Objective To evaluate the association between consumption of ultra-processed foods and all cause mortality. Design Prospective cohort study. Setting Seguimiento Universidad de Navarra (SUN) cohort of university graduates, Spain 1999-2018. Participants 19 899 participants (12 113 women and 7786 men) aged 20-91 years followed-up every two years between December 1999 and February 2014 for food and drink consumption, classified according to the degree of processing by the NOVA classification, and evaluated through a validated 136 item food frequency questionnaire. Main outcome measure Association between consumption of energy adjusted ultra-processed foods categorised into quarters (low, low-medium, medium-high, and high consumption) and all cause mortality, using multivariable Cox proportional hazard models. Results 335 deaths occurred during 200 432 persons years of follow-up. Participants in the highest quarter (high consumption) of ultra-processed foods consumption had a higher hazard for all cause mortality compared with those in the lowest quarter (multivariable adjusted hazard ratio 1.62, 95% confidence interval 1.13 to 2.33) with a significant dose-response relation (P for linear trend=0.005). For each additional serving of ultra-processed foods, all cause mortality relatively increased by 18% (adjusted hazard ratio 1.18, 95% confidence interval 1.05 to 1.33). Conclusions A higher consumption of ultra-processed foods (>4 servings daily) was independently associated with a 62% relatively increased hazard for all cause mortality. For each additional serving of ultra-processed food, all cause mortality increased by 18%. Study registration ClinicalTrials.gov NCT02669602.

The PREDIMED (in Spanish: PREvención con DIeta MEDiterránea) primary prevention trial ^1–3 reported in 2013 that long-term adherence to an energy-unrestricted Mediterranean diet (MedDiet), supplemented with either extra-virgin olive oil (EVOO) or nuts, reduced cardiovascular disease (CVD). PREDIMED showed a 30% relative reduction in the composite cardiovascular primary endpoint (stroke, myocardial infarction or cardiovascular death). ^{2,, 3} However, the PREDIMED trial tested only the composition of the diet, but did not test other lifestyle interventions (i.e. energy reduction, increased physical activity (PA) and behavioural modification) frequently applied in the context of the current unprecedented obesity pandemic. ^{4,, 5} With the exception of the null results of the Look-AHEAD trial, ⁶ and the successful results of the EXERDIET-HTA study that found improvements in blood pressure, cardio-respiratory fitness and body composition (though they encouraged adherence to an hypocaloric DASH diet, instead of a Mediterranean diet), ⁷ lifestyle interventions including such components have never been tested in long-term randomized trials using hard cardiovascular events as endpoints.

Background & Aims: No multi‐national prospective study of drug‐induced liver injury (DILI) has originated in Europe. The design of a prospective European DILI registry, clinical features and short‐term outcomes of the cases and controls is reported. Methods: Patients with suspected DILI were prospectively enrolled in the United Kingdom, Spain, Germany, Switzerland, Portugal and Iceland, 2016–2021. DILI cases or non‐DILI acute liver injury controls following causality assessment were enrolled. Results: Of 446 adjudicated patients, 246 DILI patients and 100 had acute liver injury due to other aetiologies, mostly autoimmune hepatitis ( n = 42) and viral hepatitis ( n = 34). DILI patients (mean age 56 years), 57% women, 60% with jaundice and 3.6% had pre‐existing liver disease. DILI cases and non‐DILI acute liver injury controls had similar demographics, clinical features and outcomes. A single agent was implicated in 199 (81%) DILI cases. Amoxicillin‐clavulanate, flucloxacillin, atorvastatin, nivolumab/ipilimumab, infliximab and nitrofurantoin were the most commonly implicated drugs. Multiple conventional medications were implicated in 37 (15%) and 18 cases were caused by herbal and dietary supplements. The most common single causative drug classes were antibacterials (40%) and antineoplastic/immunomodulating agents (27%). Overall, 13 (5.3%) had drug‐induced autoimmune‐like hepatitis due to nitrofurantoin, methyldopa, infliximab, methylprednisolone and minocycline. Only six (2.4%) DILI patients died (50% had liver‐related death), and another six received liver transplantation. Conclusions: In this first multi‐national European prospective DILI Registry study, antibacterials were the most commonly implicated medications, whereas antineoplastic and immunomodulating agents accounted for higher proportion of DILI than previously described. This European initiative provides an important opportunity to advance the study on DILI.

Conducting randomised clinical trials (RCTs) in idiosyncratic drug-induced liver injury (DILI) is challenging. This systematic review aims to summarise the design and findings of RCTs in the prevention and management of idiosyncratic DILI. A systematic literature search up to January 31^st, 2020 was performed. Recognised scales were used to assess methodological bias and quality of the studies. Quantitative and qualitative analyses were performed. Heterogeneity was assessed with I² statistic. Overall, 22 RCTs were included: 12 on prevention (n = 2,471 patients) and 10 in management (n = 797) of DILI/non-acetaminophen DILI-related acute liver failure (ALF). Silymarin (eight studies), bicyclol (four), magnesium isoglycyrrhizinate (three), N-acetylcysteine (three), tiopronin (one), L-carnitine (one), and traditional Chinese medicines (two) were tested in the intervention arm, while control arm mostly received standard supportive care or placebo. Main efficacy criteria in the prevention RCTs was DILI incidence or peak of liver enzymes value. In management RCTs, the efficacy parameter was usually 50 % decrease or normalisation of liver enzymes, or survival rate in DILI-related ALF patients. Overall, 15 trials described the randomisation method, eight were double-blind (n = 672) and nine had sample size estimation (n = 880). Four RCTs involving 377 patients used an intention-to-treat analysis. Based on the scarce number of trials available, tested agents showed limited efficacy in DILI prevention and management and a favourable safety profile. In conclusion, heterogeneity among studies in DILI case qualification and methodologic quality was evident, and the RCTs performed demonstrated limited efficacy of specific interventions. International research networks are needed to establish a framework on RCTs design and therapeutic endpoints.

Background: Inverse associations of the Mediterranean diet (MedDiet) and physical activity with cardiovascular disease have been previously reported. We investigated the individual and combined contributions of both to this inverse association in a Mediterranean cohort. Design: We used data from 19,536 participants from a prospective cohort of Spanish university graduates, the ‘Seguimiento Universidad de Navarra’ (SUN) cohort, followed up between December 1999 and December 2016. Methods: Adherence to the MedDiet was obtained from a 136-item validated food-frequency questionnaire and categorized in tertiles using four previously reported dietary scores. A validated questionnaire assessed the physical activity levels according to volume, intensity and frequency. Results: Participants were followed up during a median time of 10.4 years. Compared with the lowest category of adherence to the MedDiet (≤3 in the Mediterranean Diet Score), higher adherence (6–9 points) was strongly inversely associated with cardiovascular disease (multivariable adjusted hazard ratio = 0.33; 95% confidence interval (CI) 0.20–0.55). Also, engaging in an active lifestyle (6–8 points in an eight-item score) compared with low activity (<2 points) was associated with a reduced risk of incident cardiovascular disease (hazard ratio = 0.43; 95% CI 0.20–0.90). Greater adherence to the MedDiet and engaging in high levels of active lifestyle showed a 75% relatively reduced risk of cardiovascular disease (hazard ratio = 0.25; 95% CI 0.13–0.48). Conclusions: The combined effect of adherence to the MedDiet and adopting an active lifestyle showed a synergistic inverse association with cardiovascular disease risk.