bluuebunny/crossref_metadata_2025 huggingface dataset:
A role of gut microbiota metabolites in HLA-E and NKG2 blockage immunotherapy against tumors: new insights for clinical application
Authors: Cheng Wenyue , Zhu Ningning , Wang Juanjuan , Yang Rongcun
Published: August 2024

One of major breakthroughs in immunotherapy against tumor is from blocking immune checkpoint molecules on tumor and reactive T cells. The development of CTLA-4 and PD-1 blockage antibodies has triggered to search for additional effective therapeutic strategies. This causes recent findings that blocking the interaction of checkpoint molecule NKG2A in NK and CD8 T cells with HLA-E in tumors is effective in defensing tumors. Interestingly, gut microbiota also affects this immune checkpoint immunotherapy against tumor. Gut microbiota such as bacteria can contribute to the regulation of host immune response and homeostasis. They not only promote the differentiation and function of immunosuppressive cells but also the inflammatory cells through the metabolites such as tryptophan (Trp) and bile acid (BA) metabolites as well as short chain fatty acids (SCFAs). These gut microbiota metabolites (GMMs) educated immune cells can affect the differentiation and function of effective CD8 and NK cells. Notably, these metabolites also directly affect the activity of CD8 and NK cells. Furthermore, the expression of CD94/NKG2A in the immune cells and/or their ligand HLA-E in the tumor cells is also regulated by gut microbiota associated immune factors. These findings offer new insights for the clinical application of gut microbiota in precise and/or personalized treatments of tumors. In this review, we will discuss the impacts of GMMs and GMM educated immune cells on the activity of effective CD8 and NK cells and the expression of CD94/NKG2A in immune cells and/or their ligand HLA-E in tumor cells.
The emerging links between immunosenescence in innate immune system and neurocryptococcosis
Authors: Soraci Luca , Beccacece Alessia , Princiotto Maria , Villalta Savedra Edlin , Gambuzza Maria Elsa , Aguennouz M’Hammed , Corsonello Andrea , Luciani Filippo , Muglia Lucia , Filicetti Elvira , Greco Giada Ida , Volpentesta Mara , Biscetti Leonardo
Published: August 2024

Immunosenescence refers to the age-related progressive decline of immune function contributing to the increased susceptibility to infectious diseases in older people. Neurocryptococcosis, an infectious disease of central nervous system (CNS) caused by Cryptococcus neoformans (C. Neoformans) and C. gattii, has been observed with increased frequency in aged people, as result of the reactivation of a latent infection or community acquisition. These opportunistic microorganisms belonging to kingdom of fungi are capable of surviving and replicating within macrophages. Typically, cryptococcus is expelled by vomocytosis, a non-lytic expulsive mechanism also promoted by interferon (IFN)-I, or by cell lysis. However, whereas in a first phase cryptococcal vomocytosis leads to a latent asymptomatic infection confined to the lung, an enhancement in vomocytosis, promoted by IFN-I overproduction, can be deleterious, leading the fungus to reach the blood stream and invade the CNS. Cryptococcus may not be easy to diagnose in older individuals and, if not timely treated, could be potentially lethal. Therefore, this review aims to elucidate the putative causes of the increased incidence of cryptococcal CNS infection in older people discussing in depth the mechanisms of immunosenscence potentially able to predispose to neurocryptococcosis, laying the foundations for future research. A deepest understanding of this relationship could provide new ways to improve the prevention and recognition of neurocryptococcosis in aged frail people, in order to quickly manage pharmacological interventions and to adopt further preventive measures able to reduce the main risk factors.
Genetically predicted circulating concentrations of micronutrients and risk of autoimmune thyroiditis: a Mendelian randomized study
Authors: Qiu Rongliang , Sha Xuemei , Kuang Penghao , Chen Fangsen , Fu Jinbo
Published: August 2024

Background

Micronutrients play pivotal roles in modulating various aspects of the immune response. However, the existing literature on the association between micronutrients and autoimmune thyroiditis (AIT) remains limited and contentious. To address this gap, we conducted Mendelian randomization (MR) to investigate potential links between genetically predicted concentrations of six micronutrients (Copper (Cu), Iron (Ir), Calcium (Ca), Vitamin D (VD), Vitamin C (VC), Zinc (Zn)) and the risk of AIT.

Method

Utilizing summary statistics from genome-wide association studies (GWAS) in individuals of European descent, we employed MR methodologies to elucidate the interplay between micronutrients and AIT. Three distinct MR techniques were employed: Inverse Variance Weighted (IVW), MR-Egger regression, and Weighted Median Estimator (WME). Additionally, we evaluated outcome heterogeneity using Cochran’s Q statistic and assessed pleiotropy using the MR-Egger intercept.

Result

IVW analysis revealed no substantial evidence supporting a significant impact of genetically predicted micronutrient concentrations on AIT risk (Cu: OR = 0.918, P = 0.875; Ir: OR = 0.653, P = 0.264; Ca: OR = 0.964, P = 0.906; VD: OR = 0.717, P = 0.378; VC: OR = 0.986, P = 0.875; Zn: OR = 0.789, P = 0.539). Cochran’s Q test for IVW indicated no notable heterogeneity. Moreover, the MR-Egger intercept method suggested the presence of horizontal pleiotropy between serum VC levels and AIT (MR-Egger intercept = −0.037, p = 0.026), while no such pleiotropy was observed for other micronutrients.

