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Objective:Observational studies have linked elevated homocysteine to vascular conditions. Folate intake has been associated with lower homocysteine concentration, although randomised controlled trials of folic acid supplementation to decrease the incidence of vascular conditions have been inconclusive. We investigated determinants of maternal homocysteine during pregnancy, particularly in a folic acid-fortified population.Design:Data were from the Ottawa and Kingston Birth Cohort of 8085 participants. We used multivariable regression analyses to identify factors associated with maternal homocysteine, adjusted for gestational age at bloodwork. Continuous factors were modelled using restricted cubic splines. A subgroup analysis examined the modifying effect of MTHFR 677C>T genotype on folate, in determining homocysteine concentration.Setting:Participants were recruited in Ottawa and Kingston, Canada, from 2002 to 2009.Participants:Women were recruited when presenting for prenatal care in the early second trimester.Results:In 7587 participants, factors significantly associated with higher homocysteine concentration were nulliparous, smoking and chronic hypertension, while factors significantly associated with lower homocysteine concentration were non-Caucasian race, history of a placenta-mediated complication and folic acid supplementation. Maternal age and BMI demonstrated U-shaped associations. Folic acid supplementation of >1 mg/d during pregnancy did not substantially increase folate concentration. In the subgroup analysis, MTHFR 677C>T modified the effect of folate status on homocysteine concentration.Conclusions:We identified determinants of maternal homocysteine relevant to the lowering of homocysteine in the post-folic acid fortification era, characterised by folate-replete populations. A focus on periconceptional folic acid supplementation and improving health status may form an effective approach to lower homocysteine.

A cross-sectional study identified cases of mucinous breast carcinoma from pathology records (2004-2012). Two radiologists classified imaging features by consensus and two pathologists classified cases into pure or mixed subtypes. Bi-variable analyses were performed using relevant statistical tests.We identified 80 lesions in 77 female patients (median age 65 years, range 29-88): 58 lesions on mammograhy, 72 on ultrasound, and 25 on MRI. Statistically significant findings (p0.05) are as follows. On mammography, tumour margins tended to be indistinct (12, 48%) and spiculated (11, 44%) for pure and mixed lesions, respectively. Pure mucinous masses were less microcalcified (23, 77%) and mixed masses equally so. On ultrasound, pure tumours tended towards an irregular or oval shape (44, 42%) with mixed tumours having an irregular shape (78%). More pure tumours (53%) had posterior acoustic enhancement than mixed lesions (33%), and all pure tumours lacked posterior acoustic shadowing. Pure lesions had a heterogeneous echo pattern more than mixed tumours (78% vs 39%). On MRI, pure tumours tended towards a persistent kinetic curve (42%) whereas mixed tumours predominantly had a washout pattern (75%). Most pure tumours were TAn analysis of imaging features can help to infer underlying histology of pure and mixed forms of mucinous breast carcinoma.Pure mucinous carcinomas present less suspicious imaging features than mixed mucinous carcinomas and could be mistaken for non malignant lesions. An imaging analysis of mucinous breast carcinoma can help infer their underlying histology.

ObjectiveTo examine the association between BMI and folate concentrations in serum and red blood cells (RBC) in pregnant women.DesignA cross-sectional comparison of folate concentrations in serum and RBC sampled simultaneously from the same individual.SettingThe Ottawa Hospital and Kingston General Hospital, Ontario, Canada.SubjectsPregnant women recruited between 12 and 20 weeks of gestation.ResultsA total of 869 pregnant women recruited from April 2008 to April 2009 were included in the final analysis. Serum folate was inversely associated and RBC folate positively associated with BMI, after adjusting for folic acid supplementation, age, gestational age at blood sample collection, race, maternal education, annual income, smoking and MTHFR 677C→T genotype. In stratified analyses, this differential association was significant in women with the MTHFR CC variant. In women with the CT and TT variants, the differential associations were in the same direction but not significant. Folic acid supplementation during pregnancy did not alter the differential association of BMI with serum and RBC folate concentration. This indicates that the current RBC folate cut-off approach for assessing risk of neural tube defects in obese women may be limited.ConclusionsBMI is inversely associated with serum folate and positively associated with RBC folate in pregnant women, especially for those with the MTHFR CC variant.

