Focal cortical dysplasia II caused by brain somatic mutation of IRS-1 is associated with ERK signaling pathway activation.

Somatic mutations have been identified in 10% to 63% of focal cortical dysplasia type II samples, primarily linked to the mTOR pathway. When the causative genetic mutations are not identified, this opens the possibility of discovering new pathogenic genes or pathways that could be contributing to the condition. In our previous study, we identified a novel candidate pathogenic somatic variant of IRS-1 c.1791dupG in the brain tissue of a child with focal cortical dysplasia type II. This study further explored the variant's role in causing type II focal cortical dysplasia through in vitro overexpression in 293T and SH-SY5Y cells and in vivo evaluation via in utero electroporation in fetal brains, assessing effects on neuronal migration, morphology, and network integrity. It was found that the mutant IRS-1 variant led to hyperactivity of p-ERK, increased cell volume, and was predominantly associated with the MAPK signaling pathway. In vivo, the IRS-1 c.1791dupG variant induced abnormal neuron migration, cytomegaly, and network hyperexcitability. Notably, the ERK inhibitor GDC-0994, rather than the mTOR inhibitor rapamycin, effectively rescued the neuronal defects. This study directly highlighted the ERK signaling pathway's role in the pathogenesis of focal cortical dysplasia II and provided a new therapeutic target for cases of focal cortical dysplasia II that are not treatable by rapamycin analogs.

Congenital Heart Defects in Patients with Anorectal Malformations: A Retrospective Cohort Study of 281 Patients.

In patients born with anorectal malformations (ARM), additional congenital heart defects (CHD) can occur. We aimed to provide an overview on disease and treatment details of CHD identified in patients born with ARM, from a unique large cohort of a very rare disease. We performed a retrospective single-center cohort study between January 2000 and July 2023. All consecutive patients with ARM were included. Outcomes were the number of patients with CHD, and screening percentage and percentage of patients diagnosed with CHD over 3 time periods (2000-2006, 2007-2014, 2015-2023). We used uni- and multi-variable logistic regression analyses to search for associations between CHD present and baseline characteristics. In total, 281 patients were included. Some 241 (85.8%) underwent echocardiography, of whom 80 (33.2%) had CHD. Screening percentage with echocardiography increased (74.1% vs. 85.7% vs. 95.9%, p < 0.001) and percentage of patients diagnosed with CHD remained similar over time (30.2% vs. 34.5% vs. 34.0%, p = 0.836). Atrial and ventricular septal defects (n = 36, n = 29), and persistent left superior vena cava (n = 17) were most identified. The presence of VACTERL-association or a genetic syndrome was independently associated with the presence of CHD. CHD were present in 33% of patients with ARM that underwent echocardiography. Over time, the number of CHD identified through screening remained similar. Patients with the presence of VACTERL-association or a genetic syndrome had a higher risk of having CHD. Therefore, acknowledging the potential presence of CHD in patients with ARM remains important.

Time-of-flight MRA of intracranial vessels at 7 T.

BACKGROUND: Three-dimensional time-of-flight magnetic resonance angiography (TOF-MRA) is a largely adopted non-invasive technique for assessing cerebrovascular diseases. We aimed to optimize the 7-T TOF-MRA acquisition protocol, confirm that it outperforms conventional 3-T TOF-MRA, and compare 7-T TOF-MRA with digital subtraction angiography (DSA) in patients with different vascular pathologies. METHODS: Seven-tesla TOF-MRA sequences with different spatial resolutions acquired in four healthy subjects were compared with 3-T TOF-MRA for signal-to-noise and contrast-to-noise ratios as well as using a qualitative scale for vessel visibility and the quantitative Canny algorithm. Four patients with cerebrovascular disease (primary arteritis of the central nervous system, saccular aneurism, arteriovenous malformation, and dural arteriovenous fistula) underwent optimized 7-T TOF-MRA and DSA as reference. Images were compared visually and using the complex-wavelet structural similarity index. RESULTS: Contrast-to-noise ratio was higher at 7 T (4.5 ± 0.8 (mean ± standard deviation)) than at 3 T (2.7 ± 0.9). The mean quality score for all intracranial vessels was higher at 7 T (2.89) than at 3 T (2.28). Angiogram quality demonstrated a better vessel border detection at 7 T than at 3 T (44,166 versus 28,720 pixels). Of 32 parameters used for diagnosing cerebrovascular diseases on DSA, 27 (84%) were detected on 7-T TOF-MRA; the similarity index ranged from 0.52 (dural arteriovenous fistula) to 0.90 (saccular aneurysm). CONCLUSIONS: Seven-tesla TOF-MRA outperformed conventional 3-T TOF-MRA in evaluating intracranial vessels and exhibited an excellent image quality when compared to DSA. Seven-tesla TOF-MRA might improve the non-invasive diagnostic approach to several cerebrovascular diseases. RELEVANCE STATEMENT: An optimized TOF-MRA sequence at 7 T outperforms 3-T TOF-MRA, opening perspectives to its clinical use for noninvasive diagnosis of paradigmatic pathologies of intracranial vessels. KEY POINTS: • An optimized 7-T TOF-MRA protocol was selected for comparison with clinical 3-T TOF-MRA for assessing intracranial vessels. • Seven-tesla TOF-MRA outperformed 3-T TOF-MRA in both quantitative and qualitative evaluation. • Seven-tesla TOF-MRA is comparable to DSA for the diagnosis and characterization of intracranial vascular pathologies.

