tbuckley/cabot-search huggingface dataset:
<scp>Erdheim‐Chester</scp> disease in bone marrow
Authors: Matthew R. Wilson, William Gordon, John Goodlad, Mike Leach, Barbara J. Bain
Journal: American Journal of Hematology (2020)

A 67-year-old man presented with bone pain, fatigue, weight loss, and dyspnea. A blood count showed mild normocytic anemia (hemoglobin concentration 114 g/L) with normal leukocyte and platelet counts. The erythrocyte sedimentation rate was elevated at 136 mm/hour as was C-reactive protein at 40 mg/L. Biochemical studies showed normal calcium and phosphate but minor elevation in alkaline phosphatase (156 U/L). Long bone radiographs demonstrated diffuse cortical thickening and sclerosis of the distal femora. A Positron Emission Tomography/Computed Tomography scan showed intense 18F-fluorodeoxyglucose uptake in the distal femora and proximal tibiae (Images, bottom left and centre). Bone sclerosis was apparent in the distal femora (Image, bottom right). A core biopsy of the left distal femur demonstrated marked expansion and irregularity of the bone trabeculae (Image, top left). Normal hematopoiesis was virtually absent with a significant infiltrate of foamy histiocytes evident on hematoxylin and eosin staining (Image, top centre). Reticulin staining demonstrated focal fibrosis surrounding the abnormal histiocytes (Image, top right). Further immunohistochemical staining showed the histiocytes to be positive for CD68R and factor XIIIA but negative for S100 and CD1a. Next generation sequencing performed on bone marrow material detected a sequence variant c.1799 T > A p.(Val600Glu) in codon 600 of the BRAF gene. The radiological and histopathological features, along with the presence of a BRAFV600E mutation, were diagnostic of Erdheim-Chester disease (ECD). ECD is a rare neoplastic disorder characterized by infiltration of multiple tissues by foamy CD68+CD1a− histiocytes. The disease can have protean manifestations but, most characteristically, long-bone pain and osteosclerosis. Recently, mutations activating the MAPK pathway have been found in more than 80% of patients with ECD, mainly BRAFV600E. This condition is related to Langerhans cell histiocytosis, which is characterized by the same mutation. Treatment traditionally involved interferon-alpha, corticosteroids, and sometimes cytotoxic chemotherapy but more recently BRAF inhibitors, such as vemurafenib, have been shown to induce frequent durable responses. No conflict of interest.
Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes
Authors: Elsa Bernard, Yasuhito Nannya, Robert P. Hasserjian, Sean M. Devlin, Heinz Tuechler, Juan S. Medina-Martinez, Tetsuichi Yoshizato, Yusuke Shiozawa, Ryunosuke Saiki, Luca Malcovati, Max F. Levine, Juan E. Arango, Yangyu Zhou, Francesc Solé, Catherine A. Cargo, Detlef Haase, Maria Creignou, Ulrich Germing, Yanming Zhang, Gunes Gundem, Araxe Sarian, Arjan A. van de Loosdrecht, Martin Jädersten, Magnus Tobiasson, Olivier Kosmider, Matilde Y. Follo, Felicitas Thol, Ronald F. Pinheiro, Valeria Santini, Ioannis Kotsianidis, Jacqueline Boultwood, Fabio P. S. Santos, Julie Schanz, Senji Kasahara, Takayuki Ishikawa, Hisashi Tsurumi, Akifumi Takaori-Kondo, Toru Kiguchi, Chantana Polprasert, John M. Bennett, Virginia M. Klimek, Michael R. Savona, Monika Belickova, Christina Ganster, Laura Palomo, Guillermo Sanz, Lionel Ades, Matteo Giovanni Della Porta, Harold K. Elias, Alexandra G. Smith, Yesenia Werner, Minal Patel, Agnès Viale, Katelynd Vanness, Donna S. Neuberg, Kristen E. Stevenson, Kamal Menghrajani, Kelly L. Bolton, Pierre Fenaux, Andrea Pellagatti, Uwe Platzbecker, Michael Heuser, Peter Valent, Shigeru Chiba, Yasushi Miyazaki, Carlo Finelli, Maria Teresa Voso, Lee-Yung Shih, Michaela Fontenay, Joop H. Jansen, José Cervera, Yoshiko Atsuta, Norbert Gattermann, Benjamin L. Ebert, Rafael Bejar, Peter L. Greenberg, Mario Cazzola, Eva Hellström-Lindberg, Seishi Ogawa, Elli Papaemmanuil
