Developmental delay can precede neurologic regression in early onset metachromatic leukodystrophy.

OBJECTIVE: Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disorder. Emerging therapies are most effective in the presymptomatic phase, and thus defining this window is critical. We hypothesize that early development delay may precede developmental plateau. With the advent of presymptomatic screening platforms and transformative therapies, it is essential to define the onset of neurologic disease. METHODS: The specific ages of gain and loss of developmental milestones were captured from the medical records of individuals affected by MLD. Milestone acquisition was characterized as: on target (obtained before the age limit of 90th percentile plus 2 standard deviations compared to a normative dataset), delayed (obtained after 90th percentile plus 2 standard deviations), or plateau (skills never gained). Regression was defined as the age at which skills were lost. LI-MLD was defined by age at onset before 2.5 years. RESULTS: Across an international cohort, 351 subjects were included (n = 194 LI-MLD subcohort). The median age at presentation of the LI-MLD cohort was 1.4 years (25th-75th %ile: 1.0-1.5). Within the LI-MLD cohort, 75/194 (39%) had developmental delay (or plateau) prior to MLD clinical presentation. Among the LI-MLD cohort with a minimum of 1.5 years of follow-up (n = 187), 73 (39.0%) subjects never attained independent ambulation. Within LI-MLD + delay subcohort, the median time between first missed milestone target to MLD decline was 0.60 years (maximum distance from delay to onset: 1.9 years). INTERPRETATION: Early developmental delay precedes regression in a subset of children affected by LI-MLD, defining the onset of neurologic dysfunction earlier than previously appreciated. The use of realworld data prior to diagnosis revealed an early deviation from typical development. Close monitoring for early developmental delay in presymptomatic individuals may help in earlier diagnosis with important consequences for treatment decisions.

Remote work transition amidst COVID-19: Impacts on presenteeism, absenteeism, and worker well-being-A scoping review.

BACKGROUND: The COVID-19 pandemic has accelerated the transition to remote work, leading to increased attention on presenteeism and absenteeism among remote workers. Understanding the implications of these phenomena on worker health and productivity is crucial for optimizing remote work arrangements and developing policies to improve employee well-being. OBJECTIVES: This scoping review aims to examine the occurrence of presenteeism and absenteeism among remote workers during the COVID-19 pandemic and the interrelated physical and mental health issues during these periods. METHODS: PsycINFO, Medline, Embase, CINAHL, Eric, Business Source Premier, SCOPUS, and sociological abstracts were searched resulting in 1792 articles. Articles were included if the population of interest was 18+ (i.e., working age), engaged in full or part-time work, and the employees shifted from in-person to remote work due to the COVID-19 pandemic. All study designs, geographical areas, and papers written post-onset of the COVID-19 pandemic were included; however, systematic reviews were excluded. Data was charted into Microsoft Excel by 2 independent reviewers. RESULTS: The literature search identified 10 studies (i.e., seven cross-sectional studies, two qualitative studies, and one observational study). Five major overarching themes were identified specifically (1) telework and mental health (2) telework and physical health (3) worker benefits (4) gender dynamics and (5) difficulty navigating the teleworking environment. While remote work offers flexibility in terms of saved commute time and flexible work schedules, it also exacerbates challenges related to presenteeism, absenteeism, and work-life balance. These challenges include experiencing psychological distress, depression, anxiety, stress, sleep deprivation, musculoskeletal pain, difficulties concentrating at work for both women and working parents, struggles disconnecting after hours, and the inability to delineate between the work and home environment. DISCUSSION: The findings suggest that remote work during the COVID-19 pandemic has both positive and negative implications for worker well-being and productivity. However, future research needs to incorporate the potential effects of telework frequency (full time vs. part time) on employee productivity and its role on presenteeism and absenteeism, to gain a more comprehensive understanding on remote work difficulties. Addressing these challenges requires proactive interventions and support mechanisms to promote worker health and productivity in remote settings.

