Search

Multiple investigations have shown that a well-designed strategy for managing acute chest pain in patients can result in shorter length of stay and improved resource utilization ([1][1],[2][2]). Care in specialized chest pain units has been shown to achieve a better quality of life at lower cost, a

NK cells provide immune surveillance and host protection against viruses and tumors through their cytotoxic effector function. Cytoskeletal rearrangement is necessary for NK cell lytic granule trafficking and immune synapse formation to trigger apoptosis of targeted cells. LIM kinase (LIMK) regulates F-actin remodeling by phosphorylating cofilin to inhibit actin severing and depolymerization. In this study, in human NK cells, the glucocorticoid dexamethasone downregulated LIMK expression, F-actin accumulation at the immune synapse, lytic granule trafficking, and cytotoxicity. In contrast, the specialized proresolving mediator lipoxin A4 promoted NK cell LIMK expression, lytic granule polarization to the immune synapse and cytotoxicity. Using a LIMK inhibitor, we show that LIMK activity is necessary for NK cell cytotoxicity, including lipoxin A4’s proresolving actions. Together, our findings identify LIMK as an important control mechanism for NK cell cytoskeletal rearrangement that is differentially regulated by glucocorticoids and specialized proresolving mediators to influence NK cell cytotoxicity.

Dysregulation of the immune response to bacterial infection can lead to sepsis, a condition with high mortality. Multiple whole-blood gene-expression studies have defined sepsis-associated molecular signatures, but have not resolved changes in transcriptional states of specific cell types. Here, we used single-cell RNA-sequencing to profile the blood of people with sepsis (n = 29) across three clinical cohorts with corresponding controls (n = 36). We profiled total peripheral blood mononuclear cells (PBMCs, 106,545 cells) and dendritic cells (19,806 cells) across all subjects and, on the basis of clustering of their gene-expression profiles, defined 16 immune-cell states. We identified a unique CD14+ monocyte state that is expanded in people with sepsis and validated its power in distinguishing these individuals from controls using public transcriptomic data from subjects with different disease etiologies and from multiple geographic locations (18 cohorts, n = 1,467 subjects). We identified a panel of surface markers for isolation and quantification of the monocyte state and characterized its epigenomic and functional phenotypes, and propose a model for its induction from human bone marrow. This study demonstrates the utility of single-cell genomics in discovering disease-associated cytologic signatures and provides insight into the cellular basis of immune dysregulation in bacterial sepsis. Single-cell transcriptomic analysis identifies a distinct gene signature associated with peripheral monocyte populations that distinguishes people with sepsis from those with sterile inflammation and uninfected controls.

Stress granules (SGs) are stress-induced membraneless condensates that store non-translating mRNA and stalled translation initiation complexes. Although metazoan SGs are dynamic compartments where proteins can rapidly exchange with their surroundings, yeast SGs seem largely static. To gain a better understanding of yeast SGs, we identified proteins that sediment after heat shock using mass spectrometry. Proteins that sediment upon heat shock are biased toward a subset of abundant proteins that are significantly enriched in intrinsically disordered regions (IDRs). Heat-induced SG localization of over 80 proteins were confirmed using microscopy, including 32 proteins not previously known to localize to SGs. We found that several IDRs were sufficient to mediate SG recruitment. Moreover, the dynamic exchange of IDRs can be observed using fluorescence recovery after photobleaching, whereas other components remain immobile. Lastly, we showed that the IDR of the Ubp3 deubiquitinase was critical for yeast SG formation. This work shows that IDRs can be sufficient for SG incorporation, can remain dynamic in vitrified SGs, and can play an important role in cellular compartmentalization upon stress.This article has an associated First Person interview with the first author of the paper.

Canadian lung transplant centers currently use a subjective and dichotomous "Status" ranking to prioritize waitlisted patients for lung transplantation. The lung allocation score (LAS) is an objective composite score derived from clinical parameters associated with both waitlist and post-transplant survival. We performed a retrospective cohort study to determine whether clinical judgment (Status) or LAS better predicted waitlist mortality. All adult patients listed for lung transplantation between 2007 and 2012 at three Canadian lung transplant programs were included. Status and LAS were compared in their ability to predict waitlist mortality using Cox proportional hazards models and C-statistics. Status and LAS were available for 1122 patients. Status 2 patients had a higher LAS compared to Status 1 patients (mean 40.8 (4.4) vs 34.6 (12.5), P = .0001). Higher LAS was associated with higher risk of waitlist mortality (HR 1.06 per unit LAS, 95% CI 1.05, 1.07, P < .001). LAS predicted waitlist mortality better than Status (C-statistic 0.689 vs 0.674). Patients classified as Status 2 and LAS ≥ 37 had the worst survival awaiting transplant, HR of 8.94 (95% CI 5.97, 13.37). LAS predicted waitlist mortality better than Status; however, the best predictor of waitlist mortality may be a combination of both LAS and clinical judgment.

Aims The goal of this study was to determine the number of scans needed for novice learners to attain proficiency in B‐line quantification compared with expert interpretation. Methods and results This was a prospective, multicentre observational study of novice learners, physicians and non‐physicians from three academic institutions. Learners received a 2 h lung ultrasound (LUS) training session on B‐line assessment, including lecture, video review to practice counting and hands‐on patient scanning. Learners quantified B‐lines using an eight‐zone scanning protocol in patients with suspected acute heart failure. Ultrasound (US) machine settings were standardized to a depth of 18 cm and clip length of 6 s, and tissue harmonics and multibeam former were deactivated. For quantification, the intercostal space with the greatest number of B‐lines within each zone was used for scoring. Each zone was given a score of 0–20 based on the maximum number of B‐lines counted during one respiratory cycle. The B‐line score was determined by multiplying the percentage of the intercostal space filled with B‐lines by 20. We compared learner B‐line counts with a blinded expert reviewer (five US fellowship‐trained faculty with > 5 years of clinical experience) for each lung zone scanned; proficiency was defined as an intraclass correlation of > 0.7. Learning curves for each learner were constructed using cumulative sum method for statistical analysis. The Wilcoxon rank‐sum test was used to compare the number of scans required to reach proficiency between different learner types. Twenty‐nine learners (21 research associates, 5 residents and 3 non‐US‐trained emergency medicine faculty) scanned 2629 lung zones with acute pulmonary oedema. After a mean of 10.8 (standard deviation 14.0) LUS zones scanned, learners reached the predefined proficiency standard. The number of scanned zones required to reach proficiency was not significantly different between physicians and non‐physicians (P = 0.26), learners with no prior US experience vs. > 25 prior patient scans (P = 0.64) and no prior vs. some prior LUS experience (P = 0.59). The overall intraclass correlation for agreement between learners and experts was 0.74 and 0.80 between experts. Conclusions Our results show that after a short, structured training, novice learners are able to achieve proficiency for quantifying B‐lines on LUS after scanning 11 zones. These findings support the use of LUS for B‐line quantification by non‐physicians in clinical and research applications.

