4,144 results on '"E. Alexander"'
Search Results
352. Liver‐Targeted Angiotensin Converting Enzyme 2 Therapy Inhibits Chronic Biliary Fibrosis in Multiple Drug‐Resistant Gene 2‐Knockout Mice
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Chandana B Herath, Ian E. Alexander, Lakmie S Gunarathne, Sharon C. Cunningham, Alexandra F. Sharland, Indu G Rajapaksha, Khashayar Asadi, and Peter W Angus
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medicine.medical_specialty ,Genetic enhancement ,Primary sclerosing cholangitis ,03 medical and health sciences ,Liver disease ,0302 clinical medicine ,Internal medicine ,Renin–angiotensin system ,medicine ,lcsh:RC799-869 ,030304 developmental biology ,Liver injury ,0303 health sciences ,Hepatology ,business.industry ,Original Articles ,medicine.disease ,3. Good health ,Endocrinology ,Angiotensin-converting enzyme 2 ,Hepatic stellate cell ,lcsh:Diseases of the digestive system. Gastroenterology ,Original Article ,030211 gastroenterology & hepatology ,Hepatic fibrosis ,business ,hormones, hormone substitutes, and hormone antagonists - Abstract
There is a large unmet need for effective therapies for cholestatic disorders, including primary sclerosing cholangitis (PSC), a disease that commonly results in liver failure. Angiotensin (Ang) II of the renin Ang system (RAS) is a potent profibrotic peptide, and Ang converting enzyme 2 (ACE2) of the alternate RAS breaks down Ang II to antifibrotic peptide Ang‐(1‐7). In the present study, we investigated long‐term effects of ACE2 delivered by an adeno‐associated viral vector and short‐term effects of Ang‐(1‐7) peptide in multiple drug‐resistant gene 2‐knockout (Mdr2‐KO) mice. These mice develop progressive biliary fibrosis with pathologic features closely resembling those observed in PSC. A single intraperitoneal injection of ACE2 therapy markedly reduced liver injury (P more...
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- 2019
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353. Systemic AAV8-mediated delivery of a functional copy of muscle glycogen phosphorylase (Pygm) ameliorates disease in a murine model of McArdle disease
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Kristen J. Nowak, Elyshia McNamara, Joshua S. Clayton, Kimberley L. Dilworth, Gianina Ravenscroft, Tomàs Pinós, Ian E. Alexander, Nigel G. Laing, Astrid Brull, Leszek Lisowski, Rhonda L. Taylor, and Hayley Goullee more...
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Male ,medicine.medical_specialty ,Genetic enhancement ,Disease ,Biology ,Mice ,03 medical and health sciences ,Glycogen phosphorylase ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Genetics ,medicine ,Animals ,Muscle, Skeletal ,Molecular Biology ,Genetics (clinical) ,030304 developmental biology ,Inflammation ,0303 health sciences ,Kidney ,Glycogen ,Myoglobinuria ,Skeletal muscle ,General Medicine ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Glycogen Phosphorylase, Muscle Form ,Glycogen Storage Disease Type V ,Female ,030217 neurology & neurosurgery ,Glycogen storage disease type V - Abstract
McArdle disease is a disorder of carbohydrate metabolism that causes painful skeletal muscle cramps and skeletal muscle damage leading to transient myoglobinuria and increased risk of kidney failure. McArdle disease is caused by recessive mutations in the muscle glycogen phosphorylase (PYGM) gene leading to absence of PYGM enzyme in skeletal muscle and preventing access to energy from muscle glycogen stores. There is currently no cure for McArdle disease. Using a preclinical animal model, we aimed to identify a clinically translatable and relevant therapy for McArdle disease. We evaluated the safety and efficacy of recombinant adeno-associated virus serotype 8 (rAAV8) to treat a murine model of McArdle disease via delivery of a functional copy of the disease-causing gene, Pygm. Intraperitoneal injection of rAAV8-Pygm at post-natal day 1–3 resulted in Pygm expression at 8 weeks of age, accompanied by improved skeletal muscle architecture, reduced accumulation of glycogen and restoration of voluntary running wheel activity to wild-type levels. We did not observe any adverse reaction to the treatment at 8 weeks post-injection. Thus, we have investigated a highly promising gene therapy for McArdle disease with a clear path to the ovine large animal model endemic to Western Australia and subsequently to patients. more...
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- 2019
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354. A library of human gut bacterial isolates paired with longitudinal multiomics data enables mechanistic microbiome research
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J. E. Alexander, Justin M. Scott, Kerry A. Pierce, Xiaofang Jiang, Alison Perrotta, Jonathan Livny, Tami D. Lieberman, S. Roesemann, Eric J. Alm, Clary B. Clish, Sean M. Gibbons, Mark Smith, Julian Avila-Pacheco, Ramnik J. Xavier, Mathieu Groussin, Paige Swanson, Kevin Bullock, B. Berdy, Amy Deik, Shijie Zhao, Sean M. Kearney, Mathilde Poyet, Hera Vlamakis, and S. A. Rich more...
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0301 basic medicine ,education.field_of_study ,Population ,Genomics ,General Medicine ,Computational biology ,Biology ,Biobank ,Genome ,General Biochemistry, Genetics and Molecular Biology ,Bacterial genetics ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Phylogenetics ,030220 oncology & carcinogenesis ,Microbiome ,education ,Gene - Abstract
Our understanding of how the gut microbiome interacts with its human host has been restrained by limited access to longitudinal datasets to examine stability and dynamics, and by having only a few isolates to test mechanistic hypotheses. Here, we present the Broad Institute-OpenBiome Microbiome Library (BIO-ML), a comprehensive collection of 7,758 gut bacterial isolates paired with 3,632 genome sequences and longitudinal multi-omics data. We show that microbial species maintain stable population sizes within and across humans and that commonly used ‘omics’ survey methods are more reliable when using averages over multiple days of sampling. Variation of gut metabolites within people over time is associated with amino acid levels, and differences across people are associated with differences in bile acids. Finally, we show that genomic diversification can be used to infer eco-evolutionary dynamics and in vivo selection pressures for strains within individuals. The BIO-ML is a unique resource designed to enable hypothesis-driven microbiome research. A comprehensive biobank of bacterial isolates with longitudinal and multi-omics characterization will advance understanding of the diversity and functions of human gut bacteria. more...
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- 2019
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355. Surface-Tethered Antimicrobial Peptides: An Invention To Create Effective Antimicrobial Coatings
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Lindsay D. Lozeau, Todd E. Alexander, and Terri A. Camesano
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Chemistry ,Antimicrobial peptides ,Antimicrobial ,Combinatorial chemistry - Published
- 2019
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356. Assessing the impacts of the introduced channel catfish Ictalurus punctatus using the comparative functional response approach
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Mhairi E. Alexander, Jean Ricardo Simões Vitule, and Larissa Faria
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0106 biological sciences ,Ecology ,business.industry ,010604 marine biology & hydrobiology ,Fish farming ,Zoology ,Introduced species ,Aquatic Science ,Biology ,biology.organism_classification ,010603 evolutionary biology ,01 natural sciences ,Aquaculture ,Abundance (ecology) ,Animal ecology ,Ictalurus ,business ,Relative species abundance ,Catfish - Abstract
In the metric “Relative Impact Potential” (RIP), the functional response (FR) of a non‐native species can be compared with that of a native analogue and combined with the species abundance to predict its environmental impact. Here, using the River Guaraguacu (Brazil) as a case study, this methodology was implemented to identify the impacts of the non‐native channel catfish Ictalurus punctatus (Rafinesque) compared with a native species Rhamdia quelen (Quoy & Gaimard) towards small prey fish. Both species exhibited Type II FRs, but handling times were lower for I. punctatus, resulting in a greater maximum feeding rate in this species. Consequently, an RIP > 1 was found, indicating that I. punctatus represents a superior impact to prey compared with its native analogue. These results demonstrate that I. punctatus is a potential threat to small endangered fish species; therefore, policies to avoid escapes from aquaculture should be created and the abundance of I. punctatus controlled. more...
