tbuckley/cabot-search huggingface dataset:
Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases
Authors: Manon Boivin, Jianwen Deng, Véronique Pfister, Erwan Grandgirard, Mustapha Oulad-Abdelghani, Bastien Morlet, Frank Ruffenach, Luc Negroni, Pascale Koebel, Hugues Jacob, Fabrice Riet, Anke A. Dijkstra, Kathryn McFadden, Wiley A. Clayton, Daojun Hong, Hiroaki Miyahara, Yasushi Iwasaki, Jun Sone, Zhaoxia Wang, Nicolas Charlet-Berguerand
Journal: Neuron (2021)

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by the presence of intranuclear inclusions of unknown origin. NIID is caused by an expansion of GGC repeats in the 5′ UTR of the NOTCH2NLC (N2C) gene. We found that these repeats are embedded in a small upstream open reading frame (uORF) (uN2C), resulting in their translation into a polyglycine-containing protein, uN2CpolyG. This protein accumulates in intranuclear inclusions in cell and mouse models and in tissue samples of individuals with NIID. Furthermore, expression of uN2CpolyG in mice leads to locomotor alterations, neuronal cell loss, and premature death of the animals. These results suggest that translation of expanded GGC repeats into a novel and pathogenic polyglycine-containing protein underlies the presence of intranuclear inclusions and neurodegeneration in NIID.
<i>Notes from the Field</i>: Update on Excess Deaths Associated with the COVID-19 Pandemic — United States, January 26, 2020–February 27, 2021
Authors: Lauren M. Rossen, Amy M. Branum, Farida B. Ahmad, Paul D. Sutton, Robert N. Anderson
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Estimates of excess deaths, defined as the number of persons who have died from all causes, above the expected number of deaths for a given place and time, can provide a comprehensive account of mortality likely related to the COVID-19 pandemic, including deaths that are both directly and indirectly associated with COVID-19.Since April 2020, CDC's National Center for Health Statistics (NCHS) has published weekly data on excess deaths associated with the COVID-19 pandemic (1).A previous report identified nearly 300,000 excess deaths during January 26-October 3, 2020, with two thirds directly associated with .Using more recent data from the National Vital Statistics System (NVSS), CDC estimated that 545,600-660,200 excess deaths occurred in the United States during January 26, 2020-February 27, 2021.Using weekly historical and provisional NVSS mortality data from 2013 through February 27, 2021, expected numbers of deaths were estimated using overdispersed Poisson regression models with spline terms to account for seasonal patterns (1,2).The average expected number, as well as the upper bound of the 95% prediction interval, were used as thresholds to determine the number of excess deaths.*Observed numbers of deaths were weighted to account for incomplete reporting by jurisdictions (50 states and the District of Columbia), primarily in the most recent 8 weeks, where the weights were estimated based on completeness of provisional data during the past year (1).Weekly NVSS data on excess deaths occurring from January 26 (the week ending February 1, 2020) through February 27, 2021, were then examined to quantify the number of excess deaths from all causes and the number of deaths from all causes other than COVID-19.† During January 26, 2020-February 27, 2021, an estimated 545,600-660,200 more persons than expected died in the United States from all causes (Figure).The estimated
Thrombosis is associated with worse survival in children with acute lymphoblastic leukemia: A report from <scp>CYP‐C</scp>
Authors: Marie‐Claude Pelland‐Marcotte, Ketan Kulkarni, Uma H. Athale, Jason D. Pole, Leonardo R. Brandão, Lillian Sung
Journal: American Journal of Hematology (2021)

