Somatic mutation landscape in a cohort of meningiomas that have undergone grade progression.

BACKGROUND: A subset of meningiomas progress in histopathological grade but drivers of progression are poorly understood. We aimed to identify somatic mutations and copy number alterations (CNAs) associated with grade progression in a unique matched tumour dataset. METHODS: Utilising a prospective database, we identified 10 patients with meningiomas that had undergone grade progression and for whom matched pre- and post-progression tissue (n = 50 samples) was available for targeted next-generation sequencing. RESULTS: Mutations in NF2 were identified in 4/10 patients, of these 94% were non-skull base tumours. In one patient, three different NF2 mutations were identified in four tumours. NF2 mutated tumours showed large-scale CNAs, with highly recurrent losses in 1p, 10, 22q, and frequent CNAs on chromosomes 2, 3 and 4. There was a correlation between grade and CNAs in two patients. Two patients with tumours without detected NF2 mutations showed a combination of loss and high gain on chromosome 17q. Mutations in SETD2, TP53, TERT promoter and NF2 were not uniform across recurrent tumours, however did not correspond with the onset of grade progression. CONCLUSION: Meningiomas that progress in grade generally have a mutational profile already detectable in the pre-progressed tumour, suggesting an aggressive phenotype. CNA profiling shows frequent alterations in NF2 mutated tumours compared to non NF2 mutated tumours. The pattern of CNAs may be associated with grade progression in a subset of cases.

Severe complications in a 25-year-old male after brown recluse spider bite treated by therapeutic plasma exchange: A case report and review of other case studies.

Although in the majority of patients (90%), the bite wound of brown recluse spider resolves spontaneously, some patients may experience a severe reaction requiring hospitalization. A 25-year-old male developed severe hemolytic anemia, jaundice, and other complications following a brown recluse spider bite on his posterior right thigh. He was treated with methylprednisolone, antibiotics, and red blood cells (RBCs) transfusion without response. Therapeutic plasma exchange (TPE) was added to the treatment regimen, and his hemoglobin (Hb) was eventually stabilized, leading to significant clinical improvement. The beneficial effect of TPE in the current case was compared to three other reported cases. We recommend close monitoring of Hb levels in patients with systemic loxoscelism during the first week after brown recluse spider bite and early implementation of TPE in the management of severe acute hemolysis when patients do not respond to usual treatment modalities and RBC transfusion.

Circulating tumor DNA for malignant peripheral nerve sheath tumors in neurofibromatosis type 1.

PURPOSE: The leading cause of early death in patients with neurofibromatosis type 1 (NF1) is malignant peripheral nerve sheath tumor (MPNST). The principles of management include early diagnosis, surgical clearance and close monitoring for tumor recurrence. Current methods for diagnosis, detection of residual disease and monitoring tumor burden are inadequate, as clinical and radiological features are non-specific for malignancy in patients with multiple tumors and lack the sensitivity to identify early evidence of malignant transformation or tumor recurrence. Circulating tumor DNA (ctDNA) is a promising tool in cancer management and has the potential to improve the care of patients with NF1. In the following article we summarise the current understanding of the genomic landscape of MPNST, report on the previous literature of ctDNA in MPNST and outline the potential clinical applications for ctDNA in NF1 associated MPNST. Finally, we describe our prospective cohort study protocol investigating the utility of using ctDNA as an early diagnostic tool for MPNSTs in NF1 patients.

Engaging parents using web-based feedback on child growth to reduce childhood obesity: a mixed methods study.

