bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estrogen-modulating treatment among mid-life women and COVID-19 morbidity and mortality: a multiregister nationwide matched cohort study in Sweden
Authors: Elenis Evangelia , Kallner Helena Kopp , Karalexi Maria A. , Hägg David , Linder Marie , Fall Katja , Papadopoulos Fotios C. , Skalkidou Alkistis 
Published: February 2024

Abstract
Background
It has been repeatedly shown that men infected by SARS-CoV-2 face a twofold higher likelihood of dying, being hospitalized or admitted to the intensive care unit compared to women, despite taking into account relevant confounders. It has been hypothesized that these discrepancies are related to sex steroid hormone differences with estrogens being negatively correlated with disease severity. The objective of this study was therefore to evaluate COVID-19-related mortality and morbidity among peri- and postmenopausal women in relation to estrogen-containing menopause hormonal treatments (MHT).

Methods
This is a national register-based matched cohort study performed in Sweden between January 1 to December 31, 2020. Study participants comprised women over the age of 53 years residing in Sweden. Exposure was defined as prescriptions of local estrogens, systemic estrogens with and without progestogens, progestogens alone, or tibolone. MHT users were then compared with a matched cohort of non-users. The primary outcome consisted of COVID-19 mortality, whereas the secondary outcomes included inpatient hospitalizations/outpatient visits and confirmed SARS-CoV-2 infection. Multivariable adjusted Cox regression-derived hazard ratios (HRs) were calculated.

Results
Use of systemic estrogens alone is associated with increased COVID-19 mortality among older women (aHR 4.73, 1.22 to 18.32), but the association is no longer significant when discontinuation of estrogen use is accounted for. An increased risk for COVID-19 infection is further observed for women using combined systemic estrogens and progestogens (aHR 1.06, 1.00 to 1.13) or tibolone (aHR 1.21, 1.01 to 1.45). Use of local estrogens is associated with an increased risk for COVID-19-related death (aHR 2.02,1.45 to 2.81) as well as for all secondary outcomes.

Conclusions
Systemic or local use of estrogens does not decrease COVID-19 morbidity and mortality to premenopausal background levels. Excess risk for COVID-19 morbidity and mortality was noted among older women and those discontinuing systemic estrogens. Higher risk for death was also noted among women using local estrogens, for which non-causal mechanisms such as confounding by comorbidity or frailty seem to be the most plausible underlying explanations.

Trial registration details
Not applicable.
Identification of neuropathogenic Varicellovirus equidalpha1 as a potential cause of respiratory disease outbreaks among horses in North Xinjiang, China, from 2021-2023
Authors: Tong Panpan , Yang Enhui , Liu Bin , tian Shuyao , Suo Youtu , Pan JuanJuan , Dang Yueyi , Palidan Nuerlan , Jia Chenyang , Kuang Ling , Xie Jinxin 
Published: February 2024

Abstract
Background
Varicellovirus equidalpha1 (formerly Equid alphaherpesvirus 1, EqAHV-1) is among the most important viruses responsible for respiratory disease outbreaks among horses throughout the world. No reports to date have detailed the association between EqAHV-1 and respiratory disease among horses in China. This study described one such outbreak among a population of horses in north Xinjiang that occurred from April 2021 - May 2023.

Results
qPCR revealed that EqAHV-1 was detectable in all samples and this virus was identified as a possible source of respiratory disease, although a limited subset of these samples were also positive for EqAHV-2, EqAHV-4, and EqAHV-5. In total, three EqAHV-1 strains responsible for causing respiratory illness in horses were isolated successfully, and full-length ORF33 sequence comparisonsand phylogenetic analyses indicated that these isolates may have originated from EqAHV-1 strains detected in Yili horse abortions. ORF30 sequence data additionally suggested that these strains were neuropathic, as evidenced by the presence of a guanine residue at nucleotide position 2254 corresponding to the aspartic acid present at position 752 in the DNA polymerase encoded by this virus.

