bluuebunny/crossref_metadata_2025 huggingface dataset:
ON THE PHYSICAL REPRESENTATION OF QUANTUM SYSTEMS
Authors:   Planalto Research, Mountain View, CA, USA, GERCK Edgardo
Published: May 2022

The Schrödinger equation for bound states depends on a second derivative, that only exists if the solution is continuous, which is - by itself - contradictory, and cannot be digitally calculated. Photons can be created in-phase by stimulated emission or annihilated by spontaneous absorption, and break the LEM, more likely at lower frequencies, and even in vacuum. Thus, the number of particles is not conserved, e.g., in the double-slit experiment, even at low-light intensity. Physical representations of quantum computation (QC), cannot, thus, follow some customarily assumed aspects of quantum mechanics. This is solved by considering the Schrödinger equation depending on the curvature, which is expressed exactly as a difference equation, works for any wavelength, and is variationally solved for natural numbers, representing naturally the quantum energy levels. This leads to accepting both forms in a universality model. Further, one follows the Bohr model in QC, in a software-defined QC, where GF(2m) can be used with binary logic to implement in software Bohr’s idea of “many states at once”, without breaking the LEM, in the macro, without necessarily using special hardware (e.g. quantum annealing), or incurring in decoherence, designed with today’s binary computers, even a cell phone.
EFFICIENCY DETERMINATION PROBLEMS FOR SIC*/SI MICROSTRUCTURES AND CONTACT FORMATION
Authors:   Samara National Research University named after Academician S.P. Korolev, Samara, Russian Federation, CHEPURNOV VIKTOR , RAJAPOV SALI , DOLGOPOLOV MIKHAIL , PUZYRNAYA GALINA , GURSKAYA ALBINA
Published: May 2022

The paper discusses the efficiency of converting radionuclide energy into electrical energy inside a semiconductor structure in the context of the betavoltaic application. In the molecular composition of Silicon Carbide semiconductor structures, Carbon-14 atoms functionally serve as the source of radiochemical decay energy, and the conductivity component of the n- or p-type semiconductor structure is able to directly convert this energy into electrical form. The proposed version of the beta-converter based on the C-14 radionuclide has a worldwide novelty, since this radionuclide is used in the concentration at the level of an alloying impurity that replaces the stable Carbon-12 atoms in the Silicon Carbide molecule. The presence in small quantities, one atom of the radioisotope C-14 per thousand or even a million atoms of the stable radioisotope C-12, gives the semiconductor material new energy-useful properties. The manifestations of the betavoltaic effect when replacing Silicon Carbide C-12 with radionuclide C-14 in a molecule determine the efficiency and choice of the contact formation options for practical use of charge generation in Silicon Carbide heterostructures.
Role of Gut Microbiota in Pulmonary Arterial Hypertension
Authors: Wu Panyun , Zhu Tengteng , Tan Zhen , Chen Shenglan , Fang Zhenfei
Published: May 2022

Gut microbiota and its metabolites play an important role in maintaining host homeostasis. Pulmonary arterial hypertension (PAH) is a malignant clinical syndrome with a frightening mortality. Pulmonary vascular remodeling is an important feature of PAH, and its pathogenesis is not well established. With the progress of studies on intestinal microbes in different disease, cumulative evidence indicates that gut microbiota plays a major role in PAH pathophysiology. In this review, we will systematically summarize translational and preclinical data on the correlation between gut dysbiosis and PAH and investigate the role of gut dysbiosis in the causation of PAH. Then, we point out the potential significance of gut dysbiosis in the diagnosis and treatment of PAH as well as several problems that remain to be resolved in the field of gut dysbiosis and PAH. All of this knowledge of gut microbiome might pave the way for the extension of novel pathophysiological mechanisms, diagnosis, and targeted therapies for PAH.
Stakeholders' Perceptions of the Outcomes of Translocated Eland in Nyae Nyae Conservancy, Namibia
Authors: Lendelvo Selma , Suich Helen , Mfune John K. E.
Published: May 2022

Translocation of wildlife species from one area to another is a conservation tool that contributes to the restoration of depleted populations, augments declining populations, or establishes of new populations. This paper documents one of the first studies examining in detail stakeholders' perceptions of the factors influencing the outcomes of translocations of wildlife into a community conservation area, using the case of eland (Taurotragus oryx) translocations into the Nyae Nyae Conservancy in Namibia. The translocations took place between 2000 and 2005 as part of the national community-based natural resource management programme and were monitored through annual waterpoint counts. These data on perceptions were collected through a household survey and focused group discussions involving community members and leaders and key informant interviews with external stakeholders. Community members' perceptions could not confirm that the translocated eland decreased or increased, however, reflected that eland individuals moved away from the release site soon after translocation to more distant locations further away from human settlements. The outcomes of the translocations were perceived to be most strongly associated with anthropogenic factors compared to habitat or environmental factors. However, stakeholders exhibited divergent perceptions regarding which of the anthropogenic factors was of most importance, particularly with respect to the roles of the different types of hunting, and to a lesser degree, the role of traditional burning of landscapes on translocation outcomes. The paper illustrates the complexities associated with translocations of wildlife into community conservation areas compared to state protected areas, given the strong influence of human disturbances on translocation success. It highlights the importance of understanding the social factors influencing how and why translocated individuals may adapt well or poorly to their new environment. Building this understanding is essential to improving the outcomes of similar translocations in the future.
ECG-Based Techniques to Optimize Peripherally Inserted Central Catheters: Rationale for Tip Positioning and Practical Use
Authors: Gullo Giuseppe , Qanadli Salah D.
Published: May 2022

