bluuebunny/crossref_metadata_2025 huggingface dataset:
Performance in the Medicare Shared Savings Program by Accountable Care Organizations Disproportionately Serving Dual and Disabled Populations
Authors: Sen Aditi P. , Chen Lena M. , Wong Samson Lok , Epstein Arnold M. , Joynt Maddox Karen E.
Published: July 2018

Background:

The growth of accountable care organizations (ACOs) and other alternative payment models has prompted concern about whether these models will disadvantage providers who serve vulnerable populations, particularly those living in poverty or with a disability.

Objective:

To examine performance by ACOs in the top quintile of their proportion of beneficiaries dually enrolled in Medicare and Medicaid (high-dual) and the top quintile of disabled beneficiaries (high-disabled).

Research Design:

This is a retrospective cohort study.

Subjects:

The 333 ACOs in the Medicare Shared Savings Program in 2014, followed through 2016.

Measures:

Quality scores, savings per beneficiary, whether or not the ACO shared savings, and amount of shared savings.

Results:

High-dual and high-disabled ACOs had slightly lower quality and similar or higher baseline spending than other ACOs, but achieved greater savings per beneficiary than other ACOs ($212 vs. $51 for high-dual ACOs, P=0.04; $241 vs. $44 for high-disabled ACOs, P=0.012). Further, these ACOs were equally or more likely to earn shared savings; just over 30% of high-dual ACOs earned shared savings compared with 25% of non–high-dual ACOs (P=0.35) and 38% of high-disabled ACOs earned shared savings compared with 23% of non–high-disabled ACOs (P=0.013). In longitudinal analyses, we found a decrease in the differences in quality between high-social risk and other ACOs over time. Savings remained higher for high-dual and high-disabled ACOs relative to other ACOs over 2014–2016 though the gap narrowed over time.

Conclusions:

High-dual and high-disabled ACOs had similar or higher spending than other ACOs at baseline, but achieved greater savings and were equally or more likely to earn shared savings, suggesting that alternative payment models can have positive financial outcomes for providers who serve vulnerable populations.
Subverting bradykinin-evoked inflammation by co-opting the contact system: lessons from survival strategies of Trypanosoma cruzi
Authors: Scharfstein Julio
Published: July 2018

Purpose of review

During Chagas disease,Trypanosoma cruzialternates between intracellular and extracellular developmental forms. After presenting an overview about the roles of the contact system in immunity, I will review experimental studies showing that activation of the kallikrein-kinin system (KKS) translates into mutual benefits to the host/parasite relationship.

Recent findings

T. cruzitrypomastigotes initiate inflammation by activating tissue-resident innate sentinel cells via the TLR2/CXCR2 pathway. Following neutrophil-evoked microvascular leakage, the parasite's major cysteine protease (cruzipain) cleaves plasma-borne kininogens and complement C5. Tightly regulated by angiotensin-converting enzyme (ACE), kinins and C5a in turn further propagate inflammation via iterative cycles of mast cell degranulation, contact system activation, bradykinin release and activation of endothelial bradykinin B2 receptors (B2R). Recently, studies in the intracardiac model of infection revealed a dichotomic role for bradykinin and endothelin-1: generated upon contact activation (mast cell/KKS pathway), these pro-oedematogenic peptides reciprocally stimulate trypomastigote invasion of heart cells that naturally overexpress B2R and endothelin receptors (ETaR/ETbR).

Studies focusing on the immunopathogenesis of Chagas disease revealed that the contact system plays a dual role in host/parasite balance:T. cruzico-opts bradykinin-induced plasma leakage as a strategy to increment heart parasitism and increase immune resistance by upregulating type-1 effector T-cell production in secondary lymphoid tissues.
Advances in computer-aided design for bony free-flap reconstruction
Authors: Sahovaler Axel , Fung Kevin
Published: July 2018

Purpose of review

The current article reviews the most recent publications of computer-assisted reconstruction using bony free flaps, emphasizing on comparative reports using these novel techniques.

Recent findings

Computer-aided reconstruction has shown some benefits in comparison with traditional techniques and some of the perceived limitations are currently being addressed in the latest reports. Still, there is a lack of appropriate comparative studies and unblinded measurements to establish solid conclusions.

Despite the application of new technologies showed encouraging results, it is premature to state that the traditional technique should be replaced by the modern approaches.
Assessment of vestibular function in elderly patients
Authors: Krager Rachael
Published: July 2018

Purpose of review

Individuals over the age of 60 are at an increased risk of falls, even if they do not have an isolated dysfunction of the vestibular system. The aim of this article is to review the various vestibular testing currently available and its usefulness in determining the presence of vestibular dysfunction in the elderly population. The primary vestibular tests to be reviewed include: balance function testing, vestibular evoked myogenic potentials (VEMPs), and video head impulse testing (vHIT).

Recent findings

Balance function testing is important as it evaluates the integration of vestibular information along with sensory and visual information, which may also be impaired. VEMP testing provides a small diagnostic yield as most elderly patients have absent or reduced responses. vHIT gain is reduced in this population, but will still be within the normal range for individuals with normal balance function.