Conclusion

Our MR analysis does not support a causal relationship between genetically predicted concentrations of six micronutrients (Cu, Ir, Ca, VD, VC, and Zn) and the risk of AIT.
Impact of E. muris infection on B. burgdorferi–induced joint pathology in mice
Authors: Bonin Jesse L. , Torres Steven R. , Marcinkiewicz Ashley L. , Duhamel Gerald E. , Yang Xiuli , Pal Utpal , DiSpirito Julia M. , Nowak Tristan A. , Lin Yi-Pin , MacNamara Katherine C.
Published: August 2024

Tick-borne infections are increasing in the United States and around the world. The most common tick-borne disease in the United States is Lyme disease caused by infection with the spirochete Borrelia burgdorferi (Bb), and pathogenesis varies from subclinical to severe. Bb infection is transmitted by Ixodes ticks, which can carry multiple other microbial pathogens, including Ehrlichia species. To address how the simultaneous inoculation of a distinct pathogen impacted the course of Bb-induced disease, we used C57BL/6 (B6) mice which are susceptible to Bb infection but develop only mild joint pathology. While infection of B6 mice with Bb alone resulted in minimal inflammatory responses, mice co-infected with both Bb and the obligate intracellular pathogen Ehrlichia muris (Em) displayed hematologic changes, inflammatory cytokine production, and emergency myelopoiesis similar to what was observed in mice infected only with Em. Moreover, infection of B6 mice with Bb alone resulted in no detectable joint inflammation, whereas mice co-infected with both Em and Bb exhibited significant inflammation of the ankle joint. Our findings support the concept that co-infection with Ehrlichia can exacerbate inflammation, resulting in more severe Bb-induced disease.
Immunogenicity and safety of different combinations involving a third booster dose of SARS-CoV-2 inactivated vaccine, inactivated quadrivalent influenza vaccine, and 23-valent pneumococcal polysaccharide vaccine in adults aged ≥60 years: a phase 4, randomized, open-label study
Authors: Bai Shuang , Zhou Shanshan , Zhang Junnan , Chen Weixin , Lv Min , Wang Jian , Zhang Ao , Wu Jiang , Zhao Wei
Published: August 2024

Background

Concomitant administration of COVID-19, influenza, and pneumococcal vaccines could reduce the burden on healthcare systems. However, the immunogenicity and safety of various combinations of a third booster dose of SARS-CoV-2 inactivated vaccine (CoronaVac), inactivated quadrivalent influenza vaccine (IIV4), and 23-valent pneumococcal polysaccharide vaccine (PPV23), particularly in different age groups, is still unknown.

Methods

A phase 4, randomized, open-label, controlled trial was conducted in Beijing, China. 636 healthy adults were divided into two age groups (18-59 and ≥60 years) and randomized equally into three groups: CoronaVac and IIV4 followed by PPV23; CoronaVac and PPV23 followed by IIV4; or CoronaVac followed by IIV4 and PPV23, with a 28-day interval between vaccinations. Immunogenicity was evaluated by measuring antibody titers, and safety was monitored. ClinicalTrials.gov Identifier: NCT05298800.

Results

Co-administration of a third dose of CoronaVac, IIV4, and PPV23 in any combination was safe. Among adults aged 18-59, co-administration with PPV23 maintained non-inferiority of antibody levels for CoronaVac and IIV4, despite a slight reduction in antibody responses. This reduction was not observed in participants ≥60 years. Furthermore, co-administration of IIV4 and PPV23 affected seroconversion rates for both vaccines.

Conclusions

Co-administration of the third dose of SARS-CoV-2 inactivated vaccine with the influenza vaccine, followed by PPV23, may be optimal for adults aged 18-59. In adults ≥60, all vaccine combinations were immunogenic, suggesting a flexible vaccination approach. Since antibody measurements were taken 28 days post-vaccination, ongoing surveillance is essential to assess the longevity of the immune responses.
Comprehensive landscapes of the causal network between immunity and sarcopenia
Authors: Liu Mingchong , Wang Jiaming , Han Yi , Fu Xiao , Pan Yutao , Yang Chensong , Sun Guixin
Published: August 2024

Background

Inflammaging, an immune status characterized by a sustained increase in pro-inflammatory markers and a decline in anti-inflammatory mechanisms, is a critical risk factor in the development of sarcopenia. Landscapes of the causal relationships between immunity and sarcopenia are needed to understand the mechanism of sarcopenia and provide novel treatments comprehensively.

Methods

We used Mendelian Randomization (MR) as the basic method in this study. By setting immune proteins, immune cells, and sarcopenia as exposures and outcomes alternatively, and then combining them in different directions, we potentially estimated their causal relationships and directions and subsequently mapped the comprehensive causal landscape based on this information efficiently. To further understand the network, we developed a method based on rank-sums to integrate multiple algorithms and identify the key immune cells and proteins.

Results

More than 1,000 causal relationships were identified between immune cell phenotypes, proteins, and sarcopenia traits (p < 0.05), and the causal maps of these linkages were established. In the threshold of FDR < 0.05, hundreds of causal linkages were still significant. The final comprehensive map included 13 immune cell phenotypes and 8 immune proteins. The star factors in the final map included EM CD8br %CD8br, EM DN (CD4- CD8-) %DN, SIRT2, and so on.

