bluuebunny/crossref_metadata_2025 huggingface dataset:
HPR1000 pressurizer degassing system design and analysis
Authors: Cui Huaiming , Cai Zhiyun
Published: June 2024

In the Hualong-1 Unit (HPR1000), the hydrogen (H2) concentration should be reduced to 15 mL (STP)/kg 24 h before reactor shutdown when the reactor vessel is scheduled to be opened. The traditional degassing method, i.e., letting down the reactor coolant through a chemical and volume control system, will take longer, and its operation is more complicated. To shorten the degassing time and simplify the operation, this paper proposes a pressurizer degassing system design for HPR1000 by applying the pressurizer as thermal degassing equipment. Then, the degassing system optimization analysis is carried out under a full range of steady operating conditions during shutdown, and the optimal size of the flow-limiting orifice plate is obtained. Meanwhile, in order to verify the transient characteristic during the degassing process to ensure operating safety, a dedicated transient degassing program based on an improved non-equilibrium multi-region pressurizer model and a transient degassing model is used to carry out a transient simulation analysis of this process. The transient simulation results show that, under bounding conditions of hot–zero-power operation, during the degassing process, the pressure of the pressurizer decreases by a maximum of 0.038 MPa and the water level increases by 0.016 m above the normal level. As can be seen, both the pressure and water level are within the normal operation band and shall not initiate any safety signal. Meanwhile, the entire transient process lasts approximately 24 min and then enters a stable degassing period. It takes approximately 5.2 h to remove the gas dissolved in the reactor coolant from 35 mL (STP)/kg to 15 mL (STP)/kg. The analysis shows that the pressurizer degassing system designed for HPR1000 is safe, effective, and reliable.
The performance evaluation of NIPT for fetal chromosome microdeletion/microduplication detection: a retrospective analysis of 68,588 Chinese cases
Authors: Shen Shichun , Qi Haimei , Yuan Xianping , Gan Jinhui , Chen Junkun , Huang Jungao
Published: June 2024

Background

Chromosomal abnormalities are the main cause of birth defects in newborns. Since the inception of noninvasive prenatal testing (NIPT) technology, it has primarily been applied to the detection of common trisomy (T21, T18, T13). However, the application of NIPT in microdeletion and microduplication detection is still controversial.

Methods

This study retrospectively analyzed the data of 68,588 cases that underwent NIPT at Ganzhou Maternal and Child Health Hospital in China. These data were used to evaluate the performance of NIPT in fetal chromosome microdeletion/microduplication detection and to investigate the key factors affecting the NIPT performance.

Results

A total of 281 cases (0.41%) had positive NIPT results with copy number variants (CNVs), of which 161 were validated by karyotyping and chromosome microarray analysis (CMA). Among the 161 cases, 92 were confirmed as true positives through karyotyping or CMA, including 61 microdeletion cases and 31 microduplication cases, resulting in a positive predictive value (PPV) of 57.14%. Improvements in library construction methods increased the fraction of cell-free fetal DNA (cffDNA) from 13.76% to 18.44%, leading to a significant improvement in the detection rate (0.47% vs. 0.15%) and PPV (59.86% vs. 28.57%) of NIPT for CNVs.

Conclusion

This study proved the robust performance of NIPT for fetal chromosome microdeletion/microduplication detection. In addition, the cffDNA fraction is a key factor influencing NIPT, with increased cffDNA fraction improving the performance of NIPT.
DNA methylation signatures provide novel diagnostic biomarkers and predict responses of immune therapy for breast cancer
Authors: Chen Zhishan , Jiang Han , Qin Qingqing , Li Qiyuan , Hong Liqing
Published: June 2024

Breast cancer (BRCA) is one of the most common malignant tumors affecting women worldwide. DNA methylation modifications can influence oncogenic pathways and provide potential diagnostic and therapeutic targets for precision oncology. In this study, we used non-parametric permutation tests to identify differentially methylated positions (DMPs) between paired tumor and normal BRCA tissue samples from the Cancer Genome Atlas (TCGA) database. Then, we applied non-negative matrix factorization (NMF) to the DMPs to derive eight distinct DNA methylation signatures. Among them, signatures Hyper-S3 and Hypo-S4 signatures were associated with later tumor stages, while Hyper-S1 and Hypo-S3 exhibited higher methylation levels in earlier stages. Signature Hyper-S3 displayed an effect on overall survival. We further validated the four stage-associated signatures using an independent BRCA DNA methylation dataset from peripheral blood samples. Results demonstrated that 24 commonly hypomethylated sites in Hypo-S4 showed lower methylation in BRCA patients compared to healthy individuals, suggesting its potential as an early diagnostic biomarker. Furthermore, we found that methylation of 23 probes from four stage-related signatures exhibited predictive power for immune therapy response. Notably, methylation levels of all three probes from the Hypo-S4 and activity of the Hypo-S4 demonstrated highly positive relevance to PD-L1 gene expression, implying their significant predictive values for immunotherapy outcomes. GO and KEGG pathway enrichment analysis revealed that genes with these 23 immunotherapy-related methylation probes are mainly involved in glycan degradation or protein deglycosylation. These methylation signatures and probes may serve as novel epigenetic biomarkers for predicting tumor immunotherapy response. Our findings provide new insights into precision oncology approaches for BRCA.
New insights into the pathogenesis of SARS-CoV-2 during and after the COVID-19 pandemic
Authors: Carvajal Jonatan J. , García-Castillo Valeria , Cuellar Shelsy V. , Campillay-Véliz Claudia P. , Salazar-Ardiles Camila , Avellaneda Andrea M. , Muñoz Christian A. , Retamal-Díaz Angello , Bueno Susan M. , González Pablo A. , Kalergis Alexis M. , Lay Margarita K.
Published: June 2024

