tbuckley/cabot-search huggingface dataset:
Development of a prognostic model of respiratory insufficiency or death in amyotrophic lateral sclerosis
Authors: Jason Ackrivo, John Hansen-Flaschen, E. Paul Wileyto, Richard J. Schwab, Lauren Elman, Steven M. Kawut
Journal: European Respiratory Journal (2019)

A clinically useful model to prognose onset of respiratory insufficiency in amyotrophic lateral sclerosis (ALS) would inform disease interventions, communication and clinical trial design. We aimed to derive and validate a clinical prognostic model for respiratory insufficiency within 6 months of presentation to an outpatient ALS clinic. We used multivariable logistic regression and internal cross-validation to derive a clinical prognostic model using a single-centre cohort of 765 ALS patients who presented between 2006 and 2015. External validation was performed using the multicentre Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database with 7083 ALS patients. Predictors included baseline characteristics at first outpatient visit. The primary outcome was respiratory insufficiency within 6 months, defined by initiation of noninvasive ventilation, forced vital capacity (FVC) &lt;50% predicted, tracheostomy, or death. Of 765 patients in our centre, 300 (39%) had respiratory insufficiency or death within 6 months. Six baseline characteristics (diagnosis age, delay between symptom onset and diagnosis, FVC, symptom onset site, amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) total score and ALSFRS-R dyspnoea score) were used to prognose the risk of the primary outcome. The derivation cohort c-statistic was 0.86 (95% CI 0.84–0.89) and internal cross-validation produced a c-statistic of 0.86 (95% CI 0.85–0.87). External validation of the model using the PRO-ACT cohort produced a c-statistic of 0.74 (95% CI 0.72–0.75). We derived and externally validated a clinical prognostic rule for respiratory insufficiency in ALS. Future studies should investigate interventions on equivalent high-risk patients.
CDC42 Deletion Elicits Cerebral Vascular Malformations via Increased MEKK3-Dependent KLF4 Expression
Authors: Marco Castro, Bàrbara Laviña, Koji Ando, Alberto Álvarez-Aznar, Abdallah Abu Taha, Cord Brakebusch, Elisabetta Dejana, Christer Betsholtz, Konstantin Gaengel
Journal: Circulation Research (2019)

Aberrant formation of blood vessels precedes a broad spectrum of vascular complications; however, the cellular and molecular events governing vascular malformations are not yet fully understood.Here, we investigated the role of CDC42 (cell division cycle 42) during vascular morphogenesis and its relative importance for the development of cerebrovascular malformations.To avoid secondary systemic effects often associated with embryonic gene deletion, we generated an endothelial-specific and inducible knockout approach to study postnatal vascularization of the mouse brain. Postnatal endothelial-specific deletion of Cdc42 elicits cerebrovascular malformations reminiscent of cerebral cavernous malformations (CCMs). At the cellular level, loss of CDC42 function in brain endothelial cells (ECs) impairs their sprouting, branching morphogenesis, axial polarity, and normal dispersion within the brain tissue. Disruption of CDC42 does not alter EC proliferation, but malformations occur where EC proliferation is the most pronounced during brain development-the postnatal cerebellum-indicating that a high, naturally occurring EC proliferation provides a permissive state for the appearance of these malformations. Mechanistically, CDC42 depletion in ECs elicited increased MEKK3 (mitogen-activated protein kinase kinase kinase 3)-MEK5 (mitogen-activated protein kinase kinase 5)-ERK5 (extracellular signal-regulated kinase 5) signaling and consequent detrimental overexpression of KLF (Kruppel-like factor) 2 and KLF4, recapitulating the hallmark mechanism for CCM pathogenesis. Through genetic approaches, we demonstrate that the coinactivation of Klf4 reduces the severity of vascular malformations in Cdc42 mutant mice. Moreover, we show that CDC42 interacts with CCMs and that CCM3 promotes CDC42 activity in ECs.We show that endothelial-specific deletion of Cdc42 elicits CCM-like cerebrovascular malformations and that CDC42 is engaged in the CCM signaling network to restrain the MEKK3-MEK5-ERK5-KLF2/4 pathway.
Validity of a Novel Point-of-Care Troponin Assay for Single-Test Rule-Out of Acute Myocardial Infarction
Authors: Luca Koechlin, Valentina Troester, Christian Mueller
Journal: JAMA Cardiology (2019)

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Percutaneous endoscopic gastrostomy (PEG): a practical approach for long term management
Authors: Karima Farrag, Yogesh M Shastri, Ulrike Beilenhoff, Ayşegül Aksan, Jürgen Stein
Journal: BMJ (2019)

### What you need to know

Non-specialists may be involved in care of patients with gastrostomy tubes, in a nursing facility, hospital, or at a patient’s home. In this article, we describe common complications of percutaneous endoscopic gastrostomy to help non-specialists prevent and recognise severe or potentially life-threatening situations and to refer them on for specialist management. 

