bluuebunny/crossref_metadata_2025 huggingface dataset:
Measuring Airway Resistance and Characterizing the Flow‐Volume Envelope with External Expiratory Loading in Healthy Adults
Authors: Erram Jyotika , Bari Monica , Cannon Daniel
Published: April 2020

Expiratory flow limitation is a key characteristic in chronic obstructive pulmonary disease (COPD). Increased airway resistance occurs due to bronchoconstriction, destruction of elastic tissue in the airways, and mucus hypersecretion from goblet cells caused by irritation of the epithelium. Obstruction can lead to dynamic hyperinflation, dyspnea, and exercise intolerance. However, increased airway resistance is just one of many abnormalities in COPD and asthma ‐ COPD in particular is an exceedingly heterogeneous disease. Therefore, isolating the effects of expiratory airflow limitation is challenging.

PURPOSE

In order to study abnormal lung mechanics in isolation, we measured pulmonary function with and without expiratory loading in healthy adults.

METHODS

Forty‐eight volunteers (26±5 yr, 171.8±10.2 cm, 72.2±13.3 kg) completed spirometry and body plethysmography according to the ATS/ERS standards under three randomized conditions: control, expiratory loading of 7 and 11 cmH2O. The expiratory load was added by installing a threshold inspiratory muscle trainer in reverse. We analyzed the shape of the flow‐volume (F‐V) loops with rectangular area ratio (RAR) using custom MATLab software.

RESULTS

Airway resistance was increased (F[1.5, 27.5]= 446.0, p<0.05) with 7 and 11 cmH2O vs control (9.20±1.02 and 11.76±1.68 cmH2O vs. 2.53± 0.80 cmH2O). RAR (F[1.9, 77.9]= 3.71, p>0.05) was reduced with 7 and 11 cmH2O vs control (0.45±0.07 and 0.47±0.09L vs. 0.48±0.08L). FEV1 was reduced (F[1.6, 60.38.6]= 67.54, p<0.05) with 7 and 11 cmH2O vs control (3.26±0.82 and 3.23±0.79L vs. 4.03±1.04L). FVC was also reduced (F[1.5, 55.31] = 77.71, p<0.05) with 7 and 11 cmH2O vs control (4.15±1.01 and 4.17±1.02L L vs. 5.05±1.33L L). PEF was reduced (F[1.5, 55.99] = 72.69, p<0.05) with 7 and 11 cmH2O vs control (6.02±1.65 and 5.95±1.85L vs. 8.39±2.85L L). FEV1/FVC (F[1.9, 69.17] = 5.5, p> 0.05) and FRC (F[1.863, 33.53]= 0.93, p<0.05) were not different between resistance conditions or compared to the control.

CONCLUSIONS

Expiratory loading reduced FEV1, FVC, PEF and provided a doseresponse in airway resistance and RAR. There were no differences in FEV1/FVC. While RAR was reduced with expiratory loading, the magnitude was of little clinical importance. Therefore, a concave expiratory F‐V relationship was consistently absent – a key limitation for model comparison with pulmonary function in COPD. This is most likely due to the imposed resistance being applied outside of the airways, leading to higher airway pressures. The higher airway pressures are likely to resist dynamic airway compression and either maintain the equal pressure point position or possibly move it proximally.
Exercise Training Attenuates Sarcopenic Obesity‐Induced Insulin Resistance and Mitochondrial Dysfunction in the Rat Skeletal Muscle
Authors: Kwak Hyo-Bum , Heo Jun-Won , No Mi-Hyun , Cho Jin-Kyung , Choi Young-Ju , Cho Eun-Jeong , Chang Eun-Wook , Park Dong-Ho , Kang Ju-Hee , Jang Young Charles
Published: April 2020

The purpose of this study was to determine the effects of sarcopenic obesity (aging‐induced sarcopenia plus high fat diet‐induced obesity) and exercise training on insulin resistance, mitochondrial function (hydrogen peroxide (H2O2) emission and calcium(Ca2+) retention capacity) and mitochondrial dynamics (fusion; Opa1, Mfn1, Mfn2 and fission; Drp1, Fis1) in the rat skeletal muscle.

Sprague‐Dawley rats were randomly divided into four groups: 4‐month young control (YC), 20‐month old control (OC; sarcopenia), old high fat diet group (OH; sarcopenic obesity), and old high fat diet and exercise group (OH+EX). After obesity was induced by 7 weeks of 60% high fat feeding in old groups, treadmill exercise was performed 6 times a week for 7 weeks. Oral glucose tolerance test was performed to determine insulin resistance. Mitochondrial function (H2O2 emission, Ca2+ retention capacity) was measured in permeabilized skeletal muscle (soleus and white gastrocnemius). Also, mitochondrial dynamics (fusion and fission) were analyzed using Western immunoblot in skeletal muscle.

Insulin resistance was induced in OC and OH compared with YC. Conversely, insulin resistance was mitigated in OH+EX compared with OC and OH. Excessive mitochondrial H2O2 emission was found in white gastrocnemius of OC and OH compared with YC. However, exercise training attenuated aging and obesity‐induced mitochondrial H2O2 emission in OH+EX compared with OC and OH. Although mitochondrial Ca2+ retention capacity was not significant between groups in type I muscle (soleus), it was dramatically downregulated by aging and obesity and conversely upregulated by exercise training in type IIb muscle (white gastrocnemius) in OH+EX compared with OC and OH. In addition, exercise training protected against the imbalance between mitochondrial fusion and fission, showing that aerobic exercise training improved aging and obesity (sarcopenic obesity)‐induced decrease in Opa1 and Mfn2 protein levels and, conversely, reduced the increase in Drp1 and Fis1 protein levels in type IIb muscle in OH+EX compared with OC and OH.

