bluuebunny/crossref_metadata_2025 huggingface dataset:
MMR gene patterns evaluation provides novel insights for personalized immunotherapy compared to neoadjuvant chemotherapy in lung adenocarcinama
Authors: Cai Liangliang , Hua Hujia , Jiang Xingyu , Xu Xintian , Bai Hua , Qian Li , Duan Jianchun
Published: June 2023

Background

The association involving mismatch repair (MMR) genes, molecular subtype and specific immune cell group in tumor microenvironment has been focused by more recent studies. Its prognosis value in lung adenocarcinoma (LUAD) neoadjuvant chemotherapy remains elusive.

Methods

The correlation between the MMR gene patterns and the immune landscape were comprehensively evaluated. The MMRScore was calculated using principal component analysis (PCA) after grouping using R/mclust package. The prognostic significance of the MMRScore was evaluated by Kaplan-merrier analysis. Then a cohort of 103 Chinese LUAD patients was collected for neoadjuvant chemotherapy prognosis evaluation and validation using MMRScore.

Results

Four MMRclusters (mc1, 2, 3, 4)-characterized by differences in extent of aneuploidy, expression of immunomodulatory (IM) genes, mRNA expression, lncRNA expression and prognosis were identified. We established MMRscore to quantify the MMR pattern of individual LUAD patients. As is shown in further analyses, the MMRscore was a potential independent prognostic factor of LUAD. Finally, the prognostic value of the MMRscore and its association with tumor immune microenvironment (TIME) of LUAD were verified in Chinese LUAD cohort.

Conclusions

We demonstrated the correlation between MMR gene pattern, the CNV and tumor immune landscape in LUAD. A MMRcluster mc2 with high MMRscore, high TMB and high CNV subtype was identified with poor prognosis and infiltrating immunocyte. The comprehensive evaluation of MMR patterns in individual LUAD patients enhances the understanding of TIME and gives a new insight toward improved immune treatment strategies for LUAD patients compared to neoadjuvant chemotherapy.
Corneal biophysical changes after upper eyelid blepharoplasty and ptosis surgery: a review
Authors: Heidari Mostafa , Haydar Ali A. , Rajabi Mohammad Taher , Rafizadeh Seyed Mohsen
Published: June 2023

Upper eyelid surgeries, such as blepharoplasty and ptosis correction, are commonly performed procedures worldwide. This review examines the effects of these surgeries on ocular properties and visual function. A search of the PubMed and Google Scholar databases was conducted to identify relevant articles published after 2000. The results demonstrate that the ocular and adnexal organs function as a unified visual system, with changes in one component affecting the functions of others. Eyelid surgery can alter ocular properties and functions by modifying retinal lighting and ocular optics. These alterations can affect intraocular pressure estimation, corneal curvature, corneal epithelial thickness, refractive power of the cornea, and intraocular lens calculation. Additionally, eyelid surgery can exacerbate dry eye symptoms and impact contrast sensitivity, which is a significant factor in visual quality. Therefore, understanding these interactions is crucial before performing eyelid surgery and during follow-up. This review summarizes recent literature on the effects of upper eyelid surgery on corneal properties and visual function, emphasizing the importance of considering these factors when planning or undergoing such procedures.
Impact of social and demographic factors on the spread of the SARS-CoV-2 epidemic in the town of Nice
Authors: Mariné Barjoan Eugènia , Chaarana Amel , Festraëts Julie , Géloen Carole , Prouvost-Keller Bernard , Legueult Kevin , Pradier Christian
Published: June 2023

Introduction

Socio-demographic factors are known to influence epidemic dynamics. The town of Nice, France, displays major socio-economic inequalities, according to the National Institute of Statistics and Economic Studies (INSEE), 10% of the population is considered to live below the poverty threshold, i.e.60% of the median standard of living.

Objective

To identify socio-economic factors related to the incidence of SARS-CoV-2 in Nice, France.

Methods

The study included residents of Nice with a first positive SARS-CoV-2 test (January 4-February 14, 2021). Laboratory data were provided by the National information system for Coronavirus Disease (COVID-19) screening (SIDEP) and socio-economic data were obtained from INSEE. Each case’s address was allocated to a census block to which we assigned a social deprivation index (French Deprivation index, FDep) divided into 5 categories. For each category, we computed the incidence rate per age and per week and its mean weekly variation. A standardized incidence ratio (SIR) was calculated to investigate a potential excess of cases in the most deprived population category (FDep5), compared to the other categories. Pearson’s correlation coefficient was computed and a Generalized Linear Model (GLM) applied to analyse the number of cases and socio-economic variables per census blocks.

Results

We included 10,078 cases. The highest incidence rate was observed in the most socially deprived category (4001/100,000 inhabitantsvs2782/100,000 inhabitants for the other categories of FDep). The number of observed cases in the most social deprivated category (FDep5:N = 2019) was significantly higher than in the others (N = 1384); SIR = 1.46 [95% CI:1.40–1.52;p < 0.001]. Socio-economic variables related to poor housing, harsh working conditions and low income were correlated with the new cases of SARS-CoV-2.

