bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oral Prescription Opioids as a High-Risk Indicator for Hepatitis C Infection: Another Step Toward HCV Elimination
Authors: Hack Benjamin , Timalsina Utsav , Tefera Eshetu , Wilkerson Brittany , Paku Emily , Fernandez Stephen , Fishbein Dawn 
Published: September 2021

Background The opioid epidemic across the U.S. poses an array of public health concerns, especially HCV transmission. HCV is now widely curable, yet incident rates are increasing due to the opioid epidemic. Despite the established trajectory from oral prescription opioids (OPOs) to opioid use disorder (OUD), OUD to injection drug use (IDU), and IDU to hepatitis C virus (HCV), OPOs are not a defined risk factor (RF) for HCV infection. The objective of this study was to observe rates of HCV testing and Ab reactivity (HCVAb+) in patients receiving OPOs to substantiate them as a RF, ultimately contributing to HCV elimination. Methods Data from MedStar Health patients receiving OPOs from 1/2017 to 12/2018 were collected and analyzed using chi-squared or student t-tests and logistic regression for uni- or multi-variable analyses, respectively. Statistical significance was defined as P < .05; Epi Info and SAS v 9·4 were used for statistical analyses; IRB approval was received. Results There were 115 415 individuals prescribed OPOs over the study period. In this population, 8.6% (932) were HCVAb+ when tested and not previously diagnosed (10 900); 3.4% (3893) had an OUD diagnosis, 20.6% (803) of whom were HCV tested; 25.4% (361) of all HCVAb+ (1421) had an OUD diagnosis. OUD (ORadj 8.53 [7.22-10.07]) was an independent predictor of HCVAb+ in this population. Conclusions (1) In a large population prescribed oral opioids, HCVAb+ was 8.6%, higher than our previously published data (2.5%) and the US rate (1.7%); (2) only 20% of patients diagnosed with OUD were tested; and (3) only 25% of HCVAb+ patients were classified with OUD; this suggests underreporting of OUD in this population. Primary Care and Community Health Recommendations: (1) Re-testing for HCV in patients taking OPOs; (2) increased HCV testing among OUD patients; and (3) improved surveillance and reporting of OUD.
Factor VIIa suppresses inflammation and barrier disruption through the release of EEVs and transfer of microRNA 10a
Authors: Das Kaushik , Keshava Shiva , Pendurthi Usha R. , Rao L. Vijaya Mohan 
Published: September 2021

Abstract
Coagulation protease, factor VIIa (FVIIa), binds to endothelial cell protein C receptor (EPCR) and induces anti-inflammatory and endothelial barrier protective responses via protease-activated receptor-1 (PAR1)–mediated, biased signaling. Our recent studies had shown that the FVIIa-EPCR-PAR1 axis induces the release of extracellular vesicles (EVs) from endothelial cells. In the present study, we investigated the mechanism of FVIIa release of endothelial EVs (EEVs) and the contribution of FVIIa-released EEVs to anti-inflammatory and vascular barrier protective effects, in both in vitro and in vivo models. Multiple signaling pathways regulated FVIIa release of EVs from endothelial cells, but the ROCK-dependent pathway appeared to be a major mechanism. FVIIa-released EEVs were enriched with anti-inflammatory microRNAs (miRs), mostly miR10a. FVIIa-released EEVs were taken up readily by monocytes/macrophages and endothelial cells. The uptake of FVIIa-released EEVs by monocytes conferred anti-inflammatory phenotype to monocytes, whereas EEV uptake by endothelial cells resulted in barrier protection. In additional experiments, EEV-mediated delivery of miR10a to monocytes downregulated the expression of TAK1 and activation of the NF-κB–mediated inflammatory pathway. In in vivo experiments, administration of FVIIa-released EEVs to wild-type mice attenuated LPS-induced increased inflammatory cytokines in plasma and vascular leakage into vital tissues. The incorporation of anti-miR10a into FVIIa-released EEVs diminished the ability of FVIIa-released EEVs to confer cytoprotective effects. Administration of the ROCK inhibitor Y27632, which significantly inhibits FVIIa release of EEVs into the circulation, to mice attenuated the cytoprotective effects of FVIIa. Overall, our study revealed novel insights into how FVIIa induces cytoprotective effects and communicates with various cell types.
Challenging the paradigm: moving from umbrella labels to treatable traits in airway disease
Authors: Bush Andrew , Pavord Ian D. 
Published: September 2021

