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Lipid phosphate phosphatases are a family of enzymes with diverse cellular metabolic functions. Phospholipid phosphatase 6 (PLPP6) is a regulator of cellular polyisoprenyl phosphates; however, its

Neutrophil-mediated secondary tissue injury underlies acute respiratory distress syndrome (ARDS) and progression to multi-organ-failure (MOF) and death, processes linked to COVID-19-ARDS. This secondary tissue injury arises from dysregulated neutrophils and neutrophil extracellular traps (NETs) intended to kill pathogens, but instead cause cell-injury. Insufficiency of pleiotropic therapeutic approaches delineate the need for inhibitors of dysregulated neutrophil-subset(s) that induce subset-specific apoptosis critical for neutrophil function-shutdown. We hypothesized that neutrophils expressing the pro-survival dual endothelin-1/VEGF-signal peptide receptor, DEspR, are apoptosis-resistant like DEspR+ cancer-cells, hence comprise a consequential pathogenic neutrophil-subset in ARDS and COVID-19-ARDS. Here, we report the significant association of increased peripheral DEspR+CD11b+ neutrophil-counts with severity and mortality in ARDS and COVID-19-ARDS, and intravascular NET-formation, in contrast to DEspR[-] neutrophils. We detect DEspR+ neutrophils and monocytes in lung tissue patients in ARDS and COVID-19-ARDS, and increased neutrophil RNA-levels of DEspR ligands and modulators in COVID-19-ARDS scRNA-seq data-files. Unlike DEspR[-] neutrophils, DEspR+CD11b+ neutrophils exhibit delayed apoptosis, which is blocked by humanized anti-DEspR-IgG4S228P antibody, hu6g8, in ex vivo assays. Ex vivo live-cell imaging of Rhesus-derived DEspR+CD11b+ neutrophils showed hu6g8 target-engagement, internalization, and induction of apoptosis. Altogether, data identify DEspR+CD11b+ neutrophils as a targetable ‘rogue’ neutrophil-subset associated with severity and mortality in ARDS and COVID-19-ARDS.

Nitroglycerin, a fast-acting vasodilator, is commonly used as a first-line agent for angina in the emergency department and to manage chest pain due to acute coronary syndromes. It is also a treatment option for other disease states such as acute heart failure, pulmonary edema, and aortic dissection. Nitroglycerin is converted to nitric oxide, a potent vasodilator, in the body, leading to venodilation at lower dosages and arteriodilation at higher dosages that results in both preload and afterload reduction, respectively. Although nitroglycerin has historically been administered as a sublingual tablet and/or spray, it is often given intravenously in the emergency department as this enables titration to effect with predictable pharmacokinetics. In this review article, we outline the indications, mechanism of action, contraindications, and adverse effects of nitroglycerin as well as review relevant literature and make general recommendations regarding the use of nitroglycerin in the emergency department.

Preventing, treating, and promoting recovery from critical illness due to pulmonary disease are foundational goals of the critical care community and the National Heart, Lung, and Blood Institute. Decades of clinical research in acute respiratory distress syndrome, acute respiratory failure, pneumonia, and sepsis have yielded improvements in supportive care, which have translated into improved patient outcomes. Novel therapeutics have largely failed to translate from promising pre-clinical findings into improved patient outcomes in late-phase clinical trials. Recent advances in personalized medicine, "big data", causal inference using observational data, novel clinical trial designs, pre-clinical disease modeling, and understanding recovery from acute illness promise to transform the methods of pulmonary and critical care clinical research. To assess the current state, research priorities, and future directions for adult pulmonary and critical care research, the NHLBI assembled a multidisciplinary working group of investigators. This working group identified recommendations for future research, including: (1) focusing on understanding the clinical, physiological, and biological underpinnings of heterogeneity in syndromes, diseases, and treatment-response with the goal of developing targeted, personalized interventions; (2) optimizing pre-clinical models by incorporating comorbidities, co-interventions, and organ support; (3) developing and applying novel clinical trial designs; and (4) advancing mechanistic understanding of injury and recovery in order to develop and test interventions targeted at achieving long-term improvements in the lives of patients and families. Specific areas of research are highlighted as especially promising for making advances in pneumonia, acute hypoxemic respiratory failure, and acute respiratory distress syndrome.

Objectives Hypertension is one of the most common chronic illnesses among adults in the United States. While poor hypertension control is a risk factor for many emergent conditions, asymptomatic hypertension is rarely an emergency. Despite this, patients may present to the emergency department (ED) with a chief complaint of hypertension, and there may be significant variability in the management of these patients. Our objective was to characterize national trends in ED visits for chief complaint of hypertension between 2006 and 2015. Methods We used the National Hospital Ambulatory Medical Care Survey (NHAMCS) from 2006 to 2015 to examine ED visits for chief complaint of hypertension. We examined trends in demographics, diagnostic resource utilization, and clinical management of these patients. Results Between 2006 and 2015, visits with hypertension as the primary chief complaint represented 0.6% of all ED visits, or 6,215,787 national-level ED visits. Of these, 63.9% received a primary diagnosis of hypertension. While there was no significant growth in these visits over the study period, 79.3% of visits received any form of diagnostic testing, with 35.5% of patients receiving an antihypertensive medication. Increasing blood pressure and non-white race were associated with increased odds of receiving antihypertensive medications. Conclusions Despite clinical policies and guidelines recommending against routine diagnostic testing for asymptomatic hypertension, roughly 4 out of 5 ED visits received diagnostic testing, and more than 1 out of 3 received medications. These visits may represent an opportunity for improvement to reduce overutilization, as well as for innovative approaches as EDs expand their role in care coordination across settings.