Background Homocysteine is an intermediate metabolite implicated in the risk of placenta-mediated complications, including preeclampsia, placental abruption, fetal growth restriction, and pregnancy loss. Large cohort and case-control studies have reported inconsistent associations between homocysteine and these complications. The purpose of this study was to investigate whether elevated maternal plasma homocysteine concentration in the early to mid-second trimester is associated with an increased risk of placenta-mediated complications. We examined the following potential moderating factors that may explain discrepancies among previous studies: high-risk pregnancy and the MTHFR 677C>T polymorphism. Methods We analyzed data from participants recruited to the Ottawa and Kingston (OaK) Birth Cohort from 2002 to 2009 in Ottawa and Kingston, Canada. The primary outcome was a composite of any placenta-mediated complication, defined as a composite of small for gestational age (SGA) infant, preeclampsia, placental abruption, and pregnancy loss. Secondary outcomes were, individually: SGA infant, preeclampsia, placental abruption, and pregnancy loss. We conducted multivariable logistic regression analyses with homocysteine as the primary continuous exposure, adjusting for gestational age at the time of bloodwork and explanatory maternal characteristics. The functional form, i.e., the shape of the homocysteine association with the outcome was examined using restricted cubic splines and information criteria (Akaike’s/Bayesian Information Criterion statistics). Missing data were handled with multiple imputation. Results 7587 cohort participants were included in the study. Maternal plasma homocysteine concentration was significantly associated (linearly) with an increased risk of both the composite outcome of any placenta-mediated complication (p = 0.0007), SGA (p = 0.0010), severe SGA, and marginally with severe preeclampsia, but not preeclampsia, placental abruption and pregnancy loss. An increase in homocysteine concentration significantly increased the odds of any placenta-mediated complication (odds ratio (OR) for a 5 μmol/L increase: 1.63, 95% Confidence Interval (CI) 1.23–2.16) and SGA (OR 1.76, 95% CI 1.25–2.46). Subgroup analyses indicated some potential for modifying effects of the MTHFR 677C>T genotype and high-risk pregnancy, although the interaction was not statistically significant (high-risk subgroup OR 2.37, 95% CI 1.24–4.53, p-value for interaction =0.14). Conclusions Our results suggest an independent effect of early to mid-pregnancy elevated maternal homocysteine on placenta-mediated pregnancy complications. Electronic supplementary material The online version of this article (10.1186/s12884-019-2219-5) contains supplementary material, which is available to authorized users.

Background Cluster randomized trials (CRTs) complicate the interpretation of standard research ethics guidelines for several reasons. For one, the units of allocation, intervention, and observation often may differ within a single trial. In the absence of tailored and internationally accepted ethics guidelines for CRTs, researchers and research ethics committees have no common standard by which to judge ethically appropriate practices in CRTs. Moreover, lack of familiarity with and consideration of the unique features of the CRT design by research ethics committees may cause difficulties in the research ethics review process, and amplify problems such as variability in the requirements and decisions reached by different research ethics committees. Purpose We aimed to characterize research ethics review of CRTs, examine investigator experiences with the ethics review process, and assess the need for ethics guidelines for CRTs. Methods An electronic search strategy implemented in MEDLINE was used to identify and randomly sample 300 CRTs published in English language journals from 2000 to 2008. A web-based survey with closed- and open-ended questions was administered to corresponding authors in a series of six contacts. Results The survey response rate was 64%. Among 182 of 285 eligible respondents, 91% indicated that they had sought research ethics approval for the identified CRT, although only 70% respondents reported research ethics approval in the published article. Nearly one-third (31%) indicated that they have had to meet with ethics committees to explain aspects of their trials, nearly half (46%) experienced variability in the ethics review process in multijurisdictional trials, and 38% experienced negative impacts of the ethics review process on their trials, including delays in trial initiation (28%), increased costs (10%), compromised ability to recruit participants (16%), and compromised methodological quality (9%). Most respondents (74%; 95% confidence interval (CI): 67%–80%) agreed or strongly agreed that there is a need to develop ethics guidelines for CRTs, and (70%; 95% CI: 63%–77%) that ethics committees could be better informed about distinct ethical issues surrounding CRTs. Limitations Thirty-six percent of authors did not respond to the survey. Due to the absence of comparable results from a representative sample of authors of individually randomized trials, it is unclear to what extent the reported challenges result from the CRT design. Conclusions CRT investigators are experiencing challenges in the research ethics review of their trials, including excessive delays, variability in process and outcome, and imposed requirements that can have negative consequences for study conduct. Investigators identified a clear need for ethics guidelines for CRTs and education of research ethics committees about distinct ethical issues in CRTs.

Background Low response rates and inadequate question comprehension threaten the validity of survey results. We describe a simple procedure to implement personalized—as opposed to generically worded—questionnaires in the context of a complex web-based survey of corresponding authors of a random sample of 300 published cluster randomized trials. The purpose of the survey was to gather more detailed information about informed consent procedures used in the trial, over and above basic information provided in the trial report. We describe our approach—which allowed extensive personalization without the need for specialized computer technology—and discuss its potential application in similar settings. Results The mail merge feature of standard word processing software was used to generate unique, personalized questionnaires for each author by incorporating specific information from the article, including naming the randomization unit (e.g., family practice, school, worksite), and identifying specific individuals who may have been considered research participants at the cluster level (family doctors, teachers, employers) and individual level (patients, students, employees) in questions regarding informed consent procedures in the trial. The response rate was relatively high (64 %, 182/285) and did not vary significantly by author, publication, or study characteristics. The refusal rate was low (7 %). Conclusion While controlled studies are required to examine the specific effects of our approach on comprehension, quality of responses, and response rates, we showed how mail merge can be used as a simple but useful tool to add personalized fields to complex survey questionnaires, or to request additional information required from study authors. One potential application is in eliciting specific information about published articles from study authors when conducting systematic reviews and meta-analyses.

