Genome-wide meta-analysis of short-tandem repeats for Parkinson's disease risk using genotype imputation.

Idiopathic Parkinson's disease is determined by a combination of genetic and environmental factors. Recently, the first genome-wide association study on short-tandem repeats in Parkinson's disease reported on eight suggestive short-tandem repeat-based risk loci (α = 5.3 × 10-6), of which four were novel, i.e. they had not been implicated in Parkinson's disease risk by genome-wide association analyses of single-nucleotide polymorphisms before. Here, we tested these eight candidate short-tandem repeats in a large, independent Parkinson's disease case-control dataset (n = 4757). Furthermore, we combined the results from both studies by meta-analysis resulting in the largest Parkinson's disease genome-wide association study of short-tandem repeats to date (n = 43 844). Lastly, we investigated whether leading short-tandem repeat risk variants exert functional effects on gene expression regulation based on methylation quantitative trait locus data in human 'post-mortem' brain (n = 142). None of the eight previously reported short-tandem repeats were significantly associated with Parkinson's disease in our independent dataset after multiple testing correction (α = 6.25 × 10-3). However, we observed modest support for short-tandem repeats near CCAR2 and NCOR1 in the updated meta-analyses of all available data. While the genome-wide meta-analysis did not reveal additional study-wide significant (α = 6.3 × 10-7) short-tandem repeat signals, we identified seven novel suggestive Parkinson's disease short-tandem repeat risk loci (α = 5.3 × 10-6). Of these, especially a short-tandem repeat near MEIOSIN showed consistent evidence for association across datasets. CCAR2, NCOR1 and one novel suggestive locus identified here (LINC01012) emerged from colocalization analyses showing evidence for a shared causal short-tandem repeat variant affecting both Parkinson's disease risk and cis DNA methylation in brain. Larger studies, ideally using short-tandem repeats called from whole-sequencing data, are needed to more fully investigate their role in Parkinson's disease.

Adherence to practice parameters in Medicare beneficiaries with amyotrophic lateral sclerosis.

OBJECTIVE: Physician adherence to evidence-based clinical practice parameters impacts outcomes of amyotrophic lateral sclerosis (ALS) patients. We sought to investigate compliance with the 2009 practice parameters for treatment of ALS patients in the United States, and sociodemographic and provider characteristics associated with adherence. METHODS: In this population-based, retrospective cohort study of incident ALS patients in 2009-2014, we included all Medicare beneficiaries age ≥20 with ≥1 International Classification of Diseases, Ninth Revision, Clinical Modification ALS code (335.20) in 2009 and no prior years (N = 8,575). Variables of interest included race/ethnicity, sex, age, urban residence, Area Deprivation Index (ADI), and provider specialty (neurologist vs. non-neurologist). Outcomes were use of practice parameters, which included feeding tubes, non-invasive ventilation (NIV), riluzole, and receiving care from a neurologist. RESULTS: Overall, 42.9% of patients with ALS received neurologist care. Black beneficiaries (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.47-0.67), older beneficiaries (OR 0.964, 95% CI 0.961-0.968 per year), and those living in disadvantaged areas (OR 0.70, 95% CI 0.61-0.80) received less care from neurologists. Overall, only 26.7% of beneficiaries received a feeding tube, 19.2% NIV, and 15.3% riluzole. Neurologist-treated patients were more likely to receive interventions than other ALS patients: feeding tube (OR 2.80, 95% CI 2.52-3.11); NIV (OR 10.8, 95% CI 9.28-12.6); and riluzole (OR 7.67, 95% CI 6.13-9.58), after adjusting for sociodemographics. These associations remained marked and significant when we excluded ALS patients who subsequently received a code for other diseases that mimic ALS. CONCLUSIONS: ALS patients treated by neurologists received care consistent with practice parameters more often than those not treated by a neurologist. Black, older, and disadvantaged beneficiaries received less care consistent with the practice parameters.

Olfactory tract/bulb metal concentration in Manganese-exposed mineworkers.