Training in research methodology represents an important aspect of emergency medicine (EM) resident education, but best methods for design, implementation, and dissemination of resident research remain elusive. Here we describe recommendations and best practices from the existing literature on EM resident research, including helpful tips on how to best implement a resident research program.

Protein self-organization is a hallmark of biological systems. Although the physicochemical principles governing protein–protein interactions have long been known, the principles by which such nanoscale interactions generate diverse phenotypes of mesoscale assemblies, including phase-separated compartments, remain challenging to characterize. To illuminate such principles, we create a system of two proteins designed to interact and form mesh-like assemblies. We devise a new strategy to map high-resolution phase diagrams in living cells, which provide self-assembly signatures of this system. The structural modularity of the two protein components allows straightforward modification of their molecular properties, enabling us to characterize how interaction affinity impacts the phase diagram and material state of the assemblies in vivo. The phase diagrams and their dependence on interaction affinity were captured by theory and simulations, including out-of-equilibrium effects seen in growing cells. Finally, we find that cotranslational protein binding suffices to recruit a messenger RNA to the designed micron-scale structures. A synthetic phase separation system consisting of two protein components with tunable parameters was developed to visualize and characterize phase diagrams in living cells, revealing that increasing the interaction affinity enhances phase separation and the viscosity of condensates in vivo.

Objective: The aim of the study was to describe and analyze the risk factors associated with patient safety events (PSEs), defined as adverse events (AEs), preventable AEs (PAEs), and near-miss events (NMEs), in the emergency department (ED). Methods: It was a retrospective cohort study using ED patients' data retrieved from January 2010 to December 2016. Quality assurance issues (QAIs) used as triggers included the following: issues during procedural sedation, death within 24 hours of admission, patients' and physicians' complaints, returns to the ED within 72 hours, and transfers to an intensive care unit within 24 hours. Results: Of 383,586 ED visits, 6519 (1.7%) QAIs were reported with a PSEs incidence of 6.1%. Among the 397 PSEs, 258 were AEs including 82 PAEs, and 139 NMEs. During the 7-year period, we observed a fourfold increase in NMEs, and despite a decrease in the rate of AEs with the highest (3.1%) and lowest (0.8%) incidence in 2011 and 2016, respectively, the incidence of PAEs events remained relatively constant. Unadjusted analysis showed that ED waiting time, boarding time, ED length of stay (LOS), ED disposition, as well as diagnostic and QAIs were significantly related to PSEs (P < 0.05). Multivariable analysis showed that the type of QAIs and diagnostic were associated with PSEs (P < 0.001). Type of QAIs was a risk factor for AEs and PAEs occurrence and factors involved in NMEs were type of QAIs (P = 0.02) and ED LOS (P < 0.001). “The odds of a PSE occurring increased by 0.2% for each additional minute increase in the ED waiting time, by 5.2% for each additional boarding hour, and by 4.5% for each ED LOS hour.” Conclusions: This study showed several potential risk factors for PSEs, especially ED LOS, type of QAIs, and diagnostic. Systematic interventions might have more impact on risk of PSE.

Combined elevated sputum eosinophils+neutrophils in asthma associated with lowest lung function, greater healthcare utilization, and longitudinally, further spirometric loss, implicating cell-cell interactions or overlapping inflammatory pathways while increased eosinophils or neutrophils alone show less effect.

IntroductionOpioid overdoses claim tens of thousands of lives every year. Many of these deaths might be prevented if overdose-reversal medications such as naloxone are administered in a timely manner. Drones may help overcome barriers to timely arrival on scene for opioid overdoses. This study analyses the time required for a drone carrying naloxone to traverse various distances, simulating the response time for a drone to the scene of an opioid overdose. For comparison, we used the time required for ambulances to traverse similar distances while responding to the scene of actual or suspected opioid overdoses.MethodsFifty flight trials, using a modified Dà-Jiāng Innovations (DJI) ‘Inspire 2’ drone, were conducted across seven distances, and the travel time for the drone was then compared with historical response time data from 200 actual or suspected opioid overdose cases that occurred within Detroit, Michigan.ResultsWe determined with 95% certainty that drone arrival times were discernibly quicker than ambulance arrival times at all distances where sufficient data were available to perform statistical comparisons including 0.5 km, 1.0 km, 1.5 km, 2.0 km and 3.0 km.ConclusionWe have shown that a drone is capable of travelling several ranges of straight-line (ie, ‘as the crow flies’) distance faster than an ambulance. Further exploration into the use of drones to deliver life-saving therapies in urban and rural settings is warranted. Head-to-head prospective trials that consider the practical challenges of medical drone delivery are needed to better understand the viability of incorporating this technology into existing emergency response infrastructure.

