Abstract Background 3D printing has a number of applications within medicine and healthcare. In applications involving radiography, the internal infill structure and external geometry of a 3D printed part can produce undesirable artifacts, limiting the full potential of 3D printing as a manufacturing technology. While the mechanical performance of a 3D printed part can be easily simulated, it is difficult to simulate the radiographic artifact produced. Purpose The purpose of this work was to develop a tool that allows users to simulate the radiographic artifact produced by a 3D printed object. Methods Three regular hexagons of identical geometry were sliced and 3D printed using polylactic acid (PLA) filament on a fused deposition modeling (FDM) 3D printer with varying infill patterns: rectilinear grid, cubic, and gyroid. The hexagons were then radiographed using clinical‐standard scanning protocols. The captured radiographs were compared to simulated radiographs generated using the G‐Code developed when the objects were sliced. The physical and simulated virtual radiographs were compared to one another, and the simulated angle of least and greatest artifact was noted. Results Strong visual agreement was found between the physically captured and simulated virtual radiographs. The projection angles that produced the least amount of artifact were 22.5°, 22.5°, and 12.25° for grid, cubic, and gyroid infills, respectively. The projection angles that produced the greatest amount of artifact were 0°, 45°, and 45° for grid, cubic, and gyroid infills, respectively. Conclusions This work provides designers of 3D printed components with a new way to evaluate a design's radiographic performance. Previously, designers would have to physically print and radiograph a part to determine the artifact produced. This work outlines the development of a tool that simulates the radiograph of a 3D printed part from multiple different projections, saving designers time to iterate to their final design.
Abstract Background ExacTrac Dynamic (ETD) is a novel patient positioning and motion management system for radiation therapy that combines surface guidance, thermal imaging, and stereoscopic x‐rays for image guidance. This combination of technology enables both intrafraction monitoring and surface‐based breath hold gating capabilities. Purpose The purpose of this study was to use the American Association of Physicists in Medicine (AAPM) TG‐302 framework to commission two independent ETD systems for performing breath hold gated lung radiotherapy. Methods A series of static and dynamic tests were performed using an anthropomorphic thorax phantom placed on a dynamic motion platform. Static tests included localization accuracy and reproducibility, and the impact of reference surface selection on localization. Spatial drift was evaluated during system warmup, during typical treatment session duration, and with changing temperature. Dynamic tests assessed localization accuracy and reproducibility, as well as gating latency. Finally, end‐to‐end testing of a simulated breath hold lung stereotactic body radiation therapy (SBRT) treatment was performed, with both gated and ungated dose measurements being acquired. Results Static and dynamic localization accuracy averaged less than 1 mm, with reproducibility within 0.4 mm. An optimal Hounsfield Unit (HU) threshold of‐700 for the reference surface contour was demonstrated to have the best localization accuracy. The maximum observed spatial drift for all tests was less than 1 mm. Congruence between surface guidance, x‐ray imaging, and CBCT were all within 1 mm. Mean beam on and off latency averaged 1023 and 527.1 ms, respectively. End‐to‐end testing demonstrated less than 1% dose difference between gated and non‐gated treatment delivery. The independent ETD systems demonstrated consistent performance across all commissioning tests. Conclusions All commissioning tests were within acceptable tolerances published in the AAPM TG‐302 report. This study demonstrated that the ETD system is suitable for performing surface‐guided breath hold gated lung SBRT treatments.
Abstract UDP ‐glucose dehydrogenase ( UGDH ) variants have been associated with hypotonia, developmental delay, and epilepsy. We report the first pathologic evidence of dystroglycanopathy in siblings with UGDH variants. Both presented around 6 months with developmental delay and elevated creatinine kinase. Sibling A developed epilepsy at age 9 years. Muscle biopsy from sibling A showed necrotizing myopathy with reduced matriglycan immunostaining. Western blot revealed α‐dystroglycan with abnormally low molecular weight. The siblings shared pathogenic UGDH variants in trans: c.305G>A p.(R102Q) is predicted to disrupt protein structure and function; c.265‐6C>G is deleterious to splicing. We propose that UGDH is an additional dystroglycanopathy gene.