Conclusion
This study is the first report of an outbreak of respiratory disease among horses in China caused by EqAHV-1. ORF30 sequence characterization revealed that these EqAHV-1 strains harbored a neuropathogenic genotype. Given the detection of this virus in horses suffering from respiratory disease, concern is warranted with respect to this neuropathogenic EqAHV-1 outbreak.
Reduced interleukin-18 secretion by human monocytic cells in response to infections with hyper-virulent Streptococcus pyogenes
Authors: Tölken Lea A. , Paulikat Antje D. , Jachmann Lana H. , Reder Alexander , Salazar Manuela Gesell , Medina Laura M. Palma , Michalik Stephan , Völker Uwe , Svensson Mattias , Norrby-Teglund Anna , Hoff Katharina J. , Lammers Michael , Siemens Nikolai 
Published: February 2024

Abstract
Background
Streptococcus pyogenes (group A streptococcus, GAS) causes a variety of diseases ranging from mild superficial infections of the throat and skin to severe invasive infections, such as necrotizing soft tissue infections (NSTIs). Tissue passage of GAS often results in mutations within the genes encoding for control of virulence (Cov)R/S two component system leading to a hyper-virulent phenotype. Dendritic cells (DCs) are innate immune sentinels specialized in antigen uptake and subsequent T cell priming. This study aimed to analyze cytokine release by DCs and other cells of monocytic origin in response to wild-type and natural covR/S mutant infections.

Methods
Human primary monocyte-derived (mo)DCs were used. DC maturation and release of pro-inflammatory cytokines in response to infections with wild-type and covR/S mutants were assessed via flow cytometry. Global proteome changes were assessed via mass spectrometry. As a proof-of-principle, cytokine release by human primary monocytes and macrophages was determined.

Results
In vitro infections of moDCs and other monocytic cells with natural GAS covR/S mutants resulted in reduced secretion of IL-8 and IL-18 as compared to wild-type infections. In contrast, moDC maturation remained unaffected. Inhibition of caspase-8 restored secretion of both molecules. Knock-out of streptolysin O in GAS strain with unaffected CovR/S even further elevated the IL-18 secretion by moDCs. Of 67 fully sequenced NSTI GAS isolates, 28 harbored mutations resulting in dysfunctional CovR/S. However, analyses of plasma IL-8 and IL-18 levels did not correlate with presence or absence of such mutations.

Conclusions
Our data demonstrate that strains, which harbor covR/S mutations, interfere with IL-18 and IL-8 responses in monocytic cells by utilizing the caspase-8 axis. Future experiments aim to identify the underlying mechanism and consequences for NSTI patients.
Effects of vitamin D supplementation on liver fibrogenic factors, vitamin D receptor and liver fibrogenic microRNAs in metabolic dysfunction-associated steatotic liver disease (MASLD) patients: an exploratory randomized clinical trial
Authors: Ebrahimpour-Koujan Soraiya , Sohrabpour Amir Ali , Giovannucci Edward , Vatannejad Akram , Esmaillzadeh Ahmad 
Published: February 2024

Abstract
Background and aims
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global metabolic problem which can lead to irreversible liver fibrosis. It has been shown that vitamin D and its receptors contribute to fibrogenic pathways in the liver. However, the effect of vitamin D supplementation on liver fibrosis related factors have not been examined. This double blinded placebo controlled clinical trial was designed to investigate the effects on vitamin D supplementation on serum levels of VDR, fibrogenic factors and fibrogenic MicroRNAs in MASLD patients.

Methods
Forty six MASLD patients after block matching for sex and BMI were randomly assigned to receive 4000 IU/d vitamin D or placebo for 12 weeks. Weight, height and waist circumference were measured. Serum fibrogenic microRNAs, laminin, collagen type IV, hyaluronic acid, vitamin D, VDR, PTH, blood fasting glucose, serum fasting insulin, lipid profile, ALT and AST were determined at the baseline and at the end of the trial. Insulin resistance and insulin sensitivity were calculated using the HOMA-IR and QUICKI equation.

Results
Supplementation with vitamin D for 12 weeks led to the significant increases in serum 25(OH) vitamin D, VDR and HDL-C compared to placebo (P < 0.001, P = 0.008 and P < 0.001). There were significant decreases in ALT, AST, FBS and LDL-C levels in the vitamin D group as compared to the placebo (P < 0.05). Laminin and hyaluronic acid concentrations were significantly decreased in the vitamin D group as compared to the placebo group, by -10.6 and − 28.7 ng/mL, respectively. Supplementation with vitamin D for 12 weeks resulted in a significant lower MiR-21 and MiR-122 gene expressions compared to the placebo group (P = 0.01 and P < 0.001, respectively).

