bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative analysis of the intestinal microbiota of black−necked cranes (Grus nigricollis) in different wintering areas
Authors: Wang Zhongbin , Zhang Erhao , Tang Ying , Wu Jiujiu , Muhammad Suliman , Shang Peng , Zong Cheng , Rong Ke , Ma Jianzhang
Published: January 2024

Fecal microbiota is essential for host health because it increases digestive effectiveness. The crane species Grus nigricollis (G. nigricollis) is considered to be near threatened. The fecal microbial composition of crane is less understood, particularly in the Tibet, China. This study was performed to investigate the differences in fecal microbial composition and diversity of crane in different wintering areas using third-generation single-molecule real-time sequencing technology in the Tibet, China. According to the findings, 20 samples were used to generate 936 bacterial amplicon sequence variants (ASVs) and 1,800 fungal ASVs, only 4 bacterial ASVs and 20 fungal ASVs were shared in four distinct locations. Firmicutes were the dominant bacterial phylum in all samples, and Ascomycota and Basidiomycota were the dominant fungal phylum. At the genus level, Lactobacillus was the dominant genus in Linzhi City (LZ), Shannan City (SN), and Lasa City (LS), whereas Megamonas was the dominant genus in Rikaze City (RKZ). Naganishia and Mycosphaerella were the dominant fungal genera in SN and RKZ. Mycosphaerella and Tausonia were the dominant fungal genera in LZ. Naganishia and Fusarium were the dominant fungal genera in LS. And the fecal microbial composition varied between the four groups, as shown by the underweighted pair-group method with arithmetic means and principal coordinates analysis. This study offers a theoretical basis for understanding the fecal microbial composition of crane.
Clinical implications of trichomonads detected in bronchoalveolar fluid by metagenomic next-generation sequencing: a multicenter retrospective study
Authors: Jiang Juan , Li Yuanyuan , Wang Qiong , Zeng Huihui , Yang Wei , Wu Yanhao , Peng Wenzhong , Pan Pinhua , Hu Chengping , Deng Pengbo
Published: January 2024

Background

Pulmonary trichomoniasis is considered a neglected disease due to failures in recognizing it, stemming from insensitive microbial methods and a lack of specific clinical features. This study aims to analyze the clinical implications of trichomonads detected in bronchoalveolar lavage fluid (BALF) by metagenomic next-generation sequencing (mNGS).

Methods

This multicenter retrospective study included patients diagnosed with pneumonia, admitted to three tertiary hospitals in China from July 2018 to September 2022, with trichomonads detected in BALF through mNGS. The analysis covered demographics, comorbidities, symptoms, laboratory findings, mNGS results, clinical treatment, and outcomes of these patients.

Results

A total of 17 patients were enrolled, comprising 14 males and 3 females. Trichomonas tenax and Trichomonas vaginalis were detected by mNGS in BALF samples of 15 and 2 patients, respectively. Patients were categorized into two groups based on the presence of risk factors for trichomonad infection, including immunocompromised conditions, uncontrolled diabetes mellitus, oral/periodontal diseases, and aspiration. Among 11 patients with risk factors (Case 1-11), 4 received nitromidazoles as part of comprehensive treatment, achieving a 100% treatment success rate. The remaining 7 patients, who did not receive nitromidazoles, had only one achieving relief after broad-spectrum antimicrobial therapy, resulting in a 14.3% treatment success rate. For the 6 patients without any risk factors for trichomonad infection (Case 12-17), none received nitromidazoles during hospitalization. However, 4 out of these 6 patients (66.7%) eventually recovered.

Conclusion

mNGS proves to be an efficient tool for detecting trichomonads in BALF samples. Comprehensive analysis of clinical features and laboratory indicators is essential to distinguish between infection and colonization of trichomonads. Pulmonary trichomoniasis should not be overlooked when trichomonads are detected in BALF from patients with risk factors.
Cooperation and the social brain hypothesis in primate social networks
Authors: MacLaren Neil G. , Meng Lingqi , Collier Melissa , Masuda Naoki
Published: January 2024

The social brain hypothesis posits that species with larger brains tend to have greater social complexity. Various lines of empirical evidence have supported the social brain hypothesis, including evidence from the structure of social networks. Cooperation is a key component of group living, particularly among primates, and theoretical research has shown that particular structures of social networks foster cooperation more easily than others. Therefore, we hypothesized that species with a relatively large brain size tend to form social networks that better enable cooperation. In the present study, we combine data on brain size and social networks with theory on the evolution of cooperation on networks to test this hypothesis in non-human primates. We have found a positive effect of brain size on cooperation in social networks even after controlling for the effect of other structural properties of networks that are known to promote cooperation.
Effects of length-to-diameter ratio and strain rate on strain energy accumulation and dissipation in sandstone
Authors: Liu Xiaodie , Liu Zhixi
Published: January 2024

