Global trends and decision-making in the management of arachnoid cysts.

OBJECTIVE: In pediatric patients, middle cranial fossa (MCF) arachnoid cysts are often discovered incidentally on imaging in asymptomatic patients during workup for other indications. This study aims to describe current management gestalt and threshold for surgical intervention by surveying an international cohort of neurosurgeons. METHODS: A web-based survey was circulated via email list of attendants of the 2019 Canadian Pediatric Neurosurgery Study Group (CPNSG) and International Society of Pediatric Neurosurgery (ISPN) mailing list. The survey consisted of 8 clinical scenarios involving patients with MCF arachnoid cysts. Demographic variables of respondents and their decisions regarding management for each scenario were analyzed using R computing software. RESULTS: A total of 107 respondents were included. Cysts in asymptomatic patients (92%), younger age at diagnosis (81%), and presence of a mild learning delay were predominantly managed non-surgically (80.7 ± 9.4%). Patients with cyst enlargement, headaches, new seizures, or hemorrhage were divided between non-surgical (55.8 ± 3.3%) and surgical (44.2 ± 2.9%) management. Patients with contralateral hemiparesis were treated predominantly surgically (67%). For both Galassi I and II, papilledema was favored as the primary indication for surgical intervention in 54% of patients. Those inclined to surgery (n = 17) were more likely to practice and train outside North America compared to those not pro-surgical (adjusted P = 0.092). CONCLUSION: Incidental MCF arachnoid cysts in asymptomatic patients and younger age of diagnosis are predominantly managed non-surgically. Mild learning delay was not considered an indication to intervene. In contrast, radiological progression, hemorrhagic evolution, or non-focal neurological deficits lead to uncertainty in management, while focal neurological deficits and papilledema with MCF cysts were favored to be intervened surgically. Among the provider level factors, only location of training and practice trended towards a pro-surgery approach.

Arrhythmia Variant Associations and Reclassifications in the eMERGE-III Sequencing Study.

BACKGROUND: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results is unclear. In addition, the majority of discovered variants are currently classified as variants of uncertain significance, limiting clinical actionability. METHODS: The eMERGE-III study (Electronic Medical Records and Genomics Phase III) is a multicenter prospective cohort that included 21 846 participants without previous indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with electronic health record-derived phenotypes and follow-up clinical examination. Selected variants of uncertain significance (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells. RESULTS: As previously reported, 3.0% of participants had P/LP variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared with noncarriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their electronic health records. Fifty-four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long-QT syndrome), and 12 of these 19 diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance, we reclassified 11 variants: 3 to likely benign and 8 to P/LP. CONCLUSIONS: Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As the genomes of large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, electronic health record phenotypes, and in vitro functional studies. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier; NCT03394859.

Added value of corpus callosotomy following vagus nerve stimulation in children with Lennox-Gastaut syndrome: A multicenter, multinational study.

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is a severe form of epileptic encephalopathy, presenting during the first years of life, and is very resistant to treatment. Once medical therapy has failed, palliative surgeries such as vagus nerve stimulation (VNS) or corpus callosotomy (CC) are considered. Although CC is more effective than VNS as the primary neurosurgical treatment for LGS-associated drop attacks, there are limited data regarding the added value of CC following VNS. This study aimed to assess the effectiveness of CC preceded by VNS. METHODS: This multinational, multicenter retrospective study focuses on LGS children who underwent CC before the age of 18 years, following prior VNS, which failed to achieve satisfactory seizure control. Collected data included epilepsy characteristics, surgical details, epilepsy outcomes, and complications. The primary outcome of this study was a 50% reduction in drop attacks. RESULTS: A total of 127 cases were reviewed (80 males). The median age at epilepsy onset was 6 months (interquartile range [IQR] = 3.12-22.75). The median age at VNS surgery was 7 years (IQR = 4-10), and CC was performed at a median age of 11 years (IQR = 8.76-15). The dominant seizure type was drop attacks (tonic or atonic) in 102 patients. Eighty-six patients underwent a single-stage complete CC, and 41 an anterior callosotomy. Ten patients who did not initially have a complete CC underwent a second surgery for completion of CC due to seizure persistence. Overall, there was at least a 50% reduction in drop attacks and other seizures in 83% and 60%, respectively. Permanent morbidity occurred in 1.5%, with no mortality. SIGNIFICANCE: CC is vital in seizure control in children with LGS in whom VNS has failed. Surgical risks are low. A complete CC has a tendency toward better effectiveness than anterior CC for some seizure types.

