A New Hierarchy of Research Evidence for Tumor Pathology: A Delphi Study to Define Levels of Evidence in Tumor Pathology.

The hierarchy of evidence is a fundamental concept in evidence-based medicine, but existing models can be challenging to apply in laboratory-based health care disciplines, such as pathology, where the types of evidence and contexts are significantly different from interventional medicine. This project aimed to define a comprehensive and complementary framework of new levels of evidence for evaluating research in tumor pathology-introducing a novel Hierarchy of Research Evidence for Tumor Pathology collaboratively designed by pathologists with help from epidemiologists, public health professionals, oncologists, and scientists, specifically tailored for use by pathologists-and to aid in the production of the World Health Organization Classification of Tumors (WCT) evidence gap maps. To achieve this, we adopted a modified Delphi approach, encompassing iterative online surveys, expert oversight, and external peer review, to establish the criteria for evidence in tumor pathology, determine the optimal structure for the new hierarchy, and ascertain the levels of confidence for each type of evidence. Over a span of 4 months and 3 survey rounds, we collected 1104 survey responses, culminating in a 3-day hybrid meeting in 2023, where a new hierarchy was unanimously agreed upon. The hierarchy is organized into 5 research theme groupings closely aligned with the subheadings of the WCT, and it consists of 5 levels of evidence-level P1 representing evidence types that merit the greatest level of confidence and level P5 reflecting the greatest risk of bias. For the first time, an international collaboration of pathology experts, supported by the International Agency for Research on Cancer, has successfully united to establish a standardized approach for evaluating evidence in tumor pathology. We intend to implement this novel Hierarchy of Research Evidence for Tumor Pathology to map the available evidence, thereby enriching and informing the WCT effectively.

Moving Forward on Tumor Pathology Research Reporting: A Guide for Pathologists From the World Health Organization Classification of Tumors Living Evidence Gap Map by Tumour Type Group.

Evidence-based medicine (EBM) can be an unfamiliar territory for those working in tumor pathology research, and there is a great deal of uncertainty about how to undertake an EBM approach to planning and reporting histopathology-based studies. In this article, reviewed and endorsed by the Word Health Organization International Agency for Research on Cancer's International Collaboration for Cancer Classification and Research, we aim to help pathologists and researchers understand the basics of planning an evidence-based tumor pathology research study, as well as our recommendations on how to report the findings from these. We introduce some basic EBM concepts, a framework for research questions, and thoughts on study design and emphasize the concept of reporting standards. There are many study-specific reporting guidelines available, and we provide an overview of these. However, existing reporting guidelines perhaps do not always fit tumor pathology research papers, and hence, here, we collate the key reporting data set together into one generic checklist that we think will simplify the task for pathologists. The article aims to complement our recent hierarchy of evidence for tumor pathology and glossary of evidence (study) types in tumor pathology. Together, these articles should help any researcher get to grips with the basics of EBM for planning and publishing research in tumor pathology, as well as encourage an improved standard of the reports available to us all in the literature.

Toenail zinc and risk of prostate cancer in the MCC-Spain case-control study.

BACKGROUND: Some researchers have suggested that zinc (Zn) could reduce the risk of prostate cancer (PC). However, research from observational studies on the relationship between PC risk and biomarkers of Zn exposure shows conflicting results. OBJECTIVES: To evaluate the association between toenail Zn and PC, considering tumour extension and aggressiveness, along with a gene-environment approach, exploring the interaction of individual genetic susceptibility to PC in the relationship between toenail Zn and PC. METHODS: In MCC-Spain study we invited all incident PC cases diagnosed in the study period (2008-2013) and recruited randomly selected general population controls. In this report we included 913 cases and 1198 controls with toenail Zn determined by inductively coupled plasma mass spectrometry. To measure individual genetic susceptibility, we constructed a polygenic risk score based on known PC-related single nucleotide polymorphisms. The association between toenail Zn and PC was explored with mixed logistic and multinomial regression models. RESULTS: Men with higher toenail Zn had higher risk of PC (OR quartile 4 vs.1: 1.41; 95% CI: 1.07-1.85). This association was slightly higher in high-grade PC [(ISUP≤2 Relative risk ratio (RRR) quartile 4 vs.1: 1.36; 1.01-1.83) vs. (ISUP3-5 RRR quartile 4 vs.1: 1.64; 1.06-2.54)] and in advanced tumours [(cT1-cT2a RRR quartile 4 vs.1: 1.40; 95% CI: 1.05-1.89) vs. (cT2b-cT4 RRR quartile 4 vs.1: 1.59; 1.00-2.53)]. Men with lower genetic susceptibility to PC were those at higher risk of PC associated with high toenail Zn (OR quartile 4 vs.1: 2.18; 95% CI: 1.08-4.40). DISCUSSION: High toenail Zn levels were related to a higher risk for PC, especially for more aggressive or advanced tumours. This effect was stronger among men with a lower genetic susceptibility to PC.

