tbuckley/cabot-search huggingface dataset:
Characterization of <i>GDF2</i> Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension
Authors: Joshua Hodgson, Emilia M. Swietlik, Richard M. Salmon, Charaka Hadinnapola, Ivana Nikolic, John Wharton, Jingxu Guo, James Liley, Matthias Haimel, Marta Bleda, Laura Southgate, Rajiv D. Machado, Jennifer M. Martin, Carmen M. Treacy, Katherine Yates, Louise C. Daugherty, Olga Shamardina, Deborah Whitehorn, Simon Holden, Harm J. Bogaard, Colin Church, Gerry Coghlan, Robin Condliffe, Paul A. Corris, Cesare Danesino, Mélanie Eyries, Henning Gall, Stefano Ghio, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Barbara Girerd, Arjan C. Houweling, Luke Howard, Marc Humbert, David G. Kiely, Gabor Kovacs, Allan Lawrie, Robert V. MacKenzie Ross, Shahin Moledina, David Montani, Andrea Olschewski, Horst Olschewski, Willem H. Ouwehand, Andrew J. Peacock, Joanna Pepke-Zaba, Inga Prokopenko, Christopher J. Rhodes, Laura Scelsi, Werner Seeger, Florent Soubrier, Jay Suntharalingam, Mark R. Toshner, Richard C. Trembath, Anton Vonk Noordegraaf, Stephen J. Wort, Martin R. Wilkins, Paul B. Yu, Wei Li, Stefan Gräf, Paul D. Upton, Nicholas W. Morrell
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor.Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH.Methods: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with GDF2 variants and in control subjects. Levels were also measured in a larger cohort of control subjects (n = 120) and patients with idiopathic PAH (n = 260).Measurements and Main Results: We identified a novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations.Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.
Abstract 285: Higher Walk Score Associated With Higher Rates of Bystander AED Use in Street-Level Cardiac Arrest
Authors: John Chen, Valery Effoe, John Lisko, Nabil Sabbak, Shawn Reginauld, Yi-An Ko, Frank Corrigan, Stamatios Lerakis
Journal: Circulation (2018)

Introduction: Bystander CPR (BCPR) and AED use are crucial life-saving measures in out-of-hospital cardiac arrest (OHCA). OHCA occurring in low-income black neighborhoods are less likely to receive bystander assistance. In addition to socioeconomic disparities, characteristics of the built environment may also contribute to large variation in BCPR and bystander AED rates. Hypothesis: We hypothesized that pedestrian-friendly spaces have higher rates of BCPR and bystander AED use. Methods: Using the Cardiac Arrest Registry to Enhance Survival, we studied OHCA occurring in street/highway locations in the US in 2016. We excluded cardiac arrests that were witnessed by a 911 responder. Each incident address was assigned a 0-100 Walk Score® using an open-source algorithm and linked to census tract race and income data. We analyzed the relationship between Walk Score and key elements of bystander behavior: witness of arrest, provision of BCPR, and use of AED. Results: Of 3225 OHCA, 1666 (51.7%) were witnessed, 934 (29.0%) received BCPR, and 165 (5.1%) used an AED. After adjusting for age, gender, neighborhood median household income, and neighborhood percent black, every 10-point increase in Walk Score was associated with higher odds of bystander AED use (OR, 1.23; 95% CI, 1.14 to 1.32) but lower odds of witnessed arrest (OR, 0.95; 95% CI, 0.93 to 0.97) and BCPR (OR, 0.92; 95% CI, 0.90 to 0.95) (Table). Lower neighborhood household income predicted less BCPR and AED use; higher neighborhood black composition also predicted less BCPR. Conclusions: After adjusting for neighborhood-level race and income, OHCA occurring in walkable areas had higher rates of bystander AED use but lower rates of witnessed arrest and BCPR. The effects of built environments on bystander behavior and AED availability warrant closer investigation.
Shared decision making in routine clinical care of patients with rheumatoid arthritis: an assessment of audio-recorded consultations
Authors: Elke G E Mathijssen, Johanna E Vriezekolk, Calin D Popa, Bart J F van den Bemt
Journal: Annals of the Rheumatic Diseases (2019)

