Toenail selenium status and the risk of Barrett’s esophagus: the Netherlands Cohort Study

Objective: To investigate the association between selenium and the risk of Barrett's esophagus (BE), the precursor lesion of esophageal adenocarcinoma. Methods: Data from the prospective Netherlands Cohort Study were used. This cohort study was initiated in 1986, when 120,852 subjects aged 55-69 years completed a questionnaire on dietary habits and lifestyle, and provided toenail clippings for the determination of baseline selenium status. After 16.3 years of follow-up, 253 BE cases (identified through linkage with the nationwide Dutch pathology registry) and 2,039 subcohort members were available for case-cohort analysis. Cox proportional hazards models were used to calculate incidence rate ratios (RR). Results: The multivariable-adjusted RR for the highest versus the lowest quartile of toenail selenium was 1.06 (95% CI 0.71-1.57). No dose-response trend was seen (p trend = 0.99). No association was found in subgroups defined by sex, smoking status, body mass index (BMI), or intake of antioxidants. For BE cases that later progressed to high-grade dysplasia or adenocarcinoma, the RR for a selenium level above the median vs. below the median was 0.64 (95% CI 0.24-1.76). Conclusions: In this large prospective cohort study, we found no evidence of an association between selenium and risk of BE. © 2010 The Author(s)

A systematic SNP selection approach to identify mechanisms underlying disease aetiology: Linking height to post-menopausal breast and colorectal cancer risk

Data from GWAS suggest that SNPs associated with complex diseases or traits tend to co-segregate in regions of low recombination, harbouring functionally linked gene clusters. This phenomenon allows for selecting a limited number of SNPs from GWAS repositories for large-scale studies investigating shared mechanisms between diseases. For example, we were interested in shared mechanisms between adult-attained height and post-menopausal breast cancer (BC) and colorectal cancer (CRC) risk, because height is a risk factor for these cancers, though likely not a causal factor. Using SNPs from public GWAS repositories at p-values < 1 × 10-5 and a genomic sliding window of 1 mega base pair, we identified SNP clusters including at least one SNP associated with height and one SNP associated with either post-menopausal BC or CRC risk (or both). SNPs were annotated to genes using HapMap and GRAIL and analysed for significantly overrepresented pathways using ConsensuspathDB. Twelve clusters including 56 SNPs annotated to 26 genes were prioritised because these included at least one height- and one BC risk- or CRC risk-associated SNP annotated to the same gene. Annotated genes were involved in Indian hedgehog signalling (p-value = 7.78 × 10-7) and several cancer site-specific pathways. This systematic approach identified a limited number of clustered SNPs, which pinpoint potential shared mechanisms linking together the complex phenotypes height, post-menopausal BC and CRC

Energy Restriction during Childhood and Early Adulthood and Ovarian Cancer Risk

Dietary energy restriction may protect against cancer. In parts of the Netherlands, mostly in larger cities, periods of chronically impaired nutrition and even severe famine (Hunger Winter 1944–1945) existed during the 1930s and World War II (1940–1945). We studied the association between energy restriction during childhood and early adulthood on the risk of ovarian cancer later in life. In 1986, the Netherlands Cohort Study was initiated. A self-administered questionnaire on dietary habits and other cancer risk factors was completed by 62,573 women aged 55–69 years at baseline. Follow-up for cancer was established by record linkage to the Netherlands Cancer Registry. After 16.3 years of follow-up, 364 invasive epithelial ovarian cancer cases and 2220 subcohort members (sampled from the total cohort directly after baseline) with complete information confounders were available for case-cohort analyses. In multivariable analysis, ovarian cancer risk was lower for participants with an unemployed father during the 1930s (Hazard Ratio (HR), 0.70; 95% Confidence Interval (CI), 0.47–1.06) compared to participants with an employed father as well as for participants living in a city during World War II (HR, 0.69; 95% CI, 0.54–0.90) compared to participants living in the country-side. Residence in a Western City during the famine (Hunger Winter) was not associated with a decreased risk. Our results show a relation between proxy variables for modest energy restriction over a longer period of time during childhood or early adulthood and a reduced ovarian cancer risk

A pragmatic cluster randomised trial evaluating three implementation interventions

