A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH.

BACKGROUND: Management of nonalcoholic steatohepatitis (NASH) is an unmet clinical need. Lanifibranor is a pan-PPAR (peroxisome proliferator-activated receptor) agonist that modulates key metabolic, inflammatory, and fibrogenic pathways in the pathogenesis of NASH. METHODS: In this phase 2b, double-blind, randomized, placebo-controlled trial, patients with noncirrhotic, highly active NASH were randomly assigned in a 1:1:1 ratio to receive 1200 mg or 800 mg of lanifibranor or placebo once daily for 24 weeks. The primary end point was a decrease of at least 2 points in the SAF-A score (the activity part of the Steatosis, Activity, Fibrosis [SAF] scoring system that incorporates scores for ballooning and inflammation) without worsening of fibrosis; SAF-A scores range from 0 to 4, with higher scores indicating more-severe disease activity. Secondary end points included resolution of NASH and regression of fibrosis. RESULTS: A total of 247 patients underwent randomization, of whom 103 (42%) had type 2 diabetes mellitus and 188 (76%) had significant (moderate) or advanced fibrosis. The percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher among those who received the 1200-mg dose, but not among those who received the 800-mg dose, of lanifibranor than among those who received placebo (1200-mg dose vs. placebo, 55% vs. 33%, P = 0.007; 800-mg dose vs. placebo, 48% vs. 33%, P = 0.07). The results favored both the 1200-mg and 800-mg doses of lanifibranor over placebo for resolution of NASH without worsening of fibrosis (49% and 39%, respectively, vs. 22%), improvement in fibrosis stage of at least 1 without worsening of NASH (48% and 34%, respectively, vs. 29%), and resolution of NASH plus improvement in fibrosis stage of at least 1 (35% and 25%, respectively, vs. 9%). Liver enzyme levels decreased and the levels of the majority of lipid, inflammatory, and fibrosis biomarkers improved in the lanifibranor groups. The dropout rate for adverse events was less than 5% and was similar across the trial groups. Diarrhea, nausea, peripheral edema, anemia, and weight gain occurred more frequently with lanifibranor than with placebo. CONCLUSIONS: In this phase 2b trial involving patients with active NASH, the percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher with the 1200-mg dose of lanifibranor than with placebo. These findings support further assessment of lanifibranor in phase 3 trials. (Funded by Inventiva Pharma; NATIVE ClinicalTrials.gov number, NCT03008070.).

Polychlorinated Naphthalenes in Foods from the French Market: Occurrence, Dietary Exposure, and Evaluation of Relative Contributions to Dioxin-like Contaminants.

Despite the growing interest in PCNs and the dioxin-like toxicity exhibited by a number of congeners, a comprehensive assessment of their contribution to the cocktail of dioxin-like contaminants is still lacking. To address such a shortcoming, this study investigated the PCN contamination in foodstuffs recently acquired in France, together with that of the regulatory polychlorinated dibenzodioxins/furans (PCDD/Fs) and polychlorinated biphenyls (PCBs). PCNs were ubiquitous at levels (∑70 PCNs = 2.5-150 pg g-1 wet weight) similar to those reported in other countries, with maximum concentrations observed in fish and fishery products from the North-East Atlantic Ocean. Their congener patterns further suggested unintentional releases of PCNs, while those of the other foodstuffs were correlated to the historical PCN profiles. Low risk from dietary exposure was estimated (∑70 PCNs-EDIs of 60-360 pg kg-1 bw d-1, ∑24 PCNs-TEQ-EDIs of 8 × 10-3-2.2 × 10-2 pg TEQ kg-1 bw d-1), with milk and dairy products being the highest contributors, followed by meat and meat products. Finally, the rather high contributions of PCNs to the total PCNs+PCDD/Fs+PCBs concentrations (0.9-50%, average of 9%) and the toxic equivalents (0.2-24%, average of 5%) show that these substances are not minor components of the PCNs+PCDD/Fs+PCBs cocktail.

Blood levels of persistent organic pollutants among women in France in the 90's: Main profiles and individual determinants.

