tbuckley/cabot-search huggingface dataset:
Abstract 17319: Distinct Effects of Human Calmodulinopathy on the Function of Small Conductance Ca <sup>2+</sup> -Activated K <sup>+</sup> (SK) Channels
Authors: Hannah A Ledford, Seojin Park, Duncan Muir, Wen Smith, Ryan L Woltz, Choong-Ryoul Sihn, Padmini Sirish, Ebenezer N Yamoah, Vladimir Yarov-Yarovoy, Xiao-Dong Zhang, Nipavan Chiamvimonvat
Journal: Circulation (2018)

Background: Calmodulin (CaM) plays a critical role in intracellular signaling and regulation of Ca 2+ -dependent ion channels. Mutations in CALM1, CALM2, and CALM3 have recently been linked to cardiac arrhythmias, such as Long QT Syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and familial idiopathic ventricular fibrillation (IVF). Small-conductance Ca 2+ - activated K + channels (SK) are voltage-independent channels that are regulated solely from beat-to-beat changes in intracellular calcium. CaM regulates the function of multiple ion channels, including SK channels, although the effect of CaM mutations on these channels is not yet understood. We hypothesize that human CaM mutations linked to sudden cardiac death disrupt SK channel function by distinct mechanisms. Methods and Results: We tested the effects of LQTS (CaM D96V , CaM D130G ), CPVT (CaM N54I , CaM N98S ), and IVF (CaM F90L ) CaM mutants compared to CaM WT on SK channel function. Using whole-cell voltage-clamp recordings, we found that CaM D96V and CaM D130G mutants significantly inhibited apamin-sensitive currents. Similarly, action potential studies in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) also revealed significant knockdown of apamin-sensitive currents. Immunofluorescent confocal microscopy confirmed that this effect was not due to changes in SK channel trafficking. Rather, co-immunoprecipitation studies showed a significant decrease in the association of these CaM mutants with the SK channel. Rosetta molecular modeling was used to identify a conformational change in CaM F90L structure compared to that of CaM WT . Conclusions: We found that CaM D96V and CaM D130G mutants significantly reduced apamin-sensitive currents, through a dominant negative effect on SK channel function. Consistent with our hypothesis, CaM F90L resulted in the least inhibitory effects. The data suggests that specific mutations with phenylalanine to leucine (CaM F90L ) may disrupt the interaction between apo-CaM with CaMBD on the SK2 channel.
Mental Diseases. A Public Health Problem.
Journal: JAMA (1922)

This is not a textbook of mental diseases. In Part I, which occupies the first 250 pages, Dr. May has compiled from many sources a mass of extremely valuable data, statistical and historical, which demonstrate the wide contact of psychiatry with problems of modern social life, indicate the growth and present status of psychiatric science and of the public care of mental disease, and point out the need for a common ground to serve as a basis for statistical studies essential for determining causes, and thus laying the foundation for rational steps towards prevention. This portion of the book can be most heartily recommended to the consideration of physicians and others interested in this most important field of public health work. Part II is a condensed account of the history, characteristics and relations with other systems of nomenclature of the various types of mental disease which comprise the standard classification
Abstract 162: Major Differences in the Intended Operation and Default Energy Setting in Automated External Defibrillators in Pediatric Cardiac Arrest
Authors: Cecilie Budolfsen, Dung T Nguyen, Kasper G Lauridsen, Mathilde Stærk, Anders S Schmidt, Bo Løfgren
Journal: Circulation (2018)