ABSTRACT Objective Dystonia is one of the most prevalent movement disorders, characterized by significant clinical and etiological heterogeneity. Despite considerable heritability (~25%), the etiology in most patients remains elusive. Moreover, understanding correlations between clinical manifestations and genetic variants has become increasingly complex. Methods Exome sequencing was conducted on 1924 genetically unsolved, mainly late‐onset isolated dystonia patients, recruited primarily from two dystonia registries (DysTract and the Dystonia Coalition). Rare variants in genes previously linked to dystonia ( n = 406) were examined, confirmed via Sanger sequencing, and analyzed for segregation when possible. Results We identified 137 distinct likely pathogenic/pathogenic variants (according to ACMG criteria) across 51 genes in 163/1924 patients, including 153/1895 index patients (diagnostic yield 8.1%). The strongest predictors of a genetic diagnosis were generalized dystonia (28.6% yield) and age at onset (20.4% yield in patients with onset < 30 years). Notably, 56.2% of these variants were novel, with recurrent variants in EIF2AK2 , VPS16 , KCNMA1 , and SLC2A1 . Additionally, 321 index patients (16.9%) harbored variants of uncertain significance in 102 genes. The most frequently implicated genes included VPS16 , THAP1 , GCH1 , SGCE , GNAL , and KMT2B. Presumably pathogenic variants in less well‐established dystonia genes were also found, including KCNMA1 , KIF1A , and ZMYND11. At least six variants (in ADCY5 , GNB1 , IR2BPL, KCNN2 , KMT2B , and VPS16 ) occurred de novo, supporting pathogenicity. Interpretation This study provides valuable insights into the genetic landscape of dystonia, underscores the utility of exome sequencing for diagnosis, substantiates several candidate genes, and expands the phenotypic spectrum of some genes to include prominent, sometimes isolated dystonia.
ABSTRACT Objective To examine the associations of LRRK2 p.G2019S, GBA1 p.N409S, polygenic risk scores (PRS), and APOE E4 on PD penetrance, risk, and symptoms. Methods We conducted a US‐based observational case–control study using data from the 23andMe Inc. and Fox Insight Genetic Substudy (FIGS) databases. The total cohort included 7,586,842 participants ( n = 35,163 PD); 8791 LRRK2 p.G2019S carriers (565 with PD), 37,427 GBA1 p.N409S carriers (524 with PD), 244 dual LRRK2 /GBA1 carriers (37 with PD), and 7.5 million noncarriers (34,037 with PD). PRS was calculated from the most recently published European genome‐wide association study. Survival models estimated the cumulative incidence of PD. Logistic regressions estimated the relative odds of reporting motor and non‐motor symptoms according to genetic exposure. Results By the age of 80 years, the cumulative incidence of PD was 30% for dual carriers, 24% for LRRK2 p.G2019S carriers, 4% for GBA1 p.N409S carriers, and 2% for noncarriers. Higher PRS was associated with increased penetrance of the variants and earlier time to PD diagnosis. GBA1 p.N409S PD was associated with the highest burden of non‐motor symptoms, including REM sleep behavior disorder and cognitive/memory deficits, and LRRK2 p.G2019S with the lowest. APOE E4 dosage was associated with greater odds of reporting hallucinations and cognitive impairment in addition to carrier status. Interpretation Our findings support the use of genetic screening to enrich candidate selection for neuroprotective trials and better define outcome measures based on genetics.
