Lifetime exposure to brominated trihalomethanes in drinking water and swimming pool attendance are associated with chronic lymphocytic leukemia: a Multicase-Control Study in Spain (MCC-Spain)

Background: Chronic lymphocytic leukemia (CLL) etiology is poorly understood, and carcinogenic chemicals in drinking and recreational water are candidates. Objective: To evaluate the association between drinking-water exposure to trihalomethanes (THMs) and nitrate as well as lifetime swimming pool attendance and CLL. Methods: During 2010-2013, hospital-based CLL cases and population-based controls were recruited in Spain, providing information on residential histories, type of water consumed and swimming pool attendance. Average THMs and nitrate levels in drinking water were linked to lifetime water consumption. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using mixed models. Results: Final samples for residential tap water analyses and swimming pool attendance analyses were 144 cases/1230 controls and 157 cases/1240 controls, respectively. Mean (SD) values for average lifetime residential brominated THMs and chloroform in tap water (μg/L), and ingested nitrate (mg/day) were 48.1 (35.6), 18.5 (6.7) and 13.7 (9.6) respectively in controls; and 72.9 (40.7), 17.9 (5.4), and 14.1 (8.8) in CLL cases. For each 10 μg/L increase of brominated THMs and chloroform lifetime-average levels, the ORs (95% CI) were 1.22 (1.14, 1.31) and 0.54 (0.34, 0.87), respectively. For each 5 mg/day increase of ingested nitrate, the OR of CLL was 0.91 (0.80, 1.04). The OR of lifetime pool users (vs. non-users) was 2.38 (1.61, 3.52). Upon performing annual frequency of attending pools analysis through categorization, the second and third categories showed an ORs of 2.36 (1.49, 3.72) and 2.40 (1.51, 3.83), respectively, and P-trend of 0.001. Impact statement: This study identifies an association of long-term exposure to THMs in drinking water, at concentrations below the regulatory thresholds and WHO guidelines, and swimming pool attendance, with chronic lymphocytic leukemia (CLL). These unprecedented findings are highly relevant since CLL is an incurable cancer with still unknown etiology and because the widespread exposure to chlorination by-products that remain in drinking and recreational water worldwide. Despite the demonstrated carcinogenicity in animals of several chlorination by-products, little is known about their potential risks on human health. This study makes a significant contribution to the search for environmental factors involved in the etiology of CLL and to the evidence of the health impact of these high prevalent water contaminants.The study was partially funded by the “Accion Transversal del Cancer”, approved on the Spanish Ministry Council on the 11th October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359, PS09/00773, PS09/01286, PS09/01903, PS09/02078, PS09/01662, PI11/01889, PI11/00226, PI12/01270, PI12/00715, PI14/0613, PI15/00914, PI17CIII/00034), by the Fundación Marqués de Valdecilla (API 10/09), by the Conselleria de Sanitat of the Generalitat Valenciana (AP_061/10), by the European Commission grants FOOD-CT-2006-036224-HIWATE, by the Spanish Association Against Cancer (AECC) Scientific Foundation, by the Catalan Government Agency for Management of University and Research Grants (AGAUR) grants 2017SGR723, 2021SGR01354 and 2014SGR850, by the Fundación Caja de Ahorros de Asturias and by the University of Oviedo. ISGlobal acknowledges support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program.S

Long-Term Exposure to Nitrate and Trihalomethanes in Drinking Water and Prostate Cancer: A Multicase–Control Study in Spain (MCC-Spain)

BACKGROUND: Nitrate and trihalomethanes (THMs) in drinking water are widespread and are potential human carcinogens.OBJECTIVE: We evaluated the association between drinking-water exposure to nitrate and THMs and prostate cancer.METHODS: During the period 2008-2013, 697 hospital-based incident prostate cancer cases (97 aggressive tumors) and 927 population-based controls were recruited in Spain, providing information on residential histories and type of water consumed. Average nitrate and THMs levels in drinking water were linked with lifetime water consumption to calculate waterborne ingestion. Odds ratios (OR) and 95% confidence intervals (CI) were esti-mated using mixed models with recruitment area as random effect. Effect modification by tumor grade (Gleason score), age, education, lifestyle, and dietary factors was explored.RESULTS: Mean ( +/- standard deviation) adult lifetime waterborne ingested nitrate (milligrams per day), brominated (Br)-THMs (micrograms per day), and chloroform (micrograms per day) were 11.5 ( +/- 9.0), 20.7 ( +/- 32.4), and 15.1 ( +/- 14.7) in controls. Waterborne ingested nitrate >13.8 vs. = 8. Associations were higher in the youngest and those with lower intakes of fiber, fruit/vegetables, and vitamin C. Waterborne ingested THMs were not associated with prostate cancer. Residential tap water levels of Br-THMs and chloroform showed, respectively, inverse and positive associations with prostate cancer.CONCLUSIONS: Findings suggest long-term waterborne ingested nitrate could be a risk factor of prostate cancer, particularly for aggressive tumors. High intakes of fiber, fruit/vegetables and vitamin C may lower this risk. Association with residential levels but not ingested chloroform/Br-THM may suggest inhalation and dermal routes could be relevant for prostate cancer. https://doi.org/10.1289/EHP1139

