Chromothriptic cure of WHIM syndrome.

Chromothripsis is a catastrophic cellular event recently described in cancer in which chromosomes undergo massive deletion and rearrangement. Here, we report a case in which chromothripsis spontaneously cured a patient with WHIM syndrome, an autosomal dominant combined immunodeficiency disease caused by gain-of-function mutation of the chemokine receptor CXCR4. In this patient, deletion of the disease allele, CXCR4(R334X), as well as 163 other genes from one copy of chromosome 2 occurred in a hematopoietic stem cell (HSC) that repopulated the myeloid but not the lymphoid lineage. In competitive mouse bone marrow (BM) transplantation experiments, Cxcr4 haploinsufficiency was sufficient to confer a strong long-term engraftment advantage of donor BM over BM from either wild-type or WHIM syndrome model mice, suggesting a potential mechanism for the patient's cure. Our findings suggest that partial inactivation of CXCR4 may have general utility as a strategy to promote HSC engraftment in transplantation.

Demographic, military, and health comorbidity variables by mild TBI and PTSD status in the LIMBIC-CENC cohort.

OBJECTIVE: To describe associations of demographic, military, and health comorbidity variables between mild traumatic brain injury (mTBI) history and posttraumatic stress disorder (PTSD) status in a sample of Former and current military personnel. SETTING: Participants recruited and tested at seven VA sites and one military training facility in the LIMBIC-CENC prospective longitudinal study (PLS), which examines the long-term mental health, neurologic, and cognitive outcomes among previously combat-deployed U.S. Service Members and Veterans (SM/Vs). PARTICIPANTS: A total of 1,540 SM/Vs with a history of combat exposure. Data were collected between 1/1/2015 through 3/31/2019. DESIGN: Cross-sectional analysis using data collected at enrollment into the longitudinal study cohort examining demographic, military, and health comorbidity variables across PTSD and mTBI subgroups. MAIN MEASURES: PTSD Checklist for DSM-5 (PCL-5), mTBI diagnostic status, Patient Health Questionnaire 9-item (PHQ-9), Pittsburgh Sleep Quality Index (PSQI), AUDIT-C, and other self-reported demographic, military, and health comorbidity variables. RESULTS: Ten years following an index date of mTBI exposure or mid-point of military deployment, combat-exposed SM/Vs with both mTBI history and PTSD had the highest rates of depression symptoms, pain, and sleep apnea risk relative to SM/Vs without both of these conditions. SM/Vs with PTSD, irrespective of mTBI history, had high rates of obesity, sleep problems, and pain. CONCLUSION: The long-term symptom reporting and health comorbidities among SM/Vs with mTBI history and PTSD suggest that ongoing monitoring and intervention is critical for addressing symptoms and improving quality of life.

A high-grade glioma with SOS1 amplification.

The molecular alterations underlying progression of low-grade glial/glioneuronal tumors remain to be elucidated. We present a case of a 56-year-old male with an enhancing left temporal lobe tumor. Histology revealed a high-grade glioma adjacent to a low-grade glioneuronal component with abundant Rosenthal fibers, focal eosinophilic granular bodies, and CD34-positive neurons. The tumor was negative for IDH1 (R132H), BRAF-V600E, and the KIAA1549-BRAF fusion. Comparative genomic hybridization detected a large amplification (> 15 copies) of the Son of Sevenless 1 (SOS1) gene, a component of the MAPK pathway. Although activating mutations in the MAPK pathway occur frequently in gliomas and glioneuronal tumors, SOS1 gene amplification has not been reported previously. This case indicates another potential mechanism for MAPK activation in glial tumors.

Evaluation of a Brief, Skill-Building, Supportive, and Educational Intervention for Couples After Brain Injury.