Network analysis of toxic endpoints of fungicides in zebrafish.

Zebrafish being the best animal model to study, every attempt has been made to decipher the toxic mechanism of every fungicide of usage and interest. It is important to understand the multiple targets of a toxicant to estimate the toxic potential in its totality. A total of 22 fungicides of different classes like amisulbrom, azoxystrobin, carbendazim, carboxin, chlorothalonil, difenoconazole, etridiazole, flusilazole, fluxapyroxad, hexaconazole, kresoxim methyl, mancozeb, myclobutanil, prochloraz, propiconazole, propineb, pyraclostrobin, tebuconazole, thiophanate-methyl, thiram, trifloxystrobin and ziram were reviewed and analyzed for their multiple explored targets in zebrafish. Toxic end points in zebrafish are highly informative when it comes to network analysis. They provide a window into the molecular and cellular pathways that are affected by a certain toxin. This can then be used to gain insights into the underlying mechanisms of toxicity and to draw conclusions on the potential of a particular compound to induce toxicity. This knowledge can then be used to inform decisions about drug development, environmental regulation, and other areas of research. In addition, the use of zebrafish toxic end points can also be used to better understand the effects of environmental pollutants on ecosystems. By understanding the pathways affected by a given toxin, researchers can determine how pollutants may interact with the environment and how this could lead to health or environmental impacts.

Vascular Malformations.

Vascular malformations are intricate anomalies of the circulatory system, presenting a diverse array of clinical manifestations, and posing significant challenges in diagnosis and treatment. The pathogenesis of vascular malformations is explored through the lens of genetic and molecular mechanisms, shedding light on the pivotal role of somatic mutations and dysregulated signaling pathways. Clinical presentations of vascular malformations are widely variable, ranging from cosmetic concerns to life-threatening complications. The utility of imaging techniques, such as magnetic resonance imaging (MRI), computed tomography (CT), and angiography, are discussed in detail, emphasizing their role in precise delineation and characterization. Therapeutic strategies for vascular malformations are multifaceted, considering factors such as lesion size, location, potential complications, and patient-specific factors. Traditional interventions, including surgical excision and embolization, are appraised alongside emerging approaches like targeted molecular therapies and minimally invasive procedures. The manuscript underscores the need for an individualized treatment approach, optimizing outcomes while minimizing risks and complications. In summation, this manuscript offers a comprehensive analysis of vascular malformations, encompassing their underlying pathogenesis, clinical nuances, diagnostic methods, and therapeutic considerations. By synthesizing current knowledge and highlighting gaps in understanding, this review serves as a valuable resource for clinicians, researchers, and medical practitioners, fostering an enhanced comprehension of vascular malformations and paving the way for improved patient care and innovative research endeavors.

Single-cell and bulk RNA-seq unveils the immune infiltration landscape associated with cuproptosis in cerebral cavernous malformations.