Journal: Nature Medicine (2020)
Covid-19 and chronic fatigue
Authors: Frances M K Williams, Nina Muirhead, Carmine Pariante
Journal: BMJ (2020)

Salisbury’s article on patients with prolonged symptoms of covid-19 should be distributed to all healthcare practitioners.1 Chronic fatigue is an important and distressing symptom in rheumatic2 and other diseases3 as well as in the complex multisystem disease myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).4 It is poorly covered in many medical school curriculums. At last there is …
Myocardial injury and COVID-19: Serum hs-cTnI level in risk stratification and the prediction of 30-day fatality in COVID-19 patients with no prior cardiovascular disease
Authors: Jiatian Cao, Yan Zheng, Zhe Luo, Zhendong Mei, Yumeng Yao, Zilong Liu, Chao Liang, Hongbo Yang, Yanan Song, Kaihuan Yu, Yan Gao, Chouwen Zhu, Zheyong Huang, Juying Qian, Junbo Ge
Journal: Theranostics (2020)

Introduction:To explore the involvement of the cardiovascular system in coronavirus disease 2019 , we investigated whether myocardial injury occurred in COVID-19 patients and assessed the performance of serum high-sensitivity cardiac Troponin I (hs-cTnI) levels in predicting disease severity and 30-day in-hospital fatality.Methods: We included 244 COVID-19 patients, who were admitted to Renmin Hospital of Wuhan University with no preexisting cardiovascular disease or renal dysfunction.We analyzed the data including patients' clinical characteristics, cardiac biomarkers, severity of medical conditions, and 30-day in-hospital fatality.We performed multivariable Cox regressions and the receiver operating characteristic analysis to assess the association of cardiac biomarkers on admission with disease severity and prognosis.Results: In this retrospective observational study, 11% of COVID-19 patients had increased hs-cTnI levels (>40 ng/L) on admission.Of note, serum hs-cTnI levels were positively associated with the severity of medical conditions (median [interquartile range (IQR)]: 6.00 [6.00-6.00]ng/L in 91 patients with moderate conditions, 6.00 [6.00-18.00]ng/L in 107 patients with severe conditions, and 11.00 [6.00-56.75]ng/L in 46 patients with critical conditions, P for trend=0.001).Moreover, compared with those with normal cTnI levels, patients with increased hs-cTnI levels had higher in-hospital fatality (adjusted hazard ratio [95% CI]: 4.79 [1.46-15.69]).The receiver-operating characteristic curve analysis suggested that the inclusion of hs-cTnI levels into a panel of empirical prognostic factors substantially improved the prediction performance for severe or critical conditions (area under the curve (AUC): 0.71 (95% CI: 0.65-0.78)vs. 0.65 (0.58-0.72),P=0.01), as well as for 30-day fatality (AUC: 0.91 (0.85-0.96) vs. 0.77 (0.62-0.91),P=0.04).A cutoff value of 20 ng/L of hs-cTnI level led to the best prediction to 30-day fatality.Conclusions: In COVID-19 patients with no preexisting cardiovascular disease, 11% had increased hs-cTnI levels.Besides empirical prognostic factors, serum hs-cTnI levels upon admission provided independent prediction to both the severity of the medical condition and 30-day in-hospital fatality.These findings may shed important light on the clinical management of COVID-19.
