bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chromatin modifier developmental pluripotency associated factor 4 (DPPA4) is a candidate gene for alcohol-induced developmental disorders
Authors: Auvinen P. , Vehviläinen J. , Marjonen H. , Modhukur V. , Sokka J. , Wallén E. , Rämö K. , Ahola L. , Salumets A. , Otonkoski T. , Skottman H. , Ollikainen M. , Trokovic R. , Kahila H. , Kaminen-Ahola N. 
Published: December 2022

Abstract
Background
Prenatal alcohol exposure (PAE) affects embryonic development, causing a variable fetal alcohol spectrum disorder (FASD) phenotype with neuronal disorders and birth defects. We hypothesize that early alcohol-induced epigenetic changes disrupt the accurate developmental programming of embryo and consequently cause the complex phenotype of developmental disorders. To explore the etiology of FASD, we collected unique biological samples of 80 severely alcohol-exposed and 100 control newborns at birth.

Methods
We performed genome-wide DNA methylation (DNAm) and gene expression analyses of placentas by using microarrays (EPIC, Illumina) and mRNA sequencing, respectively. To test the manifestation of observed PAE-associated DNAm changes in embryonic tissues as well as potential biomarkers for PAE, we examined if the changes can be detected also in white blood cells or buccal epithelial cells of the same newborns by EpiTYPER. To explore the early effects of alcohol on extraembryonic placental tissue, we selected 27 newborns whose mothers had consumed alcohol up to gestational week 7 at maximum to the separate analyses. Furthermore, to explore the effects of early alcohol exposure on embryonic cells, human embryonic stem cells (hESCs) as well as hESCs during differentiation into endodermal, mesodermal, and ectodermal cells were exposed to alcohol in vitro.

Results
DPPA4, FOXP2, and TACR3 with significantly decreased DNAm were discovered—particularly the regulatory region of DPPA4 in the early alcohol-exposed placentas. When hESCs were exposed to alcohol in vitro, significantly altered regulation of DPPA2, a closely linked heterodimer of DPPA4, was observed. While the regulatory region of DPPA4 was unmethylated in both control and alcohol-exposed hESCs, alcohol-induced decreased DNAm similar to placenta was seen in in vitro differentiated mesodermal and ectodermal cells. Furthermore, common genes with alcohol-associated DNAm changes in placenta and hESCs were linked exclusively to the neurodevelopmental pathways in the enrichment analysis, which emphasizes the value of placental tissue when analyzing the effects of prenatal environment on human development.

Conclusions
Our study shows the effects of early alcohol exposure on human embryonic and extraembryonic cells, introduces candidate genes for alcohol-induced developmental disorders, and reveals potential biomarkers for prenatal alcohol exposure.
Improved natural melanin production by Aspergillus nidulans after optimization of factors involved in the pigment biosynthesis pathway
Authors: Medeiros William Bartolomeu , Medina Kelly Johana Dussán , Sponchiado Sandra Regina Pombeiro 
Published: December 2022

Abstract
Background
Melanin is a natural pigment that can be applied in different fields such as medicine, environment, pharmaceutical, and nanotechnology. Studies carried out previously showed that the melanin produced by the mel1 mutant from Aspergillus nidulans exhibits antioxidant, anti-inflammatory, and antimicrobial activities, without any cytotoxic or mutagenic effect. These results taken together suggest the potential application of melanin from A. nidulans in the pharmaceutical industry. In this context, this study aimed to evaluate the effect of factors L-tyrosine, glucose, glutamic acid, l-DOPA, and copper on melanin production by the mel1 mutant and to establish the optimal concentration of these factors to maximize melanin production.

Results
The results showed that l-DOPA, glucose, and copper sulfate significantly affected melanin production, where l-DOPA was the only factor that exerted a positive effect on melanin yield. Besides, the tyrosinase activity was higher in the presence of l-DOPA, considered a substrate required for enzyme activation, this would explain the increased production of melanin in this condition. After establishing the optimal concentrations of the analyzed factors, the melanin synthesis was increased by 640% compared to the previous studies.

