bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact and outcomes of cancer-macrophage fusion
Authors: Li Mengtao , Basile John R. , Mallya Sanjay , Lin Yi-Ling
Published: June 2023

Background

Cancer’s hallmark feature is its ability to evolve, leading to metastasis and recurrence. Although genetic mutations and epigenetic changes have been implicated, they don’t fully explain the leukocytic traits that many cancers develop. Cell fusion between cancer and somatic cells, particularly macrophages, has been suggested as an alternative pathway for cancer cells to obtain new traits by acquiring exogenous genetic material.

Methods

This study aims to investigate the potential biological outcomes of tumor-myeloid cell fusion by generating tumor-macrophage hybrid cells. Two clones with markedly different tumorigenicity were selected, and RNA-seq was used to compare their RNA expressions with that of the control cells. Based on the results that the hybrid cells showed differential activation in several upstream regulator pathways that impact their biological behaviors, the hybrid cells’ abilities to recruit stromal cells and establish angiogenesis as well as their cell cycle distributions were investigated through in vitro and in vivo studies.

Results

Although both hybrid clones demonstrated p53 activation and reduced growth rates, they exhibited distinct cell cycle distributions and ability to grow in vivo. Notably, while one clone was highly tumorigenic, the other showed little tumorigenicity. Despite these differences, both hybrid clones were potent environmental modifiers, exhibiting significant abilities to recruit stromal and immune cells and establish angiogenesis.

Conclusions

The study revealed that tumor-somatic cell fusion is a potent environmental modifier that can modulate tumor survival and evolution, despite its relatively low occurrence. These findings suggest that tumor-somatic cell fusion could be a promising target for developing new cancer therapies. Furthermore, this study provides an experimental animal platform to investigate cancer-myeloid fusion and highlights the potential role of tumor-somatic cell fusion in modulating the tumor environment.
The potential of high-order features of routine blood test in predicting the prognosis of non-small cell lung cancer
Authors: Luo Liping , Tan Yubo , Zhao Shixuan , Yang Man , Che Yurou , Li Kezhen , Liu Jieke , Luo Huaichao , Jiang Wenjun , Li Yongjie , Wang Weidong
Published: June 2023

Background

Numerous studies have demonstrated that the high-order features (HOFs) of blood test data can be used to predict the prognosis of patients with different types of cancer. Although the majority of blood HOFs can be divided into inflammatory or nutritional markers, there are still numerous that have not been classified correctly, with the same feature being named differently. It is an urgent need to reclassify the blood HOFs and comprehensively assess their potential for cancer prognosis.

Methods

Initially, a review of existing literature was conducted to identify the high-order features (HOFs) and classify them based on their calculation method. Subsequently, a cohort of patients diagnosed with non-small cell lung cancer (NSCLC) was established, and their clinical information prior to treatment was collected, including low-order features (LOFs) obtained from routine blood tests. The HOFs were then computed and their associations with clinical features were examined. Using the LOF and HOF data sets, a deep learning algorithm called DeepSurv was utilized to predict the prognostic risk values. The effectiveness of each data set’s prediction was evaluated using the decision curve analysis (DCA). Finally, a prognostic model in the form of a nomogram was developed, and its accuracy was assessed using the calibration curve.

Results

From 1210 documents, over 160 blood HOFs were obtained, arranged into 110, and divided into three distinct categories: 76 proportional features, 6 composition features, and 28 scoring features. Correlation analysis did not reveal a strong association between blood features and clinical features; however, the risk value predicted by the DeepSurv LOF- and HOF-models is significantly linked to the stage. Results from DCA showed that the HOF model was superior to the LOF model in terms of prediction, and that the risk value predicted by the blood data model could be employed as a complementary factor to enhance the prognosis of patients. A nomograph was created with a C-index value of 0.74, which is capable of providing a reasonably accurate prediction of 1-year and 3-year overall survival for patients.

Conclusions

This research initially explored the categorization and nomenclature of blood HOF, and proved its potential in lung cancer prognosis.
Oral cancer screening knowledge and practices among dental professionals at the University of Toronto
Authors: Mavedatnia Dorsa , Cuddy Karl , Klieb Hagen , Blanas Nick , Goodman Jade , Gilbert Melanie , Eskander Antoine
Published: May 2023

Introduction

Opportunistic oral cancer screening during visits to the dentist is a non-invasive and accessible option for detection of pre-malignant lesions and early-stage malignancies. The objective of this study was to investigate the knowledge, practices, and attitudes towards oral cancer screening among dentists.

Methods

A 42-item survey was sent to 650 dental professionals affiliated with the University of Toronto. Data regarding training/practice characteristics, knowledge of oral cavity cancer, current screening practices, attitudes towards screening, and remuneration were collected.

Results

Ninety-one dentists responded. Most obtained their dental degree from Canada (71.4%) and were practicing in large urban centers (87.9%). Most dentists correctly identified the oral tongue (87.8%) and floor of mouth (80%) as the two of most common sites of oral cavity cancer but only 56% correctly identified the most common presentation. 91% performed intra/extra oral examinations at every patient visit. Only 9.9% of dentists discussed the risk factors of oral cancer and 33% were not familiar with resources for smoking cessation and alcohol abuse. International medical graduates were more likely to discuss risk factor management than Canadian medical graduates (p < 0.01). Over 80% of dentists referred to a specialist when a suspected lesion was found. The greatest barrier for oral cancer screening was lack of time. Almost all dentists (98.8%) reported that their screening practices do not differ depending on the patient’s insurance status and 63.8% reported compensation would not influence their decision to perform oral examinations.