Leukocyte DNA methylation patterns associated with habitual diet may reveal molecular mechanisms involved in the pathogenesis of diet-related chronic diseases and highlight targets for prevention and treatment. We aimed to examine peripheral blood derived leukocyte DNA methylation signatures associated with diet quality. We meta-analyzed epigenome-wide associations between diet quality and DNA methylation levels at over 400,000 cytosine-guanine dinucleotides (CpGs). We conducted analysis primarily in 6,662 European ancestry (EA) participants and secondarily in a group additionally including 3,062 participants of non-European ancestry from five population-based cohort studies. DNA methylation profiles were measured in whole blood, CD4 + T-cells, or CD14 + monocytes. We used food frequency questionnaires to assess habitual intake and constructed two diet quality scores: the Mediterranean-style diet score (MDS) and Alternative Healthy Eating Index (AHEI). Our primary analysis identified 32 diet-associated CpGs, 12 CpGs for MDS and 24 CpGs for AHEI (at FDR < 0.05, corresponding p-values = 1.2×10-6 and 3.1×10-6, respectively) in EA participants. Four of these CpGs were associated with both MDS and AHEI. In addition, Mendelian randomization analysis indicated that seven diet-associated CpGs were causally linked to at least one of the CVD risk factors. For example, hypermethylation of cg11250194 (FADS2), which was associated with higher diet quality scores, was also associated with lower fasting triglycerides concentrations (p-value = 1.5×10-14) and higher high-density lipoprotein cholesterol concentrations (p-value = 1.7×10-8). Transethnic meta-analysis identified nine additional CpGs associated with diet quality (either MDS or AHEI) at FDR < 0.05. Overall quality of habitual diet was associated with differential peripheral leukocyte DNA methylation levels of 32 CpGs in EA participants. The diet-associated CpGs may serve as biomarkers and targets for preventive measures in CVD health. Future studies are warranted to examine diet-associated DNA methylation patterns in larger, ethnically diverse study samples.

Objective: To demonstrate the noninferiority of the fundamentals of robotic surgery (FRS) skills curriculum over current training paradigms and identify an ideal training platform. Summary Background Data: There is currently no validated, uniformly accepted curriculum for training in robotic surgery skills. Methods: Single-blinded parallel-group randomized trial at 12 international American College of Surgeons (ACS) Accredited Education Institutes (AEI). Thirty-three robotic surgery experts and 123 inexperienced surgical trainees were enrolled between April 2015 and November 2016. Benchmarks (proficiency levels) on the 7 FRS Dome tasks were established based on expert performance. Participants were then randomly assigned to 4 training groups: Dome (n ¼ 29), dV-Trainer (n ¼ 30), and DVSS (n ¼ 32) that trained to benchmarks and control (n ¼ 32) that trained using locally available robotic skills curricula. The primary outcome was participant performance after training based on task errors and duration on 5 basic robotic tasks (knot tying, continuous suturing, cutting, dissection, and vessel coagulation) using an avian tissue model (transfer-test). Secondary outcomes included cognitive test scores, GEARS ratings, and robot familiarity checklist scores. Results: All groups demonstrated significant performance improvement after skills training (P < 0.01). Participating residents and fellows performed tasks faster (DOME and DVSS groups) and with fewer errors than controls (DOME group; P < 0.01). Inter-rater reliability was high for the checklist scores (0.82-0.97) but moderate for GEARS ratings (0.40-0.67). Conclusions: We provide evidence of effectiveness for the FRS curriculum by demonstrating better performance of those trained following FRS compared with controls on a transfer test. We therefore argue for its implementation across training programs before surgeons apply these skills clinically. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Background Individuals from low-income groups report disproportionate rates of cigarette use, secondhand smoke (SHS) exposure with increased morbidity and mortality. Smoking bans in public housing have been enacted in attempt to reduce tobacco use and SHS exposure among lower income individuals. This study investigated the support needs of tobacco users living in two public housing complexes in Detroit, Michigan (USA), including their perspectives on smoking, resources and barriers for smoking cessation, and the impact of policy changes. Methods This is a mixed-methods study, using a qualitative focus groups approach and a short survey, public housing residents interview data was analyzed to explore themes related to smoking-related issues. Specifically, six themes were assessed across four focus groups: (1) Quitting Smoking, (2) Current Smoking Cessation Resources, (3) Legal Mandates, (4) Education and Perceptions of Smoking, (5) Community Needs and Barriers, and (6) Medical Experiences. Results There were 59 participants; the majority (39/42, 93%) of smokers reported at least one quit attempt. During the focus groups, several participants indicated a desire to quit smoking but reported barriers to smoking cessation, such as lack of access to medications, social triggers to continue smoking, and socioeconomic stressors. A number of suggestions were provided to improve smoking cessation resources, including support groups, graphic images of smoking-related diseased tissue, and better communication with health care providers. Conclusions These findings demonstrate smoking bans in two public housing complexes can be effective yet are dependent upon a complex set of issues, including numerous barriers to care.

Objectives The UK & Ireland Implanters' registry is a multicenter registry which reports on real-world experience with novel transcatheter heart valves. Background The 34 mm Evolut R transcatheter aortic valve is a self-expanding and fully recapturable transcatheter aortic valve, designed to treat patients with a large aortic annulus. Methods Between January 2017 and April 2018, clinical, procedural and 30-day outcome data were prospectively collected from all patients receiving the 34 mm Evolut R valve across 17 participating centers in the United Kingdom and Ireland. The primary efficacy outcome was the Valve Academic Research Consortium-2(VARC-2)-defined endpoint of device success. The primary safety outcome was the VARC-2-defined composite endpoint of early safety at 30 days. Results A total of 217 patients underwent attempted implant. Mean age was 79.5 ± 8.8 years and Society of Thoracic Surgeons Predicted Risk of Mortality Score 5.2% ± 3.4%. Iliofemoral access was used in 91.2% of patients. Device success was 79.7%. Mean gradient was 7.0 ± 4.6 mmHg and effective orifice area 2.0 ± 0.6 cm2 . Paravalvular regurgitation was more than mild in 7.2%. A new permanent pacemaker was implanted in 15.7%. Early safety was demonstrated in 91.2%. At 30 days, all-cause mortality was 3.2%, stroke 3.7%, and major vascular complication 2.3%. Conclusions Real-world experience of the 34 mm Evolut R transcatheter aortic valve demonstrated acceptable procedural success, safety, valve function, and incidence of new permanent pacemaker implantation.