BACKGROUND: Manganese (Mn) is an essential micronutrient as well as a well-established neurotoxicant. Occupational and environmental exposures may bypass homeostatic regulation and lead to increased systemic Mn levels. Translocation of ultrafine ambient airborne particles via nasal neuronal pathway to olfactory bulb and tract may be an important pathway by which Mn enters the central nervous system. OBJECTIVE: To measure olfactory tract/bulb tissue metal concentrations in Mn-exposed and non-exposed mineworkers. METHODS: Using inductively coupled plasma-mass spectrometry (ICP-MS), we measured and compared tissue metal concentrations in unilateral olfactory tracts/bulbs of 24 Mn-exposed and 17 non-exposed South African mineworkers. We used linear regression to investigate the association between cumulative Mn exposures and olfactory tract/bulb Mn concentration. RESULTS: The difference in mean olfactory tract/bulb Mn concentrations between Mn-exposed and non-Mn exposed mineworkers was 0.16 µg/g (95% CI -0.11, 0.42); but decreased to 0.09 µg/g (95% CI 0.004, 0.18) after exclusion of one influential observation. Olfactory tract/bulb metal concentration and cumulative Mn exposure suggested there may be a positive association; for each mg Mn/m3-year there was a 0.05 µg/g (95% CI 0.01, 0.08) greater olfactory tract/bulb Mn concentration overall, but -0.003 (95% CI -0.02, 0.02) when excluding the three influential observations. Recency of Mn exposure was not associated with olfactory tract/bulb Mn concentration. CONCLUSIONS: Our findings suggest that Mn-exposed mineworkers might have higher olfactory tract/bulb tissue Mn concentrations than non-Mn exposed mineworkers, and that concentrations might depend more on cumulative dose than recency of exposure.

Fine Particulate Matter and Parkinson Disease Risk Among Medicare Beneficiaries.

BACKGROUND AND OBJECTIVES: Numerous studies suggest that environmental exposures play a critical role in Parkinson disease (PD) pathogenesis, and large, population-based studies have the potential to advance substantially the identification of novel PD risk factors. We sought to study the nationwide geographic relationship between PD and air pollution, specifically PM2.5 (particulate matter with a diameter <2.5 micrometers), using population-based US Medicare data. METHODS: We conducted a population-based geographic study of Medicare beneficiaries aged 66-90 years geocoded to US counties and zip+4. We used integrated nested Laplace approximation to create age, sex, race, smoking, and health care utilization-adjusted relative risk (RR) at the county level for geographic analyses with PM2.5 as the primary exposure of interest. We also performed an individual-level analysis using logistic regression with cases and controls with zip+4 centroid PM2.5. We adjusted a priori for the same covariates and verified no confounding by indicators of socioeconomic status or neurologist density. RESULTS: Among 21,639,190 Medicare beneficiaries, 89,390 had incident PD in 2009. There was a nationwide association between average annual PM2.5 and PD risk whereby the RR of PD was 56% (95% CI 47%-66%) greater for those exposed to the median level of PM2.5 compared with those with the lowest level of PM2.5. This association was linear up to 13 µg/m3 corresponding to a 4.2% (95% CI 3.7%-4.8%) greater risk of PD for each additional µg/m3 of PM2.5 (p trend < 0.0001). We identified a region with high PD risk in the Mississippi-Ohio River Valley, where the risk of PD was 19% greater compared with the rest of the nation. The strongest association between PM2.5 and PD was found in a region with low PD risk in the Rocky Mountains. PM2.5 was also associated with PD in the Mississippi-Ohio River Valley where the association was relatively weaker, due to a possible ceiling effect at average annual PM2.5 levels of ∼13 µg/m3. DISCUSSION: State-of-the-art geographic analytic techniques revealed an association between PM2.5 and PD that varied in strength by region. A deeper investigation into the specific subfractions of PM2.5 may provide additional insight into regional variability in the PM2.5-PD association.

Application and performance of disease activity indices proposed for patients with systemic sclerosis in an international cohort of patients with juvenile systemic sclerosis.