Airway diseases were initially described by nonspecific patterns of symptoms, for example “dry and wheezy” and “wet and crackly”. The model airway disease is cystic fibrosis, which has progressed from nonspecific reactive treatments such as antibiotics for airway infection to molecular sub-endotype, proactive therapies with an unequivocal evidence base, early diagnosis, and biomarkers of treatment efficacy. Unfortunately, other airway diseases lag behind, not least because nonspecific umbrella labels such as “asthma” are considered to be diagnoses not mere descriptions.Pending the delineation of molecular sub-endotypes in other airway disease the concept of treatable traits, and consideration of airway disease in a wider context is preferable. A treatable trait is a characteristic amenable to therapy, with measurable benefits of treatment. This approach determines what pathology is actually present and treatable, rather than using umbrella labels. We determine if airway inflammation is present, and whether there is airway eosinophilia which will likely respond to inhaled corticosteroids; whether there is variable airflow obstruction due to bronchoconstriction which will respond to β2-agonists; and whether there is unsuspected underlying airway infection which should be treated with antibiotics unless there is an underlying endotype which can be addressed, as for example an immunodeficiency. The context of airway disease should also be extrapulmonary comorbidities, social and environmental factors, and a developmental perspective, particularly this last aspect if preventive strategies are being contemplated. This approach allows targeted treatment for maximal patient benefit, as well as preventing the discarding of therapies which are useful for appropriate subgroups of patients. Failure to appreciate this almost led to the discarding of valuable treatments such as prednisolone.Educational aimsTo use cystic fibrosis as a paradigm to show the benefits of the journey from nonspecific umbrella terms to specific endotypes and sub-endotypes, as a road map for other airway diseases to follow.Demonstrate that nonspecific labels to describe airway disease can and should be abandoned in favour of treatable traits to ensure diagnostic and therapeutic precision.Begin to learn to see airway disease in the context of extrapulmonary comorbidities, and social and environmental factors, as well as with a developmental perspective.
The definition of tuberculosis infection based on the spectrum of tuberculosis disease
Authors: Migliori Giovanni Battista , Ong Catherine W.M. , Petrone Linda , D'Ambrosio Lia , Centis Rosella , Goletti Delia  
Published: September 2021

Latent tuberculosis infection was the term traditionally used to indicate tuberculosis (TB) infection. This term was used to define “a state of persistent immune response to stimulation byMycobacterium tuberculosisantigens through tests such as the tuberculin skin test (TST) or an interferon-γ release assay (IGRA) without clinically active TB”. Recent evidence indicates that the spectrum from TB infection to TB disease is much more complex, including a “continuum” of situations didactically reported as uninfected individual, TB infection, incipient TB, subclinical TB without signs/symptoms, subclinical TB with unrecognised signs/symptoms, and TB disease with signs/symptoms. Recent evidence suggests that subclinical TB is responsible for importantM. tuberculosistransmission. This review describes the different stages described above and their relationships. It also summarises the new developments in prevention, diagnosis and treatment of TB infection as well as their public health and policy implications.Educational aimsTo describe the evolution of the definition of “tuberculosis infection” and didactically describe the continuum of stages existing between TB infection and disease.To discuss the recommended approaches to prevent, diagnose and treat TB infection.
Marasmius oreades agglutinin enhances resistance of Arabidopsis against plant-parasitic nematodes and a herbivorous insect
Authors: Moradi Aboubakr , Austerlitz Tina , Dahlin Paul , Robert Christelle AM , Maurer Corina , Steinauer Katja , van Doan Cong , Himmighofen Paul Anton , Wieczorek Krzysztof , Künzler Markus , Mauch Felix 
Published: September 2021

Abstract
Background
Plant-parasitic nematodes and herbivorous insects have a significant negative impact on global crop production. A successful approach to protect crops from these pests is the in planta expression of nematotoxic or entomotoxic proteins such as crystal proteins from Bacillus thuringiensis (Bt) or plant lectins. However, the efficacy of this approach is threatened by emergence of resistance in nematode and insect populations to these proteins. To solve this problem, novel nematotoxic and entomotoxic proteins are needed. During the last two decades, several cytoplasmic lectins from mushrooms with nematicidal and insecticidal activity have been characterized. In this study, we tested the potential of Marasmius oreades agglutinin (MOA) to furnish Arabidopsis plants with resistance towards three economically important crop pests: the two plant-parasitic nematodes Heterodera schachtii and Meloidogyne incognita and the herbivorous diamondback moth Plutella xylostella.

