Focal Type Research Articles

Contribution of the Activated mTOR-STAT3 Pathway to the Pathogenesis of Focal Cortical Dysplasia Type IIIa in Pediatric Patients through Astrocyte Proliferation Mediation.

The aim of this study was to detect the association between the mTOR-STAT3 pathway and focal cortical dysplasia type IIIa (FCD IIIa) in children. A retrospective review was conducted based on 26 pediatric patients diagnosed with FCD IIIa who underwent surgical intervention. These patients were selected from a cohort of 157 individuals presenting with temporal lobe epilepsy. For comparative analysis, a control group consisting of 5 children who underwent intracranial decompression was established. Immunohistochemistry, immunofluorescence, and western blot techniques were used to assess the expression levels of mTOR, P-mTOR, P-70s6k, STAT3, P-STAT3, and GFAP in brain tissue specimens obtained from the two groups. The mTOR-STAT3 pathway exhibited activation in the FCD IIIa group (all P < 0.01). Additionally, immunofluorescence analysis revealed that cells positive for PSTAT3 were identified as astrocytes. Moreover, within the FCD IIIa group, there was a marked elevation in the expression of the mTOR-STAT3 pathway in the hippocampus compared to the brain cortex tissue. The mTOR-STAT3 pathway was demonstrated to be substantially associated with FCD IIIa in pediatric patients. The activation of the mTOR-STAT3 signaling pathway may contribute to the pathogenesis of FCD IIIa in pediatric patients by modulating the proliferation of astrocytes.

Excitatory neurons and oligodendrocyte precursor cells are vulnerable to focal cortical dysplasia type IIIa as suggested by single-nucleus multiomics.

Focal cortical dysplasia (FCD) is a heterogeneous group of cortical developmental malformations that constitute a common cause of medically intractable epilepsy. FCD type IIIa (FCD IIIa) refers to temporal neocortex alterations in architectural organisation or cytoarchitectural composition in the immediate vicinity of hippocampal sclerosis. Slight alterations in the temporal neocortex of FCD IIIa patients pose a challenge for the preoperative diagnosis and definition of the resection range. We have performed multimodal integration of single-nucleus RNA sequencing and single-nucleus assay for transposase-accessible chromatin sequencing in the epileptogenic cortex of four patients with FCD IIIa, and three relatively normal temporal neocortex were chosen as controls. Our study revealed that the most significant dysregulation occurred in excitatory neurons (ENs) and oligodendrocyte precursor cells (OPCs) in the epileptogenic cortex of FCD IIIa patients. In ENs, we constructed a transcription factor (TF)-hub gene regulatory network and found DAB1high ENs subpopulation mediates neuronal immunity characteristically in FCD IIIa. Western blotting and immunofluorescence were used to validate the changes in protein expression levels caused by some of the key genes. The OPCs were activated and exhibited aberrant phenotypes in FCD IIIa, and TFs regulating reconstructed pseudotime trajectory were identified. Finally, our results revealed aberrant intercellular communication between ENs and OPCs in FCD IIIa patients. Our study revealed significant and intricate alterations in the transcriptomes and epigenomes in ENs and OPCs of FCD IIIa patients, shedding light on their cell type-specific regulation and potential pathogenic involvement in this disorder. This work will help evaluate the pathogenesis of cortical dysplasia and epilepsy and explore potential therapeutic targets. Paired snRNA-seq and snATAC-seq data were intergrated and analysed to identify crucial subpopulations of ENs and OPCs in the epileptogenic cortex of FCD IIIa patients and explore their possible pathogenic role in the disease. A TF-hub gene regulatory network was constructed in ENs, and the DAB1high Ex-1 mediated neuronal immunity was characterstically in FCD IIIa patients. The OPCs were activated and exhibited aberrant phenotypes in FCD IIIa patients, and TFs regulating reconstructed pseudotime traectory were identified. Aberrant intercelluar communications between ENs and OPCs in FCD IIIa patients were identified.