Conclusion

By reading the landscapes in this study, we may not only find the factors and the pathways that have been reported and proven but also identify multiple novel immunity cell phenotypes and proteins with enriched upstream and downstream pathways.
Immunomodulatory properties of naïve and inflammation-informed dental pulp stem cell derived extracellular vesicles
Authors: Umar Sadiq , Debnath Koushik , Leung Kasey , Huang Chun-Chieh , Lu Yu , Gajendrareddy Praveen , Ravindran Sriram
Published: August 2024

Mesenchymal stem cell derived extracellular vesicles (MSC EVs) are paracrine modulators of macrophage function. Scientific research has primarily focused on the immunomodulatory and regenerative properties MSC EVs derived from bone marrow. The dental pulp is also a source for MSCs, and their anatomical location and evolutionary function has primed them to be potent immunomodulators. In this study, we demonstrate that extracellular vesicles derived from dental pulp stem cells (DPSC EVs) have pronounced immunomodulatory effect on primary macrophages by regulating the NFκb pathway. Notably, the anti-inflammatory activity of DPSC-EVs is enhanced following exposure to an inflammatory stimulus (LPS). These inhibitory effects were also observed in vivo. Sequencing of the naïve and LPS preconditioned DPSC-EVs and comparison with our published results from marrow MSC EVs revealed that Naïve and LPS preconditioned DPSC-EVs are enriched with anti-inflammatory miRNAs, particularly miR-320a-3p, which appears to be unique to DPSC-EVs and regulates the NFκb pathway. Overall, our findings highlight the immunomodulatory properties of DPSC-EVs and provide vital clues that can stimulate future research into miRNA-based EV engineering as well as therapeutic approaches to inflammation control and disease treatment.
Histone modifications and their roles in macrophage-mediated inflammation: a new target for diabetic wound healing
Authors: Wang Jing , Feng Jiawei , Ni Yiming , Wang Yuqing , Zhang Ting , Cao Yemin , Zhou Mingmei , Zhao Cheng
Published: August 2024

Impaired wound healing is one of the main clinical complications of type 2 diabetes (T2D) and a major cause of lower limb amputation. Diabetic wounds exhibit a sustained inflammatory state, and reducing inflammation is crucial to diabetic wounds management. Macrophages are key regulators in wound healing, and their dysfunction would cause exacerbated inflammation and poor healing in diabetic wounds. Gene regulation caused by histone modifications can affect macrophage phenotype and function during diabetic wound healing. Recent studies have revealed that targeting histone-modifying enzymes in a local, macrophage-specific manner can reduce inflammatory responses and improve diabetic wound healing. This article will review the significance of macrophage phenotype and function in wound healing, as well as illustrate how histone modifications affect macrophage polarization in diabetic wounds. Targeting macrophage phenotype with histone-modifying enzymes may provide novel therapeutic strategies for the treatment of diabetic wound healing.
Apramycin kills replicating and non-replicating Mycobacterium tuberculosis
Authors: Kaur Parvinder , V. K. Ramya , C. N. Naveenkumar , K. Bharathkumar , Singh Mayas , Hobbie Sven N. , Shandil Radha Krishan , Narayanan Shridhar
Published: August 2024

Introduction

Mycobacterium tuberculosis (Mtb) has the capability to dodge the immune system by escaping into alternate physiological forms by forming drug tolerant populations under the immune pressure in the host. New drugs are urgently needed to treat these non-replicating persisters. In the past, aminoglycoside antibiotics have played a pivotal role in TB chemotherapy.

Methods

Here, we explored the therapeutic potential of a monosubstituted deoxystreptamine aminoglycoside, apramycin (APR) which is different in its chemical structure from the other clinically relevant aminoglycoside antibiotics that are all disubstituted, e.g., amikacin (AMI). We determined the APR MIC as 0.25-1 µg/ml for sensitive and multidrug-resistant Mtb (MDRTB), including amikacin (AMI) resistant strains.

Results

In standard time-kill kinetic assays, the bactericidal activity of APR was similar to that of AMI demonstrating dose-dependent killing of planktonic Mtb. However, in biofilm and macrophage intracellular killing assays, APR appeared significantly more potent than AMI. Further, APR monotherapy was efficacious in a mouse chronic TB lung infection model (~0.92 log10 CFU/lung reduction). APR combination therapy with the current 1st line standard of care (SoC) antibiotic combination of isoniazid (H), rifampicin (R), ethambutol (E), and pyrazinamide (Z) was found to be additive (HREZ=1.88 vs. HREZ-APR=2.78 log10CFU/lung reduction).

Discussion

The results indicate the potential of apramycin-based combinations for the treatment of human tuberculosis.
Experimental investigation of mechanical and durability performances of self-compacting concrete blended with bagasse ash, metakaolin, and glass fiber
Authors: Wagh Monali , Waghe Uday , Bahrami Alireza , Ansari Khalid , Özkılıç Yasin Onuralp , Nikhade Anshul
Published: August 2024

This study investigated the effects of using bagasse ash (BA) and metakaolin (MK) together as substitutes for cement in self-compacting concrete (SCC), together with the addition of glass fiber (GF), on the physical and mechanical characteristics of concrete. Eighteen SCC mixes were created, each containing different proportions of BA (0%, 10%, 15%, and 20%), MK (0%, 10%, 15%, and 20%), and BA and MK collectively (10% + 5% and 10% + 10%) as cement replacements with and without 0.1% GF. Using the results of the slump flow, T500 slump flow, V-funnel, and L-box tests, the performance of fresh SCC was determined. Furthermore, this study evaluated the strength, durability, and microstructural properties of the SCC samples. The SCC mix blended with 10% BA and 5% MK revealed better flowability as the slump flow increased from 692 mm to 715 mm. A strong linear correlation was discovered between the slump flow values (mm) and V-funnel duration (sec) and blocking ratio (H2/H1) with R2 = 0.8876 and R2 = 0.8467, respectively. Of all test mixes, the SCC mix blended with 10% BA, 5% MK, and 0.1% GF (SCC1B10M5) demonstrated the highest degree of strength. At 56 days, the 10% BA, 5% MK, and 0.1 GF mix had 12.8%, 25.7%, and 22.2% higher compressive, flexural, and splitting tensile strengths than the control mix, respectively. SCC, combined with BA, MK, and GF, outperformed the control mix. After immersion in a 3% H2SO4 solution, the SCC mix having 10% BA, 5% MK, and 0.1% GF experienced a minimum reduction in weight loss and ultrasonic pulse velocity of 1.01% and 3.1%, respectively. Additionally, there was a decrease of 29.4% in the percentage of charges passed. The ideal composition was achieved by incorporating 10% BA, 5% MK, and 0.1% GF into the SCC mixture, resulting in a dense structure without any visible pores or cracks during the microstructural analysis.
Degradation and life prediction of mechanical equipment based on multivariate stochastic process
Authors: Lin Chengwang
Published: August 2024

