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Neurofibromin 1 (NF1) loss of function (LoF) mutations are frequent in melanoma and drive hyperactivated RAS and tumor growth. NF1LoF melanoma cells, however, do not show consistent sensitivity to individual MEK, ERK, or PI3K/mTOR inhibitors. To identify more effective therapeutic strategies for treating NF1LoF melanoma, we performed a targeted kinase inhibitor screen. A tool compound named MTX-216 was highly effective in blocking NF1LoF melanoma growth in vitro and in vivo. Single-cell analysis indicated that drug-induced cytotoxicity was linked to effective cosuppression of proliferation marker Ki-67 and ribosomal protein S6 phosphorylation. The antitumor efficacy of MTX-216 was dependent on its ability to inhibit not only PI3K, its nominal target, but also SYK. MTX-216 suppressed expression of a group of genes that regulate mitochondrial electron transport chain and are associated with poor survival in patients with NF1LoF melanoma. Furthermore, combinations of inhibitors targeting either MEK or PI3K/mTOR with an independent SYK kinase inhibitor or SYK knockdown reduced the growth of NF1LoF melanoma cells. These studies provide a path to exploit SYK dependency to selectively target NF1LoF melanoma cells. Significance: A kinase inhibitor screen identifies SYK as a targetable vulnerability in melanoma cells with NF1 loss of function.

OBJECTIVE Endoscopic third ventriculostomy (ETV) is an option for treatment of hydrocephalus, including for patients who have a history of previous treatment with CSF shunt insertion. The purpose of this study was to report the success of postshunt ETV by using data from a multicenter prospective registry. METHODS Prospectively collected data in the Hydrocephalus Clinical Research Network (HCRN) Core Data Project (i.e., HCRN Registry) were reviewed. Children who underwent ETV between 2008 and 2019 and had a history of previous treatment with a CSF shunt were included. A Kaplan-Meier survival curve was created for the primary outcome: time from postshunt ETV to subsequent CSF shunt placement or revision. Univariable Cox proportional hazards models were created to evaluate for an association between clinical and demographic variables and subsequent shunt surgery. Postshunt ETV complications were also identified and categorized. RESULTS A total of 203 children were included: 57% male and 43% female; 74% White, 23% Black, and 4% other race. The most common hydrocephalus etiologies were postintraventricular hemorrhage secondary to prematurity (56, 28%) and aqueductal stenosis (42, 21%). The ETV Success Score ranged from 10 to 80. The median patient age was 4.1 years. The overall success of postshunt ETV at 6 months was 41%. Only the surgeon’s report of a clear view of the basilar artery was associated with a lower likelihood of postshunt ETV failure (HR 0.43, 95% CI 0.23–0.82, p = 0.009). None of the following variables were associated with postshunt ETV success: age at the time of postshunt ETV, etiology of hydrocephalus, sex, race, ventricle size, number of previous shunt operations, ETV performed at time of shunt infection, and use of external ventricular drainage. Overall, complications were reported in 22% of patients, with CSF leak (8.6%) being the most common complication. CONCLUSIONS Postshunt ETV was successful in treating hydrocephalus, without subsequent need for a CSF shunt, in 41% of patients, with a clear view of the basilar artery being the only variable significantly associated with success. Complications occurred in 22% of patients. ETV is an option for treatment of hydrocephalus in children who have previously undergone shunt placement, but with a lower than expected likelihood of success.

OBJECTIVE In utero repair of fetal posterior cephaloceles (meningocele and encephalocele) is being performed based on the premise that fetal surgery prevents progressive herniation of neural tissue and brain damage during pregnancy. However, the extent to which progressive herniation occurs during pregnancy, specifically from prenatal diagnosis to after delivery, is not well known. The objective of this study was to describe the natural history of patients with fetal cephaloceles focusing on the incidence of progressive herniation. METHODS The authors conducted a retrospective cohort study of all patients referred to their center for posterior fetal cephalocele between 2006 and 2021. All patients underwent prenatal and postnatal MRI. Progressive herniation (primary outcome) was defined as an increase in the absolute volume of neural tissue within the cephalocele of > 5% or new herniation of a critical structure into the cephalocele. Total brain and cephalocele volumes were calculated to determine herniation progression from prenatal to postnatal MRI. Information on the presence of hydrocephalus, epilepsy, and developmental delay (secondary outcomes) was collected at 1 year of age. RESULTS Twenty patients met all study criteria. Ten patients (50%; 95% CI 0.27–0.73) demonstrated progressive herniation from prenatal to postnatal MRI. Three patients with progressive herniation were diagnosed with a meningocele prenatally and had an encephalocele postnatally. Two patients without progression had meningocele identified prenatally that regressed and became atretic by birth. Both prenatal hindbrain herniation (p = 0.03) and prenatal microcephaly (p = 0.05) were predictive of progressive herniation. The rates of hydrocephalus (44%), epilepsy (44%), and developmental delay (63%) were not associated with the occurrence of progressive herniation in this study. CONCLUSIONS In this study, progressive herniation was not a rare event (50%). Fetal hindbrain herniation and fetal microcephaly were associated with the occurrence of progressive herniation. These results support further investigations into why progressive herniation occurs in utero and if progressive cerebral herniation in utero plays a significant role in determining clinical outcome.

