tbuckley/cabot-search huggingface dataset:
Rituximab and antimetabolite treatment of granulomatous and lymphocytic interstitial lung disease in common variable immunodeficiency
Authors: James W. Verbsky, Mary K. Hintermeyer, Pippa M. Simpson, Mingen Feng, Jody Barbeau, Nagarjun Rao, Carlyne D. Cool, Luis A. Sosa-Lozano, Dhiraj Baruah, Erin Hammelev, Alyssa Busalacchi, Amy Rymaszewski, Jeff Woodliff, Shaoying Chen, Mary Bausch-Jurken, John M. Routes
Journal: Journal of Allergy and Clinical Immunology (2020)
Abstract 15619: Stress Myocardial Elastography for Improved Ischemia and Infarction Detection
Authors: Jad El Harake, Vincent Sayseng, Julien Grondin, Rachel Weber, Kathleen R Flaherty, Sabahat Bokhari, Elisa Konofagou
Journal: Circulation (2019)

Introduction: Coronary artery disease is typically diagnosed via nuclear imaging or angiography, which are expensive and/or invasive, impeding early diagnosis. Myocardial Elastography (ME) is a qua...
SAT0537 ANALYSIS OF ADULTS PATIENTS WITH NOD2-ASSOCIATED AUTOINFLAMMATORY DISEASE
Authors: A. Ruiz Roman, S. García Morillo
Journal: Annals of the Rheumatic Diseases (2020)

Background: More than 100 mutations of the NOD2 gene have been described, some of which have been related to diseases such as Crohn’s disease, Blau syndrome, early-onset sarcoidosis and NOD2-associated autoinflammatory disease (NAID), the latter of polygenic character. The inflammatory disease associated with a NOD 2 gene is characterized by periodic fever, dermatitis, polyarthritis, gastrointestinal symptoms and symptoms similar to those of the dry syndrome and currently associated with the NOD2 variants. Objectives: Describe the clinical characteristics and genetic variants of a cohort of patients in adulthood with autoinflammatory disease associated with the NOD2 gene with follow-up in a third level hospital in southern Spain Methods: Retrospective descriptive study of patients in adulthood with diagnostic suspicion of autoinflammatory disease and with genetic mutation in NOD2 gene. Patients with follow-up from 2013 to the present and in which another diagnosis of autoimmune disease (inflammatory bowel disease, sarcoidosis, etc.) were excluded. Data were obtained by review of medical records. Results: 17 patients with alterations in the NOD2 gene were included. 14 cases (76.4%) were women. The mean age at diagnosis was 34.3 years (± 13.2). In the 17 patients, 19 mutations were found at the level of the NOD2 gene, the most frequent was with 9 cases (47.3%) the mutation in exon 4 (R702W), followed by mutation in exon 11 (1007finsC) with 5 cases (26.3%) and mutation in exon 4 (P268S) with 3 cases (15.4%). Other mutations obtained were mutation in exon 4 (R311w), mutation in exon 6 (M863V) and mutation in exon 11 (G908R) with a single case in each of them. In 6 cases (35.3%) there were first-degree relatives with a similar clinic, although not in all cases they were studied. Regarding the clinical manifestations, joint involvement (arthralgia and / or arthritis) with 12 cases (70.6%) was the most frequent followed by rash skin involvement with 10 cases (58.9%) and nonspecific abdominal pain with 9 cases (52.3%). Other less frequent manifestations were evening predominance fever and the elevation of acute phase reactants (CRP and ESR) with 8 cases (47.1%), oral thrush present in 5 patients (27.8%) and diarrhea with 4 cases (23.5%). Conclusion: The autoinflammatory disease associated with the NOD2 gene is an entity that can occur in adulthood and that can occur in a similar way to other auto-inflammatory diseases of a monogenic nature and in which the joint, cutaneous and abdominal involvement may predominate. We must maintain a high degree of suspicion and always include inflammatory bowel diseases in the differential diagnosis. Disclosure of Interests: None declared
Implementation of the Addendum Guidelines for Peanut Allergy Prevention by US allergists, a survey conducted by the NIAID, in collaboration with the AAAAI
Authors: Jacqueline L. Johnson, Ruchi S. Gupta, Lucy A. Bilaver, Jack W. Hu, Jennifer Martin, Jialing Jiang, Alexandria Bozen, Matthew M. Davis, Jamie Reese, Susan Cooper, Alkis Togias, Samuel J. Arbes
Journal: Journal of Allergy and Clinical Immunology (2020)
Analysis of breast cancer risk modifying candidate genes in BRCA1 and BRCA2 mutation carriers
Authors: David Hughes, Isabelle Coupier, Laure Barjhoux, Sophie Ginolhac, David Goldgar, Dominique Stoppa-Lyonnet, Olga M. Sinilnikova
Journal: Cancer Research (2004)