Discussion
As the first randomized controlled trial on the effect of vitamin D supplementation on serum levels of VDR, fibrogenic factors and fibrogenic MicroRNAs in MASLD patients, we found a significant reduction in some liver fibrogenic factors, in liver transaminases and corresponding changes in some fibrosis-related MiRs and some metabolic factors. Further clinical trials with larger sample sizes and direct measures of liver fibrosis are needed to confirm these findings.

Trial registration number
(available at: http://www.irct.ir, identifier: IRCT201405251485N13), Registration date: 14-03-2017.
Integrative single-cell transcriptomic analyses reveal the cellular ontological and functional heterogeneities of primary and metastatic liver tumors
Authors: Gui Menghui , Huang Shilin , Li Shizhou , Chen Yuying , Cheng Furong , Liu Yulin , Wang Ji-ao , Wang Yuting , Guo Rui , Lu Yiming , Cao Pengbo , Zhou Gangqiao 
Published: February 2024

Abstract
Background
The global cellular landscape of the tumor microenvironment (TME) combining primary and metastatic liver tumors has not been comprehensively characterized.

Methods
Based on the scRNA-seq and spatial transcriptomic data of non-tumor liver tissues (NTs), primary liver tumors (PTs) and metastatic liver tumors (MTs), we performed the tissue preference, trajectory reconstruction, transcription factor activity inference, cell–cell interaction and cellular deconvolution analyses to construct a comprehensive cellular landscape of liver tumors.

Results
Our analyses depicted the heterogeneous cellular ecosystems in NTs, PTs and MTs. The activated memory B cells and effector T cells were shown to gradually shift to inhibitory B cells, regulatory or exhausted T cells in liver tumors, especially in MTs. Among them, we characterized a unique group of TCF7+ CD8+ memory T cells specifically enriched in MTs that could differentiate into exhausted T cells likely driven by the p38 MAPK signaling. With regard to myeloid cells, the liver-resident macrophages and inflammatory monocyte/macrophages were markedly replaced by tumor-associated macrophages (TAMs), with TREM2+ and UBE2C+ TAMs enriched in PTs, while SPP1+ and WDR45B+ TAMs in MTs. We further showed that the newly identified WDR45B+ TAMs exhibit an M2-like polarization and are associated with adverse prognosis in patients with liver metastases. Additionally, we addressed that endothelial cells display higher immune tolerance and angiogenesis capacity, and provided evidence for the source of the mesenchymal transformation of fibroblasts in tumors. Finally, the malignant hepatocytes and fibroblasts were prioritized as the pivotal cell populations in shaping the microenvironments of PTs and MTs, respectively. Notably, validation analyses by using spatial or bulk transcriptomic data in clinical cohorts concordantly emphasized the clinical significance of these findings.

Conclusions
This study defines the ontological and functional heterogeneities in cellular ecosystems of primary and metastatic liver tumors, providing a foundation for future investigation of the underlying cellular mechanisms.
Ethnobotanical study of wild edible plants in Dibatie district, Metekel zone, Benishangul Gumuz Regional State, western Ethiopia
Authors: Anbessa Baressa , Lulekal Ermias , Getachew Paulos , Hymete Ariaya 
Published: February 2024

Abstract
Background
Plants deliver livelihood and food for millions of people in the world. Indeed, wild edible plants support rural communities in developing countries to overcome seasonal unfavorable conditions. In rural areas of Ethiopia, wild edible plants play an indispensable role in fighting food insecurity as emergency or supplementary foods. Hence, this research was aimed at studying the ethnobotanical assessment of wild edible plants in Dibatie district, Metekel zone, western Ethiopia.

Methods
Ethnobotanical data was collected using a semi-structured interview, field observation, focus group discussions, a market survey, and the ranking of selected plants. Besides, voucher specimens were collected and stored at the National Herbarium of Ethiopia. Descriptive statistics, preference ranking, direct matrix ranking, and familiarity index were computed for data analysis.