Our data demonstrated that sarcopenic obesity induced more insulin resistance, mitochondrial dysfunction, and mitochondrial remodeling than sarcopenia in skeletal muscle. However, exercise training mitigated sarcopenic obesity‐induced impairment in insulin resistance and mitochondrial function in skeletal muscle, suggesting that aerobic exercise training plays an essential role in attenuating sarcopenic obesity‐induced insulin resistance through the regulation of mitochondrial function in the skeletal muscle.

Support or Funding Information

This work was supported by the Ministry of Education of the Republic of Korea and the National Research Foundation (2018R1A2A3074577, 2019S1A5C2A03082727).
Hosta longipes and its Active Compounds Control Melanogenesis in B16F10 Melanoma Cells
Authors: Sohn Eun-Hwa , Kim Sung Hyeok , Ha Chang Woo , Lee Jinwoo , Kim Youngseok , Chae Doobyeong , Sung Sikwon , Ham Jungyeob , Kim Su-Nam
Published: April 2020

Hosta longipes (FR. et SAV.) MATSUMURA (Liliaceae) is an edible vegetable in Korea and widely distributed throughout Korea, China, and Japan. It is called “Bi‐Bi‐Chu” in Korea, and its young leaves are consumed raw as a salad. This plant has been used as a Korean traditional medicine for the treatment of swelling, inflammation and snake bites. In this study, we confirmed the whitening effects of Hosta longipes ethanol extract in B16F10 cells and identified that hexane fraction had the highest whitening effect by serial solvent fractionation. To identify the active ingredients in the hexane fraction we performed column chromatography and it was confirmed that linolenic acid and linoleic acid reduced the melanin contents in B16F10 cells. The anti‐melanogenesis potential of linolenic acid and linoleic acid in Hosta longipes will provide insight into the development of new skin whitening products.

Support or Funding Information

This research was financially supported by the Ministry of Small and Medium‐sized Enterprises(SMEs) and Startups(MSS), Korea, under the “Regional Star‐Enterprise Development Program(R&D, P0010100)” supervised by the Korea Institute for Advancement of Technology(KIAT)
Mechanisms for Temporal Information Coding in Inflammatory JNK Signaling
Authors: Tomida Taichiro , Yamaguchi Kimitaka , Ito Masanori , Mikami Yoshinori , Ohshima Daisuke , Adachi-Akahane Satomi
Published: April 2020

JNK (c‐Jun‐N‐terminal kinase) is a stress‐activated protein kinase that plays key roles in mediating stress and inflammatory response such as cell death, proliferation, and cytokine production. Several studies have uncovered that the duration of JNK signaling determines the specificity of downstream cellular events that lead to either cell‐death or survival. However, the question of how JNK is dynamically regulated in cells remains elusive. In this study, we aimed to reveal the physiological importance of the dynamics of JNK signaling in downstream gene expression by elucidating how inflammatory cytokine IL‐1β regulates a temporal pattern of JNK signaling in living HeLa cells. Here, using fluorescence imaging and our novel JNK activity reporter based on FRET, we succeeded in the quantitative evaluation of JNK dynamics at single cell resolution upon IL‐1β stimulation. Periodic pulsatile IL‐1β‐stimuli to cells were employed to analyze the regulatory mechanism of JNK activity. Our analysis revealed that JNK can be activated either transiently or repeatedly depending on the interval of stimulation pulses, while the initial peak amplitude of JNK activity was almost the same. We found that a simple negative‐feedback loop from a MAPK phosphatase MKP1 to its upstream kinase p38 MAPK accounts for the observed temporal dynamics of JNK activity, which was further verified by biochemical analysis and mathematical model simulation. The temporal aspects of IL‐1β stimulation were reflected in the gene expression profile obtained from HeLa cells after stimulation, in which the specific set of JNK‐dependent genes were more upregulated by repetitive IL‐1β stimulation pulses compared to that by continuous IL‐1β exposure. Our results indicate that the dynamic behavior of JNK in response to IL‐1β stimulation is regulated through dephosphorylation of JNK by MKP1 whose expression is positively regulated by p38 MAPK and down‐regulated by its phosphatase activity on p38 MAPK. In addition, JNK activity as well as downstream gene expression specificity could be modulated just by altering the temporal pattern of input IL‐1β stimuli. In conclusion, we demonstrated that the information of temporally fluctuating cytokine stimulation can be converted into the activation dynamics of JNK signaling, and the downstream gene expression specificity can be encoded by the temporal dynamics of JNK activity. Such a temporal information coding mechanism may have physiological relevance for inducing an adequate cellular response to a wide range of fluctuating cytokine levels through precise control of gene expression.

Support or Funding Information

This work was supported in part by JSPS KAKENHI [Grant numbers JP19K06548, JP17H06017 to T.T., JP18K06859 to S.A‐A.].
The expression of TMEM16 scramblases in the neurovascular unit
Authors: Lee Byoung-cheol
Published: April 2020

Biological membranes, composed of a double layer of lipids, define the boundaries of living cells and their subcompartments. In eukaryotes, the outer and inner leaflets of the plasma membrane differ in their lipid compositions, with the outer leaflet containing mostly phosphatidylcholine (PC) and sphingolipids, while the inner leaflet is composed of phosphatidylethanolamine (PE), the negatively charged phosphatidylserine (PS), and phosphoinositides. Two classes of ATP‐driven pumps, flippases and floppases, create and maintain the membrane asymmetry, whose rapid collapse occurs during a process called phospholipid scrambling. Members of the TMEM16/ANO family of membrane proteins are Ca2+‐activated phospholipid scramblases and/or Cl− channels. As phospholipid scramblases, they generate key physiological signal by translocating phosphatidylserine (PS), an effector in numerous cell activities such as blood coagulation and the phagocytic clearance of apoptotic cells. Here, we investigated the expression profile of each TMEM16 scramblase in the neurovascular unit (NVU). NVU is a complex functional and anatomical structure composed of endothelial cells, pericytes, smooth muscular and neural cells, including astrocytes, neurons, and interneurons. Also, we investigated the expression of TMEM16 in various brain regions such as cerebral cortex, hippocampus, hypothalamus, medulla, midbrain, etc. The studies on the expression profile of TMEM16 would enhance our understanding the physiological roles of specific TMEM16 scramblase in NVU.