Conclusion

Social deprivation was correlated with a higher incidence of SARS-CoV-2 during the 2021 epidemic in Nice. Local surveillance of epidemics provides complementary data to national and regional surveillance. Mapping socio-economic vulnerability indicators at the census block level and correlating these with incidence could prove highly useful to guide political decisions in public health.
Increasing the accuracy of the asthma diagnosis using an operational definition for asthma and a machine learning method
Authors: Joo Hyonsoo , Lee Daeun , Lee Sang Haak , Kim Young Kyoon , Rhee Chin Kook
Published: June 2023

Introduction

Analysis of the National Health Insurance data has been actively carried out for the purpose of academic research and establishing scientific evidences for health care service policy in asthma. However, there has been a limitation for the accuracy of the data extracted through conventional operational definition. In this study, we verified the accuracy of conventional operational definition of asthma, by applying it to a real hospital setting. And by using a machine learning technique, we established an appropriate operational definition that predicts asthma more accurately.

Methods

We extracted asthma patients using the conventional operational definition of asthma at Seoul St. Mary’s hospital and St. Paul’s hospital at the Catholic University of Korea between January 2017 and January 2018. Among these extracted patients of asthma, 10% of patients were randomly sampled. We verified the accuracy of the conventional operational definition for asthma by matching actual diagnosis through medical chart review. And then we operated machine learning approaches to predict asthma more accurately.

Results

A total of 4,235 patients with asthma were identified using a conventional asthma definition during the study period. Of these, 353 patients were collected. The patients of asthma were 56% of study population, 44% of patients were not asthma. The use of machine learning techniques improved the overall accuracy. The XGBoost prediction model for asthma diagnosis showed an accuracy of 87.1%, an AUC of 93.0%, sensitivity of 82.5%, and specificity of 97.9%. Major explanatory variable were ICS/LABA,LAMA and LTRA for proper diagnosis of asthma.

Conclusions

The conventional operational definition of asthma has limitation to extract true asthma patients in real world. Therefore, it is necessary to establish an accurate standardized operational definition of asthma. In this study, machine learning approach could be a good option for building a relevant operational definition in research using claims data.
Long noncoding RNA signatures in intrauterine infection/inflammation-induced lung injury: an integrative bioinformatics study
Authors: Pan Jiarong , Zhan Canyang , Yuan Tianming , Gu Weizhong , Wang Weiyan , Sun Yi , Chen Lihua
Published: June 2023

Background

Intrauterine infection/inflammation can result in fetal and neonatal lung injury. However, the biological mechanisms of intrauterine infection/inflammation on fetal and neonatal lung injury and development are poorly known. To date, there are no reliable biomarkers for improving intrauterine infection/inflammation-induced lung injury.

Methods

An animal model of intrauterine infection/inflammation-induced lung injury was established with pregnant Sprague–Dawley rats inoculated with Escherichia coli suspension. The intrauterine inflammatory status was assessed through the histological examination of the placenta and uterus. A serial of histological examinations of the fetal and neonatal rats lung tissues were performed. The fetal and neonatal rat lung tissues were harvested for next generation sequencing at embryonic day 17 and postnatal day 3, respectively. Differentially expressed mRNAs and lncRNAs were identified by conducting high-throughput sequencing technique. The target genes of identified differentially expressed lncRNAs were analyzed. Homology analyses for important differentially expressed lncRNAs were performed.

Results

The histopathological results showed inflammatory infiltration, impaired alveolar vesicular structure, less alveolar numbers, and thickened alveolar septa in fetal and neonatal rat lung tissues. Transmission electron micrographs revealed inflammatory cellular swelling associated with diffuse alveolar damage and less surfactant-storing lamellar bodies in alveolar epithelial type II cells. As compared with the control group, there were 432 differentially expressed lncRNAs at embryonic day 17 and 125 differentially expressed lncRNAs at postnatal day 3 in the intrauterine infection group. The distribution, expression level, and function of these lncRNAs were shown in the rat genome. LncRNA TCONS_00009865, lncRNA TCONS_00030049, lncRNA TCONS_00081686, lncRNA TCONS_00091647, lncRNA TCONS_00175309, lncRNA TCONS_00255085, lncRNA TCONS_00277162, and lncRNA TCONS_00157962 may play an important role in intrauterine infection/inflammation-induced lung injury. Fifty homologous sequences in Homo sapiens were also identified.

Conclusions

This study provides genome-wide identification of novel lncRNAs which may serve as potential diagnostic biomarkers and therapeutic targets for intrauterine infection/inflammation-induced lung injury.
A practical method for the retrieval of tulip-head polyaxial pedicle screw by reusing the rod in revision and implants removal surgery: introduction of technique and evaluation of clinical outcomes
Authors: Zhang Yao , Song Jipeng , Lu Yuzheng , Yi Meng , Xu Xiaohang , Ding Lixiang
Published: June 2023

Background

The removal of spinal implants is needed in revision surgery or in some cases whose fracture had healed or fusion had occurred. The slip of polyaxial screw or mismatch of instruments would make this simple procedure intractable. Here we introduce a simple and practical method to address this clinical dilemma.