Results
This study has documented 54 wild edible plant species belonging to 33 plant families and 46 genera. Of these, most (38.90%) had tree growth habits. Wild edible plants bear mostly fruits (72.20%) as edible parts. Local people usually consume these plants freshly raw as complementary foods, though some wild edibles require processing. They were mostly harvested in the January (31.48%) and May (27.78%) months, with the least collected in September (7.41%). Most wild edible plants (78.57%) were available in uncontrolled habitats, while others (21.43%) live in farmlands, home gardens, and as live fences. Out of the recorded plants, about 98% had additional uses besides their nutritional values.

Conclusion
Wild edible plants assist the livelihoods of the local people in food security, agriculture, energy sources, construction, medicines, ecological services, aesthetics, income generation, and household utensils. Nevertheless, wild edible plants are recently threatened due to various anthropogenic factors in the study area. Thus, they need wise use and in-situ and ex-situ conservation measures from all the concerned bodies for sustainable use in the future.
The effect of the whole-process care model of the medical union on the improvement of kinesiophobia and bone mineral density in patients with osteoporosis
Authors: Qian Xiaoli , Cao Xiaodong , Zhu Liyan , Yao Xiaojuan , Gu Lina , Yu Xin 
Published: February 2024

Abstract
Objective
To observe the effect of the whole-process care model of the medical union on the improvement of kinesiophobia and bone mineral density in patients with osteoporosis.

Methods
In this descriptive study, a convenient sampling method was used to select 148 patients with osteoporosis who visited the hospital from January 2020 to December 2021. Patients aged ≥ 18 years and diagnosed with osteoporosis through quantitative computed tomography (QCT) were included in the study. They were able to cooperate during follow-up and had normal cognitive function. Patients with combined spinal curvature, thoracic deformity, and pulmonary dysfunction, accompanied by severe cardiovascular or limb dysfunction, and those who withdrew midway or participated in other clinical studies were excluded. According to whether to use the whole-process care model of the medical union, they were divided into intervention group and control group, with 74 cases each. The control group used conventional care, and the intervention group used the whole-process care model of the medical association. The occurrence of kinesiophobia between the two groups were compared. The dual-energy X-ray absorption detector is used to measure differences in bone density changes.

Results
There was no significant difference between the two groups in the TSK scale score and the incidence of kinesiophobia before intervention (P > 0.05). The TSK scale scores of patients in the intervention group were higher than those in the control group at 3 months and 6 months after operation (P < 0.05). The incidence of kinesiophobia in the intervention group for 3 months and 6 months was significantly lower than that in the control group (P < 0.05). There was no significant difference in bone mineral density between the two groups before and 3 months after intervention (P > 0.05). The bone mineral density of lumbar spine, femoral neck and total hip in the intervention group was significantly higher than that in the control group after 6 months of intervention (P < 0.05).

Conclusion
The whole-process care model of the medical association is used for osteoporosis patients, which might reduce the risk of kinesiophobia and improve the bone density of the lumbar spine and total hip in patients. But further promotion and improvement of relevant support systems are needed to achieve comprehensive promotion and maximize clinical benefits in this field.
Crucial role of TFAP2B in the nervous system for regulating NREM sleep
Authors: Nakai Ayaka , Kashiwagi Mitsuaki , Fujiyama Tomoyuki , Iwasaki Kanako , Hirano Arisa , Funato Hiromasa , Yanagisawa Masashi , Sakurai Takeshi , Hayashi Yu 
Published: February 2024

AbstractThe AP-2 transcription factors are crucial for regulating sleep in both vertebrate and invertebrate animals. In mice, loss of function of the transcription factor AP-2β (TFAP2B) reduces non-rapid eye movement (NREM) sleep. When and where TFAP2B functions, however, is unclear. Here, we used the Cre-loxP system to generate mice in which Tfap2b was specifically deleted in the nervous system during development and mice in which neuronal Tfap2b was specifically deleted postnatally. Both types of mice exhibited reduced NREM sleep, but the nervous system-specific deletion of Tfap2b resulted in more severe sleep phenotypes accompanied by defective light entrainment of the circadian clock and stereotypic jumping behavior. These findings indicate that TFAP2B in postnatal neurons functions at least partly in sleep regulation and imply that TFAP2B also functions either at earlier stages or in additional cell types within the nervous system.
Splicing targeting drugs highlight intron retention as an actionable vulnerability in advanced prostate cancer
Authors: Naro Chiara , Antonioni Ambra , Medici Vanessa , Caggiano Cinzia , Jolly Ariane , de la Grange Pierre , Bielli Pamela , Paronetto Maria Paola , Sette Claudio 
Published: February 2024