BACKGROUND: Cerebral cavernous malformations (CCMs) are vascular abnormalities associated with deregulated angiogenesis. Their pathogenesis and optimal treatment remain unclear. This study aims to investigate the molecular signatures of cuproptosis, a newly identified type of cell death, associated with CCMs development. METHODS: Bulk RNA sequencing (RNA-seq) from 15 CCM and 6 control samples were performed with consensus clustering and clustered to two subtypes based on expression levels of cuproptosis-related genes (CRGs). Differentially expressed genes and immune infiltration between subtypes were then identified. Machine learning algorithms including the least absolute shrinkage and selection operator and random forest were employed to screen for hub genes for CCMs associated with cuproptosis. Furthermore, Pathway enrichment and correlation analysis were used to explore the functions of hub genes and their association with immune phenotypes in CCMs. An external dataset was then employed for validation. Finally, employing the Cellchat algorithm on a single-cell RNA-seq dataset, we explored potential mechanisms underlying the participation of these hub genes in cell-cell communication in CCMs. RESULTS: Our study revealed two distinct CCM subtypes with differential pattern of CRG expression and immune infiltration. Three hub genes (BTBD10, PFDN4, and CEMIP) were identified and validated, which may significantly associate with CCM pathogenesis. These genes were found to be significantly upregulated in CCM endothelial cells (ECs) and were validated through immunofluorescence and western blot analysis. Single-cell RNA-seq analysis revealed the cellular co-expression patterns of these hub genes, particularly highlighting the high expression of BTBD10 and PFDN4 in ECs. Additionally, a significant co-localization was also observed between BTBD10 and the pivotal cuproptosis gene FDX1 in Mki67+ tip cells, indicating the crucial role of cuproptosis for angiogenesis in CCMs. The study also explored the cell-cell communication between subcluster of ECs expressing these hub genes and immune cells, particularly M2 macrophages, suggesting a role for these interactions in CCM pathogenesis. CONCLUSION: This study identifies molecular signatures linking cuproptosis to CCMs pathogenesis. Three hub genes-PFDN4, CEMIP, and BTBD10-may influence disease progression by modulating immunity. Further research is needed to understand their precise disease mechanisms and evaluate their potential as biomarkers or therapeutic targets for CCMs.

A Long-Term Follow-Up of a Patient with a Novel PORCN Variant and Additional Clinical Features.

Introduction: Focal dermal hypoplasia (FDH) is a genodermatosis also known as Goltz-Gorlin syndrome caused by pathogenic variants in the PORCN gene and inherited in an X-linked dominant manner. Given the course of X-linked dominant inheritance, affected males can only survive in the state of mosaicism for a PORCN pathogenic variant or in the presence of XXY karyotype. FDH is a multisystemic disorder in which cutaneous, ocular, and skeletal systems are primarily affected. Patients also may display intellectual disability and central nervous system abnormalities, yet most may have normal mental development. Case Presentation: We report on a currently 11-year-old female patient with a novel missense heterozygous PORCN variant who exhibited classical ectodermal, skeletal, and ocular findings in addition to mild intellectual disability, left-side diaphragm eventration, and puberty precox, a finding yet unreported in the literature. Conclusion: With this report, we aimed to expand the mutational spectrum and give insight into the importance of neurologic and skeletal system evaluation among other clinical features of FDH. Although gastrointestinal and genitourinary problems can occur during the course of the disease, to our knowledge, left-side diaphragm eventration and puberty precox are new features that have not been reported previously.

Natural history and clinical manifestation of Pediatric Brain Arteriovenous Malformations.

Brain arteriovenous malformations (bAVMs) are aberrant arteriovenous shunts through a vascular nidus with no intervening capillary beds. They are one of the commonest causes of spontaneous intracranial haemorrhage in children and may be associated with significant morbidity and mortality in cases of rupture. Treatment strategies include microsurgical resection, endovascular embolisation, stereotactic radiosurgery, multimodality treatment with a combination thereof, and particularly in high-grade bAVMs, conservative management. Clinicians involved in treating bAVMs need to have familiarity with the natural history pertaining to bAVMs in terms of risk of rupture, risk factors elevating rupture risk as well as understanding the clinical manifestations of bAVMs. This invited review serves to provide a synthesis on natural history and clinical presentation of bAVMs with particular focus in children to inform decision-making pertaining to management.

The relationship between the caregiver burden and quality of life in parents of Turkish children with anorectal malformation or Hirschsprung's disease.