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- 2019
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357. Structured decision-making drives guidelines panels' recommendations 'for' but not 'against' health interventions
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Gordon H. Guyatt, Iztok Hozo, Adam Cuker, Holger J. Schünemann, Robby Nieuwlaat, Paul E. Alexander, Qi Zhou, Benjamin Djulbegovic, Shira Elqayam, Wojtek Wiercioch, Tea Reljic, and Shelly-Anne Li
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Adult ,Male ,medicine.medical_specialty ,Multivariate analysis ,Epidemiology ,Clinical Decision-Making ,MEDLINE ,Psychological intervention ,Group Decision Making ,Article ,Clinical Recommendations ,03 medical and health sciences ,Decision Theory ,0302 clinical medicine ,Outcome Assessment, Health Care ,Health care ,Humans ,Medicine ,030212 general & internal medicine ,Practice Guidelines ,Grading (education) ,Aged ,Evidence-Based Medicine ,business.industry ,“Yes” bias ,Uncertainty ,Hematology ,Evidence-based medicine ,Guideline ,Middle Aged ,Group decision-making ,GRADE ,Logistic Models ,Family medicine ,Multivariate Analysis ,Practice Guidelines as Topic ,Female ,business ,030217 neurology & neurosurgery - Abstract
Background and Objectives The determinants of guideline panels’ recommendations remain uncertain. The objective of this study was to investigate factors considered by members of 8 panels convened by the American Society of Hematology (ASH) to develop guidelines using Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Study Design and Setting Web-based survey of the participants in the ASH guidelines panels. Analysis: two-level hierarchical, random-effect, multivariable regression analysis to explore the relation between GRADE and non-GRADE factors and strength of recommendations (SOR). Results In the primary analysis, certainty in evidence [OR = 1.83; (95CI% 1.45–2.31)], balance of benefits and harms [OR = 1.49 (95CI% 1.30–1.69)] and variability in patients’ values and preferences [OR = 1.47 (95CI% 1.15–1.88)] proved the strongest predictors of SOR. In a secondary analysis, certainty of evidence was associated with a strong recommendation [OR = 3.60 (95% CI 2.16–6.00)] when panel members recommended “for” interventions but not when they made recommendations “against” interventions [OR = 0.98 (95%CI: 0.57–1.8)] consistent with “yes” bias. Agreement between individual members and the group in rating SOR varied (kappa ranged from −0.01 to 0.64). Conclusion GRADE's conceptual framework proved, in general, to be highly associated with SOR. Failure of certainty of evidence to be associated with SOR against an intervention, suggest the need for improvements in the process. more...
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- 2019
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358. Interdigitating Myocardial Tongues in Pediatric Cardiac Fibromas
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Tal Geva, Chrystalle Katte Carreon, Pedro J. del Nido, Edward P. Walsh, Mark E. Alexander, Antonio R. Perez-Atayde, and Stephen P. Sanders
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medicine.medical_specialty ,business.industry ,H&E stain ,Histology ,030204 cardiovascular system & hematology ,Ventricular tachycardia ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Cardiac fibroma ,Internal medicine ,cardiovascular system ,medicine ,Cardiology ,Immunohistochemistry ,Myocyte ,Trichrome stain ,Desmin ,cardiovascular diseases ,030212 general & internal medicine ,business - Abstract
Objectives This study sought to evaluate for the presence of and characterize the interdigitating and entrapped myocardium within cardiac fibromas (CF) and correlate tissue findings with symptoms and surgical outcomes. Background The mechanism of ventricular tachycardia (VT) in CF is unclear. The authors hypothesized that CF harbor tongues of interdigitating myocardium, which could be a substrate for episodes of arrhythmia analogous to peri-infarct zones. Methods A total of 29 patients (14 boys) with CF were identified; all subjects had undergone at least partial tumor resection. A semiquantitative grading system was used to assess the degree of myocardial interdigitation and entrapment, myocyte morphology (hematoxylin and eosin stain and immunohistochemical stain for desmin), tumor collagen density, and cellularity (trichrome stain). The subjects’ ages at presentation, types of arrhythmia, and responses to surgery were correlated with histology. Results CF consistently demonstrated interdigitating and entrapped myocardium, and the extent correlated negatively with age at surgery, as did cellularity, whereas collagen increased with age. Median age at arrhythmia recognition was 8 months. Sustained VT was present in 18 of 29 patients (62%), and 5 of 6 patients with prenatally diagnosed conditions developed VT before 8 months. All 8 patients who experienced cardiac arrest had clinically significant arrhythmia events. Sustained arrhythmia episodes correlated with more diffuse myocyte interdigitation. Ten patients had abnormal karyotype: chromosomes 9 (n = 3) and 3 (n = 1) deletions; isolated translocations: t(4;13), t(5;11) and t(1;9); and undefined aberrations (n = 3). All patients who underwent complete resection were cured of arrhythmias, whereas 2 of 14 patients who had subtotal resections had recurrence, with resolution following re-resection in 1 patient. Conclusions Interdigitating myocardium represents a potential histopathologic substrate for VT and cardiac arrest in CF, which may also explain the occasional recurrence of arrhythmia following incomplete resection. more...
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- 2019
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359. Comments on 'Evaluating Crown Fire Rate of Spread Predictions from Physics-Based Models'
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Miguel G. Cruz and Martin E. Alexander
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Engineering ,business.industry ,Human factors and ergonomics ,Poison control ,Physics based ,Suicide prevention ,Occupational safety and health ,Rate of spread ,Injury prevention ,Crown Fire ,Forensic engineering ,General Materials Science ,Safety, Risk, Reliability and Quality ,business - Published
- 2019
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360. Patient Values and Preferences Regarding Continuous Subcutaneous Insulin Infusion and Artificial Pancreas in Adults with Type 1 Diabetes: A Systematic Review of Quantitative and Qualitative Data
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Shelly-Anne Li, Tahira Devji, Ana-María Gomez, Gordon H. Guyatt, Diana Henao, Oscar Mauricio Muñoz-Velandia, Yuan Zhang, Paul E. Alexander, and Álvaro Ruiz-Morales
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Blood Glucose ,Pancreas, Artificial ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Qualitative evidence ,030209 endocrinology & metabolism ,Qualitative property ,Artificial pancreas ,03 medical and health sciences ,Insulin Infusion Systems ,0302 clinical medicine ,Endocrinology ,Diabetes mellitus ,Internal medicine ,medicine ,Humans ,Insulin ,030212 general & internal medicine ,Type 1 diabetes ,Adult patients ,business.industry ,Patient Preference ,medicine.disease ,Subcutaneous insulin ,Medical Laboratory Technology ,Diabetes Mellitus, Type 1 ,business ,Closed loop - Abstract
We produced, through a systematic review of quantitative and qualitative evidence, a synthesis of the issues of importance (values and preferences) to adult patients with type 1 diabetes regarding treatment with automated insulin delivery systems.We searched MEDLINE, CINAHL, EMBASE, and PsycINFO from the inception of each database through September 2018. We included studies examining patient values and preferences for outcomes related to continuous subcutaneous insulin infusion or artificial pancreas treatment. We compiled structured summaries of the results and assessed the relative importance of each outcome. GRADE (Grading of Recommendations, Assessment Development, and Evaluation) and CERQual (Confidence in Evidence from Reviews of Qualitative research) approaches provided the structure for the evaluation of the quality of evidence and confidence in the findings. A mixed-methods result-based convergent design provided the structure for integration and presentation of results.We reviewed 1665 unique citations; 19 studies (8 quantitative and 11 qualitative) proved eligible. Glycemic control is the key attribute that drives patients' preference. Reduction of glycemic variability and decreased incidence of hypoglycemia and chronic complications proved of intermediate importance and were ranked similarly to components of treatment burden, including the size and appearance of devices, cost, ease of use, and the embarrassment of public use.Clinician guidance may play a crucial role in determining patient values and preferences (for instance, patients' priority in glucose control rather than avoiding diabetic complications). Our results provide guidance for clinicians in discussing preferred insulin delivery systems with patients with type 1 diabetes. more...
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- 2019
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361. Codon-Optimization of Wild-Type Adeno-Associated Virus Capsid Sequences Enhances DNA Family Shuffling while Conserving Functionality
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Kimberley L. Dilworth, Adrian J. Thrasher, Arkadiusz Rybicki, Claus V. Hallwirth, Anais K. Amaya, Adrian C. Filip, Leszek Lisowski, Jason Ward, Sophia H.Y. Liao, Ian E. Alexander, Samantha L. Ginn, Patrick Wilmott, Hiroyuki Nakai, Giorgia Santilli, Marti Cabanes-Creus, and Adrian Westhaus more...
