Identification of pesticide mixtures to which French agricultural workers and farm-owners are exposed: Results from the Agriculture and Cancer (AGRICAN) cohort study.

Farmers, particularly in Europe, are exposed to multiple pesticides during their working life. Such exposures can cause adverse health outcomes. We aimed to identify the main pesticide mixtures to which French agricultural workers are exposed and to classify farmers into clusters based on their mixture exposure profile. The AGRICAN cohort includes farm-owners and farm workers enrolled from 2005 to 2007, with information on exact years of beginning and end of pesticide use on 11 crops and five livestock. We estimated duration of exposure to 390 pesticides identified with the PESTIMAT crop-exposure matrix for 16,905 male pesticide users from 1950 to 2009. We used a Sparse Non-negative Matrix Under-approximation to identify the main pesticide mixtures based on exposure duration, and then applied hierarchical agglomerative clustering to classify farmers sharing similar profiles of co-exposure to the mixtures. SNMU suggested 6 optimal numbers of mixtures (4, 7, 11, 15, 27, 38) explaining from 29 to 91 % of total variance. We selected 27 mixtures. Mixtures contained between four to 22 pesticides and mostly concerned the use of pesticides on wheat/barley, vineyards, corn, fruit and vegetables or on multiple crops together. We selected 11 clusters composed of 395 to 4521 farmers. Some had a higher proportion of individuals working on specific crops (as vineyard or corn), while others were characterized by the diversity of crops (cluster 8:"Permanent crops, potatoes and tobacco"). This is the first study to identify pesticide mixtures in farmers and to classify them into clusters based on their mixture exposure profiles. The next step will be to study the associations between pesticide mixtures and health outcomes such as prostate cancer in AGRICAN.

Colorectal cancer among farmers in the AGRICAN cohort study.

OBJECTIVES: Specific farming types and tasks have rarely been studied in relation to colorectal cancer (CRC). We evaluated associations between 5 types of livestock and 13 types of crops in relation to CRC and its subsites within the Agriculture and Cancer (AGRICAN) study. METHODS: AGRICAN cohort includes 181,842 agricultural workers living in 11 French geographical areas. Data on farming types and tasks was collected by self-administered questionnaires. We identified 2 609 CRC, 972 right colon, 689 left colon and 898 rectal incident cancer cases during follow-up from 2005 to 2015. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). RESULTS: Significantly increased CRC risk was observed for farmers producing horses (HR=1.18, 95% CI 1.06-1.31), sunflower (HR=1.23, 95% CI 1.03-1.45) and field vegetables (HR=1.18, 95% CI 1.02-1.36). Positive associations were also observed for pig, poultry and wheat/barley. Some associations were observed only for specific subsites: left colon cancer was associated with fruit growing (HR=1.36, 95% CI 1.09-1.70) and potato (HR=1.28, 95% CI 1.05-1.57). Tasks related to livestock (animal care, insecticide treatment, disinfection of milking equipment and building) or to crop (haymaking, sowing, pesticide treatment, seed treatment, harvesting) were also associated with CRC. Duration and size of farming types/task increased the risk for some of the associations. Analysis stratified by sex suggested an interaction with several farming types/task. CONCLUSIONS: The current study showed original and positive findings for several farming types and tasks and CRC risk, overall and by subsites.

S-Nitrosoglutathione Limits Apoptosis and Reduces Pulmonary Vascular Dysfunction After Bypass.