Results
The expression of MOA does not affect plant growth under axenic conditions which is an essential parameter in the engineering of genetically modified crops. The transgenic Arabidopsis lines showed nearly complete resistance to H. schachtii, in that the number of female and male nematodes per cm root was reduced by 86–91 % and 43–93 % compared to WT, respectively. M. incognita proved to be less susceptible to the MOA protein in that 18–25 % and 26–35 % less galls and nematode egg masses, respectively, were observed in the transgenic lines. Larvae of the herbivorous P. xylostella foraging on MOA-expression lines showed a lower relative mass gain (22–38 %) and survival rate (15–24 %) than those feeding on WT plants.

Conclusions
The results of our in planta experiments reveal a robust nematicidal and insecticidal activity of the fungal lectin MOA against important agricultural pests which may be exploited for crop protection.
Sevoflurane and isoflurane inhibit KCl-induced, Rho kinase-mediated, and PI3K-participated vasoconstriction in aged diabetic rat aortas
Authors: Yang Shaozhong , Liu Yu , Huang Shanshan , Jin Feihong , Qi Feng 
Published: September 2021

Abstract
Background
The mechanism of volatile anesthetics on vascular smooth muscle (VSM) contraction in the setting of diabetes mellitus (DM) remains unclear. The current study was designed to determine the effects of sevoflurane (SEVO) and isoflurane (ISO) on phosphoinositide 3-kinase (PI3K) and Rho kinase (ROCK) mediated KCl-induced vasoconstriction in aged type 2 diabetic rats.

Methods
KCl-induced (60 mM) contractions were examined in endothelium-denuded aortic rings from aged T2DM Otsuka Long-Evans Tokushima Fatty (OLETF) rats (65–70 weeks old), control age-matched nondiabetic Long-Evans Tokushima Otsuka (LETO) rats and young Wistar rats (6–8 weeks old). The effects of SEVO or ISO (1–3 minimum alveolar concentration, MAC) on KCl-induced vasoconstriction, as well as those of LY294002 (PI3K inhibitor) and Y27632 (ROCK inhibitor) were measured in aortic rings from the three groups using an isometric force transducer.

Results
KCl induced rapid and continuous contraction of aortic smooth muscle in the three groups, and the contraction was more obvious in OLETF rats.
SEVO and ISO inhibited KCl-induced vasoconstriction in a concentration-dependent manner and were suppressed by LY294002 (10 µM) and Y27632 (1 µM). SEVO had a stronger inhibitory effect on the aortas of young Wistar rats than ISO, especially at 2 MAC and 3 MAC (P < 0.05). In aged rats, the inhibitory effect of ISO was stronger than that of SEVO, especially OLETF rats. There was no significant difference in the effects of different concentrations of ISO on arterial contraction among the three groups (P > 0.05). The effects of 1 MAC SEVO on Wistar rats and 3 MAC SEVO on OLETF rats, however, were noticeably and significantly different (P < 0.05).
Compared with the control condition, LY294002 and Y27632 had the most noticeable effect on the KCl-induced contraction of aortic rings in OLETF rats (P < 0.01).

Conclusion
SEVO (3 MAC), ISO (1, 2, 3 MAC), LY294002 and Y27632 have more significant inhibitory effect on the contraction of vascular smooth muscle in aged T2MD rats. The mechanism of SEVO and ISO in vascular tension in T2DM is partly due to changes in PI3K and/or Rho kinase activity.
Potential utility of physical function measures to improve the risk prediction of functional disability in community-dwelling older Japanese adults: a prospective study
Authors: Chen Tao , Honda Takanori , Chen Sanmei , Kishimoto Hiro , Kumagai Shuzo , Narazaki Kenji 
Published: September 2021

Abstract
Background
While gait speed, one-leg standing balance, and handgrip strength have been shown to be independent predictors for functional disability, it is unclear whether such simple measures of physical function contribute to improved risk prediction of functional disability in older adults.

