bluuebunny/crossref_metadata_2025 huggingface dataset:
Finite element implementation of the aortic double-dispersion fibre model and development of a predictive damage model
Authors: Corvi A. , Collini L.
Published: January 2023

With the development of next-generation cardiovascular prosthesis, the requirement for more advanced simulations for predicting the mechanical response of biological tissue has arisen. Finite-element analysis represents a powerful tool capable of simulating complex behaviours within this framework. The present work proposes the computational implementation of an advanced constitutive model for the fibre-reinforced tissue making up the aortic wall. The formulation available in literature is numerically implemented within the FE software Abaqus© through specific user subroutines, and model predictions are compared with the already available single-dispersion-model results. The influence of each dispersion parameter on the macroscopic behaviour is analysed and discussed. Finally, the model is extended by a damage regime based on strain invariants, which is capable of considering the influence of patient ageing on the mechanical response failure strain. The user subroutines are here provided in the Appendix for applications.
Determination of dynamic material properties using laser measurement technique in split Hopkinson pressure bar
Authors: Mirshafiee S , Ashrafi MJ , Mousavi E
Published: January 2023

The split Hopkinson pressure bar (SHPB) is a commonly used technique to measure the stress-strain of materials at high strain rate. Using the strain records in the input and output bars, the average stress-strain and strain rate in the sample can be calculated by SHPB formulas based on the one-dimensional wave propagation theory. The accuracy of a SHPB test is based on this assumption. In this paper, first a laser measuring system is designed, implemented, and calibrated in order to obtain the dynamic properties of different materials using split Hopkinson pressure bar test. In this method which is a non-contact one, the displacements of bar/sample interfaces are measured directly using a laser extensometer technique, by using the provided equations, in addition to the strain, the stress of the tested sample can be calculated. Moreover, the operation of the method is evaluated using numerical simulation. Aluminum 7075 and copper C10200 samples were studied to evaluate the implemented measurement method. The comparison with other measurement methods shows good agreement of numerical and experimental results. Moreover, since the one-dimensional wave propagation is not used directly in this method, we show the proposed method can be used even with shorter pressure bars which can reduce the cost of manufacturing and maintenance of the SHPB apparatus.
The Theory of Independent-Mindedness: Three Decades of Research on Organizational Communication Effectiveness
Authors: Avtgis Theodore A. , Rancer Andrew S.
Published: January 2023

The purpose of this article is to review over three decades of research supporting the organizational communication management theory known as the Theory of Independent-Mindedness. The theory is especially productive in assessing superior-subordinate communication for organizations located within individualistic cultures. The article synthesizes extant research on the Theory of Independent-Mindedness. The research reviewed in this article provides empirical support for the theory’s premises in that cultural congruity must be present between the macro-culture (larger culture within which the organization operates) and the micro-culture (the culture developed within the specific organization). Several studies clearly indicate that independent-minded employees report being more satisfied and committed to their organization, and advocate communication skills training for organizational members at all levels.
Annual Reports Readability From Linguistic and Communication Perspectives: Systematic Literature Review
Authors: Gutiérrez Ponce Herenia , Chamizo González Julián , Al-Mohareb Manar
Published: January 2023

This research presents a new theoretical framework through assessing readability research based on the linguistics and communication perspectives to determine the obfuscation probabilities and how to mitigate them. Therefore, this systematic literature review analyzed 219 papers using the SCOPUS and Web of Science databases. Findings show that in every language approach, there is an obfuscation level for annual reports, depending on the weakness of a particular component of the text communication process, starting from the use of a complex writing style and ending with the imposition of specific methods of presentation, while suggesting ways to mitigate the obfuscation.
Training and Development in Argumentative and Aggressive Communication: Contributions of Dr. Andrew S. Rancer
Authors: Avtgis Theodore A.
Published: January 2023

This article discusses the work of Professor Andrew S. Rancer and his contributions to theory-building and application efforts of argumentative and aggressive communication. Germinal training efforts in constructive and destructive communication are presented, empirical efficacy and learning outcomes highlighted, and implications for training professionals are discussed. Finally, insights into argumentative and aggressive communication training are offered.
Factor IXa variants resistant to plasma inhibitors enhance clot formation in vivo
Authors: Ivanciu Lacramioara , Arruda Valder R. , Camire Rodney M.
Published: February 2023

Factor IXa (FIXa) plays a pivotal role in coagulation by contributing to FX activation via the intrinsic pathway. Although antithrombin (AT) and other plasma inhibitors are thought to regulate FIXa procoagulant function, the impact of FIXa inhibition on thrombin generation and clot formation in vivo remains unclear. Here, we generated FIXa variants with altered reactivity to plasma inhibitors that target the FIXa active site but maintain procoagulant function when bound to its cofactor, FVIIIa. We found that selected FIXa variants (eg, FIXa-V16L) have a prolonged activity half-life in the plasma due, in part, to AT resistance. Studies using hemophilia B mice have shown that delayed FIXa inhibition has a major impact on reducing the bleeding phenotype and promoting thrombus formation following administration of FIX protein. Overall, these results demonstrate that the regulation of FIXa inhibition contributes in a major way to the spatial and temporal control of coagulation at the site of vascular injury. Our findings provide novel insights into the physiological regulation of FIXa, enhance our understanding of thrombus formation in vivo via the intrinsic pathway, and suggest that altering FIXa inhibition could have therapeutic benefits.
Coronary artery disease in a patient with Addison’s disease: a case report and literature review
Authors: Zhao Ruohan , Luo Suxin , Wang Shuzhen , Wen Yi , Xiong Feng
Published: January 2023

Background

Addison’s disease which is due to dysfunction of the adrenal gland, with abnormal secretion of glucocorticoids and mineralocorticoids, is rare. By inducing inflammation and disorders of water and electrolyte metabolism, Addison’s disease may accelerate progression of co-existed cardiovascular diseases. Addison’s disease combined with cardiovascular disease is infrequent, only 10 cases in the literature.

