Genome-wide study of longitudinal brain imaging measures of multiple sclerosis progression across six clinical trials.

While the genetics of MS risk susceptibility are well-described, and recent progress has been made on the genetics of disease severity, the genetics of disease progression remain elusive. We therefore investigated the genetic determinants of MS progression on longitudinal brain MRI: change in brain volume (BV) and change in T2 lesion volume (T2LV), reflecting progressive tissue loss and increasing disease burden, respectively. We performed genome-wide association studies of change in BV (N = 3401) and change in T2LV (N = 3513) across six randomized clinical trials from Biogen and Roche/Genentech: ADVANCE, ASCEND, DECIDE, OPERA I & II, and ORATORIO. Analyses were adjusted for randomized treatment arm, age, sex, and ancestry. Results were pooled in a meta-analysis, and were evaluated for enrichment of MS risk variants. Variant colocalization and cell-specific expression analyses were performed using published cohorts. The strongest peaks were in PTPRD (rs77321193-C/A, p = 3.9 × 10-7) for BV change, and NEDD4L (rs11398377-GC/G, p = 9.3 × 10-8) for T2LV change. Evidence of colocalization was observed for NEDD4L, and both genes showed increased expression in neuronal and/or glial populations. No association between MS risk variants and MRI outcomes was observed. In this unique, precompetitive industry partnership, we report putative regions of interest in the neurodevelopmental gene PTPRD, and the ubiquitin ligase gene NEDD4L. These findings are distinct from known MS risk genetics, indicating an added role for genetic progression analyses and informing drug discovery.

Occupational Safety and Health Equity Impacts of Artificial Intelligence: A Scoping Review.

Artificial intelligence (AI) has the potential to either reduce or exacerbate occupational safety and health (OSH) inequities in the workplace, and its impact will be mediated by numerous factors. This paper anticipates challenges to ensuring that the OSH benefits of technological advances are equitably distributed among social groups, industries, job arrangements, and geographical regions. A scoping review was completed to summarize the recent literature on AI's role in promoting OSH equity. The scoping review was designed around three concepts: artificial intelligence, OSH, and health equity. Scoping results revealed 113 articles relevant for inclusion. The ways in which AI presents barriers and facilitators to OSH equity are outlined along with priority focus areas and best practices in reducing OSH disparities and knowledge gaps. The scoping review uncovered priority focus areas. In conclusion, AI's role in OSH equity is vastly understudied. An urgent need exists for multidisciplinary research that addresses where and how AI is being adopted and evaluated and how its use is affecting OSH across industries, wage categories, and sociodemographic groups. OSH professionals can play a significant role in identifying strategies that ensure the benefits of AI in promoting workforce health and wellbeing are equitably distributed.

Development of the Healthy Work Collaborative: Findings From an Action Research Study to Inform a Policy, Systems, and Environmental Change Capacity-Building Initiative Addressing Precarious Employment.

Precarious employment (PE) is a complex problem that affects an increasing number of workers across all economic sectors who experience low wages, hazardous conditions, and few benefits, and results in adverse health outcomes. PE is characterized by nontraditional work arrangements, precluding workplace-based interventions. Policy, systems, and environmental initiatives that engage cross-sectoral stakeholders may be an applicable health promotion approach to address PE. The University of of Illinois at Chicago Center for Healthy Work's Healthy Communities through Healthy Work (HCHW) is an outreach project of the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health-funded Center of Excellence for Total Worker Health that conducted a multiphased qualitative action research (AR) study. AR designs may be a novel approach to develop initiatives to address problems like PE. This article reports on HCHW's first AR phase to answer four research questions: (1) What are participants' perceptions of PE? (2) What are participants' perceptions of their roles in addressing PE? (3) What initiatives are under way that address PE? and (4) How can the findings be used to facilitate opportunities for healthy work? Key informant interviews with health (public health and health care; N = 23) and labor sector organizations (worker centers, worker advocacy organizations, and unions; N = 21) were conducted. Data were thematically analyzed alongside a chart-based content analysis, and shared in 11 key stakeholder meetings. Findings revealed an opportunity for the labor sector to improve health sector readiness to address PE in the context of health, and were used to develop the Healthy Work Collaborative, a cross-sectoral health promotion capacity building policy, systems, and environmenta change initiative to address PE.