BACKGROUND: Anorectal malformation (ARM) or Hirschsprung's disease (HD) in children impact on parents' burden of care and quality of life (QoL). The aim of this study was to investigate the relationship between caregiver burden and QoL in parents of children with ARM or HD. DESIGN AND METHODS: This cross-sectional study was conducted with 51 parents who completed the Zarit Burden Inventory (ZBI) and World Health Organization Quality of Life Scale-Short Form Turkish Version (WHOQOL-BREF-TR). RESULTS: The mean (±SD) ZBI score was 33.6 (±12.7), and 47.1% of parents (n = 24) perceived their caregiver burden as mild, 31.4% (n = 16) as moderate, and 3.9% (n = 2) as severe. According to the multivariate linear regression, associated anomalies (ß1 = 5.912), family income (ß1 = -6.007), stoma care (ß1 = 8.287), and diagnosis were identified to be significant determinants of caregiver burden. A negative, moderate, and significant relationship was identified between the ZBI scores and the physical domain (r = -0.417, p < .01), psychological domain (r = -0.421, p < .01), social relations domain (r = -0.398, p < .01), and environmental domain (r = -0.495, p < .01) scores of the WHOQOL-BREF-TR. CONCLUSIONS: The mothers perceived their caregiver burden as mild. However, a significant number of parents suffer from moderate to heavy caregiver burden. An increase in the caregiver burden of parents reduces their quality of life. PRACTICE IMPLICATIONS: Heightened awareness of the potential for caregiver burden and its association with quality of life among parents of children with ARM and HD may contribute to improved.

Opioid analgesic exposure during the first trimester of pregnancy and the risk of major congenital malformations in infants: a systematic review and meta-analysis†.

BACKGROUND: Prescribed opioid analgesics are frequently used to manage pain in pregnancy. However, the available literature regarding the teratogenic potential of opioid use during pregnancy has not been systematically summarised. This systematic review and meta-analysis aimed to assess the quality of the evidence on these potential risks and calculate a pooled estimate of risk for any opioid analgesic and individual opioids. METHODS: We searched PubMed, Embase and CINAHL for published studies assessing the risk of major congenital malformations in infants following first-trimester exposure to opioid analgesics compared with a reference group, excluding studies examining opioid agonist therapy or illicit opioid use. We assessed the risk of bias using the Risk of Bias in Non-Randomised Studies of Intervention tool. We pooled adjusted risk estimates from studies rated at serious risk of bias or better in a random-effects meta-analysis. RESULTS: Of 12 identified studies, 11 were at high risk of bias (eight serious; three critical). Relative to unexposed infants, those exposed to any opioid use during the first trimester of pregnancy were not at an increased risk of major congenital malformations overall (relative risk 1.04, 95%CI 0.98-1.11); cardiovascular malformations (relative risk 1.07, 95%CI 0.96-1.20); or central nervous system malformations (relative risk 1.06, 95%CI 0.92-1.21). Raised risk estimates were observed for gastrointestinal malformations (relative risk 1.40, 95%CI 0.38-5.16) and cleft palate (relative risk 1.57, 95%CI 0.48-5.13) following any opioid exposure and atrial septal defects (relative risk 1.20, 95%CI 1.05-1.36) following codeine exposure. CONCLUSIONS: Although the meta-analysis did not indicate substantial increased risk for most malformations examined, this risk remains uncertain due to the methodological limitations of the included studies. Healthcare professionals and pharmaceutical regulators should be aware of the issues related to the quality of research in this field.

Sudden pediatric death unveiling pulmonary arteriovenous malformations.

Pulmonary arteriovenous malformations (PAVMs) are abnormal vascular connections between pulmonary arteries and veins, often associated with hereditary hemorrhagic telangiectasia (HHT). Most PAVMs are asymptomatic, but life-threatening complications like pulmonary hemorrhage, brain abscesses, and paradoxical emboli can emerge, so prompt diagnosis and treatment are crucial. We report a case of sudden pediatric death in a two-year-old female with no past medical history. Initial vomiting and fast deterioration resulted in a sudden cardiac arrest. The postmortem examination found histological evidence of consistent, extensive lung damage. The absence of the characteristic symptoms made for some challenges when it came to diagnosis, showing precisely that in early life, you could well have many difficulties in catching PAVMs. This case highlights the need to take PAVMs into account as a potential cause of sudden death, particularly when there are no conspicuous symptoms. Awareness among forensic pathologists and consideration of genetic analysis for HHT in such cases is crucial for accurate diagnosis and management.

Early stress exposure on zebrafish development: effects on survival, malformations and molecular alterations.

