bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic influence of mechanical cardiopulmonary resuscitation on survival in patients with out-of-hospital cardiac arrest undergoing ECPR on VA-ECMO
Authors: Springer A. , Dreher A. , Reimers J. , Kaiser L. , Bahlmann E. , van der Schalk H. , Wohlmuth P. , Gessler N. , Hassan K. , Wietz J. , Bein B. , Spangenberg T. , Willems S. , Hakmi S. , Tigges E.
Published: January 2024

Introduction

The use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) in extracorporeal cardiopulmonary resuscitation (ECPR) in selected patients after out-of-hospital cardiac arrest (OHCA) is an established method if return of spontaneous circulation cannot be achieved. Automated chest compression devices (ACCD) facilitate transportation of patients under ongoing CPR and might improve outcome. We thus sought to evaluate prognostic influence of mechanical CPR using ACCD in patients presenting with OHCA treated with ECPR including VA-ECMO.

Methods

We retrospectively analyzed data of 171 consecutive patients treated for OHCA using ECPR in our cardiac arrest center from the years 2016 to 2022. A Cox proportional hazards model was used to identify characteristics related with survival.

Results

Of the 171 analyzed patients (84% male, mean age 56 years), 12% survived the initial hospitalization with favorable neurological outcome. The primary reason for OHCA was an acute coronary event (72%) followed by primary arrhythmia (9%) and non-ischemic cardiogenic shock (6.7%). In most cases, the collapse was witnessed (83%) and bystander CPR was performed (83%). The median time from collapse to VA-ECMO was 81 min (Q1: 69 min, Q3: 98 min). No survival benefit was seen for patients resuscitated using ACCD. Patients in whom an ACCD was used presented with overall longer times from collapse to ECMO than those who were resuscitated manually [83 min (Q1: 70 min, Q3: 98 min) vs. 69 min (Q1: 57 min, Q3: 84 min), p = 0.004].

Conclusion

No overall survival benefit of the use of ACCD before ECPR is established was found, possibly due to longer overall CPR duration. This may arguably be because of the limited availability of ACCD in pre-clinical paramedic service at the time of observation. Increasing the availability of these devices might thus improve treatment of OHCA, presumably by providing efficient CPR during transportation and transfer.
Case report: Widely split P' waves in a patient with focal atrial tachycardia
Authors: Jiang Hao , Ruan Zhongbao , Ren Yin , Ding Xiangwei
Published: January 2024

Background

Widely split P waves in sinus rhythm have been reported previously. However, widely split P' waves in focal atrial tachycardia (AT) on a surface electrocardiogram (ECG) have rarely been reported. The electrophysiological mechanism is relatively difficult to clarify, requiring a electrophysiological study.

Case summary

A 67-year-old patient, who had undergone two radiofrequency ablations for atrial fibrillation, presented with recurrent palpitation. During the palpitation episode, the 12-lead ECG showed AT with a 3:1 atrioventricular conduction rate. P' waves were markedly prolonged in duration and widely split in morphology. An electrophysiological study showed that the tachycardia arose from the left atrial appendage (LAA) and was conducted through two distinct pathways. The impulse of one pathway was transmitted solely via the superior part of the atrium, including the Bachmann bundle. The second pathway was conducted via the coronary sinus and transmitted the impulse from the LAA to the ventricle. After the site showed that the earliest activation was ablated, repeated intravenous infusion of isoprenaline and programmed atrial stimulation did not induce tachycardia.

Conclusion

Widely split P' waves in AT indicate intra- and interatrial conduction blocks, which can be easily overlooked due to the presence of low-voltage areas. Therefore, an electrophysiological study is crucial for identifying the origin of the tachycardia and elucidating the mechanistic details.
Congenital heart disease research landscape in the Arab world: a 25-year bibliometric review
Authors: Bitar Fouad , Arabi Mariam , Bulbul Ziad , Nemer Georges , Jassar Yehya , Bitar Fadi F. , Abdul Sater Zahi
Published: January 2024

Background

While research on congenital heart disease has been extensively conducted worldwide, comprehensive studies from developing countries and the Arab world remain scarce.

Aim

This study aims to perform a bibliometric review of research on congenital heart disease in the Arab world from 1997 to 2022.

Methods

We analyzed data from the Web of Science, encompassing various aspects such as topics, countries, research output, citations, authors, collaborations, and affiliations. This comprehensive science mapping analysis was done using the R statistical software's Bibliometrix Package.

Results

The research output from Arab countries over the 25 years showed an average annual growth rate of 11.5%. However, Arab countries exhibited lower research productivity than the United States and Europe, with a 24-fold difference. There was substantial variation in research output among 22 Arab countries, with five countries contributing to 78% of the total publications. Most of the published research was clinical, with limited innovative contributions and a preference for regional journals. High-income Arab countries displayed higher research productivity and citation rates than their low-income developing counterparts. Despite being categorized as upper-middle-income, post-conflict countries exhibited low research productivity. About one-quarter of the published articles (26%) resulted from collaborative efforts among multiple countries, with the United States being the most frequent collaborator. Enhanced research productivity and impact output were strongly associated with increased international cooperation.