A systematic review of the literature: Gender-based violence in the construction and natural resources industry.

Gender-based violence (GBV) poses a significant concern in the construction and natural resources industries, where women, due to lower social status and integration, are at heightened risk. This systematic review aimed to identify the prevalence and experience of GBV in the construction and natural resources industries. A systematic search across databases including PubMed, OVID, Scopus, Web of Science, and CINAHL was conducted. The Risk of Bias Instrument for Cross-sectional Surveys of Attitudes and Practices by McMaster University and the Critical Appraisal of Qualitative Studies by the Center for Evidence Based Medicine at the University of Oxford were used to assess the studies included in the review. Six articles were included after full-text analysis. GBV was reported in the construction, mining, urban forestry, and arboriculture sectors. Workplace GBV was measured differently across the studies, and all studies examined more than one form of GBV. The main forms of GBV discussed in these studies were discrimination, sexual harassment, and sexism. The studies provided some insight for demographic factors that may or may not be associated with GBV, such as age, region of work, and number of years working in the industry. The review also suggests that workplace GBV has a negative impact on mental health and well-being outcomes, such as higher levels of stress and lower job satisfaction. The current research has not established the effectiveness of interventions, tools, or policies in these workplaces. Thus, additional research should include intervention studies that aim to minimize or prevent GBV in male-dominated workplaces. The current study can bring awareness and acknowledgement towards GBV in the workplace and highlight the importance of addressing it as this review outlines the negative consequences of GBV on mental health and well-being in these male-dominated industries.

Leriglitazone halts disease progression in adult patients with early cerebral adrenoleukodystrophy.

Cerebral adrenoleukodystrophy (CALD) is an X-linked rapidly progressive demyelinating disease leading to death usually within a few years. The standard of care is hematopoietic stem cell transplantation (HSCT), but many men are not eligible due to age, absence of a matched donor, or lesions of the corticospinal tracts (CST). Based on the ADVANCE study showing that leriglitazone decreases the occurrence of CALD, we treated 13 adult CALD patients (19-67 years of age) either not eligible to HSCT (n= 8) or awaiting HSCT (n= 5). Patients were monitored every 3 months with standardized neurological scores, plasma biomarkers and brain MRI comprising lesion volumetrics and diffusion tensor imaging. The disease stabilized clinically and radiologically in 10 patients with up to 2 years of follow-up. Five patients presented with gadolinium enhancing CST lesions that all turned gadolinium negative and, remarkably, regressed in four patients. Plasma neurofilament light chain levels stabilized in all 10 patients and correlated with lesion load. The two patients who continued to deteriorate were over 60 years of age with prominent cognitive impairment. One patient rapidly died from Covid19. These results suggest that leriglitazone can arrest disease progression in adults with early-stage CALD and may be an alternative treatment to HSCT.

Unsupervised MRI motion artifact disentanglement: introducing MAUDGAN.