BACKGROUND: During hypoxia or acidosis, S-nitrosoglutathione (GSNO) has been shown to protect the cardiomyocyte from ischemia-reperfusion injury. In a randomized double-blinded control study of a porcine model of paediatric cardiopulmonary bypass (CPB), we aimed to evaluate the effects of 2 different doses (low and high) of GSNO. METHODS: Pigs weighing 15-20 kg were exposed to CPB with 1 hour of aortic cross-clamp. Prior to and during CPB, animals were randomized to receive low-dose (up to 20 nmol/kg/min) GSNO (n = 8), high-dose (up to 60 nmol/kg/min) GSNO (n = 6), or normal saline (n = 7). Standard cardiac intensive care management was continued for 4 hours post-bypass. RESULTS: There was a reduction in myocyte apoptosis after administration of GSNO (P = .04) with no difference between low- and high-dose GSNO. The low-dose GSNO group had lower pulmonary vascular resistance post-CPB (P = .007). Mitochondrial complex I activity normalized to citrate synthase activity was higher after GSNO compared with control (P = .02), with no difference between low- and high-dose GSNO. CONCLUSIONS: In a porcine model of CPB, intravenous administration of GSNO limits myocardial apoptosis through preservation of mitochondrial complex I activity, and improves pulmonary vascular resistance. There appears to be a dose-dependent effect to this protection.

Agriculture Exposure and Time to Pregnancy Among Women Enrolled in the French Prospective Cohort AGRICAN.

OBJECTIVES: In few retrospective studies, prolonged time-to-pregnancy (TTP) was observed for women exposed to pesticides especially in flower production. The present study investigated time-to-pregnancy in the AGRICAN cohort. METHODS: Analyses were performed on 616 women reporting a pregnancy (2005 to 2017), and data on agricultural activities performed before the last pregnancy was retrospectively collected. Fecundability odds ratios (fOR) were estimated using a discrete time analogue of Cox proportional hazard model adjusted on maternal and paternal age, body mass index (BMI), and alcohol consumption. RESULTS: A decrease in fecundability was non-significantly associated with farm work (adjusted fOR = 0.86; 95% confidence interval [CI]: 0.71 to 1.05). Decreases were also observed for nightwork (afOR = 0.75; 95% CI: 0.49 to 1.15) and exposure to vibrations (afOR = 0.68; 95% CI: 0.43 to 1.09). CONCLUSION: Women working on a farm before conception appeared to experience a longer TTP. Negative associations were suggested for some agricultural activities and working conditions.

Paediatric multisystem inflammatory syndrome associated with COVID-19: filling the gap between myocarditis and Kawasaki?

Myocarditis and Kawasaki disease are common but usually distinct diseases in children. During the coronavirus pandemic (COVID-19), reports of a new form of myocarditis with clinical features of Kawasaki appeared. We investigated the place of this new disease in the spectrum encompassing Kawasaki disease and myocarditis.Thirty two consecutive children referred to our centre for a suspicion of Kawasaki or a diagnosis of myocarditis were included and eventually divided into four groups: 11 Kawasaki diseases, 6 Kawasaki syndromes (children with another diagnosis), 7 myocarditis without Kawasaki clinical feature and 7 myocarditis with incomplete Kawasaki clinical features. All were treated with immunoglobulins except those of the myocarditis group. The survival rate was 91%. The 7 children with myocarditis and clinical features of incomplete Kawasaki were all positive for SARS-CoV-2. They had a transient myocardial failure with a favourable course and none had coronary artery disease.Conclusion: Every COVID-19 child within our population had a mild to severe myocarditis and presented with fever plus two or three Kawasaki clinical features. Short-term evolution was good for these children. This new disease seems to fill the gap between isolated myocarditis and Kawasaki disease. What is Known: • A new paediatric disease close to Kawasaki disease appeared during the COVID-19 pandemic What is New: • In our population, children presented with fever, vivid Kawasaki clinical features (although the Kawasaki syndrome was always incomplete) and a myocarditis without coronary abnormalities. • The new disease fills the gap between paediatric myocarditis and Kawasaki disease but its prognosis is much better.

Left ventricular assist device-associated infections: incidence and risk factors.

