Institut du Savoir Montfort

BACKGROUND: A complete remission is essential for prolonging survival in patients with acute myeloid leukemia (AML). Daunorubicin is a cornerstone of the induction regimen, but the optimal dose is unknown. In older patients, it is usual to give daunorubicin at a dose of 45 to 50 mg per square meter of body-surface area. METHODS: Patients in whom AML or high-risk refractory anemia had been newly diagnosed and who were 60 to 83 years of age (median, 67) were randomly assigned to receive cytarabine, at a dose of 200 mg per square meter by continuous infusion for 7 days, plus daunorubicin for 3 days, either at the conventional dose of 45 mg per square meter (411 patients) or at an escalated dose of 90 mg per square meter (402 patients); this treatment was followed by a second cycle of cytarabine at a dose of 1000 mg per square meter every 12 hours [DOSAGE ERROR CORRECTED] for 6 days. The primary end point was event-free survival. RESULTS: The complete remission rates were 64% in the group that received the escalated dose of daunorubicin and 54% in the group that received the conventional dose (P=0.002); the rates of remission after the first cycle of induction treatment were 52% and 35%, respectively (P<0.001). There was no significant difference between the two groups in the incidence of hematologic toxic effects, 30-day mortality (11% and 12% in the two groups, respectively), or the incidence of moderate, severe, or life-threatening adverse events (P=0.08). Survival end points in the two groups did not differ significantly overall, but patients in the escalated-treatment group who were 60 to 65 years of age, as compared with the patients in the same age group who received the conventional dose, had higher rates of complete remission (73% vs. 51%), event-free survival (29% vs. 14%), and overall survival (38% vs. 23%). CONCLUSIONS: In patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, effects a more rapid response and a higher response rate than does the conventional dose, without additional toxic effects. (Current Controlled Trials number, ISRCTN77039377; and Netherlands National Trial Register number, NTR212.)

IMPORTANCE: Patients with atrial fibrillation (AF) who use a direct oral anticoagulant (DOAC) and request elective surgery or procedure present a common clinical situation yet perioperative management is uncertain. OBJECTIVE: To investigate the safety of a standardized perioperative DOAC management strategy. DESIGN, SETTING, AND PARTICIPANTS: The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) cohort study conducted at 23 clinical centers in Canada, the United States, and Europe enrolled and screened patients from August 1, 2014, through July 31, 2018. Participants (n = 3007) had AF; were 18 years of age or older; were long-term users of apixaban, dabigatran etexilate, or rivaroxaban; were scheduled for an elective surgery or procedure; and could adhere to the DOAC therapy interruption protocol. INTERVENTIONS: A simple standardized perioperative DOAC therapy interruption and resumption strategy based on DOAC pharmacokinetic properties, procedure-associated bleeding risk, and creatinine clearance levels. The DOAC regimens were omitted for 1 day before a low-bleeding-risk procedure and 2 days before a high-bleeding-risk procedure. The DOAC regimens were resumed 1 day after a low-bleeding-risk procedure and 2 to 3 days after a high-bleeding-risk procedure. Follow-up of patients occurred for 30 days after the operation. MAIN OUTCOMES AND MEASURES: Major bleeding and arterial thromboembolism (ischemic stroke, systemic embolism, and transient ischemic attack) and the proportion of patients with an undetectable or minimal residual anticoagulant level (<50 ng/mL) at the time of the procedure. RESULTS: The 3007 patients with AF (mean [SD] age of 72.5 [9.39] years; 1988 men [66.1%]) comprised 1257 (41.8%) in the apixaban cohort, 668 (22.2%) in the dabigatran cohort, and 1082 (36.0%) in the rivaroxaban cohort; 1007 patients (33.5%) had a high-bleeding-risk procedure. The 30-day postoperative rate of major bleeding was 1.35% (95% CI, 0%-2.00%) in the apixaban cohort, 0.90% (95% CI, 0%-1.73%) in the dabigatran cohort, and 1.85% (95% CI, 0%-2.65%) in the rivaroxaban cohort. The rate of arterial thromboembolism was 0.16% (95% CI, 0%-0.48%) in the apixaban cohort, 0.60% (95% CI, 0%-1.33%) in the dabigatran cohort, and 0.37% (95% CI, 0%-0.82%) in the rivaroxaban cohort. In patients with a high-bleeding-risk procedure, the rates of major bleeding were 2.96% (95% CI, 0%-4.68%) in the apixaban cohort and 2.95% (95% CI, 0%-4.76%) in the rivaroxaban cohort. CONCLUSIONS AND RELEVANCE: In this study, patients with AF who had DOAC therapy interruption for elective surgery or procedure, a perioperative management strategy without heparin bridging or coagulation function testing was associated with low rates of major bleeding and arterial thromboembolism.