The range of pathology in adults that can produce abdominal pain is broad and necessitates an imaging approach to evaluate many different organ systems. Although localizing pain prompts directed imaging/management, clinical presentations may vary and result in nonlocalized symptoms. This review focuses on imaging the adult population with nonlocalized abdominal pain, including patients with fever, recent abdominal surgery, or neutropenia. Imaging of the entire abdomen and pelvis to evaluate for infectious or inflammatory processes of the abdominal viscera and solid organs, abdominal and pelvic neoplasms, and screen for ischemic or vascular etiologies is essential for prompt diagnosis and treatment. Often the first-line modality, CT quickly evaluates the abdomen/pelvis, providing for accurate diagnoses and management of patients with abdominal pain. Ultrasound and tailored MRI protocols may be useful as first-line imaging studies, especially in pregnant patients. In the postoperative abdomen, fluoroscopy may help detect anastomotic leaks/abscesses. While often performed, abdominal radiographs may not alter management. 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.

A Complex Deposit A 26-year-old man with a history of community-acquired pneumonia several weeks earlier presented with chest pain, chills, and night sweats.

Introduction AchieveBP is a randomized controlled trial (RCT) of an education intervention for patients with chronic hypertension who have uncontrolled blood pressure (BP) at discharge from an urban emergency department (ED). The study examined efficacy and moderators of an educational intervention in an RCT on BP control at 180-day post-intervention. Methods Participants were recruited from a single, urban ED and randomized to receive or not to receive hypertension education. To minimize potential bias, participants were all started on an evidence-based anti-hypertensive regimen and medications were dispensed directly to participants by the study team. Bivariate analysis was performed to examine differences in sociodemographic characteristics between patients achieving BP control and those who did not. Paired t-test was used to compare the difference of systolic and diastolic BP between baseline and 180 days post-discharge. Multiple logistic regression analysis examined interaction of covariates and intervention on achieving BP control. Results One hundred and thirty-nine participants were randomized into the study. All were African-American with a mean age of 47.6 (SD = 10.8) years; 51% were male, 63% had smoked cigarettes and 15% had diabetes. A total of 66 patients completed the study (47.4%), 44 of whom (67%) achieved BP control. However, there was no difference in BP reduction or control between the two groups. Age and smoking status showed moderation effects on intervention efficacy. Conclusion Despite a neutral effect of our intervention, a high level of BP control was achieved overall, suggesting that the ED may be a viable location for efforts aimed at reducing the impact of chronic hypertension in predominantly African American communities.

Rapid HIV testing programs in emergency departments (EDs) have been shown to promote early diagnosis and linkage to specialty care. However, sensitivity of the subject-matter and stigmatization of disclosing associated risk factors may make patients reluctant to consent to testing in this setting. This study sought to determine whether men are more likely to refuse rapid HIV testing in the ED as compared to women and to analyze the influence of tester gender on the response. This retroactive study utilized demographic and testing information from a rapid HIV testing program housed within two urban EDs for a 5-month period. Gender and age were collected for both testers and patients, along with patient consent outcome. A total of 5358 patients (males = 2230; females = 3128) were approached and offered an HIV test by one of 19 testers during the study period. From the sample population, male and female patient refusal rates were similar (30.0% vs 29.1%, respectively). Female testers approached 57.8% (n = 3,095) of the patients; however, they had a significantly higher refusal rate compared to male testers (35.6% vs 21.4%; p

This study examined whether insulin-like growth factor binding protein-7 (IGFBP7) would aid in the diagnosis and prognosis of acute heart failure (HF) beyond N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration.IGFBP7 is associated with impaired ventricular relaxation and worse prognosis.The ICON-RELOADED (International Collaborative of NT-proBNP-Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department) study was a prospective, multicenter clinical trial that enrolled subjects presenting with dyspnea. Six-month prognosis for death or repeat hospitalization was obtained.Among 1,449 patients, 274 (18.9%) were diagnosed with acute HF. Those with IGFBP7 concentrations in the highest quartile were older, male, had hypertension and HF, had lower estimated glomerular filtration rate (eGFR) and lowest ejection fraction (41 ± 20%; all p 0.001). Independent predictors of IGFBP7 were age, male sex, history of diabetes, history of HF, and eGFR. Median concentrations of NT-proBNP (2,844 ng/ml vs. 99 ng/ml) and IGFBP7 (146.1 ng/ml vs. 86.1 ng/ml) were higher in those with acute HF (both; p 0.001). Addition of IGFBP7 to NT-proBNP concentrations improved discrimination, therefore increasing the area under the receiver operating curve for diagnosis of acute HF (from 0.91 to 0.94; p 0.001 for differences). Addition of IGFBP7 to a complete model of independent predictors of acute HF improved model calibration. IGFBP7 significantly reclassified acute HF diagnosis beyond NT-proBNP (net reclassification index: +0.25). Higher logAmong patients with acute dyspnea, concentrations of IGFBP7 add to NT-proBNP for diagnosis of acute HF and provide added prognostic utility for short-term risk.

In Brief Noonan syndrome (NS) is caused by hyperactive SHP2 and is associated with cognitive deficits. Levy et al. find that NMDA receptor (NMDAR)-mediated currents are disrupted in NS and identify GluN2B Y1252 as a neural substrate of SHP2. Y1252 in turn binds the actin regulator Nck2 to control spine actin and regulate NMDAR currents., SUMMARY Hyperactivating mutations in the non-receptor tyro-sine phosphatase SHP2 cause Noonan syndrome (NS). NS is associated with cognitive deficits, but how hyperactivation of SHP2 in NS changes neuron function is not well understood. We find that mice bearing an NS-associated SHP2 allele (NS mice) have selectively impaired Schaffer collateral-CA1 NMDA (N-methyl-D-aspartate) receptor (NMDAR)-mediated neurotransmission and that residual NMDAR-mediated currents decay faster in NS mice because of reduced contribution of GluN1:GluN2B diheteromers. Consistent with altered GluN2B function, we identify GluN2B Y1252 as an NS-associated SHP2 substrate both in vitro and in vivo. Mutation of Y1252 does not alter recombinant GluN1:GluN2B receptor kinetics. Instead, phospho-Y1252 binds the actin-regulatory adaptor protein Nck2, and this interaction is required for proper NMDAR function. These results establish SHP2 and Nck2 as NMDAR regulatory proteins and strongly suggest that NMDAR dysfunction contributes to NS cognitive deficits., Graphical Abstract

