Food additive emulsifiers and the risk of type 2 diabetes: analysis of data from the NutriNet-Santé prospective cohort study.

BACKGROUND: Experimental studies have suggested potential detrimental effects of emulsifiers on gut microbiota, inflammation, and metabolic perturbations. We aimed to investigate the associations between exposures to food additive emulsifiers and the risk of type 2 diabetes in a large prospective cohort of French adults. METHODS: We analysed data from 104 139 adults enrolled in the French NutriNet-Santé prospective cohort study from May 1, 2009, to April 26, 2023; 82 456 (79·2%) were female and the mean age was 42·7 years (SD 14·5). Dietary intakes were assessed with three 24 h dietary records collected over three non-consecutive days, every 6 months. Exposure to additive emulsifiers was evaluated through multiple food composition databases and ad-hoc laboratory assays. Associations between cumulative time-dependent exposures to food additive emulsifiers and the risk of type 2 diabetes were characterised with multivariable proportional hazards Cox models adjusted for known risk factors. The NutriNet-Santé study is registered at ClinicalTrials.gov (NCT03335644). FINDINGS: Of 104 139 participants, 1056 were diagnosed with type 2 diabetes during follow-up (mean follow-up duration 6·8 years [SD 3·7]). Intakes of the following emulsifiers were associated with an increased risk of type 2 diabetes: total carrageenans (hazard ratio [HR] 1·03 [95% CI 1·01-1·05] per increment of 100 mg per day, p<0·0001), carrageenans gum (E407; HR 1·03 [1·01-1·05] per increment of 100 mg per day, p<0·0001), tripotassium phosphate (E340; HR 1·15 [1·02-1·31] per increment of 500 mg per day, p=0·023), acetyl tartaric acid esters of monoglycerides and diglycerides of fatty acids (E472e; HR 1·04 [1·00-1·08] per increment of 100 mg per day, p=0·042), sodium citrate (E331; HR 1·04 [1·01-1·07] per increment of 500 mg per day, p=0·0080), guar gum (E412; HR 1·11 [1·06-1·17] per increment of 500 mg per day, p<0·0001), gum arabic (E414; HR 1·03 [1·01-1·05] per increment of 1000 mg per day, p=0·013), and xanthan gum (E415, HR 1·08 [1·02-1·14] per increment of 500 mg per day, p=0·013). INTERPRETATION: We found direct associations between the risk of type 2 diabetes and exposures to various food additive emulsifiers widely used in industrial foods, in a large prospective cohort of French adults. Further research is needed to prompt re-evaluation of regulations governing the use of additive emulsifiers in the food industry for better consumer protection. FUNDING: European Research Council, French National Cancer Institute, French Ministry of Health, IdEx Université de Paris, and Bettencourt-Schueller Foundation.

Analysis of the obstetrician's posture and movements during a simulated forceps delivery.

BACKGROUND: The objective of this study was to identify and qualify, by means of a three-dimensional kinematic analysis, the postures and movements of obstetricians during a simulated forceps birth, and then to study the association of the obstetricians' experience with the technique adopted. METHOD: Fifty-seven volunteer obstetricians, 20 from the Limoges and 37 from the Poitiers University hospitals, were included in this multi-centric study. They were classified into 3 groups: beginners, intermediates, and experts, beginners having performed fewer than 10 forceps deliveries in real conditions, intermediates between 10 and 100, and experts more than 100. The posture and movements of the obstetricians were recorded between December 2020 and March 2021 using an optoelectronic motion capture system during simulated forceps births. Joint angles qualifying these postures and movements were analysed between the three phases of the foetal traction. These phases were defined by the passage of a virtual point associated with the forceps blade through two anatomical planes: the mid-pelvis and the pelvic outlet. Then, a consolidated ascending hierarchical classification (AHC) was applied to these data in order to objectify the existence of groups of similar behaviours. RESULTS: The AHC distinguished four different postures adopted when crossing the first plane and three different traction techniques. 48% of the beginners adopted one of the two raised posture, 22% being raised without trunk flexion and 26% raised with trunk flexion. Conversely, 58% of the experts positioned themselves in a "chevalier servant" posture (going down on one knee) and 25% in a "squatting" posture before initiating traction. The results also show that the joint movement amplitude tends to reduce with the level of expertise. CONCLUSION: Forceps delivery was performed in different ways, with the experienced obstetricians favouring postures that enabled observation at the level of the maternal perineum and techniques reducing movement amplitude. The first perspective of this work is to relate these different techniques to the traction force generated. The results of these studies have the potential to contribute to the training of obstetricians in forceps delivery, and to improve the safety of women and newborns.

Food additive emulsifiers and cancer risk: Results from the French prospective NutriNet-Santé cohort.

