bluuebunny/crossref_metadata_2025 huggingface dataset:
Systemic immune–inflammation index for predicting postoperative atrial fibrillation following cardiac surgery: a meta-analysis
Authors: Chen Yu-Chou , Liu Chien-Cheng , Hsu Hui-Chen , Hung Kuo-Chuan , Chang Ying-Jen , Ho Chun-Ning , Hsing Chung-Hsi , Yiu Ching-Yi
Published: February 2024

Background

Postoperative atrial fibrillation (POAF) is a frequent complication that may increase morbidity and mortality risk following cardiac surgery. The systemic immune–inflammation index (SII) is an emerging biomarker that provides an integrated measure of inflammation by incorporating neutrophil, lymphocyte, and platelet counts. Recent studies have reported associations between elevated SII and increased POAF risk; however, significant heterogeneity exists regarding its predictive efficacy. This meta-analysis aimed to assess SII's diagnostic efficacy for predicting POAF risk.

Methods

To synthesize existing evidence on the ability of perioperative SII for predicting POAF in patients undergoing cardiac surgery, a systematic review and meta-analysis was conducted. In August 2023, a comprehensive literature search was performed to identify relevant studies reporting SII cutoff values with corresponding sensitivity and specificity. The primary aim was to evaluate SII's diagnostic utility for predicting POAF, whereas secondary outcomes included the pooled incidence of POAF and the relationship between the SII and POAF.

Results

Eight studies published between 2021 and 2023 with 3,245 patients were included. Six studies involved coronary artery bypass grafting (CABG) surgery; one encompassed various cardiac procedures, and another focused solely on mitral valve surgery. The pooled incidence of POAF was 23.6% [95% confidence interval (CI), 18.7%–29.2%]. Elevated SII significantly increased the odds of POAF by 3.24-fold (odds ratio, 3.24; 95% CI, 1.6–6.55; p = 0.001). SII's pooled sensitivity and specificity for predicting POAF were 0.80 (95% CI, 0.68–0.89) and 0.53 (95% CI, 0.23–0.8), respectively. The SII had moderate predictive accuracy based on a hierarchical summary receiver operating characteristic (HSROC) area under the curve of 0.78 (95% CI, 0.74–0.81). Subgroup analyses, whether focusing on CABG alone or CABG with cardiopulmonary bypass (CPB), both indicated an area under the HSROC curve of 0.78 (95% CI, 0.74–0.81).

Conclusion

Elevated SII is significantly correlated with an increased POAF risk following cardiac surgery, highlighting its utility as a predictive biomarker. Considering its moderate diagnostic accuracy, further research is essential for clarifying SII's clinical effectiveness, either as an independent predictor or combined with other risk factors, for stratifying patients at high POAF risk.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/, identifier [CRD42023456128].
Anticoagulants for atrial fibrillation: from warfarin and DOACs to the promise of factor XI inhibitors
Authors: Kumar Vineet , Ilkhanoff Leonard
Published: February 2024

Anticoagulation is the mainstay of stroke prevention in appropriate patients with atrial fibrillation. Due to advances in pharmacotherapy the anticoagulants used for this purpose have evolved significantly over the past decades with the aim of optimizing effectiveness while minimizing bleeding risks. Though significant improvements have been made toward this goal, bleeding risk remains the major concern with these therapies. An investigational class of agents which inhibit Factor XI have shown promise in pre-clinical and early clinical trials to significantly minimize bleeding while maintaining efficacy against stroke and systemic embolism. This mini-review will discuss anticoagulants currently used for stroke prevention in patients with atrial fibrillation including warfarin and direct oral anticoagulants. We will also review the mechanism of action and data from early clinical trials for Factor XI inhibitors and discuss their potential advantages and shortcomings.
A qualitative interview study of patients' attitudes towards and intention to use digital interventions for depressive disorders on prescription
Authors: Posselt Jacqueline , Baumann Eva , Dierks Marie-Luise
Published: February 2024

Background

Depressive disorders are an emerging public health topic. Due to their increasing prevalence, patients with depressive disorders suffer from the lack of therapeutic treatment. Digital health interventions may offer an opportunity to bridge waiting times, supplement, or even substitute in-person treatment. Among others, the Unified Theory of Acceptance and Use of Technology (UTAUT) explains that actual technology use is affected by users' behavioural intention. However, patients' perspectives on digital interventions are rarely discussed within the specific context of primary care provided by general practitioners (GP) and need further exploration.

Method

A qualitative study design with semi-structured interviews was used to explore DTx-acceptance of patients with mild or moderate depression (n = 17). The audio-recorded interviews were transcribed verbatim, coded, and thematically analysed by qualitative content analysis.

Results

Patients' performance expectancies reveal that DTx are not perceived as a substitute for face-to-face treatment. Effort expectancies include potential advantages and efforts concerning technical, motivational, and skill-based aspects. Moreover, we identified health status and experience with depressive disorders as other determinants and potential barriers to patients' DTx acceptance: Difficult stages of depression or long-time experience are perceived hurdles for DTx use. GPs' recommendations were just partly relevant for patients and varied according to patients' consultancy preferences. But still, GPs have a crucial role for access due to prescription. GPs' influence on patients' DTx acceptance varies between three situations: (1) pre-use for consultation, (2) pre-use for access and (3) during DTx-use. Further, GPs' guidance could be especially relevant for patients during DTx-use in routine care.