Exposure to residential traffic and trajectories of unhealthy ageing: results from a nationally-representative cohort of older adults.

BACKGROUND: Traffic exposure has been associated with biomarkers of increased biological ageing, age-related chronic morbidities, and increased respiratory, cardiovascular, and all-cause mortality. Whether it is associated with functional impairments and unhealthy ageing trajectories is unknown. METHODS: Nationally representative population-based cohort with 3,126 community-dwelling individuals aged ≥60 years who contributed 8,291 biannual visits over a 10 year period. Unhealthy ageing was estimated with a deficit accumulation index (DAI) based on the number and severity of 52 health deficits, including 22 objectively-measured impairments in physical and cognitive functioning. Differences in DAI at each follow-up across quintiles of residential traffic density (RTD) at 50 and 100 meters, and closest distance to a petrol station, were estimated using flexible marginal structural models with inverse probability of censoring weights. Models were adjusted for sociodemographic and time-varying lifestyle factors, social deprivation index at the census tract and residential exposure to natural spaces. RESULTS: At baseline, the mean (SD) age and DAI score of the participants were 69.0 (6.6) years and 17.02 (11.0) %, and 54.0% were women. The median (IQR) RTD at 50 and 100 meters were 77 (31-467) and 509 (182-1802) vehicles/day, and the mean (SD) distance to the nearest petrol station of 962 (1317) meters. The average increase in DAI (95%CI) for participants in quintiles Q2-Q5 (vs Q1) of RTD at 50 meters was of 1.51 (0.50, 2.53), 0.98 (-0.05, 2.01), 2.20 (1.18, 3.21) and 1.98 (0.90, 3.05), respectively. Consistent findings were observed at 100 meters. By domains, most of the deficits accumulated with increased RTD were of a functional nature, although RTD at 50 meters was also associated with worse self-reported health, increased vitality problems and higher incidence of chronic morbidities. Living closer to a petrol station was associated with a higher incidence of functional impairments and chronic morbidities. CONCLUSIONS: Exposure to nearby residential traffic is associated with accelerated trajectories of unhealthy ageing. Diminishing traffic pollution should become a priority intervention for adding healthy years to life in the old age.

Modifying effect of urban parks on socioeconomic inequalities in diabetes prevalence: a cross-sectional population study of Madrid City, Spain.

BACKGROUND: Evidence has shown contradicting results on how the density of urban green spaces may reduce socioeconomic inequalities in type 2 diabetes (equigenic hypothesis). The aim of this study is to test whether socioeconomic inequalities in diabetes prevalence are modified by park density. METHODS: We designed a population-wide cross-sectional study of all adults registered in the primary healthcare centres in the city of Madrid, Spain (n=1 305 050). We obtained georeferenced individual-level data from the Primary Care Electronic Health Records, and census-tract level data on socioeconomic status (SES) and park density. We modelled diabetes prevalence using robust Poisson regression models adjusted by age, country of origin, population density and including an interaction term with park density, stratified by gender. We used this model to estimate the Relative Index of Inequality (RII) at different park density levels. FINDINGS: We found an overall RII of 2.90 (95% CI 2.78 to 3.02) and 4.50 (95% CI 4.28 to 4.74) in men and women, respectively, meaning that the prevalence of diabetes was three to four and a half times higher in low SES compared with high SES areas. These inequalities were wider in areas with higher park density for both men and women, with a significant interaction only for women (p=0.008). INTERPRETATION: We found an inverse association between SES and diabetes prevalence in both men and women, with wider inequalities in areas with more parks. Future works should study the mechanisms of these findings, to facilitate the understanding of contextual factors that may mitigate diabetes inequalities.