Next-generation sequencing (NGS) increasingly influences diagnosis, prognosis and management of myelodysplastic syndrome (MDS). In addition to marrow morphology and flow cytometry, our institution performs cytogenetics (CG) and NGS-based testing routinely in patients with suspected MDS. We evaluated the relative value of NGS in the assessment of patients with suspected MDS. We initially compared the diagnostic and prognostic information derived from CG and NGS in 134 patients. NGS enhanced the diagnostic yield compared to CG for clonal myeloid disorders (sensitivity 77% vs. 42·2%; specificity 90·2% vs. 78%; positive predictive value 92·8% vs. 76%; and negative predictive value 70·8% vs. 45·5%). The identification of poor prognosis mutations by NGS altered risk category in 27/39 (69·2%) patients with MDS with good/intermediate risk CG. Subsequently, we prospectively evaluated 70 patients with suspected MDS using an 'NGS-first approach' with CG restricted to samples with morphological abnormalities. We rarely identified mutations or CG abnormalities in patients without dysplastic features. NGS has a superior diagnostic performance compared to CG in patients with suspected MDS. We estimate that by using an 'NGS-first approach' we could reduce karyotyping by approximately 30%.

Despite substantial advances in the study, treatment, and prevention of cardiovascular disease, numerous challenges relating to optimally screening, diagnosing, and managing patients remain. Simultaneous improvements in computing power, data storage, and data analytics have led to the development of new techniques to address these challenges. One powerful tool to this end is machine learning (ML), which aims to algorithmically identify and represent structure within data. Machine learning’s ability to efficiently analyze large and highly complex data sets make it a desirable investigative approach in modern biomedical research. Despite this potential and enormous public and private sector investment, few prospective studies have demonstrated improved clinical outcomes from this technology. This is particularly true in cardiology, despite its emphasis on objective, data-driven results. This threatens to stifle ML’s growth and use in mainstream medicine. We outline the current state of ML in cardiology and outline methods through which impactful and sustainable ML research can occur. Following these steps can ensure ML reaches its potential as a transformative technology in medicine.

About 5,400 heart transplantations are performed around the world annually. Survival in allograft recipients has improved substantially over the years with effective immunosuppressive therapy. However, acute cellular or antibody-mediated allograft rejection in the first 6 to 12 months remains a

Background Transcatheter aortic valve implantation (TAVI) is most commonly performed via the femoral approach. Small caliber ilio-femoral arteries, severe calcification and tortuosity are often prohibitive reasons for TAVI via the femoral approach. Mid-aortic syndrome is a rare condition describing congenital or acquired coarctation of the abdominal aorta. Case summary To the best of our knowledge, this case report describes the world’s first TAVI in a patient with mid-aortic syndrome with challenging vascular access that would preclude conventional TAVI access routes. A 76-year-old woman with intermittent claudication, underwent work-up for axillo-bifemoral bypass, underwent a TAVI for incidental severe asymptomatic severe aortic stenosis via right common carotid TAVI facilitated by innominate artery angioplasty achieved vascular access for TAVI. Percutaneous coronary intervention to a right coronary artery vein graft was simultaneously performed via a left brachial artery cut down. Discussion We demonstrate that complex angioplasty to coronary artery bypass grafts and the innominate artery alongside TAVI via a variety of arterial access sites is both safe and feasible.

Aims Concentrations of insulin‐like growth factor binding protein‐7 (IGFBP7) have been linked to abnormal cardiac structure and function in patients with chronic heart failure (HF), but cardiovascular correlates of the biomarker in patients with more acute presentations are lacking. We aimed to determine the relationship between IGFBP7 concentrations and cardiac structure and to evaluate the impact of IGFBP7 on the diagnosis of acute HF among patients with acute dyspnoea. Methods and results In this pre‐specified subgroup analysis of the International Collaborative of N‐terminal pro‐B‐type Natriuretic Peptide Re‐evaluation of Acute Diagnostic Cut‐Offs in the Emergency Department (ICON‐RELOADED) study, we included 271 patients with and without acute HF. All patients presented to an emergency department with acute dyspnoea, had blood samples for IGFBP7 measurement, and detailed echocardiographic evaluation. Higher IGFBP7 concentrations were associated with numerous cardiac abnormalities, including increased left atrial volume index (LAVi; r = 0.49, P

Small-bowel obstruction is a common cause of abdominal pain and accounts for a significant proportion of hospital admissions. Radiologic imaging plays the key role in the diagnosis and management of small-bowel obstruction as neither patient presentation, the clinical examination, nor laboratory testing are sufficiently sensitive or specific enough to diagnose or guide management. This document focuses on the imaging evaluation of the two most commonly encountered clinical scenarios related to small-bowel obstruction: the acute presentation and the more indolent, low-grade, or intermittent presentation. This document hopes to clarify the appropriate utilization of the many imaging procedures that are available and commonly employed in these clinical settings. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Background Inhaled β-agonists are the cornerstone of acute treatment for asthma and chronic lung disease. Upon emergency department (ED) discharge, patients optimally receive prescriptions for metered-dose inhalers (MDIs) with instructions on their proper use. Yet prior studies suggest that ED personnel have limited knowledge of proper MDI techniques. It is unclear how effectively brief education will improve this knowledge to enable them to provide adequate patient instructions. Objective Our aim was to evaluate ED medical personnel's baseline knowledge of MDI use and the utility of brief education on their ability to use MDIs. Methods After providing written consent, a spirometry nurse evaluated emergency physicians and nurses on their ability to properly perform three (open-mouth/two-finger, spacer, and closed-mouth) MDI techniques. The same spirometry nurse then gave a short educational session demonstrating the proper MDI techniques. Two weeks later, the nurse re-evaluated the same personnel on their MDI techniques. Results All emergency medical personnel initially performed poorly in demonstrating proper MDI technique, averaging 29.8% steps done correctly. Two weeks after their educational session, they improved greatly, averaging 89.4% steps done correctly. Conclusions This study demonstrated both that ED personnel had poor initial knowledge about MDI techniques and that a brief educational intervention improved most people's ability to use, and presumably to instruct patients/parents in proper use of, MDIs.

