tbuckley/cabot-search huggingface dataset:
An Evaluation of the Safety of Pilots With Insulin-Treated Diabetes in Europe Flying Commercial and Noncommercial Aircraft
Authors: Gillian L. Garden, Julia L. Hine, Stuart J. Mitchell, Ewan J. Hutchison, Thomas P. Gaffney, Veronika Hofmann, Brian M. Frier, Kenneth M. Shaw, Simon R. Heller, Gerd Koehler, Graham A. Roberts, David L. Russell-Jones
Journal: Diabetes Care (2020)

The risk of hypoglycemia in people with insulin-treated diabetes has debarred them from certain "safety-critical" occupations, including flying commercial aircraft. This report evaluates the effectiveness of a protocol enabling a large cohort of insulin-treated pilots to fly commercially.This was an observational study of pilots with insulin-treated diabetes who were granted medical certification to fly commercial and noncommercial aircraft. Clinical details, pre- and in-flight (hourly and 30 min before landing) blood glucose values were correlated against the protocol-specified ranges: green (5-15 mmol/L), amber (low, 4-4.9 mmol/L; high, 15.1-20 mmol/L), and red (low, <4 mmol/L; high, >20 mmol/L).A total of 49 pilots with type 1 (84%) or type 2 (16%) diabetes who had been issued class 1 or class 2 certificates were studied. Median diabetes duration was 10.9 years. Mean HbA1c was 7.2% (55.0 mmol/mol) before certification and 7.2% (55.1 mmol/mol) after certification (P = 0.97). Blood glucose values (n = 38,621) were recorded during 22,078 flying hours. Overall, 97.69% of measurements were within the green range, 1.42% within the low amber range, and 0.75% within the high amber range. Only 0.12% of readings were within the low red range and 0.02% within the high red range. Out-of-range readings declined from 5.7% in 2013 to 1.2% in 2019. No episodes of pilot incapacitation occurred, and glycemic control did not deteriorate.The protocol is practical to implement, and no events compromising safety were reported. This study represents what is, to our knowledge, the most extensive data set from people with insulin-treated diabetes working in a "safety-critical" occupation, which may be relevant when estimating risk in other safety-critical occupations.
Pervasive Selection against MicroRNA Target Sites in Human Populations
Authors: Andrea Hatlen, Antonio Marco
Journal: Molecular Biology and Evolution (2020)

Abstract MicroRNA target sites are often conserved during evolution and purifying selection to maintain such sites is expected. On the other hand, comparative analyses identified a paucity of microRNA target sites in coexpressed transcripts, and novel target sites can potentially be deleterious. We proposed that selection against novel target sites pervasive. The analysis of derived allele frequencies revealed that, when the derived allele is a target site, the proportion of nontarget sites is higher than expected, particularly for highly expressed microRNAs. Thus, new alleles generating novel microRNA target sites can be deleterious and selected against. When we analyzed ancestral target sites, the derived (nontarget) allele frequency does not show statistical support for microRNA target allele conservation. We investigated the joint effects of microRNA conservation and expression and found that selection against microRNA target sites depends mostly on the expression level of the microRNA. We identified microRNA target sites with relatively high levels of population differentiation. However, when we analyze separately target sites in which the target allele is ancestral to the population, the proportion of single-nucleotide polymorphisms with high Fst significantly increases. These findings support that population differentiation is more likely in target sites that are lost than in the gain of new target sites. Our results indicate that selection against novel microRNA target sites is prevalent and, although individual sites may have a weak selective pressure, the overall effect across untranslated regions is not negligible and should be accounted when studying the evolution of genomic sequences.
Filgotinib suppresses HIV-1–driven gene transcription by inhibiting HIV-1 splicing and T cell activation
Authors: Yang-Hui Jimmy Yeh, Katharine M. Jenike, Rachela M. Calvi, Jennifer Chiarella, Rebecca Hoh, Steven G. Deeks, Ya-Chi Ho
Journal: Journal of Clinical Investigation (2020)