To investigate the influence of the length-to-diameter (L/D) ratio and strain rate on the evolution of strain energy of sandstone under uniaxial compression, experimental tests were conducted using the RMT-150B rock mechanics test system. Specifically, uniaxial compression experiments (UCE), uniaxial loading-unloading experiment(ULUE) and uniaxial cyclic loading-unloading experiments (UCLUE) were performed. The results show that: 1) Based on an investigation of the Kaiser effect in UCLUE, it is postulated that a small degree of loading-unloading has negligible impact on the storage of strain energy in rock masses. The hypothesis regarding the limited influence of loading-unloading on the elastic strain energy storage of rocks is confirmed through a comparative analysis between the elastic strain energy storage in UCLUE and ULUE. 2) By analyzing the ESED and ISED of sandstone under different L/D ratios and strain rates, it is found that it follows the linear energy storage law. The evolution of elastic strain energy is not affected by strain rate. Therefore, the UCLUE at any strain rate can analyze the elastic strain energy of uniaxial compression experiment with the same size at any strain rate, and provide a new method for strain energy analysis at different length-diameter ratios and strain rates. 3) When the stress of sandstone samples of equal size is equal, the smaller the strain rate, the longer the loading experiment of sandstone, the more time the friction development and interconnection of cracks in sandstone are, and the more dissipated strain energy and input strain energy are generated. 4) Smaller L/D ratios are associated with larger ESED and DSED values in sandstone. As the stress intensifies, the ESED and DSED of certain sandstones with larger L/D ratios experience a sharp increase when approaching the failure stress. Under equal stress levels, it is possible for sandstones with larger L/D ratios to exhibit higher ESED and DSED values compared to those with smaller L/D ratios.
Deep learning–based inverse analysis of GPR data for landslide hazards
Authors: Qin Yulong , Jiang Ze , Tian Yongqiang , Jiang Yuan , Zhao Guanyi , Yan Jiang , Li Zhentao , Cui Ziwang , Zhao Zihui , Huang Linke , Zhang Fuping , Du Junfeng , Rong Zhongdi
Published: January 2024

In mountainous landscapes, the diverse geotechnical conditions amplify landslide susceptibility. Factors such as precipitation and seismic activity can trigger landslides, while inherent hazards such as voids, fissures, and compaction deficits jeopardize long-term slope stability. Detecting and forecasting these susceptibilities accurately is crucial. In this paper, the time-domain finite-difference approach and the gprMax software are used to conduct forward modeling of landslide susceptibility. An electrical model of subsurface aqueous structures is created, including water-filled and air-filled cavities, fracture zones, and fault lines. The distinctive radar signal responses within these environments are examined, and a dataset of B-scan images associated with their electrical models is constructed. By employing deep learning algorithms and the robust nonlinear mapping ability of convolutional neural networks in the Pix2Pix generative adversarial network, we accelerate the intelligent inversion of the geological radar data on landslide susceptibility. This innovative approach effectively reconstructs hazard models, offering a reliable basis for interpretation of radar signals.
Causal mechanisms and evolution processes of “block-burst” debris flow hazard chains in mountainous urban areas: a case study of Meilong gully in Danba county, Sichuan Province, China
Authors: Shen Haowen , Yang Zhiquan , Hu Guisheng , Tian Shufeng , Rahman Mahfuzur , Ren Jincheng , Zhang Yong
Published: January 2024

The research interest in multi-hazard chains lies in the comprehension of how various hazards, such as debris flows, floods, and landslides, can interact and amplify one another, resulting in cascading or interconnected hazards. On 17 June 2020, at approximately 3:20 a.m., a debris flow occurred in Meilong gully (MLG), located in Banshanmen Town, Danba County, in southwest China’s Sichuan Province. The debris flow had a discharge volume of approximately 40 × 104 m3 and rushed out to block the Xiaojinchuan (XJC) river, subsequently forming a barrier lake. This event ultimately induced a hazard chain that included heavy rainfall, debris flow, landslides, the formation of a barrier lake, and an outburst flood. The impact of this chain resulted in the displacement of 48 households and affected 175 individuals. Furthermore, it led to the destruction of an 18 km section of National Highway G350, stretching from Xiaojin to Danba County, causing economic losses estimated at 65 million yuan. The objective of this study is to analyze the factors leading to the formation of this hazard chain, elucidate its triggering mechanisms, and provide insights for urban areas in the western mountainous region of Sichuan to prevent similar dam-break type debris flow hazard chains. The research findings, derived from field investigations, remote sensing imagery analysis, and parameter calculations, indicate that prior seismic disturbances and multiple dry-wet cycle events increased the volume of loose solid materials within the MLG watershed. Subsequently, heavy rainfall triggered the initiation of the debris flow in MLG. The cascading dam-break, resulting from three unstable slopes and boulders within the channel, amplified the scale of the hazard chain, leading to a significant amount of solid material rushing into the XJC river, thus creating a dam that constricted the river channel. With the intensification of river scouring, the reactivation and destabilization of the Aniangzhai (ANZ) paleolandslide occurred, ultimately leading to the breach of the dam and the formation of an outburst flood. The research comprehensively and profoundly reveals the causal mechanism of the MLG hazard chain, and proposes measures to disrupt the chain at various stages, which can aid in enhancing monitoring, early warning, forecasting systems, and identifying key directions for ecological environmental protection in urban areas within the western mountainous region of Sichuan. Additionally, it could also serve as a reference for mountainous urban areas such as the Tianshan, Alps, Rocky Mountains, and Andes, among others.
Gamebooks and branching narratives in education: fostering sustainability competences to promote positive social change
Authors: Fenici Marco , Mosca Ivan
Published: January 2024

