Search

There is emerging evidence that spouses of patients with cancer may have a higher prevalence of mental illness, but these studies have been limited by pre-post designs, focus on a single mental illness, and short follow-up periods.To assess the overall burden of psychiatric disorders among spouses of patients with cancer vs spouses of individuals without cancer and to describe possible changes in this burden over time.This population based cohort study included spouses of patients with cancer (diagnosed 1986-2016 in Denmark and 1973-2014 in Sweden; exposed group) and spouses of individuals without cancer (unexposed group). Members of the unexposed group were individually matched to individuals in the exposed group on the year of birth, sex, and country. Spouses with and without preexisting psychiatric morbidity were analyzed separately. Data analysis was performed between May 2021 and January 2022.Being spouse to a patient with cancer.The main outcome was a clinical diagnosis of psychiatric disorders through hospital-based inpatient or outpatient care. Flexible parametric models and Cox models were fitted to estimate hazard ratios (HRs) with 95% CIs, adjusted for sex, age and year at cohort entry, country, household income, and cancer history.Among 546 321 spouses in the exposed group and 2 731 574 in the unexposed group who had no preexisting psychiatry morbidity, 46.0% were male participants, with a median (IQR) age at cohort entry of 60 (51-68) years. During follow-up (median, 8.4 vs 7.6 years), the incidence rate of first-onset psychiatric disorders was 6.8 and 5.9 per 1000 person-years for the exposed and unexposed groups, respectively (37 830 spouses of patients with cancer [6.9%]; 153 607 of spouses of individuals without cancer [5.6%]). Risk of first-onset psychiatric disorders increased by 30% (adjusted HR, 1.30; 95% CI, 1.25-1.34) during the first year after cancer diagnosis, especially for depression (adjusted HR, 1.38; 95% CI, 1.30-1.47) and stress-related disorders (adjusted HR, 2.04; 95% CI, 1.88-2.22). Risk of first-onset psychiatric disorders increased by 14% (adjusted HR, 1.14; 95% CI, 1.13-1.16) during the entire follow-up, which was similar for substance abuse, depression, and stress-related disorders. The risk increase was more prominent among spouses of patients diagnosed with a cancer with poor prognosis (eg, pancreatic cancer: adjusted HR, 1.41; 95% CI, 1.32-1.51) or at an advanced stage (adjusted HR, 1.31; 95% CI, 1.26-1.36) and when the patient died during follow-up (adjusted HR, 1.29; 95% CI, 1.27-1.31). Among spouses with preexisting psychiatric morbidity, the risk of psychiatric disorders (first-onset or recurrent) increased by 23% during the entire follow-up (adjusted HR, 1.23; 95% CI, 1.20-1.25).In this cohort study of 2 populations in Denmark and Sweden, spouses of patients with cancer experienced increased risk of several psychiatric disorders that required hospital-based specialist care. Our results support the need for clinical awareness to prevent potential mental illness among the spouses of patients with cancer.

BackgroundThe association between cardiovascular disease (CVD) and selected psychiatric disorders has frequently been suggested while inadequate control of familial factors and comorbidities has halted causal inferences.MethodsWe identified 869 056 patients newly diagnosed with CVD from 1987 to 2016 in Sweden while no history of psychiatric disorders, and 910 178 full siblings of these patients and 10 individually age- and sex-matched unrelated population controls (N=8 690 560). Adjusting for multiple comorbid conditions, we used flexible parametric models and Cox regression to estimate the association of CVD with risk of all subsequent psychiatric disorders, comparing rates of first incident psychiatric disorder among CVD patients with rates among unaffected full siblings and population controls.ResultsThe median age at diagnosis was 60 years for patients with cardiovascular disease and 59.2% were male. During up to thirty years of follow-up, the crude incidence rates of psychiatric disorder were 7.1, 4.6 and 4.0 per 1000 person-years for patients with cardiovascular disease, their siblings and population controls. In the sibling comparison, we observed an increased risk of psychiatric disorder during the first year after cardiovascular diagnosis (hazard ratio [HR], 2.74; 95% confidence interval [CI], 2.62-2.87) and thereafter (1.45; 95% CI, 1.42-1.48). Increased risks were observed for all types of psychiatric disorders and among all diagnoses of cardiovascular disease. We observed similar associations in the population comparison. Cardiovascular patients who developed a comorbid psychiatric disorder during the first year after diagnosis were at increased risk of subsequent cardiovascular death compared to patients without such comorbidity (HR 1.55; 95% CI 1.44-1.67).ConclusionsPatients diagnosed with cardiovascular disease are at an elevated risk for subsequent psychiatric disorders independent of familial factors and comorbid conditions. Cardiovascular patients with comorbid psychiatric disorders are at increased risk of cardiovascular mortality suggesting that surveillance and treatment of psychiatric comorbidities should be considered as an integral part of clinical management of newly diagnosed patients with cardiovascular disease.Fundingthis work was supported by the EU Horizon 2020 Research and Innovation Action Grant (CoMorMent, Grant nr. 847776 to UV, PFS and FF), Grant of Excellence, Icelandic Research Fund (grant no. 163362-051 to UV), ERC Consolidator Grant (StressGene, grant no: 726413 to UV), Swedish Research Council (Vetenskapsrådet, award D0886501 to PFS) and US NIMH R01 MH123724 (to PFS).

Objective:To determine if inflammation in proximity of the motor unit may contribute to neurodegeneration in amyotrophic lateral sclerosis (ALS). Methods: We identified all patients diagnosed in Sweden with concurrent ALS and multiple sclerosis (MS), myasthenia gravis (MG), inflammatory polyneuropathies (IP), or dermatopolymyositis (DMPM) during 1991-2014 according to the Swedish Patient Register (N = 263). We validated medical records for 92% of these patients (18 records were not retrieved and three did not contain enough information) and compared patients with a confirmed overlap (N = 28) with an independent sample of patients with solely ALS (N = 271). Results: Ninety-one patients were deemed as not having ALS (34.6%). Among the remaining 151 with validated ALS, 12 had also a confirmed MS diagnosis, nine a confirmed MG diagnosis, four a confirmed IP diagnosis, and three a confirmed DMPM diagnosis. Seventeen of the patients were women and 11 were men. Seventy-nine percent of the patients with a confirmed overlap had MS, MG, IP, or DMPM diagnosed prior to ALS. Compared to patients with only ALS, the concurrent patients were significantly older at symptoms onset, had higher prevalence of bulbar onset, but used Riluzole and noninvasive ventilation less frequently. Conclusions: We found that a high concurrence of ALS and MS/MG/IP/DMPM diagnoses is largely due to diagnostic uncertainty. A minority of patients had a true concurrence, where MS, MG, IP, and DMPM preceded the ALS diagnosis, which might be due to chance alone. Four patients were diagnosed with MG shortly after onset of ALS, suggesting that neurodegeneration might trigger autoimmunity.

Purpose: Esophageal cancer is the sixth leading cause of cancer-related death worldwide, and is associated with a poor prognosis. Stromal tumor infiltrating lymphocytes (sTIL) and certain single nucleotide polymorphisms (SNPs) have been found to be predictive of patient survival. In this study, we explored the association between SNPs and sTIL regarding the predictability of disease-free survival in patients with esophageal squamous cell carcinoma (ESCC). Materials and methods: We collected 969 pathologically confirmed ESCC patients from 2010 to 2013 and genotyped 101 SNPs from 59 genes. The number of sTIL for each patient was determined using an automatic algorithm. A Kruskal-Wallis test was used to determine the association between genotype and sTIL. The genotypes and clinical factors related to survival were analyzed using a Kaplan-Meier curve, Cox proportional hazards model, and log-rank test. Results: The median age of the patients was 67 (42-85 years), there was a median follow-up of 851.5 days and 586 patients died. The univariable analysis showed that 10 of the 101 SNPs were associated with sTIL. Six SNPs were also associated with disease-free survival. A multivariable analysis revealed that sTIL, rs1801131, rs25487, and rs8030672 were independent prognostic markers for ESCC patients. The model combining SNPs, clinical characteristics and sTIL outperformed the model with clinical characteristics alone for predicting outcomes in ESCC patients. Conclusion: We discovered 10 SNPs associated with sTIL in ESCC and we built a model of sTIL, SNPs and clinical characteristics with improved prediction of survival in ESCC patients.

Background: The potential effect of alcohol or tea intake on the risk of nasopharyngeal carcinoma (NPC) remains controversial. Methods: In a population-based case–control study in southern China, we assessed alcohol or tea intake from 2,441 histopathologically confirmed NPC cases and 2,546 controls. We calculated mean daily ethanol (g/day) and tea intake (mL/day). Fully adjusted ORs with 95% confidence intervals (CI) were estimated using logistic regression; potential dose–response trends were evaluated using restricted cubic spline analysis. Results: Compared with nondrinkers, no significantly increased NPC risk in men was observed among current alcohol drinkers overall (OR, 1.08; 95% CI, 0.93–1.25), nor among current heavy drinkers (OR for ≥90 g/day ethanol vs. none, 1.32; 95% CI, 0.95–1.84) or former alcohol drinkers. Current tea drinking was associated with a decreased NPC risk (OR, 0.73; 95% CI, 0.64–0.84). Compared with never drinkers, those with the low first three quintiles of mean daily current intake of tea were at significantly lower NPC risk (OR, 0.53, 0.68, and 0.65, respectively), but not significant for the next two quintiles. Current daily tea intake had a significant nonlinear dose–response relation with NPC risk. Conclusions: Our study suggests no significant association between alcohol and NPC risk. Tea drinking may moderately reduce NPC risk, but the lack of a monotonic dose–response association complicates causal inference. Impact: Tea drinking might be a healthy habit for preventing NPC. More studies on biological mechanisms that may link tea with NPC risk are needed.

