Healthcare disparities in pediatric neurosurgery: a scoping review.

OBJECTIVE: The aim of this scoping review was to identify relevant articles that have contributed to the body of knowledge describing pediatric neurosurgical healthcare disparities. Identifying healthcare disparities in pediatric neurosurgery is essential to understanding how to best provide care for this unique patient population. Although it is undoubtedly important to increase the knowledge of pediatric neurosurgical healthcare disparities, it is also important to understand the current state of the literature. METHODS: This scoping review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. The search terms "pediatric neurosurgical disparities" and "pediatric neurosurgical inequities" were entered into the following databases: PubMed, Scopus, and Embase. RESULTS: The initial database search returned a total of 366 results from the PubMed, Embase, and Scopus databases. One hundred thirty-seven duplicates were removed, and the remaining articles were screened by title and abstract. Articles were excluded on the basis of the inclusion and exclusion criteria. Of the remaining 229 articles, 168 were excluded. Sixty-one full-text articles were then examined for eligibility, and 28 did not reach the specified inclusion and exclusion criteria. The remaining 33 articles were included for final review. The results of the reviewed studies were stratified on the basis of disparity type. CONCLUSIONS: Although there has been an increase in the number of publications discussing pediatric neurosurgical healthcare disparities within the last decade, there still remains a scarcity of information regarding healthcare disparities in neurosurgery. Furthermore, less information exists that specifically addresses healthcare disparities in the pediatric population.

Evaluation of Nonmodified Wireframe DNA Origami for Acute Toxicity and Biodistribution in Mice.

Wireframe DNA origami can be used to fabricate virus-like particles for a range of biomedical applications, including the delivery of nucleic acid therapeutics. However, the acute toxicity and biodistribution of these wireframe nucleic acid nanoparticles (NANPs) have not been previously characterized in animal models. In the present study, we observed no indications of toxicity in BALB/c mice following a therapeutically relevant dosage of nonmodified DNA-based NANPs via intravenous administration, based on liver and kidney histology, liver and kidney biochemistry, and body weight. Further, the immunotoxicity of these NANPs was minimal, as indicated by blood cell counts and type-I interferon and pro-inflammatory cytokines. In an SJL/J model of autoimmunity, we observed no indications of NANP-mediated DNA-specific antibody response or immune-mediated kidney pathology following the intraperitoneal administration of NANPs. Finally, biodistribution studies revealed that these NANPs accumulate in the liver within one hour, concomitant with substantial renal clearance. Our observations support the continued development of wireframe DNA-based NANPs as next-generation nucleic acid therapeutic delivery platforms.

Evaluation of non-modified wireframe DNA origami for acute toxicity and biodistribution in mice.

Wireframe DNA origami can be used to fabricate virus-like particles for a range of biomedical applications, including the delivery of nucleic acid therapeutics. However, the acute toxicity and biodistribution of these wireframe nucleic acid nanoparticles (NANPs) have not previously been characterized in animal models. In the present study, we observed no indications of toxicity in BALB/c mice following therapeutically relevant dosage of unmodified DNA-based NANPs via intravenous administration, based on liver and kidney histology, liver biochemistry, and body weight. Further, the immunotoxicity of these NANPs was minimal, as indicated by blood cell counts and type-I interferon and pro-inflammatory cytokines. In an SJL/J model of autoimmunity, we observed no indications of NANP-mediated DNA-specific antibody response or immune-mediated kidney pathology following the intraperitoneal administration of NANPs. Finally, biodistribution studies revealed that these NANPs accumulate in the liver within one hour, concomitant with substantial renal clearance. Our observations support the continued development of wireframe DNA-based NANPs as next-generation nucleic acid therapeutic delivery platforms.

Germline genetic mutations in pediatric cerebrovascular anomalies: a multidisciplinary approach to screening, testing, and management.

