bluuebunny/crossref_metadata_2025_split huggingface dataset:
Co-expression network analysis identifies potential candidate hub genes in severe influenza patients needing invasive mechanical ventilation
Authors: Chen Liang , Hua Jie , He Xiaopu 
Published: October 2022

Abstract
Background
Influenza is a contagious disease that affects people of all ages and is linked to considerable mortality during epidemics and occasional outbreaks. Moreover, effective immunological biomarkers are needed for elucidating aetiology and preventing and treating severe influenza. Herein, we aimed to evaluate the key genes linked with the disease severity in influenza patients needing invasive mechanical ventilation (IMV). Three gene microarray data sets (GSE101702, GSE21802, and GSE111368) from blood samples of influenza patients were made available by the Gene Expression Omnibus (GEO) database. The GSE101702 and GSE21802 data sets were combined to create the training set. Hub indicators for IMV patients with severe influenza were determined using differential expression analysis and Weighted correlation network analysis (WGCNA) from the training set. The receiver operating characteristic curve (ROC) was also used to evaluate the hub genes from the test set's diagnostic accuracy. Different immune cells' infiltration levels in the expression profile and their correlation with hub gene markers were examined using single-sample gene set enrichment analysis (ssGSEA).

Results
In the present study, we evaluated a total of 447 differential genes. WGCNA identified eight co-expression modules, with the red module having the strongest correlation with IMV patients. Differential genes were combined to obtain 3 hub genes (HLA-DPA1, HLA-DRB3, and CECR1). The identified genes were investigated as potential indicators for patients with severe influenza who required IMV using the least absolute shrinkage and selection operator (LASSO) approach. The ROC showed the diagnostic value of the three hub genes in determining the severity of influenza. Using ssGSEA, it has been revealed that the expression of key genes was negatively correlated with neutrophil activation and positively associated with adaptive cellular immune response.

Conclusion
We evaluated three novel hub genes that could be linked to the immunopathological mechanism of severe influenza patients who require IMV treatment and could be used as potential biomarkers for severe influenza prevention and treatment.
Transcriptomes of Clusterin- and S100B-transfected neuronal cells elucidate protective mechanisms against hypoxia and oxidative stress in the hooded seal (Cystophora cristata) brain
Authors: Martens Gerrit A. , Geßner Cornelia , Osterhof Carina , Hankeln Thomas , Burmester Thorsten 
Published: October 2022

Abstract
Background
The hooded seal (Cystophora cristata) exhibits impressive diving skills and can tolerate extended durations of asphyxia, hypoxia and oxidative stress, without suffering from irreversible neuronal damage. Thus, when exposed to hypoxia in vitro, neurons of fresh cortical and hippocampal tissue from hooded seals maintained their membrane potential 4–5 times longer than neurons of mice. We aimed to identify the molecular mechanisms underlying the intrinsic neuronal hypoxia tolerance. Previous comparative transcriptomics of the visual cortex have revealed that S100B and clusterin (apolipoprotein J), two stress proteins that are involved in neurological disorders characterized by hypoxic conditions, have a remarkably high expression in hooded seals compared to ferrets. When overexpressed in murine neuronal cells (HN33), S100B and clusterin had neuroprotective effects when cells were exposed to hypoxia. However, their specific roles in hypoxia have remained largely unknown.

Methods
In order to shed light on potential molecular pathways or interaction partners, we exposed HN33 cells transfected with either S100B, soluble clusterin (sCLU) or nuclear clusterin (nCLU) to normoxia, hypoxia and oxidative stress for 24 h. We then determined cell viability and compared the transcriptomes of transfected cells to control cells. Potential pathways and upstream regulators were identified via Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA).

Results
HN33 cells transfected with sCLU and S100B demonstrated improved glycolytic capacity and reduced aerobic respiration at normoxic conditions. Additionally, sCLU appeared to enhance pathways for cellular homeostasis to counteract stress-induced aggregation of proteins. S100B-transfected cells sustained lowered energy-intensive synaptic signaling. In response to hypoxia, hypoxia-inducible factor (HIF) pathways were considerably elevated in nCLU- and sCLU-transfected cells. In a previous study, S100B and sCLU decreased the amount of reactive oxygen species and lipid peroxidation in HN33 cells in response to oxidative stress, but in the present study, these functional effects were not mirrored in gene expression changes.