Discussion

The UTAUT-based exploration suggests that acceptance determinants should be considered independently and embedded in personal and situational aspects. DTx require a healthcare professional to prescribe or diagnose the disease, unlike other digital offerings. We identified prescription- and depression-related determinants, exceeding existing theoretical constructs. GPs' guidance can compensate for some barriers to DTx use e.g., by increasing commitment and motivational support to strengthen patients' acceptance.

Conclusion

We argue for a multidimensional integration of acceptance determinants for further development of health technology acceptance research. Future research should specify how DTx can be integrated into routine care to strengthen user acceptance.
Water level control of nuclear steam generators using intelligent hierarchical autonomous controller
Authors: Peng Binsen , Ma Xintong , Xia Hong
Published: February 2024

The challenge of water level control in steam generators, particularly at low power levels, has always been a critical aspect of nuclear power plant operation. To address this issue, this paper introduces an IHA controller. This controller employs a CPI controller as the primary controller for direct water level control, coupled with an agent-based controller optimized through a DRL algorithm. The agent dynamically optimizes the parameters of the CPI controller in real-time based on the system’s state, resulting in improved control performance. Firstly, a new observer information is obtained to get the accurate state of the system, and a new reward function is constructed to evaluate the status of the system and guide the agent’s learning process. Secondly, a deep ResNet with good generalization performance is used as the approximator of action value function and policy function. Then, the DDPG algorithm is used to train the agent-based controller, and an advanced controller with good performance is obtained after training. Finally, the popular UTSG model is used to verify the effectiveness of the algorithm. The results demonstrate that the proposed method achieves rise times of 73.9 s, 13.6 s, and 16.4 s at low, medium, and high power levels, respectively. Particularly, at low power levels, the IHA controller can restore the water level to its normal state within 200 s. These performances surpass those of the comparative methods, indicating that the proposed method excels not only in water level tracking but also in anti-interference capabilities. In essence, the IHA controller can autonomously learn the control strategy and reduce its reliance on the expert system, achieving true autonomous control and delivering excellent control performance.
Pressure pulsation of pump turbine at runaway condition based on Hilbert Huang transform
Authors: Xiao Wei , Gui Zhonghua , Lu Zhaoheng , Xiao Ruofu , Tao Ran
Published: February 2024

Pumped storage is an important component of electrified wire netting. The safe and stable operation of pump turbines is extremely important. Among them, pressure pulsation is one of the main causes of pump turbine vibration. The characteristics of pressure pulsation are relatively complex, and it is difficult to directly observe their temporal changes using commonly used FFT methods. The division of frequency characteristics is often vague. Meanwhile, it is difficult to explain some phenomena such as frequency doubling. This article focuses on a certain model of pump turbine and uses SST model to numerically simulate the runaway condition of the pump turbine. And the Hilbert Huang transform method is used to analyze the pressure pulsation in the vaneless region and draft tube. The results show that the main characteristic frequencies of the vaneless region are blade passing frequency 112.5 Hz and rotational frequency 12.5 Hz. The main characteristic frequencies of the draft tube are vortex rope frequency near 3 Hz which energy ratio is up to 50%, rotational frequency, and blade passing frequency. The pressure pulsation characteristics in the vaneless region have changed from a complex composition of double blade passing frequency and rotational frequency to a distribution dominated by blade passing frequency. In the passage of the guide vane, the pressure pulsation is almost only characterized by blade passing frequency. The frequency characteristics of the vaneless region between the runner and the guide vane become complex again. Meanwhile, the results show that the characteristic frequencies of the vaneless region and the draft tube propagate upstream and downstream.
Occurrence and path pollution of emerging organic contaminants in mineral water of Hranice hypogenic Karst
Authors: Oppeltová Petra , Vlček Vítězslav , Geršl Milan , Chaloupský Pavel , Ulrich Ondřej , Sedláček Jozef , Vavrouchová Hana , Kohoutková Kristýna , Klepárník Radim , Šimečková Jana
Published: February 2024

The Hranice hypogenic karst region includes urban, spa and agricultural areas and industry complexes that affect water quality in the region. Emerging organic contaminants (EOCs), especially pesticides and pharmaceuticals, are released into the complex aquatic system. These substances and their metabolites can affect aquatic and human life, as well as the regional development of the wider area traditionally associated with the spa. In this study, we conducted preliminary screening for pesticides and pharmaceuticals at 33 sampling sites and across different location types, including surface water, drainage water, a shallow well, groundwater and thermal karst water. Sampling occurred between February 2022 and June 2023. The results generally confirm that current land use is causing pollution in the karst system. The monitored substances were present in all water types, and in most cases the concentrations of pesticides were lower than those of their metabolites. Chloridazon desphenyl (DESPH) is the most widespread pesticide in surface, ground and hypogenic waters. Its concentrations in surface waters were 5.7 ng·L−1–2,230 ng·L−1, in groundwaters were 11.3 ng·L−1–1,490 ng·L−1 and in karst hypogenic waters 5.4 ng·L−1–378 ng·L−1. Diclofenac was the most widespread substance from the pharmaceutical group. Its concentrations ranged from 5.6 ng·L−1–549 ng·L−1 in surface waters, 8.4 ng·L−1–112 ng·L−1 in groundwaters and 5.1 ng·L−1–47.4 ng·L−1 in karst hypogenic waters. Directly in the karst hypogenic waters, the following EOCs were repeatedly detected: atrazine and its metabolites, simazin, metazachlor ethane sulfonic acid (ESA), metolachlor ESA, alachlor ESA, chloridazon DESPH, diclofenac, ibuprofen, azithromycin, bisphenol A and diethyltoluamide (DEET). The initial research hypothesis is that hydrothermal karst waters are of sub-recent age and deep circulation and, unlike surface and groundwaters, are not contaminated by recent pollutants. A certain component of these waters is therefore a shallow and shorter circulation.
The impact of slope and rainfall on the contaminant transport from mountainous groundwater to the lowland surface water
Authors: Xu Xiaojun , Zhu Ming , Zhou Ling , Ma Mingxia , Heng Jingmei , Lu Li , Qu Weiyi , Xu Zhongyuan
Published: February 2024