Author(s): Gordon, Richard D.; Kwon, Nancy S.; Levy, Phillip D.; Madsen, Tracy E.; Greenberg, Marna Rayl | Abstract: On behalf of the ACEP Research CommitteeIntroduction: To study diversity of researchers and barriers to success among Emergency Medicine Foundation (EMF) grant recipients in the last 10 years.Methods: EMF grant awardees were approached to complete a brief survey, which included demographics, queries related to contributions to the literature, success in obtaining grants, and any perceived barriers they encountered.Results: Of the 342 researchers contacted by email, a total of 147 completed the survey for a response rate of 43%. The respondents were predominately mid to late career white-male-heterosexual-Christian with an average age of 44 years (range 25-69 years of age). With regards to training and education, the majority of respondents (50%) were either Associate or Professor clinical rank (8% instructor/resident/fellow and 31% Assistant). Sixty-two percent of the respondents reported perceived barriers to career advancement since completion of residency. The largest perceived barrier to success was medical specialty (26%), followed by gender (21%) and age (16%).Conclusion: Our survey of EMF grant recipients in the last 10 years shows a considerable lack of diversity. The most commonly perceived barriers to career advancement by this cohort were medical specialty, gender, and age. An opportunity exists for further definition of barriers and development of mechanisms to overcome them, with a goal of increased success for those that are underrepresented.

BACKGROUND Elevated blood pressure (BP) is pervasive among patients that visit emergency departments (EDs) for their care. METHODS In this review article, we outline the current approach to the management of these individuals and highlight the crucial role emergency medicine clinicians play in reducing the morbidity associated with elevated BP. RESULTS We highlight the critical importance of immediate treatment when elevated BP contributes to new or worsening end-organ injury but emphasize that such hypertensive emergencies are rare. For the vast majority of patients with elevated BP in the ED who do not have new or worsening end-organ injury from elevated BP, immediate BP reduction within the ED is not recommended or safe. Nonetheless, within weeks after an ED visit, there is a pressing need to improve the care of patients with elevated or previously undiagnosed hypertension. For many, it may be their only regular point of engagement with the healthcare system. To address this, we present novel perspectives that envision a new role for emergency medicine in chronic hypertension management—one that acknowledges the significant population-level gaps in BP control that contribute to disparities in cardiovascular disease and sets the stage for future changes in systems-based practice. CONCLUSIONS Emergency medicine plays a key and evolving role in reducing morbidity associated with elevated BP.

By pointing to deep philosophical confusions endemic to cognitive science, Wittgenstein might seem an enemy of computational approaches. We agree (with Mills 1993) that while Wittgenstein would reject the classicist’s symbols and rules approach, his observations align well with connectionist or neural network approaches. While many connectionisms that dominated the later twentieth century could fall prey to criticisms of biological, pedagogical, and linguistic implausibility, current connectionist approaches can resolve those problems in a Wittgenstein-friendly manner. We (a) present the basics of a Vector Symbolic Architecture formalism, inspired by Smolensky (1990), and indicate how high-dimensional vectors can operate in a context-sensitive and object-independent manner in biologically plausible time scales, reflecting Wittgenstein’s notions of language-games and family resemblance; we (b) show how “soft” symbols for such a formalism can be formed with plausible learning cycles using Sparse Distributed Memory, resolving disputes surrounding Wittgenstein’s private language argument; and (c) show how connectionist networks can extrapolate meaningful patterns to solve problems, providing “ways to go on” without explicit rules, which indicates linguistic plausibility. Connectionism thus provides a systematicity and productivity that is more than a mere implementation of a classical approach, and provides Wittgenstein-friendly and Wittgenstein-illuminating models of mind and language for cognitive science.

Nicholas Hewitt, Montmartre: A Cultural History (Liverpool: Liverpool University Press, 2017).David Spector, La Gauche, la droite, et le marché: Histoire d’une idée controversée (XIXe–XXIe siècle) (Paris: Odile Jacob, 2017)Graham M. Jones, Magic’s Reason: An Anthropology of Analogy (Chicago: University of Chicago Press, 2017).Minayo Nasiali, Native to the Republic: Empire, Social Citizenship, and Everyday Life in Marseille since 1945 (Ithaca: Cornell University Press, 2016).Joseph Bohling, The Sober Revolution: Appellation Wine and the Transformation of France (Ithaca and London: Cornell University Press, 2018).Venus Bivar, Organic Resistance: The Struggle over Industrial Farming in Postwar France (Chapel Hill: University of North Carolina Press, 2018).Todd Shepard, Sex, France, and Arab Men, 1962–1979 (Chicago: University of Chicago Press, 2017).Donald Reid, Opening the Gates: The Lip Affair, 1968–1981 (London: Verso, 2018).Bruno Perreau, Queer Theory: The French Response (Stanford, CA: Stanford University Press, 2016).Oana Sabo, The Migrant Canon in Twenty-First-Century France (Lincoln: University of Nebraska Press, 2018).