Support or Funding Information

This research was supported by KBRI basic research program through Korea Brain Research Institute funded by Ministry of Science and ICT(20‐BR‐01‐07) and National Research Foundation of Korea (NRF) grant funded by the Korea government(MSIT) (2019R1C1C1002699)
Dietary supplementation of Ganoderma lucidum improves fatty liver hemorrhagic syndrome in laying hens
Authors: Liao Pei-Xin , Hwang Ting Wei , Lin Chiao Wei , Ding Shih-Torng
Published: April 2020

Fatty liver hemorrhagic syndrome (FLHS) is a common metabolic disease in birds. FLHS have highly incidence rate in cage system. The syndrome can be characterized by abnormal lipid accumulation in liver which trigger inflammation and hemorrhage syndrome. Moreover, FLHS decrease egg production severely and have huge impact to the poultry industry. Additionally, FLHS is similar diagnosis to non‐alcoholic fatty liver disease (NAFLD). NAFLD is a spectrum of liver disorders and characterized by excessive hepatic fat accumulation. Ganoderma lucidum (G. lucidum) is a medicinal mushroom. G. lucidum is rich in bioactive components comprises and has hepatoprotective activity. Dipeptidyl‐peptidase 4 (DPP4) is a type II transmembrane protein and strongly associated with FLHS and NAFLD. The objective of this study was to determine the effects of feeding diets containing different ratio of G. lucidum on FLHS and the association of plasma DPP4 in hens and to use LMH cell to study the role of DPP4 in FLHS. Thirty 7‐week‐old, ISA hens were allotted to 5 treatments with 6 hens per replicate and fed high cholesterol low choline (CLC), CLC + 0.25% G. lucidum, CLC + 0.5% G. lucidum, CLC + 0.75% G. lucidum, and CLC + 1% G. lucidum, respectively, for six weeks. Body weight and plasma were recorded every three week. At the end of experiment, livers were photographed, excised, weighed, and scored for liver hemorrhages. The results showed that CLC + 1% G. lucidum body weight was significantly higher than CLC + 0.25% G. lucidum and treatment of G. lucidum decreased the level of triglyceride in the plasma. Oleic acid induced DPP4 mRNA expression in LMH cells, suggesting that there is an association between lipid and DPP4 expression in the liver cell. In conclusion, G. lucidum could be a dietary additive or medicine for reducing fatty liver in laying hens.
Investigating the Mechanisms Underlying the Link Between Diabetes and Cancer
Authors: Minch Benjamin , Englund Dylan , Sterken Crystal , LaBounty Zachary , Kim Jinsil
Published: April 2020

Diabetes is one of the most common diseases, with its prevalence having increased significantly over the last two decades. A growing number of evidence indicates a higher risk of cancer among patients with diabetes, but the mechanisms underlying the link between diabetes and cancer remain elusive. Hyperglycemia (high blood glucose levels) is a key metabolic abnormality that characterizes diabetes, and could potentially play a role in the pathogenic process of cancer. This study aims to investigate the effects of hyperglycemic conditions on cancer development and progression. The results of cell proliferation assays support cancer‐promoting effects of hyperglycemic conditions in SW620 colorectal cancer cells. High‐glucose treatments, however, did not have any effect on the rate of apoptotic cell death. Analysis of selected RNA‐binding proteins (RBPs) revealed expression changes of the RBPs involved in the methylation of adenosine at the nitrogen‐6 position (N6A) in RNA in response to elevated glucose levels. In line with these changes, there were alterations in N6‐methyladenosine (m6A) levels in high glucose‐treated SW620 cells compared to control cells exposed to normal glucose conditions. Our study also suggests that hyperglycemia causes oxidative stress through the production of reactive oxygen species (ROS). Given that elevated levels of ROS and m6A RNA methylation have been significantly implicated in human cancer, oxidative stress and altered m6A levels caused by dysregulation of the RBPs involved in m6A modification may play, at least, a partial role in diabetes‐induced cancer, which warrants future exploration. Collectively, our study provides potentially important insight that could add to the understanding of the mechanisms explaining the link between diabetes and cancer.

Support or Funding Information

This work was supported by the Stewart Science Honors Program, the School of Science, Technology and Health, and the Department of Biological Sciences at Biola University, CA, USA.
The genetic basis for medium‐dependent bacteriophage infection
Authors: Weiner Iddo Nadav
Published: April 2020

While broad spectrum antibiotics have served a major role in combatting bacterial pathogens over the past decades, we are currently witnessing the rise of antibiotic‐resistant pathogenic strains. Moreover, the harmful effects of broad spectrum antibiotics on the natural human microbiome have been demonstrated in numerous cases. For these reasons, bacteriophages have been recently gaining attention as promising candidates for treatment of bacterial‐related diseases. Bacteriophages are natural viruses that infect and often kill specific bacterial strains; it is the phages’ high accuracy and specificity, alongside their natural origin, that highlights their value as an alternative treatment for diseases with bacterial involvement.

