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Osteoporosis and loss of muscle mass are secondary issues with spinal cord injury. Robotic gait training has provided evidence of increasing bone density and muscle mass, but its effect on bone strength is undetermined. The purpose of this study was to determine the effect of a 6-week robotic locomotion training program on skeletal muscle mass and bone characteristics. Twelve female Sprague-Dawley rats received a mid-thoracic spinal cord transection at 5 days old and at 3 weeks old were assigned to a Control or Trained Group. The Trained Group performed 5-min sessions on the Rat Stepper 5 days a week for 6 weeks with 90% of body weight supported. At the end of the 6 weeks, body mass was obtained and right femurs and four lower extremity muscles were harvested. Femur bone mineral density was measured with DXA and mechanical characteristics of the femur were determined via 3-point bending testing. Independent t-tests, effects sizes and percent differences were computed between the two groups (p < 0.05). The Trained Group had significantly larger normalized femur mass (p = 0.007) and normalized soleus muscle mass (p = 0.033) when compared to the Control Group. There was a medium or large effect size with the Trained Groups' femurs having larger mass, bone mineral density, rupture loads, cortical wall thickness, shaft cross sectional area, soleus mass, normalized gastrocnemius mass, and smaller shaft inner diameters compared to the Control Group. These changes may contribute to decreasing osteoporosis and fracture risk in those with spinal cord injuries., (© 2024 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Context: Bone-stress injury (BSI) is common in collegiate athletes. Injury rates and health care use in running athletes are not well documented., Objective: To describe the rate and classification of injury and associated health care use in collegiate cross-country runners with BSI., Design: Descriptive epidemiology study., Setting: Sports medicine facilities participating in the Pac-12 Health Analytics Program., Patients or Other Participants: Pac-12 Conference collegiate cross-country athletes., Main Outcome Measure(s): Counts of injury and health care resources used for each injury. Injury rates were calculated based on athlete-seasons., Results: A total of 168 BSIs were reported over 4 seasons from 80 team-seasons (34 men's and 46 women's team-seasons) and 1220 athlete-seasons, resulting in 1764 athletic training services and 117 physician encounters. Bone-stress injuries represented 20% of all injuries reported by cross-country athletes. The average BSI rate was 0.14 per athlete-season. Injury rates were higher in female (0.16) than male (0.10) athletes and higher in the 2019-2020 season (0.20) than the 2020-2021 (0.14), 2018-2019 (0.12), and 2021-2022 (0.10) seasons. Most BSIs occurred in the lower leg (23.8%) and the foot (23.8%). The majority of injuries were classified as overuse and time loss (72.6%) and accounted for most of the athletic training services (75.3%) and physician encounters (72.6%). We found a mean of 10.89 athletic training services per overuse and time-loss injury and 12.20 athletic training services per overuse and non-time-loss injury. Mean occurrence was lower for physician encounters (0.70), prescription medications (0.04), tests (0.75), procedures (0.01), and surgery (0.02) than for athletic training services (10.50)., Conclusions: Bone-stress injuries are common in collegiate cross-country runners and require considerable athletic training resources. Athletic trainers should be appropriately staffed for this population, and suspected BSIs should be confirmed with a medical diagnosis. Future investigators should track treatment codes associated with BSI to determine best-practice patterns., (© by the National Athletic Trainers' Association, Inc.)