Conclusions
sCLU and S100B overexpression increased neuronal survival by decreasing aerobic metabolism and synaptic signaling in advance to hypoxia and oxidative stress conditions, possibly to reduce energy expenditure and the build-up of deleterious reactive oxygen species (ROS). Thus, a high expression of CLU isoforms and S100B is likely beneficial during hypoxic conditions.
What GPs do to meet accreditation standards – implementation activities and perceived improvements attributed to general practice accreditation
Authors: Mølgaard Cecilie , Bro Flemming , Mygind Anna 
Published: October 2022

Abstract
Background
Healthcare accreditation is a widely implemented tool used to enhance the quality of care and underpin quality control. However, research is sparse on the accreditation process in general practice. The aim of this study was to explore how team-based implementation activities preceding accreditation were associated with self-perceived improvements in emergency preparedness (preparedness for urgent disease and cardiac arrest) and handling of prescription renewals in Danish general practice.

Methods
GPs (general practitioners) completed a questionnaire exploring practice-team activities conducted to implement two specific accreditation standards and the related improvements as perceived by the GPs. The following implementation activities were selected, inspired by Normalization Process Theory: Common understanding (obtaining a common understanding of the purpose of implementing changes according to the accreditation standard), key person (assigning a key person responsible for working with the standard), and easy integration (finding it easy to integrate changes into existing working procedures). Data were analysed with logistic regression, and adjusted analyses included practice type, number of GP partners, number of staff, training site for junior GPs and administrative region.

Results
The total response rate was 74% (n = 920). Around 80% of the clinics reported having conducted team-based implementation activities. Almost half of the clinics (48%) reported perceived improvements in the emergency preparedness, and 30% reported perceived improvements in the handling of prescription renewals. Obtaining a common understanding was found to have a strong, significant association with perceived improvements in the emergency preparedness (OR = 5.07 (3.06–8.40)) and handling of prescription renewals (OR = 3.66 (2.07–6.46)). Easy integration of changes was also significantly associated with improvements in both emergency preparedness (OR = 1.88 (1.24–2.85)) and handling of prescription renewals (OR = 2.34 (1.44–3.79)), whereas assigning a key person was only significantly associated with improved emergency preparedness (OR = 1.95 (1.19–3.19)).

Conclusion
Clinical quality initiatives that involve collaboration within a practice team are more likely to cause improvements if specific team-based implementation activities are conducted. It is particularly important to facilitate a common understanding of the purpose of the initiative. Therefore, external support for quality initiatives aiming at the practice level in general practice should facilitate such team-based activities.
Perception of providers on use of the WHO mental health Gap Action Programme-Intervention Guide (mhGAP-IG) electronic version and smartphone-based clinical guidance in Nigerian primary care settings
Authors: Ojagbemi Akin , Daley Stephanie , Kola Lola , Taylor Salisbury Tatiana , Feeney Yvonne , Makhmud Akerke , Lempp Heidi , Thornicroft Graham , Gureje Oye 
Published: October 2022

Abstract
Background
Taking advantage of the rapidly increasing access to digital technology in low- and middle-income countries, the World Health Organization has launched an electronic version of the mental health Gap Action Programme intervention guide (emhGAP-IG). This is suitable for use on smartphones or tablets by non-specialist primary healthcare providers (PHCWs) to deliver evidence-based intervention for priority mental, neurological and substance use disorders. We assessed the perceptions of PHCWs on the feasibility, acceptability, and benefits of using smartphone-based clinical guidance and the emhGAP-IG in the management of people with mental health conditions in Nigeria.

Methods
Exploration of the views of PHCWs from 12 rural and urban primary health clinics (PHCs) in South-Western Nigeria were carried out using 34 in-depth key informant qualitative interviews with nurses (n = 10), community health officers (n = 13) and community health extension workers (n = 11). An additional two focus group discussions, each comprising eight participants drawn from across the range of characteristics of PHCWs, were also conducted. Thematic analysis was conducted using a three-staged constant comparison technique to refine and categorise the data.