ABSTRACT Objective The optimal treatment for neurosarcoidosis myelitis is uncertain. We characterize incident neurosarcoidosis myelitis and assess treatment response by MRI and clinical scales. Methods Incident probable or definite neurosarcoidosis myelitis in adults was retrospectively identified from 13 academic medical centers. Cases were analyzed by initial treatment. The primary outcome was T1 post‐contrast gadolinium enhancement resolution at 6 months post‐treatment. Secondary outcomes were changes in modified Rankin scale (mRS) and Expanded Disability Status Scale (EDSS) from nadir to final follow‐up. Results Two hundred two patients were identified (median diagnosis age: 47 years (IQR 39–55); male: female 1.3:1). Median nadir mRS and EDSS were 2 (IQR 2–3) and 4 (IQR 2.5–6). At initial treatment, 129 (63.9%) received prolonged corticosteroids ≥ 4 weeks (group A 1 ), 36 (17.8%) received corticosteroids < 4 weeks (B 1 ), 21 (10.4%) received corticosteroids plus sarcoidosis‐directed immunosuppressant (E), and 16 (7.9%) received corticosteroids plus non‐sarcoidosis‐directed agents (F). In 167 cases with sufficient imaging, there were no significant differences in contrast enhancement resolution at 6 months (A 1 27/106 (25.5%), B 1 9/28 (32.1%), E 5/19 (26.3%), F 5/14 (35.7%); Fisher's exact p = 0.76). There were no significant differences in changes in mRS or EDSS among treatment groups (Kruskal–Wallis p = 0.69 and 0.63, respectively) after median follow‐up of 46.5 months (IQR 18–91.3). Interpretation Different initial immunosuppression strategies did not correlate with MRI contrast enhancement resolution at 6 months or clinical scales (mRS, EDSS). However, conclusions are limited by retrospective design, imbalanced cohorts, and insensitivity of binary MRI outcomes and available clinical scales for treatment response in neurosarcoidosis.
ABSTRACT The primary purpose of this study was to examine the relationships between driving‐specific meta‐mental beliefs, anger rumination and anger experiences with driver inattention. A sample of 527 adult Australian drivers completed an online survey about their driving‐related anger and attention. Bivariate correlations revealed positive relationships between meta‐mental beliefs, anger rumination, anger experiences and the frequency of driver inattention (errors and lapses). In contrast, negative associations were typically found between the anger‐related variables and the self‐reported ability to regulate attention (i.e., attentional presence, flexibility, capacity) while driving. Notably, however, driving anger shared a positive relationship with attentional flexibility. Structural equation modelling demonstrated hierarchical relationships existed between the variables, whereby meta‐mental beliefs indirectly affected driving attention, via the effects they had toward driving‐related anger. The findings of this study offer valuable insights into how anger‐related experiences are developed on the road and how these experiences influence driver attention.
Objective We aimed to assess differences in baseline characteristics, efficacy, and safety of advanced therapies between male and female patients with axial spondyloarthritis (axSpA) in randomized controlled trials (RCTs). Methods We conducted a systematic literature search for RCTs assessing the efficacy of advanced therapies in patients with axSpA until March 19, 2023. We extracted the following outcomes by sex: baseline participant characteristics, Assessment in Spondylarthritis International Society (ASAS) 20/40 criteria, and Axial Spondyloarthritis Disease Activity Score low disease activity or inactive disease (ASDAS‐LDA/ID). Random‐effects models were used to calculate pooled effects for responses in men versus women for different medication classes. Results We included 79 RCTs (n = 23,748 patients, 69.7% male). Only 9 trials (11.4%), 22 trials (28%), and 9 trials (11.4%) reported baseline characteristics, efficacy end points, and safety end points by sex, respectively. At baseline, women were significantly older and had higher pain scores, whereas men had higher C‐reactive protein levels. Overall, male patients were more likely to achieve an ASAS40 response compared to female patients for all advanced therapies (odds ratio [OR] 1.88, 95% confidence interval [CI] 1.44–2.46) and for interleukin‐17A (IL‐17A) inhibitors (IL‐17Ai) (OR 1.82) and tumor necrosis factor inhibitor (TNFi) (OR 2.42), and male patients had numerically higher values for IL‐17A/Fi. Male patients were also more likely to achieve an ASDAS‐LDA/ID (OR 2.19, 95% CI 1.47–3.26) across all advanced therapies and for IL‐17Ai (OR 2.08) and TNFi (OR 2.42) individually. Conclusion Female patients with axSpA are less likely to achieve efficacy outcomes on advanced therapies compared to their male counterparts, with similar differences across medication classes. Future studies should study the biologic (sex‐related) and sociocultural (gender‐related) mechanisms underlying these differences.