Outcomes and complications for individual neurosurgeons for the treatment of Chiari I malformation at a children's hospital.

PURPOSE: The aim of this study was to evaluate the outcomes and complications for individual surgeons at British Columbia Children's Hospital for the treatment of Chiari I Malformation (CMI) in children. METHODS: This was a retrospective review of patients with CMI who had surgery from 1986 to 2015. We assessed the Chicago Chiari Outcome Scores (CCOS) and complication rates by surgeon. RESULTS: Seventy patients, 38 males and 32 females, underwent posterior fossa decompression including 14 extradural and 56 intradural approaches. Syringomyelia was present in 74.3%. Most syringomyelia improved with no difference between intradural and extradural surgeries. After initial surgery, 13 patients (18.6%) had complications including 2/14 (14.3%) of extradural and 11/56 (19.6%) of intradural surgeries. Two patients required surgical intervention for complications whereas 11 had transient complications. The complication rate by surgeon ranged from 11 to 20% for extradural (2 surgeons only) and 10.5 to 40% for intradural surgeries (4 surgeons). The CCOS ranged from 12 to 15 for extradural and 6 to 16 for intradural. The CCOS ranges for surgeons 1 and 2 were 12-15 and 13-15 respectively for extradural. The CCOS ranges for surgeons 1, 2, 3, and 4 were 12-16, 6-15, 12-16, and 12-16 respectively for intradural. Thirteen patients had a second surgery for CMI. The final CCOS was good in 86% and moderate in 14%. CONCLUSION: There was variability in surgeries performed at BCCH by different surgeons, with variations in CCOS and complication rates. This information is important during decision making, consent process, and for quality improvement.

Cyclodextrins: Assessing the Impact of Cavity Size, Occupancy, and Substitutions on Cytotoxicity and Cholesterol Homeostasis.

Cyclodextrins (CDs) are cyclic oligosaccharides; the most common CDs contain six, seven, or eight glucose units called α-CDs, ß-CDs, and γ-CDs, respectively. The use of CDs in biomedical research is increasing due to their ability to interact with membrane lipids as well as a wide variety of poorly water-soluble molecules. We assessed the impact of CD cavity size, occupancy, and substitutions on cytotoxicity and cholesterol homeostasis. The potency of CD-mediated cytotoxicity was in the order of ß-CDs, α-CDs, and γ-CDs. Substitutions with hydroxypropyl or carboxymethyl group attenuated cytotoxicity compared with the native CDs, whereas CDs substituted with methyl groups exhibited cytotoxicity that was similar to that of the native CDs. The lipid components in blood exerted remarkable hemolysis-alleviating effects in methyl-ß-CD-induced hemolysis. Occupancy of the CD cavity with cholesterol or a structurally related lipid molecule abrogated the cytotoxic capacity of the CDs. Interestingly, hydroxypropyl-γ-CD (HPγCD) was able to reduce intracellular cholesterol accumulation in Niemann⁻Pick disease type C (NPC) patient-derived fibroblasts as efficiently as HPßCD. Proteomic study indicated that HPßCD and HPγCD treatments altered the expression pattern of cellular proteins, suggesting that some of the CD-induced cellular proteins may play an important function in modulating intracellular cholesterol homeostasis.

Impact of Early Follow-Up Intervention on Parent-Reported Postconcussion Pediatric Symptoms: A Feasibility Study.

