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.

Consumption of aspartame and other artificial sweeteners and risk of cancer in the Spanish multicase-control study (MCC-Spain).

Use of artificial sweeteners (AS) such as aspartame, cyclamate, saccharin and sucralose is widespread. We evaluated the association of use of aspartame and other AS with cancer. In total 1881 colorectal, 1510 breast, 972 prostate and 351 stomach cancer and 109 chronic lymphocytic leukaemia (CLL) cases and 3629 population controls from the Spanish Multicase-Control (MCC-Spain) study were recruited (2008-2013). The consumption of AS, from table-top sweeteners and artificially sweetened beverages, was assessed through a self-administered and validated food frequency questionnaire (FFQ). Sex-specific quartiles among controls were determined to compare moderate consumers (

High adherence to Western dietary pattern and prostate cancer risk: findings from the EPIC-Spain cohort.

OBJECTIVE: To explore the association between three previously identified dietary patterns (Western, Prudent and Mediterranean) and prostate cancer (PCa) risk by tumour aggressiveness. SUBJECTS AND METHODS: The Spanish cohort of the European Prospective Investigation into Cancer and Nutrition study provided dietary and epidemiological information from 15 296 men recruited during the period 1992-1996. The associations between the adherence to the three dietary patterns and PCa risk (global, for Gleason grade groups 6 and >6, and for International Society of Urological Pathology [ISUP] grade 1 + 2 and ISUP grade 3 + 4 + 5) was explored with multivariable Cox proportional hazards regression models stratified by centre and age. RESULTS: While no effect on PCa risk was detected for the Prudent and Mediterranean dietary patterns, a suggestion of a detrimental effect of the Western dietary pattern was found (hazard ratio [HR]Q4vsQ1 1.29 [95% confidence interval {CI} 0.96;1.72]). This effect was only observed for Gleason grade group >6 (HRQ3vsQ1 1.61 [95% CI 1.00; 2.59] and HRQ4vsQ1 1.60 [95% CI 0.96; 2.67]) and in particular ISUP grade 3 + 4 + 5 tumours (HRQ2vsQ1 1.97 [95% CI 0.98; 3.93]; HRQ3vsQ1 2.72 (95% CI 1.35; 5.51); HRQ4vsQ1 2.29 [95% CI 1.07; 4.92]). CONCLUSIONS: Our results suggest that a high adherence to a healthy diet such as that represented by the Prudent and Mediterranean dietary patterns is not enough to prevent prostate cancer. Additionally, reducing adherence to a Western-type diet seems to be necessary.

SARS-CoV-2 Infection During the First and Second Pandemic Waves in Spain: the ENE-COVID Study.

Objectives. To describe participant characteristics associated with severe acute respiratory syndrome coronavirus 2 infection in Spain's first 2 COVID-19 waves per the Spanish National Seroepidemiological Survey of SARS-CoV-2 Infection (ENE-COVID). Methods. A representative cohort of the noninstitutionalized Spanish population, selected through stratified 2-stage sampling, answered a questionnaire and received point-of-care testing April to June 2020 (first wave: n = 68 287); previously seronegative participants repeated the questionnaire and test November 2020 (second wave: n = 44 451). We estimated seropositivity by wave and participant characteristics, accounting for sampling weights, nonresponse, and design effects. Results. We found that 6.0% (95% confidence interval [CI] = 5.7%, 6.4%) of Spain's population was infected by June and 3.8% (95% CI = 3.5%, 4.1%) more by November 2020. Both genders were equally affected. Seroprevalence decreased with age in adults 20 years and older in the second wave; socioeconomic differences increased. Health care workers were affected at 11.1% (95% CI = 9.0%, 13.6%) and 6.1% (95% CI = 4.4%, 8.5%) in the first and second waves, respectively. Living with an infected person increased infection risk to 22.1% (95% CI = 18.9%, 25.6%) in the first and 35.0% (95% CI = 30.8%, 39.4%) in the second wave. Conclusions. ENE-COVID characterized the first 2 pandemic waves, when information from surveillance systems was incomplete. (Am J Public Health. 2023;113(5):533-544. https://doi.org/10.2105/AJPH.2023.307233).

