bluuebunny/crossref_metadata_2025 huggingface dataset:
Sick leave and return to work after surgery for type II SLAP lesions of the shoulder: a secondary analysis of a randomised sham-controlled study
Authors: Brox Jens Ivar , Skare Øystein , Mowinckel Petter , Brox Jostein Skranes , Reikerås Olav , Schrøder Cecilie Piene
Published: April 2020

Objectives

To compare days on sick leave and assess predictors of return to work following shoulder surgery.

Design

A secondary analysis of a randomised controlled trial.

Setting

Orthopaedic department.

Participants

114 patients with type II superior labral tear from anterior to posterior of the shoulder.

Interventions

Labral repair, biceps tenodesis or sham surgery.

Outcome measures

Sick leave was obtained from national registers for the last year before and 2 years following surgery. Total and shoulder related number of days on sick leave were obtained, using international diagnostic codes. We applied the difference-in-difference approach to compare the differences in the change in mean work days on sick leave between groups over time, backwards logistic regression and lasso regression to evaluate predictors.

Results

Mean total number of work days on sick leave during the 2 years after surgery was 148 (range 0–460) days. More than 80% of the sick leave days were taken by 22% of the patients. Days on sick leave classified as shoulder-related constituted 80% of the total. In all three treatment groups, the mean total number of days on sick leave doubled the year after surgery. Sham surgery and labral repair had fewer postoperative sickness absence days compared with biceps tenodesis but differences were not significant when adjusted for days of sick leave the year before surgery. Predictors of return to work at 2 years analysed by logistic regression were no sick leave (OR 8.0, 95% CI 2.4 to 26.0) and moderate symptoms of anxiety or depression (OR 0.16, 95% CI 0.05 to 0.5) at inclusion. Similar results were obtained by lasso regression but manual work was an additional predictor.

Conclusions

Change in mean work days on sick leave comparing sham surgery, labral repair and biceps tenodesis, was not significantly different. Sick leave, symptoms of anxiety and depression, and manual work at inclusion predicted work status 2 years after surgery.

Trial registration number

NCT00586742.
Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection
Authors: Lin Lu , Jiang Xiayang , Zhang Zhenling , Huang Siwen , Zhang Zhenyi , Fang Zhaoxiong , Gu Zhiqiang , Gao Liangqing , Shi Honggang , Mai Lei , Liu Yuan , Lin Xianqi , Lai Renxu , Yan Zhixiang , Li Xiaofeng , Shan Hong
Published: April 2020

Objective

To study the GI symptoms in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients.

Design

We analysed epidemiological, demographic, clinical and laboratory data of 95 cases with SARS-CoV-2 caused coronavirus disease 2019. Real-time reverse transcriptase PCR was used to detect the presence of SARS-CoV-2 in faeces and GI tissues.

Results

Among the 95 patients, 58 cases exhibited GI symptoms of which 11 (11.6%) occurred on admission and 47 (49.5%) developed during hospitalisation. Diarrhoea (24.2%), anorexia (17.9%) and nausea (17.9%) were the main symptoms with five (5.3%), five (5.3%) and three (3.2%) cases occurred on the illness onset, respectively. A substantial proportion of patients developed diarrhoea during hospitalisation, potentially aggravated by various drugs including antibiotics. Faecal samples of 65 hospitalised patients were tested for the presence of SARS-CoV-2, including 42 with and 23 without GI symptoms, of which 22 (52.4%) and 9 (39.1%) were positive, respectively. Six patients with GI symptoms were subjected to endoscopy, revealing oesophageal bleeding with erosions and ulcers in one severe patient. SARS-CoV-2 RNA was detected in oesophagus, stomach, duodenum and rectum specimens for both two severe patients. In contrast, only duodenum was positive in one of the four non-severe patients.

Conclusions

GI tract may be a potential transmission route and target organ of SARS-CoV-2.
Practice of endoscopy during COVID-19 pandemic: position statements of the Asian Pacific Society for Digestive Endoscopy (APSDE-COVID statements)
Authors: Chiu Philip Wai Yan , Ng Siew C , Inoue Haruhiro , Reddy D Nageshwar , Ling Hu Enqiang , Cho Joo Young , Ho Lawrence KY , Hewett David G , Chiu Han-Mo , Rerknimitr Rungsun , Wang Hsiu-Po , Ho Shiaw Hooi , Seo Dong Wan , Goh Khean-Lee , Tajiri Hisao , Kitano Seigo , Chan Francis K L
Published: April 2020

Coronavirus-19 (COVID-19) caused by SARS-CoV-2 has become a global pandemic. Risk of transmission may occur during endoscopy and the goal is to prevent infection among healthcare professionals while providing essential services to patients. Asia was the first continent to have a COVID-19 outbreak, and this position statement of the Asian Pacific Society for Digestive Endoscopy shares our successful experience in maintaining safe and high-quality endoscopy practice at a time when resources are limited. Sixteen experts from key societies of digestive endoscopy in Asia were invited to develop position statements, including patient triage and risk assessment before endoscopy, resource prioritisation and allocation, regular monitoring of personal protective equipment, infection control measures, protective device training and implementation of a strategy for stepwise resumption of endoscopy services after control of the COVID-19 outbreak.
Clinical Update on Pulmonary Hypertension
Authors: Yaghi Salim , Novikov Anastasia , Trandafirescu Theo
Published: April 2020

