically placed human support. MethodsPatient demographic information, triage visit outcomes, multidimensional patient-reported outcome measure, enrollment, and engagement with the DMHIs were analyzed using data from the electronic health record and vendor-reported data files. The RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework was used to evaluate the implementation and clinical effectiveness outcomes of PBH. ResultsPBH had a 47.58% reach rate, defined as patients accepting the PBH referral from their behavioral health integrated clinician. PBH patients had high DMHI registration rates (79.62%), high activation rates (76.54%), and high retention rates at 15 days (57.69%) and 30 days (44.58%) compared to literature benchmarks. In total, 74.01% (n=168) of patients showed clinical improvement, 22.47% (n=51) showed no clinical change, and 3.52% (n=8) showed clinical deterioration in symptoms. PBH had high adoption rates, with behavioral health integrated clinicians referring on average 4.35 (SD 0.46) patients to PBH per month and 90%-100% of clinicians (n=12) consistently referring at least 1 patient to PBH each month. A third (32%, n=1114) of patients were offered PBH as a treatment option during their triage visit. ConclusionsPBH as a care model with evidence-based DMHIs, human support for patients, and integration within routine settings offers a credible service to support patients with mild to moderate mental health challenges. This type of model has the potential to address real-life access to care problems faced by health care settings.

IntroductionThe objective of this analysis is to describe patient demographics, the context, characteristics and outcomes of a substance-related poisoning, and the recorded mental disorder of people with housing and those experiencing homelessness. MethodsHospitalization data for Canada (except Quebec) from 1 April 2019 to 31 March 2020 were retrieved from the Canadian Institute for Health Information (CIHI) Discharge Abstract Database using ICD-10-CA codes for up to 25 diagnoses for substance-related poisonings, homelessness status and other characteristics relevant to the patient’s hospitalization. We compared the characteristics of people experiencing homelessness with those of people who were housed, and their substance-related poisoning hospitalizations, using chi-square, t tests and Fisher exact test. ResultsThere was a higher proportion of males, younger individuals and people with recorded mental disorders among people experiencing homelessness hospitalized for a substance-related poisoning than among their housed counterparts. Substance-related poisonings among people experiencing homelessness were more likely to be accidental, involve opioids and stimulants (most frequently fentanyl and its analogues and heroin), result in lengthier hospitalizations and end with leaving the hospital against medical advice. ConclusionThese findings can be used to strengthen strategies and interventions to reduce substance-related harms in priority populations, particularly those experiencing homelessness.