tbuckley/cabot-search huggingface dataset:
Ten-year longitudinal molecular epidemiology study of Escherichia coli and Klebsiella species bloodstream infections in Oxfordshire, UK
Authors: Samuel Lipworth, Karina-Doris Vihta, Kevin Chau, Leanne Barker, Sophie George, James Kavanagh, Timothy Davies, Alison Vaughan, Monique Andersson, Katie Jeffery, Sarah Oakley, Marcus Morgan, Susan Hopkins, Timothy E. A. Peto, Derrick W. Crook, Ann Sarah Walker, Nicole Stoesser
Journal: Genome Medicine (2021)

Abstract Background The incidence of Gram-negative bloodstream infections (BSIs), predominantly caused by Escherichia coli and Klebsiella species, continues to increase; however, the causes of this are unclear and effective interventions are therefore hard to design. Methods In this study, we sequenced 3468 unselected isolates over a decade in Oxfordshire (UK) and linked this data to routinely collected electronic healthcare records and mandatory surveillance reports. We annotated genomes for clinically relevant genes, contrasting the distribution of these within and between species, and compared incidence trends over time using stacked negative binomial regression. Results We demonstrate that the observed increases in E. coli incidence were not driven by the success of one or more sequence types (STs); instead, four STs continue to dominate a stable population structure, with no evidence of adaptation to hospital/community settings. Conversely in Klebsiella spp., most infections are caused by sporadic STs with the exception of a local drug-resistant outbreak strain (ST490). Virulence elements are highly structured by ST in E. coli but not Klebsiella spp. where they occur in a diverse spectrum of STs and equally across healthcare and community settings. Most clinically hypervirulent (i.e. community-onset) Klebsiella BSIs have no known acquired virulence loci. Finally, we demonstrate a diverse but largely genus-restricted mobilome with close associations between antimicrobial resistance (AMR) genes and insertion sequences but not typically specific plasmid replicon types, consistent with the dissemination of AMR genes being highly contingent on smaller mobile genetic elements (MGEs). Conclusions Our large genomic study highlights distinct differences in the molecular epidemiology of E. coli and Klebsiella BSIs and suggests that no single specific pathogen genetic factors (e.g. AMR/virulence genes/sequence type) are likely contributing to the increasing incidence of BSI overall, that association with AMR genes in E. coli is a contributor to the increasing number of E. coli BSIs, and that more attention should be given to AMR gene associations with non-plasmid MGEs to try and understand horizontal gene transfer networks.
Towards clinical significance of the <i>MUC5B</i> promoter variant and risk of rheumatoid arthritis-associated interstitial lung disease
Authors: Jeffrey A Sparks
Journal: Annals of the Rheumatic Diseases (2021)

While rheumatoid arthritis-associated interstitial lung disease (RA-ILD) has been known to be a serious extra-articular rheumatoid arthritis (RA) manifestation for decades, RA-ILD and other pulmonary sequelae of RA have been of intense interest in recent years. Patients with RA have excess respiratory mortality of RA compared with the general population.1 2 This respiratory burden of RA seems to be specific for patients with seropositive RA,1 and RA-ILD is likely a key contributor to the respiratory burden of RA. Median survival after clinical RA-ILD detection is poor, ranging from 3 years to 8 years in previous studies.3–5 Unlike nearly all other outcomes in RA, prevalence of RA-ILD does not seem to be decreasing over calendar time.5 This may be explained by several factors that include increased longevity of patients, improved articular disease activity unmasking symptoms of dyspnoea on exertion, increased awareness by clinicians of RA-ILD, greater ease in obtaining advanced chest imaging, or perhaps by medications used to treat RA-ILD. Thus, RA-ILD is a serious public health condition for patients with RA. Establishing the risk and identifying risk factors for RA-ILD are therefore of utmost importance. In Annals of the Rheumatic Diseases , Palomaki and colleagues investigate the lifetime risk of RA-ILD related to the MUC5B promoter variant.6 