Cortical and subcortical morphometric changes in patients with frontal focal cortical dysplasia type II

Cortical and subcortical morphometric changes in patients with frontal focal cortical dysplasia type II

Focal cortical dysplasia (type II) detection with multi-modal MRI and a deep-learning framework

Focal cortical dysplasia type II (FCD-II) is a prominent cortical development malformation associated with drug-resistant epileptic seizures that leads to lifelong cognitive impairment. Efficient MRI, followed by its analysis (e.g., cortical abnormality distinction, precise localization assistance, etc.) plays a crucial role in the diagnosis and supervision (e.g., presurgery planning and postoperative care) of FCD-II. Involving machine learning techniques particularly, deep-learning (DL) approaches, could enable more effective analysis techniques. We performed a comprehensive study by choosing six different well-known DL models, three image planes (axial, coronal, and sagittal) of two MRI modalities (T1w and FLAIR), demographic characteristics (age and sex) and clinical characteristics (brain hemisphere and lobes) to identify a suitable DL model for analysing FCD-II. The outcomes show that the DenseNet201 model is more suitable because of its superior classification accuracy, high-precision, F1-score, and large area under the receiver operating characteristic (ROC) curve and precision–recall (PR) curve.

Clinical characteristics of children with anti-neutrophil cytoplasmic antibody-associated vasculitis

To study the clinical characteristics of children with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). A retrospective analysis was conducted on the clinical data of 25 children diagnosed with AAV at the Second Xiangya Hospital of Central South University from January 2010 to June 2022. Among the AAV children, there were 5 males and 20 females, with a median age of onset of 11.0 years. Involvement of the urinary system was seen in 18 cases (72%); respiratory system involvement in 10 cases (40%); skin involvement in 6 cases (24%); eye, ear, and nose involvement in 5 cases (20%); joint involvement in 4 cases (16%); digestive system involvement in 2 cases (8%). Eleven cases underwent kidney biopsy, with 5 cases (46%) showing focal type, 2 cases (18%) showing crescentic type, 2 cases (18%) showing mixed type, and 2 cases (18%) showing sclerotic type. Immune complex deposits were present in 5 cases (45%). Seven cases reached chronic kidney disease (CKD) stage V, with 2 cases resulting in death. Two cases underwent kidney transplantation. At the end of the follow-up period, 2 cases were at CKD stage II, and 1 case was at CKD stage III. Of the 16 cases of microscopic polyangiitis (MPA) group, 13 (81%) involved the urinary system. Of the 9 cases of granulomatosis with polyangiitis (GPA), 6 cases (66%) had sinusitis. Serum creatinine and uric acid levels were higher in the MPA group than in the GPA group (P<0.05), while red blood cell count and glomerular filtration rate were lower in the MPA group (P<0.05). AAV is more common in school-age female children, with MPA being the most common clinical subtype. The onset of AAV in children is mainly characterized by renal involvement, followed by respiratory system involvement. The renal pathology often presents as focal type with possible immune complex deposits. Children with MPA often have renal involvement, while those with GPA commonly have sinusitis. The prognosis of children with AAV is poor, often accompanied by renal insufficiency.

Drug-coated balloon angioplasty versus drug-eluting stent implantation in ACS patients with different angiographic patterns of in-stent restenosis

BackgroundDrug-coated balloon (DCB) angioplasty and drug-eluting stents (DES) are two widely used treatments for in-stent restenosis (ISR). Focal and non-focal types of ISR affect the clinical outcomes. The present study aims to compare DES reimplantation versus DCB angioplasty in acute coronary syndrome (ACS) patients with focal ISR and non-focal ISR lesions. MethodsPatients with ISR lesions underwent percutaneous coronary intervention (PCI) were retrospectively evaluated and divided into DES group and DCB group. The primary endpoint was the incidence of target lesion failure (TLF) at 24 months follow up. Propensity score matching (PSM) was conducted to balance the baseline characteristics. ResultsFor focal ISR, TLF was comparable in the DES and DCB groups at 24 months of follow-up (Before PSM, hazard ratio [HR]: 0.70; 95% confidence interval [CI]: 0.39–1.27; p = 0.244; After PSM, HR: 0.83; 95% CI: 0.40–1.73; p = 0.625). For non-focal ISR, TLF was significantly decreased in DES compared with DCB group (Before PSM, HR: 0.43; 95% CI: 0.29–0.63; p < 0.001; After PSM, HR: 0.33; 95% CI: 0.19–0.59; p < 0.001), which was mainly attributed to the lower incidence of clinically indicated target lesion revascularization (CD-TLR) (Before PSM, HR: 0.39; 95% CI: 0.26–0.59; p < 0.001; After PSM, HR: 0.28; 95% CI: 0.15–0.54; p < 0.001). ConclusionsThe clinical outcomes for DES and DCB treatment are similar in focal type of ISR lesions. For non-focal ISR, the treatment of DES showed a significant decrease in TLF which was mainly attributed to a lower incidence of CD-TLR.