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the respiratory distress condition known as COVID-19. This disease broadly affects several physiological systems, including the gastrointestinal, renal, and central nervous (CNS) systems, significantly influencing the patient’s overall quality of life. Additionally, numerous risk factors have been suggested, including gender, body weight, age, metabolic status, renal health, preexisting cardiomyopathies, and inflammatory conditions. Despite advances in understanding the genome and pathophysiological ramifications of COVID-19, its precise origins remain elusive. SARS-CoV-2 interacts with a receptor-binding domain within angiotensin-converting enzyme 2 (ACE2). This receptor is expressed in various organs of different species, including humans, with different abundance. Although COVID-19 has multiorgan manifestations, the main pathologies occur in the lung, including pulmonary fibrosis, respiratory failure, pulmonary embolism, and secondary bacterial pneumonia. In the post-COVID-19 period, different sequelae may occur, which may have various causes, including the direct action of the virus, alteration of the immune response, and metabolic alterations during infection, among others. Recognizing the serious adverse health effects associated with COVID-19, it becomes imperative to comprehensively elucidate and discuss the existing evidence surrounding this viral infection, including those related to the pathophysiological effects of the disease and the subsequent consequences. This review aims to contribute to a comprehensive understanding of the impact of COVID-19 and its long-term effects on human health.
Deletion of an immune evasion gene, steD, from a live Salmonella enterica serovar Typhimurium vaccine improves vaccine responses in aged mice
Authors: Allen Jessica C. , Natta Shanaliz S. , Nasrin Shamima , Toapanta Franklin R. , Tennant Sharon M.
Published: June 2024

Introduction

Non-typhoidal Salmonella (NTS) generally causes self-limiting gastroenteritis. However, older adults (≥65 years) can experience more severe outcomes from NTS infection. We have previously shown that a live attenuated S. Typhimurium vaccine, CVD 1926 (I77 ΔguaBA ΔclpP ΔpipA ΔhtrA), was immunogenic in adult but not aged mice. Here we describe modification of CVD 1926 through deletion of steD, a Salmonella effector responsible for host immune escape, which we hypothesized would increase immunogenicity in aged mice.

Methods

Mel Juso and/or mutuDC cells were infected with S. Typhimurium I77, CVD 1926, and their respective steD mutants, and the MHC-II levels were evaluated. Aged (18-month-old) C57BL/6 mice received two doses of PBS, CVD 1926, or CVD 1926 ΔsteD perorally (109 CFU) and the number of FliC-specific CD4+ T cells were determined. Lastly, aged C57BL/6 mice received three doses of PBS, CVD 1926, or CVD 1926 ΔsteD perorally (109 CFU) and then were challenged perorally with wild-type S. Typhimurium SL1344 (108 CFU). These animals were also evaluated for antibody responses.

Results

MHC-II induction was higher in cells treated with steD mutants, compared to their respective parental strains. Compared to PBS-vaccinated mice, CVD 1926 ΔsteD elicited significantly more FliC-specific CD4+ T cells in the Peyer’s Patches. There were no significant differences in FliC-specific CD4+ T cells in the Peyer’s patches or spleen of CVD 1926- versus PBS-immunized mice. CVD 1926 and CVD 1926 ΔsteD induced similar serum and fecal anti-core and O polysaccharide antibody titers after three doses. After two immunizations, the proportion of seroconverters for CVD 1926 ΔsteD was 83% (10/12) compared to 42% (5/12) for CVD 1926. Compared to PBS-immunized mice, mice immunized with CVD 1926 ΔsteD had significantly lower S. Typhimurium counts in the spleen, cecum, and small intestine upon challenge. In contrast, there were no differences in bacterial loads in the tissues of PBS-vaccinated and CVD 1926-immunized animals.

Conclusion

These data suggest that the steD deletion enhanced the immunogenicity of our live attenuated S. Typhimurium vaccine. Deletion of immune evasion genes could be a potential strategy to improve the immunogenicity of live attenuated vaccines in older adults.
Escalating SARS-CoV-2 specific humoral immune response in rheumatoid arthritis patients and healthy controls
Authors: Nemeth Dora , Vago Hajnalka , Tothfalusi Laszlo , Ulakcsai Zsuzsanna , Becker David , Szabo Zsofia , Rojkovich Bernadett , Gunkl-Toth Lilla , Merkely Bela , Nagy Gyorgy
Published: June 2024

Background

Immunocompromised patients are at particular risk of Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) infection and previous findings suggest that the infection or vaccination induced immune response decreases over time. Our main goal was to investigate the SARS-CoV-2-specific immune response in rheumatoid arthritis patients and healthy controls over prolonged time.

Methods

The SARS-CoV-2-specific humoral immune response was measured by Elecsys Anti-SARS-CoV-2 Spike (S) immunoassay, and antibodies against SARS-CoV-2 nucleocapsid protein (NCP) were also evaluated by Euroimmun enzyme-linked immunosorbent assay (ELISA) test. The SARS-CoV-2-specific T-cell response was detected by an IFN- γ release assay.