The surface water and groundwater in the mountainous area are vulnerable to contamination from the mining and transportation construction in Sichuan Province, China. Pollutants produced by anthropogenic activities transport within the groundwater from mountains to rivers on the plain, transferring contamination to the surface water. This study investigates the process of groundwater flow and contaminant transport from mountains to the lowlands based on synthetic numerical models. Two key factors are considered: precipitation and the slope of the mountain. Based on the real situation in Sichuan Province, four rainfall recharge rates are defined as 600, 800, 1,000, and 1,200 mm/yr, and five slope angles are considered: 20°, 25°, 30°, 35°, and 40°. The simulation results reveal that the groundwater level and solute transport are strongly influenced by the precipitation amounts and slope angles. The mountains with lower slopes maintain a relatively higher groundwater level under steady-state rainfall conditions; for example, groundwater levels decrease from 340 m to 300 m as slope angles increase at a 1,200 mm/yr precipitation level. Contaminant transport from the source in the mountain to the surface river is faster with increasing precipitations and decreasing slope angles. The model with 20° slope angle and 1,200 mm/yr precipitation exhibits the fastest solute migration, with the contaminant arrival time of 65 years. Furthermore, the models with 35° and 40° slope angles at a 600 mm/yr precipitation level show the slow transport speed with the contaminant arrival time of more than 75 years. In addition, higher precipitation may lead to more contaminant transport to the river. The analysis and findings of this study offer valuable insights into groundwater protection at the boundaries of mountains and plains.
Intramuscular vaccination against SARS-CoV-2 transiently induces neutralizing IgG rather than IgA in the saliva
Authors: Winklmeier Stephan , Rübsamen Heike , Özdemir Ceren , Wratil Paul R. , Lupoli Gaia , Stern Marcel , Schneider Celine , Eisenhut Katharina , Ho Samantha , Wong Hoi Kiu , Taskin Damla , Petry Marvin , Weigand Michael , Eichhorn Peter , Foesel Bärbel U. , Mader Simone , Keppler Oliver T. , Kümpfel Tania , Meinl Edgar
Published: February 2024

The mucosal immunity is crucial for restricting SARS-CoV-2 at its entry site. Intramuscularly applied vaccines against SARS-CoV-2 stimulate high levels of neutralizing Abs in serum, but the impact of these intramuscular vaccinations on features of mucosal immunity is less clear. Here, we analyzed kinetic and functional properties of anti-SARS-CoV-2 Abs in the saliva after vaccination with BNT162b2. We analyzed a total of 24 healthy donors longitudinally for up to 16 months. We found that specific IgG appeared in the saliva after the second vaccination, declined thereafter and reappeared after the third vaccination. Adjusting serum and saliva for the same IgG concentration revealed a strong correlation between the reactivity in these two compartments. Reactivity to VoCs correlated strongly as seen by ELISAs against RBD variants and by live-virus neutralizing assays against replication-competent viruses. For further functional analysis, we purified IgG and IgA from serum and saliva. In vaccinated donors we found neutralizing activity towards authentic virus in the IgG, but not in the IgA fraction of the saliva. In contrast, IgA with neutralizing activity appeared in the saliva only after breakthrough infection. In serum, we found neutralizing activity in both the IgA and IgG fractions. Together, we show that intramuscular mRNA vaccination transiently induces a mucosal immunity that is mediated by IgG and thus differs from the mucosal immunity after infection. Waning of specific mucosal IgG might be linked to susceptibility for breakthrough infection.
IRF3 function and immunological gaps in sepsis
Authors: Basak Bristy , Akashi-Takamura Sachiko
Published: February 2024

Lipopolysaccharide (LPS) induces potent cell activation via Toll-like receptor 4/myeloid differentiation protein 2 (TLR4/MD-2), often leading to septic death and cytokine storm. TLR4 signaling is diverted to the classical acute innate immune, inflammation-driving pathway in conjunction with the classical NF-κB pivot of MyD88, leading to epigenetic linkage shifts in nuclear pro-inflammatory transcription and chromatin structure-function; in addition, TLR4 signaling to the TIR domain-containing adapter-induced IFN-β (TRIF) apparatus and to nuclear pivots that signal the association of interferons alpha and beta (IFN-α and IFN-β) with acute inflammation, often coupled with oxidants favor inhibition or resistance to tissue injury. Although the immune response to LPS, which causes sepsis, has been clarified in this manner, there are still many current gaps in sepsis immunology to reduce mortality. Recently, selective agonists and inhibitors of LPS signals have been reported, and there are scattered reports on LPS tolerance and control of sepsis development. In particular, IRF3 signaling has been reported to be involved not only in sepsis but also in increased pathogen clearance associated with changes in the gut microbiota. Here, we summarize the LPS recognition system, main findings related to the IRF3, and finally immunological gaps in sepsis.
Genetic susceptibility and causal pathway analysis of eye disorders coexisting in multiple sclerosis
Authors: Qiu Xuecheng , Huang Mi Ni , Ping Suning
Published: February 2024