Background Selection of high-risk subjects for endoscopic screening of esophageal squamous cell carcinoma (ESCC) lacks individual predictive tools based on environmental risk factors. Methods We performed a large population-based case-control study of 1418 ESCC cases and 1992 controls in a high-risk area of China. Information on potential risk factors was collected via face-to-face interview using an electronic structured questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models, and predictive nomograms were established accordingly. A weighted analysis was further conducted to introduce age into predictive nomograms due to frequency matching study design. Results Most cases were usually exposed to 4 to 6 risk factors, but most controls were usually exposed to 3 to 5 risk factors. The AUCs of male and female predictive nomograms were 0.75 (95%CI: 0.72, 0.77) and 0.76 (95%CI: 0.73, 0.79), respectively. The weighted analysis adding age in the predictive model improved the AUC in both men and women (0.81 (95%CI: 0.79, 0.84) and 0.88 (95%CI: 0.85, 0.90), respectively). Conclusions An easy-to-use preclinical predictive tool is provided to select candidate population with high ESCC risk for endoscopic screening. Its usefulness needs to be further evaluated in future screening practice.

Background The health consequences of the use of Swedish snus, including its relationship with mortality, have not been fully established. We investigated the relationship between snus use and all-cause and cause-specific mortality (death due to cardiovascular diseases, cancer diseases and all other reasons, respectively) in a nationwide collaborative pooling project. Methods We followed 169 103 never-smoking men from eight Swedish cohort studies, recruited in 1978–2010. Shared frailty models with random effects at the study level were used in order to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of mortality associated with snus use. Results Exclusive current snus users had an increased risk of all-cause mortality (aHR 1.28, 95% CI 1.20–1.35), cardiovascular mortality (aHR 1.27, 95% CI 1.15–1.41) and other cause mortality (aHR 1.37, 95% CI 1.24–1.52) compared with never-users of tobacco. The risk of cancer mortality was also increased (aHR 1.12, 95% CI 1.00–1.26). These mortality risks increased with duration of snus use, but not with weekly amount. Conclusions Snus use among men is associated with increased all-cause mortality, cardiovascular mortality, with death from other causes and possibly with increased cancer mortality.

Cell phone use and radio-frequency electromagnetic radiation (RF-EMF) are rapidly increasing and may be associated with lower semen quality, yet results from epidemiological studies are inconclusive. Information on electronic devices use was collected through standard questionnaires from 1454 men aged 22-45 years old. Semen volume, sperm concentration, total sperm count, total motility, progressive motility, and normal morphology in repeated specimens were determined by trained clinical technicians. Percent changes [95% confidence intervals (CIs)] were estimated as (10

Background Accumulating evidence suggests a survival benefit after curative oesophageal cancer surgery in women compared with men. The aim of this study was to explore sex disparities in survival after surgery with curative intent in patients with oesophageal cancer. Methods This was a population-based cohort study, including all patients with oesophageal or gastric cancer who underwent surgery with a curative intent between 2006 and 2017 in Sweden. Female versus male mortality rate ratio (MRR) and excess mortality rate ratio (EMRR) were used as measures of survival. Two different parametric models were designed to account for potential confounders. Patients with gastric cancer were used as a comparison group as no differences in survival between sexes were expected among these patients. Results A total of 1301 patients underwent resection for oesophageal adenocarcinoma and 305 patients for oesophageal squamous cell carcinoma. Women had a lower EMRR (0.76, 95 per cent c.i. 0.58 to 1.01, P = 0.056; 0.52, 95 per cent c.i. 0.32 to 0.84, P = 0.007 respectively) in both histological subtypes. The effect was more profound in early clinical stages, in patients receiving neoadjuvant treatment, and without postoperative complications. No sex-related difference was observed in survival of patients with gastric cancer. Conclusions Women undergoing resection for oesophageal carcinoma have better survival compared with men.

Background The vagus nerve provides essential parasympathetic innervation to the gastrointestinal system and is known to have anti-inflammatory properties. Aims To explore the relationship between vagotomy and the risk of inflammatory bowel disease (IBD) and its major categories: Crohn's disease (CD) and ulcerative colitis (UC). Methods A matched cohort comprising 15 637 patients undergoing vagotomy was identified through the Swedish Patient Register from 1964 to 2010. Each vagotomised patient was matched for birth year and gender with 40 nonvagotomised individuals on the date of vagotomy. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for IBD using flexible parametric models adjusted for matching variables, year of vagotomy, birth country, chronic obstructive pulmonary disease and comorbidity index. Results We observed 119 (0.8%) patients with vagotomy developed IBD compared to 3377 (0.5%) IBD cases in nonvagotomised individuals. The crude incidence of IBD (per 1000 person-years) was 0.38 for vagotomised patients and 0.25 for nonvagotomised individuals. We observed a time-dependent elevated risk of IBD associated with vagotomy, for instance, the HR (95% CI) was 1.80 (1.40-2.31) at year 5 and 1.49 (1.14-1.96) at year 10 post-vagotomy. The association appeared to be stronger for truncal than selective vagotomy and limited to CD (HR was 3.63 [1.94-6.80] for truncal and 2.06 [1.49-2.84] for selective vagotomy) but not UC (1.36 [0.71-2.62] for truncal and 1.25 [0.95-1.63] for selective vagotomy). Conclusions We found a positive association between vagotomy and later IBD, particularly for CD. The finding indirectly underlines the beneficial role of the vagal tone in IBD.

Gait disturbance is considered to be a significant clinical manifestation of cerebral small vessel disease (CSVD). We aimed to investigate the association between different imaging markers of CSVD or total CSVD burden and gait disturbance in a community-dwelling population. In the cross-sectional Taizhou Imaging Study (TIS), 314 participants free of neurological disorders underwent MRI scanning and gait assessment with quantitative wearable devices as well as clinical rating scales. In linear regression, after adjustment for demographics and vascular risks, total CSVD burden was associated with prolonged 3-m walking (β=0.118, P=0.035), shorter stride length (β=-0.106, P=0.042), and poorer Timed-Up-and-Go (TUG) performance (β=0.146, P=0.009). Lacunes were positively associated with 3-m walking (β=0.118, P=0.037) and duration of TUG test (β=0.112, P=0.047). White matter hyperintensities and cerebral microbleeds were associated with prolonged stride time (β=0.134, P=0.024) and increased stance phase time percentage (β=0.115, P=0.038), respectively. Logistic regression revealed that participants with high CSVD burden or more lacunes were more likely to have an impaired gait velocity and an impaired TUG test. These results suggest that total CSVD burden and CSVD imaging markers are associated with gait disturbance among community-dwelling elderly people. Different CSVD imaging markers may cause gait disturbance through different pathways.

Previous findings concerning gastric atrophy as a potential risk factor for esophageal squamous cell carcinoma (ESCC) have been inconsistent. We aimed to test whether gastric atrophy and, further, its interaction with poor oral health elevated the risk of ESCC in a high-risk region of China. Our population-based case-control study in Taixing, China (2010–2014), recruited cases from local hospitals and the local cancer registry. Controls were selected randomly from the local population registry. Ultimately, 1,210 cases and 1,978 controls answered questionnaires and provided blood samples for assay of pepsinogens. Unconditional logistic regression models were used to estimate odds ratios and 95% confidence intervals. Gastric atrophy (defined as a serum level of pepsinogen I of

Aims We aimed to examine the associations of four extracranial artery indicators with cerebral small vessel disease (CSVD) and its total burden. Methods A total of 904 individuals aged 55-65 years old were included from the Taizhou Imaging Study. CSVD markers, including lacunes (LAC), white matter hyperintensities (WMH), cerebral microbleeds (CMB), and perivascular spaces (PVS), were rated based on brain magnetic resonance imaging. We also measured extracranial artery indices, including the brachial-ankle pulse wave velocity (baPWV), the ankle-brachial index, the carotid intima-media thickness (IMT), and carotid plaque. Linear and binary logistic regressions were adopted to test the associations among these four artery indicators and each CSVD marker when appropriate. Additionally, ordinal and multinomial logistic regressions were performed to assess the relationships between artery indicators and total CSVD score (range from 0-4 points). Results A total of 443 (49.0%) participants were found to have at least one of the CSVD markers, including 172 (19.0%) with WMH, 184 (20.4%) with LAC, 147 (16.3%) with CMB, and 226 (25.0%) with PVS. Increased baPWV was significantly associated with each CSVD marker, increasing carotid IMT was associated with LAC and PVS, and the presence of carotid plaque was associated with WMH volume and PVS. Moreover, per SD increment of baPWV (odds ratio [OR]: 1.29, 95% confidence interval [CI]: 1.11-1.50) and the presence of carotid plaque (OR: 1.42, 95% CI: 1.05-1.92) were significantly associated with greater total CSVD scores. Conclusion Increased baPWV and the presence of carotid plaque appear to be associated with total CSVD burden in rural regions in China.