Pulmonary hypertension (PH) is a chronic, complex and challenging disease. Advances in treatment are for the subset of patients with pulmonary arterial hypertension. Selected review of the literature was conducted incorporating the European Society of Cardiology/European Respiratory Society 2015 guidelines and recommendations from the Sixth World Symposium on Pulmonary Hypertension. PH is classified into five groups based on WHO classification. Echocardiography remains the initial test of choice, and careful assessment of the right system aids in the diagnosis and prognosis of the disease. Right heart catheterization remains the gold standard of diagnosis and key guidance of treatment. Multidisciplinary approach is recommended for the care of patients with PH. Treatment selection is based on individual risk stratification of patients, and early referral to specialized PH centers improves outcomes of patients. Treating PH is complex and is best carried out in PH centers and with multidisciplinary approach. Early diagnosis and referral to those centers are key not to delay treatment.
Occupational exposure to soft paper dust and mortality
Authors: Torén Kjell , Neitzel Richard , Sallsten Gerd , Andersson Eva
Published: April 2020

Objectives

Occupational exposure to soft paper dust is associated with impaired lung function. Whether there is an increased risk for asthma or chronic obstructive pulmonary disease (COPD) is unclear.

Methods

We studied 7870 workers from three Swedish soft paper mills, and defined high-exposed workers, as having been exposed to soft paper dust exceeding 5 mg/m3 for at least 5 years. The remaining workers were classified as ‘low exposed’. Person-years at risk were calculated and stratified according to gender, age and calendar-year. The follow-up time was from 1960 to 2013. The expected numbers of deaths were calculated using the Swedish population as reference and standardised mortality ratios (SMRs) with 95% CIs were assessed.

Results

There was an increased mortality due to obstructive lung disease (asthma and COPD), among high-exposed workers, SMR 1.89, 95% CI 1.20 to 2.83, based on 23 observed cases. High-exposed workers had an increased mortality from asthma, SMR 4.13, 95% CI 1.78 to 8.14, based on eight observed cases. The increased asthma mortality was also observed among high-exposed men, SMR 4.38, 95% CI 1.42 to 10.2, based on five observed cases. The asthma mortality among low-exposed workers, both men and women, was not increased. The COPD mortality was not clearly increased among high-exposed workers (SMR 1.52, 95% CI 0.85 to 2.50).

Conclusion

High occupational exposure to soft paper dust increases the mortality due to asthma, and the results suggest that soft paper dust levels in workplaces should be below 5 mg/m3.
Threshold concepts and sustainability: features of a contested paradigm
Authors: Loring Philip A.
Published: April 2020

Threshold concepts describe the core concepts that people must master if they are to effectively think from within a new discipline or paradigm. Here, I discuss threshold concepts relevant to the science and practice of sustainability, unpacking the persistent challenges and critiques that sustainability has faced over the decades. Sustainability is immensely popular, but also endlessly critiqued as being naïve, vague, and easy to co-opt. I argue that these challenges can be traced to sustainability’s status as a robust, alternative world view to the industrial, neoliberal paradigm. The threshold concepts discussed below are troublesome, and new learners face significant challenges when trying to learn them and move into the paradigm. Here, I review five threshold concepts that are widely discussed as important to sustainability: complexity, collaborative institutions, multiple ways of knowing, no panaceas, and adaptability. This list is not intended as comprehensive but exemplary of sustainability as a pluralistic paradigm. Recognizing the special status of these and other threshold concepts within sustainability, and the linkages and dependencies among them, is an important advance for sustainability education and practice. I also offer some suggestions on classroom activities that have proved effective in helping people through the process of learning these concepts.
Resolving the low mass puzzle of $$\Lambda _c(2940)^+$$
Authors: Luo Si-Qiang , Chen Bing , Liu Zhan-Wei , Liu Xiang
Published: April 2020

For the long standing low mass puzzle of $$\Lambda _c(2940)^+$$Λc(2940)+, we propose an unquenched picture. Our calculation explicitly shows that the mass of the $$\Lambda _c(2P,3/2^-)$$Λc(2P,3/2-) state can be lowered down to be consistent with the experimental data of $$\Lambda _c(2940)^+$$Λc(2940)+ by introducing the $$D^*N$$D∗N channel contribution. It means that the low mass puzzle of $$\Lambda _c(2940)^+$$Λc(2940)+ can be solved. What is more important is that we predict a mass inversion relation for the 2P$$\Lambda _{c}^+$$Λc+ states, i.e., the $$\Lambda _c(2P,1/2^-)$$Λc(2P,1/2-) state is higher than the $$\Lambda _c(2P,3/2^-)$$Λc(2P,3/2-), which is totally different from the result of conventional quenched quark model. It provides a criterion to test such an unquenched scenario for $$\Lambda _c(2940)^+$$Λc(2940)+. We expect the future experimental progress from the LHCb and Belle II.
Structural constraints on Lower Carboniferous shale gas exploration in the Craven Basin, NW England
Authors: de Jonge-Anderson Iain , Underhill John R.
Published: April 2020

Detailed interpretation of a 3D seismic data volume reveals the detrimental effect that post-depositional tectonic deformation has had on buried Lower Carboniferous (Dinantian–Namurian) shales and its consequences for shale gas exploration in the SW part (Fylde area) of the Craven Basin in NW England. The structural styles primarily result from Devono-Carboniferous (syn-sedimentary) extension, post-rift subsidence and Variscan inversion, a renewed phase of Permo-Triassic extension, and Cenozoic uplift and basin exhumation. In contrast to the shallow dips and bedding continuity that characterizes productive shale gas plays in other basins (e.g. in the USA and Argentina), our mapping shows that the area is affected by deformation that results in the Bowland Shale Formation targets being folded and dissected into fault-bound compartments defined by SW–NE striking (Lower Carboniferous and Variscan) reverse faults and SSW–NNE to N–S striking (Permo-Triassic) normal faults. The fault networks and the misalignment between the elongate compartments they contain and the present-day minimum horizontal stress orientation limit the length over which long lateral boreholes can remain in a productive horizon, placing an important constraint on optimal well positioning, reducing the size of the shale gas resource and affecting well productivity. Our subsurface mapping using this high-fidelity dataset provides an accurate picture of the Upper Palaeozoic structure and demonstrates that faulting is denser and more complex than apparent from geological mapping of the surface outcrop. That structural complexity has direct and significant consequences for: the location of well pads; the lateral continuity of target shale gas horizons; the evaluation of the risk of inducing seismicity on seismically resolvable (large displacement) fault planes prior to drilling; and the likelihood of faults with small throws (below seismic resolution) being present.
Variants of Courcelle's Theorem for complexity classes inside P
Authors: Elberfeld Michael
Published: April 2020