1317  Marked variability in individual cancer risk has been observed among BRCA1/2 mutation carriers, both between and within families. While some of this difference may result from the respective methodological approaches, it is likely that the observed variation is due to other genetic and/or environmental modifying factors that affect individual risk. Lifestyle events such as parity and oral contraceptive use alter breast / ovarian cancer risk. Mutation penetrance in the BRCA genes may also vary depending on the presence of specific alleles of a genetic modifier. Identification of such variants will provide good candidates to test as low penetrance predisposing genes in general. We are using association studies to assess the influence of variants (mainly SNPs) in biologically plausible candidate loci on the penetrance of BRCA1/2 mutations (i.e., differences in age of onset or tissue-specificity of disease) from the breast / ovarian cancer families characterised from our laboratories. We are focusing on typing SNPs in several DNA repair genes previously examined as modifier loci or as breast cancer susceptibility alleles in general, and from genes whose protein products interact with the BRCA proteins. The SNPs are typed in around 1000 BRCA1/2 mutation carriers from our families by TaqmanTM (ABI) using the ABI Prism 3700 Sequence Detection System. The first statistical analysis of our genotype data concern common polymorphisms in the BRCA2 genes (203G>A and N372H). These SNPs were previously tested as breast cancer susceptibility alleles in general by Healey and colleagues (2000). We tested these alleles as potential modifiers of breast cancer penetrance in our 656 BRCA1 mutation carriers but found no evidence of a modifying effect. Adjusting for age of birth and parity or stratifying by family did not significantly alter these results. In contrast to the result of Healey et al (2000) on newborn females and adult female controls, we found no departure from HW equilibrium in the distribution of N372H alleles for our female BRCA1 carriers. An understanding of the modifying effects on breast cancer risk in BRCA1/2 mutation carriers should help refine individual risk estimates. The discovery of BRCA1/2 modifiers may clarify our functional understanding of these genes. Many of these modifiers may themselves be moderate to low penetrance predisposing genes in general.
Autoantibody Detection for Diagnosis in Direct Immunofluorescence-Negative Mucous Membrane Pemphigoid
Authors: John Dart, Jane Setterfield, Richard W. Groves, John B. Mee, Gilles F.H. Diercks, Hendri H. Pas, Darwin Minassian, Debbie Booth, Elaina Reid, Nicole Carnt, Stefano Gugliemetti, Vijay Shanmuganathan, Martin Watson, Valerie Saw, Mark Wilkins, Vicky McCudden, Saj Ahmad, Catey Bunce, Virginia Calder, Stephen Challacombe, Mike Gleeson, Sarah Ali, Valerie Lund, Guri Sandhu
Journal: Ophthalmology (2020)
Feasibility and clinical impact of out-of-ICU noninvasive respiratory support in patients with COVID-19-related pneumonia
Authors: Cosimo Franco, Nicola Facciolongo, Roberto Tonelli, Roberto Dongilli, Andrea Vianello, Lara Pisani, Raffaele Scala, Mario Malerba, Annalisa Carlucci, Emanuele Alberto Negri, Greta Spoladore, Giovanna Arcaro, Paolo Amedeo Tillio, Cinzia Lastoria, Gioachino Schifino, Luca Tabbì, Luca Guidelli, Giovanni Guaraldi, V. Marco Ranieri, Enrico Clini, Stefano Nava
Journal: European Respiratory Journal (2020)