Purpose While there is growing scientific evidence for and significant advances in the use of genomic technologies in medicine, there is a significant lag in the clinical adoption and sustainability of genomic medicine. Here we describe the findings from the National Human Genome Research Institute’s (NHGRI) Implementing GeNomics In pracTicE (IGNITE) Network in identifying key constructs, opportunities, and challenges associated with driving sustainability of genomic medicine in clinical practice. Methods Network members and affiliates were surveyed to identify key drivers associated with implementing and sustaining a genomic medicine program. Tallied results were used to develop and weigh key constructs/drivers required to support sustainability of genomic medicine programs. Results The top 3 driver-stakeholder dyads were 1. Genomic training for providers, 2. Genomic clinical decision support (CDS) tools embedded in the Electronic Health Record (EHR), 3. Third party reimbursement for genomic testing. Conclusion Priorities may differ depending on healthcare systems when comparing the current state of key drivers vs. projected needs for supporting genomic medicine sustainability. Thus we provide gap-filling guidance based on IGNITE members’ experiences. Although results are limited to findings from the IGNITE network, their implementation, scientific and clinical experience may be used as a road map by others considering implementing genomic medicine programs.

Asthma is a chronic disorder characterized by persistent inflammation of the airways with mucosal infiltration of eosinophils, T lymphocytes, and mast cells, and release of proinflammatory cytokines and lipid mediators. The natural resolution of airway inflammation is now recognized as an active host response, with highly coordinated cellular events under the control of endogenous pro-resolving mediators that enable the restoration of tissue homeostasis. Lead members of proresolving mediators are enzymatically derived from essential polyunsaturated fatty acids, including arachidonic acid-derived lipoxins, eicosapentaenoic acid-derived E-series resolvins, and docosahexaenoic acid-derived D-series resolvins, protectins, and maresins. Functionally, these specialized pro-resolving mediators can limit further leukocyte recruitment, induce granulocyte apoptosis, and enhance efferocytosis by macrophages. They can also switch macrophages from classical to alternatively activated cells, promote the return of non-apoptotic cells to lymphatics and blood vessels, and help initiate tissue repair and healing. In this review, we highlight cellular and molecular mechanisms for successful resolution of inflammation, and describe the main specialized pro-resolving mediators that drive these processes. Furthermore, we report recent data suggesting that the pathobiology of severe asthma may result in part from impaired resolution of airway inflammation, including defects in the biosynthesis of these specialized pro-resolving mediators. Finally, we discuss resolution-based therapeutic perspectives.

OBJECTIVES The objective was to determine the national lumbar puncture (LP) practice patterns relative to the incidence of central nervous system (CNS) infections among children presenting to the emergency department (ED) with complex febrile seizures (CFS). METHODS This was a retrospective study of ED visits for CFS from 2007 to 2014 in patients aged 0 to 5 years using a national sample. Primary outcomes include the frequency of LP, incidence of CNS infections, and ED disposition. RESULTS Of 28,810 ED visits for CFS (44.4% female; mean age = 1.39 years), LP was performed in 7,445 (25.8%, 95% confidence interval [CI] 23.5%-28.2%). There was no significant difference in the proportion due to hospital teaching status or geographical region. The proportion decreased from 31.4% to 17.8% over the study period (Rao-Scott statistic = 5.85, p

Specialized proresolving mediators (SPMs) decrease NF-κB activity to prevent excessive tissue damage and promote the resolution of acute inflammation. Mechanisms for NF-κB regulation by SPMs remain to be determined. In this study, after LPS challenge, the SPMs 15-epi-lipoxin A4 (15-epi-LXA4), resolvin D1, resolvin D2, resolvin D3, and 17-epi-resolvin D1 were produced in vivo in murine lungs. In LPS-activated human bronchial epithelial cells, select SPMs increased expression of the NF-κB regulators A20 and single Ig IL-1R–related molecule (SIGIRR). Of interest, 15-epi-LXA4 induced A20 and SIGIRR in an lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2) receptor–dependent manner in epithelial cells and in murine pneumonia. This SPM regulated NF-κB–induced cytokines to decrease pathogen-mediated inflammation. In addition to dampening lung inflammation, surprisingly, 15-epi-LXA4 also enhanced pathogen clearance with increased antimicrobial peptide expression. Taken together, to our knowledge these results are the first to identify endogenous agonists for A20 and SIGIRR expression to regulate NF-κB activity and to establish mechanisms for NF-κB regulation by SPMs for pneumonia resolution.

Background Squeaking is an on-going complication with a variable incidence of 0.5%-20.7%. The mechanism of squeaking has not been understood completely and is most likely multifactorial in nature. Previously, we have reported on a squeaking rate of 7.3% at 2 years. Our current results show a substantial increase in the squeaking incidence from 7.3% to 17.4% with the DeltaMotion articulation at the 5-year follow-up. Methods Two hundred six total hip arthroplasties with a large ceramic-on-ceramic bearing were performed on 195 patients by 2 senior authors. The minimum duration of follow-up was 5 years (range 5-6.2). Results The mean Harris Hip Score remained stable at 91.7 at 5 years compared to 92 after 2 years. However, we observed an increase in the squeaking rate from 7.3% after 2 years to 17.4% after 5 years. As in previous studies, we did not find significant differences between the silent and squeaking group in relation to age, height, weight, and femoral head diameter. In contrast, others reported no significant differences regarding range of motion and gender between the silent and the squeaking hip group at 2 years of follow-up, whereas at 5 years, the squeaking group showed a significantly higher combined range of motion and a higher relative risk of squeaking in women compared to the silent group. Conclusion While large diameter ceramic bearings may produce squeaking, especially in female patients, our mid-term clinical results of a large ceramic-on-ceramic bearing in total hip arthroplasty are encouraging. Nevertheless, long-term follow-up is recommended.

Background Although pre-puberty asthma is more prevalent in males, after puberty through middle-age, asthma is more prevalent in females. The surge of sex hormones with puberty might explain this gender switch. Methods To examine the effects of sex hormones on lung function and symptoms with puberty, Tanner stage was assessed in 187 children 6–18 years of age (59% severe) enrolled in the NIH/NHLBI Severe Asthma Research Program (SARP). The effects of circulating sex hormones (n = 68; testosterone, dehydroepiandrosterone sulfate (DHEA-S), estrogen, and progesterone) on lung function and 4 week symptom control (ACQ6) in cross-section were tested by linear regression. Results From pre−/early to late puberty, lung function did not change significantly but ACQ6 scores improved in males with severe asthma. By contrast females had lower post-BD FEV1% and FVC% and worse ACQ6 scores with late puberty assessed by breast development. In males log DHEA-S levels, which increased by Tanner stage, associated positively with pre- and post-BD FEV1%, pre-BD FVC %, and negatively (improved) with ACQ6. Patients treated with high-dose inhaled corticosteroids had similar levels of circulating DHEA-S. In females, estradiol levels increased by Tanner stage, and associated negatively with pre-BD FEV1% and FVC %. Conclusions These results support beneficial effects of androgens on lung function and symptom control and weak deleterious effects of estradiol on lung function in children with asthma. Longitudinal data are necessary to confirm these cross-sectional findings and to further elucidate hormonal mechanisms informing sex differences in asthma features with puberty. Trial registration ClinicalTrials.gov registration number: NCT01748175. Electronic supplementary material The online version of this article (10.1186/s12890-018-0612-x) contains supplementary material, which is available to authorized users.

