bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of fixed doses of intranasal Esketamine as an add-on therapy to Oral antidepressants in Japanese patients with treatment-resistant depression: a phase 2b randomized clinical study
Authors: Takahashi Nagahide , Yamada Aya , Shiraishi Ayako , Shimizu Hiroko , Goto Ryosuke , Tominaga Yushin 
Published: October 2021

Abstract
Background
Esketamine nasal spray (Spravato) in conjunction with oral antidepressants (ADs) is approved in the European Union, United States, and other markets for treatment-resistant depression (TRD). Efficacy, safety, and tolerability of esketamine nasal spray in Japanese patients with TRD needs to be assessed.

Methods
This Phase 2b, randomized, double-blind (DB), placebo-controlled study was conducted in adult Japanese patients with TRD meeting the Diagnostic and Statistical Manual of Mental Disorders (fifth edition) criteria of major depressive disorder with nonresponse to ≥ 1 but < 5 different ADs in the current episode at screening. Patients were treated with a new oral AD for 6 weeks (prospective lead-in phase); nonresponders were randomized (2:1:1:1) to placebo or esketamine (28-, 56-, or 84-mg) nasal spray along with the continued use of AD for 4 weeks (DB induction phase). Responders (≥50% reduction from baseline in the Montgomery-Asberg Depression Rating Scale [MADRS] total score) from the DB induction phase continued into the 24-week posttreatment phase and patients who relapsed could participate in a 4-week open-label (OL) second induction (flexibly-dosed esketamine). The primary efficacy endpoint, change from baseline in the MADRS total score at Day 28 in the DB induction phase, was based on mixed-effects model using repeated measures pairwise comparisons using a Dunnett adjustment.

Results
Of the 202 patients randomized in the DB induction phase (esketamine [n = 122] or placebo [n = 80]), the MADRS total scores decreased from baseline to Day 28 of the DB induction phase (− 15.2, − 14.5, − 15.1, and − 15.3 for esketamine 28 mg, 56 mg, 84 mg, and placebo groups, respectively), indicating an improvement in depressive symptoms; however, the difference between the esketamine and placebo groups was not statistically significant. The most common treatment-emergent adverse events during the DB induction phase in the combined esketamine group (incidences ranging from 12.3 to 41.0%) were blood pressure increased, dissociation, dizziness, somnolence, nausea, hypoaesthesia, vertigo, and headache; the incidence of each of these events was > 2-fold higher than the corresponding incidence in the placebo group.

Conclusions
Efficacy of esketamine plus oral AD in Japanese TRD patients was not established; further investigation is warranted. All esketamine doses were safe and tolerated.

Trial registration
ClinicalTrials.gov Identifier: NCT02918318. Registered: 28 September 2016.
Education on palliative care for Parkinson patients: development of the “Best care for people with late-stage Parkinson’s disease” curriculum toolkit
Authors: Gatsios Dimitrios , Antonini Angelo , Gentile Giovanni , Konitsiotis Spyridon , Fotiadis Dimitrios , Nixina Irini , Taba Pille , Weck Christiane , Lorenzl Stefan , Lex Katharina Maria , Paal Piret 
Published: October 2021

Abstract
Background
Palliative care education among all stakeholders involved in the care of patients with late-stage Parkinson’s disease is not adequate. In fact, there are many unmet educational and training needs as confirmed with a targeted, narrative literature review.

Methods
To address these needs we have developed the “Best Care for People with Late-Stage Parkinson’s Disease” curriculum toolkit. The toolkit is based on recommendations and guidelines for training clinicians and other healthcare professionals involved in palliative care, educational material developed in recent research efforts for patients and caregivers with PD and consensus meetings of leading experts in the field. The final version of the proposed toolkit was drafted after an evaluation by external experts with an online survey, the feedback of which was statistically analysed with the chi-square test of independence to assess experts’ views on the relevance and importance of the topics. A sentiment analysis was also done to complement statistics and assess the experts positive and negative sentiments for the curriculum topics based on their free text feedback.