BACKGROUND: Left ventricular assist device (LVAD)-associated infections are major complications that can lead to critical outcomes. The aims of this study were to assess the incidence of and to determine the risk factors for LVAD-associated infections. METHODS: We included all consecutive patients undergoing LVAD implantation between January 1, 2010, and January 1, 2019, in a single institution. Infection-related data were retrospectively collected by review of patient's medical files. LVAD-associated infections were classified into three categories: percutaneous driveline infections, pocket infections and pump and/or cannula infections. RESULTS: We enrolled 72 patients. Twenty-one (29.2%) patients presented a total of 32 LVAD-associated infections. Eight (38.1%) patients had more than one infection. Five (62.5%) pocket infections and one (50.0%) pump and/or cannula infection were preceded by a driveline infection. The median delay between the operation and LVAD-associated infection was 6.5 (1.4-12.4) months. The probability of having a LVAD-associated infection at one year after receiving an implant was 26.6% (95% CI: 17.5-40.5%). Percutaneous driveline infections represented 68.7% of all LVAD-associated infections. Staphylococcus aureus and coagulase-negative staphylococci were the predominant bacteria in LVAD-associated infections (53.1% and 15.6%, respectively). Hospital length of stay (sdHR =1.22 per 10 days; P=0.001) and postoperative hemodialysis (sdHR =0.17; P=0.004) were statistically associated with infection. Colonization with multidrug-resistant bacteria was more frequent in patients with LVAD-associated infections than in others patients (42.9% vs. 15.7%; P=0.013). CONCLUSIONS: LVAD-associated infections remain an important complication and are mostly represented by percutaneous driveline infections. Gram-positive cocci are the main pathogens isolated in microbiological samples. Patients with LVAD-associated infections are more frequently colonized with multidrug-resistant bacteria.

Minimally invasive surgery for left ventricular assist device implantation is safe and associated with a decreased risk of right ventricular failure.

BACKGROUND: Right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation is associated with significant mortality and morbidity. The objective of this study was to determine pre- and postoperative risk factors associated with the occurrence of RVF after LVAD implantation. METHODS: This retrospective study included 68 patients who received LVADs between 2010 and 2018 either for bridge to transplant (40 patients, 58.8%) or bridge to destination therapy (28 patients, 41.2%). RVF after LVAD implantation was defined according to the INTERMACS classification. The primary endpoint was the occurrence of RVF. The secondary endpoints were hospital mortality and morbidity and long-term survival. RESULTS: The majority of patients (61.8%) had an INTERMACS profile 1 (36.8%) or 2 (25.0%). The LVAD was implanted either by sternotomy (37 patients, 54.4%) or thoracotomy (31 patients, 45.6%). RVF after LVAD implantation was observed in 32 patients (47.1%). In univariate analysis, an elevated serum glutamic oxaloacetic transaminase (SGOT) (P=0.028) and a high preoperative vasoactive inotropic score (VIS) (P=0.028) were significantly associated with an increased risk of RVF, whereas the implantation of LVAD through a thoracotomy approach was associated with a significant reduction in this risk (P=0.006). The multivariate analysis demonstrated that only the thoracotomy approach was significantly associated with decreased risk of RVF (odds ratio =0.33, 95% confidence interval: 0.17-0.96; P=0.042). Hospital mortality was 53.1% and 5.6% in the RVF and control groups, respectively (P<0.0001). The incidence of stroke and postoperative acute renal failure were significantly increased in the RVF group compared with the control group. The survival after LVAD implantation was 33.5%±9.0% and 85.4%±6.0% at 1 year in the RVF and control groups, respectively (P<0.0001). CONCLUSIONS: LVAD implantation by thoracotomy significantly reduced the risk of postoperative RVF. This surgical approach should, therefore, be favored.

Multiple left-sided stenotic lesions: outcomes after mitral valve surgery. Arguments for abandoning the eponym 'Shone syndrome'.