Background Contemporary reconsideration of diagnostic N-terminal pro–B-type natriuretic peptide (NT-proBNP) cutoffs for diagnosis of heart failure (HF) is needed. Objectives This study sought to evaluate the diagnostic performance of NT-proBNP for acute HF in patients with dyspnea in the emergency department (ED) setting. Methods Dyspneic patients presenting to 19 EDs in North America were enrolled and had blood drawn for subsequent NT-proBNP measurement. Primary endpoints were positive predictive values of age-stratified cutoffs (450, 900, and 1,800 pg/ml) for diagnosis of acute HF and negative predictive value of the rule-out cutoff to exclude acute HF. Secondary endpoints included sensitivity, specificity, and positive (+) and negative (−) likelihood ratios (LRs) for acute HF. Results Of 1,461 subjects, 277 (19%) were adjudicated as having acute HF. The area under the receiver-operating characteristic curve for diagnosis of acute HF was 0.91 (95% confidence interval [CI]: 0.90 to 0.93; p Conclusions In acutely dyspneic patients seen in the ED setting, age-stratified NT-proBNP cutpoints may aid in the diagnosis of acute HF. An NT-proBNP

BACKGROUND. The link between mucus plugs and airflow obstruction has not been established in chronic severe asthma, and the role of eosinophils and their products in mucus plug formation is unknown. METHODS. In clinical studies, we developed and applied a bronchopulmonary segment–based scoring system to quantify mucus plugs on multidetector computed tomography (MDCT) lung scans from 146 subjects with asthma and 22 controls, and analyzed relationships among mucus plug scores, forced expiratory volume in 1 second (FEV1), and airway eosinophils. Additionally, we used airway mucus gel models to explore whether oxidants generated by eosinophil peroxidase (EPO) oxidize cysteine thiol groups to promote mucus plug formation. RESULTS. Mucus plugs occurred in at least 1 of 20 lung segments in 58% of subjects with asthma and in only 4.5% of controls, and the plugs in subjects with asthma persisted in the same segment for years. A high mucus score (plugs in ≥ 4 segments) occurred in 67% of subjects with asthma with FEV1 of less than 60% of predicted volume, 19% with FEV1 of 60%–80%, and 6% with FEV1 greater than 80% (P < 0.001) and was associated with marked increases in sputum eosinophils and EPO. EPO catalyzed oxidation of thiocyanate and bromide by H2O2 to generate oxidants that crosslink cysteine thiol groups and stiffen thiolated hydrogels. CONCLUSION. Mucus plugs are a plausible mechanism of chronic airflow obstruction in severe asthma, and EPO-generated oxidants may mediate mucus plug formation. We propose an approach for quantifying airway mucus plugging using MDCT lung scans and suggest that treating mucus plugs may improve airflow in chronic severe asthma. TRIAL REGISTRATION. Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01718197","term_id":"NCT01718197"}}NCT01718197, {"type":"clinical-trial","attrs":{"text":"NCT01606826","term_id":"NCT01606826"}}NCT01606826, {"type":"clinical-trial","attrs":{"text":"NCT01750411","term_id":"NCT01750411"}}NCT01750411, {"type":"clinical-trial","attrs":{"text":"NCT01761058","term_id":"NCT01761058"}}NCT01761058, {"type":"clinical-trial","attrs":{"text":"NCT01761630","term_id":"NCT01761630"}}NCT01761630, {"type":"clinical-trial","attrs":{"text":"NCT01759186","term_id":"NCT01759186"}}NCT01759186, {"type":"clinical-trial","attrs":{"text":"NCT01716494","term_id":"NCT01716494"}}NCT01716494, and {"type":"clinical-trial","attrs":{"text":"NCT01760915","term_id":"NCT01760915"}}NCT01760915. FUNDING. NIH grants P01 HL107201, R01 HL080414, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109146","term_id":"1051682664"}}HL109146, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109164","term_id":"1051682685"}}HL109164, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109172","term_id":"1051682699"}}HL109172, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109086","term_id":"1051682577"}}HL109086, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109250","term_id":"1051682815"}}HL109250, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109168","term_id":"1051682692"}}HL109168, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109257","term_id":"1051682826"}}HL109257, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109152","term_id":"1051682671"}}HL109152, and P01 HL107202 and National Center for Advancing Translational Sciences grants UL1TR0000427, UL1TR000448, and KL2TR000428.

Objective Sexual minority men (SMM) in the United States continue to experience adverse health problems and psychosocial burdens. However, there is limited psychometric research seeking to quantify the life worries of this population. Informed by syndemic theory, the Life Worries Scale (LWS) was developed to measure the concerns of young SMM. Method Analyses of the scale were undertaken using baseline data (n = 665) from an ongoing cohort study of emerging adult, SMM. Results Exploratory factor analyses (EFA) of an initial set of 24 Likert-type items, followed by confirmatory factor analysis (CFA) and an exploratory structural equation model (ESEM), indicated a structure consisting of 6 domains of worries: financial stability, social stability, self esteem, loneliness, physical appearance, and physical health. These 6 subscales were highly correlated and also demonstrated high levels of internal consistency. Differences in life worries were noted across demographic states, specifically HIV serostatus, sexual attraction, housing status, and self-rated health. High levels of association were also detected between all 6 subscales with both depression and PTSD, while significant correlations were detected between suicidality and both self esteem and loneliness related worries. Conclusions The results of our analyses provide evidence for the strong psychometric characteristics of the LWS. This newly developed instrument should be utilized in research to examine the extent to which life worries explain health outcomes and risk behaviors in sexual minority males, and may be potentially extended for use in other populations. (PsycINFO Database Record

Bronchi are exposed daily to irritants, microbes and allergens as well as extremes of temperature and acid. The airway mucosal epithelium plays a pivotal role as a sentinel, releasing alarmins when danger is encountered. To maintain homeostasis, an elaborate counter-regulatory network of signals and cellular effector mechanisms are needed. Specialized pro-resolving mediators (SPMs) are chemical mediators that enact resolution programs in response to injury, infection or allergy. SPMs are enzymatically derived from essential polyunsaturated fatty acids with potent cell-type specific immunoresolvent properties. SPMs signal by engaging cell-based receptors to turn off acute inflammatory responses and restore tissue homeostasis. Several common lung diseases involving the airways, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), are characterized by unresolved bronchial inflammation. In preclinical murine models of lung disease, SPMs carry potent bronchoprotective actions. Here, we review cellular and molecular effects for SPM-initiated catabasis in the lung and their human translation.