However, a major challenge in screening for bacteriophages relevant for treatment of human diseases is the phages’ medium‐dependent infection trait. Several factors have been suggested to take a role in explaining this discrepancy, including the mechanism of infection, the spatial structure of the phage capsid, the biochemical characteristics of the bacterial cell wall, and other phage life‐cycle features. However, a comprehensive model for characterizing the media‐range for phage infection is still missing. This uncertainty often translates into multiple laborious screening rounds, since common practice in vitro assays are typically based on either liquid or solid medium infection, whereas the state of matter relevant for in vivo application is often hard to determine; thus, one must screen the same phages using multiple assays.

In attempt to lay the groundwork for such a model, in this work we set out to determine the genetic‐basis for medium‐dependent infection of pathogenic Klebsiella pneumoniae phages. To this end we obtained 285 K. pneumonia strains, that span across the entire domain of known K. pneumonia genotypes. Subsequently we obtained 50 phages that were able to propagate on at least some of these hosts. For each phage‐host pair we determined whether infection occurs in two different assays: in liquid culture, and on solid agar plates. As expected, the results show that liquid medium enables more phage infections compared to solid; this is traditionally associated with the higher mobility enabled by the liquid. However, cases where a phage was able to infect its host in solid, but not in liquid, were observed as well. Finally, by analyzing genomic differences between the phages in the experiment we were able to discern several genetic features that correlate with the observed phenotype. Further exploration of these genetic features are the basis for a constructing a model for characterizing the media‐range for phage infection.
Mitochondrial Signatures in Circulating Extracellular Vesicles of Older Adults with Parkinson’s Disease: Results from the EXosomes in PArkiNson’s Disease (EXPAND) Study
Authors: Picca Anna
Published: April 2020

Systemic inflammation and mitochondrial dysfunction are involved in neurodegeneration in Parkinson’s disease (PD). Extracellular vesicle (EV) trafficking may link inflammation and mitochondrial dysfunction. In the present study, circulating small EVs (sEVs) from 16 older adults with PD and 12 controls were purified and characterized. A panel of circulating inflammatory biomolecules was measured by multiplex immunoassay. Protein levels of three tetraspanins (CD9, CD63, and CD81) and selected mitochondrial markers [adenosine triphosphate 5A (ATP5A), mitochondrial cytochrome C oxidase subunit I (MTCOI), NADH:ubiquinone oxidoreductase subunit B8 (NDUFB8), NADH:ubiquinone oxidoreductase subunit S3 (NDUFS3), succinate dehydrogenase complex iron sulfur subunit B (SDHB), and ubiquinol‐cytochrome C reductase core protein 2 (UQCRC2)] were quantified by immunoblotting. Relative to controls, PD participants showed a greater amount of circulating sEVs. Levels of CD9 and CD63 were lower in the sEV fraction of PD participants, while those of CD81 were similar between groups. Lower levels of ATP5A, NDUFS3, and SDHB were detected in sEVs from PD participants. No signal was retrieved for UQCRC2, MTCOI, or NDUFB8 in either participant group. To identify a molecular signature in circulating sEVs in relationship to systemic inflammation, a low level‐fused (multi‐platform) partial least squares ‐ discriminant analysis was applied. The model correctly classified 94.2±6.1% PD participants and 66.7±5.4% controls, and identified as relevant seven biomolecules (CD9, NDUFS3, C‐reactive protein, fibroblast growth factor 21, interleukin 9, macrophage inflammatory protein 1b, and tumor necrosis factor alpha). In conclusion, a mitochondrial signature was identified in circulating sEVs from older adults with PD, in association with a specific inflammatory profile. In‐depth characterization of sEV trafficking may allow identifying new biomarkers for PD and possible targets for personalized interventions.

Support or Funding Information

Innovative Medicine Initiative‐Joint Undertaking (IMI‐JU #115621)
Acute Effects of Caffeinated Chewing Gum on Central Arterial Stiffness and Hemodynamics
Authors: Lapierre Stephanie , Holmer Brady , Lim Jisok , Hwang Chueh-Lung , Sakarya Yasemin , New William , Eagle Michael , Schwartz Cody , Bhattal Gurjaspreet , Maharrey Phillip , Handberg Eileen M. , Alviar Carlos L. , Christou Demetra D.
Published: April 2020

Caffeine is widely consumed daily as a stimulant, ergogenic aid or performance enhancer. In addition to the traditional forms of caffeine consumption (e.g., coffee, tea and caffeinated soft drinks), alternative sources are becoming increasingly popular such as caffeinated tablets/capsules and gum. Caffeinated chewing gum offers rapid caffeine absorption and is commercially available. Although the acute cardiovascular effects of caffeine consumption from traditional sources are well documented, the effects of caffeinated chewing gum are unknown. Therefore, this double‐blinded, randomized, placebo‐controlled, crossover study sought to investigate the acute effects of caffeinated chewing gum on central arterial stiffness and aortic blood pressure, independent predictors of cardiovascular disease. Sixteen young (21±1 yrs, means±SE), male, light caffeine users, free of clinical disease, who did not use tobacco products, or medications participated in this study. Central arterial stiffness (carotid to femoral pulse wave velocity; cfPWV) and aortic blood pressures (systolic and diastolic blood pressure; aoSBP and aoDBP, and pulse pressure; aoPP) were assessed using SphygmoCor XCEL (AtCor Medical) on two visits, separated by at least one week. During each visit, vascular measures were obtained before, and 1‐ and 2‐hrs following consumption of caffeinated or placebo chewing gum. We found that cfPWV increased at 2‐hrs following consumption of caffeinated chewing gum (6.3±0.1 vs. 6.5±0.1 m·s−1; pre vs. 2‐hrs; P=0.017), but did not change after placebo (P>0.05). AoMAP and aoDBP increased by 6±2 and 6±1 mmHg, respectively, at 1‐hr following caffeinated chewing gum (P≤0.008) and remained elevated at 2‐hrs, but did not change in response to placebo (P>0.05). AoSBP, aoPP and heart rate did not significantly change in response to caffeinated or placebo chewing gum (P>0.05). In conclusion, caffeinated chewing gum acutely increases central arterial stiffness and aortic blood pressure in young healthy men. Future investigations should confirm these findings in women and examine whether the response is exaggerated in individuals who are hypertensive or have other risk factors for cardiovascular disease.