OBJECTIVES: To investigate the effectiveness and feasibility of early intervention telephone counseling with parents in limiting postconcussion symptoms and impacts on children and youth. SETTING: Recruitment occurred postdischarge from one pediatric emergency department. PARTICIPANTS: Sixty-six parents of children aged 5 to 16 years with a diagnosis of a concussion injury. DESIGN: A pilot, randomized controlled study compared the efficacy of telephone counseling (reviewing symptom management and return to activity with parents at 1 week and 1 month postinjury) with usual care (no formalized follow-up). MAIN MEASURES: The Post-Concussion Symptom Inventory and the Family Burden of Injury Interview administered with parents by a blinded therapist at 3 months postinjury. RESULTS: No significant difference between the groups at 3 months postinjury in postconcussion symptoms (P = .67) and family stress (P = .647). CONCLUSION: The findings suggest that the early counseling intervention strategy trialed herein may not be effective for children and youth who experience significant postconcussion symptoms. Further research is needed to determine whether more intensive and integrated care would better serve children.

The role of resection alone in select children with intracranial ependymoma: the Canadian Pediatric Brain Tumour Consortium experience.

PURPOSE: Gross total resection (GTR) of intracranial ependymoma is an accepted goal. More controversial is radiotherapy deferral. This study reports on children treated with gross total resection who did not receive upfront adjuvant radiotherapy. METHODS: We conducted a retrospective review of children with intracranial ependymoma in 12 Canadian centers. Patients who had GTR of their tumor and no upfront radiotherapy were identified. Immunostaining was performed for Ki-67, epidermal growth factor receptor (EGFR), and EZH2 on archived tissue. The Kaplan-Meier survival analysis was performed and compared with those who had GTR followed by radiation. RESULTS: Twenty-six children were identified treated with GTR alone at diagnosis; 12 posterior fossa ependymoma (PFE) WHO grade II, and 14 supratentorial ependymoma (STE). Progression-free survival (PFS) in ependymoma treated with GTR alone at diagnosis was inferior in those with high Ki-67 or positive EZH2 immunostaining. Survival was inferior for patients less than 2 years old at diagnosis (p = 0.002). Survival was comparable to PFE WHO grade II and STE who had GTR followed by radiation (p = 0.62). Five-year PFS and overall survival (OS) of those treated with GTR alone were 60 and 70% respectively for PFE and 45 and 70% respectively for STE (p = 0.2; 0.55). CONCLUSIONS: This study suggests that there is a subset of children with certain biologic features who, in the setting of a prospective clinical trial, might be candidates for observation following GTR. Good risk factors for this approach include age of 2 years or older, low Ki-67, and negative EZH2. If relapse occurs, it may be confined to the primary site, allowing for possible salvage with GTR followed by XRT.

Withdrawal of Life-Sustaining Treatment for Pediatric Patients With Severe Traumatic Brain Injury.