Design and Implementation of a Nationwide Population-Based Longitudinal Survey of SARS-CoV-2 Infection in Spain: The ENE-COVID Study.

Data System. The Spanish National Seroepidemiological Survey of SARS-CoV-2 (or ENE-COVID; SARS-CoV-2 [severe acute respiratory syndrome coronavirus 2] is the causative agent of COVID-19) was funded by the Spanish Ministry of Health, the Instituto de Salud Carlos III, and the Spanish National Health System. Data Collection/Processing. A stratified 2-stage probability sampling was used to select a representative cohort of the noninstitutionalized population of Spain. ENE-COVID collected longitudinal data from epidemiological questionnaires and 2 SARS-CoV-2 IgG antibody tests. From April 27 to June 22, 2020, 68 287 participants (77.0% of contacted persons) received a point-of-care test and 61 095 (68.9%) also underwent a laboratory immunoassay. A second follow-up phase was conducted between November 16 and 30, 2020. Data Analysis/Dissemination. Analyses use weights to adjust for oversampling and nonresponse and account for design effects of stratification and clustering. ENE-COVID data for research purposes will be available upon request from the official study Web page. Public Health Implications. ENE-COVID, a nationwide population-based study, allowed monitoring seroprevalence of antibodies against SARS-CoV-2 at the national and regional levels, providing accurate figures by gender, age (from babies to nonagenarians), and selected risk factors; characterizing symptomatic and asymptomatic infections; and estimating the infection fatality risk during the first pandemic wave. (Am J Public Health. 2023;113(5):525-532. https://doi.org/10.2105/AJPH.2022.307167).

Duration of the patient interval in breast cancer and factors associated with longer delays in low-and middle-income countries: A systematic review with meta-analysis.

OBJECTIVE: Breast cancer survival is lower in low- and middle-income countries (LMICs) partially due to many women being diagnosed with late-stage disease. The patient interval refers to the time elapsed between the detection of symptoms and the first consultation with a healthcare provider and is considered one of the core indicators for early diagnosis and treatment. The goal of the current research was to conduct a meta-analysis of the duration of the patient interval in LMICs and investigate the socio-demographic and socio-cultural factors related to longer delays in presentation. METHODS: We conducted a systematic review with meta-analysis (pre-registered protocol CRD42020200752). We searched seven information sources (2009-2022) and included 50 articles reporting the duration of patient intervals for 18,014 breast cancer patients residing in LMICs. RESULTS: The longest patient intervals were reported in studies from the Middle East (3-4 months), followed by South-East Asia (2 months), Africa (1-2 months), Latin America (1 month), and Eastern Europe (1 month). Older age, not being married, lower socio-economic status, illiteracy, low knowledge about cancer, disregarding symptoms or not attributing them to cancer, fear, negative beliefs about cancer, and low social support were related to longer delays across most regions. Longer delays were also related to use of alternative medicine in the Middle East, South-East Asia, and Africa and distrust in the healthcare system in Eastern Europe. CONCLUSIONS: There is large variation in the duration of patient intervals across LMICs in different geographical regions. Patient intervals should be reduced and, for this purpose, it is important to explore their determinants taking into account the social, cultural, and economic context.

The association of age at menarche and adult height with mammographic density in the International Consortium of Mammographic Density.

BACKGROUND: Early age at menarche and tall stature are associated with increased breast cancer risk. We examined whether these associations were also positively associated with mammographic density, a strong marker of breast cancer risk. METHODS: Participants were 10,681 breast-cancer-free women from 22 countries in the International Consortium of Mammographic Density, each with centrally assessed mammographic density and a common set of epidemiologic data. Study periods for the 27 studies ranged from 1987 to 2014. Multi-level linear regression models estimated changes in square-root per cent density (√PD) and dense area (√DA) associated with age at menarche and adult height in pooled analyses and population-specific meta-analyses. Models were adjusted for age at mammogram, body mass index, menopausal status, hormone therapy use, mammography view and type, mammographic density assessor, parity and height/age at menarche. RESULTS: In pooled analyses, later age at menarche was associated with higher per cent density (ß√PD = 0.023 SE = 0.008, P = 0.003) and larger dense area (ß√DA = 0.032 SE = 0.010, P = 0.002). Taller women had larger dense area (ß√DA = 0.069 SE = 0.028, P = 0.012) and higher per cent density (ß√PD = 0.044, SE = 0.023, P = 0.054), although the observed effect on per cent density depended upon the adjustment used for body size. Similar overall effect estimates were observed in meta-analyses across population groups. CONCLUSIONS: In one of the largest international studies to date, later age at menarche was positively associated with mammographic density. This is in contrast to its association with breast cancer risk, providing little evidence of mediation. Increased height was also positively associated with mammographic density, particularly dense area. These results suggest a complex relationship between growth and development, mammographic density and breast cancer risk. Future studies should evaluate the potential mediation of the breast cancer effects of taller stature through absolute breast density.

Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci.

BACKGROUND: Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants. METHODS: We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia. RESULTS: We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes. CONCLUSIONS: Our findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.

The patient, diagnostic, and treatment intervals in adult patients with cancer from high- and lower-income countries: A systematic review and meta-analysis.

BACKGROUND: Longer time intervals to diagnosis and treatment are associated with worse survival for various types of cancer. The patient, diagnostic, and treatment intervals are considered core indicators for early diagnosis and treatment. This review estimated the median duration of these intervals for various types of cancer and compared it across high- and lower-income countries. METHODS AND FINDINGS: We conducted a systematic review with meta-analysis (prospectively registered protocol CRD42020200752). Three databases (MEDLINE, Embase, and Web of Science) and information sources including grey literature (Google Scholar, OpenGrey, EThOS, ProQuest Dissertations & Theses) were searched. Eligible articles were published during 2009 to 2022 and reported the duration of the following intervals in adult patients diagnosed with primary symptomatic cancer: patient interval (from the onset of symptoms to first presentation to a healthcare professional), diagnostic interval (from first presentation to diagnosis), and treatment interval (from diagnosis to treatment start). Interval duration was recorded in days and study medians were combined in a pooled estimate with 95% confidence intervals (CIs). The methodological quality of studies was assessed using the Aarhus checklist. A total of 410 articles representing 68 countries and reporting on 5,537,594 patients were included. The majority of articles reported data from high-income countries (n = 294, 72%), with 116 (28%) reporting data from lower-income countries. Pooled meta-analytic estimates were possible for 38 types of cancer. The majority of studies were conducted on patients with breast, lung, colorectal, and head and neck cancer. In studies from high-income countries, pooled median patient intervals generally did not exceed a month for most cancers. However, in studies from lower-income countries, patient intervals were consistently 1.5 to 4 times longer for almost all cancer sites. The majority of data on the diagnostic and treatment intervals came from high-income countries. Across both high- and lower-income countries, the longest diagnostic intervals were observed for hematological (71 days [95% CI 52 to 85], e.g., myelomas (83 days [47 to 145])), genitourinary (58 days [50 to 77], e.g., prostate (85 days [57 to 112])), and digestive/gastrointestinal (57 days [45 to 67], e.g., colorectal (63 days [48 to 78])) cancers. Similarly, the longest treatment intervals were observed for genitourinary (57 days [45 to 66], e.g., prostate (75 days [61 to 87])) and gynecological (46 days [38 to 54], e.g., cervical (69 days [45 to 108]) cancers. In studies from high-income countries, the implementation of cancer-directed policies was associated with shorter patient and diagnostic intervals for several cancers. This review included a large number of studies conducted worldwide but is limited by survivor bias and the inherent complexity and many possible biases in the measurement of time points and intervals in the cancer treatment pathway. In addition, the subintervals that compose the diagnostic interval (e.g., primary care interval, referral to diagnosis interval) were not considered. CONCLUSIONS: These results identify the cancers where diagnosis and treatment initiation may take the longest and reveal the extent of global disparities in early diagnosis and treatment. Efforts should be made to reduce help-seeking times for cancer symptoms in lower-income countries. Estimates for the diagnostic and treatment intervals came mostly from high-income countries that have powerful health information systems in place to record such information.

Differences in breast cancer-risk factors between screen-detected and non-screen-detected cases (MCC-Spain study).