It is well known that monadic-second order logic (MSO) expresses many natural NP-complete problems. However, a famous theorem of Courcelle states that every problem expressible in MSO can be solved in linear time for input graphs whose tree width is bounded by a fixed constant [Courcelle 1990]. Courcelle's Theorem is the prototypical example of an algorithmic "meta theorem", which states an algorithmic upper bound for a whole family of problems. This column reviews a series of meta theorems several of which refine Courcelle's Theorem by more precisely classifying the complexity of natural families of problems.
Nominal techniques
Authors: Pitts Andrew
Published: April 2020

Programming languages abound with features making use of names in various ways. There is a mathematical foundation for the semantics of such features which uses groups of permutations of names and the notion of the
support
of an object with respect to the action of such a group. The relevance of this kind of mathematics for the semantics of names is perhaps not immediately obvious. That it is relevant and useful has emerged over the last 15 years or so in a body of work that has acquired its own name:
nominal techniques.
At the same time, the application of these techniques has broadened from semantics to computation theory in general. This article introduces the subject and is based upon a tutorial at LICS-ICALP 2015 [Pitts 2015a].
Strengthening the Public Health Impacts of the Supplemental Nutrition Assistance Program Through Policy
Authors: Bleich Sara N. , Moran Alyssa J. , Vercammen Kelsey A. , Frelier Johannah M. , Dunn Caroline G. , Zhong Anthony , Fleischhacker Sheila E.
Published: April 2020

The US Department of Agriculture (USDA) Supplemental Nutrition Assistance Program (SNAP) is the cornerstone of the US nutrition safety net. Each month, SNAP provides assistance to 40 million low-income Americans—nearly half of them children. A number of changes could strengthen the public health impacts of SNAP. This review first presents a framework describing the mechanisms through which SNAP policy can influence public health, particularly by affecting the food security, the diet quality, and, subsequently, the health of SNAP participants. We then discusspolicy opportunities with the greatest potential to strengthen the public health impacts of SNAP, organized into three areas: ( a) food production and distribution, ( b) benefit allocation, and ( c) eligibility and enrollment. For each section, we describe current policy and limitations of the status quo, suggest evidence-based opportunities for policy change to improve public health, and identify important areas for future research.
A Public Health Approach to Global Child Sex Trafficking
Authors: Greenbaum Jordan
Published: April 2020

Human trafficking and child sex trafficking and sexual exploitation in particular are global public health issues with widespread, lasting impacts on children, families, and communities. Traditionally, human trafficking has been treated as a law enforcement problem with an emphasis on the arrest and prosecution of traffickers. However, use of a public health approach focuses efforts on those impacted by exploitation: trafficked persons, their families, and the population at large. It promotes strategies to build a solid scientific evidence base that allows development, implementation, and evaluation of prevention and intervention efforts, informs policy and program development, and guides international efforts at eradication. This article uses the public health approach to address human trafficking, with a focus on child sex trafficking and exploitation. Recommendations are made for public health professionals to contribute to antitrafficking efforts globally.
Thermal Runaway of a Li-Ion Battery Studied by Combined ARC and Multi-Length Scale X-ray CT
Authors: Patel Drasti , Robinson James B. , Ball Sarah , Brett Daniel J. L. , Shearing Paul R.
Published: April 2020

Lithium ion battery failure occurs across multiple length scales. In this work, the properties of thermal failure and its effects on electrode materials were investigated in a commercial battery using a combination of accelerating rate calorimetry (ARC) and multi-length scale X-ray computed tomography (CT). ARC measured the heat dissipated from the cell during thermal runaway and enabled the identification of key thermal failure characteristics such as onset temperature and the rate of heat generation during the failure. Analysis before and after failure using scanning electron microscopy (SEM) and X-ray CT were performed to reveal the effects of failure on the architecture of the whole cell and microstructure of the cathode material. Mechanical deformations to the cell architecture were revealed due to gas generation at elevated temperatures (>200 °C). The extreme conditions during thermal runaway caused the cathode particles to reduce in size by a factor of two. Electrode surface analysis revealed surface deposits on both the anode and cathode materials. The link between electrode microstructure and heat generation within a cell during failure is analysed and compared to commercially available lithium ion cells of varying cathode chemistries. The optimisation of electrode designs for safer battery materials is discussed.
High-Rate Performance Solid-State Lithium Batteries with Silica-Gel Solid Nanocomposite Electrolytes using Bis(fluorosulfonyl)imide-Based Ionic Liquid
Authors: Sagara Akihiko , Chen Xubin , Gandrud Knut B. , Murata Mitsuhiro , Mees Maarten , Kaneko Yukihiro , Arase Hidekazu , Vereecken Philippe M.
Published: April 2020