Case presentation

We reported a 51-year-old male patient with unstable angina pectoris and hypotension. Changes on coronary angiography within 2 years suggested rapid progression of coronary artery disease in a patient with low cardiovascular risk. An additional clue of skin hyperpigmentation, fatigue and further examination confirmed the diagnosis of Addison’s disease caused by adrenal tuberculosis. After hormone replacement treatment, the frequency and severity of the angina pectoris were alleviated significantly, as were hypotension, hyperpigmentation and fatigue.

Conclusions

The combination of Addison’s disease and coronary artery disease in one patient is rare. Addison’s disease can induce inflammation and disorders of water and electrolyte metabolism, which may further accelerate the course of coronary artery disease. Meanwhile, the hypotension in Addison’s disease may affect the coronary blood flow, which may result in an increased susceptibility to unstable angina in the presence of coronary stenosis. So, we should analyze comprehensively if the coronary artery disease progress rapidly.
Empirical evaluation of internal validation methods for prediction in large-scale clinical data with rare-event outcomes: a case study in suicide risk prediction
Authors: Coley R Yates , Liao Qinqing , Simon Noah , Shortreed Susan M.
Published: February 2023

Background

There is increasing interest in clinical prediction models for rare outcomes such as suicide, psychiatric hospitalizations, and opioid overdose. Accurate model validation is needed to guide model selection and decisions about whether and how prediction models should be used. Split-sample estimation and validation of clinical prediction models, in which data are divided into training and testing sets, may reduce predictive accuracy and precision of validation. Using all data for estimation and validation increases sample size for both procedures, but validation must account for overfitting, oroptimism. Our study compared split-sample and entire-sample methods for estimating and validating a suicide prediction model.

Methods

We compared performance of random forest models estimated in a sample of 9,610,318 mental health visits (“entire-sample”) and in a 50% subset (“split-sample”) as evaluated in a prospective validation sample of 3,754,137 visits. We assessed optimism of three internal validation approaches: for the split-sample prediction model, validation in the held-out testing set and, for the entire-sample model, cross-validation and bootstrap optimism correction.

Results

The split-sample and entire-sample prediction models showed similar prospective performance; the area under the curve, AUC, and 95% confidence interval was 0.81 (0.77–0.85) for both. Performance estimates evaluated in the testing set for the split-sample model (AUC = 0.85 [0.82–0.87]) and via cross-validation for the entire-sample model (AUC = 0.83 [0.81–0.85]) accurately reflected prospective performance. Validation of the entire-sample model with bootstrap optimism correction overestimated prospective performance (AUC = 0.88 [0.86–0.89]). Measures of classification accuracy, including sensitivity and positive predictive value at the 99th, 95th, 90th, and 75thpercentiles of the risk score distribution, indicated similar conclusions: bootstrap optimism correction overestimated classification accuracy in the prospective validation set.

Conclusions

While previous literature demonstrated the validity of bootstrap optimism correction for parametric models in small samples, this approach did not accurately validate performance of a rare-event prediction model estimated with random forests in a large clinical dataset. Cross-validation of prediction models estimated with all available data provides accurate independent validation while maximizing sample size.
Characterisation of tumour-immune phenotypes and PD-L1 positivity in squamous bladder cancer
Authors: Jung Max , Rose Michael , Knuechel Ruth , Loeffler Chiara , Muti Hannah , Kather Jakob Nikolas , Gaisa Nadine T. ,   on behalf of the German Study Group of Bladder Cancer (DFBK e.V.)
Published: February 2023

Aims

Immune checkpoint inhibitor (ICI) therapy has become a viable treatment strategy in bladder cancer. However, treatment responses vary, and improved biomarkers are needed. Crucially, the characteristics of immune cells remain understudied especially in squamous differentiated bladder cancer (sq-BLCA). Here, we quantitatively analysed the tumour-immune phenotypes of sq-BLCA and correlated them with PD-L1 expression and FGFR3 mutation status.

Methods

Tissue microarrays (TMA) of n = 68 non-schistosomiasis associated pure squamous cell carcinoma (SCC) and n = 46 mixed urothelial carcinoma with squamous differentiation (MIX) were subjected to immunohistochemistry for CD3, CD4, CD8, CD56, CD68, CD79A, CD163, Ki67, perforin and chloroacetate esterase staining. Quantitative image evaluation was performed via digital image analysis.