Conclusion

Research productivity in the Arab region closely correlates with a country's GDP. Success hinges on governmental support, funding, international collaboration, and a clear research vision. These findings offer valuable insights for policymakers, educational institutions, and governments to strengthen research programs and nurture a research culture.
Infection remediation after septic device extractions: analysis of three treatment strategies including a 1-year follow-up
Authors: Burger Heiko , Strauß Mona , Chung Da-Un , Richter Manfred , Ziegelhöffer Tibor , Hakmi Samer , Reichenspurner Hermann , Choi Yeong-Hoon , Pecha Simon
Published: January 2024

Introduction

In CIED infections, all device material needs to be removed. But, especially in pacemaker-dependent patients it is often not possible to realize a device-free interval for infection remediation. In those patients, different treatment options are available, however the ideal solution needs still to be defined.

Methods

This retrospective analysis includes 190 patients undergoing CIED extractions due to infection. Three different treatment algorithms were analyzed: Group 1 included 89 patients with system removal only (System removal group). In Group 2, 28 patients received an epicardial electrode during extraction procedure (Epicardial lead group) while 78 patients in group 3 (contralateral reimplantation group) received implantation of a new system contralaterally during extraction procedure. We analyzed peri- and postoperative data as well as 1-year outcomes of the three groups.

Results

Patients in the system removal and epicardial lead groups were significantly older, had more comorbidities, and suffered more frequently from systemic infections than those in contralateral reimplantation group. Lead extraction procedures had comparable success rates: 95.5%, 96.4%, and 93.2% of complete lead removal in the System removal, Epicardial Lead, Contralateral re-implantation group respectively. Device reimplantation was performed in all patients in Epicardial lead and Contralateral reimplantation group, whereas only 49.4% in System removal group received device re-implantation. At 1-year follow-up, freedom from infection and absence of pocket irritation were comparable for all groups (94.7% Contralateral reimplantation group and Epicardial lead group, 100% System removal group). No procedure-related mortality was observed, whereas 1-year mortality was 3.4% in System removal group, 4.1% in Contralateral re-implantation group and 21.4% in Epicardial lead group (p < 0.001).

Conclusion

In patients with CIED infection, systems should be removed completely and reimplanted after infection remediation. In pacemaker-dependent patients, simultaneous contralateral CIED re-implantation or epicardial lead placement may be performed, depending on route, severity and location of infection.
Role of artificial intelligence in early detection of congenital heart diseases in neonates
Authors: Ejaz Haris , Thyyib Tarannum , Ibrahim Ahmed , Nishat Aroob , Malay Jhancy
Published: January 2024

In the domain of healthcare, most importantly pediatric healthcare, the role of artificial intelligence (AI) has significantly impacted the medical field. Congenital heart diseases represent a group of heart diseases that are known to be some of the most critical cardiac conditions present at birth. These heart diseases need a swift diagnosis as well as an intervention to ensure the wellbeing of newborns. Fortunately, with the help of AI, including the highly advanced algorithms, analytics and imaging involved, it provides us with a promising era for neonatal care. This article reviewed published data in PubMed, Science Direct, UpToDate, and Google Scholar between the years 2015–2023. To conclude The use of artificial intelligence in detecting congenital heart diseases has shown great promise in improving the accuracy and efficiency of diagnosis. Several studies have demonstrated the efficacy of AI-based approaches for diagnosing congenital heart diseases, with results indicating that the systems can achieve high levels of sensitivity and specificity. In addition, AI can help reduce the workload of healthcare professionals allowing them to focus on other critical aspects of patient care. Despite the potential benefits of using AI, in addition to detecting congenital heart disease, there are still some challenges to overcome, such as the need for large amounts of high-quality data and the requirement for careful validation of the algorithms. Nevertheless, with ongoing research and development, AI is likely to become an increasingly valuable tool for improving the diagnosis and treatment of congenital heart diseases.
Advancing very short-term rainfall prediction with blended U-Net and partial differential approaches
Authors: Ha Ji-Hoon , Park Junsang
Published: January 2024

Accurate and timely prediction of short-term rainfall is crucial for reducing the damages caused by heavy rainfall events. Therefore, various precipitation nowcasting models have been proposed. However, the performance of these models still remains limited. In particular, the current operational precipitation nowcasting method, which is based on radar echo tracking, such as the McGill Algorithm for Precipitation Nowcasting by Lagrangian Extrapolation (MAPLE), has a critical drawback when predicting newly developed or decayed precipitation fields. Recently proposed deep learning models, such as the U-Net convolutional neural network outperform the models based on radar echo tracking. However, these models are unsuitable for operational precipitation nowcasting due to their blurry predictions over longer lead times. To address these blurry effects and enhance the performance of U-Net-based rainfall prediction, we propose a blended model that combines a partial differential equation (PDE) model based on fluid dynamics with the U-Net model. The evaluation of the forecast skill, based on both qualitative and quantitative methods for 0–3-h lead times, demonstrates that the blended model provides less blurry and more accurate rainfall predictions compared with the U-Net and partial differential equation models. This indicates the potential to enhance the field of very short-term rainfall prediction. Additionally, we also evaluated the monthly-averaged forecast skills for different seasons, and confirmed the operational feasibility of the blended model, which contributes to the performance enhancement of operational nowcasting.
Arching of force chains in excavated granular material
Authors: Wang Meimei , Wang Jin-An , Li Fei , Liang Chao , Yang Liu
Published: January 2024