Gamebooks and branching narratives are a specific form of interactive literature that allows the reader to participate in the story, making decisions that affect its final outcome. We describe one case-study of introducing branching stories in the context of higher education, and discuss how it possibly enhanced communication and collaboration skills as well as prosocial attitudes. We further generalize this experience to discuss how educators can use branching narratives to promote positive social change. To this aim, we clarify what social development and sustainability competences are, and show how educational activities based on branching narratives can effectively promote their acquisition.
The driving factors of spatial differences on the whole life cycle carbon emissions of the construction industry: from the analysis perspective of total factor productivity
Authors: Zhang Zhengyan , Wu Zhaoqi , Yang Xiaolu , Cai Binqing , Lin Zhensi
Published: January 2024

The energy saving and emissions reduction of the construction industry are crucial for China to achieve the “carbon peaking and carbon neutrality” goals. In order to promote the green development of the life cycle of the construction industry and improve the efficiency of emissions reduction. This paper examines the spatial-temporal distribution of life cycle carbon emissions in China’s construction industry (LCCECI) from 2004 to 2018. It uses the SBM-Malmquist total factor productivity (TFP) index to measure technological progress and establishes the spatial econometric model based on the STIRPAT model. The study investigates the driving factors of the LCCECI at the provincial and regional levels, aiming to provide suggestions for low-carbon development in the construction industry. The research results are as follows. ① The growth in the SBM-Malmquist TFP index of the construction industry distinctly curbs the LCCECI. ② Total population and urbanization level are not the primary driving factors for the LCCECI. The growth of per capita GDP significantly induces the LCCECI, while concurrently exhibiting a notable inhibitory effect on the LCCECI of neighboring regions. ③ The improvement of the SBM-Malmquist TFP index is conducive to the reduction of the LCCECI in the three major regions. The per capita GDP has the largest positive driving effect of the LCCECI in the eastern region, and the urbanization level the urbanization rate only significantly inhibits the growth of the LCCECI in the central region.
Research on optimization of approach procedures for airports in an alpine environment
Authors: Lu Li , Lai Xin , Jiang Junliang , Zhou Juncheng
Published: January 2024

Obstacles in alpine environments pose significant challenges to aircraft safety during terminal operations. Key challenges include constraints from obstacles within the terminal clearance area and the labor-intensive manual calculations of flight procedures. The focal point of concern lies in the design of approach procedures, particularly due to the heightened risk of collisions with obstacles during the descent segment in such terrain. To address these challenges, initially, this paper proposes processing the terrain data and visualizing and extracting the topographic data of the alpine airport by adopting a bi-cubic b-spline interpolation and cellular automatic machine model. Then, the paper proposes improving the A* path algorithm to make sure it can obey the standards of flight procedure design, utilizing the improved A* path algorithm to design approach procedures. As fuel consumption is directly connected with the economy of aviation companies, this research finally suggests employing the fuel consumption evaluation model to select the most efficient approach flight procedures. This research takes a case study of a Yunnan airport and simulates and designs the optimized approach procedures by A* path algorithm and evaluation based on fuel consumption. Results indicate that the parameters of optimized approach procedures align with the regulation of flight procedure design and meet the requirements of real flight operation. Therefore, the core tenant of this research can provide a feasible idea for flight procedures with alpine airports and has the potential to reduce workload and enhance operational efficiency.
Exploring the landscape pattern change analysis for the transboundary Nyungwe-Kibira Forest (2000–2019): a spatially explicit assessment
Authors: Udahogora Madeleine , Zhaoping Yang , Fang Han , Kayumba Patient Mindje , Mind’je Richard
Published: January 2024

Introduction and aim

Ensuring the protection and restoration of forest ecosystems is vital to maintaining and restoring ecological balance in deforested or degraded landscapes. However, sustainable development faces challenges from high human impacts on natural forest ecosystems, insufficient advanced conservation measures, and limited engagement of local communities in developing nations. The aim of this study was to explore the utility of spatial remote sensing datasets in examining the landscape pattern changes within the transboundary Nyungwe-Kibira Forest from 2000 to 2019. This aimed to emphasize the necessity of understanding the intricate dynamics of this ecosystem and its susceptibility to human activities in order to bolster diverse restoration initiatives throughout the region.

Methods

The landscape pattern change in the Nyungwe-Kibira between 2000 and 2019 was analysed using high-resolution Landsat data. This analysis encompassed an evaluation of the dynamics of changes in built-up, cropland, and forest areas within the region. Especially, primary data derived from the Landsat dataset and secondary data from reports such as the Outlook Report were employed to elucidate the ongoing landscape transformation within and surrounding the transboundary forest.