Results

Immune infiltration was generally higher in stroma than in tumour regions. B-cells (CD79A) were almost exclusively found in stromal areas (sTILs), T-lymphocytes and macrophages were also present in tumour cell areas (iTILs), while natural killer cells (CD56) were nearly missing in any area. Tumour-immune phenotype distribution differed depending on the immune cell subset, however, hot tumour-immune phenotypes (high density of immune cells in tumour areas) were frequently found for CD8 + T-cells (33%), especially perforin + lymphocytes (52.2%), and CD68 + macrophages (37.6%). Perforin + CD8 lymphocytes predicted improved overall survival in sq-BLCA while high PD-L1 expression (CPS ≥ 10) was significantly associated with higher CD3 + , CD8 + and CD163 + immune cell density and high Ki67 (density) of tumour cells. Furthermore, PD-L1 expression was positively associated with CD3 + /CD4 + , CD3 + /CD8 + and CD68 + /CD163 + hot tumour-immune phenotypes. FGFR3 mutation status was inversely associated with CD8 + , perforin + and CD79A + lymphocyte density.

Conclusions

Computer-based image analysis is an efficient tool to analyse immune topographies in squamous bladder cancer. Hot tumour-immune phenotypes with strong PD-L1 expression might pose a promising subgroup for clinically successful ICI therapy in squamous bladder cancer and warrant further investigation.
Physical activity and psychological adjustment among retirees: a systematic review
Authors: Sharifi Mehdi , Nodehi Davud , Bazgir Behzad
Published: January 2023

Background

Health-related behaviors may change after retirement and induce changes in the mental health. This systematic review aimed to investigate the nature of changes in physical activity and leisure activities, as well as the relationship between physical activity, leisure, and psychological adjustment among retirees.

Methods

Search of papers was done in three electronic databases of PubMed, ISI Web of Science, and Scopus without constraints on time, geographical regions, or languages in February 2022. The papers that had examined the relationship between physical activity and adjustment among retirees using observational design (cross-sectional or longitudinal) were included in the present study. To evaluate the methodological quality of cross-sectional studies, Joanna Briggs Institute (JBI) Critical Appraisal Checklist, and for longitudinal studies, Newcastle-Ottawa Scale (NOS) were used.

Results

The search results identified 1458 records. Twenty-six papers were included in this review based on the inclusion and exclusion criteria. The findings of most of these studies indicated a significant positive correlation between physical activity, leisure, and psychological adjustment in retirees. Retirees were mostly engaged in passive leisure activities such as reading, watching TV and movies, and less engaged in physical activities, sport, or physical exercise. General organized assessment of the total physical activity among retirees was not possible.

Conclusions

Based on the study findings, it can be stated that there is a positive correlation between physical activity, leisure, and the retirees’ adjustment. Usage of the same and valid measurement method specific to old age and retirement period can be useful in more precise assessment of physical activity and its association with adjustment among retirees.
A decade of child pedestrian safety in England: a bayesian spatio-temporal analysis
Authors: Shoari Niloofar , Heydari Shahram , Blangiardo Marta
Published: February 2023

Background

Child pedestrian injury is a public health and health equality challenge worldwide, including in high-income countries. However, child pedestrian safety is less-understood, especially over long time spans. The intent of this study is to understand factors affecting child pedestrian safety in England over the period 2011–2020.

Methods

We conducted an area-level study using a Bayesian space-time interaction model to understand the association between the number of road crashes involving child pedestrians in English Local Authorities and a host of socio-economic, transport-related and built-environment variables. We investigated spatio-temporal trends in child pedestrian safety in England over the study period and identified high-crash local authorities.

Results

We found that child pedestrian crash frequencies increase as child population, unemployment-related claimants, road density, and the number of schools increase. Nevertheless, as the number of licensed vehicles per capita and zonal-level walking/cycling increase, child pedestrian safety increases. Generally, child pedestrian safety has improved in England since 2011. However, the socio-economic inequality gap in child pedestrian safety has not narrowed down. In addition, we found that after adjusting for the effect of covariates, the rate of decline in crashes varies between local authorities. The presence of localised risk factors/mitigation measures contributes to variation in the spatio-temporal patterns of child pedestrian safety.

Conclusions

Overall, southern England has experienced more improvement in child pedestrian safety over the last decade than the northern regions. Our study revealed socio-economic inequality in child pedestrian safety in England. To better inform safety and public health policy, our findings support the importance of a targeted system approach, considering the identification of high-crash areas while keeping track of how child pedestrian safety evolves over time.
Impact of pre-pandemic sick leave diagnoses on the length of COVID-19-related sick leave: a nationwide registry-based study
Authors: Abzhandadze Tamar , Westerlind Emma , Persson Hanna C.
Published: January 2023

Background

The COVID-19 pandemic has caused difficulties and changes in many aspects of people’s health and lives. Although infection affected work capacity, during the first wave policies for sick leave due to COVID-19 were unclear. The aim of this study was to investigate the impact of sick leave diagnoses in the year before the COVID-19 diagnosis  on sick leave duration due to COVID-19 in a nationwide non-hospitalised population.

Methods

Data from three Swedish registries were analysed for sick leave commencing between 1 March and 31 August 2020, with a follow-up period of 4 months. Sick leave due to COVID-19 was considered the number of days that sickness benefits were used and included at least one registered COVID-19 diagnosis. Sick leave in the year before COVID-19 diagnosis were categorised into five diagnostic groups and one reference group (participants without prior sick leave).