Objectives: Juvenile systemic sclerosis is a rare childhood disease. Three disease activity indices have been published for adult patients with systemic sclerosis: the European Scleroderma Study Group Index, a modified version of the European Scleroderma Study Group Index and the revised European Scleroderma Trials and Research index. The objective of this study was to determine the feasibility and performance of the three disease activity indices in a prospectively followed cohort of patients with juvenile systemic sclerosis. Methods: The analysis cohort was selected from the prospective international inception cohort enrolling juvenile systemic sclerosis patients. The correlation of the disease activity indices with the physicians' and the patients' global assessment of disease activity was determined. The disease activity indices were compared between patients with active and inactive disease. Sensitivity to change between 6- and 12-month follow-up was investigated by mixed models. Results: Eighty percent of the 70 patients had a diffuse cutaneous subtype. The revised European Scleroderma Trials and Research index was highly correlated with the physician-reported global disease activity/parents-reported global disease activity (r = 0.74/0.64), followed by the European Scleroderma Study Group activity index (r = 0.61/0.55) and the modified version of the European Scleroderma Study Group activity index (r = 0.51/0.43). The disease activity indices significantly differed between active and inactive patients. The disease activity indices showed sensitivity to change between 6- and 12-month follow-up among patients who improved or worsened according to the physician-reported global disease activity and the parents-reported global disease activity. Conclusion: Overall, no disease activity score is superior to the other, and all three scores have limitations in the application in juvenile systemic sclerosis patients. Furthermore, research on the concept of disease activity and suitable scores to measure disease activity in patients with juvenile systemic sclerosis is necessary in future.

Gender differences in juvenile systemic sclerosis patients: Results from the international juvenile scleroderma inception cohort.

Objective: To compare organ involvement and disease severity between male and female patients with juvenile onset systemic sclerosis. Methods: Demographics, organ involvement, laboratory evaluation, patient-reported outcomes and physician assessment variables were compared between male and female juvenile onset systemic sclerosis patients enrolled in the prospective international juvenile systemic sclerosis cohort at their baseline visit and after 12 months. Results: One hundred and seventy-five juvenile onset systemic sclerosis patients were evaluated, 142 females and 33 males. Race, age of onset, disease duration, and disease subtypes (70% diffuse cutaneous) were similar between males and females. Active digital ulceration, very low body mass index, and tendon friction rubs were significantly more frequent in males. Physician global assessment of disease severity and digital ulcer activity was significantly higher in males. Composite pulmonary involvement was also more frequent in males, though not statistically significantly. After 12 months, they are the pattern of differences changed female patients had significantly more frequent pulmonary involvement. Conclusion: In this cohort, juvenile onset systemic sclerosis had a more severe course in males at baseline and but the pattern changed after 12 months. Some differences from adult findings persisted, there is no increased signal of pulmonary arterial hypertension or heart failure in male pediatric patients. While monitoring protocols of organ involvement in juvenile onset systemic sclerosis need to be identical for males and females.

Neuroinflammation and white matter alterations in occupational manganese exposure assessed by diffusion basis spectrum imaging.

OBJECTIVE: To evaluate in-vivo neuroinflammation and white matter (WM) microstructural integrity in occupational manganese (Mn) exposure. METHODS: We assessed brain inflammation using Diffusion Basis Spectrum Imaging (DBSI) in 26 Mn-exposed welders, 17 Mn-exposed workers, and 26 non-exposed participants. Cumulative Mn exposure was estimated from work histories and the Unified Parkinson's Disease Rating Scale motor subsection 3 (UPDRS3) scores were completed by a movement specialist. Tract-based Spatial Statistics allowed for whole-brain voxel-wise WM analyses to compare WM DBSI-derived measures between the Mn-exposed and non-exposed groups. Exploratory grey matter region of interest (ROI) analyses examined the presence of similar alterations in the basal ganglia. We used voxelwise general linear modeling and linear regression to evaluate the association between cumulative Mn exposure, WM or basal ganglia DBSI metrics, and UPDRS3 scores, while adjusting for age. RESULTS: Mn-exposed welders had higher DBSI-derived restricted fraction (DBSI-RF), higher DBSI-derived nonrestricted fraction (DBSI-NRF), and lower DBSI-derived fiber fraction (DBSI-FF) in multiple WM tracts (all p < 0.05) in comparison to less-exposed workers and non-exposed participants. Basal ganglia ROI analyses revealed higher average caudate DBSI-NRF and DBSI-derived radial diffusion (DBSI-RD) values in Mn-exposed welders relative to non-exposed participants (p < 0.05). Caudate DBSI-NRF was also associated with greater cumulative Mn exposure and higher UPRDS3 scores. CONCLUSIONS: Mn-exposed welders demonstrate greater DBSI-derived indicators of neuroinflammation-related cellularity (DBSI-RF), greater extracellular edema (DBSI-NRF), and lower apparent axonal density (DBSI-FF) in multiple WM tracts suggesting a neuroinflammatory component in the pathophysiology of Mn neurotoxicity. Caudate DBSI-NRF was positively associated with both cumulative Mn exposure and clinical parkinsonism, indicating a possible dose-dependent effect on extracellular edema with associated motor effects.

