tbuckley/cabot-search huggingface dataset:
One hundred and ten years of Allergen Immunotherapy: A journey from empiric observation to evidence
Authors: Oliver Pfaar, Jean Bousquet, Stephen R. Durham, Jörg Kleine‐Tebbe, Mark Larché, Graham Roberts, Mohamed H. Shamji, Roy Gerth van Wijk
Journal: Allergy (2021)

One hundred and ten years after Noon's first clinical report of the subcutaneous application of allergen extracts, allergen immunotherapy (AIT) has evolved as the most important pillar of the treatment of allergic patients. It is the only disease-modifying treatment option available and the evidence for its clinical efficacy and safety is broad and undisputed. Throughout recent decades, more insights into the underlying mechanisms, in particular the modulation of innate and adaptive immune responses, have been described. AIT is acknowledged by worldwide regulatory authorities, and following the regulatory guidelines for product development, AIT products are subject to a rigorous evaluation before obtaining market authorization. Knowledge and practice are anchored in international guidelines, such as the recently published series of the European Academy of Allergy and Clinical Immunology (EAACI). Innovative approaches continue to be further developed with the focus on clinical improvement by, for example, the usage of adjuvants, peptides, recombinants, modification of allergens, new routes of administration, and the concomitant use of biologicals. In addition, real-life data provide complementary and valuable information on the effectiveness and tolerability of this treatment option in the clinical routine. New mobile health technologies and big-data approaches will improve daily treatment convenience, adherence, and efficacy of AIT. However, the current coronavirus disease 2019 (COVID-19) pandemic has also had some implications for the feasibility and practicability of AIT. Taken together, AIT as the only disease-modifying therapy in allergic diseases has been broadly investigated over the past 110 years laying the path for innovations and further improvement.
Abstract 17909: Association of Neighborhood Socioeconomic Status with Angina, Rehospitalization, and Mortality After Acute Myocardial Infarction
Authors: Brian Wayda, Sachin J Shah, Donna M Buchanan, Philip G Jones, Fengming Tang, Kensey Gosch, John A Spertus, Harlan M Krumholz
Journal: Circulation (2012)

Background Although low socioeconomic status (SES) is associated with increased mortality after acute myocardial infarction (AMI), few studies have examined the influence of both patients’ personal...
Role of Balloon Aortic Valvuloplasty in the Management of Aortic Stenosis
Authors: P. Syamasundar Rao
Journal: Clinical Cardiology and Cardiovascular Interventions (2021)

Balloon aortic valvuloplasty (BAV) provides an excellent alternative to surgical intervention and has become the preferred intervention for initial palliation for aortic stenosis in neonates, infants, children, adolescents, and young adults. The elderly patients with calcific aortic stenosis do not benefit from BAV. With the exception of neonates, most patients can be discharged home within 24-hours of the procedure. Although there is definitive evidence for pressure gradient relief immediately after as well as at follow-up and postponement of surgical intervention following BAV, the progression of aortic insufficiency at late follow up remain a major concern. In the neonatal population, severe aortic insufficiency may develop requiring surgical intervention. Despite these limitations, balloon aortic valvuloplasty is currently considered as therapeutic procedure of choice in the management of congenital aortic stenosis in the pediatric and young adult population. Careful follow-up to detect recurrence of stenosis and development of significant aortic insufficiency is recommended.