Percutaneous endoscopic gastrostomy (PEG) is performed to deliver enteral nutrition directly to the gastrointestinal tract, bypassing the oral cavity.1 Along with alternatives, such as nasal tubes or jejunal feeding, it plays an important role in maintaining nutrition in patients unable to eat orally. Such patients include those with dysphagia, intestinal failure, head or neck cancer, or as treatment in patients with gastrointestinal disease.123 PEG is first line treatment for patients with a functional gastrointestinal tract but inadequate oral nutrient intake who require long term nutritional support (>30 days).45

A gastrostomy tube is inserted percutaneously (through the skin) into the stomach via a small incision performed under local anaesthetic and positioned using an endoscope through the mouth.6 The entry point is known as the PEG …
Abstract 238: Loss of AKAP150 Promotes Pathological Remodeling and Heart Failure Propensity by Disrupting Calcium Homeostasis and Contractile Reserve
Authors: Lei Li, Jing Li, Benjamin Drum, Yi Chen, Haifeng Yin, Xiaoyun Guo, Stephen Luckey, Merle Gilbert, G. S McKnight, John Scott, Luis F Santana, Qinghang Liu
Journal: Circulation Research (2016)

Impaired Ca 2+ cycling and myocyte contractility are a hallmark of heart failure triggered by pathological stress such as hemodynamic overload. The A-Kinase anchoring protein AKAP150 has been shown to coordinate key aspects of adrenergic regulation of Ca 2+ cycling and excitation-contraction in cardiomyocytes. However, the role of the AKAP150 signaling complexes in the pathogenesis of heart failure is largely unknown. Here we investigate how AKAP150 signaling complexes impact Ca 2+ cycling, myocyte contractility, and heart failure susceptibility following pathological stress. We detected a significant reduction of AKAP150 expression in the failing mouse heart induced by pressure overload. Importantly, cardiac-specific AKAP150 knockout mice were predisposed to develop dilated cardiomyopathy with severe cardiac dysfunction and fibrosis after pressure overload. Loss of AKAP150 also promoted pathological remodeling and heart failure progression following myocardial infarction. However, ablation of AKAP150 did not appear to affect chronic activation of calcineurin-NFAT signaling in cardiomyocytes or pressure overload- or agonist- induced cardiac hypertrophy. Immunoprecipitation studies showed that AKAP150 was associated with SERCA2, phospholamban, and ryanodine receptor-2, providing a targeted control of sarcoplasmic reticulum Ca 2+ regulatory proteins. Mechanistically, loss of AKAP150 led to impaired Ca 2+ cycling and reduced myocyte contractility reserve following adrenergic stimulation or pressure overload. These findings define a critical role for AKAP150 in maintaining Ca 2+ homeostasis and myocardial ionotropy following pathological stress, suggesting the AKAP150 signaling pathway may serve as a novel therapeutic target for heart failure.
Annals Graphic Medicine - Progress Notes: Senior
Authors: Michael Natter
Journal: Annals of Internal Medicine (2019)