Background Relative enlargement of the pulmonary artery (PA) on chest CT imaging is associated with respiratory exacerbations in patients with COPD or cystic fibrosis. We sought to determine whether similar findings were present in patients with asthma and whether these findings were explained by differences in ventricular size. Methods We measured the PA and aorta diameters in 233 individuals from the Severe Asthma Research Program III cohort. We also estimated right, left, and total epicardial cardiac ventricular volume indices (eERVVI, eELVVI, and eETVVI, respectively). Associations between the cardiac and PA measures (PA-to-aorta [PA/A] ratio, eERVVI-to-eELVVI [eRV/eLV] ratio, eERVVI, eELVVI, eETVVI) and clinical measures of asthma severity were assessed by Pearson correlation, and associations with asthma severity and exacerbation rate were evaluated by multivariable linear and zero-inflated negative binomial regression. Results Asthma severity was associated with smaller ventricular volumes. For example, those with severe asthma had 36.1 mL/m2 smaller eETVVI than healthy control subjects (P = .003) and 14.1 mL/m2 smaller eETVVI than those with mild/moderate disease (P = .011). Smaller ventricular volumes were also associated with a higher rate of asthma exacerbations, both retrospectively and prospectively. For example, those with an eETVVI less than the median had a 57% higher rate of exacerbations during follow-up than those with eETVVI greater than the median (P = .020). Neither PA/A nor eRV/eLV was associated with asthma severity or exacerbations. Conclusions In patients with asthma, smaller cardiac ventricular size may be associated with more severe disease and a higher rate of asthma exacerbations. Trial Registry ClinicalTrials.gov; No.: NCT01761630; URL: www.clinicaltrials.gov

Significance Although resistance to glucocorticoids is a major clinical problem, the underlying mechanisms are unknown. It is known that glucocorticoid use can suppress adrenal androgen production. In population studies, animal models, and cell culture experiments, androgens are associated with several benefits in asthma, but neither androgen use in glucocorticoid-resistant asthma nor the genetic determinants of androgen responsiveness have been studied in humans. A missense-encoding variant in HSD3B1 is known to regulate conversion from adrenal precursors to potent androgens and clinical outcomes in prostate cancer. This is the first genetic evidence to our knowledge that implicates an androgen synthesis variant in resistance to glucocorticoids for asthma or any other inflammatory disease. Furthermore, this study demonstrates an adverse consequence of adrenal androgen suppression with glucocorticoid therapy., Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. HSD3B1 encodes for 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive HSD3B1(1245A) allele limits conversion, whereas the adrenal permissive HSD3B1(1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEV1PP). HSD3B1(1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEV1PP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined (n = 318). Validation was performed in a second cohort (SARP I&II; n = 184). DHEA-sulfate is associated with FEV1PP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEV1PP compared with noGC patients (54.3% vs. 75.1%; P < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEV1PP difference in GC vs. noGC patients (73.4% vs. 78.9%; P = 0.39). Results were independently confirmed: FEV1PP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 (P < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 (P = 0.92). The adrenal restrictive HSD3B1(1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3β-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.

Gastroesophageal reflux disease (GERD) is a common condition and impairs the quality of life for millions of patients, accounts for considerable health care spending, and is a primary risk factor for esophageal adenocarcinoma. There have been substantial advances in understanding the pathogenesis of GERD and its complications and much progress in diagnosis and management of GERD; however, these have not been comprehensively discussed in the recent radiology literature. Understanding the role of imaging in GERD and its complications is important to aid in multidisciplinary treatment of GERD. GERD results from prolonged or recurrent reflux of gastric contents into the esophagus. Common symptoms include heartburn or regurgitation. Prolonged reflux of gastric contents into the esophagus can cause erosive esophagitis. Over time, the inflammatory response related to esophagitis can lead to deposition of fibrous tissue and development of strictures. Alternatively, the esophageal mucosa can undergo metaplasia (Barrett esophagus), a precursor to dysplasia (which can lead to adenocarcinoma). Conventional barium esophagography has long been considered the primary imaging modality for the esophagus, and the fluoroscopic findings for diagnosis of GERD have been well established. Multimodality imaging has a clear role in detection and assessment of the complications of GERD, specifically reflux esophagitis and Barrett esophagus; differentiation of benign and malignant strictures; and detection, staging, and posttreatment surveillance of esophageal adenocarcinoma. Given the dramatic changes in utilization of abdominal imaging during the past 2 decades, with significantly declining volume of fluoroscopic procedures and concomitant increase in CT and MRI studies, it is crucial that modern radiologists appreciate the value of barium esophagography in the workup of GERD and recognize the key imaging features of GERD and its complications at CT and MRI.