The combination of various vestibular tests provides complimentary information instead of redundant information on the patient's balance function. Each test evaluates various aspects of the vestibular system which are all needed to determine stable balance in the elderly population.
Nursing Students’ Perceptions of Skills Learning
Authors: Aldridge Michael D. , Hummel Faye
Published: July 2018

Background

Deliberate practice (DP) and cognitive load theory have renewed educators’ interest in effective psychomotor skills teaching.

Purpose

The purpose of this research was to explore how prelicensure nursing students learned psychomotor skills.

Methods

Nine senior nursing students participated in this phenomenological study to capture how they experienced learning nursing skills. Colaizzi’s method was used to analyze in-depth interviews of open-ended questions.

Results

Six themes emerged: (a) the umbrella of emotion, (b) practice, (c) learning through technology, (d) fidelity affects learning, (e) teaching matters, and (f) importance of peers. Students found creative ways to learn nursing skills. Research findings contributed to a greater understanding of student experiences in gaining competency in nursing skills.

Conclusions

Participants used aspects of DP, cognitive load theory, and technology to learn skills. These findings provide current information to nurse educators about skills learning and recommendations for effective skills teaching.
Transforming Health Care Through Meaningful Doctor of Nursing Practice Community Partnerships
Authors: Hooshmand Mary , Foronda Cynthia , Snowden Kenya , de Tantillo Lila , Williams Jessica Roberts
Published: July 2018

Background

A critical component of doctor of nursing practice (DNP) education is practice immersion. DNP programs require 1000 hours of clinical practice experience to obtain the DNP degree.

Problem

Faculty struggle with providing meaningful clinical experiences congruent with the role of the DNP.

Approach

This article describes a unique practice immersion course joining DNP students with community health care partners to provide meaningful experiences with the potential to transform health care. DNP students are assigned system-level projects designed to create organizational change.

Outcomes

Over the course of 4 years, the practice immersion opportunities more than doubled from 30 to 66 live projects. Integrating collaborative practice immersion into the curriculum builds students’ leadership skills and strengthens long-standing bonds among academia, practice, and the community.

Conclusions

The creation of structured, meaningful collaborations between DNP students and community partners is an approach that has the potential to facilitate transformative, sustainable change in health care.
Medical Errors in Iowa: Prevalence and Patients' Perspectives
Authors: Lind David P. , Andresen David R. , Williams Andrew
Published: July 2018

Objectives

The following primary objectives of this study were to: (1) establish baselines of prevalence and causes of medical errors experienced by Iowans in medical settings, (2) determine whether Iowa patients were informed of the errors by the responsible healthcare providers, (3) understand reasons why Iowans who experienced medical errors did or did not report the errors, and (4) discover how Iowans view mandatory reporting of medical errors.

Methods

A total of 1010 Iowa adults took part in a telephone survey in summer 2017. Interviews were completed via random landlines and random digit dialing of cell phone numbers.

Results

Nearly one fifth of surveyed Iowa adults (18.8%) reported being involved in a medical error in their own care or in the care of someone close to them, and yet only four in 10 (39.1%) were notified of the error by the responsible provider. Most Iowans strongly agree that Iowa hospitals (79.5%), physicians (74.1%), and nursing homes (82.2%) should be required to report all medical errors to the patient and to a state agency.

Conclusions

A significant proportion of Iowans will experience a medical error. They also desire full transparency from healthcare providers with respect to medical errors, including notifying the patient when an error occurs and mandating that providers report errors to a state-based agency. Iowa regulators should carefully assess and initiate stringent regulatory guidelines for mandatory reporting of medical errors.
“It Matters What I Think, Not What You Say”: Scientific Evidence for a Medical Error Disclosure Competence (MEDC) Model
Authors: Hannawa Annegret F. , Frankel Richard M.
Published: July 2018

Objective

This study sought to validate the ability of a “Medical Error Disclosure Competence” (MEDC) model to predict the effects of physicians’ communication skills on error disclosure outcomes in a simulated context.

Method

A random sample of 721 respondents was assigned to 16 experimental disclosure conditions that tested the MEDC model’s constructs across 2 severity conditions (i.e., minor error and sentinel event).

Results

Severity did not affect survey respondents’ perceptions of the physician’s disclosure style. Respondents who viewed the nonverbally skilled disclosure perceived the disclosure as more adequate compared to respondents in the “low nonverbal skill” disclosure condition. Interpersonal adaptability did not affect respondents’ adequacy ratings. Consistent with the MEDC model, those who viewed the physician’s error disclosure as inadequate indicated that they would be more prone to engage in relational distancing behaviors, while those who rated the disclosure as adequate were more likely to reinvest into their relationship with their physician. These respondents also had higher resilience scores. In the context of a sentinel event, perceived adequacy significantly predicted endorsing legal redress or remedies (e.g., lawsuit). Verbal apology (e.g., “I’m sorry,” “I apologize”) did not predict any significant variance in the model beyond the physician’s nonverbal skill.