Results

We prospectively enrolled 84 patients diagnosed with rheumatoid arthritis (RA) and 43 healthy controls in our longitudinal study. Our findings demonstrate that RA patients had significantly lower anti-S antibody response and reduced SARS-CoV-2-specific T-cell response compared to healthy controls (p<0.01 for healthy controls, p<0.001 for RA patients). Furthermore, our results present evidence of a notable increase in the SARS-CoV-2-specific humoral immune response during the follow-up period in both study groups (p<0.05 for healthy volunteers, p<0.0001 for RA patients, rank-sum test). Participants who were vaccinated against Coronavirus disease-19 (COVID-19) during the interim period had 2.72 (CI 95%: 1.25–5.95, p<0.05) times higher anti-S levels compared to those who were not vaccinated during this period. Additionally, individuals with a confirmed SARS-CoV-2 infection exhibited 2.1 times higher (CI 95%: 1.31–3.37, p<0.01) anti-S levels compared to those who were not infected during the interim period. It is worth noting that patients treated with targeted therapy had 52% (CI 95%: 0.25–0.94, p<0.05) lower anti-S levels compared to matched patients who did not receive targeted therapy. Concerning the SARS-CoV-2-specific T-cell response, our findings revealed that its level had not changed substantially in the study groups.

Conclusion

Our present data revealed that the level of SARS-CoV-2-specific humoral immune response is actually higher, and the SARS-CoV-2-specific T-cell response remained at the same level over time in both study groups. This heightened humoral response, the nearly permanent SARS-CoV-2-specific T-cell response and the coexistence of different SARS-CoV-2 variants within the population, might be contributing to the decline in severe COVID-19 cases.
Increased efficacy of influenza virus vaccine candidate through display of recombinant neuraminidase on virus like particles
Authors: Guzman Ruiz Leticia , Zollner Alexander M. , Hoxie Irene , Arcalis Elsa , Krammer Florian , Klausberger Miriam , Jungbauer Alois , Grabherr Reingard
Published: June 2024

Vaccination against influenza virus can reduce the risk of influenza by 40% to 60%, they rely on the production of neutralizing antibodies specific to influenza hemagglutinin (HA) ignoring the neuraminidase (NA) as an important surface target. Vaccination with standardized NA concentration may offer broader and longer-lasting protection against influenza infection. In this regard, we aimed to compare the potency of a NA displayed on the surface of a VLP with a soluble NA. The baculovirus expression system (BEVS) and the novel virus-free Tnms42 insect cell line were used to express N2 NA on gag-based VLPs. To produce VLP immunogens with high levels of purity and concentration, a two-step chromatography purification process combined with ultracentrifugation was used. In a prime/boost vaccination scheme, mice vaccinated with 1 µg of the N2-VLPs were protected from mortality, while mice receiving the same dose of unadjuvanted NA in soluble form succumbed to the lethal infection. Moreover, NA inhibition assays and NA-ELISAs of pre-boost and pre-challenge sera confirm that the VLP preparation induced higher levels of NA-specific antibodies outperforming the soluble unadjuvanted NA.
Consuming royal jelly alters several phenotypes associated with overwintering dormancy in mosquitoes
Authors: Bianco Olivia E. , Abdi Aisha , Klein Matthias S. , Wei Xueyan , Sim Cheolho , Meuti Megan E.
Published: June 2024

Introduction

Females of the Northern house mosquito, Culex pipiens, enter an overwintering dormancy, or diapause, in response to short day lengths and low environmental temperatures that is characterized by small egg follicles and high starvation resistance. During diapause, Culex pipiens Major Royal Jelly Protein 1 ortholog (CpMRJP1) is upregulated in females of Cx. pipiens. This protein is highly abundant in royal jelly, a substance produced by honey bees (Apis mellifera), that is fed to future queens throughout larval development and induces the queen phenotype (e.g., high reproductive activity and longer lifespan). However, the role of CpMRJP1 in Cx. pipiens is unknown.

Methods

We first conducted a phylogenetic analysis to determine how the sequence of CpMRJP1 compares with other species. We then investigated how supplementing the diets of both diapausing and nondiapausing females of Cx. pipiens with royal jelly affects egg follicle length, fat content, protein content, starvation resistance, and metabolic profile.

Results

We found that feeding royal jelly to females reared in long-day, diapause-averting conditions significantly reduced the egg follicle lengths and switched their metabolic profiles to be similar to diapausing females. In contrast, feeding royal jelly to females reared in short-day, diapause-inducing conditions significantly reduced lifespan and switched their metabolic profile to be similar nondiapausing mosquitoes. Moreover, RNAi directed against CpMRJPI significantly increased egg follicle length of short-day reared females, suggesting that these females averted diapause.