OBJECTIVE: Genetic alterations are increasingly recognized as etiologic factors linked to the pathogenesis and development of cerebrovascular anomalies. Their identification allows for advanced screening and targeted therapeutic approaches. The authors aimed to describe the role of a collaborative approach to care and genetic testing in pediatric patients with neurovascular anomalies, with the objectives of identifying what genetic testing recommendations were made, the yield of genetic testing, and the implications for familial screening and management at present and in the future. METHODS: The authors performed a descriptive retrospective cohort study examining pediatric patients genetically screened through the Pediatric Neurovascular Program of a single treatment center. Patients 18 years of age and younger with neurovascular anomalies, diagnosed radiographically or histopathologically, were evaluated for germline genetic testing. Patient demographic data and germline genetic testing and recommendation, clinical, treatment, and outcome data were collected and analyzed. RESULTS: Sixty patients were included; 29 (47.5%) were female. The mean age at consultation was 11.0 ± 4.9 years. Diagnoses included cerebral arteriovenous malformations (AVMs) (n = 23), cerebral cavernous malformations (n = 19), non-neurofibromatosis/non-sickle cell moyamoya (n = 8), diffuse cerebral proliferative angiopathy, and megalencephaly-capillary malformation. Of the 56 patients recommended to have genetic testing, 40 completed it. Genetic alterations were found in 13 (23%) patients. Four patients with AVMs had RASA1, GDF2, and ACVRL1 mutations. Four patients with cavernous malformations had Krit1 mutations. One with moyamoya disease had an RNF213 mutation. Three patients with megalencephaly-capillary malformation had PIK3CA mutations, and 1 patient with a cavernous sinus lesion had an MED12 mutation. The majority of AVM patients were treated surgically. Patients with diffuse cerebral proliferative angiopathy were treated medically with sirolimus. At-risk relatives of 3 patients positive for genetic anomalies had also been tested. CONCLUSIONS: This study demonstrates a role for exploring genetic alterations in the identification and treatment of pediatric neurovascular disease pathogenesis. Germline genetic mutations were found in almost one-quarter of the patients screened in this study, results that helped to identify medically targeted treatment modalities for some pediatric neurovascular patients. Insight into the genetic etiology of vascular anomalies may provide broader clinical implications for risk assessment, family screening, follow-up surveillance, and medical management.

Innate Immune Stimulation Using 3D Wireframe DNA Origami.

Three-dimensional wireframe DNA origami have programmable structural and sequence features that render them potentially suitable for prophylactic and therapeutic applications. However, their innate immunological properties, which stem from parameters including geometric shape and cytosine-phosphate-guanine dinucleotide (CpG) content, remain largely unknown. Here, we investigate the immunostimulatory properties of 3D wireframe DNA origami on the TLR9 pathway using both reporter cell lines and primary immune cells. Our results suggest that bare 3D polyhedral wireframe DNA origami induce minimal TLR9 activation despite the presence of numerous internal CpG dinucleotides. However, when displaying multivalent CpG-containing ssDNA oligos, wireframe DNA origami induce robust TLR9 pathway activation, along with enhancement of downstream immune response as evidenced by increases in Type I and Type III interferon (IFN) production in peripheral blood mononuclear cells. Further, we find that CpG copy number and spatial organization each contribute to the magnitude of TLR9 signaling and that NANP-attached CpGs do not require phosphorothioate stabilization to elicit signaling. These results suggest key design parameters for wireframe DNA origami that can be programmed to modulate immune pathway activation controllably for prophylactic and therapeutic applications.

Pediatric traumatic brain injury prehospital guidelines: a systematic review and appraisal.

BACKGROUND: Traumatic brain injury (TBI) disproportionately affects children within low- and middle-income countries (LMICs). Prehospital emergency care can mitigate secondary brain injury and improve outcomes. Here, we systematically review clinical practice guidelines (CPGs) for pediatric TBI with the goal to inform LMICs prehospital care. METHODS: A systematic search was conducted in PubMed/Medline, Embase, and Web of Science databases. We appraised evidence-based CPGs addressing prehospital management of pediatric TBI using the Appraisal of Guidelines for Research & Evaluation (AGREE) tool. CPGs were rated as high-quality if ≥ 5 (out of 6) AGREE domains scored > 60%. RESULTS: Of the 326 articles identified, 10 CPGs were included in analysis. All 10 were developed in HICs, and 4 were rated as high-quality. A total of 154 pediatric prehospital recommendations were grouped into three subcategories, initial assessment (35.7%), prehospital treatment (38.3%), and triage (26.0%). Of these, 79 (51.3%) were evidence-based with grading, and 31 (20.1%) were consensus-based without direct evidence. CONCLUSION: Currently available CPGs for prehospital pediatric TBI management were all developed in HICs. Four CPGs have high-quality, and recommendations from these can serve as frameworks for LMICs or resource-limited settings. Context-specific evaluation and implementation of evidence-based recommendations allow LMIC settings to respond to the public health crisis of pediatric TBI and address gaps in trauma care systems.