CONTEXT AND OBJECTIVES: Persistent organic pollutants (POPs) are a group of organic chemical compounds potentially toxic to human health. The objectives of this study were 1) to describe the levels of POPs biomarkers in blood samples from French women collected during the 1990s and to compare them with levels measured in two more recent French studies, 2) to identify POPs exposure profiles, and 3) to explore their main determinants. METHODS: 73 POPs biomarkers were measured in the blood of 468 women from the French E3N cohort (aged 45-73 years), collected between 1994 and 1999: 28 per- and polyfluoroalkyl substances, 27 organochlorine pesticides, 14 polychlorinated biphenyls and 4 polybrominated diphenyl ethers. POPs biomarker levels were described and compared with levels measured in two more recent French studies conducted by the French National Public Health Agency, the ENNS and Esteban studies. Principal component analysis was performed on POPs quantified in at least 75% of samples to identify the main exposure profiles. Linear regression models were used to estimate the associations between anthropometric, socio-demographic and lifestyle characteristics and exposure to these profiles. RESULTS: Among the 73 biomarkers measured, 41 were quantified in more than 75% of samples. Levels of most pollutants that were also measured in the Esteban of ENNS studies have decreased over time. Six POPs exposure profiles were revealed, explaining 62.1% of the total variance. Most of the characteristics studied were associated with adherence to at least one of these profiles. CONCLUSION: This study highlighted that most of the pollutants for which a comparison was possible decreased over the 10 or 20 years following the E3N blood collection, and identified those which, on the contrary, tended to increase. The health effects of the profiles identified could be assessed in future studies. The determinants identified should be confirmed in larger populations.

Mixtures of persistent organic pollutants and ovarian function in women undergoing IVF.

RESEARCH QUESTION: Do internal levels of persistent organic pollutants (POP) in serum and follicular fluid affect ovarian function of women attending IVF? DESIGN: This cohort study included 136 women undergoing IVF in the assisted reproductive technology (ART) service of University Hospital from Nantes (France). Representative POP were measured using gas and liquid chromatography coupled with tandem mass spectrometry. Polyfluoroalkylated and perfluoroalkylated substances were measured in serum and polychlorinated biphenyls and organochlorinated pesticides in follicular fluid. Statistical associations between POP and ovarian reserve markers (anti-Müllerian Hormone [AMH] and antral follicle count [AFC], and ovarian responsiveness markers (Ovarian Sensitivity Index [OSI] and Follicular Output RaTe [FORT]), were explored in single and multipollutant regression models. RESULTS: Twenty-seven out of 53 POP congeners were frequently detected in almost all women attending IVF. Adjusted models did not show statistically significant associations between POP and ovarian reserve markers. Positive associations were found between some POP, i.e. hexachlorobenzene with FORT (ß 0.42, 95% CI 0.13 to 0.71, P = 0.005) or PCB52 with Ovarian Sensitivity Index (ß 0.22; 95% CI, 0.07 to 0.38, P = 0.005). Negative associations between some polyfluoroalkylated and perfluoroalkylated substances, PCB189 and trans-nonachlor with AFC and AMH were found among current smokers. CONCLUSIONS: Globally, associations between POP and the markers of ovarian function or responsiveness were lacking. Nonetheless, the stratification analysis suggested that current smoking could be a risk modifier, and extension of the study to a larger population sample size is needed.

Persistent organochlorine pesticides in periprostatic adipose tissue from men with prostate cancer: Ethno-geographic variations, association with disease aggressiveness.