BACKGROUND: To measure trends in child growth and combat rising levels of obesity, Manchester University NHS Foundation Trust and the University of Manchester have developed Children's Health and Monitoring Programme (CHAMP). CHAMP collects an annual measurement for primary school children (aged 4 to 11) in Manchester, England, and offers feedback of Body Mass Index (BMI) results to parents via a secure website. No similar digital tool exists that both provides high resolution data on the trajectory of child growth and acts as a feedback and monitoring system. This study investigates how effectively this intervention engaged with parents and supported the reduction of childhood obesity. METHODS: Anonymised CHAMP registration and BMI data (UK1990) were collected between September 2013 and March 2017 from a total of 63,337 children. BMI change over time was compared in matched cohorts of 24,551 children, whose parents had and had not registered with the CHAMP website. Qualitative focus groups and interviews were used to explore perspectives among 29 key informants (parents, school and healthcare professionals) from six schools in Manchester. RESULTS: Overweight children whose parents had not registered with the CHAMP website gained a median of 0.14 BMI centile between measurements, whilst children of CHAMP-registered parents reduced their BMI by a median of 0.4 centile per year (P = 0.02). Normal weight children of registered parents decreased their BMI by 0.3 centile each year, whilst those not registered increased their BMI by 0.8 centile per year (P = 0.001). There was no significant association between registration and BMI centile change in children already classified as obese (P = 0.34). A qualitative, thematic analysis revealed that the annual measurement programme was widely supported by parents and staff. A range of psychological and behavioural impacts on families were reported as a result of the monitoring and feedback processes, in some cases prompting reflection and monitoring of health and lifestyle choices. CONCLUSION: These early findings indicate that CHAMP, as both a monitoring system and a digital intervention, could encourage positive lifestyle change and support healthier child growth trajectories.

Age and gender differences in children and adolescents' attitudes toward noise.

OBJECTIVE: Most school-aged children experience exposure to hazardous sound levels via high-risk noise activities (e.g. loud music/concerts, firearms). Little information exists regarding factors influencing pediatric engagement in these activities and use of hearing protection devices. This study explores effects of age, gender, and attitudes toward noise on participation in acoustic risk-taking behaviors and hearing conservation practices in children and adolescents. DESIGN: Cross-sectional. STUDY SAMPLE: Children and adolescents (10-19 years) with normal hearing. RESULTS: Most children and adolescents (86.5%) participate in at least one potentially high-risk noise behavior. The most frequently cited activities include sporting events, concerts, and playing a musical instrument. Use of hearing protection devices varies by activity, with consistent wear while using firearms but inconsistent application during all other activities. Gender, but not age, influences acoustic risk-taking behaviors: Boys engage in significantly more high-risk noise activities than girls. Participants expressed a neutral attitude toward noise that persisted across age and gender, but a trend shifting toward a pro-noise attitude emerges in later adolescence. CONCLUSIONS: The proliferation of acoustic risk-taking behaviors and lack of hearing conservation practices in children and adolescents requires attention at an early age to prevent future noise-induced hearing loss and subsequent quality of life effects.

Stratification of the impact of inappropriate empirical antimicrobial therapy for Gram-negative bloodstream infections by predicted prognosis.

The bloodstream infection mortality risk score (BSIMRS) predicts the outcome of patients with Gram-negative bloodstream infections (BSI) with high discrimination. This retrospective cohort study examined the impact of inappropriate antimicrobial therapy on mortality in adult patients with Gram-negative BSI admitted to Palmetto Health Hospitals in Columbia, SC, USA, from 1 January 2011 to 31 December 2012 after stratification by predicted prognosis at initial presentation using BSIMRS. A multivariate Cox regression model was used to identify independent risk factors for 28-day mortality overall and within each predefined BSIMRS category (<5, 5 to 9, and ≥ 10). Relative risk reduction (RRR), absolute risk reduction (ARR), and number needed to treat (NNT) were calculated from a predictive logistic regression model of mortality. Overall, 390 unique patients with first episodes of Gram-negative BSI were identified. The median age was 66 years, and 229 (59%) were women. There was significant association between inappropriate antimicrobial therapy and mortality in patients with BSIMRS of 5 to 9 (adjusted hazard ratio [aHR], 3.55; 95% confidence intervals [CI], 1.22 to 8.31; P = 0.02) and BSIMRS of ≥ 10 (aHR, 4.99; 95% CI, 1.09 to 22.87; P = 0.04) but not in those with BSIMRS of <5 (aHR, 3.34; 95% CI, 0.17 to 22.77; P = 0.34). RRR, ARR, and NNT were 0.25, 0.02, and 63 for BSIMRS of <5; 0.56, 0.32, and 3 for BSIMRS of 5 to 9; and 0.39, 0.39, and 3 for BSIMRS of ≥ 10, respectively. There is a significant benefit from appropriate antimicrobial therapy in patients with Gram-negative BSI with guarded (BSIMRS of 5 to 9) and poor (BSIMRS of ≥ 10) predicted prognosis. Survival difference remains unclear among those with good predicted prognosis (BSIMRS of <5) at initial presentation.