Intracavitary electrocardiography is an accurate guidance technique for peripherally inserted central catheters (PICC) tip location that is spreading widely among providers using non x-ray-based facilities. The principle behind this technology relies on the transmission of the electrocardiographic signal at the tip of the catheter and its use as an internal mobile electrode, allowing the system to identify the cavo-atrial junction (CAJ) through internal P-wave amplitude modulations. The gain in popularity of intracavitary electrography and its large diffusion have led manufacturers to offer various devices with heterogeneous properties, among which clinician who place PICCs have to choose. It is therefore important to understand differences between available techniques and devices. The potential impact might not only affect availability and costs but also the clinical impact through advantages and limitations regarding electric signal transmission PICC selection. Current perspectives on intracavitary electrocardiography will also be discussed, to give the reader a global view of the management of electrocardiographically guided PICCs, especially in an environment without x-ray support.
Short QRS Duration After His-Purkinje Conduction System Pacing Predicts Left Ventricular Complete Reverse Remodeling in Patients With True Left Bundle Branch Block and Heart Failure
Authors: Guan Xu-Min , Li Dan-Na , Zhao Fu-Lu , Zhao Yan-Ni , Yang Yi-Heng , Dai Bai-Ling , Dai Shi-Yu , Gao Lian-Jun , Xia Yun-Long , Dong Ying-Xue
Published: May 2022

Objective

This study aimed to explore the outcomes of His-Purkinje conduction system pacing (HPCSP) and to screen the predictors of left ventricular (LV) complete reverse remodeling in patients with true left bundle branch block (LBBB) and heart failure with reduced ejection fraction (HFrEF).

Methods

Patients who underwent HPCSP for true LBBB and HFrEF from April 2018 to August 2020 were consecutively enrolled. All participants were followed up for at least 1 year. Thrombosis, infection, lead dislodgement, perforation, and other complications were observed after HPCSP. Clinical data, including echocardiographic parameters, electrocardiogram measurements, and cardiac function, were assessed before and after the procedure.

Results

A total of 46 patients were enrolled. HPCSP was successfully deployed in 42 cases (91.30%), which included 37 cases with His bundle pacing (HBP) and 5 cases with left bundle branch pacing (LBBP). The QRS duration decreased significantly (169.88 ± 19.17 ms vs. 113.67 ± 20.68 ms, P < 0.001). Left ventricular end-systolic volume (LVESV) (167.67 ± 73.20 ml vs. 85.97 ± 62.24 ml, P < 0.001), left ventricular end-diastolic diameter (LVEDD) (63.57 ± 8.19 mm vs. 55.46 ± 9.63 mm, P = 0.003) and left ventricular ejection fraction (LVEF) (26.52 ± 5.60% vs. 41.86 ± 11.56%, P < 0.001) improved dramatically. Complete reverse remodeling of the LV with normalized LVEF and LVEDD was found in nearly half of the patients (45.24%). A short QRS duration after HPCSP was a strong predictor of normalized LVEF and LVEDD (P < 0.001). The thresholds increased markedly in two patients approximately 6 months after HBP. No patients died during the total follow-up period of 20.07 ± 6.45 months.

Conclusion

Complete reverse remodeling of the LV could be found in nearly half of the patients with HFrEF and true LBBB after HPCSP, and the short QRS duration after HPCSP was a strong predictor.
Systemically Silencing Long Non-coding RNAs Maclpil With Short Interfering RNA Nanoparticles Alleviates Experimental Ischemic Stroke by Promoting Macrophage Apoptosis and Anti-inflammatory Activation
Authors: Wang Yan , Liu Cuiying , Chen Yong , Chen Tiffany , Han Tao , Xue Lixiang , Xu Baohui
Published: May 2022

Background

Maclpil is a proinflammatory long non-coding RNA highly expressed on monocyte-derived macrophages in the ischemic brain. This study investigated the impact and the mechanisms of systemically delivering nanoparticle Maclpil short interfering RNA (siRNA) on experimental ischemic stroke in a mouse model.

Methods

Ischemic stroke (focal cerebral ischemia) was induced in male C57BL/6 mice through the middle cerebral artery occlusion. Three hours thereafter, mice were intravenously injected with Maclpil siRNA or scramble siRNA nanoparticles. Bone marrow cell-derived macrophages were transfected with Maclpil or scramble siRNA and subjected to oxygen glucose deprivation culture. The influence of silencing Maclpil on stroke outcomes, neuroinflammation, and macrophage fates was assessed via histology, flow cytometry, Western blotting, and quantitative PCR analysis.

Results

Three days following stroke induction, siRNA silencing Maclpil substantially reduced ischemic infarction size and improved neurological behaviors. Silencing Maclpil also markedly attenuated the accumulation of monocyte-derived macrophages, CD4+ T cells, and CD8+ T cells in the ischemic hemisphere without affecting microglia cellularity. Reciprocally, myeloid cells and both subsets of T cells were elevated in mouse peripheral blood following Maclpil siRNA treatment. Under oxygen glucose deprivation conditions that mimicked hypoxia and hypoglycemia in vitro, Maclpil siRNA silencing augmented macrophage apoptosis in conjunction with upregulation of proapoptotic Bax and caspase 3 expressions. siRNA knocking down Maclpil skewed macrophages from proinflammatory classical toward anti-inflammatory alternative activation as evidenced by increased arginase 1, Ym1, and Fizz1 and reduced inducible nitric oxide synthase, IL-1β, and TNF-α mRNA levels. Consistent with macrophage phenotype switching, silencing Maclpil by siRNA enhanced fatty acid oxidation as indicated by increased mRNA levels of 3 key metabolic enzymes (ACADM, ACADVL, and HADHA).