Objective.This study developed an unsupervised motion artifact reduction method for magnetic resonance imaging (MRI) images of patients with brain tumors. The proposed novel design uses multi-parametric multicenter contrast-enhanced T1W (ceT1W) and T2-FLAIR MRI images.Approach.The proposed framework included two generators, two discriminators, and two feature extractor networks. A 3-fold cross-validation was used to train and fine-tune the hyperparameters of the proposed model using 230 brain MRI images with tumors, which were then tested on 148 patients'in-vivodatasets. An ablation was performed to evaluate the model's compartments. Our model was compared with Pix2pix and CycleGAN. Six evaluation metrics were reported, including normalized mean squared error (NMSE), structural similarity index (SSIM), multi-scale-SSIM (MS-SSIM), peak signal-to-noise ratio (PSNR), visual information fidelity (VIF), and multi-scale gradient magnitude similarity deviation (MS-GMSD). Artifact reduction and consistency of tumor regions, image contrast, and sharpness were evaluated by three evaluators using Likert scales and compared with ANOVA and Tukey's HSD tests.Main results.On average, our method outperforms comparative models to remove heavy motion artifacts with the lowest NMSE (18.34±5.07%) and MS-GMSD (0.07 ± 0.03) for heavy motion artifact level. Additionally, our method creates motion-free images with the highest SSIM (0.93 ± 0.04), PSNR (30.63 ± 4.96), and VIF (0.45 ± 0.05) values, along with comparable MS-SSIM (0.96 ± 0.31). Similarly, our method outperformed comparative models in removingin-vivomotion artifacts for different distortion levels except for MS- SSIM and VIF, which have comparable performance with CycleGAN. Moreover, our method had a consistent performance for different artifact levels. For the heavy level of motion artifacts, our method got the highest Likert scores of 2.82 ± 0.52, 1.88 ± 0.71, and 1.02 ± 0.14 (p-values≪0.0001) for our method, CycleGAN, and Pix2pix respectively. Similar trends were also found for other motion artifact levels.Significance.Our proposed unsupervised method was demonstrated to reduce motion artifacts from the ceT1W brain images under a multi-parametric framework.

International validation of meaningfulness of postural sway and gait to assess myeloneuropathy in adults with adrenoleukodystrophy.

BACKGROUND: The most common manifestation of X-linked adrenoleukodystrophy (ALD) is a slowly progressive myeloneuropathy, which leads to imbalance and gait disturbances. The variable progression of the disease complicates evaluation of its progression rate. Wearable sensors allow for easy and frequent balance and gait collection. This study reports baseline data from a longitudinal study on the quantitative assessment of balance and gait with wearable sensors and their clinical relevance. METHODS: Data were collected from adult patients in two institutions. Postural body sway and gait parameters were measured using accelerometers. Disease severity was measured by the Expanded Disability Severity Scale (EDSS). Falling frequency and quality of life (QOL) were collected in men. The relationship between sway and gait variables and EDSS score, participants' use of a walking aid, and falling frequency was evaluated. RESULTS: One hundred twenty individuals with ALD were included. Sway variables significantly differentiate participants' assistive device use. Sway and gait variables were correlated to the EDSS in both sexes. Both gait speed and sway were correlated with falling frequency in men from one institution. Select QOL subscores were correlated with the EDSS in males from one institution. Accelerometry generated comparable results across sites. DISCUSSION: This study confirms the clinical correlation between spinal cord disease and imbalance and gait in ALD. For the first time, this study shows clinically meaningful relationships for sway and gait with use of an assistive device, falling frequency and QOL. Wearable accelerometers are a valid means to measure sway and gait in ALD. These measures are promising outcomes for clinical trial designs to assess myeloneuropathy in ALD and to monitor disease progression in individuals.

Consensus guidelines for the monitoring and management of metachromatic leukodystrophy in the United States.

Metachromatic leukodystrophy (MLD) is a fatal, progressive neurodegenerative disorder caused by biallelic pathogenic mutations in the ARSA (Arylsulfatase A) gene. With the advent of presymptomatic diagnosis and the availability of therapies with a narrow window for intervention, it is critical to define a standardized approach to diagnosis, presymptomatic monitoring, and clinical care. To meet the needs of the MLD community, a panel of MLD experts was established to develop disease-specific guidelines based on healthcare resources in the United States. This group developed a consensus opinion for best-practice recommendations, as follows: (i) Diagnosis should include both genetic and biochemical testing; (ii) Early diagnosis and treatment for MLD is associated with improved clinical outcomes; (iii) The panel supported the development of newborn screening to accelerate the time to diagnosis and treatment; (iv) Clinical management of MLD should include specialists familiar with the disease who are able to follow patients longitudinally; (v) In early onset MLD, including late infantile and early juvenile subtypes, ex vivo gene therapy should be considered for presymptomatic patients where available; (vi) In late-onset MLD, including late juvenile and adult subtypes, hematopoietic cell transplant (HCT) should be considered for patients with no or minimal disease involvement. This document summarizes current guidance on the presymptomatic monitoring of children affected by MLD as well as the clinical management of symptomatic patients. Future data-driven evidence and evolution of these recommendations will be important to stratify clinical treatment options and improve clinical care.