Net synaptic drive of fast-spiking interneurons is inverted towards inhibition in human FCD I epilepsy

Focal cortical dysplasia type I (FCD I) is the most common cause of pharmaco-resistant epilepsy with the poorest prognosis. To understand the epileptogenic mechanisms of FCD I, we obtained tissue resected from patients with FCD I epilepsy, and from tumor patients as control. Using whole-cell patch clamp in acute human brain slices, we investigated the cellular properties of fast-spiking interneurons (FSINs) and pyramidal neurons (PNs) within the ictal onset zone. In FCD I epilepsy, FSINs exhibited lower firing rates from slower repolarization and action potential broadening, while PNs had increased firing. Importantly, excitatory synaptic drive of FSINs increased progressively with the scale of cortical activation as a general property across species, but this relationship was inverted towards net inhibition in FCD I epilepsy. Further comparison with intracranial electroencephalography (iEEG) from the same patients revealed that the spatial extent of pathological high-frequency oscillations (pHFO) was associated with synaptic events at FSINs.

The transmantle sign: a characteristic MRI finding of focal cortical dysplasia type II

The transmantle sign: a characteristic MRI finding of focal cortical dysplasia type II

Strong controlling effect of stress evolution on the 2022 Ms5.0 Honghe earthquake sequence

Understanding stress evolution patterns as a response to earthquake ruptures at geologically complex tectonic faults is vital because of the role of fault geometry as a source for the stress evolutionary constraints. Here, we analyze the 2022 Ms5.0 Honghe earthquake sequence and calculate the tectonic stress distribution of the two Ms. ≥ 3.5 earthquakes in this sequence. Results indicate that the focal mechanism type of the sequence obtained corresponds to strike-slip motion with an ESE-oriented strike and a steeply dipping NE-oriented nodal plane. The focal region is subjected to NNW-oriented horizontal compression and ENE-oriented horizontal tension. We find that the adjacent Ailaoshan fault constituted the major seismogenic fault of the mainshock and the regional stress field exerted a strong controlling effect on the associated postseismic events. Our results suggest that the stabilization of tectonic faults may help to enhance the effects of stress accumulation on the occurrence of medium-to-strong earthquakes.

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.

Distinct profiles of cerebral oxygenation in focal vs. secondarily generalized EEG seizures in children undergoing cardiac surgery.

Seizures are common in children undergoing cardiopulmonary bypass (CPB). Cerebral oxygen saturation (ScO2) by near-infrared spectroscopy is routinely monitored in many centers, but the relations between the levels and changes of ScO2 and brain injuries remain incompletely understood. We aimed to analyze the postoperative profiles of ScO2 and cerebral blood flow velocity in different types of EEG seizures in relation to brain injuries on MRI. We monitored continuous EEG and ScO2 in 337 children during the first 48 h after CPB, which were analyzed in 3 h periods. Cerebral blood flow peak systolic velocity (PSV) in the middle cerebral artery was measured daily by transcranial Doppler. Postoperative cerebral MRI was performed before hospital discharge. Based on the occurrence and spreading types of seizures, patients were divided into three groups as patients without seizures (Group N; n = 309), those with focal seizures (Group F; n = 13), or with secondarily generalized seizures (Group G; n = 15). There were no significant differences in the onset time and duration of seizures and incidence of status epilepticus between the two seizures groups (Ps ≥ 0.27). ScO2 increased significantly faster across Group N, Group G, and Group F during the 48 h (p < 0.0001) but its overall levels were not significantly different among the three groups (p = 0.30). PSV was significantly lower (p = 0.003) but increased significantly faster (p = 0.0003) across Group N, Group G, and Group F. Group F had the most severe brain injuries and the highest incidence of white matter injuries on MRI among the three groups (Ps ≤ 0.002). Postoperative cerebral oxygenation showed distinct profiles in secondarily generalized and particularly focal types of EEG seizures in children after CPB. A state of 'overshooting' ScO2 with persistently low PSV was more frequently seen in those with focal seizures and more severe brain injury. Information from this study may have important clinical implications in detecting brain injuries when monitoring cerebral oxygenation in this vulnerable group of children after CPB.