A nanocomposite electrolyte composed of a non-volatile ionic liquid, organic Li-salt and porous-inorganic material can be a promising option as a solid electrolyte material. We present a high-rate performance in solid-state lithium metal and Li-ion batteries using a silica-gel solid nanocomposite electrolyte (nano-SCE) made by the sol-gel method with a bis(fluorosulfonyl)imide (FSI)-based ionic liquid. The nano-SCE, composed of 1-ethyl-3-methylimidazolium bis(fluorosulfonyl) imide (EMI-FSI) and Li-FSI confined in the mesoporous silica matrix, exhibits an ionic conductivity of 6.2 mS cm−1 at room temperature. The capacity of the Li-LiFePO4 cell using the EMI-FSI based nano-SCE reaches 150 mAh g−1 at 0.1C and 113 mAh g−1 at 1C, which is higher than that achieved by the other reported batteries that use a similar composite electrolyte. The C-rate performance of the prepared solid batteries is comparable to that of cells with the conventional lithium hexafluorophosphate (LiPF6) electrolyte. Our results show that impregnation of a liquid precursor is an efficient approach for an excellent electrode/electrolyte interface contact in the solid composite electrode as the reaction kinetics at the interface of the active mass and nano-SCE are sufficiently fast, and thus is advantageous compared with the other types of solid electrolytes.
Sex and BNIP3 genotype, rather than acute lipid injection, modulate hepatic mitochondrial function and steatosis risk in mice
Authors: Fuller Kelly N. Z. , McCoin Colin S. , Allen Julie , Bell-Glenn Shelby , Koestler Devin C. , Dorn Gerald W. , Thyfault John P.
Published: April 2020

This is the first study focusing on hepatic mitochondrial respiratory outcomes in response to lipid overload via a high-fat diet (HFD) combined with intralipid injection. Novel findings include no effect of intralipid injection on mitochondrial outcomes of interest, despite increased circulating lipid concentrations. However, we report pronounced differences in hepatic mitochondrial respiration, complex protein expression, and H2O2 production by sex and BCL-2/adenovirus EIB 19-kDa interacting protein (BNIP3) genotype. Specifically, female mice had lower H2O2 emission globally and on an acute HFD, females had greater hepatic mitochondrial respiration than males, whereas BNIP3 knockout (KO) animals had greater mitochondrial coupling and complex protein expression than wild-type (WT) animals.
Combined influence of inspiratory loading and locomotor subsystolic cuff inflation on cardiovascular responses during submaximal exercise
Authors: Smith Joshua R. , Bruhn Eric J. , Berg Jessica D. , Nur Amran A. , Villarraga Nicolas , Olson Thomas P.
Published: April 2020

Reflexes arising from the respiratory and locomotor muscles influence cardiovascular regulation during exercise. However, it is unclear how the respiratory and locomotor muscle reflexes interact when simultaneously stimulated. Herein, we demonstrate that stimulation of the respiratory and locomotor muscle reflexes yielded additive cardiovascular responses during submaximal exercise.
Silencing of PRDX2 Inhibits the Proliferation and Invasion of Non‐Small Cell Lung Cancer Cells
Authors: Jing Xu , Du Lutao , Niu Aijun , Wang Yunshan , Wang Yuli , Wang Chuanxin
Published: April 2020

Peroxiredoxin 2 (PRDX2), a member of the peroxiredoxin family of antioxidant enzymes, has been revealed to be an important player in cancer progression. However, the biological role of PRDX2 in the progression of non‐small cell lung cancer (NSCLC) is poor reported. In the present study, the loss‐of‐function experiments were performed to investigate the specific role of PRDX2 in the growth and invasion of NSCLC. The results revealed that knockdown of PRDX2 by siRNA interference significantly suppressed the proliferation, migration, and invasion of A549 and H1299 cells, as well as diminished the activity of MMP9. Additionally, the decrease in PRDX2 expression significantly promoted apoptosis in NSCLC cells by downregulating expression of Bcl‐2 and upregulating the expression of Bax, cleaved caspase 3 and cleaved caspase 9, but had no significant effect on the apoptosis of normal lung epithelial cells BEAS‐2B. Moreover, PRDX2 inhibitor also inhibited the proliferation, migration, and invasion of A549 cells and promoted apoptosis. Further, our data demonstrated that silencing of PRDX2 markedly reduced the phosphorylation of Akt and mTOR and expression of downstream proteins Cyclin D1 and p70S6k. In conclusion, our findings indicate that PRDX2 exerts a prooncogenic role in the progression of NSCLC and might be a potential therapeutic target for NSCLC treatment.
Human Epididymis Protein 4 Levels in Neonates with Respiratory Disorder
Authors: Surmiak Piotr , Szymkowiak Martyna , Baumert Małgorzata
Published: April 2020

Introduction. Transient tachypnea of the newborn (TTN) is one of the most common causes of respiratory distress in the full‐term neonates. The diagnosis of TTN in early postnatal period remains problematic for clinicians, and unfortunately, there exist no reliable diagnostic tests for TTN. The elevated human epididymis protein 4 (HE4) levels were observed in the cases of severe bronchitis, pneumonia, and inflammatory processes. However, little is known about the fluctuation of this biomarker concentrations in respiratory disorders in neonatal period. The authors investigated the HE4 levels found in the umbilical cord blood and venous blood samples of the newborns with respiratory disorder (TTN) and blood samples of their mothers. Materials and Methods. The investigated neonates were divided into two groups: 23 neonates with the respiratory insufficiency (transient tachypnea of the newborn, TTN) as the study group and 28 newborns of healthy mothers constituted the control group (CG). The C‐reactive protein (CRP) and procalcitonin (PCT) as well as HE4 levels were determined in umbilical cord blood and venous blood for all the examined neonates and their mothers. Results. There were no differences found in the HE4 levels determined for the mothers’ blood samples and umbilical cord blood samples in all investigated groups. In comparison with healthy children, the elevated HE4 levels were observed in neonates with TTN. Significant positive correlation between HE4 and CRP as well as PCT levels was observed in all investigated neonates. The receiver operating characteristic (ROC) curve analysis demonstrated the cut‐off value for the serum HE4 in the researched neonates at the level of 318.5 pmol/L, yielding the sensitivity of 73.9% and specificity of 66.7% for the early diagnosis of TTN. Conclusions. Serum HE4 could be considered as a candidate biomarker for the early diagnosis of pulmonary dysfunction in the newborns.
The Role of MicroRNAs in Regulatory T Cells
Authors: Liu Chao , Li Nannan , Liu Guijian
Published: April 2020