BACKGROUND: Emulsifiers are widely used food additives in industrially processed foods to improve texture and enhance shelf-life. Experimental research suggests deleterious effects of emulsifiers on the intestinal microbiota and the metabolome, leading to chronic inflammation and increasing susceptibility to carcinogenesis. However, human epidemiological evidence investigating their association with cancer is nonexistent. This study aimed to assess associations between food additive emulsifiers and cancer risk in a large population-based prospective cohort. METHODS AND FINDINGS: This study included 92,000 adults of the French NutriNet-Santé cohort without prevalent cancer at enrolment (44.5 y [SD: 14.5], 78.8% female, 2009 to 2021). They were followed for an average of 6.7 years [SD: 2.2]. Food additive emulsifier intakes were estimated for participants who provided at least 3 repeated 24-h dietary records linked to comprehensive, brand-specific food composition databases on food additives. Multivariable Cox regressions were conducted to estimate associations between emulsifiers and cancer incidence. Overall, 2,604 incident cancer cases were diagnosed during follow-up (including 750 breast, 322 prostate, and 207 colorectal cancers). Higher intakes of mono- and diglycerides of fatty acids (FAs) (E471) were associated with higher risks of overall cancer (HR high vs. low category = 1.15; 95% CI [1.04, 1.27], p-trend = 0.01), breast cancer (HR = 1.24; 95% CI [1.03, 1.51], p-trend = 0.04), and prostate cancer (HR = 1.46; 95% CI [1.09, 1.97], p-trend = 0.02). In addition, associations with breast cancer risk were observed for higher intakes of total carrageenans (E407 and E407a) (HR = 1.32; 95% CI [1.09, 1.60], p-trend = 0.009) and carrageenan (E407) (HR = 1.28; 95% CI [1.06, 1.56], p-trend = 0.01). No association was detected between any of the emulsifiers and colorectal cancer risk. Several associations with other emulsifiers were observed but were not robust throughout sensitivity analyses. Main limitations include possible exposure measurement errors in emulsifiers intake and potential residual confounding linked to the observational design. CONCLUSIONS: In this large prospective cohort, we observed associations between higher intakes of carrageenans and mono- and diglycerides of fatty acids with overall, breast and prostate cancer risk. These results need replication in other populations. They provide new epidemiological evidence on the role of emulsifiers in cancer risk. TRIAL REGISTRATION: ClinicalTrials.gov NCT03335644.

Effects of sodium nitrite reduction, removal or replacement on cured and cooked meat for microbiological growth, food safety, colon ecosystem, and colorectal carcinogenesis in Fischer 344 rats.

Epidemiological and experimental evidence indicated that processed meat consumption is associated with colorectal cancer risks. Several studies suggest the involvement of nitrite or nitrate additives via N-nitroso-compound formation (NOCs). Compared to the reference level (120 mg/kg of ham), sodium nitrite removal and reduction (90 mg/kg) similarly decreased preneoplastic lesions in F344 rats, but only reduction had an inhibitory effect on Listeria monocytogenes growth comparable to that obtained using the reference nitrite level and an effective lipid peroxidation control. Among the three nitrite salt alternatives tested, none of them led to a significant gain when compared to the reference level: vegetable stock, due to nitrate presence, was very similar to this reference nitrite level, yeast extract induced a strong luminal peroxidation and no decrease in preneoplastic lesions in rats despite the absence of NOCs, and polyphenol rich extract induced the clearest downward trend on preneoplastic lesions in rats but the concomitant presence of nitrosyl iron in feces. Except the vegetable stock, other alternatives were less efficient than sodium nitrite in reducing L. monocytogenes growth.

Food additive emulsifiers and risk of cardiovascular disease in the NutriNet-Santé cohort: prospective cohort study.