BACKGROUND: Cytarabine (ara-C) is an important drug in the treatment of acute myeloid leukemia (AML). High-dose cytarabine (2000 to 3000 mg per square meter of body-surface area) is toxic but results in higher rates of relapse-free survival than does the conventional dose of 100 to 400 mg per square meter. Intermediate dose levels have not been thoroughly evaluated. METHODS: We compared two induction regimens in patients 18 to 60 years of age (median, 49) who had newly diagnosed AML. The intermediate-dose group, totaling 431 patients, received cytarabine at a dose of 200 mg per square meter given by continuous intravenous infusion for 24 hours during cycle 1 of induction therapy and 1000 mg per square meter by infusion for 3 hours twice daily during cycle 2 of induction therapy. The high-dose group, totaling 429 patients, received a dose-escalated regimen of 1000 mg of cytarabine per square meter every 12 hours in cycle 1 and 2000 mg per square meter twice daily in cycle 2. Patients with a complete response did not receive additional cytarabine but received consolidation therapy in a third cycle of chemotherapy (mitoxantrone-etoposide) or underwent autologous or allogeneic stem-cell transplantation. Complete remission rates, survival rates, and toxic effects were assessed for each treatment group. RESULTS: At a median follow-up of 5 years, no significant differences were noted between the intermediate-dose group and the high-dose group with respect to complete remission rates (80% and 82%, respectively), probability of relapse, event-free survival at 5 years (34% and 35%), or overall survival (40% and 42%). High-dose cytarabine provided no clear advantage in any prognostic subgroup. The high-dose treatment resulted in higher incidences of grade 3 and grade 4 toxic effects (in cycle 1), prolonged hospitalization, and delayed neutrophil recovery (in cycle 2) and platelet recovery (in cycles 2 and 3). CONCLUSIONS: Induction therapy with cytarabine at the lower dose already produced maximal antileukemic effects for all response end points, suggesting a plateau in the dose-response relationship above this dose level. High-dose cytarabine results in excessive toxic effects without therapeutic benefit. (Netherlands Trial Register number, NTR230.).

The paper presents the current status of the Maritime Aerosol Network (MAN), which has been developed as a component of the Aerosol Robotic Network (AERONET). MAN deploys Microtops handheld Sun photometers and utilizes the calibration procedure and data processing (Version 2) traceable to AERONET. A web site dedicated to the MAN activity is described. A brief historical perspective is given to aerosol optical depth (AOD) measurements over the oceans. A short summary of the existing data, collected on board ships of opportunity during the NASA Sensor Intercomparison and Merger for Biological and Interdisciplinary Oceanic Studies (SIMBIOS) Project is presented. Globally averaged oceanic aerosol optical depth (derived from island‐based AERONET measurements) at 500 nm is ∼0.11 and Angstrom parameter (computed within spectral range 440–870 nm) is calculated to be ∼0.6. First results from the cruises contributing to the Maritime Aerosol Network are shown. MAN ship‐based aerosol optical depth compares well to simultaneous island and near‐coastal AERONET site AOD.