The severe acute respiratory syndrome-coronavirus 2 outbreak spread rapidly in Italy and the lack of intensive care unit (ICU) beds soon became evident, forcing the application of noninvasive respiratory support (NRS) outside the ICU, raising concerns over staff contamination. We aimed to analyse the safety of the hospital staff and the feasibility and outcomes of NRS applied to patients outside the ICU.In this observational study, data from 670 consecutive patients with confirmed coronavirus disease 2019 referred to pulmonology units in nine hospitals between March 1 and May 10, 2020 were analysed. Data collected included medication, mode and usage of NRS (i.e. high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), noninvasive ventilation (NIV)), length of stay in hospital, endotracheal intubation (ETI) and deaths.42 (11.1%) healthcare workers tested positive for infection, but only three of them required hospitalisation. Data are reported for all patients (69.3% male), whose mean±sd age was 68±13 years. The arterial oxygen tension/inspiratory oxygen fraction ratio at baseline was 152±79, and the majority (49.3%) of patients were treated with CPAP. The overall unadjusted 30-day mortality rate was 26.9%, with 16%, 30% and 30% for HFNC, CPAP and NIV, respectively, while the total ETI rate was 27%, with 29%, 25% and 28%, respectively; the relative probability of death was not related to the NRS used after adjustment for confounders. ETI and length of stay were not different among the groups. Mortality rate increased with age and comorbidity class progression.The application of NRS outside the ICU is feasible and associated with favourable outcomes. Nonetheless, it was associated with a risk of staff contamination.
Living systematic reviews at <i>The BMJ</i>
Authors: Helen Macdonald, Elizabeth Loder, Kamran Abbasi
Journal: BMJ (2020)

In many areas of medicine the rapid accumulation of evidence is unmanageable.The covid-19 pandemic has further accelerated the production of research and produced an urgent need for timely access to high quality, up-to-date syntheses of this evidence.Systematic reviews and meta-analyses are the best way to aggregate and appraise studies that examine a particular research question, but they take time to produce.Even when published rapidly, they may lag behind accumulated evidence by months or years.Living systematic reviews overcome this problem by allowing authors to update previously vetted and peer reviewed evidence syntheses in response to relevant new information. 1 25 Cochrane Community.Living systematic reviews.https://community.cochrane.
Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda
Authors: Aline Uwimana, Eric Legrand, Barbara H. Stokes, Jean-Louis Mangala Ndikumana, Marian Warsame, Noella Umulisa, Daniel Ngamije, Tharcisse Munyaneza, Jean-Baptiste Mazarati, Kaendi Munguti, Pascal Campagne, Alexis Criscuolo, Frédéric Ariey, Monique Murindahabi, Pascal Ringwald, David A. Fidock, Aimable Mbituyumuremyi, Didier Menard
Journal: Nature Medicine (2020)

Abstract Artemisinin resistance (delayed P. falciparum clearance following artemisinin-based combination therapy), is widespread across Southeast Asia but to date has not been reported in Africa 1–4 . Here we genotyped the P. falciparum K13 ( Pfkelch13 ) propeller domain, mutations in which can mediate artemisinin resistance 5,6 , in pretreatment samples collected from recent dihydroarteminisin-piperaquine and artemether-lumefantrine efficacy trials in Rwanda 7 . While cure rates were &gt;95% in both treatment arms, the Pfkelch13 R561H mutation was identified in 19 of 257 (7.4%) patients at Masaka. Phylogenetic analysis revealed the expansion of an indigenous R561H lineage. Gene editing confirmed that this mutation can drive artemisinin resistance in vitro. This study provides evidence for the de novo emergence of Pfkelch13 -mediated artemisinin resistance in Rwanda, potentially compromising the continued success of antimalarial chemotherapy in Africa.
Synthesis and biological evaluation of aminoalkyloxy derivatives of 1, 3, 5(10) estratriene-like steroids as potential anti-cancer agents
Authors: Devora A. Simmons, John S. Cooperwood
Journal: Cancer Research (2006)