Exposure to green spaces, cardiovascular risk biomarkers and incident cardiovascular disease in older adults: The Seniors-Enrica II cohort.

INTRODUCTION: The impact of residential green spaces on cardiovascular health in older adults remains uncertain. METHODS: Cohort study involving 2114 adults aged ≥ 65 years without cardiovascular disease (CVD), residing in five dense municipalities (Prince et al., 2015) of the Madrid region and with detailed characterization of their socioeconomic background, health behaviors, CVD biological risk factors, and mental, physical, and cognitive health. Greenness exposure was measured using the Normalized Difference Vegetation Index (NDVI) at varying distances from participants' homes. Traffic exposure, neighborhood environment, neighborhood walkability, and socioeconomic deprivation at the census level were also assessed. Serum N-terminal pro-B-type natriuretic peptide (NT-ProBNP), high-sensitivity troponin T (hs-TnT), interleukin 6 (IL-6), and Growth Differentiation Factor 15 (GDF-15) were measured at baseline, and incident CVD events identified through electronic medical records (International Classification of Primary Care-2 codes K74, K75, K77, K90, and K92). RESULTS: After adjusting for sex, age, educational attainment, financial hardship and socioeconomic deprivation at the census level, an interquartile range (IQR) increase in NDVI at 250, 500, 750, and 1000 m around participants' homes was associated with mean differences in ProBNP of -5.56 % (95 %CI: -9.77; -1.35), -5.05 % (-9.58; -0.53), -4.24 % (-8.19, -0.19), and -4.16 % (-7.59; -0.74), respectively; and mean differences in hs-TnT among diabetic participants of -8.03 % (95 %CI: -13.30; -2.77), -9.52 % (-16.08; -2.96), -8.05 % (-13.94, -2.16) and -5.56 % (-10.75; -0.54), respectively. Of similar magnitude, although only statistically significant at 250 and 500 m, were the observed lower IL-6 levels with increasing greenness. GDF-15 levels were independent of NDVI. In prospective analyses (median follow-up 6.29 years), an IQR increase in residential greenness at 500, 750, and 1000 m was associated with a lower risk of incident CVD. The variables that contributed most to the apparent beneficial effects of greenness on CVD were lower exposure to traffic, improved cardiovascular risk factors, and enhanced physical performance. Additionally, neighborhood walkability and increased physical activity were notable contributors among individuals with diabetes. CONCLUSION: Increased exposure to residential green space was associated with a moderate reduction in CVD risk in older adults residing in densely populated areas.

Blood Selenium Concentrations Are Inversely Associated with the Risk of Undernutrition in Older Adults.

BACKGROUND: Selenium is an essential trace element with an antioxidant and anti-inflammatory capacity that has been associated in experimental studies with beneficial effects on appetite control, the regulation of the gut microbiota, and control of the anabolic-catabolic balance. The main aim of the present study was to evaluate the association between circulating selenium concentrations and the risk of developing undernutrition in older adults. METHODS: This was a cohort study with 1398 well-nourished community-dwelling individuals aged ≥ 65 years residing in Spain in 2017, who were followed for a mean of 2.3 years. Whole blood selenium was measured at baseline using inductively coupled plasma-mass spectrometry. Undernutrition was assessed at baseline and at follow-up, and defined as having at least one of the three GLIM phenotypic criteria (involuntary weight loss, a low body mass index, and a reduced muscle mass) and at least one of the two etiologic criteria (reduced food consumption or nutrient assimilation and inflammation/disease burden). RESULTS: During the follow-up, 142 participants (11%) developed moderate undernutrition and 113 (8.8%) severe undernutrition. The standardized relative risks of moderate and severe undernutrition at the 75th percentile of Se levels versus the 25th were 0.90 and 0.70, respectively. In dose-response analyses, the risk of severe undernutrition decreased linearly with increasing selenium concentrations. This association was independent of protein intake or diet quality and was stronger among participants with a diagnosis of a musculoskeletal disorder. CONCLUSIONS: The results suggest that an adequate dietary selenium status is needed to prevent undernutrition in older adults. Also, this may open the door for clinical trials with selenium supplementation, at doses considered as safe, to prevent undernutrition.