Abstract There are conflicting data about whether the development of cancer‐associated thrombo‐embolism (TE) negatively impacts survival in children. The objective was to determine whether TE during treatment was associated with overall survival (OS) and event‐free survival (EFS) in children with acute lymphoblastic leukemia (ALL). We performed a population‐based retrospective cohort study using the Cancer in Young People‐Canada registry. Children &lt;15 years of age were diagnosed with de novo ALL (2000–2016). The primary exposure variable was radiologically‐confirmed thrombo‐embolism requiring medical intervention. Multivariable Cox regression models were used to determine the impact of thrombo‐embolism on survival, where TE was time‐dependent. We included 2006 children (median age: 4 years, 88.5% precursor B‐cell ALL). Thrombo‐embolism occurred in 113 patients (5.6%), at a median time of 107 days (interquartile range: 35–184 days) after ALL diagnosis. Among standard/low‐risk patients, 41/1165 (3.5%) developed TE while among high/very high‐risk patients, 72/841 (8.6%) developed TE. Patients with TE had a significantly worse OS (adjusted HR [aHR] of death: 2.61, 95% CI: 1.62–4.22, p &lt; 0.001) and EFS (aHR of an event [death, relapse, second malignancy]: 2.03, 95% CI: 1.35–3.05, p = 0.001), compared with patients without TE. No statistically significant difference was seen in standard/low risk ALL for OS and EFS, but TE was associated with a significantly lower OS and EFS in children with high/very high‐risk ALL (aHR of death: 2.90, 95% CI: 1.79–4.72, p &lt; 0.001; aHR of an event: 2.02, 95% CI: 1.30–3.12, p = 0.002). Thus, TE led to a statistically significant reduction in OS and EFS in children with high risk/very high‐risk leukemia.
Abstract 15762: Intensive Weight Management Improves Functional Capacity in Heart Failure With Preserved Ejection Fraction
Authors: Milad El Hajj, Elia El Hajj, Brandon Sykes, Renee Baxley, Melissa Lamicq, Tanja Ashe, Michael R Zile, Robert Malcolm, Patrick O'Neil, Sheldon Litwin
Journal: Circulation (2020)

Background: Obesity is associated with incident heart failure (HF), particularly HF with preserved ejection fraction (HFpEF). Weight loss is difficult to achieve in patients with limited physical capacity and the benefits remain uncertain in established HF. Methods: Patients with EF &gt; 50% and at least 1 objective criteria for HFpEF (BNP 200 pg/ml, elevated resting or exercise wedge pressure (15 or 25 mmHg) or pulmonary edema on CXR) and BMI 30 kg/m2 were enrolled in a 15-week weight management program that entailed weekly counseling, weight checks, and meal replacement (twice daily weeks 1-8, once daily weeks 9-12). Primary endpoints were change from baseline to 15-weeks for weight, Minnesota Living With HF (MLWHF) score and 6 minute walk (6MW). Paired t-test was used to test for differences from baseline to the 15 week clinical endpoint, and one-way ANOVA was used to evaluate if these differences persisted at 26 week follow up. Results: 65 patients signed consent, 41 completed the 15-week program and 37 had 26-week follow up. Mean age was 67±9 years, BMI 41±6 kg/m 2 , 65% were female, and 43% black. Mean weight decreased by 8.1±6.6 kg at the 15-week endpoint (p&lt;0.001) and persisted at 26-week follow up (p&lt;0.001). 74% of patients lost more than 5% of their baseline body weight at week 15. Blacks lost a mean of 6±6% body weight compared to 9±4% in Caucasians (p&lt;0.05). At 15 weeks, mean 6MW distance increased from 221±111 m to 286±99 m (p&lt;0.001) and then fell to 275±144 m at 26 weeks (p=0.043). MLWHF score improved from 60±24 to 38±27 (p&lt;0.001) and 38±26 (p&lt;0.001) at 15 and 26 weeks, respectively. BNP did not change (109 to 114 pg/ml). E/e’ decreased significantly from 13.9±6.8 to 11.9±5.6 at 26 weeks follow up (p&lt;0.01). BNP levels decreased by 39±103 pg/ml in blacks vs. an increase of 17±53 mg/dl in Caucasians (p&lt;0.05) at 15-week follow up. Conclusions: Clinically relevant weight loss is possible in patients with established HFpEF and when it occurs, this is associated with significant improvements in quality of life and exercise capacity. There may be racial differences in the biochemical response to weight management in this population.
PTU-034 Post colonoscopy significant polyps and colorectal cancers detection in 5-year interval in glan clwyd hospital
Authors: M Ishtiaq, M Zahid, D Ramanaden, A Baghomian
Journal: Gut (2017)