The physical arch and the arch effect are related to many geotechnical problems, such as the stability of mine openings, a tunnel’s shape, and disaster prevention. However, observing the arch in geo-material is challenging due to Earth’s invisible force network distribution. The arch shape is a critical parameter related to the arching effect, which is still an open question. Specifically, the force network evolution after local excavation in granular material is revealed using the photo-elastic technique, and the system pressure variation is calculated qualitatively in particle scale according to the G2 algorithm. Besides, the force chain arch is formed by strong force chains, which are important in redistributing the stress field. The principal direction of the spatial correlation colormap represents the direction of the strong force chains in the network. Based on this preferred angle between the strong force chain and the horizontal direction, a simplified force chain arch trajectory is iteratively rebuilt. Then, the total force chain distribution is studied considering both G2 and the total length of strong force chains, with the corresponding results demonstrating a relationship between the changes in these characteristics and the force chain arch formation.
Study on bearing characteristics of super-long and super-large diameter pipe piles in silt foundation of alluvial plain of Yellow River
Authors: Zhang Sifeng , Ren Zhicheng , Zhang Yingguang , Fan Wei , Li Chao , Liu Chao , Wang Yushuai
Published: January 2024

In recent years, super-long and super-large diameter pipe piles have been gradually applied to the foundation in the Yellow River flood area. However, its bearing mechanism is not clear, especially the unclear bearing characteristics of the pile under the eccentric state, which limits its application and development. In this regard, this paper uses the method of combining field test and numerical simulation to analyze the bearing characteristics of super-long and super-large diameter pipe piles under different pile lengths, different pile diameters, different diameter-thickness ratios, and different offsets. Combined with the specific deviation form of the pipe pile, the calculation formula of the vertical ultimate bearing capacity of the super-long and super-long diameter pipe pile in the Yellow River flooding area under the influence of the construction effect is modified. The results show that when the length of the pipe pile changes, the vertical bearing capacity changes the most, and the vertical ultimate bearing capacity of the pipe pile increases linearly with the increase of the length of the pipe pile. When the wall thickness of the pipe pile increases, the vertical bearing capacity increases approximately linearly, but the reduction of the pile displacement decreases exponentially. The greater the deflection of the pipe pile, the smaller the vertical ultimate bearing capacity. When the deflection of the pipe pile is greater than 0.35°, the vertical ultimate bearing capacity decreases rapidly with the increase of the deflection. On the basis of the traditional formula, considering the deviation form of the pipe pile, the reduction coefficient of the bearing capacity correction formula of the super-long and super-large diameter pipe pile is proposed, and the correction formula is compared with the field example. It is proved that the formula can accurately calculate the bearing capacity of the super-long and super-large diameter pipe pile. The research results of this paper are of great significance to the application and promotion of super-long and super-large diameter pipe piles in the Yellow River flood area and the evaluation of vertical ultimate bearing capacity. At the same time, the research results of this paper can also provide a reference for the study of bearing characteristics of super-long and super-large diameter pipe piles in other foundations.
Inclusive Waldorf schools today: what can we build on and what is necessary in the 21st century?
Authors: Barth Ulrike , Wiehl Angelika
Published: January 2024

In this article we deal with questions of inclusion or inclusive educational requirements in schools and pay special attention to Waldorf schools. In doing so, we are first concerned with the question of how inclusive Waldorf education is in its foundations in order to then look more closely at the situation in Waldorf schools today and explore what potential Waldorf education has. A contribution to this is the research we are doing on the methodology of perception vignettes. For four years we have been using this methodology to develop an approach of “understanding” diagnostics for our students and future Waldorf teachers, so that they can consult different perspectives in their everyday dealings with children and adolescents and learn to ask the appropriate questions.
Assessment of math abilities before school entry: a tool development
Authors: Cruz Joana , Alves Diana , Carvalho Marisa , Mendes Sofia Abreu , Rodrigues Bruna , Cadime Irene
Published: January 2024

Introduction

The years preceding school entry are pivotal for children to develop fundamental skills that bolster their learning in literacy and math in the following years. Skills like counting and subitizing stand as key predictors of future math abilities. Hence, the availability of universal screening tools is vital to promptly identify children who are lacking in these skills, allowing for tailored classroom practices to meet their needs. This study aimed to develop a mathematical screening tool and assess its psychometric properties.

Methods

The tool encompasses both group and individual tasks, to evaluate counting, cardinality, subitizing, quantity discrimination, addition, and subtraction. The tool was administered twice to 257 children, aged 5-6, in their final year of kindergarten in Portugal, at both the start and end of the school year.

Results

The findings reveal that the tasks generally present a low level of difficulty, especially by the end of kindergarten. Factor analysis demonstrated an adequate structure, and all dimensions showed high internal consistency (>0.80). There was a medium-to-high intercorrelation among the various tasks. Correlations between task scores at the beginning and end of the school year were high. Furthermore, scores across all tasks correlated with math achievement in the first grade of primary education.

