Head growth in patients with myelomeningocele treated with prenatal and postnatal surgery.

OBJECTIVE: The need for permanent CSF diversion is lower in patients who have undergone prenatal surgery for myelomeningocele (MMC) than in those who have undergone postnatal closure. Differences in brain development and head growth between treatment groups are not known, particularly for those who do not require surgical treatment for hydrocephalus. The objective of this study was to determine differences in head growth and to generate MMC-specific head circumference (HC) growth curves for patients who underwent either prenatal or postnatal surgery. METHODS: The authors retrospectively identified patients from St. Louis Children's Hospital who were treated for MMC between 2016 and 2021. HC data were obtained from birth until the most recent follow-up or hydrocephalus treatment. Nonlinear least-squares regression analysis was performed to fit the data into four models: two-term power, Gompertz, West ontogenetic, and Weibull. Subsequently, the curves were assessed for their utility in predicting hydrocephalus treatment. RESULTS: Sixty-one patients (29 females [47.5%], 25 [41%] underwent prenatal surgery, mean gestational age at birth 36.6 weeks) were included in the study. The Weibull model best fit the HC data (prenatal adjusted R2 = 0.95, postnatal adjusted R2 = 0.95), while the Gompertz model had the worst fit (prenatal adjusted R2 = 0.56, postnatal adjusted R2 = 0.39) across both cohorts. Prenatal MMC repair patients had significantly larger HC measurements than their postnatal repair counterparts. The 50th percentile of the Weibull curve was determined as a useful threshold for hydrocephalus treatment: children with HC measurements that crossed and remained above this threshold were significantly more likely to have hydrocephalus treatment regardless of time of MMC repair (prenatal relative risk [RR] 10.0 [95% CI 1.424-70.220], sensitivity 85.7% [95% CI 0.499-0.984], and specificity 82.4% [95% CI 0.600-0.948]; postnatal RR 4.750 [95% CI 1.341-16.822], sensitivity 90.5% [95% CI 0.728-0.980], and specificity 75.0% [95% CI 0.471-0.924]). The HC growth curves of the MMC patients treated prenatally were significantly larger than the WHO HC curves (p < 0.001). CONCLUSIONS: The Weibull model was identified as the HC growth curve with the best fit for MMC patients and serves as a useful predictor of hydrocephalus treatment. For MMC patients with hydrocephalus, prenatal repair patients fit the model well but postnatal repair patients did not, potentially indicating different mechanisms of hydrocephalus development. Those treated prenatally had significantly larger HC measurements compared with both the general population and those treated postnatally. Further study is needed to understand the long-term cognitive outcomes and optimal management of clinically asymptomatic patients with large HC measurements who were treated prenatally for MMC.

Predictors and timing of hydrocephalus treatment in patients undergoing prenatal versus postnatal surgery for myelomeningocele.

OBJECTIVE: Although hydrocephalus rates have decreased with intrauterine surgery for myelomeningocele (MMC), 40%-85% of children with MMC still go on to develop hydrocephalus. Prenatal ventricle size is known to be associated with later development of hydrocephalus; however, it is not known how prediction measures or timing of hydrocephalus treatment differ between pre- and postnatal surgery for MMC. The goal of this study was to determine anatomical, clinical, and radiological characteristics that are associated with the need for and timing of hydrocephalus treatment in patients with MMC. METHODS: The authors retrospectively identified patients from Barnes Jewish Hospital or St. Louis Children's Hospital between 2016 and 2021 who were diagnosed with MMC prenatally and underwent either pre- or postnatal repair. Imaging, clinical, and demographic data were examined longitudinally between treatment groups and hydrocephalus outcomes. RESULTS: Fifty-eight patients were included (27 females, 46.6%), with a mean gestational age at birth of 36.8 weeks. Twenty-three patients (39.7%) underwent prenatal surgery. For the overall cohort, the ventricle size at prenatal ultrasound (HR 1.175, 95% CI 1.071-1.290), frontal-occipital horn ratio (FOHR) at birth > 0.50 (HR 3.603, 95% CI 1.488-8.720), and mean rate of change in head circumference (HC) in the first 90 days after birth (> 0.10 cm/day: HR 12.973, 95% CI 4.262-39.486) were identified as predictors of hydrocephalus treatment. The factors associated with hydrocephalus in the prenatal cohort were FOHR at birth > 0.50 (HR 27.828, 95% CI 2.980-259.846) and the rate of change in HC (> 0.10 cm/day: HR 39.414, 95% CI 2.035-763.262). The factors associated with hydrocephalus in the postnatal cohort were prenatal ventricle size (HR 1.126, 95% CI 1.017-1.246) and the mean rate of change in HC (> 0.10 cm/day: HR 24.202, 95% CI 5.119-114.431). FOHR (r = -0.499, p = 0.008) and birth HC (-0.409, p = 0.028) were correlated with time to hydrocephalus across both cohorts. For patients who underwent treatment for hydrocephalus, those in the prenatal surgery group were significantly more likely to develop hydrocephalus after 3 months than those treated with postnatal surgery, although the overall rate of hydrocephalus was significantly higher in the postnatal surgery group (p = 0.018). CONCLUSIONS: Clinical and imaging factors associated with hydrocephalus treatment differ between those receiving pre- versus postnatal MMC repair, and while the overall rate of hydrocephalus is lower, those undergoing prenatal repair are more likely to develop hydrocephalus after 3 months of age. This has implications for clinical follow-up timing for patients treated prenatally, who may live at a distance from the treatment site.

Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus.

Hydrocephalus, characterized by cerebral ventricular dilatation, is routinely attributed to primary defects in cerebrospinal fluid (CSF) homeostasis. This fosters CSF shunting as the leading reason for brain surgery in children despite considerable disease heterogeneity. In this study, by integrating human brain transcriptomics with whole-exome sequencing of 483 patients with congenital hydrocephalus (CH), we found convergence of CH risk genes in embryonic neuroepithelial stem cells. Of all CH risk genes, TRIM71/lin-41 harbors the most de novo mutations and is most specifically expressed in neuroepithelial cells. Mice harboring neuroepithelial cell-specific Trim71 deletion or CH-specific Trim71 mutation exhibit prenatal hydrocephalus. CH mutations disrupt TRIM71 binding to its RNA targets, causing premature neuroepithelial cell differentiation and reduced neurogenesis. Cortical hypoplasia leads to a hypercompliant cortex and secondary ventricular enlargement without primary defects in CSF circulation. These data highlight the importance of precisely regulated neuroepithelial cell fate for normal brain-CSF biomechanics and support a clinically relevant neuroprogenitor-based paradigm of CH.

DIAPH1 Variants in Non-East Asian Patients With Sporadic Moyamoya Disease.

Importance: Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non-East Asian individuals. Objective: To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk. Design, Setting, and Participants: A genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016-2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort. Main Outcomes and Measures: Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue. Results: Of the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10-6) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non-East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways. Conclusions and Relevance: These findings provide the largest collection to date of non-East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk gene and impaired vascular cell actin remodeling in MMD pathogenesis, with diagnostic and therapeutic ramifications.

Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia.

Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated de novo mutation (p.Cys188Trp) in the GABAA receptor Cl- channel γ-1 subunit (GABRG1) exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na+ and Ca+ channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca2+ channel Cav3.2 (CACNA1H). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis.

Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.

The impact of telemedicine on patient self-management processes and clinical outcomes for patients with Types I or II Diabetes Mellitus in the United States: A scoping review.

OBJECTIVE: The objective of this scoping review was to identify peer-reviewed medical literature on the use of telemedicine in patients with Types I or II DM in the United States, assess its impact on self-management processes and clinical outcomes of care, and to delineate research gaps. METHODS: We utilized a structured scoping review protocol to conduct this research. We searched the published medical literature utilizing two databases, PubMed and CINHAL, and we included all original research articles published prior to July 20th, 2018. Using a 4-step systematic approach, we identified, reviewed, extracted and summarized data from all relevant studies. RESULTS: We identified 47 articles overall. Telemedicine impact was reported as positive in articles addressing the following components of patient self-management: adherence to blood glucose monitoring, day-to-day decision-making related to self-care, and adherence with medications. The most commonly reported clinical outcome was HbA1c level. Few or no studies evaluated impact on long term clinical outcomes such as blindness, amputation, cardiovascular events, development of chronic kidney disease, or mortality. DISCUSSION: This scoping review provides important information about studies conducted in the United States evaluating the impact of telemedicine on patient self-management and on clinical outcomes in patients with DM. CONCLUSIONS: Results suggest that telemedicine has a positive impact on self-management processes and on HbA1c levels. However, future evaluative reviews are necessary to confirm and quantitate the impact of telemedicine on self-management processes and primary studies are necessary to evaluate its impact on long term clinical outcomes.

GemC1 is a critical switch for neural stem cell generation in the postnatal brain.

The subventricular zone (SVZ) is one of two main niches where neurogenesis persists during adulthood, as it retains neural stem cells (NSCs) with self-renewal capacity and multi-lineage potency. Another critical cellular component of the niche is the population of postmitotic multiciliated ependymal cells. Both cell types are derived from radial glial cells that become specified to each lineage during embryogenesis. We show here that GemC1, encoding Geminin coiled-coil domain-containing protein 1, is associated with congenital hydrocephalus in humans and mice. Our results show that GemC1 deficiency drives cells toward a NSC phenotype, at the expense of multiciliated ependymal cell generation. The increased number of NSCs is accompanied by increased levels of proliferation and neurogenesis in the postnatal SVZ. Finally, GemC1-knockout cells display altered chromatin organization at multiple loci, further supporting a NSC identity. Together, these findings suggest that GemC1 regulates the balance between NSC generation and ependymal cell differentiation, with implications for the pathogenesis of human congenital hydrocephalus.

A Phase I Clinical Trial of Targeted Intraoperative Molecular Imaging for Pulmonary Adenocarcinomas.