Despite effective antiretroviral therapy, HIV-1–infected cells continue to produce viral antigens and induce chronic immune exhaustion. We propose to identify HIV-1–suppressing agents that can inhibit HIV-1 reactivation and reduce HIV-1–induced immune activation. Using a newly developed dual-reporter system and a high-throughput drug screen, we identified FDA-approved drugs that can suppress HIV-1 reactivation in both cell line models and CD4+ T cells from virally suppressed HIV-1–infected individuals. We identified 11 cellular pathways required for HIV-1 reactivation as druggable targets. Using differential expression analysis, gene set enrichment analysis, and exon-intron landscape analysis, we examined the impact of drug treatment on the cellular environment at a genome-wide level. We identified what we believe to be a new function of a JAK inhibitor, filgotinib, that suppresses HIV-1 splicing. First, filgotinib preferentially suppresses spliced HIV-1 RNA transcription. Second, filgotinib suppresses HIV-1–driven aberrant cancer-related gene expression at the integration site. Third, we found that filgotinib suppresses HIV-1 transcription by inhibiting T cell activation and by modulating RNA splicing. Finally, we found that filgotinib treatment reduces the proliferation of HIV-1–infected cells. Overall, the combination of a drug screen and transcriptome analysis provides systematic understanding of cellular targets required for HIV-1 reactivation and drug candidates that may reduce HIV-1–related immune activation.
ESGO–SIOPE guidelines for the management of adolescents and young adults with non-epithelial ovarian cancers
Authors: Cristiana Sessa, Dominik T Schneider, François Planchamp, Katja Baust, Elena Ioana Braicu, Nicole Concin, Jan Godzinski, W Glenn McCluggage, Daniel Orbach, Patricia Pautier, Fedro A Peccatori, Philippe Morice, Gabriele Calaminus
Journal: The Lancet Oncology (2020)
Pneumonia vaccination timing in relation to starting conventional synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis
Authors: Ruth E Costello, Jenny H Humphreys, Kevin L Winthrop, William G Dixon
Journal: Annals of the Rheumatic Diseases (2020)

Patients with rheumatoid arthritis (RA) are at increased risk of infections, and pneumococcal vaccination is recommended. With some evidence that pneumococcal vaccinations are not as effective when administered after starting disease-modifying antirheumatic drugs (DMARDs), in particular methotrexate,1 guidance on when best to vaccinate, in relation to DMARDs, has become more consistent in recent years. Early European League Against Rheumatism guidelines (2011) only referred to B-cell depleting biological DMARDs, but more recent guidelines (2019)2 recommend vaccination prior to commencement of all DMARD types. Since 2011, British Society for Rheumatology (BSR) guidance advises vaccination prior to starting any DMARD.3 4 The aims of this study were to explore the timing of pneumococcal vaccination in patients with RA in relation to starting conventional synthetic DMARDs (csDMARDs) and examine whether this has changed over time.

This was a cross-sectional study using data from the Clinical Practice Research Datalink GOLD (UK primary care electronic health records). The study period was from 1 January 2000 to 31 December 2018. To be included, patients were required to (1) have a diagnosis of RA identified …
The Effect of Tube Location on Corneal Endothelial Cells in Patients with Ahmed Glaucoma Valve
Authors: Qi Zhang, Yingna Liu, Sukhumal Thanapaisal, Julius Oatts, Yetao Luo, Gui-Shuang Ying, Junming Wang, Stephen D. McLeod, Steven J. Gedde, Ying Han
Journal: Ophthalmology (2020)
Assessment of Racial Differences in Rates of Autopsy in the US, 2008-2017
Authors: Arjun Gupta, Naveen Premnath, Pei-Lun Kuo, Ramy Sedhom, Otis W. Brawley, Fumiko Chino
Journal: JAMA Internal Medicine (2020)