OBJECTIVES: Management of patients with left ventricular inflow and outflow stenotic lesions can be challenging. Our purpose was to characterize such patients and review the long-term outcomes of those requiring mitral valve (MV) surgery. METHODS: We performed a retrospective study of 40 patients with subaortic, aortic and/or arch stenotic lesion(s) who underwent MV surgery between 1985 and 2016. RESULTS: Associated left-sided stenotic lesions included aortic valve stenosis in 20 patients (50%), subaortic stenosis in 19 (47.5%) patients, coarctation in 23 (57.5%) patients and hypoplastic aortic arch in 16 (40%) patients. Nineteen patients (47.5%) had a supravalvular mitral ring and 15 (37.5%) patients had a parachute MV. The overall mortality rate was 32.5% (13 patients) with a mean follow-up of 16.3 ± 1.8 years. Being <6 months of age at the time of MV surgery (P = 0.02) and having had previous neonatal aortic valve and/or arch surgery (P = 0.01) were associated with death. The incidence of reoperation (95% confidence interval) at 1, 5, 10 and 15 years was 38% (23-53%), 54% (38-70%), 68% (53-84%) and 85% (72-98%), respectively. CONCLUSIONS: Results after MV surgery for children with associated left-sided stenotic lesions are closely age-related. The need for mitral intervention shortly after the initial aortic valve and/or arch intervention was a predictor of dismal outcomes.

Occupational exposure to pesticides and multiple myeloma in the AGRICAN cohort.

PURPOSE: Epidemiological studies have found an increased risk of multiple myeloma (MM) in farmers. Few studies have investigated the detailed circumstances of occupational pesticide exposure which could explain these increased risks (pesticide use on crops, seeds or on animals, contact with treated crops) and the role of other exposures. In the Agriculture and Cancer cohort (AGRICAN), we assessed the associations between MM and crop- or animal-related activities, with specific attention to pesticide exposure via use on animals and crops or contact with treated crops and to disinfectant exposure. METHODS: Analyses concerned 155,192 participants, including 269 incident MM identified by cancer registries from enrolment (2005-2007) to 2013. Cox models using attained age as time scale were run to calculate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: MM risk was increased in farmers (i) who started using pesticides on crops in the 1960s, especially among those applying pesticides on corn (≥ 20 years: HR 1.73, 95% CI 1.08, 2.78, p for trend < 0.01) and (ii) using insecticides on animals (HR 1.48, 95% CI 1.11, 1.98), especially among horse farmers (≥ 10 years: HR 2.77, 95% CI 1.22-6.27, p for trend = 0.01). We also observed significant elevated risks with disinfectant use in animal barns. CONCLUSIONS: Findings support the role of pesticide use on crops and animals in the occurrence of MM risk in farmers.

EPA:DHA 6:1 is a superior omega-3 PUFAs formulation attenuating platelets-induced contractile responses in porcine coronary and human internal mammary artery by targeting the serotonin pathway via an increased endothelial formation of nitric oxide.

At arterial sites of endothelial denudation and dysfunction, activated platelets contribute to vascular injury through the release of potent contracting factors such as serotonin (5-HT). This study evaluated whether omega-3 polyunsaturated fatty acids (PUFAs), known to protect the vascular system, are able to prevent platelets-induced contractile responses in isolated arteries and, if so, to investigate the underlying mechanism and the importance of the omega-3 PUFAs formulation. Porcine coronary arteries (PCA), human internal mammary arteries (IMA) and washed human platelets were prepared and vascular reactivity was studied in organ chambers. In PCA rings, aggregating platelets caused concentration-dependent contractions that were significantly inhibited by the 5-HT2A receptor antagonist ketanserin, and by EPA:DHA 6:1 but not EPA:DHA 1:1 at 0.4% v/v. EPA:DHA 6:1 also prevented the 5-HT-induced contractions but affected only slightly those to the thromboxane A2 analogue U46619. The inhibitory effect of EPA:DHA 6:1 on platelets-induced contractions was not observed in rings without endothelium, and prevented by an eNOS inhibitor but not by inhibitors of endothelium-dependent hyperpolarization. In IMA rings, EPA:DHA 6:1 but not EPA:DHA 1:1 at 0.4% v/v significantly prevented the 5-HT-induced contraction, and induced greater endothelium-dependent relaxations than bradykinin and acetylcholine sensitive to an eNOS inhibitor. EPA:DHA 6:1 strongly inhibits platelets- and 5-HT-induced contractions in PCA rings and those to 5-HT in IMA rings most likely through an increased endothelial formation of NO. These findings suggest that the omega-3 PUFAs EPA:DHA 6:1 formulation may be of interest to prevent platelets-induced vascular injury at arterial sites of endothelial dysfunction.