Conclusion

In a simulated disclosure setting, physicians’ communicative skills—particularly effective nonverbal communication during a disclosure—trigger outcomes that affect the patient, the physician, and the provider-patient relationship. Findings from this study suggest that MEDC guidelines may be helpful in reducing financial and reputational risks to individual providers and institutions, particularly in the context of a sentinel event.
Lung Ultrasound as a Screening Method for Interstitial Lung Disease in Patients With Systemic Sclerosis
Authors: Hassan Romina Isabel , Lubertino Lucia I. , Barth Maria Angeles , Quaglia Maria Fernanda , Montoya Sandra Fabiana , Kerzberg Eduardo , Binda Maria del Carmen
Published: July 2018

Background

Patients with systemic sclerosis (SSc) undergo chest radiographs and high-resolution computed tomography (HRCT) of the thorax both for interstitial lung disease (ILD) detection and for disease progression monitoring.

Objective

The aim of this study was to assess whether lung ultrasound (LUS) is a useful screening tool for ILD in patients with SSc in comparison with HRCT.

Methods

This was a longitudinal cohort study carried out from December 2015 to April 2016. An LUS was performed to examine B-lines in 67 consecutive patients who met the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for SSc and had a previous HRCT. B-lines were quantified and classified according to the score modified from Picano. Severity and extent of lung involvement on the HRCT were determined by means of the Warrick score.

Results

Twenty-nine patients had both abnormal HRCT (Warrick score >7) and abnormal LUS, 2 had a mild score (6–15 B-lines), and 27 had either moderate or severe scores (≥16 B-lines). Of the 38 patients with negative HRCT, 25 presented some degree of lung involvement on the LUS. Thus, LUS has a sensitivity of 100% and a specificity of 34%. Receiver operating characteristic curve analysis showed the analytic relation between the number of B-lines and the presence of ILD on the HRCT (area under the curve, 0.80; 95% confidence interval, 0.69–0.90).

Conclusions

Lung ultrasound may be a method to detect abnormal lung findings in a noninvasive manner in patients with SSc. Because of its high sensitivity, a low score almost rules out the need for an HRCT.
Pan-American League of Associations for Rheumatology–Central American, Caribbean and Andean Rheumatology Association Consensus-Conference Endorsements and Recommendations on the Diagnosis and Treatment of Chikungunya-Related Inflammatory Arthropathies in Latin America
Authors: Monge Pablo , Vega José Manuel , Sapag Ana María , Moreno Ilsa , Montúfar Rubén , Khoury Vianna , Camilo Pablo , Rivera Ruddy , Rueda Juan C. , Jaramillo-Arroyave Daniel , Londoño John , del Carmen Ruiz María , Fernández Félix , Quintero Maritza , Fuentes-Silva Yurilis , Aguilar José Luis , Vallejo-Flores Carlos , Caballero-Uribe Carlo V. , Sandoval Hugo , Pineda Carlos
Published: July 2018

Background/Objective

Although mortality rates related with chikungunya (CHIK) outbreaks in Latin America's (LA's) dengue-endemic rural and new urban regions are low, dealing with symptoms and sequelae can both produce a significant burden of disease and diminish quality of life—from many months to years—after the acute phase of the infection, with a significant impact on public and individual health.

The aim of this work was to establish Pan-American League of Associations for Rheumatology–Central American, Caribbean and Andean Rheumatology Association (ACCAR) consensus-conference endorsements and recommendations on the diagnosis and treatment of CHIK-related inflammatory arthropathies transmitted by Aedes aegypti and Aedes albopictus in LA.

Methods

Based on the Consensus Development Conference format, a panel of ACCAR rheumatologist voting members (n = 10) took part in this Pan-American League of Associations for Rheumatology initiative. Experts voted from a previous content analysis of the medical literature on CHIK, 4 subsequent topic conferences, and a workshop. Consensus represents the majority agreement (≥80%) achieved for each recommendation.

Results

The experts' panel reached 4 overarching principles: (1) CHIK virus (CHIKV) is a re-emergent virus transmitted by 2 species of mosquitoes: A. aegypti and A. albopictus; (2) CHIKV caused massive outbreaks in LA; (3) chronic CHIKV infection produces an inflammatory joint disease that, in some cases, can last for several months to years, and (4) currently, there are no vaccines or antivirals licensed for CHIKV infections.

Recommendations

Pan-American League of Associations for Rheumatology–ACCAR achieved 13 endorsements and recommendations on CHIK categorized in 3 groups: (1) epidemiology and clinical manifestations, (2) diagnosis, and (3) treatment, representing the consensus agreement from the panel's members.
Clinical Associations of Uveitis in Axial Spondyloarthritis Group and Ankylosing Spondylitis Group
Authors: Wong Oi Man , Tsang Helen Hoi Lun , Chan Shirley Chiu Wai , Lee Kam Ho , Li Philip Hei , Lau Chak Sing , Chung Ho Yin
Published: July 2018

Objective

The aim of this study was to determine the prevalence and associated factors for uveitis in ethnic Chinese patients with axial spondyloarthritis (SpA) and ankylosing spondylitis (AS).