Methods

This is a retrospective study. The patients underwent new technique for retrieving the implants from July 2019 to July 2022 were labeled as group A, while the patients underwent traditional implants retrieval technique from January 2017 to January 2020 were labeled as group B. Patients in each group were subdivided into revision surgery group (r group) and simple implants removal group (s group) according to the surgery fashion. For the new technique, the retrieved rod was cut off to a proper length which was matched with the size of tulip head, and was replaced into the tulip head. After tightened with nut, a monoaxial screw-rod “construct” was formed. Then the “construct” can be retrieved by a counter torque. The operation duration, intraoperative blood loss, post-operative bacteria culture, hospital stay and costs were analyzed.

Results

A total of 116 polyaxial screws with difficult retrieval (43 screws in group A, 73 screws in group B) in 78 patients were recorded, in which 115 screws were successfully retrieved. Significant differences were found in the mean operation duration, intraoperative blood loss when comparing the r group in group A and B, as well as the s group in group A and B (P < 0.05). There were no significant differences in hospital stay and costs between group A and B. Three patients were found positive bacteria culture of drainage tube/tape in group A (3/30), while 7 patients in group B (7/48). The most prevalent bacteria was Propionibacterium acnes.

Conclusion

This technique is practical and safe in retrieving tulip head poly-axial screw. Reduced operation duration and intraoperative bloods loss may potentially alleviate the hospitalization burden of patients. Positive bacterial cultivation results are common after implants removal surgery, but they rarely represent an organized infection. A positive culture with P. acnes or S. epidermidis should be interpreted with caution.
Upper brainstem cholinergic neurons project to ascending and descending circuits
Authors: Zhao Peilin , Jiang Tao , Wang Huading , Jia Xueyan , Li Anan , Gong Hui , Li Xiangning
Published: June 2023

Background

Based on their anatomical location, rostral projections of nuclei are classified as ascending circuits, while caudal projections are classified as descending circuits. Upper brainstem neurons participate in complex information processing and specific sub-populations preferentially project to participating ascending or descending circuits. Cholinergic neurons in the upper brainstem have extensive collateralizations in both ascending and descending circuits; however, their single-cell projection patterns remain unclear because of the lack of comprehensive characterization of individual neurons.

Results

By combining fluorescent micro-optical sectional tomography with sparse labeling, we acquired a high-resolution whole-brain dataset of pontine-tegmental cholinergic neurons (PTCNs) and reconstructed their detailed morphology using semi-automatic reconstruction methods. As the main source of acetylcholine in some subcortical areas, individual PTCNs had abundant axons with lengths up to 60 cm and 5000 terminals and innervated multiple brain regions from the spinal cord to the cortex in both hemispheres. Based on various collaterals in the ascending and descending circuits, individual PTCNs were grouped into four subtypes. The morphology of cholinergic neurons in the pedunculopontine nucleus was more divergent, whereas the laterodorsal tegmental nucleus neurons contained richer axonal branches and dendrites. In the ascending circuits, individual PTCNs innervated the thalamus in three different patterns and projected to the cortex via two separate pathways. Moreover, PTCNs targeting the ventral tegmental area and substantia nigra had abundant collaterals in the pontine reticular nuclei, and these two circuits contributed oppositely to locomotion.

Conclusions

Our results suggest that individual PTCNs have abundant axons, and most project to various collaterals in the ascending and descending circuits simultaneously. They target regions with multiple patterns, such as the thalamus and cortex. These results provide a detailed organizational characterization of cholinergic neurons to understand the connexional logic of the upper brainstem.
Neutrophil activation may trigger tau burden contributing to cognitive progression of chronic sleep disturbance in elderly individuals not living with dementia
Authors: Sun Lin , Zhang Jie , Li Wei , Sheng Jianhua , Xiao Shifu ,   Alzheimer’s Disease Neuroimaging Initiative
Published: June 2023

Background

To investigate the complex connection between chronic sleep disturbance (CSD) and cognitive progression.

Methods

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) database was used to assign 784 non-dementia elderly into two groups: a normal sleep group (528 participants) and a CSD group (256 participants) via the Neuropsychiatric Inventory (NPI)-sleep subitem. Blood transcriptomics, blood neutrophil, cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD), and neutrophil-related inflammatory factors were measured. We also investigated gene set enrichment analysis (GSEA), Cox proportional hazards model for risk factors, and mediation and interaction effects between indicators. Cognitive progression is defined as the progression from cognitively normal to mild cognitive impairment (MCI)/dementia or from MCI to dementia.

Results

CSD could significantly affect cognitive function. The activated neutrophil pathways for cognitive progression in CSD were identified by transcriptomics GSEA, which was reflected by increased blood neutrophil level and its correlation with cognitive progression in CSD. High tau burden mediated the influence of neutrophils on cognitive function and exacerbated the CSD-related risk of left hippocampal atrophy. Elevated neutrophil-related inflammatory factors were observed in the cognitive progression of CSD and were associated with brain tau burden.

Conclusions

Activated neutrophil pathway triggering tau pathology may underline the mechanism of cognitive progression in CSD.
Pien-Tze-Huang prevents hepatocellular carcinoma by inducing ferroptosis via inhibiting SLC7A11-GSH-GPX4 axis
Authors: Yan Xiangying , Liu Yudong , Li Congchong , Mao Xia , Xu Tengteng , Hu Zhixing , Zhang Chu , Lin Na , Lin Ya , Zhang Yanqiong
Published: June 2023

Background

Malignant transformation from hepatic fibrosis to carcinogenesis may be a therapeutic target for hepatocellular carcinoma (HCC). The aim of this study was to evaluate anti-cancer efficacy of Pien-Tze-Huang (PZH), and to investigate the underlying mechanisms by integrating transcriptional regulatory network analysis and experimental validation.