Importance: The decision to withdraw life-sustaining treatment for pediatric patients with severe traumatic brain injury (TBI) is challenging for clinicians and families with limited evidence quantifying existing practices. Given the lack of standardized clinical guidelines, variable practice patterns across trauma centers seem likely. Objective: To evaluate the factors influencing decisions to withdraw life-sustaining treatment across North American trauma centers for pediatric patients with severe TBI and to quantify any existing between-center variability in withdrawal of life-sustaining treatment practices. Design, Setting, and Participants: This retrospective cohort study used data collected from 515 trauma centers through the American College of Surgeons Trauma Quality Improvement Program between 2017 and 2020. Pediatric patients younger than 19 years with severe TBI and a documented decision for withdrawal of life-sustaining treatment were included. Data were analyzed from January to May 2023. Main Outcomes and Measures: A random intercept multilevel logistic regression model was used to quantify patient, injury, and hospital characteristics associated with the decision to withdraw life-sustaining treatment; the median odds ratio was used to characterize residual between-center variability. Centers were ranked by their conditional random intercepts and quartile-specific adjusted mortalities were computed. Results: A total of 9803 children (mean [SD] age, 12.6 [5.7]; 2920 [29.8%] female) with severe TBI were identified, 1003 of whom (10.2%) had a documented decision to withdraw life-sustaining treatment. Patient-level factors associated with an increase in likelihood of withdrawal of life-sustaining treatment were young age (younger than 3 years), higher severity intracranial and extracranial injuries, and mechanism of injury related to firearms. Following adjustment for patient and hospital attributes, the median odds ratio was 1.54 (95% CI, 1.46-1.62), suggesting residual variation in withdrawal of life-sustaining treatment between centers. When centers were grouped into quartiles by their propensity for withdrawal of life-sustaining treatment, adjusted mortality was higher for fourth-quartile compared to first-quartile centers (odds ratio, 1.66; 95% CI, 1.45-1.88). Conclusions and Relevance: Several patient and injury factors were associated with withdrawal of life-sustaining treatment decision-making for pediatric patients with severe TBI in this study. Variation in withdrawal of life-sustaining treatment practices between trauma centers was observed after adjustment for case mix; this variation was associated with differences in risk-adjusted mortality rates. Taken together, these findings highlight the presence of inconsistent approaches to withdrawal of life-sustaining treatment in children, which speaks to the need for guidelines to address this significant practice pattern variation.

Neurological morbidity of surgical resection of pediatric cerebellar astrocytomas.

BACKGROUND: Review of children with low-grade cerebellar astrocytoma (LGCA) prior to 1992 showed a 98% rate of gross total resection (GTR) but a concerning incidence of permanent neurological dysfunction. The purpose of this study was to determine the rate of GTR of LGCA since 1992 and frequency of neurologic injury. METHODS: Retrospective review of children with LGCA was performed. CT/MR scans were rereviewed to assess extent of resection. Primary outcomes included incidence of GTR and incidence of permanent new neurological deficits. Other outcomes included late effects severity score (LESS), Bloom score for functional status, and educational assessment. RESULTS: Of 50 LGCA, GTR was achieved in 38 (76%) compared to 43 of 44 (98%) prior to 1992 (p < 0.004). Permanent new neurologic deficits from surgery occurred in 16% compared to 18% in the prior era (p = 0.61). For 35 patients operated on by the 2 surgeons in the prior study, 74% had GTR, with permanent neurological deficits in 8.6%. At latest follow-up, all patients were alive, 16% with residual tumor. LESS was two or less (mild or no deficit) in 94%. Bloom score was one or two (no or mild disability) in 90%. Eighty-six percent attended normal school. CONCLUSIONS: Less aggressive resection of LGCA in children may reduce postoperative neurologic deficits in the hands of the same surgeons as in the prior study but not overall at our institution. The good long-term outcomes suggest that it may be appropriate to do incomplete resection rather than risk additional neurological deficit.

A Case Study of Enhancing the Data Science Capacity of an RCMI Program at a Historically Black Medical College.

As data grows exponentially across diverse fields, the ability to effectively leverage big data has become increasingly crucial. In the field of data science, however, minority groups, including African Americans, are significantly underrepresented. With the strategic role of minority-serving institutions to enhance diversity in the data science workforce and apply data science to health disparities, the National Institute for Minority Health Disparities (NIMHD) provided funding in September 2021 to six Research Centers in Minority Institutions (RCMI) to improve their data science capacity and foster collaborations with data scientists. Meharry Medical College (MMC), a historically Black College/University (HBCU), was among the six awardees. This paper summarizes the NIMHD-funded efforts at MMC, which include offering mini-grants to collaborative research groups, surveys to understand the needs of the community to guide project implementation, and data science training to enhance the data analytics skills of the RCMI investigators, staff, medical residents, and graduate students. This study is innovative as it addressed the urgent need to enhance the data science capacity of the RCMI program at MMC, build a diverse data science workforce, and develop collaborations between the RCMI and MMC's newly established School of Applied Computational Science. This paper presents the progress of this NIMHD-funded project, which clearly shows its positive impact on the local community.

