tbuckley/cabot-search huggingface dataset:
Prenatal Exposure to Perfluoroalkyl Substances Associated With Increased Susceptibility to Liver Injury in Children
Authors: Nikos Stratakis, David V. Conti, Ran Jin, Katerina Margetaki, Damaskini Valvi, Alexandros P. Siskos, Léa Maitre, Erika Garcia, Nerea Varo, Yinqi Zhao, Theano Roumeliotaki, Marina Vafeiadi, Jose Urquiza, Silvia Fernández‐Barrés, Barbara Heude, Xavier Basagana, Maribel Casas, Serena Fossati, Regina Gražulevičienė, Sandra Andrušaitytė, Karan Uppal, Rosemary R.C. McEachan, Eleni Papadopoulou, Oliver Robinson, Line Småstuen Haug, John Wright, Miriam B. Vos, Hector C. Keun, Martine Vrijheid, Kiros T. Berhane, Rob McConnell, Lida Chatzi
Journal: Hepatology (2020)

Background and Aims Per‐ and polyfluoroalkyl substances (PFAS) are widespread and persistent pollutants that have been shown to have hepatotoxic effects in animal models. However, human evidence is scarce. We evaluated how prenatal exposure to PFAS associates with established serum biomarkers of liver injury and alterations in serum metabolome in children. Approach and Results We used data from 1,105 mothers and their children (median age, 8.2 years; interquartile range, 6.6‐9.1) from the European Human Early‐Life Exposome cohort (consisting of six existing population‐based birth cohorts in France, Greece, Lithuania, Norway, Spain, and the United Kingdom). We measured concentrations of perfluorooctane sulfonate, perfluorooctanoate, perfluorononanoate, perfluorohexane sulfonate, and perfluoroundecanoate in maternal blood. We assessed concentrations of alanine aminotransferase, aspartate aminotransferase, and gamma‐glutamyltransferase in child serum. Using Bayesian kernel machine regression, we found that higher exposure to PFAS during pregnancy was associated with higher liver enzyme levels in children. We also measured child serum metabolomics through a targeted assay and found significant perturbations in amino acid and glycerophospholipid metabolism associated with prenatal PFAS. A latent variable analysis identified a profile of children at high risk of liver injury (odds ratio, 1.56; 95% confidence interval, 1.21‐1.92) that was characterized by high prenatal exposure to PFAS and increased serum levels of branched‐chain amino acids (valine, leucine, and isoleucine), aromatic amino acids (tryptophan and phenylalanine), and glycerophospholipids (phosphatidylcholine [PC] aa C36:1 and Lyso‐PC a C18:1). Conclusions Developmental exposure to PFAS can contribute to pediatric liver injury.
Fundus autofluorescence imaging
Authors: Steffen Schmitz-Valckenberg, Maximilian Pfau, Monika Fleckenstein, Giovanni Staurenghi, Janet R. Sparrow, Almut Bindewald-Wittich, Richard F. Spaide, Sebastian Wolf, Srinivas R. Sadda, Frank G. Holz
Journal: Progress in Retinal and Eye Research (2020)
Women Physicians and the COVID-19 Pandemic
Authors: Linda Brubaker
Journal: JAMA (2020)

Women Physicians and the COVID-19 Pandemic Despite the complexity and challenges inherent in the US health care system and the unprecedented demands in and disruptions of clinical practice created by the coronavirus disease 2019 (COVID-19) pandemic, it remains a privilege to be a physician.This privilege comes with many responsibilities, including a responsibility to reflect on the profession and address the entrenched dysfunctional ways of the work involved in medicine.The medical profession has missed opportunities to establish reasonable demands and expectations for physicians.Instead, physicians are often asked to do more that moves them away from the deep thinking that is needed for patient care.This has led to a loss of professional fulfillment and a moral crisis for an increasing number of physicians. 1,2ven before the COVID-19 pandemic, physicians have been affected by systemic issues that foster unhealthful work environments, with expectations of 24/7 availability and a persistent life-work imbalance. 3While some younger physicians are making intentional changes to their personal and professional lives, far too few physicians have effectively prioritized commitments to the personal roles they value.These preferences and other human factors that each physician brings to their vocation in medicine are framed by their personal experiences.This mix of personal attributes and professional skills can keep physicians healthy and thriving.
AB0240 EXAMINING THE RELATIONSHIP BETWEEN RHEUMATOID ARTHRITIS, MULTIMORBIDITY AND ADVERSE HEALTH-RELATED OUTCOMES: A SYSTEMATIC REVIEW
Authors: J. Canning, S. Siebert, B. Jani, F. Mair, B. Nicholl
Journal: Annals of the Rheumatic Diseases (2020)