Discussion

These outcomes suggest that the tool is both valid and reliable, making it a useful resource for assessing and intervening in math skills during the critical years before school entry.
Association between human blood metabolome and the risk of delirium: a Mendelian Randomization study
Authors: Long Chubing , Lin Dong , Zhang Lieliang , Lin Yue , Yao Qing , Zhang Guangyong , Li Longshan , Liu Hailin , Ying Jun , Wang Xifeng , Hua Fuzhou
Published: January 2024

Background

Delirium significantly contributes to both mortality and morbidity among hospitalized older adults. Furthermore, delirium leads to escalated healthcare expenditures, extended hospital stays, and enduring cognitive deterioration, all of which are acknowledged detrimental outcomes. Nonetheless, the current strategies for predicting and managing delirium remain constrained. Our aim was to employ Mendelian randomization (MR) to investigate the potential causal relationship between metabolites and delirium, as well as to identify potential therapeutic targets.

Methods

We identified 129 distinct blood metabolites from three genome-wide association studies (GWASs) conducted on the metabolome, involving a total of 147,827 participants of European descent. Genetic information pertaining to delirium was sourced from the ninth iteration of the Finngen Biobank, encompassing 359,699 individuals of Finnish ancestry. We conducted MR analyses to evaluate the connections between blood metabolites and delirium. Additionally, we extended our analysis to encompass the entire phenome using MR, aiming to uncover potential on-target consequences resulting from metabolite interventions.

Results

In our investigation, we discovered three metabolites serving as causal mediators in the context of delirium: clinical low density lipoprotein cholesterol (LDL-C) (odds ratio [OR]: 1.47, 95% confidence interval [CI]: 1.25-1.73, p = 3.92 x 10-6), sphingomyelin (OR: 1.47, 95% CI: 1.25-1.74, p = 5.97 x 10-6), and X-11593–O-methylascorbate (OR: 0.21, 95% CI: 0.10-0.43, p = 1.86 x 10-5). Furthermore, utilizing phenome-wide MR analysis, we discerned that clinical LDL-C, sphingomyelin, and O-methylascorbate not only mediate delirium susceptibility but also impact the risk of diverse ailments.

Limitations

(1) Limited representation of the complete blood metabolome, (2) reliance on the PheCode system based on hospital diagnoses may underrepresent conditions with infrequent hospital admissions, and (3) limited to European ancestry.

Conclusion

The genetic prediction of heightened O-methylascorbate levels seems to correspond to a diminished risk of delirium, in contrast to the association of elevated clinical LDL-C and sphingomyelin levels with an amplified risk. A comprehensive analysis of side-effect profiles has been undertaken to facilitate the prioritization of drug targets. Notably, O-methylascorbate emerges as a potentially auspicious target for mitigating and treating delirium, offering the advantage of lacking predicted adverse side effects.
The relationship between electricity consumption, trade, and GDP and the effect of COVID-19: a panel ARDL approach on the Visegrad countries
Authors: Uğurlu Erginbay , Jindřichovská Irena
Published: January 2024

The aim of the study is to explore the linkage between electricity consumption, international trade and GDP during the COVID-19 pandemic in a sample of the Visegrad Four (V4) countries. The study uses data from the period of 2010 Q1–2021 Q3. Applying the panel-pooled mean group-autoregressive distributed lag (PMG-ARDL) model, we evaluate both long-run and short-run linkages among electricity consumption, trade, GDP, and the COVID-19 pandemic. We tested both the long-run and short-run linkages among electricity consumption, trade, GDP, and a COVID-19 dummy variable for the Visegrad countries. The main contribution of this study to the literature is testing the effect of COVID-19 on electricity demand by considering trade and GDP for the Visegrad countries. Our empirical findings show that there is no long-term causal relationship among these variables for the Visegrad countries. But, on the other hand, even if the trade variable is not significant in the long run, it is significant in the short run and for the cross-section models as it concerns the policy implications stemming from this exceptional and unique situation. We learned that it is difficult to frame any viable policy implications from such an extraordinary situation when many states have not tested their ad hoc measures. The best way, we consider, would be to renew trade and improve production before the next crisis. Nonetheless, in the area of technology, this painful period brought faster digitalization in all segments and the rationing of natural resources.
Improved VSG strategy of grid-forming inverters for supporting inertia and damping
Authors: Liu Dan , Jiang Kezheng , Ji Xiaotong , Cao Kan , Xu Chi , Sang Shun , Yang Dejian
Published: January 2024

A virtual synchronous generator (VSG) strategy can introduce the rotational inertia and damping characteristics of the synchronous generator to the static inverter, e.g., PV, wind generation, and ESS, which are used to enhance the system frequency support characteristics of the micro-grid. However, under various operations of the VSG, the inertia and damping support capabilities are different, and the conventional VSG strategy with a fixed control coefficient sacrifices a certain degree of dynamic regulation performance with less robustness. This research proposes an improved VSG strategy with adaptive inertia and damping coefficients to increase the flexibility of VSG. To this end, a mathematical model is first established to analyze the impact of various parameters on the characteristics of VSG, and then the root trajectory is used to explore the impacts of various rotational inertia and damping coefficients on the stability of the VSG system. Second, an improved control strategy with adaptive inertia and damping coefficients is proposed based on the characteristics of the second-order system and the system frequency deviations. Finally, a simulation system with the VSG is constructed based on MATLAB/Simulink. The effectiveness of the proposed control strategy is verified by comparing the simulation results to the conventional control strategy with the fixed control coefficients under over-frequency and under-frequency disturbances.
Bibliometric and visual analysis of single-cell sequencing from 2010 to 2022
Authors: Chen Ling , Wan Yantong , Yang Tingting , Zhang Qi , Zeng Yuting , Zheng Shuqi , Ling Zhishan , Xiao Yupeng , Wan Qingyi , Liu Ruili , Yang Chun , Huang Guozhi , Zeng Qing
Published: January 2024

