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Olive oil consumption is associated with a lower risk of cardiovascular disease and stroke
(Elsevier, 2022-01-01) Sánchez Pérez, María José; Martínez-González, Miguel Ángel, 1957-; Guallar Castillón, Pilar; Donat Vargas, Carolina; Sandoval Insausti, Helena; Peñalvo, José L.; Moreno Iribas, Conchi; Amiano, Pilar; Molina Montes, Esther; Agudo Trigueros, Antonio; Lasheras, Cristina; Laclaustra, Martín; Bes Rastrollo, Maira; Moreno Franco, Belén; De La Fuente Arrillaga, Carmen; Chirlaque López, María Dolores
Background & aims: The specific association of olive oil consumption with coronary heart disease (CHD) or stroke has not been totally established. Objective: to examine whether olive oil consumption is associated with subclinical atherosclerosis, the risk of total cardiovascular disease (CVD), CHD, and stroke. Methods: Three cohorts were included: AWHS (2318 men), SUN Project (18,266 men and women), and EPIC-Spain (39,393 men and women). Olive oil consumption was measured at baseline using validated questionnaires. Results: In the AWHS, 747 participants had a positive coronary artery calcium score (CACS>0), and the OR (95% CI) was 0.89 (0.72, 1.10) in those with virgin olive oil consumption ≥30 g/day (v. <10 g/day). In the SUN Project (follow-up 10.8 years) 261 total CVD cases occurred, and the HR was 0.57 (0.34, 0.96) for consumptions ≥30 g/day (v. <10 g/day). In the EPIC-Spain (follow-up 22.8 years) 1300 CHD cases and 938 stroke cases occurred; the HRs for stroke according, 0 to <10 (ref), 10 to <20, 20 to <30, and ≥30 g/day of olive oil consumption, were 0.84 (0.70, 1.02), 0.80 (0.66, 0.96), 0.89 (0.74, 1.07). A weaker association was observed for CHD. The association was stronger among those consuming virgin olive oil, instead of common (refined). Conclusions: Olive oil is associated with lower risk of CVD and stroke. The maximum benefit could be obtained with a consumption between 20 and 30 g/day. The association could be stronger for virgin olive oil and might operate from the early stages of the disease.
Food consumption based on the nutrient profile system underlying the Nutri-Score and renal function in older adults
(Elsevier, 2022-05-14) Montero-Salazar, Henry; Guallar Castillón, Pilar; Banegas, José Ramón; Åkesson, Agneta; Rey García, Jimena; Rodríguez-Artalejo, Fernando; Donat Vargas, Carolina
Background: The impact of the Nutri-Score labelling system on renal function is unknown. Objective: To assess the association between food consumption based on the nutrient profile system underlying the Nutri-Score and renal function decline in older adults. Methods: We used data from the Spain-based Seniors-ENRICA cohort, a study with 1312 community-dwelling adults aged ≥60 years recruited during 2008-2010 and followed up to December 2015. At baseline, a validated dietary history was obtained. Based on their nutritional quality, foods consumed were categorized into five labels (A/Green-best quality, B, C, D, E/Red-worst quality) using the established Nutri-Score algorithm. For each participant, a Nutri-Score dietary index (DI) was calculated in g/day/kg of weight. At baseline and at follow-up, measured serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) levels were obtained, and time changes were calculated. A combined outcome for renal decline was defined as: any increase in SCr or any decrease in eGFR beyond expected-for-age. Statistical analyses were performed with logistic regression adjusting for socioeconomic, lifestyle, total energy intake, fresh foods, and comorbidity confounders. Results: A total of 183 cases of renal-function decline occurred over a mean 6-year follow-up. Participants with a higher (less favorable) Nutri-Score DI (interquartile range (IQR)13.2-17.7 (g/day/kg of weight); 46 cases) had higher probability of renal decline than those with a lower Nutri-Score DI (IQR 36.6-46.2; 44 cases); the corresponding odds ratios (95% confidence interval) across increasing quartiles of Nutri-Score DI were 1 (reference), 1.26 (0.78-2.04), 1.55 (0.92-2.62), and 1.82 (1.01-3.30), P-trend = 0.045. Per each 10-point increase in the Nutri-Score DI the odds of renal decline increased by 27% (6%-52%). Conclusions: Higher Nutri-Score DI, reflecting the consumption of foods with less favourable Nutri-Score rating, was associated with higher kidney function decline in older adults. Consequently, Nutri-Score labeling might be a useful policy tool for preventing kidney function decline, adding to the potential health benefits of this front-of-pack labelling system.
