Citations

BackgroundThe medial thigh is a well‐hidden area. The two most common flaps from this area are the transverse upper gracilis (TUG) and profunda artery perforator (PAP) flaps. Herein, we explored the applications of combined TUGPAP flap to reconstruct large and complex defects in different regions.MethodsBetween November 2015 and May 2017, 28 patients who underwent reconstruction and extensive soft tissue coverage with the TUGPAP flap for the breasts, head and neck, and pelvi‐perineal regions were included. The defects size ranged from 22 to 29 × 6–8 cm. All flaps were based on the two pedicles: the medial circumflex femoral artery for TUG flap and the profunda artery perforator for PAP flap. They were each anastomosed to a set of recipient vessels. A “Y”‐shaped interposition vein graft (YVG) was used if only one recipient artery was available.ResultsThe harvested skin paddle had dimensions ranged from 20 to 30 × 6–9 cm and all flaps survived completely. Postoperative complications included one case each of donor and recipient site seroma, and one case of wound dehiscence. They were all successfully managed conservatively. During an average follow‐up period of 12.7 months, one patient reported permanent paresthesia in the donor site and another developed hypertrophic scar. All patients were able to resume daily activity without major concerns.ConclusionThe combined TUGPAP flap is a safe, effective, and a good alternative to the common workhorse flaps as it offers the potential for a large skin paddle and decent soft tissue volume with low donor site morbidity in a well‐concealed area.

INTRODUCTION The human cerebral cortex has undergone an extraordinary increase in size and complexity during mammalian evolution. Cortical cell lineages are specified in the embryo, and genetic and epidemiological evidence implicates early cortical development in the etiology of neuropsychiatric disorders such as autism spectrum disorder (ASD), intellectual disabilities, and schizophrenia. Most of the disease-implicated genomic variants are located outside of genes, and the interpretation of noncoding mutations is lagging behind owing to limited annotation of functional elements in the noncoding genome. RATIONALE We set out to discover gene-regulatory elements and chart their dynamic activity during prenatal human cortical development, focusing on enhancers, which carry most of the weight upon regulation of gene expression. We longitudinally modeled human brain development using human induced pluripotent stem cell (hiPSC)–derived cortical organoids and compared organoids to isogenic fetal brain tissue. RESULTS Fetal fibroblast–derived hiPSC lines were used to generate cortically patterned organoids and to compare oganoids’ epigenome and transcriptome to that of isogenic fetal brains and external datasets. Organoids model cortical development between 5 and 16 postconception weeks, thus enabling us to study transitions from cortical stem cells to progenitors to early neurons. The greatest changes occur at the transition from stem cells to progenitors. The regulatory landscape encompasses a total set of 96,375 enhancers linked to target genes, with 49,640 enhancers being active in organoids but not in mid-fetal brain, suggesting major roles in cortical neuron specification. Enhancers that gained activity in the human lineage are active in the earliest stages of organoid development, when they target genes that regulate the growth of radial glial cells. Parallel weighted gene coexpression network analysis (WGCNA) of transcriptome and enhancer activities defined a number of modules of coexpressed genes and coactive enhancers, following just six and four global temporal patterns that we refer to as supermodules, likely reflecting fundamental programs in embryonic and fetal brain. Correlations between gene expression and enhancer activity allowed stratifying enhancers into two categories: activating regulators (A-regs) and repressive regulators (R-regs). Several enhancer modules converged with gene modules, suggesting that coexpressed genes are regulated by enhancers with correlated patterns of activity. Furthermore, enhancers active in organoids and fetal brains were enriched for ASD de novo variants that disrupt binding sites of homeodomain, Hes1, NR4A2, Sox3, and NFIX transcription factors. CONCLUSION We validated hiPSC-derived cortical organoids as a suitable model system for studying gene regulation in human embryonic brain development, evolution, and disease. Our results suggest that organoids may reveal how noncoding mutations contribute to ASD etiology. Summary of the study, analyses, and main results. Data were generated for iPSC-derived human telencephalic organoids and isogenic fetal cortex. Organoids modeled embryonic and early fetal cortex and show a larger repertoire of enhancers. Enhancers could be divided into activators and repressors of gene expression. We derived networks of modules and supermodules with correlated gene and enhancer activities, some of which were implicated in autism spectrum disorders (ASD).

