Search

Assessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk.To enable integrated genetic risk assessment, the eMERGE (electronic MEdical Records and GEnomics) network is enrolling 25,000 diverse individuals in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores (PRS), monogenic risks, family history, and clinical risk assessments via a Genome Informed Risk Assessment (GIRA) report and will assess uptake of care recommendations after return of results.GIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports. The return of high-risk GIRA to individuals and providers includes guidelines for care and lifestyle recommendations. Assembling the GIRA required infrastructure and workflows for ingesting and presenting content from multiple sources. Recruitment began in February 2022.Return of a novel report for communicating monogenic, polygenic, and family history based risk factors will inform the benefits of integrated genetic risk assessment for routine health care.

Huntington’s disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion in the Huntingtin (HTT) gene. The resulting polyglutamine (polyQ) tract alters the function of the HTT protein. Although HTT is expressed in different tissues, the medium spiny projection neurons (MSNs) in the striatum are particularly vulnerable in HD. Thus, we sought to define the proteome of human HD patient-derived MSNs. We differentiated HD72 induced pluripotent stem cells and isogenic controls into MSNs and carried out quantitative proteomic analysis by two approaches. First, using data-dependent acquisitions with FAIMS (FAIMS-DDA) for label-free quantification on the Orbitrap Lumos mass spectrometer, we identified 6,323 proteins with at least two unique peptides (FDR ≤ 0.01). Of these, 901 proteins were significantly altered in the HD72-MSNs, compared to isogenic controls. Second, we quantitatively validated protein candidates by comprehensive data-independent acquisitions on a TripleTOF 6600 mass spectrometer quantifying 3,106 proteins with at least two unique peptides. Functional enrichment analysis identified pathways related to the extracellular matrix, including TGF-ý regulation of extracellular matrix, epithelial-mesenchymal transition, DNA replication, senescence, cardiovascular system, organism development, regulation of cell migration and locomotion, aminoglycan glycosaminoglycan proteoglycan, growth factor stimulus and fatty acid processes. Conversely, processes associated with the downregulated proteins included neurogenesis-axogenesis, the brain-derived neurotrophic factor-signaling pathway, Ephrin-A: EphA pathway, regulation of synaptic plasticity, triglyceride homeostasis cholesterol, plasmid lipoprotein particle immune response, interferon-γ signaling, immune system major histocompatibility complex, lipid metabolism and cellular response to stimulus. Moreover, proteins involved in the formation and maintenance of axons, dendrites, and synapses (e.g., Septin protein members) are dysregulated in HD72-MSNs. Importantly, lipid metabolism pathways were altered, and we found that lipid droplets accumulated in the HD72-MSNs, suggesting a deficit in lipophagy. Our proteomics analysis of HD72-MSNs identified relevant pathways that are altered in MSNs and confirm current and new therapeutic targets for HD.

From 2016-17, academics at a leading Irish university collaborated with a group of self- advocates with intellectual disabilities to co-design, co-deliver, and co-assess an entire disability module...

Mandibular condyle fractures can result in short-term and long-term morbidity. As a weak area of the mandible, the condyle is vulnerable to injury by a direct impact or an indirect force. Current treatment recommendations aim to better match the severity of the fracture with the choice of closed or open approach. Long-term follow-up of patients provides the best opportunity to monitor the degree of functional restoration after treatment. There is a growing consensus regarding the use of standardized fracture classification methods and outcomes measures that will allow better assessment of treatment results and strengthen the quality of outcomes research.

BackgroundIctal asystole is the transient cessation of cardiac electrical activity during an epileptic seizure. It has been described in association with focal seizures, most often arising from the left temporal lobe in patients with refractory epilepsy.Case and Results of InvestigationsA 31-year-old right-handed male had a first generalised seizure at work following a period of increased alcohol consumption and sleep deprivation. There was no family history of epilepsy and neurological examination was normal. Generalised sharpened discharges with polyspikes occurred in an EEG two days later. A second EEG performed three months later contained a photopar- oxysmal response followed by a generalised seizure accompanied by a 7.5-second period of asystole. Electrographically the seizure was generalised in onset, without lateralising features, although the clinical semiology was notable for some initial focal features. MRI brain did not reveal any focal abnormality. The patient was commenced on levetiracetam and has remained seizure-free since.DiscussionThis is a rare case of ictal asystole in a patient with a generalised-onset seizure, and probable underlying primary generalised epilepsy.

Chronic kidney disease (CKD) and acute kidney injury (AKI) are common, heterogeneous, and morbid diseases. Mechanistic characterization of CKD and AKI in patients may facilitate a precision medicine approach to prevention, diagnosis, and treatment. The Kidney Precision Medicine Project aims to ethically and safely obtain kidney biopsies from participants with CKD or AKI, create a reference kidney atlas, and characterize disease subgroups to stratify patients based on molecular features of disease, clinical characteristics, and associated outcomes. An additional aim is to identify critical cells, pathways, and targets for novel therapies and preventive strategies. This project is a multicenter prospective cohort study of adults with CKD or AKI who undergo a protocol kidney biopsy for research purposes. This investigation focuses on kidney diseases that are most prevalent and therefore substantially burden the public health, including CKD attributed to diabetes or hypertension and AKI attributed to ischemic and toxic injuries. Reference kidney tissues (for example, living kidney donor biopsies) will also be evaluated. Traditional and digital pathology will be combined with transcriptomic, proteomic, and metabolomics analysis of the kidney tissue as well as deep clinical phenotyping for supervised and unsupervised subgroup analysis and systems biology analysis. Participants will be followed prospectively for ten years to ascertain clinical outcomes. Cell types, locations, and functions will be characterized in health and disease in an open, searchable, online kidney tissue atlas. All data from the Kidney Precision Medicine Project will be made readily available for broad use by scientists, clinicians, and patients.