OBJECTIVE The aim of this study was to determine differences in complications and outcomes between posterior fossa decompression with duraplasty (PFDD) and without duraplasty (PFD) for the treatment of pediatric Chiari malformation type I (CM1) and syringomyelia (SM). METHODS The authors used retrospective and prospective components of the Park-Reeves Syringomyelia Research Consortium database to identify pediatric patients with CM1-SM who received PFD or PFDD and had at least 1 year of follow-up data. Preoperative, treatment, and postoperative characteristics were recorded and compared between groups. RESULTS A total of 692 patients met the inclusion criteria for this database study. PFD was performed in 117 (16.9%) and PFDD in 575 (83.1%) patients. The mean age at surgery was 9.86 years, and the mean follow-up time was 2.73 years. There were no significant differences in presenting signs or symptoms between groups, although the preoperative syrinx size was smaller in the PFD group. The PFD group had a shorter mean operating room time (p < 0.0001), fewer patients with > 50 mL of blood loss (p = 0.04), and shorter hospital stays (p = 0.0001). There were 4 intraoperative complications, all within the PFDD group (0.7%, p > 0.99). Patients undergoing PFDD had a 6-month complication rate of 24.3%, compared with 13.7% in the PFD group (p = 0.01). There were no differences between groups for postoperative complications beyond 6 months (p = 0.33). PFD patients were more likely to require revision surgery (17.9% vs 8.3%, p = 0.002). PFDD was associated with greater improvements in headaches (89.6% vs 80.8%, p = 0.04) and back pain (86.5% vs 59.1%, p = 0.01). There were no differences between groups for improvement in neurological examination findings. PFDD was associated with greater reduction in anteroposterior syrinx size (43.7% vs 26.9%, p = 0.0001) and syrinx length (18.9% vs 5.6%, p = 0.04) compared with PFD. CONCLUSIONS PFD was associated with reduced operative time and blood loss, shorter hospital stays, and fewer postoperative complications within 6 months. However, PFDD was associated with better symptom improvement and reduction in syrinx size and lower rates of revision decompression. The two surgeries have low intraoperative complication rates and comparable complication rates beyond 6 months.

BACKGROUND AND AIMS: The Rome Foundation Global Epidemiology Study (RFGES) assessed the prevalence, burden, and associated factors of Disorders of Gut-Brain Interaction (DGBI) in 33 countries around the world. Achieving worldwide sampling necessitated use of two different surveying methods: In-person household interviews (9 countries) and Internet surveys (26 countries). Two countries, China and Turkey, were surveyed with both methods. This paper examines the differences in the survey results with the two methods, as well as likely reasons for those differences. METHODS: The two RFGES survey methods are described in detail, and differences in DGBI findings summarized for household versus Internet surveys globally, and in more detail for China and Turkey. Logistic regression analysis was used to elucidate factors contributing to these differences. RESULTS: Overall, DGBI were only half as prevalent when assessed with household vs Internet surveys. Similar patterns of methodology-related DGBI differences were seen within both China and Turkey, but prevalence differences between the survey methods were dramatically larger in Turkey. No clear reasons for outcome differences by survey method were identified, although greater relative reduction in bowel and anorectal versus upper gastrointestinal disorders when household versus Internet surveying was used suggests an inhibiting influence of social sensitivity. CONCLUSIONS: The findings strongly indicate that besides affecting data quality, manpower needs and data collection time and costs, the choice of survey method is a substantial determinant of symptom reporting and DGBI prevalence outcomes. This has important implications for future DGBI research and epidemiological research more broadly. ispartof: NEUROGASTROENTEROLOGY AND MOTILITY vol:35 issue:6 ispartof: location:England status: accepted

BACKGROUND & AIMS: The Rome criteria are widely accepted for diagnosing disorders of gut-brain interaction, but their global applicability has been debated. This study aimed to evaluate the validity of the Rome IV criteria by factor analysis globally, across geographical regions, by sex, and by age groups. METHODS: Data were collected in 26 countries using the Rome IV questionnaire. Forty-nine ordinal variables were used in exploratory factor analysis (EFA) to identify clusters of inter-correlated variables (factors) within the data set. Confirmatory factor analysis with predefined factors of the disorders of gut-brain interaction was compared with the factors in the EFA. Analyses were performed globally, for each geographical region (North and Latin America, Western and Eastern Europe, Middle East, Asia), sex, and age groups (18-34, 35-49, 50-64, ≥65). RESULTS: A total of 54,127 people were included. The EFA identified 10 factors accounting for 57% of the variance: irritable bowel syndrome, constipation, diarrhea, upper gastrointestinal symptoms, globus, regurgitation/retching, chest pain, nausea/vomiting, and 2 right upper quadrant pain factors. Most factors had close correspondence to a Rome IV criteria diagnosis, but notably, functional dysphagia and heartburn symptoms were often included in the same factor and/or in upper gastrointestinal symptoms. Most factors were consistent across geographical regions, sex, and age groups, and compatible to the global results. All prespecified factors in the confirmatory analysis had a loading ≥0.4, indicating validity of the Rome IV criteria. CONCLUSIONS: The results indicate that the Rome IV criteria for irritable bowel syndrome, functional dyspepsia, functional constipation, globus, and biliary pain are globally valid and represent universal diagnostic entities that are similar across sex and age groups. ispartof: GASTROENTEROLOGY vol:164 issue:7 pages:1211-1222 ispartof: location:United States status: published

BACKGROUND AND AIMS: Conditions such as irritable bowel syndrome (IBS), functional dyspepsia, and functional constipation are among the prevalent gastrointestinal (GI) disorders classified as disorders of gut-brain interaction (DGBI), which can adversely affect the lives of sufferers. This study aimed to assess the degree and consequences of overlapping DGBI in a large population-based global scale. METHODS: Internet survey data from 54,127 adults (49.1% women) in 26 countries were analyzed by 4 GI anatomic regions (esophageal, gastroduodenal, bowel, and anorectal). The number of DGBI-affected GI regions was assessed, including associations with sex, age, disease severity, quality of life, psychosocial variables, and health care utilization. RESULTS: A total of 40.3% of surveyed individuals met Rome IV criteria for a DGBI. The percentages with 1-4 DGBI-affected GI regions were 68.3%, 22.3%, 7.1%, and 2.3%, respectively. The IBS symptom severity score increased significantly from 1 (207.6) to 4 (291.6) regions, as did non-GI symptom reporting (somatization), anxiety and depression, concerns and embarrassment about bowel function, doctor visits, medications, and abdominal surgeries (all P < .0001). Quality of life decreased with increasing number of DGBI regions (P < .0001). In a logistic mixed model, non-GI symptoms (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.08-1.10), being very vs not concerned (OR, 2.55; 95% CI, 2.27-2.90), being very vs not embarrassed about bowel function (OR, 1.20; 95% CI, 1.08-1.33), and mean number of doctor visits (OR, 1.23; 95% CI, 1.115-1.32) were most strongly associated with number of DGBI regions. CONCLUSIONS: DGBI in multiple anatomic GI regions is associated with increased psychological comorbidity, health care utilization, and IBS severity. Physician awareness of overlap could improve quality of care, prevent unnecessary interventions, and yield more positive health outcomes. ispartof: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY vol:20 issue:5 pages:E945-E956 ispartof: location:United States status: published