Background: Single-cell sequencing (SCS) is a technique used to analyze the genome, transcriptome, epigenome, and other genetic data at the level of a single cell. The procedure is commonly utilized in multiple fields, including neurobiology, immunology, and microbiology, and has emerged as a key focus of life science research. However, a thorough and impartial analysis of the existing state and trends of SCS-related research is lacking. The current study aimed to map the development trends of studies on SCS during the years 2010–2022 through bibliometric software.

Methods: Pertinent papers on SCS from 2010 to 2022 were obtained using the Web of Science Core Collection. Research categories, nations/institutions, authors/co-cited authors, journals/co-cited journals, co-cited references, and keywords were analyzed using VOSviewer, the R package “bibliometric”, and CiteSpace.

Results: The bibliometric analysis included 9,929 papers published between 2010 and 2022, and showed a consistent increase in the quantity of papers each year. The United States was the source of the highest quantity of articles and citations in this field. The majority of articles were published in the periodical Nature Communications. Butler A was the most frequently quoted author on this topic, and his article “Integrating single-cell transcriptome data across diverse conditions, technologies, and species” has received numerous citations to date. The literature and keyword analysis showed that studies involving single-cell RNA sequencing (scRNA-seq) were prominent in this discipline during the study period.

Conclusion: This study utilized bibliometric techniques to visualize research in SCS-related domains, which facilitated the identification of emerging patterns and future directions in the field. Current hot topics in SCS research include COVID-19, tumor microenvironment, scRNA-seq, and neuroscience. Our results are significant for scholars seeking to identify key issues and generate new research ideas.
Case Report: From epilepsy and uterus didelphys to Turner syndrome-associated dysgerminoma
Authors: Li Jinghua , Zhu Haipeng , Ma Xuelian , Li Jia , Xue Jing , Feng Limin
Published: January 2024

Dysgerminoma is a rare occurrence in Turner syndrome patients without Y chromosome mosaicism or hormone therapy during puberty. We present a unique case of a 33-year-old nulliparous Chinese woman with intermittent epilepsy and Mullerian anomalies carrying a double uterus, cervix, and vagina. The patient is also characterized as having Turner syndrome accompanied by 46,X, del(Xp22.33-11.23) and del(2)(q11.1-11.2). MRI exhibited a 17.0 cm × 20.0 cm × 10.5 cm solid ovarian lesion. Radical surgery and pathology revealed dysgerminoma at stage IIIc with lymphatic metastases and a KIT gene mutation identified in exon 13. Furthermore, the tumor microenvironment (TME) displayed robust expression of CD4+ T lymphocytes and PD-1, whereas the distribution of CD8+ T lymphocytes and PDL-1 was sporadic. Despite the administration of enoxaparin to prevent thromboembolism, the patient experienced multiple cerebral infarctions during chemotherapy. Subsequently, the patient chose to decline further treatment and was discharged. This exceptional case imparts several noteworthy lessons. First, the coexistence of Mullerian anomalies, although rare, is not incompatible with Turner syndrome. Second, screening for KIT mutations is imperative to reduce the risk of dysgerminoma in Turner syndrome, especially for patients with Y mosaicism who are recommended for hormone replacement therapy. Lastly, comprehensive anticoagulation therapy is crucial for Turner syndrome patients undergoing cisplatin-based chemotherapy.
Empirical validation of ProteinMPNN’s efficiency in enhancing protein fitness
Authors: Wang Tianshu , Jin Xiaocheng , Lu Xiaoli , Min Xiaoping , Ge Shengxiang , Li Shaowei
Published: January 2024

Introduction: Protein engineering, which aims to improve the properties and functions of proteins, holds great research significance and application value. However, current models that predict the effects of amino acid substitutions often perform poorly when evaluated for precision. Recent research has shown that ProteinMPNN, a large-scale pre-training sequence design model based on protein structure, performs exceptionally well. It is capable of designing mutants with structures similar to the original protein. When applied to the field of protein engineering, the diverse designs for mutation positions generated by this model can be viewed as a more precise mutation range.

Methods: We collected three biological experimental datasets and compared the design results of ProteinMPNN for wild-type proteins with the experimental datasets to verify the ability of ProteinMPNN in improving protein fitness.

Results: The validation on biological experimental datasets shows that ProteinMPNN has the ability to design mutation types with higher fitness in single and multi-point mutations. We have verified the high accuracy of ProteinMPNN in protein engineering tasks from both positive and negative perspectives.