Conclusion

Most dentists have a good knowledge of the presentation and risk factors associated with oral cavity cancer. Most dentists perform screening with every patient, with no influence from compensation and insurance status. Dentists are therefore an excellent first contact for oral cavity cancer screening for the general public and for high-risk populations.
The menstrual cycle regularity and skin: irregular menstrual cycle affects skin physiological properties and skin bacterial microbiome in urban Chinese women
Authors: Ma Laiji , Jiang Hong , Han Tingting , Shi Yanqin , Wang Man , Jiang Shanshan , Yang Suzhen , Yao Lingyun , Jia Qingwen , Shao Li
Published: May 2023

Background

The regularity of the menstrual cycle directly affects women’s health. Many studies have focused on menstrual health; however, menstrual cycle regularity-related variations in skin physiological characteristics and skin microbiota have been seldom investigated.

Methods

To investigate the menstrual cycle regularity-related variations in skin physiological characteristics and skin microbiota of 197 cases of Chinese women aged 18–35 years living in shanghai in 2021. Based on a self-evaluation questionnaire, the volunteers were divided into three groups C1 (those with a regular menstrual cycle), C2 (those with a less regular menstrual cycle) and C3 (those with an irregular menstrual cycle). The physiological parameters of facial skin were measured by non-invasive methods and the skin microbiome was analyzed by 16S rRNA high-throughput sequencing.

Results

In the C3 group, the hydration content was significantly decreased (p < 0.05), the TEWL was significantly increased (p < 0.05), and the sebum content was increased (p > 0.05), indicating that the skin barrier integrity weakened with increased menstrual cycle irregularity. Additionally, the melanin level, L value and b value were significantly decreased (p < 0.05) in the C3 group, but the a value was significantly increased (p < 0.001), which indicated that the skin color became darker. Furthermore, the skin microbiota diversity decreased with increasing cycle irregularity, but the differences were not significant. The skin microbiota composition showed that the proportion of Firmicutes, Acinetobacter, Staphylococcus and Cutibacterium were increased in those with an irregular menstrual cycle, indicating that alterations in the ratio of bacterial phyla and/or genera might disturb skin homeostasis. Spearman correlation analysis revealed strong correlations between the microbiota and skin physiological parameters. Based on the associations among hormones, skin physiological parameters and skin microbiota, it is possible that the skin physiological parameters, as well as the skin microbial diversity and composition, change with hormonal fluctuations during the menstrual cycle.

Conclusions

An irregular menstrual cycle can affect skin physiological characteristics and the skin microbiota. Female with an irregular menstrual cycle should strengthen skin care practices and use skin care products with moisturising and soothing effects to protect their skin.
Screening of key functional components of Taohong Siwu Decoction on ischemic stroke treatment based on multiobjective optimization approach and experimental validation
Authors: Xu Anqi , Li Wenxing , Cai Jieqi , Wen Zhuohua , Wang Kexin , Chen Yupeng , Li Xifeng , Guan Daogang , Duan Chuanzhi
Published: June 2023

Background

Taohong Siwu Decoction (THSWD) is a widely used traditional Chinese medicine (TCM) prescription in the treatment of ischemic stroke. There are thousands of chemical components in THSWD. However, the key functional components are still poorly understood. This study aimed to construct a mathematical model for screening of active ingredients in TCM prescriptions and apply it to THSWD on ischemic stroke.

Methods

Botanical drugs and compounds in THSWD were acquired from multiple public TCM databases. All compounds were initially screened by ADMET properties. SEA, HitPick, and Swiss Target Prediction were used for target prediction of the filtered compounds. Ischemic stroke pathological genes were acquired from the DisGeNet database. The compound–target–pathogenic gene (C-T-P) network of THSWD was constructed and then optimized using the multiobjective optimization (MOO) algorithm. We calculated the cumulative target coverage score of each compound and screened the top compounds with 90% coverage. Finally, verification of the neuroprotective effect of these compounds was performed with the oxygen-glucose deprivation and reoxygenation (OGD/R) model.

Results

The optimized C-T-P network contains 167 compounds, 1,467 predicted targets, and 1,758 stroke pathological genes. And the MOO model showed better optimization performance than the degree model, closeness model, and betweenness model. Then, we calculated the cumulative target coverage score of the above compounds, and the cumulative effect of 39 compounds on pathogenic genes reached 90% of all compounds. Furthermore, the experimental results showed that decanoic acid, butylphthalide, chrysophanol, and sinapic acid significantly increased cell viability. Finally, the docking results showed the binding modes of these four compounds and their target proteins.

Conclusion

This study provides a methodological reference for the screening of potential therapeutic compounds of TCM. In addition, decanoic acid and sinapic acid screened from THSWD were found having potential neuroprotective effects first and verified with cell experiments, however, further in vitro and in vivo studies are needed to explore the precise mechanisms involved.
Development and validation of an instrument to measure the Micro-Learning Environment of Students (MLEM)
Authors: Akbar Zainab , Khan Rehan Ahmed , Khan Humaira Fayyaz , Yasmeen Rahila
Published: May 2023

Background

There are multiple instruments to measure different learning environments but no valid and reliable instrument is present for measuring the micro-learning environment. This study aimed to develop and validate an instrument to measure the micro-learning environment of students. Measuring the micro-learning environment can give insight into the real-life experiences of students and enlighten us about the disparity between taught, delivered, and learned curricula.