6-Methacryloyl-alpha-D-galactopyranose (MG) was synthesized, and characterized by Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectrometry, and single-crystal X-ray diffraction. A series of interpenetrating polymer network (IPN) hydrogels was fabricated by simultaneously photocuring MG crosslinked by poly(ethylene glycol) diacrylate and chemically crosslinking type I collagen with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide. The successful incorporation of the glycopolymer, polymer MG, into collagen hydrogel was confirmed by FTIR and solid-state (13)C NMR. The optical characteristics of the IPN hydrogels are comparable to those of human corneas. The tensile strength and modulus of the hydrogels are enhanced by incorporation of polymer MG in comparison to that of the control collagen hydrogel. Biodegradation results indicated that polymer MG enhanced the stability of the composite hydrogels against collagenase. In vitro results demonstrated that the IPN hydrogel supported the adhesion and proliferation of human corneal epithelial cells and outperformed human cornea in blocking bacteria adhesion. Taken together, the IPN hydrogel might be a promising material for use in corneal lamellar keratoplasty.

Background Cluster randomized trials are an increasingly important methodological tool in health research. In cluster randomized trials, intact social units or groups of individuals, such as medical practices, schools, or entire communities – rather than individual themselves – are randomly allocated to intervention or control conditions, while outcomes are then observed on individual cluster members. The substantial methodological differences between cluster randomized trials and conventional randomized trials pose serious challenges to the current conceptual framework for research ethics. The ethical implications of randomizing groups rather than individuals are not addressed in current research ethics guidelines, nor have they even been thoroughly explored. The main objectives of this research are to: (1) identify ethical issues arising in cluster trials and learn how they are currently being addressed; (2) understand how ethics reviews of cluster trials are carried out in different countries (Canada, the USA and the UK); (3) elicit the views and experiences of trial participants and cluster representatives; (4) develop well-grounded guidelines for the ethical conduct and review of cluster trials by conducting an extensive ethical analysis and organizing a consensus process; (5) disseminate the guidelines to researchers, research ethics boards (REBs), journal editors, and research funders. Methods We will use a mixed-methods (qualitative and quantitative) approach incorporating both empirical and conceptual work. Empirical work will include a systematic review of a random sample of published trials, a survey and in-depth interviews with trialists, a survey of REBs, and in-depth interviews and focus group discussions with trial participants and gatekeepers. The empirical work will inform the concurrent ethical analysis which will lead to a guidance document laying out principles, policy options, and rationale for proposed guidelines. An Expert Panel of researchers, ethicists, health lawyers, consumer advocates, REB members, and representatives from low-middle income countries will be appointed. A consensus conference will be convened and draft guidelines will be generated by the Panel; an e-consultation phase will then be launched to invite comments from the broader community of researchers, policy-makers, and the public before a final set of guidelines is generated by the Panel and widely disseminated by the research team.

Background Cluster randomized trials (CRTs) pose ethical challenges for investigators and ethics committees. This study describes the views and experiences of CRT researchers with respect to: (1) ethical challenges in CRTs; (2) the ethics review process for CRTs; and (3) the need for comprehensive ethics guidelines for CRTs. Methods Descriptive qualitative analysis of interviews conducted with a purposive sample of 20 experienced CRT researchers. Results Informants expressed concern over the potential for bias that may result from requirements to obtain informed consent from research participants in CRTs. Informants suggested that the need for informed consent ought to be related to the type of intervention under study in a CRT. Informants rarely expressed concern regarding risks to research participants in CRTs, other than risks to privacy. Important issues identified in the research ethics literature, including fair subject selection and other justice issues, were not mentioned by informants. The ethics review process has had positive and negative impacts on CRT conduct. Informants stated that variability in ethics review between jurisdictions, and increasingly stringent ethics review in recent years, have hampered their ability to conduct CRTs. Many informants said that comprehensive ethics guidelines for CRTs would be helpful to researchers and research ethics committees. Conclusions Informants identified key ethical challenges in the conduct of CRTs, specifically relating to identifying subjects, seeking informed consent, and the use of gatekeepers. These data have since been used to identify topics for in-depth ethical analysis and to guide the development of comprehensive ethics guidelines for CRTs.