Results and discussion

The analysis revealed a net change of +62.3% and +18.07% in built-up and cropland areas, resulting in a gross change of 14,133 ha and 6,322 ha in built-up and cropland areas, respectively. Furthermore, the forest experienced an overall gain of 9.11%, corresponding to a net loss of 6.92% due to deforestation, estimated at -14,764 ha. The analysis also indicated that built-up areas accounted for approximately 33.02% of the net forest loss, primarily affecting the northern edge of the Rwanda region, while cropland expansion contributed to a net loss of forest (-9.48%), predominantly impacting the southeast portion of the forest in Burundi. Additionally, the forest is predicted to decrease by 0.74% by 2030, with current findings showing aggregated forest and cropland at 66% and 7%, dissected rangeland at 24%, and created built-up areas at 3%. The findings indicate that the Nyungwe-Kibira Forest is undergoing notable transformations, highlighting the necessity of land-based projects and mitigation plans to facilitate the restoration of the forest from its historical changes. Without proactive measures, an ongoing decrease in forest area by 2030 is anticipated.
Canine diabetes mellitus demonstrates multiple markers of chronic inflammation including Th40 cell increases and elevated systemic-immune inflammation index, consistent with autoimmune dysregulation
Authors: Vaitaitis Gisela , Webb Tracy , Webb Craig , Sharkey Christina , Sharkey Steve , Waid Dan , Wagner David H.
Published: January 2024

Introduction

Canine diabetes mellitus (CDM) is a relatively common endocrine disease in dogs. Many CDM clinical features resemble human type 1 diabetes mellitus (T1DM), but lack of autoimmune biomarkers makes calling the disease autoimmune controversial. Autoimmune biomarkers linking CDM and T1DM would create an alternative model for drug development impacting both human and canine disease.

Methods

We examined peripheral blood of diagnosed CDM dog patients comparing it to healthy control (HC) dogs. Dogs were recruited to a study at the Colorado State University Veterinary Teaching Hospital and blood samples collected for blood chemistry panels, complete blood counts (CBC), and immunologic analysis. Markers of disease progression such as glycated albumin (fructosamine, the canine equivalent of human HbA1c) and c-peptide were addressed.

Results

Significant differences in adaptive immune lymphocytes, innate immune macrophages/monocytes and neutrophils and differences in platelets were detected between CDM and HC based on CBC. Significant differences in serum glucose, cholesterol and the liver function enzyme alkaline phosphatase were also detected. A systemic immune inflammation index (SII) and chronic inflammation index (CII) as measures of dynamic changes in adaptive and innate cells between inflammatory and non-inflammatory conditions were created with highly significant differences between CDM and HC. Th40 cells (CD4+CD40+ T cells) that are demonstrably pathogenic in mouse T1DM and able to differentiate diabetic from non-diabetic subjects in human T1DM were significantly expanded in peripheral blood mononuclear cells.

Conclusions

Based on each clinical finding, CDM can be categorized as an autoimmune condition. The association of significantly elevated Th40 cells in CDM when compared to HC or to osteoarthritis, a chronic but non-autoimmune disease, suggests peripheral blood Th40 cell numbers as a biomarker that reflects CDM chronic inflammation. The differences in SII and CII further underscore those findings.
Immune evasion by proteolytic shedding of natural killer group 2, member D ligands in Helicobacter pylori infection
Authors: Anthofer Margit , Windisch Markus , Haller Rosa , Ehmann Sandra , Wrighton Sebastian , Miller Michael , Schernthanner Lorenz , Kufferath Iris , Schauer Silvia , Jelušić Barbara , Kienesberger Sabine , Zechner Ellen L. , Posselt Gernot , Vales-Gomez Mar , Reyburn Hugh T. , Gorkiewicz Gregor
Published: January 2024

Background

Helicobacter pylori (H. pylori) uses various strategies that attenuate mucosal immunity to ensure its persistence in the stomach. We recently found evidence that H. pylori might modulate the natural killer group 2, member 2 (NKG2D) system. The NKG2D receptor and its ligands are a major activation system of natural killer and cytotoxic T cells, which are important for mucosal immunity and tumor immunosurveillance. The NKG2D system allows recognition and elimination of infected and transformed cells, however viruses and cancers often subvert its activation. Here we aimed to identify a potential evasion of the NKG2D system in H. pylori infection.

Methods

We analyzed expression of NKG2D system genes in gastric tissues of H. pylori gastritis and gastric cancer patients, and performed cell-culture based infection experiments using H. pylori isogenic mutants and epithelial and NK cell lines.

Results

In biopsies of H. pylori gastritis patients, NKG2D receptor expression was reduced while NKG2D ligands accumulated in the lamina propria, suggesting NKG2D evasion. In vitro, H. pylori induced the transcription and proteolytic shedding of NKG2D ligands in stomach epithelial cells, and these effects were associated with specific H. pylori virulence factors. The H. pylori-driven release of soluble NKG2D ligands reduced the immunogenic visibility of infected cells and attenuated the cytotoxic activity of effector immune cells, specifically the anti-tumor activity of NK cells.