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterised by inflammation of the synovial joints causing pain, swelling and stiffness. Multimorbidity (the presence of two or more long-term conditions) affects approximately two thirds of people with RA. However, the relationship between RA and multimorbidity is poorly understand, as is the effect of this relationship on mortality and other health-related outcomes, particularly those relating to physical functioning and well-being. Objectives: To explore existing literature to determine what is known about the effect, if any, of multimorbidity on mortality and other health-related outcomes in people with RA. Methods: A systematic review was conducted following a protocol prepared using PRISMA-P 2015 reporting guidelines, ensuring the quality of the review. Studies were sourced from electronic medical databases, specifically MEDLINE, Embase, CINAHL, PsycINFO, The Cochrane Library and Scopus, using a pre-defined search strategy. Studies were selected based on specified eligibility criteria and quality appraised using the Cochrane Prognosis Methods Group-developed, Quality in Prognostic Studies (QUIPS) tool. A narrative synthesis of findings was conducted. Results: In total, 15 studies fulfilled our criteria for inclusion in our review. Of these, 7 studies had mortality as an outcome, with 6 reporting a significant association between multimorbidity and increased risk of all-cause mortality in people with RA. Nine studies had functional status/disability as an outcome, with 2 of these studies also including quality of life. All 9 studies reported significant associations between multimorbidity and the aforementioned health-related outcomes, demonstrating poorer functional status/increased disability and reduced quality of life in people with RA and multimorbidity. Conclusion: Multimorbidity in people with RA is significantly associated with increased mortality and poor health-related outcomes in current literature. A better understanding of this relationship will provide an important foundation of knowledge to guide future health service design. Acknowledgments: This work was supported by the Medical Research Council (MRC) [Grant Reference: MR/N013166/1]. Disclosure of Interests: Jordan Canning: None declared, Stefan Siebert Grant/research support from: BMS, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Janssen, Novartis, Pfizer, UCB, Consultant of: AbbVie, Boehringer Ingelheim, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Celgene, Janssen, Novartis, Bhautesh Jani: None declared, Frances Mair: None declared, Barbara Nicholl: None declared
Misleading media coverage of Sweden’s response to covid-19
Authors: Rachel E Irwin
Journal: BMJ (2020)

Sweden does not have a herd immunity strategy, and it is irresponsible for The BMJ to perpetuate this myth.1 Similarly, the decision not to “lockdown” is only “controversial” because the media have framed it as such. It is time for the word lockdown to be replaced with precise, non-sensational language that describes the measures taken.

Most of the media coverage has focused on country level data, which is misleading. Stockholm county has …
SNS-032, a novel inhibitor of cyclin-dependent kinases 2, 7 and 9, blocks transcription of cyclin D1 and Mcl-1, causing cell death in mantle cell lymphoma cell lines
Authors: Rong Chen, Sherri Chubb, Ute Hoch, Rachel Hawtin, Judith Fox, Varsha Gandhi, William Plunkett
Journal: Cancer Research (2008)