OBJECTIVE: To assess the associations between exposure to food additive emulsifiers and risk of cardiovascular disease (CVD). DESIGN: Prospective cohort study. SETTING: French NutriNet-Santé study, 2009-21. PARTICIPANTS: 95 442 adults (>18 years) without prevalent CVD who completed at least three 24 hour dietary records during the first two years of follow-up. MAIN OUTCOME MEASURES: Associations between intake of food additive emulsifiers (continuous (mg/day)) and risk of CVD, coronary heart disease, and cerebrovascular disease characterised using multivariable proportional hazard Cox models to compute hazard ratios for each additional standard deviation (SD) of emulsifier intake, along with 95% confidence intervals. RESULTS: Mean age was 43.1 (SD 14.5) years, and 79.0% (n=75 390) of participants were women. During follow-up (median 7.4 years), 1995 incident CVD, 1044 coronary heart disease, and 974 cerebrovascular disease events were diagnosed. Higher intake of celluloses (E460-E468) was found to be positively associated with higher risks of CVD (hazard ratio for an increase of 1 standard deviation 1.05, 95% confidence interval 1.02 to 1.09, P=0.003) and coronary heart disease (1.07, 1.02 to 1.12, P=0.004). Specifically, higher cellulose E460 intake was linked to higher risks of CVD (1.05, 1.01 to 1.09, P=0.007) and coronary heart disease (1.07, 1.02 to 1.12, P=0.005), and higher intake of carboxymethylcellulose (E466) was associated with higher risks of CVD (1.03, 1.01 to 1.05, P=0.004) and coronary heart disease (1.04, 1.02 to 1.06, P=0.001). Additionally, higher intakes of monoglycerides and diglycerides of fatty acids (E471 and E472) were associated with higher risks of all outcomes. Among these emulsifiers, lactic ester of monoglycerides and diglycerides of fatty acids (E472b) was associated with higher risks of CVD (1.06, 1.02 to 1.10, P=0.002) and cerebrovascular disease (1.11, 1.06 to 1.16, P<0.001), and citric acid ester of monoglycerides and diglycerides of fatty acids (E472c) was associated with higher risks of CVD (1.04, 1.02 to 1.07, P=0.004) and coronary heart disease (1.06, 1.03 to 1.09, P<0.001). High intake of trisodium phosphate (E339) was associated with an increased risk of coronary heart disease (1.06, 1.00 to 1.12, P=0.03). Sensitivity analyses showed consistent associations. CONCLUSION: This study found positive associations between risk of CVD and intake of five individual and two groups of food additive emulsifiers widely used in industrial foods. TRIAL REGISTRATION: ClinicalTrials.gov NCT03335644.

Transcriptional profiling and genetic analysis of a cystic fibrosis airway-relevant model shows asymmetric responses to growth in a polymicrobial community.

Bacterial infections in the lungs of persons with cystic fibrosis are typically composed of multispecies biofilm-like communities, which modulate clinically relevant phenotypes that cannot be explained in the context of a single species culture. Most analyses to date provide a picture of the transcriptional responses of individual pathogens; however, there is relatively little data describing the transcriptional landscape of clinically relevant multispecies communities. Harnessing a previously described cystic fibrosis-relevant, polymicrobial community model consisting of Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus sanguinis, and Prevotella melaninogenica, we performed an RNA-Seq analysis on the biofilm population to elucidate the transcriptional profiles of the community grown in artificial sputum medium (ASM) as compared to growth in monoculture, without mucin, and in fresh medium supplemented with tobramycin. We provide evidence that, although the transcriptional profile of P. aeruginosa is community agnostic, the transcriptomes of S. aureus and S. sanguinis are community aware. Furthermore, P. aeruginosa and P. melaninogenica are transcriptionally sensitive to the presence of mucin in ASM, whereas S. aureus and S. sanguinis largely do not alter their transcriptional profiles in the presence of mucin when grown in a community. Only P. aeruginosa shows a robust response to tobramycin. Genetic studies of mutants altered in community-specific growth provide complementary data regarding how these microbes adapt to a community context. IMPORTANCE Polymicrobial infections constitute the majority of infections in the cystic fibrosis (CF) airway, but their study has largely been neglected in a laboratory setting. Our lab previously reported a polymicrobial community that can help explain clinical outcomes in the lungs of persons with CF. Here, we obtained transcriptional profiles of the community versus monocultures to provide transcriptional information about how this model community responds to CF-related growth conditions and perturbations. Genetic studies provide complementary functional outputs to assess how the microbes adapt to life in a community.

A new approach to assessing the obstetrician's posture and movement during an instrumental forceps delivery.

INTRODUCTION: The number of deliveries by forceps decreases significantly in favour of the vacuum. Now, when the use of forceps is necessary, physicians less experimented with this procedure are likely to induce serious and preventable perineal or foetal injuries. Training therefore becomes essential. However, there are no clear recommendations on the technique to perform a delivery by forceps, namely the body posture and gesture to adopt. Our goal is then to provide a protocol that can help to determine if there is an optimal technique to perform a delivery by forceps. METHOD: We will include voluntary participants whose level of experience and type of practice differ. We will propose to record their postures and gestures using an optoelectronic motion analysis system during a forceps delivery simulated on a mannequin. We will also measure the traction force produced by the subject on the forceps using force platforms and technical markers placed on the forceps. We will then perform a principal component analysis to look for similar motion patterns. EXPECTED RESULTS: We plan to analyse about fifty participants (25 seniors and 25 juniors). Our hypothesis is that the realism of the simulation will be deemed satisfactory by the participants, that the experimental conditions will not modify their gestures, and that the degree of experience will result in different techniques. CONCLUSION: A better knowledge on the posture and gesture to adopt to realise a forceps delivery should improve the safety of women and new-borns. The results of this study could also be a valuable contribution for the training of obstetricians.