MicroRNAs are a class of conserved, 20 nt-23 nt long, noncoding small RNAs that inhibit expression of their respective target genes in different cell types. Regulatory T cells (Tregs) are a subpopulation of T cells that negatively regulate immune responses, which is essential to immune homeostasis. Recent studies have indicated that microRNAs play an important role in the proliferation, differentiation, and functions of Treg. Here, we review the recent progress in understanding the roles of microRNAs in Treg and their dysregulation in immune-related diseases. This ongoing research continues to expand the understanding of Treg regulation and the mechanisms of immune disorders.
Establishment and Evaluation of a 6‐Gene Survival Risk Assessment Model Related to Lung Adenocarcinoma Microenvironment
Authors: Wang Zhitian , Xu Huiling , Zhu Linhai , He Tianyu , Lv Wang , Wu Zhigang
Published: April 2020

Objective. A survival risk assessment model associated with a lung adenocarcinoma (LUAD) microenvironment was established and evaluated to identify effective independent prognostic factors for LUAD. Methods. The public data were downloaded from the TCGA database, and ESTIMATE prediction software was used to score immune cells and stromal cells for tumor purity prediction. The samples were divided into the high‐score group and the low‐score group by the median value of the immune score (or stromal score). The Wilcoxon test was used for differential analysis. GO and KEGG enrichment analysis of differentially expressed genes (DEGs) was performed using “clusterProfiler” of R package. Meanwhile, univariate and multivariate regression analysis was performed on DEGs to construct a multivariate Cox risk regression model with variable gene expression levels as independent prognostic factors affecting a tumor microenvironment (TME) and tumor immunity. Results. This study found that LUAD patients with high immune cell (stromal cell) infiltration had better prognosis and were in earlier staging. Functional enrichment analysis revealed that most DEGs were related to the proliferation and activation of immune cells or stromal cells. A survival prediction model composed of 6 TME‐related genes (CLEC17A, TAGAP, ABCC8, BCAN, FLT3, and CCR2) was established, and finally, the 6 feature genes closely related to the prognosis of LUAD were proved. The AUC value of the ROC curve in this model was 0.7, indicating that the model was reliable. Conclusion. Six genes related to the LUAD microenvironment have a predictive prognostic value in LUAD.
Inflammatory Factors Induce Thrombosis through the miR‐146b‐3p/p38MAPK/COX‐2 Pathway
Authors: Su Zhengjia , Wu Fang
Published: April 2020

Objective. Inflammatory responses play important roles in the pathogenesis of atherosclerosis. The purpose of this study was to investigate the relationship between microRNA‐146b‐3p (miR‐146b‐3p) and inflammatory factors in thrombosis. Method. THP‐1 cells were cultured in vitro, Western blot was used to determine the protein levels of COX‐2 and p38MAPK in the cells, and real‐time PCR was used to detect the mRNA expression of miRNA‐146b‐3p and COX‐2. A lentiviral expression vector of miRNA‐146b‐3p and its inhibitor were constructed to transfect THP‐1 cells. COX‐2 and p38MAPK expression in transfected cells was detected by Western blot and real‐time PCR, respectively. Results. Ang II and TNF‐α could elevate the expression of COX‐2 in monocytes. The expression of COX‐2 was upregulated by p38MAPK, which could be phosphorylated by Ang II, while there was an increasing tendency of p38MAPK phosphorylation after TNF‐α stimulation. In addition, COX‐2 expression and P38MAPK phosphorylation could be downregulated by miRNA‐146b‐3p and upregulated by the miRNA‐146b‐3p inhibitor. Ang II could increase miR‐146b‐3p expression, although there was no significant difference; however, the expression of miR‐146b‐3p was enhanced significantly by TNF‐α. Conclusion. Our data implied that altered expression of miR‐146b‐3p was closely related to the progression of inflammation mediating the P38MAPK/COX‐2 pathway. We suggest that the miR‐146b‐3p/p38MAPK/COX‐2 pathway plays a key role in inflammation and arterial thrombosis.
Rapid Expansion of Highly Functional Antigen-Specific T Cells from Patients with Melanoma by Nanoscale Artificial Antigen-Presenting Cells
Authors: Ichikawa Junya , Yoshida Tatsuya , Isser Ariel , Laino Andressa S. , Vassallo Melinda , Woods David , Kim Sojung , Oelke Mathias , Jones Kristi , Schneck Jonathan P. , Weber Jeffrey S.
Published: April 2020

Purpose:

Generation of antigen-specific T cells from patients with cancer employs large numbers of peripheral blood cells and/or tumor-infiltrating cells to generate antigen-presenting and effector cells commonly requiring multiple rounds of restimulation ex vivo. We used a novel paramagnetic, nanoparticle-based artificial antigen-presenting cell (nano-aAPC) that combines anti-CD28 costimulatory and human MHC class I molecules that are loaded with antigenic peptides to rapidly expand tumor antigen–specific T cells from patients with melanoma.