Rationale: The oncogenesis of head and neck squamous cell carcinoma (HNSCC) is believed to result from oncogene activation and tumor suppressor inactivation. Here, we identified a new oncogenic role for the EREG gene in HNSCC. Methods: The TCGA database and immunohistochemistry assay were used to analyze expression of EREG in HNSCC tissues. Immunoblotting was performed to identify the EGFR-mediated pathways altered by EREG. The role of EREG in oncogenesis was investigated in vivo and in vitro. Results: Upregulated EREG expression predicted a poor prognosis and triggered HNSCC oncogenic transformation by activating the epidermal growth factor receptor (EGFR) signaling pathway. We also demonstrated the direct association of EREG with EGFR and that this binding required EGFR domains I and III and the N57 residue of EREG. Moreover, EREG overexpression was shown to promote HNSCC oncogenesis by inducing C-Myc expression, and the pharmacological inhibition of C-Myc rescued EREG-promoted HNSCC oncogenesis. Unlike other EGFR ligands, EREG could mimic EGFR mutations by sustaining the activation of the EGFR-Erk pathway, and high EREG expression was positively associated with the response to treatment with the EGFR inhibitor erlotinib. Furthermore, knockdown of EREG decreased sensitivity to erlotinib treatment in vitro and in vivo. Conclusions: These results identify the EREG-EGFR-C-Myc pathway as a crucial axis that drives HNSCC oncogenesis and show that EREG expression could be a predictive functional marker of sensitivity to erlotinib therapy in HNSCC.

Eosinophilic gastrointestinal disorders (EGIDs) include inflammatory conditions with enteric infiltration of eosinophils and resulting symptoms. This study aims to examine a population-based sample of patients for prevalence, mortality, and cancer risk in EGIDs distal to the esophagus.Nationwide, population-based cohort study. EGID was identified through relevant biopsy codes from Sweden's all 28 pathology departments through the ESPRESSO cohort. Individuals with EGID were then matched to general population reference individuals with similar age and sex. Study participants were linked to Swedish healthcare registers. Through Cox regression, we calculated adjusted hazard ratios (aHRs) adjusting for sex, age, county, calendar period, and education.In total, 2429 patients (56% female) were found to have EGID distal to the esophagus, representing a prevalence of about 1/4800 in the Swedish population. Mean age was 44 years with 11% children at the time of diagnosis. Mortality was increased 17% in patients with EGIDs compared to reference individuals (aHR = 1.17; 95%CI = 1.04-1.33). Excess mortality was seen in gastric and small bowel eosinophilic disease, but not colonic disease (aHR = 1.81; 95%CI = 1.32-2.48, aHR = 1.50; 95%CI = 1.18-1.89, and aHR = 0.99; 95%CI = 0.85-1.16, respectively). Cause specific mortality was driven by cancer-related death (aHR = 1.33; 95%CI = 1.05-1.69). However, this study failed to show an increase in incident cancers (aHR = 1.14; 95%CI = 0.96-1.35). Comparison of EGID individuals with their siblings yielded similar aHRs.This study found an increased risk of death in patients with EGIDs distal to the esophagus, with cancer death driving the increase. Proximal gut disease seems to confer the greatest risk. There was no increase in incident cancers.

Background: To explore the relationship between family history of esophageal cancer, SNPs, and the risk of esophageal squamous cell carcinoma (ESCC), we performed a population-based case–control study and developed a genetic family history–related risk (GFR) score and non–family history-related risk (GnFR) score to quantify the cumulative number of risk genotypes carried by each individual. Methods: We used data of 700 patients with nonfamilial ESCC, 341 patients with familial ESCC, 1,445 controls without a family history of esophageal cancer, and 319 controls with a family history. We genotyped 87 genetic variants associated with the risk for ESCC, and constructed GFR and GnFR scores for cases and controls. Results: Our results show that ESCC risk increased with higher GFR score (Ptrend = 0.0096). Among the familial subgroup, we observed a nearly 7-fold [95% confidence interval (CI), 1.92–24.77] higher risk of ESCC in the highest GFR score group. The corresponding estimate was only 2-fold (95% CI, 1.41–3.93) higher risk of ESCC, in the stratum without a reported family history of esophageal cancer. Certain cell signaling pathways and immune-related pathways were enriched, specifically in familial ESCC. Results from a reconstructed cohort analysis demonstrated that cumulative risk to get esophageal cancer by age 75 years was 13.3%, 10.2%, 8.2%, and 5.1%, respectively, in four subgroups as defined by first-degree relatives of cases or controls with high or low genetic risk score. In particular, the cohort of relatives of ESCC cases with low genetic risk score exhibit a higher cumulative risk than the cohort of relatives of controls with high genetic risk score. It demonstrates that environmental factors play a major role in esophageal cancer. Conclusions: Further studies are warranted to dissect the mechanisms of shared environmental and genetic susceptibility affecting the risk of getting ESCC. Impact: Our study highlights that the need of preventive strategies to screen certain genetic polymorphisms, especially in individuals whose relatives had ESCC.

Summary Background and aims Malnutrition is common among patients with end stage liver disease including liver cirrhosis and liver cancer. Optimal nutrition is important to reduce morbidity and mortality of these patients. There is limited qualitative data on nutritional status and management of chronic liver disease patients. We aimed to explore the knowledge, opinions and practices of cirrhosis patients and health workers in nutritional management of cirrhosis in Ghana, in order to determine whether there is a need to improve nutritional care for cirrhosis patients. Methods We conducted a qualitative study using semi-structured interviews of cirrhotic patients (n = 16) and healthcare providers (n = 27) in three academic centers in Accra, Kumasi and Cape Coast (Ghana). Recruitment was by purposive sampling of patients attending specialist liver disease clinics. The recorded data were analyzed using NVivo 11 software, with generation of codes, themes and subthemes. Results The major themes that emerged from the data included nutrition as part of care delivery during the hospital visit, nutritional recommendations, dietary changes and long-term practice improvement. The results showed that patients and health workers felt dietary recommendations for patients were frequently addressed, but could be significantly improved. We found that in the opinion of study participants, local guidelines are important and necessary in nutritional management of cirrhosis patients, and that participants felt it was difficult to change dietary habits following cirrhosis diagnosis. Conclusions These results suggest that nutritional management of cirrhosis patients in Ghana requires improvement. Strategies to improve this could include a multi-disciplinary approach to nutritional management, development of local guidelines and continued nutritional assessment, monitoring and follow-up.

Background Physical inactivity is a known risk factor for cardiovascular disease, but it is unclear if total and leisure time activity have different impact on the risk of myocardial infarction and stroke. In this cohort, we aimed to investigate the associations between both total and leisure time physical activity in detail, and the risks of myocardial infarction and stroke, both overall and for men and women separately. Methods We assessed the association between total and leisure time physical activity on the risk of myocardial infarction and stroke in a cohort of 31,580 men and women through record linkages from 1997–2016. We used Cox proportional hazards regression models to estimate hazard ratios (HR) with 95% confidence intervals (CI) based on detailed self-reported physical activity. In the adjusted analyses, we included age, sex, body mass index, level of education, cigarette smoking, alcohol consumption, diabetes, lipid disturbance and hypertension as potential confounders. Results We identified 1,621 incident cases of myocardial infarction and 1,879 of stroke. Among men, there was an inverse association between leisure time activity and myocardial infarction in the third tertile compared to the first (HR: 0.78; 95% CI: 0.62–0.98; p for trend = 0.03). We also found an inverse association between leisure time activity and stroke in the third tertile compared to the first (HR: 0.78; 95% CI: 0.61–0.99; p for trend = 0.04), while the corresponding HR for stroke among women was 0.91; 95% CI: 0.74–1.13. We found no significant association between total physical activity and MI (HR: 1.12; 95% CI: 0.93–1.34) or stroke (HR: 1.14 95% CI: 0.94–1.39) comparing the highest to the lowest tertile in men. Women in the highest tertile of total physical activity had a 22% lower risk of myocardial infarction compared to the lowest tertile (HR: 0.78; 95% CI: 0.63–0.97; p for trend = 0.02) and an 8% (95% CI: 0.87–0.98) reduced risk of myocardial infarction with each 1 METh/day increase of leisure time physical activity. Conclusion Total physical activity was inversely associated with the risk of myocardial infarction in women, while leisure time physical activity was inversely associated with the risk of myocardial infarction and stroke in men.