756  SNS-032 is a potent, selective inhibitor of cyclin-dependent kinases (Cdk) 2, 7 and 9 that inhibits both the cell cycle and transcription. Cdk7/cyclin H and Cdk9/cyclin T control RNA polymerase II (pol II)-dependent transcription. Phosphorylation of Ser5 (Cdk7) and Ser2 (Cdk9) of the pol II C-terminal domain (CTD) activates transcription initiation and elongation. Because lymphoid malignancies are dependent upon the continual expression of anti-apoptotic proteins for survival, we hypothesize that transient inhibition of transcription will cause a critical decrease in such proteins (e.g., Mcl-1, XIAP) and initiate apoptosis. Thus, Cdk7 and Cdk9 are attractive targets for cancer therapy in this context. Our studies in primary chronic lymphocytic leukemia (CLL) lymphocytes demonstrated that SNS-032 effectively decreases the phosphorylation of pol II CTD and inhibits transcription; this is associated with diminished levels of anti-apoptotic proteins and activation of apoptosis. The present study focuses on mantle cell lymphoma (MCL) cell lines (Granta 519, Jeko-1, Mino and SP-53) to evaluate this hypothesis in a growing cell model. The biology of MCL is characterized by the t(11:14)(q13;q32) translocation, which leads to the over-expression of Cyclin D1 which sustains the malignancy. Interestingly, the transcript and protein of Cyclin D1 are both short-lived, and thus may be targeted by SNS-032, providing further biological context to test this strategy. In addition, Cdk2, which is highly expressed in MCL cells, is also blocked by SNS-032. SNS-032 (0.3 to 1 µM) inhibited the phosphorylation of RNA pol II CTD at both the Ser2 and Ser5 sites; this is associated with inhibition of RNA synthesis in all MCL lines. As a result, the transcripts and protein levels of short lived protein decreased, including Cyclin D1 and Mcl-1, and apoptosis was induced within 24 hr in all cell lines except for Granta, shown by PARP cleavage and the emergence of a subG1 population. This is consistent with SNS-032 acting as a transcriptional inhibitor. Apoptosis was strongly induced by 0.3 µM SNS-032 in Jeko and Mino cells after a 24 hr exposure, despite their deficiency in p53 function, indicating that the SNS-032 induced apoptosis was independent of p53. Although apoptosis was not detected in Granta cells, clonogenic assays showed a strong, time-dependent inhibition of colony formation, with an IC50 of about 50 nM after 24 hr incubation, indicating that SNS-032 effectively jeopardized MCL repopulating ability. Thus, SNS-032 appears to block transcription by inhibition of Cdk7 and Cdk9, an action that leads to the decrease of survival proteins and Cyclin D1, and the death of MCL cell lines.
FRI0385 MUSCLE FUNCTION AND QUALITY BUT NOT MASS PROTECT AGAINST MORE SEVERE KNEE PAIN TRAJECTORIES
Authors: F. Pan, J. Tian, F. Cicuttini, G. Jones
Journal: Annals of the Rheumatic Diseases (2020)

Background: Evidence suggests that periarticular muscles have a role in the pathogenesis of pain, but results have not been consistent. We recently reported that pain population is heterogenous and consists of different subgroups of which the causes and mechanisms differ. Objectives: To examine the association of muscle mass, leg strength, knee extensor strength, low-limb muscle quality with knee pain trajectories. Methods: Data on 975 participants from a population-based older adult cohort study were utilised. Dual-energy X-ray absorptiometry was used to assess muscle/fat mass. Leg strength in both legs and dominant knee extensor strength were measured. Low-limb muscle quality was calculated (i.e. leg strength divided by lower-limb muscle mass). The Western Ontario and McMaster Universities Osteoarthritis Index pain questionnaire was used to measure knee pain at each time-point. Radiographic knee osteoarthritis (ROA) was assessed by X-ray. Group-based trajectory modelling was applied to identify pain trajectories. Multi-nominal logistic regression was used for the analyses. Results: A total of 975 participants [Mean±SD: age 62.2±7.4 years, body mass index (BMI) 27.8±4.6 kg/m 2 and 51% of females] were included in the analysis. Three distinct pain trajectories were identified: ‘Minimal pain’ (53%), ‘Mild pain’ (34%) and ‘Moderate pain’ (13%). In multivariable analysis, both greater total and low-limb muscle mass were associated with an increased risk of ‘Mild pain’ [total muscle mass: relative risk (RR): 1.51 per SD increase, 95%CI: 1.14−1.98; low-limb muscle mass RR: 1.33 per SD increase, 95%CI: 1.07−1.66] and ‘Moderate pain’ [total muscle mass: RR: 2.57 per SD increase, 95%CI: 1.70−3.89); low-limb muscle mass RR: 2.03 per SD increase, 95%CI: 1.47−3.80)] compared to the ‘Minimal pain’ trajectory group. After further adjustment for fat mass, these associations disappeared. Total muscle mass percentage was associated with a reduced risk of being worse pain trajectories. In relative to the ‘Minimal pain’ trajectory group, leg strength, knee extensor strength and quality were associated with a reduced risk of being in more severe pain trajectories after adjustment for covariates (RR=0.56 to 0.71 per SD increase, all P&lt;0.05). Similar results were observed in those with ROA. Conclusion: Muscle percentage, strength and quality, but not muscle mass itself are associated with a reduced risk of being more severe pain trajectories, suggesting that improving muscle composition, muscle function and power are of more clinically relevance to preventing the development and maintenance of worse pain trajectories. Disclosure of Interests: None declared
The meconium microbiota shares more features with the amniotic fluid microbiota than the maternal fecal and vaginal microbiota
Authors: Qiuwen He, Lai-Yu Kwok, Xiaoxia Xi, Zhi Zhong, Teng Ma, Haiyan Xu, Haixia Meng, Fangqing Zhao, Heping Zhang
Journal: Gut Microbes (2020)