A pipeline for complete characterization of complex germline rearrangements from long DNA reads
Authors: Satomi Mitsuhashi, Sachiko Ohori, Kazutaka Katoh, Martin C. Frith, Naomichi Matsumoto
Journal: Genome Medicine (2020)

Abstract Background Many genetic/genomic disorders are caused by genomic rearrangements. Standard methods can often characterize these variations only partly, e.g., copy number changes or breakpoints. It is important to fully understand the order and orientation of rearranged fragments, with precise breakpoints, to know the pathogenicity of the rearrangements. Methods We performed whole-genome-coverage nanopore sequencing of long DNA reads from four patients with chromosomal translocations. We identified rearrangements relative to a reference human genome, subtracted rearrangements shared by any of 33 control individuals, and determined the order and orientation of rearranged fragments, with our newly developed analysis pipeline. Results We describe the full characterization of complex chromosomal rearrangements, by filtering out genomic rearrangements seen in controls without the same disease, reducing the number of loci per patient from a few thousand to a few dozen. Breakpoint detection was very accurate; we usually see ~ 0 ± 1 base difference from Sanger sequencing-confirmed breakpoints. For one patient with two reciprocal chromosomal translocations, we find that the translocation points have complex rearrangements of multiple DNA fragments involving 5 chromosomes, which we could order and orient by an automatic algorithm, thereby fully reconstructing the rearrangement. A rearrangement is more than the sum of its parts: some properties, such as sequence loss, can be inferred only after reconstructing the whole rearrangement. In this patient, the rearrangements were evidently caused by shattering of the chromosomes into multiple fragments, which rejoined in a different order and orientation with loss of some fragments. Conclusions We developed an effective analytic pipeline to find chromosomal aberration in congenital diseases by filtering benign changes, only from long read sequencing. Our algorithm for reconstruction of complex rearrangements is useful to interpret rearrangements with many breakpoints, e.g., chromothripsis. Our approach promises to fully characterize many congenital germline rearrangements, provided they do not involve poorly understood loci such as centromeric repeats.
Factors Contributing to the Rising National Cost of Glucose-Lowering Medicines for Diabetes During 2005–2007 and 2015–2017
Authors: Xilin Zhou, Sundar S. Shrestha, Hui Shao, Ping Zhang
Journal: Diabetes Care (2020)

OBJECTIVE We examined changes in glucose-lowering medication spending and quantified the magnitude of factors that are contributing to these changes. RESEARCH DESIGN AND METHODS Using the Medical Expenditure Panel Survey, we estimated the change in spending on glucose-lowering medications during 2005–2007 and 2015–2017 among adults aged ≥18 years with diabetes. We decomposed the increase in total spending by medication groups: for insulin, by human and analog; and for noninsulin, by metformin, older, newer, and combination medications. For each group, we quantified the contributions by the number of users and cost-per-user. Costs were in 2017 U.S. dollars. RESULTS National spending on glucose-lowering medications increased by $40.6 billion (240%), of which insulin and noninsulin medications contributed $28.6 billion (169%) and $12.0 billion (71%), respectively. For insulin, the increase was mainly associated with higher expenditures from analogs (156%). For noninsulin, the increase was a net effect of higher cost for newer medications (+88%) and decreased cost for older medications (−34%). Most of the increase in insulin spending came from the increase in cost-per-user. However, the increase in the number of users contributed more than cost-per-user in the rise of most noninsulin groups. CONCLUSIONS The increase in national spending on glucose-lowering medications during the past decade was mostly associated with the increased costs for insulin, analogs in particular, and newer noninsulin medicines, and cost-per-user had a larger effect than the number of users. Understanding the factors contributing to the increase helps identify ways to curb the growth in costs.