Introduction

The comorbidity of optic neuritis with multiple sclerosis has been well recognized. However, the causal association between multiple sclerosis and optic neuritis, as well as other eye disorders, remains incompletely understood. To address these gaps, we investigated the genetically relationship between multiple sclerosis and eye disorders, and explored potential drugs.

Methods

In order to elucidate the genetic susceptibility and causal links between multiple sclerosis and eye disorders, we performed two-sample Mendelian randomization analyses to examine the causality between multiple sclerosis and eye disorders. Additionally, causal single-nucleotide polymorphisms were annotated and searched for expression quantitative trait loci data. Pathway enrichment analysis was performed to identify the possible mechanisms responsible for the eye disorders coexisting with multiple sclerosis. Potential therapeutic chemicals were also explored using the Cytoscape.

Results

Mendelian randomization analysis revealed that multiple sclerosis increased the incidence of optic neuritis while reducing the likelihood of concurrent of cataract and macular degeneration. Gene Ontology enrichment analysis implicated that lymphocyte proliferation, activation and antigen processing as potential contributors to the pathogenesis of eye disorders coexisting with multiple sclerosis. Furthermore, pharmaceutical agents traditionally employed for allograft rejection exhibited promising therapeutic potential for the eye disorders coexisting with multiple sclerosis.

Discussion

Multiple sclerosis genetically contributes to the development of optic neuritis while mitigating the concurrent occurrence of cataract and macular degeneration. Further research is needed to validate these findings and explore additional mechanisms underlying the comorbidity of multiple sclerosis and eye disorders.
Ecotoxicological consequences of polystyrene naturally leached in pure, fresh, and saltwater: lethal and nonlethal toxicological responses in Daphnia magna and Artemia salina
Authors: Esterhuizen Maranda , Lee Sang-Ah , Kim Youngsam , Järvinen Riikka , Kim Young Jun
Published: February 2024

Polystyrene is widely used in disposable products and is now a ubiquitous plastic pollutant in aquatic environments, where it degrades into smaller particles that leach potentially toxic chemicals. However, knowledge regarding the impacts of plastic leachates remains limited. This study investigates the lethal and nonlethal effects of polystyrene leachate on two ecologically significant aquatic organisms, Daphnia magna (water flea) and Artemia salina (brine shrimp). Polystyrene leachates were prepared in seawater, freshwater, and sterile, pure water by incubating the material in each of the media under natural conditions for six months. D. magna and A. salina were exposed to varying concentrations of the leachates under controlled laboratory conditions, monitoring their survival, as well as measuring reactive oxygen species and antioxidant responses as superoxide dismutase and catalase activity. The data show that A. salina was more significantly affected with higher mortality observed at lower leachate concentrations, potentially linked to seawater enhancing the leaching of toxic additives. Moreover, at non-lethal concentrations, the antioxidative responses maintained homeostasis in both organisms. Considering the current reported microplastic concentrations in the aquatics and the adequate antioxidative response, leachate from plastic potentially does not pose a severe threat to these organisms. Nevertheless, hydrological characteristics of waterbodies may cause microplastic hotspots, which could significantly concentrate plastics and thus their leachates, necessitating action to reduce the current microplastic pollution level and avoid future surges. This study highlights the ecological significance of polystyrene pollution, emphasizing the need for more comprehensive regulatory measures and the development of sustainable alternatives to polystyrene-based products. The distinct responses of D. magna and A. salina imply that the impact of plastic pollution varies among species, necessitating further research to elucidate broader ecological consequences. Understanding how polystyrene leachate affects keystone species provides crucial insights into the overall implications for aquatic ecosystems.
Analysis of the wake mechanism in external flow around tandem bluff bodies with different aspect ratios
Authors: Abbasi Waqas Sarwar , Ehsan Muhammad , Rahman Hamid , Uddin Zia , Hassan Mohammad Mehedi , Saleem Kashif
Published: February 2024

The interaction mechanism of external flow with two inline rectangular cylinders having different aspect ratios under the impact of gap spacing (G) is the subject of this research. The gap spacing between the cylinders was varied from 0.25 to 20 times their size. Both cylinders were vertically mounted, with the first having a higher aspect ratio than the second. The results revealed five distinct flow patterns under the influence of G: single slender body, shear layer reattachment, intermittent shedding, binary vortex street, and single-row vortex street. The mean pressure on both cylinders was found to vary due to changes in flow patterns. Both cylinders bore the same shedding frequency but had different pressure variations. The second cylinder placed in the wake of first experienced negative average drag force for some spacing values, while the first cylinder had positive average drag values for all chosen G. Due to the change in flow pattern from shear layer reattachment to intermittent shedding flow, the negative drag force on the second cylinder jumped to a positive drag. It was also observed that the rms values of drag and lift force coefficients, as well as their amplitudes for the second cylinder, were mostly higher than corresponding values for the first cylinder at all selected G. This study revealed that G = 4 and 8 are the critical gap spacing values due to sudden changes in fluid force parameters.
Clinical and microbiological features of host-bacterial interplay in chronic venous ulcers versus other types of chronic skin ulcers
Authors: Mihai Mara Mădălina , Popa Mircea Ioan , Holban Alina Maria , Gheorghe-Barbu Irina , Popa Liliana Gabriela , Chifiriuc Mariana-Carmen , Giurcăneanu Călin , Bleotu Coralia , Cucu Corina Ioana , Lazăr Veronica
Published: February 2024