Changing practice to improve quality of life in glioma.

As treatment for glioma advances, with an attendant improvement in length of patient survival, the quality of that survival has rightly become an increasingly important patient-centered metric, and health-related quality of life (HRQOL) an important outcome measure. HRQOL is a self-assessed, multidimensional concept encompassing the physical, emotional, and social components of quality of life associated with illness and its treatment. Neurosurgeons caring for patients with gliomas should be aware of the latest research on HRQOL to understand mechanisms by which it can be improved. Neurosurgical outcomes related to surgical complications and neurological deficits can be important determinants of HRQOL and are well understood by neurosurgeons. However, an understanding of more general or global determinants of HRQOL not commonly addressed in the clinic, and implementation of the attendant evidence-based interventions to address them, would be transformative. The authors explore HRQOL determinants related to patient-, social-, tumor-, and treatment-related factors, with a particular emphasis on the strongest determinants, fatigue, sleep disturbance, anxiety, depression, neurocognitive dysfunction, caregiver distress, and end-of-life concerns. Evidence-based interventions are reviewed, including fatigue management, cognitive rehabilitation, insomnia interventions exercise, caregiver training, palliative care, and an overall multidisciplinary team approach. Lastly, features of a program are outlined that would embed HRQOL in neurosurgical care to the benefit of both patients and staff.

Development of a clinical questionnaire to support contraception decisions in an adolescent reproductive health clinic in Colorado.

CONTEXT: Adolescents need support to make informed decisions about contraception. Few clinical questionnaires exist to help adolescents and their healthcare providers align contraception decisions with patient needs and preferences. METHODS: Our mixed-methods study involved a convenience sample of English-speaking, female patients aged 13-19 seeking contraception services at an adolescent reproductive health clinic in Colorado, USA. Qualitative interviews informed development of clinical questionnaire items. The questionnaire elicited demographic characteristics, pregnancy and contraception use history, preferred contraception attributes, peer and family involvement, healthcare information and support needs, motivations for contraceptive use, and barriers to contraceptive services. We identified key decision-making factors and reduced the number of questionnaire items through principal components analysis. Using multivariable analyses, we examined the correlation between questionnaire responses and current contraceptive method. RESULTS: Twenty individuals participated in interviews and 373 individuals completed the preliminary questionnaire with 63 candidate items. We identified five contraceptive decision-making factors: side-effect avoidance (eight items, Cronbach's alpha = 0.84), preferred method attributes (six items, Cronbach's alpha = 0.67), parental involvement (three items, Cronbach's alpha = 0.67), life goals prior to parenting (four items, Cronbach's alpha = 0.88), and access to a contraceptive provider (two items, Cronbach's alpha = 0.92) and nine stand-alone items. In multivariable analyses, we found that questionnaire responses for decision-making factors varied among participants using different contraceptive methods. CONCLUSIONS: Multiple priorities may influence adolescent contraceptive decisions. This clinical questionnaire can elicit these priorities before or during a healthcare encounter. Future studies should assess generalizability of the questionnaire and examine impact on method choice, continuation, satisfaction, and reproductive health outcomes.