Correlation and agreement between arterial and venous blood gas analysis in patients with hypotension-an emergency department-based cross-sectional study.

BACKGROUND: Blood gas analysis is integral to assessing emergency department (ED) patients with acute respiratory or metabolic disease. Arterial blood gas (ABG) is the gold standard for oxygenation, ventilation, and acid-base status but is painful to obtain. Peripheral venous blood gas (VBG) is a valuable alternative as it is less painful and easy to collect. The comparability of ABG and VBG was studied in various conditions. But in hypotension, previous findings were inconsistent. So, we studied the correlation and agreement between ABG and VBG in hypotensive patients. METHODOLOGY: The study was conducted at the emergency department of a tertiary healthcare center in Northern India. Patients with hypotension above 18 years who satisfied the inclusion criteria were clinically evaluated. Patients who require ABG as a part of routine care were sampled. ABG was collected from the radial artery. VBG was obtained from the cubital or dorsal hand veins. Both samples were collected within 10 min and were analyzed. All ABG and VBG variables were entered in premade proforma. The patient was then treated and disposed of according to institutional protocol. RESULTS: A total of 250 patients were enrolled. The mean age was 53.25 ± 15.71 years. 56.8% were male. The study included 45.6% septic, 34.4% hypovolemic, 18% cardiogenic, and 2% obstructive shock patients. The study found a strong correlation and agreement for ABG and VBG pH, pCO2, HCO3, lactate, sodium, potassium, chloride, ionized calcium, blood urea nitrogen, base excess, and arterial/alveolar oxygen ratio. Hence, regression equations were made for the aforementioned. There was no correlation observed between ABG and VBG pO2 and SpO2. Our study concluded that VBG could be a reasonable alternative for ABG in hypotensive patients. We can also mathematically predict values of ABG from VBG using regression equations derived. CONCLUSIONS: ABG sampling causes most unpleasant experiences to patients and is associated with complications like arterial injury, thrombosis, air or clotted-blood embolism, arterial occlusion, hematoma, aneurysm formation, and reflex sympathetic dystrophy. The study has shown strong correlations and agreements for most ABG and VBG parameters and can predict ABG mathematically using regression formulas formulated from VBG. This will decrease needle stick injury, consume less time, and make blood gas evaluation easy in hypotensive settings.

Endoscopic fenestration of cavum velum interpositum cysts: a case study of two symptomatic patients.

INTRODUCTION: Cavum velum interpositum (CVI) is commonly an incidental asymptomatic finding on imaging studies. Encystment can occur and, in most situations, is also asymptomatic. Clinical symptoms occurring in patients with CVI cysts have been reported infrequently with the result that the relationship of these symptoms and the cyst are usually unclear. This report contributes to the knowledge base of symptoms that can occur in patients with CVI and the response of symptoms to effective treatment. PATIENTS AND METHODS: We report the clinical outcomes of a 3-year-old male patient and a 13-year-old female patient with symptoms and CVI cysts on imaging who were treated successfully with endoscopic fenestration. RESULTS: The developmental delay and occasional headache present in the 3-year-old male patient resolved after endoscopic fenestration; however, the 13-year-old patient who had neuropsychiatric symptoms did not improve. CONCLUSIONS: Our cases add to the literature describing the response to cyst treatment in symptomatic patients harboring CVI cysts. Symptoms due to CSF pathway obstruction may respond to cyst fenestration, while the response of symptoms in patents who do not have clear CSF circulation disorders is less predictable.

Acetazolamide to treat symptomatic ruptured arachnoid cysts: illustrative cases.