Results
The toolkit is compliant with Kern’s foundational framework for curriculum development, recently adapted to online learning. The statistical analysis of the online survey, aiming at toolkit evaluation from external experts (27 in total), confirms that all but one (nutrition in advanced Parkinson’s disease) topics included, as well as their objectives and content, are highly relevant and useful.

Conclusions
In this paper, the methods for the development of the toolkit, its stepwise evolution, as well as the toolkit implementation as a Massive Open Online Course (MOOC), are presented. The “Best Care for People with Late-Stage Parkinson’ s disease” curriculum toolkit can provide high-quality and equitable education, delivered by an interdisciplinary team of educators. The toolkit can improve communication about palliative care in neurological conditions at international and multidisciplinary level. It can also offer continuing medical education for healthcare providers.
Equine vitiligo-like depigmentation in grey horses is related to genes involved in immune response and tumor metastasis
Authors: Druml Thomas , Brem Gottfried , Velie Brandon , Lindgren Gabriella , Horna Michaela , Ricard Anne , Grilz-Seger Gertrud 
Published: October 2021

Abstract
Background
In horses, the autoimmune disease vitiligo is characterized by the loss of melanocytes and results in patchy depigmentation of the skin around the eyes, muzzle and the perianal region. Vitiligo-like depigmentation occurs predominantly in horses displaying the grey coat colour and is observed at a prevalence level of 26.0–67.0% in grey horses compared with only 0.8–3.5% in non-grey horses. While the polygenetic background of this complex disease is well documented in humans, the underlying candidate genes for this skin disorder in horses remain unknown. In this study we aim to perform a genome-wide association study (GWAS) for identifying putative candidate loci for vitiligo-like depigmentation in horses.

Methods
In the current study, we performed a GWAS analysis using high-density 670 k single nucleotide polymorphism (SNP) data from 152 Lipizzan and 104 Noriker horses, which were phenotyped for vitiligo-like depigmentation by visual inspection. After quality control 376,219 SNPs remained for analyses, the genome-wide Bonferroni corrected significance level was p < 1.33e-7.

Results
We identified seven candidate genes on four chromosomes (ECA1, ECA13, ECA17, ECA20) putatively involved in vitiligo pathogenesis in grey horses. The highlighted genes PHF11, SETDB2, CARHSP1 and LITAFD, are associated with the innate immune system, while the genes RCBTB1, LITAFD, NUBPL, PTP4A1, play a role in tumor suppression and metastasis. The antagonistic pathogenesis of vitiligo in relation to cancer specific enhanced cell motility and/or metastasis on typical melanoma predilection sites underlines a plausible involvement of RCBTB1, LITAFD, NUBPL, and PTP4A1.

Conclusions
The proposed candidate genes for equine vitiligo-like depigmentation, indicate an antagonistic relation between vitiligo and tumor metastasis in a horse population with higher incidence of melanoma. Further replication and expression studies should lead to a better understanding of this skin disorder in horses.
CircCD44 plays oncogenic roles in triple-negative breast cancer by modulating the miR-502–5p/KRAS and IGF2BP2/Myc axes
Authors: Li Jie , Gao Xinya , Zhang Zhanqiang , Lai Yuanhui , Lin Xunxun , Lin Bo , Ma Maoguang , Liang Xiaoli , Li Xixi , Lv Weiming , Lin Ying , Zhang Nu 
Published: October 2021

Abstract

Background
Emerging studies have revealed the potent functions of circRNAs in breast cancer tumorigenesis. However, the biogenesis, biofunction and mechanism of circRNAs in triple-negative breast cancer (TNBC) are largely unknown.

Methods
High-throughput RNA sequencing was applied to identify dysregulated circRNAs in TNBCs and paired normal tissues. RNA pulldown and luciferase assays were performed to investigate the interaction between circular CD44 (circCD44, also annotated as hsa_circ_0021735) and miR-502–5p. RNA pulldown and RIP assays were used to investigate the interaction between circCD44 and IGF2BP2. Cell viability, colony formation, migration/invasion assays and in vivo tumorigenesis were used to investigate circCD44 biological functions.

Results
CircCD44 is an uncharacterized circRNA, which is highly expressed in TNBC, and its expression is negatively correlated with the prognosis of TNBC patients. CircCD44 promotes TNBC proliferation, migration, invasion and tumorigenesis at least partially by sponging miR-502–5p and interacting with IGF2BP2.