Conclusion

H. pylori manipulates the NKG2D system. This so far unrecognized strategy of immune evasion by H. pylori could potentially facilitate chronic bacterial persistence and might also promote stomach cancer development by allowing transformed cells to escape immune recognition and grow unimpeded to overt malignancy.
The RNA m6A writer METTL3 in tumor microenvironment: emerging roles and therapeutic implications
Authors: Su Weiqi , Che Lin , Liao Wenting , Huang Huilin
Published: January 2024

The tumor microenvironment (TME) is a heterogeneous ecosystem comprising cancer cells, immune cells, stromal cells, and various non-cellular components, all of which play critical roles in controlling tumor progression and response to immunotherapies. Methyltransferase-like 3 (METTL3), the core component of N6-methyladenosine (m6A) writer, is frequently associated with abnormalities in the m6A epitranscriptome in different cancer types, impacting both cancer cells and the surrounding TME. While the impact of METTL3 on cancer cells has been extensively reviewed, its roles in TME and anti-cancer immunity have not been comprehensively summarized. This review aims to systematically summarize the functions of METTL3 in TME, particularly its effects on tumor-infiltrating immune cells. We also elaborate on the underlying m6A-dependent mechanism. Additionally, we discuss ongoing endeavors towards developing METTL3 inhibitors, as well as the potential of targeting METTL3 to bolster the efficacy of immunotherapy.
Berotralstat in hereditary angioedema due to C1 inhibitor deficiency: first real-world evidence from a Canadian center
Authors: Srinivasan Cindy , Ritchie Bruce , Adatia Adil
Published: January 2024

Background

Hereditary angioedema due to C1 inhibitor deficiency is a rare genetic condition that causes recurrent swelling with consequent functional impairment and decreased quality of life. Long-term prophylaxis (LTP) to prevent angioedema episodes is a key component of disease management. Berotralstat, an oral, once-daily plasma kallikrein inhibitor, was approved for LTP by Health Canada in 2022.

Methods

We conducted a retrospective, real-world study investigating the effectiveness and adverse effects of berotralstat. Data on angioedema frequency, disease control, and adverse events were tabulated. Patient satisfaction with treatment was scored on a 5-point Likert scale, with 1 representing very unsatisfied and 5 representing very satisfied with therapy.

Results

From June, 2022 and May, 2023, 8 patients with HAE type 1 or type 2 received berotralstat. Effectiveness data were available for 7 patients who continued the drug for at least 3 months, 4 of whom switched to berotralstat from plasma-derived C1 inhibitor LTP. In these 7 patients, the average number of attacks per month decreased from 3.3 to 1.6 (p<0.05), representing a ~52% reduction in attack frequency. Median angioedema control test score numerically improved from 8 to 13 (p=0.0781). Of the 8 patients who received berotralstat, 3 reported no adverse effects and 5 experienced gastrointestinal side effects, which were mild and transient in 3 and led to discontinuation in 1. Average treatment satisfaction was between satisfied and very satisfied at 4.3.

Conclusion

Berotralstat is an effective agent for long-term prophylaxis in HAE. Most patients experienced no adverse effects or mild, transient gastrointestinal symptoms.
Real-world impact of the introduction of chemo-immunotherapy in extended small cell lung cancer: a multicentric analysis
Authors: Bonanno Laura , Calvetti Lorenzo , Dal Maso Alessandro , Pavan Alberto , Bao Loc Carlo , De Nuzzo Mattia , Frega Stefano , Sartori Giulia , Ferro Alessandra , Pasello Giulia , Morandi Paolo , Aprile Giuseppe , Guarneri Valentina
Published: January 2024

Background

Recent clinical trials demonstrated longer survival in extended small cell lung cancer (SCLC) patients treated with immunotherapy in addition to chemotherapy. However, the magnitude of benefit is modest and the impact in real-world setting has to be fully established.

Methods

We collected clinical data and radiological imaging of patients affected by extended or relapsing SCLC and consecutively treated according to clinical practice between 2016 and 2023. As primary end-point, we compared pre-defined outcome indicators before and after the introduction of chemo-immunotherapy (May 2020): 6-month and 12-month progression free survival (PFS) rate, 12-month and 18-month overall survival (OS). Among those who were treated after May 2020, patients who did not receive immunotherapy according to treating physician’s choice were included in the analysis to minimize clinical selection bias.

Results

The analysis included 214 patients: 132 (61.7%) were treated in an Academic cancer center and 82 (38.3%) in two community hospitals; 104 were treated before May 2020. Median PFS of the overall study population was 4.8 months (95% confidence interval [95% CI]: 4.4-5.4), median OS was 7.1 months (95% CI: 6.3-7.7). Estimated PFS and OS were significantly longer in patients treated after May 2020 with hazard ratio (HR) for PFS and OS of 0.61 (95% CI: 0.46-0.81, p < 0.001) and 0.70 (95% CI: 0.52-0.93, p = 0.015), respectively. 6-month PFS rate increased from 27% to 40% (p = 0.04) while 12-months PFS raised from 1% to 11% (p = 0.003). 12-month and 18-month OS rate increased from 15% to 28% (p = 0.03) and from 2.1% to 12% (p = 0.009), respectively. After May 2020 the median number of hospitalization days per patient decreased significantly and the incidence of severe AEs was similar. Among patients treated with chemo-immunotherapy, the onset of immune-related AEs was associated with improved PFS and OS (HR 0.55, 95% CI: 0.35-0.89, p = 0.012 and HR 0.47, 95%CI 0.28-0.77, p = 0.002, respectively).