Introduction: Background  Colorectal cancer (CRC) is the 4th most common cancer in UK. Most CRC arise in adenoma and removal of adenoma reduces the risk of colorectal cancer. Colonoscopy is considered gold standard for detection of adenomatous polyps.Most societies recommend counselling patients undergoing colonoscopy about a miss rate of 2.1% to 5.9% for significant polyp/cancers.  Method  Aim: a). Audit post-colonoscopy CRC as per auditable outcome of UK key performance indicators for Colonoscopy. 1 b). This is a repeat audit to ensure standards are maintained as well as expanding on recommendations made to us by the BSG assessors at the 2012 BSG conference, to include polyps, which they felt were a more relevant benchmark regarding missed pathology in the time frame. 2  Data Collection:  Data of all patients who had colonoscopy in 2010 (January to end of December) and repeat colonoscopy in the next five years was collected from hospital database. Polyp ≥1 cm was defined as significant polyp.  Results  Total 1242 patients underwent colonoscopy in 2010 while 440 patients had repeat colonoscopy in the next five years. Cancer miss rate was 1.13% (5/440), while significant polyp miss rate was 5.45% (24/440). 4 out of 5 missed CRC were left sided while significant polyps were missed throughout the colon.  Conclusion  The data shows that our post colonoscopy CRC rate remains low i-e 1.13% (target of   Poor bowel prep contributed to missed pathology in 1 case and are no longer accepted as acceptable and are repeated.The unit will also be auditing colonoscopy withdrawl times.  Polyps were reported/treated in the same area where cancer was later diagnosed in 2 cases therefore diligent examination of previous pathology site is important.  References  . Rees CJ, et al. UK key performance indicators and quality assurance standards for colonoscopy. Gut2016.  . Somasundaram CS, et al. Post colonoscopy cancers in 5-year interval. Gut2012.  Disclosure of Interest  None Declared
Association of Health-Care System With Prostate Cancer-Specific Mortality in African American and Non-Hispanic White Men
Authors: Daniella Klebaner, P Travis Courtney, Isla P Garraway, John Einck, Abhishek Kumar, Maria Elena Martinez, Rana McKay, James D Murphy, Humberto Parada, Ajay Sandhu, Tyler Stewart, Kosj Yamoah, Brent S Rose
Journal: JNCI Journal of the National Cancer Institute (2021)

Disparities in prostate cancer-specific mortality (PCSM) between African American and non-Hispanic White (White) patients have been attributed to biological and systemic factors. We evaluated drivers of these disparities in the Surveillance, Epidemiology, and End Results (SEER) national registry and an equal-access system, the Veterans Health Administration (VHA).We identified African American and White patients diagnosed with prostate cancer between 2004 and 2015 in SEER (n = 311 691) and the VHA (n = 90 749). We analyzed the association between race and metastatic disease at presentation using multivariable logistic regression adjusting for sociodemographic factors and PCSM using sequential competing-risks regression adjusting for disease and sociodemographic factors.The median follow-up was 5.3 years in SEER and 4.7 years in the VHA. African American men were more likely than White men to present with metastatic disease in SEER (adjusted odds ratio = 1.23, 95% confidence interval [CI] = 1.17 to 1.30) but not in the VHA (adjusted odds ratio = 1.07, 95% CI = 0.98 to 1.17). African American vs White race was associated with an increased risk of PCSM in SEER (subdistribution hazard ratio [SHR] = 1.32, 95% CI = 1.10 to 1.60) but not in the VHA (SHR = 1.00, 95% CI = 0.93 to 1.08). Adjusting for disease extent, prostate-specific antigen, and Gleason score eliminated the association between race and PCSM in SEER (aSHR = 1.04, 95% CI = 0.93 to 1.16).Racial disparities in PCSM were present in a nationally representative registry but not in an equal-access health-care system, because of differences in advanced disease at presentation. Strategies to increase health-care access may bridge the racial disparity in outcomes. Longer follow-up is needed to fully assess mortality outcomes.
Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50%
Authors: Martin Reck, Delvys Rodríguez-Abreu, Andrew G. Robinson, Rina Hui, Tibor Csőszi, Andrea Fülöp, Maya Gottfried, Nir Peled, Ali Tafreshi, Sinead Cuffe, Mary O'Brien, Suman Rao, Katsuyuki Hotta, Ticiana A. Leal, Jonathan W. Riess, Erin Jensen, Bin Zhao, M. Catherine Pietanza, Julie R. Brahmer
Journal: Journal of Clinical Oncology (2021)