In vivo measurement of the elastic properties of pelvic floor muscles in pregnancy using shear wave elastography.

OBJECTIVE: We aimed to investigate changes in the elastic properties of levator ani muscle (LAM) and external anal sphincter (EAS) during pregnancy using shear wave elastography (SWE). Our secondary objective was to examine the association between the elastic properties of pelvic floor muscles (PFM) and perineal tears at childbirth. METHODS: This was a prospective monocentric study, including nulliparous women. Three visits were planned (14-18, 24-28, and 34-38 weeks) with a SWE assessment of the LAM and EAS at rest and during Valsalva maneuver. Then, we collected data about the delivery's characteristics. Assessments were performed using an Aixplorer V12® device (SL 18-5 linear probe) using a transperineal approach, reporting the shear modulus in kPa. We looked for changes in PFM's elastic properties during pregnancy using one-way ANOVA for repeated measures. We compared the mean shear modulus in late pregnancy for each muscle and condition between women with an intact perineum at delivery and those with a perineal tear using Student's t test. RESULTS: Forty-seven women were considered. Forty-five women had vaginal delivery of which 38 (84.4%) had perineal tears. We did not report any significant changes in the elastic properties of PFM during pregnancy. Women with an intact perineum at delivery had a stiffer EAS at Valsalva maneuver in late pregnancy (27.0 kPa vs. 18.2 kPa; p < 0.005). CONCLUSIONS: There were no significant changes in the elastic properties of the PFM in pregnancy. Stiffer EAS in late pregnancy appears to be associated with a lower incidence of perineal tears.

Transcriptional Profiling and Genetic Analysis of a Cystic Fibrosis Airway-Relevant Model Shows Asymmetric Responses to Growth in a Polymicrobial Community.

Bacterial infections in the lungs of persons with cystic fibrosis are typically composed of multispecies biofilm-like communities, which modulate clinically relevant phenotypes that cannot be explained in the context of a single species culture. Most analyses to-date provide a picture of the transcriptional responses of individual pathogens, however, there is relatively little data describing the transcriptional landscape of clinically-relevant multispecies communities. Harnessing a previously described cystic fibrosis-relevant, polymicrobial community model consisting of Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus sanguinis and Prevotella melaninogenica , we performed an RNA-Seq analysis to elucidate the transcriptional profiles of the community grown in artificial sputum medium (ASM) as compared to growth in monoculture, without mucin, and in fresh medium supplemented with tobramycin. We provide evidence that, although the transcriptional profile of P. aeruginosa is community agnostic, the transcriptomes of S. aureus and S. sanguinis are community aware. Furthermore, P. aeruginosa and P. melaninogenica are transcriptionally sensitive to the presence of mucin in ASM, whereas S. aureus and S. sanguinis largely do not alter their transcriptional profiles in the presence of mucin when grown in a community. Only P. aeruginosa shows a robust response to tobramycin. Genetic studies of mutants altered in community-specific growth provide complementary data regarding how these microbes adapt to a community context. Importance: Polymicrobial infections constitute the majority of infections in the cystic fibrosis (CF) airway, but their study has largely been neglected in a laboratory setting. Our lab previously reported a polymicrobial community that can explain clinical outcomes in the lungs of persons with CF. Here we obtain transcriptional profiles of the community versus monocultures to provide transcriptional information about how this model community responds to CF-related growth conditions and perturbations. Genetic studies provide complementary functional outputs to assess how the microbes adapt to life in a community.

Food-grade titanium dioxide translocates across the buccal mucosa in pigs and induces genotoxicity in an in vitro model of human oral epithelium.

The whitening and opacifying agent titanium dioxide (TiO2) is used worldwide in various foodstuffs, toothpastes and pharmaceutical tablets. Its use as a food additive (E171 in EU) has raised concerns for human health. Although the buccal mucosa is the first area exposed, oral transmucosal passage of TiO2 particles has not been documented. Here we analyzed E171 particle translocation in vivo through the pig buccal mucosa and in vitro on human buccal TR146 cells, and the effects on proliferating and differentiated TR146 cells. In the buccal floor of pigs, isolated TiO2 particles and small aggregates were observed 30 min after sublingual deposition, and were recovered in the submandibular lymph nodes at 4 h. In TR146 cells, kinetic analyses showed high absorption capacities of TiO2 particles. The cytotoxicity, genotoxicity and oxidative stress were investigated in TR146 cells exposed to E171 in comparison with two TiO2 size standards of 115 and 21 nm in diameter. All TiO2 samples were reported cytotoxic in proliferating cells but not following differentiation. Genotoxicity and slight oxidative stress were reported for the E171 and 115 nm TiO2 particles. These data highlight the buccal mucosa as an absorption route for the systemic passage of food-grade TiO2 particles. The greater toxicity on proliferating cells suggest potential impairement of oral epithelium renewal. In conclusion, this study emphasizes that buccal exposure should be considered during toxicokinetic studies and for risk assessment of TiO2 in human when used as food additive, including in toothpastes and pharmaceutical formulations.