PURPOSE: The variation in breast cancer (BC)-risk factor associations between screen-detected (SD) and non-screen-detected (NSD) tumors has been poorly studied, despite the interest of this aspect in risk assessment and prevention. This study analyzes the differences in breast cancer-risk factor associations according to detection method and tumor phenotype in Spanish women aged between 50 and 69. METHODS: We examined 900 BC cases and 896 controls aged between 50 and 69, recruited in the multicase-control MCC-Spain study. With regard to the cases, 460 were detected by screening mammography, whereas 144 were diagnosed by other means. By tumor phenotype, 591 were HR+, 153 were HER2+, and 58 were TN. Lifestyle, reproductive factors, family history of BC, and tumor characteristics were analyzed. Logistic regression models were used to compare cases vs. controls and SD vs. NSD cases. Multinomial regression models (controls used as a reference) were adjusted for case analysis according to phenotype and detection method. RESULTS: TN was associated with a lower risk of SD BC (OR 0.30 IC 0.10-0.89), as were intermediate (OR 0.18 IC 0.07-0.44) and advanced stages at diagnosis (OR 0.11 IC 0.03-0.34). Nulliparity in postmenopausal women and age at menopause were related to an increased risk of SD BC (OR 1.60 IC 1.08-2.36; OR 1.48 IC 1.09-2.00, respectively). Nulliparity in postmenopausal women was associated with a higher risk of HR+ (OR 1.66 IC 1.15-2.40). Age at menopause was related to a greater risk of HR+ (OR 1.60 IC 1.22-2.11) and HER2+ (OR 1.59 IC 1.03-2.45) tumors. CONCLUSION: Reproductive risk factors are associated with SD BC, as are HR+ tumors. Differences in BC-risk factor associations according to detection method may be related to prevailing phenotypes among categories.

SARS-CoV-2 surveillance strategy in essential workers of the Madrid City Council during the first epidemic wave in Spain, March-July 2020.

OBJECTIVES: To study prevalence of infection in essential workers of Madrid City Council by occupation, related characteristics, use of protective devices, risk perception, and main concerns about COVID-19 during lockdown. METHODS: A total of 30 231 workers were PCR tested for SARS-CoV-2 infection. Information was collected on COVID-19-related symptoms, risk factors, preventive equipment, and risk perception. The crude prevalence was calculated for infection, use of protective devices, perceived risk and main concerns. Additionally, adjusted prevalence and prevalence ratios (PR) were estimated for these variables using logistic regression models with age, gender, occupation, epidemiological week and laboratory as confounding factors. RESULTS: Overall prevalence of infection was 3.2% (95% CI 3.0% to 3.4%), being higher among policemen (4.4%) and bus drivers (4.2%), but lower among emergency healthcare personnel, firefighters, food market workers and burial services (<2%). Lower excess risk was observed in workers reporting occupational contact with COVID-19 cases only (PR=1.42; 95% CI 1.18 to 1.71) compared with household exposure only (PR=2.75; 95% CI 2.32 to 3.25). Infection was more frequent in symptomatic workers (PR=1.28; 95% CI 1.11 to 1.48), although 42% of detected infections were asymptomatic. Use of facial masks (78.7%) and disinfectants (86.3%) was common and associated with lower infection prevalence (PRmasks=0.68; 95% CI 0.58 to 0.79; PRdisinfectants=0.75; 95% CI 0.61 to 0.91). Over 50% of workers felt being at high risk of infection and worried about infecting others, yet only 2% considered quitting their work. CONCLUSIONS: This surveillance system allowed for detecting and isolating SARS-CoV-2 cases among essential workers, identifying characteristics related to infection and use of protective devices, and revealing specific needs for work-safety information and psychological support.

The importance of physical exercise in cardiovascular fitness in breast cancer survivors. A cross-sectional study: women in Motion 2.0.