Results

The study comprised 8935 individuals who received sickness benefits due to COVID-19 in Sweden during the first pandemic wave (mean age 46.7 years, 67% females, and 24% had diagnoses for sick leave in the year before COVID-19 diagnosis). The duration of sick leave due to COVID-19 was significantly higher in the groups with prior sick leave owing to musculoskeletal system diseases (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.01–1.15); respiratory system diseases (OR: 1.22, 95% CI: 1.14–1.31); all other isolated diagnoses (OR: 1.08, 95% CI: 1.03–1.14); and multiple diagnoses (OR: 1.32, 95% CI: 1.21–1.43).

Conclusions

The results of this nationwide registry-based study indicate that individuals with premorbid conditions are more prone to longer sick leave durations due to COVID-19. Prediction of sick leave duration during the first wave of the COVID-19 pandemic is complex and several factors played a role.
In vitro evaluation of dental color stability using various aesthetic restorative materials after immersion in different drinks
Authors: Faris Tavga Mustafa , Abdulrahim Rukhosh Hasan , Mahmood Mohammed Abdalla , Mhammed Dalloo Gollshang Ahmad , Gul Sarhang Sarwat
Published: January 2023

Background

Currently, the demands for restorations have increased considerably; thus, improvements and modifications have been made in dental composite technologies especially using materials that have been claimed to improve color stability.

Objective

This study aimed to determine the effect of various solutions on the color stability of different restorative materials in vitro study.

Methods

This study used three types of esthetic restorative materials. The samples comprised 45 discs, including 15 micro-hybrids, 15 nano-hybrids, and 15 glass ionomers). These discs were immersed in various beverages an hour a day for one month at room temperature. The color stability was measured using a spectrophotometer before/after immersion (days 7 and 30).

Results

We realized a significant difference in color change with Coca-Cola and tea-milk solution after seven days and 30 days (p < 0.05). However, no significant difference was found in the samples immersed in DM after seven days and 30 days (p > 0.05). The highest value of lightness (∆L) and stainability (∆a) was seen in micro-hybrid after 30 days of immersion in tea-milk solution (− 12.16 ± 1.74 and 11.4 ± 3.82, respectively), while most samples had a positive ∆b value.

Conclusion

After one month, the tea-milk solution affected the color stability of all used restorative materials. In addition, micro-hybrid had higher color stability than nano-hybrid and glass ionomer.
Intimate partner violence and associated factors among HIV positive women attending antiretroviral therapy clinics in Gondar city, Northwest Ethiopia
Authors: Alemie Amsal Seraw , Yeshita Hedija Yenus , Zeleke Ejigu Gebeye , Mekonnen Birye Dessalegn
Published: February 2023

Introduction

Intimate partner violence against women is a behavior within an intimate relationship that causes sexual, physical, or psychological harm to the women. It occurs among all socioeconomic, religious, and cultural groups in all settings, and affects the health of women, families, and the community at large. Determining the magnitude and determinants of intimate partner violence against HIV positive women could help to design preventive and control strategies. However, there is a dearth of information regarding the magnitude and determinants of intimate partner violence against HIV positive women in Ethiopia. Thus, this study aimed to assess the magnitude and associated factors of intimate partner violence against HIV positive women in Gondar city, Northwest Ethiopia.

Method

A facility-based cross-sectional study was carried out from February to May 2021 in selected public health facilities of Gondar city among 626 HIV positive women. A systematic random sampling technique was used to select study participants. Data were analyzed using Statistical Package of Social Science (SPSS) version 20 software. Bivariable and Multivariable logistic regression models were done. Adjusted odds ratio (AOR) with a 95% confidence interval (CI) was used to identify determinants of intimate partner violence. Statistical significance was considered at a p value < 0.05.

Results

The overall prevalence of intimate partner violence against HIV positive women within the last 12 months was 64.2% (95% CI 60.4, 68.2). Physical violence was the most common type (54.8%), followed by sexual (51.1%) and emotional (48.9%) violence. Intimate partner violence among HIV positive women was associated with women’s age 19–24 (AOR = 0.13, 95% CI 0.02, 0.79), monthly income of 500–2500 (AOR = 6.5, 95% CI 1.72, 25.0), urban residence (AOR = 0.35, 95% CI 0.13, 0.91), partner drink alcohol (AOR = 2.14, 95% CI 1.42, 4.06), and a husband with no multiple sexual partners (AOR = 0.75, 95% CI 0.34, 0.94).

Conclusion

The result of this study revealed that intimate partner violence against HIV positive women was found to be high. Thus, protective measures that could increase the community’s and women’s awareness about the consequences of various forms of violence, and women empowerment are paramount. Priorities in programs of gender-based violence prevention should involve women from rural residences, older age, and males who consume alcohol.
Platelet P2Y1 receptor exhibits constitutive G protein signaling and β-arrestin 2 recruitment
Authors: Ribes Agnès , Garcia Cédric , Gratacap Marie-Pierre , Kostenis Evi , Martinez Laurent O. , Payrastre Bernard , Sénard Jean-Michel , Galés Céline , Pons Véronique
Published: February 2023

Background

Purinergic P2Y1 and P2Y12 receptors (P2Y1-R and P2Y12-R) are G protein-coupled receptors (GPCR) activated by adenosine diphosphate (ADP) to mediate platelet activation, thereby playing a pivotal role in hemostasis and thrombosis. While P2Y12-R is the major target of antiplatelet drugs, no P2Y1-R antagonist has yet been developed for clinical use. However, accumulating data suggest that P2Y1-R inhibition would ensure efficient platelet inhibition with minimal effects on bleeding. In this context, an accurate characterization of P2Y1-R antagonists constitutes an important preliminary step.