Gastric atrophy caused by Helicobacter pylori infection was suggested to influence the risk of adenocarcinoma of the esophagogastric junction (AEGJ), however, the evidence remains limited. We aimed to examine the associations of H. pylori infection and gastric atrophy (defined using serum pepsinogen [PG] I to PGII ratio) with AEGJ risk, based on a population-based case-control study in Taixing, China (2010-2014), with 349 histopathologically confirmed AEGJ cases and 1859 controls. We explored the potential effect modification by H. pylori serostatus and sex on the association of serum PGs with AEGJ risk. We used unconditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). H. pylori seropositivity was associated with an elevated AEGJ risk (OR: 1.95, 95% CI: 1.47-2.63). Neither CagA-positive nor VacA-positive strains dramatically changed this association. Gastric atrophy (PGI/PGII ratio ≤ 4) was positively associated with AEGJ risk (OR: 2.36, 95% CI: 1.72-3.22). The fully adjusted ORs for AEGJ progressively increased with the increasing levels of PGII (P-trend

Smoking has been associated with acquisition and increased persistence of Helicobacter pylori infection, as well as with lower effectiveness of its eradication. A greater prevalence of infection among smokers could contribute to the increased risk for gastric cancer. We aimed to estimate the association between smoking and seropositivity to H. pylori through an individual participant data pooled analysis using controls from 14 case- control studies participating in the Stomach Cancer Pooling Project. Summary odds ratios and prevalence ratios (PRs), adjusted for age, sex and social class, and the corresponding 95% confidence intervals (CIs) were estimated through random-effects meta-analysis. Heterogeneity was quantified using the I 2 statistic and publication bias with Egger’s test. There was no significant association between smoking (ever vs. never) and H. pylori seropositivity (adjusted odds ratio = 1.08; 95% CI: 0.89 – 1.32; adjusted PR = 1.01; 95% CI: 0.98 – 1.05). The strength of the association did not increase with the intensity or duration of smoking; stratified analyses according to sex, age, region or type of sample did not yield a consistent pattern of variation or statistically significant results, except for participants younger than 55 years and who had been smoking for more than 30 years (adjusted PR = 1.08; 95% CI: 1.02 – 1.15). This is the first collaborative analysis providing pooled estimates for the association between smoking and H. pylori seropositivity, based on detailed and uniform information and adjusting for major covariates. The results do not support an association between smoking and H. pylori infection.

The relationship between risk of esophageal squamous cell carcinoma (ESCC) and adult height, changes in individual body mass index (BMI) and body shape is not established. We performed a large population‐based case‐control study, which enrolled a total of 1414 ESCC cases and 1989 controls in a high‐incidence area in China. Using face‐to‐face interview with a structured questionnaire, information on participants' heights, weights, and perceived body shapes at 20 years of age was collected. Additionally, data on weight and perceived body shape among the same participants 10 years prior to ascertainment were collected using the same method. Odd ratios (ORs) of ESCC risk in relation to BMI and body shape were estimated using unconditional logistic regression models. The adjusted results indicated that ESCC risk in adults rapidly rose as height increased, plateauing at 170 cm among men and 157 cm among women. Among participants who were underweight, normal weight, or thinner than body shape 4, body weight loss was associated with increased risk of ESCC, and body weight gain was associated with decreased incidence of ESCC (ORs ranging from 0.40 to 0.76). Notably, however, changes in body weight did not significantly affect ESCC risk among participants who were overweight, obese, or larger than body shape 3. Maintaining a fit body shape and a reasonable BMI is advisable and of vital importance to reduce the risk of ESCC, especially in high‐risk areas.

Background Helicobacter pylori (H. pylori) infection is more frequent among men, though the magnitude of the association might be inaccurate due to potential misclassification of lifetime infection and publication bias. Moreover, infection is common, and most studies are cross-sectional. Thus, prevalence ratios (PRs) may be easier to interpret than odds ratios (ORs). Aim The aim of this study was to quantify the association between sex and H. pylori infection using controls from 14 studies from the Stomach Cancer Pooling (StoP) Project. Participants and methods H. pylori infection was defined based on IgG serum antibody titers or multiplex serology. Participants were also classified as infected if gastric atrophy was present, based on histological examination or serum pepsinogen (PG) levels (PG I≤70 and PG I/II ratio≤3). Summary ORs and PRs, adjusted for age, social class and smoking, and corresponding 95% confidence intervals (CIs), were estimated through random-effects meta-analysis. Results Men had significantly higher OR (OR: 1.33, 95% CI: 1.04-1.70) and PR (PR: 1.05, 95% CI: 1.00-1.10) of infection, with stronger associations among hospital-based or older controls. Results were similar when considering the presence of gastric atrophy to define infection status, particularly among participants older than 65 years. Conclusion This collaborative pooled-analysis supports an independent effect of sex on the prevalence of H. pylori infection, while minimizing misclassification of lifetime infection status and publication bias.

Low socioeconomic position (SEP) is a strong risk factor for incidence and premature mortality from several cancers. Our study aimed at quantifying the association between SEP and gastric cancer (GC) risk through an individual participant data meta-analysis within the “Stomach cancer Pooling (StoP) Project”. Educational level and household income were used as proxies for the SEP. We estimated pooled odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) across levels of education and household income by pooling study-specific ORs through random-effects meta-analytic models. The relative index of inequality (RII) was also computed. A total of 9,773 GC cases and 24,373 controls from 25 studies from Europe, Asia and America were included. The pooled OR for the highest compared to the lowest level of education was 0.60 (95% CI, 0.44–0.84), while the pooled RII was 0.45 (95% CI, 0.29–0.69). A strong inverse association was observed both for noncardia (OR 0.39, 95% CI, 0.22–0.70) and cardia GC (OR 0.47, 95% CI, 0.22–0.99). The relation was stronger among H. pylori negative subjects (RII 0.14, 95% CI, 0.04–0.48) as compared to H. pylori positive ones (RII 0.29, 95% CI, 0.10–0.84), in the absence of a significant interaction (p = 0.28). The highest household income category showed a pooled OR of 0.65 (95% CI, 0.48–0.89), while the corresponding RII was 0.40 (95% CI, 0.22–0.72). Our collaborative pooled-analysis showed a strong inverse relationship between SEP indicators and GC risk. Our data call for public health interventions to reduce GC risk among the more vulnerable groups of the population. This project was supported by the “Associazione Italiana per la Ricerca sul Cancro” (AIRC), Projects no. 16715 and 21378 (Investigator Grant), by the “Fondazione Italiana per la Ricerca sul Cancro” (FIRC) and by the Italian Ministry of Health (Young Researchers, GR-2011-02347943 to SB). MR is grateful to the FIRC who supported his work from 2015 to 2017. Our study was also funded by FEDER through the Operational Programme Competitiveness and Internationalization and national funding from the Foundation for Science and Technology – FCT (Portuguese Ministry of Science, Technology and Higher Education) under the Unidade de Investigação em Epidemiologia – Instituto de Saúde Pública da Universidade do Porto (EPIUnit; POCI-01-0145-FEDER-006862; Ref. UID/DTP/04750/2013). AF (PD/BD/105823/2014) was awarded an individual scholarship through national funding from FCT/MCTES.

It remains open whether gastric precancerous lesions are associated with an elevated risk of pancreatic cancer. Our aim was to investigate the association between gastric mucosal status and pancreatic cancer risk.Patients with gastric biopsies [normal, minor changes, superficial gastritis, and atrophic gastritis/intestinal metaplasia/dysplasia (AG/IM/Dys)] from the Swedish histopathology registers during 1979 to 2011 were included. Cross-linkages with several nationwide registries allowed complete follow-up and identification of pancreatic cancer cases until 2014. Standardized incidence ratios (SIR) and HRs were estimated.During 3,438,248 person-years of follow-up with 318,653 participants, 3,540 cases of pancreatic cancer were identified. The same pattern of excess risk of pancreatic cancer compared with the general population was observed across all groups: a peak of 12- to 21-fold excess risk in the first year after biopsy [e.g., normal: SIR = 17.4; 95% confidence interval (CI), 15.7-19.3; AG/IM/Dys: SIR = 11.5; 95% CI, 9.9-13.4], which dropped dramatically during the second and third years, followed by 20% to 30% increased risk after the third year (e.g., normal: SIR = 1.2; 95% CI, 1.1-1.4; AG/IM/Dys: SIR = 1.3; 95% CI, 1.1-1.5). However, no significant excess risk was observed with the normal gastric mucosa as reference.This unique, large pathologic cohort study did not find evidence that abnormal gastric mucosal status is causally associated with a long-term pancreatic cancer risk. However, a highly increased short-term risk was observed for people undergoing gastroscopy with biopsy sampling compared with the general population.Further studies for a long-term risk of pancreatic cancer in patients with gastric biopsies are needed, with further adjustments.

