bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing the impact of the Good Samaritan Law in the state of Connecticut: a system dynamics approach
Authors: Sabounchi Nasim S. , Heckmann Rebekah , D’Onofrio Gail , Walker Jennifer , Heimer Robert 
Published: January 2022

Abstract
Background
Although Good Samaritan laws (GSLs) have been widely adopted throughout the United States, their efficacy in individual states is often unknown. This paper offers an approach for assessing the impact of GSLs and insight for policy-makers and public health officials who wish to know whether they should expect to see outcomes from similar policy interventions.

Methods
Utilizing a system dynamics (SD) modeling approach, the research team conducted a policy evaluation to determine the impact of GSLs on opioid use disorder (OUD) in Connecticut and evaluated the GSL based upon the following health outcomes: (1) emergency department (ED) visits for overdose, (2) behavioral changes of bystanders, and (3) overdose deaths.

Results
The simulation model suggests that Connecticut’s GSL has not yet affected overdose deaths but has resulted in bystander behavioral changes, such as increased 911 calls for overdose. ED visits have increased as the number of opioid users has increased.

Conclusions
The simulation results indicate that the number of opioid-related deaths will continue to increase and that the GSL alone cannot effectively control the crisis. However, the SD approach that was used will allow policymakers to evaluate the effectiveness of the GSL over time using a simulation framework. This SD model demonstrates great potential by producing simulations that allow policymakers to assess multiple strategies for combating the opioid crisis and select optimal public health interventions.
Clinical and patient-centered implementation outcomes of mHealth interventions for type 2 diabetes in low-and-middle income countries: a systematic review
Authors: Mokaya Moses , Kyallo Florence , Vangoitsenhoven Roman , Matthys Christophe 
Published: January 2022

Abstract
Background
The prevalence of Type 2 Diabetes is rising in Low- and Middle-Income Countries (LMICs), affecting all age categories and resulting in huge socioeconomic implications. Mobile health (mHealth) is a potential high-impact approach to improve clinical and patient-centered outcomes despite the barriers of cost, language, literacy, and internet connectivity. Therefore, it is valuable to examine the clinical and implementation outcomes of mHealth interventions for Type 2 Diabetes in LMICs.

Methods
The Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) guidelines were applied in framing and reporting the review criteria. A systematic search of Cochrane Library, Web of Science, PubMed, Scopus, and Ovid databases was performed through a combination of search terms. Randomized Controlled Trials (RCTs) and cohort studies published in English between January 2010 and August 2021 were included. Risk of bias for missing results in the included studies was assessed using the Cochrane risk-of-bias tool for randomized trials (RoB 2). Quantitative and qualitative methods were used to synthesize the results.

Results
The search identified a total of 1161 articles. Thirty studies from 14 LMICs met the eligibility criteria. On clinical outcomes, 12 and 9 studies reported on glycated hemoglobin (HbA1c )and fasting blood glucose (FBG) respectively. Text messages was the most commonly applied mHealth approach, used in 19 out of the 30 studies. Ten out of the 12 studies (83.3%) that reported on HbA1c had a percentage difference of <0.3% between the mHealth intervention and the comparison group. Additionally, studies with longer intervention periods had higher effect size and percentage difference on HbA1c (1.52 to 2.92%). Patient-centred implementation outcomes were reported variedly, where feasibility was reported in all studies. Acceptability was reported in nine studies, appropriateness in six studies and cost in four studies. mHealth evidence reporting and assessment (mERA) guidelines were not applied in all the studies in this review.

Conclusion
mHealth interventions in LMICs are associated with clinically significant effectiveness on HbA1 but have low effectiveness on FBG. The application of mERA guidelines may standardize reporting of patient-centered implementation outcomes in LMICs.

Trial registration
PROSPERO: Registration ID 154209.
Importance of characterising sleep breaks within the 24-h movement behaviour framework
Authors: Sabia Séverine , Yerramalla Manasa Shanta , Liu-Ambrose Teresa 
Published: January 2022