The early-life gut microbiota is associated with potential development of diseases in adulthood. The sterile womb paradigm has been challenged by recent reports that revealed the presence of the meconium, amniotic fluid, and placenta microbiome. This study aimed to explore the maternal origin of the microbiota of neonate meconium by using the PacBio single-molecule real-time circular consensus sequencing technology. Such technology could produce high fidelity reads of full-length 16S rRNA genes, improving the sensitivity and specificity of taxonomic profiling. It also reduced the risk of false positives. This study analyzed the full-length 16S rRNA-based microbiota of maternal samples (amniotic fluid, feces, vaginal fluid, saliva) and first-pass meconium of 39 maternal-neonate pairs. Alpha- and beta-diversity analyses revealed sample type-specific microbiota features. Most sample types were dominated by sequences representing different genera (Lactobacillus and Curvibacter in the amniotic fluid and vaginal fluid microbiota; Bacillus and Escherichia/Shigella in the meconium microbiota; Bacteroides and Faecalibacterium in the maternal fecal microbiota; Streptococcus and Prevotella in the maternal saliva microbiota). Moreover, specific operational taxonomic units (OTUs) were identified in all sample types. Dyad analysis revealed common OTUs between the meconium microbiota and microbiota of multiple maternal samples. The meconium microbiota shared more features with the amniotic fluid microbiota than the maternal fecal and vaginal microbiota. Our results strongly suggested that the meconium microbiota was seeded from multiple maternal body sites, and the amniotic fluid microbiota contributed most to the seeding of the meconium microbiota among the investigated maternal body sites.
Electronic reporting improves timeliness and completeness of infectious disease notification, The Netherlands, 2003
Authors: M Ward, P Brandsema, E van Straten, A Bosman
Journal: Eurosurveillance (2005)

In 2002, the internet based reporting system OSIRIS was introduced in the Netherlands and by the end of that year had fully replaced the paper-based reporting system. The objectives of OSIRIS were to improve timeliness and completeness of surveillance data on infectious diseases reported from regional to national level. We compared the timeliness of infectious diseases reported by the conventional paper-based system in 2001 with those reported by OSIRIS in 2003. Two distinct types of delay were compared: total delay: defined as time between sympton onset and reporting at national level and central delay: defined as time between regional and national reporting. Median delays between both systems were compared using the Wilcoxon Rank Sum-Test. We also compared electronic reports received via OSIRIS in 2003 to those received through the conventional system for 2001 for completeness of specific data fields. The Fisher exact test and the Mantel-Haenzel test with Yates correction were used to determine the significance of proportions of completed data fields in each system.
The reliability of the Self‐Assessment Cutaneous Inflammatory Disease Extent Score (SA‐CIDES) and the rule of hands to assess the involved body surface area in psoriasis and eczema
Authors: R. Speeckaert, J. Lambert, L. Delbaere, T. Lesseliers, N. Geel
Journal: British Journal of Dermatology (2020)

The reliability of the Self-Assessment Cutaneous Inflammatory Disease Extent Score (SA-CIDES) and the rule of hands to assess the involved body surface area in psoriasis and eczema
IgGs drive COVID-19 myeloid hyperinflammation
Authors: Matthew D. Park
Journal: Nature reviews. Immunology (2020)

Hoepel, W. et al. Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses. Preprint at bioRxiv https://doi.org/10.1101/2020.07.13.190140 (2020) Article Google Scholar Download references Sinai Immunology Review Project, Icahn School of Medicine at Mount Sinai, New York, NY, USA Matthew D. Park You can also search for this author in PubMed Google Scholar Correspondence to Matthew D. Park. The author declares no competing interests. Reprints and Permissions Park, M.D. IgGs drive COVID-19 myeloid hyperinflammation. Nat Rev Immunol (2020). https://doi.org/10.1038/s41577-020-00415-9 Download citation Published: 31 July 2020 DOI: https://doi.org/10.1038/s41577-020-00415-9
The role and contribution of treatment and imaging modalities in global cervical cancer management: survival estimates from a simulation-based analysis
Authors: Zachary J Ward, Surbhi Grover, Andrew M Scott, Sungmin Woo, Dina H Salama, Elizabeth C Jones, Tarek El-Diasty, Bradley R Pieters, Edward L Trimble, H Alberto Vargas, Hedvig Hricak, Rifat Atun
Journal: The Lancet Oncology (2020)
Abstract 15612: Activation of Invariant Natural Killer T Cells Ameliorates Doxorubicin-Induced Cardiomyopathy
Authors: Masashi Sada, Shouji Matsushima, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Tomonori Tadokoro, Nobuyuki Enzan, Taishi Yamamoto, Hiroko Deguchi, Masataka Ikeda, Tomomi Ide, Hiroyuki Tsutsui
Journal: Circulation (2019)

