Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma.

Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.

Failure of human rhombic lip differentiation underlies medulloblastoma formation.

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

A multi-scale map of cell structure fusing protein images and interactions.

The cell is a multi-scale structure with modular organization across at least four orders of magnitude1. Two central approaches for mapping this structure-protein fluorescent imaging and protein biophysical association-each generate extensive datasets, but of distinct qualities and resolutions that are typically treated separately2,3. Here we integrate immunofluorescence images in the Human Protein Atlas4 with affinity purifications in BioPlex5 to create a unified hierarchical map of human cell architecture. Integration is achieved by configuring each approach as a general measure of protein distance, then calibrating the two measures using machine learning. The map, known as the multi-scale integrated cell (MuSIC 1.0), resolves 69 subcellular systems, of which approximately half are to our knowledge undocumented. Accordingly, we perform 134 additional affinity purifications and validate subunit associations for the majority of systems. The map reveals a pre-ribosomal RNA processing assembly and accessory factors, which we show govern rRNA maturation, and functional roles for SRRM1 and FAM120C in chromatin and RPS3A in splicing. By integration across scales, MuSIC increases the resolution of imaging while giving protein interactions a spatial dimension, paving the way to incorporate diverse types of data in proteome-wide cell maps.

Trends in racial and ethnic discrimination in hiring in six Western countries.

We examine trends in racial and ethnic discrimination in hiring in six European and North American countries: Canada, France, Germany, Great Britain, the Netherlands, and the United States. Our sample includes all available discrimination estimates from 90 field experimental studies of hiring discrimination, encompassing more than 170,000 applications for jobs. The years covered vary by country, ranging from 1969 to 2017 for Great Britain to 1994 to 2017 for Germany. We examine trends in discrimination against four racial-ethnic origin groups: African/Black, Asian, Latin American/Hispanic, and Middle Eastern or North African. The results indicate that levels of discrimination in callbacks have remained either unchanged or slightly increased overall for most countries and origin categories. There are three notable exceptions. First, hiring discrimination against ethnic groups with origins in the Middle East and North Africa increased during the 2000s relative to the 1990s. Second, we find that discrimination in France declined, although from very high to "merely" high levels. Third, we find evidence that discrimination in the Netherlands has increased over time. Controls for study characteristics do not change these trends. Contrary to the idea that discrimination will tend to decline in Western countries, we find that discrimination has not fallen over the last few decades in five of the six Western countries we examine.

Childhood cerebellar tumours mirror conserved fetal transcriptional programs.

Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin+ stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood.

AmyloidPETNet: Classification of Amyloid Positivity in Brain PET Imaging Using End-to-End Deep Learning.

Background Visual assessment of amyloid PET scans relies on the availability of radiologist expertise, whereas quantification of amyloid burden typically involves MRI for processing and analysis, which can be computationally expensive. Purpose To develop a deep learning model to classify minimally processed brain PET scans as amyloid positive or negative, evaluate its performance on independent data sets and different tracers, and compare it with human visual reads. Materials and Methods This retrospective study used 8476 PET scans (6722 patients) obtained from late 2004 to early 2023 that were analyzed across five different data sets. A deep learning model, AmyloidPETNet, was trained on 1538 scans from 766 patients, validated on 205 scans from 95 patients, and internally tested on 184 scans from 95 patients in the Alzheimer's Disease Neuroimaging Initiative (ADNI) fluorine 18 (18F) florbetapir (FBP) data set. It was tested on ADNI scans using different tracers and scans from independent data sets. Scan amyloid positivity was based on mean cortical standardized uptake value ratio cutoffs. To compare with model performance, each scan from both the Centiloid Project and a subset of the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study were visually interpreted with a confidence level (low, intermediate, high) of amyloid positivity/negativity. The area under the receiver operating characteristic curve (AUC) and other performance metrics were calculated, and Cohen κ was used to measure physician-model agreement. Results The model achieved an AUC of 0.97 (95% CI: 0.95, 0.99) on test ADNI 18F-FBP scans, which generalized well to 18F-FBP scans from the Open Access Series of Imaging Studies (AUC, 0.95; 95% CI: 0.93, 0.97) and the A4 study (AUC, 0.98; 95% CI: 0.98, 0.98). Model performance was high when applied to data sets with different tracers (AUC ≥ 0.97). Other performance metrics provided converging evidence. Physician-model agreement ranged from fair (Cohen κ = 0.39; 95% CI: 0.16, 0.60) on a sample of mostly equivocal cases from the A4 study to almost perfect (Cohen κ = 0.93; 95% CI: 0.86, 1.0) on the Centiloid Project. Conclusion The developed model was capable of automatically and accurately classifying brain PET scans as amyloid positive or negative without relying on experienced readers or requiring structural MRI. Clinical trial registration no. NCT00106899 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Bryan and Forghani in this issue.