Assessment of the rate of premolar extraction space closure in the maxillary arch with the AcceleDent Aura appliance vs no appliance in adolescents: A single-blind randomized clinical trial.

INTRODUCTION: The purpose of this 2-arm parallel trial was to assess the effect of the AcceleDent Aura appliance (OrthoAccel Technologies, Houston, Tex) on the rate of maxillary premolar extraction space closure in adolescent patients. METHODS: Forty Class II adolescents treated with full fixed appliances and maxillary premolar extractions participated in this randomized clinical trial. They were recruited in a private practice and treated by 1 clinician. Randomization was accomplished in blocks of 10 patients assigned to either a no-appliance group or the AcceleDent Aura appliance group with the allocations concealed in opaque, sealed envelopes. Both the operator and the outcome assessor were blinded; however, it was not feasible to blind the patients. Models were taken of the maxillary arch at the start of space closure and just before complete space closure. The space was measured parallel to the occlusal plane from the cusp tips of the teeth mesial and distal to the extraction spaces. RESULTS: There was no clinically (0.05 mm per month; 95% confidence interval [CI], -0.24, 0.34) or statistically significant difference in the rate of space closure (P = 0.74). In both the univariable and multivariable analyses, the mean rate of tooth movement was slower by 0.13 mm per month (95% CI, -.26, .005) on the left side compared with the right side, but this was not statistically significant (P = 0.06). CONCLUSIONS: The AcceleDent Aura appliance had no effect on the rate of maxillary premolar extraction space closure. Only a few participants were considered to be good compliers with the appliance. However, the rate of space closure in the good compliers was similar to the overall group and did not appear to influence the result. REGISTRATION: This trial was not registered. PROTOCOL: The protocol was not published before trial commencement.

Assessment of the changes in arch perimeter and irregularity in the mandibular arch during initial alignment with the AcceleDent Aura appliance vs no appliance in adolescents: A single-blind randomized clinical trial.

INTRODUCTION: The purpose of this 2-arm parallel trial was to assess the effects of the AcceleDent Aura (OrthoAccel Technologies, Houston, Tex) appliance on the increase in mandibular anterior arch perimeter, the reduction in mandibular arch irregularity, and the amount of discomfort during initial alignment of the mandibular arch with fixed appliances. METHODS: Forty Class II adolescent patients with full fixed appliances and treated with maxillary premolar extractions and no extractions in the mandibular arch participated in this randomized clinical trial. They were recruited in a private practice and treated by 1 clinician. Randomization to either a no-appliance group or the AcceleDent Aura appliance group was accomplished with permuted blocks of 10 patients with the allocations concealed in opaque, sealed envelopes. Both the operator and the outcome assessor were blinded, but it was not feasible to blind the patients. Discomfort was recorded during the first week of treatment. Mandibular anterior arch perimeter and anterior irregularity were measured from plaster models taken at the start of treatment and after 5, 8, and 10 weeks. RESULTS: No patients were lost to follow-up, and no data were missing. There was no difference in anterior arch perimeter at the start of treatment (P = 0.85; median, 0.6 mm; 95% confidence interval [CI], -1.6, +1.8 mm) or at any other time point (5 weeks: P = 0.84; median, -0.2 mm; 95% CI, -1.6, +1.2 mm; 8 weeks: P = 0.56; median, -0.3 mm; 95% CI, -1.6, +0.7 mm; 10 weeks: P = 0.67; median, -0.1 mm; 95% CI, -1.5, +1.1 mm). There was also no difference between groups for incisor irregularity (P = 0.46; median, -0.5 mm; 95% CI, -2.2, +2.8 mm; P = 0.80; median, 0.0 mm; 95% CI, -1.0, +1.1 mm; P = 0.70; median, 0.1 mm; 95% CI, -0.7, +0.8 mm; P = 0.65; median, 0.2 mm; 95% CI, -0.6, +0.6 mm). No difference was detected at any time during the first week for discomfort (baseline: P = 0.84; median, -1.5 mm; 95% CI, -15.9, +9.8 mm; 6 hours: P = 0.96; median, 0.3 mm; 95% CI, -23.5, +21.8 mm; 1 day: P, 0.75; median, -3.5 mm; 95% CI, -27.1, +26.9 mm; 3 days: P = 0.98; median, -0.6 mm; 95% CI, -20.6, +20.0; 7 days: P = 0.57; median, 0.5 mm; 95% CI, -5.0, +5.3 mm). However, significantly fewer participants in the AcceleDent Aura group used analgesics at day 1 (P = <0.01). CONCLUSIONS: The AcceleDent Aura appliance had no effect compared with no appliance on increasing anterior arch perimeter, or reducing irregularity or perceived discomfort during initial alignment with fixed appliances, although more subjects used painkillers at 24 hours in the no-appliance group. REGISTRATION: This trial was not registered. PROTOCOL: The protocol was not published before trial commencement. FUNDING: A special research grant was obtained from the Australian Society of Orthodontists Foundation for Research and Education to purchase the AcceleDent Aura appliances and fund the statistical analysis.

