bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetics and clinical phenotype of Erdheim–Chester disease: A case report of constrictive pericarditis and a systematic review of the literature
Authors: Bartoli Lorenzo , Angeli Francesco , Stefanizzi Andrea , Fabrizio Michele , Paolisso Pasquale , Bergamaschi Luca , Broccoli Alessandro , Zinzani Pier Luigi , Galiè Nazzareno , Rucci Paola , Foà Alberto , Pizzi Carmine
Published: August 2022

Background

Erdheim–Chester disease (ECD) is a rare form of histiocytosis. An increasing number of genetic mutations have been associated with this syndrome, confirming its possible neoplastic origin. Recently, a connection between the BRAF mutational status and a specific phenotype was described; however, no studies have yet evaluated the correlations between other mutations and the clinical features of the disease.

Objectives

This study aims to clarify the association between the clinical phenotype and genetic mutations identified in the neoplastic cell lines of ECD.

Methods

We describe a case of ECD characterized by pericardial involvement and a KRAS mutation shared with chronic myelomonocytic leukemia. Hence, through a meta-analysis of individual participant data of all genetically and clinically described cases of ECD in the literature, we aimed to elucidate the association between its clinical phenotype and baseline genetic mutations.

Results

Of the 760 studies screened, our review included 133 articles published from 2012 to April 2021. We identified 311 ECD patients whose genotype and phenotype were described. We found five main genes (BRAF, KRAS, NRAS, PIK3CA, and MAP2K1) whose mutation was reported at least three times. Mutation of BRAF led to a neurological disease (183 of 273 patients, 67%; p < 0.001); KRAS- and NRAS-mutated patients mainly showed cutaneous (five of six patients, 83.3%, p < 0.004) and pleural (four of nine patients, 44%, p = 0.002) involvement, respectively; PIK3CA was not associated with specific organ involvement; and MAP2K1 mutations caused the disease to primarily involve the peritoneum and retroperitoneum (4 of 11, 36.4%, p = 0.01).

Conclusion

This work implies a possible influence of baseline mutation over the natural history of ECD, underscoring the importance of a thorough genetic analysis in all cases with the ultimate goal of identifying a possible targeted therapy for each patient.
Case report: Spontaneous coronary artery rupture presenting with acute coronary syndrome: A rare diagnosis of common disease
Authors: Sayed Ahmed Ibrahim
Published: August 2022

Acute coronary syndrome (ACS), myocardial infarction, and sudden death have all been linked to spontaneous coronary artery rapture (SCAR). Patients primarily afflicted by SCAR are those with or without cardiovascular risk factors, notably men, implying a mechanism distinct from the more prevalent atherosclerosis. Both medical and interventional treatment should consider the diverse causes of ACS as well as the patient's clinical stability. I herein report an unusual case of a 33 years old male who presented with acute chest pain to the emergency department. His physical exam was normal. The electrocardiogram showed non-specific ST segment changes in anterior leads, and the echocardiogram revealed mild anterior wall hypokinesia with no evidence of pericardial effusion. He underwent coronary angiography which revealed a contained rupture in the anterior descending coronary artery. The patient underwent uneventful lifesaving coronary artery perforation repair. It concluded that, though rare, SCAR should be considered as a differential diagnosis in patients with ACS, even in the absence of pericardial effusion in adult patients of all ages.
Associations between sleep duration and cardiovascular diseases: A meta-review and meta-analysis of observational and Mendelian randomization studies
Authors: Wang Shanshan , Li Zhexi , Wang Xiaoyu , Guo Sheng , Sun Yujing , Li Guohua , Zhao Chenhao , Yuan Wenhui , Li Meng , Li Xiaolei , Ai Sizhi
Published: August 2022

The associations between sleep duration and cardiovascular diseases (CVDs) have been explored in many observational studies. However, the causality of sleep duration and many CVDs, such as coronary artery disease (CAD), heart failure (HF), and stroke, remains unclear. In this study, we conducted a systematic meta-review and meta-analysis of the results of observational and Mendelian randomization (MR) studies to examine how sleep duration impacts the risk of CVDs. We searched articles published in English and before 10 September 2021 in PubMed, Web of Science, and Embase. The articles were screened independently by two reviewers to minimize potential bias. We combined the meta-analyses of observational studies and 11 MR studies and summarized evidence of the effect of sleep duration on the risk of CAD, HF, stroke, and cardiovascular and all-cause mortality. Results showed that (a) evidence is accumulating that short sleep duration is a causal risk factor for CAD and HF; (b) abundant evidence from observational studies supports that long sleep duration is associated with the risk of CAD, stroke, and mortality, and long sleep duration has no causal associations with stroke and CAD in the MR studies; the causation of long sleep duration and other CVDs should be further studied; and (c) emerging evidence indicates that an increase in hours of sleep is associated with a decreased risk of CAD. Finally, we discussed the underlying pathophysiological mechanisms underlying short sleep duration and CVDs and suggested that increasing sleep duration benefits cardiovascular health.
Liver biomarkers, genetic and lifestyle risk factors in relation to risk of cardiovascular disease in Chinese
Authors: Wang Xinyu , Cheng Si , Lv Jun , Yu Canqing , Guo Yu , Pei Pei , Yang Ling , Millwood Iona Y. , Walters Robin , Chen Yiping , Du Huaidong , Duan Haiping , Gilbert Simon , Avery Daniel , Chen Junshi , Pang Yuanjie , Chen Zhengming , Li Liming
Published: August 2022

Background and aims

Liver biomarkers and metabolic associated fatty liver disease (MAFLD) have been shown to be associated with cardiovascular disease (CVD). However, there is limited evidence on CVD subtypes [myocardial infarction (MI), ischemic stroke (IS), and intracerebral hemorrhage (ICH)], especially in the Chinese population. We examined these associations overall, by genetic predisposition to non-alcoholic fatty liver disease (NAFLD), and by lifestyle risk factors.