Methods

Multi-institutional Mixed methods study design with consecutive qualitative and, quantitative components was used based on information processing theory. Literature review, results of semi-structured interviews, and focus group discussion were combined to develop a questionnaire. Content and response process validity were established followed by pilot testing, reliability calculation, and exploratory and confirmatory factor analysis.

Results

A forty-nine-item preliminary draft instrument was reduced to a total of twenty-four items final instrument having five themes regarding teaching practices, learners support, competence in teaching, progressive faculty, and teaching environment. The values of SCVI/Ave and S-CVI/UA were calculated to be 0.92 and 0.62 respectively. Reliability was calculated to be 0.94. Fit indices values were within the normal range.

Conclusion

The instrument for measuring the micro-learning environment has excellent content, construct, response process validity, and reliability.
Cost-utility analysis of biologic disease-modifying antirheumatic drugs (bDMARDs), targeted synthetic DMARDs (tsDMARDs) and biosimilar DMARDs (bsDMARDs) combined with methotrexate for Thai rheumatoid arthritis patients with high disease activity
Authors: Prawjaeng Juthamas , Leelahavarong Pattara , Budtarad Nuttakarn , Pilasant Songyot , Chanjam Chonticha , Katchamart Wanruchada , Narongroeknawin Pongthorn , Kitumnuaypong Tasanee
Published: May 2023

Background

New biologic disease-modifying antirheumatic drugs (bDMARDs), targeted synthetic DMARDs (tsDMARDs) and biosimilar DMARDs (bsDMARDs) all showed greater clinical benefits in the treatment of patients with rheumatoid arthritis (RA) with high disease activity, but imposed higher costs than standard treatment. This study evaluated the cost-effectiveness of 11 alternative treatment strategies for RA patients with high disease activity whose treatment with three conventional synthetic DMARDs (csDMARDs) failed.

Methods

A Markov model was constructed using a societal perspective to estimate relevant costs and health outcomes in terms of quality-adjusted life years (QALYs) for a lifetime horizon (100 years), given a 3% annual discount. Alternative treatment strategies including five bDMARDs, two tsDMARDs, and four bsDMARDs in combination with methotrexate (MTX) were compared with the standard of care (SoC), i.e., cyclosporine and azathioprine. Direct and non-medical care costs were estimated by identifying the resources used, then multiplied by the standard costing menu in the year 2022. Utility and transitional probabilities were collected in three advanced tertiary hospitals. A network meta-analysis was used to estimate the efficacy of each treatment. Lifetime cost, QALYs and an incremental cost-effectiveness ratio were calculated and compared to the cost-effectiveness threshold of 160,000 THB per QALY gained (US $4,634, where 1 USD = 34.53 THB in 2022). Probabilistic and one-way sensitivity analyses were performed to estimate parameter uncertainties.

Results

The bDMARDs, tsDMARDs or bsDMARDs combined with MTX provided 0.09 to 0.33 QALYs gained with additional costs of 550,986 to 2,096,744 THB (US $15,957 to $60,722) compared to the SoC. The ICER ranged from 2.3 to 8.1 million THB per QALY (US $65,935 to $234,996) compared to the SoC. None of these combinations was cost-effective in the Thai context. The results were sensitive to the mortality hazard ratio of patients with high disease activity.

Conclusions

Combinations of MTX with either bDMARDs, tsDMARDs or bsDMARDs were not economically attractive compared to the standard practice. However, they reduced disease activity and improved patient quality of life. The price negotiation process for these treatments must be conducted to ensure their financial value and affordability before they are included in the pharmaceutical reimbursement list.
A serological survey of pathogens associated with the respiratory and digestive system in the Polish European bison (Bison bonasus) population in 2017–2022
Authors: Didkowska Anna , Klich Daniel , Nowak Magdalena , Wojciechowska Marlena , Prolejko Kinga , Kwiecień Ewelina , Rzewuska Magdalena , Olech Wanda , Anusz Krzysztof
Published: June 2023

Background

The European bison (Bison bonasus) is a near threatened species and requires health monitoring. The aim of the present study was to determine the prevalence of antibodies to pathogens known to cause respiratory and digestive illness in ruminants.

Results

In the studied 328 European bison, the highest seroprevalence was observed for Bovine herpesvirus-1 (BoHV-1) (50.27%), Bovine Coronavirus (BCoV) (26.36%), and Bluetongue Virus (BTV) (12.83%). For Mycoplasma bovis strains and Bovine Viral Diarrhea Virus (BVDV), positive results were rare. Interestingly, a higher prevalence of BTV antibodies was noted in the northeastern populations and older animals.