Supplementary Dataset S5

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Neurofibromin 1 (NF1) loss of function (LoF) mutations are frequent in melanoma and drive hyperactivated RAS and tumor growth. NF1LoF melanoma cells, however, do not show consistent sensitivity to individual MEK, ERK, or PI3K/mTOR inhibitors. To identify more effective therapeutic strategies for treating NF1LoF melanoma, we performed a targeted kinase inhibitor screen. A tool compound named MTX-216 was highly effective in blocking NF1LoF melanoma growth in vitro and in vivo. Single-cell analysis indicated that drug-induced cytotoxicity was linked to effective cosuppression of proliferation marker Ki-67 and ribosomal protein S6 phosphorylation. The antitumor efficacy of MTX-216 was dependent on its ability to inhibit not only PI3K, its nominal target, but also SYK. MTX-216 suppressed expression of a group of genes that regulate mitochondrial electron transport chain and are associated with poor survival in patients with NF1LoF melanoma. Furthermore, combinations of inhibitors targeting either MEK or PI3K/mTOR with an independent SYK kinase inhibitor or SYK knockdown reduced the growth of NF1LoF melanoma cells. These studies provide a path to exploit SYK dependency to selectively target NF1LoF melanoma cells.Significance:A kinase inhibitor screen identifies SYK as a targetable vulnerability in melanoma cells with NF1 loss of function.

OBJECTIVE The goal of this study was to assess the social determinants that influence access and outcomes for pediatric neurosurgical care for patients with Chiari malformation type I (CM-I) and syringomyelia (SM). METHODS The authors used retro- and prospective components of the Park-Reeves Syringomyelia Research Consortium database to identify pediatric patients with CM-I and SM who received surgical treatment and had at least 1 year of follow-up data. Race, ethnicity, and insurance status were used as comparators for preoperative, treatment, and postoperative characteristics and outcomes. RESULTS A total of 637 patients met inclusion criteria, and race or ethnicity data were available for 603 (94.7%) patients. A total of 463 (76.8%) were non-Hispanic White (NHW) and 140 (23.2%) were non-White. The non-White patients were older at diagnosis (p = 0.002) and were more likely to have an individualized education plan (p < 0.01). More non-White than NHW patients presented with cerebellar and cranial nerve deficits (i.e., gait ataxia [p = 0.028], nystagmus [p = 0.002], dysconjugate gaze [p = 0.03], hearing loss [p = 0.003], gait instability [p = 0.003], tremor [p = 0.021], or dysmetria [p < 0.001]). Non-White patients had higher rates of skull malformation (p = 0.004), platybasia (p = 0.002), and basilar invagination (p = 0.036). Non-White patients were more likely to be treated at low-volume centers than at high-volume centers (38.7% vs 15.2%; p < 0.01). Non-White patients were older at the time of surgery (p = 0.001) and had longer operative times (p < 0.001), higher estimated blood loss (p < 0.001), and a longer hospital stay (p = 0.04). There were no major group differences in terms of treatments performed or complications. The majority of subjects used private insurance (440, 71.5%), whereas 175 (28.5%) were using Medicaid or self-pay. Private insurance was used in 42.2% of non-White patients compared to 79.8% of NHW patients (p < 0.01). There were no major differences in presentation, treatment, or outcome between insurance groups. In multivariate modeling, non-White patients were more likely to present at an older age after controlling for sex and insurance status (p < 0.01). Non-White and male patients had a longer duration of symptoms before reaching diagnosis (p = 0.033 and 0.004, respectively). CONCLUSIONS Socioeconomic and demographic factors appear to influence the presentation and management of patients with CM-I and SM. Race is associated with age and timing of diagnosis as well as operating room time, estimated blood loss, and length of hospital stay. This exploration of socioeconomic and demographic barriers to care will be useful in understanding how to improve access to pediatric neurosurgical care for patients with CM-I and SM.

OBJECTIVE The primary objective of this trial was to determine if shunt entry site affects the risk of shunt failure. METHODS The authors performed a parallel-design randomized controlled trial with an equal allocation of patients who received shunt placement via the anterior entry site and patients who received shunt placement via the posterior entry site. All patients were children with symptoms or signs of hydrocephalus and ventriculomegaly. Patients were ineligible if they had a prior history of shunt insertion. Patients received a ventriculoperitoneal shunt after randomization; randomization was stratified by surgeon. The primary outcome was shunt failure. The planned minimum follow-up was 18 months. The trial was designed to achieve high power to detect a 10% or greater absolute difference in the shunt failure rate at 1 year. An independent, blinded adjudication committee determined eligibility and the primary outcome. The study was conducted by the Hydrocephalus Clinical Research Network. RESULTS The study randomized 467 pediatric patients at 14 tertiary care pediatric hospitals in North America from April 2015 to January 2019. The adjudication committee, blinded to intervention, excluded 7 patients in each group for not meeting the study inclusion criteria. For the primary analysis, there were 229 patients in the posterior group and 224 patients in the anterior group. The median patient age was 1.3 months, and the most common etiologies of hydrocephalus were postintraventricular hemorrhage secondary to prematurity (32.7%), myelomeningocele (16.8%), and aqueductal stenosis (10.8%). There was no significant difference in the time to shunt failure between the entry sites (log-rank test, stratified by age < 6 months and ≥ 6 months; p = 0.061). The hazard ratio (HR) of a posterior shunt relative to an anterior shunt was calculated using a univariable Cox regression model and was nonsignificant (HR 1.35, 95% CI, 0.98–1.85; p = 0.062). No significant difference was found between entry sites for the surgery duration, number of ventricular catheter passes, ventricular catheter location, and hospital length of stay. There were no significant differences between entry sites for intraoperative complications, postoperative CSF leaks, pseudomeningoceles, shunt infections, skull fractures, postoperative seizures, new-onset epilepsy, or intracranial hemorrhages. CONCLUSIONS This randomized controlled trial comparing the anterior and posterior shunt entry sites has demonstrated no significant difference in the time to shunt failure. Anterior and posterior entry site surgeries were found to have similar outcomes and similar complication rates.