Targeting pathological cells with senolytic drugs reduces seizures in neurodevelopmental mTOR-related epilepsy

Cortical malformations such as focal cortical dysplasia type II (FCDII) are associated with pediatric drug-resistant epilepsy that necessitates neurosurgery. FCDII results from somatic mosaicism due to post-zygotic mutations in genes of the PI3K-AKT-mTOR pathway, which produce a subset of dysmorphic cells clustered within healthy brain tissue. Here we show a correlation between epileptiform activity in acute cortical slices obtained from human surgical FCDII brain tissues and the density of dysmorphic neurons. We uncovered multiple signatures of cellular senescence in these pathological cells, including p53/p16 expression, SASP expression and senescence-associated β-galactosidase activity. We also show that administration of senolytic drugs (dasatinib/quercetin) decreases the load of senescent cells and reduces seizure frequency in an MtorS2215F FCDII preclinical mouse model, providing proof of concept that senotherapy may be a useful approach to control seizures. These findings pave the way for therapeutic strategies selectively targeting mutated senescent cells in FCDII brain tissue.

A controversial question: Can morphometry and clinical history be enough to diagnose hippocampal dysplasia?

The presence of dysmorphic neurons with strong cytoplasmatic accumulation of heavy non-phosphorylated neurofilament is crucial for the diagnostics of focal cortical dysplasia type II (FCDII). While ILAE's classification describes neocortical dysplasias, some groups have reported patients with mesial t abnormal neurons in the hippocampus of mesial temporal lobe epilepsy. Here we report a patient with such abnormal neurons in the hippocampus and compared it with previous reports of hippocampal dysplasia. Finally, we discuss the need for diagnostic criteria of hippocampal dysplasia.

Spatial omics reveals molecular changes in focal cortical dysplasia type II

Focal cortical dysplasia (FCD) represents a group of diverse localized cortical lesions that are highly epileptogenic and occur due to abnormal brain development caused by genetic mutations, involving the mammalian target of rapamycin (mTOR). These somatic mutations lead to mosaicism in the affected brain, posing challenges to unravel the direct and indirect functional consequences of these mutations. To comprehensively characterize the impact of mTOR mutations on the brain, we employed here a multimodal approach in a preclinical mouse model of FCD type II (Rheb), focusing on spatial omics techniques to define the proteomic and lipidomic changes. Mass Spectrometry Imaging (MSI) combined with fluorescence imaging and label free proteomics, revealed insight into the brain's lipidome and proteome within the FCD type II affected region in the mouse model. MSI visualized disrupted neuronal migration and differential lipid distribution including a reduction in sulfatides in the FCD type II-affected region, which play a role in brain myelination. MSI-guided laser capture microdissection (LMD) was conducted on FCD type II and control regions, followed by label free proteomics, revealing changes in myelination pathways by oligodendrocytes. Surgical resections of FCD type IIb and postmortem human cortex were analyzed by bulk transcriptomics to unravel the interplay between genetic mutations and molecular changes in FCD type II. Our comparative analysis of protein pathways and enriched Gene Ontology pathways related to myelination in the FCD type II-affected mouse model and human FCD type IIb transcriptomics highlights the animal model's translational value. This dual approach, including mouse model proteomics and human transcriptomics strengthens our understanding of the functional consequences arising from somatic mutations in FCD type II, as well as the identification of pathways that may be used as therapeutic strategies in the future.

Seizures as Initial Presentation and Enduring Predisposition to Seizures in Autoimmune Encephalitis

Purpose. This retrospective study is aimed at investigating the clinical characteristics of autoimmune encephalitis (AE) and long-term prognosis of patients who initially present with seizures as well as risk factors for enduring predisposition to seizures in AE. Methods. From January 1, 2013, to October 31, 2021, a total of 343 AE patients from a single center diagnosed with autoimmune encephalitis (AE) were enrolled in this study, including 198 antibody-positive AE and 145 antibody-negative but probable AE. According to initial symptoms, AE patients were divided into two groups: onset with seizure group and onset with nonseizure group. The clinical characteristics were retrospectively reviewed. Patients were clinically evaluated at onset and at 6, 12, and 24 months of follow-up. Modified Rankin Scale (MRS) score, Clinical Assessment Scale in Autoimmune Encephalitis (CASE) score, and seizure-related information were assessed. Results. In AE, patients with seizures as the first presentation were younger, with a median-onset age of 28 years old. Compared with other types of antibody-positive AE, anti-GABABR AE more frequently began with seizures, while anti-CASPR2, anti-AMPAR, and anti-DPPX encephalitis usually began with symptoms other than seizures. The most common type of initial seizures in AE was focal to bilateral seizure (67.6%), with a significant prevalence in antibody-positive AE (P=0.001). In addition, compared with nonseizure group, patients with seizures as an initial presentation had higher MRS and CASE scores at 24 months of follow-up. Older age at onset and focal nonmotor seizure type were independent risk factors for an enduring predisposition to seizures in AE patients. Conclusion. The younger and anti-GABABR-positive AE patients are more prone to onset with seizures. AE patients who initially presented with seizures had worse long-term neurological recovery. Onset age and seizure type should be highly appreciated when formulating the strategy for therapy at post-AE status.