Discussion

Taken together, our data show that consuming royal jelly reverses several key seasonal phenotypes of Cx. pipiens and that these responses are likely mediated in part by CpMRJP1.
Effect of air exposure time on erodibility of intertidal mud flats
Authors: van Rees Floris F. , Hanssen Jill , Gamberoni Stefano , Talmon Arno M. , van Kessel Thijs
Published: June 2024

This study investigates the influence of air exposure time on the erodibility of intertidal mud flats, emphasizing the role of evaporation in altering sediment strength and cohesion. Through a comprehensive approach combining laboratory experiments, fieldwork, and numerical modelling, it explores the dynamic interactions between sediment properties and environmental conditions. The research reveals that drying significantly reduces sediment erodibility, with pronounced effects observed during the initial hours of air exposure. Laboratory tests demonstrate a direct correlation between drying time and increased yield stress for both artificial and field-derived mud samples. Field observations further support these results, showing spatial and temporal variations in water content and shear strength across various locations on a tidal flat. The study emphasizes the critical impact of mud content on water retention and the subsequent effect on sediment stability. The incorporation of drying time into erosion formulations within a numerical model highlights the importance of considering evaporation processes in predicting the morphological evolution of tidal flats. This research contributes to a better understanding of sediment transport dynamics in intertidal zones, offering insights into the mechanisms driving the growth and stability of mud flats. It underscores the necessity of integrating evaporation effects into cohesive sediment transport models to enhance the accuracy of predictions concerning the erosion and accretion of intertidal environments.
A dynamic routing scheme for underwater acoustic sensor networks in submarine disaster applications
Authors: Jiang Peng , Wang Hao , Xiong Zhiwen
Published: June 2024

Introduction

The ocean economy serves as a critical engine for the development of human society and economy, and its stable growth is of utmost importance. However, the frequent and unexpected occurrence of natural disasters, such as submarine disasters, poses significant threats to human society, especially disasters related to wave phenomena like the Ekman current, which has particularly prominent impacts.

Methods

The study proposes a dynamic routing scheme for underwater acoustic sensor networks. It establishes a cone-shaped distributed network, utilizing autonomous underwater vehicles to collect crucial data from nodes deployed on the seabed and transmitting it through the underwater cone-shaped distributed sensor network. Additionally, it adopts source location protection (SLP) technology to ensure the privacy of source locations. To validate the practicality and stability of this scheme, simulation experiments targeting the Ekman current were conducted in MATLAB.

Results

The experimental results demonstrate that the cone–SLP network significantly reduces the frequency of routing information exchange and energy consumption among acoustic sensors, effectively enhancing the economy and durability of the sensor network. Furthermore, it exhibits robust practicality and high stability in complex and variable submarine environments.

Discussion

This research not only provides a practical method for effectively monitoring submarine disasters but also offers valuable experience and significant reference value for other similar projects, playing a more crucial role in the sustainable development of the ocean economy.
Conduction mechanisms in a planar nanocomposite resistive switching device based on cluster-assembled Au/ZrOx films
Authors: Cipollini Davide , Profumo Filippo , Schomaker Lambert , Milani Paolo , Borghi Francesca
Published: June 2024

Nanostructured zirconia and gold films (ns-Au/ZrOx) have been demonstrated as devices characterized by non-linear and hysteretic electrical behavior, with short-term memory and potentiation/depression activity. Here we investigate the conduction mechanisms regulating the non-linear behavior of the nanostructured bilayer Au/ZrOx films. In particular, we investigated the hysteretic I-V curves following the Chua’s approach to memristive systems and separately modelling ion migration and electron transport in the films. The conduction mechanisms exhibited by the bilayered nanostructured system are strongly influenced by the nanogranular morphology that dynamically changes because of electrical stimuli; structural rearrangements are particularly promoted by intense local electric fields and high mobility along bottlenecks and edges in the microstructure. Electron transport is accounted for the Schottky barrier at the electrode interfaces and Poole-Frenkel effect in the bulk nanogranular material, according to a dynamic reorganization of the cluster-assembled network. A model for Poole-Frenkel effect is here discussed to include saturation of the Coulombic traps in the high applied field regime; the proposed model has been validated with experimental voltage ramps with varying sweep-velocity and at different temperatures (from 300 to 200 K), as also by a power exponent parameter analysis.
Construction of a preoperative nomogram model for predicting perineural invasion in advanced gastric cancer
Authors: Cong Ruochen , Xu Ruonan , Ming Jialei , Zhu Zhengqi
Published: June 2024

Objective

This study aimed to develop and validate a clinical and imaging-based nomogram for preoperatively predicting perineural invasion (PNI) in advanced gastric cancer.

Methods

A retrospective cohort of 351 patients with advanced gastric cancer who underwent surgical resection was included. Multivariable logistic regression analysis was conducted to identify independent risk factors for PNI and to construct the nomogram. The performance of the nomogram was assessed using calibration curves, the concordance index (C-index), the area under the curve (AUC), and decision curve analysis (DCA). The disparity in disease-free survival (DFS) between the nomogram-predicted PNI-positive group and the nomogram-predicted PNI-negative group was evaluated using the Log-Rank test and Kaplan–Meier analysis.

Results

Extramural vascular invasion (EMVI), Borrmann classification, tumor thickness, and the systemic inflammation response index (SIRI) emerged as independent risk factors for PNI. The nomogram model demonstrated a commendable AUC value of 0.838. Calibration curves exhibited excellent concordance, with a C-index of 0.814. DCA indicated that the model provided good clinical net benefit. The DFS of the nomogram-predicted PNI-positive group was significantly lower than that of the nomogram-predicted PNI-negative group (p < 0.001).