Longitudinal natural history studies based on real-world data in rare diseases: Opportunity and a novel approach.

Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records. Prospective studies are uniquely challenging for rare diseases. Delays in diagnosis and overall rarity limit the timely collection of natural history data. When feasible, prospective studies are often cross-sectional rather than longitudinal and are unlikely to capture pre- or early- symptomatic disease trajectories, limiting their utility in characterizing the full natural history of the disease. Therapeutic development in leukodystrophies is subject to these same obstacles. The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) comprises of a network of research institutions across the United States, supported by a multi-center biorepository protocol, to map the longitudinal clinical course of disease across leukodystrophies. As part of GLIA-CTN, we developed Standard Operating Procedures (SOPs) that delineated all study processes related to staff training, source documentation, and data sharing. Additionally, the SOP detailed the standardized approach to data extraction including diagnosis, clinical presentation, and medical events, such as age at gastrostomy tube placement. The key variables for extraction were selected through face validity, and common electronic case report forms (eCRF) across leukodystrophies were created to collect analyzable data. To enhance the depth of the data, clinical notes are extracted into "original" and "imputed" encounters, with imputed encounter referring to a historic event (e.g., loss of ambulation 3 months prior). Retrospective Functional Assessments were assigned by child neurologists, using a blinded dual-rater approach and score discrepancies were adjudicated by a third rater. Upon completion of extraction, data source verification is performed. Data missingness was evaluated using statistics. The proposed methodology will enable us to leverage existing medical records to address the persistent gap in natural history data within this unique disease group, allow for assessment of clinical trajectory both pre- and post-formal diagnosis, and promote recruitment of larger cohorts.

De novo variants in DENND5B cause a neurodevelopmental disorder.

The Rab family of guanosine triphosphatases (GTPases) includes key regulators of intracellular transport and membrane trafficking targeting specific steps in exocytic, endocytic, and recycling pathways. DENND5B (Rab6-interacting Protein 1B-like protein, R6IP1B) is the longest isoform of DENND5, an evolutionarily conserved DENN domain-containing guanine nucleotide exchange factor (GEF) that is highly expressed in the brain. Through exome sequencing and international matchmaking platforms, we identified five de novo variants in DENND5B in a cohort of five unrelated individuals with neurodevelopmental phenotypes featuring cognitive impairment, dysmorphism, abnormal behavior, variable epilepsy, white matter abnormalities, and cortical gyration defects. We used biochemical assays and confocal microscopy to assess the impact of DENND5B variants on protein accumulation and distribution. Then, exploiting fluorescent lipid cargoes coupled to high-content imaging and analysis in living cells, we investigated whether DENND5B variants affected the dynamics of vesicle-mediated intracellular transport of specific cargoes. We further generated an in silico model to investigate the consequences of DENND5B variants on the DENND5B-RAB39A interaction. Biochemical analysis showed decreased protein levels of DENND5B mutants in various cell types. Functional investigation of DENND5B variants revealed defective intracellular vesicle trafficking, with significant impairment of lipid uptake and distribution. Although none of the variants affected the DENND5B-RAB39A interface, all were predicted to disrupt protein folding. Overall, our findings indicate that DENND5B variants perturb intracellular membrane trafficking pathways and cause a complex neurodevelopmental syndrome with variable epilepsy and white matter involvement.

The Effects of Systemic Lupus-Related Cognitive Impairments on Activities of Daily Living and Life Role Participation: A Qualitative Framework Study.