Think Aloud (TA) has been used as a tool to promote self-regulation and reflection in coaches, yet it has not been employed in the same context to support athletes. The aim of the present study was to understand golfers’ perceptions of using TA at two time points: immediately postperformance and after a 6- to 8-week reflection period. Six golfers (five male, one female; age: M = 30.8 years, SD = 14.8; handicap: M = 6.92, SD = 3.9) used TA during the performance on six holes of golf and listened back to their TA audio. Using semistructured interviews and subsequent thematic analyses, we generated four themes: increased awareness, awareness of how behavior influences performance, disruption of thought processes and performance, and application to coaching. Preliminary evidence provides support for TA as a potential tool to promote self-regulation in golfers, which could be used to inform coaching interventions.

The current study aimed to explore the perceptions of football academy coaches on their use of a novel reflective tool (Think Aloud [TA]) and to understand if this can support the development of knowledge within coaches. Eight male coaches (Mage = 36) employed full time at a Category 1 football academy within the United Kingdom took part. All coaches attended a 2-hr workshop on the use of TA as a reflective tool, with the opportunity to practice TA while coaching. Participants were interviewed on their perceptions of TA as a reflective tool using a semistructured approach. Data were analyzed abductively, which allowed the generation of initial codes and the involvement of the triad of knowledge (professional, interpersonal, and intrapersonal knowledge), which has been adopted within coaching and identified as an approach to developing coaching expertise, within the analysis process. Findings suggest that all three types of knowledge can be developed through the use of TA, with subthemes identified within each type of knowledge: professional knowledge (player and coach development and session design), interpersonal knowledge (communication and relationships), and intrapersonal knowledge (biases, self-awareness, and reflection). This research offers a novel perspective on coach development through the implementation of TA, with potential to support the development of coaching knowledge and expertise.

Combined with a common fuel binder, solid hypergols can simplify the overall complexity of hybrid rocket engines, as the fuel grain can be ignited and reignited without any external power source or...

The purpose of this paper is to explore the interconnectedness between physical literacy, intentionality and the notion of embodied beckoning. We coin the term ‘embodied beckoning’ to explain our innate transactional relationship and desire as human beings to explore the world through movement, and how the environment also calls us to move. We draw upon a range of perspectives including post-humanism, social-materialism and Deleuzian theory and explore how these paradigms may enable us to continue to blur the lines between mind and body, self and environment, and view human embodiment, interaction and intentionality more holistically. Our ultimate goal is to try to better understand engagement in physical activity, for holistic health, wellbeing and flourishment.\ud \ud Physical literacy could have a significant contribution to make in understanding, exploring and nurturing embodied experiences. Physical literacy may be able to provide a much-needed philosophical framework from which the promotion of engagement in physical activity, physical education and wider sport, leisure and recreational activities are undertaken with an holistic appreciation of human embodiment.

Benign anorectal disorders of structure and function are common in clinical practice. These guidelines summarize the preferred approach to the evaluation and management of defecation disorders, proctalgia syndromes, hemorrhoids, anal fissures, and fecal incontinence in adults and represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence for these guidelines was assessed using the Grading of Recommendations Assessment, Development and Evaluation process. When the evidence was not appropriate for Grading of Recommendations Assessment, Development and Evaluation, we used expert consensus to develop key concept statements. These guidelines should be considered as preferred but are not the only approaches to these conditions.

Background Irritable bowel syndrome (IBS) is highly prevalent worldwide but mechanisms for healthcare seeking behaviours in this patient group are poorly understood. Objective To describe healthcare utilization and identify factors associated with seeking healthcare amongst IBS subjects in the general population. Methods An internet survey was completed by 6,300 individuals equally distributed between United States, United Kingdom and Canada. The Rome IV diagnostic questionnaire was used to identify subjects with IBS. Data on demographics, medical history, gastrointestinal (GI) and non‐GI symptoms, quality of life and health care consumption was collected. Results A total of 5,931 subjects were included; 274 (4.6%) IBS subjects and 5657 (95.3%) non‐IBS controls. IBS subjects reported more doctor consultations for both GI and other health problems as well as increased use of medication and rate of abdominal surgery (appendectomy excluded). Having healthcare insurance or access to free public healthcare (adjusted odds ratio (AOR) 4.49, 95% confidence interval (CI) 1.31–15.44), followed by high frequency of bloating (AOR 2.65, 95% CI 1.42–4.93) and increasing age (AOR 1.02, 95% CI 1.01–1.05) were found to be independently associated with being an IBS consulter while doctor‐diagnosed IBS subjects were more likely to be female and to report abdominal pain as their most bothersome GI symptom than other consulters with IBS. Conclusion IBS subjects have higher healthcare utilization than non‐IBS controls, medication use and abdominal surgery included. Furthermore, consulters with and without an IBS diagnosis differ in sex distribution and symptom profiles. Hence, awareness of the possibility of unnecessary medical and surgical treatment in IBS subjects and a sex‐related diagnostic bias by doctors is warranted.

In-utero repair of open neural tube defects (ONTD) is an accepted treatment option with demonstrated superior outcomes for eligible patients. While current guidelines recommend genetic testing by chromosomal microarray analysis (CMA) when a major congenital anomaly is detected prenatally, the requirement for an in-utero repair, based on the Management of Myelomeningocele Study (MOMS) criteria, is a normal karyotype. In this study, we aimed to evaluate if CMA should be recommended as a prerequisite for in-utero ONTD repair.This was a retrospective cohort study that included pregnancies complicated by ONTD for which laparotomy-assisted fetoscopic repair or an open hysterotomy fetal surgery was performed at a single tertiary center between September 2011 and July 2021. All patients met the MOMS eligibility criteria and had a normal karyotype. For a subset of the pregnancies (n=77), CMA testing was also conducted. We reviewed the results of the CMA and divided the cohort into two groups: group A - no detected CNV, and group B - reportable CNV detected. We then compared the groups' surgical characteristics, complications, and maternal and early neonatal outcomes. Standard parametric and non-parametric statistical methods were employed as appropriate.One hundred and forty-six fetuses with ONTD were eligible and underwent in-utero repair during the study period. CMA results were available for 77 (52.7%) patients. Of those, 65 (84%) had a normal CMA, and 12 (16%) had a reportable CNV, 2 (2.6%) of which were classified as pathogenic. Maternal demographics, clinical characteristics, operative data, and post-operative complications were similar between those with normal CMA results and those with reportable CNVs. There were no significant differences in gestational age at delivery or any obstetrical and early neonatal outcome between the study groups.Standard diagnostic testing with CMA should be offered when an ONTD is detected prenatally, as this approach has implications for counseling about prognosis and recurrence risk. Our results indicate that the presence of a reportable CNV should not a priori affect eligibility for in-utero repair, as overall outcomes for pregnancies are similar to those with normal CMA. Nevertheless, significant CMA results will require a case-by-case multidisciplinary discussion to evaluate eligibility. To generalize the conclusion of this single-center series, a larger long-term study should be considered. This article is protected by copyright. All rights reserved.

