bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electronic common technical document submission with analysis using R
Authors: Zhao Yujie , Xiao Nan , Anderson Keaven , Zhang Yilong 
Published: September 2022

Background: In clinical trial development, it is a critical step to submit applications, amendments, supplements, and reports on medicinal products to regulatory agencies. The electronic common technical document is the standard format to enable worldwide regulatory submission. There is a growing trend of using R for clinical trial analysis and reporting as part of regulatory submissions, where R functions, analysis scripts, analysis results, and all proprietary code dependencies are required to be included. One unmet and significant gap is the lack of tools, guidance, and publicly available examples to prepare submission R programs following the electronic common technical document specification. Methods: We introduce a simple and sufficient R package, pkglite, to convert analysis scripts and associated proprietary dependency R packages into a compact, text-based file, which makes the submission document self-contained, easy to restore, transfer, review, and submit following the electronic common technical document specification and regulatory guidelines (e.g. the study data technical conformance guide from the US Food and Drug Administration). The pkglite R package is published on Comprehensive R Archive Network and developed on GitHub. Results: As a tool, pkglite can pack and unpack multiple R packages with their dependencies to facilitate the reproduction and make it an off-the-shelf tool for both sponsors and reviewers. As a grammar, pkglite provides an explicit trace of the packing scope using the concept of file specifications. As a standard, pkglite offers an open file format to represent and exchange R packages as a text file. We use a mock-up example to demonstrate the workflow of using pkglite to prepare submission programs following the electronic common technical document specification. Conclusion: pkglite and the proposed workflow enable the sponsor to submit well-organized R scripts following the electronic common technical document specification. The workflow has been used in the first publicly available R-based submission to the US Food and Drug Administration by the R Consortium R submission working group ( https://www.r-consortium.org/blog/2022/03/16/update-successful-r-based-test-package-submitted-to-fda ).
Root Causes of Migration, Development, and US Aid to Northern Triangle States
Authors: Gerschutz-Bell Jill Marie 
Published: September 2022

For decades, governments have sought to deter migration by investing in the development of migrant-sending communities, despite macroeconomic data that shows that development can increase emigration. However, emerging research suggests that well-designed aid can promote rootedness in home communities. The US Agency for International Development (USAID) has increasingly attempted to use development to deter migration from the Northern Triangle states of Central America. Is this policy sound? This paper argues that development should not be instrumentalized to discourage people from migrating. It examines migration and development policies from the lens of Catholic social teaching, which recognizes the need for states to respect the agency of individuals. This is particularly important when it comes to complex and consequential decisions like whether to migrate. The Catholic Church recognizes both a right to migrate, when necessary, and the responsibility of states, particularly wealthy nations, to help people realize the right not to migrate; that is, to thrive in their home communities. The paper argues for US government assistance to alleviate poverty and invest in human capital in Central America, but independently of efforts to deter migration. Prioritizing aid to potential migrants risks reducing its effectiveness. The United States should instead pursue a whole-of-government strategy that emphasizes the right relationships with aid recipients, and that prioritizes and empowers the poor and marginalized. The paper is strongly influenced by the author's 15 years of work for Catholic agencies on migration and development, more than one-half of those with Catholic Relief Services.
Identifying genes associated with brain volumetric differences through tissue specific transcriptomic inference from GWAS summary data
Authors: Mai Hung , Bao Jingxuan , Thompson Paul M. , Kim Dokyoon , Shen Li 
Published: September 2022