Although several studies have examined the relationship between organochlorine pesticides (OCPs) and prostate cancer (PCa) risk, no data are available concerning the association between OCPs concentrations in periprostatic adipose tissue (PPAT), which reflects cumulative exposure, and PCa aggressiveness. Moreover, no previous study has compared OCPs exposure in two distinct ethno-geographical populations. The objectives were to analyze OCPs in PPAT of PCa patients from either Mainland France or French West Indies in correlation with features of tumor aggressiveness, after adjusting for potential confounders such age, BMI, and polyunsaturated fatty acid (PUFA) content of PPAT. PPAT was analyzed in 160 patients (110 Caucasians and 50 African-Caribbeans), 80 with an indolent tumor (ISUP group 1 + pT2), and 80 with an aggressive tumor (ISUP group more than 3 + pT3). The concentrations of 29 OCPs were measured in PPAT concomitantly with the characterization of PUFA content. Exposure patterns of OCPs differed according to the ethno-geographical origin. Most OCPs were found at higher concentration in Caucasian patients, whereas pp'-DDE content was twice as high in African-Caribbeans. Chlordecone was only detected in PPAT from African-Caribbean patients. Most OCP concentrations were positively correlated with age, and some with BMI. After adjusting for age, BMI, and PUFA composition of PPAT, no significant association was found between OCPs content and risk of aggressive disease, except of mirex which appeared inversely associated with aggressive features of PCa in Caucasian patients. These results highlight a significant ethno-geographic variation in internal exposure to OCPs, which likely reflects differences in consumption patterns. The inverse relationship observed between mirex concentration and markers of PCa aggressiveness need to be further investigated.

A percutaneous ultrasound-guided iliotibial band release technique reduces surgical time and costs compared to an endoscopic technique.

PURPOSE: External snapping hip is caused by the iliotibial band snapping from the greater trochanter during hip movement. The aim of this study was to compare a technique of ultrasound-guided iliotibial band release versus a similar endoscopic technique. METHODS: An anatomical study was performed on 10 cadavers i.e. 20 hips. The same operator performed ultrasound-guided and endoscopic iliotibial band release on either side of each specimen. An independent operator performed an open control to verify the outcome measures. The primary outcome was iliotibial cutting percentage, defined as the ratio of the transversal cut distance and the width of the iliotibial at the most prominent portion of the great trochanter. Secondary outcomes included nerve injuries. The surgical time was assessed and disposable medical supplies costs were estimated. RESULTS: The average cutting percentage was 95% ± 8 by ultrasound, compared with 91% ± 11 by endoscopy (n.s.). No iatrogenic lesions were found, particularly nerve damage. The average duration of the ultrasound procedure was 12.3 minutes ± 6 compared to 21 minutes ± 10.7 for endoscopy (p=0.04), with a 3-fold decrease between the first and last procedure, regardless of the technique. The ultrasound procedure was 3 times less expensive in terms of disposable medical supplies (120.5€ versus 353.5€). CONCLUSION: This technique of ultrasound-guided iliotibial band release appears to be as effective and safe as a similar endoscopic technique. The surgical time is reasonable for a surgeon trained in ultrasound, with lower disposable supplies costs. A comparative clinical study is further needed to assess the actual benefits of each technique.

Varus stem positioning does not affect long-term functional outcome in cementless anatomical total hip arthroplasty.

INTRODUCTION: Varus positioning is the most common femoral malposition in total hip arthroplasty (THA). We compared the long-term outcomes of an anatomical cementless femoral stem positioned in varus versus neutral alignment. MATERIALS AND METHODS: Data were retrospectively reviewed for all patients receiving a cementless anatomical femoral stem in THA for osteoarthritis between 1998 and 2008. Exclusion criteria were complex cases, incomplete data or follow-up < 1 year. Primary outcome was survival rate with complications and secondary outcomes were clinical scores, thigh pain, radiological score, cortical hypertrophy and filling rate. RESULTS: Of the 283 included patients, 127 stems were classified as varus and 156 neutral. Mean follow-up was 10 years. Femoral stem size was smaller in the varus group (4.1 vs. 4.4, p = 0.047). A stem-filling rate < 80% was more frequent in the varus group (p < 0.001). The long-term survival rate without any revision procedure was 94.8% ± 2.3% (95%CI 88.4-98.7) in the varus group and 94.1% ± 2.0% (95%CI 91.3-99.1) in the neutral group (p = 0.55). There was no difference in clinical scores, thigh pain or complication occurrence between groups. The Engh-Massin score was lower in the varus group (p < 0.01) and cortical hypertrophy was higher (p < 0.001). CONCLUSIONS: A varus alignment of a cementless anatomic femoral stem does not affect survivorship, clinical outcomes or complication rate on an average follow-up of 10 years, despite increasing stress-shielding rates.