BACKGROUND: Individuals with chronic conditions require ongoing disease management to reduce risks of adverse health outcomes. During the COVID-19 pandemic, health care for non-COVID-19 cases was affected due to the reallocation of resources towards urgent care for COVID-19 patients, resulting in inadequate ongoing care for chronic conditions. METHODS: A keyword search was conducted in PubMed, Google Scholar, Science Direct, and Scopus for English language articles published between January 2020 and January 2021. FINDINGS: During the COVID-19 pandemic, in-person care for individuals with chronic conditions have decreased due to government restriction of elective and non-urgent healthcare visits, greater instilled fear over potential COVID-19 exposure during in-person visits, and higher utilization rates of telemedicine compared to the pre-COVID-19 period. Potential benefits of a virtual-care framework during the pandemic include more effective routine disease monitoring, improved patient satisfaction, and increased treatment compliance and follow-up rates. However, more needs to be done to ensure timely and effective access to telemedicine, particularly for individuals with lower digital literacy. Capitation primary care models have been proposed as a more financially-robust approach during the COVID-19 pandemic than fee-for-service primary care models; however, the interplay between different primary models and the health outcomes is still poorly understood and warrants further investigation. Shortages of medication used to manage chronic conditions were also observed at the beginning of the COVID-19 pandemic due to global supply chain disruptions. Finally, patients with chronic conditions faced lifestyle disruptions due to the COVID-19 pandemic, specifically in physical activity, sleep, stress, and mental health, which need to be better addressed. INTERPRETATION: Overall, this review elucidates the disproportionately greater barriers to primary and specialty care that patients with chronic diseases face during the COVID-19 pandemic and emphasizes the urgent need for better chronic disease management strategies moving forward.

Background Although the benefits of physical activity (PA) are well known, physical inactivity is highly prevalent among people with obesity. The objective of this systematic review was to i) appraise knowledge on PA motives, barriers, and preferences in individuals with obesity, and ii) quantify the most frequently reported PA motives, barriers and preferences in this population. Methods Six databases (Pubmed, CINAHL, Psyarticle, SportDiscus, Web of science and Proquest) were searched by independent reviewers to identify relevant quantitative or qualitative articles reporting PA motives, barriers or preferences in adults with body mass index ≥ 30 kg/m 2 (last searched in June 2020). Risk of bias for each study was assessed by two independent reviewers with the Mixed Methods Appraisal Tool (MMAT). Results From 5,899 papers identified, a total of 27 studies, 14 quantitative, 10 qualitative and 3 mixed studies were included. About 30% of studies have a MMAT score below 50% (k = 8). The three most reported PA motives in people with obesity were weight management, energy/physical fitness, and social support. The three most common PA barriers were lack of self-discipline/motivation, pain or physical discomfort, and lack of time. Based on the only 4 studies available, walking seems to be the preferred mode of PA in people with obesity. Conclusions Weight management, lack of motivation and pain are key PA motives and barriers in people with obesity, and should be addressed in future interventions to facilitate PA initiation and maintenance. Further research is needed to investigate the PA preferences of people with obesity.

Abstract. The Maritime Aerosol Network (MAN) has been collecting data over the oceans since November 2006. Over 80 cruises were completed through early 2010 with deployments continuing. Measurement areas included various parts of the Atlantic Ocean, the Northern and Southern Pacific Ocean, the South Indian Ocean, the Southern Ocean, the Arctic Ocean and inland seas. MAN deploys Microtops hand-held sunphotometers and utilizes a calibration procedure and data processing traceable to AERONET. Data collection included areas that previously had no aerosol optical depth (AOD) coverage at all, particularly vast areas of the Southern Ocean. The MAN data archive provides a valuable resource for aerosol studies in maritime environments. In the current paper we present results of AOD measurements over the oceans, and make a comparison with satellite AOD retrievals and model simulations.