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0301 basic medicine ,lcsh:QH426-470 ,viruses ,Computational biology ,Biology ,medicine.disease_cause ,DNA sequencing ,Article ,codon optimization ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Genetics ,medicine ,capsid ,directed evolution ,lcsh:QH573-671 ,Molecular Biology ,Adeno-associated virus ,DNA shuffling ,Shuffling ,lcsh:Cytology ,library ,AAV ,Directed evolution ,lcsh:Genetics ,030104 developmental biology ,chemistry ,Capsid ,030220 oncology & carcinogenesis ,Codon usage bias ,Molecular Medicine ,DNA - Abstract
Adeno-associated virus (AAV) vectors have become one of the most widely used gene transfer tools in human gene therapy. Considerable effort is currently being focused on AAV capsid engineering strategies with the aim of developing novel variants with enhanced tropism for specific human cell types, decreased human seroreactivity, and increased manufacturability. Selection strategies based on directed evolution rely on the generation of highly variable AAV capsid libraries using methods such as DNA-family shuffling, a technique reliant on stretches of high DNA sequence identity between input parental capsid sequences. This identity dependence for reassembly of shuffled capsids is inherently limiting and results in decreased shuffling efficiency as the phylogenetic distance between parental AAV capsids increases. To overcome this limitation, we have developed a novel codon-optimization algorithm that exploits evolutionarily defined codon usage at each amino acid residue in the parental sequences. This method increases average sequence identity between capsids, while enhancing the probability of retaining capsid functionality, and facilitates incorporation of phylogenetically distant serotypes into the DNA-shuffled libraries. This technology will help accelerate the discovery of an increasingly powerful repertoire of AAV capsid variants for cell-type and disease-specific applications. Keywords: AAV, library, directed evolution, codon optimization, DNA shuffling, capsid more...
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- 2019
362. The Real-World Utility of the LINQ Implantable Loop Recorder in Pediatric and Adult Congenital Heart Patients
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Maria Martuscello, Douglas Y. Mah, Dominic Abrams, Kimberlee Gauvreau, Mark E. Alexander, Laura Bevilacqua, Amy Z. Walsh, Vassilios J. Bezzerides, Geralyn Lam, John K. Triedman, and Carolina A. Escudero more...
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Adult ,Heart Defects, Congenital ,Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Heart disease ,Cardiomyopathy ,030204 cardiovascular system & hematology ,Syncope ,Young Adult ,03 medical and health sciences ,Electrophysiology study ,0302 clinical medicine ,medicine ,Implantable loop recorder ,Humans ,030212 general & internal medicine ,Child ,Cardiac device ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,Arrhythmias, Cardiac ,Prostheses and Implants ,medicine.disease ,Cohort ,Electrocardiography, Ambulatory ,Clinical electrophysiology ,Female ,Genetic diagnosis ,business - Abstract
This study sought to determine the practical use of the recently introduced LINQ implantable loop recorder (LINQ-ILR) in a cohort of pediatric and adult congenital arrhythmia patients.Correlating symptoms to a causative arrhythmia is a key aspect of diagnosis and management in clinical electrophysiology.Retrospective review of clinical data, implantation indications, findings, and therapeutic decisions in patients who underwent LINQ-ILR implantation from April 1st, 2014 to January 30th, 2017 at Boston Children's Hospital.A total of 133 patients were included, of which 76 (57%) were male. The mean age at implantation was 15.7 ± 9.1 years with a duration of follow-up of 11.8 months. Congenital heart disease was present in 34 patients (26%), a confirmed genetic diagnosis in 50 (38%), and cardiomyopathy in 22 (26%), and the remainder were without a previous diagnosis. Syncope was the most common indication for LINQ-ILR implantation, occurring in 59 patients (44%). The median time to diagnosis was 4.5 months, occurring in 78 patients (59%). Cardiac device placement occurred in 17 patients (22%), a medication change in 9 (12%), electrophysiology study/ablation in 5 (6%), or LINQ-ILR explantation in 42 (54%). Infection or erosion occurred in 5 patients. Syncope was correlated with a diagnostic transmission (54% vs. 31%, p = 0.01).The LINQ-ILR is an important diagnostic tool, providing useful data in more than one-half of patients in 6 months. Adverse events are low. Patient selection is critical and undiagnosed syncope represents an important presenting indication for which a LINQ-ILR implant should be considered. more...
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- 2019
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363. Correction to: Implications of Payment for Acute Myocardial Infarctions as a 90-Day Bundled Single Episode of Care: A Cost of Illness Analysis
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Keith B. Allen, James E. Alexander, Joshua N. Liberman, and Susan Gabriel
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Pharmacology ,Health Policy ,Pharmacology (medical) - Published
- 2022
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364. 633P Determining the prognostic value of end of treatment (EOT) 18F-choline positron emission tomography (PET) in patients treated with primary central nervous system lymphoma (PCNSL) who respond to first-line therapy: A single centre retrospective study at the Royal Marsden Hospital (RMH)
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S. Li, B. Sharma, Y. Du, D. El-Sharkawi, S. Iyengar, E. Nicholson, M. Potter, M. Ethell, C. Arias, S. Easdale, E. Alexander, D. Cunningham, and I. Chau
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Oncology ,Hematology - Published
- 2022
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365. Fast hierarchical noniterative registration algorithm.
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M. E. Alexander
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- 1999
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366. Genome editing in the human liver: Progress and translational considerations
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Samantha L, Ginn, Sharntie, Christina, and Ian E, Alexander
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Gene Editing ,Genome ,Liver ,Humans ,Genetic Therapy ,CRISPR-Cas Systems - Abstract
Liver-targeted genome editing offers the prospect of life-long therapeutic benefit following a single treatment and is set to rapidly supplant conventional gene addition approaches. Combining progress in liver-targeted gene delivery with genome editing technology, makes this not only feasible but realistically achievable in the near term. However, important challenges remain to be addressed. These include achieving therapeutic levels of editing, particularly in vivo, avoidance of off-target effects on the genome and the potential impact of pre-existing immunity to bacteria-derived nucleases, when used to improve editing rates. In this chapter, we outline the unique features of the liver that make it an attractive target for genome editing, the impact of liver biology on therapeutic efficacy, and disease specific challenges, including whether the approach targets a cell autonomous or non-cell autonomous disease. We also discuss strategies that have been used successfully to achieve genome editing outcomes in the liver and address translational considerations as genome editing technology moves into the clinic. more...
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- 2021
367. Functional Neural Correlates of a Useful Field of View (UFOV)-Based fMRI Task in Older Adults
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Samantha G. Smith, Adam J. Woods, Emily J. Van Etten, Samuel S. Wu, Emanuel M. Boutzoukas, Hyun Song, Gene E. Alexander, Steven T. DeKosky, Jessica N. Kraft, Alejandro Albizu, Andrew O’Shea, Cheshire Hardcastle, Georg A. Hishaw, Nicole D. Evangelista, Pradyumna K. Bharadwaj, Eric C. Porges, Hanna K. Hausman, Ronald A. Cohen, and Michael Marsiske more...
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Aging ,Cognitive Neuroscience ,media_common.quotation_subject ,behavioral disciplines and activities ,Task (project management) ,Stimulus (psychology) ,Cellular and Molecular Neuroscience ,Cognition ,Task Performance and Analysis ,medicine ,Contrast (vision) ,Humans ,Cognitive decline ,media_common ,Aged ,Neural correlates of consciousness ,medicine.diagnostic_test ,Brain ,Magnetic Resonance Imaging ,Cognitive training ,Useful field of view ,Original Article ,Functional magnetic resonance imaging ,Psychology ,psychological phenomena and processes ,Cognitive psychology - Abstract
Declines in processing speed performance occur in aging and are a critical marker of functional independence in older adults. Studies suggest that Useful Field of View (UFOV) training may ameliorate cognitive decline. Despite its efficacy, little is known about the neural correlates of this task. Within the current study, 233 healthy older adults completed a UFOV-based task while undergoing functional magnetic resonance imaging (fMRI). During the “stimulus” portion of this task, participants must identify a target in the center of the screen and the location of a target in the periphery, among distractors. During the “probe” portion, participants must decide if the object in the center and the location of the target in the periphery were identical to the “stimulus” screen. Widespread bilateral whole-brain activation was observed when activation patterns of the “probe” contrast were subtracted from the “stimulus” contrast. Conversely, the subtraction of “stimulus” from “probe” was associated with discrete activation patterns consisting of 13 clusters. Additionally, when evaluating the variance associated with task accuracy, specific subregions were identified that may be critical for task performance. Our data elucidate the functional neural correlates of a UFOV-based task, a task used in both cognitive training paradigms and assessment of function. more...