Conclusions

The real-world analysis shows a meaningful improvement of outcome indicators after the introduction of chemo-immunotherapy, with reduction of the duration of hospitalization, thus supporting the use of chemo-immunotherapy and the need for further biomarker research.
Exogenous factors impact on bacterial-microalgal growth and chromophoric dissolved organic matter: a case study of Chrysotila dentata and Marinobacter hydrocarbonoclasticus
Authors: Wang Xueru , Sun Jun
Published: January 2024

The relationship between Chrysolia dentata and bacteria that play an important role in the carbon cycle is complex yet closely intertwined. However, there is still limited knowledge about how phytoplankton interacts with heterotrophic bacteria under external influences. The transformation and processing of dissolved organic matter (DOM) by epiphytic bacteria for phytoplankton especially, under vitamin B12 (VB12) and abscisic acid (ABA) introducing have rarely been investigated. In this experiment, Marinobacter hydrocarbonoclasticus (CA6) was cultured with Chrysotila dentata to investigate growth and DOM release and transformation under the influence of VB12 and ABA. Three-dimensional (3D)-EEM, combined with fluorescence regional integration and the peak selecting method, was used to obtain fluorescent peaks (B, T, A, and C) and four indexes for DOM analysis. Our findings indicate that the incubation of CA6 significantly enhances the release of protein-like components (peak T) and humic-like components (peak C) during the incubation period. However, 100 μg/L VB12 or abscisic acid does not promote axenic microalgae growth or release of C. dentata-derived DOM. However, they have different effects on C. dentata-CA6 growth and the derived DOM. Abscisic acid can facilitate steady growth of both C. dentata and CA6 cells while enhancing the amounts of humic-like components. Conversely, VB12 inhibits the growth of CA6 and results in a rapid decrease in protein-like signal, but it does not significantly enhance C. dentata growth or the transformation of DOM. This indicates that ABA can support stable co-grown of microalgal and bacteria in a water environment, while VB12 may hinder CA6 bacterial growth, resulting in a less stable co-cultured environment. This study uncovers and verifies the impact of exogenous factors and heterotrophic bacteria in the growth of microalgae, underlining their role in transforming and generating algae-derived dissolved organic matter (DOM) within laboratory settings.
Real-life study to assess effectiveness and safety of eculizumab in patients with neuromyelitis optica spectrum disorders in France: protocol for ECUP4, an observational study
Authors: Marignier Romain , Laplaud David , Zéphir Hélène , Papeix Caroline , Leray Emmanuelle , Amri Ekbel , Piotaix Mickaël , de Sèze Jérôme
Published: January 2024

Background

Eculizumab, a humanized monoclonal antibody targeting the C5 complement protein, has been approved for the treatment of neuromyelitis optica spectrum disorders (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive (Ab+). The aim of this study is to evaluate the long-term effectiveness and safety of eculizumab in French adults with NMOSD and to describe patients' characteristics, disability, and quality of life using data collected in a real-world setting.

Methods

This is the protocol for ECUP4, an ongoing prospective, observational, non-comparative, multicenter study conducted in 32 reference centers in France. Eligible patients must also be enrolled in NOMADMUS, a nested cohort of the French national multiple sclerosis registry (OFSEP). The primary endpoint is the annualized relapse rate. Secondary endpoints include the long-term safety of eculizumab, as well as patients' characteristics, treatment outcomes, disability, pain, visual acuity, and quality of life. Visits and treatments follow routine clinical practice. The case report forms (CRF) comprise data recorded in the context of the NOMADMUS cohort, collected during routine visits. The inclusion period is planned for 3 years, with no limitation on the number of patients enrolled. The maximum follow-up duration will be 5.5 years.

Conclusion

The efficacy and safety of eculizumab in patients with AQP4+ NMOSD have been demonstrated in randomized clinical trials that showed a significant reduction in the risk of relapse, with a safety profile consistent with other indications. This study will provide clinical and patient-reported evidence of the benefits of eculizumab, using data from a real-world setting in France.

Trial registration number

This study is registered at the French public repertory Health data Hub, N° F20211228123801. All information can be accessed at: https://www.health-data-hub.fr/.
Robotic assistance during cochlear implantation: the rationale for consistent, controlled speed of electrode array insertion
Authors: Kashani Rustin G. , Henslee Allan , Nelson Rick F. , Hansen Marlan R.
Published: January 2024

Cochlear implants (CI) have revolutionized the treatment of patients with severe to profound sensory hearing loss by providing a method of bypassing normal hearing to directly stimulate the auditory nerve. A further advance in the field has been the introduction of “hearing preservation” surgery, whereby the CI electrode array (EA) is carefully inserted to spare damage to the delicate anatomy and function of the cochlea. Preserving residual function of the inner ear allows patients to receive maximal benefit from the CI and to combine CI electric stimulation with acoustic hearing, offering improved postoperative speech, hearing, and quality of life outcomes. However, under the current paradigm of implant surgery, where EAs are inserted by hand, the cochlea cannot be reliably spared from damage. Robotics-assisted EA insertion is an emerging technology that may overcome fundamental human kinetic limitations that prevent consistency in achieving steady and slow EA insertion. This review begins by describing the relationship between EA insertion speed and generation of intracochlear forces and pressures. The various mechanisms by which these intracochlear forces can damage the cochlea and lead to worsened postoperative outcomes are discussed. The constraints of manual insertion technique are compared to robotics-assisted methods, followed by an overview of the current and future state of robotics-assisted EA insertion.
Effect of epiretinal electrical stimulation on the glial cells in a rabbit retinal eyecup model
Authors: Henze Dean , Majdi Joseph A. , Cohen Ethan D.
Published: January 2024

Introduction

We examined how pulse train electrical stimulation of the inner surface of the rabbit retina effected the resident glial cells. We used a rabbit retinal eyecup preparation model, transparent stimulus electrodes, and optical coherence tomography (OCT). The endfeet of Müller glia processes line the inner limiting membrane (ILM).