Introduction

Chronic venous ulcers of the lower limbs develop in the context of advanced venous disease and have a significant impact on the patient’s quality of life, being associated with depression and worrisome suicide rates, as well as with an economic burden caused by increased medical care costs and high epidemiological risks of healthcare associated infections and emergence of strains resistant to multiple classes of antibiotics and/ or antiseptics. Although numerous studies have investigated the composition of the chronic wounds microbiome, either by culture-dependent or independent methods, there are no data on the association between virulence and resistance profiles of strains isolated from venous ulcers and the clinical picture of this pathology. The elucidation of pathogenic mechanisms, at both phenotypic and molecular level, is crucial in the fight against these important human microbial agents, in order to develop novel biomarkers and discover new therapeutic targets.

Methods

In this study we aimed to characterize the phenotypic virulence profiles (including the ability to develop biofilms) of microorganisms isolated from chronic skin wounds and to correlate them with the clinical symptomatology. Considering the high incidence of Staphylococcus aureus infections in chronic ulcers, but also the ability of this species to develop multi-drug resistance, we performed an more in-depth study of the phenotypic and genotypic virulence profiles of methicillin-resistant Staphylococcus.

Results

The study revealed important differences regarding the clinical evolution and virulence profiles of microorganisms isolated from lower limb wounds, as well as between patients diagnosed with chronic venous ulcers and those with lesions of different etiology.
The prognosis of TP53 and EGFR co-mutation in patients with advanced lung adenocarcinoma and intracranial metastasis treated with EGFR-TKIs
Authors: Gu Weiguo , Liu Penghui , Tang Jiaming , Lai Jianfei , Wang Siya , Zhang Jiaming , Xu Jinbiao , Deng Jianxiong , Yu Feng , Shi Chao , Qiu Feng
Published: February 2024

Background

TP53 mutation is a poor factor for non-small cell lung cancer (NSCLC), while the effect of TP53 on prognosis in epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (LUAD) with brain metastasis remains elusive and needs further exploration.

Methods

We retrospectively analyzed 236 patients and tested for TP53- and EGFR-mutant status in metastasis LUAD patients who had received first-line EGFR-tyrosine kinase inhibitor (TKI) treatment. Survival rates were calculated by the Kaplan–Meier method. Furthermore, univariate and multivariate Cox analyses were performed to identify the independent prognostic factors.

Results

There were 114 patients with confirmed non-brain metastasis (NBM), 74 patients with preliminary diagnosis early brain metastasis (EBM), and 48 patients with late brain metastasis (LBM). TP53 and EGFR co-mutations were found in 35/236 patients (14.8%). The median progression-free survival (PFS) and overall survival (OS) in the EGFR mutation and TP53 wild-type group were significantly longer than those in the EGFR and TP53 co-mutation group in all advanced LUAD or NBM. Concurrently, PFS and OS were found to be not significant in EBM and LBM patients. Subgroup analysis revealed longer median PFS and OS in the TP53 wild-type group compared to the TP53 mutant group in L858R patients and not significant in EGFR Exon 19 deletion patients. In LBM patients, the time to brain metastasis in the EGFR mutation and TP53 wild-type group was longer than that in the EGFR and TP53 co-mutation group, and TP53 mutant status was an independent prognostic factor for brain metastasis. The TP53 wild-type group exhibited a higher objective remission rate (ORR) and disease control rate (DCR) than the TP53 mutant group in NBM, EBM, and LBM patients, irrespective of primary lung and brain metastatic lesions.

Conclusion

TP53/EGFR co-mutation patients receiving first-line EGFR-TKI treatment had poor prognoses in advanced LUAD, especially with L858R mutation. Moreover, TP53/EGFR co-mutation patients treated with EGFR-TKIs may more easy developed intracranial metastasis.
The role of blood metabolites in oral cancer: insights from a Mendelian randomization approach
Authors: Hu Ziyang , Xu Zhe , Yue Qu , Pan Xuhong , Shi Ping , Zhang Dandan , Zhang Jiexia , Deng Runzhi , Lin Zitong
Published: February 2024

Aim

This research aimed to explore the causal impact of blood metabolites on oral cancer using a two-sample Mendelian randomization (MR) analysis. The study endeavored to identify potential biomarkers for oral cancer’s clinical management.

Materials and methods

Based on the large individual-level datasets from UK Biobank as well as GWAS summary datasets, we first constructed genetic risk scores (GRSs) of 486 human blood metabolites and evaluated the effect on oral cancer. Various statistical methods, including inverse variance weighted (IVW), MR-Egger, and weighted median, among others, were employed to analyze the potential causal relationship between blood metabolites and oral cancer. The sensitivity analyses were conducted using Cochran’s Q tests, funnel plots, leave-one-out analyses, and MR-Egger intercept tests.