Introduction: Automated external defibrillators (AEDs) should be easy to use to improve survival from cardiac arrest. In pediatric cardiac arrest, defibrillation is recommended to be delivered with less energy compared with adults. Consequently, many AED manufacturers provide the possibility of “converting” an AED from adult to pediatric use. Aim: To study how different AEDs are intended to be operated in case of pediatric cardiac arrest and to investigate the default pediatric defibrillation energy levels. Methods: This nationwide cross-sectional study included information on all commercially available AEDs sold to laypersons in Denmark. Technical specifications and information on AED use in pediatric cardiac arrest were extracted from user manuals, data sheets, and from contact with AED distributors in Denmark. Results: Overall, 28 different AEDs were available in Denmark. Data on pediatric use were available for all 28 (100%) devices. Separate pediatric electrodes were required for 19 (68%) AEDs which were sold as an accessory. Activation of “pediatric mode” was available in 10 (36%) AEDs leading to an automatic adjustment of shock energy level thereby making the use of adult electrodes in children possible. This feature consisted of a “pediatric button” in 8 (29%) devices and 1 (4%) device required insertion of an accessory “child key”. Data on default energy levels were available for 27 (96%) of devices. Median first shock energy level was 50J (Q1; 50J, Q3; 50J) with a range from 15-50J. Median third shock energy level was 50J (Q1; 50J, Q3; 83.5J) with a range from 50-140J. Conclusion: There are major differences in the intended operation and default energy settings in automated external defibrillators used in pediatric cardiac arrest. Standardizing how AEDs should be operated in pediatric cardiac arrest may reduce the risk of human errors and improve survival.
Abstract 17022: Pericardial Decompression Syndrome: Incidence in a Large Consecutive Series of Echocardiographic-Guided Pericardiocentesis Procedures
Authors: Chadi Ayoub, Annop Lekhakul, Chalailak Assawakawintip, Eric Fenstad, Sorin Pislaru, Lawrence Sinak, Kane C Garvan
Journal: Circulation (2018)

Introduction: Pericardial decompression syndrome (PDS) has been reported as a spectrum of cardiac decompensation following pericardiocentesis including ventricular failure, cardiogenic shock and pulmonary edema. PDS has been reported in patients undergoing drainage ≥450 mL of pericardial fluid. Hence judicious drainage of large volume effusions to avoid complication has been recommended Hypothesis: PDS complicating undergoing transthoracic echocardiography (TTE) guided pericardiocentesis is uncommen Methods: Consecutive patients undergoing TTE guided pericardiocentesis at our center from 1/2007 to 12/2016 were reviewed. Procedures were performed in a standard fashion under moderate conscious sedation with TTE determining the location of aspiration and determining adequate resolution of pericardial fluid post procedure. All fluid was removed at time of centesis regardless of the size of effusion, except for patients with severe pulmonary hypertension (n=9), who had staged removal of 100cc every 10 minutes. Post procedure, a pigtail catheter was left in the pericardial space for ongoing intermittent drainage and removed after the total net output was &lt;50 mL/24 hours. Patients were monitored in an intermediate level care unit. All patients underwent repeat TTE at the time of catheter removal. Large volume was defined as ≥450 mL of fluid. Patients in whom pericardiocentesis was technically unsuccessful were excluded Results: Over a 10-year period a total of 1067 patients (57% male, mean age 62±16 years) underwent 1164 technically successful pericardiocentesis procedures. Of these, 561 patients had large volume (≥450 mL) aspirated (mean 750±345 mL aspirated, range 450 - 4300 mL). Patients had a pericardial catheter in place for a mean 2.9±2 days. One patient with pre-existing severe biventricular dysfunction after aspiration of 400cc developed hypotension that improved with reversal of sedation, but proceeded to have PEA arrest and die. No other patient developed clinical events of acute left or right heart failure, ventricular dysfunction, unexplained hypotension, cardiogenic shock or other clinical events that could relate to PDS Conclusions: At most one episode of PDS was observed after technically successful percutaneous pericardiocentesis in 1164 cases (561 were large volume), although whether this case was PDS is unclear. PDS appears to be very rare, and staging pericardial decompression over time may be unnecessary, other than, perhaps, in patients with severe ventricular dysfunction or severe pulmonary hypertension
Glia fuel neurons with locally synthesized ketone bodies to sustain memory under starvation
Authors: Bryon Silva, Olivier L. Mantha, Johann Schor, Alberto Pascual, Pierre-Yves Plaçais, Alice Pavlowsky, Thomas Preat
Journal: Nature Metabolism (2022)

Abstract During starvation, mammalian brains can adapt their metabolism, switching from glucose to alternative peripheral fuel sources. In the Drosophila starved brain, memory formation is subject to adaptative plasticity, but whether this adaptive plasticity relies on metabolic adaptation remains unclear. Here we show that during starvation, neurons of the fly olfactory memory centre import and use ketone bodies (KBs) as an energy substrate to sustain aversive memory formation. We identify local providers within the brain, the cortex glia, that use their own lipid store to synthesize KBs before exporting them to neurons via monocarboxylate transporters. Finally, we show that the master energy sensor AMP-activated protein kinase regulates both lipid mobilization and KB export in cortex glia. Our data provide a general schema of the metabolic interactions within the brain to support memory when glucose is scarce.
Clinical Experience and Quality of Health Care
Journal: Annals of Internal Medicine (2005)