AbstractBackgroundBrain volume has been widely studied in the neuroimaging field, since it is an important and heritable trait associated with brain development, aging and various neurological and psychiatric disorders. Genome-wide association studies (GWAS) have successfully identified numerous associations between genetic variants such as single nucleotide polymorphisms and complex traits like brain volume. However, it is unclear how these genetic variations influence regional gene expression levels, which may subsequently lead to phenotypic changes. S-PrediXcan is a tissue-specific transcriptomic data analysis method that can be applied to bridge this gap. In this work, we perform an S-PrediXcan analysis on GWAS summary data from two large imaging genetics initiatives, the UK Biobank and Enhancing Neuroimaging Genetics through Meta Analysis, to identify tissue-specific transcriptomic effects on two closely related brain volume measures: total brain volume (TBV) and intracranial volume (ICV).ResultsAs a result of the analysis, we identified 10 genes that are highly associated with both TBV and ICV. Nine out of 10 genes were found to be associated with TBV in another study using a different gene-based association analysis. Moreover, most of our discovered genes were also found to be correlated with multiple cognitive and behavioral traits. Further analyses revealed the protein–protein interactions, associated molecular pathways and biological functions that offer insight into how these genes function and interact with others.ConclusionsThese results confirm that S-PrediXcan can identify genes with tissue-specific transcriptomic effects on complex traits. The analysis also suggested novel genes whose expression levels are related to brain volumetric traits. This provides important insights into the genetic mechanisms of the human brain.
Lactase bacteria in intestinal mucosa are associated with diarrhea caused by high-fat and high-protein diet
Authors: Zhou Kang , Peng Maijiao , Deng Na , Tan Zhoujin , Xiao Nenqun 
Published: September 2022

Abstract
Background
Excessive fat and protein in food can cause diarrhea by disturbing the intestinal microecology. Lactase is a functional enzyme strongly associated with diarrhea, while lactase bacteria in the intestine are an important source of microbial lactase. Therefore, we reconnoiter the relationship between diarrhea induced by a high-fat and high-protein diet (HFHPD) and intestinal mucosal lactase bacteria from the perspective of functional genes.

Result
Operational Taxonomic Units (OTUs) were 23 and 31 in the normal group (NM) and model group (MD), respectively, and 11 of these were identical. The Chao1 and Observed specie indexes in the MD were higher than those in the NM, but this was not significant (P > 0.05). Meanwhile, the Principal coordinate analysis (PCoA) and Adonis test showed that the community structures of lactase bacteria in NM and MD were significantly different (P < 0.05). In taxonomic composition, lactase bacteria on the intestinal mucosa were sourced from Actinobacteria and Proteobacteria. Where Actinobacteria were higher in NM, and Proteobacteria were higher in MD. At the genus level, Bifidobacterium was the dominant genus (over 90% of the total). Compared to NM, the abundance of Bifidobacterium were lower in MD, while MD added sources for lactase bacteria of Rhizobium, Amycolatopsis, and Cedecea.

Conclusions
Our data demonstrate that HFHPD altered the community structure of lactase bacteria in the intestinal mucosa, decreased the abundance of the critical lactase bacteria, and promoted the occurrence of diarrhea.
Levels of depressive symptoms in cardiac patients attending cardiac rehabilitation with a history of depression: pre Covid-19 and Covid-19 period comparison
Authors: Sever Serdar , Harrison Alexander Stephen , Doherty Patrick 
Published: September 2022

Abstract
Background
The large-scale changes in cardiac rehabilitation (CR) programme delivery in response to COVID-19 has led to diminished provision. The influence of these service changes on the depression symptoms of patients in CR programmes is unknown. Our study investigated the extent of depressive symptoms prior to and during the COVID-19 periods in patients with a previous history of depression at the start of CR.

Methods
Use of Registry routine practice data, National Audit of Cardiac Rehabilitation (NACR), from COVID-19 period Feb 2020 and Jan 2021, as well as pre COVID-19 period Feb 2019 and Jan 2020, was extracted. Depressive symptoms were defined according to Hospital Anxiety and Depression Score ≥ 8. Chi-square tests and independent samples t-tests were used to investigate baseline characteristics. Additionally, a binary logistic regression to examine the factors associated with high levels of depressive symptoms.

Results
In total 3661 patients with a history of depression were included in the analysis. Patients attending CR during COVID-19 were found to be 11% more likely to have high levels of acute depressive symptoms compared to patients attending CR prior to COVID-19. Physical inactivity, increased anxiety, a higher total number of comorbidities, increased weight, and living in the most deprived areas were statistically significant factors associated with high levels of acute depressive symptoms at the start of CR following multivariate adjustments.