Associations of PFAS-related plasma metabolites with cholesterol and triglyceride concentrations
(Elsevier, 2022-10-13) Schillemans, Tessa; Bergdahl, Ingvar A.; Hanhineva, Kati; Shi, Lin; Donat Vargas, Carolina; Koponen, J.; Kiviranta, Hannu; Landberg, Rikard; Åkesson, Agneta; Brunius, Carl
The wide-spread environmental pollutants per- and polyfluoroalkyl substances (PFAS) have repeatedly been associated with elevated serum cholesterol in humans. However, underlying mechanisms are still unclear. Furthermore, we have previously observed inverse associations with plasma triglycerides. To better understand PFAS-induced effects on lipid pathways we investigated associations of PFAS-related metabolite features with plasma cholesterol and triglyceride concentrations. We used 290 PFAS-related metabolite features that we previously discovered from untargeted liquid chromatography-mass spectometry metabolomics in a case-control study within the Swedish Västerbotten Intervention Programme cohort. Herein, we studied associations of these PFAS-related metabolite features with plasma cholesterol and triglyceride concentrations in plasma samples from 187 healthy control subjects collected on two occasions between 1991 and 2013. The PFAS-related features did not associate with cholesterol, but 50 features were associated with triglycerides. Principal component analysis on these features indicated that one metabolite pattern, dominated by glycerophospholipids, correlated with longer chain PFAS and associated inversely with triglycerides (both cross-sectionally and prospectively), after adjustment for confounders. The observed time-trend of the metabolite pattern resembled that of the longer chain PFAS, with higher levels during the years 2004-2010. Mechanisms linking PFAS exposures to triglycerides may thus occur via longer chain PFAS affecting glycerophospholipid metabolism. If the results reflect a cause-effect association, as implied by the time-trend and prospective analyses, this may affect the general adult population.
Only virgin type of olive oil consumption reduces the risk of mortality. Results from a Mediterranean population-based cohort
(Nature Publishing Group, 2022-10-14) Donat Vargas, Carolina; López-García, Esther; Banegas, José Ramón; Martínez-González, Miguel Ángel, 1957-; Rodríguez-Artalejo, Fernando; Guallar Castillón, Pilar
Background: Evidence on the association between virgin olive oil (OO) and mortality is limited since no attempt has previously been made to discern about main OO varieties.Objective: We examined the association between OO consumption (differentiating by common and virgin varieties) and total as well as cause-specific long-term mortality METHODS: 12,161 individuals, representative of the Spanish population ≥18 years old, were recruited between 2008 and 2010 and followed up through 2019. Habitual food consumption was collected at baseline with a validated computerized dietary history. The association between tertiles of OO main varieties and all-cause, cardiovascular and cancer mortality were analyzed using Cox models.Results: After a mean follow-up of 10.7 years (129,272 person-years), 143 cardiovascular deaths, and 146 cancer deaths occurred. The hazard ratio (HR) (95% confidence interval) for all-cause mortality in the highest tertile of common and virgin OO consumption were 0.96 (0.75-1.23; P-trend 0.891) and 0.66 (0.49-0.90; P-trend 0.040). The HR for all-cause mortality per a 10 g/day increase in virgin OO was 0.91 (0.83-1.00). Virgin OO consumption was also inversely associated with cardiovascular mortality, with a HR of 0.43 (0.20-0.91; P-trend 0.017), but common OO was not, with a HR of 0.88 (0.49-1.60; P-trend 0.242). No variety of OO was associated with cancer mortality.Conclusion: Daily moderate consumption of virgin OO (1 and 1/2 tablespoons) was associated with a one-third lower risk of all-cause as well as half the risk of cardiovascular mortality. These effects were not seen for common OO. These findings may be useful to reappraise dietary guidelines.
Urinary phosphate is associated with cardiovascular disease incidence
(Wiley, 2023-06-26) Donat Vargas, Carolina; Guallar Castillón, Pilar; Nyström, Jenny; Larsson, Susanna C.; Kippler, Maria; Vahter, Marie; Faxén-Irving, Gerd; Michaëlsson, Karl; Wolk, Alicja; Stenvinkel, Peter; Åkesson, Agneta
Introduction: Elevated phosphate (P) in urine may reflect a high intake of inorganic P salts from food additives. Elevated P in plasma is linked to vascular dysfunction and calcification. Objective: To explore associations between P in urine as well as in plasma and questionnaire-estimated P intake, and incidence of cardiovascular disease (CVD). Methods: We used the Swedish Mammography Cohort-Clinical, a population-based cohort study. At baseline (2004-2009), P was measured in urine and plasma in 1625 women. Dietary P was estimated via a food-frequency questionnaire. Incident CVD was ascertained via register-linkage. Associations were assessed using Cox proportional hazards regression. Results: After a median follow-up of 9.4 years, 164 composite CVD cases occurred (63 myocardial infarctions [MIs] and 101 strokes). Median P (percentiles 5-95) in urine and plasma were 2.4 (1.40-3.79) mmol/mmol creatinine and 1.13 (0.92-1.36) mmol/L, respectively, whereas dietary P intake was 1510 (1148-1918) mg/day. No correlations were observed between urinary and plasma P (r = -0.07) or dietary P (r = 0.10). Urinary P was associated with composite CVD and MI. The hazard ratio of CVD comparing extreme tertiles was 1.57 (95% confidence interval 1.05, 2.35; P trend 0.037)-independently of sodium excretion, the estimated glomerular filtration rate, both P and calcium in plasma, and diuretic use. Association with CVD for plasma P was 1.41 (0.96, 2.07; P trend 0.077). Conclusion: Higher level of urinary P, likely reflecting a high consumption of highly processed foods, was linked to CVD. Further investigation is needed to evaluate the potential cardiovascular toxicity associated with excessive intake of P beyond nutritional requirements.