We report the first 5-year follow-up of any first-line phase III immunotherapy trial for non-small-cell lung cancer (NSCLC). KEYNOTE-024 (ClinicalTrials.gov identifier: NCT02142738) is an open-label, randomized controlled trial of pembrolizumab compared with platinum-based chemotherapy in patients with previously untreated NSCLC with a programmed death ligand-1 (PD-L1) tumor proportion score of at least 50% and no sensitizing
IFITM3 incorporation sensitizes influenza A virus to antibody-mediated neutralization
Authors: Caroline Lanz, Michael Schotsaert, Carsten Magnus, Umut Karakus, Annika Hunziker, Milagros Sempere Borau, Carles Martínez-Romero, Eva E. Spieler, Sira C. Günther, Eva Moritz, Benjamin G. Hale, Alexandra Trkola, Adolfo García-Sastre, Silke Stertz
Journal: The Journal of Experimental Medicine (2021)

The disease severity of influenza is highly variable in humans, and one genetic determinant behind these differences is the IFITM3 gene. As an effector of the interferon response, IFITM3 potently blocks cytosolic entry of influenza A virus (IAV). Here, we reveal a novel level of inhibition by IFITM3 in vivo: We show that incorporation of IFITM3 into IAV particles competes with incorporation of viral hemagglutinin (HA). Decreased virion HA levels did not reduce infectivity, suggesting that high HA density on IAV virions may be an antagonistic strategy used by the virus to prevent direct inhibition. However, we found that IFITM3-mediated reduction in HA content sensitizes IAV to antibody-mediated neutralization. Mathematical modeling predicted that this effect decreases and delays peak IAV titers, and we show that, indeed, IFITM3-mediated sensitization of IAV to antibody-mediated neutralization impacts infection outcome in an in vivo mouse model. Overall, our data describe a previously unappreciated interplay between the innate effector IFITM3 and the adaptive immune response.
Imitation learning for improved 3D PET/MR attenuation correction
Authors: Kerstin Kläser, Thomas Varsavsky, Pawel Markiewicz, Tom Vercauteren, Alexander Hammers, David Atkinson, Kris Thielemans, Brian Hutton, M.J. Cardoso, Sébastien Ourselin
Journal: Medical Image Analysis (2021)

The assessment of the quality of synthesised/pseudo Computed Tomography (pCT) images is commonly measured by an intensity-wise similarity between the ground truth CT and the pCT. However, when using the pCT as an attenuation map (μ-map) for PET reconstruction in Positron Emission Tomography Magnetic Resonance Imaging (PET/MRI) minimising the error between pCT and CT neglects the main objective of predicting a pCT that when used as μ-map reconstructs a pseudo PET (pPET) which is as similar as possible to the gold standard CT-derived PET reconstruction. This observation motivated us to propose a novel multi-hypothesis deep learning framework explicitly aimed at PET reconstruction application. A convolutional neural network (CNN) synthesises pCTs by minimising a combination of the pixel-wise error between pCT and CT and a novel metric-loss that itself is defined by a CNN and aims to minimise consequent PET residuals. Training is performed on a database of twenty 3D MR/CT/PET brain image pairs. Quantitative results on a fully independent dataset of twenty-three 3D MR/CT/PET image pairs show that the network is able to synthesise more accurate pCTs. The Mean Absolute Error on the pCT (110.98 HU ± 19.22 HU) compared to a baseline CNN (172.12 HU ± 19.61 HU) and a multi-atlas propagation approach (153.40 HU ± 18.68 HU), and subsequently lead to a significant improvement in the PET reconstruction error (4.74% ± 1.52% compared to baseline 13.72% ± 2.48% and multi-atlas propagation 6.68% ± 2.06%).
Abstract 16453: Risk Factors for Obstructive Sleep Apnea in Patients With Pulmonary Hypertension
Authors: Kayvon Ghoreshi, Noura Alturaif, Robert Roth, Yeilim Cho, Christopher Harding, Nishaki M Mehta, Eric Davis, Andrew Mihalek, Sula Mazimba, Younghoon Kwon
Journal: Circulation (2019)