Approach and results

This is a nested case-control study of CVD (10,298 cases and 5,388 controls) within the China Kadoorie Biobank. Cox regression was used to estimate adjusted hazard ratios (HRs) for CVD associated with liver biomarkers and MAFLD and by stratum of genetic risk and a combined high-risk lifestyle score. For liver enzymes, there were positive associations with MI and IS, but no associations with ICH or carotid plaque. There were positive associations of NAFLD with risks of MI, IS, and ICH (HR 1.43 [95% CI 1.30–1.57], 1.25 [1.16–1.35], and 1.12 [1.02–1.23]) as well as carotid plaque (odds ratio 2.36 [1.12–4.96]). The associations of NAFLD with CVD and carotid plaque were stronger among individuals with a high genetic risk (ICH: p-interaction < 0.05), while the associations with stroke were stronger among those with a favorable lifestyle (p-interaction < 0.05). The results for MAFLD mirrored those for NAFLD.

Conclusion

In Chinese adults, liver biomarkers and MAFLD were associated with risk of CVD, with different magnitudes of associations by CVD subtypes. Genetic predisposition to NAFLD and lifestyle factors modified the associations of fatty liver with stroke.
Long-term prognostic value of macrophage migration inhibitory factor in ST-segment elevation myocardial infarction patients with metabolic syndrome after percutaneous coronary intervention
Authors: Yu Xiao-Lin , Zhao Qian , Liu Fen , Yuan Yu-Juan , Fang Bin-Bin , Zhang Xue-He , Li Wen-Ling , Li Xiao-Mei , Du Guo-Li , Gao Xiao-Ming , Yang Yi-Ning
Published: August 2022

Metabolic syndrome (MetS) is a major risk factor for cardiovascular disease and negatively affecting the prognosis of patients with ST elevation myocardial infarction (STEMI). Macrophage migration inhibitory factor (MIF) is a multipotent cytokine involved in various cardiovascular and inflammatory diseases. In this prospective study, we investigate the value of MIF in the long-term prognosis of STEMI combined with MetS after emergency PCI. Circulating MIF levels were measured at admission, and major adverse cardiovascular and cerebrovascular events (MACCE) were monitored during the follow-up period of 4.9 (3.9–5.8) years. MACCE occurred in 92 patients (22.9%), which was significantly higher in MetS (69/255, 27.1%) than in the non-MS subgroup (23/146, 15.8%, P < 0.05). Patients with MetS developed MACCE had the highest admission MIF level. Kaplan-Meier survival analysis using the cutoff value of admission MIF (143 ng/ml) showed that patients with a higher MIF level had a greater incidence of MACCE than those with lower MIF levels in both the MetS (P < 0.0001) and non-MetS groups (P = 0.016). After adjustment for clinical variables, the value of MIF ≥ 143 ng/ml still had the predictive power for the MetS group [HR 9.56, 95% CI (5.397–16.944),P < 0.001]; nevertheless, it was not the case in the non-MetS group. Our findings indicated that MetS is a critical risk factor for adverse clinical outcomes in patients with STEMI, and a high admission MIF level has predictive power for the long-term MACCE, which is superior in STEMI patients with MetS and better than other traditional predictors.
Uric acid and arterial stiffness in children and adolescents: Role of insulin resistance and blood pressure
Authors: Genovesi Simonetta , Montelisciani Laura , Viazzi Francesca , Giussani Marco , Lieti Giulia , Patti Ilenia , Orlando Antonina , Antolini Laura , Salvi Paolo , Parati Gianfranco
Published: August 2022