Although shared decision making (SDM) is advocated in rheumatoid arthritis (RA) treatment, it is largely unclear when, how and to what extent SDM is applied in routine clinical care of patients with RA. This study aimed to investigate the level of SDM in RA treatment from an observer perspective and to assess associations between the level of SDM and characteristics of the clinician, patient and consultation.The level of SDM was investigated by scoring audio-recordings of 168 routine consultations with unique patients with the observer patient involvement (OPTION) scale (scale 0-100, higher OPTION scores indicating higher levels of SDM). Associations between the level of SDM and characteristics of the clinician, patient and consultation were assessed using multilevel modelling. Statistical significance was set at p<0.05.The mean OPTION score was 28.3 (SD=15.1). The multilevel model included four characteristics: clinician age, patient age, consultation duration and type of treatment decision. There were significant, positive associations between the level of SDM and the consultation duration (b=0.63, 95% CI 0.16 to 1.11), decision for stopping and/or starting medication (b=14.30, 95% CI 5.62 to 22.98), decision for adjusting medication doses (b=8.36, 95% CI 3.92 to 12.81) and decision for administering single dose glucocorticoids (b=15.03, 95% CI 9.12 to 20.93). Thus, a higher level of SDM was significantly associated with a longer consultation duration and the type of treatment decision. No other significant associations were found.Overall, the level of SDM in RA treatment leaves room for improvement. To foster SDM in routine clinical care, training programmes on patient-centred communication skills may be helpful.
Science and creativity: the root of knowledge
Authors: Juliet Dobson
Journal: BMJ (2019)

Richard H Smith

Hidden away in a quiet part of London SW3, on the edge of the river Thames, is the Chelsea Physic Garden. London’s oldest botanic garden, it was set up in 1673 by apothecaries to grow medicinal plants and to teach apprentice apothecaries about the plants’ uses. The garden has an important role in the history of medicine, evident in the living collection of around 5000 different …
Endogenous oxygen generating multifunctional theranostic nanoplatform for enhanced photodynamic-photothermal therapy and multimodal imaging
Authors: Kun Wu, Honghai Zhao, Zhiquan Sun, Bing Wang, Xueying Tang, Yeneng Dai, Meixing Li, Qingming Shen, Hui Zhang, Quli Fan, Wei Huang
Journal: Theranostics (2019)

Phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT), has been considered as a noninvasive option for cancer therapy. However, insufficient penetration depth, tumor hypoxia, and a single treatment method severely limit the effectiveness of treatment. Methods: In this study, a multifunctional theranostic nanoplatform has been fabricated based on Au/Ag-MnO2 hollow nanospheres (AAM HNSs). The Au/Ag alloy HNSs were first synthesized by galvanic replacement reaction and then the MnO2 nanoparticles were deposited on the Au/Ag alloy HNSs by the reaction between Ag and permanganate (KMnO4), finally obtained the AAM HNSs. Then, SH-PEG was modified on the surface of AAM HNSs by the interaction of sulfhydryl and Au/Ag alloy, which improved the dispersibility and biocompatibility of the HNS. Next, the PDT photosensitizer Ce6 was loaded into AAM HNSs, benefiting from the hollow interior of the structure, and the AAM-Ce6 HNSs were obtained. Results: The AAM HNSs exhibit broad absorption at the near infrared (NIR) biological window and remarkable photothermal conversion ability in the NIR-II window. The MnO2 nanoparticles can catalyze endogenous H2O2 to generate O2 and enhance the therapeutic effect of PDT on tumor tissue. Simultaneously, MnO2 nanoparticles intelligently respond to the tumor microenvironment and degrade to release massive Mn2+ ions, which introduce magnetic resonance imaging (MRI) properties. When AAM-Ce6 HNSs are loaded with Ce6, the AAM-Ce6 HNSs can be used for triple-modal imaging (fluorescence/photoacoustic/magnetic resonance imaging, FL/PAI/MRI) guided combination tumor phototherapy (PTT/PDT). Conclusion: This multifunctional nanoplatform shows synergistic therapeutic efficacy better than any single therapy by achieving multimodal imaging guided cancer combination phototherapy, which are promising for the diagnosis and treatment of cancer.
Static and Dynamic Contributors to Ventilator-induced Lung Injury in Clinical Practice. Pressure, Energy, and Power
Authors: John J. Marini, Patricia R. M. Rocco, Luciano Gattinoni
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Ventilation is inherently a dynamic process. The present-day clinical practice of concentrating on the static inflation characteristics of the individual tidal cycle (plateau pressure, positive end-expiratory pressure, and their difference [driving pressure, the ratio of Vt to compliance]) does not take into account key factors shown experimentally to influence ventilator-induced lung injury (VILI). These include rate of airway pressure change (influenced by flow amplitude, inspiratory time fraction, and inspiratory inflation contour) and cycling frequency. Energy must be expended to cause injury, and the product of applied stress and resulting strain determines the energy delivered to the lungs per breathing cycle. Understanding the principles of VILI energetics may provide valuable insights and guidance to intensivists for safer clinical practice. In this interpretive review, we highlight that the injuring potential of the inflation pattern depends upon tissue vulnerability, the number of intolerable high-energy cycles applied in unit time (mechanical power), and the duration of that exposure. Yet, as attractive as this energy/power hypothesis for encapsulating the drivers of VILI may be for clinical applications, we acknowledge that even these all-inclusive and measurable ergonomic parameters (energy per cycle and power) are still too bluntly defined to pinpoint the precise biophysical link between ventilation strategy and tissue injury.
Prevalence and development of chronic critical illness in acute patients admitted to a respiratory intensive care setting
Authors: A. Marchioni, R. Tonelli, A. Sdanganelli, F. Gozzi, L. Musarò, R. Fantini, L. Tabbì, A. Andreani, G. Cappiello, S. Costi, I. Castaniere, E. Clini
Journal: Pulmonology (2019)