OBJECTIVE: To examine the effectiveness of an intervention (Therapeutic Couples Intervention, TCI) designed to improve relationship quality for couples after acquired brain injury. SETTING: Outpatient brain injury rehabilitation center. PARTICIPANTS: Persons with brain injury (n = 75) and their intimate partners (n = 75). DESIGN: Two-arm parallel, randomized, controlled trial with wait-listed control. METHODS: Composed of 5 to 6 2-hour sessions, the TCI is a manualized, treatment program designed to enhance relationship quality by addressing issues and concerns most often identified by persons with brain injury and their partners. MAIN MEASURE: Revised Dyadic Adjustment Scale completed by the persons with brain injury and their partners. RESULTS: Persons with brain injury and their partners in the treatment group showed an improvement in relationship quality, both compared with their own baseline values and the control group. CONCLUSIONS: Investigation provided evidence that a curriculum-based education, skill-building, and supportive intervention can benefit couples for up to 3 months after treatment. Additional research is needed to ascertain the long-term benefits of intervention and the efficacy of alternative delivery methods (eg, Internet, telephone, and group).

Efficacy of the resilience and adjustment intervention after traumatic brain injury: a randomized controlled trial.

OBJECTIVE: Examine a psychoeducational and skill-building intervention's effectiveness for individuals after traumatic brain injury (TBI), using a two-arm, parallel, randomized, controlled trial with wait-listed control. METHODS: The Resilience and Adjustment Intervention (RAI) targets adjustment challenges and emphasizes education, skill-building and psychological support. Overall, 160 outpatients were randomly assigned to a treatment or wait-list control (WLC) group. The manualized treatment was delivered in seven 1-h sessions. The Connor-Davidson Resilience Scale (CD-RISC) was the primary outcome measure. Secondary measures included the Mayo Portland Adaptability Inventory-4 (MPAI-4), Brief Symptom Inventory-18 (BSI-18) and 13-Item Stress Test. RESULTS: After adjusting for injury severity, education and time postinjury, the RAI group (N = 75) demonstrated a significantly greater increase in resilience (effect size = 1.03) compared to the WLC group (N = 73). Participants in the RAI group demonstrated more favourable scores on the MPAI-4 Adjustment and Ability Indices, BSI-18 and the 13-item Stress Test. However, only the CD-RISC and BSI-18 demonstrated a clinically significant difference. In addition, RAI participants demonstrated maintenance of gains from pre-treatment to 3-month follow-up; however, only the BSI-18 maintained a clinically significant difference. CONCLUSIONS: Investigation provided evidence that a resilience-focused intervention can improve psychological health and adjustment after TBI. Additional research is needed to ascertain the longer term benefits of intervention and the efficacy of alternative delivery methods (e.g., via telephone, Internet).

Duration of Posttraumatic Amnesia Predicts Neuropsychological and Global Outcome in Complicated Mild Traumatic Brain Injury.

OBJECTIVES: Examine the effects of posttraumatic amnesia (PTA) duration on neuropsychological and global recovery from 1 to 6 months after complicated mild traumatic brain injury (cmTBI). PARTICIPANTS: A total of 330 persons with cmTBI defined as Glasgow Coma Scale score of 13 to 15 in emergency department, with well-defined abnormalities on neuroimaging. METHODS: Enrollment within 24 hours of injury with follow-up at 1, 3, and 6 months. MEASURES: Glasgow Outcome Scale-Extended, California Verbal Learning Test II, and Controlled Oral Word Association Test. Duration of PTA was retrospectively measured with structured interview at 30 days postinjury. RESULTS: Despite all having a Glasgow Coma Scale Score of 13 to 15, a quarter of the sample had a PTA duration of greater than 7 days; half had PTA duration of 1 of 7 days. Both cognitive performance and Extended Glasgow Outcome Scale outcomes were strongly associated with time since injury and PTA duration, with those with PTA duration of greater than 1 week showing residual moderate disability at 6-month assessment. CONCLUSIONS: Findings reinforce importance of careful measurement of duration of PTA to refine outcome prediction and allocation of resources to those with cmTBI. Future research would benefit from standardization in computed tomographic criteria and use of severity indices beyond Glasgow Coma Scale to characterize cmTBI.

Novel age-dependent targets in vestibular schwannomas.