Methods

A diethylnitrosamine (DEN)-induced HCC model in rats was established and used to evaluate the anti-cancer efficacy of PZH. After detecting a transcriptomic profiling, the “disease-related gene–drug effective target” interaction network was constructed, and the candidate targets of PZH against malignant transformation from hepatic fibrosis to HCC were identified and verified in vitro.

Results

PZH effectively alleviated the pathological changes of hepatic fibrosis and cirrhosis, and inhibited tumor formation and growth in DEN-induced HCC rats. Additionally, the administration of PZH reduced the levels of various hepatic function-related serological indicators significantly. Mechanically, a ferroptosis-related SLC7A11-GSH-GPX4 axis might be one of potential targets of PZH against malignant transformation from hepatic fibrosis to HCC. Especially, high SLC7A11 expression may be associated with poor prognosis of HCC patients. Experimentally, the administration of PZH markedly increased the trivalent iron and ferrous ion, suppressed the expression levels of SLC7A11 and GPX4 proteins, and reduced the GSH/GSSG ratio in the liver tissues of DEN-induced HCC rats.

Conclusions

Our data offer an evidence that PZH may effectively improve the hepatic fibrosis microenvironment and prevent the occurrence of HCC through promoting ferroptosis in tumor cells via inhibiting the SLC7A11-GSH-GPX4 axis, implying that PZH may be a potential candidate drug for prevention and treatment of HCC at an early stage.
Functionality of technical working groups in enabling evidence-informed decision-making within Malawi's Ministry of Health: a cross-sectional qualitative study
Authors: Sakala Melody , Chawani Marlen Stacey , Kazanga-Chiumia Isabel , Hara Hleziwe , Abdullahi Leila , Kambalame Dzinkambani , Banda Josephine , Mitambo Collins , Terlouw Anja , Oronje Rose
Published: June 2023

Background

The roles and functionality of technical working groups (TWGs) in the health sectors vary across countries, still they aim to support government and ministries in formulating evidence-informed recommendations for policies and facilitate dialogue and alignment of activities among stakeholders within the health sector. Thus, TWGs have a role in enhancing the functionality and effectiveness of the health system structure. However, in Malawi, the functionality of TWGs and how they utilize research evidence to contribute to decision-making is not monitored. This study sought to understand the TWGs' performance and functionality in enabling evidence-informed decision-making (EIDM) in Malawi's health sector.

Methods

A cross-sectional descriptive qualitative study. Data were collected through interviews, documents review and observation of three TWG meetings. Qualitative data were analysed using a thematic approach. The WHO-UNICEF Joint Reporting Form (JRF) was used to guide the assessment of TWG functionality.

Results

TWG functionality varied in the Ministry of Health (MoH) in Malawi. The reasons for those perceived to be functioning well included meeting frequently, diverse representation of members, and that their recommendations to MoH were usually considered when decisions were made. For the TWGs that were perceived as not functioning well, the main reasons included lack of funding, periodic meetings and discussions that needed to provide clear decisions on the actions to be taken. In addition, evidence was recognized as important in decision-making, and research was valued by decision-makers within the MoH. However, some of the TWGs lacked reliable mechanisms for generating, accessing and synthesizing research. They also needed more capacity to review and use the research to inform their decisions.

Conclusions

TWGs are highly valued and play a critical role in strengthening EIDM within the MoH. Our paper highlights the complexity and barriers of TWG functionality in supporting pathways for health policy-making in Malawi. These results have implications for EIDM in the health sector. This suggests that the MoH should actively develop reliable interventions and evidence tools, strengthen capacity-building and increase funding for EIDM.
Stakeholder perceptions and experiences from the implementation of the Gratuité user fee exemption policy in Burkina Faso: a qualitative study
Authors: Banke-Thomas Aduragbemi , Offosse Marie-Jeanne , Yameogo Pierre , Manli Astrid Raissa , Goumbri Aude , Avoka Cephas , Boxshall Matt , Eboreime Ejemai
Published: June 2023

Background

In 2016, the Gratuité policy was initiated by the Government of Burkina Faso to remove user fees for maternal, newborn, and child Health (MNCH) services. Since its inception, there has not been any systematic capture of experiences of stakeholders as it relates to the policy. Our objective was to understand the perceptions and experiences of stakeholders regarding the implementation of the Gratuité policy.

Methods

We used key informant interviews (KIIs) and focus group discussions (FGDs) to engage national and sub-national stakeholders in the Centre and Hauts-Bassin regions. Participants included policymakers, civil servants, researchers, non-governmental organizations in charge of monitoring the policy, skilled health personnel, health facility managers, and women who used MNCH services before and after the policy implementation. Topic guides aided sessions, which were audio recorded and transcribed verbatim. A thematic analysis was used for data synthesis.

