bluuebunny/crossref_metadata_2025_split huggingface dataset:
Study protocol for a randomised controlled trial evaluating the effect of folic acid supplementation beyond the first trimester on maternal plasma unmetabolised folic acid in late gestation
Authors: Sulistyoningrum Dian , Green Tim , Palmer Debbie , Sullivan Thomas , Wood Simon , Makrides Maria , Skubisz Monika , Best Karen P 
Published: November 2020

IntroductionTaking folic acid containing supplements prior to and during early pregnancy reduces the risk of neural tube defects. Neural tube defects occur prior to 28 days postconception, after which, there is no proven benefit of continuing to take folic acid. However, many women continue to take folic acid containing supplements throughout the pregnancy. At higher intakes, folic acid is not converted to its active form and accumulates in circulation as unmetabolised folic acid (UMFA). Recently, concerns have been raised about possible links between late gestation folic acid supplementation and childhood allergy, metabolic disease and autism spectrum disorders. We aim to determine if removing folic acid from prenatal micronutrient supplements after 12 weeks gestation reduces circulating levels of maternal UMFA at 36 weeks gestation.Methods and analysisThis is a parallel-design, double-blinded randomised controlled trial. Women ≥12 and <16 weeks’ gestation with a singleton pregnancy and able to give informed consent are eligible to participate. Women (n=100; 50 per group) will be randomised to receive either a micronutrient supplement containing 0.8 mg of folic acid or a micronutrient supplement without folic acid daily from enrolment until delivery. The primary outcome is plasma UMFA concentration at 36 weeks gestation. Secondary outcomes include red blood cell folate and total plasma folate concentration. We will assess whether there is a difference in mean UMFA levels at 36 weeks gestation between groups using linear regression with adjustment for baseline UMFA levels and gestational age at trial entry. The treatment effect will be described as a mean difference with 95% CI.Ethics and disseminationEthical approval has been granted from the Women’s and Children’s Health Network Research Ethics Committee (HREC/19/WCHN/018). The results of this trial will be presented at scientific conferences and published in peer-reviewed journals.Trial registration numberACTRN12619001511123.
Education and pneumonia mortality: a trend analysis of its inequalities in Colombian adults
Authors: Alvis-Zakzuk Nelson J. , Arroyave Ivan , Castañeda-Orjuela Carlos , De La Hoz-Restrepo Fernando , Alvis-Guzman Nelson 
Published: November 2020

ObjectiveTo explore the existence and trends of social inequalities related to pneumonia mortality in Colombian adults using educational level as a proxy of socioeconomic status.MethodsWe obtained individual and anonymised registries from death certificates due to pneumonia for 1998–2015. Educational level data were gathered from microdata of the Colombian Demography Health Surveys. Rate ratios (RR) were estimated by using Poisson regression models, comparing mortality of educational groups with mortality in the highest education group. Relative index of inequality (RII) was measured to assess changes in disparities, regressing mortality on the midpoint of the cumulative distribution of education, thereby considering the size of each educational group.ResultsFor adults 25+ years, the risk of dying was significantly higher among lower educated. The RRs depict increased risks of dying comparing lower and highest education level, and this tendency was stronger in woman than in men (RR for primary education=2.34 (95% CI 2.32 to 2.36), RR for secondary education=1.77 (95% CI 1.75 to 1.78) versus RR for primary education=1.83 (95% CI 1.81 to 1.85), RR for secondary education=1.51 (95% CI 1.50 to 1.53)). According to age groups, young adults (25–44 years) showed the largest inequality in terms of educational level; RRs for pneumonia mortality regarding the tertiary educated groups show increased mortality in the lower and secondary educated, and these differences decreased with ages. RII in pneumonia mortality among adult men was 2.01 (95% CI 2.00 to 2.03) and in women 2.46 (95% CI 2.43 to 2.48). The RII was greatest at young ages, for both sexes. Time trends showed steadily significant increases for RII in both men and women (estimated annual percentage change (EAPC)men=3.8; EAPCwomen=2.6).ConclusionA significant increase on the educational inequalities in mortality due to pneumonia during all period was found among men and women. Efforts to reduce pneumonia mortality in adults improving population health by raising education levels should be strengthened with policies that assure widespread access to economic and social opportunities.
RANKL-Targeted Combination Therapy with Osteoprotegerin Variant Devoid of TRAIL Binding Exerts Biphasic Effects on Skeletal Remodeling and Antitumor Immunity
Authors: Wang Hong , Ashton Reading , Hensel Jonathan A. , Lee Joo Hyoung , Khattar Vinayak , Wang Yong , Deshane Jessy S. , Ponnazhagan Selvarangan 
Published: November 2020