BACKGROUND: Schwannomas are the most common neurofibromatosis type 2 (NF2)-associated tumors with significant phenotypic heterogeneity in patients. The most severe subtype has an early and rapid progression and the mild type has a later onset and a less aggressive course. The aim of this study was to elucidate the underlying molecular differences between these groups. We compared the gene expression pattern between patients with early to late age of onset. RESULTS: A gene signature of 21 genes was constructed to differentiate between early-onset and late-onset patients. We confirmed these results by real-time PCR for SNF1LK2, NGFRAP1L1 (BEX 5), GMNN, and EPHA2. CONCLUSION: Genes identified here may be additional aberrations in merlin-depleted cells that govern the disease onset. A significant number of these genes have been suggested as having a role in carcinogenesis and are used as biomarkers for prognosis in several other cancers. The role of these genes in NF2 carcinogenesis and their potential as biomarkers or drug target are worthwhile exploring.

Schwannomas exhibit distinct size-dependent gene-expression patterns.

AIM: Neurofibromatosis type 2 (NF2)-associated vestibular schwannomas have variable size at presentation which presents a unique challenge in NF2 patient management. Therefore, we investigated the molecular signature characteristic of the differences in size for improved individualized precise therapy. MATERIALS & METHODS: RNA expression analysis was performed on 15 small and 27 large NF2-associated vestibular schwannoma tumors using a microarray analyzing over 47,000 transcripts. RESULTS: A signature of 11 genes was found to be correlated with NF2 tumor size. CONCLUSION: We have identified the genetic hallmark that differentiates large NF2-associated tumors from smaller tumors. This is the first time that these genes have been shown to be the hallmark for NF2 tumor size.

Relationship Between Resilience, Adjustment, and Psychological Functioning After Traumatic Brain Injury: A Preliminary Report.

OBJECTIVE: To examine the relationship between resilience, psychological distress, adjustment, and community participation after traumatic brain injury (TBI). SETTING: Large university health system. PARTICIPANTS: Adult survivors of mild to severe TBI (N = 96). DESIGN: Descriptive, preliminary. MAIN MEASURES: The Connor-Davidson Resilience Scale (10-item version) was used to assess resilience, the Brief Symptom Inventory (BSI-18) was used to characterize psychological distress, and the Mayo-Portland Adaptability Index (MPAI-4) was used to measure ability, adjustment, and participation. RESULTS: Resilience scores were substantially lower than those of the general population. Significant relationships were found between resilience, psychological distress, and adjustment. Partial correlations (adjusting for the other MPAI-4 indices) showed significant correlation (P < .05) between MPAI-4 Adjustment and resilience. Partial correlations (adjusting for the other BSI-18 scales) also showed significance for Depression (P < .01) and resilience. Resilience scores differed significantly (P < .001) between individuals meeting BSI-18 caseness criteria for psychological distress (n = 55) and those not meeting criteria (n = 41). CONCLUSIONS: Individuals with TBI are at risk for low resilience, which was found to correlate with psychological distress and psychosocial maladjustment. Developing interventions to strengthen resilience skills has the potential to improve postinjury psychosocial adjustment, an important area for future research.

Treatment challenges with profound behaviour disturbance after traumatic brain injury: a case report.

BACKGROUND: Severe behavioural disturbances exhibited during the earliest stages of recovery from severe traumatic brain injury often limit the ability to provide standard care. Studies that focus on treatment options for inpatients with such behaviours are scarce. There is limited guidance on how to approach therapy that will maximize the patient's tolerance and participation and how to measure meaningful progress. CASE REPORT: This case study describes how the use of an innovative treatment approach to improve attention was beneficial in rehabilitation of a patient with severe traumatic brain injury whose profound behaviour disturbances substantially precluded participation in traditional therapies. The study shows how rehabilitation utilizing an interactive virtual reality-robotics environment that minimized distractions was associated with improved engagement in therapy, decreased disruptive behaviour during treatment and more sensitive measurement of progress. CONCLUSION: These results may be instructive in how technology can be used to modify therapy sessions to make them accessible to patients with profound behaviour disturbance and how meaningful progress can be measured even in the absence of gains in traditional metrics.

A "virtually minimal" visuo-haptic training of attention in severe traumatic brain injury.