Local magnetic delivery of adeno-associated virus AAV2(quad Y-F)-mediated BDNF gene therapy restores hearing after noise injury
Authors: Subhendu Mukherjee, Maya Kuroiwa, Wendy Oakden, Brandon T. Paul, Ayesha Noman, Joseph Chen, Vincent Lin, Andrew Dimitrijevic, Greg Stanisz, Trung N. Le
Journal: Molecular Therapy (2021)

Moderate noise exposure may cause acute loss of cochlear synapses without affecting the cochlear hair cells and hearing threshold; thus, it remains "hidden" to standard clinical tests. This cochlear synaptopathy is one of the main pathologies of noise-induced hearing loss (NIHL). There is no effective treatment for NIHL, mainly because of the lack of a proper drug-delivery technique. We hypothesized that local magnetic delivery of gene therapy into the inner ear could be beneficial for NIHL. In this study, we used superparamagnetic iron oxide nanoparticles (SPIONs) and a recombinant adeno-associated virus (AAV) vector (AAV2(quad Y-F)) to deliver brain-derived neurotrophic factor (BDNF) gene therapy into the rat inner ear via minimally invasive magnetic targeting. We found that the magnetic targeting effectively accumulates and distributes the SPION-tagged AAV2(quad Y-F)-BDNF vector into the inner ear. We also found that AAV2(quad Y-F) efficiently transfects cochlear hair cells and enhances BDNF gene expression. Enhanced BDNF gene expression substantially recovers noise-induced BDNF gene downregulation, auditory brainstem response (ABR) wave I amplitude reduction, and synapse loss. These results suggest that magnetic targeting of AAV2(quad Y-F)-mediated BDNF gene therapy could reverse cochlear synaptopathy after NIHL. Moderate noise exposure may cause acute loss of cochlear synapses without affecting the cochlear hair cells and hearing threshold; thus, it remains "hidden" to standard clinical tests. This cochlear synaptopathy is one of the main pathologies of noise-induced hearing loss (NIHL). There is no effective treatment for NIHL, mainly because of the lack of a proper drug-delivery technique. We hypothesized that local magnetic delivery of gene therapy into the inner ear could be beneficial for NIHL. In this study, we used superparamagnetic iron oxide nanoparticles (SPIONs) and a recombinant adeno-associated virus (AAV) vector (AAV2(quad Y-F)) to deliver brain-derived neurotrophic factor (BDNF) gene therapy into the rat inner ear via minimally invasive magnetic targeting. We found that the magnetic targeting effectively accumulates and distributes the SPION-tagged AAV2(quad Y-F)-BDNF vector into the inner ear. We also found that AAV2(quad Y-F) efficiently transfects cochlear hair cells and enhances BDNF gene expression. Enhanced BDNF gene expression substantially recovers noise-induced BDNF gene downregulation, auditory brainstem response (ABR) wave I amplitude reduction, and synapse loss. These results suggest that magnetic targeting of AAV2(quad Y-F)-mediated BDNF gene therapy could reverse cochlear synaptopathy after NIHL.
Physical activity, sedentary behaviour and incidence of obstructive sleep apnoea in three prospective US cohorts
Authors: Yue Liu, Lin Yang, Meir J. Stampfer, Susan Redline, Shelley S. Tworoger, Tianyi Huang
Journal: European Respiratory Journal (2021)

Background Reduced physical activity and increased sedentary behaviour may independently contribute to the development of obstructive sleep apnoea (OSA) through increased adiposity, inflammation, insulin resistance and body fluid retention. However, epidemiological evidence remains sparse and is primarily limited to cross-sectional studies. Methods We prospectively followed 50 332 women from the Nurses’ Health Study (2002–2012), 68 265 women from the Nurses’ Health Study II (1995–2013) and 19 320 men from the Health Professionals Follow-up Study (1996–2012). Recreational physical activity (quantified by metabolic equivalent of task (MET)-h per week) and sitting time spent watching TV and at work/away from home were assessed by questionnaires every 2–4 years. Physician-diagnosed OSA was identified by validated self-report. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals for OSA incidence associated with physical activity and sedentary behaviour. Results During 2 004 663 person-years of follow-up, we documented 8733 incident OSA cases. After adjusting for potential confounders, the pooled HR for OSA comparing participants with ≥36.0 versus &lt;6.0 MET-h per week of physical activity was 0.46 (95% CI 0.43–0.50; p trend &lt;0.001). Compared with participants spending &lt;4.0 h per week sitting watching TV, the multivariable-adjusted HR was 1.78 (95% CI 1.60–1.98) for participants spending ≥28.0 h per week (p trend &lt;0.001). The comparable HR was 1.49 (95% CI 1.38–1.62) for sitting hours at work/away from home (p trend &lt;0.001). With additional adjustment for several metabolic factors, including body mass index and waist circumference, the associations with physical activity and sitting hours at work/away from home were attenuated but remained significant (p trend &lt;0.001), whereas the association with sitting hours watching TV was no longer statistically significant (p trend =0.18). Conclusions Higher levels of physical activity and fewer sedentary hours were associated with lower OSA incidence. The potential mediating role of metabolic factors in the association between sedentary behaviour and OSA incidence may depend on the type of sedentary behaviour. Our results suggest that promoting an active lifestyle may reduce OSA incidence.