Surgical stabilization for multiple rib fractures: whom the benefit? -a prospective observational study.

BACKGROUND: Surgical repair has demonstrated a beneficial effect on outcome for patients presenting with flail chest or with multiple rib fractures. We hypothesized that benefit on outcome parameters concerns predominantly patients being extubated within 24 hours post-operatively. METHODS: We prospectively recorded all patients presenting with chest traumatism eligible for surgical repair with anticipated early extubation according to our institutional consensus (flail chest, major deformity, poor pain control, associated lesions requiring thoracotomy). We compared outcomes of patients extubated within 24 hours post-operatively to those who required prolonged ventilator support. We tested predictive factors for prolonged intubation with univariate and multivariate analysis. RESULTS: From 2010 to 2014, 132 patients required surgical repair. Two thirds were extubated within 24 hours following surgical repair. Pneumonia was the main complication and occurred in 30.3% of all patients. Patients extubated within 24 hours following surgical repair had significantly shorter ICU stay and shorter in-hospital stay (P<0.0001 both). Pneumonia occurred significantly more often in patients with longer mechanical ventilation (over 24 hours) (P<0.0001) and the overall post-operative complications rate was higher (P=0.0001). Main independent risk factors for delayed extubation were bilateral chest rib fractures and initially associated pneumothorax. CONCLUSIONS: We conclude that patients extubated within 24 hours after repair have an improved outcome with reduced complication rate and shorter hospital stay. The initial extent of the trauma is an important risk factor for delayed extubation and high complication rate despite surgical stabilization.

Partition of Common Atrioventricular Valve in a Patient With Dextrocardia and Univentricular Circulation.

Long-term outcomes in children with atrioventricular septal defect (AVSD) and univentricular palliation are of concern, with <60% survival at 25 years.1 Common atrioventricular valves (AVV) often become insufficient in patients with univentricular physiology, leading to heart failure.1,2 We have recently observed that outcomes of children with AVSD who reach Fontan circulation are not as bad as previously thought, provided that the AVV remains competent.1 Common AVV surgery is associated with substantial mortality and reoperation rates.3 Although successful AVV repair is associated with better survival and freedom from reoperation, good quality repair is difficult to achieve in univentricular circulation,3 especially in patients with dextrocardia.4 Herein, we report a patient with unbalanced AVSD and dextrocardia who underwent AVV repair using the "polytetrafluoroethylene (Gore-Tex, W.L. Gore & Associates, Flagstaff, AZ) bridge" technique5 with excellent early outcome.

Right coronary artery arising within an aorta-to-left ventricle tunnel: surgical repair in a neonate.

We herein describe the successful surgical repair of a very rare combination of an aorta-to-left ventricle tunnel with the right coronary artery arising from it. The neonate presented with signs of heart failure due to significant regurgitation of blood via the tunnel. The closure of the tunnel was feasible during neonatal period without patches.

Surgical Management of Extensive Perinatal Myocardial Infarction.

Extensive perinatal myocardial infarction caused by coronary artery thrombosis is extremely rare and has a dismal prognosis. We report a 3.5-kg neonate who presented at birth with an extensive myocardial infarction caused by aortic root and left main coronary artery thrombus after an emergency cesarean section. We performed emergency surgical thrombectomy and insertion of extracorporeal membrane oxygenation support. After subsequent conversion to long-term left ventricular assist device with an EXCOR device (Berlin Heart, Berlin, Germany), the patient had no ventricular recovery after 163 days of support. He was successfully bridged to transplantation.