Conclusion
Our data suggested that overexpressed circCD44 promotes TNBC progression. CircCD44 is potentially a novel diagnostic and therapeutic marker for TNBC patients.
Diverse inflammatory threats modulate astrocytes Ca2+ signaling via connexin43 hemichannels in organotypic spinal slices
Authors: Panattoni Giulia , Amoriello Roberta , Memo Christian , Thalhammer Agnes , Ballerini Clara , Ballerini Laura 
Published: October 2021

AbstractNeuroinflammation is an escalation factor shared by a vast range of central nervous system (CNS) pathologies, from neurodegenerative diseases to neuropsychiatric disorders. CNS immune status emerges by the integration of the responses of resident and not resident cells, leading to alterations in neural circuits functions. To explore spinal cord astrocyte reactivity to inflammatory threats we focused our study on the effects of local inflammation in a controlled micro-environment, the organotypic spinal slices, developed from the spinal cord of mouse embryos. These organ cultures represent a complex in vitro model where sensory-motor cytoarchitecture, synaptic properties and spinal cord resident cells, are retained in a 3D fashion and we recently exploit these cultures to model two diverse immune conditions in the CNS, involving different inflammatory networks and products. Here, we specifically focus on the tuning of calcium signaling in astrocytes by these diverse types of inflammation and we investigate the mechanisms which modulate intracellular calcium release and its spreading among astrocytes in the inflamed environment. Organotypic spinal cord slices are cultured for two or three weeks in vitro (WIV) and exposed for 6 h to a cocktail of cytokines (CKs), composed by tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1 β) and granulocyte macrophage-colony stimulating factor (GM-CSF), or to lipopolysaccharide (LPS). By live calcium imaging of the ventral horn, we document an increase in active astrocytes and in the occurrence of spontaneous calcium oscillations displayed by these cells when exposed to each inflammatory threat. Through several pharmacological treatments, we demonstrate that intracellular calcium sources and the activation of connexin 43 (Cx43) hemichannels have a pivotal role in increasing calcium intercellular communication in both CKs and LPS conditions, while the Cx43 gap junction communication is apparently reduced by the inflammatory treatments.
Meglitinide (repaglinide) therapy in permanent neonatal diabetes mellitus: two case reports
Authors: Razzaghy-Azar Maryam , Nourbakhsh Mitra , Talea Ali , Mohammad Amoli Mahsa , Nourbakhsh Mona , Larijani Bagher 
Published: October 2021

Abstract
Background
Permanent neonatal diabetes mellitus (PNDM) presents with dehydration and hyperglycemia, which usually occurs during the first 12 months of life. Activating mutations of beta-cell adenosine triphosphate-sensitive potassium [KATP] channel subunits that cause opening of the channel are associated with PNDM. Some patients with PNDM respond to administration of a sulfonylurea derivative, which has long action on blood glucose even during hypoglycemia and has an apoptotic effect on beta cells. However, there have been no reports regarding treatment with meglitinide (repaglinide), which has rapid and short duration of action during the rise in blood glucose after meals that is more similar to beta cell function. It has no effects during hypoglycemia, so it does not cause neurological damage, and has no apoptotic effect on beta cells. We report herein the effects of repaglinide administration in the management and clinical outcome of two patients with PNDM during 9 and 10 years of follow-up.

Case presentation
Two Iranian infants were brought to our institution with poor general condition, dehydration, lethargy, and poor feeding. They had diabetic ketoacidosis at 52 days and 3.5 months of age, respectively. Their genetic analysis revealed mutations in the KCNJ11 gene encoding KIR6.2, so they both had PNDM. After treatment of diabetic ketoacidosis with insulin, they responded to sulfonylurea (glibenclamide) treatment, but were switched to repaglinide because of blood sugar fluctuations in terms of hyper- and hypoglycemia. Repaglinide was administered with the dosage of 0.04 mg/kg/day divided before every meal.

Results
The patients were 10 and 9 years old at the last visit, with normal growth parameters. The values of self-monitored blood glucose were well-controlled, and the hemoglobin A1C (HbA1C) levels ranged from 3.6 to 6.4% during the follow-up period. There was no complication of diabetes, neurological disorder, or adverse effects related to repaglinide.