This cohort study assesses the racial differences in rates of autopsy in groups of decedents older than 18 years from 2008 to 2017 in the US Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database.
A phase I study of toripalimab, an anti‐PD‐1 antibody, in patients with refractory malignant solid tumors
Authors: Xiao‐Li Wei, Chao Ren, Feng‐Hua Wang, Yang Zhang, Hong‐Yun Zhao, Ben‐Yan Zou, Zhi‐Qiang Wang, Miao‐Zhen Qiu, Dong‐Sheng Zhang, Hui‐Yan Luo, Feng Wang, Sheng Yao, Rui‐Hua Xu
Journal: Cancer Communications (2020)

Abstract Background Several programmed cell death ligand 1 (PD‐L1)/programmed cell death protein 1 (PD‐1) antibodies have been approved for cancer treatment worldwide. Their pharmacokinetic and pharmacodynamic characteristics have been reported mainly in western countries, but related data in Chinese patients are limited. This study was conducted to investigate the safety, efficacy, pharmacokinetics, and pharmacodynamics of an anti‐PD‐1 antibody, toripalimab, in Chinese patients. Methods A single‐center phase I study was conducted in Sun Yat‐sen University Cancer Center. Eligible patients were adults with histologically confirmed, treatment‐refractory, advanced, solitary malignant tumors. Toripalimab was intravenously infused every 2 weeks in dose‐escalating cohorts at 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, and 240 mg. The study followed standard 3 + 3 design. Results Between 15 th March 2016 and 27 th September 2016, 25 patients were enrolled, of whom 3 (12.0%), 7 (28.0%), 6 (24.0%), 6 (24.0%), 3 (12.0%) received 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, and 240 mg toripalimab, respectively. After a median follow‐up time of 5.0 months (range: 1.5‐19.8 months), we observed that the commonest treatment‐related adverse events (TRAEs) were fatigue (64.0%) and rash (24.0%). No grade 3 or higher TRAEs were observed. No dose‐limiting toxicity, treatment‐related serious adverse events (SAEs), or treatment‐related death occurred. Objective response rate was 12.5%. The half‐life of toripalimab was 150‐222 h after a single dose infusion. Most patients, including those from the 0.3 mg/kg group, maintained complete PD‐1 receptor occupancy (&gt; 80%) on activated T cells since receiving the first dose of toripalimab. Conclusions Toripalimab is a promising anti‐PD‐1 antibody, which was well tolerated and demonstrated anti‐tumor activity in treatment‐refractory advanced solitary malignant tumors. Further exploration in various tumors and combination therapies is warranted.
Controlling timing and location in vaccines
Authors: Darrell J. Irvine, Aereas Aung, Murillo Silva
Journal: Advanced Drug Delivery Reviews (2020)

Vaccines are one of the most powerful technologies supporting public health. The adaptive immune response induced by immunization arises following appropriate activation and differentiation of T and B cells in lymph nodes. Among many parameters impacting the resulting immune response, the presence of antigen and inflammatory cues for an appropriate temporal duration within the lymph nodes, and further within appropriate subcompartments of the lymph nodes– the right timing and location– play a critical role in shaping cellular and humoral immunity. Here we review recent advances in our understanding of how vaccine kinetics and biodistribution impact adaptive immunity, and the underlying immunological mechanisms that govern these responses. We discuss emerging approaches to engineer these properties for future vaccines, with a focus on subunit vaccines.
Relative contribution of nonstructural protein 1 in dengue pathogenesis
Authors: Pei Xuan Lee, Donald Heng Rong Ting, Clement Peng Hee Boey, Eunice Tze Xin Tan, Janice Zuo Hui Chia, Fakhriedzwan Idris, Yukei Oo, Li Ching Ong, Yen Leong Chua, Chanditha Hapuarachchi, Lee Ching Ng, Sylvie Alonso
Journal: The Journal of Experimental Medicine (2020)