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- 2021
368. Point of care virtual surgical planning and 3D printing in facial gender confirmation surgery: a narrative review
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Samyd S. Bustos, Maria Yan, Amy E. Alexander, Basel Sharaf, Doga Kuruoglu, and Jonathan M. Morris
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medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Gender Confirmation Surgery ,Orthognathic surgery ,030206 dentistry ,General Medicine ,Free flap ,030230 surgery ,Surgical planning ,03 medical and health sciences ,0302 clinical medicine ,Quality of life (healthcare) ,Transgender ,Medicine ,Narrative review ,Medical physics ,Review Article on Transgender Surgery ,business ,Point of care - Abstract
Facial gender confirmation surgery (FGCS) is a powerful set of procedures in the armamentarium of plastic surgeons that can transform the male face into a gender-congruent female face and provide the transgender individual with improved quality of life, positive body image and help in social integration. The goals of the FGCS procedures are to address the individual patients’ concerns and expectations about their facial appearance, offer safely executed surgery, minimize complications, and optimize surgical outcomes. Pre-operative computed tomography (CT) scanning and three-dimensional (3D) reconstruction before facial feminization or masculinization delineates important skeletal and sinus anatomy and can also be a useful tool in patient consultation. Virtual surgical planning (VSP) is a valuable tool in facial surgery. From free flap bony reconstruction after tumor resection and orthognathic surgery to craniosynostosis planning, VSP has become widely utilized in modern day cranio-maxillofacial surgery. The use of patient-specific cutting guides and implants helps in improving symmetry and safety of these procedures. Furthermore, 3D printed models are valuable tools in patient education and counseling prior to surgery. In this article we describe our approach to FGCS through the integration of point of care (POC) VSP and 3D printing (3DP) to help deliver safer and accurate FGCS outcomes. more...
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- 2021
369. Comparing Renal Replacement Therapy Modalities in Critically Ill Patients With Acute Kidney Injury: A Systematic Review and Network Meta-Analysis
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Liang Yao, Philipp Kolb, Sean M. Bagshaw, Emilie P. Belley-Côté, Rachel Couban, Long Ge, Fang Fang, Wimonchat Tangamornsuksan, Ron Wald, Linan Zeng, Abdullah Mohammed Algarni, Gordon H. Guyatt, Michael Walsh, Paul E. Alexander, Lonnie Pyne, Zhikang Ye, Matt Scaum, Qi Wang, Ying Wang, Waleed Alhazzani, Borna Tadayon Najafabadi, Bram Rochwerg, Liangying Hou, David Collister, Simon Oczkowski, Francois Lamontagne, and Christian Rabbat more...
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medicine.medical_specialty ,critically ill ,medicine.medical_treatment ,continuous renal replacement therapy ,Review Article ,law.invention ,Peritoneal dialysis ,Randomized controlled trial ,law ,Hemofiltration ,medicine ,Renal replacement therapy ,Dialysis ,intermittent hemodialysis ,business.industry ,RC86-88.9 ,Acute kidney injury ,Medical emergencies. Critical care. Intensive care. First aid ,General Medicine ,medicine.disease ,Relative risk ,Emergency medicine ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,network meta-analysis ,renal replacement therapy ,Hemodialysis ,business - Abstract
Supplemental Digital Content is available in the text., Objectives: To compare different modalities of renal replacement therapy in critically ill adults with acute kidney injury. Data Sources: We searched Medline, PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to 25 May, 2020. We included randomized controlled trials comparing the efficacy and safety of different renal replacement therapy modalities in critically ill patients with acute kidney injury. Study Selection: Ten reviewers (working in pairs) independently screened studies for eligibility, extracted data, and assessed risk of bias. Data Extraction: We performed random-effects frequentist network meta-analyses and used the Grading of Recommendations, Assessment, Development, and Evaluation approach to assess certainty of evidence. The primary analysis was a four-node analysis: continuous renal replacement therapy, intermittent hemodialysis, slow efficiency extended dialysis, and peritoneal dialysis. The secondary analysis subdivided these four nodes into nine nodes including continuous veno-venous hemofiltration, continuous veno-venous hemodialysis, continuous veno-venous hemodiafiltration, continuous arterio-venous hemodiafiltration, intermittent hemodialysis, intermittent hemodialysis with hemofiltration, slow efficiency extended dialysis, slow efficiency extended dialysis with hemofiltration, and peritoneal dialysis. We set the minimal important difference threshold for mortality as 2.5% (relative difference, 0.04). Data Synthesis: Thirty randomized controlled trials (n = 3,774 patients) proved eligible. There may be no difference in mortality between continuous renal replacement therapy and intermittent hemodialysis (relative risk, 1.04; 95% CI, 0.93–1.18; low certainty), whereas continuous renal replacement therapy demonstrated a possible increase in mortality compared with slow efficiency extended dialysis (relative risk, 1.06; 95% CI, 0.85–1.33; low certainty) and peritoneal dialysis (relative risk, 1.16; 95% CI, 0.92–1.49; low certainty). Continuous renal replacement therapy may increase renal recovery compared with intermittent hemodialysis (relative risk, 1.15; 95% CI, 0.91–1.45; low certainty), whereas both continuous renal replacement therapy and intermittent hemodialysis may be worse for renal recovery compared with slow efficiency extended dialysis and peritoneal dialysis (low certainty). Peritoneal dialysis was probably associated with the shortest duration of renal support and length of ICU stay compared with other interventions (low certainty for most comparisons). Slow efficiency extended dialysis may be associated with shortest length of hospital stay (low or moderate certainty for all comparisons) and days of mechanical ventilation (low certainty for all comparisons) compared with other interventions. There was no difference between continuous renal replacement therapy and intermittent hemodialysis in terms of hypotension (relative risk, 0.92; 95% CI, 0.72–1.16; moderate certainty) or other complications of therapy, but an increased risk of hypotension and bleeding was seen with both modalities compared with peritoneal dialysis (low or moderate certainty). Complications of slow efficiency extended dialysis were not sufficiently reported to inform comparisons. Conclusions: The results of this network meta-analysis suggest there is no difference in mortality between continuous renal replacement therapy and intermittent hemodialysis although continuous renal replacement therapy may increases renal recovery compared with intermittent hemodialysis. Slow efficiency extended dialysis with hemofiltration may be the most effective intervention at reducing mortality. Peritoneal dialysis is associated with good efficacy, and the least number of complications however may not be practical in all settings. Importantly, all conclusions are based on very low to moderate certainty evidence, limited by imprecision. At the very least, ICU clinicians should feel comfortable that the differences between continuous renal replacement therapy, intermittent hemodialysis, slow efficiency extended dialysis, and, where clinically appropriate, peritoneal dialysis are likely small, and any of these modalities is a reasonable option to employ in critically ill patients. more...
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- 2021
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370. An optimum solution for scale-invariant object recognition based on the multiresolution approximation.
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Sung H. Yoon, Jung H. Kim, Winser E. Alexander, Seong M. Park, and Kwang H. Sohn
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- 1998
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371. A mean field annealing approach to robust corner detection.
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Kwanghoon Sohn, Jung H. Kim, and Winser E. Alexander
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- 1998
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372. The Asian Gang Revisited : Changing Muslim Masculinities
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Claire E. Alexander and Claire E. Alexander
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- Islam, Gangs, Masculinity
- Abstract
In her groundbreaking ethnography The Asian Gang, published in 2000, Claire Alexander explored the creation of Asian Muslim masculinities in South London. Set against the backdrop of the moral panic over'Asian gangs'in the mid-1990s, and based on 5 years of ethnographic fieldwork, the book explored the idea of'the gang', friendships, and the role of'brothers'in the formation, performance and negotiation of ethnic, religious and gendered identities.The Asian Gang Revisited picks up the story of'the Asian gang'over the subsequent two decades, examining the changing identities of the original participants as they transition into adulthood in the context of increased public and political concerns over Muslim masculinities, spanning the War on Terror,'grooming gangs'and increased Islamophobia. Building on her ongoing relationships with the men over 25 years, the book explores education, employment, friendship, marriage and fatherhood, and religious identity, and examines both the changes and the continuities that have shaped this group. It traces the lives of its participants from their teenage years through to their early-mid 40s. A unique longitudinal study of this small, diverse but still close cohort of men, the book offers an intimate, rich and textured account of what it means to be a Muslim man in contemporary Britain. more...
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- 2024
373. Fast registration algorithm using a variational principle for mutual information.
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Murray E. Alexander and Randy Summers
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- 2003
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374. Migration Sampling by Trapping: A Brief Review
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Bergstrom, E. Alexander and Drury,, William H.
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- 1956
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375. The South Windsor Bank Swallow Colony
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Bergstrom, E. Alexander
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- 1951
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376. English Game Laws and Colonial Food Shortages
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Bergstrom, E. Alexander
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- 1939
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377. A Dataflow Framework for DSP Algorithm Refinement.
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Youngsoo Kim, Winser E. Alexander, and William W. Edmonson
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- 2012
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378. Parallel image processing with the block data parallel architecture.
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Winser E. Alexander, Douglas S. Reeves, and Clay S. Gloster Jr.
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- 1996
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379. Ub-ISAP: a streamlined UNIX pipeline for mining unique viral vector integration sites from next generation sequencing data.
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Atul Kamboj, Claus V. Hallwirth, Ian E. Alexander, Geoffrey B. McCowage, and Belinda Kramer
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- 2017
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380. Acceleration of Synthetic Aperture Radar (SAR) Algorithms using Field Programmable Gate Arrays (FPGAs) (Abstract Only).