Chronic Critical Illness (chronic CI) is a condition associated to patients surviving an episode of acute respiratory failure (ARF). The prevalence and the factors associated with the development of chronic CI in the population admitted to a Respiratory Intensive Care Unit (RICU) have not yet been clarified. An observational prospective cohort study was undertaken at the RICU of the University Hospital of Modena (Italy). Patients mechanically ventilated with ARF in RICU were enrolled. Demographics, severity scores (APACHEII, SOFA, SAPSII), and clinical condition (septic shock, pneumonia, ARDS) were recorded on admission. Respiratory mechanics and inflammatory-metabolic blood parameters were measured both on admission and over the first week of stay. All variables were tested as predictors of chronic CI through univariate and multivariate analysis. Chronic CI occurred in 33 out of 100 patients observed. Higher APACHEII, the presence of septic shock, diaphragmatic dysfunction (DD) at sonography, multidrug-resistant (MDR) bacterial infection, the occurrence of a second infection during stay, and a C-reactive protein (CRP) serum level inceasing 7 days over admission were associated with chronic CI. Septic shock was the strongest predictor of chronic CI (AUC = 0.92 p < 0.0001). Chronic CI is frequent in patients admitted to RICU and mechanically ventilated due to ARF. Infection-related factors seem to play a major role as predictors of this syndrome.
OA03.02 Outcomes of Patients with Metastatic Non-Small Cell Lung Cancer (MNSCLC) with Brain Metastases Treated with Pembrolizumab
Authors: L. Sun, C. Davis, M. Marmarelis, A. Singh, A. Berman, S. Feigenberg, W. Levin, J. Bauml, R. Cohen, C. Langer, C. Aggarwal
Journal: Journal of Thoracic Oncology (2019)
Pulmonary Outcomes Associated with Long-Term Azithromycin Therapy in Cystic Fibrosis
Authors: Dave P. Nichols, Katherine Odem-Davis, Jonathan D. Cogen, Christopher H. Goss, Clement L. Ren, Michelle Skalland, Ranjani Somayaji, Sonya L. Heltshe
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Chronic azithromycin is commonly used in cystic fibrosis based on short controlled clinical trials showing reductions in pulmonary exacerbations and improved FEV1. Long-term effects are unknown.Objectives: Examine pulmonary outcomes among chronic azithromycin users compared with matched controls over years of use and consider combined azithromycin use in cohorts using chronic inhaled tobramycin or aztreonam.Methods: This retrospective cohort study used the U.S. cystic fibrosis Foundation Patient Registry. Incident chronic azithromycin users were compared with matched controls by FEV1% predicted rate of decline and rates of intravenous antibiotic use to treat pulmonary exacerbations. Propensity score methods were utilized to address confounding by indication. Predefined sensitivity analyses based on lung function, Pseudomonas aeruginosa (PA) status, and follow-up time intervals were conducted.Measurements and Main Results: Across 3 years, FEV1% predicted per-year decline was nearly 40% less in those with PA using azithromycin compared with matched controls (slopes, −1.53 versus −2.41% predicted per yr; difference: 0.88; 95% confidence interval [CI], 0.30–1.47). This rate of decline did not differ based on azithromycin use in those without PA. Among all cohorts, use of intravenous antibiotics was no different between azithromycin users and controls. Users of inhaled tobramycin and azithromycin had FEV1% predicted per-year decline of −0.16 versus nonusers (95% CI, −0.44 to 0.13), whereas users of inhaled aztreonam lysine and azithromycin experienced a mean 0.49% predicted per year slower decline than matched controls (95% CI, −0.11 to 1.10).Conclusions: Results from this study provide additional rationale for chronic azithromycin use in PA-positive patients to reduce lung function decline.
Factors associated with long-term cardiac dysfunction in neonatal lupus
Authors: Amit Saxena, Peter M Izmirly, Rebecca P Bomar, Rachel Shireen Golpanian, Deborah M Friedman, Ruth Eisenberg, Mimi Y Kim, Jill P Buyon
Journal: Annals of the Rheumatic Diseases (2019)