RA-ILD is a heterogeneous condition that is notoriously difficult to diagnose. Usual interstitial pneumonia (UIP) is the most common RA-ILD, considered to be fibrotic and progressive. A recent meta-analysis found that the UIP subtype had worse prognosis compared with other RA-ILD subtypes.7 Idiopathic pulmonary fibrosis (IPF) shares many of the same clinical and imaging features of UIP in RA-ILD. A common promoter variant of MUC5B (G>T at the rs35705950 single-nucleotide polymorphism) was identified as an important genetic risk factor for IPF.8 Subsequently, the MUC5B promoter variant …
Effect on genital warts in Australian female and heterosexual male individuals after introduction of the national human papillomavirus gender-neutral vaccination programme: an analysis of national sentinel surveillance data from 2004–18
Authors: Eric P F Chow, Allison Carter, Tobias Vickers, Christopher K Fairley, Anna McNulty, Rebecca J Guy, David G Regan, Andrew E Grulich, Denton Callander, Laila Khawar, Dorothy A Machalek, Basil Donovan
Journal: The Lancet Infectious Diseases (2021)
Myiasis from Larvae of Human Botfly
Authors: Genevieve Kaunitz, Miriam Keltz Pomeranz
Journal: New England Journal of Medicine (2021)

A 62-year-old woman presented with pruritic, draining nodules on her back and buttocks after recent travel to South America. The physical examination showed nodules with drainage, and larval movement was observed. Six human botfly larvae were extracted (shown in a video).
Olokizumab, a monoclonal antibody against interleukin 6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by methotrexate: efficacy and safety results of a randomised controlled phase III study
Authors: Evgeniy Nasonov, Saeed Fatenejad, Eugen Feist, Mariana Ivanova, Elena Korneva, Diana G Krechikova, Aleksey L Maslyanskiy, Mikhail Samsonov, Rumen Stoilov, Elena V Zonova, Mark Genovese
Journal: Annals of the Rheumatic Diseases (2021)

To evaluate the efficacy and safety of olokizumab (OKZ) in patients with active rheumatoid arthritis despite treatment with methotrexate (MTX).In this 24-week multicentre, placebo-controlled, double-blind study, patients were randomised 1:1:1 to receive subcutaneously administered OKZ 64 mg once every 2 weeks, OKZ 64 mg once every 4 weeks, or placebo plus MTX. The primary efficacy endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at week 12. The secondary efficacy endpoints included percentage of subjects achieving Disease Activity Score 28-joint count based on C reactive protein <3.2, Health Assessment Questionnaire Disability Index at week 12, ACR50 response and Clinical Disease Activity Index ≤2.8 at week 24. Safety and immunogenicity were assessed throughout the study.A total of 428 patients were randomised. ACR20 responses were more frequent with OKZ every 2 weeks (63.6%) and OKZ every 4 weeks (70.4%) than placebo (25.9%) (p<0.0001 for both comparisons). There were significant differences in all secondary efficacy endpoints between OKZ-treated arms and placebo. Treatment-emergent serious adverse events (TESAEs) were reported by more patients in the OKZ groups compared with placebo. Infections were the most common TESAEs. No subjects developed neutralising antidrug antibodies.Treatment with OKZ was associated with significant improvement in signs, symptoms and physical function of rheumatoid arthritis without discernible differences between the two regimens. Safety was as expected for this class of agents. Low immunogenicity was observed. Trial registration number NCT02760368.
NKTR-255 is a polymer-conjugated IL-15 with unique mechanisms of action on T and natural killer cells
Authors: Tanya O. Robinson, Shweta M. Hegde, Allison Chang, Achintyan Gangadharan, Sarai Rivas, Loui Madakamutil, Jonathan Zalevsky, Takahiro Miyazaki, Kimberly S. Schluns
Journal: Journal of Clinical Investigation (2021)