AbstractComplexities in treating breast cancer with bone metastasis are enhanced by a vicious protumorigenic pathology, involving a shift in skeletal homeostasis toward aggressive osteoclast activity and polarization of immune cells supporting tumor growth and immunosuppression. Recent studies signify the role of receptor activator of NF-κB ligand (RANKL) beyond skeletal pathology in breast cancer, including tumor growth and immunosuppression. By using an osteoprotegerin (OPG) variant, which we developed recently through protein engineering to uncouple TNF-related apoptosis-inducing ligand (TRAIL) binding, this study established the potential of a cell-based OPGY49R therapy for both bone damage and immunosuppression in an immunocompetent mouse model of orthotopic and metastatic breast cancers. In combination with agonistic death receptor (DR5) activation, the OPGY49R therapy significantly increased both bone remolding and long-term antitumor immunity, protecting mice from breast cancer relapse and osteolytic pathology. With limitations, cost, and toxicity issues associated with the use of denosumab, bisphosphonates, and chemotherapy for bone metastatic disease, use of OPGY49R combination could offer a viable alternate therapeutic approach.
A molecular phylogeny of the long-horned bees in the genus Melissodes Latreille (Hymenoptera: Apidae: Eucerinae)
Authors: Wright Karen W. , Miller Kelly B. , Song Hojun 
Published: November 2020

Abstract
The genus Melissodes Latreille in the subfamily Eucerinae (Hymenoptera: Apidae) is a widespread and common group of bees. There are 129 described Melissodes species that range throughout the western hemisphere with the center of diversity in the warm deserts of southwestern North America. Despite its widespread nature and importance in agriculture, the evolutionary relationships among the species have never been investigated. Here, we present a molecular phylogeny using five loci for 89 species of Melissodes with representatives from all subgenera. We confirm all of the subgeneric delineations constructed by LaBerge, except for a paraphyletic M. (Tachymelissodes) and the placement of M. (Heliomelissodes), which renders M. (Eumelissodes) paraphyletic. We also discuss the unexpected placement of M. tristis Cockerell, M. paucipuncta LaBerge, M. dagosus Cockerell, and M. pexa LaBerge. Finally, we combine this analysis with previous data to support the placement of Melissodes within the subfamily Eucerinae.
Revisiting the Severe Classification of Abū Ḥātim al-Rāzī: an Analysis of Technical Terminology in Ḥadīth Transmitter Criticism
Authors: Jamilin Ahmad Kamil Bin , Muhammad Yusoff Muhammad Fawwaz Bin 
Published: November 2020

Abstract
Abū Ḥātim Muḥammad b. Idrīs al-Rāzī was a leading figure in the science of ḥadīth transmission and considered among the early generation in ḥadīth transmitter criticism (what are known as al-ǧarḥ wa al-taʿdīl, impugning and approving). However, later ḥadīth scholars classified Abū Ḥātim as a mutašaddid (severe) ḥadīth critic, based on his abundant evaluations and criticisms of the ḥadīth transmitters. The evaluation of his criticism is sometimes ambiguous and sometimes supplemented by clear statements and proofs. This ambiguity usually occurs as a result of the sophisticated terminologies, different uses of multiple meanings of a word, inconsistencies and the unusual presence of contradictions. This matter may lead to confusion and misunderstanding among contemporary scholars and students of ḥadīth transmitter criticism. Among the terms he used were ‘laysa bi al-qawī’ and ‘laysa bi qawī’, which literally means ‘not strong’ and deny the credibility of a transmitter, or totally rejects his or her ḥadīth. However, based on our exploratory analysis of how Abū Ḥātim employed those terms, they cannot be accepted in a literal sense. Therefore, this article aims to thoroughly scrutinize the severity of Abū Ḥātim when he evaluates a transmitter in comparison to other master ḥadīth critics. To summarize, Abū Ḥātim’s terminology is very important for understanding his methodology, which certainly has an impact on ḥadīth transmitter criticism as well as the ultimate goals of al-ǧarḥ wa al-taʿdīl, i.e., the authenticity of prophetic ḥadīth.
Pharmacists’ experiences with the Bloom Program application process
Authors: Murphy Andrea L. , Jacobs Lisa M. , Gardner David M. 
Published: November 2020