Introduction: Patients with pulmonary hypertension (PH) have been shown to have a high prevalence of obstructive sleep apnea (OSA). However, prevalence of OSA is partly dependent on the threshold o...
Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis
Authors: Toni K. Choueiri, Todd M. Bauer, Kyriakos P. Papadopoulos, Elizabeth R. Plimack, Jaime R. Merchan, David F. McDermott, M. Dror Michaelson, Leonard J. Appleman, Sanjay Thamake, Rodolfo F. Perini, Naseem J. Zojwalla, Eric Jonasch
Journal: Nature Medicine (2021)
Abstract 15788: In-Hospital Outcomes of Pericardiocentesis versus Pericardial Surgical Interventions: A Population-Based Cohort
Authors: Mohamed M Gad, Islam Y Elgendy, Ahmed N Mahmoud, Ayman Elbadawi, Toug Tanavin, Ali E Denktas, Ernest Jimenez, Samir R Kapadia, Hani Jneid
Journal: Circulation (2019)

Background: Large studies comparing different pericardial interventions are scarce. In this study, we aimed to compare pericardiocentesis with pericardial surgical interventions in a large populati...
Targeting MCL-1 in cancer: current status and perspectives
Authors: Haolan Wang, Ming Guo, Hudie Wei, Yongheng Chen
Journal: Journal of Hematology & Oncology (2021)

Abstract Myeloid leukemia 1 (MCL-1) is an antiapoptotic protein of the BCL-2 family that prevents apoptosis by binding to the pro-apoptotic BCL-2 proteins. Overexpression of MCL-1 is frequently observed in many tumor types and is closely associated with tumorigenesis, poor prognosis and drug resistance. The central role of MCL-1 in regulating the mitochondrial apoptotic pathway makes it an attractive target for cancer therapy. Significant progress has been made with regard to MCL-1 inhibitors, some of which have entered clinical trials. Here, we discuss the mechanism by which MCL-1 regulates cancer cell apoptosis and review the progress related to MCL-1 small molecule inhibitors and their role in cancer therapy.
Abstract 16477: Sacubitril/valsartan as a Treatment for Resistant Hypertension in Patients With Heart Failure and Preserved Ejection Fraction
Authors: Pardeep S Jhund, Alice M 1, Marc A Pfeffer, Faiez ZANNAD, Martin P Lefkowitz, Victor SHI, Orly Vardeny, Scott Solomon, John J McMurray
Journal: Circulation (2020)