Methods

This was a cross-sectional study. Patients fulfilling the Assessment of SpondyloArthritis international Society axial SpA criteria were recruited consecutively from 3 rheumatology centers in Hong Kong from March 2014 to July 2017. Clinical and biochemical parameters were collected. History of uveitis was inquired from both history and medical records. All patients received lumbosacral spine x-rays and whole-spine and sacroiliac joint magnetic resonance imaging. Patients were defined as axial SpA if they fulfilled the Assessment of SpondyloArthritis international Society criteria and AS if they fulfilled the modified New York criteria. Clinical and radiological findings were compared between patients with and without uveitis in the 2 groups. Factors associated with uveitis were identified with univariate analyses and multivariate logistic regression analyses.

Results

Among 252 patients, 67 patients (26.6%) had a history of uveitis. The male-to-female ratio was 55.4 to 44.6. Disease duration was 12.3 ± 11.7 years. In the axial SpA group, multivariate regression showed that older age (odds ratio [OR], 1.05; p = 0.01), human leukocyte antigen B27 positivity (OR, 11.79; p = 0.01), and history of inflammatory bowel disease (OR, 9.74; p = 0.04) were positively associated with uveitis. In the AS group, multivariate regression showed that back pain duration (OR, 1.05; p = 0.01) and male sex (OR, 3.46; p = 0.03) were associated with uveitis.

Conclusions

Axial SpA represents a spectrum of diseases. Its clinical associations with uveitis should be distinguished from those of traditional AS.
Chronic Cavitary Infections Other than Tuberculosis
Authors: Holt Michael R. , Chan Edward D.
Published: July 2018

Lung cavitation may be due to infectious or noninfectious pathologic processes. The latter category includes nonmalignant conditions, such as granulomatosis with polyangiitis, and malignant conditions, such as squamous cell carcinoma of the lung. Infectious etiologies that produce lung cavitation usually cause chronic illness, although some, particularly pyogenic bacteria, may produce acute cavitary disease. Tuberculosis is the most common cause of chronic pulmonary infection with cavitation. The goal of this review was to highlight a selection of the better-known infectious agents, other than tuberculosis, that can cause chronic lung disease with cavitation. Emphasis is placed on the following organisms: nontuberculous mycobacteria, Histoplasma, Blastomyces, Coccidioides, Paracoccidioides, Aspergillus, Burkholderia pseudomallei, Paragonimus westermani, and Rhodococcus equi. These organisms generally produce clinical features and radiologic findings that overlap or mimic those of tuberculosis. In a companion article, we have further emphasized aspects of the same conditions that are more pertinent to radiologists.
Imaging of Community-acquired Pneumonia
Authors: Franquet Tomás
Published: July 2018

Community-acquired pneumonia refers to an acute infection of the lung in patients who did not meet any of the criteria for health care–acquired pneumonia, and is associated with at least some symptoms of acute infection, accompanied by the presence of an acute infiltrate on a chest radiograph. Chest radiography remains an important component of the evaluation of a patient with a suspicion of pneumonia, and is usually the first examination to be obtained. The diagnosis of community-acquired pneumonia is based on the presence of select clinical features and is supported by imaging of the lung, usually by chest radiography. Infection of the lower respiratory tract typically presents radiologically as one of 3 patterns: (a) focal nonsegmental or lobar pneumonia, (b) multifocal bronchopneumonia or lobular pneumonia, and (c) focal or diffuse “interstitial” pneumonia. High-resolution computed tomography allows a better depiction of the pattern and distribution of pneumonia than the radiograph but is seldom required in the evaluation of patients with suspected or proven bacterial pneumonia. However, high-resolution computed tomography is a useful adjunct to conventional radiography in selected cases.
Celiac-like Enteropathy Associated With Mycophenolate Sodium in Renal Transplant Recipients
Authors: Filiopoulos Vassilis , Sakellariou Stratigoula , Papaxoinis Konstantinos , Melexopoulou Christina , Marinaki Smaragdi , Boletis John N. , Delladetsima Ioanna
Published: July 2018

Background

Although colonic injury is a well-known complication of mycophenolic acid (MPA), the involvement of the upper gastrointestinal tract is less extensively documented. We present the occurrence of celiac-like duodenopathy manifested as a severe diarrhea syndrome in 2 renal transplant recipients on enteric-coated mycophenolate sodium.

Methods

The patients belong to a setting of 16 renal transplant recipients under MPA suffering from chronic diarrhea in the absence of MPA-related colitis.

Results

Both patients had a history of persistent diarrhea with significant weight loss. Colonic mucosa was unremarkable, whereas duodenal biopsies revealed celiac-like changes with increased epithelial cell apoptosis. Clinical symptoms completely resolved, and follow-up biopsies demonstrated normalization of histology after enteric-coated mycophenolate sodium withdrawal and switching to azathioprine.