Oral treatment for mucopolysaccharidosis VI: Outcomes of the first phase IIa study with odiparcil.

Mucopolysaccharidosis (MPS) disorders are a group of rare, progressive lysosomal storage diseases characterized by the accumulation of glycosaminoglycans (GAGs) and classified according to the deficient enzyme. Enzyme replacement therapy (ERT) of MPS VI has limited effects on ophthalmic, cardiovascular, and skeletal systems. Odiparcil is an orally available small molecule that results in the synthesis of odiparcil-linked GAGs facilitating their excretion and reducing cellular and tissue GAG accumulation. Improve MPS treatment was a Phase 2a study of the safety, pharmacokinetics/pharmacodynamics, and efficacy of two doses of odiparcil in patients with MPS VI. The core study was a 26-week, randomized, double-blind, placebo-controlled trial in patients receiving ERT and an open-label, noncomparative, single-dose cohort not receiving ERT. Patients aged ≥ 16 years receiving ERT were randomized to odiparcil 250 or 500 mg twice daily or placebo. Patients without ERT received odiparcil 500 mg twice daily. Of 20 patients enrolled, 13 (65.0%) completed the study. Odiparcil increased total urine GAGs (uGAGs), chondroitin sulfate, and dermatan sulfate concentrations. A linear increase in uGAG levels and odiparcil exposure occurred with increased odiparcil dose. Odiparcil demonstrated a good safety and tolerability profile. Individual analyses found more improvements in pain, corneal clouding, cardiac, vascular, and respiratory functions in the odiparcil groups vs placebo. This study confirmed the mechanism of action and established the safety of odiparcil with clinical beneficial effects after only a short treatment duration in an advanced stage of disease. Further assessment of odiparcil in younger patients is needed.

Perfluorinated alkylated substances serum concentration and breast cancer risk: Evidence from a nested case-control study in the French E3N cohort.

Endocrine-disrupting chemicals are proposed to increase breast cancer (BC) incidence. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), two perfluorinated alkylated substances (PFASs), are suspected to be ubiquitously present in the blood of human population worldwide. We investigated the associations between serum concentrations of these substances and BC risk. Etude Epidémiologique auprès de femmes de l'Education Nationale is a cohort of 98,995 French women born in 1925-1950 and followed up since 1990. We sampled 194 BC cases and 194 controls from women with available blood samples. Serum concentrations of PFASs were measured by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Adjusted conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two sided. While PFASs concentrations were not associated with BC risk overall, we found positively linear associations between PFOS concentrations and the risk of ER+ (3rd quartile: OR = 2.22 [CI = 1.05-4.69]; 4th quartile: OR = 2.33 [CI = 1.11-4.90]); Ptrend = 0.04) and PR+ tumors (3rd quartile: OR = 2.47 [CI = 1.07-5.65]; 4th quartile: OR = 2.76 [CI = 1.21-6.30]; Ptrend = 0.02). When considering receptor-negative tumors, only the 2nd quartile of PFOS was associated with risk (ER-: OR = 15.40 [CI = 1.84-129.19]; PR-: OR = 3.47 [CI = 1.29-9.15]). While there was no association between PFOA and receptor-positive BC risk, the 2nd quartile of PFOA was positively associated with the risk of receptor-negative tumors (ER-: OR = 7.73 [CI = 1.46-41.08]; PR-: OR = 3.44 [CI = 1.30-9.10]). PFAS circulating levels were differentially associated with BC risk. While PFOS concentration was linearly associated with receptor-positive tumors, only low concentrations of PFOS and PFOA were associated with receptor-negative tumors. Our findings highlight the importance of considering exposure to PFASs as a potential risk factor for BC.

Plasma concentration of brominated flame retardants and postmenopausal breast cancer risk: a nested case-control study in the French E3N cohort.

