tbuckley/cabot-search huggingface dataset:
Topical Calcineurin Inhibitors and Skin Cancer—Another Piece of the Puzzle
Authors: Aaron M. Drucker, Mina Tadrous
Journal: JAMA Dermatology (2020)

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A phase I study of lenalidomide plus chemotherapy with idarubicin and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high‐risk myelodysplastic syndrome
Authors: Caner Saygin, Karilyn Larkin, James S. Blachly, Shelley Orwick, Apollinaire Ngankeu, Charles T. Gregory, Mitch A. Phelps, Shylaja Mani, Alison Walker, Ramiro Garzon, Sumithira Vasu, Katherine J. Walsh, Bhavana Bhatnagar, Rebecca B. Klisovic, Michael R. Grever, Guido Marcucci, John C. Byrd, William Blum, Alice S. Mims
Journal: American Journal of Hematology (2020)

Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and hematopoietic cell transplantation (HCT) is the only curative treatment. New targeted therapies improved survival in select patients with specific mutations, however management of patients without these molecular alterations is an unmet need. We conducted a phase one study of lenalidomide in combination with cytarabine/idarubicin salvage chemotherapy in patients with R/R AML and high-risk myelodysplastic syndromes. A total of 33 patients were enrolled in the study (30 AML, 3 MDS), and treated at three dose levels with 3 + 3 design. Dose-limiting toxicity (DLT) was seen in eight patients, including four hematologic DLTs. The most commonly observed non-hematologic serious adverse events were febrile neutropenia, rash, sepsis and renal injury. Dose level -1, consisting of 25 mg/d lenalidomide D1-21, 1 g/m2 cytarabine D5-8, and 8 mg/m2 idarubicin D5-7 was determined to be the maximum tolerated dose. Note, 15/33 (45%) of patients were able to receive pre-planned 21 days of lenalidomide. Overall, 18 patients achieved complete remission (CR) (n = 14) or CR with incomplete count recovery (CRi) (n = 4) with total CR/CRi rate of 56%. The 1-year and 2-year overall survival (OS) were 24% and 10%, respectively. Among responders, 10/18 underwent allogeneic HCT and had a 1-year OS of 40%. There was no molecular pattern associated with response. These data demonstrate that the combination had clinical activity in R/R AML. This regimen should be further investigated for patients who relapsed after HCT, and as a bridge therapy to HCT. (ClinicalTrials.gov identifier: NCT01132586).
Outcomes of the Neonatal Trial of High-Frequency Oscillation at 16 to 19 Years
Authors: Christopher Harris, Alessandra Bisquera, Alan Lunt, Janet L. Peacock, Anne Greenough
Journal: New England Journal of Medicine (2020)

and only extended-spectrum cephalosporinresistant 7PET isolates from sporadic or smalloutbreak cases had been observed in Africa before 2018. 1 It is noteworthy that a large typhoid outbreak (>3000 suspected cases) that was caused by a ciprofloxacin-resistant strain -and that led to the use of extended-spectrum cephalosporins -occurred in Harare, Zimbabwe, between October 2017 and February 2018. 4,5 This situation might have contributed to the extendedspectrum cephalosporin-resistant patterns that were seen among the cholera outbreak strain several months later.The 2018 Zimbabwean isolates were susceptible to azithromycin, which was consequently used to treat severe cases of cholera during the outbreak.However, azithromycin-resistance genes, such as mph(A) or mph(E), were sporadically identified in CTX-M-15-producing 7PET isolates obtained in Zimbabwe (Table S4), the Democratic Republic of Congo, 1 and Kenya 2 from 2010 through 2015.The acquisition by this T13 7PET strain of an IncA/C2 plasmid with both the mph and tet genes would jeopardize the oral antibiotic treatment of cholera.We emphasize the need for cross-border collaboration and continued laboratory surveillance to stem this highly drug-resistant T13 cholera strain in Africa.
ERS Scientific Working Group 09.04, “Psychologists and behavioural scientists”: the next step towards multidisciplinary respiratory care
Authors: Andreas von Leupoldt, Lisa Jane Brighton, Jeannette Peters, Eleonora Volpato, Marieke Verkleij, Ann Hutchinson, Monique Heijmans, Ingeborg Farver-Vestergaard, Daniel Langer, Martijn A. Spruit
Journal: European Respiratory Journal (2020)