A predictive algorithm to identify ever smoking in medical claims-based epidemiologic studies.

PURPOSE: To develop and validate an algorithm to estimate probability of ever smoking using administrative claims. METHODS: Using population-based samples of Medicare-aged individuals (121,278 Behavioral Risk Factor Surveillance System survey respondents and 207,885 Medicare beneficiaries), we developed a logistic regression model to predict probability of ever smoking from demographic and claims data. We applied the model in 1,657,266 additional Medicare beneficiaries and calculated area under the receiver operating characteristic curve (AUC) using presence or absence of a tobacco-specific diagnosis or procedure code as our "gold standard." We used these "gold standard" and lung/laryngeal cancer codes to over-ride predicted probability as 100%. We calculated Spearman's rho between probability from this full algorithm and smoking assessed in prior Parkinson disease studies, by substituting our observed and prior ("true") smoking-Parkinson disease odds ratios into the attenuation equation. RESULTS: The predictive model contained 23 variables, including basic demographics, high alcohol consumption, asthma, cardiovascular disease and associated risk factors, selected cancers, and indicators of routine medical usage. The AUC was 67.6% (95% confidence interval 67.5%-67.7%) comparing smoking probability to tobacco-specific diagnosis or procedure codes. Spearman's rho for the full algorithm was 0.82. CONCLUSIONS: Ever smoking might be approximated in administrative data for use as a continuous, probabilistic variable in epidemiologic analyses.

Biologic targets of prescription medications and risk of neurodegenerative disease in United States Medicare beneficiaries.

OBJECTIVE: To identify prescription medications associated with a lower risk of three neurodegenerative diseases: Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis. METHODS: We conducted a population-based, case-control study of U.S. Medicare beneficiaries in 2009 (42,885 incident neurodegenerative disease cases, 334,387 randomly selected controls). Using medication data from 2006-2007, we categorized all filled medications according to their biological targets and mechanisms of action on those targets. We used multinomial logistic regression models, while accounting for demographics, indicators of smoking, and health care utilization, to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for 141 target-action pairs and each neurodegenerative disease. For target-action pairs inversely associated with all three diseases, we attempted replication in a cohort study that included an active comparator group. We constructed the cohort by following controls forward for incident neurodegenerative disease from the beginning of 2010 until death or end of 2014, i.e., up to five years after the two-year exposure lag. We used Cox proportional hazards regression while accounting for the same covariates. RESULTS: The most consistent inverse association across both studies and all three neurodegenerative diseases was for xanthine dehydrogenase/oxidase blockers, represented by the gout medication, allopurinol. Allopurinol was associated with a 13-34% lower risk for each neurodegenerative disease group in multinomial regression, and a mean reduction of 23% overall, as compared to individuals who did not use allopurinol. In the replication cohort we observed a significant 23% reduction for neurodegenerative disease in the fifth year of follow-up, when comparing allopurinol users to non-users, and more marked associations with an active comparator group. We observed parallel associations for a related target-action pair unique to carvedilol. DISCUSSION/CONCLUSION: Xanthine dehydrogenase/oxidase blockade might reduce risk of neurodegenerative disease. However, further research will be necessary to confirm that the associations related to this pathway are causal or to examine whether this mechanism slows progression.

Inflammatory Biomarkers Can Differentiate Acute Lymphoblastic Leukemia with Arthropathy from Juvenile Idiopathic Arthritis Better Than Standard Blood Tests.