Several studies describe the association between serum uric acid (SUA) and arterial stiffness in adults. Uric acid contributes through several mechanisms to the increase in blood pressure (BP) and adversely affects the insulin signaling pathway. Moreover, SUA predict the development of hypertension and insulin resistance up to type 2 diabetes. Early arterial stiffening, estimated by carotid-femoral pulse wave velocity (PWV), may already be present in pediatric age. Aim of our study was to investigate the relationship between SUA and PWV in a pediatric population and its interaction with insulin resistance and BP. In 322 children and adolescents (56.2% male, mean age 11.3 [SD 2.8] years), we measured weight, height, waist circumference, BP and PWV. We also assayed SUA and estimated glomerular filtration rate (eGFR) and calculated HOMA-index as a marker of insulin resistance. Simple and multiple regression analyses were performed to assess variables associated with PWV. Mediation models were applied to identify the direct and indirect effects of individual variables on PWV. On univariate analysis, age (p < 0.001), waist circumference-to-height ratio (p = 0.036), systolic and diastolic BP (SBP and DBP) z-score (p < 0.001), heart rate (p = 0.028), SUA (p = 0.002), HOMA-index (p < 0.001), and eGFR (p = 0.014) were significantly associated with PWV. The multiple regression model showed that only age (p = 0.028), SBP z-score (p = 0.006), and heart rate (p = 0.001) were significantly associated with PWV. The results were superimposable when the DBP z-score replaced the SBP z-score in the model. Mediation models showed that the effect of eGFR on PWV was fully mediated by SUA (p = 0.015) and that the effect of SUA on PWV was totally mediated by HOMA-index (p < 0.001). Both SUA (p < 0.01) and HOMA-index (p < 0.01) had a significant association with higher SBP (DBP) z-scores. The double mediation model including both BP and HOMA-index showed that the SUA effect on PWV was totally mediated by both variables (p = 0.005, for HOMA-index, p = 0.004, for SBP z-score and p = 0.007, for combined effect). The results were superimposable when the DBP z-score replaced the SBP z-score in the model. In conclusion, insulin resistance and BP are both important mediators of the association between SUA and vascular stiffness in pediatric age.
A New Blasting Permeability Enhancement Scheme For Deep-Buried Soft Coal Mining Face Based on Borehole Deformation Characteristics
Authors: Xuan Dequan , Zhang Jianhua , Huang Gang , Li Peng , Zhang Zhifeng
Published: August 2022

When blasting to enhance permeability in deep-buried soft coal mining face with a hard roof whose gas drainage requirement is higher, the charging hole and control hole (which doubles as drainage hole) are easy to be deformed and damaged, seriously affecting the blasting implementation and effect. Combining with the stratum characteristics of soft coal seam and hard surrounding rock, the idea of arranging boreholes near the surrounding rock to reduce deformation, inspired by the end effect, is put forward. Then, the experimental research on the deformation characteristics of boreholes at different distances from the surrounding rock is carried out, and the results show that the closer the borehole is to the roof (floor), the smaller the deformation, under the same stress conditions and within a certain distance. Based on this, a new scheme of arranging control holes and blasting holes near the roof and floor is proposed and designed. The field test results show that the blasting of 60 m deep holes are successfully realized and the remarkable permeability enhancement effect is achieved, verifying the feasibility and effectiveness of the improved scheme. This study explores a new blasting permeability enhancement scheme with practical value and reference significance for deep-buried soft coal mining face with a hard roof.
Trauma-informed initial teacher education training: A necessary step in a system-wide response to addressing childhood trauma
Authors: L’Estrange Lyra , Howard Judith
Published: August 2022

The growing prevalence of students affected by complex trauma, and the significant implications of unresolved trauma for these students later in life, highlights the imperative for a system-wide response to address the effects of complex trauma in student populations. An important step in this system-level response is increasing the knowledge of pre-service teachers in trauma-informed education practice through initial teacher education programs. Trauma-informed education settings are increasingly being recognised as critical in the resolution of complex trauma for impacted learners; however, trauma-informed training in pre-service teacher education is lacking. While a small body of recent research has shown promise in increasing pre-service teacher knowledge and confidence in teaching children and young people affected by complex trauma, there is scant longitudinal data that informs us of how pre-service teachers may be implementing the knowledge they have learnt in their practice after they have graduated. Through survey data, the current study explored the perceptions of 124 Australian pre-service teachers’ knowledge, self-efficacy, and resilience related to working with trauma-affected students before and after completing a 6-week initial teacher education unit in managing student behaviours related to complex trauma, and 1 year after graduating. Key findings indicated pre-service teachers’ knowledge, self-efficacy, and resilience in teaching students with complex trauma increased dramatically from pre- to post- study of the 6-week unit and this learning continued to be evident 1 year into their teaching career. However, the data also suggest that these attributes are not something that develops quickly or without ongoing professional learning and practice. Although pre-service and early career teachers seem keen to advance their trauma awareness, it is important they receive ongoing support to develop their skills into their early careers. These findings have implications for the design of trauma-informed initial teacher education and the importance of additional early career professional learning.
AI-PiM—Extending the RISC-V processor with Processing-in-Memory functional units for AI inference at the edge of IoT
Authors: Verma Vaibhav , Stan Mircea R.
Published: August 2022

The recent advances in Artificial Intelligence (AI) achieving “better-than-human” accuracy in a variety of tasks such as image classification and the game of Go have come at the cost of exponential increase in the size of artificial neural networks. This has lead to AI hardware solutions becoming severely memory-bound and scrambling to keep-up with the ever increasing “von Neumann bottleneck”. Processing-in-Memory (PiM) architectures offer an excellent solution to ease the von Neumann bottleneck by embedding compute capabilities inside the memory and reducing the data traffic between the memory and the processor. But PiM accelerators break the standard von Neumann programming model by fusing memory and compute operations together which impedes their integration in the standard computing stack. There is an urgent requirement for system-level solutions to take full advantage of PiM accelerators for end-to-end acceleration of AI applications. This article presents AI-PiM as a solution to bridge this research gap. AI-PiM proposes a hardware, ISA and software co-design methodology which allows integration of PiM accelerators in the RISC-V processor pipeline as functional execution units. AI-PiM also extends the RISC-V ISA with custom instructions which directly target the PiM functional units resulting in their tight integration with the processor. This tight integration is especially important for edge AI devices which need to process both AI and non-AI tasks on the same hardware due to area, power, size and cost constraints. AI-PiM ISA extensions expose the PiM hardware functionality to software programmers allowing efficient mapping of applications to the PiM hardware. AI-PiM adds support for custom ISA extensions to the complete software stack including compiler, assembler, linker, simulator and profiler to ensure programmability and evaluation with popular AI domain-specific languages and frameworks like TensorFlow, PyTorch, MXNet, Keras etc. AI-PiM improves the performance for vector-matrix multiplication (VMM) kernel by 17.63x and provides a mean speed-up of 2.74x for MLPerf Tiny benchmark compared to RV64IMC RISC-V baseline. AI-PiM also speeds-up MLPerf Tiny benchmark inference cycles by 2.45x (average) compared to state-of-the-art Arm Cortex-A72 processor.
Empagliflozin reduces diffuse myocardial fibrosis by extracellular volume mapping: A meta-analysis of clinical studies
Authors: Wang Haipeng , Ding Lin , Tian Liwen , Tian Yutian , Liao Lin , Zhao Junyu
Published: August 2022