Rationale of the association between Mediterranean diet and the risk of frailty in older adults and systematic review and meta-analysis
(Elsevier, 2023-04-24) Dominguez, Ligia J.; Donat Vargas, Carolina; Sayón Orea, Carmen; Barberia-Latasa, Maria; Veronese, Nicola; Rey García, Jimena; Rodríguez-Artalejo, Fernando; Guallar Castillón, Pilar; Martínez-González, Miguel Ángel, 1957-; Barbagallo, Mario
Frailty is a geriatric syndrome whose frequency is increasing in parallel with population aging and is of great interest due to its dire consequences: increased disability, hospitalizations, falls and fractures, institutionalization, and mortality. Frailty is multifactorial but nutritional factors, which are modifiable, play a crucial role in its pathogenesis. Epidemiologic evidence supports that high-quality dietary patterns can prevent, delay or even reverse the occurrence of frailty. In order to add new knowledge bridging the gap as the main purpose of the present article we performed a comprehensive review of the rationale behind the association of MedDiet with frailty and a systematic review and meta-analysis updating the latest ones published in 2018 specifically examining the relationship of Mediterranean diet (MedDiet) and incident frailty. Adding the updated information, our results confirmed a robust association of a higher adherence to MedDiet with reduced incident frailty. Key components of the MedDiet, i.e., abundant consumption of vegetables and fruit as well as the use of olive oil as the main source of fat, all of which have been associated with a lower incidence of frailty, may help explain the observed benefit. Future well-designed and sufficiently large intervention studies are needed to confirm the encouraging findings of the current observational evidence. Meanwhile, based on the existing evidence, the promotion of MedDiet, a high-quality dietary pattern, adapted to the conditions and traditions of each region, and considering lifelong and person-tailored strategies, is an open opportunity to reduced incident frailty. This could also help counteract the worrying trend towards the spread of unhealthy eating and lifestyle models such as those of Western diets that greatly contribute to the genesis of chronic non-communicable diseases and disability.
Global assessment of chemical quality of drinking water: The case of trihalomethanes
(Elsevier Ltd., 2023-01-03) Eng, Amanda; Janák, Karel; Rush, Samantha C.; Reckhow, David; Krasner, Stuart W.; Vineis, Paolo; Richardson, Susan D.; Kogevinas, Manolis; Rodriguez-Susa, Manuel; Luzati, Arben; de Cássia Dos Santos Nery, Telma; Pastén, Pablo A.; Quiñones, Marisa; Regli, Stig; Weisman, Richard; Dong, Shaoxia; Ha, Mina; Phattarapattamawong, Songkeart; Villanueva, Cristina M.; Evlampidou, Iro; Ibrahim, Fathelrahman; Donat Vargas, Carolina; Valentín, Antònia; Tugulea, Anca Maria; Echigo, Shinya; Jovanovic, Dragana; Lebedev, Albert T.; Lemus-Pérez, Mildred; Manasfi, Tarek; Musah, Shaibu-Imodagbe Egbenya
Background: Trihalomethanes (THM), a major class of disinfection by-products, are widespread and are associated with adverse health effects. We conducted a global evaluation of current THM regulations and concentrations in drinking water.Methods: We included 120 countries (∼7000 million inhabitants in 2016), representing 94% of the world population. We searched for country regulations and THM routine monitoring data using a questionnaire addressed to referent contacts. Scientific and gray literature was reviewed where contacts were not identified or declined participation. We obtained or estimated annual average THM concentrations, weighted to the population served when possible.Results: Drinking water regulations were ascertained for 116/120 (97%) countries, with 89/116 (77%) including THM regulations. Routine monitoring was implemented in 47/89 (53%) of countries with THM regulations. THM data with a varying population coverage was obtained for 69/120 (58%) countries consisting of ∼5600 million inhabitants (76% of world's population in 2016). Population coverage was ≥90% in 14 countries, mostly in the Global North, 50-89% in 19 countries, 11-49% among 21 countries, and ≤10% in 14 countries including India, China, Russian Federation and Nigeria (40% of world's population).Discussion: An enormous gap exists in THM regulatory status, routine monitoring practice, reporting and data availability among countries, especially between high- vs. low- and middle-income countries (LMICs). More efforts are warranted to regulate and systematically assess chemical quality of drinking water, centralize, harmonize, and openly report data, particularly in LMICs.
The Mediterranean diet protects renal function in older adults: A prospective cohort study
(MDPI, 2022-01-19) Bayán-Bravo, A.; Banegas, José Ramón; Donat Vargas, Carolina; Sandoval Insausti, Helena ; Gorostidi, Manuel; Rodríguez-Artalejo, Fernando; Guallar-Castillón, Pilar
Background: Chronic kidney disease entails a high disease burden that is progressively increasing due to population aging. However, evidence on the effect of the Mediterranean diet on renal function is limited, in particular among older adults in Mediterranean countries. Methods: Prospective cohort study with 975 community-dwelling adults aged ≥ 60 recruited during 2008-2010 in Spain and followed up to 2015. At baseline, food consumption was obtained using a validated dietary history. Two Mediterranean dietary patterns were used: (i) An a priori-defined pattern, the Mediterranean Diet Adherence Screener (MEDAS score: low adherence: 0-5 points; moderate: 6-8 points; high: 9-14 points); (ii) An a posteriori Mediterranean-like dietary pattern, based on 36 food groups, which was generated using factor analysis. Renal function decline was calculated as an estimated glomerular filtration rate (eGFR) decrease ≥1 mL/min/1.73 m2 per year of follow-up. Results: A total of 104 cases of renal function decline occurred. Compared with participants with a low MEDAS adherence, the multivariable-adjusted odds ratios (95% confident interval) for renal function decline risk were 0.63 (0.38-1.03) for moderate adherence, and 0.52 (0.29-0.95) for high adherence (p-trend: 0.015). Multivariable-adjusted odds ratios (95% confidence interval) for renal function decline risk according to increasing quartiles of the adherence to the a posteriori Mediterranean-like dietary pattern were 1.00, 0.67 (0.38-1.20), 0.65 (0.35-1.19), and 0.47 (0.23-0.96) (p-trend: 0.042). Conclusion: A higher adherence to a Mediterranean diet was associated with a lower risk of renal function decline in older adults, suggesting benefits to health of this dietary pattern in Mediterranean countries.