OBJECTIVE: Cognitive impairment (CI) in systemic lupus erythematosus (SLE) negatively impacts health-related quality of life leading to activity limitations. This qualitative study aimed to (1) explore the effect of SLE-related CI on activities of daily living and life role participation and (2) describe factors influencing activity restriction and life role participation. METHODS: Semistructured, in-depth interviews of lived experience of CI in SLE were conducted with 24 participants with SLE. Sociodemographic and clinical data, and objective and subjective cognitive function, were collected to characterize participants. A qualitative thematic content analysis was undertaken guided by a framework analytical approach. RESULTS: Participants reported problems in multiple cognitive domains, with multiple perceived causes. CI was felt to impact work, social, domestic, and family life, health, and independence. Five overarching themes were represented in the data: (1) characterization of SLE-reported CI, (2) perceived cause of CI, (3) perceived impact of CI on activities of daily living and life role participation, (4) adaptations for managing CI, and (5) influence of CI adaptations on activities of daily living and life role participation. CONCLUSION: This study provides a better understanding of the patient experience of CI in SLE, how it impacts their lives, and what coping strategies they employ. It highlights the long-term challenges those with CI in SLE undergo and provides evidence for the urgent need to implement multidisciplinary treatment options. When managing CI, it may be beneficial to evaluate and understand available psychosocial support resources to help identify and reinforce relevant adaptations to improve health-related quality of life.

MRI motion artifact reduction using a conditional diffusion probabilistic model (MAR-CDPM).

BACKGROUND: High-resolution magnetic resonance imaging (MRI) with excellent soft-tissue contrast is a valuable tool utilized for diagnosis and prognosis. However, MRI sequences with long acquisition time are susceptible to motion artifacts, which can adversely affect the accuracy of post-processing algorithms. PURPOSE: This study proposes a novel retrospective motion correction method named "motion artifact reduction using conditional diffusion probabilistic model" (MAR-CDPM). The MAR-CDPM aimed to remove motion artifacts from multicenter three-dimensional contrast-enhanced T1 magnetization-prepared rapid acquisition gradient echo (3D ceT1 MPRAGE) brain dataset with different brain tumor types. MATERIALS AND METHODS: This study employed two publicly accessible MRI datasets: one containing 3D ceT1 MPRAGE and 2D T2-fluid attenuated inversion recovery (FLAIR) images from 230 patients with diverse brain tumors, and the other comprising 3D T1-weighted (T1W) MRI images of 148 healthy volunteers, which included real motion artifacts. The former was used to train and evaluate the model using the in silico data, and the latter was used to evaluate the model performance to remove real motion artifacts. A motion simulation was performed in k-space domain to generate an in silico dataset with minor, moderate, and heavy distortion levels. The diffusion process of the MAR-CDPM was then implemented in k-space to convert structure data into Gaussian noise by gradually increasing motion artifact levels. A conditional network with a Unet backbone was trained to reverse the diffusion process to convert the distorted images to structured data. The MAR-CDPM was trained in two scenarios: one conditioning on the time step t $t$ of the diffusion process, and the other conditioning on both t $t$ and T2-FLAIR images. The MAR-CDPM was quantitatively and qualitatively compared with supervised Unet, Unet conditioned on T2-FLAIR, CycleGAN, Pix2pix, and Pix2pix conditioned on T2-FLAIR models. To quantify the spatial distortions and the level of remaining motion artifacts after applying the models, quantitative metrics were reported including normalized mean squared error (NMSE), structural similarity index (SSIM), multiscale structural similarity index (MS-SSIM), peak signal-to-noise ratio (PSNR), visual information fidelity (VIF), and multiscale gradient magnitude similarity deviation (MS-GMSD). Tukey's Honestly Significant Difference multiple comparison test was employed to quantify the difference between the models where p-value  < 0.05 $ < 0.05$ was considered statistically significant. RESULTS: Qualitatively, MAR-CDPM outperformed these methods in preserving soft-tissue contrast and different brain regions. It also successfully preserved tumor boundaries for heavy motion artifacts, like the supervised method. Our MAR-CDPM recovered motion-free in silico images with the highest PSNR and VIF for all distortion levels where the differences were statistically significant (p-values < 0.05 $< 0.05$ ). In addition, our method conditioned on t and T2-FLAIR outperformed (p-values < 0.05 $< 0.05$ ) other methods to remove motion artifacts from the in silico dataset in terms of NMSE, MS-SSIM, SSIM, and MS-GMSD. Moreover, our method conditioned on only t outperformed generative models (p-values < 0.05 $< 0.05$ ) and had comparable performances compared with the supervised model (p-values > 0.05 $> 0.05$ ) to remove real motion artifacts. CONCLUSIONS: The MAR-CDPM could successfully remove motion artifacts from 3D ceT1 MPRAGE. It is particularly beneficial for elderly who may experience involuntary movements during high-resolution MRI imaging with long acquisition times.