Defining the principles underlying the organization of biomolecules within cells is a key challenge of current cell biology research. Persson et al. now identify a powerful layer of regulation that allows cells to decouple diffusion from temperature by modulating their intracellular viscosity. This so-called viscoadaptation is mediated through trehalose and glycogen activities, which alter diffusion dynamics and self-assembly propensity inside the cell globally.

Introduction Les infections a Bartonella sp. peuvent s’associer a la presence d’anticorps anti-cytoplasme des polynucleaires neutrophiles (ANCA), avant tout en cas d’endocardite. Ceci peut conduire a poser a tort le diagnostic d’une vascularite associee aux ANCA plutot que celui d’infection evolutive. L’objectif de cette etude est de preciser les caracteristiques cliniques, biologiques et histologiques ainsi que l’evolution des infections a Bartonelle mimant une vascularite primitive. Patients et methodes Nous avons etudie retrospectivement des patients ayant une infection a Bartonelle confirmee par une serologie, une culture specifique et/ou une technique de PCR, associee a la presence de manifestations cliniques compatibles avec une vascularite (purpura, arthralgies, myalgies, atteinte renale, neuropathie…), ainsi que des stigmates biologiques (ANCA, cryoglobulinemie, …) ou histologique (glomerulonephrite, vascularite leucocytoclasique, …) de vascularite. Nous avons complete ce travail par une revue de la litterature a partir de PubMed et Web of Science en appliquant les memes criteres d’inclusion. Resultats Nous avons inclus 6 patients originaux et 18 cas issus de la revue de la litterature. L’âge moyen au diagnostic etait de 57 ans . L’infection etait le plus souvent une endocardite dans 88 %. Un terrain predisposant (valvulopathie ou valve prothetique) etait present chez 54 % des patients. La serologie sanguine etait positive dans 19 cas (79 %), la PCR sur piece operatoire dans 9 cas (38 %) et la PCR sanguine dans 4 cas (17 %). Le pathogene identifie etait B. henselae dans 67 % des cas, B. quintana dans 29 % des cas et B. bacilliformis dans un cas. Les tableaux de vascularite se presentaient comme une vascularite a ANCA dans 83 %, une cryoglobulinemie dans 8 %, et une vascularite leucocytoclasique et une vascularite a IgA dans 4 % chacun. Les patients avaient de la fievre (59 %), un purpura (41 %) et des arthralgies (23 %). Seul un patient avait une rhinite crouteuse, et un autre des lesions pulmonaires excavees dans un contexte d’endocardite tricuspide. Une atteinte renale etait en revanche retrouvee chez 92 % des patients. Parmi les 20 patients ayant des ANCA positifs, la specificite etait anti-PR3 dans 80 %, anti-MPO dans 1 cas, avec double positivite dans 2 cas et sans specificite dans 1 cas. Chez les patients ANCA positifs, une hypocomplementemie etait observee dans 82 %, touchant plus souvent le C3 que le C4. Le facteur rhumatoide etait positif chez 11/13 (85 %) patients. La biopsie renale retrouvait une glomerulonephrite proliferative dans 89 %, souvent extra-capillaire et plus rarement endocapillaire, mesangiale ou membranoproliferative. L’etude en immunofluorescence montrait des depots d’Ig et de complement dans 11/16 (69 %) cas, tandis qu’il s’agissait de glomerulonephrite extra-capillaire pauci-immune dans 5/16 cas (31 %). Tous les patients ont recu une antibiotherapie adaptee. Quinze patients ont ete traites par immunosuppresseurs (63 %), avec une corticotherapie 15/15 cas, du cyclophosphamide dans 6/15 cas et au moins un echange plasmatique dans 3/15 cas. L’evolution etait globalement favorable avec aucun deces lie a l’infection ou a la vascularite. Le pronostic renal etait bon, avec un seul cas d’insuffisance renale terminale a l’issue de l’infection. Conclusion L’infection a Bartonelle et plus particulierement l’atteinte valvulaire cardiaque peut mimer une vascularite, avec une glomerulonephrite proliferative et des ANCA anti-PR3, sans atteinte ORL ni pulmonaire. Une hypocomplementemie doit egalement faire evoquer une origine infectieuse devant un tableau de glomerulonephrite rapidement progressive avec ANCA anti-PR3, de meme que la presence de depots glomerulaires d’immunoglobulines et de complement. L’evolution renale semble etre plus favorable qu’au cours des vascularites primitives.

RATIONALE: Non-invasive energy expenditure (EE) measurement is used to monitor physical activity in chronic lung disease. Unlike widely used motion-based devices calibrated in healthy populations, ...

Protein structures are key to understanding biomolecular mechanisms and diseases, yet their interpretation is hampered by limited knowledge of their biologically relevant quaternary structure (QS). A critical challenge in inferring QS information from crystallographic data is distinguishing biological interfaces from fortuitous crystal-packing contacts. Here, we tackled this problem by developing strategies for aligning and comparing QS states across both homologs and data repositories. QS conservation across homologs proved remarkably strong at predicting biological relevance and is implemented in two methods, QSalign and anti-QSalign, for annotating homo-oligomers and monomers, respectively. QS conservation across repositories is implemented in QSbio (http://www.QSbio.org), which approaches the accuracy of manual curation and allowed us to predict >100,000 QS states across the Protein Data Bank. Based on this high-quality data set, we analyzed pairs of structurally conserved interfaces, and this analysis revealed a striking plasticity whereby evolutionary distant interfaces maintain similar interaction geometries through widely divergent chemical properties.