Dengue is a major public health concern in the tropical and subtropical world, with no effective treatment. The controversial live attenuated virus vaccine Dengvaxia has boosted the pursuit of subunit vaccine approaches, and nonstructural protein 1 (NS1) has recently emerged as a promising candidate. However, we found that NS1 immunization or passive transfer of NS1 antibodies failed to confer protection in symptomatic dengue mouse models using two non–mouse-adapted DENV2 strains that are highly virulent. Exogenous administration of purified NS1 also failed to worsen in vivo vascular leakage in sublethally infected mice. Neither method of NS1 immune neutralization changed the disease outcome of a chimeric strain expressing a vascular leak-potent NS1. Instead, virus chimerization involving the prME structural region indicated that these proteins play a critical role in driving in vivo fitness and virulence of the virus, through induction of key proinflammatory cytokines. This work highlights that the pathogenic role of NS1 is DENV strain dependent, which warrants reevaluation of NS1 as a universal dengue vaccine candidate.
Ipilimumab plus nivolumab for patients with metastatic uveal melanoma: a multicenter, retrospective study
Authors: Yana G Najjar, Kristina Navrazhina, Fei Ding, Roma Bhatia, Katy Tsai, Kelly Abbate, Barbara Durden, Zeynep Eroglu, Shailender Bhatia, Song Park, Akansha Chowdhary, Sunandana Chandra, Jonathan Kennedy, Igor Puzanov, Marc Ernstoff, Pankit Vachhani, Joseph Drabick, Arun Singh, Tan Xu, Jessica Yang, Richard Carvajal, Daniel Manson, John M Kirkwood, Justine Cohen, Ryan Sullivan, Douglas Johnson, Pauline Funchain, Alexander Shoushtari
Journal: Journal for ImmunoTherapy of Cancer (2020)

Uveal melanoma (UM) is the most common intraocular malignancy in adults. In contrast to cutaneous melanoma (CM), there is no standard therapy, and the efficacy and safety of dual checkpoint blockade with nivolumab and ipilimumab is not well defined.
Obstructive Sleep Apnea, Other Sleep Characteristics, and Risk of CKD in the Atherosclerosis Risk in Communities Sleep Heart Health Study
Authors: Kelsie M. Full, Chandra L. Jackson, Casey M. Rebholz, Kunihiro Matsushita, Pamela L. Lutsey
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement Obstructive sleep apnea may be associated with development of CKD, but because individuals with this sleep disorder also are at increased risk for established CKD risk factors such as obesity, hypertension, and type 2 diabetes, more evidence is needed to clarify the relationship. To examine the association between this common sleep disorder and risk of incident CKD (stage ≥3) in late midlife, the authors leveraged polysomnography data from a prospective community-based cohort of 1525 adults who were free of CKD and followed for a median of 19 years. Although severe obstructive sleep apnea was associated with an increased risk of incident CKD, this association was not independent of obesity. Given the high prevalence of obstructive sleep apnea, CKD, and obesity, further investigation in this area is needed. Background Obstructive sleep apnea may be associated with development of CKD through hypoxia, inflammation, and oxidative stress. Individuals with this sleep disorder are also at increased risk for established CKD risk factors, including obesity, hypertension, and type 2 diabetes. Methods We examined the association between obstructive sleep apnea, other sleep characteristics, and risk of incident CKD (stage 3 or higher) in 1525 participants (mean age, 62.5 years; 52.4% women) in the Atherosclerosis Risk in Communities (ARIC) study who completed in-home polysomnography assessments. We used the apnea-hypopnea index (events per hour) to define obstructive sleep apnea severity (normal, &lt;5.0; mild, 5.0–14.9; moderate, 15.0–29.9; and severe, ≥30.0) and defined incident CKD (stage 3 or higher) as eGFR&lt;60 ml/min per 1.73 m 2 and ≥25% decline from baseline, CKD-related hospitalization or death, or ESKD. Cox proportional hazards regression was used to estimate obstructive sleep apnea severity with risk of incident CKD, adjusting for demographics, lifestyle behaviors, and cardiometabolic conditions. Results During 19 years (median) of follow-up, 461 CKD events occurred. After adjustment for demographics and lifestyle behaviors, severe obstructive sleep apnea associated with increased risk of CKD (hazard ratio [HR], 1.51; 95% confidence interval [95% CI], 1.08 to 2.10), which was attenuated after adjustment for body mass index (HR, 1.07; 95% CI, 0.75 to 1.52). No other sleep characteristics associated with incident CKD. Conclusions We found a link between obstructive sleep apnea and an elevated risk of stage 3 CKD or higher, but this association was no longer significant after adjusting for obesity, a risk factor for both conditions. Given the high prevalence of obstructive sleep apnea and CKD among adults, further investigation is warranted.
Long-term outcome of endoscopic resection for intramucosal esophageal squamous cell cancer: a secondary analysis of the Japan Esophageal Cohort study
Authors: Ichiro Oda, Yuichi Shimizu, Toshiyuki Yoshio, Chikatoshi Katada, Tetsuji Yokoyama, Tomonori Yano, Haruhisa Suzuki, Satoshi Abiko, Kenichi Takemura, Tomoyuki Koike, Kohei Takizawa, Motohiro Hirao, Hiroyuki Okada, Takako Yoshii, Atsushi Katagiri, Takenori Yamanouchi, Yasumasa Matsuo, Hirofumi Kawakubo, Nozomu Kobayashi, Tadakazu Shimoda, Atsushi Ochiai, Hideki Ishikawa, Akira Yokoyama, Manabu Muto
Journal: Endoscopy (2020)