Radiotherapy for pediatric brain tumor has been associated with late cognitive effects. Compared to conventional photon radiotherapy (XRT), proton radiotherapy (PRT) delivers lower doses of radiation to healthy brain tissue. PRT has been associated with improved long-term cognitive outcomes compared to XRT. However, there is limited research comparing the effects of XRT and PRT on verbal memory.Survivors of pediatric brain tumor treated with either XRT (Overall, patients receiving PRT demonstrated superior verbal learning and recall compared to those treated with XRT. Encoding and retrieval deficits were more common in the XRT group than the PRT group, with encoding problems being most prevalent. The PRT group was more likely to engage in semantic clustering strategies, which predicted better encoding and retrieval. Encoding ability was associated with higher intellectual and adaptive functioning, and fewer parent-reported concerns about day-to-day attention and cognitive regulation.Results suggest that PRT is associated with verbal memory sparing, driven by effective encoding and use of learning strategies. Future work may help to clarify underlying neural mechanisms associated with verbal memory decline, which will better inform treatment approaches. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

OBJECTIVE Fetal repair of an open neural tube defect (ONTD) by open hysterotomy has been shown to reduce the need for ventriculoperitoneal shunting and improve motor outcomes for infants, but increases the risk of Cesarean section and prematurity. Fetoscopic repair is an alternative approach that may confer similar neurological benefits but allows for vaginal delivery and reduces the incidence of hysterotomy-related complications. We sought to compare the costs of care from fetal surgery until neonatal discharge, as well as the clinical outcomes, associated with each surgical approach. METHODS This was a retrospective cohort study of patients who underwent prenatal ONTD repair, using either the open-hysterotomy or the fetoscopic approach, at a single institution between 2012 and 2018. Clinical outcomes were collected by chart review. A cost-consequence analysis was conducted from the hospital perspective, and included all inpatient and ambulatory hospital and physician costs incurred for the care of mothers and their infants, from the time of maternal admission for fetal ONTD repair up to postnatal maternal and infant discharge. Costs were estimated using cost-to-charge ratios for hospital billing and the Medicare physician fee schedule for physician billing. RESULTS Seventy-eight patients were included in the analysis, of whom 47 underwent fetoscopic repair and 31 underwent open-hysterotomy repair. In the fetoscopic-repair group, compared with the open-repair group, fewer women underwent Cesarean section (53% vs 100%; P

OBJECTIVE To determine the impact of the lesion type (cystic [myelomeningocele] or flat [myeloschisis]) on the fetal motor function (MF) in cases candidates for prenatal open neural tube defect (ONTD) repair. METHODS Retrospective cohort study of patients with ONTD who underwent prenatal repair at a single institution between 2011 and 2019. The lesion type and the measurements of the length and width of the lesions to calculate the surface of the ellipsoid lesion were performed using MR scans. Prenatal MF of the lower extremities was evaluated by ultrasound following a metameric distribution at the time of referral. Intact MF was defined as the observation of plantar flexion of the ankle. Logistic regression was performed to determine the predictive value of the type of lesion for having an intact MF at the time of referral. RESULTS 103 patients were included at 22.9 (19-25.4) weeks; 65% had cystic and 35% had flat lesions. At the time of referral, there was a higher proportion of cases with an intact MF in the presence of flat lesions (34/36; 94.4%) as compared to cystic lesion (48/67; 71.6%, p

Pediatric central nervous system (CNS) phaeohyphomycosis is a rare invasive fungal infection associated with high mortality.We describe a child with progressive neurologic symptoms whose ultimate diagnosis was Cladophialophora bantiana -associated CNS phaeohyphomycosis. We discuss her clinical presentation, medical and surgical management and review the current literature.A 9-year-old female presented with acute onset of headaches, ophthalmoplegia and ataxia. Initial infectious work-up was negative, including serial fungal cerebrospinal fluid cultures. Over 2 months, she experienced progressive cognitive and motor declines, and imaging revealed worsening meningitis, ventriculitis and cerebritis. Ultimately, Cladophialophora was detected by plasma metagenomic next-generation sequencing (mNGS). Fourth ventricle fluid sampling confirmed the diagnosis of C. bantiana infection. Given the extent of her disease, complete surgical resection was not feasible. She required multiple surgical debridement procedures and prolonged antifungal therapy, including the instillation of intraventricular amphotericin B. With aggressive surgical and medical management, despite her continued neurologic deficits, she remains alive 3 years after her initial diagnosis. To our knowledge, this is one of a few published pediatric cases of CNS phaeohyphomycosis and the first with the causative pathogen identified by plasma mNGS.CNS phaeohyphomycosis is a serious, life-threatening infection. The preferred management includes a combination of surgical resection and antifungal therapy. In cases complicated by refractory ventriculitis, intraventricular antifungal therapy can be considered as adjuvant therapy. Direct sampling of the CNS for pathogen identification and susceptibility testing is the gold standard for diagnosis; however, the use of plasma mNGS may expedite the diagnosis.