We present the case of a 26‐year‐old female restrained front‐seat passenger who presents following a motor vehicle accident, with CT angiogram features suggestive of possible acute aortic injury. However, clinical features including relative hemodynamic stability and absence of typical symptoms were discordant with these imaging findings. This case illustrates that even with ECG‐gating, CT angiogram artifact mimicking acute aortic injury may still occur. Careful evaluation and clinical correlation is of vital importance, both to ensure acute aortic injury is not missed and that patients are not erroneously sent for aortic surgery when there is no aortic injury. Careful clinical evaluation must be combined with imaging in all cases of suspected aortic trauma, and at times multimodality imaging is indicated to direct the decision making strategy.

Abstract BACKGROUND Flow diversion (FD) is effective for treatment of intracranial internal carotid artery (ICA) aneurysms. OBJECTIVE To determine whether carotid siphon (CS) geometry influences the efficacy of FD when employed for ICA aneurysms. METHODS Outcomes of a consecutive series of patients with ICA aneurysms treated with FD were retrospectively reviewed. CS anatomy was quantified through measurement of the posterior, anterior, and anterosuperior bend angles in accordance with previously described methodology. The relationship of CS geometry to likelihood of incomplete aneurysm occlusion at 1 yr after treatment was assessed with multivariate logistic regression analysis. RESULTS There were 167 ICA aneurysms in 164 patients treated with FD during the study period. The mean age of our cohort was 55.7 yr (standard deviation [SD]: 12.3) and a majority of patients were female (145/164, 86.8%). Anterior (47.4 degrees vs 8.5, P < .001) and anterosuperior bend angles (100.9 vs 76.5, P = .002) were significantly greater in aneurysms that required repeat FD after initial treatment. On multivariate logistic regression analysis, increasing patient age (unit odds ratio [OR]: 1.05, 95% confidence interval [CI] 1.01-1.08; P = .003) and anterior bend angle ≥–3.5 (OR: 2.47, 95% CI 1.04-5.86; P = .046) were associated with increased odds of incomplete aneurysm occlusion at 1 yr after treatment. CONCLUSION These findings suggest that variations in CS anatomy may influence the efficacy of FD treatment and should be analyzed prior to offering FD for treatment of ICA aneurysms. Further investigation into the hemodynamic effects of CS geometry is warranted.

ABSTRACT The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell‐released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV‐associated functional activities. Finally, a checklist is provided with summaries of key points.

SOX2 is a transcription factor that is essential for maintenance of pluripotency and has several conserved roles in early embryonic development. Heterozygous loss‐of‐function variants in SOX2 are identified in approximately 40% of all cases of bilateral anophthalmia/micropthalmia (A/M). Increasingly SOX2 mutation‐positive patients without major eye findings, but with a range of other developmental disorders including autism, mild to moderate intellectual disability with or without structural brain changes, esophageal atresia, urogenital anomalies, and endocrinopathy are being reported, suggesting that the clinical phenotype associated with SOX2 loss is much broader than previously appreciated. In this report we describe six new cases, four of which carry novel pathogenic SOX2 variants. Four cases presented with bilateral anophthalmia in addition to extraocular involvement. Another individual presented with only unilateral anophthalmia. One individual did not have any eye findings but presented with a suprasellar teratoma in infancy and was found to have the recurrent c.70del20 mutation in SOX2 (c.70_89del, p.Asn24Argfs*65). This is this first time this tumor type has been reported in the context of a de novo SOX2 mutation. Notably, individuals with hypothalamic hamartomas and slow‐growing hypothalamo‐pituitary tumors have been reported previously, but it is still unclear how SOX2 loss contributes to their formation.