RNA-Seq reveals the existence of a CDKN1C-E2F1-TP53 axis that is altered in human T-cell lymphoblastic lymphomas

BACKGROUND: Precursor T-cell lymphoblastic lymphomas (T-LBL) are rare aggressive hematological malignancies that mainly develop in children. As in other cancers, the loss of cell cycle control plays a prominent role in the pathogenesis in these malignancies that is primarily attributed to loss of CDKN2A (encoding protein p16INK4A). However, the impact of the deregulation of other genes such as CDKN1C, E2F1, and TP53 remains to be clarified. Interestingly, experiments in mouse models have proven that conditional T-cell specific deletion of Cdkn1c gene may induce a differentiation block at the DN3 to DN4 transition, and that the loss of this gene in the absence of Tp53 led to aggressive thymic lymphomas. RESULTS: In this manuscript, we demonstrated that the simultaneous deregulation of CDKN1C, E2F1, and TP53 genes by epigenetic mechanisms and/or the deregulation of specific microRNAs, together with additional impairing of TP53 function by the expression of dominant-negative isoforms are common features in primary human T-LBLs. CONCLUSIONS: Previous experimental work in mice revealed that T-cell specific deletion of Cdkn1c accelerates lymphomagenesis in the absence of Tp53. If, as expected, the consequences of the deregulation of the CDKN1C-E2F1-TP53 axis were the same as those experimentally demonstrated in mouse models, the disruption of this axis might be useful to predict tumor aggressiveness, and to provide the basis towards the development of potential therapeutic strategiesin human T-LBL.The authors would like to thank the Spanish Ministry of Economy and Competitiveness (SAF2015–70561-R; MINECO/FEDER, EU) and the Autonomous Community of Madrid, Spain (B2017/BMD-3778; LINFOMAS-CM) for funding this work. Institutional grants from the Fundación Ramón Areces and Banco de Santander are also acknowledged.S

A Latin American Perspective to Agricultural Ethics

The mixture of political, social, cultural and economic environments in Latin America, together with the enormous diversity in climates, natural habitats and biological resources the continent offers, make the ethical assessment of agricultural policies extremely difficult. Yet the experience gained while addressing the contemporary challenges the region faces, such as rapid urbanization, loss of culinary and crop diversity, extreme inequality, disappearing farming styles, water and land grabs, malnutrition and the restoration of the rule of law and social peace, can be of great value to other regions in similar latitudes, development processes and social problems. This chapter will provide a brief overview of these challenges from the perspective of a continent that is exposed to the consequences of extreme inequality in multiple dimensions and conclude by arguing for the need to have a continuous South-South dialogue on the challenges of establishing socially and environmentally sustainable food systems

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk

Mammographic density reflects the amount of stromal and epithelial tissues in relation to adipose tissue in the breast and is a strong risk factor for breast cancer. Here we report the results from meta-analysis of genome-wide association studies (GWAS) of three mammographic density phenotypes: dense area, non-dense area and percent density in up to 7,916 women in stage 1 and an additional 10,379 women in stage 2. We identify genome-wide significant (P<5×10−8) loci for dense area (AREG, ESR1, ZNF365, LSP1/TNNT3, IGF1, TMEM184B, SGSM3/MKL1), non-dense area (8p11.23) and percent density (PRDM6, 8p11.23, TMEM184B). Four of these regions are known breast cancer susceptibility loci, and four additional regions were found to be associated with breast cancer (P<0.05) in a large meta-analysis. These results provide further evidence of a shared genetic basis between mammographic density and breast cancer and illustrate the power of studying intermediate quantitative phenotypes to identify putative disease susceptibility loci

Multiple Scenario Generation of Subsurface Models:Consistent Integration of Information from Geophysical and Geological Data throuh Combination of Probabilistic Inverse Problem Theory and Geostatistics