Validation of a Genome-Wide Polygenic Score for Coronary Artery Disease in South Asians
Authors: Minxian Wang, Ramesh Menon, Sanghamitra Mishra, Aniruddh P Patel, Mark Chaffin, Deepak Tanneeru, Manjari Deshmukh, Oshin Mathew, Sanika Apte, Christina S Devanboo, Sumathi Sundaram, Praveena Lakshmipathy, Sakthivel Murugan, Krishna Kumar Sharma, Karthikeyan Rajendran, Sam Santhosh, Rajesh Thachathodiyl, Hisham Ahamed, Aniketh Vijay Balegadde, Thomas Alexander, Krishnan Swaminathan, Rajeev Gupta, Ajit S Mullasari, Alben Sigamani, Muralidhar Kanchi, Andrew S Peterson, Adam S Butterworth, John Danesh, Emanuele Di Angelantonio, Aliya Naheed, Michael Inouye, Rajiv Chowdhury, Ramprasad L Vedam, Sekar Kathiresan, Ravi Gupta, Amit V Khera
Journal: Journal of the American College of Cardiology (2020)
Antimicrobial susceptibility testing of Mycobacterium tuberculosis complex isolates – the EUCAST broth microdilution reference method for MIC determination
Authors: Thomas Schön, Jim Werngren, Diana Machado, Emanuele Borroni, Maria Wijkander, Gerard Lina, Johan Mouton, Erika Matuschek, Gunnar Kahlmeter, Christian Giske, Miguel Santin, Daniela Maria Cirillo, Miguel Viveiros, Emmanuelle Cambau
Journal: Clinical Microbiology and Infection (2020)

ScopeSeveral methods are used worldwide for antibiotic susceptibility testing (AST) for the Mycobacterium tuberculosis complex (MTBC). The variability in the results obtained with these methods hampers setting epidemiological cut-off (ECOFF) values and clinical breakpoints according to EUCAST guidelines. Methods for susceptibility testing and determination of the minimal inhibitory concentrations (MICs) need to be standardized for MTBC isolates for old and new agents. Our objective was to establish a standardized reference method for MIC determination for MTBC.MethodsThe EUCAST antimycobacterial susceptibility testing subcommittee (AMST) compared protocols of MIC determination with regard to medium, inoculum preparation, antituberculous agent preparation, incubation, reading of the results and interpretation.RecommendationsThe EUCAST reference method of MIC determination for MTBC is the broth microdilution method in Middlebrook 7H9-10% OADC medium. The final inoculum is a 105 CFU/mL suspension, obtained from a 10−2 dilution of a 0.5 McFarland suspension prepared after vortexing bacterial colonies with glass beads before suspending them in sterile water. The culture is maintained in a U-shaped 96-well polystyrene microtitre sterile plate with a lid incubated at 36° ± 1°C. Reading is done using an inverted mirror as soon as the 1:100 diluted control (i.e. 103 CFU/mL suspension) shows visual growth. The MIC, expressed in mg/L, is the lowest concentration that inhibits visual growth. Mycobacterium tuberculosis H37Rv ATCC 27294 is used as the reference strain and its targeted MIC values are within the range 0.03–0.12 for isoniazid, 0.12–0.5 for levofloxacin and 0.25–1 mg/L for amikacin.ConclusionsThe EUCAST reference method for MTBC was endorsed by EUCAST after public consultation and will from now on be used to define EUCAST ECOFFs and clinical breakpoints. This reference method is not primarily intended to be used under routine conditions and the AST methods will need to be calibrated against this reference method to be used with EUCAST breakpoints.