Conclusion

Systemically silencing Maclpil by siRNA nanoparticles attenuated experimental ischemic stroke by promoting macrophage apoptosis and anti-inflammatory alternative activation. Identifying and targeting Maclpil human homolog(s) may help develop a novel therapy for stroke clinical management.
Association Between the Frailty and New-Onset Atrial Fibrillation/Flutter Among Elderly Hypertensive Patients
Authors: Hang Fei , Chen Jieruo , Wang Zefeng , Yan Jiafu , Wu Yongquan
Published: May 2022

Background

Frailty was found to be common in patients with atrial fibrillation/flutter (AF), but there was still a lack of evidence regarding the relationship between frailty and new-onset AF.

Methods

We performed a post hoc analysis of data from the Systolic Blood Pressure Intervention Trial (SPRINT). In addition, we evaluated the relationship between baseline frailty status and new-onset AF in older adult patients with hypertension.

Results

In total, 7,316 participants were included in our analysis, and a total of 115 new-onset AF occurred during an average of 3.54 years of follow-up. Using SPRINT frailty index criteria, 1,535 fit, 4,041 less fit, and 1,740 frailty were enrolled. Compared with other groups, the incidence of new-onset AF in the frailty group was significantly higher. We constructed three Cox models to assess the relationship between the frailty status (fit group as reference) and new-onset AF. Participants with frailty had a significantly higher risk of new-onset AF compared with the fit group in all the models we used. We combined the fit group and the less fit group into a no frailty group to assess the impact of frailty on new-onset AF in various subgroups. After full adjustment (Model 3), frailty remained associated with the increased risk of new-onset AF compared with the no frailty group [hazard ratio [HR] = 2.09, 95% CI:(1.41, 3.09), p < 0.001]. Additionally, we examined the frailty index as continuous variable to assess the relationship between the frailty index and new-onset AF. The smooth curve showed that log HR appeared to increase linearly. And there was a significant interaction between baseline systolic blood pressure (SBP) categories and frailty on the risk of new-onset AF (p for interaction = 0.030).

Conclusion

This study found baseline frailty status was a strong independent risk factor for new-onset AF among older adult patients with hypertension. Screening for frailty should be considered in older adult patients with hypertension to prevent new-onset AF.
Performance of a HeartLogicTM Based Care Path in the Management of a Real-World Chronic Heart Failure Population
Authors: Feijen Michelle , Egorova Anastasia D. , Treskes Roderick W. , Mertens Bart J. A. , Jukema J. Wouter , Schalij Martin J. , Beeres Saskia L. M. A.
Published: May 2022

Aim

Early detection of impending fluid retention and timely adjustment of (medical) therapy can prevent heart failure related hospitalizations. The multisensory cardiac implantable electronic device (CIED) based algorithm HeartLogicTM aims to alert in case of impending fluid retention. The aim of the current analysis is to evaluate the performance of the HeartLogicTM guided heart failure care path in a real-world heart failure population and to investigate whether the height of the index and the duration of the alert state are indicative of the degree of fluid retention.

Methods

Consecutive adult heart failure patients with a CIED and an activated HeartLogicTM algorithm were eligible for inclusion. Patients were followed up according to the hospital's heart failure care path. The device technician reviewed alerts for a technical CIED checkup. Afterwards, the heart failure nurse contacted the patient to identify impending fluid retention. An alert was either true positive or false positive. Without an alert a patient was true negative or false negative.

Results

Among 107 patients, [82 male, 70 (IQR 60–77) years, left ventricular ejection fraction 37 ± 11%] 130 HeartLogicTM alerts were available for analysis. Median follow up was 14 months [IQR 8–23]. The sensitivity to detect impending fluid retention was 79%, the specificity 88%. The positive predictive was value 71% and the negative predictive value 91%. The unexplained alert rate was 0.23 alerts/patient year and the false negative rate 0.17 alerts/patient year. True positive alerts [42 days (IQR 28–63)] lasted longer than false positive alerts [28 days (IQR 21–44)], p = 0.02. The maximal HeartLogicTM index was higher in true positive alerts [26 (IQR 21–34)] compared to false positive alerts [19 (IQR 17–24)], p < 0.01. Patients with higher HeartLogicTM indexes required more intense treatment (index height in outpatient setting 25 [IQR 20–32], day clinic treatment 28 [IQR 24–36] and hospitalized patients 45 [IQR 35–58], respectively), p < 0.01.