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Youngsoo Kim, William Harding, Clay S. Gloster Jr., and Winser E. Alexander
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- 2015
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381. The effect of sex hormones on skeletal muscle adaptation in females
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Sarah E. Alexander, Alexander C Pollock, and Séverine Lamon
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Male ,medicine.medical_specialty ,Secondary sex characteristic ,Skeletal muscle adaptation ,030209 endocrinology & metabolism ,Physical Therapy, Sports Therapy and Rehabilitation ,03 medical and health sciences ,0302 clinical medicine ,Sex hormone-binding globulin ,Internal medicine ,medicine ,Humans ,Orthopedics and Sports Medicine ,Testosterone ,Gonadal Steroid Hormones ,Muscle, Skeletal ,Progesterone ,biology ,Skeletal muscle ,Estrogens ,030229 sport sciences ,General Medicine ,Androgen receptor ,Endocrinology ,medicine.anatomical_structure ,Cross-Sectional Studies ,Human reproductive system ,biology.protein ,Androgens ,Female ,Steroids ,Progestins ,Hormone - Abstract
Sex steroids, commonly referred to as sex hormones, are integral to the development and maintenance of the human reproductive system. In addition, male (androgens) and female (estrogens and progestogens) sex hormones promote the development of secondary sex characteristics by targeting a range of other tissues, including skeletal muscle. The role of androgens on skeletal muscle mass, function and metabolism has been well described in males, yet female specific studies are scarce in the literature. This narrative review summarises the available evidence around the mechanistic role of androgens, estrogens and progestogens in female skeletal muscle. An analysis of the literature indicates that sex steroids play important roles in the regulation of female skeletal muscle mass and function. The free fractions of testosterone and progesterone in serum were consistently associated with the regulation of muscle mass, while estrogens may be primarily involved in mediating the muscle contractile function in conjunction with other sex hormones. Muscle strength was however not directly associated with any hormone in isolation when at physiological concentrations. Importantly, recent evidence suggests that intramuscular sex hormone concentrations may be more strongly associated with muscle size and function than circulating forms, providing interesting opportunities for future research. By combining cross-sectional, interventional and mechanical studies, this review aims to provide a broad, multidisciplinary picture of the current knowledge of the effects of sex steroids on skeletal muscle in females, with a focus on the regulation of muscle size and function and an insight into their clinical implications. HighlightsFree testosterone, but not total testosterone, is associated with lean mass but not strength in pre- and post-menopausal females.Progesterone and estrogens may regulate muscle mass and strength, respectively, in females.Intra-muscular steroids may be more closely associated to muscle mass and strength, compared to systemic fractions. more...
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- 2021
382. Association of Virtual Surgical Planning With External Incisions in Complex Maxillectomy Reconstruction
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Johnathan M Morris, Ethan T Moore, Eli Martin, Amy E. Alexander, Eric J. Moore, J.R. Janus, Daniel L. Price, and Kathryn M. Van Abel
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Male ,Patient-Specific Modeling ,Partial Maxillectomy ,medicine.medical_specialty ,Free flap ,030230 surgery ,Tertiary care ,Surgical planning ,Surgical Flaps ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Fibula ,030223 otorhinolaryngology ,Fixation (histology) ,Retrospective Studies ,business.industry ,Virtual Reality ,Retrospective cohort study ,Middle Aged ,Plastic Surgery Procedures ,Maxillary Diseases ,Surgery ,Otorhinolaryngology ,Surgery, Computer-Assisted ,Female ,business ,Cohort study - Abstract
Importance Maxillectomy can commonly be performed through a transoral approach, but maxillectomy defect reconstruction can be difficult to precisely design, contour, and inset through this approach. Objective To evaluate whether the use of virtual surgical planning (VSP) and 3-dimensional (3-D) modeling is associated with a decrease in the requirement of lateral rhinotomy (LR) for patients undergoing total and partial maxillectomy reconstruction. Design, setting, and participants This retrospective cohort study was conducted among patients undergoing subtotal or total maxillectomy with microvascular free flap reconstruction with or without VSP and 3-D modeling at a single tertiary care academic medical center between January 1, 2008, and October 3, 2019. Interventions Maxillectomy and free flap reconstruction with or without VSP. Main outcomes and measures Necessity of LR or other external incision for contouring, placement, and fixation of reconstruction as well as surgical complications. Results Fifteen patients (12 men [80%]; mean age, 64 years) underwent maxillectomy with free flap reconstruction without VSP. Eight patients (53%) in this group underwent total maxillectomy, and 4 patients in this group (27%) underwent partial maxillectomy. Twenty-three patients (18 men [78%]; mean age, 58 years) underwent maxillectomy with free flap reconstruction and VSP and 3-D modeling. Twelve of these patients (52%) underwent total maxillectomy, and 11 (48%) underwent partial maxillectomy. Lateral rhinotomy was necessary for 1 patient (4%) in the VSP group vs 12 patients (80%; 95% CI, 54%-98%) in the pre-VSP group. There were no LR complications in the VSP group vs 6 in the pre-VSP group. Among both groups, 14 patients underwent fibula free flap, 22 patients underwent subscapular system free flap, and 2 patients underwent cutaneous or osteocutaneous radial forearm free flap. There were no flap failures in the LR group and 1 flap failure in the group without LR. Conclusions and relevance This cohort study suggests that the use of VSP and 3-D modeling for maxillectomy reconstruction is associated the a decrease in the need for external incisions without compromising reconstructive flap utility. more...
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- 2021
383. Short‐ and long‐term outcomes of <scp>three‐dimensional</scp> printed surgical guides and virtual surgical planning versus conventional methods for fibula free flap reconstruction of the mandible: Decreased nonunion and complication rates
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Benjamin M. Howe, Jonathon M. Morris, Thomas J. O'Byrne, Daniel L. Price, Jan L. Kasperbauer, Matthew M. May, Amy E. Alexander, Eric J. Moore, Kathryn M. Van Abel, Jeffrey R. Janus, and Hunter J. Dickens more...
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medicine.medical_specialty ,Radiography ,Nonunion ,Mandible ,Free flap ,Free Tissue Flaps ,Surgical planning ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Fibula ,Retrospective Studies ,business.industry ,Retrospective cohort study ,030206 dentistry ,Plastic Surgery Procedures ,medicine.disease ,Surgery ,Surgery, Computer-Assisted ,Otorhinolaryngology ,030220 oncology & carcinogenesis ,Mandibular Reconstruction ,business ,Complication - Abstract
Background To determine whether virtual surgical planning and three-dimensional printed cutting guides (3D/VSP) improved radiographic bone union compared to conventional methods (CM) in fibula free flap (FFF) reconstruction of the mandibles. Methods Retrospective study from the years 2000-2018 at a tertiary hospital. Osseous union was evaluated by a radiologist blinded to each patient's treatment. Results Two hundred sixty patients who underwent FFF tissue transfer, 28 with VSP and 3D cutting guides. Bony union was not achieved in 46 (20%) patients who underwent CM compared to 1 (4%) of patients with VSP and guides (p = 0.036). FFF complication was significantly higher in CM with 87 patients (38%) compared to three patients (11%) in 3D/VSP (p = 0.005). Median time to bony union for patients who underwent CM was 1.4 years compared to 0.8 years in 3D/VSP. Conclusions 3D/VSP reduced the rate of radiographic nonunion and flap-related complications in FFF reconstruction for mandibular defects. more...
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- 2021
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384. Gain-of-function factor H–related 5 protein impairs glomerular complement regulation resulting in kidney damage
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Ian E. Alexander, E Christina Hiemeyer, Mawj Mandwie, Linda B. Moran, Alyssa C. Gilmore, Talat H. Malik, Grant J Logan, Hannah J. Lomax-Browne, Kevin J. Marchbank, Allan Bradley, Amina Ahmad, Matthew C. Pickering, Katharina Boroviak, H. Terence Cook, Deborah P. Lavin, and Daniel P. Gitterman more...