Objective

The aim of the study was to evaluate the effect of empagliflozin on diffuse myocardial fibrosis by cardiac magnetic resonance (CMR) T1 mapping.

Research methods and procedures

Databases including PubMed, Cochrane library, Embase, and Sinomed for clinical studies of empagliflozin on myocardial fibrosis were searched. Two authors extracted the data and evaluated study quality independently. Weighted mean difference (WMD) and 95% confidence intervals (CI) were used for continuous variables. Review Manager 5.3 was used to performed the analysis.

Results

Six studies were included in this meta-analysis. One of the six studies was assessed as poor quality by the assessment of methodological quality; however, the remaining five studies were considered good. The WMD value of △extracellular volume (ECV) was merged by the fixed-effect model, and the pooled effect size was -1.48 (95% CI -1.76 to -1.21, P < 0.00001), which means in favor of empagliflozin. Heterogeneity analysis did not find any heterogeneity (chi2 = 0.39, P = 0.82, I2 = 0%). In addition, empagliflozin had a tendency to reduce ECV compared to treatment before with no statistical significance (WMD = -0.29, 95% CI -1.26 to 0.67, P = 0.55; heterozygosity test, chi2 = 2.66, P = 0.45, I2 = 0%). The WMD value of △native T1 was also merged by the fixed-effect model, but the pooled effect size showed neither statistical difference between empagliflozin and placebo treatment (WMD = -5.40, 95% CI -21.63 to 10.83, P = 0.51) nor heterogeneity (chi2 = 0.05, P = 0.83, I2 = 0%).

Conclusions

Empagliflozin has cardiovascular benefits by reducing diffuse myocardial fibrosis. ECV could act as a non-invasive imaging tool to assess diffuse myocardial fibrosis and monitor disease progression.

Systematic Review Registration

https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=324804, identifier: CRD42022324804
Pain and health-related quality of life in patients with hypophosphatasemia with and without ALPL gene mutations
Authors: Santurtún Maite , Mediavilla-Martinez Eva , Vega Ana I. , Gallego Natalia , Heath Karen E. , Tenorio Jair A. , Lapunzina Pablo , Riancho-Zarrabeitia Leyre , Riancho José A.
Published: August 2022

Background

Low serum alkaline phosphatase levels are the hallmark of hypophosphatasia, a disorder due to pathogenic variants of the ALPL gene. However, some patients do not carry ALPL variants and the cause of low alkaline phosphatase remains unknown. We aimed to determine health-related quality of life in adults with low alkaline phosphatase and explore the differences between patients with and without ALPL mutations.

Methods

We studied 35 adult patients with persistently low alkaline phosphatase unrelated to secondary acquired causes who had ALPL sequenced, and 35 controls of similar age. Three questionnaires about body pain (Brief Pain Inventory, BPI), physical disability (Health Assessment Questionnaire Disability Index, HAQ-DI), and health-related quality of life (36-item Short-Form Health Survey, SF-36) were delivered by telephone interviews.

Results

The mean BPI intensity and interference scores were higher in the patient group (p=0.04 and 0.004, respectively). All domains of the HAQ instrument tended to score better in the control group, with significant differences in the “reach” score (p=0.037) and the overall mean score (0.23 vs 0.09; p=0.029). Patients scored worse than controls in several SF-36 dimensions (Role physical, p=0.039; Bodily pain p=0.046; Role emotional, p=0.025). Patients with and without pathogenic variants scored similarly across all tests, without between-group significant differences.

Conclusions

Patients with persistently low levels of alkaline phosphatase have significantly worse scores in body pain and other health-related quality of life dimensions, without differences between patients with and without pathogenic variants identified in ALPL gene. This is consistent with the latter ones carrying mutations in regulatory regions.
Unraveling Moreton Bay reef history: An urban high-latitude setting for coral development
Authors: Hammerman Nicholas M. , Roff George , Lybolt Tracy , Eyal Gal , Pandolfi John M.
Published: August 2022

