To investigate whether metabolic signature composed of multiple plasma metabolites can be used to characterize adherence and metabolic response to the Mediterranean diet and whether such a metabolic signature is associated with cardiovascular disease (CVD) risk. Our primary study cohort included 1859 participants from the Spanish PREDIMED trial, and validation cohorts included 6868 participants from the US Nurses’ Health Studies I and II, and Health Professionals Follow-up Study (NHS/HPFS). Adherence to the Mediterranean diet was assessed using a validated Mediterranean Diet Adherence Screener (MEDAS), and plasma metabolome was profiled by liquid chromatography-tandem mass spectrometry. We observed substantial metabolomic variation with respect to Mediterranean diet adherence, with nearly one-third of the assayed metabolites significantly associated with MEDAS (false discovery rate < 0.05). Using elastic net regularized regressions, we identified a metabolic signature, comprised of 67 metabolites, robustly correlated with Mediterranean diet adherence in both PREDIMED and NHS/HPFS (r = 0.28–0.37 between the signature and MEDAS; P = 3 × 10⁻³⁵ to 4 × 10⁻¹¹⁸). In multivariable Cox regressions, the metabolic signature showed a significant inverse association with CVD incidence after adjusting for known risk factors (PREDIMED: hazard ratio [HR] per standard deviation increment in the signature = 0.71, P < 0.001; NHS/HPFS: HR = 0.85, P = 0.001), and the association persisted after further adjustment for MEDAS scores (PREDIMED: HR = 0.73, P = 0.004; NHS/HPFS: HR = 0.85, P = 0.004). Further genome-wide association analysis revealed that the metabolic signature was significantly associated with genetic loci involved in fatty acids and amino acids metabolism. Mendelian randomization analyses showed that the genetically inferred metabolic signature was significantly associated with risk of coronary heart disease (CHD) and stroke (odds ratios per SD increment in the genetically inferred metabolic signature = 0.92 for CHD and 0.91 for stroke; P < 0.001). We identified a metabolic signature that robustly reflects adherence and metabolic response to a Mediterranean diet, and predicts future CVD risk independent of traditional risk factors, in Spanish and US cohorts.

As the global population ages, it is critical to identify diets that, beyond preventing noncommunicable diseases, optimally promote healthy aging. Here, using longitudinal questionnaire data from the Nurses’ Health Study (1986–2016) and the Health Professionals Follow-Up Study (1986–2016), we examined the association of long-term adherence to eight dietary patterns and ultraprocessed food consumption with healthy aging, as assessed according to measures of cognitive, physical and mental health, as well as living to 70 years of age free of chronic diseases. After up to 30 years of follow-up, 9,771 (9.3%) of 105,015 participants (66% women, mean age = 53 years (s.d. = 8)) achieved healthy aging. For each dietary pattern, higher adherence was associated with greater odds of healthy aging and its domains. The odds ratios for the highest quintile versus the lowest ranged from 1.45 (95% confidence interval (CI) = 1.35–1.57; healthful plant-based diet) to 1.86 (95% CI = 1.71–2.01; Alternative Healthy Eating Index). When the age threshold for healthy aging was shifted to 75 years, the Alternative Healthy Eating Index diet showed the strongest association with healthy aging, with an odds ratio of 2.24 (95% CI = 2.01–2.50). Higher intakes of fruits, vegetables, whole grains, unsaturated fats, nuts, legumes and low-fat dairy products were linked to greater odds of healthy aging, whereas higher intakes of trans fats, sodium, sugary beverages and red or processed meats (or both) were inversely associated. Our findings suggest that dietary patterns rich in plant-based foods, with moderate inclusion of healthy animal-based foods, may enhance overall healthy aging, guiding future dietary guidelines.