Conclusion

The CIED-based HeartLogicTM algorithm facilitates early detection of impending fluid retention and thereby enables clinical action to prevent this at early stage. The current analysis illustrates that higher and persistent alerts are indicative for true positive alerts and higher index values are indicative for more severe fluid retention.
Effects of Feature-Based Explanation and Its Output Modality on User Satisfaction With Service Recommender Systems
Authors: Zhang Zhirun , Chen Li , Jiang Tonglin , Li Yutong , Li Lei
Published: May 2022

Recent advances in natural language based virtual assistants have attracted more researches on application of recommender systems (RS) into the service product domain (e.g., looking for a restaurant or a hotel), given that RS can assist users in more effectively obtaining information. However, though there is emerging study on how the presentation of recommendation (vocal vs. visual) would affect user experiences with RS, little attention has been paid to how the output modality of its explanation (i.e., explaining why a particular item is recommended) interacts with the explanation content to influence user satisfaction. In this work, we particularly consider feature-based explanation, a popular type of explanation that aims to reveal how relevant a recommendation is to the user in terms of its features (e.g., a restaurant's food quality, service, distance, or price), for which we have concretely examined three content design factors as summarized from the literature survey: feature type, contextual relevance, and number of features. Results of our user studies show that, for explanation presented in different modalities (text and voice), the effects of those design factors on user satisfaction with RS are different. Specifically, for text explanations, the number of features and contextual relevance influenced users' satisfaction with the recommender system, but the feature type did not; while for voice explanations, we found no factors influenced user satisfaction. We finally discuss the practical implications of those findings and possible directions for future research.
Help-Seeking and Help-Outreach Intentions of Healthcare Workers—The Role of Mental Health Literacy and Stigma in the Workplace
Authors: Wulf Ines Catharina
Published: May 2022

Due to the demanding work environment, healthcare workers are often affected by mental health problems. Besides negative effects on individual wellbeing, mental health problems can reduce professional effort and increase turnover rates in healthcare. Those who develop mental health problems often receive necessary treatment with a great time delay. Two reasons for this are low mental health literacy and stigma. However, empirical investigations regarding the role of workplace mental health literacy and stigma on help-seeking and help-outreach intentions of healthcare workers in the workplace are currently missing. To bridge this gap, survey data was collected among trainees of different healthcare professions in Germany. The variables of interest were measured separately with the help of two times of measurement to avoid common method bias and to strengthen the causal interpretability of the hypothesized model. The response rate of the questionnaire was 21% (Nt1 = 525, Nt2 = 112). For measuring subjective mental health literacy at the workplace the MHL-W-G was used. Results of the structural equation modeling (SEM) indicate that workplace mental health literacy increases workplace help-seeking intention and help-outreach intention significantly. Further, it indicates that workplace mental health literacy decreases self-stigma and that personal stigma decreases overall workplace help-outreach intention. In order to uncover underlying mechanisms of the relationship between the mental health literacy and workplace help-seeking intention and help-outreach intention, the mediation of mental health stigma was tested, but could not be confirmed. The present study reduces the lack of empirical information regarding mental health help-seeking and help-outreach in the workplace. Therefore, the research contributes to the relevance of social contacts in the working context as potential gatekeepers to professional mental health support. Further, the study provides important insights into the way that mental health help-seeking and help-outreach intentions at the workplace are affected by mental health literacy and into the role of personal and self-stigma in healthcare profession. The results are of particular importance in light of the increased need for healthcare workers and the rising prevalence of mental diseases.
Students’ Transitions Through English Medium Instruction Environment: A Kyrgyz Case
Authors: Eusafzai Hamid Ali Khan
Published: May 2022

This qualitative exploratory research investigates Kyrgyz students’ transition experience in an English Medium Instruction (EMI) environment through the Multiple and Multi-dimensional Transitions (MMT) theoretical lens. Data were collected from a small purposive sample of students through semi-structured interviews. The findings of the study reveal that the students experienced transitions in the academic, psychological, and social domains of their life. The academic transitions were in the form of gaining linguistic competencies, the psychological transitions were toward changing the students’ outlook and their image of self, and the social transitions were toward a readjustment of the students’ role in their family and community. Thus, these mostly positive and multi-directional transitions were developmental and transformational in nature
A Case Report: First Long-Term Treatment With Burosumab in a Patient With Cutaneous-Skeletal Hypophosphatemia Syndrome
Authors: Merz Lea Maria , Buerger Florian , Ziegelasch Niels , Zenker Martin , Wieland Ilse , Lipek Tobias , Wallborn Tillmann , Terliesner Nicolas , Prenzel Freerk , Siekmeyer Manuela , Dittrich Katalin
Published: May 2022

Epidermal nevus syndromes encompass a highly heterogeneous group of systemic disorders, characterized by epidermal nevi, and a spectrum of neuromuscular, ocular, and bone abnormalities. Cutaneous-skeletal hypophosphatemia syndrome (CSHS) constitutes a specific sub-entity in which elevated levels of fibroblast growth factor-23 cause hypophosphatemic rickets that are, to date, not amenable to causal therapy. Here, we report the first long-term follow-up of causal treatment with burosumab in a 3-year-old female patient with CSHS. 4 weeks after initiation of burosumab treatment, serum phosphate normalized to age-appropriate levels. Furthermore, long-term follow-up of 42 months revealed significant improvement of linear growth and gross physical functions, including respiratory insufficiency. Radiographic rickets severity as well as subjective bone pain were strongly reduced, and no side effects were observed over the course of treatment. In summary, we, here, report about a successful treatment of hypophosphatemic rickets in CSHS with burosumab over the time course of 42 months. In our patient, burosumab showed convincing efficacy and safety profile, without any loss of effect or increase of dose.
Antibiotic Consumption Patterns in European Countries Might Be Associated with the Prevalence of Type 1 and 2 Diabetes
Authors: Ternák Gábor , Németh Márton , Rozanovic Martin , Bogár Lajos
Published: May 2022