Results

There were five key themes emerging. First, majority of stakeholders have a positive perception of the Gratuité policy. Its implementation approach is deemed to have strengths including government leadership, multi-stakeholder involvement, robust internal capacity, and external monitoring. However, collateral shortage of financial and human resources, misuse of services, delays in reimbursement, political instability and health system shocks were highlighted as concerns that compromise the government's objective of achieving universal health coverage (UHC). However, many beneficiaries were satisfied at the point of use of MNHC services, though Gratuité did not always mean free to the service users. Broadly, there was consensus that the Gratuité policy has contributed to improvements in health-seeking behavior, access, and utilization of services, especially for children. However, the reported higher utilization is leading to some perceived increased workload and altered health worker attitude.

Conclusions

There is a general perception that the Gratuité policy is achieving what it set out to do, which is to increase access to care by removing financial barriers. While stakeholders recognized the intention and value of the Gratuité policy, and many beneficiaries were satisfied at the point of use, inefficiencies in its implementation undermines progress. As the country moves towards the goal of realizing UHC, reliable investment in the Gratuité policy is needed.
Knowledge level and access barriers related to sexual and reproductive health information among youth with disabilities in China: a cross-sectional study
Authors: Qi Wenjuan , Li Hongyan , Lian Qiguo , Zuo Xiayun , Yu Chunyan , Lou Chaohua , Tu Xiaowen
Published: June 2023

Background

Youth with disabilities have the same right to sexual and reproductive health (SRH) as their peers without disabilities. However, their needs and rights are often ignored. Little is known about the knowledge, needs and access barriers related to SRH information among youth with different types of disabilities in China.

Methods

A cross-sectional survey was carried out among 473 unmarried youth aged 15–24 with visual, hearing, physical disabilities in both urban and rural areas in China.

Results

Out of a maximum possible score of 100, respondent’s median score ranged from 30 to 50 for knowledge related to sexual physiology, STIs/HIV/AIDS and contraception. For these three categories of knowledge, respondents with hearing and physical disabilities or from rural areas scored lower than their counterparts with visual disabilities or from urban areas. The multivariate analyses showed that the residential area and education level were strong correlates of knowledge among respondents with visual and hearing disabilities. Other significant correlates were age for respondents with visual impairment and physical impairment, and single child status in the family and father’s education level for respondents with hearing impairment. Sources of and barriers and preferences in accessing SRH information differed by type of disabilities, residential areas and gender. In general, school teachers were the primary and most preferred sources of SRH knowledge, followed by the Internet, peers/friends and parents. Unaware of where to get accurate information and feeling embarrassed to seek information were the two most frequently mentioned barriers in accessing SRH information.

Conclusion

Respondents had poor knowledge of SRH and limited access to SRH information, especially those from rural areas. Efforts should be made to promote school and family-based sexuality education tailored for youth with different types of disabilities.
Managers perception of hospital employees’ effort-reward imbalance
Authors: Heming Meike , Siegrist Johannes , Erschens Rebecca , Genrich Melanie , Hander Nicole R. , Junne Florian , Küllenberg Janna K. , Müller Andreas , Worringer Britta , Angerer Peter
Published: June 2023

Objective

Hospitals are frequently associated with poor working conditions that can lead to work stress and increase the risk for reduced employee well-being. Managers can shape and improve working conditions and thereby, the health of their teams. Thus, as a prerequisite, managers need to be aware of their employees’ stress levels. This study had two objectives: At first, it aimed to test the criterion validity of the Effort-Reward Imbalance (ERI) questionnaire measuring psychosocial workload in hospital employees. Secondly, mean scales of the ERI questionnaire filled in by employees were compared with mean scales of an adapted ERI questionnaire, in which managers assessed working conditions of their employees.

Methods

Managers (n = 141) from three hospitals located in Germany assessed working conditions of their employees with an adapted external, other-oriented questionnaire. Employees (n = 197) of the mentioned hospitals completed the short version of the ERI questionnaire to assess their working conditions. Confirmatory factor analyses (CFA) were applied to test factorial validity, using the ERI scales for the two study groups. Criterion validity was assessed with multiple linear regression analysis of associations between ERI scales and well-being among employees.

Results

The questionnaires demonstrated acceptable psychometric properties in terms of internal consistency of scales, although some indices of model fit resulting from CFA were of borderline significance. Concerning the first objective, effort, reward, and the ratio of effort-reward imbalance were significantly associated with well-being of employees. With regard to the second objective, first tentative findings showed that managers’ ratings of their employees’ effort at work was quite accurate, whereas their reward was overestimated.

Conclusions

With its documented criterion validity the ERI questionnaire can be used as a screening tool of workload among hospital employees. Moreover, in the context of work-related health promotion, managers’ perceptions of their employees’ workload deserve increased attention as first findings point to some discrepancies between their perceptions and those provided by employees.
Integration of transcriptomics and proteomics to elucidate inhibitory effect and mechanism of rosmarinic acid from Perilla frutescens (L.) Britt. in treating Trichophyton mentagrophytes
Authors: Xu Yang-ding , Guo Yu-jie , Mao He-rong , Xiong Zhi-xiang , Luo Meng-yu , Luo Rui-qi , Lu Shan , Huang Lu , Hong Yi
Published: June 2023

Background

Dermatophyte caused by Trichophyton mentagrophytes is a global disease with a growing prevalence that is difficult to cure. Perilla frutescens (L.) Britt. is an edible and medicinal plant. Ancient books of Traditional Chinese Medicine and modern pharmacological studies have shown that it has potential anti-fungi activity. This is the first study to explore the inhibitory effects of compounds from P. frutescens on Trichophyton mentagrophytes and its mechanism of action coupled with the antifungal activity in vitro from network pharmacology, transcriptomics and proteomics.