Conclusions

Celiac-like enteropathy seems to represent a rare side effect of MPA-associated immunosuppressive therapy and should be taken into account in the differential diagnosis of diarrhea in transplant recipients treated with MPA particularly in the absence of MPA-related colitis. As macroscopic lesions are usually missing, blind duodenal biopsies are necessary to establish the diagnosis.
Liver Allograft Failure After Nivolumab Treatment—A Case Report With Systematic Literature Research
Authors: Gassmann Dimitri , Weiler Stefan , Mertens Joachim C. , Reiner Cäcilia S. , Vrugt Bart , Nägeli Mirjam , Mangana Joanna , Müllhaupt Beat , Jenni Fabienne , Misselwitz Benjamin
Published: July 2018

Background

Orthotopic liver transplantation (OLT) is a potential curative treatment in patients with hepatocellular carcinoma (HCC); however, treatment options for recurrent HCC after OLT are limited. Immune checkpoint inhibitors, such as nivolumab, an inhibitor of programmed cell death protein 1, have been successfully used for metastatic HCC but data on safety of nivolumab following solid organ transplantation are limited.

Methods

We report a 53-year-old woman with HCC who was treated with OLT. After 2 years, HCC recurred. Initial treatment with sorafenib was discontinued due to side effects and disease progression. Progressive HCC in the lung and lymph nodes was subsequently treated with nivolumab. One week after the first nivolumab dose, rapid progressive liver dysfunction was noted. Liver biopsy revealed severe cellular graft rejection prompting treatment with intravenous steroids and tacrolimus. Liver function continued to decline, leading to severe coagulopathy. The patient succumbed to intracranial hemorrhage.

Results

A systematic PubMed search revealed 29 cases treated with a checkpoint inhibitor following solid organ transplantation. Loss of graft was described in 4 (36%) of 11 cases with OLT and in 7 (54%) of 13 cases after kidney transplantation. However, cases with favorable outcome were also described. Eighteen cases with adverse events were identified upon searching the World Health Organization database VigiBase, including 2 cases with fatal outcome in liver transplant recipients due to graft loss.

Conclusion

Experience with checkpoint inhibitors in solid organ transplant recipients is limited. Published cases so far suggest severe risks for graft loss as high as 36% to 54%.
How useful is muscle ultrasound in the diagnostic workup of neuromuscular diseases?
Authors: van Alfen Nens , Gijsbertse Kaj , de Korte Chris L.
Published: July 2018

Purpose of review

This review focuses on developments in muscle ultrasound as a noninvasive and accurate tool for the diagnosis and follow-up of neuromuscular disease. It discusses current muscle ultrasound applications with already proven clinical value, and highlights recent technical developments that may further advance muscle ultrasounds’ diagnostic qualities.

Recent findings

The sensitivity and specificity of muscle ultrasound for detecting a neuromuscular disorder are high (90–95%), and quantitative ultrasound is well suited to monitor disease progression in several disorders. Adding ultrasound to electromyography significantly improves diagnostic certainty in patients with suspected motor neuron disease, and ultrasound increases the detection of fasciculations with 30–50%. New developments include speckle tracking of tissue motion to quantify diaphragm excursions and diminished muscle contractility in dystrophy, and strain elastography to detect changes in muscle stiffness and anisotropy during contraction and in disease states. Deep learning algorithms are being developed to predict the presence of a muscle disease and differentiate between disorders.

Muscle ultrasound is excellent for screening, diagnosing, and follow-up of neuromuscular disease. New developments are underway to automate and objectify the diagnostic process, and to quantify tissue motion that can provide new insights in pathophysiology and serve as a biomarker.
Emerging antisense oligonucleotide and viral therapies for amyotrophic lateral sclerosis
Authors: Ly Cindy V. , Miller Timothy M.
Published: July 2018

Purpose of review

Amyotrophic lateral sclerosis (ALS) is a rapidly fatal disease for which there is currently no effective therapy. The present review describes the current progress of existing molecular therapies in the clinical trial pipeline and highlights promising future antisense oligonucleotide (ASO) and viral therapeutic strategies for treating ALS.

Recent findings

The immense progress in the design of clinical trials and generation of ASO therapies directed towards superoxide dismutase-1 (SOD1) and chromosome 9 open reading frame 72 (C9orf72) repeat expansion related disease have been propelled by fundamental work to identify the genetic underpinnings of familial ALS and develop relevant disease models. Preclinical studies have also identified promising targets for sporadic ALS (sALS). Moreover, encouraging results in adeno-associated virus (AAV)-based therapies for spinal muscular atrophy (SMA) provide a roadmap for continued improvement in delivery and design of molecular therapies for ALS.

Advances in preclinical and clinical studies of ASO and viral directed approaches to neuromuscular disease, particularly ALS, indicate that these approaches have high specificity and are relatively well tolerated.
Myasthenia gravis: from autoantibodies to therapy
Authors: Mantegazza Renato , Bernasconi Pia , Cavalcante Paola
Published: July 2018

Purpose of review

The current article reviews the recent advances in the field of myasthenia gravis, which span from autoantibody profiling and pathogenic mechanisms to therapy innovation. The overview is highlighting specifically the data and the needs of targeted treatments in the light of precision medicine in myasthenia gravis.

Recent findings

Novel data published recently further increased our knowledge on myasthenia gravis. The use of cell-based assays has greatly improved autoantibody detection in myasthenia gravis patients, and the mechanisms of action of these antibodies have been described. The role of Toll-like receptor activation in the generation of thymic alterations and anti-acetylcholine receptor autosensitization has been further investigated implementing our understanding on the relationships between innate immunity and autoimmunity. Additional studies have been focused on the alterations of T-cell/B-cell regulatory mechanisms in thymus and peripheral blood of myasthenia gravis patients. microRNAs and genetic factors are also emerging as key biomarkers in myasthenia gravis pathogenesis and prediction of drug efficacy in individual patients.