Results

Here, we investigated the pharmacology of P2Y1-R signaling through Gq and β-arrestin pathways in HEK293T cells and in mouse and human platelets using highly sensitive resonance energy transfer-based technologies (BRET/HTRF). We demonstrated that at basal state, in the absence of agonist ligand, P2Y1-R activates Gq protein signaling in HEK293T cells and in mouse and human platelets, indicating that P2Y1-R is constitutively active in physiological conditions. We showed that P2Y1-R also promotes constitutive recruitment of β-arrestin 2 in HEK293T cells. Moreover, the P2Y1-R antagonists MRS2179, MRS2279 and MRS2500 abolished the receptor dependent-constitutive activation, thus behaving as inverse agonists.

Conclusions

This study sheds new light on P2Y1-R pharmacology, highlighting for the first time the existence of a constitutively active P2Y1-R population in human platelets. Given the recent interest of P2Y12-R constitutive activity in patients with diabetes, this study suggests that modification of constitutive P2Y1-R signaling might be involved in pathological conditions, including bleeding syndrome or high susceptibility to thrombotic risk. Thus, targeting platelet P2Y1-R constitutive activation might be a promising and powerful strategy for future antiplatelet therapy.
PMCA inhibition reverses drug resistance in clinically refractory cancer patient-derived models
Authors: Park Ki Cheong , Kim Jung Min , Kim Sang Yong , Kim Seok-Mo , Lim Jin Hong , Kim Min Ki , Fang Sungsoon , Kim Yonjung , Mills Gordon B. , Noh Sung Hoon , Cheong Jae-Ho
Published: February 2023

Background

Cancer cells have developed molecular strategies to cope with evolutionary stressors in the dynamic tumor microenvironment. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) is a metabolic rheostat that regulates diverse cellular adaptive behaviors, including growth and survival. However, the mechanistic role of PGC1α in regulating cancer cell viability under metabolic and genotoxic stress remains elusive.

Methods

We investigated the PGC1α-mediated survival mechanisms in metabolic stress (i.e., glucose deprivation-induced metabolic stress condition)-resistant cancer cells. We established glucose deprivation-induced metabolic stress-resistant cells (selected cells) from parental tumor cells and silenced or overexpressed PGC1α in selected and parental tumor cells.

Results

Several in vitro and in vivo mouse experiments were conducted to elucidate the contribution of PGC1α to cell viability in metabolic stress conditions. Interestingly, in the mouse xenograft model of patient-derived drug-resistant cancer cells, each group treated with an anti-cancer drug alone showed no drastic effects, whereas a group that was co-administered an anti-cancer drug and a specific PMCA inhibitor (caloxin or candidate 13) showed marked tumor shrinkage.

Conclusions

Our results suggest that PGC1α is a key regulator of anti-apoptosis in metabolic and genotoxic stress-resistant cells, inducing PMCA expression and allowing survival in glucose-deprived conditions. We have discovered a novel therapeutic target candidate that could be employed for the treatment of patients with refractory cancers.
Risk factors and molecular epidemiology of fecal carriage of carbapenem resistant Enterobacteriaceae in patients with liver disease
Authors: Tian Fangbing , Li Yin , Wang Yue , Yu Bing , Song Jianxin , Ning Qin , Jian Cui , Ni Ming
Published: January 2023

Background

Carbapenem resistant Enterobacteriaceae (CRE) colonization is a risk factor for CRE infection. CRE infection results in an increase in mortality in patients with cirrhosis. However, minimal data regarding the prevalence and the risk factors of CRE colonization in patients with liver disease yet without liver transplantation are available. The present study aimed to investigate the prevalence, risk factors and molecular epidemiology characteristics of CRE fecal carriage among patients with liver disease.

Methods

Stool specimens from 574 adult inpatients with liver disease were collected from December 2020 to April 2021. CRE were screened using selective chromogenic agar medium and identified by the Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS). Antimicrobial susceptibility was determined using the broth microdilution method. Carbapenemase genes were characterized by polymerase chain reaction (PCR) and DNA sequencing. Multilocus sequence typing (MLST) was performed for Carbapenem Resistant Klebsiella pneumoniae (CR-KPN) isolates and Carbapenem Resistant Escherichia Coli (CR-ECO) isolates.

Results

The total number of stool specimens (732) were collected from 574 patients with liver disease. 43 non-duplicated CRE strains were isolated from 39 patients with a carriage rate of 6.79% (39/574). The carriage rate was 15.60% (17/109) in patients with acute-on-chronic liver failure (ACLF). Multivariate analysis indicated that ACLF (P = 0.018), the history of pulmonary infection within past 3 months (P = 0.001) and the use of third generation cephalosporin/β-lactamases inhibitor within past 3 months (P = 0.000) were independent risk factors of CRE colonization in patients with liver disease. Klebsiella Pnuemoniae (KPN) (51.28%) and Escherichia coli (ECO) (30.77%) were main strains in these patients. All CRE strains showed high resistance to most antimicrobials except for polymyxin B and tigecycline. Most (83.72%, 36/43) of the CRE carried carbapenemase genes. blaKPC-2 was the major carbapenemase gene. The molecular epidemiology of KPN were dominated by ST11, while the STs of ECO were scattered.