NKTR-255 is a PEG conjugate of recombinant human IL-15 (rhIL-15) being examined as a potential cancer immunotherapeutic. Since IL-15 responses can be mediated by trans or cis presentation via IL-15Rα or soluble IL-15/IL-15Rα complexes, we investigated the role of IL-15Rα in driving NKTR-255 responses using defined naive and memory OVA-specific CD8+ T cells (OT-I) and NK cells in mice. NKTR-255 induced a 2.5- and 2.0-fold expansion of CD8+ T and NK cells, respectively, in WT mice. In adoptive transfer studies, proliferation of naive and memory WT OT-I T cells in response to NKTR-255 was not impaired in IL-15Rα−/− mice, suggesting trans presentation was not utilized by NKTR-255. Interestingly, naive IL-15Rα−/− OT-I cells had deficient responses to NKTR-255, while memory IL-15Rα−/− OT-I cell responses were partially impaired, suggesting that naive CD8+ T cells are more dependent on cis presentation of NKTR-255 than memory CD8+ T cells. In bone marrow chimera studies, IL-15Rα−/− and WT NK cells present in WT recipients had similar responses to NKTR-255, suggesting that cis presentation is not utilized by NK cells. NKTR-255 could form soluble complexes with IL-15Rα; binding to murine IL-15Rα generated superagonists that preferentially stimulated NK cells, showing that conversion to IL-15Rβ agonist biases the response toward NK cells. These findings highlight the ability of NKTR-255 to utilize IL-15Rα for cis presentation and act as an IL-15Rαβ agonist on CD8+ T cells.
Pulmonary vascular resistance predicts mortality in patients with pulmonary hypertension associated with interstitial lung disease: results from the COMPERA registry
Authors: Karen M. Olsson, Marius M. Hoeper, Christine Pausch, Ekkehard Grünig, Doerte Huscher, David Pittrow, Stephan Rosenkranz, Henning Gall
Journal: European Respiratory Journal (2021)

<b>In patients with pulmonary hypertension associated with interstitial lung disease, pulmonary vascular resistance provides stronger prognostic information than mean pulmonary arterial pressure</b>https://bit.ly/3w1QcIS
Untangling huge literature to disinter genetic underpinnings of Alzheimer’s Disease: A systematic review and meta-analysis
Authors: Hema Sree G N S, V Lakshmi Prasanna Marise, Kshreeraja S Satish, Abhijna Vithal Yergolkar, Mamatha Krishnamurthy, Saraswathy Ganesan Rajalekshmi, K Radhika, Raghunadha R Burri
Journal: Ageing Research Reviews (2021)
A Dynamic Epigenetic Landscape in Genetic and Immunophenotypic Stable Pediatric AML
Authors: Diana Hanekamp, Jennifer R. Scheick, Yaseswini Neelamraju, Edwin Sonneveld, Valerie de Haas, Gert J. Ossenkoppele, Gerrit J. Schuurhuis, Gertjan J.L. Kaspers, Francine E. Garrett-Bakelman, Jacqueline Cloos
Journal: Blood (2017)
Tofacitinib for the treatment of antineutrophil cytoplasm antibody-associated vasculitis: a pilot study
Authors: Yun Liu, Zongfei Ji, Wensu Yu, Sifan Wu, Huiyong Chen, Lili Ma, Zhenqi Ding, Lindi Jiang
Journal: Annals of the Rheumatic Diseases (2021)

Antineutrophil cytoplasm antibody-associated vasculitis (AAV) is a group of necrotising vasculitis involving small vessels characterised by upper and lower respiratory tract, kidney, eye, ears–nose–throat, skin, gastrointestinal and neurological involvement. AAV includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA).1 To date, maintenance therapy to prevent disease relapse remains the main therapeutic challenge for patients with AAV.