1131  Breast cancer is second to cardiovascular disease in causing death in women between the ages of 35 and 55 years. It is also the second most common cause of death in women older than 55 years of age. Estrogens are important hormones in the female body. These steroids interact with multiple organ systems and make major impacts on the physiological events that occur throughout the female’s life. Among the estrogens, estradiol is the most potent because of its high binding affinity for the estrogen receptors. Tamoxifen, a therapeutically and clinically available SERM has been shown to be effective in the treatment of breast cancer. Nevertheless, tamoxifen have been associated with endometrial cancer due to its estrogenic activity within the uterus. Several chemically unrelated compounds have been found to demonstrate activities similar to that of SERMs through interaction with estrogen receptors. To synthesize compounds by combining a portion of the chemical features of tamoxifen, the aminoalkyloxy functional group, with the rigid structure of estradiol and compare the activity. Through modifying the 3-OH position on the Estradiol A-ring with different aminoalkyloxy derivatives; and opening the D-ring at the 17th position the synthesis of these compounds have been achieved. Receptor binding assays and gene proliferation studies will be done using MCF-7 cells, in vitro, to evaluate their effectiveness in treatment of breast cancer. The compounds have been successfully synthesized and their activity has been evaluated from the following studies: receptor binding studies, gene proliferation assays and gene expression. In synthesizing these specific types of compounds, it has been shown that have activity equal to or better than that of 4-hydroxytamoxifen, the active metabolite of Tamoxifen. Therefore, these compounds could be of use in the market for effectively treating patients affected by breast cancer.
Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis
Authors: Efstathios Kastritis, Xavier Leleu, Bertrand Arnulf, Elena Zamagni, María Teresa Cibeira, Fiona Kwok, Peter Mollee, Roman Hájek, Philippe Moreau, Arnaud Jaccard, Stefan O. Schönland, Robin Filshie, Emmanuelle Nicolas-Virelizier, Bradley Augustson, María-Victoria Mateos, Ashutosh Wechalekar, Eric Hachulla, Paolo Milani, Meletios A. Dimopoulos, Jean-Paul Fermand, Andrea Foli, Maria Gavriatopoulou, Catherine Klersy, Antonio Palumbo, Pieter Sonneveld, Hans Erik Johnsen, Giampaolo Merlini, Giovanni Palladini
Journal: Journal of Clinical Oncology (2020)

Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex).This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016.A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received ≥ 1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79% v 52%; P = .002). Higher rates of very good partial or complete response rates (64% v 39%; hazard ratio [HR], 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed.BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis.
Choosing the best approach for laterally spreading lesions at the anorectal junction
Authors: João Santos-Antunes, Margarida Marques, Fátima Carneiro, Guilherme Macedo
Journal: Gut (2020)

We read with great interest the paper by Shahidi N et al concerning the resection of rectal lesions, particularly those in the anorectal junction, by endoscopic mucosal resection (EMR).1 They found that EMR is effective, with good safety and recurrence outcomes.

Our Department has a large experience in both EMR and endoscopic submucosal dissection (ESD).2 Most of the colonic lesions are removed by EMR, with the exception of those with high-risk features, that are removed by ESD. By contrast, we remove all the rectal lesions by ESD. This approach is based on our large experience in ESD (nearly 550 procedures), the very good outcome and safety profiles, the endoscopic accessibility of these lesions compared with those located in the colon and the aggressive complementary treatment that could be required after a piecemeal resection of a malignant lesion. In our …
Four Aspects about Solid‐State Nanopores for Protein Sensing: Fabrication, Sensitivity, Selectivity, and Durability
Authors: Rui Hu, Xin Tong, Qing Zhao
Journal: Advanced Healthcare Materials (2020)

Abstract Solid‐state nanopores are a mimic of innate biological nanopores embedded on lipid membranes. They are fabricated on thin suspended layers of synthetic materials that provide superior thermal, mechanical, chemical stability, and geometry flexibility. As their counterpart biological nanopores reach the goal of DNA sequencing and become commercial, solid‐state nanopores thrive in aspects of protein sensing and have become an important research component for clinical diagnostic technologies. This review focuses on resistive pulse sensing modes, which are versatile for low‐cost, portable sensing devices and summarizes four main aspects toward commercially available resistive pulse‐based protein sensing techniques using solid‐state nanopores. In each aspect of fabrication, sensitivity, selectivity, and durability, brief fundamentals are introduced and the challenges and improvements are discussed. The rapid advance of a practical technique requires greater multidisciplinary cooperation. The review aims at clarifying existing obstacles in solid‐state nanopore based protein sensing, intriguing readers with existing solutions and finally encouraging multidisciplinary researchers to advance the development of this promising protein sensing methodology.
Dapagliflozin and Cardiac, Kidney, and Limb Outcomes in Patients With and Without Peripheral Artery Disease in DECLARE-TIMI 58
Authors: Marc P. Bonaca, Stephen D. Wiviott, Thomas A. Zelniker, Ofri Mosenzon, Deepak L. Bhatt, Lawrence A. Leiter, Darren K. McGuire, Erica L. Goodrich, Remo Holanda De Mendonca Furtado, John P.H. Wilding, Avivit Cahn, Ingrid A.M. Gause-Nilsson, Per Johanson, Martin Fredriksson, Peter A. Johansson, Anna Maria Langkilde, Itamar Raz, Marc S. Sabatine
Journal: Circulation (2020)

