bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of calcium dobesilate in treating Chinese patients with mild-to-moderate non-proliferative diabetic retinopathy (CALM-DR): protocol for a single-blind, multicentre, 24-armed cluster-randomised, controlled trial
Authors: Hu Hao , Liu Jiang , Wang Duolao , Qiu Shanhu , Yuan Yang , Wang Fenghua , Wen Liang , Song Qi , Sun Zi-lin 
Published: May 2021

IntroductionCalcium dobesilate (CaD) has been used in the treatment of diabetic retinopathy (DR) due to its potential in protecting against retinal vascular damage. However, there is limited evidence exploring its efficacy in combating DR progression. This study is aimed at evaluating whether CaD could prevent DR progression into an advanced stage among Chinese patients with mild-to-moderate non-proliferative DR (NPDR).Methods and analysisThis study is a single-blind, multicentre, cluster-randomised, controlled superiority trial. A total of 1272 patients with mild-to-moderate NPDR will be enrolled and randomly assigned at a 1:1 ratio into the control group (conventional treatment group) and the intervention group (conventional treatment plus CaD (500 mg three times per day) for 12 months). Patients will be followed at 1, 3, 6 and 12 months after randomisation and receiving treatments, with the severity of DR assessed by the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. The primary endpoint is the progression of DR during follow-up, which is defined as an increase of two or more steps in the ETDRS scale. The secondary endpoints include the concomitant changes in visual acuity, presence, number, location and type of retinal lesions, and retinal blood vessel diameter as well as the arteriovenous ratio at different visits.Ethics and disseminationEach local ethics committee (first Vote: Ethical Review Committees of Zhongda Hospital of Southeast University (2019ZDSYLL132-P01)) has approved the study. The results will be published in high impact peer-reviewed scientific journals aimed at the general reader.Trial registration numbersNCT04283162.
Work stress and oral conditions: a systematic review of observational studies
Authors: Sato Yukihiro , Saijo Yasuaki , Yoshioka Eiji 
Published: May 2021

ObjectivesAlthough psychological stress is a risk factor for oral diseases, there seems to be no review on work stress. This study aimed to review the evidence on the association between work stress and oral conditions, including dental caries, periodontal status and tooth loss.DesignA systematic review of published observational studies.Data sourcesA systematic literature search was conducted in PubMed and Scopus databases on 12 August 2020.Study selectionArticles were screened based on the following inclusion criteria: published after 1966; in English only; epidemiological studies on humans (except case studies, reviews, letters, commentaries and editorials); and examined the association of work stress with dental caries, periodontal status and tooth loss.Data extractionData were extracted from eligible studies. A quality assessment was conducted using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies.ResultsOf 402 articles identified, 11 met the inclusion criteria, and 1 study assessed the association of work stress with dental caries and periodontal status. Of 11 studies, 1 reported a non-significant association between work stress and dental caries; 8 of 9 studies reported a significant association between work stress and worse periodontal status; and 1 of 2 studies reported a significant association between work stress and tooth loss. Nine of 11 studies were cross-sectional, while the remaining 2 studies had unclear methodology. Only two studies were sufficiently adjusted for potential confounders. Eight studies assessed work stress but did not use the current major measures. Three studies were rated as fair, while eight studies had poor quality.ConclusionsThere is a lack of evidence on the association of work stress with dental caries and tooth loss. Eight studies suggested potential associations between periodontal status and work stress. Cohort studies using the major work stress measures and adjusting for the potential confounders are needed.
Intimate partner violence and social connection among married women in rural Bangladesh
Authors: Stoff Laura W , Bates Lisa M , Schuler Sidney Ruth , Renner Lynette M , Erickson Darin J , Osypuk Theresa L 
Published: May 2021

Background
Intimate partner violence (IPV) is high among married women in Bangladesh. Social isolation is a well-established correlate of women’s exposure to IPV, but the role of such factors in low-income and middle-income countries is not well understood. In this study, we explore whether social connection is protective against IPV among married women in rural Bangladesh.

Methods
Data were drawn from a multistage, stratified, population-based longitudinal sample of 3355 married women in rural Bangladesh, who were surveyed on individual and contextual risk factors of IPV. Negative binomial regression models were used to estimate the association between three different domains of social connection (natal family contact, female companionship and instrumental social support), measured at baseline in 2013, and the risk of three different forms of IPV (psychological, physical and sexual), approximately 10 months later, adjusted for woman’s level of education, spouse’s level of education, level of household wealth, age and age of marriage.