Needs, Roles, and Challenges of Young Asian Neurosurgeons.

BACKGROUND: Asia has a marked shortage of neurosurgical care, with approximately 2.5 million critical cases left untreated. The Young Neurosurgeons Forum of the World Federation of Neurosurgical Societies surveyed Asian neurosurgeons to identify research, education, and practice. METHODS: A cross-sectional study using a pilot-tested e-survey was circulated to the Asian neurosurgical community from April to November 2018. Descriptive statistics were used to summarize variables pertaining to demographics and neurosurgical practices. The chi-square test was used to explore the relationship between World Bank income level and variables on neurosurgical practices. RESULTS: A total of 242 responses were analyzed. Respondents were mostly from the low- and middle-income countries (70%). Most represented institutions were teaching hospitals (53%). More than 50% of the hospitals had between 25and 50 neurosurgical beds. Access to an operating microscope (P = 0.038) or image guidance system (P = 0.001) appeared to increase in correlation to a higher World Bank income level. Limited opportunities for conducting research (56%) and hands-on operating opportunities (45%) were leading challenges in daily academic practice. The leading challenges were limited numbers of intensive care unit beds (51%), inadequate or absent insurance coverage (45%), and lack of organized perihospital care (43%). Inadequate insurance coverage decreased with increasing World Bank income levels (P < 0.001). Organized perihospital care (P = 0.001), regular magnetic resonance imaging access (P = 0.032), and equipment necessary for microsurgery (P = 0.007) increased with higher World Bank income levels. CONCLUSIONS: Improving neurosurgical care hinges on regional and international collaboration and national policies to ensure universal access to essential neurosurgical care.

Adult medulloblastoma in an Australian population.

Medulloblastoma in adult patients is a rare condition with limited contemporary demographic and treatment outcome data available in an Australian population. We conducted a retrospective review of patterns of care and outcomes of adult patients diagnosed with medulloblastoma treated at major neuro-oncology centres across Australia between January 2010 and December 2019. A total of 80 patients were identified and the median follow-up after diagnosis was 59.2 (range 0.5-204) months. A variety of chemotherapy regimens were used in the adjuvant and recurrent settings. The median overall survival (mOS) was 78 months (IQR 17.5-94.8). Patients who had no residual disease post-resection or with SHH-subtype tumours had a numerically longer 5-year survival rate than those with residual disease post resection or non-SHH subtypes respectively. The median time to recurrence from diagnosis was 18.4 months. The median OS from 1st relapse was 22.1 months (95% CI 11.7-31.4) and mOS from second relapse was 10.2 months (95% CI 6.6 - NR). This is the largest dataset examining patterns of care of adult patients with medulloblastoma in an Australian population. Substantial variation existed in the chemotherapy agents used in the adjuvant and recurrent setting. As has been demonstrated in a paediatric population, trials such as the upcoming EORTC 1634-BTG/NOA-23 trial (PersoMed-1 study) which are tailoring treatments to molecular profiles are likely to improve outcome in adult medulloblastoma.

Intraventricular pseudolymphoma a case review.

Intracranial pseudolymphoma is a rare entity. We report the case of a 44 year old female who presented with headaches and was noted to have a right lateral ventricular lesion on a background history of Burkitt's lymphoma. She underwent biopsy of said lesion and was found to have benign reactive lymphoid tissue. This is the third reported case in literature of intracranial pseudolymphoma and the first reported intraventricular lesion.

Differential requirement for beta-catenin in epithelial and fiber cells during lens development.