Conclusions

Our findings indicate that the Polish European bison population appears to have considerable contact with BoHV-1; however, this does not appear to be of great significance, as clinical symptoms and post-mortem lesions are rarely noted in Polish European bison population. The high seroprevalence of BTV in the north-east of Poland is an ongoing trend, also noted in previous studies. It is possible that European bison may perpetuate the virus in this region. This is the first report of antibodies for BCoV in European bison.
Unusual clinical spectra of childhood severe malaria during malaria epidemic in eastern Uganda: a prospective study
Authors: Namayanja Cate , Eregu Egiru Emma Isaiah , Ongodia Paul , Okalebo Charles Benard , Okiror William , Okello Francis , Okibure Ambrose , Paasi George , Kakungulu Hellen , Grace Abongo , Muhindo Rita , Banks Duncan , Martin Chebet , Taylor-Robinson Simon , Olupot-Olupot Peter
Published: June 2023

Background

In sub-Saharan Africa (SSA), malaria remains a public health problem despite recent reports of declining incidence. Severe malaria is a multiorgan disease with wide-ranging clinical spectra and outcomes that have been reported to vary by age, geographical location, transmission intensity over time. There are reports of recent malaria epidemics or resurgences, but few data, if any, focus on the clinical spectrum of severe malaria during epidemics. This describes the clinical spectrum and outcomes of childhood severe malaria during the disease epidemic in Eastern Uganda.

Methods

This prospective cohort study from October 1, 2021, to September 7, 2022, was nested within the ‘Malaria Epidemiological, Pathophysiological and Intervention studies in Highly Endemic Eastern Uganda’ (TMA2016SF-1514-MEPIE Study) at Mbale Regional Referral Hospital, Uganda. Children aged 60 days to 12 years who at admission tested positive for malaria and fulfilled the clinical WHO criteria for surveillance of severe malaria were enrolled on the study. Follow-up was performed until day 28. Data were collected using a customized proforma on social demographic characteristics, clinical presentation, treatment, and outcomes. Laboratory analyses included complete blood counts, malaria RDT (SD BIOLINE Malaria Ag P.f/Pan, Ref. 05FK60-40-1) and blood slide, lactate, glucose, blood gases and electrolytes. In addition, urinalysis using dipsticks (Multistix® 10 SG, SIEMENS, Ref.2300) at the bedside was done. Data were analysed using STATA V15.0. The study had prior ethical approval.

Results

A total of 300 participants were recruited. The median age was 4.6 years, mean of 57.2 months and IQR of 44.5 months. Many children, 164/300 (54.7%) were under 5 years, and 171/300 (57.0%) were males. The common clinical features were prostration 236/300 (78.7%), jaundice in 205/300 (68.3%), severe malarial anaemia in 158/300 (52.7%), black water fever 158/300 (52.7%) and multiple convulsions 51/300 (17.0%), impaired consciousness 50/300(16.0%), acidosis 41/300(13.7%), respiratory distress 26/300(6.7%) and coma in 18/300(6.0%). Prolonged hospitalization was found in 56/251 (22.3%) and was associated with acidosis, P = 0.041. The overall mortality was 19/300 (6.3%). Day 28 follow-up was achieved in 247/300 (82.3%).

Conclusion

During the malaria epidemic in Eastern Uganda, severe malaria affected much older children and the spectrum had more of prostration, jaundice severe malarial anaemia, black water fever and multiple convulsions with less of earlier reported respiratory distress and cerebral malaria.
Non-disclosure of developmental neurotoxicity studies obstructs the safety assessment of pesticides in the European Union
Authors: Mie Axel , Rudén Christina
Published: June 2023

Background

In the European Union (EU), the safety assessment of plant protection products relies to a large extent on toxicity studies commissioned by the companies producing them. By law, all performed studies must be included in the dossier submitted to authorities when applying for approval or renewal of the active substance.

Methods

For one type of toxicity, i.e. developmental neurotoxicity (DNT), we evaluated if studies submitted to the U.S. Environmental Protection Agency (EPA) had also been disclosed to EU authorities.

Results

We identified 35 DNT studies submitted to the U.S. EPA and with the corresponding EU dossiers available. Of these, 9 DNT studies (26%) were not disclosed by the pesticide company to EU authorities. For 7 of these studies, we have identified an actual or potential regulatory impact.

Conclusions

We conclude that (1) non-disclosure of DNT studies to EU authorities, in spite of clear legal requirements, seems to be a recurring phenomenon, (2) the non-disclosure may introduce a bias in the regulatory risk assessment, and (3) without full access to all performed toxicity studies, there can be no reliable safety evaluation of pesticides by EU authorities. We suggest that EU authorities should cross-check their data sets with their counterparts in other jurisdictions. In addition, applications for pesticide approval should be cross-checked against lists of studies performed at test facilities operating under Good Laboratory Practice (GLP), to ensure that all studies have been submitted to authorities. Furthermore, rules should be amended so that future studies should be commissioned by authorities rather than companies. This ensures the authorities’ knowledge of existing studies and prevents the economic interest of the company from influencing the design, performance, reporting and dissemination of studies. The rules or practices should also be revised to ensure that non-disclosure of toxicity studies carries a significant legal risk for pesticide companies.
Immunotherapy with Pru p 3 for food allergy to peach and non-specific lipid transfer protein: a systematic review
Authors: Rossi Carlo Maria , Lenti Marco Vincenzo , Merli Stefania , Licari Amelia , Marseglia Gian Luigi , Di Sabatino Antonio
Published: May 2023

Background

Non-specific lipid-transfer protein (nsLTP) is a pan-allergen in the plant world, and a cause of significant concern as food allergen in the Mediterranean area, due to its general heat- and acid-resistance and hence the risk of severe allergic reactions.Pru p 3, the peach nsLTP, is considered the primary sensitizer to this allergen family and this allergy is usually persistent. Allergen-free diet and acute treatment of manifestations are the main recognized management goals in food allergy.