Discussion: Our research indicates that using large-scale pre trained models to design protein mutants provides a new approach for protein engineering, providing strong support for guiding biological experiments and applications in biotechnology.
Is ChatGPT ready to change mental healthcare? Challenges and considerations: a reality-check
Authors: Pandya Apurvakumar , Lodha Pragya , Ganatra Amit
Published: January 2024

As mental healthcare is highly stigmatized, digital platforms and services are becoming popular. A wide variety of exciting and futuristic applications of AI platforms are available now. One such application getting tremendous attention from users and researchers alike is Chat Generative Pre-trained Transformer (ChatGPT). ChatGPT is a powerful chatbot launched by open artificial intelligence (Open AI). ChatGPT interacts with clients conversationally, answering follow-up questions, admitting mistakes, challenging incorrect premises, and rejecting inappropriate requests. With its multifarious applications, the ethical and privacy considerations surrounding the use of these technologies in sensitive areas such as mental health should be carefully addressed to ensure user safety and wellbeing. The authors comment on the ethical challenges with ChatGPT in mental healthcare that need attention at various levels, outlining six major concerns viz., (1) accurate identification and diagnosis of mental health conditions; (2) limited understanding and misinterpretation; (3) safety, and privacy of users; (4) bias and equity; (5) lack of monitoring and regulation; and (6) gaps in evidence, and lack of educational and training curricula.
Clinical-grade human skin-derived ABCB5+ mesenchymal stromal cells exert anti-apoptotic and anti-inflammatory effects in vitro and modulate mRNA expression in a cisplatin-induced kidney injury murine model
Authors: Rendra Erika , Crigna Adriana Torres , Daniele Cristina , Sticht Carsten , Cueppers Maike , Kluth Mark Andreas , Ganss Christoph , Frank Markus H. , Gretz Norbert , Bieback Karen
Published: January 2024

Acute kidney injury (AKI) is characterized by a rapid reduction in renal function and glomerular filtration rate (GFR). The broadly used anti-cancer chemotherapeutic agent cisplatin often induces AKI as an adverse drug side effect. Therapies targeted at the reversal of AKI and its potential progression to chronic kidney disease or end-stage renal disease are currently insufficiently effective. Mesenchymal stromal cells (MSCs) possess diverse immunomodulatory properties that confer upon them significant therapeutic potential for the treatment of diverse inflammatory disorders. Human dermal MSCs expressing ATP-Binding Cassette member B5 (ABCB5) have shown therapeutic efficacy in clinical trials in chronic skin wounds or recessive dystrophic epidermolysis bullosa. In preclinical studies, ABCB5+ MSCs have also shown to reverse metabolic reprogramming in polycystic kidney cells, suggesting a capacity for this cell subset to improve also organ function in kidney diseases. Here, we aimed to explore the therapeutic capacity of ABCB5+ MSCs to improve renal function in a preclinical rat model of cisplatin-induced AKI. First, the anti-apoptotic and immunomodulatory capacity was compared against research-grade adipose stromal cells (ASCs). Then, cross-species immunomodulatory capacity was checked, testing first inhibition of mitogen-driven peripheral blood mononuclear cells and then modulation of macrophage function. Finally, therapeutic efficacy was evaluated in a cisplatin AKI model. First, ABCB5+ MSCs suppressed cisplatin-induced apoptosis of human conditionally-immortalized proximal tubular epithelial cells in vitro, most likely by reducing oxidative stress. Second, ABCB5+ MSCs inhibited the proliferation of either human or rat peripheral blood mononuclear cells, in the human system via the Indoleamine/kynurenine axis and in the murine context via nitric oxide/nitrite. Third, ABCB5+ MSCs decreased TNF-α secretion after lipopolysaccharide stimulation and modulated phagocytosis and in both human and rat macrophages, involving prostaglandin E2 and TGF-β1, respectively. Fourth, clinical-grade ABCB5+ MSCs grafted intravenously and intraperitoneally to a cisplatin-induced AKI murine model exerted modulatory effects on mRNA expression patterns toward an anti-inflammatory and pro-regenerative state despite an apparent lack of amelioration of renal damage at physiologic, metabolic, and histologic levels. Our results demonstrate anti-inflammatory and pro-regenerative effects of clinical grade ABCB5+ MSCs in vitro and in vivo and suggest potential therapeutic utility of this cell population for treatment or prevention of cisplatin chemotherapy-induced tissue toxicity.
Germinal centers are permissive to subdominant antibody responses
Authors: Robert Philippe A. , Arulraj Theinmozhi , Meyer-Hermann Michael
Published: January 2024

Introduction

A protective humoral response to pathogens requires the development of high affinity antibodies in germinal centers (GC). The combination of antigens available during immunization has a strong impact on the strength and breadth of the antibody response. Antigens can display various levels of immunogenicity, and a hierarchy of immunodominance arises when the GC response to an antigen dampens the response to other antigens. Immunodominance is a challenge for the development of vaccines to mutating viruses, and for the development of broadly neutralizing antibodies. The extent by which antigens with different levels of immunogenicity compete for the induction of high affinity antibodies and therefore contribute to immunodominance is not known.

Methods

Here, we perform in silico simulations of the GC response, using a structural representation of antigens with complex surface amino acid composition and topology. We generate antigens with complex domains of different levels of immunogenicity and perform simulations with combinations of these domains.