Introduction

Accurately predicting the remaining mechanical equipment is of great significance for ensuring the safe operation of the equipment and improving economic efficiency.

Methods

To accurately assess the mechanical equipment degradation, predict its remaining useful life, and ensure efficient, stable, and safe operation, a degradation and life prediction model for mechanical equipment based on multivariate stochastic processes is studied. The study innovatively predicts the remaining life of mechanical equipment using multivariate stochastic processes, and facilitates the correlation analysis between performance indicators based on the characteristics of Copula functions.

Results and discussion

The results showed that the Root Mean Squared Error value of the prediction results based on the trivariate Wiener process was 2.58, which decreased by 46.91% and 35.82% compared with the univariate and bivariate Wiener processes, respectively. The prediction value based on the trivariate gamma process was 3.49, which decreased by 44.95% and 40.54% compared with the univariate and bivariate gamma processes, respectively. In conclusion, the degradation and life prediction model with multivariate stochastic processes can effectively assess the mechanical equipment degradation and predict its remaining useful life. This provides an important reference for the maintenance and management of mechanical equipment, improving equipment efficiency and extend its service life.
Trends of drug expenditure in Taiwan National Health Insurance before and during COVID-19 pandemic
Authors: Wu Shu-I , Lee An-Sheng , Chung Ching-Hu
Published: August 2024

Background

The Taiwanese government adopted the National Health Insurance (NHI) system in March 1995. This study aimed to understand the difference in medication costs before (year 2019) and during the COVID-19 pandemic (2020–2021) among different hospitals for treating their patients.

Methods

The NHI claims database consisting of claims of prescription drugs for inpatients (IPD) and outpatients (OPD) in Taiwan was used to determine drug expenditure in different hospitals, particularly the top 10 prescription Anatomical Therapeutic Chemical (ATC) categories.

Results

In medical centers, L01X (other antineoplastic agents) showed the highest drug expenditure, followed by L04A (immunosuppressants) and J05A (direct-acting antivirals). The drug expenditure pattern in regional hospitals was similar to that in medical centers, with L01X (other antineoplastic agents) showing the highest drug expenditure. L01X (other antineoplastic agents) also showed the highest drug expenditure in district hospitals, followed by N05A (antipsychotics) and A10B (blood glucose-lowering drugs, excluding insulin). In clinics, A10B (blood glucose-lowering drugs, excluding insulin) showed the highest drug expenditure. The total medication costs in 2021 were lower or similar to those in 2019. The use of systemic use anti-infectives decreased over time in OPDs among all hospita1 levels but increased in IPDs in medical centers and district hospitals. Furthermore, our analysis revealed that the trend in drug expenditure closely mirrored the trend in drug prescription volume for the highest annual sum cost item among the top 10 drug subgroups across different hospital levels.

Conclusion

Our analysis found that annual drug expenditures in 2021 were lower or similar to those in 2019, suggesting that the COVID-19 pandemic has contributed to this reduction in drug expenditure.
Sexual dimorphism in hepatic PPAR alpha and CYP4a12a expression is associated with reduced development of drug-induced non-alcoholic steatohepatitis in female IL-33−/− mice
Authors: Thomas Chloe , Njoku Dolores B.
Published: August 2024

Males are at higher risk for developing metabolic dysfunction-associated steatohepatitis (MASH) than females; however, mechanisms mediating sexual dimorphism in MASH development are not completely understood. Nutrition-based mouse models suggest that dysregulated fatty acid biosynthesis promotes MASH. Drugs recapitulate MASH without diet variabilities. This brief report investigates associations of sexual dimorphism with male susceptibility to MASH utilizing a drug-induced MASH model and focuses on very-long-chain fatty acid biosynthesis pathways. We assessed male and female mouse livers at 5 and 15 weeks following MASH induction by immunizations and age-matched un-immunized controls utilizing Western blot. Our results suggest that PPAR alpha and CYP4a12a protect females, while CYP4v2 does not protect males from MASH development. Our results have important implications for understanding sexual dimorphism in the pathogenesis of MASH.
Quality improvement in neonatal care through enhanced patient safety and clinical risk management: a before-and-after study about neonatal sepsis
Authors: Ferorelli Davide , Goffredo Vito Maria , Graziano Elena , Mastrapasqua Maurizio , Telegrafo Michele , Vinci Annachiara , Visci Paolo , Benevento Marcello , Zotti Fiorenza , Foglianese Alessandra , Panza Raffaella , Solarino Biagio , Dell’Erba Alessandro , Laforgia Nicola
Published: August 2024

Introduction

Neonatal sepsis, classified into early-onset and late-onset based on symptom timing, poses significant risks of morbidity and mortality, especially in low birth weight infants. Effective clinical risk management protocols are crucial in reducing these risks.