Main text

The role of immunotherapy for treating food allergy in adult patients is controversial, but immunotherapy forPru p 3could potentially represent a relevant therapeutic strategy. We systematically searched databases for studies assessing the role of immunotherapyPru p 3in food allergy. Overall, nine studies were included. Immunotherapy withPru p 3appears to be effective and with a good safety profile in both peach and LTP allergy for some foods, such as peanut, in both RCT and real-life studies.

Conclusions

Immunotherapy withPru p 3is a possible treatment option for food allergy to the peach LTP in the Mediterranean area, although at present have not reached routinary clinical practice. Larger studies are needed to confirm these findings and identify predictive biomarkers.
A bifunctional bortezomib-loaded porous nano-hydroxyapatite/alginate scaffold for simultaneous tumor inhibition and bone regeneration
Authors: Chen Jiafei , Wen Junru , Fu Yike , Li Xiang , Huang Jie , Guan Xiaoxu , Zhou Yi
Published: June 2023

Treatments of osteolytic lesions due to malignant metastasis remain one of the major clinical challenges. The residual tumor cells after surgical resections and an acidic tumor microenvironment are unfavorable for osteogenic induction. Bortezomib (BTZ), a proteasome inhibitor used in chemotherapy, also has an osteogenic potential in concentration- and Ca2+-dependent manners. In this study, controlled delivery of BTZ in a novel bifunctional scaffold based on nano-hydroxyapatite (nHA) and sodium alginate (SA) nanocomposite, namely BTZ/nHA@SA, has been explored. By smartly adjusting microenvironments, a sustainable release of Ca2+ from nHA could be achieved, which was not only able to cross-link SA but also to regulate the switch between the dual functions of tumor inhibition and bone regeneration of BTZ to promote the osteogenic pathway. The freeze-dried BTZ/nHA@SA scaffold has excellent interconnectivity, is capable to promote the attachment and proliferation of mouse embryonic osteoblast precursor cells, as well as effectively induces breast cancer cell death in vitro. Furthermore, in vivo, studies using a mouse tumor model and a rabbit femoral defect model showed that the BTZ/nHA@SA scaffold could promote tumor ablation, and also enhance bone repair. Therefore, the BTZ/nHA@SA scaffold has unique dual functions of inhibiting tumor recurrence and promoting bone tissue regeneration simultaneously. This smart bi-functional scaffold offers a promising novel approach for oncological treatments by synchronously orchestrating tumor inhibition and tissue regeneration for the repair of neoplastic bone defects.
A qualitative exploration of barriers and facilitators to drug treatment services among people who inject drugs in West Virginia
Authors: Winiker Abigail K. , Schneider Kristin E. , Hamilton White Rebecca , O’Rourke Allison , Grieb Suzanne M. , Allen Sean T.
Published: June 2023

Background

The opioid overdose crisis in the USA has called for expanding access to evidence-based substance use treatment programs, yet many barriers limit the ability of people who inject drugs (PWID) to engage in these programs. Predominantly rural states have been disproportionately affected by the opioid overdose crisis while simultaneously facing diminished access to drug treatment services. The purpose of this study is to explore barriers and facilitators to engagement in drug treatment among PWID residing in a rural county in West Virginia.

Methods

From June to July 2018, in-depth interviews (n = 21) that explored drug treatment experiences among PWID were conducted in Cabell County, West Virginia. Participants were recruited from locations frequented by PWID such as local service providers and public parks. An iterative, modified constant comparison approach was used to code and synthesize interview data.

Results

Participants reported experiencing a variety of barriers to engaging in drug treatment, including low thresholds for dismissal, a lack of comprehensive support services, financial barriers, and inadequate management of withdrawal symptoms. However, participants also described several facilitators of treatment engagement and sustained recovery. These included the use of medications for opioid use disorder and supportive health care workers/program staff.

Conclusions

Our findings suggest that a range of barriers exist that may limit the abilities of rural PWID to successfully access and remain engaged in drug treatment in West Virginia. Improving the public health of rural PWID populations will require expanding access to evidence-based drug treatment programs that are tailored to participants’ individual needs.
A multi-phase approach for developing a conceptual model for human resources for health observatory (HRHO) toward integrating data and evidence: a case study of Iran
Authors: Najafpour Zhila , Arab Mohammad , Shayanfard Kamran
Published: June 2023

Background

Evidence-informed policymaking on human resources for health (HRH) has been directly linked with health system productivity, accessibility, equity, quality, and efficiency. The lack of reliable HRH data has made the task of planning the HRH more difficult in all settings.

Aim

This study aimed to develop a conceptual model to integrate HRH data and evidence.

Methods

The current study is a mixed-method study conducted in three phases: a rapid literature review, a qualitative phase, and an expert panel. Firstly, the electronic databases were searched up to 2018. Then, in the qualitative phase, semi-structured interviews with 50 experts were conducted. Data analysis was performed using the content analysis approach. After several expert panels, the draft of the model was validated with 15 key informants via two Delphi rounds.