Clinical Usefulness of Genetic Testing For Patients with Moyamoya Disease: A Systematic Review.

BACKGROUND: The effect of genetic factors on presentation and outcomes of moyamoya disease (MMD) is unclear. We aimed to examine differences in presentation of MMD by genetic variant, delineate the influence of genetic factors on outcomes, and characterize the applicability of genetic testing to management. METHODS: A systematic review was conducted using the PubMed, Embase, and Scopus databases. Title/abstract screening, full-text screening, and data extraction were conducted. RESULTS: Of 1329 articles, 12 were included. Genes included RNF213 (ring finger protein 213), VEGF (vascular endothelial growth factor), and soluble VEGR receptor (sVEGFR) 1 and 2. Patients heterozygous and homozygous for the p.R1480K variant of RNF213 had younger age of onset; were more frequently familial, had posterior cerebral artery involvement, had bilateral lesions; and were more likely to present with cerebral infarction or transient ischemic attack. The heterozygous p.4810K variant is associated with improved postoperative collateral formation. Stroke recurrence, stroke-free survival, neurologic status, and functional condition after surgery are not associated with the p.4180K genotype. Patients homozygous for p.4180K more frequently experience long-term cognitive impairment. Patients with the C/C genotype of VEGF 2634 or decreased sVEGFR-1 and sVEGFR levels postoperatively had greater postoperative collateral formation. CONCLUSIONS: Genetic factors correlate with MMD presentation including age of onset, severity, and symptoms, and angiographic and clinical outcomes after surgery. Incorporation of genetic testing panels into practice may allow for risk stratification, management, and follow-up of children and adults with MMD. However, future studies are necessary to validate the usefulness of genetic testing for MMD before this situation occurs.

Time-Out and Its Role in Neurosurgery.

BACKGROUND: Safety checklists have improved surgical outcomes; however, much of the literature comes from general surgery. OBJECTIVE: To identify the role of time-outs in neurosurgery, understand neurosurgeons' attitudes toward time-out, and highlight areas for improvement. METHODS: A cross-sectional study using a 15-item survey to evaluate how time-outs were performed across 5 hospitals affiliated with a single neurosurgery training program. RESULTS: Surveys were sent to 51 neurosurgical faculty, fellows, and residents across 5 hospitals with a 72.5% response rate. At all hospitals, surgeons, anesthesiologists, registered nurses, and circulators were involved in time-outs. Although all required time-out before incision, there was no consensus regarding the precise timing of time-out, in policy or in practice. Overall, respondents believed the existing time-out was adequate for neurosurgical procedures (H1: 17, 65.4%; H2: 19, 86.4%; H3: 14, 70.0%; H4: 20, 80.0%; and H5: 18, 78.3%). Of the respondents, 97.2% believed time-out made surgery safe, 94.6% agreed that time-outs reduce the risk of wrong-side or wrong-level neurosurgery, and 17 (45.9%) saw a role for a neurosurgery-specific safety checklist. Pragmatic challenges (n = 20, 54.1%) and individual beliefs and attitudes (n = 20, 54.1%) were common barriers to implementation of standardized time-outs. CONCLUSION: Multidisciplinary time-outs have become standard of care in neurosurgery. Despite proximity and overlapping personnel, there is considerable variability between hospitals in the practice of time-outs. This lack of uniformity, allowed for by flexible World Health Organization guidelines, may reflect the origins of surgical time-outs in general surgery, rather than neurosurgery, underscoring the potential for time-out optimization with neurosurgery-specific considerations.

Arteriovenous Malformations-Associated Epilepsy in Pediatrics.