Per- and polyfluoroalkyl substances and risk of myocardial infarction and stroke: A nested case-control study in Sweden
(National Institute of Environmental Health Science, 2022-03-14) Schillemans, Tessa; Donat Vargas, Carolina; Lindh, Christian H.; de Faire, Ulf; Wolk, Alicja; Leander, Karin; Åkesson, Agneta
BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are widespread and persistent pollutants that have been associated with elevated cholesterol levels. However, data on incident cardiovascular disease (CVD) is lacking. OBJECTIVES: We investigated the association of exposure to PFAS with risk of myocardial infarction and stroke and, subsidiary, with baseline blood lipids. METHODS: This population-based nested case–control study included first incident myocardial infarction and stroke cases with matched controls from two Swedish cohorts: the Swedish Mammography Cohort-Clinical (SMC-C) and the Cohort of 60-year-olds (60YO). Baseline blood sampling occurred during 2003–2009 and 1997–1999 with follow-up through 2017 and 2014 for the SMC-C and the 60YO, respectively. Eight plasma PFAS concentrations were measured using targeted liquid chromatography–triple quadrupole mass spectrometry. Five of these were quantifiable in both cohorts; individual values and their standardized sum were categorized into tertiles based on the controls. First incident myocardial infarction (n= 345) and ischemic stroke (n= 354) cases were ascertained via linkage to the National Inpatient Register and the Cause of Death Register. Controls were randomly selected from each cohort after matching for age, sex, and sample date. Baseline blood lipids were measured in plasma or serum after overnight fasting. RESULTS: Among the 1,528 case–control subjects, the mean (standard deviation) age was 66 (7.7) y and 67% of them were women. In multivariableadjusted analyses, the third tertile of the standardized sum of five PFAS associated with higher cholesterol and lower triglyceride levels among controls at baseline (n= 631). The corresponding results were odds ratios = 0:70 [95% confidence interval (CI): 0.53, 0.93] for CVD, 0.60 (95% CI: 0.39, 0.92) for myocardial infarction, and 0.83 (95% CI: 0.46, 1.50) for stroke. DISCUSSION: This study indicated that exposure to PFAS, although associated with increased cholesterol levels, did not associate with an increased risk of myocardial infarction, stroke, or their composite end point. The findings improve our knowledge on potential health effects of environmental contaminants in the CVD context
Cooking methods are associated with inflammatory factors, renal function, and other hormones and nutritional biomarkers in older adults
(Nature Publishing Group, 2022-10-01) Rodríguez-Ayala, M.; Banegas, José Ramón; Ortolá, Rosario; Gorostidi, Manuel; Donat Vargas, Carolina; Rodríguez-Artalejo, Fernando; Guallar-Castillón, Pilar
Evidence of the role of cooking methods on inflammation and metabolic health is scarce due to the paucity of large-size studies. Our aim was to evaluate the association of cooking methods with inflammatory markers, renal function, and other hormones and nutritional biomarkers in a general population of older adults. In a cross sectional analysis with 2467 individuals aged ≥ 65, dietary and cooking information was collected using a validated face-to-face dietary history. Eight cooking methods were considered: raw, boiling, roasting, pan-frying, frying, toasting, sautéing, and stewing. Biomarkers were analyzed in a central laboratory following standard procedures. Marginal effects from generalized linear models were calculated and percentage differences (PD) of the multivariable-adjusted means of biomarkers between extreme sex-specific quintiles (Q) of cooking methods consumption were computed ([Q5 - Q1/Q1] × 100). Participants' mean age was 71.6 years (53% women). Significant PD for the highest vs lowest quintile of raw food consumption was - 54.7% for high sensitivity-C reactive protein (hs-CRP), - 11.9% for neutrophils, - 11.9% for Growth Differentiation Factor-15, - 25.0% for Interleukin-6 (IL-6), - 12.3% for urinary albumin, and - 10.3% for uric acid. PD for boiling were - 17.8% for hs-CRP, - 12.4% for urinary albumin, and - 11.3% for thyroid-stimulating hormone. Concerning pan-frying, the PD was - 23.2% for hs-CRP, - 11.5% for IL-6, - 16.3% for urinary albumin and 10.9% for serum vitamin D. For frying, the PD was a 25.7% for hs-CRP, and - 12.6% for vitamin D. For toasting, corresponding figures were - 21.4% for hs-CRP, - 11.1% for IL-6 and 10.6% for vitamin D. For stewing, the PD was 13.3% for hs-CRP. Raw, boiling, pan-frying, and toasting were associated with healthy profiles as for inflammatory markers, renal function, thyroid hormones, and serum vitamin D. On the contrary, frying and, to a less extent, stewing showed unhealthier profiles. Cooking methods not including added fats where healthier than those with added fats heated at high temperatures or during longer periods of time.