The advent of personalized medicine has driven the development of novel approaches for obtaining detailed cellular and molecular information from clinical tissue samples. Tissue cytometry is a promising new technique that can be used to enumerate and characterize each cell in a tissue and, unlike flow cytometry and other single-cell techniques, does so in the context of the intact tissue, preserving spatial information that is frequently crucial to understanding a cell’s physiology, function, and behavior. However, the wide-scale adoption of tissue cytometry as a research tool has been limited by the fact that published examples utilize specialized techniques that are beyond the capabilities of most laboratories. Here we describe a complete and accessible pipeline, including methods of sample preparation, microscopy, image analysis, and data analysis for large-scale three-dimensional tissue cytometry of human kidney tissues. In this workflow, multiphoton microscopy of unlabeled tissue is first conducted to collect autofluorescence and second-harmonic images. The tissue is then labeled with eight fluorescent probes, and imaged using spectral confocal microscopy. The raw 16-channel images are spectrally deconvolved into 8-channel images, and analyzed using the Volumetric Tissue Exploration and Analysis (VTEA) software developed by our group. We applied this workflow to analyze millimeter-scale tissue samples obtained from human nephrectomies and from renal biopsies from individuals diagnosed with diabetic nephropathy, generating a quantitative census of tens of thousands of cells in each. Such analyses can provide useful insights that can be linked to the biology or pathology of kidney disease. The approach utilizes common laboratory techniques, is compatible with most commercially-available confocal microscope systems and all image and data analysis is conducted using the VTEA image analysis software, which is available as a plug-in for ImageJ. Tissue cytometry is a promising new microscopy technique that can be used to enumerate and characterize each cell in a tissue. Here the authors describe a complete and accessible pipeline, including methods of sample preparation, microscopy, image analysis, and data analysis for large-scale three-dimensional tissue cytometry of human kidney tissues.

Introduction: Past studies comparing perioperative outcomes of hysterectomy (HYST) and uterine artery embolization (UAE) do not control for demographically and insurer diverse populations. This study sought to identify the 30‑day readmission, 15‑day complication, and minimum 1‑year surveillance reintervention rates of diverse, propensity matched patients undergoing UAE or HYST for uterine leiomyoma. Methods: Adults from the New York’s Statewide Planning and Research Cooperative System (SPARCS) database 2009‑2013 who underwent HYST or UAE for uterine leiomyoma were retrospectively reviewed and 1:1 propensity matched. Univariate analysis compared demographics, complications, readmissions, and reintervention rates. Binary logistic and linear regression models identified independent predictors of outcomes. Results: A total of 682 patients were identified, where the number (n) of patients in each cohort was n=341, HYST, and n=341, UAE. Significance levels are shown with p values. No significant differences were identified between HYST and UAE demographics, complication (2.60% HYST vs 2.90% UAE, p=0.816) or readmission rates (3.20% HYST vs 3.80% UAE, p=0.678); 0.30% of UAE patients had a reintervention UAE and 2.90% of UAE patients had reintervention hysterectomy. HYST patients had a significantly longer average length of stay (2.59 days HYST vs 1.63 days UAE, p

This paper describes the architecture and functionality of a work zone traffic information system that uses vehicle-to-vehicle communication, based on dedicated short-range communications (DSRC), and a newly designed hopping algorithm. (“Hopping” involves transmitting traffic messages via intermediate hosts to a target designation. The term is commonly used in the radio and wireless communication industry.) The proposed hopping algorithm can deliver in-vehicle messages transmitted by a roadside unit installed at a work zone site to faraway vehicles traveling toward the work zone on predefined routes. This newly designed hopping algorithm uses rectangular regions to define a hopping route and can hop messages to vehicles on multiple routes at the same time without the risk of creating a broadcast storm. Although the messages hopped by the proposed hopping algorithm will generally be applicable to vehicles on only one side of the road (traveling toward the work zone), the DSRC-equipped vehicles present on both sides of the road will participate in hopping to maximize the number of available hopping nodes in situations with lighter traffic flow or low DSRC market penetration. Furthermore, the hopping algorithm increases message security by not requiring the hopping nodes (i.e., the DSRC-equipped vehicles) to modify the contents of the hopped message. Numerical simulations have been performed to evaluate the performance of the hopping algorithm. The simulation results show that the proposed hopping algorithm works as expected and successfully disseminates DSRC messages along a predefined route.

The concept and techniques of Yield Management (YM) have received widespread attention and application within the travel industry, particularly airline operations, over the last five to ten years. However, more recently interest in YM has been increasingly evident in the hospitality industry as hotel companies have sought to maximise revenue and profitability from the sale of accommodation. Developing from initial concerns with market management, YM applications are being extended to a strategic level by focusing attention upon both short- and long-term product-market fit configurations designed to maximise revenue and profit yield.