PURPOSE: Seizures are the second most common presentation of cerebral arteriovenous malformations (AVMs); pediatric patients are more likely to develop AVM-associated epilepsy. We examined the role of multimodality AVM treatment in pediatric AVM-associated epilepsy to characterize long-term epilepsy outcomes. METHODS: A retrospective chart review identified pediatric patients with AVM-associated epilepsy seen at our institution from 2005 to 2018. Variables measured included demographic and descriptive data. Primary outcomes included seizure freedom, seizure control, and functional outcomes. RESULTS: Of 105 pediatric patients with AVMs, 18 had AVM-related epilepsy. Thirteen underwent surgical resection, of which 6 underwent preoperative embolization. Twelve (92.31%) had complete resection; one (7.69%) with residual underwent redo craniotomy with subsequent complete resection. All had radiographic cure at most recent follow-up, with no recurrence seen during length of follow-up (mean 2.17 years, SD 1.40, range 0.25-4.41). Eight (61.54%) experienced seizure freedom postoperatively; 12 (92.31%) were modified Engel Class I at last follow-up. Five patients underwent treatment without open surgical resection, with conservative management (3, 60%) or endovascular embolization (2, 40%). None in our cohort underwent radiosurgery. Of those embolized, one had complete AVM obliteration and two had partial obliteration. Four of the 5 patients (80%) treated without open surgery achieved seizure freedom. CONCLUSION: Long-term outcomes of AVM-related epilepsy are poorly characterized in children. We found that in addition to improved AVM outcomes regarding obliteration, treatment of residual, and recurrence, pediatric patients undergoing surgical AVM treatment had improved AVM-associated epilepsy outcomes, with 61.54% achieving seizure freedom and 92.31% classified as modified Engel Class I seizure control.

The role of surgery in the management of Lennox-Gastaut syndrome: A systematic review and meta-analysis of the clinical evidence.

Lennox-Gastaut syndrome (LGS) is a severe form of childhood onset epilepsy in which patients require multiple medications and may be candidates for palliative surgical intervention. In this meta-analysis, we sought to evaluate the impact of palliative vagus nerve stimulation (VNS), corpus callosotomy (CC), and resective surgery (RS) by analyzing their impact on seizure control, antiepileptic drug (AED) usage, quality of life (QOL), behavior, cognition, prognostic factors, and complications. A systematic search of PubMed MEDLINE, Scopus, and Cochrane Database of Systematic Reviews was performed to find articles that met the following criteria: (1) prospective/retrospective study with original data, (2) at least one LGS surgery patient aged less than 18 years, and (3) information on seizure frequency reduction (measured as percentage, Engel class, or qualitative comment). Seizures were analyzed quantitatively in a meta-analysis of proportions and a random-effects model, whereas other outcomes were analyzed qualitatively. Forty studies with 892 LGS patients met the selection criteria, with 19 reporting on CC, 17 on VNS, four on RS, two on RS + CC, one on CC + VNS, and one on deep brain stimulation. CC seizure reduction rate was 74.1% (95% confidence interval [CI] = 64.5%-83.7%), and VNS was 54.6% (95% CI = 42.9%-66.3%), which was significantly different (p < .001). RS seizure reduction was 88.9% (95% CI = 66.1%-99.7%). Many VNS patients reported alertness improvements, and most had no major complications. VNS was most effective for atonic/tonic seizures; higher stimulation settings correlated with better outcomes. CC patients reported moderate cognitive and QOL improvements; disconnection syndrome, transient weakness, and respiratory complications were noted. Greater callosotomy extent correlated with better outcomes. AED usage most often did not change after surgery. RS showed considerable QOL improvements for patients with localized seizure foci. In the reported literature, CC appeared to be more effective than VNS for seizure reduction. VNS may provide a similar or higher level of QOL improvement with lower aggregate risk of complications. Patient selection, anatomy, and seizure type will inform decision-making.

Implementation and Feasibility of the Re-Engineered Discharge for Surgery (RED-S) Intervention: A Pilot Study.

INTRODUCTION: Adapting Project Re-Engineered Discharge (Project RED), an intervention for reducing internal medicine hospital readmissions, is a promising option for reducing colorectal surgery readmissions. METHODS: We conducted a pilot study for the adaptation and implementation of Project RED with patients admitted for colectomy at a regional VA tertiary care center between July 2014 and January 2015. Implementation was evaluated using adherence to intervention components and results from the Survey of Healthcare Experiences of Patients. The adapted Project RED for Surgery has five components: surgical wound/ostomy-care education, scheduled follow-up appointments, medication reconciliation, an After Hospital Care Plan, and postdischarge phone calls. RESULTS: All (n = 21) participants received postoperative wound care education, and 77% of ostomy patients received education. Follow-up appointments were scheduled for 76% with surgery clinic and 67% with primary care. Half received pharmacist-led medication reconciliation. Seventy-five percent received a postdischarge phone call. Ninety five percent of participants reported positive or satisfactory care transitions versus less than 60% of a comparison group of surgery patients from the same institution. We summarized lessons learned from this intervention study to facilitate future dissemination efforts. CONCLUSION: The lessons learned from this pilot can guide quality improvement teams seeking to implement the Re-Engineered Discharge for Surgery intervention within their existing workflows.