Previous studies indicate that T cells and associated cytokine production (eg, interleukin (IL)-6, IL-10, IL-12, IL-23 and type l interferons) play an important role in the pathogenesis of AAV2–4 via activation of the Janus kinase (JAK)/signal transducer and activator of transcription pathway.5 Tofacitinib is a JAK1/3 inhibitor that functions by suppressing the activity of the JAK family of non-receptor tyrosine kinases (RTKs) and has been used successfully for the treatment of rheumatoid arthritis, psoriatic arthritis, Behcet’s disease and systemic lupus erythematosus6–9; however, the use of tofacitinib for the treatment of AAV has not been reported. Of particular interest, imatinib mesylate, an RTK inhibitor, has been reported to be an effective treatment for patients with EGPA.10 Therefore, we hypothesised that tofacitinib-mediated inhibition of JAK signalling …
EDIL3 deficiency ameliorates adverse cardiac remodelling by neutrophil extracellular traps (NET)-mediated macrophage polarization
Authors: Xiaoqiong Wei, Song Zou, Zhonghui Xie, Zhen Wang, Nongyu Huang, Zhifu Cen, Yan Hao, Chengxin Zhang, Zhenyu Chen, Fulei Zhao, Zhonglan Hu, Xiu Teng, Yiyue Gui, Xiao Liu, Huaping Zheng, Hong Zhou, Shuwen Chen, Juan Cheng, Fanlian Zeng, Yifan Zhou, Wenling Wu, Jing Hu, Yuquan Wei, Kaijun Cui, Jiong Li
Journal: Cardiovascular Research (2021)