Biomolecular condensate formation has been implicated in a host of biological processes and has found relevance in biology and disease. Understanding the physical principles and underlying characteristics of how these macromolecular assemblies form and are regulated has become a central focus of the field. In this Review, we introduce features of phase-separating biomolecules from a general physical viewpoint and highlight how molecular features, including affinity, valence and a competition between inter- and intramolecular contacts, affect phase separation. We then discuss sequence properties of proteins that serve to mediate intermolecular interactions. Finally, we review how the intracellular environment can affect structural and sequence determinants of proteins and modulate physical parameters of their phase transitions. The works reviewed highlight that a complex interplay exists between structure, sequence and environmental determinants in the formation of biomolecular condensates.

Understanding the molecular consequences of mutations in proteins is essential to map genotypes to phenotypes and interpret the increasing wealth of genomic data. While mutations are known to disrupt protein structure and function, their potential to create new structures and localization phenotypes has not yet been mapped to a sequence space. To map this relationship, we employed two homo-oligomeric protein complexes in which the internal symmetry exacerbates the impact of mutations. We mutagenized three surface residues of each complex and monitored the mutations' effect on localization and assembly phenotypes in yeast cells. While surface mutations are classically viewed as benign, our analysis of several hundred mutants revealed they often trigger three main phenotypes in these proteins: nuclear localization, the formation of puncta, and fibers. Strikingly, more than 50% of random mutants induced one of these phenotypes in both complexes. Analyzing the mutant's sequences showed that surface stickiness and net charge are two key physicochemical properties associated with these changes. In one complex, more than 60% of mutants self-assembled into fibers. Such a high frequency is explained by negative design: charged residues shield the complex from self-interacting with copies of itself, and the sole removal of the charges induces its supramolecular self-assembly. A subsequent analysis of several other complexes targeted with alanine mutations suggested that such negative design is common. These results highlight that minimal perturbations in protein surfaces' physicochemical properties can frequently drive assembly and localization changes in a cellular context.

The Protein Data Bank in Europe – Knowledge Base (PDBe-KB, https://pdbe-kb.org) is an open collaboration between world-leading specialist data resources contributing functional and biophysical annotations derived from or relevant to the Protein Data Bank (PDB). The goal of PDBe-KB is to place macromolecular structure data in their biological context by developing standardised data exchange formats and integrating functional annotations from the contributing partner resources into a knowledge graph that can provide valuable biological insights. Since we described PDBe-KB in 2019, there have been significant improvements in the variety of available annotation data sets and user functionality. Here, we provide an overview of the consortium, highlighting the addition of annotations such as predicted covalent binders, phosphorylation sites, effects of mutations on the protein structure and energetic local frustration. In addition, we describe a library of reusable web-based visualisation components and introduce new features such as a bulk download data service and a novel superposition service that generates clusters of superposed protein chains weekly for the whole PDB archive., ELIXIR [IDP implementation study]; Biotechnology and Biological Sciences Research Council via the 3D-Gateway [BB/T01959X/1]; FunPDBe [BB/P024351/1]; European Molecular Biology Laboratory-European Bioinformatics Institute who supported this work; J.D. acknowledges support from the Ministry of Education, Youth and Sport of the Czech Republic [INBIO CZ.02.1.01/0.0/0.0/16_026/0008451]; R.S., K.B. and J.D. also acknowledge support from the Ministry of Education, Youth and Sport of the Czech Republic [ELIXIR-CZ LM2018131]; L.M. acknowledges support from the European Union's Horizon 2020 Programme (H2020-INFRAIA-2018-1) [823839]; Research Foundation Flanders (FWO) [G032816N, G042518N, G028821N]; W.V. acknowledges support from the Research Foundation Flanders (FWO) [G032816N, G028821N]; A.R. acknowledges support from the Fondazione Cassa Di Risparmio di Firenze [24316]; European Commission [101017567]; M.H.C. acknowledges the AIRC project to MHC [IG 23539]; J.F.-R. acknowledges support from the Spanish Ministry of Science and Innovation [PID2019-110167RB-I00]; N.R. acknowledges support from the Norwegian Research Council (Norges Forskningsråd) [288008]; E.D.L. acknowledges support from the European Union's Horizon 2020 research and innovation programme [819318]; M.J.E.S. acknowledges support from the Wellcome Trust [104955/Z/14/Z, 218242/Z/19/Z]. Funding for open access charge: Biotechnology and Biological Sciences Research Council grant [BB/T01959X/1]; Wellcome Trust [104955/Z/14/Z and 218242/Z/19/Z].

The identification of physiologically relevant quaternary structures (QSs) in crystal lattices is challenging. To predict the physiological relevance of a particular QS, QSalign searches for homologous structures in which subunits interact in the same geometry. This approach proved accurate but was limited to structures already present in the Protein Data Bank (PDB). Here, we introduce a webserver (www.QSalign.org) allowing users to submit homo-oligomeric structures of their choice to the QSalign pipeline. Given a user-uploaded structure, the sequence is extracted and used to search homologs based on sequence similarity and PFAM domain architecture. If structural conservation is detected between a homolog and the user-uploaded QS, physiological relevance is inferred. The web server also generates alternative QSs with PISA and processes them the same way as the query submitted to widen the predictions. The result page also shows representative QSs in the protein family of the query, which is informative if no QS conservation was detected or if the protein appears monomeric. These representative QSs can also serve as a starting point for homology modeling.

Correction for ‘Fully-automated and field-deployable blood leukocyte separation platform using multi-dimensional double spiral (MDDS) inertial microfluidics’ by Hyungkook Jeon et al., Lab Chip, 2020, 20, 3612–3624, https://doi.org/10.1039/D0LC00675K.