Objectives Cardiac manifestations of neonatal lupus (NL) have been associated with significant morbidity and mortality; however, there is minimal information on long-term outcomes of affected individuals. This study was initiated to evaluate the presence of and the risk factors associated with cardiac dysfunction in NL after birth in multiple age groups to improve counselling, to further understand pathogenesis and to provide potential preventative strategies. Methods Echocardiogram reports were evaluated in 239 individuals with cardiac NL: 143 from age 0–1 year, 176 from age &gt;1–17 years and 64 from age &gt;17 years. Logistic regression analyses evaluated associations of cardiac dysfunction at each age group with demographic, fetal and postnatal factors, using imputation to address missing data. Results Cardiac dysfunction was identified in 22.4% at age 0–1 year, 14.8% at age &gt;1–17 years and 28.1% at age &gt;17 years. Dysfunction in various age groups was significantly associated with male sex, black race, lower fetal heart rates, fetal extranodal cardiac disease and length of time paced. In 106 children with echocardiograms at ages 0–1 year and &gt;1–17 years, 43.8% with dysfunction at age 0–1 year were also affected at age &gt;1–17 years, while the others reverted to normal. Of children without dysfunction at age 0–1 year, 8.9% developed new dysfunction between ages &gt;1 and 17 years. Among 34 with echocardiograms at ages &gt;1–17 years and &gt;17 years, 6.5% with normal function at age &gt;1–17 years developed dysfunction in adulthood. Conclusions Risk factors in fetal life can influence cardiac morbidity into adulthood. Although limited by a small number of cases, cardiac dysfunction in the first year often normalises by later childhood. New-onset dysfunction, although rare, can occur de novo after the first year.
Sex Differences in Cardiometabolic Traits and Determinants of Exercise Capacity in Heart Failure With Preserved Ejection Fraction
Authors: Emily S. Lau, Thomas Cunningham, Kathryn M. Hardin, Elizabeth Liu, Rajeev Malhotra, Matthew Nayor, Gregory D. Lewis, Jennifer E. Ho
Journal: JAMA Cardiology (2019)