Conclusion
In every neonate or infant < 6 months of age with diabetes mellitus, PNDM should be considered. A trial of oral repaglinide can be performed and substituted for glibenclamide for prevention of hypoglycemia, neurological damage, and apoptosis of beta cells during long-term administration.
Fragmentation of microspheres after bronchial artery injection: a case report and review of the literature
Authors: Luo Wei , Hu Tongchen , Mao Yu , Yu Qi 
Published: October 2021

Abstract
Background
Massive hemoptysis due to aspergilloma is a rare but life-threatening complication. Bronchial artery embolization is recommended as a definitive treatment for massive hemoptysis. Polyvinyl alcohol is widely used in bronchial artery embolization. A very small number of studies have reported disrupted polyvinyl alcohol, which may cause ectopic embolism.

Case presentation
This case highlights an unusual phenomenon in which polyvinyl alcohol fragments appeared on pathological examination in a 61-year-old man, ethnic Han, with massive hemoptysis caused by aspergilloma for whom bronchial artery embolization failed. Lobectomy was carried out successfully. Hematoxylin and eosin stain provides clear images of polyvinyl alcohol fragments, while alpha-smooth muscle cell actin and cluster of differentiation-34 immunohistochemistry revealed their localization in bronchioles.

Conclusion
Thus far, only two cases of polyvinyl alcohol fragments in the lung have been reported, and the mechanism has not been elucidated. These two cases revealed no counter-indication for the use of polyvinyl alcohol. However, in some cases of off-target embolization causing fatal complications, such as stroke, paraplegia, and myocardial, polyvinyl alcohol fragmentation needs to be taken into consideration.
Oral health of the 65+ age group in Israel-2020
Authors: Berg-Warman Ayelet , Schiffman Ile Kermel , Zusman Shlomo P. , Natapov Lena 
Published: October 2021

Abstract
Background
In 2019, a reform of dental services for older adults was implemented in Israel to improve access and reduce barriers that stood in their way. The reform stipulated that preventive and restorative dentistry would be included in the basket of services of the National Health Insurance Law. The current study was conducted by the Myers-JDC-Brookdale Institute (MJB) and the Division of Dental Health of Israel’s Ministry of Health to examine the dental status and patterns of utilizations of dental services among the 65+ age group. This paper reports on the dental status of the 65+ age group in comparison with the same population two decades earlier.

Goals
To describe the dental status of Israel’s 65+ age group, and to identify the population at risk of dental morbidity.

Methodology
Telephone interviews were conducted with a representative sample of 512 older adults aged 65+, from February to April 2020.

Main findings
Some two-thirds of the 65+ age group assessed their oral health as good or very good. Twenty-four percent did not have natural teeth, while the rest had 19 teeth on average. Ten percent had not lost any teeth. In the 65–74 age group, 19% had no natural teeth and the rest had 20 teeth on average. In contrast, in the 85+ age group, 38% were edentulous and the rest had 13 teeth on average. Of the older adults who found it difficult to cover their monthly expenses, 39% were edentulous—twice the percentage of those who did manage to cover their monthly expenses (19%). Of the 65+ age group 44% had dentures—37% in the 65–74 age group, and 66% in the 85+ age group. Approximately 40% of the 65+ age group saw a dentist for preventive check-ups. The rest did not, mainly due to lack of awareness of the importance of doing so.

Conclusions and recommendations
The perceived status of oral health among the 65+ age group is currently better than it was 22 years ago. However, despite the improvement in oral health and health behavior, there are still barriers to the utilization of dental services. The main barriers are a lack of awareness of the importance of proper health behavior, and the cost of care for people with financial difficulty. This study provides decision-makers with data on the status of oral health, the utilization of dental services and the geographical disparities. The findings will help policy makers evaluate the effectiveness of the reform and fine tuning it in the future. Policies should be instated to increase awareness of constituencies and their access to the services, in addition to the entitlements the reform granted.
Conceptual causal framework to assess the effect of SARS-CoV-2 variants on COVID-19 disease severity among hospitalized patients
Authors: Van Goethem Nina , Serrien Ben , Vandromme Mathil , Wyndham-Thomas Chloé , Catteau Lucy , Brondeel Ruben , Klamer Sofieke , Meurisse Marjan , Cuypers Lize , André Emmanuel , Blot Koen , Van Oyen Herman 
Published: October 2021