Letters5 July 2005Clinical Experience and Quality of Health CareThe EditorsThe EditorsSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-143-1-200507050-00021 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:We are glad that potential conflicts of interest related to Choudhry and colleagues' provocative article have been addressed (1). The intent of our required conflict-of-interest disclosure forms is to have authors disclose any financial interest or potential financial conflict between authors, authors' employees, or authors' institutions and subject matter or materials discussed in manuscripts.Reference1. Choudhry NK, Fletcher RH, Soumerai SB. Systematic review: the relationship between clinical experience and quality of health care. Ann Intern Med. 2005;142:260-73. [PMID: 15710959] LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoSystematic Review: The Relationship between Clinical Experience and Quality of Health Care Niteesh K. Choudhry , Robert H. Fletcher , and Stephen B. Soumerai Clinical Experience and Quality of Health Care Martin A. Samuels and Allan H. Ropper Clinical Experience and Quality of Health Care Roy M. Poses and Joseph A. Diaz Clinical Experience and Quality of Health Care Ronald S. Szabo Clinical Experience and Quality of Health Care Geoffrey R. Norman and Kevin W. Eva Clinical Experience and Quality of Health Care Elizabeth W. Loder Clinical Experience and Quality of Health Care Niteesh K. Choudhry , Robert H. Fletcher , and Stephen B. Soumerai Metrics 5 July 2005Volume 143, Issue 1Page: 87KeywordsConflicts of interestDisclosureHealth care quality ePublished: 5 July 2005 Issue Published: 5 July 2005 Copyright & PermissionsCopyright © 2005 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Parenteral nutrition.
Authors: S H Anderson, T J Charles
Journal: BMJ (1985)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following Parenteral nutrition. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Molecular characterization to delineate the clonal evolution of primary prostate cancer with synchronous lymph node metastasis.
Authors: Udit Singhal, Srinivas Nallandhighal, Jeffrey J. Tosoian, Trinh Pham, Chia-Jen Liu, Razeen Kareem, Komal Ramesh Kunder, Todd Matthew Morgan, Roberta Lucianò, Shahrokh F Shariat, Lucia Dambrosio, Claudio Doglioni, Scott A. Tomlins, Alberto Briganti, Ganesh S. Palapattu, Aaron M. Udager, Simpa Salami
Journal: Journal of Clinical Oncology (2022)

266 Background: Primary prostate cancers (PCa) harbor multiple spatially distinct tumors with significant inter-lesion molecular heterogeneity. This diversity can result in many subclones that compete for biological and clinical dominance. The defining features of primary PCa that give rise to lymph node (LN) metastases is unknown. We performed multiregional targeted DNA/RNA next generation sequencing (NGS) of primary PCa with synchronous LN metastases to identify primary PCa foci capable of metastasis. Methods: Patients who underwent radical prostatectomy and LN dissection with pathologic node positive disease were identified. Punch biopsies were performed from pre-identified regions of cancer on formalin fixed paraffin embedded (FFPE) prostate and LN specimens and DNA/RNA samples were co-isolated. Targeted NGS was performed to characterize the genomic profile of each tumor region and to evaluate gene fusion status of each sample. We compared somatic DNA mutations, copy number alterations (CNA), and gene fusion status between primary and LN disease. Phylogenetic analysis was performed using the Phylip’s dollo and parsimony, neighbor-joining method to determine the likely clonal source of LN metastasis. Results: We analyzed 88 primary tumor (1 ° ) and 23 LN-metastases samples from 14 patients. After quality control, 11 patients (69 and 18 primary and LN tumor samples, respectively) had sufficient quality data for analyses. Seven had evidence of extraprostatic extension (EPE), with phylogenetic analysis supporting this as the source of LN-metastasis in 4 cases. One patient had concordant TP53 and TPR non-synonymous mutations and broad CNAs between all 1 ° and two LN-metastasis foci, with two of the 1 ° regions showing high-level CNAs with both LN-metastasis foci. In two patients with pT2N1 disease, sub-clonal seeding and clonal evolution was observed with metastases arising from a GG5 area. Seven had cribriform pattern in both LN and 1 ° foci. One patient showed CDK12 mutation within the 1 ° and LN foci. FOXA1 was mutated in two patients within 1 ° and LN foci. Conclusions: Using targeted DNA/RNA NGS to assess primary PCa and synchronous LN metastases, we demonstrate that LN metastases is related to a combination of histopathologic and genomic factors. This highlights the need to develop robust prognostic biomarkers for identification of novel therapeutic targets for LN metastasis.
Real-world experience (RWE) of safety and efficacy of 6-weekly pembrolizumab 400mg (pem6w) plus axitinib (axi) in patients (pts) with advanced renal cell carcinoma (aRCC).
Authors: Sonam Ansel, Anirban Ray-Chaudhuri, Robert J. Jones, Mark Stares, Tze-en Ding, Stefan N. Symeonides, Christine Crearie, Sarah Slater, Maria Almudena Cascales Garcia, Aravindhan Sundaramurthy, Jahangeer Malik, Nicola Thomson, Marie Pringle, Gillian Barmack, Balaji Venugopal
Journal: Journal of Clinical Oncology (2022)