BACKGROUND: Although common during the early stages of recovery from severe traumatic brain injury (TBI), attention deficits have been scarcely investigated. Encouraging evidence suggests beneficial effects of attention training in more chronic and higher functioning patients. Interactive technology may provide new opportunities for rehabilitation in inpatients who are earlier in their recovery. METHODS: We designed a "virtually minimal" approach using robot-rendered haptics in a virtual environment to train severely injured inpatients in the early stages of recovery to sustain attention to a visuo-motor task. 21 inpatients with severe TBI completed repetitive reaching toward targets that were both seen and felt. Patients were tested over two consecutive days, experiencing 3 conditions (no haptic feedback, a break-through force, and haptic nudge) in 12 successive, 4-minute blocks. RESULTS: The interactive visuo-haptic environments were well-tolerated and engaging. Patients typically remained attentive to the task. However, patients exhibited attention loss both before (prolonged initiation) and during (pauses during motion) a movement. Compared to no haptic feedback, patients benefited from haptic nudge cues but not break-through forces. As training progressed, patients increased the number of targets acquired and spontaneously improved from one day to the next. CONCLUSIONS: Interactive visuo-haptic environments could be beneficial for attention training for severe TBI patients in the early stages of recovery and warrants further and more prolonged clinical testing.

Cytogenetic and Molecular Characterization of IDH-Wildtype Glioblastomas and Grade 4 IDH-Mutant Astrocytomas with Unusual Histology.

Glioblastoma (GBM) is a highly heterogenous tumor. Though several well-defined histological patterns of GBMs are known, these are infrequent, and the molecular correlates of several of these histological patterns are not well understood. We identified 31 adult-type infiltrating grade 4 gliomas with unusual histology in our institutional archives from 2016 to 2020, including tumors with a preponderant component of giant cell (n = 15), gemistocytes (n = 6), spindle cells (n = 5), small cells (n = 3), and ependymoma-like features (n = 2). We performed molecular and cytogenetic profiles of IDH-wildtype GBMs with unusual histology and compared to 48 tumors with conventional histology. We found that the majority (85%) of giant cell GBM had increased numbers of whole chromosome loss and genomic haploidization compared to conventional GBMs and other variants. Furthermore, we identified a genetically confirmed GBM with prominent ependymal features, indicating that glial tumors with ependymal features should be considered in the differential diagnosis of GBM. We also identified 6 IDH-mutant grade 4 astrocytomas with unusual histology and similar molecular and cytogenetic profiles to conventional appearing grade 4 IDH-mutant astrocytomas. These findings emphasize the role of molecular/cytogenetic analyses in the diagnostic clarification of GBMs with unusual histological patterns, refine the classification of unusual GBMs, and potentially pave the way for personalized therapies.

Declarative memory and WCST-64 performance in subjects with schizophrenia and healthy controls.

The Wisconsin Card Sorting Test (WCST) is a set-switching task used extensively to study impaired executive functioning in schizophrenia. Declarative memory deficits have also been associated with schizophrenia and may affect WCST performance because continued correct responding depends on remembering the outcome of previous responses. This study examined whether performance in visual and verbal declarative memory tasks were associated with WCST performance. Subjects comprised 30 patients with schizophrenia or schizoaffective disorder (SCZ) and 30 demographically matched healthy controls (CON) who were tested on the WCST, the Benton Visual Retention Test (BVRT), the California Verbal Learning Test (CVLT), and the Continuous Performance Test (CPT). SCZ subjects showed significant correlations between visual and verbal declarative memory and performance on the WCST-64 that were in the hypothesized direction such that worse memory performance was associated with worse performance on the WCST. CON subjects did not show a significant relationship between visual or verbal memory and WCST-64 performance. Fisher's r to z transformations indicated that the associations between declarative memory and WCST-64 performance in the SCZ subjects differed significantly from those of CON subjects. The findings suggest that interpretations of WCST-64 scores for subjects with schizophrenia should be considered in light of their declarative memory functioning.

Tolerance of a virtual reality intervention for attention remediation in persons with severe TBI.