Conclusion

This study successfully developed a preoperative nomogram model that not only effectively predicted PNI in gastric cancer but also facilitated postoperative risk stratification.
Does the nurse-led case management benefit rheumatoid arthritis patients in reducing distressing symptoms and C-reactive protein: a 2-year follow-up study in Taiwan
Authors: Chang Wei-Chiao , Livneh Hanoch , Huang Hua-Lung , Li Hsin-Hua , Lu Ming-Chi , Lin Miao-Chiu , Chen Wei-Jen , Tsai Tzung-Yi
Published: June 2024

Background

Rheumatoid arthritis (RA) is a chronic disease and may worsen over time. Today, nurse-led case management (NLCM) has been recommended to improve clinical outcomes for chronic disease patients, yet little is known regarding its impact on pain, fatigue, and C-reactive protein (CRP) among RA patients. We aimed to explore this issue among such groups via a two-group pre- and post-test approach.

Methods

All subjects were recruited from one hospital in Taiwan from January 2017 to June 2018 and assigned to either a 6-month NLCM program in addition to usual care or to a control group that received usual care only. All of them were followed for 2 years. Outcomes of interests were compared at four time points: baseline, the third day after NLCM completion, and at 6 and 24 months after NLCM. Effects between them were tested using the generalized estimating equations (GEE) model after adjusting for differences at baseline.

Results

A total of 50 patients in the NLCM group and 46 in the control group were recruited for data analysis. Results from the GEE model indicated that integrating NLCM into conventional care benefited patients in decreasing levels of pain and fatigue, as well as CRP value. These improvements were still observed for 2 years after NLCM.

Conclusion

NLCM was shown to be helpful in lowering pain, fatigue, and CRP, which implies that NLCM may be a reference in the provision of tailored care for those affected by rheumatism.
Repurposing lipid-lowering drugs as potential treatment for acne vulgaris: a Mendelian randomization study
Authors: Fang Man , Lei Jing , Zhang Yue , Zhang Bo
Published: June 2024

Background

Acne vulgaris, a chronic inflammatory skin condition predominantly seen in teenagers, impacts more than 640 million people worldwide. The potential use of lipid-lowering medications as a treatment for acne vulgaris remains underexplored. This study seeks to investigate the impact of lipid-lowering therapies on the risk of developing acne vulgaris using two-sample Mendelian randomization (MR) analysis.

Method

The two-sample MR method was employed for analysis, and information on lipid-lowering drugs was obtained from the DrugBank and ChEMBL databases. The summary data for blood low-density lipoprotein (LDL) and triglycerides were sourced from the Global Lipids Genetics Consortium, while genome-wide association studies (GWAS) summary data for acne vulgaris were obtained from the FinnGen database. Heterogeneity was examined using the Q-test, horizontal pleiotropy was assessed using MR-Presso, and the robustness of analysis results was evaluated using leave-one-out analysis.

Results

The MR analysis provided robust evidence for an association between lowering LDL cholesterol through two drug targets and acne vulgaris, with PCSK9 showing an odds ratio (OR) of 1.782 (95%CI: 1.129–2.812, p = 0.013) and LDL receptor (LDLR) with an OR of 1.581 (95%CI: 1.071–2.334, p = 0.021). Similarly, targeting the lowering of triglycerides through lipoprotein lipase (LPL) was significantly associated with an increased risk of acne vulgaris, indicated by an OR of 1.607 (95%CI: 1.124–2.299, p = 0.009).

Conclusion

The current MR study presented suggestive evidence of a positive association between drugs targeting three genes (PCSK9, LDLR, and LPL) to lower lipids and a reduced risk of acne vulgaris.
The hospitalization burden of inflammatory bowel disease in a southwestern highland region of China: a territory-wide study from 2015 to 2020
Authors: Tao Yan , Li Maojuan , Gao Huabin , Sun Yang , Zhang Fengrui , Wu Jing , Liang Hao , He Liping , Gong Min , Niu Junkun , Miao Yinglei
Published: June 2024

Background

Yunnan, a southwest highland and newly industrialized region of China, has an unknown hospitalization burden of inflammatory bowel disease (IBD). The study was conducted to explore territorial hospitalization burden of IBD.

Methods

The formatted medical records of patients with IBD were collected from a territory-wide database in Yunnan Province, China, from 2015 to 2020. General characteristics of the study population were reported using descriptive statistics. To evaluate the length of stay, hospitalization costs, surgery, complications, and trends in patients with inflammatory bowel disease. The logistic regression analysis was established to explore the factors affecting the hospitalization costs.

Results

A total of 12,174 records from 8192 patients were included. The annual hospitalization cost of IBD in Yunnan Province increased significantly from 2015 to 2020. From 2015 to 2020, the regional hospitalization burden of IBD increased, but it represented a decline in cost per hospitalization (r = −0.024, P = 0.008) and the length of stay (r = −0.098, P < 0.001). Surgery rates for hospitalized patients with Crohn’s disease (CD) did not decrease (r = −0.002, P = 0.932), and even increased for patients with ulcerative colitis (UC) (r = 0.03, P = 0.002). The costs per hospitalization were $ 827.49 (540.11–1295.50) for UC and $ 1057.03 (644.26–1888.78) for CD. Among the identifiable cost items during the period, drug costs accounted for the highest proportion, accounting for 33% and 37.30% in patients with UC and CD, respectively. Surgical intervention [OR 4.87 (3.75–6.31), P < 0.001], comorbidities [OR 1.72 (1.52–1.94), P < 0.001], complications [OR 1.53 (1.32–1.78), P < 0.001], and endoscopy [OR 2.06 (1.86–2.28), P < 0.001] were predictor of high hospitalization costs.