Experimental Design:

Nano-aAPC–expressing HLA-A*0201 molecules and costimulatory anti-CD28 antibody and HLA-A*0201 molecules loaded with MART-1 or gp100 class I–restricted peptides were used to stimulate CD8 T cells purified from the peripheral blood of treatment-naïve or PD-1 antibody–treated patients with stage IV melanoma. Expanded cells were restimulated with fresh peptide-pulsed nano-aAPC at day 7. Phenotype analysis and functional assays including cytokine release, cytolysis, and measurement of avidity were conducted.

Results:

MART-1–specific CD8 T cells rapidly expanded up to 1,000-fold by day 14 after exposure to peptide-pulsed nano-aAPC. Expanded T cells had a predominantly stem cell memory CD45RA+/CD62L+/CD95+ phenotype; expressed ICOS, PD-1, Tim3, and LAG3; and lacked CD28. Cells from patients with melanoma were polyfunctional; highly avid; expressed IL2, IFNγ, and TNFα; and exhibited cytolytic activity against tumor cell lines. They expanded 2- to 3-fold after exposure to PD-1 antibody in vivo, and expressed a highly diverse T-cell receptor V beta repertoire.

Conclusions:

Peptide-pulsed nano-aAPC rapidly expanded polyfunctional antigen-specific CD8 T cells with high avidity, potent lytic function, and a stem cell memory phenotype from patients with melanoma.
Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models
Authors: Kulukian Anita , Lee Patrice , Taylor Janelle , Rosler Robert , de Vries Peter , Watson Daniel , Forero-Torres Andres , Peterson Scott
Published: April 2020

HER2 is a transmembrane tyrosine kinase receptor that mediates cell growth, differentiation, and survival. HER2 is overexpressed in approximately 20% of breast cancers and in subsets of gastric, colorectal, and esophageal cancers. Both antibody and small-molecule drugs that target HER2 and block its tyrosine kinase activity are effective in treating HER2-driven cancers. In this article, we describe the preclinical properties of tucatinib, an orally available, reversible HER2-targeted small-molecule tyrosine kinase inhibitor. In both biochemical and cell signaling experiments, tucatinib inhibits HER2 kinase activity with single-digit nanomolar potency and provides exceptional selectivity for HER2 compared with the related receptor tyrosine kinase EGFR, with a >1,000-fold enhancement in potency for HER2 in cell signaling assays. Tucatinib potently inhibits signal transduction downstream of HER2 and HER3 through the MAPK and PI3K/AKT pathways and is selectively cytotoxic in HER2-amplified breast cancer cell lines in vitro. In vivo, tucatinib is active in multiple HER2+ tumor models as a single agent and shows enhanced antitumor activity in combination with trastuzumab or docetaxel, resulting in improved rates of partial and complete tumor regression. These preclinical data, taken together with the phase-I tucatinib clinical trial results demonstrating preliminary safety and activity, establish the unique pharmacologic properties of tucatinib and underscore the rationale for investigating its utility in HER2+ cancers.
Characterization of 7A5: A Human CD137 (4-1BB) Receptor Binding Monoclonal Antibody with Differential Agonist Properties That Promotes Antitumor Immunity
Authors: Kotanides Helen , Sattler Rose Marie , Lebron Maria B. , Carpenito Carmine , Shen Juqun , Li Jingxing , Surguladze David , Haidar Jaafar N. , Burns Colleen , Shen Leyi , Inigo Ivan , Pennello Anthony L. , Forest Amelie , Chen Xinlei , Chin Darin , Sonyi Andreas , Topper Michael , Boucher Lauren , Sharma Prachi , Zhang Yiwei , Burtrum Douglas , Novosiadly Ruslan D. , Ludwig Dale L. , Plowman Gregory D. , Kalos Michael
Published: April 2020

The CD137 receptor plays a key role in mediating immune response by promoting T cell proliferation, survival, and memory. Effective agonism of CD137 has the potential to reinvigorate potent antitumor immunity either alone or in combination with other immune-checkpoint therapies. In this study, we describe the discovery and characterization of a unique CD137 agonist, 7A5, a fully human IgG1 Fc effector-null monoclonal antibody. The biological properties of 7A5 were investigated through in vitro and in vivo studies. 7A5 binds CD137, and the binding epitope overlaps with the CD137L binding site based on structure. 7A5 engages CD137 receptor and activates NF-κB cell signaling independent of cross-linking or Fc effector function. In addition, T cell activation measured by cytokine IFNγ production is induced by 7A5 in peripheral blood mononuclear cell costimulation assay. Human tumor xenograft mouse models reconstituted with human immune cells were used to determine antitumor activity in vivo. Monotherapy with 7A5 inhibits tumor growth, and this activity is enhanced in combination with a PD-L1 antagonist antibody. Furthermore, the intratumoral immune gene expression signature in response to 7A5 is highly suggestive of enhanced T cell infiltration and activation. Taken together, these results demonstrate 7A5 is a differentiated CD137 agonist antibody with biological properties that warrant its further development as a cancer immunotherapy.
Decision Tree Clinical Algorithm for Screening of Mild Cognitive Impairment in the Elderly in Primary Health Care: Development, Test of Accuracy, and Time-Effectiveness Analysis
Authors: Pandhita S. Gea , Sutrisna Bambang , Wibowo Samekto , Adisasmita Asri C. , Rahardjo Tri Budi Wahyuni , Amir Nurmiati , Rustika Rustika , Kosen Soewarta , Syarif Syahrizal , Wreksoatmodjo Budi Riyanto
Published: April 2020