AB0800 CLINICAL ASSOCIATION BETWEEN URIC ACID/25-HYDROXYVITAMIN D SERUM LEVELS RATIO IN PATIENTS WITH PSORIATIC ARTHRITIS
Authors: F. Masini, K. Gjeloshi, E. Pinotti, F. Danzo, F. Guarino, M. Tardugno, R. Ferrara, G. Cuomo
Journal: Annals of the Rheumatic Diseases (2020)

Background: The association between hyperuricemia and psoriatic arthritis (PsA) is actually generally accepted. Previous studies have demonstrated that uric acid suppress 25(OH)D metabolism [1]. More evidence is required to demonstrate the immune modulatory effects in psoriasis, psoriatic arthritis and other autoimmune diseases. In particular, the potential association between 25-hydroxyvitamin D serum levels and PsA still remains unknown. Objectives: To assess a clinical association between uric acid/25(OH)D serum levels ratio related to PASI, BASDAI and DAPSA, if any, in patients with psoriatic arthritis. Methods: We retrospectively observed 61 patients with psoriatic arthritis referred to our outpatients clinic, independently from already being on therapy or naïve. All selected patients underwent only conventional non-biological therapy at baseline and none received vitamin D supplementation and either allopurinol or febuxostat previously. Blood samples were drawn from all participants for assessment of 25-hydroxyvitamin D and uric acid serum levels. Disease activity of psoriasis and psoriatic arthritis were assessed by the Psoriasis Area and Severity Index (PASI), the Disease Activity Index for Psoriatic Arthritis (DAPSA) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). We assessed the covariates of interest by the Wilcoxon non parametric test, through the SPSS 24 Software. Results: We observed 61 patients, mainly females (83.6%). At the univariate analysis, the uric acid/25(OH)D serum levels ratio revealed significantly associated with DAPSA and BASDAI indexes (p&lt;0.001 and p&lt;0.001, respectively), whilst no significant association emerged with the PASI index (p=0.462). Conclusion: Data in the literature about these associations in the context of psoriatic arthritis are really poor. As a consequence, our findings, though preliminary, suggest us to hypothesize a potential role of uric acid/25(OH)D serum levels ratio as potential inflammation marker in order to better assess the disease activity. However, future larger studies are needed to investigate more in depth this association. [1]Charoenngam N, Ponvilawan B, Ungprasert P. Vitamin D insufficiency and deficiency are associated with a higher level of serum uric acid: A systematic review and meta-analysis. Mod Rheumatol. 2019 Mar 4:1-6. Disclosure of Interests: None declared
Corrigendum to “Large-Scale Identification and Time-Course Quantification of Ubiquitylation Events during Maize Seedling De-Etiolation” [Genomics Proteomics Bioinformatics 17 (6) (2019) 603–622]
Authors: Yue-Feng Wang, Qing Chao, Zhe Li, Tian-Cong Lu, Hai-Yan Zheng, Cai-Feng Zhao, Zhuo Shen, Xiao-Hui Li, Bai-Chen Wang
Journal: Genomics Proteomics & Bioinformatics (2020)
Hugh James Hoyland
Authors: Kevin Barraclough
Journal: BMJ (2020)

Hugh James Hoyland (“Jim”) was a general practitioner of the old school. He started in rural Painswick in the Cotswolds in 1959, initially helping Dr Tinker, for whom four years as a Japanese prisoner of war had taken its toll. He eventually retired from the practice, which now bears his name, 35 years later in 1994. He was on call for much of those 35 years. His was an era in which general practitioners did most things.