<b>The new ERS Scientific Working Group 09.04 "Psychologists and Behavioural Scientists" will support psychological and behavioural aspects of respiratory care, in order to improve multidisciplinary clinical practice, education, and research</b>https://bit.ly/2OPJF0U
Prioritising primary care patients with unexpected weight loss for cancer investigation: diagnostic accuracy study
Authors: Brian D Nicholson, Paul Aveyard, Sarah J Price, FD Richard Hobbs, Constantinos Koshiaris, Willie Hamilton
Journal: BMJ (2020)

To quantify the predictive value of unexpected weight loss (WL) for cancer according to patient's age, sex, smoking status, and concurrent clinical features (symptoms, signs, and abnormal blood test results).
A little too technical: The threat of intellectualising technical reasoning
Authors: Ian Robertson
Journal: Behavioral and Brain Sciences (2020)

Osiurak and Reynaud (O&R) claim that research into the origin of cumulative technological culture has been too focused on social cognition and has consequently neglected the importance of uniquely human reasoning capacities. This commentary raises two interrelated theoretical concerns about O&R's notion of technical-reasoning capacities, and suggests how these concerns might be met.
Abstract B09: Epigenetic changes mediated by H3.3 G34R mutation in a CRISPR-edited pediatric glioblastoma cell line
Authors: Shriya Deshmukh, Carol C.L. Chen, Amira Ouanouki, Nada Jabado
Journal: Cancer Research (2020)

Abstract Background: Pediatric glioblastomas (pGBM) are aggressive and lethal brain tumors with few effective treatment options. Since the discovery of recurrent histone H3 mutations in pGBMs, multiple groups have sought to uncover the mechanism by which these mutations drive tumorigenesis. One striking aspect of histone H3 mutations is their tumor location and age-specificity: the K27M mutation occurs in midline brain structures in infants and young children, whereas the G34R/V mutations occur in the cerebral hemisphere of adolescents. Efforts to elucidate the mechanism underlying K27M tumorigenesis have centered on K27M-mediated inhibition of the PRC2 complex and the resulting drastic loss of the repressive H3K27me3 mark in these tumors. Studies have shown that G34 mutations affect methylation of the adjacent K36 residue, resulting in a local decrease of the active H3K36me3 mark on the mutant histone. It remains uncertain whether the G34R/V mutations promote global changes in the epigenome that drive tumorigenesis. Methods: To investigate the epigenetic consequences of the G34R mutation, we generated an isogenic in vitro model using CRISPR/Cas9 to correct the G34R mutation in a pGBM-derived cell line. We then comprehensively characterized and compared the epigenome and transcriptome of CRISPR-unedited clones (carrying the G34R mutation) and CRISPR-edited (wild-type) clones. Using ChIP-seq, we profiled H3K36me3 and H3K27me3 marks to study G34R-mediated regulation of these antagonistic marks. Results: ChIP-seq profiling revealed that CRISPR editing of the G34R mutation had minimal effects on total levels or genomic distribution and profile of H3K36me3 and H3K27me3 marks. In contrast, we previously showed that CRISPR editing of the K27M mutation in pGBM cell lines rescued total H3K27me3 levels and genomic distribution to that of histone wild-type pGBMs. In agreement with their similar epigenetic profiles, there were very few transcriptomic differences between G34R and wildtype cells. Conclusions: Our results suggest that the epigenome in G34R-mutant pGBM cells may be less dynamic or amenable to epigenetic perturbation from removal of the initial driver oncomutation than K27M-mutant tumors. These findings underscore that different strategies may be required to target and treat G34R and K27M-mutant pGBM tumors. Citation Format: Shriya Deshmukh, Carol C.L. Chen, Amira Ouanouki, Nada Jabado. Epigenetic changes mediated by H3.3 G34R mutation in a CRISPR-edited pediatric glioblastoma cell line [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B09.
Erratum to ‘When not to start antibiotics:avoiding antibiotic overuse in the intensive care unit’ [Clin Microbiol Infect 26 (1) (January 2020) 35–40] (Clinical Microbiology and Infection (2020) 26(1) (35–40), (S1198743X19303969), (10.1016/j.cmi.2019.07.007))
Authors: K. J. Denny, J. De Waele, K. B. Laupland, P. N.A. Harris, J. Lipman
Journal: Clinical Microbiology and Infection (2020)
Clinical outcomes of hospitalised patients with COVID-19 and chronic inflammatory and autoimmune rheumatic diseases: a multicentric matched cohort study
Authors: Jose L Pablos, María Galindo, Loreto Carmona, Ana Lledó, Miriam Retuerto, Ricardo Blanco, Miguel A Gonzalez-Gay, David Martinez-Lopez, Isabel Castrejón, José M Alvaro-Gracia, David Fernández Fernández, Antonio Mera-Varela, Sara Manrique-Arija, Natalia Mena Vázquez, Antonio Fernandez-Nebro
Journal: Annals of the Rheumatic Diseases (2020)