BACKGROUND: Champions have been documented in the literature as an important strategy for implementation, yet their effectiveness has not been well synthesized in the health care literature. The aim of this systematic review was to determine whether champions, tested in isolation from other implementation strategies, are effective at improving innovation use or outcomes in health care. METHODS: The JBI systematic review method guided this study. A peer-reviewed search strategy was applied to eight electronic databases to identify relevant articles. We included all published articles and unpublished theses and dissertations that used a quantitative study design to evaluate the effectiveness of champions in implementing innovations within health care settings. Two researchers independently completed study selection, data extraction, and quality appraisal. We used content analysis and vote counting to synthesize our data. RESULTS: After screening 7566 records titles and abstracts and 2090 full text articles, we included 35 studies in our review. Most of the studies (71.4%) operationalized the champion strategy by the presence or absence of a champion. In a subset of seven studies, five studies found associations between exposure to champions and increased use of best practices, programs, or technological innovations at an organizational level. In other subsets, the evidence pertaining to use of champions and innovation use by patients or providers, or at improving outcomes was either mixed or scarce. CONCLUSIONS: We identified a small body of literature reporting an association between use of champions and increased instrumental use of innovations by organizations. However, more research is needed to determine causal relationship between champions and innovation use and outcomes. Even though there are no reported adverse effects in using champions, opportunity costs may be associated with their use. Until more evidence becomes available about the effectiveness of champions at increasing innovation use and outcomes, the decision to deploy champions should consider the needs and resources of the organization and include an evaluation plan. To further our understanding of champions' effectiveness, future studies should (1) use experimental study designs in conjunction with process evaluations, (2) describe champions and their activities and (3) rigorously evaluate the effectiveness of champions' activities. REGISTRATION: Open Science Framework ( https://osf.io/ba3d2 ). Registered on November 15, 2020.

Contains fulltext : 229845.pdf (Publisher’s version ) (Open Access)

OBJECTIVES: To develop effective interventions to prevent publishing in presumed predatory journals (ie, journals that display deceptive characteristics, markers or data that cannot be verified), it is helpful to understand the motivations and experiences of those who have published in these journals. DESIGN: An online survey delivered to two sets of corresponding authors containing demographic information, and questions about researchers' perceptions of publishing in the presumed predatory journal, type of article processing fees paid and the quality of peer review received. The survey also asked six open-ended items about researchers' motivations and experiences. PARTICIPANTS: Using Beall's lists, we identified two groups of individuals who had published empirical articles in biomedical journals that were presumed to be predatory. RESULTS: Eighty-two authors partially responded (~14% response rate (11.4%[44/386] from the initial sample, 19.3%[38/197] from second sample) to our survey. The top three countries represented were India (n=21, 25.9%), USA (n=17, 21.0%) and Ethiopia (n=5, 6.2%). Three participants (3.9%) thought the journal they published in was predatory at the time of article submission. The majority of participants first encountered the journal via an email invitation to submit an article (n=32, 41.0%), or through an online search to find a journal with relevant scope (n=22, 28.2%). Most participants indicated their study received peer review (n=65, 83.3%) and that this was helpful and substantive (n=51, 79.7%). More than a third (n=32, 45.1%) indicated they did not pay fees to publish. CONCLUSIONS: This work provides some evidence to inform policy to prevent future research from being published in predatory journals. Our research suggests that common views about predatory journals (eg, no peer review) may not always be true, and that a grey zone between legitimate and presumed predatory journals exists. These results are based on self-reports and may be biased thus limiting their interpretation.