Clinician Conceptualization of the Benefits of Treatments for Individual Patients
Authors: Daniel J. Morgan, Lisa Pineles, Jill Owczarzak, Larry Magder, Laura Scherer, Jessica P. Brown, Chris Pfeiffer, Chris Terndrup, Luci Leykum, David Feldstein, Andrew Foy, Deborah Stevens, Christina Koch, Max Masnick, Scott Weisenberg, Deborah Korenstein
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Knowing the expected effect of treatment on an individual patient is essential for patient care. <h3>Objective</h3> To explore clinicians' conceptualizations of the chance that treatments will decrease the risk of disease outcomes. <h3>Design, Setting, and Participants</h3> This survey study of attending and resident physicians, nurse practitioners, and physician assistants was conducted in outpatient clinical settings in 8 US states from June 2018 to November 2019. The survey was an in-person, paper, 26-item survey in which clinicians were asked to estimate the probability of adverse disease outcomes and expected effects of therapies for diseases common in primary care. <h3>Main Outcomes and Measures</h3> Estimated chance that treatments would benefit an individual patient. <h3>Results</h3> Of 723 clinicians, 585 (81%) responded, and 542 completed all the questions necessary for analysis, with a median (interquartile range [IQR]) age of 32 (29-44) years, 287 (53%) women, and 294 (54%) White participants. Clinicians consistently overestimated the chance that treatments would benefit an individual patient. The median (IQR) estimated chance that warfarin would prevent a stroke in the next year was 50% (5%-80%) compared with scientific evidence, which indicates an absolute risk reduction (ARR) of 0.2% to 1.0% based on a relative risk reduction (RRR) of 39% to 50%. The median (IQR) estimated chance that antihypertensive therapy would prevent a cardiovascular event within 5 years was 30% (10%-70%) vs evidence of an ARR of 0% to 3% based on an RRR of 0% to 28%. The median (IQR) estimated chance that bisphosphonate therapy would prevent a hip fracture in the next 5 years was 40% (10%-60%) vs evidence of ARR of 0.1% to 0.4% based on an RRR of 20% to 40%. The median (IQR) estimated chance that moderate-intensity statin therapy would prevent a cardiovascular event in the next 5 years was 20% (IQR 5%-50%) vs evidence of an ARR of 0.3% to 2% based on an RRR of 19% to 33%. Estimates of the chance that a treatment would prevent an adverse outcome exceeded estimates of the absolute chance of that outcome for 60% to 70% of clinicians. Clinicians whose overestimations were greater were more likely to report using that treatment for patients in their practice (eg, use of warfarin: correlation coefficient, 0.46; 95% CI, 0.40-0.53;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> In this survey study, clinicians significantly overestimated the benefits of treatment to individual patients. Clinicians with greater overestimates were more likely to report using treatments in actual patients.