Methods

Five most potential inhibitory compounds against fungi in P. frutescens was screened with network pharmacology. The antifungal activity of the candidates was detected by a broth microdilution method. Through in vitro antifungal assays screening the compound with efficacy, transcriptomics and proteomics were performed to investigate the pharmacological mechanisms of the effective compound against Trichophyton mentagrophytes. Furthermore, the real-time polymerase chain reaction (PCR) was applied to verify the expression of genes.

Results

The top five potential antifungal compounds in P. frutescens screened by network pharmacology are: progesterone, luteolin, apigenin, ursolic acid and rosmarinic acid. In vitro antifungal assays showed that rosmarinic acid had a favorable inhibitory effect on fungi. The transcriptomic findings exhibited that the differentially expressed genes of fungus after rosmarinic acid intervention were mainly enriched in the carbon metabolism pathway, while the proteomic findings suggested that rosmarinic acid could inhibit the average growth of Trichophyton mentagrophytes by interfering with the expression of enolase in the glycolysis pathway. Comparison of real-time PCR and transcriptomics results showed that the trends of gene expression in glycolytic, carbon metabolism and glutathione metabolic pathways were identical. The binding modes and interactions between rosmarinic acid and enolase were preliminary explored by molecular docking analysis.

Conclusion

The key findings of the present study manifested that rosmarinic acid, a medicinal compound extracted from P. frutescens, had pharmacological activity in inhibiting the growth of Trichophyton mentagrophytes by affecting its enolase expression to reduce metabolism. Rosmarinic acid is expected to be an efficacious product for prevention and treatment of dermatophytes.
Achondroplasia natural history study (CLARITY): 60-year experience in orthopedic surgery from four skeletal dysplasia centers
Authors: Nahm Nickolas J. , Mackenzie W. G. Stuart , Mackenzie William G. , Gough Ethan , Hashmi S. Shahrukh , Hecht Jacqueline T. , Legare Janet M. , Little Mary Ellen , Modaff Peggy , Pauli Richard M. , Rodriguez-Buritica David F. , Serna Maria Elena , Smid Cory J. , Hoover-Fong Julie , Bober Michael B.
Published: June 2023

Background

The purpose of this study was to describe the frequency and risk factors for orthopedic surgery in patients with achondroplasia. CLARITY (The Achondroplasia Natural History Study) includes clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the United States from 1957 to 2018. Data were entered and stored in a Research Electronic Data Capture (REDCap) database.

Results

Information from one thousand three hundred and seventy-four patients with achondroplasia were included in this study. Four hundred and eight (29.7%) patients had at least one orthopedic surgery during their lifetime and 299 (21.8%) patients underwent multiple procedures. 12.7% (n = 175) of patients underwent spine surgery at a mean age at first surgery of 22.4 ± 15.3 years old. The median age was 16.7 years old (0.1–67.4). 21.2% (n = 291) of patients underwent lower extremity surgery at a mean age at first surgery of 9.9 ± 8.3 years old with a median age of 8.2 years (0.2–57.8). The most common spinal procedure was decompression (152 patients underwent 271 laminectomy procedures), while the most common lower extremity procedure was osteotomy (200 patients underwent 434 procedures). Fifty-eight (4.2%) patients had both a spine and lower extremity surgery. Specific risk factors increasing the likelihood of orthopedic surgery included: patients with hydrocephalus requiring shunt placement having higher odds of undergoing spine surgery (OR 1.97, 95% CI 1.14–3.26); patients having a cervicomedullary decompression also had higher odds of undergoing spine surgery (OR 1.85, 95% CI 1.30–2.63); and having lower extremity surgery increased the odds of spine surgery (OR 2.05, 95% CI 1.45–2.90).

Conclusions

Orthopedic surgery was a common occurrence in achondroplasia with 29.7% of patients undergoing at least one orthopedic procedure. Spine surgery (12.7%) was less common and occurred at a later age than lower extremity surgery (21.2%). Cervicomedullary decompression and hydrocephalus with shunt placement were associated with an increased risk for spine surgery. The results from CLARITY, the largest natural history study of achondroplasia, should aid clinicians in counseling patients and families about orthopedic surgery.
Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer’s Disease drug candidate
Authors: Nemergut Michal , Marques Sérgio M. , Uhrik Lukas , Vanova Tereza , Nezvedova Marketa , Gadara Darshak Chandulal , Jha Durga , Tulis Jan , Novakova Veronika , Planas-Iglesias Joan , Kunka Antonin , Legrand Anthony , Hribkova Hana , Pospisilova Veronika , Sedmik Jiri , Raska Jan , Prokop Zbynek , Damborsky Jiri , Bohaciakova Dasa , Spacil Zdenek , Hernychova Lenka , Bednar David , Marek Martin
Published: June 2023

Background

Apolipoprotein E (ApoE) ε4 genotype is the most prevalent risk factor for late-onset Alzheimer’s Disease (AD). Although ApoE4 differs from its non-pathological ApoE3 isoform only by the C112R mutation, the molecular mechanism of its proteinopathy is unknown.