Background Prospectively collected long-term data of patients undergoing endoscopic resection for superficial esophageal squamous cell carcinoma (ESCC) are limited. The aim of this study was to determine the prospectively collected long-term outcomes of endoscopic resection for ESCC as a secondary analysis of the Japan Esophageal Cohort (JEC) study. Methods Patients who underwent endoscopic resection of intramucosal ESCC at 16 institutions between September 2005 and May 2010 were enrolled in the JEC study. All patients underwent endoscopic examination with iodine staining at 3 and 6 months after resection, and every 6 months thereafter. We investigated clinical courses after endoscopic resection, survival rates, and cumulative incidence of metachronous ESCC. Results 330 patients (mean age 67.0 years) with 396 lesions (mean size 20.4 mm) were included in the analysis. Lesions were diagnosed as high-grade intraepithelial neoplasia in 17.4 % and as squamous cell carcinoma in 82.6 % (limited to epithelium in 28.4 %, to lamina propria in 55.4 %, and to muscularis mucosa in 16.2 %). En bloc resection was achieved in 291 (73.5 %). The median follow-up period was 49.4 months. Local recurrences occurred in 13 patients (3.9 %) and were treated by endoscopic procedures. Lymph node metastasis occurred in two patients (0.6 %) after endoscopic resection. The 5-year overall, disease-specific, and metastasis-free survival rates were 95.1 %, 99.1 %, and 94.6 %, respectively. The 5-year cumulative incidence rate of metachronous ESCC was 25.7 %. Conclusions Our study demonstrated that endoscopic resection is an effective treatment for intramucosal ESCC, with favorable long-term outcomes.
Ensuring Uptake of Vaccines against SARS-CoV-2
Authors: Michelle M. Mello, Ross D. Silverman, Saad B. Omer
Journal: New England Journal of Medicine (2020)

Ensuring Uptake of Vaccines against SARS-CoV-2 Although a SARS-CoV-2 vaccine remains months to years away, now is the time to develop a policy strategy to ensure vaccine uptake — including consider...
Judge approves £2m award for girl brain damaged at birth after both sides halt court case
Authors: Clare Dyer
Journal: BMJ (2020)

A judge has approved a £2m (€2.2m; $2.5m) settlement from the NHS for a five year old girl who was brain damaged at birth after both sides agreed to halt a High Court trial part way through.1

Mr Justice Martin Spencer approved the deal after two days of evidence but before hearing from the expert obstetric witness for the defendant, Royal Free London NHS Foundation Trust.