Urinary Metabolome Analysis Reveals Potential Microbiota Alteration and Electrophilic Burden Induced by High Red Meat Diet: Results from the French NutriNet-Santé Cohort and an In Vivo Intervention Study in Rats.

SCOPE: High red and processed meat consumption is associated with several adverse outcomes such as colorectal cancer and overall global mortality. However, the underlying mechanisms remain debated and need to be elucidated. METHODS AND RESULTS: Urinary untargeted Liquid Chromatography-Mass Spectrometry (LC-MS) metabolomics data from 240 subjects from the French cohort NutriNet-Santé are analyzed. Individuals are matched and divided into three groups according to their consumption of red and processed meat: high red and processed meat consumers, non-red and processed meat consumers, and at random group. Results are supported by a preclinical experiment where rats are fed either a high red meat or a control diet. Microbiota derived metabolites, in particular indoxyl sulfate and cinnamoylglycine, are found impacted by the high red meat diet in both studies, suggesting a modification of microbiota by the high red/processed meat diet. Rat microbiota sequencing analysis strengthens this observation. Although not evidenced in the human study, rat mercapturic acid profile concomitantly reveals an increased lipid peroxidation induced by high red meat diet. CONCLUSION: Novel microbiota metabolites are identified as red meat consumption potential biomarkers, suggesting a deleterious effect, which could partly explain the adverse effects associated with high red and processed meat consumption.

Community composition shapes microbial-specific phenotypes in a cystic fibrosis polymicrobial model system.

Interspecies interactions can drive the emergence of unexpected microbial phenotypes that are not observed when studying monocultures. The cystic fibrosis (CF) lung consists of a complex environment where microbes, living as polymicrobial biofilm-like communities, are associated with negative clinical outcomes for persons with CF (pwCF). However, the current lack of in vitro models integrating the microbial diversity observed in the CF airway hampers our understanding of why polymicrobial communities are recalcitrant to therapy in this disease. Here, integrating computational approaches informed by clinical data, we built a mixed community of clinical relevance to the CF lung composed of Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus sanguinis, and Prevotella melaninogenica. We developed and validated this model biofilm community with multiple isolates of these four genera. When challenged with tobramycin, a front-line antimicrobial used to treat pwCF, the microorganisms in the polymicrobial community show altered sensitivity to this antibiotic compared to monospecies biofilms. We observed that wild-type P. aeruginosa is sensitized to tobramycin in a mixed community versus monoculture, and this observation holds across a range of community relative abundances. We also report that LasR loss-of-function, a variant frequently detected in the CF airway, drives tolerance of P. aeruginosa to tobramycin specifically in the mixed community. Our data suggest that the molecular basis of this community-specific recalcitrance to tobramycin for the P. aeruginosa lasR mutant is increased production of phenazines. Our work supports the importance of studying a clinically relevant model of polymicrobial biofilms to understand community-specific traits relevant to infections.

In vivo assessment of the elastic properties of the external anal sphincter in term pregnant women using shear wave elastography.

INTRODUCTION AND HYPOTHESIS: The objective was to assess the intraobserver intersession and interobserver intrasession reliability of shear wave elastography applied to the external anal sphincter in term pregnant women. METHODS: This prospective study involved nulliparous pregnant women at 37 weeks or more with two visits (V1: one observer; V2 two observers) planned within a 12-h to 7-day interval. Measurements were performed using an Aixplorer V12® device with an SL 18-5 linear probe using a transperineal approach, allowing a measurement of the shear modulus (SM) in kPa. Measures were performed at rest, Valsalva maneuver, and maximal contraction. Reliability was assessed using the intraclass correlation coefficient (ICC). The study was approved by an ethics committee (ID RCB: 2020-A00764-65). RESULTS: A total of 37 women were included. Intraobserver reliability was excellent at rest (ICC = 0.91 [0.84-0.95) and good during the Valsalva maneuver (ICC = 0.83 [0.72-0.90]) and contraction (ICC = 0.85 [0.75-0.91]). Interobserver reliability was good at rest (ICC = 0.79 [0.66-0.87]) and during Valsalva (ICC = 0.84 [0.73-0.90]), but moderate during contraction (ICC = 0.70 [0.53-0.82]). CONCLUSIONS: Shear wave elastography is a reliable tool for assessing the elastic properties of the external anal sphincter in term pregnant women.