Conclusions
This study contributed to elucidating the mechanisms involved in melanin synthesis in A. nidulans as well as to determining the optimal composition of the culture medium for greater melanin production that will make it possible to scale the process for a future biotechnological application.
The whole-of-society approach of mass COVID-19 vaccination in China: a qualitative study
Authors: Wang Qian , Qu Zhiqiang , Tu Shiyi , Chen Xi , Hou Zhiyuan 
Published: December 2022

Abstract
Background
Many countries have an inefficient vaccination system, which hinders global exit from the COVID-19 pandemic. It is vital to summarize COVID-19 vaccination practices in countries with high vaccination coverage and provide implications for other countries. This study aimed to investigate China’s COVID-19 vaccination system and to summarize its implementation experience from a health system perspective.

Methods
We conducted key informant interviews in five representative cities of China in late 2021. Guided by the health systems framework proposed by WHO, we developed our interview guidelines which included seven building blocks—leadership and governance, health workforce, vaccination service delivery, vaccination mobilization and communication, financing, access to vaccines, and information systems. Semi-structured interviews and COVID-19 vaccination policy documents were collected and coded using a thematic analysis approach.

Results
A total of 61 participants (nine vaccination programme directors of the local Center for Disease Control and Prevention, four government staff and 48 vaccination service workers) were interviewed. We found that China adopted a whole-of-society approach with adequate government engagement and linked health and non-health sectors to promote COVID-19 vaccination. Key measures included the collaboration of multiple systems and departments from a governance perspective, allocating sufficient health workers and resources, large-scale vaccination mobilization and communication, expansion of vaccine financing channels, localized production and digital information systems. With the vaccination system strengthening, the two-doses vaccination coverage reached 89.5% for the total population but relatively lower coverage for older adults as of July 2022.

Conclusions
Our study highlights the importance of a government-led whole-of-society approach to promote mass vaccination. The low vaccination coverage among older adults should be paid the greatest attention to. The experiences and lessons from China may serve as a reference for other countries.
Modular hip exoskeleton improves walking function and reduces sedentary time in community-dwelling older adults
Authors: Jayaraman Chandrasekaran , Embry Kyle R. , Mummidisetty Chaithanya K. , Moon Yaejin , Giffhorn Matt , Prokup Sara , Lim Bokman , Lee Jusuk , Lee Younbaek , Lee Minhyung , Jayaraman Arun 
Published: December 2022

Abstract
Background
Despite the benefits of physical activity for healthy physical and cognitive aging, 35% of adults over the age of 75 in the United States are inactive. Robotic exoskeleton-based exercise studies have shown benefits in improving walking function, but most are conducted in clinical settings with a neurologically impaired population. Emerging technology is starting to enable easy-to-use, lightweight, wearable robots, but their impact in the otherwise healthy older adult population remains mostly unknown. For the first time, this study investigates the feasibility and efficacy of using a lightweight, modular hip exoskeleton for in-community gait training in the older adult population to improve walking function.

Methods
Twelve adults over the age of 65 were enrolled in a gait training intervention involving twelve 30-min sessions using the Gait Enhancing and Motivating System for Hip in their own senior living community.

Results
Performance-based outcome measures suggest clinically significant improvements in balance, gait speed, and endurance following the exoskeleton training, and the device was safe and well tolerated. Gait speed below 1.0 m/s is an indicator of fall risk, and two out of the four participants below this threshold increased their self-selected gait speed over 1.0 m/s after intervention. Time spent in sedentary behavior also decreased significantly.

Conclusions
This intervention resulted in greater improvements in speed and endurance than traditional exercise programs, in significantly less time. Together, our results demonstrated that exoskeleton-based gait training is an effective intervention and novel approach to encouraging older adults to exercise and reduce sedentary time, while improving walking function. Future work will focus on whether the device can be used independently long-term by older adults as an everyday exercise and community-use personal mobility device.
Trial registration This study was retrospectively registered with ClinicalTrials.gov (ID: NCT05197127).
Inhibition of NUCB2 suppresses the proliferation, migration, and invasion of rheumatoid arthritis synovial fibroblasts from patients with rheumatoid arthritis in vitro
Authors: Zhang Shuo , Zhang Tao , Xu Yayun , Rong Genxiang , Jing Juehua 
Published: December 2022