Conclusion

The increasing burden of IBD is noteworthy a newly industrialized region of China. Interventions targeting surgery, complications, and comorbidities may be effective means of controlling the increasing hospitalization costs of IBD in the regions.
The use of omics technologies in creating LBP and postbiotics based on the Limosilactobacillus fermentum U-21
Authors: Odorskaya Maya V. , Mavletova Dilara A. , Nesterov Andrey A. , Tikhonova Olga V. , Soloveva Natalia A. , Reznikova Diana A. , Galanova Olesya O. , Vatlin Aleksey A. , Slynko Nikolai M. , Vasilieva Asya R. , Peltek Sergey E. , Danilenko Valery N.
Published: June 2024

In recent years, there has been an increasing tendency to create drugs based on certain commensal bacteria of the human microbiota and their ingredients, primarily focusing on live biotherapeutics (LBPs) and postbiotics. The creation of such drugs, termed pharmacobiotics, necessitates an understanding of their mechanisms of action and the identification of pharmacologically active ingredients that determine their target properties. Typically, these are complexes of biologically active substances synthesized by specific strains, promoted as LBPs or postbiotics (including vesicles): proteins, enzymes, low molecular weight metabolites, small RNAs, etc. This study employs omics technologies, including genomics, proteomics, and metabolomics, to explore the potential of Limosilactobacillus fermentum U-21 for innovative LBP and postbiotic formulations targeting neuroinflammatory processes. Proteomic techniques identified and quantified proteins expressed by L. fermentum U-21, highlighting their functional attributes and potential applications. Key identified proteins include ATP-dependent Clp protease (ClpL), chaperone protein DnaK, protein GrpE, thioredoxin reductase, LysM peptidoglycan-binding domain-containing protein, and NlpC/P60 domain-containing protein, which have roles in disaggregase, antioxidant, and immunomodulatory activities. Metabolomic analysis provided insights into small-molecule metabolites produced during fermentation, revealing compounds with anti-neuroinflammatory activity. Significant metabolites produced by L. fermentum U-21 include GABA (γ-aminobutyric acid), niacin, aucubin, and scyllo-inositol. GABA was found to stabilize neuronal activity, potentially counteracting neurodegenerative processes. Niacin, essential for optimal nervous system function, was detected in vesicles and culture fluid, and it modulates cytokine production, maintaining immune homeostasis. Aucubin, an iridoid glycoside usually secreted by plants, was identified as having antioxidant properties, addressing issues of bioavailability for therapeutic use. Scyllo-inositol, identified in vesicles, acts as a chemical chaperone, reducing abnormal protein clumps linked to neurodegenerative diseases. These findings demonstrate the capability of L. fermentum U-21 to produce bioactive substances that could be harnessed in the development of pharmacobiotics for neurodegenerative diseases, contributing to their immunomodulatory, anti-neuroinflammatory, and neuromodulatory activities. Data of the HPLC-MS/MS analysis are available via ProteomeXchange with identifier PXD050857.
Bidirectional modulation of synaptic transmission by insulin-like growth factor-I
Authors: Noriega-Prieto José Antonio , Maglio Laura Eva , Perez-Domper Paloma , Dávila José Carlos , Gutiérrez Antonia , Torres-Alemán Ignacio , Fernández de Sevilla David
Published: June 2024

Insulin-like growth factor-I (IGF-I) plays a key role in the modulation of synaptic plasticity and is an essential factor in learning and memory processes. However, during aging, IGF-I levels are decreased, and the effect of this decrease in the induction of synaptic plasticity remains unknown. Here we show that the induction of N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) at layer 2/3 pyramidal neurons (PNs) of the mouse barrel cortex is favored or prevented by IGF-I (10 nM) or IGF-I (7 nM), respectively, when IGF-I is applied 1 h before the induction of Hebbian LTP. Analyzing the cellular basis of this bidirectional control of synaptic plasticity, we observed that while 10 nM IGF-I generates LTP (LTPIGF-I) of the post-synaptic potentials (PSPs) by inducing long-term depression (LTD) of the inhibitory post-synaptic currents (IPSCs), 7 nM IGF-I generates LTD of the PSPs (LTDIGF-I) by inducing LTD of the excitatory post-synaptic currents (EPSCs). This bidirectional effect of IGF-I is supported by the observation of IGF-IR immunoreactivity at both excitatory and inhibitory synapses. Therefore, IGF-I controls the induction of Hebbian NMDAR-dependent plasticity depending on its concentration, revealing novel cellular mechanisms of IGF-I on synaptic plasticity and in the learning and memory machinery of the brain.
Obstructive sleep apnea in the hemodialysis population: are clinicians putting existing scientific evidence into practice?
Authors: Burkhalter David Andri , Cartellá Antonio , Cozzo Domenico , Ogna Adam , Forni Ogna Valentina
Published: June 2024

Introduction

Hemodialysis (HD) populations have a high prevalence of Obstructive Sleep Apnea (OSA), which was specifically linked with fluid overload. HD fluid management targeting a low dry weight was shown to reduce OSA severity, opening to novel therapeutic options. We assessed nephrologists’ awareness of OSA diagnosis in HD patients and whether they integrate the current knowledge into their fluid management strategy.