MedFusionGAN: multimodal medical image fusion using an unsupervised deep generative adversarial network.

PURPOSE: This study proposed an end-to-end unsupervised medical fusion generative adversarial network, MedFusionGAN, to fuse computed tomography (CT) and high-resolution isotropic 3D T1-Gd Magnetic resonance imaging (MRI) image sequences to generate an image with CT bone structure and MRI soft tissue contrast to improve target delineation and to reduce the radiotherapy planning time. METHODS: We used a publicly available multicenter medical dataset (GLIS-RT, 230 patients) from the Cancer Imaging Archive. To improve the models generalization, we consider different imaging protocols and patients with various brain tumor types, including metastases. The proposed MedFusionGAN consisted of one generator network and one discriminator network trained in an adversarial scenario. Content, style, and L1 losses were used for training the generator to preserve the texture and structure information of the MRI and CT images. RESULTS: The MedFusionGAN successfully generates fused images with MRI soft-tissue and CT bone contrast. The results of the MedFusionGAN were quantitatively and qualitatively compared with seven traditional and eight deep learning (DL) state-of-the-art methods. Qualitatively, our method fused the source images with the highest spatial resolution without adding the image artifacts. We reported nine quantitative metrics to quantify the preservation of structural similarity, contrast, distortion level, and image edges in fused images. Our method outperformed both traditional and DL methods on six out of nine metrics. And it got the second performance rank for three and two quantitative metrics when compared with traditional and DL methods, respectively. To compare soft-tissue contrast, intensity profile along tumor and tumor contours of the fusion methods were evaluated. MedFusionGAN provides a more consistent, better intensity profile, and a better segmentation performance. CONCLUSIONS: The proposed end-to-end unsupervised method successfully fused MRI and CT images. The fused image could improve targets and OARs delineation, which is an important aspect of radiotherapy treatment planning.

Copy Number Variation Analysis of Aggressive Behaviour in Schizophrenia.

INTRODUCTION: An increased proclivity towards violence is often associated with those diagnosed with schizophrenia (SCZ), despite contradictory findings from prior studies exploring the association between violence and SCZ. Evidence has shown that certain comorbidities, specifically the presence of a substance use disorders, can result in increased aggression in those with SCZ. Copy number variation (CNV) load has also previously been implicated in the genetic vulnerability of individuals with SCZ. For this study, we aimed to determine whether CNV load correlates with increased violence in SCZ. METHODS: Community-dwelling patients diagnosed with SCZ spectrum disorders (n = 203) were recruited from a non-forensic population. The assessment for aggression was completed using a cross-sectional and retrospective design, and CNV analysis was conducted analysing genomic DNA using the Illumina Omni 2.5 array. RESULTS: No correlation between the number of CNV events (either deletion or duplication) and the severity of the physical violence episode index was found. However, there was a significant association between larger deletion events across the violent behaviours under investigation. DISCUSSION: These results need to be confirmed in more extensive studies using standardized tools developed for non-forensic populations, such as the Brown-Goodwin Scale of Aggression.