Neutrinos with energies above 1017 eV are detectable with the Surface Detector Array of the Pierre Auger Observatory. The identification is efficiently performed for neutrinos of all flavors interacting in the atmosphere at large zenith angles, as well as for Earth-skimming \u3c4 neutrinos with nearly tangential trajectories relative to the Earth. No neutrino candidates were found in 3c 14.7 years of data taken up to 31 August 2018. This leads to restrictive upper bounds on their flux. The 90% C.L. single-flavor limit to the diffuse flux of ultra-high-energy neutrinos with an E\u3bd-2 spectrum in the energy range 1.0 7 1017 eV -2.5 7 1019 eV is E2 dN\u3bd/dE\u3bd &lt; 4.4 7 10-9 GeV cm-2 s-1 sr-1, placing strong constraints on several models of neutrino production at EeV energies and on the properties of the sources of ultra-high-energy cosmic rays

Emergency department visits and hospital readmissions in an Argentine health system

Background and goal of study: The scope of health in the Sustainable Development Goals is much broader than the Millennium Development Goals, spanning functions such as health-system access and quality of care. Hospital readmission rate and ED-visits within 30 days from discharge are considered low-cost quality indicators. This work assesses an indicator of quality of care in a tertiary referral hospital in Argentina, using data available from clinical records. Purpose: To estimate the rate of ED-visits and the hospital readmission rate (HRR) after a first hospitalization (First-H), and to identify associated factors. Methods: This retrospective cohort included patients who had a First-H in Hospital Italiano de Buenos Aires between 2014–2015. Follow-up occurred from discharge until ED-visit, readmission, death, disaffiliation from health insurance, or 13 months. We present HRR at 30 days and ED-visits rate at 72 h, using the Cox proportional-hazards regression model to explore associated factors, and reporting adjusted hazard ratios (HR) with their respective 95 %CI. Results: The study comprised 10,598 hospitalizations (median age was 68 years). Of these, 5966 had at least one consultation to the ED during follow up, resulting in a 24 h rate of consultations to ED of 1.51 % (95 %CI 1.29−1.72); at 48 h 3.18 % (95 %CI 2.86−3.54); at 72 h 4.71 % (95 %CI 4.32−5.13). In multivariable models, factors associated for 72 h ED-visits were: age (aHR 1.06), male (aHR 1.14), Charlson Comorbidity Index (aHR 1.16), unscheduled hospitalization (aHR 1.39), prior consultation with the ED (aHR 1.08) and long hospital stay (aHR 1.39). Meanwhile, 2345 patients had at least one hospital readmission (98 % unscheduled), resulting a 24 h rate of 0.5 % (95 %CI 0.42−0.71), at 48 h 0.98 % (95 %CI 0.80−1.18), at 72 h 1.4 % (95 %CI 1.2−1.6); at 30 days 7.7 % (95 %CI 7.2−8.2); at 90 days 13 % (95 %CI 12.4–13.8); and one-year 22.5 % (95 %CI 21.7−23.4). Associated factors for HRR at 30 days were: age (HR 1.16), male (HR 1.09), Charlson comorbidities score (HR 1.27), social service requirement during First-H (HR 1.37), unscheduled First-H (HR 1.16), previous ED-visits (HR 1.03) and length of stay (HR 1.08). Conclusion: Priorities efforts to improve must include greater attention to patients’ readiness prior discharge, to explore causes of preventable readmissions, and better support for patient self-management.Fil: Giunta, Diego Hernan. Hospital Italiano. Instituto Universitario. Escuela de Medicina; ArgentinaFil: Marquez Fosser, Santiago. Université Mcgill; CanadáFil: Boietti, Bruno Rafael. Hospital Italiano. Instituto Universitario. Escuela de Medicina; ArgentinaFil: Acion, Laura. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Cálculo; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Calculo. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Calculo; ArgentinaFil: Pollan, Javier Alberto. Hospital Italiano. Instituto Universitario. Escuela de Medicina; ArgentinaFil: Martínez, Bernardo. Hospital Italiano. Instituto Universitario. Escuela de Medicina; ArgentinaFil: Luna, Daniel Roberto. Hospital Italiano. Instituto Universitario. Escuela de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bonella, Maria Belen. Hospital Italiano. Instituto Universitario. Escuela de Medicina; ArgentinaFil: Grande Ratti, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Italiano. Instituto Universitario. Escuela de Medicina; Argentin