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0301 basic medicine ,Male ,medicine.medical_specialty ,kidney ,Mutant ,Kidney Glomerulus ,Mice, Transgenic ,Biology ,immunology ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Glomerular C3 deposition ,Immunology and Inflammation ,Glomerulonephritis ,Sex Factors ,Glomerulopathy ,Internal medicine ,medicine ,Animals ,Humans ,complement ,Kidney ,Multidisciplinary ,urogenital system ,Complement C3 ,Complement System Proteins ,Biological Sciences ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Gain of Function Mutation ,CFHR5 nephropathy ,Female ,CFHR5 ,Homeostasis ,030215 immunology ,Kidney disease - Abstract
Significance The complement system is integral to innate immunity and host defense. However, inappropriate activation causes host tissue damage and disease. In health, this is prevented by a complex protein network that includes the factor H proteins. Understanding control of complement is critical to treat complement-mediated disease. We demonstrate that a gain-of-function mutant factor H–related 5 protein (FHR5) results in glomerular damage. The mutant interfered with complement regulation within the kidney, resulting in complement accumulation within glomeruli and kidney damage. Administration of a complement regulator with enhanced surface regulatory activity reduced mutant-associated glomerular complement. FHR5 can disrupt the homeostatic regulation of complement within the kidney, and targeting FHR5 represents a way to treat some types of complement-mediated kidney injury., Genetic variation within the factor H–related (FHR) genes is associated with the complement-mediated kidney disease, C3 glomerulopathy (C3G). There is no definitive treatment for C3G, and a significant proportion of patients develop end-stage renal disease. The prototypical example is CFHR5 nephropathy, through which an internal duplication within a single CFHR5 gene generates a mutant FHR5 protein (FHR5mut) that leads to accumulation of complement C3 within glomeruli. To elucidate how abnormal FHR proteins cause C3G, we modeled CFHR5 nephropathy in mice. Animals lacking the murine factor H (FH) and FHR proteins, but coexpressing human FH and FHR5mut (hFH-FHR5mut), developed glomerular C3 deposition, whereas mice coexpressing human FH with the normal FHR5 protein (hFH-FHR5) did not. Like in patients, the FHR5mut had a dominant gain-of-function effect, and when administered in hFH-FHR5 mice, it triggered C3 deposition. Importantly, adeno-associated virus vector-delivered homodimeric mini-FH, a molecule with superior surface C3 binding compared to FH, reduced glomerular C3 deposition in the presence of the FHR5mut. Our data demonstrate that FHR5mut causes C3G by disrupting the homeostatic regulation of complement within the kidney and is directly pathogenic in C3G. These results support the use of FH-derived molecules with enhanced C3 binding for treating C3G associated with abnormal FHR proteins. They also suggest that targeting FHR5 represents a way to treat complement-mediated kidney injury. more...
- Published
- 2021
385. Brain-based measures of nociception during general anesthesia with remifentanil: A randomized controlled trial
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Keerthana Deepti Karunakaran, Barry D. Kussman, Ke Peng, Lino Becerra, Robert Labadie, Rachel Bernier, Delany Berry, Stephen Green, David Zurakowski, Mark E. Alexander, and David Borsook
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Male ,Nociception ,Adolescent ,Brain ,Pain ,Arrhythmias, Cardiac ,General Medicine ,Anesthesia, General ,Analgesics, Opioid ,Remifentanil ,Oxyhemoglobins ,Humans ,Female ,Child - Abstract
Background Catheter radiofrequency (RF) ablation for cardiac arrhythmias is a painful procedure. Prior work using functional near-infrared spectroscopy (fNIRS) in patients under general anesthesia has indicated that ablation results in activity in pain-related cortical regions, presumably due to inadequate blockade of afferent nociceptors originating within the cardiac system. Having an objective brain-based measure for nociception and analgesia may in the future allow for enhanced analgesic control during surgical procedures. Hence, the primary aim of this study is to demonstrate that the administration of remifentanil, an opioid widely used during surgery, can attenuate the fNIRS cortical responses to cardiac ablation. Methods and findings We investigated the effects of continuous remifentanil on cortical hemodynamics during cardiac ablation under anesthesia. In a randomized, double-blinded, placebo (PL)-controlled trial, we examined 32 pediatric patients (mean age of 15.8 years,16 females) undergoing catheter ablation for cardiac arrhythmias at the Cardiology Department of Boston Children’s Hospital from October 2016 to March 2020; 9 received 0.9% NaCl, 12 received low-dose (LD) remifentanil (0.25 mcg/kg/min), and 11 received high-dose (HD) remifentanil (0.5 mcg/kg/min). The hemodynamic changes of primary somatosensory and prefrontal cortices were recorded during surgery using a continuous wave fNIRS system. The primary outcome measures were the changes in oxyhemoglobin concentration (NadirHbO, i.e., lowest oxyhemoglobin concentration and PeakHbO, i.e., peak change and area under the curve) of medial frontopolar cortex (mFPC), lateral prefrontal cortex (lPFC) and primary somatosensory cortex (S1) to ablation in PL versus remifentanil groups. Secondary measures included the fNIRS response to an auditory control condition. The data analysis was performed on an intention-to-treat (ITT) basis. Remifentanil group (dosage subgroups combined) was compared with PL, and a post hoc analysis was performed to identify dose effects. There were no adverse events. The groups were comparable in age, sex, and number of ablations. Results comparing remifentanil versus PL show that PL group exhibit greater NadirHbO in inferior mFPC (mean difference (MD) = 1.229, 95% confidence interval [CI] = 0.334, 2.124, p < 0.001) and superior mFPC (MD = 1.206, 95% CI = 0.303, 2.109, p = 0.001) and greater PeakHbO in inferior mFPC (MD = −1.138, 95% CI = −2.062, −0.214, p = 0.002) and superior mFPC (MD = −0.999, 95% CI = −1.961, −0.036, p = 0.008) in response to ablation. S1 activation from ablation was greatest in PL, then LD, and HD groups, but failed to reach significance, whereas lPFC activation to ablation was similar in all groups. Ablation versus auditory stimuli resulted in higher PeakHbO in inferior mFPC (MD = 0.053, 95% CI = 0.004, 0.101, p = 0.004) and superior mFPC (MD = 0.052, 95% CI = 0.013, 0.091, p < 0.001) and higher NadirHbO in posterior superior S1 (Pos. SS1; MD = −0.342, 95% CI = −0.680, −0.004, p = 0.007) during ablation of all patients. Remifentanil group had smaller NadirHbO in inferior mFPC (MD = 0.098, 95% CI = 0.009, 0.130, p = 0.003) and superior mFPC (MD = 0.096, 95% CI = 0.008, 0.116, p = 0.003) and smaller PeakHbO in superior mFPC (MD = −0.092, 95% CI = −0.680, −0.004, p = 0.007) during both the stimuli. Study limitations were small sample size, motion from surgery, indirect measure of nociception, and shallow penetration depth of fNIRS only allowing access to superficial cortical layers. Conclusions We observed cortical activity related to nociception during cardiac ablation under general anesthesia with remifentanil. It highlights the potential of fNIRS to provide an objective pain measure in unconscious patients, where cortical-based measures may be more accurate than current evaluation methods. Future research may expand on this application to produce a real-time indication of pain that will aid clinicians in providing immediate and adequate pain treatment. Trial registration ClinicalTrials.gov NCT02703090 more...
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- 2021
386. Early multidrug treatment of SARS-CoV-2 infection (COVID-19) and reduced mortality among nursing home (or outpatient/ambulatory) residents
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Robin L. Armstrong, Craig M. Wax, Peter A. McCullough, Ramin Oskoui, Harvey A. Risch, Parvez Dara, Howard C. Tenenbaum, Paul E. Alexander, John Lotus, Chad Prodromos, George Fareed, and Kulvinder K. Gill more...