Methods
A total of 1,591 adults aged ≥ 65 years and without functional disability at baseline were followed up for up to 7.9 years. Functional disability was identified using the database of Japan’s Long-term Care Insurance System. Maximum gait speed, one-leg standing time, and handgrip strength were measured at baseline. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95 % confidence intervals (CIs) for the association of physical function and functional disability incidence. The incremental predictive value of each physical function measure for risk prediction was quantified using the difference in overall C-statistic, category-free net reclassification improvement (NRI), and integrated discrimination improvement (IDI) index.

Results
During follow-up (median: 7.8 years), functional disability was identified in 384 participants. All of the physical function measures were inversely associated with the risk of functional disability, independent of potential confounding factors. The multivariable adjusted HRs (95 % CIs) for functional disability per one standard deviation increment of maximum gait speed, one-leg-standing time, and hand grip strength were 0.73 (0.65–0.83), 0.68 (0.59–0.79), and 0.72 (0.59–0.86), respectively. Incorporation of each of maximum gait speed, one-leg-stand time, and hand grip strength into a basic model with other risk factors significantly improved C-statistic from 0.770 (95 % CIs, 0.751–0.794) to 0.778 (0.759–0.803), 0.782 (0.760–0.805), and 0.775 (0.756–0.800), respectively (all p < 0.05). A model including all three measures had the highest C-statistic of 0.787 (0.765–0.810). The improvements in risk prediction were also confirmed by category-free NRI and IDI index.

Conclusions
Adding any of the three measures to a basic model with other known risk factors significantly improved the prediction of functional disability and addition of all three measures provided further improvement of the prediction in older Japanese adults. These data provide robust evidence to support the practical utility of incorporating these simple physical function measures into functional disability risk prediction tools.
Protocol of a prospective and multicentre China Teratology Birth Cohort (CTBC): association of maternal drug exposure during pregnancy with adverse pregnancy outcomes
Authors: Zhou Yangwen , Tao Jing , Wang Ke , Deng Kui , Wang Yanping , Zhao Jianxin , Chen Chunyi , Wu Tingxuan , Zhou Jiayuan , Zhu Jun , Li Xiaohong 
Published: September 2021

AbstractBackgroundAs reported, 27-93 % of pregnant women take at least one drug during pregnancy. However, drug exposure during pregnancy still lacks sufficient foetal safety evidence of human origin. It is urgent to fill the knowledge gap about medication safety during pregnancy for optimization of maternal disease treatment and pregnancy drug consultation.Methods and analysisThe China Teratology Birth Cohort (CTBC) was established in 2019 and is a hospital-based open-ended prospective cohort study with the aim of assessing drug safety during pregnancy. Pregnant women who set up the pregnancy health records in the first trimester or who seek drug consultation regardless of gestational age in the member hospitals are recruited. Enrolled pregnant women need to be investigated four times, namely, 6–14 and 24–28 weeks of gestational age, before discharge after hospital delivery, and 28–42 days after birth.Maternal medication exposure during pregnancy is the focus of the CTBC. For drugs, information on the type, name, and route of medication; start and end time of medication; single dose; frequency of medication; dosage form; manufacturer; and reason for medication is collected. The adverse pregnancy outcomes collected in the study include birth defects, stillbirth, spontaneous abortion, preterm birth, post-term birth, low birth weight, macrosomia, small for gestational age, large for gestational age and low Apgar score. CTBC uses an electronic questionnaire for data collection and a cloud system for data management. Biological samples are collected if informed consents are obtained. Multi-level logistic regression, mixed-effect negative binomial distribution regression and spline function regression are used to explore the effect of drugs on the occurrence of birth defects.DiscussionThe findings of the study will assist in further understanding the risk of birth defects and other adverse pregnancy outcomes associated with maternal drug exposure and developing the optimal treatment plans and drug counselling for pregnant women.Trial registrationThis study was approved by the Research Ethics Committee of the West China Second Hospital of Sichuan University and registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx, registration numberChiCTR1900022569).
Association of dietary intakes of vitamin B12, vitamin B6, folate, and methionine with the risk of esophageal cancer: the Japan Public Health Center-based (JPHC) prospective study
Authors: Khairan Paramita , Sobue Tomotaka , Eshak Ehab Salah , Zha Ling , Kitamura Tetsuhisa , Sawada Norie , Iwasaki Motoki , Inoue Manami , Yamaji Taiki , Shimazu Taichi , Iso Hiroyasu , Tsugane Shoichiro 
Published: September 2021