BACKGROUND: Arachnoid cysts are benign, often asymptomatic intracranial mass lesions that, when ruptured, may cause seizures, raised intracranial pressure, hemorrhage, and/or loss of consciousness. There is no widely agreed upon treatment, and there is debate as to whether a nonoperative or surgical approach is the best course of action. The carbonic anhydrase inhibitor acetazolamide may be an effective nonoperative approach in treating ruptured arachnoid cysts. OBSERVATIONS: The Pediatric Neurosurgery Clinical Database at BC Children's Hospital from 2000 to 2020 was queried, and four pediatric patients who were treated with acetazolamide after presentation with a ruptured middle cranial fossa arachnoid cyst were identified. All patients showed some degree of symptom improvement. Three of the patients showed complete reabsorption of their subdural collections in the ensuing 6 months. One patient had an inadequate response to acetazolamide and required surgical management. LESSONS: Acetazolamide is a safe and reasonable primary treatment option in pediatric patients with ruptured middle cranial fossa arachnoid cysts, and it may help avoid the need for surgery.

A qualitative study of transitioning patients with hydrocephalus from pediatric to adult care: fear of uncertainty, communication gaps, independence, and loss of relationships.

OBJECTIVE: Hydrocephalus is one of the most common condition treated by pediatric neurosurgeons. Many neurosurgeons are unable to continue to care for patients after they become adults. Although significant gaps in care are believed to exist for youth transitioning from pediatric to adult care, very little is known about how patients and their caregivers feel about the process. This qualitative study sought to examine the perceptions of adolescents, young adults, and their caregivers regarding transitioning from pediatric to adult care at a single Canadian center. METHODS: The authors explored the perceptions of patients with treated hydrocephalus and their caregivers using semistructured interviews and qualitative research methodologies. A convenience sample was recruited, composed of adolescent patients and their caregivers at the neurosurgery clinic of BC Children's Hospital, and patients and caregivers recently transitioned to adult care from the clinic. Interviews were transcribed verbatim and coded, with common themes identified. RESULTS: Four overarching themes relating to the process of transitioning from pediatric to adult hydrocephalus care for patients and their caregivers were identified from the data: 1) achieving independence, 2) communication gaps, 3) loss of significant relationships and environment, and 4) fear of uncertainty. CONCLUSIONS: Overall, patients with hydrocephalus and their families are dissatisfied with the process of transitioning. This study identified common themes and concerns among this cohort that may form the basis of an improved transition model for youth with hydrocephalus as they become adults.

Snakebite Causing Facial and Lingual Tremors: A Case Report.

Snakebite is a significant public health problem causing around 2.7 envenomations and 138,000 deaths globally. History may sometimes be unclear or misleading, which can cause a delay in diagnosis. Neuroparalytic, hemotoxic, and myotoxic are the common snake bite manifestations. Neuroparalytic snake bites rarely cause involuntary movements. Here we report a case of a 26-year-old female patient who sustained a snake bite and developed tremors in the face and tongue. She improved with mechanical ventilation, anti-snake venom, atropine-neostigmine, and calcium gluconate. She was discharged after seven days of hospital stay and now maintaining regular follow-up in the outpatient clinic.

2-Hydroxypropyl-gamma-cyclodextrin overcomes NPC1 deficiency by enhancing lysosome-ER association and autophagy.

Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder caused by mutations in NPC1 and NPC2 genes that result in an accumulation of cholesterol in lysosomes. The majority of children with NPC die in adolescence. Currently, no FDA-approved therapies exist for NPC and the mechanisms of NPC disease are not fully understood. Our recent study and the reports from other laboratories showed that 2-hydroxypropyl-γ-cyclodextrin (HPγCD) alleviates cholesterol accumulation in NPC1-deficient cells in spite of its low binding affinity for cholesterol. In this study, we explored the cellular changes that are induced upon HPγCD treatment in NPC1 patient-derived fibroblasts. We show that HPγCD treatment increases lysosome-ER association and enhances autophagic activity. Our study indicates that HPγCD induces an activation of the transcription factor EB (TFEB), a master regulator of lysosomal functions and autophagy. Lysosome-ER association could potentially function as conduits for cholesterol transport from lysosomes to the ER. Accumulating evidence suggests a role for autophagy in rescuing the cholesterol accumulation in NPC and other degenerative diseases. Collectively, our findings suggest that HPγCD restores cellular homeostasis in NPC1-deficient cells via enhancing lysosomal dynamics and functions. Understanding the mechanisms of HPγCD-induced cellular pathways could contribute to effective NPC therapies.