Abstract Aims After myocardial infarction (MI), injured cardiomyocytes recruit neutrophils and monocytes/macrophages to myocardium, which in turn initiates inflammatory and reparative cascades, respectively. Either insufficient or excessive inflammation impairs cardiac healing. As an endogenous inhibitor of neutrophil adhesion, EDIL3 plays a crucial role in inflammatory regulation. However, the role of EDIL3 in MI remains obscure. We aimed to define the role of EDIL3 in cardiac remodelling after MI. Methods and results Serum EDIL3 levels in MI patients were negatively associated with MI biomarkers. Consistently, WT mice after MI showed low levels of cardiac EDIL3. Compared with WT mice, Edil3−/− mice showed improvement of post-MI adverse remodelling, as they exhibited lower mortality, better cardiac function, shorter scar length, and smaller LV cavity. Accordingly, infarcted hearts of Edil3−/− mice contained fewer cellular debris and lower amounts of fibrosis content, with decreased collagen I/III expression and the percentage of α-smooth muscle actin myofibroblasts. Mechanistically, EDIL3 deficiency did not affect the recruitment of monocytes or T cells, but enhanced neutrophil recruitment and following expansion of pro-inflammatory Mertk−MHC-IIlo-int (myeloid-epithelial-reproductive tyrosine kinase/major histocompatibility complex II) macrophages. The injection of neutrophil-specific C-X-C motif chemokine receptor 2 antagonist eliminated the differences in macrophage polarization and cardiac function between WT and Edil3−/− mice after MI. Neutrophil extracellular traps (NETs), which were more abundant in the hearts of Edil3−/− mice, contributed to Mertk−MHC-IIlo-int polarization via Toll-like receptor 9 pathway. The inhibition of NET formation by treatment of neutrophil elastase inhibitor or DNase I impaired macrophage polarization, increased cellular debris and aggravated cardiac adverse remodelling, thus removed the differences of cardiac function between WT and Edil3−/− mice. Totally, EDIL3 plays an important role in NET-primed macrophage polarization and cardiac remodelling during MI. Conclusion We not only reveal that EDIL3 deficiency ameliorates adverse cardiac healing via NET-mediated pro-inflammatory macrophage polarization but also discover a new crosstalk between neutrophil and macrophage after MI.
Clinical Response to Immunotherapy Targeting Programmed Cell Death Receptor 1/Programmed Cell Death Ligand 1 in Patients With Treatment-Resistant Microsatellite Stable Colorectal Cancer With and Without Liver Metastases
Authors: Chongkai Wang, Jaideep Sandhu, Ching Ouyang, Jian Ye, Peter P. Lee, Marwan Fakih
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Microsatellite stable (MSS) metastatic colorectal cancer has been historically characterized as resistant to immunotherapy. Recent studies have demonstrated limited clinical activity of programmed cell death receptor 1/programmed death ligand 1 (PD-1/PD-L1) targeting in MSS metastatic colorectal cancer. The association of metastatic disease in the liver with treatment response has not been fully investigated. <h3>Objective</h3> To investigate the association of liver metastases with response to PD-1/PD-L1–targeting therapy in MSS metastatic colorectal cancer. <h3>Design, Setting, and Participants</h3> This single-center retrospective cohort study evaluated clinical responses to PD-1– or PD-L1–targeting therapy, with or without other investigational agents, in patients with MSS metastatic colorectal cancer and disease progression after standard of care therapy from January 1, 2014, to December 31, 2020. <h3>Main Outcomes and Measures</h3> Objective response rate (ORR) and progression-free survival (PFS), measured from initiation of PD-1/PD-L1–targeting therapy. <h3>Results</h3> Ninety-five patients with MSS metastatic colorectal cancer were identified (54 men [56.8%]; median age, 55 [interquartile range (IQR), 49-64] years). The overall ORR was 8.4% (8 of 95 patients). Eight of 41 patients without liver metastases achieved an ORR of 19.5%, and no response was observed in 54 patients with liver metastases. The disease control rate was 58.5% (24 of 41) in patients without liver metastasis and 1.9% (1 of 54) in patients with liver metastasis. Patients without liver metastases at the time of PD-1/PD-L1–targeting treatment had a superior median PFS compared with patients with liver metastases (4.0 [IQR, 2.0-7.5] vs 1.5 [IQR, 1.0-2.0] months;<i>P</i> &lt; .001). In addition, median PFS was 5.5 (IQR, 2.0-11.5) months for patients without any prior or current liver involvement at the time of PD-1/PD-L1–targeting treatment initiation. Using a multivariate Cox regression model correcting for Eastern Cooperative Oncology Group status, primary tumor location,<i>RAS</i>and<i>BRAF</i>status, tumor mutation burden, and metastatic sites, liver metastases was the variable with the most significant association with faster progression after PD-1/PD-L1 treatment inhibition (hazard ratio, 7.00; 95% CI, 3.18-15.42;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> Findings of this cohort study suggest that patients with MSS metastatic colorectal cancer and without liver metastases may derive clinical benefits from checkpoint inhibitors, whereas the presence of liver metastases was associated with resistance. Further prospective studies are needed to investigate PD-1/PD-L1 inhibitors in patients with MSS metastatic colorectal cancer without liver metastases.
ジメチルアルギニン・ジメチルアミノ加水分解酵素2を過剰発現させているトランスジェニック・マウスにおける、血管損傷における非対称性ジメチルアルギニンの役割
Authors: Hasegawa K, Wakino S, Tatematsu S, Yoshioka K, Homma K, Sugano N, Kimoto M, Hayashi K, Itoh H
Journal: Circulation Research (2007)
Subepithelial tunneling endoscopic resection with intratunnel morcellation for a giant esophageal leiomyoma
Authors: Ashish Gandhi, Siddharth Dharamsi, Harsh Bapaye, Amol Bapaye
Journal: Endoscopy (2021)