High-latitude habitats have become increasingly recognized as a potential climate refuge for coral communities, supporting both tropical and sub-tropical corals. Despite the increasing interest in the ecology of high-latitude corals, our current knowledge of their temporal dynamics is limited, especially within urbanized settings. Here, we examined the entire history of a high-latitude coral reef ecosystem in an urbanized setting. We surveyed Holocene fossil and modern coral communities along a water quality gradient in Moreton Bay, southeast Queensland, Australia, representing near-river (Wellington Point), intermediate (Peel Island) and near-oceanic (Myora Reef) environmental conditions. Reef accretion occurred during three discrete episodes from 7,400 to 5,800, 4,900 to 3,000, and 2,100 to 300 years BP, each separated by roughly 1,000-year hiatuses, where conditions were probably not favorable enough for reef accretion to occur. Episodic reef initiation and termination suggests strong environmental controls over reef development. Eastern Australian Holocene reef growth and cessation has been linked previously to sea level fluctuations and climatic regimes (e.g., ENSO). Within each reef building episode, there were few changes in coral assemblages over time. The fast growing and branching Acropora had a relative abundance greater than 90% in ten of the 13 sediment cores and all the submerged terrace excavations. However, substantial modification of adjacent coastal catchments from European colonization in the mid 1800’s resulted in increased sediment and nutrient discharge into the bay. This perturbation coincided with a greater abundance of stress-tolerant coral species (e.g., Dipsastraea, Goniastrea, and Goniopora) and the near extirpation of Acropora in the modern coral communities of near-river and intermediate sites due to poor water quality. In contrast, the modern coral assemblage at the near-oceanic site (Myora Reef) continues to be dominated by Acropora, likely due to the consistent oceanic input, resulting in lower sediment loading and higher water quality. In order for conditions for reef growth to improve, especially within the near-river portions of the bay, further sediment and nutrient runoff from anthropogenic land-use changes need to be mitigated. Given the historical abundance of Acropora, we recommend this genus be used as an indicator of natural resource management success in the bay.
The vertical light-gradient and its potential impact on animal distribution and behavior
Authors: Nilsson Dan-E , Smolka Jochen , Bok Michael
Published: August 2022

The visual environment provides vital cues allowing animals to assess habitat quality, weather conditions or measure time of day. Together with other sensory cues and physiological conditions, the visual environment sets behavioral states that make the animal more prone to engage in some behaviors, and less in others. This master-control of behavior serves a fundamental and essential role in determining the distribution and behavior of all animals. Although it is obvious that visual information contains vital input for setting behavioral states, the precise nature of these visual cues remains unknown. Here we use a recently described method to quantify the distribution of light reaching animals’ eyes in different environments. The method records the vertical gradient (as a function of elevation angle) of intensity, spatial structure and spectral balance. Comparison of measurements from different types of environments, weather conditions, times of day, and seasons reveal that these aspects can be readily discriminated from one another. The vertical gradients of radiance, spatial structure (contrast) and color are thus reliable indicators that are likely to have a strong impact on animal behavior and spatial distribution.
Methylation status of TK1 correlated with immune infiltrates in prostate cancer
Authors: Zhang Chenming , Ma Sicheng , Hao Xiaohui , Wang Zulong , Sun Zixue
Published: August 2022

TK1 is overexpressed in numerous cancers and is associated with to a poor prognosis. However, the relationship between methylation status of TK1 and Immune Infiltrates in Prostate Cancer (PCa) is unknown. The goal of this study was to use comprehensive bioinformatic analyses to elucidate the involvement relationship between methylation status of TK1 and Immune Infiltrates in PCa. TK1 mRNA expression and methylation data in PCa were investigated via GEPIA, TIMER, and UALCAN coupled with MEXPRESS data resources. We employed the LinkedOmics data resource to determine the signaling cascades linked to TK1 expression. Single-cell analysis was performed using the CancerSEA data resource. GeneMANIA and CancerSEA were used to analyze the correlation between TK1 and TK1 coexpressed genes. In addition, TIMER and TISIDB were adopted to assess tumor-invading immune cells and immunomodulators. CTD was utilized to detect the drugs acting on TK1. This study found that TK1 was overexpressed in PCa, and its contents were linked to tumor stage and prognosis. Genes co-expressed with TK1 were enriched in cascades involved in the ribosome, cell cycle, oxidative phosphorylation, DNA replication, oocyte meiosis, and the proteasome. The expression of TK1 along with its methylation status was found to be linked to tumor-invading immune cells, as well as PCa immunomodulators. We also examined the prospect of employing TK1 as a possible target for PCa therapy. This work provides the clinical value of TK1 hypermethylation in PCa and highlights new insights into its novel immunomodulatory functions.
Case report: Biochemical and clinical phenotypes caused by cysteine substitutions in the epidermal growth factor-like domains of fibrillin-1
Authors: Liu Xin , Liu Kaiqing , Nie Danyao , Zhang Jing , Zhang Liyun , Liu Xinhua , Wang Jiantao
Published: August 2022