Objective: Heart failure with preserved ejection fraction (HFpEF) is typically a hypertensive phenotype and many HFpEF patients have difficult to control hypertension. We examined the effect of neprilysin inhibition on resistant hypertension in HFpEF patients in the PARAGON-HF trial. Patients entered a 1 to 4-week valsartan run-in (target dose 80mg bd), followed by sacubitril/valsartan run-in, before randomization to valsartan or sacubitril/valsartan (target doses 160mg bd or 200mg bd respectively). Design and methods: Patients were examined according to different definitions of resistant hypertension using systolic blood pressure (SBP) at the end of valsartan run-in. Group 1: SBP≥140mmHg (≥135mmHg if diabetes) despite treatment with a calcium channel blocker (CCB), diuretic and valsartan, Group 2: SBP≥130mmHg despite treatment with a CCB, diuretic and valsartan, or SBP&lt;130mmHg despite treatment with a CCB, diuretic, mineralocorticoid receptor antagonist (MRA) and valsartan, and Group 3: SBP≥140mmHg (≥135mmHg if diabetes) despite treatment with a CCB, diuretic, MRA and valsartan (≥4 classes of SBP-reducing therapy, including MRA). We examined reduction in SBP from end of valsartan run-in to weeks 4 and 16 after randomization and the proportion of patients with controlled SBP at week 16 on sacubitril/valsartan vs valsartan. Results: Of 4796 patients randomized, criteria for resistant hypertension were fulfilled in 726 (15%) using the Group 1 definition, 1146 (24%) using the Group 2 definition and 132 (3%) in the third group. The combination of neprilysin inhibitor, angiotensin receptor blocker, CCB and diuretic (+/-MRA) reduced SBP and significantly increased the proportion of patients with controlled SBP (Table). Conclusion: Sacubitril/valsartan may be useful in treating resistant hypertension in patients with HFpEF, even in those who continue to have an elevated SBP despite treatment with at least 4 antihypertensive drug classes, including an MRA.
Central Nervous System Involvement of Hemophagocytic Lymphohistiocytosis
Authors: Bastien Allard, Olivier Delcroix, Servane Le Lez-Soquet, Elise Sacaze, Solène Querellou
Journal: Clinical Nuclear Medicine (2021)

Hemophagocytic lymphohistiocytosis is rare life-threatening syndrome, hereditary or acquired, mainly affecting children. Hemophagocytic lymphohistiocytosis is an immune deficiency characterized by severe inflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages. The usual biological and clinical data may associate polyadenopathy, hepatosplenomegaly, fever, multivisceral damages, and cytopenias with potential multiorgan dysfunction and death. We report the case of a 4-year-old girl, hospitalized for recurrent cerebellar symptoms (ataxia) associated later with fever and pancytopenia. 18F-FDG PET/CT revealed a node pathological uptake, which was biopsied and confirmed a diagnosis of hemophagocytic lymphohistiocytosis.
Siyabonga: a humble hero making a difference with his hands… and his heart
Authors: Jon Patricios
Journal: British Journal of Sports Medicine (2021)

Siyabonga Kunene’s athletic build and confident stance belie his humble roots. Born in an impoverished area of South Africa, he soon learnt the benefits of an education. He is now a PhD-qualified sports physiotherapist making a significant contribution in both academic and clinical realms. Remaining true to his origins and the inspirational words of Nelson Mandela, Siyabonga has created a framework for managing patellofemoral pain in under-resourced athletes. He has established himself as a physiotherapy lecturer at his university and has been appointed to national teams in his professional capacity. However, his focus primary remains on treating those with a passion for sport who would not normally be able to access high-level athletic care.
Genetic polymorphism in <i>ATIC</i> is associated with effectiveness and toxicity of pemetrexed in non-small-cell lung cancer
Authors: Sabine Visser, Stijn Koolen, Nadine van Donk, Nico van Walree, Cor van der Leest, Robin Cornelissen, Ron van Schaik, Ron Mathijssen, Joachim Aerts, Bruno H Stricker
Journal: Thorax (2021)

Patients with advanced non-small-cell lung cancer who are treated with pemetrexed display a wide variation in clinical response and toxicity. In this prospective, multicentre cohort study, we investigated the association with treatment effectiveness and toxicity of 10 polymorphisms in nine candidate genes, covering the folate pathway ( MTHFR ), cell transport ( SLC19A1/ABCC2/ABCC4 ), intracellular metabolism ( FPGS/GGH ) and target enzymes ( TYMS/DHFR/ATIC ) of pemetrexed. Adjusted for sex, ECOG performance score and disease stage, the association between ATIC (rs12995526) and overall survival (HR 1.59, 95% CI 1.06 to 2.39) was significant. Regarding toxicity, this ATIC polymorphism was significantly associated with severe laboratory (p=0.014) and clinical (p=0.016) chemotherapy-related adverse events, severe neutropenia (p=0.007) and all-grade diarrhoea (p=0.034) in multivariable analyses.