Methods

This before-and-after study evaluated the impact of a newly implemented clinical risk management protocol in the Neonatology and Neonatal Intensive Care Unit (NICU) at Policlinico Hospital-University of Bari. The study included 399 neonates over three years, comparing pre- and post-protocol outcomes. Data collection focused on maternal and neonatal demographics, infection rates, and hospital stay lengths. Statistical analysis included t-tests, Wilcoxon-Mann–Whitney tests, and logistic regression models.

Results

The study found no significant differences in neonatal pathologies or demographics between pre- and post-protocol groups. However, post-protocol implementation showed a notable reduction in umbilical venous catheter (UVC) infections (p = 0.018) and improved hospital stay lengths. Blood and urine cultures did not show significant changes in microbial patterns post-protocol.

Discussion

The findings underscore the effectiveness of structured clinical risk management protocols in enhancing neonatal outcomes, particularly in reducing specific infection risks. Despite the study’s limitations, including its observational nature and sample size, the results advocate for broader adoption and further research on these protocols in diverse healthcare settings. The positive outcomes highlight the importance of continuous clinical risk management efforts in high-risk neonatal environments.
From intra- to extra-uterine: early phase design of a transfer to extra-uterine life support through medical simulation
Authors: van Haren J. S. , Delbressine F. L. M. , Monincx M. , Hoveling T. , Meijer N. , Bangaru C. , Sterk J. , van der Woude D. A. A. , Oei S. G. , van der Hout-van der Jagt M. B.
Published: August 2024

Introduction

Extra-uterine life support technology could provide a more physiologic alternative for the treatment of extremely premature infants, as it allows further fetal growth and development ex utero. Animal studies have been carried out which involved placing fetuses in a liquid-filled incubator, with oxygen supplied through an oxygenator connected to the umbilical vessels. Hence, by delaying lung exposure to air, further lung development and maturation can take place. This medical intervention requires adjustments to current obstetric procedures to maintain liquid-filled lungs through a so-called transfer procedure.

Methods

Our objective was to develop obstetric device prototypes that allow clinicians to simulate this birth procedure to safely transfer the infant from the mother's uterus to an extra-uterine life support system. To facilitate a user-centered design, implementation of medical simulation during early phase design of the prototype development was used. First, the requirements for the procedure and devices were established, by reviewing the literature and through interviewing direct stakeholders. The initial transfer device prototypes were tested on maternal and fetal manikins in participatory simulations with clinicians.

Results & discussion

Through analysis of recordings of the simulations, the prototypes were evaluated on effectiveness, safety and usability with latent conditions being identified and improved. This medical simulation-based design process resulted in the development of a set of surgical prototypes and allowed for knowledge building on obstetric care in an extra-uterine life support context.
Genetic prediction of blood metabolites mediating the relationship between gut microbiota and Alzheimer’s disease: a Mendelian randomization study
Authors: Chen Guanglei , Jin Yaxian , Chu Cancan , Zheng Yuhao , Chen Yunzhi , Zhu Xing
Published: August 2024

Background

Observational studies have suggested an association between gut microbiota and Alzheimer’s disease (AD); however, the causal relationship remains unclear, and the role of blood metabolites in this association remains elusive.

Purpose

To elucidate the causal relationship between gut microbiota and AD and to investigate whether blood metabolites serve as potential mediators.

Materials and methods

Univariable Mendelian randomization (UVMR) analysis was employed to assess the causal relationship between gut microbiota and AD, while multivariable MR (MVMR) was utilized to mitigate confounding factors. Subsequently, a two-step mediation MR approach was employed to explore the role of blood metabolites as potential mediators. We primarily utilized the inverse variance-weighted method to evaluate the causal relationship between exposure and outcome, and sensitivity analyses including Contamination mixture, Maximum-likelihood, Debiased inverse-variance weighted, MR-Egger, Bayesian Weighted Mendelian randomization, and MR pleiotropy residual sum and outlier were conducted to address pleiotropy.

Results

After adjustment for reverse causality and MVMR correction, class Actinobacteria (OR: 1.03, 95% CI: 1.01–1.06, p = 0.006), family Lactobacillaceae (OR: 1.03, 95% CI: 1.00–1.05, p = 0.017), genus Lachnoclostridium (OR: 1.03, 95% CI: 1.00–1.06, p = 0.019), genus Ruminiclostridium9 (OR: 0.97, 95% CI: 0.94–1.00, p = 0.027) and genus Ruminiclostridium6 (OR: 1.03, 95% CI: 1.01–1.05, p = 0.009) exhibited causal effects on AD. Moreover, 1-ribosyl-imidazoleacetate levels (−6.62%), Metabolonic lactone sulfate levels (2.90%), and Nonadecanoate (19:0) levels (−12.17%) mediated the total genetic predictive effects of class Actinobacteria on AD risk. Similarly, 2-stearoyl-GPE (18:0) levels (−9.87%), Octadecanedioylcarnitine (C18-DC) levels (4.44%), 1-(1-enyl-stearoyl)-2-oleoyl-GPE (p-18:0/18:1) levels (38.66%), and X-23639 levels (13.28%) respectively mediated the total genetic predictive effects of family Lactobacillaceae on AD risk. Furthermore, Hexadecanedioate (C16-DC) levels (5.45%) mediated the total genetic predictive effects of genus Ruminiclostridium 6 on AD risk; Indole-3-carboxylate levels (13.91%), X-13431 levels (7.08%), Alpha-ketoglutarate to succinate ratio (−13.91%), 3-phosphoglycerate to glycerate ratio (15.27%), and Succinate to proline ratio (−14.64%) respectively mediated the total genetic predictive effects of genus Ruminiclostridium 9 on AD risk.