Results

29 metabolites met the stringent selection criteria. Out of these, 14 metabolites demonstrated a positive association with oral cancer risk, while 15 metabolites indicated a protective effect against oral cancer. The IVW-derived estimates were significant, and the results were consistent across different statistical methodologies. Both the Cochran Q test and the MR-Egger intercept test indicated no heterogeneity and pleiotropy.

Conclusion

This MR study offers evidence of the role specific blood metabolites play in oral cancer, pinpointing several with potential risk or protective effects. These findings could be helpful for new diagnostic tools and treatments for oral cancer. While the results are promising, additional research is necessary to fully validate and refine these conclusions. This study serves as a foundational step towards more comprehensive understandings in the future.
Potential mechanisms for osteopathic manipulative treatment to alleviate migraine-like pain in female rats
Authors: Byrd Katherine , Lund Makayla , Pan Yan , Chung Brandon H. , Child Kaitlyn , Fowler Danny , Burns-Martin Jared , Sanikommu Mythili , Henderson Hallie , Gregory Caroline , Fleming Regina K. , Xie Jennifer Yanhua
Published: February 2024

Introduction

Migraines are the leading cause of disability in the United States, and the use of non-pharmaceutical treatments like osteopathic manipulative treatment (OMT) has shown promise. Despite its potential, the lack of mechanistic understanding has hindered widespread adoption. This study aims to investigate the efficacy of OMT in treating acute migraines and unravel its underlying mechanisms of action.

Methods

Female rats were subjected to a “two-hit” approach to induce migraine-like pain. This involved bilateral injections of Complete Freund's Adjuvant (CFA) into the trapezius muscle (1st hit) followed by exposure to Umbellulone, a human migraine trigger, on Day 6 post-CFA (2nd hit). Soft tissue and articulatory techniques were applied to the cervical region for acute abortive or repeated prophylactic treatment. Cutaneous allodynia and trigeminal system activation were assessed through behavioral tests and immunohistochemical staining.

Results

Following Umbellulone inhalation, CFA-primed rats exhibited periorbital and hind paw allodynia. Immediate application of OMT after Umbellulone inhalation as an abortive treatment partially alleviated cutaneous allodynia. With OMT applied thrice as a prophylactic measure, complete suppression of tactile hypersensitivity was observed. Prophylactic OMT also prevented the increase of c-fos signals in the trigeminal nucleus caudalis and the elevation of calcitonin gene-related peptide expression in trigeminal ganglia induced by CFA and Umbellulone exposure at 2 h post-inhalation.

Discussion

These findings provide mechanistic insights into OMT's migraine-relief potential and underscore its viability as a non-pharmacological avenue for managing migraines.
European Academy of Paediatrics statement on the clinical management of children and adolescents with gender dysphoria
Authors: Brierley Joe , Larcher Vic , Hadjipanayis Adamos A. , Grossman Zachi
Published: February 2024

Gender issues have become a polarised and political subject in modern paediatrics and indeed, in broader society. These include the management of infants with disorders of sex development and transgender sports participation, but especially recently regarding the management of gender dysphoria. The European Academy of Paediatrics (EAP) acknowledges that there are deeply held beliefs about this issue based on conscience and social norms. Several European countries, led by the UK, have recently reviewed the management of gender dysphoria in children and young people. Recognising the need for far more research into treatments such as pubertal suppression and cross-sex hormones in children and young people, we review the current ethical and legal dilemmas facing children with gender dysphoria, their families and the clinical teams caring for them. We suggest an approach that maintains the child's right to an open future whilst acknowledging that the individual child is the crucial person affected by decisions made and must receive appropriate support in decision-making and care for any associated mental health or psychological issues. Noting that national approaches to this vary and are in flux, the EAP advocates a child-centred individual rights-based analytical approach.
Effectiveness of anticoagulant therapy using heparin combined with Plavix after Rex shunt
Authors: Zhang JinShan , Li Long
Published: February 2024

Purpose

Rex shunt is an optimal surgery for the treatment of extra-hepatic portal venous obstruction (EHPVO) in children. Anticoagulant therapy has been used to keep the patency of the bypass vein in the Rex shunt. This study was to investigate the effectiveness of anticoagulant therapy using heparin combined with Plavix in improving the prognosis and shunt patency of Rex shunt.

Methods

From January 2010 to September 2019, 51 children with EHPVO underwent a portal cavernoma- Rex shunt. Based on whether using the anticoagulant therapy after the Rex shunt, all patients were divided into two groups: the anticoagulant group and the non-anticoagulant group. The diameter and flow velocity of the bypass vein were measured by the post-operative ultrasound, which was used to calculate the flow volume of the bypass vein (FV) and standard portal venous flow (SPVF). The bypass venous flow index (BVFI) was used to evaluate the ability of portal blood into the liver through the bypass vein after the Rex shunt, which was a ratio of FV to SPVF. The incidence of post-operative re-bleeding, the postoperative patency rate of the bypass vein, the remission rate of postoperative hypersplenism, the remission rate of postoperative esophagogastric varices and the BVFI were compared between the two groups.