Results
Adjusted models showed that instrumental social support was associated with a lower risk of past year psychological IPV (risk ratio (RR)=0.84, 95% CI 0.769 to 0.914), sexual IPV (RR=0.90, 95% CI 0.822 to 0.997) and physical IPV (RR=0.81, 95% CI 0.718 to 0.937). Natal family contact was also associated with a lower risk of each type of IPV, but not in a graded fashion. Less consistent associations were observed with female companionship.

Conclusion
Our findings suggest that social connection, particularly in the form of instrumental support, may protect married women in rural Bangladesh from experiencing IPV.
Roles of allostatic load, lifestyle and clinical risk factors in mediating the association between education and coronary heart disease risk in Europe
Authors: Hicks Blánaid , Veronesi Giovanni , Ferrario Marco M , Forrest Hannah , Whitehead Margaret , Diderichsen Finn , Tunstall-Pedoe Hugh , Kuulasmaa Kari , Sans Susana , Salomaa Veikko , Thorand Barbara , Peters Annette , Soderberg Stefan , Cesana Giancarlo , Bobak Martin , Iacoviello Licia , Palmieri Luigi , Zeller Tanja , Blankenberg Stefan , Kee Frank 
Published: May 2021

Background
Previous studies have shown that differential exposure to lifestyle factors may mediate the association between education and coronary heart diseases (CHD). However, few studies have examined the potential roles of allostatic load (AL) or differential susceptibility.

Methods
25 310 men and 26 018 women aged 35–74 and CHD free at baseline were identified from 21 European cohorts and followed for a median of 10 years, to investigate the mediating role of AL, as well as of smoking, alcohol use and body mass index (BMI), on educational differences in CHD incidence, applying marginal structural models and three-way decomposition.

Results
AL is a mediator of the association between educational status and CHD incidence, with the highest proportion mediated observed among women and largely attributable to differential exposure, (28% (95% CI 19% to 44%)), with 8% (95% CI 0% to 16%) attributable to differential susceptibility. The mediating effects of smoking, alcohol and BMI, compared with AL, were relatively small for both men and women.

Conclusion
Overall, the educational inequalities in CHD incidence were partially mediated through differential exposure to AL. By contrast, the mediation of the educational gradient in CHD by investigated lifestyle risk factors was limited. As differential susceptibility in men was found to have a predominant role in the accumulation of AL in low educational classes, the investigation of AL-related risk factors is warranted.
Deaths from ‘diseases of despair’ in Britain: comparing suicide, alcohol-related and drug-related mortality for birth cohorts in Scotland, England and Wales, and selected cities
Authors: Walsh David , McCartney Gerry , Minton Jon , Parkinson Jane , Shipton Deborah , Whyte Bruce 
Published: May 2021

Background
The contribution of increasing numbers of deaths from suicide, alcohol-related and drug-related causes to changes in overall mortality rates has been highlighted in various countries. In Scotland, particular vulnerable cohorts have been shown to be most at risk; however, it is unclear to what extent this applies elsewhere in Britain. The aim here was to compare mortality rates for different birth cohorts between Scotland and England and Wales (E&W), including key cities.

Methods
Mortality and population data (1981–2017) for Scotland, E&W and 10 cities were obtained from national statistical agencies. Ten-year birth cohorts and cohort-specific mortality rates (by age of death, sex, cause) were derived and compared between countries and cities.

Results
Similarities were observed between countries and cities in terms of peak ages of death, and the cohorts with the highest death rates. However, cohort-specific rates were notably higher in Scotland, particularly for alcohol-related and drug-related deaths. Across countries and cities, those born in 1965–1974 and 1975–1984 had the highest drug-related mortality rates (peak age at death: 30–34 years); the 1965–1974 birth cohort also had the highest male suicide rate (peak age: 40–44 years). For alcohol-related causes, the highest rates were among earlier cohorts (1935–1944, 1945–1954, 1955–1964)—peak age 60–64 years.