Background: The Bloom Program, which began as a demonstration project, is an ongoing community pharmacy–based mental illness and addictions program funded by the government of Nova Scotia. To be eligible to offer the Bloom Program, interested pharmacists were required to complete a 9-part application on behalf of their pharmacies. A process evaluation was conducted to inform future program implementation changes of program components, including the application process. Methods: Qualitative interviews from 24 pharmacists were inductively analyzed to determine the challenges and opportunities in the program’s application process. Results: Key and impactful components of the application process included training, providing a mental health and addictions resource centre within the pharmacy and completing outreach activities with local mental health and addictions services and support organizations. The training content and format for the program was highly valued. Community outreach to local mental health and addictions resources, and other health care resources in the community, was particularly valuable in supporting patient navigation of the health care system and extending the pharmacists’ networks. Components of the application process were challenging for many pharmacists but were beneficial personally and professionally. Dedicated resources (e.g., time and staffing) are required for the efficient completion of the application process. Conclusion: Pharmacists viewed the Bloom Program application process as intensive yet necessary and relevant for preparing to deliver the Program. The demonstration project process evaluation was essential for elucidating the strengths of the application process and, importantly, identifying areas for improvement. Can Pharm J (Ott) 2021;154:xx-xx.
Extracellular matrix remodelling in COPD
Authors: Karakioulaki Meropi , Papakonstantinou Eleni , Stolz Daiana 
Published: November 2020

The extracellular matrix (ECM) of the lung plays several important roles in lung function, as it offers a low resistant pathway that allows the exchange of gases, provides compressive strength and elasticity that supports the fragile alveolar–capillary intersection, controls the binding of cells with growth factors and cell surface receptors and acts as a buffer against retention of water.COPD is a chronic inflammatory respiratory condition, characterised by various conditions that result in progressive airflow limitation. At any stage in the course of the disease, acute exacerbations of COPD may occur and lead to accelerated deterioration of pulmonary function. A key factor of COPD is airway remodelling, which refers to the serious alterations of the ECM affecting airway wall thickness, resistance and elasticity. Various studies have shown that serum biomarkers of ECM turnover are significantly associated with disease severity in patients with COPD and may serve as potential targets to control airway inflammation and remodelling in COPD. Unravelling the complete molecular composition of the ECM in the diseased lungs will help to identify novel biomarkers for disease progression and therapy.
Genetic mapping for agronomic traits in a MAGIC population of common bean (Phaseolus vulgaris L.) under drought conditions
Authors: Diaz Santiago , Ariza-Suarez Daniel , Izquierdo Paulo , Lobaton Juan David , de la Hoz Juan Fernando , Acevedo Fernando , Duitama Jorge , Guerrero Alberto F. , Cajiao Cesar , Mayor Victor , Beebe Stephen E. , Raatz Bodo 
Published: November 2020

AbstractBackgroundCommon bean is an important staple crop in the tropics of Africa, Asia and the Americas. Particularly smallholder farmers rely on bean as a source for calories, protein and micronutrients. Drought is a major production constraint for common bean, a situation that will be aggravated with current climate change scenarios. In this context, new tools designed to understand the genetic basis governing the phenotypic responses to abiotic stress are required to improve transfer of desirable traits into cultivated beans.ResultsA multiparent advanced generation intercross (MAGIC) population of common bean was generated from eight Mesoamerican breeding lines representing the phenotypic and genotypic diversity of the CIAT Mesoamerican breeding program. This population was assessed under drought conditions in two field trials for yield, 100 seed weight, iron and zinc accumulation, phenology and pod harvest index.Transgressive segregation was observed for most of these traits. Yield was positively correlated with yield components and pod harvest index (PHI), and negative correlations were found with phenology traits and micromineral contents. Founder haplotypes in the population were identified using Genotyping by Sequencing (GBS). No major population structure was observed in the population. Whole Genome Sequencing (WGS) data from the founder lines was used to impute genotyping data for GWAS. Genetic mapping was carried out with two methods, using association mapping with GWAS, and linkage mapping with haplotype-based interval screening. Thirteen high confidence QTL were identified using both methods and several QTL hotspots were found controlling multiple traits. A major QTL hotspot located on chromosome Pv01 for phenology traits and yield was identified. Further hotspots affecting several traits were observed on chromosomes Pv03 and Pv08. A major QTL for seed Fe content was contributed by MIB778, the founder line with highest micromineral accumulation. Based on imputed WGS data, candidate genes are reported for the identified major QTL, and sequence changes were identified that could cause the phenotypic variation.ConclusionsThis work demonstrates the importance of this common bean MAGIC population for genetic mapping of agronomic traits, to identify trait associations for molecular breeding tool design and as a new genetic resource for the bean research community.
Phase 2 study of lenvatinib monotherapy as second-line treatment in unresectable biliary tract cancer: primary analysis results
Authors: Ueno Makoto , Ikeda Masafumi , Sasaki Takashi , Nagashima Fumio , Mizuno Nobumasa , Shimizu Satoshi , Ikezawa Hiroki , Hayata Nozomi , Nakajima Ryo , Morizane Chigusa 
Published: November 2020