Recent studies implicate Wnt/beta-catenin signaling in lens differentiation (Stump, R. J., et al., 2003. A role for Wnt/beta-catenin signaling in lens epithelial differentiation. Dev Biol;259:48-61). Beta-catenin is a component of adherens junctions and functions as a transcriptional activator in canonical Wnt signaling. We investigated the effects of Cre/LoxP-mediated deletion of beta-catenin during lens development using two Cre lines that specifically deleted beta-catenin in whole lens or only in differentiated fibers, from E13.5. We found that beta-catenin was required in lens epithelium and during early fiber differentiation but appeared to be redundant in differentiated fiber cells. Complete loss of beta-catenin resulted in an abnormal and deficient epithelial layer with loss of E-cadherin and Pax6 expression as well as abnormal expression of c-Maf and p57(kip2) but not Prox1. There was also disrupted fiber cell differentiation, characterized by poor cell elongation, decreased beta-crystallin expression, epithelial cell cycle arrest at G(1)-S transition and premature cell cycle exit. Despite cell cycle arrest there was no induction of apoptosis. Mutant fiber cells displayed altered apical-basal polarity as evidenced by altered distribution of the tight junction protein, ZO1, disruption of apical actin filaments and abnormal deposition of extracellular matrix, resulting in a deficient lens capsule. Loss of beta-catenin also affected the formation of adhesion junctions as evidenced by dissociation of N-cadherin and F-actin localization in differentiating fiber cells. However, loss of beta-catenin from terminally differentiating fibers had no apparent effects on adhesion junctions between adjacent embryonic fibers. These data indicate that beta-catenin plays distinct functions during lens fiber differentiation and is involved in both Wnt signaling and adhesion-related mechanisms that regulate lens epithelium and early fiber differentiation.

High-frequency oscillatory ventilation is not associated with increased risk of neuropathology compared with positive pressure ventilation: a preterm primate model.

High-frequency oscillatory ventilation (HFOV) may improve pulmonary outcome in very preterm infants, but the effects on the brain are largely unknown. We hypothesized that early prolonged HFOV compared with low volume positive pressure ventilation (LV-PPV) would not increase the risk of delayed brain growth or injury in a primate model of neonatal chronic lung disease. Baboons were delivered at 127 +/- 1 d gestation (dg; term approximately 185 dg), ventilated for 22-29 d with either LV-PPV (n = 6) or HFOV (n = 5). Gestational controls were delivered at 153 dg (n = 4). Brains were assessed using quantitative histology. Body, brain, and cerebellar weights were lower in both groups of prematurely delivered animals compared with controls; the brain to body weight ratio was higher in HFOV compared with LV-PPV, and the surface folding index was lower in the LV-PPV compared with controls. In both ventilated groups compared with controls, there was an increase in astrocytes and microglia and a decrease in oligodendrocytes (p < 0.05) in the forebrain and a decrease in cerebellar granule cell proliferation (p < 0.01); there was no difference between ventilated groups. LV-PPV and HFOV ventilation in prematurely delivered animals is associated with decreased brain growth and an increase in subtle neuropathologies; HFOV may minimize adverse effects on brain growth.

Developmental and neuropathological consequences of ductal ligation in the preterm baboon.

A patent ductus arteriosus (PDA) alters pulmonary mechanics and regional blood flow in the preterm infant. Its significance with respect to brain injury and brain development are unclear. We evaluated the effects of surgical ductal ligation on the preterm baboon brain. Baboons were delivered at 125 d of gestation (dg, term approximately 185 dg) and ventilated for 14 d (n = 12). The PDA was ligated 6 d after delivery (n = 7) or left untreated (n = 5). Animals were euthanized at 139 dg and brains compared histologically with gestational control fetuses (n = 7) at 140 dg. Brain and body weights were reduced (p < 0.05) in both groups of ventilated preterm animals; however, the brain to body weight ratio was increased (p < 0.01) in ligated, but not unligated newborns compared with gestational controls. No overt lesions were observed in either premature newborn group. Astrocyte density in the neocortex and hippocampus were greatest in the unligated newborns (p < 0.01). Myelination and oligodendrocytes were reduced (p < 0.05) in both premature newborn groups. The brain growth and development index was reduced, and the damage index was increased in prematurely delivered baboons. Surgical ligation of the PDA does not increase the incidence of brain injury and may be beneficial if the PDA is contributing to persistent pulmonary and hemodynamic instability.