Conclusions
The overall similarities suggest common underlying influences across Britain; however, their effects have been greatest in Scotland, confirming greater vulnerability among that population. In addressing the socioeconomic drivers of deaths from these causes, the cohorts identified here as being at greatest risk require particular attention.
Challenges in the design, interpretation, and reporting of randomized controlled clinical studies on the health effects of whole foods
Authors: Musa-Veloso Kathy , Racey Megan , MacFarlane Amanda , Bier Dennis , Lamarche Benoît , Trumbo Paula , House James 
Published: May 2021

Given the challenges with nutrition research, the Canadian Nutrition Society and Intertek Health Sciences Inc held an expert consultation in late 2019 to discuss the development and implementation of best practices for clinical trials on whole foods. Key challenges in the design, interpretation, and reporting of clinical efficacy studies on whole foods and opportunities for the future development of best practices are reported.Novelty: Outlines existing tools, resources, and checklists for clinical nutrition trials and provides clear and tangible steps to develop best practices for studies on whole foods.
Photochemical reaction of superoxide radicals with 1-naphthol
Authors: Liu Ying , Zhu Mengyu , Hu Yadong , Zhao Yijun , Zhu Chengzhu 
Published: May 2021

The photochemical reactions between 1-naphthol (1-NP) and the superoxide anion radical (O2•–) were investigated in detail by using 365 nm UV irradiation. The results showed that the conversion rate of 1-NP decreased with the increase of the initial concentration of 1-NP, whereas by increasing the pH and riboflavin concentration, the photochemical reaction was accelerated. The second-order reaction rate constant was estimated to be (3.64 ± 0.17) × 108 L mol−1s−1. The major photolysis products identified by using gas chromatography – mass spectrometry (GC–MS) were 1,4-naphquinone and 2,3-epoxyresin-2,3-dihydro-1,4-naphquinone, and their reaction pathways were also discussed. An atmospheric model showed that both the bulk water reaction and the heterogeneous surface reaction deserve attention in atmospheric aqueous chemistry.
Rehabilitation of concrete one-way slabs using precast prestressed concrete prisms
Authors: Gerami Saeed , Svecova Dagmar 
Published: May 2021

The rehabilitation of structures is a complex process that involves many considerations. This paper presents results of a feasibility study on the use of precast prestressed concrete prisms (PCPs) as a near-surface mounted reinforcement for rehabilitation of cracked one-way slabs. The PCPs were cast with high-strength concrete and were concentrically prestressed by one 9 mm diameter stress-relieved seven-wire steel strand. Six identical one-way slabs with a length of 3000 mm, a width of 600 mm, and a depth of 200 mm were tested. They were first loaded until cracking, then were fully unloaded and subsequently rehabilitated with four PCPs before loading them to failure. Deflected profiles and crack widths of the slabs before and after rehabilitation were compared in this research. This rehabilitation method reduced the magnitude of deflection and crack width of the samples. The cracks induced in the first phase of loading before PCP rehabilitation appeared fully closed after the PCP rehabilitation until load equal to five times the original cracking loads of the slabs was reached.
Apolipoprotein E Promotes Immune Suppression in Pancreatic Cancer through NF-κB–Mediated Production of CXCL1
Authors: Kemp Samantha B. , Carpenter Eileen S. , Steele Nina G. , Donahue Katelyn L. , Nwosu Zeribe C. , Pacheco Amanda , Velez-Delgado Ashley , Menjivar Rosa E. , Lima Fatima , The Stephanie , Espinoza Carlos E. , Brown Kristee , Long Daniel , Lyssiotis Costas A. , Rao Arvind , Zhang Yaqing , Pasca di Magliano Marina , Crawford Howard C. 
Published: May 2021

AbstractPancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with few effective therapeutic options. PDAC is characterized by an extensive fibroinflammatory stroma that includes abundant infiltrating immune cells. Tumor-associated macrophages (TAM) are prevalent within the stroma and are key drivers of immunosuppression. TAMs in human and murine PDAC are characterized by elevated expression of apolipoprotein E (ApoE), an apolipoprotein that mediates cholesterol metabolism and has known roles in cardiovascular and Alzheimer's disease but no known role in PDAC. We report here that ApoE is also elevated in peripheral blood monocytes in PDAC patients, and plasma ApoE protein levels stratify patient survival. Orthotopic implantation of mouse PDAC cells into syngeneic wild-type or in ApoE−/− mice showed reduced tumor growth in ApoE−/− mice. Histologic and mass cytometric (CyTOF) analysis of these tumors showed an increase in CD8+ T cells in tumors in ApoE−/− mice. Mechanistically, ApoE induced pancreatic tumor cell expression of Cxcl1 and Cxcl5, known immunosuppressive factors, through LDL receptor and NF-κB signaling. Taken together, this study reveals a novel immunosuppressive role of ApoE in the PDAC microenvironment.Significance:This study shows that elevated apolipoprotein E in PDAC mediates immune suppression and high serum apolipoprotein E levels correlate with poor patient survival.See related commentary by Sherman, p. 4186
Epigenetic Induction of Mitochondrial Fission Is Required for Maintenance of Liver Cancer–Initiating Cells
Authors: Tang Miaoling , Yang Meisongzhu , Wu Geyan , Mo Shuang , Wu Xingui , Zhang Shuxia , Yu Ruyuan , Hu Yameng , Xu Yingru , Li Ziwen , Liao Xinyi , Li Jun , Song Libing 
Published: May 2021