An Educational Video Improves Consent in Pediatric Lumbar Puncture: A Randomized Control Trial.

BACKGROUND: Lumbar puncture is a low-risk procedure performed on pediatric patients for a variety of indications. Parents give consent to this procedure but are often left with concerns. There are no published studies on the nature of the concerns of parents in North America and no studies examining a process to improve pediatric lumbar puncture consent. Here we identify parent concerns with lumbar puncture and determine the utility of an adjunctive educational video. METHODS: Seventy-two patient-parent dyads were enrolled in a randomized control trial to receive standard consent with or without an educational video. A survey was provided to determine parent self-rated understanding of the procedure, their perception of its safety, their perception of the painfulness, and their overall comfort with their child undergoing lumbar puncture. In addition, demographic characteristics and qualitative information about parent concerns were collected. TRIAL REGISTRATION: NCT03677219. RESULTS: The video resulted in significantly greater parent understanding of the procedure (P = 0.015) and perception of its safety (P = 0.021) compared with controls. Parent comfort with the procedure increased after viewing the video (P = 0.002). Parents' top three concerns were pain, infection, and neurological injury. CONCLUSIONS: Parent concerns in pediatric lumbar puncture include pain, infection, and neurological injury, and viewing an educational video improved parent perception of understanding and safety compared with controls. In addition, there was reduced variability of responses in those who viewed the video. Thus a short educational video on a handheld device is an effective means to address parent concerns and standardize the process of pediatric lumbar puncture consent.

Hydroxypropyl-beta and -gamma cyclodextrins rescue cholesterol accumulation in Niemann-Pick C1 mutant cell via lysosome-associated membrane protein 1.

Niemann-Pick type C (NPC) disease is a fatal hereditary neurodegenerative disorder characterized by a massive accumulation of cholesterol in lysosomes and late endosomes due to a defect in intracellular cholesterol trafficking. Dysfunction in intracellular cholesterol trafficking is responsible for about 50 rare inherited lysosomal storage disorders including NPC. The lysosomal proteins NPC1 and NPC2 play a crucial role in trafficking of cholesterol from late endosomes and lysosomes to other cellular compartments. However, the detailed mechanisms of cholesterol trafficking at the late endosomes/lysosomes (LE/LY) are poorly understood. Studies showed that 2-hydroxypropyl-ß-cyclodextrin (HPßCD) alleviates the cholesterol accumulation defect in animal model and has been approved for a phase 2b/3 clinical trial for NPC. HPßCD is known to bind cholesterol; however, the mechanisms how HPßCD mediates the exit of cholesterol from the LE/LY compartments are still unknown. Further, another cyclodextrin (CD) derivative, 2-hydroxypropyl-γ-cyclodextrin (HPγCD), was shown to reduce intracellular cholesterol accumulation in NPC patient cells and NPC mice model. Herein, we identified a number of candidate proteins differentially expressed in NPC patient-derived cells compared to cells derived from a healthy donor using a proteomic approach. Interestingly, both HPßCD and HPγCD treatments modulated the expression of most of these NPC-specific proteins. Data showed that treatment with both CDs induces the expression of the lysosome-associated membrane protein 1 (LAMP-1) in NPC patient-derived cells. Remarkably, LAMP-1 overexpression in HeLa cells rescued U18666A-induced cholesterol accumulation suggesting a role of LAMP-1 in cholesterol trafficking. We propose that HPßCD and HPγCD facilitate cholesterol export from the LE/LY compartments via the LAMP-1 protein, which may play a crucial role in cholesterol trafficking at the LE/LY compartments when there is no functional NPC1 protein. Together, this study uncovers new cellular mechanisms for cholesterol trafficking, which will contribute to development of novel therapeutic approaches for lysosomal storage diseases.