The impact of inflammatory rheumatic diseases on COVID-19 severity is poorly known. Here, we compare the outcomes of a cohort of patients with rheumatic diseases with a matched control cohort to identify potential risk factors for severe illness.In this comparative cohort study, we identified hospital PCR+COVID-19 rheumatic patients with chronic inflammatory arthritis (IA) or connective tissue diseases (CTDs). Non-rheumatic controls were randomly sampled 1:1 and matched by age, sex and PCR date. The main outcome was severe COVID-19, defined as death, invasive ventilation, intensive care unit admission or serious complications. We assessed the association between the outcome and the potential prognostic variables, adjusted by COVID-19 treatment, using logistic regression.The cohorts were composed of 456 rheumatic and non-rheumatic patients, in equal numbers. Mean age was 63 (IQR 53-78) years and male sex 41% in both cohorts. Rheumatic diseases were IA (60%) and CTD (40%). Most patients (74%) had been hospitalised, and the risk of severe COVID-19 was 31.6% in the rheumatic and 28.1% in the non-rheumatic cohort. Ageing, male sex and previous comorbidity (obesity, diabetes, hypertension, cardiovascular or lung disease) increased the risk in the rheumatic cohort by bivariate analysis. In logistic regression analysis, independent factors associated with severe COVID-19 were increased age (OR 4.83; 95% CI 2.78 to 8.36), male sex (1.93; CI 1.21 to 3.07) and having a CTD (OR 1.82; CI 1.00 to 3.30).In hospitalised patients with chronic inflammatory rheumatic diseases, having a CTD but not IA nor previous immunosuppressive therapies was associated with severe COVID-19.
Metabolomic Signatures of Long-term Coffee Consumption and Risk of Type 2 Diabetes in Women
Authors: Dong Hang, Oana A. Zeleznik, Xiaosheng He, Marta Guasch-Ferre, Xia Jiang, Jun Li, Liming Liang, A. Heather Eliassen, Clary B. Clish, Andrew T. Chan, Zhibin Hu, Hongbing Shen, Kathryn M. Wilson, Lorelei A. Mucci, Qi Sun, Frank B. Hu, Walter C. Willett, Edward L. Giovannucci, Mingyang Song
Journal: Diabetes Care (2020)

Coffee may protect against multiple chronic diseases, particularly type 2 diabetes, but the mechanisms remain unclear.Leveraging dietary and metabolomic data in two large cohorts of women (the Nurses' Health Study [NHS] and NHSII), we identified and validated plasma metabolites associated with coffee intake in 1,595 women. We then evaluated the prospective association of coffee-related metabolites with diabetes risk and the added predictivity of these metabolites for diabetes in two nested case-control studies (n = 457 case and 1,371 control subjects).Of 461 metabolites, 34 were identified and validated to be associated with total coffee intake, including 13 positive associations (primarily trigonelline, polyphenol metabolites, and caffeine metabolites) and 21 inverse associations (primarily triacylglycerols [TAGs] and diacylglycerols [DAGs]). These associations were generally consistent for caffeinated and decaffeinated coffee, except for caffeine and its metabolites that were only associated with caffeinated coffee intake. The three cholesteryl esters positively associated with coffee intake showed inverse associations with diabetes risk, whereas the 12 metabolites negatively associated with coffee (5 DAGs and 7 TAGs) showed positive associations with diabetes. Adding the 15 diabetes-associated metabolites to a classical risk factor-based prediction model increased the C-statistic from 0.79 (95% CI 0.76, 0.83) to 0.83 (95% CI 0.80, 0.86) (P < 0.001). Similar improvement was observed in the validation set.Coffee consumption is associated with widespread metabolic changes, among which lipid metabolites may be critical for the antidiabetes benefit of coffee. Coffee-related metabolites might help improve prediction of diabetes, but further validation studies are needed.
Eight years of the East African Community Medicines Regulatory Harmonization initiative: Implementation, progress, and lessons learned
Authors: Jane H. Mashingia, Vincent Ahonkhai, Noel Aineplan, Aggrey Ambali, Apollo Angole, Mawien Arik, Samvel Azatyan, Peter Baak, Emmanuel Bamenyekanye, Aimable Bizoza, Chimwemwe Chamdimba, Petra Doerr, Adam Fimbo, Alex Gisagara, Hidaya Hamad, Rachelle Harris, Dan Hartman, Joseph Kabatende, Charles Karangwa, Agnes Sitta Kijo, Murray Lumpkin, Shani Maboko, David Matle, Apollo Muhairwe, John Patrick Mwesigye, Bonaventure Nyabenda, Alexander Schulze, Andreas Seiter, Gordon Sematiko, Margareth Sigonda, Hiiti Sillo, Burhani Simai, Fred Siyoi, Stanley Sonoiya, Paul Tanui, Mike Ward, Felistas Yano, David Mukanga
Journal: PLoS Medicine (2020)