Per- and polyfluoroalkyl substances and cardiometabolic diseases: A review
(Wiley, 2023-10-22) Schillemans, Tessa; Donat Vargas, Carolina; Åkesson, Agneta
Per- and polyfluoroalkyl substances (PFAS) are a group of persistent and widespread environmental pollutants that represent a high concern for human health. They have been shown to be associated with several important physiological processes such as lipid metabolism and the immune system. Consequently, PFAS are suspected to play a role in cardiometabolic disease development. However, the evidence regarding associations between PFAS and overt cardiovascular disease and type 2 diabetes remains limited and inconsistent. To address this, we conducted a review of the epidemiological evidence. A deeper understanding of potential underlying molecular mechanisms may help to explain inconsistencies in epidemiological findings. Thus, to gain more mechanistic insight, we also summarized evidence from omics and laboratory studies into an adverse outcome pathway framework. Our observations indicate the potential for associations of PFAS with multiple molecular pathways that could have opposite associations with disease risk, which could be further modified by mixture composition, lifestyle factors or genetic polymorphisms. This identifies the need for exposome studies considering mixture effects, the use of multi-omics data to gain insight in relevant pathways and the integration of epidemiological and laboratory studies to enhance mechanistic understanding and causal inference. Improved comprehension is essential for environmental health risk assessments.
Digestion and matrix interactions drive phenolic compounds transformation in tomato sauce formulations
(Elsevier B.V., 2026-09-01) Abarca-Rivas, Clara; Pérez Bosch, Maria; Lamuela Raventós, Rosa Ma.; Vallverdú i Queralt, Anna; Corrado, Marina
This study investigated the digestive fate of tomato phenolics and how processing and matrix interactions influence their release, transformation, and partitioning during digestion. Conventional tomato sauce, pomace-enriched sauce, and the enriched sauce co-digested with boiled rice underwent in vitro digestion (INFOGEST 2.0). Phenolic compounds were profiled in soluble and insoluble fractions across oral, gastric, and intestinal phases using untargeted and targeted LC-MS. Pomace enrichment did not significantly increase total phenolic concentration compared with conventional sauce. Digestion induced compound-specific transformations, including the breakdown of complex caffeoylquinic acids and dynamic redistribution between soluble and insoluble fractions. Co-digestion with rice modified phenolic partitioning in a compound-dependent manner, generally reducing soluble phenolic concentrations while increasing glycosylated flavonoids such as quercetin 3-β-D-glucoside. Digestion phase was the dominant driver of phenolic behaviour, while matrix composition modulated the direction of these changes through phase-dependent interactions. These findings suggest that phenolic accessibility during digestion depends not only on initial phenolic composition but also on matrix-dependent retention and release mechanisms. Overall, this study provides new insight into the digestion-dependent behaviour of tomato phenolics and quantifies compound-specific changes, highlighting the importance of matrix structure and meal composition when designing tomato by-product-enriched foods with improved phenolic delivery.
Topliss-guided optimization of acetanilide-basedsoluble epoxide hydrolase inhibitors: exploring thepentafluorosulfanyl group as a potency-enhancing motif
(Wiley-VCH, 2026-08-13) Sáez, Elena; Pineda-Lucena, Antonio; Hammock, Bruce D.; Luque Garriga, F. Xavier; Loza, María Isabel; Brea, José; Vázquez Cruz, Santiago; López-Ruiz, Alba; Pujol, Eugènia; Ramos Méndez, Carmen; Rizzo, Valeria; Morisseau, Christophe; Val, Cristina; Ginex, Tiziana; Vázquez Lozano, Javier; Codony Gisbert, Sandra; Turcu, Andreea L.; Pérez, Belén
The inhibition of soluble epoxide hydrolase (sEH) has emerged as an attractive therapeutic strategy through the stabilization of endogenous bioactive epoxyeicosatrienoic acids. Most of the inhibitors developed to date contain a central urea pharmacophore; however, these compounds often suffer from physicochemical limitations, particularly limited aqueous solubility. Herein, we report the design, synthesis, and biological evaluation of a new family of 2-(1-benzylpiperidin-4-yl)acetamides inspired by the reference sEH inhibitor 1-(1-propionylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (TPPU). Replacement of the urea pharmacophore in TPPU with an amide significantly improved aqueous solubility but reduced inhibitory potency. Surprisingly, substitution of the trifluoromethyl group of TPPU with a pentafluorosulfanyl substituent restored potency against human sEH, leading to the identification of a promising hit compound. Subsequent structure–activity relationship studies guided by the Topliss Batchwise Scheme (TBS) enabled systematic optimization of the aromatic substitution pattern and revealed that electronic effects are the main drivers of inhibitory potency, leading to several analogs displaying strong activity across human, mouse, and rat sEH. However, their further development was discontinued due to safety-related liabilities identified during the screening cascade. Nevertheless, these results highlight the utility of the underexplored pentafluorosulfanyl group and the TBS strategy for optimizing amide-based sEH inhibitors.