AbstractRheumatoid arthritis (RA) is an autoimmune polyarthritis in which synovial fibroblasts (SF) play a major role in cartilage and bone destruction through tumorlike proliferation, migration, and invasion. Nesfatin-1, an 82-amino-acid-long peptide discovered by Oh-I in 2006, is derived from the precursor protein nucleobindin-2 (NUCB2). NUCB2/nesfatin-1 promotes cell proliferation, migration, and invasion in various tumors. We have previously shown that increased nesfatin-1 levels in the synovium may be associated with disease severity in patients with RA. However, the effect of NUCB2 on the tumorlike transformation of RASF has not yet been reported. The expression of NUCB2 mRNA in the synovium of RA and non-RA patients was further confirmed using three individual datasets from the NCBI GEO database. Gene set enrichment analysis (GSEA) was employed to explore the association between NUCB2 mRNA and RA-related gene signatures or signaling pathways in the GSE77298 dataset. Cell proliferation, migration, and invasion abilities were determined using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), wound healing, and transwell assays, respectively. The results showed that the levels of NUCB2 mRNA in the synovium were significantly elevated in patients with RA. Moreover, GSEA showed that high expression of NUCB2 mRNA was related to gene signatures, including those involved in the cell cycle, DNA replication, extracellular matrix–receptor interaction, and focal adhesion. Furthermore, the results of CCK-8 and EdU assays indicated that inhibition of NUCB2 markedly repressed RASF proliferation. Additionally, the results of wound healing and transwell assays demonstrated that inhibition of NUCB2 significantly suppressed the migratory and invasive abilities of RASFs. Our findings are the first to demonstrate that the inhibition of NUCB2 suppresses the proliferation, migration, and invasion of RASFs in vitro.
Relation of dietary insulin index and dietary insulin load to metabolic syndrome depending on the lifestyle factors: Tehran lipid and glucose study
Authors: Khoshnoudi-Rad Bayyeneh , Hosseinpour-Niazi Somayeh , Javadi Maryam , Mirmiran Parvin , Azizi Fereidoun 
Published: December 2022

Abstract
Aim
The hypothesis of the effect of the insulinogenic effects of diet on the development of cardiovascular diseases has been proposed, but the findings of previous studies are very contradictory. We investigated the association between dietary insulin index (DII) and dietary insulin load (DIL), and metabolic syndrome (MetS) risk. Another objective was to examine the extent to which lifestyle (physical activity, smoking status, and weight change) and sex influence the relationship between DII, DIL, and MetS risk.

Materials and methods
We followed 1915 participants in the Tehran Lipid and Glucose Study. DIL and DII were calculated based on a validated food frequency questionnaire. Weight change was measured, and participants were categorized into > 3% weight loss, weight stable (± 3%), and > 3% weight gain. By joint classification, the association between DII and DIL (< median and ≥ median) and risk of MetS was assessed according to weight change, sex, physical activity levels, and smoking status. Cox proportional hazards models were used to estimate the HRs (95% CI), adjusting for potential confounders.

Results
During 8.9 years of follow-up, among 1915 participants, we documented 591 new cases of MetS. DII and DIL were not associated with MetS risk in the crude and adjusted models. However, DIL and DII were associated with weight gain (≥ 3%). In the crude model, DIL and DII were associated with a higher risk of weight gain [HR: 1.74: 95% CI 1.50–2.03, and 1.70 (1.46–1.98), respectively]. These associations remained significant after further adjustment for confounders. The HRs were 1.61 (1.35–1.92) for DIL and 1.64 (1.39–1.93) for DII. Among men, women, participants with low physical activity levels, and smokers, the risk of MetS, independent of DIL and DII, only increased in a participant with weight gain. In women with weight stability, DIL and DII, higher than the median, were positively associated with MetS risk.