The effects of stress during early vertebrate development can be especially harmful. Avoiding stressors in fish larvae is essential to ensure the health of adult fish and their reproductive performance and overall production. We examined the consequences of direct exposure to successive acute stressors during early development, including their effects on miR-29a and its targets, survival, hatching and malformation rates, larval behaviour and cartilage and eye development. Our aim was to shed light on the pleiotropic effects of early-induced stress in this vertebrate model species. Our results showed that direct exposure to successive acute stressors during early development significantly upregulated miR-29a and downregulated essential collagen transcripts col2a1a, col6a2 and col11a1a, decreased survival and increased malformation rates (swim bladder, otoliths, cardiac oedema and ocular malformations), promoting higher rates of immobility in larvae. Our results revealed that stress in early stages can induce different eye tissular architecture and cranioencephalic cartilage development alterations. Our research contributes to the understanding of the impact of stressful conditions during the early stages of zebrafish development, serving as a valuable model for vertebrate research. This holds paramount significance in the fields of developmental biology and aquaculture and also highlights miR-29a as a potential molecular marker for assessing novel larval rearing programmes in teleost species.

Coexistence of brain capillary telangiectasia and venous angioma: A case report and literature review.

While Cerebral vascular malformations exhibit distinct clinical and radiographical features, rare instances of coexisting lesions occur. This case report sheds light on the rare coexistence of brain capillary telangiectasia and venous angioma in a patient presenting with a seizure attributed to frontal lobe bleeding. Though often silent, brain capillary telangiectasia can manifest with serious life-threatening intracranial bleeding. Therefore, in cases of spontaneous intracranial bleeding, an MRI of the head is crucial to rule out such cerebral vascular malformations.

Endovascular embolization of Spetzler-Martin Grade I brain arteriovenous malformations: A case report on patient-centered neurointervention.

Brain arteriovenous malformations (AVM) present complex treatment decisions, particularly for low-grade AVM where surgical resection is often considered the standard. This case report emphasizes the importance of patient preferences and cultural considerations in selecting endovascular embolization over traditional surgical approaches for Spetzler-Martin Grade I AVM management, highlighting the evolving practice of patient-centered care in neurointervention. A 30-year-old male presented with recurrent seizures, characterized by a sudden onset of headache followed by speech arrest, without any preceding medical history of neurological deficits. Initial physical examination revealed no focal neurological deficits. Non-contrast computed tomography, magnetic resonance imaging, and magnetic resonance angiography suggested an AVM involving the cortical-subcortical regions of the left frontal lobe, measuring approximately 1.7 × 2.6 × 1.5 cm, fed by the left middle cerebral artery M3 segment, and draining into the superior sagittal sinus. Spetzler-Martin Grade I classification was confirmed via digital subtraction angiography. Given the patient's strong preference against invasive procedures, driven by personal and cultural beliefs, endovascular embolization was selected as the treatment strategy. Post-embolization, the patient showed marked symptomatic improvement with no evidence of residual AVM on follow-up imaging, and no postprocedure complications were reported. This case highlights the importance of considering patient preferences in AVM treatment planning, illustrating that endovascular embolization can be an effective and less invasive alternative to surgery in selected patients, reinforcing the need for personalized, patient-centered approaches in neurointerventional care.

Determination of mandibular distraction osteogenesis most suitable parameters. An experimental study.

BACKGROUND: Distraction osteogenesis is a process of induced bone generation. Various protocols have been described for the management of the latency period, distraction speed and consolidation period, with greater or lesser success. OBJECTIVE: To better understand the process of mandibular distraction and establish the determining factors and their optimal times. MATERIAL AND METHODS: Twenty-seven dogs were studied, which had 54 distractors placed and that underwent unidirectional, bilateral mandibular distraction osteogenesis. The distraction processes were applied using six variants, two for each factor: latency period, distraction period and distraction speed. The changes were examined by means of bone biopsies and X-rays of the area at 0, 7, 14, 21, 45 and 55 days of the process. RESULTS: The most efficient osteogenic distraction parameters were a latency period of five days, a consolidation period of six weeks, distraction speed of 1 mm/day for distances of less than 20 mm, and 3 mm/day for longer distances. CONCLUSIONS: The sequential histological study allowed to observe the appearance of cellular elements (osteocytes, osteoclasts, osteoid matrix, trabeculate, etc.) and their participation in granulation tissue, newly-formed bone and compact mature bone.