Conclusions

The present study revealed that CRE fecal carriage rates were higher in patients with ACLF than in patients without liver failure. ACLF, the history of pulmonary infection within past 3 months and the use of third generation cephalosporin/β-lactamases inhibitor within past 3 months were independent risk factors of CRE colonization in patients with liver disease. Regular CRE screening for hospitalized patients with liver disease should be conducted to limit the spread of CRE strain.
Spatiotemporal evolution of COVID-19 in Portugal’s Mainland with self-organizing maps
Authors: Duarte Igor , Ribeiro Manuel C. , Pereira Maria João , Leite Pedro Pinto , Peralta-Santos André , Azevedo Leonardo
Published: January 2023

Background

Self-Organizing Maps (SOM) are an unsupervised learning clustering and dimensionality reduction algorithm capable of mapping an initial complex high-dimensional data set into a low-dimensional domain, such as a two-dimensional grid of neurons. In the reduced space, the original complex patterns and their interactions can be better visualized, interpreted and understood.

Methods

We use SOM to simultaneously couple the spatial and temporal domains of the COVID-19 evolution in the 278 municipalities of mainland Portugal during the first year of the pandemic. Temporal 14-days cumulative incidence time series along with socio-economic and demographic indicators per municipality were analyzed with SOM to identify regions of the country with similar behavior and infer the possible common origins of the incidence evolution.

Results

The results show how neighbor municipalities tend to share a similar behavior of the disease, revealing the strong spatiotemporal relationship of the COVID-19 spreading beyond the administrative borders of each municipality. Additionally, we demonstrate how local socio-economic and demographic characteristics evolved as determinants of COVID-19 transmission, during the 1st wave school density per municipality was more relevant, where during 2nd wave jobs in the secondary sector and the deprivation score were more relevant.

Conclusions

The results show that SOM can be an effective tool to analysing the spatiotemporal behavior of COVID-19 and synthetize the history of the disease in mainland Portugal during the period in analysis. While SOM have been applied to diverse scientific fields, the application of SOM to study the spatiotemporal evolution of COVID-19 is still limited. This work illustrates how SOM can be used to describe the spatiotemporal behavior of epidemic events. While the example shown herein uses 14-days cumulative incidence curves, the same analysis can be performed using other relevant data such as mortality data, vaccination rates or even infection rates of other disease of infectious nature.
Facile synthesis of multi-faceted, biomimetic and cross-protective nanoparticle-based vaccines for drug-resistant Shigella: a flexible platform technology
Authors: Baruah Namrata , Ahamad Nadim , Halder Prolay , Koley Hemanta , Katti Dhirendra S.
Published: January 2023

Background

No commercial vaccines are available against drug-resistant Shigella due to serotype-specific/narrow-range of protection. Nanoparticle-based biomimetic vaccines involving stable, conserved, immunogenic proteins fabricated using facile chemistries can help formulate a translatable cross-protective Shigella vaccine. Such systems can also negate cold-chain transportation/storage thus overcoming challenges prevalent in various settings.

Methods

We explored facile development of biomimetic poly (lactide-co-glycolide)/PLGA 50:50 based nanovaccines (NVs), encapsulating conserved stabilized antigen(s)/immunostimulant of S. dysenteriae 1 origin surface-modified using simple chemistries. All encapsulants (IpaC/IpaB/LPS) and nanoparticles (NPs)—bare and modified (NV), were thoroughly characterized. Effect of IpaC on cellular uptake of NPs was assessed in-vitro. Immunogenicity of the NVs was assessed in-vivo in BALB/c mice by intranasal immunization. Cross-protective efficacy was assessed by intraperitoneally challenging the immunized groups with a high dose of heterologous S. flexneri 2a and observing for visible diarrhea, weight loss and survival. Passive-protective ability of the simplest NV was assessed in the 5-day old progeny of vaccinated mice.

Results

All the antigens and immunostimulant to be encapsulated were successfully purified and found to be stable both before and after encapsulation into NPs. The ~ 300 nm sized NPs with a zeta potential of ~ − 25 mV released ~ 60% antigen by 14th day suggesting an appropriate delivery kinetics. The NPs could be successfully surface-modified with IpaC and/or CpG DNA. In vitro experiments revealed that the presence of IpaC can significantly increase cellular uptake of NPs. All NVs were found to be cytocompatible and highly immunogenic. Antibodies in sera of NV-immunized mice could recognize heterologous Shigella. Immunized sera also showed high antibody and cytokine response. The immunized groups were protected from diarrhea and weight loss with ~ 70–80% survival upon heterologous Shigella challenge. The simplest NV showed ~ 88% survival in neonates.

Conclusions

Facile formulation of biomimetic NVs can result in significant cross-protection. Further, passive protection in neonates suggest that parental immunization could protect infants, the most vulnerable group in context of Shigella infection. Non-invasive route of vaccination can also lead to greater patient compliance making it amenable for mass-immunization. Overall, our work contributes towards a yet to be reported platform technology for facile development of cross-protective Shigella vaccines.