Results
Three overall themes were identified around the use of clinical guidance and mobile applications (apps) in PHCs. Apps were deployed for purposes other than clinical consultation and decision making. Although paper-based guidance was the expected practice, its utilization is not fully embedded in routine care. An app-based decision-making tool was preferred to paper by PHCWs. Future usage of the emhGAP-IG would be facilitated by training and supporting of staff, helpful design features, and obtaining patients’ buy-in.

Conclusion
Our findings suggest that the emhGAP-IG could be a viable way to embed clinical guidance and decision-making tools in the management of people with mental health conditions in Nigerian PHCs.
Incidence and type of restrictive practice use in nursing homes in Ireland
Authors: Dunbar Paul , McMahon Martin , Durkan Ciara , Walsh Kieran A. , Keyes Laura M. 
Published: October 2022

Abstract
Background
Use of restrictive practices (RP) in care settings may sometimes be warranted but can also conflict with human rights. Research to date has focused primarily on physical and chemical RP, however other forms are also used. Better understanding of practice can inform RP reduction. This study describes the incidence of all types of RP use reported from nursing homes in Ireland.

Methods
RP notifications from nursing homes reported in 2020 were extracted from the Database of Statutory Notifications from Social Care in Ireland. The primary outcome measurement was the national incidence of use (frequency of RP/occupancy per 1000 residents) of categories and types of RP. Secondary outcome measurements such as percentage of facilities reporting use and quarterly median incidence of use in these facilities were calculated.

Results
Seventy thousand six hundred sixty-three RP uses were notified from 608 facilities (33,219 beds). National incidence of RP use per 1000 residents was, all categories: 2465.1, environmental: 1324.5, physical: 922.5, chemical: 141.1; ‘other’: 77.0. The most frequently used RPs per category were, environmental: door locks; physical: bedrails; chemical (where drug specified): antipsychotics; ‘other’: privacy. 90.5% of nursing homes reported using at least one type of RP in the 12-month period. Quarterly incidence of any RP use in these facilities was median 1.642 (IQR: 0.018 to 18.608) per bed.

Conclusions
Nursing homes in Ireland regularly use RP; only 9.5% reported no RP use in the 12-month period. A wide variety of types of RP were reported. Environmental and ‘other’ (largely psychosocial) RP contributed notably to total RP use and warrant attention alongside the traditional focus on physical and chemical RP. Policy implications include the need for more comprehensive RP definitions.
Computer-aided diagnostic for classifying chest X-ray images using deep ensemble learning
Authors: Visuña Lara , Yang Dandi , Garcia-Blas Javier , Carretero Jesus 
Published: October 2022

AbstractBackgroundNowadays doctors and radiologists are overwhelmed with a huge amount of work. This led to the effort to design different Computer-Aided Diagnosis systems (CAD system), with the aim of accomplishing a faster and more accurate diagnosis. The current development of deep learning is a big opportunity for the development of new CADs. In this paper, we propose a novel architecture for a convolutional neural network (CNN) ensemble for classifying chest X-ray (CRX) images into four classes: viral Pneumonia, Tuberculosis, COVID-19, and Healthy. Although Computed tomography (CT) is the best way to detect and diagnoses pulmonary issues, CT is more expensive than CRX. Furthermore, CRX is commonly the first step in the diagnosis, so it’s very important to be accurate in the early stages of diagnosis and treatment.ResultsWe applied the transfer learning technique and data augmentation to all CNNs for obtaining better performance. We have designed and evaluated two different CNN-ensembles: Stacking and Voting. This system is ready to be applied in a CAD system to automated diagnosis such a second or previous opinion before the doctors or radiology’s. Our results show a great improvement, 99% accuracy of the Stacking Ensemble and 98% of accuracy for the the Voting Ensemble.ConclusionsTo minimize missclassifications, we included six different base CNN models in our architecture (VGG16, VGG19, InceptionV3, ResNet101V2, DenseNet121 and CheXnet) and it could be extended to any number as well as we expect extend the number of diseases to detected. The proposed method has been validated using a large dataset created by mixing several public datasets with different image sizes and quality. As we demonstrate in the evaluation carried out, we reach better results and generalization compared with previous works. In addition, we make a first approach to explainable deep learning with the objective of providing professionals more information that may be valuable when evaluating CRXs.
Gamma-secretase inhibitor does not induce cytotoxicity in adult T-cell leukemia cell lines despite NOTCH1 expression
Authors: Suzuki Shinsuke , Hourai Sawako , Uozumi Kimiharu , Uchida Yuichirou , Yoshimitsu Makoto , Miho Hachiman , Arima Naomichi , Ueno Shin-ichi , Ishitsuka Kenji 
Published: October 2022