OBJECTIVE: To evaluate the feasibility of applying virtual reality and robotics technology to improve attention in patients with severe traumatic brain injury (TBI) in the early stages of recovery. METHODS: A sample of TBI patients (n=18, aged 19-73) who were receiving acute inpatient rehabilitation completed three-dimensional cancellation exercises over two consecutive days in an interactive virtual environment that minimized distractions and that integrated both visual and haptic (tactile) stimuli. Observations of behaviour during the intervention and of the instructions needed to encourage compliance were recorded. Performance data were compiled to assess improvement across three different treatment conditions. OUTCOMES: Fifteen of the 18 patients demonstrated tolerance of the virtual environment by completing the entire treatment protocol. Within-subjects comparisons of target acquisition time during treatment showed that a treatment condition that included haptic cues produced improved performance compared to a condition in which such cues were not provided. Separating out participants who were in post-traumatic amnesia showed that this group also demonstrated improvement in performance across trials despite their memory impairment. CONCLUSIONS: It is proposed that attention exercises using virtual environments are well-tolerated and engaging and that they could be beneficial for inpatients with severe TBI.

Telehealth in Pediatric Rehabilitation.

Pediatric rehabilitation focuses on optimizing function and quality of life of children through a holistic and transdisciplinary patient-centered team approach. This article describes the incorporation of telehealth in pediatric rehabilitation and its growth over the past decade. It also reviews the experience of practitioners using telehealth by necessity during the 2020 COVID-19 pandemic. Evidence suggests many applications where telehealth can appropriately substitute for traditional in-person visits, and there are many potential applications of telehealth to be explored as a means to enhance connectivity of the interdisciplinary rehabilitation team and the outreach to patients in remote and underserved areas.

Obstructive sleep apnea due to oromandibular dystonia and treated with botulinum toxin.

None: Abnormalities of the upper airway anatomy are an underrecognized cause of obstructive sleep apnea. We present a unique case of a 51-year-old man with episodic sleep-maintenance insomnia and oromandibular dystonia requiring botulinum toxin injections of the temporalis and masseter muscles. He underwent multiple sleep studies and was found to have obstructive sleep apnea temporally associated with the severity of dystonia symptoms and dosing of botulinum toxin.

Underuse of Clinical Decision Rules and d-Dimer in Suspected Pulmonary Embolism: A Nationwide Survey of the Veterans Administration Healthcare System.

PURPOSE: The diagnosis of pulmonary embolism (PE) remains a challenge. CT pulmonary angiography (CTPA) for suspected PE has become the primary imaging modality, but concerns regarding overutilization, overdiagnosis, radiation, and costs have led to algorithms that combine a clinical decision rule (CDR) and highly sensitive d-dimer to identify patients in whom PE can be safely excluded without further studies. This has been identified as a top five Choosing Wisely recommendation in pulmonary medicine, but adherence is modest at best and actual utilization is unknown. Therefore, a survey was conducted to determine the prevalence of this approach in the Veterans Administration (VA) healthcare system. METHODS: A web-based questionnaire survey (SurveyGizmo.com) was developed and validated to query the utilization of CDR ± d-dimer in suspected PE. Key stakeholders identified from national VA mailing lists of radiology, pulmonary, and emergency medicine chiefs were sent an email describing the survey and provided a link for response. This study was reviewed and approved by our local institutional review board and accessing the link represented consent for participation. No personally identifiable data were collected and a drawing for a gift card was provided as an incentive. RESULTS: There were a total of 159 responses, with 120 fully completed surveys for analysis. The majority of respondents were chiefs (63%) with 11+ years of experience (80%), from hospitals with house staff (86%) and an emergency department (97%). Respondents were from emergency medicine (31%), pulmonary (27%), radiology (26%), and other departments (9%). The overwhelming majority of respondents (85%) did not require results of a CDR ± d-dimer before ordering a CTPA. Only 6.7% required a CDR + d-dimer, with others requiring either only a CDR (5.8%) or d-dimer (2.5%). The most common CDR was the Wells score, with only one using the Pulmonary Embolism Rule-Out Criteria. Nine of 18 (50%) regional Veterans Integrated Service Networks reported at least one site requiring a CDR before CTPA. An average of 9.6 CTPAs were estimated to be performed per week. Sorted by CDR and d-dimer use, 8 (CDR + d-dimer), 6.9 (CDR only), 8 (d-dimer only), 10.1 (no requirements) CTPA studies were performed weekly. The average CTPA yield for PE was estimated at 11.9% (CDR + d-dimer), 8% (CDR only), 2.5% (d-dimer only), and 7.6% (no requirements). CONCLUSIONS: The vast majority of hospitals within the VA system do not use a CDR ± d-dimer in the evaluation of patients with suspected PE. Utilization of a CDR and d-dimer may decrease CTPA utilization and increase yield, but this assessment is limited by the scope of the survey. CLINICAL IMPLICATIONS: CDR-guided strategies are recommended in the evaluation of suspected PE. Adherence within the VA healthcare system is very low. Further investigation is warranted to better characterize and improve the adherence to CDR-guided strategies and CTPA utilization.