Conclusion

Our mediation MR analysis provides genetic evidence suggesting the potential mediating role of blood metabolites in the causal relationship between gut microbiota and AD. Further large-scale randomized controlled trials are warranted to validate the role of blood metabolites in the specific mechanisms by which gut microbiota influence AD.
Challenges and opportunities to advance manufacturing research for sustainable battery life cycles
Authors: Johansson Björn , Despeisse Mélanie , Bokrantz Jon , Braun Greta , Cao Huizhong , Chari Arpita , Fang Qi , González Chávez Clarissa A. , Skoogh Anders , Söderlund Henrik , Wang Hao , Wärmefjord Kristina , Nyborg Lars , Sun Jinhua , Örtengren Roland , Schumacher Kelsea A. , Espinal Laura , Morris K. C. , Nunley Jason , Kishita Yusuke , Umeda Yasushi , Acerbi Federica , Pinzone Marta , Persson Hanna , Charpentier Sophie , Edström Kristina , Brandell Daniel , Gopalakrishnan Maheshwaran , Rahnama Hossein , Abrahamsson Lena , Rönnbäck Anna Öhrwall , Stahre Johan
Published: August 2024

Advanced manufacturing research for sustainable battery life cycles is of utmost importance to reach net zero carbon emissions (European Commission, 2023a) as well as several of the United Nations Sustainable Development Goals (UNSDGs), for example: 30% reduction of CO2 emission, 10 million job opportunities and access to electricity for 600 million people (World Economic Forum, 2019). This editorial paper highlights international motivations for pursuing more sustainable manufacturing practices and discusses key research topics in battery manufacturing. Batteries will be central to our sustainable future as generation and storage become key components to on-demand energy supply. Four underlying themes are identified to address industrial needs in this field: 1. Digitalizing and automating production capabilities: data-driven solutions for production quality, smart maintenance, automation, and human factors, 2. Human-centric production: extended reality for operator support and skills development, 3. Circular battery life cycles: circular battery systems supported by service-based and other novel business models, 4. Future topics for battery value chains: increased industrial resilience and transparency with digital product passports, and next-generation battery chemistries. Challenges and opportunities along these themes are highlighted for transforming battery value chains through circularity and more sustainable production, with a particular emphasis on lithium-ion batteries (LIB). The paper concludes with directions for further research to advance a circular and sustainable battery value chain through utilizing the full potential of digitalization realising a cleaner, more energy-efficient society.
Prevalence and impact of sleep-related breathing disorder in multiple system atrophy patients: a cross-sectional study and meta-analysis
Authors: Wang Hui , Zhang Ting , Fan Wenhui , Xu Yanming
Published: August 2024

Objective

Sleep-related breathing disorder (SRBD) is a prevalent non-motor symptom in multiple system atrophy (MSA). However, the reported prevalence of SRBD in MSA from different studies has shown inconsistency. Additionally, only one study has examined the impact of SRBD on both motor and non-motor symptoms in MSA.

Methods

Cross-sectional study of 66 patients with probable MSA from China. SRBD was ascertained with polysomnography (PSG). All the MSA individuals were assessed using the Epworth Sleepiness Scale (ESS), Unified Multiple-System Atrophy Rating Scale (UMSARS), Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), the Mini-mental State Examination (MMSE), Non-Motor Symptoms Scale (NMSS), and Pittsburgh Sleep Quality Index (PSQI). Moreover, a meta-analysis was conducted by searching studies related to MSA and SRBD in PubMed, Web of Science, Embase, and Cochrane databases. Data were pooled as necessary to calculate prevalence of SBRD with 95% confidence intervals (CI).

Results

Our study included 66 patients with MSA, 52 of whom had a diagnosis of SRBD (78.8%). There were no significant differences between the MSA with SRBD and without SRBD groups on the age, sex, disease onset, disease duration, UMSARS I, II, and IV, the NMSS, the HAMA, HAMD, the ESS the FSS, the MMSE, and the PSQI scales. However, MSA patients with SRBD having a significant higher obstructive apnea index and percentage of snoring during sleep than MSA patients without SRBD [10.0 (4.1–10.6) vs. 0.1 (0–0.3), and 8.3 (5.1–12.2) vs. 4.2 (0–7.5)]. Also, between the two groups, the mean and minimum oxygen concentrations during sleep were lower in MSA patients with SRBD than in those without SRBD [93.7 (93–95) vs. 95.5 (95.8–97), p = 0.001] and [83.9 (81.2–89.0) vs. 90.3 (89.8–93.3), p = 0.000]. The primary search strategy identified 701 articles, with 10 meeting the inclusion criteria. The overall prevalence of SRBD in a combined sample of 295 MSA patients was found to be 60.5% (95% CI, 43.2–76.5%). Further analysis revealed that the prevalence of SRBD in MSA patients in Asia was 79.2% (95% CI, 54.7–96.3%), which was higher than that in Europe (41.6, 95% CI, 32–51.5%).

Conclusion

The study found a prevalence of 78.8% of SRBD in MSA patients, with a notably higher prevalence in Asia compared to Europe. The majority of SRBD cases in MSA were attributed to obstructive apnea. Furthermore, the presence of SRBD did not show a significant impact on the motor and non-motor symptoms of MSA patients.
Efficacy and safety of hepatic arterial infusion chemotherapy combined with fruquintinib and tislelizumab for patients with microsatellite stable colorectal cancer liver metastasis following failure of multiple-line therapy
Authors: Zheng Kanglian , Zhu Xu , Xu Liang , Cao Guang , Niu Chuanxin , Yan Xiaoluan , Xu Da , Liu Wei , Bao Quan , Wang Lijun , Wang Kun , Xing Baocai , Wang Xiaodong
Published: August 2024

Background and aim

The prognosis of microsatellite stable (MSS)-colorectal cancer liver metastasis (CRCLM) following failure of multi-line therapy remains dismal. The aim of this study is to evaluate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) plus fruquintinib and tislelizumab (HAIC-F-T treatment) for MSS-CRCLM which failed from multiple-line therapy.