Several publications have raised the issue that the development of diabetes precedes the alteration of the microbiome (dysbiosis) and the role of environmental factors. Antibiotic use induces dysbiosis, and we wanted to estimate the associations between the consumption of antibiotics and the prevalence of diabetes (both types 1 and 2; T1D and T2D, respectively) in European countries. If such an association exists, the dominant use antibiotic classes might be reflected in the prevalence rates of T1D and T2D in different countries. Comparisons were performed between the prevalence of diabetes estimated for 2019 and featured in the Diabetes Atlas and the average yearly consumption of antibiotic classes between 2010 and 2109, calculated from the European Centre for Disease Prevention and Control (ECDC) yearly reports on antibiotic consumption in Europe. Pearson’s correlation and variance analyses were used to estimate the possible relationship. Strong positive (enhancer) associations were found between the prevalence of T1D and the consumption of tetracycline (J01A: p = 0.001) and the narrow-spectrum penicillin (J01CE: p = 0.006; CF: p = 0.018). A strong negative (inhibitor) association was observed with broad-spectrum, beta-lactamase-resistant penicillin (J01CR: p = 0.003), macrolide (J01F: p = 0.008), and quinolone (J01M: p = 0.001). T2D showed significant positive associations with cephalosporin (J01D: p = 0.048) and quinolone (J01M: p = 0.025), and a non-significant negative association was detected with broad-spectrum, beta-lactamase-sensitive penicillin (J01CA: p = 0.067). Countries showing the highest prevalence rates of diabetes (top 10) showed concordance with the higher consumption of “enhancer” and the lower consumption of “inhibitor” antibiotics (top 10), as indicated by variance analysis. Countries with high prevalence rates of T1D showed high consumption of tetracycline (p = 0.015) and narrow-spectrum, beta-lactamase sensitive penicillin (p = 0.008) and low consumption of “inhibitor” antibiotics [broad-spectrum, beta-lactamase-resistant, combination penicillin (p = 0.005); cephalosporin (p = 0.036); and quinolone (p = 0.003)]. Countries with high prevalence rates of T2D consumed more cephalosporin (p = 0.084) and quinolone (p = 0.054) and less broad-spectrum, beta-lactamase-sensitive penicillin (p = 0.012) than did other countries. The development of diabetes-related dysbiosis might be related to the higher consumption of specific classes of antibiotics, showing positive (enhancer) associations with the prevalence of diabetes, and the low consumption of other classes of antibiotics, those showing negative (inhibitory) associations. These groups of antibiotics are different in T1D and T2D.
Variability in Arrival Time of White Storks (Ciconia ciconia L.): Impact of Age, Interindividual Variation, and Global Change
Authors: Athamnia Mohammed , Belabed Bourhane-Eddine , Samraoui Kenz Raouf , Boucheker Abdennour , Touati Laïd , Samraoui Farrah , El-Serehy Hamed A. , Samraoui Boudjéma
Published: May 2022

Global changes are inducing migratory birds to advance their annual cycle. However, changes in the time of arrival at their breeding grounds have significant fitness implications. This study aims to identify factors affecting the variability in arrival time of migratory white storks (Ciconia ciconiaL.) and to determine if their arrival at North African breeding grounds is occurring earlier. We monitored the arrival of ringed white storks at a breeding colony in Algeria between 2017 and 2021. The birds arrived at this breeding colony over an extended period spanning mid-December to mid-June each year. We found that stork arrival was negatively correlated with age and year of arrival, with older birds arriving first and stragglers consisting of first- and second-year birds arriving later. Notably, arrivals have been shifting toward earlier dates at this breeding ground. Furthermore, cluster analysis of arrival dates for each age-class revealed two distinct groups comprising early and late arrivals. Advancement of the annual cycle of the North African white stork population is consistent with phenological shifts induced by global changes and that have been recorded globally in a wide range of living organisms.
Cytokine Elevation in Severe COVID-19 From Longitudinal Proteomics Analysis: Comparison With Sepsis
Authors: Ebihara Takeshi , Matsumoto Hisatake , Matsubara Tsunehiro , Togami Yuki , Nakao Shunichiro , Matsuura Hiroshi , Kojima Takashi , Sugihara Fuminori , Okuzaki Daisuke , Hirata Haruhiko , Yamamura Hitoshi , Ogura Hiroshi
Published: May 2022

Introduction

Coronavirus disease 2019 (COVID-19) is a new viral disease. Uncontrolled inflammation called “cytokine storm” is reported to contribute to disease pathogenesis as well as sepsis. We aimed to identify cytokines related to the pathogenesis of COVID-19 through a proteomics analysis of 1463 plasma proteins, validate these cytokines, and compare them with sepsis.

Materials and Methods

In a derivation cohort of 306 patients with COVID-19, 1463 unique plasma proteins were measured on days 1, 4, and 8. Cytokines associated with disease severity and prognosis were derived. In a validation cohort of 62 COVID-19 patients and 38 sepsis patients treated in the intensive care unit [ICU], these derived cytokines were measured on days 1 (day of ICU admission), 2-3, and 6-8 (maximum: 3 time points/patient). Derived cytokines were compared with healthy controls and between COVID-19 and sepsis patients, and the associations with prognosis were evaluated. The time to wean off mechanical ventilation (MV) was evaluated only for COVID-19.