Settlements usually happen before a trial starts but Spencer said it had occurred in this case at a stage when the matter was still “wholly undecided” in his mind. He said that the two results were both in play, “namely …
Neuronal interleukin-1 receptors mediate pain in chronic inflammatory diseases
Authors: Benoit Mailhot, Marine Christin, Nicolas Tessandier, Chaudy Sotoudeh, Floriane Bretheau, Roxanne Turmel, Ève Pellerin, Feng Wang, Cyril Bories, Charles Joly-Beauparlant, Yves De Koninck, Arnaud Droit, Francesca Cicchetti, Grégory Scherrer, Eric Boilard, Reza Sharif-Naeini, Steve Lacroix
Journal: The Journal of Experimental Medicine (2020)

Chronic pain is a major comorbidity of chronic inflammatory diseases. Here, we report that the cytokine IL-1β, which is abundantly produced during multiple sclerosis (MS), arthritis (RA), and osteoarthritis (OA) both in humans and in animal models, drives pain associated with these diseases. We found that the type 1 IL-1 receptor (IL-1R1) is highly expressed in the mouse and human by a subpopulation of TRPV1+ dorsal root ganglion neurons specialized in detecting painful stimuli, termed nociceptors. Strikingly, deletion of the Il1r1 gene specifically in TRPV1+ nociceptors prevented the development of mechanical allodynia without affecting clinical signs and disease progression in mice with experimental autoimmune encephalomyelitis and K/BxN serum transfer–induced RA. Conditional restoration of IL-1R1 expression in nociceptors of IL-1R1–knockout mice induced pain behavior but did not affect joint damage in monosodium iodoacetate–induced OA. Collectively, these data reveal that neuronal IL-1R1 signaling mediates pain, uncovering the potential benefit of anti–IL-1 therapies for pain management in patients with chronic inflammatory diseases.
Impaired airway epithelial cell wound‐healing capacity is associated with airway remodelling following RSV infection in severe preschool wheeze
Authors: Cecilia K. Andersson, Jua Iwasaki, James Cook, Polly Robinson, Prasad Nagakumar, Sofia Mogren, Louise Fleming, Andrew Bush, Sejal Saglani, Clare M. Lloyd
Journal: Allergy (2020)

Respiratory syncytial virus (RSV) causes exacerbations of asthma and preschool wheeze (PSW). However, the anti-viral and repair responses of the bronchial epithelium in children with severe therapy-resistant asthma (STRA) and PSW are poorly understood.Children with STRA (age 12 [6-16] years), PSW (age 2 [1-5] years) and non-asthmatic controls (age 7 [2-14] years) underwent bronchoscopy with endobronchial brushings and biopsies. Anti-viral, wound injury responses were quantified in biopsies and primary bronchial epithelial cells (PBECs) in response to RSV, poly(I:C), house dust mite (HDM) or IL-33 using RT-qPCR, Luminex and live cell imaging. Collagen deposition and tissue expression of epithelial growth factor receptor (EGFR), IL-33 and receptor ST2 were investigated in bronchial biopsies.PBECs from STRA and PSW had increased TLR3 gene expression and increased secretion of anti-viral and pro-inflammatory cytokines (IFN-γ, IL-6 and IL-13) in response to RSV compared to controls. Exposure of PBECs to concomitant TLR3 agonist poly(I:C) and HDM resulted in a significant reduction in epithelial cell proliferation in PSW compared to controls. Wound-healing was also impaired in PSW compared to controls at baseline and following IL-33 stimulation. In addition, tissue EGFR expression was significantly reduced in PSW and correlated with collagen deposition in endobronchial biopsies.Despite increased anti-viral responses, preschool children with severe wheeze had impaired airway epithelial proliferative responses following damage. This might be connected to the low expression of EGFR in PSW which may affect epithelial function and contribute to asthma pathogenesis.