Methods

From February 2021 to June 2023, 45 patients with MSS-CRCLM after failure of multiple-line therapy who received HAIC combined with fruquintinib and tislelizumab (HAIC-F-T triple treatment) were enrolled. The combination therapy included HAIC regimens with oxaliplatin and 5-fluorouracil or irinotecan, oxaliplatin, and 5-fluorouracil on days 1-2, intravenous tislelizumab (200 mg) before HAIC on day 1, and oral fruquintinb (3 mg/d) on day 3-21, every 4 weeks. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method.

Results

The follow-up ended on June 22, 2024, with a median follow-up time of 17.5 months. The objective response rate was 42.2%, and the disease control rate was 82.2%. The median OS was 15.3 months (95% confidence interval [CI]:12.634-17.966), and the median PFS was 7.5 months (95% CI:5.318-9.682). The independent risk factors related to worse OS were previous PD-1 immunotherapy (P = 0.021) and the number of HAIC-F-T triple treatment cycles of ≤ 2 (P = 0.007). The incidence of grade 3 or higher adverse events (AEs) was 20%, with the most frequent grade 3 or higher AEs being abdominal pain (3/45, 6.7%).

Conclusion

HAIC combined with fruquintinib and tislelizumab may be an alternative salvage treatment for patients with MSS-CRCLM following failure of multiple-line therapy.
Fever, convulsions, and rash: a case report of neonatal lupus erythematosus with macrophage activation syndrome
Authors: Yu Jing , Xue Guohui , Liu Xiaohui , Zhan Chunlei , Huang Jinshi
Published: August 2024

Neonatal lupus erythematosus (NLE) is a rare acquired autoimmune disease associated with the entry of maternal antibodies into the fetal circulation via the placenta during pregnancy. Macrophage activation syndrome (MAS) is a severe hyperinflammatory disease. Herein, we present a case of NLE with MAS accompanied by fever, convulsions, and rash. High-dose gamma globulin and non-shock doses of steroids can be used as a first-line treatment for NLE with MAS. Fever can be a clinical manifestation of NLE, especially cutaneous lupus. Rash recession could be used to judge whether the disease is effectively controlled by treatment.
Determinants of neonatal hypoglycemia among neonates admitted to neonatal intensive care units of public hospitals in Wolaita Zone, Southern Ethiopia, 2023: An unmatched case–control study
Authors: Wodajo Dawit Tesfaye , Gebretsadik Woiynshet , Melketsedik Zeleke Aschalew , Desalegn Nathan , Lencha Fikre Moga
Published: August 2024

Background

Globally, neonatal hypoglycemia is a common child health problem and significantly contributes to morbidity and mortality, with its impact being particularly detrimental in developing countries. Although being a prevalent metabolic condition, it is frequently overlooked. Furthermore, the problem is not adequately studied in Ethiopia, as seen by a few published studies on the topic, highlighting the lack of knowledge about its determinants.

Objective

This study aims to assess the determinants of neonatal hypoglycemia among neonates admitted to neonatal intensive care units of public hospitals in Wolaita Zone, Southern Ethiopia, 2023.

Methods

An institution-based unmatched case–control study design was conducted among 249 (83 cases and 166 controls) participants. Data were collected from 29 March to 23 May 2023 using a pretested chart review extraction tool/checklist. A consecutive sampling method was used for participant selection. Data were analyzed using Statistical Package for Social Science version 25. Binary logistic regression analysis was used to identify the determinants of neonatal hypoglycemia, and statistical significance was declared at P < 0.05.

Results

A total of 83 cases and 166 controls were included in the study. The following factors were significantly associated with neonatal hypoglycemia: preterm neonates [adjusted odds ratio (AOR) 4.888 (95% confidence interval, CI, 1.113–21.478)], age of the neonate at admission (3–5 h) [AOR 4.205 (95% CI 1.852–9.547)], hypothermia [AOR 5.485 (95% CI 2.360–12.748)], late initiation of breastfeeding [AOR 6.229 (95% CI 2.665–14.599)], mode of delivery [AOR 5.034 (95% CI 1.688–15.011)], and small for gestational age [AOR 3.645 (95% CI 1.286–10.330)].

Conclusion and recommendation

In the current study, numerous determinants of neonatal hypoglycemia have been identified. Therefore, it is crucial to give due emphasis to providing comprehensive health education to mothers regarding effective breastfeeding methods, strategies to avoid neonatal hypoglycemia, and the various factors that heighten its likelihood. In addition, healthcare professionals should emphasize implementing preventive measures to prevent this grave condition.
Mechanisms of action and applications of Polygonatum sibiricum polysaccharide at the intestinal mucosa barrier: a review
Authors: Ren Yu , Sun Yi , Liao Yu-Ying , Wang Si , Liu Qian , Duan Chun-Yan , Sun Lan , Li Xiao-Ya , Yuan Jia-Li
Published: August 2024