Patients with peripheral artery disease (PAD) are at heightened risk of cardiovascular complications. The sodium-glucose cotransporter 2 inhibitor dapagliflozin reduces the risk for hospitalization for heart failure (HHF) and kidney events in patients with type 2 diabetes mellitus. An increased risk of amputation has been observed with canagliflozin in 1 previous trial. We examined cardiovascular and kidney efficacy and the risk of limb-related events in patients with and without PAD in an exploratory analysis.A total of 17 160 patients with type 2 diabetes mellitus, including 1025 (6%) with PAD, were randomized. Key efficacy outcomes were MACE (cardiovascular [CV] death, myocardial infarction, stroke), CV death/HHF, and progression of kidney disease. Amputations, peripheral revascularization, and limb ischemic adverse events were site-reported and categorized by a blinded reviewer.Patients in the placebo arm with PAD versus those without tended to have higher adjusted risk of CV death, myocardial infarction, or stroke (adjusted hazard ratio [HR], 1.23 [95% CI, 0.97-1.56], P=0.094) and significantly higher adjusted risk of CV death/HHF (adjusted HR, 1.60 [95% CI, 1.21-2.12], P=0.0010) and progression of kidney disease (adjusted HR, 1.51 [95% CI, 1.13 - 2.03], P=0.0058), and limb adverse events (adjusted HR, 8.37, P<0.001). The relative risk reductions with dapagliflozin for CV death/HHF (HR, 0.86, PAD; HR, 0.82, no-PAD; P-interaction=0.79) and progression of kidney disease (HR, 0.78, PAD; HR, 0.76, no-PAD; P-interaction=0.84) were consistent regardless of PAD. There were 560 patients who had at least 1 limb ischemic event, 454 patients with at least 1 peripheral revascularization, and 236 patients with at least 1 amputation, with a total of 407 amputations reported. Overall, there were no significant differences in any limb outcome with dapagliflozin versus placebo including limb ischemic adverse events (HR, 1.07 [95% CI, 0.90-1.26]) and amputation (HR, 1.09 [95% CI, 0.84-1.40]), with no significant interactions by a history of PAD versus not (P-interactions=0.30 and 0.093, respectively).Patients with versus without PAD are at a higher risk of CV death of CV death, HHF, and kidney outcomes, and have a consistent benefits for CV death/HHF and progression of kidney disease with dapagliflozin. Patients with PAD had a higher risk of limb events, with no consistent pattern of incremental risk observed with dapagliflozin. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01730534.
Hypoxia-inducible factors and obstructive sleep apnea
Authors: Nanduri R. Prabhakar, Ying-Jie Peng, Jayasri Nanduri
Journal: Journal of Clinical Investigation (2020)

Intermittent hypoxia (IH) is a hallmark manifestation of obstructive sleep apnea (OSA), a widespread disorder of breathing. This Review focuses on the role of hypoxia-inducible factors (HIFs) in hypertension, type 2 diabetes (T2D), and cognitive decline in experimental models of IH patterned after O2 profiles seen in OSA. IH increases HIF-1α and decreases HIF-2α protein levels. Dysregulated HIFs increase reactive oxygen species (ROS) through HIF-1-dependent activation of pro-oxidant enzyme genes in addition to reduced transcription of antioxidant genes by HIF-2. ROS in turn activate chemoreflex and suppress baroreflex, thereby stimulating the sympathetic nervous system and causing hypertension. We also discuss how increased ROS generation by HIF-1 contributes to IH-induced insulin resistance and T2D as well as disrupted NMDA receptor signaling in the hippocampus, resulting in cognitive decline.