Results

Of the 51 patients, 12 patients in the anticoagulant group were treated with heparin combined with Plavix after Rex shunt; 39 patients in the non-anticoagulant group were not treated with any anticoagulant therapy. 8 of 51 patients suffered from postoperative re-bleeding, of whom 6 patients with thrombosis of the bypass vein and 2 patients with anastomotic stenosis of the bypass vein. All 8 patients with re-bleeding belonged to the non-anticoagulant group. The remission rate of hypersplenism was no significant difference between the two groups after surgery (91% vs. 58%, P = 0.100). However, 3 patients without hypersplenism before surgery suffered from hypersplenism after surgery, who belonged to the non-anticoagulant group. There was no significant difference in the remission rate of esophagogastric varices (33% vs. 46%, P = 1.000). The BVFI of the anticoagulant group was significantly higher than that of the non-anticoagulant group (5.71 ± 5.89 vs. 1.1 ± 1.52, P = 0.003).

Conclusions

Anticoagulant therapy using heparin combined with Plavix plays an important role in maintaining the patency of the bypass vein, which improved the portal blood flow into the liver through the bypass vein after the Rex shunt.
Concomitant inhibition of PI3K/mTOR signaling pathways boosts antiproliferative effects of lanreotide in bronchopulmonary neuroendocrine tumor cells
Authors: von Hessert-Vaudoncourt Claus , Lelek Sara , Geisler Christina , Hartung Teresa , Bröker Vanessa , Briest Franziska , Mochmann Liliana , Jost-Brinkmann Fabian , Sedding Dagmar , Benecke Joana , Freitag Helma , Wolfshöfer Sebastian , Lammert Hedwig , Nölting Svenja , Hummel Michael , Schrader Jörg , Grabowski Patricia
Published: February 2024

Introduction: Somatostatin analogues (SSAs) are commonly used in the treatment of hormone hypersecretion in neuroendocrine tumors (NETs), however the extent to which they inhibit proliferation is much discussed.

Objective: We studied the antiproliferative effects of novel SSA lanreotide in bronchopulmonary NETs (BP-NETs). We focused on assessing whether pretreating cells with inhibitors for phosphatidylinositol 3-kinase (PI3K) and mammalian target for rapamycin (mTOR) could enhance the antiproliferative effects of lanreotide.

Methods: BP-NET cell lines NCI-H720 and NCI-H727 were treated with PI3K inhibitor BYL719 (alpelisib), mTOR inhibitor everolimus and SSA lanreotide to determine the effect on NET differentiation markers, cell survival, proliferation and alterations in cancer-associated pathways. NT-3 cells, previously reported to express somatostatin receptors (SSTRs) natively, were used as control for SSTR expression.

Results: SSTR2 was upregulated in NCI-H720 and NT-3 cells upon treatment with BYL719. Additionally, combination treatment consisting of BYL719 and everolimus plus lanreotide tested in NCI-H720 and NCI-H727 led to diminished cell proliferation in a dose-dependent manner. Production of proteins activating cell death mechanisms was also induced. Notably, a multiplexed gene expression analysis performed on NCI-H720 revealed that BYL719 plus lanreotide had a stronger effect on the downregulation of mitogens than lanreotide alone.

Discussion/Conclusion: We report a widespread analysis of changes in BP-NET cell lines at the genetic/protein expression level in response to combination of lanreotide with pretreatment consisting of BYL719 and everolimus. Interestingly, SSTR expression reinduction could be exploited in therapeutic and diagnostic applications. The overall results of this study support the evaluation of combination-based therapies using lanreotide in preclinical studies to further increase its antiproliferative effect and ultimately facilitate its use in high-grade tumors.
Mitophagy regulates mitochondrial number following pharmacological induction of mitochondrial biogenesis in renal proximal tubule cells
Authors: Hurtado Kevin A. , Schnellmann Rick G.
Published: February 2024

Background: Mitochondrial biogenesis (MB) induction through the activation of the 5-Hydroxytriptamine (5-HT) 1F receptor (HTR1F) is a promising mechanism for the treatment of diseases characterized by mitochondrial dysfunction, such as acute kidney injury (AKI). While several studies report pharmacological activation of MB in the proximal tubule, it is unclear how the proximal tubule regulates itself once the pharmacological activation is removed. Mitophagy is the process of selective mitochondria degradation. We hypothesize that mitophagy decreases mitochondrial number after pharmacological stimulation and restore mitochondrial homeostasis.

Methods: Renal proximal tubules were treated at time 0hr with LY344864 or vehicle for 24 h and then removed. LY344864, a selective HTR1F agonist, induces MB in renal proximal tubules as previously reported (Gibbs et al., Am J Physiol Renal Physiol, 2018, 314(2), F260–F268). Vehicle and pharmacological reagents were added at the 24 h time point. Electron microscopy was used to assess mitochondrial morphology, number, and autolysosomes. Seahorse Bioscience XF-96 extracellular flux analyzer was used to measure maximal mitochondrial oxygen consumption rates (FCCP-OCR), a functional marker of MB.

Results: LY344864 treatment increased FCCP-OCR, phosphorylation of protein kinase B (AKT), peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α), and mitochondrial number after 24 h. These endpoints decreased to baseline 24 h after LY344864 removal. Treatment with ROC-325, an autophagy inhibitor, increased Sequestosome-1 (SQSTM1/P62) and microtubule-associated protein-1 light chain 3 (LC3B) after 24 h of treatment. Also, ROC-325 treatment sustained the elevated mitochondrial number after LY344864 pre-treatment and removal.