Homocitrullination of lysine residues mediated by myeloid-derived suppressor cells in the tumor environment is a target for cancer immunotherapy
Authors: Katherine W Cook, Wei Xue, Peter Symonds, Ian Daniels, Mohamed Gijon, David Boocock, Clare Coveney, Amanda K Miles, Sabaria Shah, Suha Atabani, Ruhul H Choudhury, Poonam Vaghela, Daisy Weston, Rachael L Metheringham, Victoria A Brentville, Lindy G Durrant
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Homocitrullination is the post-translational modification of lysine that is recognized by T cells. Methods This study identified homocitrullinated peptides from aldolase, enolase, cytokeratin and binding immunoglobulin protein and used human leukocyte antigen (HLA) transgenic mice to assess immunogenicity by enzyme-linked immunosorbent spot assay. Vaccine efficacy was assessed in tumor therapy studies using HLA-matched B16 melanoma expressing constitutive or interferon γ (IFNγ)-inducible major histocompatibility complex class II (MHC-II) as represented by most human tumors. To determine the mechanism behind the therapy, immune cell infiltrates were analyzed using flow cytometry and therapy studies in the presence of myeloperoxidase (MPO) inhibitor and T-cell depletion performed. We assessed the T-cell repertoire to homocitrullinated peptides in patients with cancer and healthy donors using flow cytometry. Results Homocitrulline (Hcit) peptide vaccination stimulated strong CD4 T-cell responses and induced significant antitumor therapy in an established tumor model. The antitumor response was dependent on CD4 T cells and the effect was driven mainly via direct tumor recognition, as responses were only observed if the tumors were induced to express MHC-II. In vitro proliferation assays show that healthy donors and patients with cancer have an oligoclonal CD4 T-cell repertoire recognizing homocitrullinated peptides. Inhibition of cyanate generation, which mediates homocitrullination, by MPO inhibition reduced tumor therapy by the vaccine induced T cells (p = 0.0018). Analysis of the tumor microenvironment (TME) suggested that myeloid-derived suppressor cells (MDSCs) were a potential source of MPO. The selected B16 melanoma model showed MDSC infiltration and was appropriate to see if the Hcit vaccine could overcome the immunosuppression associated with MDSCs. The vaccine was very effective (90% survival) as the induced CD4 T cells directly targeted the homocitrullinated tumor and likely reversed the immunosuppressive environment. Conclusion We propose that MPO, potentially produced by MDSCs, catalyzes the buildup of cyanate in the TME which diffuses into tumor cells causing homocitrullination of cytoplasmic proteins which are degraded and, in the presence of IFNγ, presented by MHC-II for direct CD4 T-cell recognition. Homocitrullinated proteins are a new target for cancer vaccines and may be particularly effective against tumors containing high levels of MPO expressing MDSCs.
Distribution of major lymphocyte subsets and memory T-cell subpopulations in healthy adults employing GLP-conforming multicolor flow cytometry
Authors: Christian R. Schultze-Florey, Ekaterina Chukhno, Lilia Goudeva, Rainer Blasczyk, Arnold Ganser, Immo Prinz, Reinhold Förster, Christian Koenecke, Ivan Odak
Journal: Leukemia (2021)

Complex flow cytometry is widely used in a broad variety of indications for prognosis, diagnosis, and therapy assessment of malignancies, infectious diseases, and immunodeficiencies [1].In order to provide valid interpretation of flow data, comparison with reference values generated from age-and sex-matched healthy populations is needed.Significant amount of research has been done to establish reference values of immune cells in healthy donors [2][3][4].However, combining those studies into one comprehensive data set is an error-prone task due to variable limitations of these studies: some studies covered