BACKGROUND: Intraoperative identification of pulmonary nodules, particularly small lesions, can be challenging. We hypothesize that folate receptor-targeted intraoperative molecular imagining can be safe and improve localization of pulmonary nodules during resection. METHODS: Twenty subjects with biopsy-proven pulmonary adenocarcinomas were enrolled in a phase I clinical trial to test the safety and feasibility of OTL38, a novel folate receptor-α (FRα) targeted optical contrast agent. During resection, tumors were imaged in situ and ex vivo and fluorescence was quantified. Resected specimens were analyzed to confirm diagnosis, and immunohistochemistry was utilized to quantify FRα expression. A multivariate analysis using clinical and tumor data was performed to determine variables impacting tumor fluorescence. RESULTS: Of the 20 subjects, three grade I adverse events were observed: all transient nausea/abdominal pain. All symptoms resolved after completing the infusion. Sixteen of 20 subjects (80%) had tumors with in situ fluorescence with a mean tumor-to-background fluorescence level of 2.9 (interquartile range, 2.1 to 4.2). The remaining 4 subjects' tumors fluoresced ex vivo. In situ fluorescence was dependent on depth from the pleural surface. Four subcentimeter nodules not identified on preoperative imaging were detected with intraoperative imaging. CONCLUSIONS: This phase I trial provides preliminary evidence suggesting that folate receptor-targeted molecular imaging with OTL38 is safe, with tolerable grade I toxicity. These data also suggest that OTL38 accumulates in known lung cancers and may improve identification of synchronous malignancies. Our group is initiating a five-center, phase II study to better understand the clinical implications of intraoperative molecular imaging using OTL38.

Identification of a Folate Receptor-Targeted Near-Infrared Molecular Contrast Agent to Localize Pulmonary Adenocarcinomas.

Non-small cell lung cancer (NSCLC) is the number one cancer killer in the United States. Despite attempted curative surgical resection, nearly 40% of patients succumb to recurrent disease. High recurrence rates may be partially explained by data suggesting that 20% of NSCLC patients harbor synchronous disease that is missed during resection. In this report, we describe the use of a novel folate receptor-targeted near-infrared contrast agent (OTL38) to improve the intraoperative localization of NSCLC during pulmonary resection. Using optical phantoms, fluorescent imaging with OTL38 was associated with less autofluorescence and greater depth of detection compared to traditional optical contrast agents. Next, in in vitro and in vivo NSCLC models, OTL38 reliably localized NSCLC models in a folate receptor-dependent manner. Before testing intraoperative molecular imaging with OTL38 in humans, folate receptor-alpha expression was confirmed to be present in 86% of pulmonary adenocarcinomas upon histopathologic review of 100 human pulmonary resection specimens. Lastly, in a human feasibility study, intraoperative molecular imaging with OTL38 accurately identified 100% of pulmonary adenocarcinomas and allowed for identification of additional subcentimeter neoplastic processes in 30% of subjects. This technology may enhance the surgeon's ability to identify NSCLC during oncologic resection and potentially improve long-term outcomes.

Intraoperative Molecular Imaging Combined With Positron Emission Tomography Improves Surgical Management of Peripheral Malignant Pulmonary Nodules.

OBJECTIVE: To determine if intraoperative molecular imaging (IMI) can improve detection of malignant pulmonary nodules. BACKGROUND: 18-Fluorodeoxyglucose positron emission tomography (PET) is commonly utilized in preoperative assessment of patients with solid malignancies; however, false negatives and false positives remain major limitations. Using patients with pulmonary nodules as a study model, we hypothesized that IMI with a folate receptor targeted near-infrared contrast agent (OTL38) can improve malignant pulmonary nodule identification when combined with PET. METHODS: Fifty patients with pulmonary nodules with imaging features suspicious for malignancy underwent preoperative PET. Patients then received OTL38 before pulmonary resection. During resection, IMI was utilized to evaluate known pulmonary nodules and identify synchronous lesions. Tumor size, PET standardized uptake value, and IMI tumor-to-background ratios were compared for known and synchronous nodules via paired and unpaired t tests, when appropriate. Test characteristics of PET and IMI with OTL38 were compared. RESULTS: IMI identified 56 of 59 (94.9%) malignant pulmonary nodules identified by preoperative imaging. IMI located an additional 9 malignant lesions not identified preoperatively. Nodules only detected by IMI were smaller than nodules detected preoperatively (0.5 vs 2.4 cm; P < 0.01), but displayed similar fluorescence (tumor-to-background ratio 3.3 and 3.1; P = 0.50). Sensitivity of IMI and PET were 95.6% and 73.5% (P = 0.001), respectively; and positive predictive values were 94.2% and 89.3%, respectively (P > 0.05). Additionally, utilization of IMI clinically upstaged 6 (12%) subjects and improved management of 15 (30%) subjects. CONCLUSIONS: These data suggest that combining IMI with PET may provide superior oncologic outcomes for patients with resectable lung cancer.