Conclusion
Our research suggests that following a cardiac event patients with prior history of depression have high levels of acute depressive symptoms at CR baseline assessment. This finding exists in both the pre Covid-19 and Covid-19 periods in patients with a history of depression.
A temporal analysis on patient and health service delays in pulmonary tuberculosis in Portugal: inter and intra‑regional differences and in(equalities) between gender and age
Authors: Chakma Bhaswar , Gomes Dulce , Filipe Patrícia A. , Soares Patrícia , de Sousa Bruno , Nunes Carla 
Published: September 2022

AbstractBackgroundTuberculosis (TB) diagnosis and treatment delays increase the period of infectiousness, making TB control difficult and increasing the fatality rates. This study aimed to determine the evolution of health care service delay (time between the patient’s first contact with the health service and the diagnosis/start of treatment) and patient delay (time between onset symptoms date and the date of first contact with health services) for Pulmonary Tuberculosis (PTB) in Portugal between 2008 and 2017 across different regions, age groups and gender.MethodsAn exploratory analysis was performed, trends of both delays were studied, and 36 months forecasts were generated. We used the permutation test to test differences between groups and the Seasonal and Trend decomposition using Loess (STL) method and Autoregressive Integrated Moving Average (ARIMA) models for forecasting for both Health and Patient delays. We used data from notified PTB cases in mainland Portugal between 2008 and 2017, provided by the national surveillance system.ResultsHealth delays remained relatively constant while patient delays increased. Females had significantly higher health delays in some regions. Individuals older than 64 had higher health delays than younger individuals, while patient delay for working-age individuals between 15 and 64 years old, presents higher patient delay.ConclusionsForecasts presage that the upward trend of the delays is unlikely to fall in the coming years. It is important to understand the evolution of the delays and predict how these will evolve. Our understanding of the delays behaviours will contribute to better health policies and resources allocation.
Consolidation radiographic morphology can be an indicator of the pathological basis and prognosis of partially solid nodules
Authors: Xie Mei , Gao Jie , Ma Xidong , Wu Chongchong , Zang Xuelei , Wang Yuanyong , Deng Hui , Yao Jie , Sun Tingting , Yu Zhaofeng , Liu Sanhong , Zhuang Guanglei , Xue Xinying , Wu Jianlin , Wang Jianxin 
Published: September 2022

Abstract
Background
Part-solid nodules (PSNs) have gradually shifted to defining special clinical subtypes. Commonly, the solid portions of PSNs show various radiological morphologies, of which the corresponding pathological basis and prognosis are unclear. We conducted a radiological–pathological evaluation to determine the histopathologic basis of different consolidation radiographic morphologies related to prognosis.

Materials and methods
A cohort of 275 patients with a surgical pathological diagnosis of lung adenocarcinoma were enrolled. Preoperative computed tomography (CT) images of the PSNs were recorded and assessed. A panel of 103 patients with complete pathological specimens was selected to examine the radiological–pathological associations, and follow-up was performed to identify the prognosis.

Results
Of the 275 patients, punctate consolidation was observed radiologically in 43/275 (15.7%), stripe consolidation in 68/275 (24.7%), and irregular consolidation in 164/275 (59.6%) patients. The radiological morphology of the solid components was significantly associated with the histopathological subtypes (P < 0.001). Visual punctate solid components on CT correlated with tertiary lymphoid structures, stripe solid components on CT correlated with fibrotic scar, and irregular solid components on CT correlated with invasion. PSNs with regular consolidation had a better prognosis than those with irregular consolidation.

Conclusion
Radiological morphology of solid components in PSNs can indicate the pathological basis and is valuable for prognosis. In particular, irregular solid components in PSNs usually indicate serious invasive growth, which should be taken with caution during assessment.
Dapagliflozin reduces the vulnerability of rats with pulmonary arterial hypertension-induced right heart failure to ventricular arrhythmia by restoring calcium handling
Authors: Wu Jinchun , Liu Tao , Shi Shaobo , Fan Zhixing , Hiram Roddy , Xiong Feng , Cui Bo , Su Xiaoling , Chang Rong , Zhang Wei , Yan Min , Tang Yanhong , Huang He , Wu Gang , Huang Congxin 
Published: September 2022

Abstract
Background
Malignant ventricular arrhythmia (VA) is a major contributor to sudden cardiac death (SCD) in patients with pulmonary arterial hypertension (PAH)-induced right heart failure (RHF). Recently, dapagliflozin (DAPA), a sodium/glucose cotransporter-2 inhibitor (SGLT2i), has been found to exhibit cardioprotective effects in patients with left ventricular systolic dysfunction. In this study, we examined the effects of DAPA on VA vulnerability in a rat model of PAH-induced RHF.