Access to essential medicines is a key pillar of any health system seeking to deliver universal health coverage.Science-based, independent regulation of medical products is a critical part of ensuring that only quality essential medicines reach the patients who need them.• In this article, we explore the progress the East African Community's Medicines Regulatory Harmonization (EAC MRH) initiative, launched in 2012, has made toward its goal of improving access to essential medicines.The initiative's initial focus was on registering generic medicines, with a plan to expand to other classes of medical products, as well as to other regulatory functions.• From 2012 to 2017, the timeline for national assessments of medicinal product applications decreased from roughly 24 months to 8-14 months, if products were assessed through the new joint assessment process (involving 2 or more national medicines regulatory authorities).• Since 2015, the initiative has conducted 10 joint product assessment sessions in which 83 medicinal product applications were considered, resulting in the recommendation of 36 products for registration by EAC Partner States.
Caring for Someone With COVID-19
Authors: Lindsey Y. Mortenson, Preeti N. Malani, Robert D. Ernst
Journal: JAMA (2020)

Caring for Someone With COVID-19Care of individuals with COVID-19 is 2-fold: support the patient and prevent yourself and others from contracting SARS-CoV-2.What Is Supportive Care?At this time, there is no cure for coronavirus disease 2019 , although some treatments are being used in severe illness.For patients recovering at home, treatment is mainly supportive.For people with mild symptoms, this means staying well rested, drinking plenty of fluids, and monitoring symptoms.The most common symptoms of COVID-19 are fever or chills, cough, difficulty breathing or shortness of breath, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, runny nose or congestion, nausea or vomiting, and diarrhea.Some people have more severe symptoms that require hospitalization. What Is Preventive Care?You can be infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) while taking care of someone with COVID-19.Although there is not yet a vaccine to prevent COVID-19, infection is preventable.The most important steps to prevent spread are wearing a mask, maintaining social distance whenever possible, washing hands often, and cleaning and sanitizing the home.
An Unbiased Molecular Approach Using 3′-UTRs Resolves the Avian Family-Level Tree of Life
Authors: Heiner Kuhl, Carolina Frankl-Vilches, Antje Bakker, Gerald Mayr, Gerhard Nikolaus, Stefan T Boerno, Sven Klages, Bernd Timmermann, Manfred Gahr
Journal: Molecular Biology and Evolution (2020)

Presumably, due to a rapid early diversification, major parts of the higher-level phylogeny of birds are still resolved controversially in different analyses or are considered unresolvable. To address this problem, we produced an avian tree of life, which includes molecular sequences of one or several species of ∼90% of the currently recognized family-level taxa (429 species, 379 genera) including all 106 family-level taxa of the nonpasserines and 115 of the passerines (Passeriformes). The unconstrained analyses of noncoding 3-prime untranslated region (3'-UTR) sequences and those of coding sequences yielded different trees. In contrast to the coding sequences, the 3'-UTR sequences resulted in a well-resolved and stable tree topology. The 3'-UTR contained, unexpectedly, transcription factor binding motifs that were specific for different higher-level taxa. In this tree, grebes and flamingos are the sister clade of all other Neoaves, which are subdivided into five major clades. All nonpasserine taxa were placed with robust statistical support including the long-time enigmatic hoatzin (Opisthocomiformes), which was found being the sister taxon of the Caprimulgiformes. The comparatively late radiation of family-level clades of the songbirds (oscine Passeriformes) contrasts with the attenuated diversification of nonpasseriform taxa since the early Miocene. This correlates with the evolution of vocal production learning, an important speciation factor, which is ancestral for songbirds and evolved convergent only in hummingbirds and parrots. As 3'-UTR-based phylotranscriptomics resolved the avian family-level tree of life, we suggest that this procedure will also resolve the all-species avian tree of life.
Do We Spend Too Much on Health Care?
Authors: Katherine Baicker, Amitabh Chandra
Journal: New England Journal of Medicine (2020)