AbstractBackgroundBiliary tract cancer (BTC) has a poor prognosis and lacks a standardized second-line therapy. Vascular endothelial growth factor (VEGF), fibroblast growth factor receptor (FGFR) 4, and platelet-derived growth factor receptor (PDGFR) are highly expressed in BTC. Therefore, lenvatinib (a known inhibitor of VEGF receptors 1–3, FGFRs 1–4, and PDGFR-α) was evaluated for second-line treatment of BTC.MethodsIn this single-arm, multicenter, open-label, phase 2 study, patients with BTC received lenvatinib 24 mg orally once daily in 28-day cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), PFS rate at 12 weeks, disease control rate, clinical benefit rate, safety and pharmacokinetic profiles.ResultsTwenty-six Japanese patients were enrolled and treated; 3 had a confirmed partial response per investigator assessment and per independent imaging review (IIR); ORR was 11.5% (90% confidence interval [CI]: 3.2–27.2). Median PFS was 3.19 months (95% CI: 2.79–7.23) per investigator assessment and 1.64 months (95% CI: 1.41–3.19) per IIR. Median OS was 7.35 months (95% CI: 4.50–11.27). Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 21 patients (80.8%) and included hypertension (n = 10 [38.5%]), proteinuria (n = 3 [11.5%]), palmar-plantar erythrodysesthesia (n = 3 [11.5%]), decreased appetite (n = 3 [11.5%]), and anemia (n = 3 [11.5%]). Two deaths occurred due to TEAEs between treatment initiation and 30 days after last dose, but neither were considered treatment related.ConclusionsLenvatinib demonstrated antitumor activity in BTC, with a tolerable safety profile, and should be further evaluated as potential second-line therapy for this difficult to treat population.Trial registrationClinicalTrials.govNCT02579616. Date of registration: October 19, 2015.
Prevalence of gastric cancer precursors in gastroscopy-screened adults by family history of gastric cancer and of cancers other than gastric
Authors: Wu Rui , Yang Cheng , Ji Lin , Fan Zhi-Ning , Tao Yu-Wen , Zhan Qiang 
Published: November 2020

Abstract
Background
People are at a high risk of gastric cancer if their first-degree relatives suffered from atrophic gastritis (AG), intestinal metaplasia (IM), intraepithelial neoplasia (IEN), dysplasia (DYS), or gastric cancer (GC). This study was performed to analyse the association between FDR-GC and GC precursors.

Methods
A cross-sectional study was performed to screen the prevalence of GC precursors from November 2016 to September 2019. A total of 1329 participants with FDR-GC, 193 participants with a family history of non-gastric cancer in FDRs (FDR-nGC), and 860 participants without a family history of cancer in FDRs (FDR-nC) were recruited in this study. The logistic regression model was used in this study.

Results
The prevalence of normal, Non-AG, AG/IM, IEN/DYS, and GC was 31.91, 44.21, 13.81, 8.73, and 1.34%, respectively. The prevalence of IEN/DYS was higher in people with FDR-GC and FDR-nGC (FDR-GC: odds ratio (OR) = 1.655; 95%CI, 1.153–2.376; FDR-nGC: OR = 1.984; 95%CI, 1.122–3.506) than those with FDR-nC. The younger the age at which FDRs were diagnosed with GC, the more likely the participants were to develop AG/IM (Ptrend = 0.019). The risk of precursors to GC was higher in participants whose FDR-GC was the mother than in those whose FDR-GC was the father or sibling (OR, non-AG: 1.312 vs. 1.007, 1.274; AG/IM: 1.430 vs. 1.296, 1.378; IEN/DYS: 1.988 vs. 1.573, 1.542). There was no statistically significant difference in non-AG (OR = 1.700; 95%CI, 0.940–3.074), AG/IM (OR = 1.291; 95%CI, 0.579–2.877), and IEN/DYS (OR = 1.265; 95%CI, 0.517–3.096) between participants with one or more FDR-GC.