Predicting post-surgical functional status in high-grade glioma with resting state fMRI and machine learning.

PURPOSE: High-grade glioma (HGG) is the most common and deadly malignant glioma of the central nervous system. The current standard of care includes surgical resection of the tumor, which can lead to functional and cognitive deficits. The aim of this study is to develop models capable of predicting functional outcomes in HGG patients before surgery, facilitating improved disease management and informed patient care. METHODS: Adult HGG patients (N = 102) from the neurosurgery brain tumor service at Washington University Medical Center were retrospectively recruited. All patients completed structural neuroimaging and resting state functional MRI prior to surgery. Demographics, measures of resting state network connectivity (FC), tumor location, and tumor volume were used to train a random forest classifier to predict functional outcomes based on Karnofsky Performance Status (KPS < 70, KPS ≥ 70). RESULTS: The models achieved a nested cross-validation accuracy of 94.1% and an AUC of 0.97 in classifying KPS. The strongest predictors identified by the model included FC between somatomotor, visual, auditory, and reward networks. Based on location, the relation of the tumor to dorsal attention, cingulo-opercular, and basal ganglia networks were strong predictors of KPS. Age was also a strong predictor. However, tumor volume was only a moderate predictor. CONCLUSION: The current work demonstrates the ability of machine learning to classify postoperative functional outcomes in HGG patients prior to surgery accurately. Our results suggest that both FC and the tumor's location in relation to specific networks can serve as reliable predictors of functional outcomes, leading to personalized therapeutic approaches tailored to individual patients.

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling.

Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1). Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.

Data-driven decomposition and staging of flortaucipir uptake in Alzheimer's disease.

INTRODUCTION: Previous approaches pursuing in vivo staging of tau pathology in Alzheimer's disease (AD) have typically relied on neuropathologically defined criteria. In using predefined systems, these studies may miss spatial deposition patterns which are informative of disease progression. METHODS: We selected discovery (n = 418) and replication (n = 132) cohorts with flortaucipir imaging. Non-negative matrix factorization (NMF) was applied to learn tau covariance patterns and develop a tau staging system. Flortaucipir components were also validated by comparison with amyloid burden, gray matter loss, and the expression of AD-related genes. RESULTS: We found eight flortaucipir covariance patterns which were reproducible and overlapped with relevant gene expression maps. Tau stages were associated with AD severity as indexed by dementia status and neuropsychological performance. Comparisons of flortaucipir uptake with amyloid and atrophy also supported our model of tau progression. DISCUSSION: Data-driven decomposition of flortaucipir uptake provides a novel framework for tau staging which complements existing systems. HIGHLIGHTS: NMF reveals patterns of tau deposition in AD. Data-driven staging of flortaucipir tracks AD severity. Learned flortaucipir patterns overlap with AD-related gene expression.

Cigarette smoking cessation, duration of smoking abstinence, and head and neck squamous cell carcinoma prognosis.

BACKGROUND: Tobacco use is a major risk factor for developing head and neck squamous cell carcinoma (HNSCC). However, the prognostic associations with smoking cessation are limited. The authors assessed whether smoking cessation and increased duration of abstinence were associated with improved overall (OS) and HNSCC-specific survival. METHODS: Clinicodemographic and smoking data from patients with HNSCC at Princess Margaret Cancer Center (2006-2019) were prospectively collected. Multivariable Cox and Fine and Gray competing-risk models were used to assess the impact of smoking cessation and duration of abstinence on overall mortality and HNSCC-specific/noncancer mortality, respectively. RESULTS: Among 2482 patients who had HNSCC, former smokers (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.58-0.87; p = .001; N = 841) had a reduced risk of overall mortality compared with current smokers (N = 931). Compared with current smokers, former smokers who quit >10 years before diagnosis (long-term abstinence; n = 615) had the most improved OS (aHR, 0.72; 95% CI, 0.56-0.93; p = .001). The 5-year actuarial rates of HNSCC-specific and noncancer deaths were 16.8% and 9.4%, respectively. Former smokers (aHR, 0.71; 95% CI, 0.54-0.95; p = .019) had reduced HNSCC-specific mortality compared with current smokers, but there was no difference in noncancer mortality. Abstinence for >10 years was associated with decreased HNSCC-specific death compared with current smoking (aHR, 0.64; 95% CI, 0.46-0.91; p = .012). Smoking cessation with a longer duration of quitting was significantly associated with reduced overall and HNSCC-specific mortality in patients who received primary radiation. CONCLUSIONS: Smoking cessation before the time of diagnosis reduced overall mortality and cancer-specific mortality among patients with HNSCC, but no difference was observed in noncancer mortality. Long-term abstinence (>10 pack-years) had a significant OS and HNSCC-specific survival benefit.