Sex differences in heart failure with preserved ejection fraction (HFpEF) have been established, but insights into the mechanistic drivers of these differences are limited.To examine sex differences in cardiometabolic profiles and exercise hemodynamic profiles among individuals with HFpEF.This cross-sectional study was conducted at a single-center tertiary care referral hospital from December 2006 to June 2017 and included 295 participants who met hemodynamic criteria for HFpEF based on invasive cardiopulmonary exercise testing results. We examined sex differences in distinct components of oxygen transport and utilization during exercise using linear and logistic regression models. The data were analyzed from June 2018 to May 2019.Resting and exercise gas exchange and hemodynamic parameters obtained during cardiopulmonary exercise testing.Of 295 participants, 121 (41.0%) were men (mean [SD] age, 64 [12] years) and 174 (59.0%) were women (mean [SD] age, 61 [13] years). Compared with men, women with HFpEF in this tertiary referral cohort had fewer comorbidities, including diabetes, insulin resistance, and hypertension, and a more favorable adipokine profile. Exercise capacity was similar in men and women (percent predicted peak oxygen [O2] consumption: 66% in women vs 68% in men; P = .38), but women had distinct deficits in components of the O2 pathway, including worse biventricular systolic reserve (multivariable-adjusted analyses: ΔLVEF β = -1.70; SE, 0.86; P < .05; ΔRVEF β = -2.39, SE=0.80; P = .003), diastolic reserve (PCWP/CO: β = 0.63; SE, 0.31; P = .04), and peripheral O2 extraction (C(a-v)O2 β=-0.90, SE=0.22; P < .001)).Despite a lower burden of cardiometabolic disease and a similar percent predicted exercise capacity, women with HFpEF demonstrated greater cardiac and extracardiac deficits, including systolic reserve, diastolic reserve, and peripheral O2 extraction. These sex differences in cardiac and skeletal muscle responses to exercise may illuminate the pathophysiology underlying the development of HFpEF and should be investigated further.
A Randomized, Double-Blind, Placebo-Controlled Phase II Study of Hepatocyte Growth Factor in the Treatment of Critical Limb Ischemia
Authors: Yongquan Gu, Shijun Cui, Qi Wang, Changjian Liu, Bi Jin, Wei Guo, Changwei Liu, Tongbin Chu, Chang Shu, Fuxian Zhang, Chengquan Han, Yue Liu
Journal: Molecular Therapy (2019)

NL003 is a plasmid engineered to simultaneously express two isoforms of hepatocyte growth factor. This phase II study was performed to assess the clinical safety and efficacy of intramuscular injection of NL003 in critical limb ischemia (CLI) patients for 6 months. Two hundred patients (Rutherford scale 4–5) were randomly assigned: placebo (n = 50), low-dose NL003 (n = 50), middle-dose NL003 (n = 50), or high-dose NL003 (n = 50). The drug was administered in the affected limb of 197 patients on days 0, 14, and 28. No significant differences in the incidence of adverse events (AEs) or serious AEs were found among the groups. At 6 months, pain severity was significantly reduced in all NL003 groups, but not in the placebo group (p < 0.05). The proportion of patients with complete ulcer healing in the high-dose group was significantly higher than that of the placebo group (p = 0.0095). There were no statistically significant differences in transcutaneous oxygen pressure (TcPO2), ankle-brachial index (ABI), or toe-brachial index (TBI) value among the four groups throughout the study period. These results provide the first effective evidence of significant improvements in total healing of ulcers in treated legs, complete pain relief without analgesics, and safety for NL003 in patients with Rutherford stage 4–5. NL003 is a plasmid engineered to simultaneously express two isoforms of hepatocyte growth factor. This phase II study was performed to assess the clinical safety and efficacy of intramuscular injection of NL003 in critical limb ischemia (CLI) patients for 6 months. Two hundred patients (Rutherford scale 4–5) were randomly assigned: placebo (n = 50), low-dose NL003 (n = 50), middle-dose NL003 (n = 50), or high-dose NL003 (n = 50). The drug was administered in the affected limb of 197 patients on days 0, 14, and 28. No significant differences in the incidence of adverse events (AEs) or serious AEs were found among the groups. At 6 months, pain severity was significantly reduced in all NL003 groups, but not in the placebo group (p < 0.05). The proportion of patients with complete ulcer healing in the high-dose group was significantly higher than that of the placebo group (p = 0.0095). There were no statistically significant differences in transcutaneous oxygen pressure (TcPO2), ankle-brachial index (ABI), or toe-brachial index (TBI) value among the four groups throughout the study period. These results provide the first effective evidence of significant improvements in total healing of ulcers in treated legs, complete pain relief without analgesics, and safety for NL003 in patients with Rutherford stage 4–5.