Although lithium is widely used in current practice to treat bipolar disorder (BD) and treatment-resistant major depressive disorder (MDD) among older adults, little is known about its efficacy and tolerability in this population, which is generally excluded from randomized clinical trials. The objective of this study was to evaluate the efficacy and tolerability of long-term use of lithium among older adults with BD and MDD.Data from the Cohort of individuals with Schizophrenia and mood disorders Aged 55 years or more (CSA) were used. Two groups of patients with BD and MDD were compared: those who were currently receiving lithium versus those who were not. The effects of lithium on psychiatric (i.e., depressive symptoms severity, perceived clinical severity, rates of psychiatric admissions in the past-year), geriatric (overall and cognitive functioning) and physical outcomes (i.e., rates of non-psychiatric medical comorbidities and general hospital admissions in the past-year) were evaluated. All analyses were adjusted for age, sex, duration of disorder, diagnosis, smoking status, alcohol use, and use of antipsychotics, antiepileptics or antidepressants.Among the 281 older participants with BD or MDD, 15.7% were taking lithium for a mean duration of 12.5(SD = 11.6) years. Lithium use was associated with lower intensity of depressive symptoms, reduced perceived clinical global severity and lower benzodiazepine use (all p 0.05), without being linked to greater rates of medical comorbidities, except for hypothyroidism.Data were cross-sectional and data on lifetime history of psychotropic medications was not assessed.Our results suggest that long-term lithium use may be efficient and relatively well-tolerated in older adults with BD or treatment-resistant MDD.

Aim:This clinical practice guideline for the evaluation and diagnosis of chest pain provides recommendations and algorithms for clinicians to assess and diagnose chest pain in adult patients.Methods:A comprehensive literature search was conducted from November 11, 2017, to May 1, 2020, encompassing randomized and nonrandomized trials, observational studies, registries, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, Agency for Healthcare Research and Quality reports, and other relevant databases. Additional relevant studies, published through April 2021, were also considered.Structure:Chest pain is a frequent cause for emergency department visits in the United States. The “2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain” provides recommendations based on contemporary evidence on the assessment and evaluation of chest pain. This guideline presents an evidence-based approach to risk stratification and the diagnostic workup for the evaluation of chest pain. Cost-value considerations in diagnostic testing have been incorporated, and shared decision-making with patients is recommended.

Younger patients (18 to 65 years old) are often excluded from delirium outcome studies. We sought to determine if delirium was associated with short-term adverse outcomes in a diverse cohort of younger and older patients with acute heart failure (AHF). We conducted a multi-center prospective cohort study that included adult emergency department patients with confirmed AHF. Delirium was ascertained using the Brief Confusion Assessment Method (bCAM). The primary outcome was a composite outcome of 30-day all-cause death, 30-day all-cause rehospitalization, and prolonged index hospital length of stay. Multivariable logistic regression was performed, adjusting for demographics, cognitive impairment without delirium, and HF risk factors. Older age (≥ 65 years old)*delirium interaction was also incorporated into the model. Odds ratios (OR) with their 95% confidence intervals (95%CI) were reported. A total of 1044 patients with AHF were enrolled; 617 AHF patients were < 65 years old and 427 AHF patients were ≥ 65 years old, and 47 (7.6%) and 40 (9.4%) patients were delirious at enrollment, respectively. Delirium was significantly associated with the composite outcome (adjusted OR = 1.64, 95%CI: 1.02 to 2.64). The older age*delirium interaction p-value was 0.47. In conclusion, delirium was common in both younger and older patients with AHF and was associated with poorer short-term outcomes in both cohorts. Younger patients with acute heart failure should be included in future delirium outcome studies.

BackgroundNon-invasive finger-cuff monitors measuring cardiac index and vascular tone (SVRI) classify emergency department (ED) patients with acute heart failure (AHF) into three otherwise-indistinguishable subgroups. Our goals were to validate these “hemodynamic profiles” in an external cohort and assess their association with clinical outcomes.MethodsAHF patients (n=257) from five EDs were prospectively enrolled in the validation cohort (VC). Cardiac index and SVRI were measured with a ClearSight finger-cuff monitor (formerly NexFin, Edwards Lifesciences) as in a previous study (derivation cohort, DC, n=127). A control cohort (CC, n=127) of ED patients with sepsis was drawn from the same study as the DC. K-means cluster analysis previously derived two-dimensional (cardiac index and SVRI) hemodynamic profiles in the DC and CC (k=3 profiles each). The VC was subgroupedde novointo three analogous profiles by unsupervised K-means consensus clustering. PERMANOVA tested whether VC profiles 1-3 differed from profiles 1-3 in the DC and CC, by multivariate group composition of cardiac index and vascular tone.Profiles in the VC were compared by a primary outcome of 90-day mortality and a 30-day ranked composite secondary outcome (death, mechanical cardiac support, intubation, new/emergent dialysis, coronary intervention/surgery) as time-to-event (survival analysis) and binary events (odds ratio, OR). Descriptive statistics were used to compare profiles by two validated risk scores for the primary outcome, and one validated score for the secondary outcome.ResultsThe VC had median age 60 years (interquartile range {49-67}), and was 45% (n=116) female. Multivariate profile composition by cardiac index and vascular tone differed significantly between VC profiles 1-3 and CC profiles 1-3 (p=0.001, R2=0.159). A difference was not detected between profiles in the VC vs. the DC (p=0.59, R2=0.016).VC profile 3 had worse 90-day survival than profiles 1 or 2 (HR = 4.8, 95%CI 1.4-17.1). The ranked secondary outcome was more likely in profile 1 (OR = 10.0, 1.2-81.2) and profile 3 (12.8, 1.7-97.9) compared to profile 2. Diabetes prevalence and blood urea nitrogen were lower in the high-risk profile 3 (pConclusionsHemodynamic profiles in ED patients with AHF, by non-invasive finger-cuff monitoring of cardiac index and vascular tone, were replicatedde novoin an external cohort. Profiles showed significantly different risks of clinically-important adverse patient outcomes.