Deep learning resting state functional magnetic resonance imaging lateralization of temporal lobe epilepsy.

OBJECTIVE: Localization of focal epilepsy is critical for surgical treatment of refractory seizures. There remains a great need for noninvasive techniques to localize seizures for surgical decision-making. We investigate the use of deep learning using resting state functional magnetic resonance imaging (RS-fMRI) to identify the hemisphere of seizure onset in temporal lobe epilepsy (TLE) patients. METHODS: A total of 2132 healthy controls and 32 preoperative TLE patients were studied. All participants underwent structural MRI and RS-fMRI. Healthy control data were used to generate training samples for a three-dimensional convolutional neural network (3DCNN). RS-fMRI was synthetically altered in randomly lateralized regions in the healthy control participants. The model was then trained to classify the hemisphere containing synthetic noise. Finally, the model was tested on TLE patients to assess its performance for detecting biological seizure onset zones, and gradient-weighted class activation mapping (Grad-CAM) identified the strongest predictive regions. RESULTS: The 3DCNN classified healthy control hemispheres known to contain synthetic noise with 96% accuracy, and TLE hemispheres clinically identified to be seizure onset zones with 90.6% accuracy. Grad-CAM identified a range of temporal, frontal, parietal, and subcortical regions that were strong anatomical predictors of the seizure onset zone, and the resting state networks that colocalized with Grad-CAM results included default mode, medial temporal, and dorsal attention networks. Lastly, in an analysis of a subset of patients with postsurgical outcomes, the 3DCNN leveraged a more focal set of regions to achieve classification in patients with Engel Class >I compared to Engel Class I. SIGNIFICANCE: Noninvasive techniques capable of localizing the seizure onset zone could improve presurgical planning in patients with intractable epilepsy. We have demonstrated the ability of deep learning to identify the correct hemisphere of the seizure onset zone in TLE patients using RS-fMRI with high accuracy. This approach represents a novel technique of seizure lateralization that could improve preoperative surgical planning.

Divergent clonal selection dominates medulloblastoma at recurrence.

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001.

BACKGROUND: Pembrolizumab plus lenvatinib is a novel combination with promising efficacy in patients with advanced and recurrent endometrial cancer. This combination demonstrated high objective response rates in a single-arm phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with advanced endometrial cancer (KEYNOTE-146/Study 111) after ≤2 previous lines of therapy. In a randomized phase 3 trial of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer (KEYNOTE-775/Study 309), after 1‒2 previous lines of therapy (including neoadjuvant/adjuvant), this combination improved objective response rates, progression-free survival, and overall survival compared with chemotherapy. PRIMARY OBJECTIVE: To compare the efficacy and safety of first-line pembrolizumab plus lenvatinib versus paclitaxel plus carboplatin in patients with newly diagnosed stage III/IV or recurrent endometrial cancer, with measurable or radiographically apparent disease. STUDY HYPOTHESIS: Pembrolizumab plus lenvatinib is superior to chemotherapy with respect to progression-free survival and overall survival in patients with mismatch repair-proficient tumors and all patients (all-comers). TRIAL DESIGN: Phase 3, randomized (1:1), open-label, active-controlled trial. Patients will receive pembrolizumab intravenously every 3 weeks plus lenvatinib orally daily or paclitaxel plus carboplatin intravenously every 3 weeks, stratified by mismatch repair status (proficient vs deficient). Patients with mismatch repair-proficient tumors will be further stratified by Eastern Cooperative Oncology Group performance status (0/1), measurable disease (yes/no), and prior chemotherapy and/or chemoradiation (yes/no). MAJOR INCLUSION/EXCLUSION CRITERIA: Adults with stage III/IV/recurrent histologically confirmed endometrial cancer that is measurable or radiographically apparent per blinded independent central review. Patients may have received previous chemotherapy only as neoadjuvant/adjuvant therapy and/or concurrently with radiation. Patients with carcinosarcoma (malignant mixed Müllerian tumor), endometrial leiomyosarcoma, or other high grade sarcomas, or endometrial stromal sarcomas were excluded. PRIMARY ENDPOINTS: Progression-free and overall survival (dual primary endpoints). SAMPLE SIZE: About 875 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Enrollment is expected to take approximately 24 months, with presentation of results in 2022. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03884101.