As a medicinal and edible homologous Chinese herb, Polygonatum sibiricum has been used as a primary ingredient in various functional and medicinal products. Damage to the intestinal mucosal barrier can lead to or worsen conditions such as type 2 diabetes and Alzheimer’s disease. Traditional Chinese medicine and its bioactive components can help prevent and manage these conditions by restoring the integrity of the intestinal mucosal barrier. This review delves into the mode of action of P. sibiricum polysaccharide in disease prevention and management through the restoration of the intestinal barrier. Polysaccharide from P. sibiricum effectively treats conditions by repairing the intestinal mucosal barrier, offering insights for treating complex diseases and supporting the application of P. sibiricum in clinical settings.
Influence of C-reactive protein on the pharmacokinetics of voriconazole in relation to the CYP2C19 genotype: a population pharmacokinetics analysis
Authors: Ling Jing , Yang Xuping , Dong Lulu , Jiang Yan , Zou Sulan , Hu Nan
Published: August 2024

Voriconazole is a broad-spectrum triazole antifungal agent. A number of studies have revealed that the impact of C-reactive protein (CRP) on voriconazole pharmacokinetics was associated with the CYP2C19 phenotype. However, the combined effects of CYP2C19 genetic polymorphisms and inflammation on voriconazole pharmacokinetics have not been considered in previous population pharmacokinetic (PPK) studies, especially in the Chinese population. This study aimed to analyze the impact of inflammation on the pharmacokinetics of voriconazole in patients with different CYP2C19 genotypes and optimize the dosage of administration. Data were obtained retrospectively from adult patients aged ≥16 years who received voriconazole for invasive fungal infections from October 2020 to June 2023. Plasma voriconazole levels were measured via high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). CYP2C19 genotyping was performed using the fluorescence in situ hybridization method. A PPK model was developed using the nonlinear mixed-effect model (NONMEM). The final model was validated using bootstrap, visual predictive check (VPC), and normalized prediction distribution error (NPDE). The Monte Carlo simulation was applied to evaluate and optimize the dosing regimens. A total of 232 voriconazole steady-state trough concentrations from 167 patients were included. A one-compartment model with first order and elimination adequately described the data. The typical clearance (CL) and the volume of distribution (V) of voriconazole were 3.83 L/h and 134 L, respectively. The bioavailability was 96.5%. Covariate analysis indicated that the CL of voriconazole was substantially influenced by age, albumin, gender, CRP, and CYP2C19 genetic variations. The V of voriconazole was significantly associated with body weight. An increase in the CRP concentration significantly decreased voriconazole CL in patients with the CYP2C19 normal metabolizer (NM) and intermediate metabolizer (IM), but it had no significant effect on patients with the CYP2C19 poor metabolizer (PM). The Monte Carlo simulation based on CRP levels indicated that patients with high CRP concentrations required a decreased dose to attain the therapeutic trough concentration and avoid adverse drug reactions in NM and IM patients. These results indicate that CRP affects the pharmacokinetics of voriconazole and is associated with the CYP2C19 phenotype. Clinicians dosing voriconazole should consider the patient’s CRP level, especially in CYP2C19 NMs and IMs.
Evolutionary distribution and mode transition in medium frequency from 50 kHz to 5 MHz of argon atmospheric pressure dielectric barrier discharge plasma
Authors: Zhao Zhibo , Yu Yilin , Nie Qiuyue , Zhang Zhonglin
Published: August 2024

Dielectric barrier discharges (DBDs) provide a promising technology for generating non-equilibrium cold plasmas at atmospheric pressure. For both application-focused and fundamental research, it is important to explore the discharge mode transition and electron heating mechanism to enable effective independent tuning of key plasma parameters in a DBD system. In this work, we report numerical studies of the effects of single-frequency excitation on atmospheric argon DBDs, which are carried out in the medium driving frequency (MF) range from 50 kHz to 5 MHz by using a one-dimensional hydrodynamics coupling model. The spatio-temporal evolution of particle density associated with the discharge mode transition and electron dynamic behavior has been investigated. By tuning different components of a single frequency, we observe the electron heating behaviors of the individual modes and mode transitions from the Townsend discharge to the glow discharge in the low frequency to the Ω mode and the hybrid mode in the medium frequency to the α-mode and the γ-mode in the radio frequency. The physical analysis is understood based on these fundamental insights into the plasma physics.
The influence of real-time quantitative feedback and verbal encouragement on adults’ performance in maximal and explosive strength and power in bench press exercise
Authors: Pacholek Martin
Published: August 2024

Background

In sports practice, a wide array of verbal and non-verbal stimuli can elicit diverse motivations and performance changes. Therefore, the primary objective of this study was to compare the impact of various stimuli on maximal strength and power in bench press exercises.

Methods

This study involved 48 university students (average age 20.5 ± 2.8 years; body mass 80.1 ± 20 kg; height 174.6 ± 6.7 cm; BMI 26.2 ± 6 kg/m2) who engaged in an 8-week resistance training program. The students were randomly divided into three experimental groups and one control group. The first group received real-time quantitative feedback (RF) on their power output during the bench press exercise, the second group received verbal encouragement (VE) from an instructor, and the third group exercised without any external stimulus (WS). The control group (CG) underwent only pre- and post-measurements. To compare differences in strength parameters among groups a Two-Way Repeated Measures ANOVA was applied.

Results

The results revealed significant improvements in the mean weight for one repetition maximum in the real-time quantitative feedback group (5 kg, 9.76%, p = 0.001, d = 0.529) and the verbal encouragement group (5.42 kg, 11.51%, p = 0.001, d = 1.201). Positive changes were also observed in the mean power at 20 and 30 kg for the RF, VE, and WS groups, but at 40 kg, significant improvement was only seen in the real-time quantitative feedback group (247 W, 31.30%, p = 0.001, d = 1.199).

Conclusion

These findings underscore the effectiveness of selected stimuli in enhancing maximum strength and power during bench press exercises, with real-time quantitative feedback proving to be the most effective stimulus for improving both maximal strength and power.