only a narrow range of leukocyte subsets analyzed due to low numbers of monoclonal antibodies (mAb) applied [5], while others included only limited numbers of samples for analysis.Furthermore, some studies primarily compared young and old age groups, or lacked the full age coverage.Another limitation of several studies is the lack of separation of γδ from αβ T cells [6].This distinction would be relevant since there is increasing evidence that γδ T cells play an important role in immunity, cancer, and infections [7].While Ballester et al. provided reference values for bulk γδ T cells, no reference values for the clinically relevant Vγ9 + subpopulation are provided in that analysis [8].A recent study [9] has advanced the field by providing reference values for B cells, NK cells, granulocytes and monocytes, but segregation into biologically relevant age groups is still under debate.A recent publication described significant changes in the transcriptome of white blood cells occurring at the age of 40 years and shortly after the age of 60 years [10], raising the need for new age-dependent reference values, as age categories had mostly been defined arbitrarily or solely based on cohort proportions.Moreover, there is a major lack of reference values regarding in-depth profiling of antigenexperienced lymphocytes.Here, CD45RA and CD62L are commonly used markers to discriminate T cells based on their antigen memory phenotype [11].We and others have shown
Immune responses and reactogenicity after ChAdOx1 in individuals with past SARS-CoV-2 infection and those without
Authors: So Yun Lim, Ji Yeun Kim, Jin Ah Lee, Ji-Soo Kwon, Ji Young Park, Hye Hee Cha, Mi Hyun Suh, Hyun Jung Lee, Hyeonju Kim, Seungtaek Kim, Seongman Bae, Jiwon Jung, Eui Ho Kim, Youngmee Jee, Sung-Han Kim
Journal: Journal of Infection (2021)
Exosomal lncRNA-H19 promotes osteogenesis and angiogenesis through mediating Angpt1/Tie2-NO signaling in CBS-heterozygous mice
Authors: Jyotirmaya Behera, Anil Kumar, Michael J. Voor, Neetu Tyagi
Journal: Theranostics (2021)

Rationale: Emerging evidence indicates that the growth of blood vessels and osteogenesis is tightly coordinated during bone development.However, the molecular regulators of intercellular communication in the bone microenvironment are not well studied.Therefore, we aim to investigate whether BMMSC-Exo promotes osteogenesis and angiogenesis via transporting lnc-H19 in the CBS-heterozygous mouse model.Methods: Using RT2 lncRNA PCR array screening, we identify a bone-specific, long noncoding RNA-H19 (lncRNA-H19/lnc-H19) in exosomes derived from bone marrow mesenchymal stem cells (BMMSC-Exo) during osteogenesis.Using bioinformatics analysis, we further discovered the seed sequence of miR-106a that could bind to lnc-H19.A luciferase reporter assay was performed to demonstrate the direct binding of miR-106a to the target gene angiopoietin 1 (Angpt1).We employed an immunocompromised Nude mouse model, to evaluate the effects of BMMSC-Exo on angiogenesis in vivo.Using a micro-CT scan, we monitored microstructural changes of bone in the experimental mice.Results: BMMSC-Exo possessed exosomal characteristics including exosome size, and typical markers including CD63, CD9, and TSD101.In vitro, BMMSC-Exo significantly promoted endothelial angiogenesis and osteogenesis.Mechanistic studies have shown that exosomal lnc-H19 acts as "sponges" to absorb miR-106 and regulate the expression of angiogenic factor, Angpt1 that activates lnc-H19/Tie2-NO signaling in mesenchymal and endothelial cells.Both of these effects on osteogenesis and angiogenesis are inhibited by antagonizing Tie2 signaling.Treatment of BMMSC-Exo also restored the bone formation and mechanical quality in vivo.Conclusion: These findings provide a novel insight into how the extracellular role of exosomal lnc-H19 affects osteogenesis and angiogenesis through competing endogenous RNA networks.