Folate fortification and supplementation in prevention of folate-sensitive neural tube defects: a systematic review of policy.

OBJECTIVE: Neural tube defects (NTDs) are common congenital neurological defects, resulting in mortality, morbidity, and impaired quality of life for patients and caregivers. While public health interventions that increase folate consumption among women who are or plan to become pregnant are shown to reduce folate-sensitive NTDs, public health policy reflecting the scientific evidence lags behind. The authors aimed to identify the types of policies applied, associated outcomes, and impact of folate fortification and supplementation on NTDs worldwide. By identifying effective legislation, the authors aim to focus advocacy efforts to more broadly effect change, reducing the burden of NTDs in neurosurgery. METHODS: A systematic review was conducted exploring folate fortification and supplementation policies using the PubMed and Scopus databases. Titles and abstracts from articles identified were read and selected for full-text review. Studies meeting inclusion criteria were reviewed in full and analyzed for study design, aim, population, interventions, and outcomes. RESULTS: Of 1637 resultant articles, 54 were included. Mandatory folate fortification was effective at reducing folate-sensitive NTDs. Mandatory fortification also decreased hospitalization rates and deaths after discharge and increased 1st-year survival for infants with NTDs. Recommended folate supplementation also resulted in decreased NTDs; however, issues with compliance and adherence were a concern and impacted effectiveness. Folate fortification and/or supplementation resulted in decreased NTD prevalence, although more change was attributed to fortification. Dual policies may hold the most promise. Furthermore, reductions in NTDs were associated with significant cost savings over time. CONCLUSIONS: Both mandatory folate fortification and recommended supplementation policies were found to effectively decrease folate-sensitive NTD rates when applied. A comprehensive approach incorporating mandatory folate fortification, appropriate folate supplementation, and improved infrastructure and access to prenatal care may lead to decreased NTDs worldwide. This approach should be context-specific, emphasize education, and account for regional access to healthcare and social determinants of health. With wide implications for NTDs, associated health outcomes, quality of life of patients and caregivers, and economic impacts, policy changes can drastically improve global NTD outcomes. As caretakers of children with NTDs, the authors as neurosurgeons advocate for a comprehensive policy, the engagement of stakeholders, and a broader global impact.

Pediatric Neurosurgery in East Africa: An Education and Needs-Based Survey.

INTRODUCTION: A pediatric neurosurgery training workshop was organized for residents and consultants in East Africa. We aimed to compile feedback from the course participants to 1) characterize the state of neurosurgical education; and 2) identify the perceived practical education needs. METHODS: The survey of demographic, clinical background and practice, and feedback questions was distributed to all attendees. Responses were elicited via yes/no questions and Likert scales, with the score ranging from 1 (not important, not useful, never) to 5 (very important, very useful, often). The data were de-identified and analyzed in aggregate. RESULTS: A total of 11 neurosurgeons and trainees completed the survey, including 6 residents (55%) and 5 consultants (45%). Although 5 countries of origin were represented, all attendees (100%) have completed their neurosurgery training in Kenya. The respondents had most frequently treated trauma (least common to most common, 1-5; mean, 4.55 ± 0.93), hemorrhagic stroke (mean, 4.27 ± 0.79), and pediatric tumors (mean, 4.27 ± 1.01). In training, the most commonly used study resources were online resources (9; 82%), textbooks (7; 64%), and online lectures (7; 64%). The areas of greatest perceived need in education and training included general neurosurgery (least to most need, 1-10: 9; 82%), pediatric (9; 82%), trauma and neurocritical care (7; 64%), and neuro-oncology (7; 64%). All 11 respondents (100%) reported that more direct operative teaching was important for educational improvement. Hydrocephalus (least to most useful, 1-5: 5.00 ± 0.00), neuro-endoscopy (4.91 ± 0.30), and tumor (4.91 ± 0.30) were considered the most useful content covered in the pediatric neurosurgery-focused training program to improve skills and knowledge base. CONCLUSIONS: The results from the present survey identified areas of education and training needs to guide further neurosurgical education efforts in East Africa.