Dietary exposure to nitrites and nitrates in association with type 2 diabetes risk: Results from the NutriNet-Santé population-based cohort study.

BACKGROUND: Nitrites and nitrates occur naturally in water and soil and are commonly ingested from drinking water and dietary sources. They are also used as food additives, mainly in processed meats, to increase shelf life and to avoid bacterial growth. Experimental studies suggested both benefits and harmful effects of nitrites and nitrates exposure on type 2 diabetes (T2D) onset, but epidemiological and clinical data are lacking. We aimed to study these associations in a large population-based prospective cohort study, distinguishing foods and water-originated nitrites/nitrates from those from food additives. METHODS AND FINDINGS: Overall, 104,168 adults from the French NutriNet-Santé cohort study (2009 to 2021, 79.1% female, mean age [SD] = 42.7 [14.5]) were included. Associations between self-reported exposure to nitrites and nitrates (evaluated using repeated 24-h dietary records, linked to a comprehensive food composition database and accounting for commercial names/brands details of industrial products) and risk of T2D were assessed using cause-specific multivariable Cox proportional hazard models adjusted for known risk factors (sociodemographic, anthropometric, lifestyle, medical history, and nutritional factors). During a median follow-up duration of 7.3 years (interquartile range: [3.2; 10.1] years), 969 incident T2D cases were ascertained. Total nitrites and foods and water-originated nitrites were both positively associated with a higher T2D risk (HRtertile 3 vs.1 = 1.27 (95% CI 1.04 to 1.54), Ptrend = 0.009 and 1.26 (95% CI 1.03 to 1.54), Ptrend = 0.02, respectively). Participants with higher exposure to additives-originated nitrites (i.e., above the sex-specific median) and specifically those having higher exposure to sodium nitrite (e250) had a higher T2D risk compared with those who were not exposed to additives-originated nitrites (HR higher consumers vs. non-consumers = 1.53 (95% CI 1.24 to 1.88), Ptrend < 0.001 and 1.54 (95% CI 1.26 to 1.90), Ptrend < 0.001, respectively). There was no evidence for an association between total, foods and water-originated, or additives-originated nitrates and T2D risk (all Ptrend = 0.7). No causal link can be established from this observational study. Main limitations include possible exposure measurement errors and the lack of validation versus specific nitrites/nitrates biomarkers; potential selection bias linked to the healthier behaviors of the cohort's participants compared to the general population; potential residual confounding linked to the observational design, as well as a self-reported, yet cross-checked, case ascertainment. CONCLUSIONS: The findings of this large prospective cohort did not support any potential benefits for dietary nitrites and nitrates. They suggested that a higher exposure to both foods and water-originated and additives-originated nitrites was associated with higher T2D risk in the NutriNet-Santé cohort. This study provides a new piece of evidence in the context of current debates about updating regulations to limit the use of nitrites as food additives. The results need to be replicated in other populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT03335644 (https://clinicaltrials.gov/ct2/show/NCT03335644).

Impact of fetal manipulation on maternal and neonatal severe morbidity during shoulder dystocia management.

PURPOSE: There are few data on maternal and neonatal morbidities associated with shoulder dystocia (SD), depending on the use of fetal manipulation (FM). A prior 5-year study was conducted in our center in 2012 for this purpose. Our objective was to compare severe maternal and neonatal morbidities according to FM execution in a larger cohort. METHODS: We conducted a retrospective study between 2007 and 2020. SD was considered when additional maneuvers were required to complete a delivery. Severe maternal morbidity was defined as the occurrence of obstetric anal sphincter injury (OASI). Severe neonatal morbidity was defined as Apgar < 7 at 5 min and/or cord arterial pH < 7.1 and/or or a permanent brachial plexus palsy. We studied these data in the FM group compared to the non- FM group. RESULTS: FM was associated with increased OASI rates (21.1% vs. 3.8%, OR = 6.72 [2.7-15.8]). We found no significant difference in severe neonatal morbidity. Maternal age > 35 and FM appear to be associated with the occurrence of OASI, with ORa = 13.3 [1.5-121.8] and ORa = 5.3 [2.2-12.8], respectively. FM was the only factor associated with the occurrence of severe neonatal morbidity (ORa = 2.3 [1.1-4.8]. The rate of episiotomy was significantly decreased (20% versus 5% p < 0.05) and there was an increase in the rate of SD managed with FM in our center. CONCLUSION: FM is the only factor associated with an increased risk of OASI. In case of failure of non-FM maneuvers, the rapid implementation of FM maneuvers resulted in no difference regarding severe neonatal morbidity.