Graphical Abstract
Targeting epigenetic features in clear cell sarcomas based on patient-derived cell lines
Authors: Karner Christina , Anders Ines , Vejzovic Djenana , Szkandera Joanna , Scheipl Susanne , Deutsch Alexander J. A. , Weiss Larissa , Vierlinger Klemens , Kolb Dagmar , Kühberger Stefan , Heitzer Ellen , Habisch Hansjörg , Zhang Fangrong , Madl Tobias , Reininger-Gutmann Birgit , Liegl-Atzwanger Bernadette , Rinner Beate
Published: January 2023

Background

Clear cell sarcomas (CCSs) are translocated aggressive malignancies, most commonly affecting young adults with a high incidence of metastases and a poor prognosis. Research into the disease is more feasible when adequate models are available. By establishing CCS cell lines from a primary and metastatic lesion and isolating healthy fibroblasts from the same patient, the in vivo process is accurately reflected and aspects of clinical multistep carcinogenesis recapitulated.

Methods

Isolated tumor cells and normal healthy skin fibroblasts from the same patient were compared in terms of growth behavior and morphological characteristics using light and electron microscopy. Tumorigenicity potential was determined by soft agar colony formation assay and in vivo xenograft applications. While genetic differences between the two lineages were examined by copy number alternation profiles, nuclear magnetic resonance spectroscopy determined arginine methylation as epigenetic features. Potential anti-tumor effects of a protein arginine n-methyltransferase type I (PRMT1) inhibitor were elicited in 2D and 3D cell culture experiments using cell viability and apoptosis assays. Statistical significance was calculated by one-way ANOVA and unpaired t-test.

Results

The two established CCS cell lines named MUG Lucifer prim and MUG Lucifer met showed differences in morphology, genetic and epigenetic data, reflecting the respective original tissue. The detailed cell line characterization especially in regards to the epigenetic domain allows investigation of new innovative therapies. Based on the epigenetic data, a PRMT1 inhibitor was used to demonstrate the targeted antitumor effect; normal tissue cells isolated and immortalized from the same patient were not affected with the IC50 used.

Conclusions

MUG Lucifer prim, MUG Lucifer met and isolated and immortalized fibroblasts from the same patient represent an ideal in vitro model to explore the biology of CCS. Based on this cell culture model, novel therapies could be tested in the form of PRMT1 inhibitors, which drive tumor cells into apoptosis, but show no effect on fibroblasts, further supporting their potential as promising treatment options in the combat against CCS. The data substantiate the importance of tailored therapies in the advanced metastatic stage of CCS.
G2 checkpoint targeting via Wee1 inhibition radiosensitizes EGFRvIII-positive glioblastoma cells
Authors: Cetin Meryem H. , Rieckmann Thorsten , Hoffer Konstantin , Riepen Britta , Christiansen Sabrina , Gatzemeier Fruzsina , Feyerabend Simon , Schoof Melanie , Schüller Ulrich , Petersen Cordula , Mynarek Martin , Rothkamm Kai , Kriegs Malte , Struve Nina
Published: January 2023

Background

The gene of the Epidermal growth factor receptor (EGFR) is one of the most frequently altered genes in glioblastoma (GBM), with deletions of exons 2–7 (EGFRvIII) being amongst the most common genomic mutations. EGFRvIII is heterogeneously expressed in GBM. We already showed that EGFRvIII expression has an impact on chemosensitivity, replication stress, and the DNA damage response. Wee1 kinase is a major regulator of the DNA damage induced G2 checkpoint. It is highly expressed in GBM and its overexpression is associated with poor prognosis. Since Wee1 inhibition can lead to radiosensitization of EGFRvIII-negative (EGFRvIII−) GBM cells, we asked, if Wee1 inhibition is sufficient to radiosensitize also EGFRvIII-positive (EGFRvIII+) GBM cells.

Methods

We used the clinically relevant Wee1 inhibitor adavosertib and two pairs of isogenetic GBM cell lines with and without endogenous EGFRvIII expression exhibiting different TP53 status. Moreover, human GBM samples displaying heterogenous EGFRvIII expression were analyzed. Expression of Wee1 was assessed by Western blot and respectively immunohistochemistry. The impact of Wee1 inhibition in combination with irradiation on cell cycle and cell survival was analyzed by flow cytometry and colony formation assay.

Results

Analysis of GBM cells and patient samples revealed a higher expression of Wee1 in EGFRvIII+ cells compared to their EGFRvIII− counterparts. Downregulation of EGFRvIII expression by siRNA resulted in a strong decrease in Wee1 expression. Wee1 inhibition efficiently abrogated radiation-induced G2-arrest and caused radiosensitization, without obvious differences between EGFRvIII− and EGFRvIII+ GBM cells.

Conclusion

We conclude that the inhibition of Wee1 is an effective targeting approach for the radiosensitization of both EGFRvIII− and EGFRvIII+ GBM cells and may therefore represent a promising new therapeutic option to increase response to radiotherapy.
Effect of intubation in the lateral position under general anesthesia induction on the position of double-lumen tube placement in patients undergoing unilateral video-assisted thoracic surgery: study protocol for a prospective, single-center, parallel group, randomized, controlled trial
Authors: Zhang Xi , Wang Dong-Xu , Zhang Qin , Shen Qi-Bin , Tong Fei , Hu Yong-He , Zhang Zhen-Duo , Liu Fei-Fan , Tang Ya-Wen , Chen Juan-Li , Liu He , Zhou Feng , Hu Si-Ping
Published: January 2023

Background

The double-lumen tube (DLT) is an essential equipment for thoracic anesthesia and the precise position of DLT placement is particularly important for anesthesia and surgery. However, the incidence of DLT malposition remains high and it leads to lung isolation failure and hypoxemia during one-lung ventilation. This trial aims to explore the clinical application and efficacy of intubation in the lateral position under general anesthesia induction to reduce the incidence of DLT malposition in patients undergoing unilateral video-assisted thoracic surgery (VATS).