Associations between dietary intake of flavonoids and adiposity: cross-sectional findings from the Fenland Study, the United Kingdom
(Nature Publishing Group, 2026-05-01) Gil Lespinard, Mercedes; Forouhi, Nita G.; Imamura, Fumiaki; Zamora-Ros, Raul
Background Prospective and experimental evidence supports beneficial effects of flavonoids on weight management and metabolic health, but their impact on specific adiposity parameters remains unclear. We aimed to investigate associations of total and subclasses of dietary flavonoids with adiposity markers, several of which have been linked to metabolic risk. Methods We evaluated cross-sectional data from 11,568 adults recruited to the Fenland Study between 2005 and 2015 in Cambridgeshire, the United Kingdom. Habitual diets were evaluated using food frequency questionnaires. Flavonoid intakes were calculated mainly using the United States Department of Agriculture food composition databases. We examined associations using robust regression adjusted for relevant confounders and corrected for false discovery rate (FDR) for multiple flavonoids and adiposity parameters: body fat (BF) (dual-energy X-ray absorptiometry), visceral fat (VAT), subcutaneous fat (SCAT), body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), VAT:SCAT ratio, and a body shape index (ABSI). Results Median flavonoid intake was 428 mg/d (interquartile range 258.5–568.6). Doubling in total flavonoid intake was inversely associated with BF [betalog2 −0.54% (95% CI −0.70; −0.40)]; VAT [−0.13 cm (−0.17; −0.08)]; SCAT [−0.05 cm (−0.08; −0.02)]; BMI [−0.33 kg/m2 (−0.44; −0.22)]; WC [−0.84 cm (−1.13; −0.55)]; and WHR [−0.004 (−0.006; −0.002)]. Most of flavonoid subclasses showed similar results, except isoflavones that were positively associated with BF, VAT and WC. Intakes of proanthocyanidins and anthocyanidins showed the strongest negative associations independently of BMI. Subgroup analyses resulted in stronger negative associations in women, older adults, and non-smokers. Conclusion Flavonoids may influence adiposity, a potential pathway for the relationship between flavonoid-rich foods and metabolic risk. Proanthocyanidins and anthocyanidins may affect site-specific fat distribution, particularly visceral adiposity. Further investigation in prospective, interventional, and mechanistic studies is warranted to understand the link between flavonoids and adiposity.
Understanding public perceptions and discussions on opioids through Twitter: Cross-sectional infodemiology study
(JMIR Publications, 2023-10-31) Carabot, Federico; Fraile-Martínez, Óscar; Donat Vargas, Carolina; Santoma-Vilaclara, Javier; García-Montero, Cielo; Pinto da Costa, Mariana; Molina-Ruiz, Rosa M.; Ortega, Miguel Ángel; Álvarez-Mon, Melchor; Álvarez-Mon, Miguel Ángel
Background: Opioids are used for the treatment of refractory pain, but their inappropriate use has detrimental consequences for health. Understanding the current experiences and perceptions of patients in a spontaneous and colloquial environment regarding the key drugs involved in the opioid crisis is of utmost significance. Objective: The study aims to analyze Twitter content related to opioids, with objectives including characterizing users participating in these conversations, identifying prevalent topics and gauging public perception, assessing opinions on drug efficacy and tolerability, and detecting discussions related to drug dispensing, prescription, or acquisition. Methods: In this cross-sectional study, we gathered public tweets concerning major opioids posted in English or Spanish between January 1, 2019, and December 31, 2020. A total of 256,218 tweets were collected. Approximately 27% (69,222/256,218) were excluded. Subsequently, 7000 tweets were subjected to manual analysis based on a codebook developed by the researchers. The remaining databases underwent analysis using machine learning classifiers. In the codebook, the type of user was the initial classification domain. We differentiated between patients, family members and friends, health care professionals, and institutions. Next, a distinction was made between medical and nonmedical content. If it was medical in nature, we classified it according to whether it referred to the drug's efficacy or adverse effects. In nonmedical content tweets, we analyzed whether the content referred to management issues (eg, pharmacy dispensation, medical appointment prescriptions, commercial advertisements, or legal aspects) or the trivialization of the drug. Results: Among the entire array of scrutinized pharmaceuticals, fentanyl emerged as the predominant subject, featuring in 27% (39,997/148,335 posts) of the tweets. Concerning user categorization, roughly 70% (101,259/148,335) were classified as patients. Nevertheless, tweets posted by health care professionals obtained the highest number of retweets (37/16,956, 0.2% of their posts received over 100 retweets). We found statistically significant differences in the distribution concerning efficacy and side effects among distinct drug categories (P<.001). Nearly 60% (84,401/148,335) of the posts were devoted to nonmedical subjects. Within this category, legal facets and recreational use surfaced as the most prevalent themes, while in the medical discourse, efficacy constituted the most frequent topic, with over 90% (45,621/48,777) of instances characterizing it as poor or null. The opioid with the greatest proportion of tweets concerning legal considerations was fentanyl. Furthermore, fentanyl was the drug most frequently offered for sale on Twitter, while methadone generated the most tweets about pharmacy delivery. Conclusions: The opioid crisis is present on social media, where tweets discuss legal and recreational use. Opioid users are the most active participants, prioritizing medication efficacy over side effects. Surprisingly, health care professionals generate the most engagement, indicating their positive reception. Authorities must monitor web-based opioid discussions to detect illicit acquisitions and recreational use.