Results

IL-6, amphiregulin, and growth differentiation factor (GDF)-15 were associated with disease severity and prognosis in the derivation cohort. In the validation cohort, IL-6 and GDF-15 were elevated in COVID-19 and sepsis on day 1, and the levels of these cytokines were higher in sepsis than in COVID-19. IL-6 and GDF-15 were associated with prognosis in sepsis. Cox proportional hazards model with time as a dependent covariate showed a significant relationship between plasma GDF-15 level and time to wean off MV (hazard ratio, 0.549 [95% confidence level, 0.382–0.789]). The GDF-15 level at ICU admission predicted late recovery.

Conclusion

GDF-15 and IL-6 derived from proteomics analysis were related with disease severity of COVID-19. Their values were higher in sepsis than in COVID-19 and were associated with prognosis in sepsis. In COVID-19 patients treated in the ICU, GDF-15 was associated with the time to wean off MV and better predicted late recovery.
T Cell Epitope Discovery in the Context of Distinct and Unique Indigenous HLA Profiles
Authors: Hensen Luca , Illing Patricia T. , Rowntree Louise C. , Davies Jane , Miller Adrian , Tong Steven Y. C. , Habel Jennifer R. , van de Sandt Carolien E. , Flanagan Katie L. , Purcell Anthony W. , Kedzierska Katherine , Clemens E. Bridie
Published: May 2022

CD8+T cells are a pivotal part of the immune response to viruses, playing a key role in disease outcome and providing long-lasting immunity to conserved pathogen epitopes. Understanding CD8+T cell immunity in humans is complex due to CD8+T cell restriction by highly polymorphic Human Leukocyte Antigen (HLA) proteins, requiring T cell epitopes to be defined for different HLA allotypes across different ethnicities. Here we evaluate strategies that have been developed to facilitate epitope identification and study immunogenic T cell responses. We describe an immunopeptidomics approach to sequence HLA-bound peptides presented on virus-infected cells by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Using antigen presenting cell lines that stably express the HLA alleles characteristic of Indigenous Australians, this approach has been successfully used to comprehensively identify influenza-specific CD8+T cell epitopes restricted by HLA allotypes predominant in Indigenous Australians, including HLA-A*24:02 and HLA-A*11:01. This is an essential step in ensuring high vaccine coverage and efficacy in Indigenous populations globally, known to be at high risk from influenza disease and other respiratory infections.
SLAMF Receptor Expression Identifies an Immune Signature That Characterizes Systemic Lupus Erythematosus
Authors: Humbel Morgane , Bellanger Florence , Horisberger Alice , Suffiotti Madeleine , Fluder Natalia , Makhmutova Mariko , Mathias Amandine , Du Pasquier Renaud , Fenwick Craig , Ribi Camillo , Comte Denis
Published: May 2022

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology, linked to alterations in both the innate and the adaptive immune system. Due to the heterogeneity of the clinical presentation, the diagnosis of SLE remains complicated and is often made years after the first symptoms manifest, delaying treatment, and worsening the prognosis. Several studies have shown that signaling lymphocytic activation molecule family (SLAMF) receptors are aberrantly expressed and dysfunctional in SLE immune cells, contributing to the altered cellular function observed in these patients. The aim of this study was to determine whether altered co-/expression of SLAMF receptors on peripheral blood mononuclear cells (PBMC) identifies SLE characteristic cell populations. To this end, single cell mass cytometry and bioinformatic analysis were exploited to compare SLE patients to healthy and autoimmune diseases controls. First, the expression of each SLAMF receptor on all PBMC populations was investigated. We observed that SLAMF1+ B cells (referred to as SLEB1) were increased in SLE compared to controls. Furthermore, the frequency of SLAMF4+ monocytes and SLAMF4+ NK were inversely correlated with disease activity, whereas the frequency SLAMF1+ CD4+ TDEM cells were directly correlated with disease activity. Consensus clustering analysis identified two cell clusters that presented significantly increased frequency in SLE compared to controls: switch memory B cells expressing SLAMF1, SLAMF3, SLAMF5, SLAMF6 (referred to as SLESMB) and circulating T follicular helper cells expressing the same SLAMF receptors (referred to as SLEcTFH). Finally, the robustness of the identified cell populations as biomarkers for SLE was evaluated through ROC curve analysis. The combined measurement of SLEcTFH and SLEB1 or SLESMB cells identified SLE patients in 90% of cases. In conclusion, this study identified an immune signature for SLE based on the expression of SLAMF receptors on PBMC, further highlighting the involvement of SLAMF receptors in the pathogenesis of SLE.
PD1 Expression in EGFRvIII-Directed CAR T Cell Infusion Product for Glioblastoma Is Associated with Clinical Response
Authors: Tang Oliver Y. , Tian Lifeng , Yoder Todd , Xu Rong , Kulikovskaya Irina , Gupta Minnal , Melenhorst Jan Joseph , Lacey Simon F. , O’Rourke Donald M. , Binder Zev A.
Published: May 2022