Abstract
Background
B vitamins and methionine are essential substrates in the one-carbon metabolism pathway involved in DNA synthesis and methylation. They may have essential roles in cancer development. We aimed to evaluate the associations of dietary intakes of vitamin B12, vitamin B6, folate, and methionine with the risk of esophageal cancer (EC) using data from the Japan Public Health Center-based Prospective Study.

Methods
We included 87,053 Japanese individuals who completed a food frequency questionnaire and were followed up from 1995–1998 to 2013 and 2015. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated by Cox proportional-hazard regression across quintiles of dietary intakes of B vitamins and methionine.

Results
After 1,456,678 person-years of follow-up, 427 EC cases were documented. The multivariable HR (95% CI) of incident EC in the highest versus lowest quintile of dietary intake of vitamin B12 was 1.75 (1.13–2.71; p-trend=0.01). Stratification analysis based on alcohol consumption showed that higher dietary intakes of vitamin B12 and methionine were associated with an increased risk of EC among never-drinkers; HRs (95% CIs) were 2.82 (1.18–6.74; p-trend=0.009; p-interaction=0.18) and 3.45 (1.32–9.06; p-trend=0.003; p-interaction 0.02) for vitamin B12 and methionine, respectively. Meanwhile, there was no association between vitamin B12 and methionine intake with the risk of EC among drinkers. There were no associations between dietary intake of folate or vitamin B6 and the risk of EC.

Conclusion
Dietary intake of vitamin B12 was positively associated with the risk of EC in the Japanese population.
Exposure to low intensity ultrasound removes paclitaxel cytotoxicity in breast and ovarian cancer cells
Authors: Amaya Celina , Luo Shihua , Baigorri Julio , Baucells Rogelio , Smith Elizabeth R. , Xu Xiang-Xi 
Published: September 2021

Abstract
Background
Paclitaxel (Taxol) is a microtubule-stabilizing drug used to treat several solid tumors, including ovarian, breast, non-small cell lung, and pancreatic cancers. The current treatment of ovarian cancer is chemotherapy using paclitaxel in combination with carboplatin as a frontline agent, and paclitaxel is also used in salvage treatment as a second line drug with a dose intensive regimen following recurrence. More recently, a dose dense approach for paclitaxel has been used to treat metastatic breast cancer with success.
Paclitaxel binds to beta tubulin with high affinity and stabilizes microtubule bundles. As a consequence of targeting microtubules, paclitaxel kills cancer cells through inhibition of mitosis, causing mitotic catastrophes, and by additional, not yet well defined non-mitotic mechanism(s).

Results
In exploring methods to modulate activity of paclitaxel in causing cancer cell death, we unexpectedly found that a brief exposure of paclitaxel-treated cells in culture to low intensity ultrasound waves prevented the paclitaxel-induced cytotoxicity and death of the cancer cells. The treatment with ultrasound shock waves was found to transiently disrupt the microtubule cytoskeleton and to eliminate paclitaxel-induced rigid microtubule bundles. When cellular microtubules were labelled with a fluorescent paclitaxel analog, exposure to ultrasound waves led to the disassembly of the labeled microtubules and localization of the signals to perinuclear compartments, which were determined to be lysosomes.

Conclusions
We suggest that ultrasound disrupts the paclitaxel-induced rigid microtubule cytoskeleton, generating paclitaxel bound fragments that undergo degradation. A new microtubule network forms from tubulins that are not bound by paclitaxel. Hence, ultrasound shock waves are able to abolish paclitaxel impact on microtubules.
Thus, our results demonstrate that a brief exposure to low intensity ultrasound can reduce and/or eliminate cytotoxicity associated with paclitaxel treatment of cancer cells in cultures.