Introduction TRV027, a 'biased' ligand of the angiotensin II type 1 receptor (AT1R), did not affect a composite clinical outcome at 30 days in a phase 2b acute heart failure (AHF) trial (BLAST-AHF).Methods Post-hoc analyses from BLAST-AHF (n = 618) examined the effects of TRV027 by baseline systolic blood pressure (SBP) on changes in renal function and 180-day outcomes. Interactions between baseline SBP and select endpoints were identified utilizing a subpopulation treatment effect pattern plots (STEPP) analysis, then grouping of patients by SBP tertile: = 127 to = 140 mmHg.Results A trend towards increased creatinine in the first 3 days was noted in the lower SBP tertile, while in those in the higher two tertiles, TRV027, especially the 1 mg/h dose, reduced creatinine at days 5 and 30. Beneficial effects on 180-day all-cause mortality and cardiovascular (CV) death or readmission were observed in the two higher SBP tertiles (SBP >= 127 mmHg) in the TRV027 1 mg/h dose group (all-cause mortality HR 0.39, 95% CI 0.14-1.06, p = 0.056; CV death or HF/RF rehospitalization HR 0.53, 95% CI 0.28-1.01, p = 0.049), while more adverse outcomes were observed in patients in the lower SBP tertile.Conclusions This post-hoc analysis of the BLAST-AHF study suggests contrasting effects of TRV027 by baseline SBP, with trends towards lower 180-day event rates in patients enrolled with higher baseline SBP, especially when given lower doses of TRV027.

Objectives The objectives were to reassess use of amino-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations for diagnosis and prognosis of acute heart failure (HF) in patients with acute dyspnea. Background NT-proBNP facilitates diagnosis, prognosis, and treatment in patients with suspected or proven acute HF. As demographics of such patients are changing, previous diagnostic NT-proBNP thresholds may need updating. Additionally, value of in-hospital NT-proBNP prognostic monitoring for HF is less understood. Methods In a prospective, multicenter study in the United States and Canada, patients presenting to emergency departments with acute dyspnea were enrolled, with demographic, medication, imaging, and clinical course information collected. NT-proBNP analysis will be performed using the Roche Diagnostics Elecsys proBNPII immunoassay in blood samples obtained at baseline and at discharge (if hospitalized). Primary end points include positive predictive value of previously established age-stratified NT-proBNP thresholds for the adjudicated diagnosis of acute HF and its negative predictive value to exclude acute HF. Secondary end points include sensitivity, specificity, and positive and negative likelihood ratios for acute HF and, among those with HF, the prognostic value of baseline and predischarge NT-proBNP for adjudicated clinical end points (including all-cause death and hospitalization) at 30 and 180 days. Results A total of 1,461 dyspneic subjects have been enrolled and are eligible for analysis. Follow-up for clinical outcome is ongoing. Conclusions The International Collaborative of N-terminal pro–B-type Natriuretic Peptide Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department study offers a contemporary opportunity to understand best diagnostic cutoff points for NT-proBNP in acute HF and validate in-hospital monitoring of HF using NT-proBNP.

Type 2 innate lymphoid cells (ILC2s) both contribute to mucosal homeostasis and initiate pathologic inflammation in allergic asthma. However, the signals that direct ILC2s to promote homeostasis versus inflammation are unclear. To identify such molecular cues, we profiled mouse lung-resident ILCs using single-cell RNA sequencing at steady state and after in vivo stimulation with the alarmin cytokines IL-25 and IL-33. ILC2s were transcriptionally heterogeneous after activation, with subpopulations distinguished by expression of proliferative, homeostatic and effector genes. The neuropeptide receptor Nmur1 was preferentially expressed by ILC2s at steady state and after IL-25 stimulation. Neuromedin U (NMU), the ligand of NMUR1, activated ILC2s in vitro, and in vivo co-administration of NMU with IL-25 strongly amplified allergic inflammation. Loss of NMU-NMUR1 signalling reduced ILC2 frequency and effector function, and altered transcriptional programs following allergen challenge in vivo. Thus, NMUR1 signalling promotes inflammatory ILC2 responses, highlighting the importance of neuro-immune crosstalk in allergic inflammation at mucosal surfaces.

Purpose Implementation research provides a structure for evaluating the clinical integration of genomic medicine interventions. This paper describes the Implementing GeNomics In PracTicE (IGNITE) Network’s efforts to promote: 1) a broader understanding of genomic medicine implementation research; and 2) the sharing of knowledge generated in the network. Methods To facilitate this goal the IGNITE Network Common Measures Working Group (CMG) members adopted the Consolidated Framework for Implementation Research (CFIR) to guide their approach to: identifying constructs and measures relevant to evaluating genomic medicine as a whole, standardizing data collection across projects, and combining data in a centralized resource for cross network analyses. Results CMG identified ten high-priority CFIR constructs as important for genomic medicine. Of those, eight didn’t have standardized measurement instruments. Therefore, we developed four survey tools to address this gap. In addition, we identified seven high-priority constructs related to patients, families, and communities that did not map to CFIR constructs. Both sets of constructs were combined to create a draft genomic medicine implementation model. Conclusion We developed processes to identify constructs deemed valuable for genomic medicine implementation and codified them in a model. These resources are freely available to facilitate knowledge generation and sharing across the field.

Introduction: While moderate to severely elevated blood pressure (BP) is present in nearly halfof all emergency department (ED) patients, the incidence of true hypertensive emergencies inED patients is low. Administration of bolus intravenous (IV) antihypertensive treatment to lowerBP in patients without a true hypertensive emergency is a wasteful practice that is discouragedby hypertension experts; however, anecdotal evidence suggests this occurs with relatively highfrequency. Accordingly, we sought to assess the frequency of inappropriate IV antihypertensivetreatment in ED patients with elevated BP absent a hypertensive emergency. Methods: We performed a retrospective cohort study from a single, urban, teaching hospital.Using pharmacy records, we identified patients age 18-89 who rec eived IV antihypertensivetreatment in the ED. We defined treatment as inappropriate if documented suspicion for anindicated cardiovascular condition or acute end-organ injury was lacking. Data abstractionincluded adverse events and 30-day readmission rates, and analysis was primarily descriptive. Results: We included a total of 357 patients over an 18-month period. The mean age was 55;51% were male and 93% black, and 127 (36.4%) were considered inappropriately treated.Overall, labetalol (61%) was the most commonly used medication, followed by enalaprilat(18%), hydralazine (18%), and metoprolol (3%). There were no significant differences betweenappropriate and inappropriate BP treatment groups in terms of clinical characteristics oradverse events. Hypotension or bradycardia occurred in three (2%) patients in the inappropriatetreatment cohort and in two (1%) patients in the appropriately treated cohort. Survival todischarge and 30-day ED revisit rates were equivalent. Conclusion: More than one in three patients who were given IV bolus antihypertensive treatmentin the ED received such therapy inappropriately by our definitio n, suggesting that significantresources could perhaps be saved through education of providers and development of clearlydefined BP treatment protocols. [West J Emerg Med. 2017;18(5)957-962.]