Projecting the burden of pancreatic cancer over time provides essential information to effectively plan measures for its management and prevention. Here, we obtained data from the Global Burden of Disease (GBD) Study between 1990 and 2019, to model how pancreatic cancer will affect the 27 countries of the European Union (EU) plus the United Kingdom (the pre-Brexit EU-28) until 2039 by conducting the Bayesian age-period-cohort analysis. The number of new pancreatic cancer cases in the EU-28 was 59 000 in 1990, 109 000 in 2019 and projected to be 147 000 in 2039. This corresponded to 60 000, 109 000 and 155 000 for deaths, and a loss of 1.3 million, 2.0 million and 2.7 million for disability-adjusted life years (DALYs), respectively. The most pronounced increase of the crude incidence rate was observed and projected to be in the population older than 80 years. The age-standardized rate (ASR) of incidence, however, increased from 8.6 to 10.1 per 100 000 person-years during 1990-2019 but was projected to remain stable during 2019-2039. At the same time, our models only predicted a mild increase in the ASR of mortality until 2039. The fraction of pancreatic cancer mortality attributable to tobacco consumption decreased during 1990-2019, but we found upward trends for the attributable fractions for high fasting plasma glucose and high body mass index. In conclusion, a substantial increase in counts of incidence, mortality and DALYs lost of pancreatic cancer in the EU-28 is projected over the next two decades, which indicates the need for future health policies and interventions.

The prevalence ofCases from 12 studies from the Stomach cancer Pooling (StoP) Project providing data onAmong non-cardia cases, the pooled prevalence of HpNGC was 22.4% (This study found a low prevalence of HpNGC, who are more likely to have a family history of gastric cancer in first-degree relatives.Our results support that

Objectives An altered microbiota, which can be described quantitatively, has been identified as playing a pivotal role in host vascular physiology, and it may contribute to various diseases. The aim of this study was to better understand the role of the gut microbiota in vascular physiology in a subclinical elderly population, and to investigate how lifestyle affects the composition of host gut microbiota to further impact the pathogenesis of vascular diseases. Methods We performed a population-based faecal metagenomic study over 569 elderly asymptomatic subclinical individuals in rural China. An association network was built based on clinical measurements and detailed epidemiologic questionnaires, including blood chemistry, arterial stiffness, carotid ultrasonography, and metagenomic datasets. Results By analyzing the breadth, depth and impact of each node of the association network, we found carotid arterial atherosclerosis indices, including intima-media thickness (IMT), were essential in the network, and were significantly associated with living habits, socio-economic status, and diet. Using mediation analysis, we found that higher frequency of eating fresh fruits and vegetables, and more exercise significantly reduced carotid atherosclerosis in terms of IMT, peak systolic velocity and end-diastolic velocity values through the mediation of Alistepes, Oligella and Prevotella. Gut microbes explained 16.5% of the mediation effect of lifestyle on the pathogenesis of carotid atherosclerosis. After adjustment, Faecalicatena [odds ratio (OR) = 0.12 ∼0.65] was shown to be protective against the formation of carotid atherosclerosis, independently, while Libanicoccus (OR = 1.46 ∼4.20 ) was associated with increased carotid arterial IMT. KEGG/KO Kyoto Encyclopedia of Genes and Genomes/ KEGG Orthology (KEGG/KO) analyses revealed a loss of anti-inflammation function in IMT subjects. Conclusion Our study revealed a Chinese population–wide phenotype–metagenomic association network and a mediation effect of gut microbiota on carotid artery atherosclerosis, hinting at potential therapeutic and preventive uses for microbiota in vascular diseases.

Purpose: Oxidative stress might play an important role in the development of osteoarthritis, but not much is known about the effect of antioxidants on osteoarthritis risk. We, therefore, aimed to investigate the effect of dietary vitamin C, E, beta-carotene, and non-enzymatic antioxidant capacity (NEAC), which measures overall antioxidant activity from the diet, on the risk of osteoarthritis. Methods: For this study 43,865 men and women from the Swedish National March Cohort (SNMC) were followed for up to 19years. We computed dietary intake of vitamin C, E and beta-carotene using information from a Food Frequency Questionnaire (FFQ). To estimate dietary NEAC we combined the information from the FFQ with food item-specific antioxidant capacity values from an antioxidant food database. Cases of osteoarthritis were identified through the Swedish National Patient Registers. We categorized all exposure variables into sex-specific quartiles and used multivariable-adjusted Cox proportional hazards regression models to estimate hazard ratios (HRs) with 95% confidence intervals (95% CIs). Results: In total, we observed 5976 cases of OA during 469,148 person-years of follow-up. After adjusting for potential confounders, we did not find any association between vitamin C, beta-carotene and NEAC (p-values for trend > 0.5), but a positive association was found with higher dietary vitamin E intake (HR Q4 vs Q1: 1.11; 95% CI 1.02–1.21; p for trend = 0.01) and the risk of OA. Conclusion: Our findings do not provide evidence for dietary antioxidants to protect from the development of OA, and a higher dietary vitamin E intake might even increase the risk.

ObjectiveTo determine whether high baseline dietary antioxidants and total nonenzymatic antioxidant capacity (NEAC) is associated with a lower risk of Parkinson disease (PD) in men and women, we prospectively studied 43,865 men and women from a large Swedish cohort.MethodsIn the Swedish National March Cohort, 43,865 men and women aged 18–94 years were followed through record linkages to National Health Registries from 1997 until 2016. Baseline dietary vitamin E, vitamin C, and beta-carotene intake, as well as NEAC, were assessed by a validated food frequency questionnaire collected at baseline. All exposure variables were adjusted for energy intake and categorized into tertiles. Multivariable Cox proportional hazard regression models were fitted to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for PD.ResultsAfter a mean follow-up time of 17.6 years, we detected 465 incidence cases of PD. In the multivariable adjusted model, dietary vitamin E (HR 0.68, 95% CI 0.52–0.90; p for trend 0.005) and vitamin C (HR 0.68, 95% CI 0.52–0.89; p for trend 0.004) were inversely associated with the risk of PD when comparing participants in the highest vs the lowest tertiles of exposure. No association was found with estimated intake of dietary beta-carotene or NEAC.ConclusionOur findings suggest that dietary vitamin E and C intake might be inversely associated with the risk of PD. No association was found with dietary beta-carotene or NEAC.Classification of EvidenceThis study provides Class III evidence that dietary vitamin E and C intake are inversely associated with the risk of PD.

Contains fulltext : 235640.pdf (Publisher’s version ) (Closed access) Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

BackgroundEnd-stage liver disease (ESLD) is a major burden on public health, particularly in sub-Saharan Africa, where hepatitis B virus (HBV) is an important risk factor. We aimed to describe clinical characteristics of ESLD from cirrhosis or hepatocellular carcinoma (HCC) and the performance of aspartate aminotransferase (AST)—platelet ratio index (APRI) and alpha fetoprotein (AFP) in Ghana.MethodsWe performed an observational cross-sectional study in outpatient hepatology clinics at three teaching hospitals in Ghana, West Africa. One hundred and forty-one HCC, 216 cirrhosis and 218 chronic HBV patients were recruited by convenience sampling. Sociodemographic, history and examination, laboratory, and disease staging information were shown using descriptive statistics. Performance of the APRI score in diagnosis of cirrhosis and AFP in the diagnosis of HCC was determined using AUROC analysis.ResultsMedian age at presentation was 44 years for HCC and 46 years for cirrhosis. HBV was found in 69.5% of HCC and 47.2% of cirrhosis cases, and HCV in 6.4% and 3.7% respectively. APRI cut-off of 2 had sensitivity of 45.4% and specificity of 95% in diagnosis of cirrhosis, and cut-off of 1 had sensitivity of 75.9% and specificity of 89%. AUC of AFP was 0.88 (95% CI 0.81–0.94) in diagnosis of HCC. Low monthly income was associated with lower odds of undertaking AFP. Thirty one percent of cirrhotic persons were Child–Pugh C, and 67.9% of HCC patients had advanced or terminal disease at presentation.ConclusionsOur findings emphasize the young age of ESLD patients in Ghana and the advanced nature at presentation. It highlights shortcomings in surveillance and the need for policies to address the burden and improve outcomes in Ghana.

INTRODUCTION: Non–Helicobacter pylori microbiota might account for some cases with unexplained chronic gastritis that may in a minority eventually progress to gastric cancer through the Correa cascade. We characterized gastric microbiota by describing the normal stomach, compared it with early precancerous lesions and other disease states, and assessed whether H. pylori status affects bacterial diversity. METHODS: In a population-based study of those with and without gastrointestinal symptoms, cytology brush samples were collected during endoscopy from 316 individuals. Mucosal status was classified as normal mucosa (171), nonatrophic H. pylori gastritis (33), atrophic gastritis (12), or antral chemical gastritis (61). The 16S rRNA gene sequencing and analysis were performed to characterize the microbiota. RESULTS: Microbiota in atrophic gastritis and nonatrophic H. pylori gastritis stomachs were dysbiotic and differed from those in the normal stomach (P = 0.001). The normal stomach had the highest microbial diversity, followed by antral chemical gastritis. The atrophic gastritis and chronic H. pylori gastritis groups had the lowest diversity, a difference that was statistically significant (P = 0.01). Besides H. pylori, non–H. pylori bacteria accounted for group differences. Microbial network analysis showed that the normal group network was most highly connected, whereas the H. pylori gastritis group had the lowest connection. We found an increasing positive co-occurrence of oral bacteria in the stomach because samples deviated from the normal network, some of which were pathogens. The H. pylori–negative group had the highest microbial diversity (Shannon index) compared with the H. pylori–positive group (P = 0.001). DISCUSSION: In this low–H. pylori prevalence general population, the gastric mucosal microbiota of the normal stomach differed significantly from those with nonatrophic or atrophic gastritis. There was an increasing abundance of pathogenic bacteria from the normal state to early precancerous states.