OBJECTIVE: To evaluate the predictive value of biomarkers of inflammation like phagocyte-related S100 proteins and a panel of inflammatory cytokines in order to differentiate the child with acute lymphoblastic leukemia (ALL) from juvenile idiopathic arthritis (JIA). STUDY DESIGN: In this cross-sectional study, we measured S100A9, S100A12, and 14 cytokines in serum from children with ALL (n = 150, including 27 with arthropathy) and JIA (n = 236). We constructed predictive models computing areas under the curve (AUC) as well as predicted probabilities in order to differentiate ALL from JIA. Logistic regression was used for predictions of ALL risk, considering the markers as the respective exposures. We performed internal validation using repeated 10-fold cross-validation and recalibration, adjusted for age. RESULTS: In ALL, the levels of S100A9, S100A12, interleukin (IL)-1 beta, IL-4, IL-13, IL-17, matrix metalloproteinase-3, and myeloperoxidase were low compared with JIA (P < .001). IL-13 had an AUC of 100% (95% CI 100%-100%) due to no overlap between the serum levels in the 2 groups. Further, IL-4 and S100A9 had high predictive performance with AUCs of 99% (95% CI 97%-100%) and 98% (95% CI 94%-99%), respectively, exceeding both hemoglobin, platelets, C-reactive protein, and erythrocyte sedimentation rate. CONCLUSIONS: The biomarkers S100A9, IL-4, and IL-13 might be valuable markers to differentiate ALL from JIA.

Protective Effects of Lovastatin in a Population-Based ALS Study and Mouse Model.

OBJECTIVE: The objective of this study was to use a novel combined pharmacoepidemiologic and amyotrophic lateral sclerosis (ALS) mouse model approach to identify potential motor neuron protective medications. METHODS: We constructed a large, population-based case-control study to investigate motor neuron disease (MND) among US Medicare beneficiaries aged 66 to 90 in 2009. We included 1,128 incident MND cases and 56,400 age, sex, race, and ethnicity matched controls. We calculated MND relative risk for >1,000 active ingredients represented in Part D (pharmacy) claims in 2006 to 2007 (>1 year before diagnosis/reference). We then applied a comprehensive screening approach to select medications for testing in SOD1G93A mice: sulfasalazine, telmisartan, and lovastatin. We treated mice with the human dose equivalent of the medication or vehicle via subcutaneous osmotic pump before onset of weakness. We then assessed weight, gait, and survival. In additional mice, we conducted histological studies. RESULTS: We observed previously established medical associations for MND and an inverse dose-response association between lovastatin and MND, with 28% reduced risk at 40 mg/day. In SOD1G93A mouse studies, sulfasalazine and telmisartan conferred no benefit, whereas lovastatin treatment delayed onset and prolonged survival. Lovastatin treated mice also had less microgliosis, misfolded SOD1, and spinal motor neuron loss in the ventral horn. INTERPRETATION: Lovastatin reduced the risk of ALS in humans, which was confirmed in an ALS mouse model by delayed symptom onset, prolonged survival, and preservation of motor neurons. Although further studies to understand the mechanism are required, lovastatin may represent a potential neuroprotective therapy for patients with ALS. These data demonstrate the utility of a combined pharmacoepidemiologic and mouse model approach. ANN NEUROL 2023;93:881-892.

New and Updated Recommendations for the Treatment of Juvenile Idiopathic Arthritis-Associated Uveitis and Idiopathic Chronic Anterior Uveitis.

OBJECTIVE: The Multinational Interdisciplinary Working Group for Uveitis in Childhood identified the need to update the current guidelines, and the objective here was to produce this document to guide clinicians managing children with juvenile idiopathic arthritis-associated uveitis (JIAU) and idiopathic chronic anterior uveitis (CAU). METHODS: The group analyzed the literature published between December 2014 and June 2020 after a systematic literature review conducted by 2 clinicians. Pediatric rheumatologists were paired with ophthalmologists to review the eligible 37 publications. The search criteria were selected to reflect those used for the 2018 Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) recommendations, in order to provide an update, rather than a replacement for that publication. The summary of the current evidence for each SHARE recommendation was presented to the expert committee. These recommendations were then discussed and revised during a video consensus meeting on January 22, 2021, with 14 voting participants, using a nominal group technique to reach consensus. RESULTS: JIAU treatment was extended to include CAU. Fourteen recommendations regarding treatment of JIAU und CAU with >90% agreement were accepted. CONCLUSION: An update to the previous 2018 SHARE recommendations for the treatment of children with JIAU with the addition of CAU was created using an evidence-based consensus process. This guideline should help support clinicians to care for children and young people with CAU.

Transitioning patients with juvenile idiopathic arthritis to adult care: the Nordic experience.