Clinical and functional consequences of GRIA variants in patients with neurological diseases.

AMPA receptors are members of the glutamate receptor family and mediate a fast component of excitatory synaptic transmission at virtually all central synapses. Thus, their functional characteristics are a critical determinant of brain function. We evaluate intolerance of each GRIA gene to genetic variation using 3DMTR and report here the functional consequences of 52 missense variants in GRIA1-4 identified in patients with various neurological disorders. These variants produce changes in agonist EC50, response time course, desensitization, and/or receptor surface expression. We predict that these functional and localization changes will have important consequences for circuit function, and therefore likely contribute to the patients' clinical phenotype. We evaluated the sensitivity of variant receptors to AMPAR-selective modulators including FDA-approved drugs to explore potential targeted therapeutic options.

Exploring the Impact of Labour Mobility on the Mental Health and Wellbeing of Skilled Trades Workers in Ontario, Canada.

Labour mobility and subsequent workers migration is an increasing trend worldwide and can be a force that counteracts Canada's shortage of skilled labour. Supercommuting allows workers facing economic challenges to pursue more financially advantageous work opportunities in other regions. This study aimed to evaluate the "supercommuting" labour mobility model and its impact on long-distance mobile workers' mental health and wellbeing. We utilized a non-experimental research design using convenience sampling from workers who participated in Blue Branch Inc.'s (Hamilton, Canada) supercommuting labour mobility model. An online questionnaire collected demographic data, work-related data, occupational stress measures related to burnout, and job-related stress data. Data collection was started on 1 April 2021, and of the total 58 participants, the majority (44, 76%) were male, born outside Canada, and had an average age of 32.8 years. Workplace Safety (95%), full-time employment opportunity (95%), career advancement possibility (95%), and income and benefits (94.9%) were found to be the most crucial factors to keep study participants working in their current position. Of the 47 participants who experienced burnout, only one showed severe burnout in each domain (personal, work-related, and colleague-related). There is a great need for preventative burnout programs and supportive employer resources for those who engage in long-distance labour commuting. The study emphasizes the need to encourage policymakers to develop solutions for training future Ontario workers to support mobile employment and long-distance labour commuting.

Core protocol development for phase 2/3 clinical trials in the leukodystrophy vanishing white matter: a consensus statement by the VWM consortium and patient advocates.

BACKGROUND: The leukodystrophy "Vanishing White Matter" (VWM) is an orphan disease with neurological decline and high mortality. Currently, VWM has no approved treatments, but advances in understanding pathophysiology have led to identification of promising therapies. Several investigational medicinal products are either in or about to enter clinical trial phase. Clinical trials in VWM pose serious challenges, as VWM has an episodic disease course; disease phenotype is highly heterogeneous and predictable only for early onset; and study power is limited by the small patient numbers. To address these challenges and accelerate therapy delivery, the VWM Consortium, a group of academic clinicians with expertise in VWM, decided to develop a core protocol to function as a template for trials, to improve trial design and facilitate sharing of control data, while permitting flexibility regarding other trial details. Overall aims of the core protocol are to collect safety, tolerability, and efficacy data for treatment assessment and marketing authorization. METHODS: To develop the core protocol, the VWM Consortium designated a committee, including clinician members of the VWM Consortium, family and patient group advocates, and experts in statistics, clinical trial design and alliancing with industries. We drafted three age-specific protocols, to stratify into more homogeneous patient groups, of ages ≥ 18 years, ≥ 6 to < 18 years and < 6 years. We chose double-blind, randomized, placebo-controlled design for patients aged ≥ 6 years; and open-label non-randomized natural-history-controlled design for patients < 6 years. The protocol describes study populations, age-specific endpoints, inclusion and exclusion criteria, study schedules, sample size determinations, and statistical considerations. DISCUSSION: The core protocol provides a shared uniformity across trials, enables a pool of shared controls, and reduces the total number of patients necessary per trial, limiting the number of patients on placebo. All VWM clinical trials are suggested to adhere to the core protocol. Other trial components such as choice of primary outcome, pharmacokinetics, pharmacodynamics, and biomarkers are flexible and unconstrained by the core protocol. Each sponsor is responsible for their trial execution, while the control data are handled by a shared research organization. This core protocol benefits the efficiency of parallel and consecutive trials in VWM, and we hope accelerates time to availability of treatments for VWM. TRIAL REGISTRATION: NA. From a scientific and ethical perspective, it is strongly recommended that all interventional trials using this core protocol are registered in a clinical trial register.