Multiple Whole Chromosomal Gains Define Angiomatous Meningiomas and Are Absent From the Tumor Vasculature.

Angiomatous meningioma is a variant with prominent vascularity that can mimic other highly vascularized tumors and present diagnostic challenges. Unlike most meningioma variants, where NF2 gene loss on chromosome 22 is the most common genetic abnormality, angiomatous meningiomas are unique in having multiple whole chromosome gains (polysomies). We analyzed 38 meningiomas, 9 angiomatous (including 2 atypical and 1 anaplastic), and 29 nonangiomatous meningiomas, using array comparative genomic hybridization (aCGH). Angiomatous meningiomas showed multiple chromosomal alterations including polysomies and copy neutral loss of heterozygosity in comparison to nonangiomatous variants. The most frequent gains were of chromosomes 5 and 20 (100% and 89% of cases, respectively); none showed chromosome 22 loss. Furthermore, using fluorescence in situ hybridization we show that the vasculature lacked chromosomal polysomy. While generally benign, we present 2 grade II and the first cytogenetically confirmed grade III angiomatous meningioma, demonstrating their potentially aggressive behavior. Thus, multiple polysomies define angiomatous meningioma and aCGH can distinguish this variant from nonangiomatous meningiomas and other histological mimics in diagnostically challenging cases. Furthermore, the prominent vasculature is not neoplastic and likely induced by angiogenic factors. Together, these findings suggest a distinct tumorigenic pathway in angiomatous meningiomas.

Racial disparities in positive airway pressure therapy adherence among veterans with obstructive sleep apnea.

STUDY OBJECTIVES: Black individuals are disproportionately affected by diabetes, cardiovascular disease, obesity, and OSA. Adherence to PAP therapy has been reported to be lower among black individuals. This study seeks to examine associations between black race and PAP adherence among veterans with OSA. METHODS: This was a retrospective study. Veterans newly diagnosed with OSA at a single Department of Veterans Affairs sleep center who were prescribed a modem-enabled PAP device between January 2015 and November 2017 were enrolled. PAP adherence was defined as ≥ 4 hours nightly usage for at least 70% of nights measured at 30 days from PAP setup. We examined the relationship between race and adherence, controlling for sex, marital status, age, socioeconomic status, residual apnea-hypopnea index), and mask leak. RESULTS: Of 3013 patients identified with OSA, 2571 (85%) were newly started on PAP therapy (95% male, aged 59 years ± 14 years, 45% married, 8% with neighborhood socioeconomic disadvantage). Twenty-five percent of participants were black, and 57% were white. PAP adherence at 30 days was 50% overall (42% among blacks, 53% among nonblacks). Black race was associated with reduced 30-day PAP adherence in unadjusted (P < .001) and adjusted logistic regression models (odds ratio = 0.64; 95% CI, 0.53 - 0.78; P < .001). CONCLUSIONS: Among veterans with OSA, black race was associated with reduced PAP adherence. These findings suggest health inequality among black individuals in the treatment of OSA.