Aims: Currently, no acute heart failure (AHF) therapy definitively improves outcomes. Reducing morbidity and mortality from acute heart failure (AHF) remains an unmet need. TRV027 is a novel ` biased' ligand of the angiotensin II type 1 receptor (AT1R), selectively antagonizing the negative effects of angiotensin II, while preserving the potential pro-contractility effects of AT1R stimulation. BLAST-AHF was designed to determine the safety, efficacy, and optimal dose of TRV027 to advance into future studies.Methods and results: BLAST-AHF was a multi-centre, international, randomized, double-blind, placebo-controlled, parallel group, phase IIb dose-ranging study, enrolling patients with AHF into 4 groups: placebo, 1, 5, or 25mg/h of TRV027. Treatment was by IV infusion for 48-96 h. The primary composite endpoint was comprised of the following: (i) time from baseline to death through day 30, (ii) time from baseline to heart failure re-hospitalization through day 30, (iii) the first assessment time point following worsening heart failure through day 5, (iv) change in dyspnea visual analogue scale (VAS) score calculated as the area under the curve (AUC) representing the change from baseline over time from baseline through day 5, and (v) length of initial hospital stay (in days) from baseline. Analyses were by modified intention-to-treat. Overall, 621 patients were enrolled. After 254 patients, a pre-specified interim analysis resulted in several protocol changes, including a lower blood pressure inclusion criterion as well as a new allocation scheme of 2: 1: 2: 1, overweighting both placebo, and the 5mg/h dose. TRV027 did not confer any benefit over placebo at any dose with regards to the primary composite endpoint or any of the individual components. There were no significant safety issues with TRV027.Conclusion: In this phase IIb dose-ranging AHF study, TRV027 did not improve clinical status through 30-day follow-up compared with placebo.

Introducing a single ‘sticky’ (hydrophobic) amino acid by point mutation into symmetric protein complexes frequently triggers their association into higher-order assemblies, without affecting their native fold and structure. The self-association of proteins into symmetric complexes is functionally useful in countless biological processes, but can make proteins prone to forming harmful fibrils. Focusing on a dozen distinct symmetric protein complexes from Escherichia coli, Emmanuel Levy and colleagues show that introducing a single 'sticky' (hydrophobic) amino acid by mutation is generally sufficient to trigger the formation of higher order assemblies, without affecting the native fold and structure. The authors identify 'hot spots' for such sticky interfaces in protein databases and show that evolution has surrounded those with hydrophilic residues, thus buffering the formation of higher-order aggregates. The results have implications in the study of disease-causing mutations and protein evolution. In addition, controlled point mutations could be considered in the design of bio-materials. The self-association of proteins into symmetric complexes is ubiquitous in all kingdoms of life1,2,3,4,5,6. Symmetric complexes possess unique geometric and functional properties, but their internal symmetry can pose a risk. In sickle-cell disease, the symmetry of haemoglobin exacerbates the effect of a mutation, triggering assembly into harmful fibrils7. Here we examine the universality of this mechanism and its relation to protein structure geometry. We introduced point mutations solely designed to increase surface hydrophobicity among 12 distinct symmetric complexes from Escherichia coli. Notably, all responded by forming supramolecular assemblies in vitro, as well as in vivo upon heterologous expression in Saccharomyces cerevisiae. Remarkably, in four cases, micrometre-long fibrils formed in vivo in response to a single point mutation. Biophysical measurements and electron microscopy revealed that mutants self-assembled in their folded states and so were not amyloid-like. Structural examination of 73 mutants identified supramolecular assembly hot spots predictable by geometry. A subsequent structural analysis of 7,471 symmetric complexes showed that geometric hot spots were buffered chemically by hydrophilic residues, suggesting a mechanism preventing mis-assembly of these regions. Thus, point mutations can frequently trigger folded proteins to self-assemble into higher-order structures. This potential is counterbalanced by negative selection and can be exploited to design nanomaterials in living cells.

Chronic recurrent multifocal osteomyelitis (CRMO) is an idiopathic inflammatory disorder primarily of children and adolescents that is characterized by multifocal nonpyogenic relapsing and remitting inflammatory bone lesions. Pulmonary abnormalities are rarely associated with CRMO, with two reported cases of consolidation on chest CT that occurred in children. We present a case of organizing pneumonia in an adult patient with CRMO. The concurrent worsening of pulmonary and bone disease suggests that CRMO may be a rare cause of organizing pneumonia.

The 2008 financial meltdown prompted an apparent revival of the dirigiste or statist economic model in France, a country with a long tradition of state-led development. French President, Nicolas Sarkozy denounced laissez-faire capitalism, which he blamed for the crisis, and launched a series of industrial policy initiatives. Yet the reality of French actions fell well short of the statist rhetoric, with the government committing few financial resources to its signature industrial policy programs and displaying little capacity to steer business strategies. This article argues that France’s neostatist turn was largely checked by the legacies of shifts in French economic policy a quarter-century earlier. Specifically, the break with the dirigiste model in 1983 deprived French authorities of many of the institutions and instruments associated with state-led development, while the massive expansion of social and labor market programs that eased the movement away from dirigisme left the government without the fiscal capacity to launch expensive new promotional policies. The broader lesson is that a country’s response to crisis is shaped by long-term structural factors, not just short-term political calculations, and that there are important institutional and fiscal prerequisites for statist revival, even when neoliberalism is widely believed to have failed.

Upper gastrointestinal bleeding (UGIB) remains a significant cause of morbidity and mortality with mortality rates as high as 14%. This document addresses the indications for imaging UGIB that is nonvariceal and unrelated to portal hypertension. The four variants are derived with respect to upper endoscopy. For the first three, it is presumed that upper endoscopy has been performed, with three potential initial outcomes: endoscopy reveals arterial bleeding source, endoscopy confirms UGIB without a clear source, and negative endoscopy. The fourth variant, "postsurgical and traumatic causes of UGIB; endoscopy contraindicated" is considered separately because upper endoscopy is not performed. When endoscopy identifies the presence and location of bleeding but bleeding cannot be controlled endoscopically, catheter-based arteriography with treatment is an appropriate next study. CT angiography (CTA) is comparable with angiography as a diagnostic next step. If endoscopy demonstrates a bleed but the endoscopist cannot identify the bleeding source, angiography or CTA can be typically performed and both are considered appropriate. In the event of an obscure UGIB, angiography and CTA have been shown to be equivalent in identifying the bleeding source; CT enterography may be an alternative to CTA to find an intermittent bleeding source. In the postoperative or traumatic setting when endoscopy is contraindicated, primary angiography, CTA, and CT with intravenous contrast are considered appropriate. 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.