- Subjects
0301 basic medicine ,medicine.medical_specialty ,corticosteroid ,Population ,Psychological intervention ,Disease ,elderly ,Article ,03 medical and health sciences ,0302 clinical medicine ,Antithrombotic ,Outpatients ,medicine ,Humans ,ambulatory treatment ,Intensive care medicine ,education ,anti-inflammatory ,Aged ,education.field_of_study ,Transmission (medicine) ,business.industry ,SARS-CoV-2 ,anticoagulant ,COVID-19 ,Hydroxychloroquine ,General Medicine ,medicine.disease ,antiplatelet agent ,mortality ,antiviral ,anti-infective ,Nursing Homes ,nursing home ,030104 developmental biology ,Ambulatory ,Cytokine storm ,business ,030217 neurology & neurosurgery ,medicine.drug ,hospitalization - Abstract
The outbreak of COVID-19 from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread all over the world with tremendous morbidity and mortality in the elderly. In-hospital treatment addresses the multifaceted nature of the illness including initial viral replication, cytokine storm, and endothelial injury with thrombosis. We identified nine reports of early treatment outcomes in COVID-19 nursing home patients. Multi-drug therapy including hydroxychloroquine with one or more anti-infectives, corticosteroids, and antithrombotic anti-blood clotting agents can be extended to seniors in the nursing home setting without hospitalization. Data from nine studies found hydroxychloroquine-based multidrug regimens were associated with a statistically significant > 60% reduction in mortality. Going forward, we conclude that early empiric treatment for the elderly with COVID-19 in the nursing home setting (or similar congregated settings with elderly residents/patients e.g. LTF or ALF) has a reasonable probability of success and acceptable safety. This group remains our highest at-risk group and warrants acute treatment focus prior to symptoms worsening. Given the rapidity and severity of SARS-CoV-2 outbreaks in nursing homes, in-center treatment of acute COVID-19 patients is a reasonable strategy to reduce the risks of hospitalization and death. If elderly high-risk patients in such congregated nursing home type settings are allowed to worsen with no early treatment, they may be too sick and fragile to benefit from in-hospital therapeutics and are at risk for pulmonary failure, life-ending micro-thrombi of the lungs, kidneys etc. The issue is timing of therapeutics, and we argue that early treatment before hospitalization, is the right time and can potentially save lives, especially among our higher-risk elderly populations hit hardest by severe illness and death from COVID-19. We must reiterate, we are talking about 'early' treatment before the disease is far along in the disease sequelae where the patient then needs hospitalization and aggressive interventions. We are referring to the initial days e.g. day one, post infection when symptoms emerge or there is strong clinical suspicion. This early therapeutic option deserves serious and urgent consideration by the medical establishment and respective decision-makers. Doctors must be allowed their clinical discretion in how they optimally treat their patients. Doctors must be brave and trust their skilled judgements and do all to save the lives of their patients. We therefore hypothesize that early outpatient ambulatory treatment, once initiated as soon as symptoms begin in high-risk positive persons, would significantly reduce hospitalizations and prevent deaths. Specifically, the provision of early multi-drug sequenced therapy with repurposed drugs will reduce hospitalization and death in elderly patients being cared for in long-term-care facilities. The most important implications of our hypothesis are: 1) hospitalizations and deaths would be reduced 2) transmission would be reduced due to the mitigation of symptoms and 3) recovery following infection and treatment provides for natural exposure immunity that is broad based, durable, and robust (helping towards natural immunity within the population). The end result is reduced strain on hospitals and systems that would allow for other non-COVID illnesses to receive care. more...
- Published
- 2021
387. Early Multidrug Outpatient Treatment of SARS-CoV-2 Infection (COVID-19) and Reduced Mortality Among Nursing Home Residents
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Craig M. Wax, Paul E. Alexander, Ramin Oskoui, George Fareed, Robin L. Armstrong, Harvey A. Risch, Peter A. McCullough, Howard C. Tenenbaum, John Lotus, Chad Prodromos, and Kulvinder K. Gill
- Subjects
medicine.medical_specialty ,Isolation (health care) ,business.industry ,Hydroxychloroquine ,Azithromycin ,medicine.disease ,Clinical trial ,Prednisone ,Intervention (counseling) ,Antithrombotic ,medicine ,business ,Intensive care medicine ,Cytokine storm ,medicine.drug - Abstract
The outbreak of COVID-19 from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread all over the world with tremendous morbidity and mortality in the elderly. In-hospital treatment addresses the multifaceted nature of the illness including viral replication, cytokine storm, and endothelial injury with thrombosis. We identified nine reports of early treatment outcomes in COVID-19 nursing home patients. Multi-drug therapy including hydroxychloroquine with one or more anti-infectives, corticosteroids, and antithrombotic agents can be extended to seniors in the nursing home setting without hospitalization. Data from nine studies found multidrug regimens relying on the use of hydroxychloroquine as well as other agents including doxycycline were associated with a statistically significant and >60% reductions in mortality. Going forward, we theorize and based on the evidence, that early empiric treatment for the elderly with COVID-19 in the nursing home setting (or similar congregated settings with elderly residents/patients) has a genuine probability of success and acceptable safety. This group remains our highest at-risk group and warrants acute treatment focus that will prevent the development and/or worsening of problems associated with COVID-19, most particularly isolation, hospitalization, and death. In fact, with the rapidity and severity of SARS-CoV-2 outbreaks in nursing homes, in-center treatment of patients with acute COVID-19 is possibly the most rational and importantly feasible strategy to reduce the risks of hospitalization and death. If the approach remains ‘wait-and-see’ and elderly high-risk patients in such congregated nursing room type settings are allowed to worsen with no early treatment, they may be too sick and fragile to benefit from in-hospital therapeutics and are at risk for pulmonary failure, life-ending micro-thrombi of the lungs, kidneys etc. We put forth the notion that the most important factor in this regard, is making available early therapeutic intervention as described here. These drugs include and under supervision by skilled doctors, combination/sequenced ivermectin, hydroxychloroquine, colchicine, azithromycin, doxycycline, bromhexine hydrochloride, and favipiravir (outside the US), along with inhaled steroids such as budesonide and oral steroids including dexamethasone and prednisone, and anti-thrombotic anti-clotting drugs such as heparin). As the clinical trials data on treatments for COVID-19 mature, this early treatment therapeutic option deserves serious, urgent, and sober consideration by the medical establishment and respective decision-makers. more...
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- 2021
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388. The Emergence of Extensively Drug-Resistant Tuberculosis (TB): TB/HIV Coinfection, Multidrug-Resistant TB and the Resulting Public Health Threat from Extensively Drug-Resistant TB, Globally and in Canada
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Paul E Alexander and Prithwish De
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Infectious and parasitic diseases ,RC109-216 ,Microbiology ,QR1-502 - Abstract
Resistance to anti-tuberculosis (TB) drugs continues to present a major challenge to global public health. Resistance usually develops due to inadequate TB management, including improper use of medications, improper treatment regimens and failure to complete the treatment course. This may be due to an erratic supply or a lack of access to treatment, as well as to patient noncompliance. However, the emergence and transmission of drug-resistant TB, including the recently detected extensively drug resistant TB (XDR-TB), is driven, in part, by the synergistic relationship between TB and HIV (TB/HIV coinfection). There is evidence that persons infected with HIV are more likely to experience XDR-TB. XDR-TB is virtually untreatable with available TB medications. XDR-TB presents a grave global public health threat, particularly in high HIV prevalence settings. The present commentary discusses the current status of XDR-TB and draws attention to the urgency in addressing this problem, for both the global and Canadian public health networks. XDR-TB and the apparent XDR-TB and HIV association warrants further study. more...
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- 2007
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389. Fast noniterative registration of magnetic resonance images.
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Nicolino J. Pizzi, Murray E. Alexander, Rodrigo A. Vivanco, and Raymond L. Somorjai
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- 2001
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390. Performance of Cardiotropic rAAV Vectors Is Dependent on Production Method
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Renuka Rao, Melad Farraha, Grant J. Logan, Sindhu Igoor, Cindy Y. Kok, James J. H. Chong, Ian E. Alexander, and Eddy Kizana
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Mice ,HEK293 Cells ,Infectious Diseases ,Virology ,Genetic Vectors ,Induced Pluripotent Stem Cells ,baculovirus ,gene therapy ,rAAV vectors ,vector production ,viral vectors ,Animals ,Humans ,Dependovirus ,Baculoviridae - Abstract
Gene therapy is making significant impact on a modest, yet growing, number of human diseases. Justifiably, the preferred viral vector for clinical use is that based on recombinant adeno-associated virus (rAAV). There is a need to scale up rAAV vector production with the transition from pre-clinical models to human application. Standard production methods based on the adherent cell type (HEK293) are limited in scalability and other methods, such as those based on the baculovirus and non-adherent insect cell (Sf9) system, have been pursued as an alternative to increase rAAV production. In this study, we compare these two production methods for cardiotropic rAAVs. Transduction efficiency for both production methods was assessed in primary cardiomyocytes, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), and in mice following systemic delivery. We found that the rAAV produced by the traditional HEK293 method out-performed vector produced using the baculovirus/Sf9 system in vitro and in vivo. This finding provides a potential caveat for vector function when using the baculovirus/Sf9 production system and underscores the need for thorough assessment of vector performance when using diverse rAAV production methods. more...
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- 2022
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391. The Application of Fire Behavior Modeling to Fuel Treatment Assessments at Army Garrison Camp Williams, Utah
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Scott M. Frost, Martin E. Alexander, and Michael J. Jenkins
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Earth and Planetary Sciences (miscellaneous) ,firebreak ,FlamMap ,fuelbreak ,fuel management ,NEXUS ,wildland-urban interface ,Forestry ,Building and Construction ,Environmental Science (miscellaneous) ,Safety, Risk, Reliability and Quality ,Safety Research - Abstract
Large wildfires (>40 ha in size) occur about every three years within Army Garrison Camp Williams, located near South Jordan, Utah, USA. In 2010 and 2012, wildfires originating on the practice firing range burned beyond the camp’s boundaries into the adjacent wildland-urban interface areas. The political and public reaction to these escaped fires was intense. Fire researchers at Utah State University were asked if a spatially organized system of fuel treatments could be developed to prevent such incidents in the future. We used a combination of empirically based guidelines and semi-physical fire modeling systems, coupled with climatological data, to make assessments of fire behavior potential for the sagebrush steppe vegetation/fuel types found in AGCW, that also considered slope steepness. The results suggested the need for removal of woody vegetation within 20 m of firebreaks and a minimum firebreak width of 8.0 m in grassland fuels. In stands of juniper, a canopy coverage of 25% or less is recommended. In Gambel oak stands along the northern boundary of the installation, a fuelbreak width of 60 m for secondary breaks (used for segmenting large areas of fuels) and 90 m for primary breaks (used for protecting urban development and valuable natural resources) is recommended. more...