Per- and polyfluoroalkyl substances (PFAS) and fetal growth: A nation-wide register-based study on PFAS in drinking water
(Elsevier Ltd., 2024-05-08) Säve-Söderbergh, Melle; Gyllenhammar, Irina; Schillemans, Tessa; Lindfeldt, Emelie; Vogs, Carolina; Donat Vargas, Carolina; Ankarberg, Emma; Glynn, Anders; Ahrens, Lutz; Helte, Emilie; Åkesson, Agneta
Background: There is inconclusive evidence for an association between per- and polyfluoroalkyl substances (PFAS) and fetal growth. Objectives: We conducted a nation-wide register-based cohort study to assess the associations of the estimated maternal exposure to the sum (PFAS4) of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorohexane sulfonic acid (PFHxS) with birthweight as well as risk of small- (SGA) and large-for-gestational-age (LGA). Materials and methods: We included all births in Sweden during 2012-2018 of mothers residing ≥ four years prior to partus in localities served by municipal drinking water where PFAS were measured in raw and drinking water. Using a one-compartment toxicokinetic model we estimated cumulative maternal blood levels of PFAS4 during pregnancy by linking residential history, municipal PFAS water concentration and year-specific background serum PFAS concentrations in Sweden. Individual birth outcomes and covariates were obtained via register linkage. Mean values and 95 % confidence intervals (CI) of β coefficients and odds ratios (OR) were estimated by linear and logistic regressions, respectively. Quantile g-computation regression was conducted to assess the impact of PFAS4 mixture. Results: Among the 248,804 singleton newborns included, no overall association was observed for PFAS4 and birthweight or SGA. However, an association was seen for LGA, multivariable-adjusted OR 1.08 (95% CI: 1.01-1.16) when comparing the highest PFAS4 quartile to the lowest. These associations remained for mixture effect approach where all PFAS, except for PFOA, contributed with a positive weight. Discussions: We observed an association of the sum of PFAS4 - especially PFOS - with increased risk of LGA, but not with SGA or birthweight. The limitations linked to the exposure assessment still require caution in the interpretation.
Analysis of user-generated posts on social media of adjuvant analgesics: A machine learning study
(Ivyspring International, 2025-01-01) Carabot, Federico; Álvarez-Mon, Miguel Ángel; Donat Vargas, Carolina; Lara-Abelenda, Francisco J.; Fraile-Martínez, Oscar; Santoma-Vilaclara, Javier; García-Montero, Cielo; Valadés, Teresa; Gutiérrez-Rojas, Luis; Martínez González, Miguel A.; Ortega, Miguel Ángel; Álvarez-Mon, Melchor
Background: Antiepileptics and antidepressants are frequently prescribed for chronic pain, but their efficacy and potential adverse effects raise concerns, including dependency issues. Increased prescriptions, sometimes fraudulent, prompted reclassification of antiepileptics in some countries. Our aim is to comprehend opinions, perceptions, beliefs, and attitudes towards co-analgesics from online discussions on X (formerly known as Twitter), offering insights closer to reality than conventional surveys. Methods: In this cross-sectional study, we collected 77,183 public posts about co-analgesics in English or Spanish from January 1st 2019 to December 31st, 2020. A total of 51,167 post were included, and 2,000 were manually analyzed using a researcher-created codebook. Machine learning classifiers were then applied to the remaining datasets to determine the number of publications for each user type and identify categories through content analysis. Results: Of the 51,167 posts analyzed, 78% discussed anticonvulsants and 24% discussed analgesic antidepressants (Percentages add up to more than 100% because there were 1,300 posts containing references to both types of medications). Only 13% were authored by healthcare professionals, while 67% were from patients. Medical content predominated, with 70% noting low medication efficacy and almost 50% referencing side effects. Non-medical content included challenges in dispensing (25%), complaints about high costs (15%), and trivialization of medication use (10%). Conclusions: This study offers valuable insights into public perceptions of co-analgesics. Findings aid in designing public health communications to raise awareness of associated risks, urging both healthcare providers and the public to optimize drug use.