Economic theories of residential location suggest that households tend to live in neighbourhoods with similar households. Yet in England we have seen increasing evidence of better off households moving to live in more deprived areas, especially since the financial crisis. Here we ask whether these household decisions are more a matter of choice or constraint. Our results suggest that household attributes are consistently important in decision making but household behaviour also relates closely both to the extent of market tension and to individual financial constraints - with households in pressured areas particularly affected by worsening affordability. Supply policy, which has tended to concentrate new building in deprived areas has helped facilitate such moves. A particularly important issue in a rapidly changing housing environment is the extent to which tenure and location appear often to be joint decisions - with many better-off households choosing to buy in more deprived areas. Those who move to or within more deprived areas as owner-occupiers are positive about both their housing and tenure choice but not about their location; private tenants on the other hand appear relatively unhappy with their dwelling, their neighbourhood and their tenure - in both cases reflecting trade-offs and constraints.

To determine if preoperative cervical length in the low-normal range increases the risk of adverse perinatal outcome in patients undergoing fetoscopic spina bifida repair.This was a retrospective cohort study of patients who underwent fetal spina bifida repair between September 2014 and May 2022 at a single center. Cervical length was measured on transvaginal ultrasound during the week before surgery. Eligibility for laparotomy-assisted fetoscopic spina bifida repair was as per the criteria of the Management of Myelomeningocele Study, although maternal body mass index (BMI) up to 40 kg/mThe study included 99 patients with a preoperative cervical length 30 mm and 12 patients with a cervix 25-30 mm in length. One further case which underwent spina bifida repair was excluded because cervical length was measured 1 week before surgery. No differences in maternal demographics, gestational age (GA) at surgery, duration of surgery or duration of carbon dioxide uterine insufflation were observed between groups. Cases with low-normal cervical length had an earlier GA at delivery (median (range), 35.2 (25.1-39.7) weeks vs 38.2 (26.0-40.9) weeks; P = 0.01), higher rates of delivery at 34 weeks (41.7% vs 10.2%; P = 0.01) and 30 weeks (25.0% vs 1.0%; P 0.01) and a higher rate of preterm prelabor rupture of membranes (PPROM) (58.3% vs 26.3%; P = 0.04) at an earlier GA (mean ± SD, 29.3 ± 4.0 weeks vs 33.0 ± 2.4 weeks; P = 0.05) compared to those with a normal cervical length. Neonates of cases with low-normal cervical length had a longer stay in the neonatal intensive care unit (20 (7-162) days vs 9 (3-253) days; P = 0.02) and higher rates of respiratory distress syndrome (50.0% vs 14.4%; P 0.01), sepsis (16.7% vs 1.0%; P = 0.03), necrotizing enterocolitis (16.7% vs 0%; P = 0.01) and retinopathy (33.3% vs 1.0%; P 0.01). There was an association between preoperative cervical length and risk of delivery at 30 weeks which was significant only for patients with a maternal BMI 25 kg/mLow-normal cervical length (25-30 mm) as measured before in-utero laparotomy-assisted fetoscopic spina bifida repair may increase the risk of adverse perinatal outcomes, including PPROM and preterm birth, leading to higher rates of neonatal complications. These data warrant further research and are of critical relevance for clinical teams considering the eligibility of patients for in-utero spina bifida repair. Based on this evidence, patients with a low-normal cervical length should be aware of their increased risk for adverse perinatal outcome. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Fecal incontinence (FI) is a debilitating gastrointestinal disorder with a devastating impact on quality of life

OBJECTIVE Iron has been implicated in the pathogenesis of brain injury and hydrocephalus after preterm germinal matrix hemorrhage-intraventricular hemorrhage, however, it is unknown how external or endogenous intraventricular clearance of iron pathway proteins affect the outcome in this group. METHODS This prospective multicenter cohort included patients with posthemorrhagic hydrocephalus (PHH) who underwent (1) temporary and permanent cerebrospinal fluid (CSF) diversion and (2) Bayley Scales of Infant Development-III testing around 2 years of age. CSF proteins in the iron handling pathway were analyzed longitudinally and compared to ventricle size and neurodevelopmental outcomes. RESULTS Thirty-seven patients met inclusion criteria with a median estimated gestational age at birth of 25 weeks; 65% were boys. Ventricular CSF levels of hemoglobin, iron, total bilirubin, and ferritin decreased between temporary and permanent CSF diversion with no change in CSF levels of ceruloplasmin, transferrin, haptoglobin, and hepcidin. There was an increase in CSF hemopexin during this interval. Larger ventricle size at permanent CSF diversion was associated with elevated CSF ferritin (p = 0.015) and decreased CSF hemopexin (p = 0.007). CSF levels of proteins at temporary CSF diversion were not associated with outcome, however, higher CSF transferrin at permanent CSF diversion was associated with improved cognitive outcome (p = 0.015). Importantly, longitudinal change in CSF iron pathway proteins, ferritin (decrease), and transferrin (increase) were associated with improved cognitive (p = 0.04) and motor (p = 0.03) scores and improved cognitive (p = 0.04), language (p = 0.035), and motor (p = 0.008) scores, respectively. INTERPRETATION Longitudinal changes in CSF transferrin (increase) and ferritin (decrease) are associated with improved neurodevelopmental outcomes in neonatal PHH, with implications for understanding the pathogenesis of poor outcomes in PHH. ANN NEUROL 2021;90:217-226.

To investigate the association of the myelomeningocele (MMC) volume with prenatal and postnatal motor function (MF) in cases who underwent a prenatal repair. Retrospective cohort study (11/2011 to 03/2019) of 63 patients who underwent a prenatal MMC repair (37 fetoscopic, 26 open-hysterotomy). At referral, measurements of the volume of MMC was performed based on ultrasound scans. A large MMC was defined as greater than the optimal volume threshold (ROC analysis) for the prediction of intact MF at referral (2.7 cc). Prenatal or postnatal intact motor function (S1) was defined as the observation of plantar flexion of the ankle based on ultrasound scan or postnatal examination. 23/63 participants presented a large MMC. Large MMC lesions was associated with an increased risk of having clubfeet by 9.5 times (CI%95[2.1–41.8], p Trial registration: Clinicaltrials.gov NCT02230072 and NCT03794011 registered on September 3rd, 2014 and January 4th, 2019.