Smoking and COVID-19 outcomes: an observational and Mendelian randomisation study using the UK Biobank cohort
Authors: Ashley K Clift, Adam von Ende, Pui San Tan, Hannah M Sallis, Nicola Lindson, Carol A C Coupland, Marcus R Munafò, Paul Aveyard, Julia Hippisley-Cox, Jemma C Hopewell
Journal: Thorax (2021)

Background Conflicting evidence has emerged regarding the relevance of smoking on risk of COVID-19 and its severity. Methods We undertook large-scale observational and Mendelian randomisation (MR) analyses using UK Biobank. Most recent smoking status was determined from primary care records (70.8%) and UK Biobank questionnaire data (29.2%). COVID-19 outcomes were derived from Public Health England SARS-CoV-2 testing data, hospital admissions data, and death certificates (until 18 August 2020). Logistic regression was used to estimate associations between smoking status and confirmed SARS-CoV-2 infection, COVID-19-related hospitalisation, and COVID-19-related death. Inverse variance-weighted MR analyses using established genetic instruments for smoking initiation and smoking heaviness were undertaken (reported per SD increase). Results There were 421 469 eligible participants, 1649 confirmed infections, 968 COVID-19-related hospitalisations and 444 COVID-19-related deaths. Compared with never-smokers, current smokers had higher risks of hospitalisation (OR 1.80, 95% CI 1.26 to 2.29) and mortality (smoking 1–9/day: OR 2.14, 95% CI 0.87 to 5.24; 10–19/day: OR 5.91, 95% CI 3.66 to 9.54; 20+/day: OR 6.11, 95% CI 3.59 to 10.42). In MR analyses of 281 105 White British participants, genetically predicted propensity to initiate smoking was associated with higher risks of infection (OR 1.45, 95% CI 1.10 to 1.91) and hospitalisation (OR 1.60, 95% CI 1.13 to 2.27). Genetically predicted higher number of cigarettes smoked per day was associated with higher risks of all outcomes (infection OR 2.51, 95% CI 1.20 to 5.24; hospitalisation OR 5.08, 95% CI 2.04 to 12.66; and death OR 10.02, 95% CI 2.53 to 39.72). Interpretation Congruent results from two analytical approaches support a causal effect of smoking on risk of severe COVID-19.
Acute Liver Failure: Design and Usability Evaluations of a 3D‐Printed Implantable Drug Delivery Device for Acute Liver Failure in Preclinical Settings (Adv. Healthcare Mater. 14/2021)
Authors: Shin‐Young Kim, Ginam Han, Da‐Bin Hwang, Dong‐Hoon Won, Yoo‐Sub Shin, Changuk Kim, Jeon Min Kang, Jung‐Hoon Park, Hyun‐Do Jung, Wooram Park, Jun‐Won Yun
Journal: Advanced Healthcare Materials (2021)

In article number 2100497 by Jun-Won Yun, Wooram Park, Hyun-Do Jung, and co-workers, a patient-customized implantable drug delivery device is developed using 3D printing technology for effective acute liver failure (ALF) treatment. The 3D-printed reservoir system can be adjusted in size and shape to fit the ALF region and effectively treat the disease by supplementing various pharmaceutical ingredients.
Association of Tube Voltage With Plaque Composition on Coronary CT Angiography
Authors: Hidenobu Takagi, Jonathon A Leipsic, Praveen Indraratna, Gaurav Gulsin, Elina Khasanova, Georgios Tzimas, Fay Y Lin, Leslee J Shaw, Sang-Eun Lee, Daniele Andreini, Mouaz H Al-Mallah, Matthew J Budoff, Filippo Cademartiri, Kavitha Chinnaiyan, Jung Hyun Choi, Edoardo Conte, Hugo Marques, Pedro de Araújo Gonçalves, Ilan Gottlieb, Martin Hadamitzky, Erica Maffei, Gianluca Pontone, Sanghoon Shin, Yong-Jin Kim, Byoung Kwon Lee, Eun Ju Chun, Ji Min Sung, Renu Virmani, Habib Samady, Peter H Stone, Daniel S Berman, Jagat Narula, Jeroen J Bax, Hyuk-Jae Chang
Journal: JACC. Cardiovascular imaging (2021)