BACKGROUND: With juvenile idiopathic arthritis (JIA), there are several protocols and practices used worldwide for the transition from paediatric to adult care. In this study, we examined the transferral rates and disease activity after transition, as well as the disease- and health-related outcomes. We also introduce the transition practices employed in the Nordic countries. METHODS: The study population comprised 408 participants with a disease onset from 1997 to 2000 who attended an 18-year follow-up visit in this population-based Nordic JIA cohort study. The patients were retrospectively divided into three subgroups: Patients transferred directly from paediatric care to adult rheumatology care, patients referred there later, and patients never transferred during the 18-year follow-up period. RESULTS: One hundred and sixty-three (40%) JIA patients had been directly transferred to an adult clinic. The cumulative transition rate was 52%, but there were significant differences between the participating centres. Fifty patients had later been referred to an adult clinic. Among the 195 patients who had never been transferred, 39% were found to have disease activity at the study visit. CONCLUSION: This study highlights the need to reconsider transition practices to avoid our undesirable finding of patients with disease activity in JIA, but no appropriate health care follow-up.

Incidence of amyotrophic lateral sclerosis in older adults.

INTRODUCTION/AIMS: We investigated the age- and sex-specific incidence and survival of Medicare beneficiaries with amyotrophic lateral sclerosis (ALS) in patients 66 to 90 years of age. METHODS: We identified all incident ALS cases within a population-based sample of Medicare beneficiaries in 2009 (total: 22 000 177 person-years at risk for ALS). We calculated age- and sex-specific incidence in 2009 according to multiple, progressively more stringent case definitions. Our most inclusive definition required one ALS code, whereas the most restrictive definition required at least one additional ALS code more than 6 months after the first code, including one from a neurologist. We identified associated imaging studies and electrodiagnostic testing and followed all cases through the end of 2014 to determine survival. RESULTS: The overall incidence for our most inclusive definition was 22.84 per 100 000 person-years for men and 16.05 per 100 000 person-years for women. The overall incidence was 5.72 per 100 000 person-years for men and 3.99 per 100 000 person-years for women for our most restrictive definition. For our most inclusive definition, fewer than 39.7% of cases ever had an ALS diagnosis from a neurologist, more than 50% had an electrodiagnostic test or imaging study, and 40.1% survived less than 1 year after diagnosis, with 25.5% of these cases surviving no more than 6 months. Cases not meeting the most restrictive definition were more likely than those who did meet the restrictive definition to be older, black, or Asian. DISCUSSION: The oldest and marginalized Medicare beneficiaries diagnosed with ALS are less likely to be included in epidemiological studies with restrictive definitions, but future studies will need to assess the accuracy of diagnosis.

Changing Patterns in Treatment, Remission Status, and Categories in a Long-Term Nordic Cohort Study of Juvenile Idiopathic Arthritis.

OBJECTIVE: To explore sustainability of achieved remission off medication and defined International League of Associations for Rheumatology (ILAR) categories in juvenile idiopathic arthritis (JIA) and describe the trajectory of disease course over time by comparing treatment, disease activity, and ILAR categories from baseline, 8 years, and 18 years after disease onset. METHODS: A total of 373 of the 510 included patients were initially recruited consecutive cases of JIA from the prospective, longitudinal, population-based Nordic JIA cohort with disease onset during 1997-2000 from Denmark, Norway, Sweden, and Finland in an 18-year follow-up study. Clinical data were collected consecutively at baseline, 8 years, and 18 years after disease onset and were evaluated regarding treatment, disease activity, and ILAR category. RESULTS: Significantly more patients (70%) were off medication after 18 years of follow-up compared to after 8 years (59.7%); nevertheless, the number of patients in remission had not increased (52% off medication versus 51% on medication). Twelve percent of patients changed ILAR category between 8 years and 18 years after disease onset. Almost half of the changes were due to updated information about heredity in a first-degree relative. In the same period, the psoriatic arthritis group increased significantly in number (P < 0.001), in contrast to the oligoarticular category, which decreased (P = 0.02). The undifferentiated group increased 24% from 8 to 18 years of follow-up; however, this increase was not significant (P = 0.06). CONCLUSION: In this Nordic JIA cohort study, the remission rate did not increase even though significantly more patients were off medication at the 18-year follow-up compared to at the 8-year follow-up after disease onset. The distribution of patients in the ILAR categories continued to change significantly throughout the 18-year study period.

Environmental manganese exposure and cognitive control in a South African population.