Conclusion
Our findings suggest that the association between MetS risk and a hyperinsulinemic diet depended on weight change.
Whole-blood methylation signatures are associated with and accurately classify multiple sclerosis disease severity
Authors: Campagna Maria Pia , Xavier Alexandre , Lea Rodney A. , Stankovich Jim , Maltby Vicki E. , Butzkueven Helmut , Lechner-Scott Jeannette , Scott Rodney J. , Jokubaitis Vilija G. 
Published: December 2022

AbstractBackgroundThe variation in multiple sclerosis (MS) disease severity is incompletely explained by genetics, suggesting genetic and environmental interactions are involved. Moreover, the lack of prognostic biomarkers makes it difficult for clinicians to optimise care. DNA methylation is one epigenetic mechanism by which gene–environment interactions can be assessed. Here, we aimed to identify DNA methylation patterns associated with mild and severe relapse-onset MS (RMS) and to test the utility of methylation as a predictive biomarker.MethodsWe conducted an epigenome-wide association study between 235 females with mild (n = 119) or severe (n = 116) with RMS. Methylation was measured with the Illumina methylationEPIC array and analysed using logistic regression. To generate hypotheses about the functional consequence of differential methylation, we conducted gene set enrichment analysis usingToppGene. We compared the accuracy of three machine learning models in classifying disease severity: (1) clinical data available at baseline (age at onset and first symptoms) built using elastic net (EN) regression, (2) methylation data using EN regression and (3) a weighted methylation risk score of differentially methylated positions (DMPs) from the main analysis using logistic regression. We used a conservative 70:30 test:train split for classification modelling. A false discovery rate threshold of 0.05 was used to assess statistical significance.ResultsFemales with mild or severe RMS had 1472 DMPs in whole blood (839 hypermethylated, 633 hypomethylated in the severe group). Differential methylation was enriched in genes related to neuronal cellular compartments and processes, and B-cell receptor signalling. Whole-blood methylation levels at 1708 correlated CpG sites classified disease severity more accurately (machine learning model 2, AUC = 0.91) than clinical data (model 1, AUC = 0.74) or the wMRS (model 3, AUC = 0.77). Of the 1708 selected CpGs, 100 overlapped with DMPs from the main analysis at the gene level. These overlapping genes were enriched in neuron projection and dendrite extension, lending support to our finding that neuronal processes, rather than immune processes, are implicated in disease severity.ConclusionRMS disease severity is associated with whole-blood methylation at genes related to neuronal structure and function. Moreover, correlated whole-blood methylation patterns can assign disease severity in females with RMS more accurately than clinical data available at diagnosis.
Brucellosis with rare complications and review of diagnostic tests: a case report
Authors: Altunçekiç Yildirim Arzu , Kurt Celali , Çetinkol Yeliz 
Published: December 2022

Abstract
Background
Brucellosis is one of the most common zoonotic diseases in the world. Osteoarticular complications, especially vertebral system involvement, are most commonly reported. However, reports and coreports of pulmonary complications and thoracal spondylodiscitis and epidural abscess are rare.

Case presentation
Spondylodiscitis was detected at the T11–12 vertebral level, followed by epidural and paravertebral abscess, and then empyema was detected in a 17-year-old Asian female patient without any additional disease. The patient had used various antibiotics and the disease could not be proven bacteriologically. Also, the Rose Bengal test was negative. However, serologically high titer Brucella positivity was detected in the blood and pleural fluid sample. Drainage was required for bilateral empyema. Disease duration prolonged due to multiple complications. The patient was cured with combined long-term treatment for brucellosis.

Conclusions
Although some are rare, brucellosis is a zoonotic disease that can cause many complications. The gold standard for diagnosis is the growth of bacteria in blood culture or tissue culture. However, isolation of the microorganism can be very difficult. Clinical suspicion and serological tests are important guides.
Pediatric sigmoid colonic perforation with Campylobacter enterocolitis: a case report and review of the literature
Authors: Chu Yung-Yu , Lin Cheng-Yi , Kuo Tien-Lin , Mu Shu-Chi , Lau Beng-Huat , Chou Yuh-Yu 
Published: December 2022

Abstract
Background
Campylobacter-related infectious gastroenteritis is common and usually self-limited. Intestinal perforation is a rare complication of the infectious colitis caused by Campylobacter, and only handful of cases have been reported. This is the first published case report of pediatric Campylobacter intestinal perforation located in the sigmoid colon.