Results

Our proposed model embraces all dominant elements on the demand and supply side of the HRH in Iran. The conceptual model consists of several components, including input (regulatory system, structure, functions), educational system (pre-service and in-service education), health labor market structure, process (technical infrastructure), and output (productions, policymaking process). We considered networking toward sustainable interaction among stakeholders, and also the existence of capacity to integrate HRH information and produce evidence for actions.

Conclusion

The proposed model can be considered a platform for developing a harmonized system based on the HRH data flow to evidence-informed decision-making via networking. We proposed a step-by-step approach for the sustainability of establishing a national human resources for health observatory (HRHO). The proposed HRHO model can be replicable and flexible enough to be used in different context domains.
Analysis of clinical features, genomic landscapes and survival outcomes in HER2-low breast cancer
Authors: Jin Juan , Li Bin , Cao Jianing , Li Ting , Zhang Jian , Cao Jun , Zhao Mingchuan , Wang Leiping , Wang Biyun , Tao Zhonghua , Hu Xichun
Published: June 2023

Background

Novel human epidermal growth factor receptor 2 (HER2)-directed antibody–drug conjugates prompt the identification of the HER2-low subtype. However, the biological significance of HER2-low expression in breast cancer is unclear.

Methods

Clinical and genomic data of 579 metastatic breast cancer patients were reviewed from our next-generation sequencing (NGS) database and genomic analysis of early breast cancer patients from TCGA was also analyzed.

Findings

First, the clinicopathological characteristics of HER2-low patients were profoundly influenced by HR status and no difference of prognosis was observed between HER2-low and HER2-zero patients when paired by HR status, but notably HER2-low patients showed similar metastatic patterns to HER2-positive patients in the HR-positive (HR+ ) subgroup, with more brain and initial lung metastases and more cases of de novo stage IV breast cancer than HER2-zero patients. Second, among patients with primary HER2-low or HER2-zero tumors, the discordance of HER2 status between primary and metastatic tumors was significant, with 48.4% of patients with HER2-zero primary tumors exhibiting HER2-low phenotype in metastatic tumors in the HR+ subgroup. Third, within HR+ and HR-negative subtypes, HER2-low and HER2-zero tumors showed no substantial differences in mutation alterations and copy number variations. Forth, germline BRCA2 mutations were observed only in HER2-low patients in our NGS database, especially in HR+ HER2-low tumors. Finally, three molecular subtypes based on genomic alterations in HER2-low breast cancer were identified, which provided novel insights into heterogeneity in HER2-low breast cancer.

Conclusions

After correcting for HR expression, only marginal differences in clinical and molecular phenotypes were determined between HER2-low and HER2-zero breast cancer. Therefore, HER2-low breast cancer is insufficient to be defined as a distinct molecular entity, but rather a heterogenous disease.
Microglia-derived TNF-α contributes to RVLM neuronal mitochondrial dysfunction via blocking the AMPK–Sirt3 pathway in stress-induced hypertension
Authors: Wang Linping , Liu Tianfeng , Wang Xueping , Tong Lei , Chen Gaojun , Zhou Shumin , Zhang Haili , Liu Haisheng , Lu Wen , Wang Guohua , Zhang Shuai , Du Dongshu
Published: June 2023

Background

Neuroinflammation in the rostral ventrolateral medulla (RVLM) has been associated with the pathogenesis of stress-induced hypertension (SIH). Neuronal mitochondrial dysfunction is involved in many pathological and physiological processes. However, the impact of neuroinflammation on neuronal mitochondrial homeostasis and the involved signaling pathway in the RVLM during SIH are largely unknown.

Methods

The morphology and phenotype of microglia and the neuronal mitochondrial injury in vivo were analyzed by immunofluorescence, Western blot, RT-qPCR, transmission electron microscopy, and kit detection. The underlying mechanisms of microglia-derived tumor necrosis factor‐α (TNF-α) on neuronal mitochondrial function were investigated through in vitro and in vivo experiments such as immunofluorescence and Western blot. The effect of TNF-α on blood pressure (BP) regulation was determined in vivo via intra-RVLM microinjection of TNF-α receptor antagonist R7050.

Results

The results demonstrated that BP, heart rate (HR), renal sympathetic nerve activity (RSNA), plasma norepinephrine (NE), and electroencephalogram (EEG) power increased in SIH rats. Furthermore, the branching complexity of microglia in the RVLM of SIH rats decreased and polarized into M1 phenotype, accompanied by upregulation of TNF‐α. Increased neuronal mitochondria injury was observed in the RVLM of SIH rats. Mechanistically, Sirtuin 3 (Sirt3) and p-AMPK expression were markedly downregulated in both SIH rats and TNF-α–treated N2a cells. AMPK activator A769662 upregulated AMPK–Sirt3 signaling pathway and consequently reversed TNF-α–induced mitochondrial dysfunction. Microinjection of TNF-α receptor antagonist R7050 into the RVLM of SIH rats significantly inhibited the biological activities of TNF-α, increased p‐AMPK and Sirt3 levels, and alleviated neuronal mitochondrial injury, thereby reducing c-FOS expression, RSNA, plasma NE, and BP.