Methods

In this prospective, single-center, parallel group, randomized, controlled trial, we will recruit 108 patients, aged 18–80 years, scheduled for elective unilateral VATS with DLT intubation under general anesthesia, and they will be randomly assigned to two groups: a lateral DLT intubation group (group L) and a conventional supine DLT intubation group (group C). The left-sided DLT will be used to intubate in patients of both groups. The position of DLT will be confirmed and adjusted by using the fiberoptic bronchoscopy (FOB). The primary outcome is the incidence of DLT malposition observed via the FOB, and the secondary outcomes include the time of intubation, the frequency and duration of re-adjustments of DLT placement under FOB, whether to re-intubate, intraoperative vital signs, and postoperative recovery.

Discussion

Accurate DLT positioning is crucially important for thoracic surgery, but the incidence of DLT malposition is still high in the present clinical practice of thoracic anesthesia. This trial aims to investigate whether lateral DLT intubation can reduce the incidence of DLT malposition, with more stable intraoperative vital signs and less postoperative complications.

Trial registration

The study protocol was registered at Chinese Clinical Trial Registry (http://www.chictr.org.cn) with registration number: ChiCTR2200060794 on June 11, 2022.
Low immunoglobulin levels affect the course of COPD in hospitalized patients
Authors: Palikhe Nami Shrestha , Niven Malcena , Fuhr Desi , Sinnatamby Tristan , Rowe Brian H. , Bhutani Mohit , Stickland Michael K. , Vliagoftis Harissios
Published: January 2023

Background

Chronic obstructive pulmonary disease (COPD) affects up to 10% of Canadians. Patients with COPD may present with secondary humoral immunodeficiency as a result of chronic disease, poor nutrition or frequent courses of oral corticosteroids; decreased humoral immunity may predispose these patients to mucosal infections. We hypothesized that decreased serum immunoglobulin (Ig) levels was associated with the severity of an acute COPD exacerbations (AECOPD).

Methods

A prospective study to examine cardiovascular risks in patients hospitalized for AECOPD, recruited patients on the day of hospital admission and collected data on length of hospital stay at index admission, subsequent emergency department visits and hospital readmissions. Immunoglobulin levels were measured in serum collected prospectively at recruitment.

Results

Among the 51 patients recruited during an admission for AECOPD, 14 (27.5%) had low IgG, 1 (2.0%) low IgA and 16 (31.4%) low IgM; in total, 24 (47.1%) had at least one immunoglobulin below the normal range. Patients with low IgM had longer hospital stay during the index admission compared to patients with normal IgM levels (6.0 vs. 3.0 days, p = 0.003), but no difference in other clinical outcomes. In the whole cohort, there was a negative correlation between serum IgM levels and length of hospital stay (R = − 0.317, p = 0.024). There was no difference in clinical outcomes between subjects with normal and low IgG levels.

Conclusion

In patients presenting with AECOPD, low IgM is associated with longer hospital stay and may indicate a patient phenotype that would benefit from efforts to prevent respiratory infections.

Trial registration statement: Retrospectively registered.
Simulation-based education to improve management of refractory anaphylaxis in an allergy clinic
Authors: Copaescu Ana M. , Graham Francois , Nadon Nathalie , Gagnon Rémi , Robitaille Arnaud , Badawy Mohamed , Claveau David , Roches Anne Des , Paradis Jean , Vincent Matthieu , Bégin Philippe
Published: January 2023

Background

High-fidelity simulations based on real-life clinical scenarios have frequently been used to improve patient care, knowledge and teamwork in the acute care setting. Still, they are seldom included in the allergy-immunology curriculum or continuous medical education. Our main goal was to assess if critical care simulations in allergy improved performance in the clinical setting.

Methods

Advanced anaphylaxis scenarios were designed by a panel of emergency, intensive care unit, anesthesiology and allergy-immunology specialists and then adapted for the adult allergy clinic setting. This simulation activity included a first part in the high-fidelity simulation-training laboratory and a second at the adult allergy clinic involving actors and a high-fidelity mannequin. Participants filled out a questionnaire, and qualitative interviews were performed with staff after they had managed cases of refractory anaphylaxis.

Results

Four nurses, seven allergy-immunology fellows and six allergy/immunologists underwent the simulation. Questionnaires showed a perceived improvement in aspects of crisis and anaphylaxis management. The in-situ simulation revealed gaps in the process, which were subsequently resolved. Qualitative interviews with participants revealed a more rapid and orderly response and improved confidence in their abilities and that of their colleagues to manage anaphylaxis.

Conclusion

High-fidelity simulations can improve the management of anaphylaxis in the allergy clinic and team confidence. This activity was instrumental in reducing staff reluctance to perform high-risk challenges in the ambulatory setting, thus lifting a critical barrier for implementing oral immunotherapy at our adult center.