Web Exclusives19 November 2019Annals Graphic Medicine - Progress Notes: SeniorFREEMichael Natter, MDMichael Natter, MDNYU School of Medicine, New York, New York (M.N.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G19-0065 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: NYU School of Medicine, New York, New York (M.N.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G19-0002.Author/Illustrator Information: Michael Natter, MD, is a current internal medicine resident at NYU School of Medicine and a graduate of Sidney Kimmel Medical College of Thomas Jefferson University in Philadelphia. His artwork is inspired by his medical training, patient encounters, and the human condition. A type 1 diabetic, Dr. Natter views himself as a patient as well as a doctor and plans to pursue a fellowship in endocrinology to help others who also share his disease. You can find more of his illustrations, stories, and comics on Instagram (www.instagram.com/mike.natter) and Twitter (@mike_natter).About Progress Notes: Progress Notes explores the everyday emotional, clinical, humorous, and ethical challenges of the medical residency training process. As implied by the title of the series, these pieces act as a visual bildungsroman, graphically dissecting the subtext of what it means to be a young doctor in today's medical world. Progress Notes appears monthly in Annals Graphic Medicine. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 19 November 2019Volume 171, Issue 10Page: W62-W63KeywordsConflicts of interestDisclosureEmotionsEndocrinologyFellowshipsGraduate medical educationResidency ePublished: 19 November 2019 Issue Published: 19 November 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Pertactin-deficient Bordetella pertussis isolates: evidence of increased circulation in Europe, 1998 to 2015
Authors: Alex-Mikael Barkoff, Jussi Mertsola, Denis Pierard, Tine Dalby, Silje Vermedal Hoegh, Sophie Guillot, Paola Stefanelli, Marjolein van Gent, Guy Berbers, Didrik Vestrheim, Margrethe Greve-Isdahl, Lena Wehlin, Margaretha Ljungman, Norman K. Fry, Kevin Markey, Qiushui He
Journal: Eurosurveillance (2019)

IntroductionPertussis outbreaks have occurred in several industrialised countries using acellular pertussis vaccines (ACVs) since the 1990s. High prevalence of pertactin (PRN)-deficient Bordetella pertussis isolates has been found in these countries.AimsTo evaluate in Europe: (i) whether proportions of PRN-deficient strains increased in consecutive collections of B. pertussis clinical isolates; (ii) if the frequency of PRN-deficient strains in countries correlated with the time since ACV introduction; (iii) the presence of pertussis toxin (PT)-, filamentous haemagglutinin (FHA)- or fimbriae (Fim)-deficient isolates.MethodsB. pertussis clinical isolates were obtained from different European countries during four periods (EUpert I-IV studies): 1998 to 2001 (n = 102), 2004 to 2005 (n = 154), 2007 to 2009 (n = 140) and 2012 to 2015 (n = 265). The isolates' selection criteria remained unchanged in all periods. PRN, PT, FHA and Fim2 and Fim3 expression were assessed by ELISA.ResultsIn each period 1.0% (1/102), 1.9% (3/154), 6.4% (9/140) and 24.9% (66/265) of isolates were PRN-deficient. In EUpert IV, PRN-deficient isolates occurred in all countries sampled and in six countries their frequency was higher than in EUpert III (for Sweden and the United Kingdom, p < 0.0001 and p = 0.0155, respectively). Sweden and Italy which used ACVs since the mid 1990s had the highest frequencies (69%; 20/29 and 55%; 11/20, respectively) while Finland, where primary immunisations with ACV containing PRN dated from 2009 had the lowest (3.6%). Throughout the study, no PT- or FHA-deficient isolate and one Fim2/3-deficient was detected.ConclusionResults suggest that the longer the period since the introduction of ACVs containing PRN, the higher the frequency of circulating PRN-deficient isolates.
Abstract P202: Cardiovascular Risk Prediction Using Machine-learning Methods in the Middle-aged Korean Population
Authors: Hyeon Chang Kim, In-Jeong Jo, Ji Min Sung, Hyuk-Jae Chang
Journal: Circulation (2017)

The purpose of the current study was to evaluate the utility of using machine-learning (ML) algorithm and their ability to integrate data inputs to make predictions of future development of cardiovascular disease (CVD) in a nationwide sample of middle-aged Korean adults. Study population was randomly sampled from the Korea National Health Insurance (NHI) database. We identified 143,453 people (79,584 men and 63869 women) who were aged 40 years or older, free from CVD or cancer, and completed health screening tests between 2002 and 2003. CVD was defined as composite of cardiovascular death, myocardial infarction, stroke, and coronary artery disease requiring coronary artery intervention or bypass surgery until 2013, and were identified from the NHI claim database. We employed multiple supervised ML algorithms to build a CVD prediction models using clinical and laboratory data during the follow-up period. Prediction performance of the ML algorithm was compared to those of traditional scoring system or logistic prediction models. ML algorithm [area under curve (AUC) 0.895, 95% confidential interval (CI) 0.889-0.902] outperformed a traditional scoring system (AUC 0.721, 95% CI 0.713-0.730), logistic regression model with baseline characteristics (AUC 0.731, 95% CI 0.723-0.739) and logistic model with time-series analysis (AUC 0.804, 95% CI 0.797-0.811) in prediction of future CVD in men. In women, ML algorithm (AUC 0.908, 95% CI 0.901-0.915) also exhibited the most accurate predictive power, compared to the traditional scoring system (AUC 0.749, 95% CI 0.740-0.758), logistic regression model with baseline characteristics (AUC 0.775, 95% CI 0.767-0.784) and logistic model with time-series analysis (AUC 0.842, 95% CI 0.834-0.849). Our findings suggest that ML algorithm with time-series data can improve the performance of CVD risk prediction.
Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma
Authors: A. Keith Stewart, Amrita Y. Krishnan, Seema Singhal, Ralph V. Boccia, Manish R. Patel, Ruben Niesvizky, Asher A. Chanan-Khan, Sikander Ailawadhi, Jochen Brumm, Kirsten E. Mundt, Kyu Hong, Jacqueline McBride, Quyen Shon-Nguyen, Yuanyuan Xiao, Vanitha Ramakrishnan, Andrew G. Polson, Divya Samineni, Douglas Leipold, Eric W. Humke, James Scott McClellan, Jesus G. Berdeja
Journal: Blood Cancer Journal (2019)