AbstractMitochondrial dynamics play vital roles in the tumorigenicity and malignancy of various types of cancers by promoting the tumor-initiating potential of cancer cells, suggesting that targeting crucial factors that drive mitochondrial dynamics may lead to promising anticancer therapies. In the current study, we report that overexpression of mitochondrial fission factor (MFF), which is upregulated significantly in liver cancer–initiating cells (LCIC), promotes mitochondrial fission and enhances stemness and tumor-initiating capability in non-LCICs. MFF-induced mitochondrial fission evoked mitophagy and asymmetric stem cell division and promoted a metabolic shift from oxidative phosphorylation to glycolysis that decreased mitochondrial reactive oxygen species (ROS) production, which prevented ROS-mediated degradation of the pluripotency transcription factor OCT4. CRISPR affinity purification in situ of regulatory elements showed that T-box transcription factor 19 (TBX19), which is overexpressed uniquely in LCICs compared with non-LCICs and liver progenitor cells, forms a complex with PRMT1 on the MFF promoter in LCICs, eliciting epigenetic histone H4R3me2a/H3K9ac-mediated transactivation of MFF. Targeting PRMT1 using furamidine, a selective pharmacologic inhibitor, suppressed TBX19-induced mitochondrial fission, leading to a profound loss of self-renewal potential and tumor-initiating capacity of LCICs. These findings unveil a novel mechanism underlying mitochondrial fission–mediated cancer stemness and suggest that regulation of mitochondrial fission via inhibition of PRMT1 may be an attractive therapeutic option for liver cancer treatment.Significance:These findings show that TBX19/PRMT1 complex–mediated upregulation of MFF promotes mitochondrial fission and tumor-initiating capacity in liver cancer cells, identifying PRMT1 as a viable therapeutic target in liver cancer.
R-Loop–Mediated ssDNA Breaks Accumulate Following Short-Term Exposure to the HDAC Inhibitor Romidepsin
Authors: Safari Maryam , Litman Thomas , Robey Robert W. , Aguilera Andrés , Chakraborty Arup R. , Reinhold William C. , Basseville Agnes , Petrukhin Lubov , Scotto Luigi , O'Connor Owen A. , Pommier Yves , Fojo Antonio T. , Bates Susan E. 
Published: May 2021

Abstract

Histone deacetylase inhibitors (HDACi) induce hyperacetylation of histones by blocking HDAC catalytic sites. Despite regulatory approvals in hematological malignancies, limited solid tumor clinical activity has constrained their potential, arguing for better understanding of mechanisms of action (MOA). Multiple activities of HDACis have been demonstrated, dependent on cell context, beyond the canonical induction of gene expression. Here, using a clinically relevant exposure duration, we established DNA damage as the dominant signature using the NCI-60 cell line database and then focused on the mechanism by which hyperacetylation induces DNA damage. We identified accumulation of DNA–RNA hybrids (R-loops) following romidepsin-induced histone hyperacetylation, with single-stranded DNA (ssDNA) breaks detected by single-cell electrophoresis. Our data suggest that transcription-coupled base excision repair (BER) is involved in resolving ssDNA breaks that, when overwhelmed, evolve to lethal dsDNA breaks. We show that inhibition of BER proteins such as PARP will increase dsDNA breaks in this context. These studies establish accumulation of R-loops as a consequence of romidepsin-mediated histone hyperacetylation. We believe that the insights provided will inform design of more effective combination therapy with HDACis for treatment of solid tumors.