Early detection has the potential to reduce cancer mortality, but an effective screening test must demonstrate asymptomatic cancer detection years before conventional diagnosis in a longitudinal study. In the Taizhou Longitudinal Study (TZL), 123,115 healthy subjects provided plasma samples for long-term storage and were then monitored for cancer occurrence. Here we report the preliminary results of PanSeer, a noninvasive blood test based on circulating tumor DNA methylation, on TZL plasma samples from 605 asymptomatic individuals, 191 of whom were later diagnosed with stomach, esophageal, colorectal, lung or liver cancer within four years of blood draw. We also assay plasma samples from an additional 223 cancer patients, plus 200 primary tumor and normal tissues. We show that PanSeer detects five common types of cancer in 88% (95% CI: 80–93%) of post-diagnosis patients with a specificity of 96% (95% CI: 93–98%), We also demonstrate that PanSeer detects cancer in 95% (95% CI: 89–98%) of asymptomatic individuals who were later diagnosed, though future longitudinal studies are required to confirm this result. These results demonstrate that cancer can be non-invasively detected up to four years before current standard of care., Patients whose disease is diagnosed in its early stages have better outcomes. In this study, the authors develop a non invasive blood test based on circulating tumor DNA methylation that can potentially detect cancer occurrence even in asymptomatic patients.

China has the largest number of patients with dementia in the world. However, dementia in the Chinese population is still poorly understood and under-researched. Given the differences in genetic, demographic, sociocultural, lifestyle, and health profiles among Chinese and other ethnic/racial groups, it is crucial to build appropriate infrastructure for long-term longitudinal studies to advance Chinese cognitive aging and dementia research. We initiated a community-based prospective cohort-the Taizhou Imaging Study (TIS)-to accelerate the understanding of dementia and cerebrovascular diseases in Chinese. This article presents the rationale, aims, study design, and organization of TIS. In addition, we described some examples of the types of studies such a resource might support. The TIS provides a new framework for facilitating Chinese dementia research, encompassing invaluable resources including detailed epidemiological, sociocultural, neuroimaging, and omics data.

Aims: Worldwide, smokeless-tobacco use is a major risk factor for oral cancer. Evidence regarding the particular association between Swedish snus use and oral cancer is, however, less clear. We used pooled individual data from the Swedish Collaboration on Health Effects of Snus Use to assess the association between snus use and oral cancer. Methods: A total of 418,369 male participants from nine cohort studies were followed up for oral cancer incidence through linkage to health registers. We used shared frailty models with random effects at the study level, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for confounding factors. Results: During 9,201,647 person-years of observation, 628 men developed oral cancer. Compared to never-snus use, ever-snus use was not associated with oral cancer (adjusted HR 0.90, 95% CI: 0.74, 1.09). There were no clear trends in risk with duration or intensity of snus use, although lower intensity use (⩽ 4 cans/week) was associated with a reduced risk (HR 0.65, 95% CI: 0.45, 0.94). Snus use was not associated with oral cancer among never smokers (HR 0.87, 95% CI: 0.57, 1.32). Conclusions: Swedish snus use does not appear to be implicated in the development of oral cancer in men.

Using Epstein-Barr virus (EBV)-based markers to screen populations at high risk for nasopharyngeal carcinoma (NPC) is an attractive preventive approach. Here, we develop a comprehensive risk score (CRS) that combines risk effects of EBV and human genetics for NPC risk stratification and validate this CRS within an independent, population-based dataset. Comparing the top decile with the bottom quintile of CRSs, the odds ratio of developing NPC is 21 (95% confidence interval: 12–37) in the validation dataset. When combining the top quintile of CRS with EBV serology tests currently used for NPC screening in southern China, the positive prediction value of screening increases from 4.70% (serology test alone) to 43.24% (CRS plus serology test). By identifying individuals at a monogenic level of NPC risk, this CRS approach provides opportunities for personalized risk prediction and population screening in endemic areas for the early diagnosis and secondary prevention of NPC., Epstein-Barr virus (EBV) is associated with high risk for nasopharyngeal carcinoma (NPC). Here, the authors develop a comprehensive risk score that combines risk effects of EBV and human genetics for NPC risk stratification.

Purpose The human commensal microbiome has been suggested to be involved in the regulation of response to anticancer therapies. However, little is known regarding changes in commensal microbes in patients with cancer during radiation therapy. We conducted a prospective, longitudinal proof-of-concept cohort study with patients with newly diagnosed nasopharyngeal carcinoma (NPC) who underwent radiation therapy-based treatment. Methods and Materials Nasopharyngeal swabs were collected before radiation therapy, twice per week during radiation therapy, and after radiation therapy. The nasopharyngeal microbiome was assessed using 16S rRNA amplicon sequencing. A patient’s response to treatment was measured 3 months after the completion of radiation therapy as a short-term clinical outcome. In total, 39 NPC patients with 445 nasopharyngeal samples were analyzed. Results There was stable temporal change in the community structure of the nasopharyngeal microbiome among patients with NPC during treatment (P = .0005). Among 73 abundant amplicon sequence variants (ASVs), 7 ASVs assigned to genus Corynebacterium decreased significantly during the treatment (W-statistic >80%); 23 ASVs showed statistically significant changes in the ratio of abundance between early and late responders during treatment (false discovery rate Conclusions This study addressed stable temporal change in the nasopharyngeal microbiome among patients with NPC during radiation therapy–based treatment and provided preliminary evidence of an association with a short-term clinical outcome.

Contains fulltext : 229320.pdf (Publisher’s version ) (Closed access) BACKGROUND & AIMS: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored. METHODS: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits. RESULTS: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, P(BONF) = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, P(BONF) = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals. CONCLUSIONS: The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.

Background In recent decades, millions of refugees and migrants have fled wars and sought asylum in Europe. The aim of this study was to quantify the risk of mortality and major diseases among migrants during the 1991–2001 Balkan wars to Sweden in comparison to other European migrants to Sweden during the same period. Methods and findings We conducted a register-based cohort study of 104,770 migrants to Sweden from the former Yugoslavia during the Balkan wars and 147,430 migrants to Sweden from 24 other European countries during the same period (1991–2001). Inpatient and specialized outpatient diagnoses of cardiovascular disease (CVD), cancer, and psychiatric disorders were obtained from the Swedish National Patient Register and the Swedish Cancer Register, and mortality data from the Swedish Cause of Death Register. Adjusting for individual-level data on sociodemographic characteristics and emigration country smoking prevalence, we used Cox regressions to contrast risks of health outcomes for migrants of the Balkan wars and other European migrants. During an average of 12.26 years of follow-up, being a migrant of the Balkan wars was associated with an elevated risk of being diagnosed with CVD (HR 1.39, 95% CI 1.34–1.43, p < 0.001) and dying from CVD (HR 1.45, 95% CI 1.29–1.62, p < 0.001), as well as being diagnosed with cancer (HR 1.16, 95% CI 1.08–1.24, p < 0.001) and dying from cancer (HR 1.27, 95% CI 1.15–1.41, p < 0.001), compared to other European migrants. Being a migrant of the Balkan wars was also associated with a greater overall risk of being diagnosed with a psychiatric disorder (HR 1.19, 95% CI 1.14–1.23, p < 0.001), particularly post-traumatic stress disorder (HR 9.33, 95% CI 7.96–10.94, p < 0.001), while being associated with a reduced risk of suicide (HR 0.68, 95% CI 0.48–0.96, p = 0.030) and suicide attempt (HR 0.57, 95% CI 0.51–0.65, p < 0.001). Later time period of migration and not having any first-degree relatives in Sweden at the time of immigration were associated with greater increases in risk of CVD and psychiatric disorders. Limitations of the study included lack of individual-level information on health status and behaviors of migrants at the time of immigration. Conclusions Our findings indicate that migrants of the Balkan wars faced considerably elevated risks of major diseases and mortality in their first decade in Sweden compared to other European migrants. War migrants without family members in Sweden or with more recent immigration may be particularly vulnerable to adverse health outcomes. Results underscore that persons displaced by war are a vulnerable group in need of long-term health surveillance for psychiatric disorders and somatic disease., Edda Bjork Thordardottir and co-workers study health outcomes among migrants from the former Yugoslavia to Sweden., Author summary Why was this study done? Understanding the toll of war on the health of migrants is a highly relevant and pressing issue in light of the global humanitarian crisis, with more people than ever affected by forced displacement. The 1991–2001 Balkan wars were marked by war crimes such as genocide, ethnic cleansing, rape, and torture. More than 100,000 adults and children migrated to Sweden from the former Yugoslavia during the Balkan wars. What did the researchers do and find? Using Swedish registry data, we assessed morbidity and mortality among 104,770 migrants to Sweden from former Yugoslavia during the Balkan wars and 147,430 migrants from 24 other European countries immigrating to Sweden from 1991 to 2001. We found that compared to other European migrants, being a migrant of the Balkan wars was associated with an elevated risk of overall psychiatric disorders, particularly post-traumatic stress disorder, along with a reduced risk of suicide and suicide attempt. Being a migrant of the Balkan wars was also associated with being diagnosed with and dying from both cancer and cardiovascular disease. Later migration to Sweden and having no first-degree relatives in Sweden at immigration was associated with the greatest risk elevation of psychiatric disorders and cardiovascular disease among migrants fleeing armed conflict. What do these findings mean? These findings indicate that being a war migrant may be associated with considerable elevations in post-traumatic stress disorder as well as risks of cardiovascular- and cancer-related morbidities and mortality, particularly among those migrating late in the wars and without family members. War migrants are a particularly vulnerable group that health professionals should monitor over the long term. Host countries should make availability and accessibility of healthcare and social services to war migrants a priority. Potential limitations of this study include lack of information about health status at the time of immigration as well as behavioral factors possibly contributing to increased disease risk such as smoking and alcohol consumption.