AbstractAccelerometers measure the acceleration of the body part they are attached and allow to estimate time spent in activity levels (sedentary behaviour, light, and moderate-to-vigorous physical activity) and sleep over a 24-h period for several consecutive days. These advantages come with the challenges to analyse the large amount of data while integrating dimensions of both physical activity/sedentary behaviour and sleep domains. This commentary raises the questions of 1) how to classify sleep breaks (i.e. wake after sleep onset) during the night within the 24-h movement behaviour framework and 2) how to assess their impact on health while also accounting for night time sleep duration and time in sedentary behaviour and physical activity during the day. The authors advocate for future collaborations between researchers from the physical activity/sedentary behaviour and sleep research fields to ensure appropriate analysis and interpretation of the tremendous amount of data recorded by the newer generation accelerometers. This is the only way forward to provide meaningfully accurate evidence to inform future 24-h movement behaviour guidelines.
Bacterial infections exacerbate myeloma bone disease
Authors: Liu Rui , Zhong Yuping , Chen Rui , Chen Shiyi , Huang Yazhu , Liu Huan 
Published: January 2022

AbstractMultiple myeloma is characterized by osteolytic lesions caused by reduced bone formation and activated bone resorption. An important feature of myeloma is a failure of bone healing after successful treatment. In this work, clinical studies indicated a highly positive correlation between bone marrow bacteria abundance and bone lesion numbers of myeloma patients in complete remission. Coculture experiments demonstrated that marrow Escherichia coli (E. coli) promotes osteoclast differentiation and inhibits osteoblast differentiation. Mechanism studies showed that E. coli lipopolysaccharides (LPS) activated NF-κB p65 signaling and reduced phosphorylated smad1/5/9 binding ability with RUNX2 promoter, leading to decreased RUNX2 expression in osteoblast progenitors. Additionally, LPS enhanced phosphorylated NF-κB p65 binding ability with NFATc1 promoter, leading to increased NFATc1 expression in osteoclast progenitors. In vivo studies revealed E. coli contributes to osteolytic bone lesion, and elimination of E. coli infection assists healing of bone lesion in mouse model of myeloma in complete remission. These findings establish a heretofore unrecognized effect for E. coli in the genesis of myeloma bone disease and suggest a new treatment strategy.
MiR-30c-5p loss-induced PELI1 accumulation regulates cell proliferation and migration via activating PI3K/AKT pathway in papillary thyroid carcinoma
Authors: Zheng Tingting , Zhou Youxing , Xu Xiaowei , Qi Xin , Liu Jiameng , Pu Yanan , Zhang Shan , Gao Xuerong , Luo Xinkai , Li Mei , Wang Xuefeng , Dong Liyang , Wang Ying , Mao Chaoming 
Published: January 2022

Abstract
Background
The aberrant expression of E3 ubiquitin ligase Pellino-1 (PELI1) contributes to several human cancer development and progression. However, its expression patterns and functional importance in papillary thyroid cancer (PTC) remains unknown.

Methods
PELI1 expression profiles in PTC tissues were obtained and analyzed through the starBase v3.0 analysis. Real-time PCR, Immunohistochemical assays (IHC) and Western blot were used to investigate the mRNA and protein levels of PELI1 in PTC. The effects of PELI1 on PTC cell progression were evaluated through CCK-8, colony formation, Transwell, and Wound healing assay in vitro, and a PTC xenograft mouse model in vivo. The downstream target signal of PELI1 in PTC was analyzed by using Kyoto encyclopedia of genes and genomes (KEGG), and bioinformatics tools were used to identify potential miRNAs targeting PELI1. Human umbilical cord mesenchymal stem cells were modified by miR-30c-5p and the miR-30c-5p containing extracellular vesicles were collected (miR-30c-5p-EVs) by ultra-high-speed centrifugation method. Then, the effects of miR-30c-5p-EVs on PELI1 expression and PTC progression were evaluated both in vitro and in vivo.

Results
Both mRNA and protein expression of PELI1 were widely increased in PTC tissues, and overexpression of PELI1 was positively correlated with bigger tumor size and lymph node metastases. PELI1 promoted PTC cell proliferation and migration in vitro. While, PELI1 silencing significantly suppressed PTC growth in vivo accompanied with reduced expression of Ki-67 and matrix metallopeptidase 2 (MMP-2). Mechanistically, PI3K-AKT pathway was identified as the downstream target of PELI1, and mediated the functional influence of PELI1 in PTC cells. Moreover, we found that the expression of miR-30c-5p was inversely correlated with PELI1 in PTC samples and further confirmed that miR-30c-5p was a tumor-suppressive miRNA that directly targeted PELI1 to inhibit PTC cell proliferation and migration. Furthermore, we showed that miR-30c-5p-EVs could effectively downregulate PELI1 expression and suppress the PTC cell growth in vitro and in vivo.