Abstract FcRH5 is a cell surface marker enriched on malignant plasma cells when compared to other hematologic malignancies and normal tissues. DFRF4539A is an anti-FcRH5 antibody-drug conjugated to monomethyl auristatin E (MMAE), a potent anti-mitotic agent. This phase I study assessed safety, tolerability, maximum tolerated dose (MTD), anti-tumor activity, and pharmacokinetics of DFRF4539A in patients with relapsed/refractory multiple myeloma. DFRF4539A was administered at 0.3–2.4 mg/kg every 3 weeks or 0.8–1.1 mg/kg weekly as a single-agent by intravenous infusion to 39 patients. Exposure of total antibody and antibody-conjugate-MMAE analytes was linear across the doses tested. There were 37 (95%) adverse events (AEs), 8 (21%) serious AEs, and 15 (39%) AEs ≥ grade 3. Anemia ( n = 10, 26%) was the most common AE considered related to DFRF4539A. Two cases of grade 3 acute renal failure were attributed to DFRF4539A. There were no deaths; the MTD was not reached. DFRF4539A demonstrated limited activity in patients at the doses tested with 2 (5%) partial response, 1 (3%) minimal response, 18 (46%) stable disease, and 16 (41%) progressive disease. FcRH5 was confirmed to be expressed and occupied by antibody post-treatment and thus remains a valid myeloma target. Nevertheless, this MMAE-based antibody-drug-conjugate targeting FcRH5 was unsuccessful for myeloma.
Determining optimal follow up for patients with anal cancer following chemoradiation.
Authors: Marissa Frazer, George Q Yang, Seth Felder, Julian Sanchez, Sophie Dessureault, Iman Imanirad, Estrella M. Carballido, Richard D. Kim, Sarah E. Hoffe, Jessica Frakes
Journal: Journal of Clinical Oncology (2019)