Methods
Rats randomly received monocrotaline (MCT, 60 mg/kg) or vehicle via a single intraperitoneal injection. A day later, MCT-injected rats were randomly treated with placebo, low-dose DAPA (1 mg/kg/day), or high-dose (3 mg/kg/day) DAPA orally for 35 days. Echocardiographic analysis, haemodynamic experiments, and histological assessments were subsequently performed to confirm the presence of PAH-induced RHF. Right ventricle (RV) expression of calcium (Ca2+) handling proteins were detected via Western blotting. RV expression of connexin 43 (Cx43) was determined via immunohistochemical staining. An optical mapping study was performed to assess the electrophysiological characteristics in isolated hearts. Cellular Ca2+ imaging from RV cardiomyocytes (RVCMs) was recorded using Fura-2 AM or Fluo-4 AM.

Results
High-dose DAPA treatment attenuated RV structural remodelling, improved RV function, alleviated Cx43 remodelling, increased the conduction velocity, restored the expression of key Ca2+ handling proteins, increased the threshold for Ca2+ and action potential duration (APD) alternans, decreased susceptibility to spatially discordant APD alternans and spontaneous Ca2+ events, promoted cellular Ca2+ handling, and reduced VA vulnerability in PAH-induced RHF rats. Low-dose DAPA treatment also showed antiarrhythmic effects in hearts with PAH-induced RHF, although with a lower level of efficacy.

Conclusion
DAPA administration reduced VA vulnerability in rats with PAH-induced RHF by improving RVCM Ca2+ handling.
Epidermal nevus syndrome with the mutation of PTCH1 gene and cerebral infarction: a case report and review of the literature
Authors: Deng QingQing , Li Yan , Liu ZhanLi , Zhou JieLin , Weng LingWei 
Published: September 2022

Abstract
Background
Epidermal nevus syndrome is a group of congenital neuroectodermal and/or mesodermal disorders characterized by the epidermal nevi in common association with cerebral, eye, skeletal, cardiovascular, and renal abnormalities. Epidermal nevus syndrome is a rare syndrome, and epidermal nevus syndrome with the mutation of PTCH1 gene and cerebral infarction is even rarer and has not been reported to the best of our knowledge.

Case presentation
We report the case of a 10-month-old Chinese female patient who presented to our pediatric neurologic department, University of Wenzhou medical teaching Hospital, Hangzhou. She has mobility disorders on the right limbs and recurrent seizures. She had congenital disorder accompanied by brownish-black and verrucose plaques on the right side of the face as well as extensive brownish-black plaques and brown nevi on the right side of the trunk and the right arm. Epidermal nevus syndrome was diagnosed on the basis of her symptoms. Somatic sebaceous nevi and hypoplastic defects of skin, cerebra, eyes, skeleton, and cardiovascular and renal system were observed. However, in addition to the typical clinical characteristics, the patient also has a mutation (c.109G > T) in PTCH1 gene and cerebral infarction. We present a novel case report and literature review.

Conclusion
To our knowledge, epidermal nevus syndrome with a mutation of PTCH1 gene and cerebral infarction has not been reported previously. This case report may contribute to characterizing the phenotype of epidermal nevus syndrome, help clinicians be aware of the association of this condition with PTCH1 gene and cerebral infarction, raise clinical suspicion, and improve early therapy.
Proteasome-mediated regulation of interleukin-1β turnover and export in human monocytes
Authors: Moors Marlena A , Mizel Steven B 
Published: September 2022

Abstract
Interleukin-1β is a secreted protein that accumulates in the cytosol as an inactive precursor (pIL-1β) before processing and release of biologically active protein. To understand the impact of this property on IL-1β production, we examined the intracellular stability of pIL-1β in lipopolysaccharide (LPS)-stimulated human monocytes. Precursor IL-1β was degraded with a relatively short half-life of 2.5 h in the promonocytic cell line, THP-1, and in primary monocytes. MG132 (carbobenzoxyl-leucinyl-leucinyl-leucinal) stabilized pIL-1β levels in THP-1 cells, suggesting that degradation was proteasome-mediated, but this inhibitor was toxic for primary monocytes, causing release of pIL-1β as well as the cytoplasmic enzyme, lactate dehydrogenase (LDH) into supernatants. In contrast, clasto-lactacystin β-lactone, a specific inhibitor of the proteasome, caused a dose-dependent stabilization of intracellular pIL-1β, and this led to a corresponding increase in mIL-1β and pIL-1β but not LDH release into culture supernatants. Therefore, by regulating intracellular levels of precursor IL-1β, the proteasome plays an important and previously unrecognized role in controlling the amount of biologically active IL-1β that is exported by activated monocytes.
The colony-stimulating factors and collagen-induced arthritis: exacerbation of disease by M-CSF and G-CSF and requirement for endogenous M-CSF
Authors: Campbell Ian K , Rich Melissa J , Bischof Robert J , Hamilton John A 
Published: September 2022