309 Background: The KEYNOTE 426 trial demonstrated pem 200mg plus axi twice daily (bd) is effective in aRCC. Pharmacokinetic modelling of pem 400 mg every six weeks demonstrated similar observed exposures to pem 200 mg every three weeks. In NHS Scotland, pem6w + axi was used during the COVID-19 pandemic to reduce hospital visits and for pts’ convenience. Here, we evaluate the RWE of pem6w + axi in aRCC. Methods: Electronic medical records of pts on pem6w + axi between 1 May 2020 &amp; 1 Jun 2021 in two large cancer centers in Scotland were analyzed retrospectively for pts’ characteristics, treatment related adverse events (TRAE) and efficacy. Results: Total of 93 pts were identified (Table). At data cut off of 8 Sep 2021, with a median follow-up of 7 months (mo) (inter-quartile range (IQR) 5 mo; range 0-15 mo), 73 pts (78%) were alive. Clinician assessed radiological response was evaluable in 87 pts. Overall response rate (ORR) including partial response + complete response was noted in 49 pts (56%) with median time to response of 80 days (d). Clinical benefit rate including pts with ORR and stable disease was seen in 72 pts (83%). At data cut off, 24 pts (26%) had progressed with a median time to progression of 117 d (IQR: 85d). Median overall and progression free survival were not reached and follow-up continues. 81 pts (87%) had any grade and 28 pts (30%) had grade 3/4 TRAE. Immune related AE (irAE) of any grade occurred in 60 pts (65%) and grade 3/4 in 19 pts (20%). Common grade 3/4 irAE were transaminitis (10%), colitis (8%), nephritis (2%) and skin (2%). 28 (30%) and 14 pts (15%) respectively required steroids and hospitalisation for irAE with median hospital stay 6 d (range: 2-43 d). 10 pts suffered a second irAE requiring steroids and 5 pts had a second hospital stay with median hospital stay of 6 d. Any grade AE and grade 3/4 AE related to axi occurred in 67 (72%) and 14 pts (15%) respectively. Axi dose was escalated from 5mg to 7mg bd in 12 pts (13%), reduced to 3mg bd in 35 pts (38%) and 2mg bd in 10 pts (11%). 21pts (23%) on Pem and 15pts (16%) on axi discontinued treatment due to TRAE. Conclusions: Our RWE demonstrates that pem6w + axi appears to have comparable safety profile to pem 200mg + axi reported in Keynote 426 study, with the added benefits of less frequent hospital visits. Further follow up continues for efficacy in this heterogeneous pts population. Pt characteristics, total=93 (%).[Table: see text]
Transcriptomic signatures can aid in post-operative risk stratification of clear cell renal cell carcinoma.
Authors: Brian M. Shuch, Elai Davicioni, Neal Patel, James Proudfoot, Yang Liu, Alexander K. Hakansson, Peter Muraki
Journal: Journal of Clinical Oncology (2022)