Importance: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. Objective: To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. Design, Setting, and Participants: In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). Interventions: Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. Results: The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm). Conclusions and Relevance: Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Abstract Tissue levels of chlorinated dioxins and furans and the physiological and biochemical responses of fish were measured upstream and downstream of a bleached kraft mill in the St. Maurice River, Quebec. Relative to fish 10 km upstream of the source, white suckers (Catostomus commersoni) downstream showed evidence of chemical exposure, chemical metabolism, stress, and altered energy use. Levels of 2,3,7,8–tetrachlorodibenzo-p-dioxin and tetrachlorodibenzofuran in gutted whole fish averaged 23 and 260 pg/g immediately downstream of the plant and declined to 18 and 112 pg/g at 95 km downstream. The activity of hepatic aryl hydrocarbon hydroxylase (AHH) was 10X higher immediately downstream and 5X higher 95 km downstream. There were corresponding increases in relative liver size, hematocrit, serum glucose, serum protein, and fin-ray asymmetries, with a pattern of response that matched enzyme induction. These responses pointed to a strong effluent effect and followed the patterns of tissue contamination by dioxins and furans and of water contamination by chlorinated phenolics and guaiacols. There were strong correlations between AHH induction and tissue contamination. Whereas lipid levels increased at all downstream sites, condition factor decreased at 95 km from the source, indicating that there may be disturbances in energy metabolism. Effects on sexual maturation, as shown by levels of serum hormones and gonad somatic index, were inconclusive.

Background and Purpose: Spontaneous intracerebral hemorrhage (ICH) is a devastating form of stroke associated with significant morbidity and mortality. Recent epidemiological data on incidence, mortality, and association with oral anticoagulation are needed. Methods: Retrospective cohort study of adult patients (≥18 years) with ICH in the entire population of Ontario, Canada (April 1, 2009–March 30, 2019). We captured outcome data using linked health administrative databases. The primary outcome was mortality during hospitalization, as well as at 1 year following ICH. Results: We included 20 738 patients with ICH. Mean (SD) age was 71.3 (15.1) years, and 52.6% of patients were male. Overall incidence of ICH throughout the study period was 19.1/100 000 person-years and did not markedly change over the study period. In-hospital and 1-year mortality were high (32.4% and 45.4%, respectively). Mortality at 2 years was 49.5%. Only 14.5% of patients were discharged home independently. Over the study period, both in-hospital and 1-year mortality reduced by 10.4% (37.5% to 27.1%, P &lt;0.001) and 7.6% (50.0% to 42.4%, P &lt;0.001), respectively. Use of oral anticoagulation was associated with both in-hospital mortality (adjusted odds ratio 1.37 [95% CI, 1.26–1.49]) and 1-year mortality (hazard ratio, 1.18 [95% CI, 1.12–1.25]) following ICH. Conclusions: Both short- and long-term mortality have decreased in the past decade. Most survivors from ICH are likely to be discharged to long-term care. Oral anticoagulation is associated with both short- and long-term mortality following ICH. These findings highlight the devastating nature of ICH, but also identify significant improvement in outcomes over time.

BACKGROUND: The positive influences of glucagon-like peptide-1 (GLP-1) on blood glucose homeostasis, appetite sensations, and food intake provide a strong rationale for its therapeutic potential in the nutritional management of obesity and type 2 diabetes. AIM: To summarize GLP-1 physiology and the nutritional modulation of its secretion in the context of obesity and type 2 diabetes management. FINDINGS: GLP-1 is mainly synthesized and secreted by enteroendocrine L-cells of the gastrointestinal tract. Its secretion is partly mediated by the direct nutrient sensing by G-protein coupled receptors which specifically bind to monosaccharides, peptides and amino-acids, monounsaturated and polyunsaturated fatty acids as well as to short chain fatty acids. Foods rich in these nutrients, such as high-fiber grain products, nuts, avocados and eggs also seem to influence GLP-1 secretion and may thus promote associated beneficial outcomes in healthy individuals as well as individuals with type 2 diabetes or with other metabolic disturbances. CONCLUSION: The stimulation of endogenous GLP-1 secretion by manipulating the composition of the diet may be a relevant strategy for obesity and type 2 diabetes management. A better understanding of the dose-dependent effects as well as the synergistic effects of nutrients and whole foods is needed in order to develop recommendations to appropriately modify the diet to enhance GLP-1 beneficial effects.