Jim went to St John’s College, …
Overexpression of Activin Receptor-Like Kinase 1 in Endothelial Cells Suppresses Development of Arteriovenous Malformations in Mouse Models of Hereditary Hemorrhagic Telangiectasia
Authors: Yong Hwan Kim, Phuong-Nhung Vu, Se-woon Choe, Chang-Jin Jeon, Helen M. Arthur, Calvin P.H. Vary, Young Jae Lee, S. Paul Oh
Journal: Circulation Research (2020)

Rationale: Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease caused by mutations in ENG , ALK1 , or SMAD4 . Since proteins from all 3 HHT genes are components of signal transduction of TGF-β (transforming growth factor β) family members, it has been hypothesized that HHT is a disease caused by defects in the ENG-ALK1-SMAD4 linear signaling. However, in vivo evidence supporting this hypothesis is scarce. Objective: We tested this hypothesis and investigated the therapeutic effects and potential risks of induced-ALK1 or -ENG overexpression (OE) for HHT. Methods and Results: We generated a novel mouse allele (ROSA26 Alk1 ) in which HA (human influenza hemagglutinin)-tagged ALK1 and bicistronic eGFP expression are induced by Cre activity. We examined whether ALK1-OE using the ROSA26 Alk1 allele could suppress the development of arteriovenous malformations (AVMs) in wounded adult skin and developing retinas of Alk1 - and Eng -inducible knockout (iKO) mice. We also used a similar approach to investigate whether ENG-OE could rescue AVMs. Biochemical and immunofluorescence analyses confirmed the Cre-dependent OE of the ALK1-HA transgene. We could not detect any pathological signs in ALK1-OE mice up to 3 months after induction. ALK1-OE prevented the development of retinal AVMs and wound-induced skin AVMs in Eng -iKO as well as Alk1 -iKO mice. ALK1-OE normalized expression of SMAD and NOTCH target genes in ENG-deficient endothelial cells (ECs) and restored the effect of BMP9 (bone morphogenetic protein 9) on suppression of phosphor-AKT levels in these endothelial cells. On the other hand, ENG-OE could not inhibit the AVM development in Alk1 -iKO models. Conclusions: These data support the notion that ENG and ALK1 form a linear signaling pathway for the formation of a proper arteriovenous network during angiogenesis. We suggest that ALK1 OE or activation can be an effective therapeutic strategy for HHT. Further research is required to study whether this therapy could be translated into treatment for humans.
AB0013 Some cytokines and bone markers in osteoarthritis
Authors: H Hulejova, P Spacek, M Adam
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Osteoarthritis (OA) is a dynamic process involving joint as an organ and causing successive loss of structural integrity of different joint compartment constituents. OA is not a single disease entity but it is a group of overlapping disorders in which articular cartilage and subchondral bone are disturbed. Synovitis and formation of granulation tissue in subchondral bone take place in many patients with OA. Therefore at least some OA forms may be classified rather as inflammatory disease rather than degenerative disease. It is also a process where different biochemical factors besides mechanical take place.<sup>1</sup> <h3>Objectives</h3> To elucidate the participation of some cytokines in OA pathological processes and to compare their values with those of bone markers. <h3>Methods</h3> In sera of 32 OA patients in early as well as late stages with levels of Il-1b, Il-6, Il-8 and TNFa were established in Immulite (DPL, Los Angeles, CA, USA). Because serum levels of Il-1b and Il-6 were normal in all patients, in extracts from tissues obtained in TEP installation, only IL-8 and TNFa levels concentration were determined. Urinary pyridinoline (UPD) and deoxypyridinoline (UDPD) were determined with HPLC in the equipment of Spectra Physics (San Jose, CA, USA, type SP).<sup>2</sup> Chondrex (YKL-40) and bone alkaline phosphatase (BAP) were measured with ELISA test (Metra Biosystems, CA, USA). Values of Il-8 and TNFa don't correlate with Upyr and chondrex levels. <h3>Results</h3> Concentration of cytokines in sera, synovial fluids and tissue extracts were increased only in some patients and mainly in synovial fluid. Markers of activity were increased in the both sera and tissue extracts. <h3>Conclusion</h3> According to the results obtained Il-1b and Il-6 do not play any role in OA processes. On the other hand tissue concentrations of Il-8 and TNFa do not correlate with bone markers and therefore they not reflex activity of pathological process. <h3>References</h3> Westacott CI, Sharif M. Cytokines in osteoarthritis: mediators or markers of joint destruction? Semin Arthritis Rheum. 1996;25(4): 254–72 paèek P, Hulejová H, Adam M. Ion exchange HPLC determination of pyridinium crosslinks in urine as markers of bone resorption. J Liq Chem Rel Technol. 1997;20(12):1921–30