Methods

To examine how epiretinal electrode stimulation affected the Müller glia, we labeled them post stimulation using antibodies against soluble glutamine synthetase (GS). After 5 min 50 Hz pulse train stimulation 30 μm from the surface, the retina was fixed, immunostained for Müller glia, and examined using confocal microscopic reconstruction. Stimulus pulse charge densities between 133–749 μC/cm2/ph were examined.

Results

High charge density stimulation (442–749 μC/cm2/ph) caused significant losses in the GS immunofluorescence of the Müller glia endfeet under the electrode. This loss of immunofluorescence was correlated with stimuli causing ILM detachment when measured using OCT. Müller cells show potassium conductances at rest that are blocked by barium ions. Using 30 msec 20 μA stimulus current pulses across the eyecup, the change in transretinal resistance was examined by adding barium to the Ringer. Barium caused little change in the transretinal resistance, suggesting under low charge density stimulus pulse conditions, the Müller cell radial conductance pathway for these stimulus currents was small. To examine how epiretinal electrode stimulation affected the microglia, we used lectin staining 0–4 h post stimulation. After stimulation at high charge densities 749 μC/cm2/ph, the microglia under the electrode appeared rounded, while the local microglia outside the electrode responded to the stimulated retina by process orientation inwards in a ring by 30 min post stimulation.

Discussion

Our study of glial cells in a rabbit eyecup model using transparent electrode imaging suggests that epiretinal electrical stimulation at high pulse charge densities, can injure the Müller and microglia cells lining the inner retinal surface in addition to ganglion cells.
Case report: Pemigatinib-induced retinopathy: a serial examination of subretinal fluid secondary to an FGFR inhibitor
Authors: Barmas-Alamdari Daniel , Jiao George , Lieberman Ronni
Published: January 2024

Background

Modern chemotherapeutic agents continue to evolve as modern monoclonal antibody treatments are designed to directly target proteins, enzymes, and focal loci. A particular class of these medications, fibroblast growth factor (FGFR) inhibitors, specifically pemigatinib (Pemazyre®; Incyte), has been approved by the US Food and Drug Administration since April 2020 for the treatment of advanced or metastatic cholangiocarcinoma. As it is a relatively new medication, its side-effect profile is manifesting in active clinical practice. The presence of FGFR receptors in the retinal pigment epithelium makes the retina susceptible to potential adverse effects secondary to pemigatinib use.

Case presentation

A 69-year-old African-American male with a tumor mutation burden 3 (TMB-3) metastatic adenocarcinoma of the liver from primary cholangiocarcinoma, who was undergoing chemotherapy with pemigatinib, was found to have asymptomatic bilateral subretinal fluid accumulation. Serial monitoring with optical coherence tomography (OCT) demonstrated complete resolution of the subretinal fluid while off-cycle and asymptomatic re-accumulation of subretinal fluid while on-cycle, with no significant changes in visual acuity.

Conclusions

Subretinal fluid accumulation secondary to pemigatinib may develop during the active treatment cycles without causing any significant visual symptoms for the patient. Serial monitoring demonstrates fluctuations of subretinal fluid during the patient’s on- and off-cycles. This case strengthens the current guidelines for continuing pemigatinib in asymptomatic patients found to have subretinal fluid. Further studies are warranted to identify patients who may be at higher risk for developing subretinal fluid.
Outpatient depression current care expenditure changes in Liaoning Province from 2015 to 2020: a study based on the “system of health accounts 2011”
Authors: Ma Yuedan , Shi Xiaoxia , Sznajder Kristin K. , Zhao Yue , Wan Quan , Chai Peipei , Yang Xiaoshi
Published: January 2024

Introduction: Depression is the leading cause of disability worldwide and has become a health issue of global concern. Based on the “System of Health Accounts 2011” (SHA 2011) for patients with depression, this paper studies the changes in the current curative expenditure (CCE) of outpatient depression in Liaoning Province, China, and provides policy recommendations.

Method: A stratified multistage random sample of 56,994 patients with depression included from 1,227 healthcare facilities in Liaoning Province were included. The significance of differences in variables within groups was analyzed by univariate analysis (including descriptive statistics analysis, Mann-Whitney U test and Kruskal–Wallis H test), and factors influencing depression outpatient CCE were analyzed by multiple linear regression analysis and constructing structural equation models (SEM).