A comprehensive assessment of the SOD1G93A low-copy transgenic mouse, which models human amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that results in the death of motor neurons in the brain and spinal cord. The disorder generally strikes in mid-life, relentlessly leading to paralysis and death, typically 3-5 years after diagnosis. No effective treatments are available. Up to 10% of ALS is familial, usually autosomal dominant. Several causative genes are known and, of these, mutant superoxide dismutase 1 (SOD1) is by far the most frequently found, accounting for up to 20% of familial ALS. A range of human mutant SOD1 transgenic mouse strains has been produced, and these largely successfully model the human disease. Of these, the most widely used is the SOD1 mouse, which expresses a human SOD1 transgene with a causative G93A mutation. This mouse model is excellent for many purposes but carries up to 25 copies of the transgene and produces a great excess of SOD1 protein, which might affect our interpretation of disease processes. A variant of this strain carries a deletion of the transgene array such that the copy number is dropped to eight to ten mutant SOD1 genes. This 'deleted' 'low-copy' mouse undergoes a slower course of disease, over many months. Here we have carried out a comprehensive analysis of phenotype, including nerve and muscle physiology and histology, to add to our knowledge of this 'deleted' strain and give baseline data for future studies. We find differences in phenotype that arise from genetic background and sex, and we quantify the loss of nerve and muscle function over time. The slowly progressive pathology observed in this mouse strain could provide us with a more appropriate model for studying early-stage pathological processes in ALS and aid the development of therapies for early-stage treatments.

Factors that predict health-related quality of life in patients with relapsing-remitting multiple sclerosis.

Health-Related Quality of Life (HRQoL) research is gaining acceptance in the field of multiple sclerosis (MS). Little is known about what precipitates quality of life change. It was hypothesized that physical aspects of quality of life decline with worsening objective disease measures and psychosocial aspects remain relatively stable regardless of change in objective measures. These assumptions are tested using data from a Phase 3 study of relapsing-remitting MS patients treated with interferon beta-1a and reassessed approximately eight years after study initiation. The Sickness Impact Profile (SIP) questionnaire is the generic quality of life measure used in this study. Three summary scores of the SIP (Physical, Psychosocial, and Total scores), Expanded Disability Status Scores, Multiple Sclerosis Functional Composite, and Brain Parenchymal Fraction were determined at baseline, year 2, and after an average of 8.1 years from study entry. SIP data collected during a clinic visit were available from 137 of the original 172 participants. All objective indicators worsened by follow-up. SIP Physical and Total scores significantly worsened from baseline to follow-up. SIP Psychosocial showed nonsignificant worsening. Regression analysis indicated that final measures of SIP Physical and Total scores were most strongly associated with change in objective measures and follow-up SIP Psychosocial was most strongly related to earlier scores on the same measure.