GWAS of biological aging to find longevity genes in schizophrenia.

Schizophrenia (SCZ) is a severe psychotic disorder associated with premature mortality and aging. Moreover, the symptoms and progression of psychiatric disorders in general are associated with decreased lifespan, biological aging, and poorer medical outcomes. In this study, we investigated the relationship between several epigenetic clocks and scanned the entire genome for association in a cohort of SCZ individuals (n = 107). Biological age was computed from blood DNA methylation (DNAm) and tested for association against  common  variants across the genome using general linear models. Genes affecting epigenetic age acceleration in our cohort were found mainly when using the telomeric length clock rather than the other biological clocks. These findings pair with existing evidence that there are some genes associated with longevity and suggest further investigations of  putative biological mechanisms for morbidity and premature mortality, not only in patients with SCZ but also in the general population.

Patient-specific geometrical distortion corrections of MRI images improve dosimetric planning accuracy of vestibular schwannoma treated with gamma knife stereotactic radiosurgery.

PURPOSE: To investigate the impact of MRI patient-specific geometrical distortion (PSD) on the quality of Gamma Knife stereotactic radiosurgery (GK-SRS) plans of the vestibular schwannoma (VS) tumors. METHODS AND MATERIALS: Three open access datasets including the MPI-Leipzig Mind-Brain-Body (318 patients), the slow event-related fMRI designs dataset (62 patients), and the VS dataset (242 patients) were used. We used first two datasets to train a 3D convolution network to predict the distortion map of third dataset that were then used to calculate and correct the PSD. GK-SRS plans of VS dataset were used to evaluate dose distribution of PSD-corrected MRI images. GK-SRS prescription dose of VS cases was 12 Gy. Geometric and dosimetric discrepancies were assessed between the dose distributions and contours before and after the PSD corrections. Geometry indices were center of the contours, Dice coefficient (DC), Hausdorff distance (HD), and dosimetric indices were D µ ${D_\mu }$ , D m a x ${D_{max}}$ , D m i n ${D_{min}}$ , and D 95 % ${D_{95{\mathrm{\% }}}}$ doses, target coverage (TC), Paddick's conformity index (PCI), Paddick's gradient index (GI), and homogeneity index (HI). RESULTS: Geometric distortions of about 1.2 mm were observed at the air-tissue interfaces at the air canal and nasal cavity borders. Average center of the targets was significantly distorted along the frequency encoding direction after the PSD-correction. Average DC and HD metrics were 0.90 and 2.13 mm. Average D µ ${D_\mu }$ , D 95 % , ${D_{95{\mathrm{\% ,}}}}$ and D m i n ${D_{min}}$ in Gy significantly increased after PSD correction from 16.85 to 17.25, 12.30 to 12.77, and from 8.98 to 9.92. D m a x ${D_{max}}$ did not significantly change after the correction. Average TC and PCI significantly increased from 0.97 to 0.98, and 0.94 to 0.96. Average GI decreased significantly from 2.24 to 2.15 after PSD correction. However, HI did not significantly change after the correction. CONCLUSION: The proposed method could predict and correct the PSD that indicates the importance of PSD correction before GK-SRS plans of the VS patients.