Material and methods

We performed a multicenter, cross-sectional study between July 2022 and July 2023, screening all HD patients of four HD units, and included those with confirmed OSA. We collected anthropometric parameters and fluid status from electronic dossiers. Predialysis fluid overload was measured by multifrequency bioelectrical impedance (BCM®). Nephrologists were asked to identify patients with known OSA, without consulting medical dossiers. The fluid management of patients identified as “OSA positive” was compared to that of patients misclassified as “OSA negative”.

Results

Among 193 HD patients, 23.0% (n=45) had confirmed OSA. The mean age was 76.0 ± 7.5 years, 82.2% were men. Only 60% were correctly identified as “OSA positive” by nephrologists; 14.7% of patients on CPAP were identified. BMI was the only factor associated with correct OSA identification. The predialysis fluid overload tended to be greater in “OSA positive” patients than in the “OSA negative” patients (2.2 ± 1.4 kg vs 1.5 ± 1.3 kg; p=0.08), but there was no difference in postdialysis achievement of dry weight between the groups (residual overweight 0.2 ± 1.0 kg and 0.1 ± 0.7 kg; p= 0.672).

Conclusions

Our study suggests that the application of scientific evidence to the management of OSA in dialysis patients is not systematic. However, nephrologists have attempted to strictly achieve dry weight in all patients, regardless of OSA status. Sensibilization of nephrologists on the clinical and diagnostic peculiarities of OSA in HD patients may improve OSA diagnosis and therapeutic care.
Towards a lifelong personalized brain health program: empowering individuals to define, pursue, and monitor meaningful outcomes
Authors: Saunders Stina , Gomes-Osman Joyce , Jannati Ali , Ciesla Marissa , Banks Russell , Showalter John , Muniz-Terrera Graciela , Luz Saturnino , Ritchie Craig , Pascual-Leone Álvaro
Published: June 2024

Incorporating person-centered outcomes into clinical trials for neurodegenerative diseases has been challenging due to a deficiency in quantitative measures. Meanwhile, the integration of personally meaningful treatment targets in clinical practice remains qualitative, failing to truly inform evaluations, therapeutic interventions and longitudinal monitoring and support. We discuss the current advances and future directions in capturing individualized brain health outcomes and present an approach to integrate person-centered outcome in a scalable manner. Our approach stems from the evidence-based electronic Person-Specific Outcome Measure (ePSOM) program which prompts an individual to define personally meaningful treatment priorities and report level of confidence in managing items that matter to the individual the most (e.g., “Do I feel confident in my ability to contribute to a conversation?”). Deployed either as a single version (person only) or a dyad version (person and care partner), our proposed tool could be used as an endpoint in clinical trials, offering proof of meaningful intervention benefits and in clinical practice, by establishing an anchor for the therapeutic objectives sought by the individual.
The influence of factors associated with past reproductive histories on migraines in middle-aged premenopausal women: a nationwide population-based study in Republic of Korea
Authors: Kim Seonghoon , Na Seunghee , Kim Young-Do , Bae Dae Woong , An Jae Young , Park Jeong Wook
Published: June 2024

Introduction

Women can experience various reproductive events, such as pregnancy, childbirth, lactation, and contraception, which cause long-term changes in female hormones. In middle-aged women, the prevalence of migraine is high, and a clear gender difference is evident. This study investigated the effects of factors associated with past reproductive events on the risk of new migraine in middle-aged premenopausal women.

Methods

The influence of reproductive factors on migraine in middle-aged women was investigated using the Korean National Health Insurance Service (KNHIS) and Korean Health Examination (KHE) databases. The reproductive factors of interest were parity, breastfeeding, and oral contraceptive (OC) use. The study included 949,704 middle-aged premenopausal women 40–60 years of age. The study population was divided into two groups based on new diagnosis of migraine during the follow-up period (2009–2018).

Results

The risk of new migraine tended to increase in the primiparous (hazard ratio, HR: 1.179; 95% confidence interval, CI: 1.137–1.221) and multiparous groups (HR: 1.181; 95% CI: 1.142–1.221) compared with the nulliparous group. The breastfeeding ≥12 months group (HR: 1.071; 95% CI: 1.052–1.091) showed a significantly increased risk of new migraine compared with the non-breastfeeding group. All women in the OC groups (< 1 year, HR: 1.048; 95% CI: 1.028–1.069 and ≥ 1 year, HR: 1.100; 95% CI: 1.067–1.134) showed a higher risk of new migraine than those in the non-OC group.

Conclusion

The results of the current study indicate that childbirth, longer breastfeeding, and OC use may be associated with a higher risk of new migraine in middle-aged premenopausal women.
Functional connectivity density aberrance in type 2 diabetes mellitus with and without mild cognitive impairment
Authors: Ge Limin , Cao Zidong , Sun Zhizhong , Yue Xiaomei , Rao Yawen , Zhao Kui , Qiu Wenbin , Li Yifan , Lu Weiye , Qiu Shijun
Published: June 2024

Purpose

The objective of this study was to investigate alterations in functional connectivity density (FCD) mapping and their impact on functional connectivity (FC) among individuals diagnosed with Type 2 diabetes mellitus (T2DM) across different cognitive states. Moreover, the study sought to explore the potential association between aberrant FCD/FC patterns and clinical or cognitive variables.