Background: Invariant natural killer T (iNKT) cells orchestrate tissue inflammation via regulating various cytokine productions. Activation of iNKT cells have been previously reported to exert prot...
Scutellarin inhibits caspase-11 activation and pyroptosis in macrophages via regulating PKA signaling
Authors: Jiezhou Ye, Bo Zeng, Meiyan Zhong, Hongchun Li, Lihui Xu, Junxiang Shu, Yaofeng Wang, Fan Yang, Chunsu Zhong, Xunjia Ye, Xianhui He, Dongyun Ouyang
Journal: Acta Pharmaceutica Sinica B (2020)

Inflammatory caspase-11 senses and is activated by intracellular lipopolysaccharide (LPS) leading to pyroptosis that has critical role in defensing against bacterial infection, whereas its excess activation under pathogenic circumstances may cause various inflammatory diseases. However, there are few known drugs that can control caspase-11 activation. We report here that scutellarin, a flavonoid from Erigeron breviscapus, acted as an inhibitor for caspase-11 activation in macrophages. Scutellarin dose-dependently inhibited intracellular LPS-induced release of caspase-11p26 (indicative of caspase-11 activation) and generation of N-terminal fragment of gasdermin D (GSDMD-NT), leading to reduced pyroptosis. It also suppressed the activation of non-canonical nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome as evidenced by reduced apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and decreased interleukin-1 beta (IL-1β) and caspase-1p10 secretion, whereas the NLRP3-specific inhibitor MCC950 only inhibited IL-1β and caspase-1p10 release and ASC speck formation but not pyroptosis. Scutellarin also suppressed LPS-induced caspase-11 activation and pyroptosis in RAW 264.7 cells lacking ASC expression. Moreover, scutellarin treatment increased Ser/Thr phosphorylation of caspase-11 at protein kinase A (PKA)-specific sites, and its inhibitory action on caspase-11 activation was largely abrogated by PKA inhibitor H89 or by adenylyl cyclase inhibitor MDL12330A. Collectively, our data indicate that scutellarin inhibited caspase-11 activation and pyroptosis in macrophages at least partly via regulating the PKA signaling pathway.
Mass drug administration with azithromycin for trachoma elimination and the population structure of Streptococcus pneumoniae in the nasopharynx
Authors: Rebecca A. Gladstone, Ebrima Bojang, John Hart, Emma M. Harding-Esch, David Mabey, Ansumana Sillah, Robin L. Bailey, Sarah E. Burr, Anna Roca, Stephen D. Bentley, Martin J. Holland
Journal: Clinical Microbiology and Infection (2020)

Mass drug administration (MDA) with azithromycin for trachoma elimination reduces nasopharyngeal carriage of Streptococcus pneumoniae in the short term. We evaluated S. pneumoniae carried in the nasopharynx before and after a round of azithromycin MDA to determine whether MDA was associated with changes in pneumococcal population structure and resistance.We analysed 514 pneumococcal whole genomes randomly selected from nasopharyngeal samples collected in two Gambian villages that received three annual rounds of MDA for trachoma elimination. The 514 samples represented 293 participants, of which 75% were children aged 0-9 years, isolated during three cross-sectional surveys (CSSs) conducted before the third round of MDA (CSS-1) and at 1 (CSS-2) and 6 (CSS-3) months after MDA. Bayesian Analysis of Population Structure (BAPS) was used to cluster related isolates by capturing variation in the core genome. Serotype and multilocus sequence type were inferred from the genotype. Antimicrobial resistance determinants were identified from assemblies, including known macrolide resistance genes.Twenty-seven BAPS clusters were assigned. These consisted of 81 sequence types (STs). Two BAPS clusters not observed in CSS-1 (n = 109) or CSS-2 (n = 69), increased in frequency in CSS-3 (n = 126); BAPS20 (8.73%, p 0.016) and BAPS22 (7.14%, p 0.032) but were not associated with antimicrobial resistance. Macrolide resistance within BAPS17 increased after treatment (CSS-1 n = 0/6, CSS-2/3 n = 5/5, p 0.002) and was carried on a mobile transposable element that also conferred resistance to tetracycline.Limited changes in pneumococcal population structure were observed after the third round of MDA, suggesting treatment had little effect on the circulating lineages. An increase in macrolide resistance within one BAPS highlights the need for antimicrobial resistance surveillance in treated villages.