Outcomes and predictors of seizure recurrence in post-stroke epilepsy, a retrospective hospital-based study

BackgroundThe occurrence of seizures following a stroke is a well-recognized complication associated with a significant increase in morbidity and mortality. Despite the numerous studies examining outcomes and risk factors related to post-stroke seizures (PSS), there remains a lack of clarity regarding the clinical characteristics, treatment, and PSS recurrence (PSSR) rates in patients experiencing their initial episode of PSS. PurposeThis study aimed to determine the risk factors for developing recurrent seizures after first PSS and their effects on functional outcomes and mortality. MethodsAll patients underwent an electroencephalography (EEG) and were monitored for a minimum of 24 months following the first PSS. The primary endpoint was the recurrence of seizures. Predictive factors for PSSR were determined by using the Cox-proportional hazards model, and the cumulative latency of recurrence at 90, 180, 360, and 720 days was estimated using Kaplan-Meier analysis. ResultsSeizure recurred in 36.8% (39/106). Significant association of PSSR was noted with female gender, use of older anti-seizure medications (ASMs) (p<0.001), EEG findings as focal slow wave activity (p<0.001), Ictal epileptiform abnormalities (p=0.015), status epilepticus (p=0.015), and with severe disability (p=0.008). However, multivariate cox-proportional hazards model showed significant association of female gender (HR=3.28; 95% CI: 1.42–7.58; p=0.006). Hazard ratio (HR) was increased with older ASMs use, focal aware seizure types, Ictal EAs, and periodic discharges on EEG; though, statistically significant. ConclusionFactors such as the type of ASMs, EEG findings, and seizure type were significantly linked to PSSR. Female gender was the only independent predictor established. Additionally, significant functional decline was reported with recurrence.

Negative MRI and a seizure onset zone close to eloquent areas in FCD type II: Application of MRg-LiTT after a SEEG re-evaluation in pediatric patients with a previous failed surgery

ObjectiveNegative MRI and an epileptogenic zone (EZ) adjacent to eloquent areas are two main issues that can be encountered during pre-surgical evaluation for epilepsy surgery. Focal Cortical Dysplasia type II (FCD type II) is the most common aetiology underlying a negative MRI.The objective of this study is to present three cases of pediatric patients exhibiting negative MRI and a seizure onset zone close to eloquent areas, who previously underwent traditional open surgery or SEEG-guided radiofrequency thermocoagulations (RF-TC). After seizure seizure recrudescence, pre-surgical SEEG was re-evaluated and Magnetic Resonance-guided laser interstitial thermal therapy (MRg-LiTT) was performed.We discuss the SEEG patterns, the planning of laser probes trajectories and the outcomes one year after the procedure. MethodsPediatric patients who underwent SEEG followed by MRg-LiTT for drug-resistant epilepsy associated with FCD type II at our Centre were included. Pre-surgical videoEEG (vEEG), stereoEEG (sEEG), and MRI were reviewed. Post-procedure clinical outcome (measured by Engel score) and complications rates were evaluated. ResultsThree patients underwent 3 MRg-LiTT procedures from January 2022 to June 2022. Epileptogenic zone was previously studied via SEEG in all the patients. All the three patients pre-surgical MRI was deemed negative. Mean age at seizure onset was 47 months (21–96 months), mean age at MRg-LiTT was 12 years (10 years 10 months – 12 years 9 months). Engel class Ia outcome was achieved in patients #2 and #3, Engel class Ib in patient #1. Mean follow-up length was of 17 months (13 months – 20 months). Complications occurred in one patient (patient #2, extradural hematoma). ConclusionsThe combined use of SEEG and MRg-LiTT in complex cases can lead to good outcomes both as a rescue therapy after failed surgery, but also as an alternative to open surgery after a successful SEEG-guided Radiofrequency Thermocoagulation (RF-TC). Specific SEEG patterns and a previous good outcome from RF-TC can be predictors of a favourable outcome.