Hypertension treatment and control prevent more cardiovascular events than management of other modifiable risk factors. Although the age-adjusted proportion of US adults with controlled blood pressure (BP) defined as

This chapter examines the debate over the retrenchment of the welfare state. It discusses Paul Pierson’s groundbreaking ‘new politics of the welfare state’ thesis, which argues that the politics of welfare retrenchment operates according to fundamentally different rules from the politics of welfare expansion. In particular, the presence of groups with a shared interest in preserving existing social policies means that the defence of the welfare state is not left just to labour and parties of the left. In addition, both recipients and providers of welfare policies stand ready to mobilize against programme cuts, making retrenchment exceedingly difficult. To the extent that retrenchment takes place, Pierson contends that it occurs primarily via techniques of obfuscation that hide the government’s responsibility for its actions. The chapter also analyses claims that retrenchment is more extensive than Pierson acknowledges if a different metric is used, such as social spending relative to need, or if recent cutbacks are taken into account, such as those that occurred in Greece in response to the sovereign debt crisis. Finally, the chapter traces an alternative trajectory of welfare reform. As against the unsavoury and conspiratorial methods emphasized by Pierson, governments may enact spending cuts by taking their case to the public, hitching retrenchment to higher objectives, negotiating with the social partners or political opposition, and addressing concerns about fairness. The two channels of reform are not mutually exclusive; rather, they point to different ways to cut, adapt, and modernize the welfare state.

This article describes our experience developing a novel mobile health unit (MHU) program in the Detroit, Michigan, metropolitan area. Our main objectives were to improve healthcare accessibility, quality and equity in our community during the novel coronavirus pandemic. While initially focused on SARS-CoV-2 testing, our program quickly evolved to include preventive health services. The MHU program began as a location-based SARS-CoV-2 testing strategy coordinated with local and state public health agencies. Community needs motivated further program expansion to include additional preventive healthcare and social services. MHU deployment was targeted to disease “hotspots” based on publicly available SARS-CoV-2 testing data and community-level information about social vulnerability. This formative evaluation explores whether our MHU deployment strategy enabled us to reach patients from communities with heightened social vulnerability as intended. From 3/20/20-3/24/21, the Detroit MHU program reached a total of 32,523 people. The proportion of patients who resided in communities with top quartile Centers for Disease Control and Prevention Social Vulnerability Index rankings increased from 25% during location-based “drive-through” SARS-CoV-2 testing (3/20/20-4/13/20) to 27% after pivoting to a mobile platform (4/13/20-to-8/31/20; p = 0.01). The adoption of a data-driven deployment strategy resulted in further improvement; 41% of the patients who sought MHU services from 9/1/20-to-3/24/21 lived in vulnerable communities (Cochrane Armitage test for trend, p

Many clinicians are wary of administering 30 cc/kg of intravenous fluid (IVF) to septic patients with reduced left-ventricular ejection fraction (rLVEF), fearing volume overload. Prior studies have used history of heart failure, rather than LVEF measured at presentation, thereby potentially distorting the relationship between rLVEF, IVF, and adverse outcomes. Our goal was to assess the relationship between IVF volume and outcomes in patients with, versus without, rLVEF.This was a prospective observational study performed at an urban Emergency Department (ED). Included patients were adults with suspected sepsis, defined as being treated for infection plus either systolic blood pressure 90 mm/Hg or lactate2 mmol/L. All patients had LVEF assessed by ED echocardiogram, prior to receipt of1 l IVF.We enrolled 73 patients, of whom 33 had rLVEF, defined as40%. Patients with rLVEF were older, had greater initial lactate, more ICU admission, and more vasopressor use. IVF volume was similar between LVEF groups at 3-h (2.2 (IQR 0.8) vs 2.0 (IQR 2.4) liters) while patients with rLVEF were more likely to achieve 30 cc/kg (61% (CI 44-75) vs 45% (CI 31-60). In the reduced versus not-reduced LVEF groups, hospital days, ICU days, and ventilator days were similar: 8 (IQR 7) vs 6.5 (8.5) days, 7 (IQR 7) vs 5 (4) days, and 4 (IQR 8) vs. 5 (10) days, respectively.Septic patients with rLVEF at presentation received similar volume of IVF as those without rLVEF, without an increase in adverse outcomes attributable to volume overload. While validation is needed, our results suggest that limiting IVF administration in the setting of rLVEF is not necessary.