Cancer Pain Syndromes.

Pain from cancer can present in a multitude of ways. In this chapter, we will identify the types of cancer pain and their etiologies. Following this, we will explore how cancer pain can present as somatic pain, visceral pain, and neuropathic pain. We will explore the aspects of the history and physical examination that point to specific diagnoses of pain and how to appropriately treat each diagnosis appropriately. Finally, we will touch upon a phenomenon known as opioid neurotoxicity.

Simulation training for the endoscopic management of upper gastrointestinal bleeding: a nationwide survey of rural surgeons' needs and preferences analysis.

BACKGROUND: Published needs analyses of rural surgeons have identified a need for training in the endoscopic management of non-variceal upper gastrointestinal bleeding (NVUGIB). The study aim was to survey rural surgeons regarding their requirements and preferences for a simulation model on which they could rehearse the endoscopic management of NVUGIB. METHODS: Rural surgeons were contacted via the American College of Surgery Advisory Council listserv and invited to complete an online survey. RESULTS: A total of 66 responses were received, representing all 4 US regional divisions. Seventy-seven percent of respondents perform > 100 endoscopy cases per year. A majority have no experience with simulation models (77%), citing cost, time, and access to training courses as the three most limiting factors. Thirty-three percent lacked confidence in managing UGIBs, and 73% were interested in receiving additional training. Preference analysis revealed that respondents preferred a portable simulation model (81%) that costs between $500 and $1000 (46%), and requires 1-2 weeks of training (34%). Verbal feedback from an expert was viewed as the most helpful type of feedback (61%). CONCLUSION: Rural surgeons frequently perform flexible endoscopy in their practice and are interested in further training for the endoscopic management of NVUGIB. These results will be used to develop a simulation platform for training in the endoscopic management of NVUGIB that meets rural surgeons' needs.

Task Deconstruction of Colonic Endoscopic Submucosal Dissection (cESD): An Expert Consensus.

BACKGROUND: Slow adoption of colonic ESD (cESD) in the US is multifactorial due to: lack of clinical training construct (e.g., gastric ESD in Japan), complication risks, and technical difficulty. More than 28,000 patients/year undergo colonic resection for benign lesions that could be managed effectively with cESD. Selected patients could avoid surgery if procedural adoption of cESD increased due to more accessible training. Current US cESD training is scarce, and existing programs are piecemeal. There is a need to develop an effective national training program for practicing endoscopists. A prerequisite to training development is a comprehensive task list delineating procedural steps. The aim of this work was to describe an evidence-based method of deconstructing cESD into the essential steps to provide a task list to guide teaching and assessment. METHODS: Subject-matter experts (SMEs) performed a literature review to create an initial procedural step list. Eleven clinical cESD SMEs and four educational SMEs formed a 'cESD Working Group' to develop consensus regarding steps. Through a two-stage modified Delphi process, a consensus on a comprehensive standard cESD deconstructed task list was reached. The aim was to standardize cESD teaching to efficiently bring a novice to safe performance. RESULTS: A literature review identified eight initial cESD steps. First-round Delphi consensus was gained on seven steps. Semi-structured focus group discussions resulted in consensus on a modified version of 7 of the initial steps, with addition of two steps. Consensus on procedural actions needed to perform each step was achieved after the hands-on laboratory. The final result was a ten-step deconstructed task list for standard cESD. CONCLUSION: The development of a standardized cESD procedural task list provides a foundation to safely and efficiently teach cESD to practicing endoscopists. This list can be used to develop a training pathway to increase procedural adoption. Selected patients currently undergoing colonic resections could benefit from increased adoption of cESD.

Clinical Experience with the Gore Hybrid Vascular Graft in Complex Revascularizations Demonstrates Safety and Efficacy.