Incivility, Mobbing, and Abusive Supervision: A Tripartite Scale Development Study

Using qualitative and quantitative methodologies, in three consecutive studies with employed samples, we developed measures of workplace incivility, mobbing, and abusive supervision sensitive to the nuances of a non-Western context (i.e., Türkiye). In Study 1, we first conducted 15 focus groups (N = 149), identified culture-specific and universal themes underlying the focal mistreatment types, and developed the initial scales. We then pilot-tested (N = 427) and refined the scales using exploratory factor analytic procedures. In Study 2, confirmatory factor analyses (N range = 456-524) and associations between the new scales and their widely used counterparts (N = 353) yielded evidence for the construct validity of the scales. Study 2 also involved the development of short forms of relatively long incivility and abusive supervision scales. In Study 3 (N = 482), we first examined the extent to which the three scales were operationally distinct. Second, we examined the scales’ ability to predict burnout and organizational commitment. Results supported operational distinctiveness as well as the criterion-related validity of the scales. A dominance analysis revealed that the three scales had equivalent contributions in explaining the two outcome variables, further justifying their distinctiveness. We argue that the use of present scales is not necessarily restricted to the Turkish context and may prove useful more broadly in other neo-traditional contexts.

New product family demand planning: AddressingSKU‐level spread bias

AbstractNew product supply chain planning is challenging, primarily due to the lack of historical demand data. Rarely, however, do the academic literature or companies differentiate the demand forecasting process for new products from existing ones, despite their increased reliance on judgmental estimates. This research focuses on how judgmental errors lead to an under‐estimation of the difference between the highest‐ and lowest‐demand stock‐keeping units (SKUs), and consequently negatively impact supply chain planning for new product family introductions. A generalized empirical model and accompanying discrete event simulation are developed and applied to data from a major consumer packaged goods (CPG) firm during the launch of a new cosmetics product family. This application allows us to identify a focal type of judgmental error (identified as the SKU‐level spread bias) inherent to new product forecasting and to provide a new theoretical understanding of how this type of bias harms supply chain performance. Via an empirically driven theory‐building approach that iterates between the simulation outcomes and existing literature, SKU‐level spread bias is demonstrated to harm demand forecasts and, thereby, supply chain plans. Our unique theory‐building approach advances theory by identifying planner SKU‐level spread bias as a new source of bias that firms should seek to mitigate when introducing new product families.

Endovascular repair of ascending aortic pathologies in patients unfit for open surgery: Case series and literature review

The number of vascular centers performing endovascular repair of ascending aortic disease is constantly increasing. Accordingly to the guidelines, open surgical repair remains the gold standard for these pathologies. However, approximately one quarter of patients are deemed unfit for open surgery. In this study, we describe three cases of ascending thoracic endovascular aortic repair (TEVAR) performed at our center. All the patients were deemed unfit for open surgery by the aortic team. Two patients had an ascending aortic pseudoaneurysm, and the third had a focal type A aortic dissection. In two cases, we used two abdominal aortic cuffs deployed from zone 0B to zone 0C, with no need for supra-aortic trunk debranching. In one case, we performed a “reverse” extrathoracic debranching, and we deployed a thoracic endograft from zone 0B to zone 2. Complications included one minor stroke and one inguinal hematoma. In one patient with an infected pseudoaneurysm, we performed ascending TEVAR as a bridge strategy for open repair. This patient developed a type Ia endoleak; however, clinical stabilization and infection control were obtained, and he was able to undergo heart surgery successfully. He underwent a second reintervention to treat superior mesenteric embolic occlusion. At 2 years of follow-up, all three patients were alive. Our preliminary experience demonstrates the technical feasibility and clinical appropriateness of ascending TEVAR using standard, commercially available endografts. However, no consensus has been reached regarding some critical aspects, such as the development of a standardized technique or the efficacy of the currently available devices. The improvements in graft design and the adoption of the “aortic team” approach could help in the near future to standardize the procedure, establish appropriate indications, and ensure good clinical outcomes.