Results: The CCE of outpatient depression was ranging from CNY 75.57 million to CNY 100.53 million in 2015–2020, with the highest of CNY 100.53 million in 2018, CNY 103.28 million in 2019. Medical expenditures are mainly concentrated in general hospitals and provincial healthcare institutions, accounting for about 90% of all provincial scope expenditures. The multiple regression results show that provincial healthcare institutions, purchase of drug, select medical treatment for depression, general hospitals and urban employees’ health insurance are the main influencing factors for depression outpatient CCE. The results of SEM show that insurance status negative impact outpatient expenditure.

Conclusion: Health insurance is an important factor in equitable access to healthcare resources for patients, and medication expenditure is the influential factor affecting the high expenditure of outpatient clinics. It is of great importance to reduce the medical burden of patients by increasing the coverage of medical insurance, increasing the proportion of bills that are eligible for reimbursement, and improving the system by guaranteeing the supply of psychotropic medication.
Compound Danshen dripping pills prevent early diabetic retinopathy: roles of vascular protection and neuroprotection
Authors: Xu Xiaoyu , Wang Mengchen , Zhang Shuxia , Wang Jing , Li Xinxin , Ma Xiaohui , Luo Yun , Sun Xiaobo
Published: January 2024

Introduction: Diabetic retinopathy (DR) represents a major cause of adult blindness, and early discovery has led to significant increase in the number of patients with DR. The drugs currently used for treatment, such as ranibizumab, mainly focus on the middle and late periods of DR, and thus do not meet the clinical need. Here, the potential mechanisms by which compound Danshen Dripping Pills (CDDP) might protect against early DR were investigated.

Methods: Db/db mice were used to establish a DR model. The initial weights and HbA1c levels of the mice were monitored, and retinal pathology was assessed by hematoxylin-eosin (HE) staining. The vascular permeability of the retina and thickness of each retinal layer were measured, and electroretinogram were performed together with fundus fluorescein angiography and optical coherence tomography. The levels of inflammatory factors were examined in retinal tissue, as well as those of intercellular adhesion molecule 1 (ICAM-1), IL-6, and monocyte chemoattractant protein 1 (MCP-1) in the serum using ELISA. Immunohistochemistry was used to evaluate levels of vascular endothelial growth factor (VEGF), B-cell lymphoma 2 (Bcl-2), and Bclassociated X protein (Bax). Retinal cell injury and apoptosis were examined by TdT-mediated dUTP Nick End Labeling (TUNEL) assays.

Results: The data showed that CDDP significantly improved cellular disarrangement. Imaging data indicated that CDDP could reduce vascular permeability and the amplitude of oscillatory potentials (OPs), and restore the thickness of the ganglion cell layer. Moreover, CDDP reduced the expression levels of inflammatory factors in both the retina and serum.

Conclusion: These findings strongly suggest that CDDP prevents early DR through vascular and neuroprotection.
Dual inhibition of MEK and PI3Kβ/δ–a potential therapeutic strategy in PTEN-wild-type docetaxel-resistant metastatic prostate cancer
Authors: Ruiz de Porras Vicenç , Bernat-Peguera Adrià , Alcon Clara , Laguia Fernando , Fernández-Saorin Maria , Jiménez Natalia , Senan-Salinas Ana , Solé-Blanch Carme , Feu Andrea , Marín-Aguilera Mercedes , Pardo Juan Carlos , Ochoa-de-Olza Maria , Montero Joan , Mellado Begoña , Font Albert
Published: January 2024

Background: Docetaxel remains the standard treatment for metastatic castration-resistant prostate cancer (mCRPC). However, resistance frequently emerges as a result of hyperactivation of the PI3K/AKT and the MEK/ERK pathways. Therefore, the inhibition of these pathways presents a potential therapeutic approach. In this study, we evaluated the efficacy of simultaneous inhibition of the PI3K/AKT and MEK/ERK pathways in docetaxel-resistant mCRPC, both in vitro and in vivo.

Methods: Docetaxel-sensitive and docetaxel-resistant mCRPC cells were treated with selumetinib (MEK1/2 inhibitor), AZD8186 (PI3Kβ/δ inhibitor) and capivasertib (pan-AKT inhibitor) alone and in combination. Efficacy and toxicity of selumetinib+AZD8186 were tested in docetaxel-resistant xenograft mice. CRISPR-Cas9 generated a PTEN-knockdown docetaxel-resistant cell model. Changes in phosphorylation of AKT, ERK and downstream targets were analyzed by Western blot. Antiapoptotic adaptations after treatments were detected by dynamic BH3 profiling.

Results: PI3K/AKT and MEK/ERK pathways were hyperactivated in PTEN-wild-type (wt) docetaxel-resistant cells. Selumetinib+AZD8186 decreased cell proliferation and increased apoptosis in PTEN-wt docetaxel-resistant cells. This observation was further confirmed in vivo, where docetaxel-resistant xenograft mice treated with selumetinib+AZD8186 exhibited reduced tumor growth without additional toxicity.

Conclusion: Our findings on the activity of selumetinib+AZD8186 in PTEN-wt cells and in docetaxel-resistant xenograft mice provide an excellent rationale for a novel therapeutic strategy for PTEN-wt mCRPC patients resistant to docetaxel, in whom, unlike PTEN-loss patients, a clinical benefit of treatment with single-agent PI3K and AKT inhibitors has not been demonstrated. A phase I-II trial of this promising combination is warranted.