Abstract
Background
Activated mutations in NOTCH1 are drivers of T-cell type acute lymphoblastic leukemia/lymphoma. The γ-secretase inhibitor (GSI), which suppresses the function of NOTCH1, is expected to be a molecular-targeted agent. NOTCH1 is also expressed in other malignant neoplasms. We aimed to determine the function of NOTCH1 expression and the effects of GSI on adult T-cell leukemia/lymphoma (ATL) caused by long-term human T-cell leukemia virus type I (HTLV-1) infection.

Methods
We analyzed the expression of NOTCH1 in six ATL- and HTLV-1-infected cell lines and investigated the influence of activated NOTCH1 (i.e., the cleaved form of NOTCH1) together with GSI on cell proliferation.

Results
Activated NOTCH1 found in ATL- and HTLV-1-infected cell lines was undetectable after incubation with GSI, regardless of Tax expression (HTLV-1-coded protein). Whole-exome sequencing revealed that activated NOTCH1 mutations were undetectable in six ATL- and HTLV-1-infected cell lines, regardless of abundant NOTCH1 expression. Moreover, GSI did not suppress the growth of ATL cell lines.

Conclusions
These findings suggested that NOTCH1 protein is constitutively activated but is likely a passenger during NOTCH1-mutation-negative ATL cell proliferation.
The frequencies of CYP2D6 alleles and their impact on clinical outcomes of adjuvant tamoxifen therapy in Syrian breast cancer patients
Authors: Ismail Al-khalil Wouroud , Al-Salhi Lana , Rijjal Sara , Aljamali Majd , Youssef Lama A. 
Published: October 2022

Abstract
Background
Tamoxifen is one of the fundamental pillars of adjuvant endocrine therapy for hormone receptor-positive breast cancer; however, 30–50% of patients receiving tamoxifen experience tumor relapse. CYP2D6, encoded by an extremely polymorphic CYP2D6 gene, is the rate-limiting enzyme of tamoxifen bioactivation. This study aimed at determining the frequencies of the most clinically relevant CYP2D6 alleles and evaluating their impact on the responsiveness to tamoxifen in a cohort of Syrian breast cancer patients.

Methods
This case–control study encompassed positive estrogen and/or progesterone receptor, stage 1–3 breast cancer female patients receiving tamoxifen at Al-Bairouni University Hospital, the major National Oncology Center in Syria. Successfully genotyped eligible patients (n = 97) were classified according to their response into; no recurrence group (n = 39) who had completed a five-year recurrence-free adjuvant tamoxifen therapy, and recurrence group (n = 58) who had experienced recurrence. Several star alleles including CYP2D6*4, CYP2D6*10, CYP2D6*41, and CYP2D6*69 were identified via targeted sequencing of specific polymerase chain reaction (PCR) products and phenotypes were assigned according to activity score (AS). The correlation between genotypes and disease-free survival (DFS) was assessed using Kaplan–Meier method and log-rank test. Hazard ratios were estimated using Cox proportional hazards regression models.

Results
The allelic frequencies of CYP2D6*41, CYP2D6*10, CYP2D6*4, and CYP2D6*69 were found to be 9.28%, 7.22%, 7.22%, and 2.58%, respectively. No statistically significant differences were observed in the frequencies of CYP2D6 phenotypes between the two arms (P = 0.24), nor the incidence of tamoxifen-induced hot flashes (P = 0.109). Poor metabolizers (PMs) tended to display shorter DFS than intermediate metabolizers (IMs) and normal metabolizers (NMs) combined (adjusted HR = 2.34, 95% CI = 0.84–6.55, P = 0.104). Notably, patients homozygous for the null CYP2D6*4 allele (1847A/A) had an elevated risk of disease recurrence compared to patients with 1847G/G genotype (adjusted HR = 5.23, 95% CI = 1.22–22.49, P = 0.026).