PURPOSE: To compare the cardiovascular fitness of breast cancer (BC) survivors with an active lifestyle to those with a sedentary lifestyle. METHODS: A cross-sectional study was conducted. Participants were classified into four groups: two groups of active women who performed more than 150 min/week of physical exercise, active with BC (Act-BCW) and active without BC (Act-HW); and two groups of sedentary women who performed less than 90 min/week of physical exercise, sedentary with BC (Sed-BCW) and sedentary without BC (Sed-HW). VO2max was estimated by the 6-min walking test (6MWT); speed, isometric strength, lower body maximum strength, explosive strength, balance, and body composition were also measured. ANOVA was used to analyze group differences and post hoc comparisons were developed with the Bonferroni test. RESULTS: A total of 92 women were recruited. Significant differences were found in VO2max between the Act-BCW and Sed-BCW groups (MeanDif = 5.86, p < 0.001). No differences in VO2max were observed between the active groups (MeanDif = 0.42, p = 0.753). Related body composition and fat mass levels were significantly lower in the Act-BCW group than in the sedentary groups (Sed-BCW MeanDif = - 6.78; p = 0.012; and Sed-HW MeanDif = - 12.07; p < 0.001). CONCLUSIONS: Women who are Act-BCW can achieve similar values in physical condition as women who are Act-HW and have better values than women who are sedentary. Furthermore, our results suggest than physical activity level may have a greater impact in body composition than a previous history of BC.

Levels and determinants of urinary cadmium in general population in Spain: Metal-MCC-Spain study.

BACKGROUND: Cadmium is a ubiquitous and persistent metal, associated with different harmful health effects and with increased morbidity and mortality. Understanding the main sources of exposure is essential to identify at risk populations and to design public health interventions. OBJECTIVE: To evaluate cadmium exposure in a random-sample of general adult population from three regions of Spain, assessed by the urinary cadmium (U-Cd) concentration, and to identify its potential determinants and sex-specific differences, including sociodemographic, lifestyle and dietary factors. MATERIALS AND METHODS: We measured U-Cd (µg/g creatinine) in single urine spot samples from 1282 controls enrolled in the multicase-control study in common tumors in Spain (MCC-Spain) with inductively coupling plasma-mass spectrometry equipped with an octopole reaction systems (ICP-ORS-MS). The association between sociodemographic, lifestyle, and dietary characteristics and U-Cd concentrations was evaluated using geometric mean ratios (GMR) estimated by multiple log-linear regression models. RESULTS: Overall, geometric mean U-Cd concentration was 0.40 (95%CI: 0.38, 0.41) µg/g creatinine. Levels were higher in women than in men (GMR]: 1.19; 95%CI: 1.07, 1.32), and increased with age in males (ptrend< 0.001). Cigarette smoking was clearly associated to U-Cd levels (GMRformer vs non-smokers: 1.16; 95%CI: 1.05, 1.29; GMRcurrent vs non-smokers: 1.42; 95%CI: 1.26, 1.60); the relationship with secondhand tobacco exposure in non-smokers, was restricted to women (pinteraction = 0.02). Sampling season and region also seemed to influence U-Cd concentrations, with lower levels in summer (GMRsummer vs average: 0.79; 95%CI: 0.71, 0.88), and higher levels in North-Spain Asturias (GMRAsturias vs average: 1.13; 95%CI: 1.04, 1.23). Regarding diet, higher U-Cd concentration was associated with eggs consumption only in men (pinteraction = 0.04), just as rice intake was associated in women (pinteraction = 0.03). CONCLUSION: These results confirmed that tobacco exposure is the main modifiable predictor of U-Cd concentrations, and remark that the role of dietary/sociodemographic factors on U-Cd levels may differ by sex.

Effect of time of day of recreational and household physical activity on prostate and breast cancer risk (MCC-Spain study).

Experimental evidence indicates that exercise performed at different times of the day may affect circadian rhythms and circadian disruption has been linked to breast and prostate cancer. We examined in a population-based case-control study (MCC-Spain) if the time-of-day when physical activity is done affects prostate and breast cancer risk. Lifetime recreational and household physical activity was assessed by in-person interviews. Information on time-of-day of activity (assessed approximately 3 years after the assessment of lifetime physical activity and confounders) was available for 781 breast cancer cases, 865 population female controls, 504 prostate cases and 645 population male controls from 10 Spanish regions, 2008-2013. We estimated odds ratios (ORs) and 95% confidence intervals (95% CI) for different activity timings compared to inactive subjects using unconditional logistic regression adjusting for confounders. Early morning (8-10 am) activity was associated with a protective effect compared to no physical activity for both breast (OR = 0.74, 95% CI = 0.48-1.15) and prostate cancer (OR = 0.73, 95% CI = 0.44-1.20); meta-OR for the two cancers combined 0.74 (95%CI = 0.53-1.02). There was no effect observed for breast or prostate cancer for late morning to afternoon activity while a protective effect was also observed for evening activity only for prostate cancer (OR = 0.75, 95% CI = 0.45-1.24). Protective effects of early morning activity were more pronounced for intermediate/evening chronotypes for both cancers. This is the first population-based investigation identifying a differential effect of timing of physical activity on cancer risk with more pronounced effects for morning hour activity. Our results, if confirmed, may improve current physical activity recommendations for cancer prevention.