Primary prevention of road traffic accident-related traumatic brain injuries in younger populations: a systematic review of helmet legislation.

OBJECTIVE: Road traffic accidents are the most frequent cause of severe traumatic brain injury (TBI), particularly among young populations worldwide. Helmets are proven to prevent injuries; however, estimates of helmet compliance are low globally. Surgical/critical care management of TBI is often used to treat these injuries, but primary prevention should be recommended. A key component in promoting TBI prevention among pediatric and young populations is through helmet legislation. The authors investigated helmet policies for motorcycles and bicycles globally to provide recommendations for how related legislation may impact TBI and guide advocacy in pediatric neurosurgery. METHODS: The authors conducted a systematic review of helmet laws and/or policies by using the National Library of Medicine PubMed and SCOPUS databases. Additional articles were identified using citation searches of key publications. Abstracts from articles of all sources were read and selected for full-text review. Details of relevant full articles were extracted and analyzed for the following: bibliographic data, study aim, design and duration, study participants, intervention characteristics, and intervention effect data. RESULTS: Of 618 search results, 53 full-text articles were analyzed for recommendations. Helmet legislation is associated with increased helmet use among bicyclists and decreased road traffic accident-related head injuries and fatalities among motorcyclists and bicyclists. Laws are more effective if comprehensive and inclusive of the following: both primary riders and passengers, all age groups, all modes of transportation made safer by helmets, a proper use clause, and standardized helmet quality measures. Cultural, socioeconomic, and infrastructural circumstances are important as well, and legislation must consider enforcement mechanisms with penalties significant enough to incentivize behavioral changes, but proportional to community socioeconomic status. CONCLUSIONS: Compulsory use laws are the optimal primary intervention; however, concurrent programs to support financial access to helmets, change cultural attitudes, increase health literacy, and improve road infrastructure will augment legislative benefits. Pediatric neurosurgeons are caretakers of children suffering from TBI. Although extensive study has explored the surgical management of TBI, the authors believe that primary prevention is instrumental to improving outcomes and reducing injury. All helmet laws are not equal; based on these findings, a comprehensive, context-specific approach is the key to success, especially in resource-limited countries.

Neurovascular findings in children and young adults with Loeys-Dietz syndromes: Informing recommendations for screening.

INTRODUCTION: Loeys-Dietz Syndromes (LDS) are a group of connective tissue disorders associated with vascular abnormalities, including arterial tortuosity, aneurysms, and dissections. While neurovascular involvement is common, no pediatric or young adult recommendations for screening exist. We aimed to review our institution's experience with special focus on neurovascular imaging to better understand the pathology and guide screening. METHODS: A retrospective cohort study of patients with LDS was performed. Demographics, genetic subtype, clinical and radiographical data were analyzed. Primary outcome measures included pathology on neurovascular imaging, time to progression, and arterial tortuosity indexes for bilateral cervical internal carotid arteries (ICA) and vertebral arteries (VA). RESULTS: Of 47 patients with LDS identified, 39 (83.0%) were found to have neuroimaging. Intracranial and cervical vascular tortuosity were seen in 79.5% and 64.1%, respectively. Twenty-one patients (44.7%) received follow-up screening, of which 3 were found to have progression. Time to progression was an average of 2.1 years. Average follow-up was 607 days (range 123-3070 days). Mean Arterial Tortuosity Index for the right ICA, left ICA, right VA, and left VA were 18, 20, 49, and 47, respectively. Comparison of interval percent change in Arterial Tortuosity Index over the course of follow-up demonstrated small changes in the right ICA (mean 5%), left ICA (mean 1%), right VA (mean 1%), and left VA (mean 2%). CONCLUSIONS: Arterial tortuosity was most prevalent, though it did not progress significantly over time. We suggest an algorithm for management and serial screening to guide management of pediatric and young adults with LDS.

Bioproduction of pure, kilobase-scale single-stranded DNA.