Background: Data for frontline healthcare workers (HCWs) and risk of SARS-CoV-2 infection are limited and whether personal protective equipment (PPE) mitigates this risk is unknown. We evaluated risk for COVID-19 among frontline HCWs compared to the general community and the influence of PPE. Methods: We performed a prospective cohort study of the general community, including frontline HCWs, who reported information through the COVID Symptom Study smartphone application beginning on March 24 (United Kingdom, U.K.) and March 29 (United States, U.S.) through April 23, 2020. We used Cox proportional hazards modeling to estimate multivariate-adjusted hazard ratios (aHRs) of a positive COVID-19 test. Findings: Among 2,035,395 community individuals and 99,795 frontline HCWs, we documented 5,545 incident reports of a positive COVID-19 test over 34,435,272 person-days. Compared with the general community, frontline HCWs had an aHR of 11·6 (95% CI: 10·9 to 12·3) for reporting a positive test. The corresponding aHR was 3·40 (95% CI: 3·37 to 3·43) using an inverse probability weighted Cox model adjusting for the likelihood of receiving a test. A symptom-based classifier of predicted COVID-19 yielded similar risk estimates. Compared with HCWs reporting adequate PPE, the aHRs for reporting a positive test were 1·46 (95% CI: 1·21 to 1·76) for those reporting PPE reuse and 1·31 (95% CI: 1·10 to 1·56) for reporting inadequate PPE. Compared with HCWs reporting adequate PPE who did not care for COVID-19 patients, HCWs caring for patients with documented COVID-19 had aHRs for a positive test of 4·83 (95% CI: 3·99 to 5·85) if they had adequate PPE, 5·06 (95% CI: 3·90 to 6·57) for reused PPE, and 5·91 (95% CI: 4·53 to 7·71) for inadequate PPE. Interpretation: Frontline HCWs had a significantly increased risk of COVID-19 infection, highest among HCWs who reused PPE or had inadequate access to PPE. However, adequate supplies of PPE did not completely mitigate high-risk exposures. Funding: Zoe Global Ltd., Wellcome Trust, EPSRC, NIHR, UK Research and Innovation, Alzheimer’s Society, NIH, NIOSH, Massachusetts Consortium on Pathogen Readiness RESEARCH IN CONTEXT: Evidence before this study: The prolonged course of the coronavirus disease 2019 (COVID-19) pandemic, coupled with sustained challenges supplying adequate personal protective equipment (PPE) for frontline healthcare workers (HCW), have strained global healthcare systems in an unprecedented fashion. Despite growing awareness of this problem, there are few data to inform policy makers on the risk of COVID-19 among HCWs and the impact of PPE on their disease burden. Prior reports of HCW infections are based on cross sectional data with limited individual-level information on risk factors for infection. A PubMed search for articles published between January 1, 2020 and May 5, 2020 using the terms “covid-19”, “healthcare workers”, and “personal protective equipment,” yielded no population-scale investigations exploring this topic. Added value of this study: In a prospective study of 2,135,190 individuals, frontline HCWs may have up to a 12-fold increased risk of reporting a positive COVID-19 test. Compared with those who reported adequate availability of PPE, frontline HCWs with inadequate PPE had a 31% increase in risk. However, adequate availability of PPE did not completely reduce risk among HCWs caring for COVID-19 patients. Implications of all the available evidence: Beyond ensuring adequate availability of PPE, additional efforts to protect HCWs from COVID-19 are needed, particularly as lockdown is lifted in many regions of the world.

Epidemiologic data suggest that parity increases risk of hormone receptor-negative breast cancer and that breastfeeding attenuates this association. Prospective data, particularly on the joint effects of higher parity and breastfeeding, are limited. We investigated parity, breastfeeding, and breast cancer risk by hormone-receptor (estrogen (ER) and progesterone receptor (PR)) and molecular subtypes (luminal A, luminal B, HER2-enriched, and basal-like) in the Nurses’ Health Study (NHS; 1976–2012) and NHSII (1989–2013). A total of 12,452 (ER+ n = 8235; ER− n = 1978) breast cancers were diagnosed among 199,514 women. We used Cox proportional hazards models, adjusted for breast cancer risk factors, to calculate hazard ratios (HR) and 95% confidence intervals (CI). Parous women had lower risk of ER+ breast cancer (vs. nulliparous, HR = 0.82 [0.77–0.88]); no association was observed for ER− disease (0.98 [0.84–1.13]; Phet = 0.03). Among parous women, breastfeeding was associated with lower risk of ER− (vs. never 0.82 [0.74–0.91]), but not ER+, disease (0.99 [0.94–1.05]; Phet < 0.001). Compared to nulliparous women, higher parity was inversely associated with luminal B breast cancer regardless of breastfeeding (≥ 3 children: ever breastfed, 0.78 [0.62–0.98]; never breastfed, 0.76 [0.58–1.00]) and luminal A disease only among women who had breastfed (≥ 3 children, 0.84 [0.71–0.99]). Basal-like breast cancer risk was suggestively higher among women with higher parity who never breastfed; associations were null among those who ever breastfed. This study provides evidence that breastfeeding is inversely associated with hormone receptor-negative breast cancers, representing an accessible and cost-effective risk-reduction strategy for aggressive disease subtypes.

Several intrinsic breast cancer subtypes, possibly representing unique etiologic processes, have been identified by gene expression profiles. Evidence suggests that associations with reproductive risk factors may vary by breast cancer subtype. In the Nurses' Health Studies, we prospectively examined associations of reproductive factors with breast cancer subtypes defined using immunohistochemical staining of tissue microarrays. Multivariate‐adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Over follow‐up, we identified 2,063 luminal A, 1,008 luminal B, 209 HER2‐enriched, 378 basal‐like and 110 unclassified tumors. Many factors appeared associated with luminal A tumors, including ages at menarche (p_{heterogeneity} = 0.65) and menopause (p_{heterogeneity} = 0.05), and current HT use (p_{heterogeneity} = 0.33). Increasing parity was not associated with any subtype (p_{heterogeneity} = 0.76), though age at first birth was associated with luminal A tumors only (per 1‐year increase HR = 1.03 95%CI (1.02–1.05), p_{heterogeneity} = 0.04). Though heterogeneity was not observed, duration of lactation was inversely associated with risk of basal‐like tumors only (7+ months vs. never HR = 0.65 95%CI (0.49–0.87), p_trend = 0.02), p_{heterogeneity} = 0.27). Years between menarche and first birth was strongly positively associated with luminal A and non‐luminal subtypes (e.g. 22‐year interval vs. nulliparous HR = 1.80, 95%CI (1.08–3.00) for basal‐like tumors; p_{heterogeneity} = 0.003), and evidence of effect modification by breastfeeding was observed. In summary, many reproductive risk factors for breast cancer appeared most strongly associated with the luminal A subtype. Our results support previous reports that lactation is protective against basal‐like tumors, representing a potential modifiable risk factor for this aggressive subtype.