Mild cognitive impairment (MCI) is predicted to be a common cognitive impairment in primary health care. Early detection and appropriate management of MCI can slow the rate of deterioration in cognitive deficits. The current methods for early detection of MCI have not been satisfactory for some doctors in primary health care. Therefore, an easy, fast, accurate and reliable method for screening of MCI in primary health care is needed. This study intends to develop a decision tree clinical algorithm based on a combination of simple neurological physical examination and brief cognitive assessment for distinguishing elderly with MCI from normal elderly in primary health care. This is a diagnostic study, comparative analysis in elderly with normal cognition and those presenting with MCI. We enrolled 212 elderly people aged 60.04–79.92 years old. Multivariate statistical analysis showed that the existence of subjective memory complaints, history of lack of physical exercise, abnormal verbal semantic fluency, and poor one-leg balance were found to be predictors of MCI diagnosis (p ≤ 0.001; p = 0.036; p ≤ 0.001; p = 0.013). The decision trees clinical algorithm, which is a combination of these variables, has a fairly good accuracy in distinguishing elderly with MCI from normal elderly (accuracy = 89.62%; sensitivity = 71.05%; specificity = 100%; positive predictive value = 100%; negative predictive value = 86.08%; negative likelihood ratio = 0.29; and time effectiveness ratio = 3.03). These results suggest that the decision tree clinical algorithm can be used for screening of MCI in the elderly in primary health care.
Idiopathic urinary bladder rupture in two mares
Authors: Lavado Ronaldo Avella , Da Silva Luis Claudio Lopes Correia , Ambrósio Aline Magalhães , Leiria Paulo Ari Tietböhl , Belli Carla Bargi
Published: April 2020

Urinary bladder rupture is rarely reported in adult horses and is usually associated with parturition, history of traumaor urethral obstruction. This paper reports two cases in mares free of these predisposing factors, diagnosed throughclinical manifestations, abdominal ultrasound and abdominocentesis, corrected by cystorrhaphy through laparotomy.While recovery was satisfactory in one case, the other case had complications in celiorraphy such as development ofincisional hernia, small colon eventration and intestinal adherences, opting by the euthanasia of the animal. These reportsare important because of the rarity with which they occur in adult mares. The different prognoses may be related to theseverity of each case, according to the location and extension of the wound, which directly or indirectly influence thetechnique and recovery of the animals.
Spatial distribution of equine seroreagent to Leptospira spp. in Northeastern Brazil
Authors: Morais Davidianne De Andrade , Bezerra Camila De Sousa , Anjos Denize Monteiro dos , Nunes Bruno Cesar , Nogueira Denise Batista , Pequeno Nebson Fernandes , Costa Diego Figueiredo da , Higino Severino Silvano dos Santos , Azevedo Sérgio Santos , Alves Clebert José
Published: April 2020

Considering the importance of leptospirosis in both equine husbandry and public health, as well as the relevance of knowledge of current serogroup and the small number of studies addressing this disease in equines in Northeastern Brazil, the present study performed a serological survey of Leptospira spp. in a serum bank of 1,267 equines originating from 177 municipalities, located in four states in Northeastern Brazil: Ceará, Rio Grande do Norte, Paraíba and Pernambuco. The microscopic agglutination test (MAT) was used for diagnosis of leptospirosis using 24 serovars as antigens. The frequency of reagent equines was 29.7% (376/1,267), and 68.9% (122/177) of municipalities had at least one positive reaction. The serogroups reagent were Australis (37.2%), Icterohaemorrhagiae (29.3%), Tarassovi (9.6%), Sejroe (5.8%), Pomona (5.3%), Grippotyphosa (4.5%), Pyrogenes (2.4%), Bataviae (1.9%), Ballum and Hebdomadis (1.3%), Mini (0.5%), Celledoni, Shermani, and Javanica (0.3% each). There were significant statistical differences regarding sex and age, with a higher frequency in females (P= 0.014), and in animals ≥ 6 years (P=0.001). We concluded that seropositivity to Leptospira spp. is high in equines in Northeastern Brazil, with a predominance of serologic reactions to the Australis serogroup in the border areas between the states, and the Icterohaemorrhagiae serogroup in coastal areas or their vicinity. The high degree of seropositivity found points to the need to implement prophylactic strategies, both intraspecies infection prophylaxis and rodent control. We also recommended avoiding animal crowding and separating animals according to sex and age group during handling.
Brazilian red pepper leaves essential oil (Schinus terebinthifolius) in diets for feedlot lambs
Authors: Bertoloni Analisa Vasques , Polizel Daniel Montanher , Ferraz Júnior Marcos Vinícius De Castro , Oliveira Gabriela Bagio , Miszura Alexandre Arantes , Barroso José Paulo Roman , Martins André Storti , Sardinha Lairana Aline , Limede Arnaldo Cintra , Ferreira Evandro Maia , Pires Alexandre Vaz
Published: April 2020