Marfan syndrome, an autosomal dominant disorder of connective tissue, is primarily caused by mutations in the fibrillin-1 (FBN1) gene, which encodes the protein fibrillin-1. The protein is composed of epidermal growth factor-like (EGF-like) domains, transforming growth factor beta-binding protein-like (TB) domains, and hybrid (Hyb) domains and is an important component of elastin-related microfibrils in elastic fiber tissue. In this study, we report a cysteine to tyrosine substitution in two different domains of fibrillin-1, both of which cause Marfan syndrome with ocular abnormalities, in two families. Using protease degradation and liquid chromatography-tandem mass spectrometry analyses, we explored the different effects of substitution of cysteine by tyrosine in an EGF-like and a calcium-binding (cb) EGF-like domain on protein stability. The results showed that cysteine mutations in the EGF domain are more likely to result in altered proteolytic sensitivity and thermostability than those in the cbEGF domain. Furthermore, cysteine mutations can lead to new enzymatic sites exposure or hidden canonical cleavage sites. These results indicate the differential clinical phenotypes and molecular pathogenesis of Marfan syndrome caused by cysteine mutations in different fibrillin-1 domains. These results strongly suggest that failure to form disulfide bonds and abnormal proteolysis of fibrillin-1 caused by cysteine mutations may be an important factor underlying the pathogenesis of diseases caused by fibrillin-1 mutations, such as Marfan syndrome.
Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment
Authors: Ihim Stella Amarachi , Abubakar Sharafudeen Dahiru , Zian Zeineb , Sasaki Takanori , Saffarioun Mohammad , Maleknia Shayan , Azizi Gholamreza
Published: August 2022

Interleukin-18 (IL-18) is a potent pro-inflammatory cytokine involved in host defense against infections and regulates the innate and acquired immune response. IL-18 is produced by both hematopoietic and non-hematopoietic cells, including monocytes, macrophages, keratinocytes and mesenchymal cell. IL-18 could potentially induce inflammatory and cytotoxic immune cell activities leading to autoimmunity. Its elevated levels have been reported in the blood of patients with some immune-related diseases, including rheumatoid arthritis, systemic lupus erythematosus, type I diabetes mellitus, atopic dermatitis, psoriasis, and inflammatory bowel disease. In the present review, we aimed to summarize the biological properties of IL-18 and its pathological role in different autoimmune diseases. We also reported some monoclonal antibodies and drugs targeting IL-18. Most of these monoclonal antibodies and drugs have only produced partial effectiveness or complete ineffectivenessin vitro,in vivoand human studies. The ineffectiveness of these drugs targeting IL-18 may be largely due to the loophole caused by the involvement of other cytokines and proteins in the signaling pathway of many inflammatory diseases besides the involvement of IL-18. Combination drug therapies, that focus on IL-18 inhibition, in addition to other cytokines, are highly recommended to be considered as an important area of research that needs to be explored.
Case report: Radiotherapy plus pneumococcal conjugate vaccine stimulates abscopal immune response in a patient with ALK+ NSCLC
Authors: Huang Yong-Sheng , Li Zhuo , Xiao Ze-Fen , Li Dan , Liu Wen-Yang
Published: August 2022

Most patients with anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer (NSCLC) could benefit from the treatment with selected tyrosine kinase inhibitors (TKIs) for a period of time, but almost inevitably progress due to drug resistance. It was reported that these patients were generally unresponsive to immune-based therapies. Here, we reported that stereotactic body radiotherapy (SBRT) combined with pneumococcal conjugate vaccine (PCV) produced excellent therapeutic outcomes in a patient after multiple lines of TKI treatment. The patient’s metastasis lesion experienced regression after SBRT for lumbar spine. Unexpectedly, the patient also experienced an abscopal complete pathological response (CPR) just after combination use of SBRT and PCV. Biopsy analysis indicated that the primary lung lesion was map-like necrotic and infiltrated by tumor-infiltrating lymphocytes (TILs), and multifocal granulomas and early tertiary lymphoid structures (TLS) were formed. Our case reported that radiotherapy plus PCV could specifically stimulate immune response and remodel the tumor immune microenvironment in TKI-resistant NSCLC, which may provide a new perspective for future immunotherapy in this challenging clinical situation.
The role of inflammation in hematopoiesis and bone marrow failure: What can we learn from mouse models?
Authors: Wang Jun , Erlacher Miriam , Fernandez-Orth Juncal
Published: August 2022

Hematopoiesis is a remarkable system that plays an important role in not only immune cell function, but also in nutrient transport, hemostasis and wound healing among other functions. Under inflammatory conditions, steady-state hematopoiesis switches to emergency myelopoiesis to give rise to the effector cell types necessary to fight the acute insult. Sustained or aberrant exposure to inflammatory signals has detrimental effects on the hematopoietic system, leading to increased proliferation, DNA damage, different forms of cell death (i.e., apoptosis, pyroptosis and necroptosis) and bone marrow microenvironment modifications. Together, all these changes can cause premature loss of hematopoiesis function. Especially in individuals with inherited bone marrow failure syndromes or immune-mediated aplastic anemia, chronic inflammatory signals may thus aggravate cytopenias and accelerate disease progression. However, the understanding of the inflammation roles in bone marrow failure remains limited. In this review, we summarize the different mechanisms found in mouse models regarding to inflammatory bone marrow failure and discuss implications for future research and clinical practice.
Primary and memory immune responses against rough Brucella canis are less robust compared to smooth B. abortus and B. melitensis following intratracheal infection in mice
Authors: Stranahan Lauren W. , Garcia-Gonzalez Daniel G. , Hensel Martha E. , Arenas-Gamboa Angela M.
Published: August 2022