Support or Funding Information

This work was supported by the Gatorade Trust through funds distributed by the University of Florida, Department of Medicine.
Repetitive Sequences Within Human PKD1 Adopt G‐quadruplex Structures
Authors: Larson Erik , Madsen Aimee , Lorber Amy , Dewey John , Alvarado Gloria , Su Kemin
Published: April 2020

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by the loss of PKD1 expression, leading to the formation of cysts and lethal kidney disease. Human PKD1 appears to be prone to inactivating mutagenesis, but the mechanisms are undefined. Interestingly, murine PKD1 is comparatively stable, and ADPKD does not naturally occur in mice. We have identified extensive guanine quadruplex repeats in human, but not murine, PKD1. Guanine quadruplex (G4) DNA is a four stranded structure that forms from patterns of tandem guanine repeats. It has been identified in gene regulatory domains and is a functional partner with oncogenic rearrangements. The abundance of G4 sequence motifs in human PKD1 implicates G4 structure formation in the mechanism of PKD1 mutagenesis. Therefore, we examined the ability of G4 sequences encoded by PKD1 to adopt G4 structures in vitro. Using more than one biophysical approach, we find that sequence repeats within human PKD1 adopt G4 conformations, but only under physiological conditions and when the G4 sequence motifs are present. The repetitive character of human PKD1 also suggests that non‐canonical G4 sequence motifs support G4 DNA structures in vivo, where they increase the potential for mutagenesis and gene inactivation. Since G4 DNA is already connected with site‐specific genetic instability, the formation of this structure within PKD1 may explain how the gene becomes somatically inactivated, leading to ADPKD.

Support or Funding Information

This research is supported by Western Michigan University Homer Stryker School of Medicine and by the NIH/NIDDK, R15DK119864 to EL
Competency Assessment in Simulation of Electronic Health Records Tool Development
Authors: McBride Susan , Thomas Laura , Decker Sharon
Published: April 2020

Rapid deployment of electronic health records has resulted in a need for simulation centers to integrate the use of electronic health records into simulation-based learning activities within the clinical workflow. To assess the quality of the documentation in the electronic health record, the Competency Assessment in Simulation of Electronic Health Records Tool was developed. Lynn's method of content validity, combined with nominal group and Delphi techniques, was used to identify 15 domains of best practice in documentation. Participants with expertise in academic education, simulation, and informatics provided input into the development of the tool. The tool evolved over three rounds of Delphi that refined the language and provided anchors to promote accurate assessment of student and nurse documentation. The results of the Delphi narrowed the 15 domains down to 10 domains for scoring best practices in electronic documentation within simulation-based learning activities. The Competency Assessment in Simulation of Electronic Health Records Tool was developed to address the electronic health record competencies of both nursing students and practicing nurses in a simulation environment.
BAP-1 Expression Status by Immunohistochemistry in Cellular Blue Nevus and Blue Nevus–like Melanoma
Authors: Chen Pei-Ling , Neishaboori Nastaran , Tetzlaff Michael T. , Chen Wei-Shen , Aung Phyu P. , Curry Jonathan L. , Nagarajan Priyadharsini , Ivan Doina , Hwu Wen-Jen , Prieto Victor G. , Torres-Cabala Carlos A.
Published: April 2020

The family of blue nevi includes the common blue nevus (BN), cellular blue nevus (CBN), and atypical BN, while melanomas with BN-like morphology can either arise in association with a blue nevus (MABN) or in the de novo setting mimicking cellular blue nevus (MMCBN). Recent molecular and immunohistochemical studies have demonstrated loss of BAP-1 in MABN/MMCBN but not in BN/CBN, suggesting that loss of BAP-1 correlates with a malignant phenotype in these lesions. In this study, we applied anti–BAP-1 antibodies to a series of CBN/BN (n = 11) and MABN/MMCBN (n = 4). Nuclear BAP-1 expression was detected in the majority of CBN/BN (n = 10/11) but was lost in 1 case. Most cases of MABN/MMCBN showed loss of nuclear BAP-1 expression (n = 3/4), with one case of MMCBN showing preserved BAP-1 expression. Demonstration of BAP-1 loss in a single case of CBN and preservation of BAP-1 expression in 1 case of MMCBN may indicate that detection of alterations in BAP-1 protein expression by immunohistochemistry may not be a completely reliable biomarker for the distinction of BN/CBN from MABN/MMCBN. Further investigation of the significance of BAP-1 loss/preservation in BN-like tumors is warranted.
Immunohistochemical Localization of Phosphorylated and Unphosphorylated Form of β-catenin With Regard to Shadow Cell and Squamous Differentiation in Cutaneous Pilomatricoma
Authors: Nakamura Toshitsugu , Fujiwara Masayuki
Published: April 2020