Methods

A total of 211 participants were recruited for this study, consisting of 75 healthy controls (HCs), 89 T2DM patients with normal cognitive function (DMCN), and 47 T2DM patients with mild cognitive impairment (DMCI). The study employed FCD analysis to pinpoint brain regions exhibiting significant FCD alterations. Subsequently, these regions showing abnormal FCD served as seeds for FC analysis. Exploratory partial correlations were conducted to explore the relationship between clinical biochemical indicators, neuropsychological test scores, and altered FCD or FC.

Results

The FCD analysis revealed an increased trend in global FCD (gFCD), local FCD (lFCD), and long-range FCD (lrFCD) within the bilateral supramarginal gyrus (SMG) among individuals with DMCN. Additionally, significant lFCD alterations were observed in the right inferior frontal gyrus and left precuneus when comparing DMCN to HCs and DMCI.

Conclusion

When comparing individuals with T2DM and healthy controls (HCs), it was revealed that DMCN exhibited significant improvements in FCD. This suggests that the brain may employ specific compensatory mechanisms to maintain normal cognitive function at this stage. Our findings provide a novel perspective on the neural mechanisms involved in cognitive decline associated with T2DM.
Subjective brain fog: a four-dimensional characterization in 25,796 participants
Authors: Alim-Marvasti Ali , Ciocca Matteo , Kuleindiren Narayan , Lin Aaron , Selim Hamzah , Mahmud Mohammad
Published: June 2024

Importance

Brain fog is associated with significant morbidity and reduced productivity and gained increasing attention after COVID-19. However, this subjective state has not been systematically characterised.

Objective

To characterise self-reported brain fog.

Design

We systematically studied the cross-sectional associations between 29 a priori variables with the presence of “brain fog.” The variables were grouped into four categories: demographics, symptoms and functional impairments, comorbidities and potential risk factors (including lifestyle factors), and cognitive score. Univariate methods determined the correlates of brain fog, with long-COVID and non-long-COVID subgroups. XGBoost machine learning model retrospectively characterised subjective brain fog. Bonferroni-corrected statistical significance was set at 5%.

Setting

Digital application for remote data collection.

Participants

25,796 individuals over the age of 18 who downloaded and completed the application.

Results

7,280 of 25,796 individuals (28.2%) reported experiencing brain fog, who were generally older (mean brain fog 35.7 ± 11.9 years vs. 32.8 ± 11.6 years, p < 0.0001) and more likely to be female (OR = 1.2, p < 0.001). Associated symptoms and functional impairments included difficulty focusing or concentrating (OR = 3.3), feeling irritable (OR = 1.6), difficulty relaxing (OR = 1.2, all p < 0.0001), difficulty following conversations (OR = 2.2), remembering appointments (OR = 1.9), completing paperwork and performing mental arithmetic (ORs = 1.8, all p < 0.0001). Comorbidities included long-COVID-19 (OR = 3.8, p < 0.0001), concussions (OR = 2.4, p < 0.0001), and higher migraine disability assessment scores (MIDAS) (+34.1%, all p < 0.0001). Cognitive scores were marginally lower with brain fog (−0.1 std., p < 0.001). XGBoost achieved a training accuracy of 85% with cross-validated accuracy of 74%, and the features most predictive of brain fog in the model were difficulty focusing and following conversations, long-COVID, and severity of migraines.

Conclusions and relevance

This is the largest study characterising subjective brain fog as an impairment of concentration associated with functional impairments in activities of daily living. Brain fog was particularly associated with a history of long-COVID-19, migraines, concussion, and with 0.1 standard deviations lower cognitive scores, especially on modified Stroop testing, suggesting impairments in the ability to inhibit cognitive interference. Further prospective studies in unselected brain fog sufferers should explore the full spectrum of brain fog symptoms to differentiate it from its associated conditions.
Novel human neurodevelopmental and neurodegenerative disease associated with IRF2BPL gene variants—mechanisms and therapeutic avenues
Authors: Bauersachs Daniel , Bomholtz Louise , del Rey Mateos Sara , Kühn Ralf , Lisowski Pawel
Published: June 2024

Recently a broad range of phenotypic abnormalities related to the neurodevelopmental and neurodegenerative disorder NEDAMSS (Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures) have been associated with rare single-nucleotide polymorphisms (SNPs) or insertion and deletion variants (Indel) in the intron-less gene IRF2BPL. Up to now, 34 patients have been identified through whole exome sequencing carrying different heterozygous pathogenic variants spanning the intron-less gene from the first polyglutamine tract at the N-terminus to the C3HC4 RING domain of the C-terminus of the protein. As a result, the phenotypic spectrum of the patients is highly heterogeneous and ranges from abnormal neurocognitive development to severe neurodegenerative courses with developmental and seizure-related encephalopathies. While the treatment of IRF2BPL-related disorders has focused on alleviating the patient’s symptoms by symptomatic multidisciplinary management, there has been no prospect of entirely relieving the symptoms of the individual patients. Yet, the recent advancement of CRISPR-Cas9-derived gene editing tools, leading to the generation of base editors (BEs) and prime editors (PEs), provide an encouraging new therapeutic avenue for treating NEDAMSS and other neurodevelopmental and neurodegenerative diseases, which contain SNPs or smaller Indels in post-mitotic cell populations of the central nervous system, due to its ability to generate site-specific DNA sequence modifications without creating double-stranded breaks, and recruiting the non-homologous DNA end joining repair mechanism.