Methods

Here, we reveal the molecular mechanism of ApoE4 aggregation using a combination of experimental and computational techniques, including X-ray crystallography, site-directed mutagenesis, hydrogen-deuterium mass spectrometry (HDX-MS), static light scattering and molecular dynamics simulations. Treatment of ApoE ε3/ε3 and ε4/ε4 cerebral organoids with tramiprosate was used to compare the effect of tramiprosate on ApoE4 aggregation at the cellular level.

Results

We found that C112R substitution in ApoE4 induces long-distance (> 15 Å) conformational changes leading to the formation of a V-shaped dimeric unit that is geometrically different and more aggregation-prone than the ApoE3 structure. AD drug candidate tramiprosate and its metabolite 3-sulfopropanoic acid induce ApoE3-like conformational behavior in ApoE4 and reduce its aggregation propensity. Analysis of ApoE ε4/ε4 cerebral organoids treated with tramiprosate revealed its effect on cholesteryl esters, the storage products of excess cholesterol.

Conclusions

Our results connect the ApoE4 structure with its aggregation propensity, providing a new druggable target for neurodegeneration and ageing.

Graphic Abstract
Targeting CXCR4 abrogates resistance to trastuzumab by blocking cell cycle progression and synergizes with docetaxel in breast cancer treatment
Authors: Liu Shuying , Xie Shelly M. , Liu Wenbin , Gagea Mihai , Hanker Ariella B. , Nguyen Nguyen , Singareeka Raghavendra Akshara , Yang-Kolodji Gloria , Chu Fuliang , Neelapu Sattva S. , Marchese Adriano , Hanash Samir , Zimmermann Johann , Arteaga Carlos L. , Tripathy Debasish
Published: June 2023

Background

Although trastuzumab and other HER2-targeted therapies have significantly improved survival in patients with HER2 overexpressed or amplified (HER2+) breast cancer, a significant proportion of patients do not respond or eventually develop clinical resistance. Strategies to reverse trastuzumab resistance remain a high clinical priority. We were the first to report the role of CXCR4 in trastuzumab resistance. The present study aims to explore the therapeutic potential of targeting CXCR4 and better understand the associated mechanisms.

Methods

Immunofluorescent staining, confocal microscopy analysis, and immunoblotting were used to analyze CXCR4 expression. BrdU incorporation assays and flow cytometry were used to analyze dynamic CXCR4 expression. Three-dimensional co-culture (tumor cells/breast cancer-associated fibroblasts/human peripheral blood mononuclear cells) or antibody-dependent cellular cytotoxicity assay was used to mimic human tumor microenvironment, which is necessary for testing therapeutic effects of CXCR4 inhibitor or trastuzumab. The FDA-approved CXCR4 antagonist AMD3100, trastuzumab, and docetaxel chemotherapy were used to evaluate therapeutic efficacy in vitro and in vivo. Reverse phase protein array and immunoblotting were used to discern the associated molecular mechanisms.

Results

Using a panel of cell lines and patient breast cancer samples, we confirmed CXCR4 drives trastuzumab resistance in HER2+ breast cancer and further demonstrated the increased CXCR4 expression in trastuzumab-resistant cells is associated with cell cycle progression with a peak in the G2/M phases. Blocking CXCR4 with AMD3100 inhibits cell proliferation by downregulating mediators of G2-M transition, leading to G2/M arrest and abnormal mitosis. Using a panel of trastuzumab-resistant cell lines and an in vivo established trastuzumab-resistant xenograft mouse model, we demonstrated that targeting CXCR4 with AMD3100 suppresses tumor growth in vitro and in vivo, and synergizes with docetaxel.

Conclusions

Our findings support CXCR4 as a novel therapeutic target and a predictive biomarker for trastuzumab resistance in HER2+ breast cancer.
Providing office workers with height-adjustable workstation to reduce and interrupt workplace sitting time: protocol for the Stand Up for Healthy Aging (SUFHA) cluster randomized controlled trial
Authors: Júdice Pedro B. , Silva Hélio , Teno Sabrina C. , Monteiro Patrícia , Silva Marlene N. , Carraça Eliana V. , Santos Inês , Pereira Sara , Luz Filipe , Viegas Patrícia C. , Oliveira Jorge , Santos Isabel F. , Palmeira António L.
Published: June 2023

Background

Sedentary behavior (SB) has been linked to several negative health outcomes. Therefore, reducing SB or breaking up prolonged periods of SB improves functional fitness, food consumption, job satisfaction, and productivity. Reducing SB can be achieved by introducing a health-enhancing contextual modification promoted by a sit-stand desk in the workplace. The primary goal will be to test the effectiveness of this intervention in reducing and breaking up SB, while improving health outcomes in office-based workers during a 6-month intervention.