Background Implementation research is concerned with bridging the gap between evidence and practice through the study of methods to promote the uptake of research into routine practice. Good quality evidence has been summarised into guideline recommendations to show that peri-operative fasting times could be considerably shorter than patients currently experience. The objective of this trial was to evaluate the effectiveness of three strategies for the implementation of recommendations about peri-operative fasting. Methods A pragmatic cluster randomised trial underpinned by the PARIHS framework was conducted during 2006 to 2009 with a national sample of UK hospitals using time series with mixed methods process evaluation and cost analysis. Hospitals were randomised to one of three interventions: standard dissemination (SD) of a guideline package, SD plus a web-based resource championed by an opinion leader, and SD plus plan-do-study-act (PDSA). The primary outcome was duration of fluid fast prior to induction of anaesthesia. Secondary outcomes included duration of food fast, patients' experiences, and stakeholders' experiences of implementation, including influences. ANOVA was used to test differences over time and interventions. Results Nineteen acute NHS hospitals participated. Across timepoints, 3,505 duration of fasting observations were recorded. No significant effect of the interventions was observed for either fluid or food fasting times. The effect size was 0.33 for the web-based intervention compared to SD alone for the change in fluid fasting and was 0.12 for PDSA compared to SD alone. The process evaluation showed different types of impact, including changes to practices, policies, and attitudes. A rich picture of the implementation challenges emerged, including inter-professional tensions and a lack of clarity for decision-making authority and responsibility. Conclusions This was a large, complex study and one of the first national randomised controlled trials conducted within acute care in implementation research. The evidence base for fasting practice was accepted by those participating in this study and the messages from it simple; however, implementation and practical challenges influenced the interventions' impact. A set of conditions for implementation emerges from the findings of this study, which are presented as theoretically transferable propositions that have international relevance. Trial registration ISRCTN18046709 - Peri-operative Implementation Study Evaluation (POISE

Dietary Acrylamide Intake and the Risk of Lymphatic Malignancies: The Netherlands Cohort Study on Diet and Cancer

BACKGROUND: Acrylamide, a probable human carcinogen, is present in many everyday foods. Since the finding of its presence in foods in 2002, epidemiological studies have found some suggestive associations between dietary acrylamide exposure and the risk of various cancers. The aim of this prospective study is to investigate for the first time the association between dietary acrylamide intake and the risk of several histological subtypes of lymphatic malignancies. METHODS: The Netherlands Cohort Study on diet and cancer includes 120,852 men and women followed-up since September 1986. The number of person years at risk was estimated by using a random sample of participants from the total cohort that was chosen at baseline (n =5,000). Acrylamide intake was estimated from a food frequency questionnaire combined with acrylamide data for Dutch foods. Hazard ratios (HRs) were calculated for acrylamide intake as a continuous variable as well as in categories (quintiles and tertiles), for men and women separately and for never-smokers, using multivariable-adjusted Cox proportional hazards models. RESULTS: After 16.3 years of follow-up, 1,233 microscopically confirmed cases of lymphatic malignancies were available for multivariable-adjusted analysis. For multiple myeloma and follicular lymphoma, HRs for men were 1.14 (95% CI: 1.01, 1.27) and 1.28 (95% CI: 1.03, 1.61) per 10 µg acrylamide/day increment, respectively. For never-smoking men, the HR for multiple myeloma was 1.98 (95% CI: 1.38, 2.85). No associations were observed for women. CONCLUSION: We found indications that acrylamide may increase the risk of multiple myeloma and follicular lymphoma in men. This is the first epidemiological study to investigate the association between dietary acrylamide intake and the risk of lymphatic malignancies, and more research into these observed associations is warranted

Graft-versus-host disease in recipients of male unrelated donor compared with parous female sibling donor transplants

