Citations

Background and Purpose— Nearly 30% of large vessel occlusion acute ischemic stroke clots are from an unknown source. We assessed histological clot composition in a series of patients with large vessel occlusion and investigated correlations between clot composition and stroke pathogenesis. Methods— As part of the multi-institutional STRIP registry (Stroke Thromboembolism Registry of Imaging and Pathology), consecutive emboli retrieved during mechanical thrombectomy were stained using Martius Scarlett Blue and analyzed using machine learning software. We assessed proportions of red blood cells, fibrin, platelets, and white blood cells. Correlations between clot components and stroke pathogenesis (large artery atherosclerosis, cardioembolism, and stroke of undetermined pathogenesis) were assessed using SPSS22. Results— One hundred five patients were included. The proportion of platelet-rich clots (55.0% versus 21.2%; P =0.005) and percentage of platelet content (22.1±4.2% versus 13.9±14.2%; P =0.03) was significantly higher in the large artery atherosclerosis group compared with the cardioembolic group. The proportion of platelet-rich clots (50.0% versus 21.2%; P =0.024) was also significantly higher in the cryptogenic group compared with cardioembolic cases. Large artery atherosclerosis and cryptogenic cases had a similar proportion of platelet-rich clots (55.0% versus 50.0%; P =0.636). There was no significant difference between stroke pathogenesis and the other major clot components. Conclusions— High platelet content of emboli is associated with a large artery atherosclerosis etiology of large vessel occlusion.

Background Bacteria and bacterial components have been associated with the activation of coagulation factors and initiating the blood clot formation. The aim of this study was to investigate whether bacterial populations are present in clots retrieved from patients that have suffered a large vessel occlusion acute ischemic stroke (AIS). Materials and methods Clot samples were collected from 20 AIS patients who underwent clot retrieval with mechanical thrombectomy. Patient clinical demographic details were noted. Expression of bacterial 16S rDNA was analyzed by standard and real-time polymerase chain reaction (PCR). Gram staining was performed to identify Gram-positive and Gram-negative bacteria. Results Both the real-time and standard PCR demonstrated no expression of 16S rDNA in any of the 20 clots samples from AIS patients. Gram staining results showed no expression of Gram-positive or Gram-negative bacteria present in the clot samples. Conclusion Our current study found no bacteria populations in the clots of AIS patients.

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).

Summary Cardiac surgery has been shown to be associated with increased risk of acute ischemic stroke. This report presents a case of a successful mechanical embolectomy procedure to treat a patient for an acute ischemic stroke, which was caused by the cardiac embolization of a ‘foreign body’ containing debris following a redo sternotomy procedure for mitral valve replacement and tricuspid valve annuloplasty.

Introduction: The composition of acute ischemic stroke (AIS) blood clots can impact their successful removal via endovascular therapy. Identification of the clot composition prior to endovascular treatment may influence the optimal treatment strategy. In this study, we aimed to investigate the relationship between the Hounsfield Unit intensity on CT and machine-learned characterization of clot composition. Methods: Prior to endovascular treatment, each patient had a non-contrast CT performed. Histopathological analysis of the clots was performed and clot composition was quantified via standard thresholding techniques using Adobe Photoshop. In addition, following representative cell labeling by an expert pathologist, image segmentation algorithms (Orbital Image Analysis, Actelion Ltd.) were trained on each case to quantify composition by cell type. The clots were categorized into 3 groups: red blood cell (RBC) dominant (>50%), RBC proportion equal to fibrin and fibrin dominant (>50%). Correlations between clot composition and Hounsfield Units (HU) density on CT were assessed. A positive Hyperdense Artery Sign was defined as ≥50 HU. Results: Twenty patients were included in the study. There was a significant correlation between clots quantified using Adobe Photoshop Image-Pro and Orbit image analysis ( ρ = 0.837, p < 0.001). A significant relationship was found between clot composition and the presence of a HAS sign, ( X 2 (2) = 6.496, p = 0.039). There is a significant positive correlation between percentage of RBC in the clot and the presence of a HAS sign ( ρ = 0.632, p = 0.002**). There is also a significant positive correlation between the presence of fibrin-rich and the absence of a HAS sign ( ρ = 0.600, p = 0.004**). Conclusion: Machine learning software can accurately quantify AIS clot composition. The Hounsfield unit density of an AIS clot on a non-contrast CT correlates with the composition of the clot. Measuring the HU of the clot on CT prior to endovascular intervention may inform the clinician of the clot type and help to determine the most appropriate treatment strategy for that clot.

Abstract Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Background: There are conflicting data on the results of irrigation and debridement with component retention in patients with acute periprosthetic hip infections. The goals of this study were to examine contemporary results of irrigation and debridement with component retention for acute infection after primary hip arthroplasty and to identify host, organism, antibiotic, or implant factors that predict success or failure. Methods: Ninety hips (57 total hip arthroplasties and 33 hemiarthroplasties) were diagnosed with acute periprosthetic hip infection (using strict criteria) and were treated with irrigation and debridement and component retention between 2000 and 2012. The mean follow-up was 6 years. Patients were stratified on the basis of McPherson criteria. Hips were managed with irrigation and debridement and retention of well-fixed implants with modular head and liner exchange (70%) or irrigation and debridement alone (30%). Seventy-seven percent of patients were treated with chronic antibiotic suppression. Failure was defined as failure to eradicate infection, characterized by a wound fistula, drainage, intolerable pain, or infection recurrence caused by the same organism strain; subsequent removal of any component for infection; unplanned second wound debridement for ongoing deep infection; and/or occurrence of periprosthetic joint infection-related mortality. Results: Treatment failure occurred in 17% (15 of 90 hips), with component removal secondary to recurrent infection in 10% (9 of 90 hips). Treatment failure occurred in 15% (10 of 66 hips) after early postoperative infection and 21% (5 of 24 hips) after acute hematogenous infection (p = 0.7). Patients with McPherson host grade A had a treatment failure rate of 8%, compared with 16% (p = 0.04) in host grade B and 44% in host grade C (p = 0.006). Most treatment failures (12 of 15 failures) occurred within the initial 6 weeks of treatment; failures subsequent to 6 weeks occurred in 3% of those treated with chronic antibiotic suppression compared with 11% of those who were not treated with suppression (hazard ratio, 4.0; p = 0.3). Conclusions: The success rate was higher in this contemporary series than in many previous series. Systemic host grade A was predictive of treatment success. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Nanoliposomal irinotecan (nal‐IRI) is a liposomal formulation of irinotecan with a longer half‐life (t1/2), higher plasma total irinotecan (tIRI), and lower SN‐38 maximum concentration (Cmax) compared with nonliposomal irinotecan. Population pharmacokinetic (PK) analysis of nal‐IRI was performed for tIRI and total SN‐38 (tSN38) using patient samples from six studies. PK‐safety association was evaluated for neutropenia and diarrhea in 353 patients. PK‐efficacy association was evaluated from a phase III study in pancreatic cancer NAPOLI1. Efficacy was associated with longer duration of unencapsulated SN‐38 (uSN38) above a threshold and higher Cavgof tIRI, tSN38, and uSN38. Neutropenia was associated with uSN38Cmaxand diarrhea with tIRICmax. Baseline predictive factors were race, body surface area, and bilirubin. Analysis identified PK factors associated with efficacy, safety, and predictive baseline factors. The results support the benefit of nal‐IRI dose of 70 mg/m2(free‐base; equivalent to 80 mg/m2salt base) Q2W over 100 mg/m2Q3W.