Brucella canis is the cause of canine brucellosis, a globally distributed, zoonotic pathogen which primarily causes disease in dogs. B. canis is unique amongst the zoonotic Brucella spp. with its rough lipopolysaccharide, a trait typically associated with attenuation in gram-negative bacteria. Unfortunately, no vaccine is available against B. canis, and vaccine development is hampered by a limited understanding of the immune response required to combat it and the course of infection following a physiologically relevant, mucosal route of inoculation. To address these concerns and analyze the impact of the rough phenotype on the immune response, we infected mice intratracheally with rough B. canis or smooth B. melitensis or B. abortus. Bacterial colonization and histologic lesions were assessed in systemic target organs as well as locally in the lungs and draining mediastinal lymph node. Mice were also reinfected with Brucella following antibiotic treatment and cytokine production by T lymphocytes in the lung and spleen was assessed by flow cytometry to investigate the memory immune response. Despite its rough phenotype, B. canis established a persistent infection at the same level of colonization as the smooth strains. However, B. canis induced significantly less granulomatous inflammation in the spleen as well as a lack of bronchial-associated lymphoid tissue (BALT) hyperplasia in the lungs. These differences coincided with increased IL-10 and decreased IFN-γ in the spleen of B. canis-infected mice. Previous exposure to all Brucella strains provided protection against colonization following secondary challenge, although induction of IFN-γ by T lymphocytes was seen only in the lungs during B. canis infection while the smooth strains induced this cytokine in the spleen as well. Neither Brucella strain induced significant polyfunctional T lymphocytes, a potential immunomodulatory mechanism that appears to be independent of lipopolysaccharide phenotype.
Membrane lipid sensitivity to ocean warming and acidification poses a severe threat to Arctic pteropods
Authors: Lischka Silke , Greenacre Michael J. , Riebesell Ulf , Graeve Martin
Published: August 2022

Ocean warming and acidification will be most pronounced in the Arctic. Both phenomena severely threaten thecosome pteropods (holoplanktonic marine gastropods) by reducing their survival (warming) and causing the dissolution of their aragonitic shell (acidification). Lipids, particularly phospholipids, play a major role in veligers and juveniles of the polar thecosome pteropodLimacina helicinacomprising more than two-thirds of their total lipids. Membrane lipids (phospholipids) are important for the temperature acclimation of ectotherms. Hence, we experimentally investigated ocean warming and acidification effects on total lipids, lipid classes, and fatty acids of Arctic early-stageL. helicina. The temperature and pCO2treatments chosen resembled Representative Concentration Pathway model scenarios for this century. We found a massive decrease in total lipids at elevated temperatures and at the highest CO2concentration (1,100μatm) of thein situtemperature. Clearly, temperature was the overriding factor. Total lipids were reduced by 47%–70%, mainly caused by a reduction of phospholipids by up to 60%. Further, based on pHTdevelopment in the incubation water of pteropods during the experiment, some evidence exists for metabolic downregulation in pteropods at high factor levels of temperature and pCO2. Consequently, the cell differentiation and energy balance of early-stage larvae were probably severely compromised. Comparison of our experimental with ‘wild’ organisms suggests phospholipid reduction to values clearly outside natural variability. Based on the well-known significance of phospholipids for membranogenesis, early development, and reproduction, negative warming effects on such a basal metabolic function may be a much more immediate threat for pteropods than so far anticipated shell dissolution effects due to acidification.
Interannual summer biodiversity changes in ichthyoplankton assemblages of the Strait of Sicily (Central Mediterranean) over the period 2001–2016
Authors: Patti Bernardo , Torri Marco , Cuttitta Angela
Published: August 2022

Interannual fluctuations in the structure and the composition of ichthyoplankton assemblages in the pelagic waters of the Strait of Sicily (SoS, Central Mediterranean) were investigated, trying to relate them to the observed variability in oceanographic conditions. Plankton data used in this study were from 16 summer surveys carried out in the SoS every year from 2001 to 2016, using oblique bongo plankton net (0–100 m) tows. Out of more than 12,000 fish larvae collected in the sampling stations included in the analysis, 9,519 of them were identified and regularly classified in 15 orders and 49 families. Ichthyoplankton assemblages, defined at the family level due to the uniform availability of this information along the time series, showed a decreasing trend over time in total larval abundance, along with taxonomic (family) richness and Shannon index (α diversity), more pronounced in the shelf area and in the slope area, respectively. Conversely, the relatively high levels of yearly compositional changes observed in the larval assemblage from both shelf and slope areas, as estimated by the Jaccard dissimilarity index (β diversity), did not show any significant linear trend. In addition, a biodiversity hotspot (both in terms of family richness and Shannon index) was evidenced in the frontal structure characterizing the southeastern part of the study area. Generalized additive models were used to evaluate the effect of oceanographic conditions on the temporal and spatial patterns of ichthyoplankton biodiversity. Results evidenced the role of salinity, surface temperature, and surface currents in modulating biodiversity indices, especially in the shelf area. Finally, the relevance of local frontal oceanographic structures in sustaining high biodiversity levels is postulated.
Effects of carbonate alkalinity on branchial gene expression in the large-scale loach (Paramisgurnus dabryanus)
Authors: Huang Mei , Wu Meng-Xiao , Zhang Lin-Jiang , Mi Di , Zhang Yun-Long
Published: August 2022