Ascites and abdominal pseudocysts following ventriculoperitoneal shunt surgery: variations of the same theme.

OBJECT: Ascites and abdominal pseudocysts are two complications that can occur following placement of a ventriculoperitoneal (VP) shunt. Although various factors have been implicated, the exact pathogenesis of the two conditions remains elusive. To the authors' knowledge, there are no studies in which these two obviously related conditions have been compared. METHODS: The authors retrospectively reviewed the cases of children with abdominal complications caused by a VP shunt. There were 15 patients who developed a pseudocyst and five patients who developed ascites. The cases were analyzed to identify common and distinguishing factors that may help in identifying the mechanism involved. Abdominal symptoms were the mode of presentation for patients with ascites, whereas shunt malfunction was the mode of presentation in 60% of those with pseudocysts. Culture-proven infection, abdominal surgery, and the number of revisions seemed to be more common in cases with pseudocysts than in ascites. The fluid in ascites was found to be a transudate irrespective of the origin of hydrocephalus. Alternative drainage sites were required in the treatment of patients with ascites, and reimplantation in the peritoneum was possible in 66.7% of those with pseudocysts. In the long-term, however, peritoneal reimplantation was possible in three of the five patients with ascites. CONCLUSIONS: Abdominal pseudocysts and ascites, after VP shunt treatment, are distinct conditions with different modes of presentation and findings during examination of fluid, and therefore they require different management strategies.

Bortezomib augments lymphocyte stimulatory cytokine signaling in the tumor microenvironment to sustain CD8+T cell antitumor function.

Tumor-induced immune tolerance poses a major challenge for therapeutic interventions aimed to manage cancer. We explored approaches to overcome T-cell suppression in murine breast and kidney adenocarcinomas, and lung fibrosarcoma expressing immunogenic antigens. We observed that treatment with a reversible proteasome inhibitor bortezomib (1 mg/kg body weight) in tumor-bearing mice significantly enhanced the expression of lymphocyte-stimulatory cytokines IL-2, IL-12, and IL-15. Notably, bortezomib administration reduced pulmonary nodules of mammary adenocarcinoma 4T1.2 expressing hemagglutinin (HA) model antigen (4T1HA) in mice. Neutralization of IL-12 and IL-15 cytokines with a regimen of blocking antibodies pre- and post-adoptive transfer of low-avidity HA518-526-specific CD8+T-cells following intravenous injection of 4T1HA cells increased the number of pulmonary tumor nodules. This neutralization effect was counteracted by the tumor metastasis-suppressing action of bortezomib treatments. In bortezomib-treated 4T1HA tumor-bearing mice, CD4+T-cells showed increased IL-2 production, CD11c+ dendritic cells showed increased IL-12 and IL-15 production, and HA-specific activated CD8+T-cells showed enhanced expression of IFNγ, granzyme-B and transcription factor eomesodermin. We also noted a trend of increased expression of IL-2, IL-12 and IL-15 receptors as well as increased phosphorylation of STAT5 in tumor-infiltrating CD8+T-cells following bortezomib treatment. Furthermore, bortezomib-treated CD8+T-cells showed increased phosphorylation of mitogen-activated protein kinase p38, and Akt, which was abrogated by phosphatidylinositide 3-kinase (PI3K) inhibitor. These data support the therapeutic potential of bortezomib in conjunction with other immunotherapies to augment the strength of convergent signals from CD8+T-cell signaling molecules including TCR, cytokine receptors and downstream PI3K/Akt/STAT5 pathways to sustain CD8+T-cell effector function in the tumor microenvironment.