Reliable, clinically useful, and globally applicable diagnostic classification of mental disorders is an essential foundation for global mental health. The World Health Organization (WHO) is nearing completion of the 11th revision of the International Classification of Diseases and Related Health Problems (ICD-11). The present study assessed inter-diagnostician reliability of mental disorders accounting for the greatest proportion of global disease burden and the highest levels of service utilization - schizophrenia and other primary psychotic disorders, mood disorders, anxiety and fear-related disorders, and disorders specifically associated with stress - among adult patients presenting for treatment at 28 participating centers in 13 countries. A concurrent joint-rater design was used, focusing specifically on whether two clinicians, relying on the same clinical information, agreed on the diagnosis when separately applying the ICD-11 diagnostic guidelines. A total of 1,806 patients were assessed by 339 clinicians in the local language. Intraclass kappa coefficients for diagnoses weighted by site and study prevalence ranged from 0.45 (dysthymic disorder) to 0.88 (social anxiety disorder) and would be considered moderate to almost perfect for all diagnoses. Overall, the reliability of the ICD-11 diagnostic guidelines was superior to that previously reported for equivalent ICD-10 guidelines. These data provide support for the suitability of the ICD-11 diagnostic guidelines for implementation at a global level. The findings will inform further revision of the ICD-11 diagnostic guidelines prior to their publication and the development of programs to support professional training and implementation of the ICD-11 by WHO member states.

Abstract Aim Current interest in forecasting changes to species ranges has resulted in a multitude of approaches to species distribution models ( SDMs ). However, most approaches include only a small subset of the available information, and many ignore smaller‐scale processes such as growth, fecundity and dispersal. Furthermore, different approaches often produce divergent predictions with no simple method to reconcile them. Here, we present a flexible framework for integrating models at multiple scales using hierarchical Bayesian methods. Location E astern N orth A merica (as an example). Methods Our framework builds a metamodel that is constrained by the results of multiple sub‐models and provides probabilistic estimates of species presence. We applied our approach to a simulated dataset to demonstrate the integration of a correlative SDM with a theoretical model. In a second example, we built an integrated model combining the results of a physiological model with presence–absence data for sugar maple ( A cer saccharum ), an abundant tree native to eastern North America. Results For both examples, the integrated models successfully included information from all data sources and substantially improved the characterization of uncertainty. For the second example, the integrated model outperformed the source models with respect to uncertainty when modelling the present range of the species. When projecting into the future, the model provided a consensus view of two models that differed substantially in their predictions. Uncertainty was reduced where the models agreed and was greater where they diverged, providing a more realistic view of the state of knowledge than either source model. Main conclusions We conclude by discussing the potential applications of our method and its accessibility to applied ecologists. In ideal cases, our framework can be easily implemented using off‐the‐shelf software. The framework has wide potential for use in species distribution modelling and can drive better integration of multi‐source and multi‐scale data into ecological decision‐making.

The fetal origins of health and disease framework has identified extremes in fetal growth and birth weight as factors associated with the lifelong generation of chronic diseases such as obesity, diabetes, cardiovascular disease, and hypertension. Maternal nutrition plays a critical role in fetal and placental development, in part by providing the methyl groups required to establish the fetus's genome structure and function, notably through DNA methylation. The goal of this narrative review is to describe the role of maternal dietary methyl donor (methionine, folate, and choline) and cofactor (zinc and vitamins B2, B6, and B12) intake in one-carbon metabolism and DNA methylation in the fetus and placenta, as well as their impacts on fetal growth and lifelong health outcomes, with specific examples in animals and humans. Based on the available evidence, it is concluded that intake of different amounts of dietary methyl donors and cofactors during pregnancy may alter fetal growth and development, thus establishing a major link between early environmental exposure and disease development in the offspring later in life.