Pilomatricoma usually contains a mutation in CTNNB1 that encodes β-catenin (BC). It also shows nuclear accumulation of BC protein, which plays an important role in tumorigenesis of pilomatricoma. In vitro studies have indicated that mutant BC protein is unphosphorylated and shows nuclear accumulation, but this theory has not been confirmed in various tumors with CTNNB1 mutation. We examined immunohistochemical localization of phosphorylated BC (pBC) and unphosphorylated BC (npBC) with regard to the modes of cell death or differentiation in 25 cases of pilomatricoma. As for the component showing shadow cell differentiation, BC was detected in cytoplasm/nucleus and along cell membrane in basaloid cells, whereas only in the latter in transitional cells in all cases. Meanwhile, npBC was localized along cell membrane of transitional cells, but not in basaloid cells, nor in nucleus of any components. The components with squamous differentiation also revealed the staining patterns similar to those seen in shadow cell differentiation in some cases. pBC was found in some cell fragments in the amorphous debris containing apoptotic bodies among shadow cell nests. These results suggested that npBC plays an important role in cell adhesion during differentiation and that pBC expression is associated with apoptosis of basaloid cells in pilomatricoma. BC accumulated in the nucleus was not immunoreactive for npBC possibly due to post-translational modification or conformational changes that resulted in loss of or masked antigenicity when BC is assumed to be unphosphorylated.
mHealth Assessment and Intervention of Depression and Anxiety in Older Adults
Authors: Grossman Jason T. , Frumkin Madelyn R. , Rodebaugh Thomas L. , Lenze Eric J.
Published: April 2020

Mobile technology is increasingly being used to enhance health and wellness, including in the assessment and treatment of psychiatric disorders. Such applications have been referred to collectively asmHealth, and this article provides a comprehensive review and clinical perspective of research regarding mHealth in late-life mood and anxiety disorders. The novel data collection offered by mHealth has contributed to a broader understanding of psychopathology, to an increased diversity of psychological interventions, and to novel methods of assessment that may ultimately provide individually adaptive mental health care for this population. Older adults face challenges (e.g., transportation, mobility) that limit their ability to receive medical and mental health care services, and mHealth may improve the capacity to reach this population. Although several mobile interventions exist for health-related issues in older adults (e.g., balance, diabetes, medication management), mHealth targeting psychiatric disorders is limited and most often focuses on problems related to dementia, cognitive dysfunction, and memory loss. Given that depression and anxiety are two of the most common mental health concerns among this population, mHealth has strong potential for broad public health interventions that may improve effectiveness of mental health care via individualized assessments and treatments.
The Titanium Angular Clip Prosthesis for Ossicular Chain Reconstruction: Long-Term Results
Authors: Stuermer Konrad Johannes , Hüttenbrink Karl-Bernd , Luers Jan Christoffer
Published: April 2020

Objectives:

To describe the long-term results of the titanium angular clip prosthesis 10 years after its initial description.

Study Design:

Clinical retrospective study.

Setting:

Tertiary referral center.

Patients:

Sixty three patients with isolated defects of the long process of the incus where the ossicular chain was reconstructed by a titanium angular clip prosthesis.

Interventions:

Therapeutic.

Main Outcome Measures:

The mean air-bone gap was calculated over the frequencies of 0.5, 1, 2, 3, and 4 kHz.

Results:

The placement of the prosthesis was straightforward in all patients, without any complication. During the first follow-up visit after 3 weeks (n = 61) the mean air-bone gap (ABG) was reduced by 10 dB HL, and from 24 dB HL preoperatively to 14 dB HL. At the long-term follow-up appointment—4 years after implantation (n = 29)—the mean ABG was still reduced by 8 dB HL, from a mean of 26 dB HL preoperatively to 18 dB HL.

Conclusion:

The use of the titanium angular clip prosthesis is a safe and reliable way to bridge an isolated erosion of the long process of the incus, leading to significant and long-lasting improvement of the ABG both in the short and long-term follow-up. A similarly large improvement of the sound transmission can be achieved both in patients with a Type A and a Type B/C tympanogram.
Prevalence, predictors, prognostic significance, and effect of techniques on outcomes of coronary lesion calcification following implantation of drug-eluting stents: a patient-level pooled analysis of stent-specific, multicenter, prospective IRIS-DES registries
Authors: Lee Cheol Hyun , Ahn Jung-Min , Lee Kyu Sup , Kang Do-Yoon , Lee Pil Hyung , Lee Seung-Whan , Lee Cheol Whan , Park Seong-Wook , Park Duk-Woo , Park Seung-Jung
Published: April 2020

Aims

There is limited information on the clinical relevance and procedural impact of coronary artery calcification (CAC) in the contemporary percutaneous coronary intervention (PCI) setting. This study sought to determine the incidence and clinical significance of procedural techniques on the outcomes in ‘real-world’ patients with CAC undergoing PCI with drug-eluting stents (DESs).

Methods and results

Using patient-level data from seven stent-specific, prospective DES registries, we evaluated 17 084 patients who underwent PCI with various DES types between July 2007 and July 2015. The primary outcome was target-vessel failure (TVF), defined as a composite of cardiac death, target-vessel myocardial infarction, or target-vessel revascularization. Outcomes through 3 years (and between 0–1 and 1–3 years) were assessed according to CAC status (none/mild vs. moderate/severe) and stenting technique (predilation or post-dilation). Among 17 084 patients with 22 739 lesions included in the pooled dataset, moderate to severe CAC was observed in 11.3% of patients (10.1% of lesions). Older age, lower BMI, diabetes, hypertension, family history of coronary artery disease, and renal failure were independent predictors of moderate/severe CAC. The presence of moderate/severe CAC was significantly associated with an adjusted risk of TVF at 3 years [hazard ratio, 1.37; 95% confidence interval (CI), 1.19–1.58; P < 0.001]. For severe CAC, optimal lesion preparation with predilation was associated with a lower 3-year rate of TVF (no vs. yes, 22.3 vs. 12.8%), in which the effect of predilation was prominent at the late period of 1–3 years (hazard ratio, 0.28; 95% CI, 0.12–0.69; P = 0.003) than at the early period through 1 year (hazard ratio, 1.16; 95% CI, 0.37–3.71; P = 0.80). However, post-dilation (with a high-pressure noncompliant balloon) had no effect on the outcome.