Results

We found that GC dynamics were driven by the most immunogenic domain and immunodominance arose as affinity maturation to less immunogenic domain was inhibited. However, this inhibition was moderate since the less immunogenic domain exhibited a weak GC response in the absence of the most immunogenic domain. Less immunogenic domains reduced the dominance of GC responses to more immunogenic domains, albeit at a later time point.

Discussion

The simulations suggest that increased vaccine valency may decrease immunodominance of the GC response to strongly immunogenic domains and therefore, act as a potential strategy for the natural induction of broadly neutralizing antibodies in GC reactions.
Gamma/delta T cells as cellular vehicles for anti-tumor immunity
Authors: Wang Chelsia Qiuxia , Lim Pei Yu , Tan Andy Hee-Meng
Published: January 2024

Adoptive cellular immunotherapy as a new paradigm to treat cancers is exemplified by the FDA approval of six chimeric antigen receptor-T cell therapies targeting hematological malignancies in recent years. Conventional αβ T cells applied in these therapies have proven efficacy but are confined almost exclusively to autologous use. When infused into patients with mismatched human leukocyte antigen, αβ T cells recognize tissues of such patients as foreign and elicit devastating graft-versus-host disease. Therefore, one way to overcome this challenge is to use naturally allogeneic immune cell types, such as γδ T cells. γδ T cells occupy the interface between innate and adaptive immunity and possess the capacity to detect a wide variety of ligands on transformed host cells. In this article, we review the fundamental biology of γδ T cells, including their subtypes, expression of ligands, contrasting roles in and association with cancer prognosis or survival, as well as discuss the gaps in knowledge pertaining to this cell type which we currently endeavor to elucidate. In addition, we propose how to harness the unique properties of γδ T cells for cellular immunotherapy based on lessons gleaned from past clinical trials and provide an update on ongoing trials involving these cells. Lastly, we elaborate strategies that have been tested or can be explored to improve the anti-tumor activity and durability of γδ T cells in vivo.
Examining the function of macrophage oxidative stress response and immune system in glioblastoma multiforme through analysis of single-cell transcriptomics
Authors: Xing Jin , Cai Huabao , Lin Zhiheng , Zhao Liang , Xu Hao , Song Yanbing , Wang Zhihan , Liu Chaobo , Hu Guangdong , Zheng Jiajie , Ren Li , Wei Zilong
Published: January 2024

Background

Glioblastoma (GBM), a prevalent malignant neoplasm within the neuro-oncological domain, has been a subject of considerable scrutiny. Macrophages, serving as the principal immunological constituents, profoundly infiltrate the microenvironment of GBM. However, investigations elucidating the intricate immunological mechanisms governing macrophage involvement in GBM at the single-cell level remain notably limited.

Methods

We conducted a comprehensive investigation employing single-cell analysis, aiming to redefine the intricate cellular landscape within both the core and peripheral regions of GBM tumors. Our analytical focus extended to the profound study of macrophages, elucidating their roles within the context of oxidative stress, intercellular information exchange, and cellular trajectories concerning GBM and its assorted subpopulations. We pursued the identification of GBM prognostic genes intricately associated with macrophages. Utilizing experimental research to investigate the relevance of MANBA in the context of GBM.

Results

Our investigations have illuminated the central role of macrophages in the intricate interplay among various subpopulations within the GBM microenvironment. Notably, we observed a pronounced intensity of oxidative stress responses within macrophages when compared to their GBM counterparts in other subpopulations. Moreover, macrophages orchestrated intricate cellular communication networks, facilitated by the SPP1-CD44 axis, both internally and with neighboring subpopulations. These findings collectively suggest the potential for macrophage polarization from an M1 to an M2 phenotype, contributing to immune suppression within the tumor microenvironment. Furthermore, our exploration unearthed GBM prognostic genes closely associated with macrophages, most notably MANBA and TCF12. Remarkably, MANBA appears to participate in the modulation of neuroimmune functionality by exerting inhibitory effects on M1-polarized macrophages, thereby fostering tumor progression. To bolster these assertions, experimental validations unequivocally affirmed the promotional impact of MANBA on GBM, elucidated through its capacity to curb cell proliferation, invasiveness, and metastatic potential.

Conclusion

These revelations represent a pivotal step towards unraveling the intricate immunological mechanisms governing the interactions between macrophages and diverse subpopulations within the GBM milieu. Furthermore, they lay the foundation for the development of an innovative GBM prognostic model, with MANBA at its epicenter, and underscore the potential for novel immunotherapeutic targets in the ongoing pursuit of enhanced treatment modalities for this formidable malignancy.
Case report: Apalutamide-induced severe lethal cutaneous adverse effects in China
Authors: Wang Qi , Cao Huali , Zhang Xuetong , Wu Huifeng , Tang Zhuangli
Published: January 2024

Introduction

Apalutamide is a novel agent for castration-resistant prostate cancer while skin rashes are the most common untoward reactions. Up to now, most of the reported dermatologic adverse events (dAEs) allocated to mild and moderate with a fair prognosis. Herein, we report a case series of severe dAEs in China caused by apalutamide.