OBJECTIVE The authors compared survival and multiple comorbidities in children diagnosed with craniopharyngioma who underwent gross-total resection (GTR) versus subtotal resection (STR) with radiation therapy (RT), either intensity-modulated radiation therapy (IMRT) or proton beam therapy (PBT). The authors hypothesized that there are differences between multimodal treatment methods with respect to morbidity and progression-free survival (PFS). METHODS The medical records of children diagnosed with craniopharyngioma and treated surgically between February 1997 and December 2018 at Texas Children’s Hospital were reviewed. Surgical treatment was stratified as GTR or STR + RT. RT was further stratified as PBT or IMRT; PBT was stratified as STR + PBT versus cyst decompression (CD) + PBT. The authors used Kaplan-Meier analysis to compare PFS and overall survival, and chi-square analysis to compare rates for hypopituitarism, vision loss, and hypothalamic obesity (HyOb). RESULTS Sixty-three children were included in the analysis; 49% were female. The mean age was 8.16 years (95% CI 7.08–9.27). Twelve of 14 children in the IMRT cohort underwent CD. The 5-year PFS rates were as follows: 73% for GTR (n = 31), 54% for IMRT (n = 14), 100% for STR + PBT (n = 7), and 77% for CD + PBT (n = 11; p = 0.202). The overall survival rates were similar in all groups. Rates of hypopituitarism (96% GTR vs 75% IMRT vs 100% STR + PBT, 50% CD + PBT; p = 0.023) and diabetes insipidus (DI) (90% GTR vs 61% IMRT vs 85% STR + PBT, 20% CD + PBT; p = 0.004) were significantly higher in the GTR group. There was no significant difference in the HyOb or vision loss at the end of study follow-up among the different groups. Within the PBT group, 2 patients presented a progressive vasculopathy with subsequent strokes. One patient experienced a PBT-induced tumor. CONCLUSIONS GTR and CD + PBT presented similar rates of 5-year PFS. Hypopituitarism and DI rates were higher with GTR, but the rate of HyOb was similar among different treatment modalities. PBT may reduce the burden of hypopituitarism and DI, although radiation carries a risk of potential serious complications, including progressive vasculopathy and secondary malignancy. Further prospective study comparing neurocognitive outcomes is necessary.

Objectives: To report a recalcitrant spontaneous cerebrospinal fluid (CSF) fistula arising from multiple, anatomically-linked lateral skull base defects, and to review the available literature to determine optimal techniques for operative repair of congenital CSF fistulae. Methods: A patient with recurrent episodes of otologic meningitis was found to have a patent tympanomeningeal fissure, also known as a Hyrtl’s fissure, and internal auditory canal (IAC) diverticulum that communicated with the jugular bulb. A systematic review of the literature characterized all reports of spontaneous congenital perilabyrinthine CSF leaks, and all cases of Hyrtl’s fissures. Results: An 11-year-old female was referred for recurrent meningitis. Imaging demonstrated a fistulous connection between the middle ear and IAC diverticulum via the jugular foramen. Specifically, a Hyrtl’s fissure was identified, as well as demineralized bone around the jugular bulb. Obliteration of the fissure was initially performed, and a fistula reformed 4 months later. Multifocal CSF egress in the hypotympanum was identified on re-exploration, and middle ear obliteration with external auditory canal (EAC) overclosure was performed. A systematic review of the literature demonstrated 19 cases of spontaneous congenital perilabyrinthine CSF leaks. In total, 6 cases had multiple sources of CSF leak and 2 had history suggestive of intracranial hypertension. All of these noted cases demonstrated leak recurrence. Middle ear obliteration with EAC overclosure was successful in 4 recalcitrant cases. Conclusions: Repair of spontaneous congenital perilabyrinthine CSF leaks in cases demonstrating multiple sources of egress or signs of intracranial hypertension should be approached with caution. Middle ear obliteration with EAC overclosure may provide the most definitive management option for these patients, particularly if initial attempt at primary repair is unsuccessful.

OBJECTIVE Posterior fossa decompression with duraplasty (PFDD) is commonly performed for Chiari I malformation (CM-I) with syringomyelia (SM). However, complication rates associated with various dural graft types are not well established. The objective of this study was to elucidate complication rates within 6 months of surgery among autograft and commonly used nonautologous grafts for pediatric patients who underwent PFDD for CM-I/SM. METHODS The Park-Reeves Syringomyelia Research Consortium database was queried for pediatric patients who had undergone PFDD for CM-I with SM. All patients had tonsillar ectopia ≥ 5 mm, syrinx diameter ≥ 3 mm, and ≥ 6 months of postoperative follow-up after PFDD. Complications (e.g., pseudomeningocele, CSF leak, meningitis, and hydrocephalus) and postoperative changes in syrinx size, headaches, and neck pain were compared for autograft versus nonautologous graft. RESULTS A total of 781 PFDD cases were analyzed (359 autograft, 422 nonautologous graft). Nonautologous grafts included bovine pericardium (n = 63), bovine collagen (n = 225), synthetic (n = 99), and human cadaveric allograft (n = 35). Autograft (103/359, 28.7%) had a similar overall complication rate compared to nonautologous graft (143/422, 33.9%) (p = 0.12). However, nonautologous graft was associated with significantly higher rates of pseudomeningocele (p = 0.04) and meningitis (p < 0.001). The higher rate of meningitis was influenced particularly by the higher rate of chemical meningitis (p = 0.002) versus infectious meningitis (p = 0.132). Among 4 types of nonautologous grafts, there were differences in complication rates (p = 0.02), including chemical meningitis (p = 0.01) and postoperative nausea/vomiting (p = 0.03). Allograft demonstrated the lowest complication rates overall (14.3%) and yielded significantly fewer complications compared to bovine collagen (p = 0.02) and synthetic (p = 0.003) grafts. Synthetic graft yielded higher complication rates than autograft (p = 0.01). Autograft and nonautologous graft resulted in equal improvements in syrinx size (p < 0.0001). No differences were found for postoperative changes in headaches or neck pain. CONCLUSIONS In the largest multicenter cohort to date, complication rates for dural autograft and nonautologous graft are similar after PFDD for CM-I/SM, although nonautologous graft results in higher rates of pseudomeningocele and meningitis. Rates of meningitis differ among nonautologous graft types. Autograft and nonautologous graft are equivalent for reducing syrinx size, headaches, and neck pain.