689 Background: U.S. health care is increasingly defined by over expenditure and inefficiency. Optimizing patient follow-up is critical especially in cancers treated with high control rates. The objective of this study was to assess time to disease recurrence or toxicity in a cohort of patients with anal carcinoma in order to optimize patient care. Methods: 140 patients diagnosed with biopsy-proven, non-metastatic anal carcinoma, treated with chemoradiation utilizing IMRT, were identified from an institutional database at our high volume center. After IRB approval, a retrospective study was conducted that evaluated local recurrence (LR), distant metastasis (DM), overall survival (OS), and late ≥ grade three toxicity (LG3T) based on National Cancer Institute Common Terminology for Adverse Events version 4. Patients were followed post-treatment every three months for two years, every six months in years 3-5 then yearly thereafter with imaging per National Comprehensive Cancer Network recommendations. Results: Median age and follow up is 58 years and 27 months, respectively. Patients were staged based on AJCC 8 th edition and 24 patients were stage I (17%), 55 stage II (39%) and 61 stage III (44%). The median radiation dose was 54 Gy (range: 40-62.5), and 11% of patients required a radiation break. The two year LC, DMFS, and OS were 93%, 94% and 89% and 5-year LC, DMFS, OS were 92%, 87% and 85% respectively. In total, there were 29 disease or treatment related events: LR occurred in nine patients, DM in 11 patients, and LG3T in nine patients. Overall, 62% of events occurred within year one and 77 % within two years. Stratified by event type, at two years 79% of LR, 64% of DM and 89% LG3T were identified. At the remaining follow-up points after 2 years there was an event incidence rate of 1.4%. Conclusions: The majority of recurrences/toxicities in patients diagnosed with non-metastatic anal carcinoma after chemoradiation occur within the first year, with 77% of any event occurring before year two. The data from individual time points suggest a reduction in follow-up during years 3-5 may provide adequate surveillance. Considering revisions of the current follow-up recommendations could maximize health care resources while also improving patient quality of life.
Phase I/II Study of CHOEP Plus Lenalidomide As Initial Therapy for Patients with Stage II-IV Peripheral T-Cell Lymphoma: Phase II Results
Authors: Matthew A. Lunning, Steven M. Horwitz, Ranjana Advani, Julie M. Vose, Hun Ju Lee, Neha Mehta-Shah, Jasmine M. Zain, Bradley M. Haverkos, Mary Jo Lechowicz, Alison J. Moskowitz, Luu Q. Pham, Elizabeth R. Lyden, Peggy Heires, Stephen M. Ansell
Journal: Blood (2018)
A novel approach to the Basophil Activation Test (BAT) for characterizing peanut allergic patients in the clinical setting
Authors: Amanda Agyemang, Maria Suprun, Mayte Suarez-Farinas, Faouria Boina, Rihane Arif, Alexander V. Grishin, Jean-Marc Busnel, Hugh A. Sampson
Journal: Journal of Allergy and Clinical Immunology (2019)
Th17 cell pathway-related genetic variants in metastatic colorectal cancer: A meta-analysis using TRIBE, MAVERICC, and FIRE-3.
Authors: Ryuma Tokunaga, Shu Cao, Francesca Battaglin, Jae Ho Lo, Fotios Loupakis, Sebastian Stintzing, Madiha Naseem, Alberto Puccini, Martin D. Berger, Wu Zhang, Christoph Mancao, Bodour Salhia, Shannon M Mumenthaler, Daniel J Weisenberger, Gangning Liang, Chiara Cremolini, Volker Heinemann, Alfredo Falcone, Joshua Millstein, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2019)

594 Background: Th17 cells constitute a subset of T-helper cells, and play a role in immune response to extracellular pathogens in the human intestinal tract. Further, Th17 cells are associated with tumor angiogenesis and enhanced efficacy of 5-FU treatment. We thus investigated associations between the Th17 cell pathway-related SNPs and clinical outcomes in patients with metastatic colorectal cancer (mCRC) treated with conventional chemotherapy. Methods: We analyzed a total of 884 patients with mCRC enrolled in three randomized clinical trials (TRIBE, MAVERICC, and FIRE-3: where patients were treated with FOLFIRI, mFOLFOX6, or FOLFOXIRI combined with bevacizumab or cetuximab as the first-line chemotherapy). Multivariable logistic regression and Cox regression were performed to evaluate the association between candidate SNPs in the Th17 cell pathway and clinical outcomes [tumor response (TR), progression-free survival (PFS), and overall survival (OS)] in each treatment cohort. The meta-analysis approach using the METASOFT software were implemented to quantify the prognostic effect of each SNP using the inverse-variance-weighted effect size, and also to evaluate the heterogeneity across cohorts using the Q statistic. SNPs were coded as additive, dominant, or recessive in the analysis. The Pegasus analysis was also used to identify effects across multiple SNPs and treatment arms. Results: Pathway analysis showed that the Th17 cell pathway was significantly associated with TR ( P = 0.011). There were suggestive associations of IL17F rs763780 with TR (log OR = 0.64, SE = 0.31; P = 0.038), of IL23R rs10889677 with TR (log OR = 0.37, SE = 0.18; P = 0.039), of IRF4 rs872071 with TR (log OR = -0.26, SE = 0.13; P = 0.037), and of IL21 rs2221903 with PFS (log HR = 0.33, SE = 0.15; P = 0.026), although these results were not significant after FDR adjustment. In addition, IL23R rs10889677 had suggestive heterogeneity of effects for PFS across the six cohorts after Cochran’s Q statistic ( P = 0.013). Conclusions: Th17 cell pathway-related SNPs may be predictors for the first-line chemotherapy in mCRC. Upon validation, our findings would provide novel insight for selecting treatment strategies for mCRC.