Conclusion
This study not only supported the first evidence that miR-30c-5p loss-induced PELI1 accumulation facilitated cell proliferation and migration by activating the PI3K-AKT pathway in PTC but also provided novel insights into PTC therapy based on miR-carrying-hUCMSC-EVs.
Nafamostat reduces systemic inflammation in TLR7-mediated virus-like illness
Authors: Yates Abi G. , Weglinski Caroline M. , Ying Yuxin , Dunstan Isobel K. , Strekalova Tatyana , Anthony Daniel C. 
Published: January 2022

Abstract
Background
The serine protease inhibitor nafamostat has been proposed as a treatment for COVID-19, by inhibiting TMPRSS2-mediated viral cell entry. Nafamostat has been shown to have other, immunomodulatory effects, which may be beneficial for treatment, however animal models of ssRNA virus infection are lacking. In this study, we examined the potential of the dual TLR7/8 agonist R848 to mimic the host response to an ssRNA virus infection and the associated behavioural response. In addition, we evaluated the anti-inflammatory effects of nafamostat in this model.

Methods
CD-1 mice received an intraperitoneal injection of R848 (200 μg, prepared in DMSO, diluted 1:10 in saline) or diluted DMSO alone, and an intravenous injection of either nafamostat (100 μL, 3 mg/kg in 5% dextrose) or 5% dextrose alone. Sickness behaviour was determined by temperature, food intake, sucrose preference test, open field and forced swim test. Blood and fresh liver, lung and brain were collected 6 h post-challenge to measure markers of peripheral and central inflammation by blood analysis, immunohistochemistry and qPCR.

Results
R848 induced a robust inflammatory response, as evidenced by increased expression of TNF, IFN-γ, CXCL1 and CXCL10 in the liver, lung and brain, as well as a sickness behaviour phenotype. Exogenous administration of nafamostat suppressed the hepatic inflammatory response, significantly reducing TNF and IFN-γ expression, but had no effect on lung or brain cytokine production. R848 administration depleted circulating leukocytes, which was restored by nafamostat treatment.

Conclusions
Our data indicate that R848 administration provides a useful model of ssRNA virus infection, which induces inflammation in the periphery and CNS, and virus infection-like illness. In turn, we show that nafamostat has a systemic anti-inflammatory effect in the presence of the TLR7/8 agonist. Therefore, the results indicate that nafamostat has anti-inflammatory actions, beyond its ability to inhibit TMPRSS2, that might potentiate its anti-viral actions in pathologies such as COVID-19.
Microbial pathogens induce neurodegeneration in Alzheimer’s disease mice: protection by microglial regulation
Authors: Ganz Tal , Fainstein Nina , Elad Amit , Lachish Marva , Goldfarb Smadar , Einstein Ofira , Ben-Hur Tamir 
Published: January 2022

Abstract
Background
Neurodegeneration is considered the consequence of misfolded proteins’ deposition. Little is known about external environmental effects on the neurodegenerative process. Infectious agent-derived pathogen-associated molecular patterns (PAMPs) activate microglia, key players in neurodegenerative diseases. We hypothesized that systemic microbial pathogens may accelerate neurodegeneration in Alzheimer’s disease (AD) and that microglia play a central role in this process.

Methods
We examined the effect of an infectious environment and of microbial Toll-like receptor (TLR) agonists on cortical neuronal loss and on microglial phenotype in wild type versus 5xFAD transgenic mice, carrying mutated genes associated with familial AD.

Results
We examined the effect of a naturally bred environment on the neurodegenerative process. Earlier and accelerated cortical neuron loss occurred in 5xFAD mice housed in a natural (“dirty”) environment than in a specific-pathogen-free (SPF) environment, without increasing the burden of Amyloid deposits and microgliosis. Neuronal loss occurred in a microglia-rich cortical region but not in microglia-poor CA regions of the hippocampus. Environmental exposure had no effect on cortical neuron density in wild-type mice. To model the neurodegenerative process caused by the natural infectious environment, we injected systemically the bacterial endotoxin lipopolysaccharide (LPS), a TLR4 agonist PAMP. LPS caused cortical neuronal death in 5xFAD, but not wt mice. We used the selective retinoic acid receptor α agonist Am580 to regulate microglial activation. In primary microglia isolated from 5xFAD mice, Am580 markedly attenuated TLR agonists-induced iNOS expression, without canceling their basic immune response. Intracerebroventricular delivery of Am580 in 5xFAD mice reduced significantly the fraction of (neurotoxic) iNOS + microglia and increased the fraction of (neuroprotective) TREM2 + microglia. Furthermore, intracerebroventricular delivery of Am580 prevented neurodegeneration induced by microbial TLR agonists.