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- 2022
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392. Exposure to air pollution and risk of incident dementia in the UK Biobank
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Kimberly L. Parra, Gene E. Alexander, David A. Raichlen, Yann C. Klimentidis, and Melissa A. Furlong
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Air Pollutants ,Alzheimer Disease ,Air Pollution ,Humans ,Neurodegenerative Diseases ,Particulate Matter ,Environmental Exposure ,Middle Aged ,Biochemistry ,Article ,United Kingdom ,Biological Specimen Banks ,General Environmental Science - Abstract
BACKGROUND: Air pollution may cause inflammatory and oxidative stress damage to the brain, leading to neurodegenerative disease. The association between air pollution and dementia, and modification by apolipoprotein E genotype 4 (APOE-ε4) has yet to be fully investigated. OBJECTIVES: To examine associations of air pollution with three types of incident dementias (Alzheimer’s disease (AD), frontotemporal dementia (FTD), and vascular dementia (VAD)), and their potential modification by APOE-ε4 genotype. METHODS: The UK Biobank enrolled >500,000 participants (2006–2010) with ongoing follow-up. We used annual averages of air pollution (PM(2.5), PM(10), PM(2.5–10), PM(2.5absorbance), NO(2), NO(X)) for 2010 scaled to interquartile ranges (IQR). We included individuals aged ≥ 60 years, with no dementia diagnosis prior to January 1, 2010. Time to incident dementia and follow-up time were reported from baseline (01/01/2010) to last censor event (death, last hospitalization, or loss to follow-up). Cox proportional hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated to estimate the association of air pollutants and incident dementia, and modification of these associations by APOE-ε4. RESULTS: Our sample included 187,194 individuals (including N= 680 AD, N=377 VAD, N= 63 FTD) with a mean follow-up of 7.04 years. We observed consistent associations of PM(2.5) with greater risk of all-cause dementia (HR=1.17, 95% CI: 1.10, 1.24) and AD (HR=1.17, 95% CI: 1.06, 1.29). NO(2) was also associated with greater risk of any incident dementia (HR=1.18, 95% CI: 1.10, 1.25), AD (HR=1.15, 95% CI: 1.04, 1.28) and VAD (HR=1.18, 95% CI: 1.03, 1.35). APOE-ε4 did not modify the association between any air pollutants and dementia. DISCUSSION: PM(2.5) and NO(2) levels were associated with several types of dementia, and these associations were not modified by APOE-ε4. Findings from the UK Biobank support and extend to other epidemiological evidence for the potential association of air pollutants with detrimental brain health during aging. more...
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- 2022
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393. Abstract No. 254 Patterns of failed reimbursement by Medicare, Medicaid, and commercial insurance for interventional radiology procedures
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J. Erinjeri, N. Kastango, S. Shah, H. Yarmohammadi, E. Ziv, E. Alexander, V. Sotirchos, K. Zhao, F. Cornelis, F. Ridouani, Y. Bryce, E. Santos, C. Sofocleous, and S. Solomon
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Radiology, Nuclear Medicine and imaging ,Cardiology and Cardiovascular Medicine - Published
- 2022
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394. The association between head motion during functional magnetic resonance imaging and executive functioning in older adults
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Hanna K. Hausman, Cheshire Hardcastle, Jessica N. Kraft, Nicole D. Evangelista, Emanuel M. Boutzoukas, Andrew O'Shea, Alejandro Albizu, Kailey Langer, Emily J. Van Etten, Pradyumna K. Bharadwaj, Hyun Song, Samantha G. Smith, Eric Porges, Georg A. Hishaw, Samuel Wu, Steven DeKosky, Gene E. Alexander, Michael Marsiske, Ronald Cohen, and Adam J. Woods more...
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General Engineering ,General Earth and Planetary Sciences ,General Environmental Science - Published
- 2022
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395. Abstract No. 248 Post-embolization global transcription changes in high grade and low grade pancreatic neuroendocrine tumors
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M. Clark, C. Samson, E. Alexander, A. Gonzalez, N. Raj, D. Reidy-Lagunes, and E. Ziv
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Radiology, Nuclear Medicine and imaging ,Cardiology and Cardiovascular Medicine - Published
- 2022
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396. Abstract No. 547 Deep learning predicts aggressive subtypes of lung adenocarcinoma
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E. Ziv, K. Nand Keshavamurthy, A. Aly, E. Alexander, and S. Solomon
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Radiology, Nuclear Medicine and imaging ,Cardiology and Cardiovascular Medicine - Published
- 2022
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397. Abstract No. 33 Yttrium-90 radioembolization of primary lung cancer metastases to the liver
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E. Alexander, E. Petre, E. Ziv, and S. Solomon
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Radiology, Nuclear Medicine and imaging ,Cardiology and Cardiovascular Medicine - Published
- 2022
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398. 001 Melanocortin-4 Receptor Agonism Modulates Sexual Brain Processing in Women with Low Sexual Desire
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T. Hunjan, L. Thurston, E. Mills, M. Wall, N. Ertl, M. Phylactou, B. Muzi, B. Patel, E. Alexander, S. Suladze, M. Modi, P. Eng, P. Bassett, A. Abbara, D. Goldmeier, A. Comninos, and W. Dhillo
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Psychiatry and Mental health ,Endocrinology ,Reproductive Medicine ,Urology ,Endocrinology, Diabetes and Metabolism - Abstract
Introduction Hypoactive sexual desire disorder (HSDD) is characterized by a persistent lack of sexual desire and sexual fantasies, causing marked interpersonal distress1. It is the most common global female sexual health problem, affecting up to 1 in 10 women2,3. Despite its significant social and economic burden4,5, the exact pathophysiology of this condition remains unknown. Furthermore, existing treatment options are limited by their efficacy and side effects6. Melanocortin-4 receptor (MC4R) agonists are a promising therapeutic avenue, although their exact mechanism of action within the CNS remains unknown. Investigating the neural pathways through which MC4Ra's exert their effect will deepen our knowledge of normal and abnormal sexual behaviour, and hence provide information which could contribute to the development of novel treatment strategies. Objective To determine the mechanism by which MC4R agonists mediate their effects on sexual behaviour in women with HSDD. Methods We performed a randomized, double-blind, placebo-controlled crossover study in 31 premenopausal women with HSDD. A combination of psychometric, functional neuroimaging and hormonal analyses was used to investigate the effect of MC4R agonism versus placebo on sexual brain processing. A standard fMRI block design task with short (20 second) erotic videos was used to examine brain activation. Additionally, a ‘naturalistic’ fMRI paradigm was used with long (ten minute) erotic videos to examine functional brain connectivity. Results MC4R agonism increased self-reported sexual desire for up to 24-hours following administration, when compared with placebo (P=0.007). The mechanism of action behind this effect may be explained by the changes in brain activation and connectivity, in response to visual erotic stimuli. In the short video task, MC4R agonism led to increased activation of the supplementary motor area and cerebellum, alongside deactivation of the secondary somatosensory cortex, when compared with placebo (Z=2.3, P Conclusions This is the first study investigating the effect of MC4R agonism on sexual brain processing in women with HSDD. These results shed light on the neural substrates through which MC4R agonism increases sexual desire. The observed changes in brain activation may serve to ease self-consciousness, enhance sexual imagery and disinhibit the sexual response in women with HSDD. This is in line with the “top-down” neurofunctional model of HSDD whereby inspecting and monitoring one's sexual response interferes with desire7. This information is important for the ongoing development of therapies for HSDD, as well as MC4R agonist development more widely, such as in obesity medicine where there their use is being rapidly developed. Disclosure Work supported by industry: yes, by AMAG Pharmaceuticals Inc. more...
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- 2022
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399. Insight Problem Solving: A Critical Examination of the Possibility of Formal Theory.
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William H. Batchelder and Gregory E. Alexander
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- 2012
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400. A Constrained Regularization Approach to Robust Corner Detection.
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Kwanghoon Sohn, Winser E. Alexander, Jung H. Kim, and Wesley E. Snyder
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- 1994
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