Introduction: Mutations in the peripherin-2 gene (PRPH2) are a common cause of inherited retinal dystrophies well known for their phenotypic diversity. We describe a novel presentation of the c.623G > A; p.(Gly208Asp) variant in association with cone-rod dystrophy and reduced penetrance., Case Description: A 39-year-old man presents with a history of decreased visual acuity, photophobia, and dyschromatopsia. Fundus examination was largely unremarkable while spectral-domain optical coherence tomography (SD-OCT) demonstrated diffuse granularity at the ellipsoid zone. Full-field electroretinogram (ffERG) revealed a cone-rod dystrophy. Genetic testing revealed a heterozygous pathogenic variant, c.623G > A; p.(Gly208Asp), in the PRPH2 gene, also found in an unaffected brother. The 50-year-old brother had no visual symptoms and no findings on fundus examination. SD-OCT showed normal retinal architecture and ffERG was within normal limits bilaterally., Conclusion: This case report broadens the known phenotypic presentations of PRPH2-associated retinopathy and suggests that the PRPH2 variant c.623G > A; p.(Gly208Asp) may be associated with reduced penetrance., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The aim of this quality improvement project was to evaluate student satisfaction and achievement of select core competencies in psychotherapy by Psychiatric Mental Health Nurse Practitioner (PMHNP) students enrolled in a newly developed, and virtually delivered psychotherapy course. Both qualitative and quantitative data were collected to assess students' competencies in five domains (i.e. professionalism, cultural diversity, ethical/legal standards of care, reflective practices, and application of knowledge and skills) and satisfaction with content and delivery using simulation and virtual sessions. Using pre- and post-training surveys, we found that competencies in the five domains increased from an average score of 3.1 to 4.5. Integrating a virtual psychotherapy course in advanced nursing education, bringing PMHNP students together to learn about interviewing clients, applying various psychotherapeutic modalities and techniques across diverse cultures, and maintaining ethical and legal standards of care is a challenging but achievable endeavor. We found that using a version of an APA self-assessment tool that was used in psychiatric residency training programs was an effective way to assess PMHNP students' knowledge, skills, and attitudes on these core competencies. Although this training course proved to be effective in imparting appropriate skills, there is a need to develop sophisticated methods to evaluate how students use complex psychotherapy skills in the clinical setting.

Background: Meningiomas are the most common intracranial tumors. Recent advancements in the genetic profiling of tumors have allowed information including DNA copy number analysis, mutational analysis, and RNA sequencing to be more frequently reported, in turn allowing better characterization of meningiomas. In recent years, analysis of tumor methylomes that reflects both cell-origin methylation signatures and somatically acquired DNA methylation changes has been utilized to better classify meningiomas with great success., Method: We report DNA methylation profiling on meningiomas from 17 patients. Formalin-fixed paraffin-embedded (FFPE) meningioma tumor samples were processed, loaded onto the Infinium Methylation EPIC array, and scanned using the Illumina IScan system. Raw IDAT files were processed through the the CNS tumor classifier developed by the Molecular Neuropathology group at the German Cancer Research Center (DKFZ). Corresponding genomics were captured using targeted sequencing panels., Result: Among the meningioma samples, 13 samples were classified as "benign," two samples as "intermediate," and the remaining three samples (from two patients) as "malignant," based on previously validated classification algorithms. In addition to tumor methylation profiling, we also present information that includes patient demographics, clinical presentations, tumor characteristics (including size and location), surgical approaches, and mutational analysis. The two patients who provided the samples with "malignant" methylation classifications had tumor recurrence, reflecting a more aggressive disease course., Conclusion: In accordance with prior reports, our case series provides support that tumor DNA methylation profiling adds meaningful classification information and may be beneficial to incorporate in clinical practice. Our report also reveals that DNA methylation combined with WHO histology classification can more accurately predict tumor behavior than WHO classification alone., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Purpose: To describe the phenotype of CLN-associated retinal dystrophy in a subset of patients at the Columbia University Medical Center, United States, and the Hospital das Clínicas de Pernambuco, Brazil, in comparison to the published literature., Methods: Eleven patients with confirmed biallelic variants in the CLN genes were evaluated via dilated fundus examination, clinical imaging, and full-field electroretinogram. A thorough literature search was conducted to determine previously published variants and associated phenotypes., Results: Genetic testing confirmed the presence of variants in CLN3, CLN7/MFSD8, CLN8, and GRN/CLN11. Five novel variants were identified, and four novel phenotypes of previously published alleles were described. The phenotype differed among patients with variants in the same gene and sometimes among patients with the same allele., Conclusions: Substantial phenotypic variability among variants in the CLN genes makes identification of genotype-phenotype or allele-phenotype correlations challenging. Further study is required to establish an extensive database for adequate patient counseling.