Methods

A two-arm (1:1), superiority parallel-group cluster RCT will be conducted to evaluate the effectiveness of this intervention in a sample of office-based workers from a university in Portugal. The intervention will consist of a psychoeducation session, motivational prompts, and contextual modification promoted by a sit-stand desk in the workplace for 6 months. The control group will work as usual in their workplace, with no contextual change or prompts during the 6-month intervention. Three assessment points will be conducted in both groups, pre-intervention (baseline), post-intervention, and a 3-month follow-up. The primary outcomes include sedentary and physical activity-related variables, which will be objectively assessed with 24 h monitoring using the ActivPAL for 7 days. The secondary outcomes include (a) biometric indices as body composition, body mass index, waist circumference, and postural inequalities; and (b) psychosocial variables such as overall and work-related fatigue, overall discomfort, life/work satisfaction, quality of life, and eating behavior. Both the primary and secondary outcomes will be assessed at each assessment point.

Discussion

This study will lean on the use of a sit-stand workstation for 6 months, prompted by an initial psychoeducational session and ongoing motivational prompts. We will aim to contribute to this topic by providing robust data on alternating sitting and standing postures in the workplace.

Trial registration

The trial was prospectively registered, and the details are at: https://doi.org/10.17605/OSF.IO/JHGPW; Registered 15 November 2022. OSF Preregistration.
Fine-scale genomic tracking of Ross River virus using nanopore sequencing
Authors: de Vries Ellen M. , Cogan Noel O. I. , Gubala Aneta J. , Rodoni Brendan C. , Lynch Stacey E.
Published: June 2023

Background

Ross River virus (RRV) is Australia’s most common and widespread mosquito-transmitted arbovirus and is of significant public health concern. With increasing anthropogenic impacts on wildlife and mosquito populations, it is important that we understand how RRV circulates in its endemic hotspots to determine where public health efforts should be directed. Current surveillance methods are effective in locating the virus but do not provide data on the circulation of the virus and its strains within the environment. This study examined the ability to identify single nucleotide polymorphisms (SNPs) within the variable E2/E3 region by generating full-length haplotypes from a range of mosquito trap-derived samples.

Methods

A novel tiled primer amplification workflow for amplifying RRV was developed with analysis using Oxford Nanopore Technology’s MinION and a custom ARTIC/InterARTIC bioinformatic protocol. By creating a range of amplicons across the whole genome, fine-scale SNP analysis was enabled by specifically targeting the variable region that was amplified as a single fragment and established haplotypes that informed spatial-temporal variation of RRV in the study site in Victoria.

Results

A bioinformatic and laboratory pipeline was successfully designed and implemented on mosquito whole trap homogenates. Resulting data showed that genotyping could be conducted in real time and that whole trap consensus of the viruses (with major SNPs) could be determined in a timely manner. Minor variants were successfully detected from the variable E2/E3 region of RRV, which allowed haplotype determination within complex mosquito homogenate samples.

Conclusions

The novel bioinformatic and wet laboratory methods developed here will enable fast detection and characterisation of RRV isolates. The concepts presented in this body of work are transferable to other viruses that exist as quasispecies in samples. The ability to detect minor SNPs, and thus haplotype strains, is critically important for understanding the epidemiology of viruses their natural environment.

Graphical Abstract
Examining the influence of pain neuroscience education followed by a Pilates exercises program in individuals with knee osteoarthritis: a pilot randomized controlled trial
Authors: Rabiei Pouya , Sheikhi Bahram , Letafatkar Amir
Published: June 2023

Background

Knee osteoarthritis (OA) is a multifactorial form of rheumatic condition contributing to physical and psychological factors. Treatments have been provided solely and often compared with each other. An alternative view is that combined treatments addressing physical and psychological factors may result in more benefits. This study aimed to investigate the effect of pain neuroscience education (PNE) followed by Pilates exercises (PEs) in participants with knee OA, compared to PE alone.

Methods

In this two-arm assessor-blind pilot randomized controlled trial, fifty-four community-dwelling adults with knee OA were randomly assigned to the PNE followed by PEs and PEs groups (27 in each group). The study was conducted between early July 2021 and early March 2022 at the university’s health center. Primary outcomes were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscales of pain and physical limitation and secondary outcomes were Pain Catastrophizing Scale, Tampa Scale for Kinesiophobia, Pain Self-Efficacy Questionnaire, and Timed "Up & Go" test covering function. The primary and secondary outcomes were measured at baseline and eight weeks post-treatment. A general linear mixed model was used for between-group comparison with a statistical significance level of 0.05.

Results

Significant within-group differences were observed in all outcomes in both groups at post-treatment. There were no statistically between-group differences in pain (adjusted mean difference: -0.8; 95% CI -2.2 to 0.7; p = 0.288), physical limitation (adjusted mean difference: -0.4; 95% CI -4 to 3.1; p = 0.812) and function (adjusted mean difference: -0.8; 95% CI -1.8 to 0.1; p = 0.069) at eight weeks. For pain catastrophizing (adjusted mean difference: -3.9; 95% CI -7.2 to -0.6; p = 0.021), kinesiophobia (adjusted mean difference: -4.2; 95% CI -8.1 to -0.4; p = 0.032), and self-efficacy (adjusted mean difference: 6.1; 95% CI 0.7 to 11.5; p = 0.028) statistically between-group improvements were observed favoring PNE followed by PEs group after the treatment.

Conclusions

Combining PNE with PEs could have superior effects on psychological characteristics but not on pain, physical limitation, and function, compared to PEs alone. This pilot study emphasizes the need to investigate the combined effects of different interventions.

Trial registration

IRCT20210701051754N1.