Implications:
Key HDAC inhibitor mechanisms of action remain unknown; we identify accumulation of DNA–RNA hybrids (R-loops) due to chromatin hyperacetylation that provokes single-stranded DNA damage as a first step toward cell death.
PRESERVE: Randomized Trial of Intensive Versus Standard Blood Pressure Control in Small Vessel Disease
Authors: Markus Hugh S. , Egle Marco , Croall Iain D. , Sari Hasan , Khan Usman , Hassan Ahamad , Harkness Kirsty , MacKinnon Andrew , O’Brien John T. , Morris Robin G. , Barrick Thomas R. , Blamire Andrew M. , Tozer Daniel J. , Ford Gary A. , Birns J. , Davies J. , Barkat A. , Cappuccio F. , Robinson T. , Grey L. , Briley D. , Bhalla A. , Hollocks M.J. , Davies L.A. , Cambridge V.C. , Moynihan B. , Tripper S. , Dixit A. , Davies J. , Davis M. , Ford G. , Dafe C. , McGirr J. , Spillane M. , Waugh D. , Ellison-Handley B. , Werring D. , Banara A. 
Published: May 2021

Background and Purpose:
In cerebral small vessel disease, cerebral blood flow and autoregulation are impaired and therefore excessive blood pressure reduction could possibly accelerate white matter damage and worsen outcome. The trial determined, in severe symptomatic cerebral small vessel disease, whether intensive blood pressure lowering resulted in progression of white matter damage assessed using diffusion tensor imaging.

Methods:
Randomized, parallel, multicenter controlled, blinded-outcomes clinical trial. One hundred eleven participants with magnetic resonance imaging confirmed symptomatic lacunar infarct and confluent white matter hyperintensities and were recruited and randomized to standard (systolic=130–140 mmHg) (N=56) or intensive (systolic<125 mmHg) (N=55) blood pressure targets. The primary end point was change in diffusion tensor imaging white matter mean diffusivity peak height between baseline and 24 months. Secondary end points were other magnetic resonance imaging markers and cognition.

Results:

Patients were mean 68 years and 60% male. Mean (SD) blood pressure reduced by −15.3 (15.4) and −23.1 (22.04) mm Hg in the standard/intensive groups, respectively (
P
<0.001). There was no difference between treatment groups for the primary end point: standard, adjusted mean (SE)=12.5×10
−3
(0.2×10
−3
); intensive, 12.5×10
−3
(0.2×10
−3
),
P
=0.92. In the whole population over 24 months follow-up, there was a significant deterioration in white matter microstructure but no detectable decrease in cognition.

Conclusions:
Intensive blood pressure lowering in severe cerebral small vessel disease was not associated with progression of white matter damage on diffusion tensor imaging or magnetic resonance imaging. In a multicentre study setting over 2 years, multimodal diffusion tensor imaging-magnetic resonance imaging was more sensitive to detecting change than cognitive testing.

Registration:

URL:
https://www.isrctn.com
; Unique identifier: ISRCTN37694103.
Dialogue State Tracking with Incremental Reasoning
Authors: Liao Lizi , Long Le Hong , Ma Yunshan , Lei Wenqiang , Chua Tat-Seng 
Published: May 2021

AbstractTracking dialogue states to better interpret user goals and feed downstream policy learning is a bottleneck in dialogue management. Common practice has been to treat it as a problem of classifying dialogue content into a set of pre-defined slot-value pairs, or generating values for different slots given the dialogue history. Both have limitations on considering dependencies that occur on dialogues, and are lacking of reasoning capabilities. This paper proposes to track dialogue states gradually with reasoning over dialogue turns with the help of the back-end data. Empirical results demonstrate that our method outperforms the state-of-the-art methods in terms of joint belief accuracy for MultiWOZ 2.1, a large-scale human--human dialogue dataset across multiple domains.
“When Mountains Can No Longer Be Seen”: A Critical History of Interpretations of an Ambiguous Shōbōgenzō Sentence
Authors: Heine Steven 
Published: May 2021

Abstract
This paper critically examines the various ways a particularly puzzling line in Dōgen’s 道元 “Genjōkōan” 現成公案 fascicle has been interpreted by premodern sources, especially the Goshō commentary by Senne 詮慧 and Kyōgō 經豪, as well as modern commentators, including sectarian figures such as Nishiari Bokusan 西有穆山 and Kurebayashi Kōdō 榑林皓堂 seen in relation to non-sectarian philosophers such as Watsurji Tetsurō 和辻哲郎. The key passage on “riding a boat out to sea, where mountains can no longer be seen (yamanaki kaichū 山なき海中),” raises crucial issues concerning Dōgen’s approach to multi-perspectivism that have been generally been construed in terms of absolutist and relativist standpoints. My analysis of the scholastic debates also sheds light on the full history of commentaries on Dōgen’s Shōbōgenzō 正法眼蔵 encompassing the late medieval and early modern periods.