Qualitative research on the impact of physical activity on quality of life (QoL) in adults diagnosed with cancer is accumulating. However, the field of physical activity and cancer survivorship lack a synthesis of this research to reliably understand the implications for future research and practice. The aim of this meta-synthesis was to identify, appraise, and synthesize qualitative research on cancer survivors’ perspectives of the impact of physical activity on their QoL. Seven electronic databases were searched for original studies published in English, and reference lists of relevant studies were hand-searched to identify additional studies. Forty studies met eligibility criteria and were included in this meta-synthesis. Study characteristics and major findings were extracted, and findings were summarized, compared, and synthesized. Themes identified in this review revealed that physical activity positively impacted four dimensions of cancer survivors’ QoL: physical (e.g., managing the physical consequences of cancer and its treatment), psychological (e.g., evoking positive self-perceptions), social (e.g., feeling understood by others), and spiritual (e.g., redefining life purpose). This meta-synthesis corroborates conclusions from reviews of quantitative research and illustrates that physical activity can be used to improve QoL in adult cancer survivors, regardless of diagnosis (i.e., stage, cancer type) and treatment status. It also provides detailed insight into specific aspects within each dimension of QoL impacted by physical activity from cancer survivors’ perspectives, which is important for understanding the meaning and utility of physical activity for them. However, more research is needed to further develop the qualitative evidence base in order to better understand how physical activity impacts on QoL experiences in men, young adults, and adults diagnosed with less common types of cancer at different points along cancer trajectory (i.e., diagnosis, treatment, post-treatment, palliation).

Abstract Expression of the ectonucleotidase CD73 by tumor cells, stromal cells, and immune cells is associated in cancer with immune suppression. In this study, we investigated the role of CD73 on the activity of the anti-HER2/ErbB2 monoclonal antibody (mAb) trastuzumab. In a prospective, randomized phase III clinical trial evaluating the activity of trastuzumab, high levels of CD73 gene expression were associated significantly with poor clinical outcome. In contrast, high levels of PD-1 and PD-L1 were associated with improved clinical outcome. In immunocompetent mouse models of HER2/ErbB2–driven breast cancer, CD73 expression by tumor cells and host cells significantly suppressed immune-mediated responses mediated by anti-ErbB2 mAb. Furthermore, anti-CD73 mAb therapy enhanced the activity of anti-ErbB2 mAb to treat engrafted or spontaneous tumors as well as lung metastases. Gene ontology enrichment analysis from gene-expression data revealed a positive association of CD73 expression with extracellular matrix organization, TGFβ genes, epithelial-to-mesenchymal transition (EMT) transcription factors and hypoxia-inducible-factor (HIF)-1 gene signature. Human mammary cells treated with TGFβ or undergoing EMT upregulated CD73 cell-surface expression, confirming roles for these pathways. In conclusion, our findings establish CD73 in mediating resistance to trastuzumab and provide new insights into how CD73 is regulated in breast cancer. Cancer Res; 77(20); 5652–63. ©2017 AACR.

Poor maternal diet increases the risk of obesity and type 2 diabetes in offspring, adding to the ever-increasing prevalence of these diseases. In contrast, we find that maternal exercise improves the metabolic health of offspring, and here, we demonstrate that this occurs through a vitamin D receptor-mediated increase in placental superoxide dismutase 3 (SOD3) expression and secretion. SOD3 activates an AMPK/TET signaling axis in fetal offspring liver, resulting in DNA demethylation at the promoters of glucose metabolic genes, enhancing liver function, and improving glucose tolerance. In humans, SOD3 is upregulated in serum and placenta from physically active pregnant women. The discovery of maternal exercise-induced cross talk between placenta-derived SOD3 and offspring liver provides a central mechanism for improved offspring metabolic health. These findings may lead to novel therapeutic approaches to limit the transmission of metabolic disease to the next generation.