Optimal donor selection is critical for successful allogeneic hematopoietic cell transplantation (HCT). Donor sex and parity are well-established risk factors for graft-versus-host disease (GVHD), with male donors typically associated with lower rates of GVHD. Well-matched unrelated donors (URDs) have also been associated with increased risks of GVHD as compared with matched sibling donors. These observations raise the question of whether male URDs would lead to more (or less) favorable transplant outcomes as compared with parous female sibling donors. We used the Center for International Blood and Marrow Transplant Research registry to complete a retrospective cohort study in adults with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome, who underwent T-cell replete HCT from these 2 donor types (parous female sibling or male URD) between 2000 and 2012. Primary outcomes included grade 2 to 4 acute GVHD (aGVHD), chronic GVHD (cGVHD), and overall survival. Secondary outcomes included disease-free survival, transplant-related mortality, and relapse. In 2813 recipients, patients receiving male URD transplants (n = 1921) had 1.6 times higher risk of grade 2 to 4 aGVHD (P \u3c .0001). For cGVHD, recipient sex was a significant factor, so donor/recipient pairs were evaluated. Female recipients of male URD grafts had a higher risk of cGVHD than those receiving parous female sibling grafts (relative risk [RR] = 1.43, P \u3c .0001), whereas male recipients had similar rates of cGVHD regardless of donor type (RR = 1.09, P = .23). Donor type did not significantly affect any other end point. We conclude that when available, parous female siblings are preferred over male URDs

Dysregulated innate and adaptive immune responses discriminate disease severity in COVID-19

The clinical spectrum of COVID-19 varies and the differences in host response characterizing this variation have not been fully elucidated. COVID-19 disease severity correlates with an excessive pro-inflammatory immune response and profound lymphopenia. Inflammatory responses according to disease severity were explored by plasma cytokine measurements and proteomics analysis in 147 COVID-19 patients. Furthermore, peripheral blood mononuclear cell cytokine production assays and whole blood flow cytometry were performed. Results confirm a hyperinflammatory innate immune state, while highlighting hepatocyte growth factor and stem cell factor as potential biomarkers for disease severity. Clustering analysis reveals no specific inflammatory endotypes in COVID-19 patients. Functional assays reveal abrogated adaptive cytokine production (interferon-gamma, interleukin-17 and interleukin-22) and prominent T cell exhaustion in critically ill patients, whereas innate immune responses were intact or hyperresponsive. Collectively, this extensive analysis provides a comprehensive insight into the pathobiology of severe to critical COVID-19 and highlight potential biomarkers of disease severity

Comparative analysis of calcineurin-inhibitor-based methotrexate and mycophenolate mofetil-containing regimens for prevention of Graft-versus-Host Disease after reduced intensity conditioning allogeneic transplantation

The combination of a calcineurin inhibitor (CNI) such as tacrolimus (TAC) or cyclosporine (CYSP) with methotrexate (MTX) or with mycophenolate mofetil (MMF) has been commonly used for graft-versus-host disease (GVHD) prophylaxis after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT), but there are limited data comparing efficacy of the 2 regimens. We evaluated 1564 adult patients who underwent RIC alloHCT for acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS) from 2000 to 2013 using HLA-identical sibling (matched related donor [MRD]) or unrelated donor (URD) peripheral blood graft and received CYSP or TAC with MTX or MMF for GVHD prophylaxis. Primary outcomes of the study were acute and chronic GVHD and overall survival (OS). The study divided the patient population into 4 cohorts based on regimen: MMF-TAC, MMF-CYSP, MTX-TAC, and MTX-CYSP. In the URD group, MMF-CYSP was associated with increased risk of grade II to IV acute GVHD (relative risk [RR], 1.78; P < .001) and grade III to IV acute GVHD (RR, 1.93; P = .006) compared with MTX-TAC. In the URD group, use of MMF-TAC (versus MTX-TAC) lead to higher nonrelapse mortality. (hazard ratio, 1.48; P = .008). In either group, no there was no difference in chronic GVHD, disease-free survival, and OS among the GVHD prophylaxis regimens. For RIC alloHCT using MRD, there are no differences in outcomes based on GVHD prophylaxis. However, with URD RIC alloHCT, MMF-CYSP was inferior to MTX-based regimens for acute GVHD prevention, but all the regimens were equivalent in terms of chronic GVHD and OS. Prospective studies, targeting URD recipients are needed to confirm these results

Ovarian cancer risk factors by tumor aggressiveness : An analysis from the Ovarian Cancer Cohort Consortium

Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in = 35 vs. 20 to <25 kg/m(2), 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.Peer reviewe