Nitrites, Nitrates, and Cardiovascular Outcomes: Are We Living "La Vie en Rose" With Pink Processed Meats?

Background Nitrates and nitrites are used as food additives in processed meats. They are also commonly ingested from water and several foods. Several short-term clinical studies suggested beneficial effects of dietary nitrates on blood pressure, while deleterious effects on oxidative damage have been suggested in some experimental studies. However, there is a lack of evidence from longitudinal epidemiological studies linking foods and water-originated and additives-originated nitrites and nitrates, separately, to hypertension and cardiovascular diseases risk. We aimed to study these associations in a large population-based cohort. Methods and Results Overall, 106 288 adults from the French NutriNet-Santé cohort (2009-2022) were included. Associations between nitrites and nitrates intakes and hypertension and cardiovascular disease risks were assessed using multi-adjusted Cox proportional hazard models. During follow-up, 3810 incident cases of hypertension and 2075 cases of cardiovascular diseases were ascertained. Participants with higher intakes of additives-originated nitrites (sodium nitrite in particular [European code e250]) had a higher hypertension risk compared with nonconsumers (hazard ratio, 1.19 [95% CI, 1.08-1.32], P=0.001, and 1.19 [95% CI, 1.08-1.32], P=0.002), respectively. No association was detected between foods and water-originated nitrites, or nitrates with hypertension risk (all P values >0.3). We found no association between nitrites or nitrates and risks of cardiovascular diseases (all P values >0.2). Conclusions These results do not support a protective role of nitrites or nitrates in cardiovascular health. Instead, they suggest a positive association between nitrites from food additives and hypertension risk, which needs confirmation in other large-scale studies. These findings provide new evidence in the context of current discussions about updating regulations on the use of nitrites as food additives.

Dietary exposure to acrylamide and breast cancer risk: results from the NutriNet-Santé cohort.

BACKGROUND: Acrylamide is classified as a probable human carcinogen by the International Agency for Research on Cancer but epidemiologic evidence on the carcinogenicity of acrylamide from dietary sources is limited. OBJECTIVES: This study aimed to investigate the associations between dietary acrylamide and breast cancer risk in the NutriNet-Santé cohort, accounting for menopausal and hormone receptor status. METHODS: This prospective cohort study included 80,597 French females (mean ± SD age at baseline: 40.8 ± 14 y) during a mean ± SD follow-up of 8.8 ± 2.3 y. Acrylamide intake was evaluated using repeated 24-h dietary records (n ± SD = 5.5 ± 3.0), linked to a comprehensive food composition database. Associations between acrylamide intake and breast cancer risk (overall, premenopausal, and postmenopausal) were assessed by Cox hazard models adjusted for known risk factors (sociodemographic, anthropometric, lifestyle, medical history, and nutritional factors). RESULTS: The mean ± SD dietary acrylamide intake was 30.1 ± 21.9 µg/d (main contributors: coffee, potato fries and chips, pastries, cakes, bread). During follow-up, 1016 first incident breast cancer cases were diagnosed (431 premenopausal, 585 postmenopausal). A borderline significant positive association was observed between dietary acrylamide exposure and breast cancer risk overall (HR for quartile 4 compared with 1: 1.21; 95% CI: 1.00, 1.47) and a positive association was observed with premenopausal cancer (HRQ4vs.Q1: 1.40; 95% CI: 1.04, 1.88). Restricted cubic spline analyses suggested evidence for nonlinearity of these associations, with higher HRs for intermediate (quartile 2) and high (quartile 4) exposures. Receptor-specific analyses revealed positive associations with estrogen receptor-positive breast cancer (total and premenopausal). Acrylamide intake was not associated with postmenopausal breast cancer. CONCLUSIONS: Results from this large prospective cohort study suggest a positive association between dietary acrylamide and breast cancer risk, especially in premenopausal females, and provide new insights that support continued mitigation strategies to reduce the content of acrylamide in food.This trial was registered at clinicaltrials.gov as NCT03335644.

Study of the colonic epithelial-mesenchymal dialogue through establishment of two activated or not mesenchymal cell lines: Activated and resting ones differentially modulate colonocytes in co-culture.