Anticipated help-seeking for cancer symptoms before and after the coronavirus pandemic: results from the Onco-barometer population survey in Spain.

BACKGROUND: The patient interval-the time patients wait before consulting their physician after noticing cancer symptoms-contributes to diagnostic delays. We compared anticipated help-seeking times for cancer symptoms and perceived barriers to help-seeking before and after the coronavirus pandemic. METHODS: Two waves (pre-Coronavirus: February 2020, N = 3269; and post-Coronavirus: August 2020, N = 1500) of the Spanish Onco-barometer population survey were compared. The international ABC instrument was administered. Pre-post comparisons were performed using multiple logistic and Poisson regression models. RESULTS: There was a consistent and significant increase in anticipated times to help-seeking for 12 of 13 cancer symptoms, with the largest increases for breast changes (OR = 1.54, 95% CI 1.22-1-96) and unexplained bleeding (OR = 1.50, 1.26-1.79). Respondents were more likely to report barriers to help-seeking in the post wave, most notably worry about what the doctor may find (OR = 1.58, 1.35-1.84) and worry about wasting the doctor's time (OR = 1.48, 1.25-1.74). Women and older individuals were the most affected. CONCLUSIONS: Participants reported longer waiting times to help-seeking for cancer symptoms after the pandemic. There is an urgent need for public interventions encouraging people to consult their physicians with symptoms suggestive of cancer and counteracting the main barriers perceived during the pandemic situation.

Trajectories of alcohol consumption during life and the risk of developing breast cancer.

BACKGROUND: Whether there are lifetime points of greater sensitivity to the deleterious effects of alcohol intake on the breasts remains inconclusive. OBJECTIVE: To compare the influence of distinctive trajectories of alcohol consumption throughout a woman's life on development of breast cancer (BC). METHODS: 1278 confirmed invasive BC cases and matched (by age and residence) controls from the Epi-GEICAM study (Spain) were used. The novel group-based trajectory modelling was used to identify different alcohol consumption trajectories throughout women's lifetime. RESULTS: Four alcohol trajectories were identified. The first comprised women (45%) with low alcohol consumption (<5 g/day) throughout their life. The second included those (33%) who gradually moved from a low alcohol consumption in adolescence to a moderate in adulthood (5 to <15 g/day), never having a high consumption; and oppositely, women in the third trajectory (16%) moved from moderate consumption in adolescence, to a lower consumption in adulthood. Women in the fourth (6%) moved from a moderate alcohol consumption in adolescence to the highest consumption in adulthood (≥15 g/day), never having a low alcohol consumption. Comparing with the first trajectory, the fourth doubled BC risk (OR 2.19; 95% CI 1.27, 3.77), followed by the third (OR 1.44; 0.96, 2.16) and ultimately by the second trajectory (OR 1.17; 0.86, 1.58). The magnitude of BC risk was greater in postmenopausal women, especially in those with underweight or normal weight. When alcohol consumption was independently examined at each life stage, ≥15 g/day of alcohol consumption in adolescence was strongly associated with BC risk followed by consumption in adulthood. CONCLUSIONS: The greater the alcohol consumption accumulated throughout life, the greater the risk of BC, especially in postmenopausal women. Alcohol consumption during adolescence may particularly influence BC risk.

Prevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study.