Conclusions
Exposure to systemic infections causes neurodegeneration in brain regions displaying amyloid pathology and high local microglia density. AD brains exhibit increased susceptibility to microbial PAMPs’ neurotoxicity, which accelerates neuronal death. Microglial modulation protects the brain from microbial TLR agonist PAMP-induced neurodegeneration.
MicroRNA-210 regulates the metabolic and inflammatory status of primary human astrocytes
Authors: Kieran Nicholas W. , Suresh Rahul , Dorion Marie-France , MacDonald Adam , Blain Manon , Wen Dingke , Fuh Shih-Chieh , Ryan Fari , Diaz Roberto J. , Stratton Jo Anne , Ludwin Samuel K. , Sonnen Joshua A. , Antel Jack , Healy Luke M. 
Published: January 2022

AbstractBackgroundAstrocytes are the most numerous glial cell type with important roles in maintaining homeostasis and responding to diseases in the brain. Astrocyte function is subject to modulation by microRNAs (miRs), which are short nucleotide strands that regulate protein expression in a post-transcriptional manner. Understanding the miR expression profile of astrocytes in disease settings provides insight into the cellular stresses present in the microenvironment and may uncover pathways of therapeutic interest.MethodsLaser-capture microdissection was used to isolate human astrocytes surrounding stroke lesions and those from neurological control tissue. Astrocytic miR expression profiles were examined using quantitative reverse transcription polymerase chain reaction (RT-qPCR). Primary human fetal astrocytes were cultured under in vitro stress conditions and transfection of a miR mimic was used to better understand how altered levels of miR-210 affect astrocyte function. The astrocytic response to stress was studied using qPCR, enzyme-linked immunosorbent assays (ELISAs), measurement of released lactate, and Seahorse.ResultsHere, we measured miR expression levels in astrocytes around human ischemic stroke lesions and observed differential expression of miR-210 in chronic stroke astrocytes compared to astrocytes from neurological control tissue. We also identified increased expression of miR-210 in mouse white matter tissue around middle cerebral artery occlusion (MCAO) brain lesions. We aimed to understand the role of miR-210 in primary human fetal astrocytes by developing an in vitro assay of hypoxic, metabolic, and inflammatory stresses.A combination of hypoxic and inflammatory stresses was observed to upregulate miR-210 expression. Transfection with miR-210-mimic (210M) increased glycolysis, enhanced lactate export, and promoted an anti-inflammatory transcriptional and translational signature in astrocytes. Additionally, 210M transfection resulted in decreased expression of complement 3 (C3) and semaphorin 5b(Sema5b).ConclusionsWe conclude that miR-210 expression in human astrocytes is modulated in response to ischemic stroke disease and under in vitro stress conditions, supporting a role for miR-210 in the astrocytic response to disease conditions. Further, the anti-inflammatory and pro-glycolytic impact of miR-210 on astrocytes makes it a potential candidate for further research as a neuroprotective agent.
Introducing the hormonal Intrauterine Device in Madagascar, Nigeria, and Zambia: results from a pilot study
Authors: Danna Kendal , Jaworski Grace , Rahaivondrafahitra Bakoly , Rasoanirina Francia , Nwala Anthony , Nqumayo Masauso , Smith Gina , Moon Pierre , Jackson Ashley , Thurston Sarah , Kalamar Amanda 
Published: January 2022

Abstract
Background
The hormonal Intrauterine Device (IUD) is a highly effective contraceptive option growing in popularity and availability in many countries. The hormonal IUD has been shown to have high rates of satisfaction and continuation among users in high-income countries. The study aims to understand the profiles of clients who choose the hormonal IUD in low- and middle-income countries (LMICs) and describe their continuation and satisfaction with the method after 12 months of use.

Methods
A prospective longitudinal study of hormonal IUD acceptors was conducted across three countries—Madagascar, Nigeria, and Zambia—where the hormonal IUD had been introduced in a pilot setting within the of a broad mix of available methods. Women were interviewed at baseline immediately following their voluntary hormonal IUD insertion, and again 3 and 12 months following provision of the method. A descriptive analysis of user characteristics and satisfaction with the method was conducted on an analytic sample of women who completed baseline, 3-month, and 12-month follow-up questionnaires. Kaplan–Meier time-to-event models were used to estimate the cumulative probability of method continuation rates up to 12 months post-insertion.