Abstract
Background
SARS-CoV-2 strains evolve continuously and accumulate mutations in their genomes over the course of the pandemic. The severity of a SARS-CoV-2 infection could partly depend on these viral genetic characteristics. Here, we present a general conceptual framework that allows to study the effect of SARS-CoV-2 variants on COVID-19 disease severity among hospitalized patients.

Methods
A causal model is defined and visualized using a Directed Acyclic Graph (DAG), in which assumptions on the relationship between (confounding) variables are made explicit. Various DAGs are presented to explore specific study design options and the risk for selection bias. Next, the data infrastructure specific to the COVID-19 surveillance in Belgium is described, along with its strengths and weaknesses for the study of clinical impact of variants.

Discussion
A well-established framework that provides a complete view on COVID-19 disease severity among hospitalized patients by combining information from different sources on host factors, viral factors, and healthcare-related factors, will enable to assess the clinical impact of emerging SARS-CoV-2 variants and answer questions that will be raised in the future. The framework shows the complexity related to causal research, the corresponding data requirements, and it underlines important limitations, such as unmeasured confounders or selection bias, inherent to repurposing existing routine COVID-19 data registries.

Trial registration
Each individual research project within the current conceptual framework will be prospectively registered in Open Science Framework (OSF identifier: 10.17605/OSF.IO/UEF29). OSF project created on 18 May 2021.
19-Hydroxybufalin inhibits non-small cell lung cancer cell proliferation and promotes cell apoptosis via the Wnt/β-catenin pathway
Authors: Yu Wei , Zhang Xiao , Zhang Wei , Xiong Minggang , Lin Yuhan , Chang Ming , Xu Lin , Lu Yi , Liu Yun , Zhang Jian 
Published: October 2021

Abstract
Background
Bufadienolides derived from the skin of toads are often regarded as the main active components with antitumor effects. 19-Hydroxybufalin (19-HB) is a monomer of bufadienolides; however, its effects and underlying molecular mechanisms on tumor growth remain to be ascertained. In this report, we focused on the antitumor effects of 19-HB on non-small cell lung cancer to provide a scientific basis for its further development and utilization.

Methods
The antitumor effects of 19-HB on the human NSCLC cell lines NCI-H1299 and NCI-H838 were examined in vitro. The cells were treated with different concentrations of 19-HB, and the inhibition of cell growth was measured by CCK-8 and colony formation assays. Furthermore, cell apoptosis was analyzed by flow cytometry, TUNEL staining, JC-1 staining, and western blotting. The effects on migration and invasion were evaluated by wound-healing assay, transwell assay, and western blotting. Finally, the antitumor effects of 19-HB were evaluated in vivo using a xenograft mouse model.

Results
19-HB-treated NSCLC cells showed inhibited cell viability and increased apoptosis. The expression levels of cleaved caspase-3, cleaved-PARP, and Bax/Bcl-2 were upregulated, while the mitochondrial membrane potential decreased. In contrast, migration, invasion, as well as the expression of MMP2, MMP7, MMP9, the epithelial–mesenchymal transition-related proteins N-cadherin and Vimentin, and the transcription factors Snail and Slug were inhibited. Furthermore, the expression levels of the key molecules in the Wnt/β-catenin signaling pathway (CyclinD1, c-Myc, and β-catenin) were decreased. In vivo, the growth of xenograft tumors in nude mice was also significantly inhibited by 19-HB, and there were no significant changes in biochemical indicators of hepatic and renal function.

Conclusions
19-HB inhibited the proliferation, migration, and invasion, and promoted the apoptosis of NSCLC cells via the Wnt/β-catenin pathway. In addition, 19-HB inhibited the growth of xenograft tumors in nude mice with little toxicity to the liver and kidney. Thus, 19-HB may be a potential antitumor agent for treating NSCLC.