BACKGROUND: Spain is one of the European countries most affected by the COVID-19 pandemic. Serological surveys are a valuable tool to assess the extent of the epidemic, given the existence of asymptomatic cases and little access to diagnostic tests. This nationwide population-based study aims to estimate the seroprevalence of SARS-CoV-2 infection in Spain at national and regional level. METHODS: 35 883 households were selected from municipal rolls using two-stage random sampling stratified by province and municipality size, with all residents invited to participate. From April 27 to May 11, 2020, 61 075 participants (75·1% of all contacted individuals within selected households) answered a questionnaire on history of symptoms compatible with COVID-19 and risk factors, received a point-of-care antibody test, and, if agreed, donated a blood sample for additional testing with a chemiluminescent microparticle immunoassay. Prevalences of IgG antibodies were adjusted using sampling weights and post-stratification to allow for differences in non-response rates based on age group, sex, and census-tract income. Using results for both tests, we calculated a seroprevalence range maximising either specificity (positive for both tests) or sensitivity (positive for either test). FINDINGS: Seroprevalence was 5·0% (95% CI 4·7-5·4) by the point-of-care test and 4·6% (4·3-5·0) by immunoassay, with a specificity-sensitivity range of 3·7% (3·3-4·0; both tests positive) to 6·2% (5·8-6·6; either test positive), with no differences by sex and lower seroprevalence in children younger than 10 years (<3·1% by the point-of-care test). There was substantial geographical variability, with higher prevalence around Madrid (>10%) and lower in coastal areas (<3%). Seroprevalence among 195 participants with positive PCR more than 14 days before the study visit ranged from 87·6% (81·1-92·1; both tests positive) to 91·8% (86·3-95·3; either test positive). In 7273 individuals with anosmia or at least three symptoms, seroprevalence ranged from 15·3% (13·8-16·8) to 19·3% (17·7-21·0). Around a third of seropositive participants were asymptomatic, ranging from 21·9% (19·1-24·9) to 35·8% (33·1-38·5). Only 19·5% (16·3-23·2) of symptomatic participants who were seropositive by both the point-of-care test and immunoassay reported a previous PCR test. INTERPRETATION: The majority of the Spanish population is seronegative to SARS-CoV-2 infection, even in hotspot areas. Most PCR-confirmed cases have detectable antibodies, but a substantial proportion of people with symptoms compatible with COVID-19 did not have a PCR test and at least a third of infections determined by serology were asymptomatic. These results emphasise the need for maintaining public health measures to avoid a new epidemic wave. FUNDING: Spanish Ministry of Health, Institute of Health Carlos III, and Spanish National Health System.

Toxic metals in toenails as biomarkers of exposure: A review.

Toenails have been used as biomarkers of exposure to toxic metals, but their validity for this purpose is not yet clear and might differ depending on the specific agent. To evaluate this issue, we reviewed the literature on: a) the time-window of exposure reflected by toenails; b) the reproducibility of toenail toxic-metal levels in repeated measures over time; c) their relationship with other biomarkers of exposure, and; d) their association with potential determinants (i.e. sociodemographic, anthropometric, or lifestyle characteristics) or with sources of exposure like diet or environmental pollution. Thus, we performed a systematic review, searching for articles that provided original data for levels of any of the following toxic metals in toenails: aluminum, beryllium, cadmium, chromium, mercury, nickel, lead, thallium and uranium. We identified 88 articles, reporting data from 67 different research projects, which were quite heterogeneous with regard to population profile, sample size and analytical technique. The most commonly studied metal was mercury. Concerning the time-window of exposure explored by toenails, some reports indicate that toenail cadmium, nickel and lead may reflect exposures that occurred 7-12 months before sampling. For repeated samples obtained 1-6 years apart, the range of intraindividual correlation coefficients of aluminum, chromium and mercury was 0.33-0.56. The correlation of toxic metal concentrations between toenails and other matrices was higher for hair and fingernails than for urine or blood. Mercury levels were consistently associated with fish intake, while other toxic metals were occasionally associated with specific sources (e.g. drinking water, place of residence, environmental pollution, and occupation). The most frequently evaluated health endpoints were cardiovascular diseases, cancer, and central nervous system diseases. Available data suggest that toenail mercury levels reflected long-term exposures and showed positive associations with fish intake. The lack of standardization in sample collection, quality control, analytical techniques and procedures - along with the heterogeneity and conflicting results among studies - mean it is still difficult to conclude that toenails are a good biomarker of exposure to toxic metals. Further studies are needed to draw solid conclusions about the suitability of toenails as biomarkers of exposure to toxic metals.