Assessment of beliefs and attitudes towards benzodiazepines using machine learning based on social media posts: An observational study
(BioMed Central, 2024-10-08) Álvarez-Mon, Melchor; Quintero Gutiérrez del Álamo, Javier; de Anta, Laura; Álvarez-Mon, Miguel Ángel; Pereira-Sanchez, Victor; Donat-Vargas, Carolina; Lara-Abelenda, Francisco J.; Arrieta, María; Montero-Torres, María; García-Montero, Cielo; Fraile-Martínez, Óscar; Mora Mínguez, Fernando; Ortega, Miguel Ángel
Background: Benzodiazepines are frequently prescribed drugs; however, their prolonged use can lead to tolerance, dependence, and other adverse effects. Despite these risks, long-term use remains common, presenting a public health concern. This study aims to explore the beliefs and opinions held by the public regarding benzodiazepines, as understanding these perspectives may provide insights into their usage patterns. Methods: We collected public tweets published in English between January 1, 2019, and October 31, 2020, that mentioned benzodiazepines. The content of each tweet and the characteristics of the users were analyzed using a mixed-method approach, including manual analysis and semi-supervised machine learning. Results: Over half of the Twitter users highlighted the efficacy of benzodiazepines, with minimal discussion of their side effects. The most active participants in these conversations were patients and their families, with health professionals and institutions being notably absent. Additionally, the drugs most frequently mentioned corresponded with those most commonly prescribed by healthcare professionals. Conclusions: Social media platforms offer valuable insights into users' experiences and opinions regarding medications. Notably, the sentiment towards benzodiazepines is predominantly positive, with users viewing them as effective while rarely mentioning side effects. This analysis underscores the need to educate physicians, patients, and their families about the potential risks associated with benzodiazepine use and to promote clinical guidelines that support the proper management of these medications.
Greater fragmentation of the daily rhythm of energy intake is associated with better insulin sensitivity in rotating shift workers
(Informa Healthcare, 2026-05-15) Pereira Marot, L.uisa; Zerón-Rugerio, María Fernanda; Cambras Riu, Trinitat; Tibiletti Balieiro, Laura Cristina; Rosa, Dayane Eusenia; Vale Cardoso Lopes, Tássia Do; Castro Moreno, Claudia Roberta de; Izquierdo Pulido, Maria; Crispim, Cibele Aparecida
Shift workers are essential to sustaining the modern 24 h society. However, they experience a higher risk of developing metabolic syndrome, a vulnerability thought to arise from recurrent misalignment between their sleep-wake and fasting-eating schedules. This study aimed to investigate the association between the daily rhythms of energy and macronutrient intake, motor activity (MA), and wrist temperature (WT) with anthropometric and biochemical parameters in rotating shift workers (RSW). Thirty male RSW participated in this 10 d cross-sectional study. Anthropometric and biochemical measurements were collected, and a 10 d 24 h food recall was used to assess energy and macronutrient intake. From these data, daily rhythms of energy intake were characterized, and actigraphy was used to evaluate daily rhythms of MA and WT. Daily rhythms were analyzed using non-parametric analyses including the intradaily variability (IV) and interdaily stability (IS), and associations with outcome variables were tested using partial correlations. A negative association was observed between the IV of the daily rhythms of energy and carbohydrate intake with insulin levels (p < 0.05), HOMA-IR (p < 0.05), and triglycerides (p < 0.05). In contrast, higher IV in the daily rhythm of WT was associated with higher total cholesterol (p < 0.05) and LDL-cholesterol (p < 0.05). These results suggest that a higher fragmentation (higher IV) of the daily rhythm of energy intake is associated with better glucose tolerance among RSW.
Fetal exposure to perfluoroalkyl substances (PFAS) in drinking water and congenital malformations: A nation-wide register-based study on PFAS in drinking water
(Elsevier Ltd., 2025-03-14) Säve-Söderbergh, Melle; Gyllenhammar, Irina; Schillemans, Tessa; Lindfeldt, Emelie; Vogs, Carolina; Donat Vargas, Carolina; Ankarberg, E. H.; Glynn, Anders; Ahrens, Lutz; Helte, Emilie; Åkesson, Agneta
Background: Teratogenic properties of perfluoroalkyl substances (PFAS) have been assessed in a few studies, however, epidemiological evidence for an association is inconclusive. Objectives: We conducted a Swedish nation-wide register-based cohort study to assess the associations of estimated fetal exposure to the sum of drinking water perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorohexane sulfonic acid (PFHxS) with major congenital malformations. Methods: We included all births in Sweden during 2012-2018 of mothers residing ≥four years prior to partus in localities served by municipal drinking water where PFAS concentrations have been measured in drinking water. We estimated the fetal PFAS4 exposure by using a one-compartment toxicokinetic model - including maternal residential history, municipal PFAS water concentration and year-specific PFAS maternal background concentrations as input data - and accounting thereafter PFAS-specific transplacental transfer factors to estimate the fetal PFAS4 exposure. By register linkage we obtained birth outcomes and covariates. Odd ratios (OR) and 95 % confidence intervals (CI) of the associations between estimated PFAS in foetuses and major congenital malformations were estimated by logistic regressions and, complementary, by quantile g-computation regression for mixture effects. Results: Analyses of 256,659 newborns of which 5,357 were diagnosed with major congenital malformations, revealed associations between fetal PFAS4 exposure and malformations on the nervous system OR, 2.84 (95 % CI: 1.38-5.84, p-trend: 0.008) and chromosomal anomalies OR, 1.50 (95 % CI: 1.07-2.10, p-trend: 0.009) comparing extreme quartiles. For the individual PFAS and in the quantile g-computation model, there were indications of an association between PFAS and urinary defects, OR 1.96 (95 % CI: 1.59-2.43, p-trend mixed effect: <0.001), primarily driven by PFOA and PFHxS. Discussion: Modelled fetal sum of PFAS4 was associated with malformations of the nervous system and chromosomal anomalies, while the mixture assessment revealed associations with defects on urinary system. As the underlying toxicological mechanisms remains unclear, further investigation is warranted.

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