Purpose The survival of esophageal and gastric cancer patients treated with chemotherapy is rarely assessed outside of clinical trials. Therefore, we compared the effectiveness of various curative or palliative chemotherapy regimens on the survival of esophageal and gastric cancer patients in a “real world” clinical setting. Methods We identified a cohort of 966 incident esophageal and gastric cancer patients in Stockholm/Gotland County (a low-risk Western population) during 2008–2013. Patients who received chemotherapy with curative intention (n = 279) and palliative intention (n = 182) were analyzed separately. Using Cox proportional hazards regression models, we estimated hazard ratios (HRs) with 95% confidence intervals (CIs) and adjusted for the potential confounding factors: age, sex, TNM stage, radiotherapy, comorbidity, marital status, education, income, and country of birth. Results In esophageal cancer patients with curative treatment intention, we observed a higher hazard for death among patients who received carboplatin-fluorouracil compared to patients who received cisplatin-fluorouracil, corresponding to a HR of 2.18 (95% CI 1.09–4.37). Conversely, in patients with cancer in the gastroesophageal junction who had a curative treatment intention at diagnosis, we observed a reduced hazard for death among those who received fluorouracil-oxaliplatin, compared to patients who received cisplatin-fluorouracil (HR 0.28; 95% CI 0.08–0.96). Conclusion Among patients with esophageal cancer who received treatment with curative intention, cisplatin-fluorouracil was associated with better survival compared to carboplatin-fluorouracil, while patients with gastroesophageal junction cancer who were treated with cisplatin-fluorouracil had worse survival compared to fluorouracil-oxaliplatin.

Physical activity has been inversely associated with the risk of hip fracture, however, few studies have been conducted on the contributions from different domains of physical activity. This study was performed to investigate the association between daily household activities, leisure time physical activity, work-related physical activity and total physical activity during a 24-h period, and the risk of hip fracture. In the Swedish National March Cohort we followed 23,881 men and women aged of 50 and over from 1997 until 2010. Information on domain-specific physical activity was collected at baseline using a questionnaire. We fitted separate multivariable adjusted Cox proportional hazard models to each domain to obtain hazard ratios (HRs) with 95% confidence intervals (CIs). Each model was mutually adjusted for the other domains of physical activity. During a mean follow-up period of 12.2 years we identified 824 incidents of hip fracture. Subjects who spent less than 1 h per week engaged in daily household activities had an 85% higher risk of hip fracture than subjects spending ≥6 h per week carrying out daily household activities (HR 1.85; 95% CI 1.01–3.38). Subjects engaged in leisure time physical activities for >3.1 MET-h/day had a 24% lower risk of hip fracture (HR 0.76; 95% CI 0.59–0.98) than subjects spending

Background: The influence of body mass index (BMI) change during adulthood on the development of oesophageal squamous-cell carcinoma (ESCC) is unknown. Methods: Based on the Japan Public Health Center-based Prospective Study, we enrolled 103 238 participants from 1990 to 1994. Anthropometric data at age 20 years, baseline, and 5- and/or 10-year follow-up surveys were collected by questionnaire. The effect of BMI change between age 20 years and baseline on ESCC risk was estimated by Cox proportional hazards regression models. The updated BMI was taken into account by fitting a simple linear regression model for each individual, where the slope was incorporated into regressions as a time-varying variable. Results: After excluding the first 5 years of observation, we identified 342 newly diagnosed ESCC cases. An increase in BMI during adulthood was linked with a decreased risk of ESCC development, with each 1% increase per 5 years corresponding to a 15% decrease in ESCC risk (95% confidence interval 9–21%). Identical estimates were obtained from time-dependent models. The importance of BMI change was not modified by gender, smoking, or alcohol drinking but confined to participants assessed as non-overweight at baseline. Conclusions: An increase in BMI during adulthood is associated with a lower risk of developing ESCC among non-overweight subjects.

Blood lead and bone turnover may be associated with the risk of amyotrophic lateral sclerosis (ALS). We aimed to assess whether these factors were also associated with time from ALS diagnosis to death through a survival analysis of 145 ALS patients enrolled during 2007 in the National Registry of Veterans with ALS. Associations of survival time with blood lead and plasma biomarkers of bone resorption (C-terminal telopeptides of type I collagen (CTX)) and bone formation (procollagen type I amino-terminal peptide (PINP)) were estimated using Cox models adjusted for age at diagnosis, diagnostic certainty, diagnostic delay, site of onset, and score on the Revised ALS Functional Rating Scale. Hazard ratios were calculated for each doubling of biomarker concentration. Blood lead, plasma CTX, and plasma PINP were mutually adjusted for one another. Increased lead (hazard ratio (HR) = 1.38; 95% confidence interval (CI): 1.03, 1.84) and CTX (HR = 2.03; 95% CI: 1.42, 2.89) were both associated with shorter survival, whereas higher PINP was associated with longer survival (HR = 0.59; 95% CI: 0.42, 0.83), after ALS diagnosis. No interactions were observed between lead or bone turnover and other prognostic indicators. Lead toxicity and bone metabolism may be involved in ALS pathophysiology.

Background & Aims The hygiene hypothesis (a lack of childhood exposure to microorganisms increases susceptibility to allergic diseases by altering immune development) has been proposed as an explanation for the increasing incidence of inflammatory bowel disease (IBD). However, there are few data on the relationship between oral hygiene and development of IBD, and study results have been inconsistent. We investigated the association between poor oral health and risks of IBD, ulcerative colitis (UC), and Crohn's disease (CD). Methods We performed a population-based cohort study of 20,162 individuals followed for 40 years (from 1973 to 2012). Residents of 2 municipalities of Uppsala County, Sweden (N = 30,118), 15 years or older, were invited, and among them 20,333 were examined for tooth loss, dental plaques, and oral mucosal lesions at the time of study entry. Other exposure data were collected from questionnaires. Patients who later developed IBD (UC or CD) were identified by international classification codes from Swedish National Patient and Cause of Death Registers. Cox proportional hazards regression was used to estimate hazard ratios for IBD, UC, and CD. Results From National Patient and Cause of Death Registers, we identified 209 individuals who developed IBD (142 developed UC and 67 developed CD), with an incidence rate of 37.3 per 100,000 person-years. We found an inverse relationship between poor oral health and IBD, especially in individuals with severe oral problems. Loss of 5–6 teeth of the 6 teeth examined was associated with a lower risk of IBD (hazard ratio, 0.56; 95% confidence interval, 0.32–0.98). Having dental plaques that covered more than 33% of tooth surface was negatively associated with CD (hazard ratio, 0.32; 95% confidence interval, 0.10–0.97). Conclusions In a population-based cohort study of more than 20,000 people in Sweden, we associated poor oral health with reduced risk of future IBD.

Amyotrophic lateral sclerosis (ALS) may be associated with low body mass index (BMI) at the time of diagnosis. However, the role of premorbid BMI in the development of ALS and survival after diagnosis remains unclear. In 2005–2010, we interviewed 467 patients with ALS from the US National Registry of Veterans with ALS and 975 frequency-matched veteran controls. In this sample, we evaluated the association of BMI and BMI change at different ages with ALS risk using unconditional logistic models and with survival after ALS diagnosis using Cox proportional hazards models. After adjustment for confounders, compared with a moderate increase in BMI between ages 25 and 40 years, stable or decreasing BMI was positively associated with ALS risk (odds ratio (OR) = 1.61, 95% confidence interval (CI): 1.20, 2.16). A 1-unit increase in BMI at age 40 years (OR = 0.95, 95% CI: 0.91, 0.98) but not at age 25 years (OR = 0.99, 95% CI: 0.95, 1.03) was inversely associated with ALS. These associations were similar for bulbar and spinal ALS but stronger for those with a delay of less than 1 year between symptom onset and diagnosis. We found no association between prediagnosis BMI and survival. A decreasing BMI from early to middle age and a low BMI in middle age may be positively associated with ALS risk.