OBJECTIVE: To characterize the association between environmental (residential air) manganese (Mn) exposure and cognitive performance, focusing on cognitive control, in a Black African population. METHODS: We administered the Go-No-Go, Digit Span, and Matrix Reasoning tests to population-based samples age ≥40 from a high Mn (smelter) exposed community, Meyerton (N = 629), and a demographically comparable low (background levels) non-exposed community, Ethembalethu, (N = 96) in Gauteng province, South Africa. We investigated the associations between community and performance on the cognitive tests, using linear regression. We adjusted a priori for age and sex, and examined the effect of adjustment for education, nonverbal IQ, smoking, and alcohol consumption. We measured airborne PM2.5-Mn to confirm community exposure differences. RESULTS: Compared to Ethembalethu residents, Meyerton residents' test scores were lower (poorer) for all tests: 0.55 (95 % confidence interval [CI] 0.08, 1.03) lower scores for Matrix Reasoning, 0.34 (95 % CI -0.07, 0.75) lower for Digit Span, and 0.15 (95 % CI 0.09, 0.21) lower for Go-No-Go (high frequency discriminability index [probability]). The latter represented the most marked difference in terms of z-scores (0.50, 95 % CI 0.30, 0.71 standard deviations lower). The mean of the z-score of each of the three tests was also lower (0.34, 95 % CI 0.18, 0.50 standard deviations lower). These associations were similar in men and women, but attenuated with adjustment for education. Differences for Matrix Reasoning and Digit Span between the two communities were observed only among those who had lived in Meyerton ≥10 years, whereas for Go-No-Go, differences were also apparent among those who had lived in Meyerton <10 years. Mean PM2.5-Mn at a long-term fixed site in Meyerton was 203 ng/m3 and 10 ng/m3 in Ethembalethu. CONCLUSION: Residence in a community near a high Mn emission source is associated with cognitive dysfunction, including aspects of cognitive control as assessed by the Go-No-Go test.

Underdetection of Interstitial Lung Disease in Juvenile Systemic Sclerosis.

OBJECTIVE: Utilizing data obtained from a prospective, international, juvenile systemic sclerosis (SSc) cohort, the present study was undertaken to determine if pulmonary screening with forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLco) is sufficient to assess the presence of interstitial lung disease (ILD) in comparison to high-resolution computed tomography (HRCT) in juvenile SSc. METHODS: The juvenile SSc cohort database was queried for patients enrolled from January 2008 to January 2020 with recorded pulmonary function tests (PFTs) parameters and HRCT to determine the discriminatory properties of PFT parameters, FVC, and DLco in detecting ILD. RESULTS: Eighty-six juvenile SSc patients had both computed tomography imaging and FVC values for direct comparison. Using findings on HRCT as the standard measure of ILD presence, the sensitivity of FVC in detecting ILD in juvenile SSc was only 40%, the specificity was 77%, and area under the curve (AUC) was 0.58. Fifty-eight juvenile SSc patients had both CT imaging and DLco values for comparison. The sensitivity of DLco in detecting ILD was 76%, the specificity was 70%, and AUC was 0.73. CONCLUSION: The performance of PFTs in juvenile SSc to detect underlying ILD was quite limited. Specifically, the FVC, which is one of the main clinical parameters in adult SSc to detect and monitor ILD, would miss ~60% of children who had ILD changes on their accompanying HRCT. The DLco was more sensitive in detecting potential abnormalities on HRCT, but with less specificity than the FVC. These results support the use of HRCT in tandem with PFTs for the screening of ILD in juvenile SSc.

Differences Sustained Between Diffuse and Limited Forms of Juvenile Systemic Sclerosis in an Expanded International Cohort.