Interview with Dr. Katherine Baicker on assessments of health care spending in the United States and moving toward higher-value use of resources. (10:07)Download Health system reforms — such as changes in insurance design, patient cost sharing, payment reform, or price regulation — should be judged by whether they move us toward higher-value use of resources, rather than by whether they reduce spending.
Tapering Canakinumab Monotherapy in Patients With Systemic Juvenile Idiopathic Arthritis in Clinical Remission: Results From a Phase IIIb/IV Open‐Label, Randomized Study
Authors: Pierre Quartier, Ekaterina Alexeeva, Tamàs Constantin, Vyacheslav Chasnyk, Nico Wulffraat, Karin Palmblad, Carine Wouters, Hermine I. Brunner, Katherine Marzan, Rayfel Schneider, Gerd Horneff, Alberto Martini, Jordi Anton, Xiaoling Wei, Alan Slade, Nicolino Ruperto, Ken Abrams
Journal: Arthritis & Rheumatology (2020)

To evaluate the efficacy and safety of 2 canakinumab monotherapy tapering regimens in order to maintain complete clinical remission in children with systemic juvenile idiopathic arthritis (JIA).The study was designed as a 2-part phase IIIb/IV open-label, randomized trial. In the first part, patients received 4 mg/kg of canakinumab subcutaneously every 4 weeks and discontinued glucocorticoids and/or methotrexate as appropriate. Patients in whom clinical remission was achieved (inactive disease for at least 24 weeks) with canakinumab monotherapy were entered into the second part of the trial, in which they were randomized 1:1 into 1 of 2 treatment arms. In arm 1, the dose of canakinumab was reduced from 4 mg/kg to 2 mg/kg and then to 1 mg/kg, followed by discontinuation. In arm 2, the 4 mg/kg dose interval was prolonged from every 4 weeks, to every 8 weeks, and then to every 12 weeks, followed by discontinuation. In both arms, canakinumab exposure could be reduced provided systemic JIA remained in clinical remission for 24 weeks with each step. The primary objective was to assess whether >40% of randomized patients in either arm maintained clinical remission of systemic JIA for 24 weeks in the first part of the study.In part 1 of the study, 182 patients were enrolled, with 75 of those patients randomized before entering part 2 of the trial. Among the 75 randomized patients, clinical remission was maintained for 24 weeks in 27 (71%) of 38 patients in arm 1 (2 mg/kg every 4 weeks) and 31 (84%) of 37 patients in arm 2 (4 mg/kg every 8 weeks) (P ≤ 0.0001 for arm 1 versus arm 2 among those meeting the 40% threshold). Overall, 25 (33%) of 75 patients discontinued canakinumab, and clinical remission was maintained for at least 24 weeks in all 25 of these patients. No new safety signals were identified.Reduction of canakinumab exposure may be feasible in patients who have achieved clinical remission of systemic JIA, but consistent interleukin-1 inhibition appears necessary to maintain this response.
COVID-19 and COPD
Authors: Janice M. Leung, Masahiro Niikura, Cheng Wei Tony Yang, Don D. Sin
Journal: European Respiratory Journal (2020)

<b>COPD patients have increased risk of severe pneumonia and poor outcomes when they develop COVID-19. This may be related to poor underlying lung reserves or increased expression of ACE-2 receptor in small airways.</b>https://bit.ly/37dSB8l
Modeling and analysis of Hi-C data by HiSIF identifies characteristic promoter-distal loops
Authors: Yufan Zhou, Xiaolong Cheng, Yini Yang, Tian Li, Jingwei Li, Tim H.-M. Huang, Junbai Wang, Shili Lin, Victor X. Jin
Journal: Genome Medicine (2020)

Current computational methods on Hi-C analysis focused on identifying Mb-size domains often failed to unveil the underlying functional and mechanistic relationship of chromatin structure and gene regulation. We developed a novel computational method HiSIF to identify genome-wide interacting loci. We illustrated HiSIF outperformed other tools for identifying chromatin loops. We applied it to Hi-C data in breast cancer cells and identified 21 genes with gained loops showing worse relapse-free survival in endocrine-treated patients, suggesting the genes with enhanced loops can be used for prognostic signatures for measuring the outcome of the endocrine treatment. HiSIF is available at https://github.com/yufanzhouonline/HiSIF .