Retinitis pigmentosa (RP) affects approximately 1 in 4000 individuals. It has many different genetic etiologies and therefore diagnosis can be challenging. Understanding the different testing methodologies is beneficial for clinicians and researchers in order to select the best testing method, whether it be panel testing, whole exome sequencing, or whole genome sequencing for individuals affected with RP. The Methods section also outlines the steps required to complete a WES assay, which has become a popular method for identifying the molecular diagnosis for individuals with RP., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Inherited retinal degenerations are clinically and genetically heterogeneous diseases characterized by progressive deterioration of vision. This study aimed at assessing the diagnostic yield of exome sequencing (ES) for an unselected cohort of individuals with hereditary retinal disorders. It is a retrospective study of 357 unrelated affected individuals, diagnosed with retinal disorders who underwent clinical ES. Variants from ES were filtered, prioritized, and classified using the ACMG recommendations. Clinical diagnosis of the individuals included rod-cone dystrophy (60%), macular dystrophy (20%), cone-rod dystrophy (9%), cone dystrophy (4%) and other phenotypes (7%). Majority of the cases (74%) were singletons and 6% were trios. A confirmed molecular diagnosis was obtained in 24% of cases. In 6% of cases, two pathogenic variants were identified with phase unknown, bringing the potential molecular diagnostic rate to ~ 30%. Including the variants of uncertain significance (VUS), potentially significant findings were reported in 57% of cases. Among cases with a confirmed molecular diagnosis, variants in EYS, ABCA4, USH2A, KIZ, CERKL, DHDDS, PROM1, NR2E3, CNGB1, ABCC6, PRPH2, RHO, PRPF31, PRPF8, SNRNP200, RP1, CHM, RPGR were identified in more than one affected individual. Our results support the utility of clinical ES in the diagnosis of genetically heterogeneous retinal disorders., (© 2022. The Author(s).)

Whole transcriptome sequencing (RNA-Seq) has gained prominence for the detection of fusions in solid tumors. Here, we describe the development and validation of an in-house RNA-Seq-based test system (FusionSeq™ 2.0) for the detection of clinically actionable gene fusions, in formalin-fixed paraffin-embedded (FFPE) specimens, using seventy tumor samples with varying fusion status. Conditions were optimized for RNA input of 50 ng, shown to be adequate to call known fusions at as low as 20% neoplastic content. Evaluation of assay performance between FFPE and fresh-frozen (FF) tissues exhibited little to no difference in fusion calling capability. Performance analysis of the assay validation data determined 100% accuracy, sensitivity, specificity, and reproducibility. This clinically developed and validated RNA-Seq-based approach for fusion detection in FPPE samples was shown to be on par if not superior to off-the-shelf commercially offered assays. With gene fusions implicated in a variety of cancer types, offering high-quality, low-cost molecular testing services for FFPE specimens will serve to best benefit the patient and the advancement of precision medicine in molecular oncology. KEY MESSAGES: A custom RNA-Seq-based test system (FusionSeq™ 2.0) for the detection of clinically actionable gene fusions, Evaluation of assay performance between FFPE and fresh-frozen (FF) tissues exhibited little to no difference in fusion calling capability. The assay can be performed with low RNA input and neoplastic content. Performance characteristics of the assay validation data determined 100% accuracy, sensitivity, specificity, and reproducibility., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Molecular features of gynecologic cancers have been investigated in comprehensive studies, but correlation of these molecular signatures with clinical significance for precision medicine is yet to be established. Towards this end, we evaluated 95 gynecologic cancer cases submitted for testing using The JAX ActionSeq™ NGS panel. Molecular profiles were studied and compared to TCGA datasets to identify similarities and distinguishing features among subtypes. We identified 146 unique clinically significant variants (Tier I and II) across 45 of the 212 genes (21%), in 87% (83/95) of cases. TP53, PTEN, ARID1A, PIK3CA and ATM were the most commonly mutated genes; CCNE1 and ERBB2 amplifications were the most frequently detected copy-number alterations. PARP inhibitors were among the most commonly reported drug class with clinical trials, consistent with the frequency of DNA damage-response pathway mutations in our cohort. Overall, our study provides additional insight into the molecular profiles of gynecologic cancers, highlighting regulatory pathways involved, raising the potential implications for targeted therapeutic options currently available., Competing Interests: Declaration of Competing Interest The authors declare no relevant conflict of interest., (Copyright © 2020. Published by Elsevier Inc.)