Conclusion
People with FDR-GC and FDR-nGC are at a high risk of IEN/DYS. When an FDR was diagnosed at a younger age, the risk of AG/IM was higher. The risk of GC precursors was higher in people whose FDR-GC was the mother.
Dose-dependent effect of human milk on Bronchopulmonary dysplasia in very low birth weight infants
Authors: Xu Yan , Yu Zhangbin , Li Qianqian , Zhou Jinjun , Yin Xiaoguang , Ma Yuelan , Yin Yujie , Jiang Shanyu , Zhu Rongping , Wu Yue , Han Liangrong , Gao Yan , Xue Mei , Qiao Yu , Zhu Lingling , Tu Wenjuan , Wu Mingfu , Wan Jun , Wang Weiyuan , Deng Xiaoyi , Li Shuangshuang , Wang Sannan , Chen Xiaoqing , Zhou Qin , Wang Jinxiu , Cheng Rui , Wang Jun , Han Shuping 
Published: November 2020

Abstract
Background and aim
Human milk has potential protective effects against bronchopulmonary dysplasia (BPD). However, studies on the association between the dose of human milk and BPD in China are limited. This study aimed to evaluate the dose-dependent effects of human milk on BPD and other neonatal morbidities in very low birth weight (VLBW) infants.

Methods
This retrospective cohort study of preterm infants was conducted on preterm infants of gestational age ≤ 34 weeks and birth weight < 1500 g admitted to the multicenter clinical research database for breastfeeding quality improvement in Jiangsu province. The multivariate analysis was performed to compare the effect outcomes of daily graded doses [1–24 mL/(kg · day), 25–49 mL/(kg · day), and ≥ 50 mL/(kg · day) of body weight] of human milk on neonatal outcomes throughout the first 4 weeks of life versus a reference group receiving no human milk. The models were adjusted for potential confounding variables.

Results
Of 964 included infants, 279 (28.9%) received exclusive preterm formula, 128 (13.3%) received 1–24 ml/(kg · day), 139 (14.4%) received 25–49 ml/(kg · day), and 418 (43.4%) received ≥50 ml/(kg · day) human milk for the first 4 weeks of life. Compared with infants receiving exclusive formula, those receiving the highest volume of human milk daily [≥50 mL/(kg · day)] had lower incidences of BPD [27.5% in ≥50 mL/(kg · day) vs 40.1% in 0 mL/(kg · day) human milk, P = 0.001)], moderate and severe BPD [8.9% in ≥50 mL/(kg · day) vs 16.1% in 0 mL/(kg · day), P = 0.004], necrotizing enterocolitis [NEC; 3.8% in ≥50 mL/(kg · day) vs 10.8% in 0 mL/(kg · day), P = 0.001], late-onset sepsis [LOS; 9.3% in ≥50 mL/(kg · day) vs 19.7% in 0 mL/(kg · day), P <0.01], and extrauterine growth retardation [EUGR; 38.5% in ≥50 mL/(kg · day) vs 57.6% in 0 mL/(kg · day), P <0.01)]. The logistic regression indicated that those receiving ≥50 ml/kg · day human milk had lower odds of BPD [adjusted odds ratio (AOR) 0.453; 95% confidence interval (CI): 0.309, 0.666], moderate and severe BPD (AOR 0.430; 95% CI: 0.249, 0.742), NEC (AOR 0.314; 95% CI: 0.162, 0. 607), LOS (AOR 0.420; 95% CI: 0.263, 0.673), and EUGR (AOR 0.685; 95% CI: 0.479, 0.979).

Conclusions
A daily threshold amount of ≥50 ml/(kg · day) human milk in the first 4 weeks of life was associated with lower incidence of BPD as well as NEC, LOS, and EUGR in VLBW infants.

Trial registration
ClinicalTrials.gov Identifier: NCT03453502. Registration date: March 5, 2018. This study was retrospectively registered.