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Objective: Our objectives were to quantify the relationships among fatigue, pain interference, and physical disability in children with juvenile idiopathic arthritis (JIA) and to test whether fatigue mediates the relationship between pain interference and physical disability in JIA. Methods: Patients enrolled within three months of JIA diagnosis in the Canadian Alliance of Pediatric Rheumatology Investigators (CAPRI) Registry between February 2017 and May 2023 were included. Their parents completed the Patient‐Reported Outcomes Measurement Information System fatigue and pain interference short proxy questionnaires and the Childhood Health Assessment Questionnaire disability index at registry enrollment. Associations were assessed using Pearson correlations and multiple linear regression. Structural equation modeling (SEM) was used to test if fatigue mediates the relationship between pain interference and physical disability. Results: Among 855 patients (61.4% female, 44.1% with oligoarthritis), most reported fatigue and pain interference scores similar to those in the reference population, but 15.6% reported severe fatigue and 7.3% reported severe pain interference, with wide variation across JIA categories. Fatigue was strongly correlated with pain interference (r = 0.72, P < 0.001) and with physical disability (r = 0.60, P < 0.001). Pain interference (β = 0.027, P < 0.001) and fatigue (β = 0.013, P < 0.001) were both associated with physical disability after controlling for each other and potential confounders. SEM supported our hypothesis that fatigue partially mediates the relationship between pain interference and physical disability. Conclusion: Our findings suggest both fatigue and pain interference are independently associated with physical disability in children newly diagnosed with JIA, and the effect of pain interference may be partly mediated by fatigue. [ABSTRACT FROM AUTHOR]

Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease.sup.1. Yet, whether this change contributes to Parkinson's disease pathogenesis is unclear.sup.2. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism--which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson's disease paradigm.sup.3,4. Dysfunction of mitochondrial complex I in mice is sufficient to cause progressive parkinsonism in which the loss of nigral dopamine release critically contributes to motor dysfunction., Author(s): Patricia González-Rodríguez [sup.1] , Enrico Zampese [sup.1] , Kristen A. Stout [sup.1] , Jaime N. Guzman [sup.1] , Ema Ilijic [sup.1] , Ben Yang [sup.1] , Tatiana Tkatch [sup.1] [...]

The ability of the Cav1 channel inhibitor isradipine to slow the loss of substantia nigra pars compacta (SNc) dopaminergic (DA) neurons and the progression of Parkinson's disease (PD) is being tested in a phase 3 human clinical trial. But it is unclear whether and how chronic isradipine treatment will benefit SNc DA neurons in vivo. To pursue this question, isradipine was given systemically to mice at doses that achieved low nanomolar concentrations in plasma, near those achieved in patients. This treatment diminished cytosolic [Ca.sup.2+] oscillations in SNc DA neurons without altering autonomous spiking or expression of [Ca.sup.2+] channels, an effect mimicked by selectively knocking down expression of Cav1.3 channel subunits. Treatment also lowered mitochondrial oxidant stress, reduced a high basal rate of mitophagy, and normalized mitochondrial mass--demonstrating that Cav1 channels drive mitochondrial oxidant stress and turnover in vivo. Thus, chronic isradipine treatment remodeled SNc DA neurons in a way that should not only diminish their vulnerability to mitochondrial challenges, but to autophagic stress as well., Introduction The loss of substantia nigra pars compacta (SNc) dopaminergic (DA) neurons is a defining feature of Parkinson's disease (PD) and is responsible for the core motor symptoms of the [...]

Introduction: Medical clearance for patients with primary psychiatric complaints presenting to the emergency department has been debated for decades. Emergency physicians have argued that clearance labs are unnecessary, yet psychiatrists may still order or require them. A retrospective review was conducted to evaluate the continued need for labs of psychiatric patients and help identify high risk groups that may need additional intervention prior to medical clearance. Methods: Charts of 163 patients from Ochsner LSU Shreveport Psychiatric Crisis Unit (PCU) were reviewed with data collected of history, physical examination, review of systems, vitals and routine lab work including complete blood count (CBC), comprehensive metabolic panel (CMP), urine drug screen (UDS), serum ethanol level (EtOH), urinalysis (UA), creatine kinase (CK), urine pregnancy test (UPT), and rapid COVID-19. Results: Review identified 82 patients (50.3%) that received interventions prior to medical clearance. Most common intervention was intravenous (IV) fluids (n = 59; 45%) followed by admission to other service (n = 15; 8.4%), imaging (n = 10; 7.6%), antihypertensive medication (n = 3; 3.1%), cardiac workup (n = 3; 2.3%), antibiotics (n = 3; 2.3%), lorazepam for undocumented reasons (n = 2; 1.5%). Additional interventions completed once included immunizations, antiseizure medication, pain medication, and additional lab work. Causes for IV fluids were reviewed with elevated creatine kinase (CK) (n = 31; 50.8%) being most common. Additional causes included undocumented (n = 12; 19.7%), tachycardia (n = 6; 9.8%), elevated EtOH level (n = 3; 4.9%), dehydration (n = 2; 3.3%), acute kidney injury (AKI) (n = 2; 3.3%), leukocytosis following a seizure (n = 1; 1.6%), elevated CK and leukocytosis (n = 1; 1.6%), and AKI and elevated CK (n = 1; 1.6%). Most common cause for medical admission was elevated CK being cited in 8 out of 15 admissions (53.3%). Additional causes for admission included AKI (n = 2; 14.3%), seizures and leukocytosis (n = 1; 6.7%), rule out of acute coronary syndrome (ACS) (n = 1; 6.7%), alcohol withdrawal (n = 1; 6.7%), encephalopathy with drop in hemoglobin and white blood cell count (n = 1; 6.7%), and encephalopathy with elevated CK (n = 1; 6.7%). Discussion: Our results support the recommended guidelines set by AAEP for laboratory testing in addition to history, vital signs and physical examination prior to medical clearance. Certain laboratory testing such as CK and CMP were identified to have higher utility for medical intervention while other lab work such as UA and UDS had less of an impact. Further, we suggest that specifically a CK and CMP be obtained on patients presenting with any of the following: agitation, abnormal vital signs, intoxication, or a history of or current stimulant use as these were factors correlated with lab abnormalities that led to interventions. [ABSTRACT FROM AUTHOR]