Driving Simulator Performance in Novice Drivers with Autism Spectrum Disorder: The Role of Executive Functions and Basic Motor Skills.

Previous studies have shown that individuals with autism spectrum disorder (ASD) demonstrate poorer driving performance than their peers and are less likely to obtain a driver's license. This study aims to examine the relationship between driving performance and executive functioning for novice drivers, with and without ASD, using a driving simulator. Forty-four males (ages 15-23), 17 with ASD and 27 healthy controls, completed paradigms assessing driving skills and executive functioning. ASD drivers demonstrated poorer driving performance overall and the addition of a working memory task resulted in a significant decrement in their performance relative to control drivers. Results suggest that working memory may be a key mechanism underlying difficulties demonstrated by ASD drivers and provides insight for future intervention programs.

Review of Upper Extremity Nerve Transfer in Cervical Spinal Cord Injury.

OBJECTIVE: Several nerve transfers have now been successfully performed for upper limb reanimation in tetraplegia. This study was performed to review the use of nerve transfers for upper limb reanimation in tetraplegia. METHODS: Medline and Embase (1950 to February 11, 2015) were searched using a search strategy designed to include any studies that reported cases of nerve transfer in persons with cervical spinal cord injury (SCI). RESULTS: A total of 103 manuscripts were selected initially and full-text analysis produced 13 studies with extractable data. Of these manuscripts, 10 reported single cases and 3 reported case series. Eighty-nine nerve transfers have been performed in 57 males and 2 females with a mean age of 34 years. The mean SCI level was C6 (range: C5-7), time to surgery post-SCI was 19.9 months (range: 4.1-156 months), and follow-up time was 18.2 months (range: 3-60 months). All case reports recorded a Medical Research Council (MRC) score of 3 or 4 for recipient muscle power, but two early case series reported more variable results. CONCLUSION: This review documents the current status of nerve transfer surgery for upper limb reanimation in tetraplegia and summarizes the functional results in 59 cases with 89 nerve transfers performed, including 15 cases of double-nerve transfer and 1 case of triple-nerve transfer.

Atypical and malignant meningiomas: Considerations for treatment and efficacy of radiotherapy.

The purpose of this study was to add to the current body of literature which is aimed at establishing the role of postoperative adjuvant radiotherapy (RT) in the treatment of atypical and malignant meningiomas. Meningiomas are the most frequently reported primary intracranial tumours, accounting for more than 35%. The majority of meningiomas are benign, with atypical and malignant tumours accounting for only 6-18%. Utilising a prospective multi-institutional database, we retrospectively reviewed 67 patients with documented World Health Organisation (WHO) Grade II/III meningiomas, diagnosed between 1989 and 2012 and resected at two major Australian hospitals. Nine patients were excluded and the remaining 58 were analysed. The patient demographics, tumour characteristics, surgical details and adjuvant therapy were retrieved. Kaplan-Meier curves were used to compare the survival of patients treated with RT versus surgery alone. The 3 year progression free survival (PFS) and overall survival (OS) were 44 and 76% for the entire cohort, respectively. Of the patients who had gross total resections, 42% had 3 years PFS and 77% had 3 years OS, which was not significantly different from those with subtotal resection. The overall median survival was 11.0 years, 12.2 for atypical and 1.6 for malignant meningiomas. The patients with malignant meningiomas were 14 times as likely to receive RT as the patients with atypical meningiomas. The patients who received RT had a 3 year PFS of 63% compared to 40% in those who did not receive radiation. The 3 year OS was 31% higher for females than males. Histopathological progression was noted in 17% of our cohort. This study reinforces a number of important factors that should be considered when treating patients presenting with WHO Grade II and III meningiomas, including sex, potential for grade progression, and the lack of evidence for adjuvant RT and the timing thereof.