OBJECTIVE: To evaluate the baseline clinical characteristics of juvenile systemic sclerosis (SSc) patients in the international juvenile SSc inception cohort, and to compare these characteristics between the classically defined juvenile diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc) subtypes and among those with overlap features. METHODS: A cross-sectional study was performed using baseline visit data. Information on demographic characteristics, organ system evaluation, treatment, and patient- and physician-reported outcomes was extracted and summary statistics applied. Comparisons between juvenile dcSSc and lcSSc subtypes and patients with and without overlap features were performed using chi-square and Mann-Whitney U tests. RESULTS: At data extraction, 150 juvenile SSc patients were enrolled across 42 centers; 83% were White, 80% were female, juvenile dcSSc predominated (72%), and 17% of the cohort had overlap features. Significant differences were found between juvenile dcSSc and juvenile lcSSc regarding modified Rodnan skin thickness score, the presence of Gottron's papules, digital tip ulceration, results of the 6-minute walk test, and composite pulmonary and cardiac involvement. All of these were more frequent in dcSSc except for cardiac involvement. Juvenile dcSSc patients had significantly worse scores for physician-rated disease activity and damage. A significantly higher occurrence of Gottron's papules and musculoskeletal and composite pulmonary involvement, and a significantly lower frequency of Raynaud's phenomenon, were seen in those with overlap features. CONCLUSION: Results from a large international juvenile SSc cohort demonstrate significant differences between juvenile dcSSc and juvenile lcSSc patients, including more globally severe disease and increased frequency of interstitial lung disease in juvenile dcSSc patients, while those with lcSSc have more frequent cardiac involvement. Those with overlap features had an unexpected higher frequency of interstitial lung disease.

Response to pneumococcal conjugate and polysaccharide vaccination in children with rheumatic disease.

Children with rheumatic disease and compromised immune system have an increased risk of infection. Streptococcus pneumoniae is a frequent pathogen, and immunization is recommended. In this study, we investigated whether immunocompromised children with rheumatic disease do respond to pneumococcal immunization with 13-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal polysaccharide vaccine. The study was conducted at two tertiary referral hospitals in Denmark from 2015 to 2018. Patients with rheumatic disease and compromised immune system aged 2-19 years were eligible. Patients were vaccinated with 13-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal polysaccharide vaccine. A blood sample was collected before vaccination and after each vaccination. IgG antibodies were quantified for twelve serotypes. Seroprotection for each serotype was defined as IgG ≥0.35 µg/mL. A total of 27 patients were enrolled. After the conjugate vaccine, an increase in antibody titres compared with pre-vaccination was found for all serotypes and 9/12 were significant. After the polysaccharide vaccine, the antibody titres for all serotypes but one was seen to increase but none reached significance. The proportion of patients protected before immunization ranged from 20.8% to 100% for the individual serotypes. Odds ratio for achieving seroprotection after the conjugate vaccine was >1 for 10/12 serotypes but only significant for three serotypes. After the polysaccharide vaccine, the odds ratio was >1 for 9/12 serotypes but none reached significance. In conclusion, children with rheumatic disease and compromised immune system respond to pneumococcal immunization with 13-valent pneumococcal conjugate vaccine and maintain antibody levels upon subsequent immunization with 23-valent pneumococcal polysaccharide vaccine.

M-ficolin: a valuable biomarker to identify leukaemia from juvenile idiopathic arthritis.

OBJECTIVE: Distinction on clinical grounds between acute lymphoblastic leukaemia presenting with arthropathy (ALLarthropathy) and juvenile idiopathic arthritis (JIA) is difficult, as the clinical and paraclinical signs of leukaemia may be vague. The primary aim was to examine the use of lectin complement pathway proteins as markers to differentiate ALLarthropathy from JIA. The secondary aims were to compare the protein levels at baseline and follow-up in a paired number of children with ALL and to examine the correlation with haematology counts, erythrocyte sedimentation reaction (ESR), C-reactive protein (CRP), blasts, relapse and death. STUDY DESIGN: In this observational study, we measured M-ficolin, CL-K1 and MASP-3 in serum from children with ALL (n=151) and JIA (n=238) by time-resolved immunofluorometric assays. Logistic regression was used for predictions of ALL risk, considering the markers as the respective exposures. We performed internal validation using repeated '10-fold cross-validation' with 100 repetitions computing the area under the curve (AUC) as well as positive and negative predictive values in order to evaluate the predictive performance. RESULTS: The level of M-ficolin was higher in JIA than ALLtotal and the ALLarthropathy subgroup. The M-ficolin level normalised after remission of ALL. M-ficolin could differentiate ALL from JIA with an AUC of 94% and positive predictive value (PPV) of 95%, exceeding CRP and haemoglobin. In a dichotomised predictive model with optimal cut-offs for M-ficolin, platelets and haemoglobin, AUC was 99% and PPV 98% in detecting ALL from JIA. CONCLUSION: M-ficolin is a valuable marker to differentiate the child with ALL from JIA.