Conclusions

In this study, moderate/severe CAC was common (~10%) and strongly associated with TVF during 3 years of follow-up. For severe CAC, optimal lesion preparation with pre-balloon dilation has a significant effect on long-term outcomes, especially during the late period beyond 1 year. Clinical Trial Registration – URL: http://www.clinicaltrials.gov. Unique identifier: NCT01186133.
Major acute cardiovascular events in patients with inflammatory bowel disease
Authors: Gill Gauravpal S. , Fernandez Stephen J. , Malhotra Nidhi , Mete Mihriye , Garcia-Garcia Hector M.
Published: April 2020

Background

Systemic inflammation and immune-mediated diseases have been associated with ischemic heart disease in addition to traditional risk factors. In this study, we investigate associations between inflammatory bowel disease (IBD) and acute cardiovascular events.

Methods

An observational study where patient data were extracted from our health system patient pool of 3 917 894. Propensity scores were calculated for all 15 292 patients (0.39%) with IBD to assemble a 1:1 matched cohort balanced for age, gender, race and known cardiovascular risk factors including hypertension, hyperlipidemia, diabetes mellitus and smoking (current and former). Secondary analyses were performed independently for 6658 patients with ulcerative colitis and 9406 patients with Crohn’s disease. ICD-9 and ICD-10 codes were used to identify cardiovascular risk factors and outcomes.

Results

Matched patients (n = 30 584) had a mean age of 51 years, with 58% being women, and 63% Caucasian. During the median follow-up of 4.4 years, all-cause mortality was observed in 1.7 versus 1.2% of patients from IBD and non-IBD groups, respectively [hazard ratio, 1.31; 95% confidence interval (CI), 1.08–1.58; P = 0.005]. Combined outcome for myocardial infarction or cardiovascular mortality was noted in 2.3 and 2.1% from IBD and non-IBD groups, respectively (hazard ratio, 1.04; 95% CI, 0.90–1.21; P = 0.588), while hazard ratios for cardiovascular mortality, myocardial infarction and unstable angina were 1.04 (0.74–1.47; P = 0.833), 1.05 (0.89–1.23; P = 0.591) and 1.10 (0.83–1.46; P = 0.524), respectively.

Conclusions

Among patients with IBD, incidence of acute coronary events did not show a statistically significant difference when compared to the matched cohort.
Antithrombotic therapy in patients with atrial fibrillation and acute coronary syndrome undergoing percutaneous coronary intervention; insights from a meta-analysis
Authors: Kuno Toshiki , Ueyama Hiroki , Ando Tomo , Briasoulis Alexandros , Takagi Hisato
Published: April 2020

Background

The optimal antithrombotic regimen for patients undergoing percutaneous coronary intervention in acute coronary syndrome with concomitant atrial fibrillation is largely under investigation.

Method

PUBMED and EMBASE were searched through October 2019 for randomized trials or subgroup analyses of randomized trials investigating different antithrombotic strategies in patients with atrial fibrillation and acute coronary syndrome undergoing percutaneous coronary intervention. We compared dual antithrombotic therapy versus triple antithrombotic therapy. Dual antithrombotic therapy was defined as vitamin K antagonist or direct oral anticoagulant plus P2Y12 inhibitor. Triple antithrombotic therapy was defined as vitamin K antagonist or direct oral anticoagulant plus dual antiplatelet therapy (aspirin plus P2Y12 inhibitor). The primary safety outcome was trial outcome was trial defined major adverse cardiovascular events.

Results

Our search identified 5 eligible subgroup analyses of randomized controlled trials that enrolled a total of 4733 patients. Dual antithrombotic therapy significantly decreased the bleeding risk when compared with triple antithrombotic therapy (hazard ratio: 0.61; 95% confidential interval [0.51–0.71], P < 0.001, I
2 = 31%). However, there were no significant differences in major adverse cardiovascular event between dual antithrombotic therapy versus triple antithrombotic therapy (hazard ratio: 1.08; 95% confidential interval: 0.89–1.31, P = 0.44, I
2 = 0%).

Conclusion

In patients with atrial fibrillation and acute coronary syndrome undergoing percutaneous coronary intervention, dual antithrombotic therapy was associated with lower bleeding risk compared with triple antithrombotic therapy while conferring similar major adverse cardiovascular event risk. Our results should be interpreted cautiously because we did not analyze the risk of stent thrombosis.
Safety of in-utero antiretroviral exposure: neurologic outcomes in children who are HIV-exposed but uninfected
Authors: Crowell Claudia S. , Williams Paige L. , Yildirim Cenk , Van Dyke Russell B. , Smith Renee , Chadwick Ellen G. , Seage George R. , Diperna Alexandria , Hazra Rohan
Published: April 2020

Objective:

To evaluate whether there is an increased risk of neurologic diagnoses in children who are HIV-exposed but uninfected (CHEU) exposed in utero to specific antiretroviral medications.

Design:

Prospective cohort study of CHEU enrolled from 2007 to 2017.

Methods:

We evaluated children for neurologic case status, including microcephaly, febrile seizures, seizure disorders, ophthalmologic disorders, and other neurologic disorders. Adjusted relative risks (aRRs) were estimated for the association between in-utero antiretroviral exposure and neurologic case using log-binomial regression, accounting for potential confounders. Sensitivity analyses were conducted to evaluate robustness of findings.