ANTECEDENTES: Respecto a la distracción osteogénica (generación ósea inducida), con mayor o menor éxito han sido descritos diversos protocolos para el manejo del período de latencia, velocidad de distracción y período de consolidación. ­. OBJETIVO: Entender mejor el proceso de la distracción mandibular y establecer los factores determinantes y sus tiempos óptimos. MATERIAL Y MÉTODOS: Se estudiaron 27 perros sometidos a distracción osteogénica unidireccional, bilateral de la mandíbula. Los procesos de distracción se aplicaron con seis variantes, dos por cada factor (período de latencia, período de distracción y velocidad de distracción). Se estudiaron los cambios mediante biopsias del hueso y radiografías de la zona a los 0, 7, 14, 21, 45 y 55 días del proceso. RESULTADOS: Los parámetros de distracción osteogénica más eficientes fueron período de latencia de cinco días, período de consolidación de seis semanas, 1 mm diario de velocidad de distracción para distancias menores a 20 mm y 3 mm diarios para distancias mayores. CONCLUSIONES: El estudio histológico secuencial permitió observar la aparición de los elementos celulares (osteocitos, osteoclastos, matriz osteoide, trabeculado, etcétera) y su participación en el tejido de granulación, el hueso neoformado y el hueso maduro compacto.

Telangiectasias, recurrent epistaxis and a strong family history-a case of Osler- Weber-Rendu Syndrome in Pakistan.

Osler-Weber-Rendu syndrome or Hereditary Haemorrhagic Telangiectasia (HHT) is a rare condition, with very few reported cases, especially in Pakistan. As healthcare workers, we encounter multiple cases of recurrent epistaxis in the emergency as well as outpatient departments. However, patients are usually treated symptomatically without a thorough workup. HHT should be considered among the differentials for recurrent epistaxis, as a clinical diagnosis can be made with detailed family history and physical examination. Here is the case of a 58-year-old male who presented to the Gastroenterology OPD, Combined Military Hospital, Lahore, in November 2021, with complaints of generalised weakness and blood in stools. He had a history of recurrent epistaxis and telangiectasias, and further inquiry revealed a strong family history of similar symptoms. He was diagnosed as a case of Osler-Weber- Rendu Syndrome. Informed consent was taken from the patient prior to the writing of the manuscript.

Clinical outcomes of posterior fossa arteriovenous malformations: a single center experience.

BACKGROUND: Posterior fossa arterio-venous malformations (pfAVMs) are challenging lesions due to the anatomical particularities of the posterior fossa, and the high incidence of hemorrhagic presentation. The two most important goals when treating AVMs are preserving neurological function and preventing rupture, or a second hemorrhage. The aim of this study was to analyze the clinical and imaging features of pfAVMs to identify the factors that influence the prognosis of these patients. METHODS: We conducted a single-center retrospective observational study that included patients treated at our institution with pfAVMs between January 1997 and December 2021. RESULTS: A total of 48 patients were included. A good modified Rankin score (mRS) was observed in 33 cases (69%) at presentation. Thirty-four patients (71%) presented with a ruptured AVM. Out of these, 19 patients (40%) had intraventricular hemorrhage. Microsurgical resection was performed in 33 cases (69%), while in the other cases, the patients opted for conservative management (7 cases, 15%), stereotactic radiosurgery (SRS) (6 cases, 12%), or endovascular treatment (2 cases, 4%). Patients ≤ 30 years old were more prone to hemorrhagic presentation (OR: 5.23; 95% CI: 1.42-17.19; p = 0.024) and this remained an independent risk factor for rupture after multivariate analysis as well (OR: 4.81; 95% CI: 1.07-21.53; p = 0.040). Following multivariate analysis, the only factor independently associated with poor prognosis in the surgically treated subgroup was a poor clinical status (mRS 3-5) at admission (OR: 96.14; 95% CI: 5.15-1793.9; p = 0.002). CONCLUSIONS: Management of posterior fossa AVMs is challenging, and patients who present with ruptured AVMs often have a poor clinical status at admission leading to a poor prognosis. Therefore, proper and timely management of these patients is essential.

Identifying potential (re)hemorrhage among sporadic cerebral cavernous malformations using machine learning.