Objective To identify differences between baseline Canadian JIA practices and the 2019 ACR guidelines for JIA. Methods Canadian paediatric rheumatologists were surveyed for their opinions on reasonable a priori target adherence rates for JIA guideline recommendations. Prospectively collected data for 266 newly diagnosed children from 2017 to 2019 were analysed to calculate observed adherence rates. Kaplan–Meier survival curves were used to estimate the cumulative incidence of starting synthetic or biologic DMARDs (sDMARD or bDMARD, respectively) for different patient groups. Results A total of 25/61 (41%) eligible physicians answered the survey. Most survey respondents (64%) felt that adherence targets should vary depending on the strength of the recommendation and quality of evidence, from a mean of 84% for strong recommendations with high-quality evidence to 29% for conditional recommendations with very low-quality evidence. Data showed 13/19 (68%) recommendations would have met proposed targets and 10/19 (53%) had ≥80% observed adherence. Exceptions were the use of subcutaneous vs oral MTX (53%) and infrequent treatment escalation from NSAIDs to bDMARDs in patients with sacroiliitis (31%) or enthesitis (0%). By 12 weeks, 95% of patients with polyarthritis received sDMARDs, 38% of patients with systemic JIA received bDMARDs and 22% of patients with sacroiliitis received bDMARDs. Conclusion Canadian paediatric rheumatology practices were in line with many 2019 JIA guideline recommendations before their publication, except for frequent use of oral MTX and infrequent direct escalation from NSAIDs to bDMARDs in sacroiliitis and enthesitis. [ABSTRACT FROM AUTHOR]

Objectives To (i) validate the JIA parent global assessment (parent global) as a health-related quality of life (HRQoL) instrument; (ii) evaluate measurement properties of accepted HRQoL measures relative to those of the parent global; and (iii) assess causal pathways determining parent global scores. Methods Data from the Research in Arthritis in Canadian Children emphasizing outcomes (ReACCh-Out) cohort were used. Measurement properties were assessed in 344 patients at enrolment and 6 months later. Causal pathways were tested by structural equation modelling to understand root causes and mediators leading to parent global scores. Results Construct validity was supported by Spearman correlations of 0.53–0.70 for the parent global with the Juvenile Arthritis Quality of Life Questionnaire, Quality of My Life health scale (HRQoML), Pediatric Quality of Life Inventory (PedsQL)-Parent, and Child Health Questionnaire (CHQ)-Physical. Exceptions were PedsQL-Child (0.44) and CHQ-Psychosocial (0.31). Correlations were lower (0.14–0.49) with disease activity measures (physician global assessment of disease activity, active joint count, ESR). Responsiveness of the parent global to improvement according to parent ratings (0.51) was acceptable and within the range (0.32–0.71) of that of other measures. Reliability estimates and measurement errors for all measures were unsatisfactory, likely due to the prolonged time between assessments. Causal pathways for the parent global matched those previously reported for HRQoML. Conclusions Our results offer support for the parent global as a valid measure of HRQoL for JIA. If confirmed, existing studies using the parent global may be re-interpreted, enhancing our knowledge of HRQoL in children with JIA. [ABSTRACT FROM AUTHOR]