Results:

Among 3747 eligible CHEU, 231 (6.2%) met neurologic case criteria (95% CI 5.4--7%). Most eligible children (86%) were exposed in utero to combination antiretroviral regimens. In adjusted models, children exposed to efavirenz at any time during pregnancy had higher risk of neurologic case status (aRR = 1.53, 95% CI 0.94--2.51). This association was stronger when comparing efavirenz exposure at conception to no exposure during pregnancy (aRR = 1.92, 95% CI 1.09--3.36) and considering follow-up and case diagnosis only through age 2 (aRR = 2.14, 95% CI 1.11--4.12). Children exposed to didanosine at conception and during the first trimester had increased risk of neurologic case status (aRR = 2.28, 95% CI 1.07--4.87 and aRR = 2.02, 95% CI 1.01--4.04, respectively), compared with didanosine-unexposed children. Children with dolutegravir exposure had some suggestion of increased risk of neurologic case (aRR = 2.43, 95% CI 0.75--7.84), which was observed consistently across several sensitivity analyses.

Conclusion:

Efavirenz and didanosine exposure during pregnancy were associated with higher risk of neurologic abnormalities in CHEU, and dolutegravir exposure showed some suggestive associations, which warrant further monitoring.
Longitudinal patterns of illicit drug use, antiretroviral therapy exposure and plasma HIV-1 RNA viral load among HIV-positive people who use illicit drugs
Authors: Liang Jiaming , Nosova Ekaterina , Reddon Hudson , Nolan Seonaid , Socías Eugenia , Barrios Rolando , Milloy M.-J.
Published: April 2020

Objectives:

HIV-positive people who use illicit drugs (PWUD) experience elevated rates of HIV-associated morbidity and mortality compared with members of other key affected populations. Although suboptimal levels of access and adherence to antiretroviral therapy (ART) are common among HIV-positive PWUD, there is a need for studies investigating the possible biological impacts of noninjection illicit drug use among people living with HIV in real-world settings.

Methods:

We accessed data from the ACCESS study, an ongoing prospective cohort of illicit drug users with systematic HIV viral load monitoring in a setting with universal care and ART dispensation records. We used multivariable generalized linear mixed models to estimate the longitudinal associations between noninjection use of crack cocaine, powder cocaine, opioids, methamphetamine, cannabis and alcohol on plasma HIV-1 RNA viral load, adjusted for ART exposure and relevant confounders.

Results:

Between 2005 and 2018, 843 individuals from the ACCESS cohort were included and contributed to 8698 interviews. At baseline, the mean age was 43 years, 566 (67%) reported male sex and 659 (78%) used crack cocaine in the previous 6 months. In multivariable models adjusted for ART exposure, only crack cocaine use in the last 6 months was found to be significantly associated with higher HIV viral load.

Conclusion:

We observed significantly higher HIV viral load during periods of crack cocaine use independent of ART exposure. Our findings support further research to investigate the possible biological mechanisms of this effect.
Leveling the Maxillary Occlusal Plane Without Orthodontic Appliances in Patients With Hemifacial Microsomia Using Unilateral Vertical Mandibular Distraction Osteogenesis
Authors: Pourtaheri Navid , Yang Robin , Lopez Joseph , Kumar Anand R.
Published: April 2020

Purpose:

To assess maxillary occlusal plane correction in patients with hemifacial microsomia (HFM) after vertical vector mandibular distraction osteogenesis (vMDO) without orthodontic appliances.

Methods:

A retrospective study was performed on consecutive patients with HFM and Kaban-Pruzansky type-II mandibular deformities who underwent unilateral vMDO by a single surgeon over an 18-month period. Patients with 12-months minimum clinical follow-up and postero-anterior (PA) cephalograms taken preoperatively and at a minimum of 3 months post-consolidation were included.

Results:

Five patients met inclusion criteria, 3 were female, median age was 13 years, median distraction length was 21.3 mm. Median radiographic follow-up was 5 months (range 3–38) post-consolidation. Median correction of the ramus height differential (difference between non-diseased and diseased side) was 97.3%. Median maxillary height differential correction was 72.2%. Median maxillary occlusal plane angle correction (towards zero) was 84.2%. Relative and absolute maxillary bone growth was greater on the diseased side (median 7.4%, 3.5 mm versus 2.8%, 1.4 mm). Dentoalveolar height decreased bilaterally in 4 of the 5 patients. Median chin point correction (towards midline) was 31.4%.

Conclusion:

Unilateral vMDO without orthodontic appliances effectively corrected mandibular ramus height, leveled the maxillary occlusal plane, and preferentially increased maxillary bone growth on the diseased side in patients with HFM.
Surgical Treatment Selection in Adult Class III Patients With Maxillary Transverse Deficiency
Authors: Xiang Zichao , Wang Yu , Helal Hussein , Wang Peng , Zhang Zhen , Li Jihua
Published: April 2020

The purpose of this study was to investigate the frequency of three commonly used treatments for skeletal class III malocclusion with maxillary transverse deficiency (MTD) (SCM) patients in East Asian, to find a quantitative method for precise discrepancy evaluation, and to find other potential indicators for treatment selection. A total of 239 adult SCM patients were divided into3 groups according to treatments.

Dentofacial features were measured and the initial skeletal discrepancy was evaluated with computer-aided surgical simulation (CASS). Relationship between the degree of skeletal transverse discrepancy (STD) and other dentofacial features were analyzed by Spearman's rank correlation. The STD in East Asian could be quantitatively grouped as: mild (<4 mm), moderate (4–8 mm), and severe (>8 mm). Most patients (81%) could be diagnosed with mild STD, and were treated without surgical expansion. The upper first molars inclination, the required relative movement and the required maxillary movement were correlated to the degree of STD. The conventional orthodontic and orthognathic treatment without surgical expansion is the most frequent choice for East Asian SCM adults. CASS facilitated analysis is useful in an accurate MTD evaluation. Some dentofacial features were closely correlated to STD, and thus were helpful for the treatment selection.