To estimate the significance of the association between mid-trimester maternal serum alpha-fetoprotein (MSAFP) level and fetal neuroanatomic findings in cases of open neural tube defect (ONTD).Retrospective study of patients referred for prenatal ONTD repair between 2012 and 2018. Cases were classified into three groups based on their MSAFP level: 1)High MSAFP (3.8MoM - n = 22), 2)Moderately high MSAFP (≤3.8 and ≥2.5MoM - n = 28), 3)Normal MSAFP (2.5MoM - n = 18). MRI scans at the time of referral were used to assess the relationship between MSAFP and: A)Type of ONTD; B) Ventriculomegaly; C) Size of the myeloschisis lesion; D) Volume of myelomeningocele; E) Anatomical level of the lesion (LL).Having a high MSAFP level was more likely to be associated ventriculomegaly at mid-gestation than a moderately high or normal MSAFP level (OR = 8.4;CI95[0.9-73.4];p = 0.05 and OR = 2.8;CI95[0.9-8.8];p = 0.07). There were no differences between the three groups regarding type of lesion, size of the myeloschisis lesion, anatomic LL, or volume of the myelomeningocele sac. Myeloschisis cases with normal MSAFP had a larger surface area when compared to myeloschisis cases with moderately high MSAFP (219.8[104.4-551] vs 155.4[38.5-502.4] mm², p = 0.04).A 2nd trimester MSAFP level3.8MoM in a fetus with ONTD is associated with mid-gestation ventriculomegaly.

The Neurological Predictor Scale (NPS) quantifies cumulative exposure to conventional treatment-related neurological risks but does not capture potential risks posed by tumors themselves. This study evaluated the predictive validity of the NPS, and the incremental value of tumor location and size, for neurocognitive outcomes in early survivorship following contemporary therapies for pediatric brain tumors.Survivors (N = 69) diagnosed from 2010 to 2016 were administered age-appropriate versions of the Wechsler Intelligence Scales. Hierarchical multiple regressions examined the predictive and incremental validity of NPS score, tumor location, and tumor size.Participants (51% female) aged 6-20 years (M = 13.22, SD = 4.09) completed neurocognitive evaluations 5.16 years (SD = 1.29) postdiagnosis. The NPS significantly predicted Full-Scale Intelligence Quotient (FSIQ; ΔRTumor size emerged as an independent predictor of neurocognitive functioning and added incrementally to the predictive utility of the NPS. Pretreatment disease burden may provide one of the earliest markers of neurocognitive risk following contemporary treatments. With perpetual treatment advances, measures quantifying treatment-related risk may need to be updated and revalidated to maintain their clinical utility.

Myelomeningocele (MMC) and congenital heart disease (CHD) are independent risk factors for increased morbidity and mortality in the newborn period and each can require significant operations shortly after birth. Few studies have examined the impact of these combined lesions. We sought to examine the incidence of CHD in patients with MMC, and to evaluate length of stay (LOS), hospital charges, and mortality. Using the Texas Inpatient Public Use Data File, ~ 6.9 million newborn records between 1/1999 and 12/2016 were examined. Hospitalizations were classified as MMC without CHD (n = 3054), CHD without MMC (n = 72,266), and MMC with CHD (n = 171). The birth prevalence of CHD with MMC was 0.3/10,000 live hospital births, with 5% of patients with MMC having CHD, and 0.2% of those with CHD having MMC. There was increased LOS in patients with both MMC and CHD (median 15 days, IQR 5–31), compared to CHD without MMC (median 6 days, IQR 2–20) and MMC without CHD (median 8 days, IQR 1–14) and higher total hospital charges (median $95,007, IQR $26,731–$222,660) compared to CHD without MMC (median $27,726, $6463–$118,370) and MMC without CHD (median $40,066, IQR $5744–$97,490). Mortality was significantly higher in patients with MMC and CHD (22.2% compared to 3.1% in MMC without CHD and 4.1% in CHD without MMC). Significance remained when limiting for patients without genetic conditions or additional major birth defects. MMC with CHD in the newborn compared to either CHD or MMC alone is associated with longer LOS, higher charges, and increased mortality.

OBJECTIVEThe primary objective of this study was to use the prospective Hydrocephalus Clinical Research Network (HCRN) registry to determine clinical predictors of fast time to shunt failure (≤ 30 days from last revision) and ultrafast time to failure (≤ 7 days from last revision).METHODSRevisions (including those due to infection) to permanent shunt placements that occurred between April 2008 and November 2017 for patients whose entire shunt experience was recorded in the registry were analyzed. All registry data provided at the time of initial shunt placement and subsequent revision were reviewed. Key variables analyzed included etiology of hydrocephalus, age at time of initial shunt placement, presence of slit ventricles on imaging at revision, whether the ventricles were enlarged at the time of revision, and presence of prior fast failure events. Univariable and multivariable analyses were performed to find key predictors of fast and ultrafast failure events.RESULTSA cohort of 1030 patients with initial shunt insertions experienced a total of 1995 revisions. Of the 1978 revision events with complete records, 1216 (61.5%) shunts remained functional for more than 1 year, and 762 (38.5%) failed within 1 year of the procedure date. Of those that failed within 1 year, 423 (55.5%) failed slowly (31–365 days) and 339 (44.5%) failed fast (≤ 30 days). Of the fast failures, 131 (38.6%) were ultrafast (≤ 7 days). In the multivariable analysis specified a priori, etiology of hydrocephalus (p = 0.005) and previous failure history (p = 0.011) were independently associated with fast failure. Age at time of procedure (p = 0.042) and etiology of hydrocephalus (p = 0.004) were independently associated with ultrafast failure. These relationships in both a priori models were supported by the data-driven multivariable models as well.CONCLUSIONSNeither the presence of slit ventricle syndrome nor ventricular enlargement at the time of shunt failure appears to be a significant predictor of repeated, rapid shunt revisions. Age at the time of procedure, etiology of hydrocephalus, and the history of previous failure events seem to be important predictors of fast and ultrafast shunt failure. Further work is required to understand the mechanisms of these risk factors as well as mitigation strategies.