Conclusions

This study revealed that microglia-derived TNF-α in the RVLM impairs neuronal mitochondrial function in SIH possibly through inhibiting the AMPK–Sirt3 pathway. Therefore, microglia-derived TNF-α in the RVLM may be a possible therapeutic target for the intervention of SIH.
Relevance of hazards in exoskeleton applications: a survey-based enquiry
Authors: Massardi Stefano , Pinto-Fernandez David , Babič Jan , Dežman Miha , Trošt Andrej , Grosu Victor , Lefeber Dirk , Rodriguez Carlos , Bessler Jule , Schaake Leendert , Prange-Lasonder Gerdienke , Veneman Jan F. , Torricelli Diego
Published: May 2023

Exoskeletons are becoming the reference technology for assistance and augmentation of human motor functions in a wide range of application domains. Unfortunately, the exponential growth of this sector has not been accompanied by a rigorous risk assessment (RA) process, which is necessary to identify the major aspects concerning the safety and impact of this new technology on humans. This situation may seriously hamper the market uptake of new products. This paper presents the results of a survey that was circulated to understand how hazards are considered by exoskeleton users, from research and industry perspectives. Our analysis aimed to identify the perceived occurrence and the impact of a sample of generic hazards, as well as to collect suggestions and general opinions from the respondents that can serve as a reference for more targeted RA. Our results identified a list of relevant hazards for exoskeletons. Among them, misalignments and unintended device motion were perceived as key aspects for exoskeletons’ safety. This survey aims to represent a first attempt in recording overall feedback from the community and contribute to future RAs and the identification of better mitigation strategies in the field.
Prevalence of udder pathogens in milk samples from Norwegian dairy cows recorded in a national database in 2019 and 2020
Authors: Smistad Marit , Bakka Haakon Christopher , Sølverød Liv , Jørgensen Hannah Joan , Wolff Cecilia
Published: June 2023

Background

Identification of aetiological agents of mastitis in dairy cattle is important for herd management of udder health. In Norway, results from mastitis diagnostics are systematically recorded in a central database, so that the dairy industry can follow trends in the recorded frequency of udder pathogens and antimicrobial resistance patterns at national level. However, bacteriological testing of milk samples is based on voluntary sampling, and data are therefore subject to some bias. The aim of this study was to examine the prevalence of udder pathogens in Norwegian dairy cows by analysing data from the national routine mastitis diagnostics and to explore how routines for sampling and diagnostic interpretations may affect the apparent prevalence of different bacterial pathogens. We also assessed associations between udder pathogen findings and the barn- and milking systems of the herds.

Results

The most frequently detected major udder pathogens among all milk samples submitted for bacterial culture (n = 36,431) were Staphylococcus aureus (24.5%), Streptococcus dysgalactiae (13.3%) and Streptococcus uberis (9.0%). In the subset of samples from clinical mastitis (n = 7598); Escherichia coli (14.5%) was the second most frequently detected pathogen following S. aureus (27.1%). Staphylococcus epidermidis (10.0%), Corynebacterium bovis (9.4%), and Staphylococcus chromogenes (6.0%) dominated among the minor udder pathogens. Non-aureus staphylococci as a group, identified in 39% of the sampling events, was the most frequently identified udder pathogen in Norway. By using different definitions of cow-level bacterial diagnoses, the distribution of minor udder pathogens changed.

Several udder pathogens were associated with the barn- and milking system but the associations were reduced in strength when data were analysed from farms with a comparable herd size. S. aureus was associated with tiestall housing, E. coli and S. dysgalactiae were associated with freestall housing, and S. epidermidis was associated with automatic milking systems.

Only 2.5% of the 10,675 tested S. aureus isolates were resistant to benzylpenicillin. Among the 2153 tested non-aureus staphylococci, altogether 34% were resistant to benzylpenicillin.

Conclusions

This study presents the recorded prevalence of udder pathogens in Norway over a two-year period and assesses the possible impact of the sampling strategies, diagnostic methods and diagnostic criteria utilized in Norway, as well as associations with different housing and milking systems. The national database with records of results from routine mastitis diagnostics in Norway provides valuable information about the aetiology of bovine mastitis at population level and can reveal shifts in the distribution and occurrence of udder pathogens.
Culture of vibrating microtome tissue slices as a 3D model in biomedical research
Authors: Siwczak Fatina , Hiller Charlotte , Pfannkuche Helga , Schneider Marlon R.
Published: June 2023

The basic idea behind the use of 3-dimensional (3D) tools in biomedical research is the assumption that the structures under study will perform at the best in vitro if cultivated in an environment that is as similar as possible to their natural in vivo embedding. Tissue slicing fulfills this premise optimally: it is an accessible, unexpensive, imaging-friendly, and technically rather simple procedure which largely preserves the extracellular matrix and includes all or at least most supportive cell types in the correct tissue architecture with little cellular damage. Vibrating microtomes (vibratomes) can further improve the quality of the generated slices because of the lateral, saw-like movement of the blade, which significantly reduces tissue pulling or tearing compared to a straight cut. In spite of its obvious advantages, vibrating microtome slices are rather underrepresented in the current discussion on 3D tools, which is dominated by methods as organoids, organ-on-chip and bioprinting. Here, we review the development of vibrating microtome tissue slices, the major technical features underlying its application, as well as its current use and potential advances, such as a combination with novel microfluidic culture chambers. Once fully integrated into the 3D toolbox, tissue slices may significantly contribute to decrease the use of laboratory animals and is likely to have a strong impact on basic and translational research as well as drug screening.
Pattern and repeatability of ascarid-specific antigen excretion through chicken faeces, and the diagnostic accuracy of coproantigen measurements as compared with McMaster egg counts and plasma and egg yolk antibody measurements in laying hens
Authors: Oladosu Oyekunle John , Hennies Mark , Stehr Manuel , Metges Cornelia C. , Gauly Matthias , Daş Gürbüz
Published: June 2023