The recent immunological and pathological findings in myasthenia gravis promise to improve myasthenia gravis treatment, via the development of more precise and personalized therapies.
Activated αIIbβ3on platelets mediates flow-dependent NETosis via SLC44A2
Authors: Constantinescu-Bercu Adela , Grassi Luigi , Frontini Mattia , Salles-Crawley Isabelle I. , Woollard Kevin J , Crawley James T.B.
Published: July 2018

Platelet-neutrophil interactions are important for innate immunity, but also contribute to the pathogenesis of deep vein thrombosis, myocardial infarction and stroke. Here we report that, under flow, von Willebrand factor/glycoprotein Ibα-dependent platelet ‘priming’ induces integrin αIIbβ3activation that, in turn, mediates neutrophil and T-cell binding. Binding of platelet αIIbβ3to SLC44A2 on neutrophils leads to mechanosensitive-dependent production of highly prothrombotic neutrophil extracellular traps. A polymorphism inSLC44A2(rs2288904-A) present in 22% of the population causes an R154Q substitution in an extracellular loop of SLC44A2 that is protective against venous thrombosis results in severely impaired binding to both activated αIIbβ3and VWF-primed platelets. This was confirmed using neutrophils homozygous for theSLC44A2R154Q polymorphism. Taken together, these data reveal a previously unreported mode of platelet-neutrophil cross-talk, mechanosensitive NET production, and provide mechanistic insight into the protective effect of theSLC44A2rs2288904-A polymorphism in venous thrombosis.

Platelets that are primed following interaction with von Willebrand factor under flow mediated direct interactions with neutrophils via activated platelet integrin, αIIbβ3, and SLC44A2 on neutrophils. This interaction initiates signaling in a mechanosensitive manner that promotes neutrophil extracellular trap formation.
Identification and characterization of yeast and human glycosphingolipid flippases
Authors: Roland Bartholomew P. , Naito Tomoki , Best Jordan T. , Arnaiz-Yépez Cayetana , Takatsu Hiroyuki , Yu Roger J. , Shin Hye-Won , Graham Todd R.
Published: July 2018

Lipid transport is an essential process with manifest importance to human health and disease. Phospholipid flippases (P4-ATPases) transport lipids across the membrane bilayer, and are involved in signal transduction, cell division, and vesicular transport. Mutations in flippase genes cause or contribute to a host of diseases such as cholestasis, neurological deficits, immunological dysfunction, and metabolic disease. Genome-wide association studies have shown thatATP10AandATP10Dvariants are associated with an increased risk of diabetes, obesity, myocardial infarction, and atherosclerosis; andATP10DSNPs are associated with elevated levels of glucosylceramide (GlcCer) in plasma from diverse European populations. Although sphingolipids are strong contributors to metabolic disease, little is known about how GlcCer is transported across cell membranes. We have identified an evolutionarily conserved clade of P4-ATPases fromSaccharomyces cerevisiae(Dnf1, Dnf2),Schizosaccharomyces pombe(Dnf2), andHomo sapiens(ATP10A, ATP10D) that transport GlcCer. Further, we establish the structural determinants necessary for the specific recognition of this sphingolipid substrate. Our molecular observations clarify the relationship between these flippases and human disease, and have fundamental implications for membrane organization and sphingolipid homeostasis.
Self-healing dyes for super-resolution microscopy
Authors: van der Velde Jasper H. M. , Smit Jochem , Punter Michiel , Cordes Thorben
Published: July 2018

In recent years optical microscopy techniques have emerged that allow optical imaging at unprecented resolution beyond the diffraction limit. Up to date, photostabilizing buffers are the method of choice to realize either photoswitching and/or to enhance the signal brightness and stability of the employed fluorescent probes. This strategy has, however, restricted applicability and is not suitable for live cell imaging. In this paper, we tested the performance of self-healing organic fluorophores with intramolecular photostabilization in super-resolution microscopy with targeted (STED) and stochastic readout (STORM). The overall goal of the study was to improve the spatial and temporal resolution of both techniques without the need for mixtures of photostabilizing agents in the imaging buffer. Due to its past superior performance we identified ATTO647N-photostabilizer conjugates as suitable candidates for STED microscopy. We characterize the photostability and resulting performance of NPA-ATTO647N oligonucleotide conjugates in STED microscopy. We find that the superior photophysical performance results in optimal STED imaging and demonstrate the possibility to obtain single-molecule fluorescent transients of individual fluorophores while illuminating with both the excitation- and STED-laser. Secondly, we show an analysis of photoswitching kinetics of self-healing Cy5 dyes (comprising TX, COT and NPA stabilizers) in the presence of TCEP- and cysteamine, which are typically used in STORM microscopy. In line with previous work, we find that intramolecular photostabilization strongly influences photoswitching kinetics and requires careful attention when designing STORM-experiments. In summary, this contribution explores the possibilities and limitations of self-healing dyes in super-resolution microscopy of differing modalities.
The structural basis for activation of voltage sensor domains in an ion channel TPC1
Authors: Kintzert Alexander F. , Green Evan M. , Dominik Pawel K. , Bridges Michael , Armache Jean-Paul , Deneka Dawid , Kim Sangwoo S. , Hubbell Wayne , Kossiakoff Anthony A. , Cheng Yifan , Stroud Robert M.
Published: July 2018