Conclusions
Our findings show no association between CYP2D6 phenotype and treatment outcomes of tamoxifen in Syrian breast cancer patients. Nevertheless, a worse DFS was revealed in patients with 1847A/A genotype (*4/*4).
PIK3CA mutations associated with a poor postoperative prognosis in patients with pulmonary pleomorphic carcinoma: a retrospective cohort study
Authors: Kojima Kensuke , Imai Saki , Samejima Hironobu , Fujiwara Ayako , Tokunaga Toshiteru , Yoon Hyungeun , Okishio Kyoichi 
Published: October 2022

Abstract
Background
Pulmonary pleomorphic carcinoma (PPC) is a rare type of non-small cell lung cancer characterized by high malignancy and a poor prognosis. PPC is associated with a high frequency of postoperative relapse, and shows resistance to chemotherapy. The high malignancy of cancers is associated with genomic instability, which is related to mutations of tumor suppressor genes, such as tumor protein p53 (TP53) and ataxia-telangiectasia mutated (ATM). In addition, signaling pathways involving the oncogenes such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and epidermal growth factor receptor (EGFR) are associated with resistance to chemotherapy. However, the association of PPC with these gene mutations remains unknown. We investigated the impact of TP53, ATM, PIK3CA, and EGFR mutations on the postoperative prognosis of PPC.

Methods
Fifty-five patients with PPC who underwent complete resection were studied. A gene mutation analysis was performed using next-generation sequencing. Postoperative overall survival of patients with gene mutations was evaluated using a multivariable Cox proportional hazards model in which the explanatory variables were the presence of each gene mutation, and the confounding factors were pathological stage and age. The robustness of the results was evaluated by a sensitivity analysis.

Results
The frequencies of pathogenic mutations in TP53, ATM, PIK3CA, and EGFR were 47, 0, 7, and 9%, respectively. A multivariable analysis adjusted for pathological stage and age showed a significant difference for only PIK3CA mutations. The hazard ratio (HR) for overall survival in cases with pathogenic mutations of PIK3CA for wild type or non-pathogenic mutations was 4.5 (95% confidence interval [CI] 1.1–18.8). Likewise, sensitivity analyses adjusted for pathological stage and sex (HR, 7.5; 95% CI 1.7–32.4) and for age and sex (HR, 5.4; 95% CI 1.4–21.7) resulted in similar findings. Although three patients with pathogenic mutations of PIK3CA that recurred postoperatively were treated by chemotherapy or immunotherapy, they survived for less than 2 years.

Conclusions
The postoperative prognosis of PPC with PIK3CA pathogenic mutations is particularly poor. Pathogenic mutations of PIK3CA may be a postoperative prognostic marker. Inhibition of signaling pathways associated with PIK3CA mutations may also be a target for chemotherapy after relapse of PPC.
The social and sexual lives of Black sexual minority men 30 years of age and older in South Africa
Authors: Crandall Amy , Phaleng Happy , Dacus Jagadīśa-devaśrī , Bista Oshin , Brouard Pierre , Nel Dawie , Reddy Vasu , Sandfort Theo , Knox Justin 
Published: October 2022

AbstractBackgroundBlack sexual minority men (SMM) ages 30 and older are under-represented in HIV studies in sub-Saharan Africa, despite being at increased risk of HIV infection and contributing to potential onward HIV transmission. To better understand the social and sexual lives of older Black South African SMM, we conducted in-depth interviews with SMM who were > 30 years old.MethodsFrom March–September 2016, we recruited a convenience sample of 37 SMM ages 30 and older by partnering with an LGBTQ+ organization in Tshwane, Pretoria. Men were interviewed about various aspects of their lives, including their sexual orientation, social connectedness, experiences with stigma and perspectives on participating in research.ResultsParticipants described their experiences with their sexual identities, cultural and social implications of disclosure, and their perspective on South Africa’s political perspectives on the LGBTQ+ community. Men described how these experiences influence their trust in research and comfort participating in studies.ConclusionsInferences drawn from these findings provide direction on how to improve middle-aged SMM’s representation in research, such as recruiting a higher proportion of older and middle-aged SMM to serve as seed participants and building stronger community partnerships to disseminate study findings to settings where data collection is conducted.