BACKGROUND: Arterial revascularizations can present significant challenges when vessels are disadvantaged and advances in technology present the surgeon with innovative opportunities. A number of studies have used the GORE® Hybrid Vascular Graft (GHVG), and we have been using this device in arterial revascularizations since it came to market. The aim of this study is therefore to present a large single-center experience using the GHVG. This series presents patients with complex revascularizations in multiple vascular beds. METHODS: We retrospectively analyzed a single-center series of 43 patients who received a total of 56 GHVGs in complex revascularization procedures at Houston Methodist Hospital from March 2012 to April 2017. We excluded 5 patients (7 grafts in total) because of loss of follow-up. An additional 8 patients were excluded from the analysis (11 grafts in total) secondary to mortalities unrelated to their grafts (7 patients died during index hospitalization and 1 patient died shortly after discharge). RESULTS: Our results demonstrated an 18-month primary patency, assisted primary patency, and secondary patency of 82, 86, and 96%, respectively. These complex revascularizations included a total of 56 devices placed. GHVGs were placed in the external iliac artery (27/56), renal artery (12/56), common femoral artery (6/56), superficial femoral artery (4/56), common iliac artery (3/56), grafts (3/56), profunda femoris artery (1/56), and the superior mesenteric artery (1/56). Early mortality in patients (7/8) was because of the nature of their disease and not related to the surgical intervention. CONCLUSIONS: The GHVG has the ability to create a sutureless anastomosis in a disadvantaged vessel or to promote a potentially better outcome by either avoiding prolonged ischemia to visceral branches or avoiding extensive abdominal or retroperitoneal exposure in an iliofemoral bypass. These results demonstrate the value of the GHVG in complex revascularizations not amenable to traditional open surgical bypass. LEVEL OF EVIDENCE: IV.

Imaging and quantifying ganglion cells and other transparent neurons in the living human retina.

Ganglion cells (GCs) are fundamental to retinal neural circuitry, processing photoreceptor signals for transmission to the brain via their axons. However, much remains unknown about their role in vision and their vulnerability to disease leading to blindness. A major bottleneck has been our inability to observe GCs and their degeneration in the living human eye. Despite two decades of development of optical technologies to image cells in the living human retina, GCs remain elusive due to their high optical translucency. Failure of conventional imaging-using predominately singly scattered light-to reveal GCs has led to a focus on multiply-scattered, fluorescence, two-photon, and phase imaging techniques to enhance GC contrast. Here, we show that singly scattered light actually carries substantial information that reveals GC somas, axons, and other retinal neurons and permits their quantitative analysis. We perform morphometry on GC layer somas, including projection of GCs onto photoreceptors and identification of the primary GC subtypes, even beneath nerve fibers. We obtained singly scattered images by: (i) marrying adaptive optics to optical coherence tomography to avoid optical blurring of the eye; (ii) performing 3D subcellular image registration to avoid motion blur; and (iii) using organelle motility inside somas as an intrinsic contrast agent. Moreover, through-focus imaging offers the potential to spatially map individual GCs to underlying amacrine, bipolar, horizontal, photoreceptor, and retinal pigment epithelium cells, thus exposing the anatomical substrate for neural processing of visual information. This imaging modality is also a tool for improving clinical diagnosis and assessing treatment of retinal disease.

Long-term clinical outcomes and prognostic indicators for focal impulse and rotor modulation guided ablation: A single-center observational study.

BACKGROUND: Electrophysiologists have developed a computational mapping approach to localize sources that may perpetuate persistent atrial fibrillation (AF). Focal impulse and rotor modulation (FIRM)-guided ablation of these sources have produced variable results. The current study further assesses single-procedure success rates of FIRM-guided ablation for preventing AF or atrial tachyarrhythmia recurrence and analyzes different baseline characteristics as prognostic indicators for individuals experiencing these undesired outcomes. METHODS: Seventy-one consecutive patients (mean age 64.58 ± 9.05 years and 36.6% female) with drug-refractory persistent AF with and without prior history of pulmonary vein antral isolation (PVAI) underwent FIRM-guided ablation. Patients without prior history of PVAI underwent FIRM-guided ablation in addition to de novo PVAI. Patients with prior history of PVAI had the pulmonary veins reassessed at the time of FIRM-guided ablation for reconnection as well as re-isolation, when necessary. These patients were then prospectively followed for AF and atrial tachyarrhythmia recurrence. RESULTS: FIRM analysis revealed rotors in the right atrium in 66.2% (1.77 ± 1.53 mean rotors per patient) and in the left atrium in 85.9% (2.65 ± 1.52 mean rotors per patient) of patients analyzed in the current study. After a single FIRM-guided ablation procedure, AF and atrial tachyarrhythmia recurrence was demonstrated in 21.1% (15/71) and 33.8% (24/71) of patients, respectively. The entire cohort of patients were followed for a mean duration of 23.20 ± 8.38 months with the mean time to AF recurrence found to be 12.35 ± 10.44 months. Furthermore, valvular heart disease (i.e. moderate mitral or tricuspid regurgitation) was found to be a statistically significant independent predictor for AF recurrence following FIRM-guided ablation (p = .033). CONCLUSIONS: FIRM-guided ablation in combination with PVAI is a suitable and effective approach for symptomatic individuals with drug-refractory persistent AF with and without prior history of PVAI. Randomized controlled studies are warranted.