Subepithelial tunneling endoscopic resection is an accepted minimally invasive therapy for esophageal subepithelial tumors arising from the muscularis propria layer [1]. Subepithelial tunneling endoscopic resection is highly successful for subepithelial tumors < 4 cm. Larger lesions pose technical challenges for this procedure and for specimen delivery with resultant inferior outcomes [2]. Several techniques have been described to overcome this problem, such as double-opening subepithelial tunneling endoscopic resection, intracorporeal morcellation, or a thoracoscopy-assisted approach [2] [3] [4] [5]. This video demonstrates subepithelial tunneling endoscopic resection for a giant esophageal leiomyoma with intratunnel morcellation.
大腸炎から癌への移行: 高Wnt活性は,結腸癌幹細胞前駆細胞の腫瘍開始ポテンシャルを維持する
Authors: K Shenoy Anitha, C Fisher Robert, A Butterworth Elizabeth, PI Liya, Chang Lung-Ji, D Appelman Henry, Chang Myron, W Scott Edward, H Huang Emina
Journal: Cancer Research (2012)
Cytogenetic and Molecular Responses after 2 Years of Tyrosine Kinase Inhibitor (TKI) Treatment in Simplicity, an Observational Study of Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Patients (Pts) in Routine Clinical Practice
Authors: Jorge E. Cortes, Stuart L. Goldberg, Mauricette Michallet, Rüdiger Hehlmann, Bengt Simonsson, Michael J. Mauro, Loretta A. Williams, Teresa Zyczynski, Ginny P Sen, Aimee Foreman, Srikanth Gajavelli, Carlo Gambacorti-Passerini
Journal: Blood (2017)
Ventral tegmental area GABAergic inhibition of cholinergic interneurons in the ventral nucleus accumbens shell promotes reward reinforcement
Authors: Ream Al-Hasani, Raajaram Gowrishankar, Gavin P. Schmitz, Christian E. Pedersen, David J. Marcus, Sofia E. Shirley, Taylor E. Hobbs, Abigail J. Elerding, Sophie J. Renaud, Miao Jing, Yulong Li, Veronica A. Alvarez, Julia C. Lemos, Michael R. Bruchas
Journal: Nature Neuroscience (2021)
Global guideline for the diagnosis and management of the endemic mycoses: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology
Authors: George R Thompson, Thuy Le, Ariya Chindamporn, Carol A Kauffman, Ana Alastruey-Izquierdo, Neil M Ampel, David R Andes, Darius Armstrong-James, Olusola Ayanlowo, John W Baddley, Bridget M Barker, Leila Lopes Bezerra, Maria J Buitrago, Leili Chamani-Tabriz, Jasper F W Chan, Methee Chayakulkeeree, Oliver A Cornely, Cao Cunwei, Jean-Pierre Gangneux, Nelesh P Govender, Ferry Hagen, Mohammad T Hedayati, Tobias M Hohl, Grégory Jouvion, Chris Kenyon, Christopher C Kibbler, Nikolai Klimko, David C M Kong, Robert Krause, Low Lee Lee, Graeme Meintjes, Marisa H Miceli, Peter-Michael Rath, Andrej Spec, Flavio Queiroz-Telles, Ebrahim Variava, Paul E Verweij, Ilan S Schwartz, Alessandro C Pasqualotto
Journal: The Lancet Infectious Diseases (2021)
Tissue specificity of DNA repair: the CRISPR compass
Authors: Joana Ferreira da Silva, Mathilde Meyenberg, Joanna I. Loizou
Journal: Trends in Genetics (2021)

CRISPR-Cas9-mediated genome editing holds great promise for the correction of pathogenic variants in humans. However, its therapeutic implementation is hampered due to unwanted editing outcomes. A better understanding of cell type- and tissue-specific DNA repair processes will ultimately enable precise control of editing outcomes for safer and effective therapies.
26738 Assessing the cosmetic changes in the facial skin using noninvasive RCM and OCT in vivo skin imaging instrumentation after use of a topical retinoid product in subjects with moderate to severe photodamage
Authors: Lisa T. Goberdhan, Giovanni Pellacani, Marco Ardigo, Katie Schneider, Elizabeth T. Makino, Rahul C. Mehta
Journal: Journal of the American Academy of Dermatology (2021)