Conclusion: These data revealed that inhibition of autophagy extends elevated mitochondrial number and function by preventing the lysosomal degradation of mitochondria after the removal of LY344864.
Mueller matrix polarization interferometry of optically anisotropic architectonics of biological tissue object fields: the fundamental and applied aspects
Authors: Ushenko Alexander , Dubolazov Alexander , Zheng Jun , Bakun Oxana , Gorsky Mykhaylo , Ushenko Yuriy , Litvinenko Olexandra , Gordey Ivan , Zhebo Chen , Sklyarchuk Valeriy
Published: February 2024

The presented results concern the diagnostic application of vector-parameter polarization mapping and polarization-interference phase scanning applied to layered azimuths and ellipticity polarization maps obtained with the help of digital holographic reproduction for phase-inhomogeneous tissue layers in the female reproductive system. The differential diagnosis of the pathological changes in optically anisotropic polycrystalline tissue components, specifically “benign (fibroids) and precancerous (endometriosis),” was investigated. All studies within the representative groups of the histological samples were conducted using circularly polarized laser radiation, ensuring azimuthal invariance and polarization measurement reliability. Integral and layered maps and polarization azimuths and ellipticity random variable distribution histograms were obtained from the microscopic images of histological sections from the female reproductive system tumors. Systematized tables present statistical moments which characterize azimuths and ellipticity polarization maps for fibroids and endometriosis tissues. It is shown that the statistical parameters (diagnostic markers) are the most sensitive to benign and precancerous changes in the female reproductive system tissues. The results of information analysis, including the accuracy determination of the diagnostic vector-parameter polarization and polarization-interference methods for detecting and differentiating the samples of fibroids and precancerous endometriosis tissues in the female reproductive system, are presented.
The crucial role of lateral root angle in enhancing drought resilience in cotton
Authors: Guo Congcong , Bao Xiaoyuan , Sun Hongchun , Chen Jing , Zhu Lingxiao , Zhang Jianhong , Zhang Haina , Zhang Yongjiang , Zhang Ke , Bai Zhiying , Li Anchang , Liu Liantao , Li Cundong
Published: February 2024

Introduction

Plant responses to drought stress are influenced by various factors, including the lateral root angle (LRA), stomatal regulation, canopy temperature, transpiration rate and yield. However, there is a lack of research that quantifies their interactions, especially among different cotton varieties.

Methods

This experiment included two water treatments: well-watered (75 ± 5% soil relative water content) and drought stress (50 ± 5% soil relative water content) starting from the three-leaf growth stage.

Results

The results revealed that different LRA varieties show genetic variation under drought stress. Among them, varieties with smaller root angles show greater drought tolerance. Varieties with smaller LRAs had significantly increased stomatal opening by 15% to 43%, transpiration rate by 61.24% and 62.00%, aboveground biomass by 54% to 64%, and increased seed cotton yield by 76% to 79%, and decreased canopy temperature by 9% to 12% under drought stress compared to the larger LRAs. Varieties with smaller LRAs had less yield loss under drought stress, which may be due to enhanced access to deeper soil water, compensating for heightened stomatal opening and elevated transpiration rates. The increase in transpiration rate promotes heat dissipation from leaves, thereby reducing leaf temperature and protecting leaves from damage.

Discussion

Demonstrating the advantages conferred by the development of a smaller LRA under drought stress conditions holds value in enhancing cotton’s resilience and promoting its sustainable adaptation to abiotic stressors.
On the concept, taxonomy, and transculturality of disordered grief
Authors: Gouveia Afonso
Published: February 2024

The enduring question of whether grief can ever be pathological (and, if so, when) has been shrouding mental health and psychiatric care over the last few years. While this discussion extends beyond the confines of psychiatry to encompass contributions from diverse disciplines such as Anthropology, Sociology, and Philosophy, scrutiny has been mainly directed toward psychiatry for its purported inclination to pathologize grief—an unavoidable facet of the human experience. This critique has gained particular salience considering the formal inclusion of prolonged grief disorder (PGD) in the 11th edition of the International Classification of Diseases (ICD-11) and the subsequent Text Revision 5th Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR). This study contends that the inclusion of prolonged grief disorder as a diagnostic entity may be excessively rooted in Western cultural perspectives and empirical data, neglecting the nuanced variations in the expression and interpretation of grief across different cultural contexts. The formalization of this disorder not only raises questions about its universality and validity but also poses challenges to transcultural psychiatry, due to poor representation in empirical research and increased risk of misdiagnosis. Additionally, it exacerbates the ongoing concerns related to normativism and the lack of genuine cultural relativism within the DSM. Furthermore, the passionate discussion surrounding the existence, or not, of disordered forms of grief may actually impede effective care for individuals genuinely grappling with pathological forms of grief. In light of these considerations, this study proposes that prolonged grief disorder should be approached as a diagnostic category with potential Western cultural bias until comprehensive cross-cultural studies, conducted in diverse settings, can either substantiate or refute its broader applicability. This recalibration is imperative for advancing a more inclusive and culturally sensitive understanding of grief within the field of psychiatry.