Continuous and rapid renewal of the colonic epithelium is crucial to resist the plethora of luminal deleterious agents. Subepithelial fibroblasts contribute to this turnover by regulating epithelial proliferation and differentiation. However, when intestinal homeostasis is disturbed, fibroblasts can acquire an activated phenotype and play a major role in the progression of intestinal pathologies. To evaluate the involvement of fibroblasts in the regulation of colonocytes under homeostatic or pathological conditions, we established resting and activated conditionally immortalized fibroblast cell lines (nF and mF) from mouse colonic mucosa. We then studied the epithelial-mesenchymal interactions between activated or resting fibroblasts and the normal mouse colonocytes (Co) using a co-culture model. Both fibroblastic cell lines were characterized by RT-qPCR, western blot and immunofluorescence assay. Our results showed that nF and mF cells were positive for fibroblastic markers such as vimentin and collagen 1, and negative for cytokeratin 18 and E-cadherin, attesting to their fibroblastic type. They also expressed proteins characteristic of the epithelial stem cell niche such as Grem1, CD90 or Wnt5a. Only rare nF fibroblasts were positive for α-SMA, whereas all mF fibroblasts strongly expressed this marker, supporting that mF cells were activated fibroblasts/myofibroblasts. In coculture, nF fibroblasts and Co cells strongly interacted via paracrine exchanges resulting in BMP4 production in nF fibroblasts, activation of BMP signaling in Co colonocytes, and decreased growth of colonocytes. Activated-type mF fibroblasts did not exert the same effects on Co cells, allowing colonocytes free to proliferate. In conclusion, these two colonic fibroblast lines, associated with Co cells in coculture, should allow to better understand the role of mesenchymal cells in the preservation of homeostasis and the development of intestinal pathologies.

Maternal heme-enriched diet promotes a gut pro-oxidative status associated with microbiota alteration, gut leakiness and glucose intolerance in mice offspring.

Maternal environment, including nutrition and microbiota, plays a critical role in determining offspring's risk of chronic diseases such as diabetes later in life. Heme iron requirement is amplified during pregnancy and lactation, while excessive dietary heme iron intake, compared to non-heme iron, has shown to trigger acute oxidative stress in the gut resulting from reactive aldehyde formation in conjunction with microbiota reshape. Given the immaturity of the antioxidant defense system in early life, we investigated the extent to which a maternal diet enriched with heme iron may have a lasting impact on gut homeostasis and glucose metabolism in 60-day-old C3H/HeN mice offspring. As hypothesized, the form of iron added to the maternal diet differentially governed the offspring's microbiota establishment despite identical fecal iron status in the offspring. Importantly, despite female offspring was unaffected, oxidative stress markers were however higher in the gut of male offspring from heme enriched-fed mothers, and were accompanied by increases in fecal lipocalin-2, intestinal para-cellular permeability and TNF-α expression. In addition, male mice displayed blood glucose intolerance resulting from impaired insulin secretion following oral glucose challenge. Using an integrated approach including an aldehydomic analysis, this male-specific phenotype was further characterized and revealed close covariations between unidentified putative reactive aldehydes and bacterial communities belonging to Bacteroidales and Lachnospirales orders. Our work highlights how the form of dietary iron in the maternal diet can dictate the oxidative status in gut offspring in a sex-dependent manner, and how a gut microbiota-driven oxidative challenge in early life can be associated with gut barrier defects and glucose metabolism disorders that may be predictive of diabetes development.

Nitrites and nitrates from food additives and natural sources and cancer risk: results from the NutriNet-Santé cohort.

BACKGROUND: Nitrates and nitrites occur naturally in water and soil. They are also used as food additives (preservatives) in processed meats. They could play a role in the carcinogenicity of processed meat. The objective was to investigate the relationship between nitrate and nitrite intakes (natural food, water and food additive sources) and cancer risk in a large prospective cohort with detailed dietary assessment. METHODS: Overall, 101    056 adults from the French NutriNet-Santé cohort (2009-ongoing, median follow-up 6.7 years) were included. Nitrites/nitrates exposure was evaluated using repeated 24-h dietary records, linked to a comprehensive composition database and accounting for commercial names/brands of industrial products. Associations with cancer risk were assessed using multi-adjusted Cox hazard models. RESULTS: In total, 3311 incident cancer cases were diagnosed. Compared with non-consumers, high consumers of food additive nitrates had higher breast cancer risk [hazard ratio (HR) = 1.24 (95% CI 1.03-1.48), P = 0.02], more specifically for potassium nitrate. High consumers of food additive nitrites had higher prostate cancer risk [HR = 1.58 (1.14-2.18), P = 0.008], specifically for sodium nitrite. Although similar HRs were observed for colorectal cancer for additive nitrites [HR = 1.22 (0.85-1.75)] and nitrates [HR = 1.26 (0.90-1.76)], no association was detected, maybe due to limited statistical power for this cancer location. No association was observed for natural sources. CONCLUSION: Food additive nitrates and nitrites were positively associated with breast and prostate cancer risks, respectively. Although these results need confirmation in other large-scale prospective studies, they provide new insights in a context of lively debate around the ban of these additives from the food industry.