Essential oil (EO) from Brazilian red pepper leaves contains antimicrobial compounds that control Gram-positive bacteria in the rumen content, improving the efficiency of ruminal fermentation. The objectives of the present study were to evaluate the effects of the Brazilian red pepper leaves EO (Schinus terebinthifolius) as a substitute for monensin on performance, occurrence of coccidiosis by Eimeria ssp., carcass characteristics and meat composition of feedlot lambs. Forty-four lambs, 16 males (12 ½ Dorper × ½ Santa Inês and 4 Santa Inês) and 28 females (16 ½ Dorper × ½ Santa Inês and 12 Santa Inês), with 21.4 ± 1.05 kg of initial body weight (BW), were used in a randomized complete block design. The experiment lasted 56 days, divided into 2 periods of 28 days each. The treatments were defined by the inclusion of 8 ppm of monensin (MON), and the doses 0.14% (14EO), 0.28% (28EO) and 0.42% (42EO) of red pepper leaves essential oil (EO). At the end of 56 days, 32 lambs were slaughtered for the measurement of carcass parameters and meat composition. There was no interaction among treatments and periods for average daily gain (ADG), dry matter intake (DMI), feed efficiency (FE) and oocyst of Eimeria ssp. in feces. The treatments did not affect the ADG, DMI and FE; however, the monensin inclusion decreased the oocyst of Eimeria ssp. (P = 0.01). There was a tendency (P = 0.06) of increase in hot carcass yield for lambs fed 28EO compared to 14EO. In addition, the cold carcass yield was higher (P = 0.02) in the animals fed 28EO and 42EO. The subcutaneous fat thickness was not affected by the experimental diets; however, there was a tendency for lambs from 28EO and 42EO treatments to present higher body wall thickness (P = 0.07) and Longissimus muscle area (P = 0.07) when compared to MON. The higher doses of red pepper leaves EO increased the percentage of crude protein (P < 0.01) and mineral matter (P = 0.02) in the chemical composition of meat. Although the performance of lambs did not change, the inclusion of 0.28 and 0.42% red pepper leaves EO improve the carcass characteristics and change the meat composition, demonstrating the potential of the use of this additive in confined lamb diets. However, the monensin has greater potential to control coccidiosis in feedlot lambs compared with red pepper leaves EO.
Ethnicity and Arterial Stiffness
Authors: Schutte Aletta E. , Kruger Ruan , Gafane-Matemane Lebo F. , Breet Yolandi , Strauss-Kruger Michél , Cruickshank J. Kennedy
Published: April 2020

Early vascular aging reflects increased arterial stiffness of central blood vessels at young chronological ages and powerfully predicts cardiovascular events and mortality, independent of routine brachial blood pressure and other risk factors. Since ethnic disparities exist in routine blood pressure, in hypertension and cardiovascular outcomes, this review evaluates major studies comparing arterial stiffness through the life course between different ethnic groups or races (which have no biological definition)—in children, adolescents, young, and middle-aged adults and the very elderly. Most report that compared with white European-origin samples, populations of black African descent have increased central arterial stiffness throughout different life stages, as well as a more rapid increase in arterial stiffness at young ages. Exceptions may include African Caribbean origin people in Europe. Differences in vascular structure and function are clearest, where obesity, socioeconomic, and psychosocial factors are most marked. Few studies evaluate a wider spectrum of ethnic groups or factors contributing to these ethnic disparities. Genetic effects are not obvious; maternal risk and intergenerational studies are scarce. Nevertheless, across all ethnic groups, for given levels of blood pressure and age, some people have stiffer central arteries than others. These individuals are most at risk of vascular events and mortality and, therefore, may benefit from early, as yet untested, preventive action and treatment.
Reduced Apolipoprotein M and Adverse Outcomes Across the Spectrum of Human Heart Failure
Authors: Chirinos Julio A. , Zhao Lei , Jia Yi , Frej Cecilia , Adamo Luigi , Mann Douglas , Shewale Swapnil V. , Millar John S. , Rader Daniel J. , French Benjamin , Brandimarto Jeff , Margulies Kenneth B. , Parks John S. , Wang Zhaoqing , Seiffert Dietmar A. , Fang James , Sweitzer Nancy , Chistoffersen Christina , Dahlbäck Björn , Car Bruce D. , Gordon David A. , Cappola Thomas P. , Javaheri Ali
Published: April 2020

Background:

Apo (apolipoprotein) M mediates the physical interaction between high-density lipoprotein (HDL) particles and sphingosine-1-phosphate (S1P). Apo M exerts anti-inflammatory and cardioprotective effects in animal models.

Methods:

In a subset of PHFS (Penn Heart Failure Study) participants (n=297), we measured apo M by Enzyme-Linked ImmunoSorbent Assay (ELISA). We also measured total S1P by liquid chromatography–mass spectrometry and isolated HDL particles to test the association between apo M and HDL-associated S1P. We confirmed the relationship between apo M and outcomes using modified aptamer-based apo M measurements among 2170 adults in the PHFS and 2 independent cohorts: the Washington University Heart Failure Registry (n=173) and a subset of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial; n=218). Last, we examined the relationship between apo M and ≈5000 other proteins (SomaScan assay) to identify biological pathways associated with apo M in heart failure.

Results:

In the PHFS, apo M was inversely associated with the risk of death (standardized hazard ratio, 0.56 [95% CI, 0.51–0.61];
P
<0.0001) and the composite of death/ventricular assist device implantation/heart transplantation (standardized hazard ratio, 0.62 [95% CI, 0.58–0.67];
P
<0.0001). This relationship was independent of HDL cholesterol or apo AI levels. Apo M remained associated with death (hazard ratio, 0.78 [95% CI, 0.69–0.88];
P
<0.0001) and the composite of death/ventricular assist device/heart transplantation (hazard ratio, 0.85 [95% CI, 0.76–0.94];
P
=0.001) in models that adjusted for multiple confounders. This association was present in both heart failure with reduced and preserved ejection fraction and was replicated in the Washington University cohort and a cohort with heart failure with preserved ejection fraction only (TOPCAT). The S1P and apo M content of isolated HDL particles strongly correlated (
R
=0.81,
P
<0.0001). The top canonical pathways associated with apo M were inflammation (negative association), the coagulation system (negative association), and liver X receptor/retinoid X receptor activation (positive association). The relationship with inflammation was validated with multiple inflammatory markers measured with independent assays.

Conclusions:

Reduced circulating apo M is independently associated with adverse outcomes across the spectrum of human heart failure. Further research is needed to assess whether the apo M/S1P axis is a suitable therapeutic target in heart failure.