Case presentation
A 15-year-old previously Taiwanese healthy boy presented with 5 days of fever up to 39.8 °C, with right lower quadrant abdominal pain and watery diarrhea. Although he received antimotility agents and antipyretics at a local clinic to relieve symptoms, he came to the emergency department with signs of shock manifesting as hypothermia to 35.2 °C, tachycardia, and low blood pressure. Laboratory testing demonstrated leukocytosis with left shift and significant elevation of C-reactive protein. Stool and blood cultures were obtained, and he was admitted for fluid challenge and antibiotic treatment. On the second day of admission, he suffered from sudden onset of severe, diffuse abdominal pain. Physical examination revealed muscle guarding, rebounding tenderness, and silent bowel sound. Abdominal X-ray showed subdiaphragmatic free air at standing view. The patient underwent emergent exploratory laparotomy, which revealed sigmoid colon perforation about 0.5 cm. Enterolysis and repair of sigmoid colon were performed. Intraoperative stool specimen nucleic acid amplification testing had turned positive for Campylobacter spp. with negative results for other bacterial pathogens. His symptoms improved and he tolerated food well, and was discharged 15 days after admission.

Conclusions
We present this case because of the rarity of Campylobacter-induced sigmoid colon perforation in the pediatric population. It is important to keep in mind that sigmoid colon perforation can be due to an infectious cause, and one of the culprits can be Campylobacter. Infectious colitis caused by Campylobacter spp. should be managed cautiously and the use of antimotility agents in such conditions should be considered judiciously.
Prescribing pattern of anti-hypertensive medications among hypertensive outpatients at selected hospitals of South Gondar Zone, Amhara, Ethiopia: a hospital based cross sectional study
Authors: Yazie Taklo Simeneh , Yimer Yohannes Shumet , Belete Abebe Muche , Desta Getaye Tessema 
Published: December 2022

Abstract
Background
Irrational prescription has a lion share for uncontrolled blood pressure. There is no study assessing prescription pattern among hypertensive patients at the study sites. Therefore, the objective of the current study was to evaluate prescription patterns for hypertension and blood pressure (BP) control at randomly selected hospitals of South Gondar Zone.

Methods
A hospital based cross sectional study was conducted from December 1, 2020 to February 30, 2021. Hypertensive patients were selected by systematic random sampling proportionally from study hospitals. Structured questionnaires were used to collect socio-demographic chacteristics and adherence. Data abstraction form was used to collect prescription patterns, BP level and other necessary information. The association of prescription patterns and other variables with blood pressure control was determined by using binary logistic regression.

Results
All recruited 423 patients were included in data analysis. Among prescriptions for hypertension, on average 93.5% were found to be in line with WHO guideline. About 53% of prescriptions for hypertension were monotherapies. Patient level low medication regimen complexity, and monotherapy were associated with blood pressure control (Ajusted Odds Ratio [AOR] = 2.04, [1.07–3.91]; AOR = 3.83 [1.42–10.35], respectively). Patients with inappropriate drug selection, and non-adherence were less likely to have controlled BP (AOR = 0.47 [0.26–0.85]; AOR = 0.52 [0.34–0.85], respectively). Moreover, patients who didn’t have health insurance and follow regular aerobic exercise were less likely to have controlled BP (AOR = 0.42 [0.26–0.68]; AOR = 0.53 [0.32–0.88], respectively).

Conclusion
Diuretics were the most frequently prescribed drug in monotherapy and in combination with calcium channel blockers (CCBs) as dual therapy. On average, more than 90% of prescription was in accordance with WHO guideline and around one-third of participants experienced at least one moderate or major drug-drug interaction. Patient level low medication regimen complexity and monotherapy were positively associated with BP control whereas, non-adherence, inappropriate drug selection, having no health insurance, and didn’t follow regular aerobic exercise were negatively associated with BP control. Clinicians should be adherent to treatment guidelines and focus on modifiable factors to improve BP control.