Voltage sensing domains (VSDs) couple changes in transmembrane electrical potential to conformational changes that regulate ion conductance through a central channel. Positively charged amino acids inside each sensor cooperatively respond to changes in voltage. Our previous structure of a TPC1 channel captured the first example of a resting-state VSD in an intact ion channel. To generate an activated state VSD in the same channel we removed the luminal inhibitory Ca2+-binding site (Cai2+), that shifts voltage-dependent opening to more negative voltage and activation at 0 mV. Cryo-EM reveals two coexisting structures of the VSD, an intermediate state 1 that partially closes access to the cytoplasmic side, but remains occluded on the luminal side and an intermediate activated state 2 in which the cytoplasmic solvent access to the gating charges closes, while luminal access partially opens. Activation can be thought of as moving a hydrophobic insulating region of the VSD from the external side, to an alternate grouping on the internal side. This effectively moves the gating charges from the inside potential to that of the outside. Activation also requires binding of Ca2+ to a cytoplasmic site (Caa2+). An X-ray structure with Caa2+ removed and a near-atomic resolution cryo-EM structure with Cai2+ removed define how dramatic conformational changes in the cytoplasmic domains may communicate with the VSD during activation. Together four structures provide a basis for understanding the voltage dependent transition from resting to activated state, the tuning of VSD by thermodynamic stability, and this channel’s requirement of cytoplasmic Ca2+-ions for activation.
High resolution AKT signaling in individual cells
Authors: Gross Sean M. , Dane Mark A. , Bucher Elmar , Heiser Laura M.
Published: July 2018

Cells sense and respond to their environment by activating distinct intracellular signaling pathways, however an individual cell’s ability to faithfully transmit and discriminate environmental signals is thought to be limited. To assess the fidelity of signal transmission in the PI3K-AKT signaling pathway, we first developed an optimized genetically encoded sensor that had an increased dynamic range and reduced variation under basal conditions. We then used this reporter to track responses to varying doses of IGF-I in live cells and found that signaling responses from individual cells overlapped across a wide range of IGF-I doses, suggesting limited transmission accuracy. However, further analysis of individual cell traces revealed that responses were constant over time without stochastic fluctuations. We devised a new information theoretic approach to calculate the channel capacity using variance of the single cell time course data‐‐rather than population-level variance as has been previously used—and predicted that cells were capable of discriminating multiple growth factor doses. We validated these predictions by tracking individual cell responses to multiple IGF-I doses and found that cells can accurately distinguish at least four different IGF-I concentrations, as demonstrated by their distinct responses. Furthermore, we found a similar discriminatory ability to pathway inhibition, as assessed by responses to the PI3K inhibitor alpelisib. Our studies indicate that cells can faithfully transmit an IGF-I input into a down-stream signaling response and that heterogeneous responses result from variation in the input-output relation across the population. These observations reveal the importance of viewing each cell as having its own communication channel and underscore the importance of understanding responses at the single cell level.
Nuclear pore density controls heterochromatin reorganization during senescence
Authors: Boumendilrid Charlene , Hari Priya , Olsen Karl C. F. , Acosta Juan Carlos , Bickmore Wendy A.
Published: July 2018

Oncogene induced senescence (OIS) is a cell cycle arrest program triggered by oncogenic signalling. An important characteristic of OIS is activation of the senescence associated secretory phenotype (SASP)1 which can reinforce cell cycle arrest, lead to paracrine senescence but also promote tumour progression2–4. Concomitant with cell cycle arrest and the SASP activation, OIS cells undergo a striking nuclear chromatin reorganization, with loss of heterochromatin from the nuclear periphery and the appearance of internal senescence-associated heterochromatin foci (SAHF)5. The mechanisms by which SAHF are formed, and their role in cell cycle arrest and expression of the SASP, remain poorly understood. Here we show that nuclear pore density increases during OIS and is responsible for SAHF formation. In particular, we show that the nucleoporin TPR is required for both SAHF formation and maintenance. The TPR-induced loss of SAHF does not affect cell cycle arrest but completely abrogates the SASP. Our results uncover a previously unknown role of nuclear pores in heterochromatin reorganization in mammalian nuclei and in senescence, which uncouples the cell cycle arrest from the SASP.
Landscape pivot points and responses to water balance in national parks of the southwest US
Authors: Thoma David P. , Munson Seth M. , Witwicki Dana L.
Published: July 2018

A recent drying trend that is expected to continue in the southwestern US underscores the need for site‐specific and near real‐time understanding of vegetation vulnerability so that land management actions can be implemented at the right time and place.

We related the annual integrated normalized difference vegetation index (iNDVI), a proxy for vegetation production, to water balance across landscapes of the Colorado Plateau. We determined how changes in production per unit of water (vegetation responses) and the water balance amounts at which production shifted from above to below average values (pivot points), varied across dominant vegetation and soil types.