Objective: The study aimed to retrospectively evaluate the positive yield rate of a custom 212-gene next-generation sequencing (NGS) panel, the JAX ActionSeq™ assay, used in molecular profiling of solid tumors for precision medicine., Methods: We evaluated 261 cases tested over a 24-month period including cancers across 24 primary tissue types and report on the mutation yield in these cases., Results: Thirty-three of the 261 cases (13%) had no detectable clinically significant variants. In the remaining 228 cases (87%), we identified 550 clinically significant variants in 88 of the 212 genes, with four of fewer clinically significant variants being detected in 62 of 88 genes (70%). TP53 had the highest number of variants (125), followed by APC (47), KRAS (47), ARID1A (20), PIK3CA (20) and EGFR (18). There were 38 tier I and 512 tier II variants, with two genes having only a tier I variant, seven genes having both a tier I and tier II variant, and 79 genes having at least one tier II variant. Overall, the ActionSeq™ assay detected clinically significant variants in 42% of the genes included in the panel (88/212), 68% of which (60/88) were detected in more than one tumor type., Conclusions: This study demonstrates that of the genes with documented involvement in cancer, only a limited number are currently clinically significant from a therapeutic, diagnostic and/or prognostic perspective.

The World Health Organization (WHO) has defined more than 130 distinct central nervous system (CNS) tumor entities, of which glioblastoma is the most fatal primary brain tumor. However, the correlation of the molecular signatures of glioblastoma with clinical significance for precision medicine is not well-known. How, and to what extent these variants may affect clinical decision making remains uncertain. Here, we evaluate 48 glioblastomas submitted for testing using the JAX ActionSeq™ Next-generation sequencing (NGS) panel. We identified 131 clinically significant variants (Tier I and II) across 30 of the 212 genes (14%). TP53, EGFR, PTEN, IDH1 were the most commonly mutated genes; EGFR, CDK4 amplifications, and CDKN2A deletion were the most frequently detected copy-number alterations. CDK4/6 and PI3K inhibitors were among the most commonly reported drug class with FDA approved therapies and investigational therapies, which is consistent with the frequencies of these genes in our cohort. Overall, our study established the molecular profiles of glioblastoma based on the 2017 joint consensus guidelines by AMP/ASCO/CAP and provides the potential implications for targeted therapeutic options currently available., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To evaluate intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) sequences for quantitative characterization of anal fistula activity., Methods: This retrospective study was approved by the institutional review board. One hundred and two patients underwent MRI for clinical suspicion of anal fistula. Forty-three patients with demonstrable anal fistulas met the inclusion criteria. Quantitative analysis included measurement of DCE and IVIM parameters. The reference standard was clinical activity based on medical records. Statistical analyses included Bayesian analysis with Markov Chain Monte Carlo, multivariable logistic regression, and receiver operating characteristic analyses., Results: Brevity of enhancement, defined as the time difference between the wash-in and wash-out, was longer in active than inactive fistulas (p = 0.02). Regression coefficients of multivariable logistic regression analysis revealed that brevity of enhancement increased and normalized perfusion area under curve decreased with presence of active fistulas (p = 0.03 and p = 0.04, respectively). By cross-validation, a logistic regression model that included quantitative perfusion parameters (DCE and IVIM) performed significantly better than IVIM only (p < 0.001). Area under the curves for distinguishing patients with active from those with inactive fistulas were 0.669 (95% confidence interval [CI]: 0.500, 0.838) for a model with IVIM only, 0.860 (95% CI: 0.742, 0.977) for a model with IVIM and brevity of enhancement, and 0.921 (95% CI: 0.846, 0.997) for a model with IVIM and all DCE parameters., Conclusion: The inclusion of brevity of enhancement measured by DCE-MRI improved assessment of anal fistula activity over IVIM-DWI only.