AbstractThere is increasing evidence that the colony-stimulating factors (CSFs) may play a part in chronic inflammatory autoimmune diseases, such as rheumatoid arthritis (RA). We examined the involvement of macrophage CSF (M-CSF or CSF-1) and granulocyte CSF (G-CSF) in collagen-induced arthritis (CIA), a murine model of RA. Daily injections of M-CSF or G-CSF, 20–24 days postprimary immunization with type II collagen, exacerbated disease symptoms in suboptimally immunized DBA/1 mice. Support for the involvement of endogenous M-CSF in CIA was obtained by studies in which neutralizing monoclonal antibody reduced the severity of established CIA and also by studies showing the resistance of M-CSF-deficient op/op mice to CIA induction. These studies show that M-CSF and G-CSF can be proinflammatory in CIA and provide evidence that macrophage- and granulocyte-lineage cells can exacerbate CIA. Our results also show that M-CSF-dependent cells are essential for CIA development, suggesting M-CSF may be a suitable target for therapeutic intervention in RA.
Adhesion of human lung mast cells to bronchial epithelium: evidence for a novel carbohydrate-mediated mechanism
Authors: Sanmugalingam Devika , Wardlaw Andrew J , Bradding Peter 
Published: September 2022

Abstract
Mast cells contribute to the pathophysiology of asthma through their immunomediator-secretory activity in response to both immunological and nonimmunological stimuli, and infiltrate the bronchial epithelium in this disease. We hypothesized that human lung mast cells (HLMC) localize to the bronchial epithelium via a specific cell-cell adhesion mechanism. We investigated the adhesion of HLMC to primary bronchial epithelial cells and the bronchial epithelial cell line BEAS-2B. HLMC adhered avidly to both primary cultures of bronchial epithelial cells and BEAS-2B cells (mean adhesion 68.4 and 60.1%, respectively) compared with eosinophil adhesion to BEAS-2B (mean adhesion 10.3%). HLMC adhesion did not alter after epithelial activation with cytokines, did not require Ca2+, and was not integrin-mediated. IgE-dependent activation of HLMC produced an approximately 40% inhibition of adhesion. There was significant attenuation of adhesion after incubation of HLMC with pronase, β-galactosidase, and endo-α-N-acetylgalactosaminidase, indicating that HLMC adhere to bronchial epithelial cells via galactose-bearing carbohydrates expressed on a cell-surface peptide(s).
Sulfatide binding and activation of leukocytes through an L-selectin-independent pathway
Authors: Ding Ziqiang , Kawashima Hiroto , Miyasaka Masayuki 
Published: September 2022

Abstract
Sulfatide has been reported to activate leukocytes through L-selectin. Here we provide evidence that sulfatide binds to and activates leukocytes through both L-selectin-dependent and -independent pathways. Rat leukocytes of various sources shed surface L-selectin after phorbol myristate acetate (PMA) treatment, however, these cells retained the ability to bind sulfatide. In addition, sulfatide also bound to an L-selectin-negative cell line EL-4, and the binding was up-regulated by PMA. Sulfatide induced aggregation of L-selectin-positive lymphocytes, which was highly dependent on divalent cations, protein tyrosine kinases (PTK), and protein kinase C (PKC), but was independent of β1 and β2 integrins. In contrast, sulfatide-induced EL-4 cell aggregation required an LFA-1/ICAM-1 adhesion pathway but not PTK and PKC. A sulfatide receptor of 65 kDa was isolated from EL-4 cells. Taken together, this study suggests that sulfatide can bind to and activate leukocytes through an L-selectin-independent molecule and triggers signal transduction pathways different from those induced by L-selectin activation.