The epidermal growth factor receptor variant III (EGFRvIII) has been investigated as a therapeutic target for chimeric antigen receptor (CAR) T cell therapy in glioblastoma. Earlier research demonstrated that phenotypic and genotypic characteristics in T cells and CAR T product predicted therapeutic success in hematologic malignancies, to date no determinants for clinical response in solid tumors have been identified. We analyzed apheresis and infusion products from the first-in-human trial of EGFRvIII-directed CAR T for recurrent glioblastoma (NCT02209376) by flow cytometry. Clinical response was quantified via engraftment in peripheral circulation and progression-free survival (PFS), as determined by the time from CAR T infusion to first radiographic evidence of progression. The CD4+CAR T cell population in patient infusion products demonstrated PD1 expression which positively correlated with AUC engraftment and PFS. On immune checkpoint inhibitor analysis, CTLA-4, TIM3, and LAG3 did not exhibit significant associations with engraftment or PFS. The frequencies of PD1+GZMB+ and PD1+HLA-DR+ CAR T cells in the CD4+ infusion products were directly proportional to AUC and PFS. No significant associations were observed within the apheresis products. In summary, PD1 in CAR T infusion products predicted peripheral engraftment and PFS in recurrent glioblastoma.
Interstitial Lung Disease in Dermatomyositis Without Myositis-Specific and Myositis-Associated Autoantibodies: Study of a Series of 72 Patients From a Single Cohort
Authors: Chen Fang , Wang Jinping , Zhang Puli , Zuo Yu , Ye Lifang , Wang Guochun , Shu Xiaoming
Published: May 2022

Objective

The clinical features of interstitial lung disease (ILD) in patients with dermatomyositis (DM) and negative myositis autoantibodies had not been exactly demonstrated previously. This study aimed to describe and expand the phenotype of interstitial lung disease (ILD) in this cohort of patients.

Methods

A total of 1125 consecutive Chinese patients with idiopathic inflammatory myopathies (IIM) between 2006 and 2020 were screened retrospectively. All proven cases of isolated ILD with both negative myositis-specific autoantibodies (MSA) and negative myositis-associated autoantibodies (MAA) were selected for inclusion. The clinical features and outcome among this group, MDA5+DM (DM patients with positive anti-MDA5 antibody) and ASS (patients with positive anti-aminoacyl tRNA synthetases antibodies were recorded and compared.

Results

Of 1125 IIM patients with an average follow-up of 6 years, 154 DM patients with negative MSA and MAA (MSA/MAA) were identified, with an ILD incidence of 46.8%. DM-ILD Patients with negative MSA/MAA presented younger age at onset (p<0.001), lower incidence of elevated CA153 (p=0.03) and fever (p=0.04)than those ILD patients with MDA5+DM and ASS.The estimated high-resolution computed tomography patterns of ILD showed non-specific interstitial pneumonia (66.6%), followed by organizing pneumonia in patients with negative MSA/MAA. OP pattern was more common in patients with MDA5+DM (69.7%), and the ratios of the OP (48.7%) and NSIP (51.3%) patterns were almost equal in patients with ASS. Of these DM-ILD patients with negative MSA/MAA, 25% developed rapidly progressive interstitial lung disease (RP-ILD). Patients with RP-ILD had a shorter disease duration (p=0.002), higher percentage of positive ANA(p=0.01) and organizing pneumonia patterns (p=0.04), elevated CYFRA211(p=0.04) and decreased FiO2/PaO2 (p<0.001) than those with chronic progressive ILD. The incidence of OP pattern in RP-ILD patients with negative MSA/MAA was lower than in those RPILD patients with MDA5+ DM (75%) and ASS (89%) (p=0.006). The cumulative 5- and 10-year survival rates in the DM-ILD patients with negative MSA/MAA were 91% and 88%, respectively, during the long-term follow-up study. And they had more favorable survival rate compared with ILD patients with MDA5+DM and ASS (p<0.001). An independent prognostic factor was identified as decreased PaO2/FiO2 (hazard ratio, 0.97; p=0.004].

Conclusions

This study indicates DM-ILD patients with negative MSA/MAA had favorable long-term outcomes. Decreased baseline PaO2/FiO2 acted as an independent prognostic factor for this group of patients.
Bone Marrow Niches and Tumour Cells: Lights and Shadows of a Mutual Relationship
Authors: Granata Valentina , Crisafulli Laura , Nastasi Claudia , Ficara Francesca , Sobacchi Cristina
Published: May 2022

The bone marrow (BM) niche is the spatial structure within the intra-trabecular spaces of spongious bones and of the cavity of long bones where adult haematopoietic stem cells (HSCs) maintain their undifferentiated and cellular self-renewal state through the intervention of vascular and nervous networks, metabolic pathways, transcriptional and epigenetic regulators, and humoral signals. Within the niche, HSCs interact with various cell types such as osteoblasts, endothelial cells, macrophages, and mesenchymal stromal cells (MSCs), which maintain HSCs in a quiescent state or sustain their proliferation, differentiation, and trafficking, depending on body needs. In physiological conditions, the BM niche permits the daily production of all the blood and immune cells and their admittance/ingress/progression into the bloodstream. However, disruption of this delicate microenvironment promotes the initiation and progression of malignancies such as those included in the spectrum of myeloid neoplasms, also favouring resistance to pharmacological therapies. Alterations in the MSC population and in the crosstalk with HSCs owing to tumour-derived factors contribute to the formation of a malignant niche. On the other hand, cells of the BM microenvironment cooperate in creating a unique milieu favouring metastasization of distant tumours into the bone. In this framework, the pro-tumorigenic role of MSCs is well-documented, and few evidence suggest also an anti-tumorigenic effect. Here we will review recent advances regarding the BM niche composition and functionality in normal and in malignant conditions, as well as the therapeutic implications of the interplay between its diverse cellular components and malignant cells.
The Current Landscape of mRNA Vaccines Against Viruses and Cancer–A Mini Review
Authors: Ladak Reese Jalal , He Alexander J. , Huang Yu-Hsun , Ding Yu
Published: May 2022