Objective:To estimate risks of neurodegenerative and psychiatric diseases among patients with amyotrophic lateral sclerosis (ALS) and their families.Methods:We conducted a register-based nested case-control study during 1990–2013 in Sweden to assess whether patients with ALS had higher risks of other neurodegenerative and psychiatric diseases before diagnosis. We included 3,648 patients with ALS and 36,480 age-, sex-, and county of birth–matched population controls. We further conducted a follow-up study of the cases and controls to assess the risks of other neurodegenerative and psychiatric diseases after ALS diagnosis. To assess the potential contribution of familial factors, we conducted similar studies for the relatives of patients with ALS and their controls.Results:Individuals with previous neurodegenerative or psychiatric diseases had a 49% increased risk of ALS (odds ratio 1.49, 95% confidence interval 1.35–1.66) compared to individuals without these diseases. After diagnosis, patients with ALS had increased risks of other neurodegenerative or psychiatric diseases (hazard ratio 2.90, 95% confidence interval 2.46–3.43) compared to individuals without ALS. The strongest associations were noted for frontotemporal dementia, Parkinson disease, other dementia, Alzheimer disease, neurotic disorders, depression, stress-related disorders, and drug abuse/dependence. First-degree relatives of patients with ALS had higher risk of neurodegenerative diseases, whereas only children of patients with ALS had higher risk of psychiatric disorders, compared to relatives of the controls.Conclusions:Familial aggregation of ALS and other neurodegenerative diseases implies a shared etiopathogenesis among all neurodegenerative diseases. The increased risk of psychiatric disorders among patients with ALS and their children might be attributable to nonmotor symptoms of ALS and severe stress response toward the diagnosis.

Objective Both observational studies and randomized trials have shown that a diet rich in antioxidants can reduce systemic inflammation and oxidative stress, two conditions that, together with obesity and smoking, are established risk factors for stroke. However, the association between antioxidant intake and risk for stroke is poorly understood, particularly when studying possible interaction with sex. We investigated the relationship of nonenzymatic antioxidant capacity (NEAC) on risk for stroke in a large Swedish prospective cohort. Methods The cohort study included 34 555 men and women from the Swedish National March Cohort. NEAC was assessed using a detailed food frequency questionnaire, collected at baseline. We achieved complete follow-up from enrollment in 1997 through 2010 by record linkage to nationwide registers. We identified 1186 incident cases of a first stroke, of which 860 were ischemic, 201 hemorrhagic, and 125 unspecified. We used multivariable Cox proportional hazards models to estimate adjusted hazard ratios (HR) with 95% confidence intervals (CIs). Results Compared with women in the lowest quartile of NEAC, women in the highest quartile had a 27% lower incidence of total stroke (HR, 0.73; 95% CI, 0.53–0.99; P trend = 0.03) and 35% lower incidence of ischemic stroke (HR, 0.65; 95% CI, 0.43–0.99; P trend = 0.01). Among men, the relationship between NEAC and risk for stroke was not statistically significant and all HRs were close to unity. Conclusion Findings from the present study suggest that dietary antioxidant capacity from different foods and beverages is inversely associated with risk for stroke, more specifically ischemic stroke, in women.

Background An association between a nonmedicinal herbal diet and nasopharyngeal carcinoma (NPC) has often been hypothesized but never thoroughly investigated. Methods This study enrolled a total of 2469 patients with incident NPC and 2559 population controls from parts of Guangdong and Guangxi Provinces in southern China between 2010 and 2014. Questionnaire information was collected on the intake of traditional herbal tea and herbal soup as well as the specific herbal plants used in soups and other potentially confounding lifestyle factors. Multivariate logistic regression models were used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for the NPC risk in association with herbal tea and soup intake. Results Ever consumption of herbal tea was not associated with NPC risk (OR, 1.03; 95% CI, 0.91-1.17). An inverse association was observed for NPC among ever drinkers of herbal soup (OR, 0.78; 95% CI, 0.67-0.90) but without any monotonic trend with an increasing frequency or duration of herbal soup consumption. Inverse associations with NPC risk were detected with 9 herbal plants used in herbal soup, including Ziziphus jujuba, Fructus lycii, Codonopsis pilosula, Astragalus membranaceus, Semen coicis, Smilax glabra, Phaseolus calcaratus, Morinda officinalis, and Atractylodes macrocephala (OR range, 0.31-0.79). Conclusions Consuming herbal soups including specific plants, but not herbal tea, was inversely associated with NPC. If replicated, these results might provide potential for NPC prevention in endemic areas.

Background Previous studies have shown an association between body mass index (BMI) and infections, but the literature on type-specific community acquired infections is still limited. Methods We included 39 163 Swedish adults who completed a questionnaire in September 1997 and were followed through record-linkages until December 2016. Information on BMI was self-reported and infections were identified from the Swedish National Patient Register using International Classification of Diseases (ICD), Tenth Revision (ICD-10) codes. We fitted multivariable Cox proportional hazards models for time-to-first-event analysis, and we used extensions of the standard Cox model when repeated events were included. Results During a 19-year follow-up 32% of the subjects had at least one infection requiring health care contact, leading to a total of 27 675 events. We found an increased incidence of any infection in obese women [hazard ratio (HR) = 1.22; 95% confidence interval (CI) = 1.12; 1.33] and obese men (HR = 1.25; 95% CI = 1.09; 1.43) compared with normal weight subjects. For specific infections, higher incidences were observed for skin infections in both genders (HR = 1.76; 95% CI = 1.47; 2.12 for obese females and HR = 1.74; 95% CI = 1.33; 2.28 for obese males) and gastrointestinal tract infections (HR = 1.44; 95% CI = 1.19; 1.75), urinary tract infections (HR = 1.30; 95% CI = 1.08; 1.55) and sepsis (HR = 2.09; 95% CI = 1.46; 2.99) in obese females. When accounting for repeated events, estimates similar to the aforementioned ones were found. Conclusions Obesity was associated with an increased risk of infections in both genders. Results from multiple-failure survival analysis were consistent with those from classic Cox models.

Deciphering the underlying genetic basis behind pancreatic cancer (PC) and its associated multimorbidities will enhance our knowledge toward PC control. The study investigated the common genetic background of PC and different morbidities through a computational approach and further evaluated the less explored association between PC and autoimmune diseases (AIDs) through an epidemiological analysis. Gene‐disease associations (GDAs) of 26 morbidities of interest and PC were obtained using the DisGeNET public discovery platform. The association between AIDs and PC pointed by the computational analysis was confirmed through multivariable logistic regression models in the PanGen European case–control study population of 1,705 PC cases and 1,084 controls. Fifteen morbidities shared at least one gene with PC in the DisGeNET database. Based on common genes, several AIDs were genetically associated with PC pointing to a potential link between them. An epidemiologic analysis confirmed that having any of the nine AIDs studied was significantly associated with a reduced risk of PC (Odds Ratio (OR) = 0.74, 95% confidence interval (CI) 0.58–0.93) which decreased in subjects having ≥2 AIDs (OR = 0.39, 95%CI 0.21–0.73). In independent analyses, polymyalgia rheumatica, and rheumatoid arthritis were significantly associated with low PC risk (OR = 0.40, 95%CI 0.19–0.89, and OR = 0.73, 95%CI 0.53–1.00, respectively). Several inflammatory‐related morbidities shared a common genetic component with PC based on public databases. These molecular links could shed light into the molecular mechanisms underlying PC development and simultaneously generate novel hypotheses. In our study, we report sound findings pointing to an association between AIDs and a reduced risk of PC. Grant sponsor: Acción Especial de Genómica, Spain; Grant numbers: #GEN2001-4748-c05-03; Grant sponsor: Swedish ALF; Grant numbers: #SLL20130022; Grant sponsor: Cancer Focus Northern Ireland and Department for Employment and Learning; Grant sponsor: EU H2020 Programme 2014-2020; Grant numbers: 634143 MedBioinformatics676559 Elixir-Excelerate; Grant sponsor: EU-6FP Integrated Project; Grant numbers: #018771-MOLDIAG-PACA; Grant sponsor: EU-FP7-HEALTH; Grant numbers: #256974-EPC-TMNet#259737-ANCERALIA#602783- Cam-Pac; Grant sponsor: Italian Foundation for Cancer Research (FIRC); Grant sponsor: Italian Ministry of Health; Grant numbers: FIMPCUP_J33G13000210001; Grant sponsor: Red Temática de Investigación Cooperativa en Cáncer, Spain; Grant numbers: #RD12/0036/0050#RD12/0036/ 0073(#RD12/0036/0034; Grant sponsor: The work was partially supported by Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III-FEDER, Spain; Grant numbers: #PI0902102#PI11/01542#PI12/00815#PI12/01635#PI13/ 00082CP10/00524PI15/01573; Grant sponsor: World Cancer Research Fund; Grant numbers: WCR #15-0391.