Abstract
Background
Advanced prostate cancer (PC) is characterized by insensitivity to androgen deprivation therapy and chemotherapy, resulting in poor outcome for most patients. Thus, advanced PC urgently needs novel therapeutic strategies. Mounting evidence points to splicing dysregulation as a hallmark of advanced PC. Moreover, pharmacologic inhibition of the splicing process is emerging as a promising option for this disease.

Method
By using a representative androgen-insensitive PC cell line (22Rv1), we have investigated the genome-wide transcriptomic effects underlying the cytotoxic effects exerted by three splicing-targeting drugs: Pladienolide B, indisulam and THZ531. Bioinformatic analyses were performed to uncover the gene structural features underlying sensitivity to transcriptional and splicing regulation by these treatments. Biological pathways altered by these treatments were annotated by gene ontology analyses and validated by functional experiments in cell models.

Results
Although eliciting similar cytotoxic effects on advanced PC cells, Pladienolide B, indisulam and THZ531 modulate specific transcriptional and splicing signatures. Drug sensitivity is associated with distinct gene structural features, expression levels and cis-acting sequence elements in the regulated exons and introns. Importantly, we identified PC-relevant genes (i.e. EZH2, MDM4) whose drug-induced splicing alteration exerts an impact on cell survival. Moreover, computational analyses uncovered a widespread impact of splicing-targeting drugs on intron retention, with enrichment in genes implicated in pre-mRNA 3’-end processing (i.e. CSTF3, PCF11). Coherently, advanced PC cells displayed high sensitivity to a specific inhibitor of the cleavage and polyadenylation complex, which enhances the effects of chemotherapeutic drugs that are already in use for this cancer.

Conclusions
Our study uncovers intron retention as an actionable vulnerability for advanced PC, which may be exploited to improve therapeutic management of this currently incurable disease.
Pediatric acute hospitalization for anorexia nervosa: an economic evaluation
Authors: Marchili Maria Rosaria , Bozzola Elena , Guolo Stefano , Marchesani Silvio , Spina Giulia , Mascolo Cristina , Vicari Stefano , De Jacobis Isabella Tarissi , Raponi Massimiliano , Villani Alberto 
Published: February 2024

Abstract
Background
Anorexia nervosa (AN) is a psychiatric disorders which may potentially led to a high risk of health medical complications, suicide and self-harming behaviour. Since Covid-19 pandemic onset in March 2020, evidence suggested an increase occurrence of AN. The main aim of the retrospective analysis is to define the cost of hospitalization in the acute phase (HAP) at IRCCS Bambino Gesù Children Hospital, Rome, Italy, over 2 years study. Secondary purposes are defining the main risk factors for a prolonged hospitalization (including age, sex and comorbidities) and the possible influence of Covid-19 pandemic on AN admission and hospital stay.

Methods
for the purpose of the study, we included children and adolescents aged less than 18 years, admitted to IRCCS Bambino Gesù Children Hospital, Rome, Italy, with a diagnosis of AN. Medical costs were calculated consulting the Lazio Regional Health Service Tariffs. Basing on the date of hospital admission, patients were later divided into two subgroups: subgroup A included patients hospitalized prior than Covid-19 onset (from March 2019 to February 2020) and subgroup B those admitted after (from March 2020 to October 2022).

Results
a total of 260 patients has been included in the study with a median age of 15 years (range 6–18 years). The total health care cost of AN hospitalized patients was of EUR 3,352,333 with a median cost of EUR 11,124 for each admission (range EUR 930 − 45,739) and a median daily cost of EUR 593 (range EUR 557–930). Median cost was higher in case of comorbidities, guarded patients, enteral feeding. A prolonged hospitalization has been documented in subgroup A with a higher economic burden.

Conclusions
the economic burden of eating disorders is of note. Adequate sanitary policies as well as health economic analyses are required to gain insight into the cost-effectiveness of AN management.

Trial registration
2526-OPBG-2021.