Both infectious viral diseases and cancer have historically been some of the most common causes of death worldwide. The COVID-19 pandemic is a decidedly relevant example of the former. Despite progress having been made over past decades, new and improved techniques are still needed to address the limitations faced by current treatment standards, with mRNA-based therapy emerging as a promising solution. Highly flexible, scalable and cost-effective, mRNA therapy is proving to be a compelling vaccine platform against viruses. Likewise, mRNA vaccines show similar promise against cancer as a platform capable of encoding multiple antigens for a diverse array of cancers, including those that are patient specific as a novel form of personalized medicine. In this review, the molecular mechanisms, biotechnological aspects, and clinical developments of mRNA vaccines against viral infections and cancer are discussed to provide an informative update on the current state of mRNA therapy research.
Salivary Xanthine Oxidase as a Potential Biomarker in Stroke Diagnostics
Authors: Maciejczyk Mateusz , Nesterowicz Miłosz , Zalewska Anna , Biedrzycki Grzegorz , Gerreth Piotr , Hojan Katarzyna , Gerreth Karolina
Published: May 2022

Stroke is one of the most common cerebrovascular diseases. Despite significant progress in understanding stroke pathogenesis, cases are still increasing. Thus, laboratory biomarkers of stroke are sought to allow rapid and non-invasive diagnostics. Ischemia-reperfusion injury is an inflammatory process with characteristic cellular changes leading to microvascular disruption. Several studies have shown that hyperactivation of xanthine oxidase (XO) is a major pathogenic factor contributing to brain dysfunction. Given the critical role of XO in stroke complications, this study aimed to evaluate the activity of the enzyme and its metabolic products in the saliva of stroke subjects. Thirty patients in the subacute phase of stroke were included in the study: 15 with hemorrhagic stroke and 15 with ischemic stroke. The control group consisted of 30 healthy subjects similar to the cerebral stroke patients regarding age, gender, and status of the periodontium, dentition, and oral hygiene. The number of individuals was determined a priori based on our previous experiment (power of the test = 0.8; α = 0.05). The study material was mixed non‐stimulated whole saliva (NWS) and stimulated saliva (SWS). We showed that activity, specific activity, and XO output were significantly higher in NWS of ischemic stroke patients than in hemorrhagic stroke and healthy controls. Hydrogen peroxide and uric acid levels were also considerably higher in NWS of ischemic stroke patients. Using receiver operating curve (ROC) analysis, we demonstrated that XO-specific activity in NWS distinguishes ischemic stroke from hemorrhagic stroke (AUC: 0.764) and controls (AUC: 0.973) with very high sensitivity and specificity. Saliva collection is stress-free, requires no specialized medical personnel, and allows continuous monitoring of the patient’s condition through non-invasive sampling multiple times per day. Salivary XO also differentiates with high accuracy (100%) and specificity (93.75%) between stroke patients with mild to moderate cognitive decline (AUC = 0.988). Thus, salivary XO assessment may be a potential screening tool for a comprehensive neuropsychological evaluation. To summarize, our study demonstrates the potential utility of salivary XO in the differential diagnosis of stroke.
Low Survivals and Rapid Demographic Decline of a Threatened Estuarine Delphinid
Authors: Lin Wenzhi , Zheng Ruiqiang , Liu Binshuai , Chen Shenglan , Lin Mingli , Liu Mingming , Liu Wenhua , Li Songhai
Published: May 2022

Beibu Gulf’s (BBG) Indo-Pacific humpback dolphins present both a genetic differentiation and phenotypical differences from conspecifics from other areas of the South China Sea. Given the recent urbanization and industrialization in southern China, humpback dolphins from the BBG warrant conservation attention. However, this population’s demographic trend is unclear, making it hard to take conservation measures. To assess the population status of humpback dolphins in the BBG, photo-identification surveys were conducted between 2015 and 2019 in the inshore region surrounding the Dafeng River Estuary, which represents the most urbanized and industrialized coastal area of the BBG region. Robust design modeling suggested a constant survival for the female adults (0.89, 95% CI: 0.83–0.94). In comparison, the survival of the juvenile and sex-undetermined adults dropped from 0.92 (95% CI: 0.75–0.98) in 2015 to 0.86 (95% CI: 0.71–0.94) in 2016 and bounced back to 0.89 (95% CI: 0.80–0.94) in 2018. The low level of survival may justify the rapid decline in the annual population size from 156 (95% CI: 133–184) in 2015 to 102 (95% CI: 98–107) in 2019. We found little impact of emigration on the dolphin demographic process. Instead, the low and fluctuating survivals, although with overlapping confidence intervals, seemingly suggested a presence of strong marine stressor(s). Our study highlighted that obtaining high-resolution data is essential to improving our understanding of the demographic dynamics. Moreover, the anthropogenic stress in the BBG region should be quantitatively studied in both temporal and spatial perspectives, to help depict the ecological response of the dolphins to anthropogenic activities.