Elucidating the mechanisms of alkaline tolerance in freshwater teleosts will help in the development of commercial saline-alkaline aquaculture. The large-scale loach (Paramisgurnus dabryanus) is a viable species for such aquaculture, but the mechanisms of its tolerance of alkaline water are unclear. Large-scale loach was exposed to 40, 50, and 60 mmol L-1 NaHCO3 for 12, 48, and 96 h to evaluate the transcriptional changes of branchial Rhesus (Rh) glycoproteins, and aquaporins (Aqp)1 and Aqp3. Rhag transcript levels increased with longer exposure times. Rhag expression also rose considerably at higher carbonate alkalinities. Rhbg mRNA levels declined significantly under carbonate alkalinity exposure. A marked up-regulation of Rhcg was observed in the gills of the loach. Exposure to 60 mmol L-1 NaHCO3 also induced a significant up-regulation of aqp1. By contrast, aqp3 expression was significantly lower after 48 h exposure. The current findings reveal that the large-scale loach up-regulates Rhag and Rhcg to enhance ammonia efflux from the gills when exposed to high alkalinity. It is proposed that this species maintains appropriate osmolality when adapting to an alkaline environment by down-regulating aqp3 (to impede urea removal) and up-regulating aqp1 in the gills (to excrete excessive internal water).
Gastroenterology in the Metaverse: The dawn of a new era?
Authors: Zhang Chi , Feng Shuyan , He Ruonan , Fang Yi , Zhang Shuo
Published: August 2022

2021 is known as the first Year of the Metaverse, and around the world, internet giants are eager to devote themselves to it. In this review, we will introduce the concept, current development, and application of the Metaverse and the use of the current basic technologies in the medical field, such as virtual reality and telemedicine. We also probe into the new model of gastroenterology in the future era of the Metaverse.
Heparin-binding protein-enhanced quick SOFA score improves mortality prediction in sepsis patients
Authors: Han Xiaotong , Dou Qingli , Zhu Yimin , Ling Peng , Shen Yi-Hsuan , Liu Jiangping , Zhang Zhongwei , Zhou Yucheng , Fan Maiying , Huang Sih-Shiang , Lee Chien-Chang
Published: August 2022

Purpose

The Quick Sequential Organ Failure Assessment (qSOFA) score proposed by Sepsis-3 as a sepsis screening tool has shown suboptimal accuracy. Heparin-binding protein (HBP) has been shown to identify early sepsis with high accuracy. Herein, we aim to investigate whether or not HBP improves the model performance of qSOFA.

Methods

We conducted a multicenter prospective observational study of 794 adult patients who presented to the emergency department (ED) with presumed sepsis between 2018 and 2019. For each participant, serum HBP levels were measured and the hospital course was followed. The qSOFA score was used as the comparator. The data was split into a training dataset (n = 556) and a validation dataset (n = 238). The primary endpoint was 30-day all-cause mortality.

Results

Compared with survivors, non-survivors had significantly higher serum HBP levels (median: 71.5 ng/mL vs 209.5 ng/mL, p < 0.001). Serum level of HBP weakly correlated with qSOFA class (r2 = 0.240, p < 0.001). Compared with the qSOFA model alone, the addition of admission HBP level to the qSOFA model significantly improved 30-day mortality discrimination (AUC, 0.70 vs. 0.80; P < 0.001), net reclassification improvement [26% (CI, 17–35%); P < 0.001], and integrated discrimination improvement [12% (CI, 9–14%); P < 0.001]. Addition of C-reactive protein (CRP) level or neutrophil-to-lymphocyte ratio (NLR) to qSOFA did not improve its performance. A web-based mortality risk prediction calculator was created to facilitate clinical implementation.

Conclusion

This study confirms the value of combining qSOFA and HBP in predicting sepsis mortality. The web calculator provides a user-friendly tool for clinical implementation. Further validation in different patient populations is needed before widespread application of this prediction model.
Case report: A rare case of retroperitoneal kaposiform hemangioendothelioma with spinal involvement without abnormal platelet count in 18F-FDG PET/CT
Authors: Qiu Yongkang , Chen Zhao , Yang Qi , Huang Wenpeng , Song Lele , Fan Yan , Kang Lei
Published: August 2022

Kaposiform hemangioendothelioma (KHE) is a rare vascular neoplasm that mostly appears in infancy or early childhood. Most KHE occurred on the limbs and trunk with cutaneous lesions. Approximately 12% of KHE patients manifested as deep masses and spinal involvement is extremely rare. KHE may develop into life-threatening thrombocytopenia and consumptive coagulopathy, known as the Kasabach-Merritt phenomenon (KMP), especially in patients with retroperitoneal involvement. The thrombocytopenia is usually severe, with a median platelet count of 21 × 109/L at the initial presentation of KMP. Here, firstly we described a case of a 13-month-old girl with KHE who presented the movement limitation of the lower extremity caused by spinal involvement with a normal platelet count. 18F-fluorodeoxyglucose-positron emission tomography/CT (18F-FDG PET/CT) showed mildly elevated metabolism in the lesion, suggesting a probably low-grade malignant tumor. Then the patient was diagnosed with KHE by biopsy. After 6-month sirolimus monotherapy, the size of the retroperitoneal lesion was reduced significantly and the patient showed improvement in clinical symptoms. This case demonstrated the advantage of 18F-FDG PET/CT in the evaluation of disease activity in KHE and the possibility of using 18F-FDG PET/CT to guide therapy and prognostication.