Results
Each country had a unique demographic profile of hormonal IUD users with different method-use histories. Across all three countries, women reported high rates of satisfaction with the hormonal IUD (67–100%) and high rates of continuation at the 12-month mark (82–90%).

Conclusions
Rates of satisfaction and continuation among hormonal IUD users in the study suggest that expanding method choice with the hormonal IUD would provide a highly effective, long-acting method desirable to many different population segments, including those with high unmet need.
Prevalence and correlates of Kaposi’s sarcoma-associated herpesvirus and herpes simplex virus type 2 infections among adults: evidence from the NHANES III data
Authors: Zhang Xin , Xu Yiyun , Li Yi , Yuan Huangbo , Liu Zhenqiu , Zhang Tiejun 
Published: January 2022

Abstract
Background
Kaposi’s sarcoma-associated herpes virus (KSHV) prevalence and risk factors exhibit considerable variations across populations in different geographic regions. Determinants and the transmission routes of KSHV infection are uncertain. We seek to identify the possible risk factors and the transmission routes of KSHV infection in non-endemic areas.

Methods
We collected annual cases and seroprevalence of KSHV and herpes simplex virus type 2 (HSV-2) from the NHANES III sampled individuals from the US general population (1988–1994). We included 13,179 and 10,720 individuals with available remaining serum samples of KSHV and HSV-2. Logistic regression was employed to explore potential risk factors for the seropositivity.

Results
The seroprevalence was 2.05% for KSHV infection and 31.03% for HSV2 infection among this population. All risk factors of sexual behaviors included were strongly associated with HSV-2 positive, however, only MSM had an approximately fivefold increased risk of KSHV infection (OR = 4.71; 95%CI 1.61 11.30). Mexican Americans (2.51%) and older (chi-squaretrend =  − 6.71, P < 0.001) individuals had a higher risk of KSHV infection. After adjustment, individuals with higher level of education and economic status had lower KSHV infection.

Conclusions
In non-endemic areas, KSHV transmission may be related to sexual activity in men, especially in male homosexuals. Higher education level and economic status are protective factors for KSHV infection.
Integrative profiling of Epstein–Barr virus transcriptome using a multiplatform approach
Authors: Fülöp Ádám , Torma Gábor , Moldován Norbert , Szenthe Kálmán , Bánáti Ferenc , Almsarrhad Islam A. A. , Csabai Zsolt , Tombácz Dóra , Minárovits János , Boldogkői Zsolt 
Published: January 2022

Abstract
Background
Epstein–Barr virus (EBV) is an important human pathogenic gammaherpesvirus with carcinogenic potential. The EBV transcriptome has previously been analyzed using both Illumina-based short read-sequencing and Pacific Biosciences RS II-based long-read sequencing technologies. Since the various sequencing methods have distinct strengths and limitations, the use of multiplatform approaches have proven to be valuable. The aim of this study is to provide a more complete picture on the transcriptomic architecture of EBV.

Methods
In this work, we apply the Oxford Nanopore Technologies MinION (long-read sequencing) platform for the generation of novel transcriptomic data, and integrate these with other’s data generated by another LRS approach, Pacific BioSciences RSII sequencing and Illumina CAGE-Seq and Poly(A)-Seq approaches. Both amplified and non-amplified cDNA sequencings were applied for the generation of sequencing reads, including both oligo-d(T) and random oligonucleotide-primed reverse transcription. EBV transcripts are identified and annotated using the LoRTIA software suite developed in our laboratory.

Results
This study detected novel genes embedded into longer host genes containing 5′-truncated in-frame open reading frames, which potentially encode N-terminally truncated proteins. We also detected a number of novel non-coding RNAs and transcript length isoforms encoded by the same genes but differing in their start and/or end sites. This study also reports the discovery of novel splice isoforms, many of which may represent altered coding potential, and of novel replication-origin-associated transcripts. Additionally, novel mono- and multigenic transcripts were identified. An intricate meshwork of transcriptional overlaps was revealed.

Conclusions
An integrative approach applying multi-technique sequencing technologies is suitable for reliable identification of complex transcriptomes because each techniques has different advantages and limitations, and the they can be used for the validation of the results obtained by a particular approach.