383 Background: The ability to risk stratify patient’s post-nephrectomy is critical to select candidates for surveillance and adjuvant therapy. Whether transcriptomic information adds value to current prognostic information is unclear. Methods: Data from confirmed clear cell renal cell carcinoma (ccRCC) used in the TCGA Pan-RCC analysis was downloaded from cBioportal and GDC bioportal. Clinicopathologic variables were used to calculate the integrated staging system, SSIGN (stage, size, grade, and necrosis). The 16 gene recurrence score (RS) signature was generated as described in Rini 2015 using the TCGA data with log TPM normalization. The RS was stratified into high and low risk groups by median. SSIGN was divided into low (0-1) intermediate (2-4) and high ( &gt; = 5) risk groups. RS and SSIGN prognostic significance were evaluated using disease recurrence as an end point, censoring by death. Results: SSIGN and recurrence scores (RS) were calculated for 369 (71.2%) of 518 available TCGA subjects with non-metastatic clear cell renal carcinoma. On multivariable analysis, the RS (continuous variable) was independently associated with disease-free status (HR 1.18 [95%CI (1.02-1.37)], p = 0.031) for each 10 point increase in RS) after adjusting for SSIGN. Categorizing SSIGN into low, intermediate and high-risk groups showed 3.9%, 18.5% and 39.8% 3-year recurrence rates. Stratifying SSIGN risk groups by RS scores we found an RS to further risk stratify the SSIGN intermediate risk group (HR 1.60 [95%CI 1.21-2.12], p &lt; 0.001]). The AUC for at 3 years for SSIGN in the intermediate risk group was 0.68, for RS was 0.74 and the combination was 0.78 (with boot-strapping for optimism adjustment). At 3 years, patients with SSIGN intermediate risk disease (n = 135) with low RS had 3-year recurrence rate of 7.1% compared to 31.0% for those with high RS scores. Conclusions: Transcriptomic recurrence scores can risk stratify intermediate SSIGN clinical risk patients. Patients with intermediate risk disease but a high RS score had poorer outcomes similar to clinically high risk patients. Transcriptomic signatures may add value to existing clinicopathologic variables in ccRCC and clinical implementation is warranted.
Contemporary outcomes of a systematic prostate cancer active surveillance program: Results from the Niagara Health System, Ontario, Canada.
Authors: Aruz Mesci, Nicole Niki Tsakiridis, Mohammad Gouran-Savadkoohi, Brent Faught, Ian Brown, Theodoros Tsakiridis
Journal: Journal of Clinical Oncology (2022)

241 Background: Surgery and radiotherapy are standard therapies for patients with early-stage prostate cancer (PrCa). However, studies show that patients with low-risk localized PrCa (Gleason 6; Grade Group (GG) 1 and prostate-specific antigen (PSA) &lt;10) could be safely monitored with active surveillance (AS), if intense patient follow up and re-biopsy schedules are utilized. Here, we reviewed clinical outcomes of AS of a program associated with the Niagara Health System (NHS) PrCa diagnostic program, which provides centralized diagnosis, systematic follow up, re-biopsy and multi-disciplinary consultation clinics for all patients in the Niagara region, Ontario, Canada. Methods: After receiving appropriate ethics approval, NHS databases were searched for patients that underwent more than one biopsy of the prostate in the period Jan. 2015 (program inception) to Dec. 2020. Cases were reviewed for clinical stage, biopsy results and treatment record data. Data were then codified for anonymity and analyzed. Criteria for inclusion into the analysis involved, i) a minimum of two PrCa biopsies before treatment and ii) detailed reporting of biopsy and clinical results (number of positive cores, % of core involvement, and PSA). Results: A total of 343 AS patient cases were identified in the initial search. Of those 52 cases did not meet inclusion criteria. The baseline GG score distribution in the 291 cases included in the analysis was, GG0: 27 (cases with negative biopsies but high PSA), GG1: 247 and GG2: 17 (patients refusing treatment). A total of 144 cases (49.5%) progressed at re-biopsy. Rates of progression to higher GG category in the three groups were 100%, has 46.5% and 50%, respectively. The average time to progression was 23.3+15.5 months. The rate of progression to treatment after entering AS was 39.17% (114/291). Average time from first biopsy to treatment was (28.4+14.5 months). Amongst those that received treatment the overall rate of progression to high-intermediate or high-risk PrCa, was 29.8%, with 20.8% of cases (30/144) progressing to GG&gt;3 (Gleason Score 7: 4+3 or higher) and 9.0% (13/144) progressing to PSA &gt; 20. Of the treated patients, 70 (61.4%) patients received radiotherapy, 42 (36.8%) combined radiotherapy and androgen deprivation therapy and (31.3%) underwent radical prostatectomy. Conclusions: This retrospective study provides contemporary real-world systematic AS outcomes from a Canadian program with unique features of systematic urological follow up and centralized diagnosis and multi-disciplinary patient assessment. We observe increased rates of disease progression and need for earlier utilization of treatment compared to those reported by other studies. Further analysis examines factors predicting increased risk for disease progression.