Precipitation (PRCP), actual evapotranspiration (AET), water deficit (D), and soil moisture (SM) explained 13%–82% of variation in vegetation production. Along an increasing water availability gradient, vegetation responses to PRCP and AET increased, responses to SM decreased, and responses to D became more negative. We found trade‐offs between vegetation responses and pivot points within and across all vegetation types that were mediated by soil properties.

Synthesis and applications. The water needed by native vegetation to maintain production depends on plant traits. The water available to vegetation depends on climate and soil properties that change along environmental gradients. Tracking this biologically relevant water availability in relation to water need provides an indicator of vegetation growth or stress that can help guide the time and place for management actions.
Brilliant health service management: challenging perceptions and changing HR practices in health services
Authors: Karimi Leila , Dadich Ann , Fulop Liz , Leggat Sandra G , Eljiz Kathy , Fitzgerald Janna Anneke , Smyth Anne , Hayes Kathryn J , Kippist Louise
Published: July 2018

To redress the scholarly preoccupation with problems, there is a need to focus on practices that exceed expectation. This study is the first to explicate healthcare professionals’ perceptions of brilliance within their health service. Via online discussions, 78 postgraduate health management students from an Australian university shared their experiences with, and perceptions of brilliant health services in their organisation. Researchers thematically analysed the text and workshopped the findings to extend current understandings of human resource management using positive organisational scholarship in health‐care (POSH). Preliminary codes organised well into six key themes – teamwork, leadership, innovation, exceptional individuals, empowerment and patient‐centred care. Although the results reflect health service management research, POSH helped to clarify those aspects of people management that are associated with brilliant health services. These include developing interagency networks; adopting an understanding of innovation; and recognising the extraordinary in the seemingly ordinary.
How workplace incivility influences job performance: the role of image outcome expectations
Authors: Jiang Wenbo , Chai Huaqi , Li Yali , Feng Taiwen
Published: July 2018

This study aimed to investigate whether workplace incivility has negative influences on two types of job performance (i.e. in‐role job performance and innovative job performance), as well as the moderating role of image outcome expectations in the context of healthcare organizations. We tested the research hypotheses using data collected from 727 employees in three Chinese hospitals. The results reveal that workplace incivility has negative influences on both in‐role job performance and innovative job performance. In addition, the negative influence of workplace incivility on in‐role job performance is alleviated by expected image risks, while the negative influence of workplace incivility on innovative job performance is buffered by both expected image gains and risks. Managers are expected to establish informal norms of desired behaviors at work and encourage employees to adopt a future‐oriented perspective. This study provides novel insights for workplace incivility literature and practice.
In Vivo Metabolic Tracing Demonstrates the Site‐Specific Contribution of Hepatic Ethanol Metabolism to Histone Acetylation
Authors: Kriss Crystina L. , Gregory‐Lott Emily , Storey Aaron J. , Tackett Alan J. , Wahls Wayne P. , Stevens Stanley M.
Published: July 2018

Background

Epigenetic dysregulation through ethanol (EtOH)‐induced changes in DNA methylation and histone modifications has been implicated in several alcohol‐related disorders such as alcoholic liver disease. EtOH metabolism in the liver results in the formation of acetate, a metabolite that can be converted to acetyl‐CoA, which can then be used by histone acetyltransferases to acetylate lysine residues. EtOH metabolism in the liver can also indirectly influence lysine acetylation through NAD+‐dependent sirtuin activity that is altered due to increases in NADH. As a proof‐of‐concept study to determine the direct influence of hepatic EtOH metabolism on histone acetylation changes, we used heavy‐labeled EtOH (13C2) and mass spectrometry (MS) to site specifically characterize lysine acetylation on histone proteins.

Methods

Eight‐week‐old male C57BL/6J mice were gavaged using a bolus dose of either 13C2‐labeled EtOH (5 g/kg) or maltose dextrin. Blood and livers were collected at 0, 4, and 24 hours followed by histone protein enrichment and derivatization using acid extraction and propionylation, respectively. Metabolic tracing and relative quantitation of acetylated histone proteins were performed using a hybrid quadrupole‐orbitrap mass spectrometer. Data were analyzed using MaxQuant, Xcalibur Qual Browser, and the Bioconductor package “mzR.” The contribution of EtOH to histone acetylation was quantified using the change in relative abundance of stable isotope incorporation in acetylated peptides detected by MS.

Results

Data show significant incorporation of the EtOH‐derived 13C2‐label into N‐terminal lysine acetylation sites on histones H3 and H4 after 4 hours, with rapid turnover of labeled histone acetylation sites and return to endogenous levels at 24 hours postgavage. Moreover, site‐specific selectivity was observed in regard to label incorporation into certain lysine acetylation sites as determined by tandem mass spectrometry and comparison to isotope simulations.

Conclusions

These data provide the first quantitative evidence of how hepatic EtOH metabolism directly influences histone lysine acetylation in a site‐specific manner and may influence EtOH‐induced gene expression through these transcriptionally activating chromatin marks.