Scalable production of kilobase single-stranded DNA (ssDNA) with sequence control has applications in therapeutics, gene synthesis and sequencing, scaffolded DNA origami, and archival DNA memory storage. Biological production of circular ssDNA (cssDNA) using M13 addresses these needs at low cost. However, one unmet goal is to minimize the essential protein coding regions of the exported DNA while maintaining its infectivity and production purity to produce sequences less than 3,000 nt in length, relevant to therapeutic and materials science applications. Toward this end, synthetic miniphage with inserts of custom sequence and size offers scalable, low-cost synthesis of cssDNA at milligram and higher scales. Here, we optimize growth conditions using an E. coli helper strain combined with a miniphage genome carrying only an f1 origin and a ß-lactamase-encoding (bla) antibiotic resistance gene, enabling isolation of pure cssDNA with a minimum sequence genomic length of 1,676 nt, without requiring additional purification from contaminating DNA. Low-cost scalability of isogenic, custom-length cssDNA is demonstrated for a sequence of 2,520 nt using a bioreactor, purified with low endotoxin levels (<5 E.U./ml). We apply these exonuclease-resistant cssDNAs to the self-assembly of wireframe DNA origami objects and to encode digital information on the miniphage genome for biological amplification.

Systematic review of clinician awareness of mycotoxin impact in neural tube defects and best practices for pediatric neurosurgeons: implications for public health and policy.

PURPOSE: In lower-income populations, high rates of neural tube defects (NTDs) are a concern. Nutritional folate deficiencies and mycotoxins in contaminated food supplies increase risk of NTDs. As physicians in public health and involved in the care of children with NTDs, pediatric neurosurgeons have an interest in the treatment and prevention of NTDs. We aimed to evaluate the literature to assess the awareness and the existence of best practices/educational materials on this issue to better guide management. METHODS: A systematic review using the National Library of Medicine PubMed database was conducted to find articles related to mycotoxins in foods causing neural tube defects. Additional citation searches of key publications and personal collections were used. Two reviewers evaluated the resulting studies for subject area analysis. Best practice recommendations were drawn from articles selected for full-text review. RESULTS: Seventy-three articles were identified. Most articles were found in "nutritional sciences" (18), "teratology" (14), and "toxicology" (13). No articles were found in neurosurgery. Thirty-two additional articles were identified through other sources to screen best practice recommendations. Of the 105 articles, 34 journal articles were included in best practice recommendation guidelines. Key recommendations included education of proper food storage, hygienic agricultural practices, decontamination techniques, diet diversification, folate supplementation, risk assessment, and food safety policy and public health initiatives. CONCLUSION: There is an absence of neurosurgical literature-related mycotoxins and NTDs. We suggest a set of best practices/educational materials on this topic and advocate pediatric neurosurgery engagement in public health initiatives targeted towards populations most affected by mycotoxins.

Amyloid-Related Imaging Abnormalities in an Aged Squirrel Monkey with Cerebral Amyloid Angiopathy.

Amyloid-related imaging abnormalities (ARIA) in magnetic resonance imaging scans have emerged as indicators of potentially serious side effects in clinical trials of therapeutics for Alzheimer's disease. These anomalies include an edematous type (ARIA-E) that appears as hyperintense (bright) regions by T2-weighted MRI, and a type characterized by the deposition of hemosiderin (ARIA-H) that elicits a hypointense signal, especially in T2* susceptibility weighted images. ARIA in general has been linked to the presence of amyloid-ß (Aß)-type cerebral amyloid angiopathy, an accumulation of misfolded Aß protein in the vascular wall that impairs the integrity of brain blood vessels. However, the pathobiology of ARIA remains poorly understood, in part due to the absence of an animal model of the disorder that would enable a contemporaneous analysis of tissue integrity in the affected region. Here we describe both ARIA-E and ARIA-H in an aged squirrel monkey (Saimiri sciureus), a nonhuman primate model of naturally occurring cerebral amyloid angiopathy. Histopathologic examination of the anomalous region revealed reactive astrocytosis and microgliosis, infiltration of systemic inflammatory/immune cells, damage to axons and myelin, and hemosiderin deposition. The disruption of axons in particular suggests that ARIA-E could have functional consequences for affected regions. The squirrel monkey model can be useful for studying the pathogenesis and long-term effects of ARIA, and for testing the safety and efficacy of emerging therapies for Alzheimer's disease.