Purpose: Radioactive seed localization (RSL) uses a titanium seed labeled with iodine-125 energy for surgery of nonpalpable breast lesions. RSL facilitates radiology-surgery scheduling and allows for improved oncoplasty compared with wire localization (WL). The purpose of this work was to compare the 2 techniques., Methods: We performed a retrospective study of all breast lesions operated with RSL between February 2013 and March 2015 at our university institution, and compared with an equivalent number of surgeries performed with a single WL. Imaging and pathology reports were reviewed for information on guidance mode, accuracy of targeting, nature of excised lesion, size and volume of surgical specimen, status of margins, and reinterventions., Results: A total of 254 lesions (247 women) were excised with RSL and compared with 257 lesions (244 women) whose surgery was guided by WL. Both groups were comparable in lesion pathology, guidance mode for RSL or WL positioning, and accuracy of targeting (98% correct). Mean delay between biopsy and surgery was 84 days for RSL versus 103 after WL (P = .04). No differences were noted after RSL or WL for surgical specimen mean weight, largest diameter, and volume excised. For malignancies, the rate of positive margins was comparable (2.8%-3%), with 5 of 10 women in the RSL group who underwent a second surgery displaying residual malignancy compared with 3 of 9 women in the WL group., Conclusions: RSL is safe and accurate, and has comparable surgical endpoints to WL. Because RSL offers flexible scheduling and facilitated oncoplasty, RSL may replace WL for resection of nonpalpable single breast lesions., (Copyright © 2017 Canadian Association of Radiologists. Published by Elsevier Inc. All rights reserved.)

In tauopathies including Alzheimer's disease, the axonal microtubule-associated protein tau becomes hyperphosphorylated at pathological epitopes and accumulates in the somato-dendritic compartment. However, it remains unclear whether tau becomes phosphorylated at these epitopes in the somato-dendritic compartment and/or in the axon. In primary hippocampal neurons where human tau was over-expressed both in the somato-dendritic compartment and the axon, the pathological epitopes recognized by the antibodies AT8 (S199/S202/T205), AT100 (T212/S214/T217), and AT180 (T231/S235) were found in the somato-dendritic compartment but not in the axon where tau was either not phosphorylated (T205 and T217) or not simultaneously phosphorylated (T231 and S235) at sites included in the above epitopes. When transfected neurons were treated with the phosphatase inhibitor, okadaic acid, AT8, AT100 and AT180 epitopes were observed in the axon, indicating that tau was dephosphorylated at selective sites of pathological epitopes in this compartment. Expression of tau mutants where one phosphorylation site included in the above epitopes was mutated in alanine showed that the formation of one of these epitopes was not required for the formation of the two others in primary hippocampal neurons. All together our results indicate that in the somato-dendritic compartment, the kinase and phosphatase activity does not prevent the formation of pathological epitopes whereas in the axon, the amount of tau phosphorylated at the pathological epitopes is regulated by phosphatase activity, most likely that of phosphoserine/phosphothreonine phosphatase 2A, the major tau phosphatase. This indicates that if the pathological epitopes are initially formed in the axon in Alzheimer's disease brain, the activation of phosphatases could be an efficient way to abolish their generation.

The question addressed in the present experiment was whether an individual who practices a task under different conditions of afferent information develops different movement representations, each of which is based on the most accurate source of afferent information for movement control. In Experiment 1, participants (N = 23) performed a manual aiming movement in a target-only condition for 520 trials before performing in a normal vision condition for an equivalent amount of practice. Control groups performed all practice trials in either a normal vision or a target-only condition. The results revealed that the movement representation developed in the initial (target-only) practice phase remained accessible for movement planning and control. The results of Experiment 2 indicated, however, that participants did not maintain such a representation when their initial practice in the target-only condition was reduced (40 or 160 trials) before they had extensive practice in normal vision. Those results indicate that extensive practice in a target-only and then in a normal vision condition enables an individual to plan and control his or her movement on the basis of the most efficient source of available afferent information. Because visual afferent information provides optimal information for ensuring movement accuracy, however, if initial practice in the target-only condition is only modest or moderate it is likely that that information source will progressively dominate all other sources of afferent information for movement planning and control.

Fatigue and depression have devastating and debilitating effects on functional status, social and occupational functioning, and quality of life in persons with human immunodeficiency virus disease. Contributing factors involved are multifaceted and bidirectional in nature. Thorough assessment of fatigue and depression are essential elements of practice leading to symptom management.

A model of partial denervation of the rat lateral gastrocnemius was used to investigate the effects of daily activity (treadmill plus voluntary wheel exercise) on the regeneration/reinnervation of motoneurons recovering from nerve crush. It appears that increased activity has no effect on axon regeneration rate, but may be detrimental to the reinnervation process.