Objective: The aim of the Paediatric Rheumatology International Trials Organisation (PRINTO) juvenile idiopathic arthritis (JIA) classification criteria, which is still in development, is to identify homogeneous groups of JIA patients. This study was undertaken to compare International League of Associations for Rheumatology (ILAR) JIA classification criteria and PRINTO JIA classification criteria using data from the ReACCh‐Out (Research in Arthritis in Canadian Children, Emphasizing Outcomes) cohort. Methods: We used clinicobiologic data recorded within 7 months of diagnosis to assign a diagnosis of JIA and identify subcategories of JIA among 1,228 patients according to the 2 JIA classification systems. We compared the proportions of patients classified and the alignment of classification categories with clinicobiologic subtypes and adult arthritis types. Results: The PRINTO criteria classified 244 patients (19.9%) as having early‐onset antinuclear antibody–positive JIA, 157 (12.8%) as having enthesitis/spondylitis–related JIA, 38 (3.1%) as having systemic JIA, and 10 (0.8%) as having rheumatoid factor–positive JIA. A total of 12% of patients were unclassifiable using the ILAR criteria, while 63.3% were unclassifiable using the PRINTO criteria (777 with other JIA and 2 with unclassified JIA). In sensitivity analyses, >50% of patients remained unclassifiable using the PRINTO criteria. Compared to the PRINTO criteria, ILAR JIA categories aligned better with clinicobiologic subtypes in 131 patients (χ2 = 44, P = 0.005, versus χ2 = 15, P = 0.07 for PRINTO), and ILAR categories aligned better with adult types of arthritis in 389 evaluable patients. Conclusion: Currently identified PRINTO disorders can only be used to classify a minority of JIA patients, leaving a large proportion of JIA patients with other disorders requiring further characterization. Current PRINTO JIA classification criteria do not align better with clinicobiologic subtypes or adult forms of arthritis compared with the older ILAR classification system. [ABSTRACT FROM AUTHOR]

Parkinson's disease is a pervasive, ageing-related neurodegenerative disease the cardinal motor symptoms of which reflect the loss of a small group of neurons, the dopaminergic neurons in the substantia nigra pars compacta (1) (SNc). Mitochondrial oxidant stress is widely viewed as being responsible for this loss (2), but why these particular neurons should be stressed is a mystery. Here we show, using transgenic mice that expressed a redox-sensitive variant of green fluorescent protein targeted to the mitochondrial matrix, that the engagement of plasma membrane L-type calcium channels during normal autonomous pacemaking created an oxidant stress that was specific to vulnerable SNc dopaminergic neurons. The oxidant stress engaged defences that induced transient, mild mitochondrial depolarization or uncoupling. The mild uncoupling was not affected by deletion of cyclophilin D, which is a component of the permeability transition pore, but was attenuated by genipin and purine nucleotides, which are antagonists of cloned uncoupling proteins. Knocking out DJ-1 (also known as PARK7 in humans and Park7 in mice), which is a gene associated with an early-onset form of Parkinson's disease, downregulated the expression of two uncoupling proteins (UCP4 (SLC25A27) and UCP5 (SLC25A14)), compromised calcium-induced uncoupling and increased oxidation of matrix proteins specifically in SNc dopaminergic neurons. Because drugs approved for human use can antagonize calcium entry through L-type channels, these results point to a novel neuroprotective strategy for both idiopathic and familial forms of Parkinson's disease., Calcium entry through L-type channels in SNc dopaminergic neurons occurs throughout the pacemaking cycle (3,4), contrasting them with neighbouring dopaminergic neurons in the ventral tegmental area (VTA), which are much [...]

Objective The COVID-19 pandemic has disrupted healthcare delivery and clinical research worldwide, with data from areas most affected demonstrating an impact on rheumatology care. This study aimed to characterize the impact of the pandemic on the initial presentation of JIA and JIA-related research in Canada. Methods Data collected from the Canadian Alliance of Pediatric Rheumatology Investigators JIA Registry from the year pre-pandemic (11 March 2019 to 10 March 2020) was compared with data collected during the first year of the pandemic (11 March 2020 to 10 March 2021). Outcomes included time from symptom onset to first assessment, disease severity at presentation and registry recruitment. Proportions and medians were used to describe categorical and continuous variables, respectively. Results The median time from symptom onset to first assessment was 138 (IQR 64–365) days pre-pandemic vs 146 (IQR 83–359) days during the pandemic. The JIA category frequencies remained overall stable (44% oligoarticular JIA pre-pandemic, 46.8% pandemic), except for systemic JIA (12 cases pre-pandemic, 1 pandemic). Clinical features, disease activity (cJADAS10), disability (CHAQ) and quality of life (JAQQ) scores were similar between the two cohorts. Pre-pandemic, 225 patients were enrolled, compared with 111 in the pandemic year, with the greatest decrease from March to June 2020. Conclusions We did not observe the anticipated delay in time to presentation or increased severity at presentation, suggesting that, within Canada, care adapted well to provide support to new patient consults without negative impacts. The COVID-19 pandemic was associated with an initial 50% decrease in registry enrolment but has since improved. [ABSTRACT FROM AUTHOR]

An increase in humanitarian challenges has resulted in an increased demand for mental health resources. Social psychiatrists face a clinical and moral imperative to study and treat mental disorders precipitated or impacted by sociocultural events. Immigration detention is but one example of a setting that can take a toll on the mental health of those detained. Psychiatrists working in detention settings do not have immunity from feeling overwhelmed and may suffer the effects of moral distress. Many question how to take action beyond direct clinical care. Here we present a case study on physician action to address the humanitarian crisis of family separation and family detention of immigrants at the US. Southern border. Subject matter and advisory committee experts for the US Department of Homeland Security were recruited to identify concerns and provide recommendations in this guide for action. [ABSTRACT FROM AUTHOR]