The (re)hemorrhage in patients with sporadic cerebral cavernous malformations (CCM) was the primary aim for CCM management. However, accurately identifying the potential (re)hemorrhage among sporadic CCM patients in advance remains a challenge. This study aims to develop machine learning models to detect potential (re)hemorrhage in sporadic CCM patients. This study was based on a dataset of 731 sporadic CCM patients in open data platform Dryad. Sporadic CCM patients were followed up 5 years from January 2003 to December 2018. Support vector machine (SVM), stacked generalization, and extreme gradient boosting (XGBoost) were used to construct models. The performance of models was evaluated by area under receiver operating characteristic curves (AUROC), area under the precision-recall curve (PR-AUC) and other metrics. A total of 517 patients with sporadic CCM were included (330 female [63.8%], mean [SD] age at diagnosis, 42.1 [15.5] years). 76 (re)hemorrhage (14.7%) occurred during follow-up. Among 3 machine learning models, XGBoost model yielded the highest mean (SD) AUROC (0.87 [0.06]) in cross-validation. The top 4 features of XGBoost model were ranked with SHAP (SHapley Additive exPlanations). All-Elements XGBoost model achieved an AUROCs of 0.84 and PR-AUC of 0.49 in testing set, with a sensitivity of 0.86 and a specificity of 0.76. Importantly, 4-Elements XGBoost model developed using top 4 features got a AUROCs of 0.83 and PR-AUC of 0.40, a sensitivity of 0.79, and a specificity of 0.72 in testing set. Two machine learning-based models achieved accurate performance in identifying potential (re)hemorrhages within 5 years in sporadic CCM patients. These models may provide insights for clinical decision-making.

A spectrum of AKT3 activating mutations cause focal malformations of cortical development (FMCDs) in cortical organoids.

Focal malformations of cortical development (FMCDs) are brain disorders mainly caused by hyperactive mTOR signaling due to both inactivating and activating mutations of genes in the PI3K-AKT-mTOR pathway. Among them, mosaic and somatic activating mutations of the mTOR pathway activators are more frequently linked to severe form of FMCDs. A human stem cell-based FMCDs model to study these activating mutations is still lacking. Herein, we genetically engineer human embryonic stem cell lines carrying these activating mutations to generate cortical organoids. Mosaic and somatic expression of AKT3 activating mutations in cortical organoids mimicking the disease presentation with overproliferation and the formation of dysmorphic neurons. In parallel comparison of various AKT3 activating mutations reveals that stronger mutation is associated with more severe neuronal migratory and overgrowth defects. Together, we have established a feasible human stem cell-based model for FMCDs that could help to better understand pathogenic mechanism and develop novel therapeutic strategy.

Risks of congenital malformations and neonatal intensive care unit admissions with gabapentin use in pregnancy: A cohort study and scoping review with meta-analysis.

BACKGROUND: The increasing and prevalent use of gabapentin among pregnant people highlights the necessity to assess its neonatal safety. OBJECTIVES: This study aimed to investigate the foetal safety of gabapentin during pregnancy using a cohort study and scoping review with a meta-analysis of published evidence. METHODS: We conducted a population-based cohort study using the Manitoba health databases between 1995 and 2019. We examined the association between gabapentin use during pregnancy and the prevalence of major congenital malformations, cardiac and orofacial malformations, and neonatal intensive care unit (NICU) admissions using multivariate regression models. We searched the literature in MEDLINE and EMBASE databases from inception to October 2022 to identify relevant observational studies and conducted a meta-analysis using random-effects models, including our cohort study results. RESULTS: Of the 289,227 included pregnancies, 870 pregnant people were exposed to gabapentin. Gabapentin exposure during the First trimester was not associated with an increased risk of any malformations (adjusted relative risk [aRR]) 1.16 (95% confidence interval [CI] 0.92, 1.46), cardiac malformations (aRR 1.29, 95% CI 0.72, 2.29), orofacial malformations (aRR 1.37, 95% CI 0.50, 3.75), and major congenital malformations (aRR 1.00, 95% CI 0.73, 1.36). whereas exposure during any trimester was associated with an increased NICU admission risk (aRR, 1.99 [95% CI 1.70, 2.32]). The meta-analysis of unadjusted results revealed an increased risk of major congenital malformations (RR 1.44, 95% CI 1.28, 1.61, I2 = 0%), cardiac malformations (RR 1.66, 95% CI 1.11, 2.47, I2 = 68%), and NICU admissions (RR 3.15, 95% CI 2.90, 3.41, I2 = 10%), and increased trend of orofacial malformations (RR 1.98, 95% CI 0.79, 5.00, I2 = 0%). CONCLUSIONS: Gabapentin use was associated with an increased risk of NICU admissions in the cohort study and pooled meta-analysis. Clinicians should prescribe gabapentin with caution during pregnancy and further studies are warranted.