Background

A coproantigen enzyme-linked immunosorbent assay (ELISA) has recently been proposed for detecting ascarid infections in chickens. The excretion pattern of ascarid antigens through chicken faeces and the consistency of measurements over the course of infections are currently unknown. This study evaluates the pattern and repeatability of worm antigen per gram of faeces (APG) and compares the diagnostic performance of the coproantigen ELISA with a plasma and egg yolk antibody ELISA and McMaster faecal egg counts (M-FEC) at different weeks post-infection (wpi).

Methods

Faecal, blood and egg yolk samples were collected from laying hens that were orally infected with a mix of Ascaridia galli and Heterakis gallinarum eggs (N = 108) or kept as uninfected controls (N = 71). Measurements including (a) APG using a coproantigen ELISA, (b) eggs per gram of faeces (EPG) using the McMaster technique and (c) ascarid-specific IgY in plasma and in egg yolks using an ascarid-specific antibody ELISA) were performed between wpi 2 and 18.

Results

Time-dependent significant differences in APG between infected and non-infected laying hens were quantified. At wpi 2 (t(164) = 0.66, P = 1.00) and 4 (t(164) = −3.09, P = 0.094) no significant differences were observed between the groups, whereas infected hens had significantly higher levels of APG than controls by wpi 6 (t(164) =  −6.74, P < 0.001). As indicated by a high overall repeatability estimate of 0.91 (CI = 0.89–0.93), APG could be measured consistently from the same individual. Compared to McMaster and antibody ELISA, coproantigen ELISA showed the highest overall diagnostic performance (area under curve, AUC = 0.93), although the differences were time-dependent. From wpi 6 to 18 coproantigen ELISA had an AUC > 0.95, while plasma IgY ELISA showed the highest diagnostic performance in wpi 2 (AUC = 0.95). M-FEC had the highest correlation with total worm burden, while APG had highest correlations with weights and lengths of A. galli.

Conclusion

Ascarid antigen excretion through chicken faeces can be measured with high accuracy and repeatability using a coproantigen ELISA. The antigen excretion increases over time, and is associated with worm maturation, particularly with the size of A. galli. Our results suggest the necessity of complementary use of different diagnostic tools for a more accurate diagnosis of infections.

Graphical Abstract
Identification of the immune-related biomarkers in Behcet’s disease by plasma proteomic analysis
Authors: Liu Huan , Zhang Panpan , Li Fuzhen , Xiao Xiao , Zhang Yinan , Li Na , Du Liping , Yang Peizeng
Published: June 2023

Background

This study aimed to investigate the expression profile of immune response-related proteins of Behcet’s disease (BD) patients and identify potential biomarkers for this disease.

Methods

Plasma was collected from BD patients and healthy controls (HC). Immune response-related proteins were measured using the Olink Immune Response Panel. Differentially expressed proteins (DEPs) were used to construct prediction models via five machine learning algorithms: naive Bayes, support vector machine, extreme gradient boosting, random forest, and neural network. The prediction performance of the five models was assessed using the area under the curve (AUC) value, recall (sensitivity), specificity, precision, accuracy, F1 score, and residual distribution. Subtype analysis of BD was performed using the consensus clustering method.

Results

Proteomics results showed 43 DEPs between BD patients and HC (P < 0.05). These DEPs were mainly involved in the Toll-like receptor 9 and NF-κB signaling pathways. Five models were constructed using DEPs [interleukin 10 (IL10), Fc receptor like 3 (FCRL3), Mannan-binding lectin serine peptidase 1 (MASP1), NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor (NF2), FAM3 metabolism regulating signaling molecule B (FAM3B), and O-6-methylguanine-DNA methyltransferase (MGMT)]. Among these models, the neural network model showed the best performance (AUC = 0.856, recall: 0.692, specificity: 0.857, precision: 0.900, accuracy: 0.750, F1 score: 0.783). BD patients were divided into two subtypes according to the consensus clustering method: one with high disease activity in association with higher expression of tripartite motif-containing 5 (TRIM5), SH2 domain-containing 1A (SH2D1A), phosphoinositide-3-kinase adaptor protein 1 (PIK3AP1), hematopoietic cell-specific Lyn substrate 1 (HCLS1), and DNA fragmentation factor subunit alpha (DFFA) and the other with low disease activity in association with higher expression of C–C motif chemokine ligand 11 (CCL11).

Conclusions

Our study not only revealed a distinctive immune response-related protein profile for BD but also showed that IL10, FCRL3, MASP1, NF2, FAM3B, and MGMT could serve as potential immune biomarkers for this disease. Additionally, a novel molecular disease classification model was constructed to identify subsets of BD.