Case presentation

The four patients all developed severe and lethal drug eruptions including Stevens-Johnson syndrome and toxic epidermal necrolysis with a mean incubation period of 40 days. On the basis of the medical condition, all the patients were suggested to withdraw apalutamide and three of them recovered. Of note, attempts of rechallenges of apalutamide may be fatal.

Discussion

The incidence of dAEs in previously conducted clinical trials exceeded 20%, with maculopapular rashes being the most common feature. However, the incidence and severity varied in different geographic regions and ethnicities. Inadequate attention was paid to severe cutaneous adverse reactions. Long latency may easily lead to the misdiagnosis of dAEs, and immediate withdrawal of apalutamide is the cornerstone of therapies.

Conclusion

Special and adequate attention should be paid to apalutamide-attributed severe cutaneous adverse effects. Besides, the prognosis of severe drug eruptions may be disappointing, and in-time withdrawal is vital.
High-grade synovitis associates with clinical markers and response to therapy in chronic inflammatory arthritis: post hoc analysis of a synovial biomarkers prospective cohort study
Authors: Garaffoni Carlo , Tamussin Marianna , Calciolari Ilaria , Lanza Giovanni , Bortoluzzi Alessandra , Scirè Carlo Alberto , Govoni Marcello , Silvagni Ettore
Published: January 2024

Background

Inflammatory arthritis (IAs), such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), are characterized by the presence of chronic synovitis. The Krenn’s synovitis score (KSS), a simple tool detectable by haematoxylin/eosin staining of synovial biopsy samples, allows the discrimination between high-grade and low-grade synovitis. The aim of this study was to identify the clinical associations of KSS and to evaluate the relationship between high-grade synovitis and treatment response in IA patients.

Methods

Clinical, laboratory and ultrasound data were retrieved from RA and PsA patients recruited in the prospective MATRIX cohort study. Inclusion criteria were age≥18 years, RA or PsA diagnosis, and presence of active disease with eligibility to start/modify therapy. Patients underwent ultrasound-guided synovial biopsy of one of the most involved joints before starting/modifying treatment according to treat-to-target strategy. The samples were analysed by an expert pathologist for KSS calculation. Univariable and multivariable logistic regression analyses were performed to evaluate the relationship between KSS and baseline variables. The association between KSS and treatment response at 24 weeks of follow-up was investigated in univariable logistic regression analysis.

Results

53 patients, 34 RA and 19 PsA, completed 24 weeks of follow-up after synovial biopsy. Patients were either treatment naïve (N=6, 11%), csDMARDs-experienced (N=46, 87%) or b/tsDMARDs-experienced (N=20, 38%). Median KSS was 6.00 (Q1-Q3 4.00-7.00) in RA and 4.00 (3.00-6.00) in PsA (p=0.040), and inflammatory infiltrates score was significantly higher in RA than in PsA patients (median 3.00 vs 2.00, p=0.021). In multivariable analysis, synovial effusion in the biopsied joint (OR 9.26, 95%CI 2.12-53.91) and erythrocyte sedimentation rate (ESR) (OR 1.04, 95%CI 1.01-1.08) associated with high KSS. High-grade synovitis significantly associated with a higher probability of achieving DAS28 remission, ACR20/50 response, and Boolean2.0 remission, independently from diagnosis.

Conclusion

Several markers of pro-inflammatory pathways associated with the presence of high-grade synovitis, and patients with higher KSS shared a higher probability of treatment targets achievement in the follow up. The integration of a simple and feasible tool like KSS in the clinical and prognostic stratification of patients with IA might help in intercepting patients with a disease more prone to respond to available treatment paradigms.
Establishment and immune phenotyping of patient-derived glioblastoma models in humanized mice
Authors: Liu Longsha , van Schaik Thijs A. , Chen Kok-Siong , Rossignoli Filippo , Borges Paulo , Vrbanac Vladimir , Wakimoto Hiroaki , Shah Khalid
Published: January 2024

Glioblastoma (GBM) is the most aggressive and common type of malignant brain tumor diagnosed in adults. Preclinical immunocompetent mouse tumor models generated using mouse tumor cells play a pivotal role in testing the therapeutic efficacy of emerging immune-based therapies for GBMs. However, the clinical translatability of such studies is limited as mouse tumor lines do not fully recapitulate GBMs seen in inpatient settings. In this study, we generated three distinct, imageable human-GBM (hGBM) models in humanized mice using patient-derived GBM cells that cover phenotypic and genetic GBM heterogeneity in primary (invasive and nodular) and recurrent tumors. We developed a pipeline to first enrich the tumor-initiating stem-like cells and then successfully established robust patient-derived GBM tumor engraftment and growth in bone marrow-liver-thymus (BLT) humanized mice. Multiplex immunofluorescence of GBM tumor sections revealed distinct phenotypic features of the patient GBM tumors, with myeloid cells dominating the immune landscape. Utilizing flow cytometry and correlative immunofluorescence, we profiled the immune microenvironment within the established human GBM tumors in the BLT mouse models and showed tumor infiltration of variable human immune cells, creating a unique immune landscape compared with lymphoid organs. These findings contribute substantially to our understanding of GBM biology within the context of the human immune system in humanized mice and lay the groundwork for further translational studies aimed at advancing therapeutic strategies for GBM.