BACKGROUND: Brominated flame retardants (BFRs) are lipophilic substances with endocrine-disrupting properties. To date, only few investigations, mainly retrospective case-control studies, have explored the link between internal levels of BFRs and the risk of breast cancer, leading to conflicting results. We investigated the associations between plasma concentrations of two main groups of BFRs, PBDEs (pentabromodiphenyl ethers) and PBBs (polybrominated biphenyls), and the risk of breast cancer in a nested case-control study. METHODS: A total of 197 incident breast cancer cases and 197 controls with a blood sample collected in 1994-1999 were included. Plasma levels of PBDE congeners (BDE-28, BDE-47, BDE-99, BDE-100, BDE153, BDE-154) and of PBB-153 were measured by gas chromatography coupled to high-resolution mass spectrometry. Conditional logistic regression models, adjusted for potential confounders, were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Women were aged 56 years on average at blood draw. All cases, except for one, were diagnosed after menopause, with an average age at diagnosis of 68 years. Overall, we found no evidence of an association between plasma levels of PBDEs and PBB-153 and postmenopausal breast cancer risk (log-concentrations of BFRs yielding non-statistically significant ORs of 0.87 to 1.07). The analysis showed a non-linear inverse association for BDE-100 and BDE-153 and postmenopausal breast cancer risk; nevertheless, these findings were statistically significant only when the exposure was modeled as ng/L plasma (third vs. first quintile: OR = 0.42, 95%CI = 0.19-0.93 and OR = 0.42, 95%CI = 0.18-0.98, respectively) and not when modeled as ng/gr of lipids (OR = 0.58, 95%CI = 0.27-1.25 and OR = 0.53, 95%CI = 0.25-1.17). These results were unchanged in stratified analyses by tumor hormone receptor expression or body mass index. CONCLUSIONS: Our results suggest no clear association between internal levels of PBDEs and PBB-153 and the risk of breast cancer in postmenopausal women. However, these findings need to be carefully interpreted, taking into account limitations due to the limited number of women included in the study, the lack of information concerning genetic susceptibility of cases, and the unavailability of exposure assessment during critical windows of susceptibility for breast cancer. More studies are warranted to further investigate the relationships between PBDE and PBB exposure and breast cancer risk.

Local neighbourhood and regional climatic contexts interact to explain tree performance.

Tree neighbourhood modelling has significantly contributed to our understanding of the mechanisms structuring communities. Investigations into the impact of neighbouring crowding on tree performance have generally been conducted at local scales, missing important regional-scale context such as the suitability of the climate for each species. Favourable climates may enhance tree performance, but this may come at the cost of increased neighbourhood crowding and competition negatively impacting survival and growth. Through the synthesis of continental-scale forest inventory and trait datasets from the northeast USA and Puerto Rico we present an analytical approach that elucidates the important interactions between local competitive and regional climatic contexts. Our results show strong asymmetries in competitive interactions and significant niche differences that are dependent on habitat suitability. The strong interaction between local neighbourhood and regional climate highlights the need for models that consider the interaction between these two processes that have been previously ignored.

Marine Socio-Environmental Covariates: queryable global layers of environmental and anthropogenic variables for marine ecosystem studies.

Biophysical conditions, including climate, environmental stress, and habitat availability, are key drivers of many ecological processes (e.g., community assembly and productivity) and associated ecosystem services (e.g., carbon sequestration and fishery production). Furthermore, anthropogenic impacts such as coastal development and fishing can have drastic effects on the structure and function of marine ecosystems. Scientists need to account for environmental variation and human impacts to accurately model, manage, and conserve marine ecosystems. Although there are many types of environmental data available from global remote sensing and open-source data products, some are inaccessible to potential end-users because they exist as global layers in high temporal and spatial resolutions which require considerable computational power to process. Additionally, coastal locations often suffer from missing data or data quality issues which limit the utility of some global marine products for coastal sites. Herein we present the Marine Socio-Environmental Covariates dataset for the global oceans, which consists of environmental and anthropogenic variables summarized in ecologically relevant ways. The dataset includes four sets of environmental variables related to biophysical conditions (net primary productivity models corrected for shallow-water reflectance, wave energy including sheltered-coastline corrections) and landscape context (coral reef and land cover within varying radii). We also present two sets of anthropogenic variables, human population density (within varying radii) and distance to large population center, which can serve as indicators of local human impacts. We have paired global, summarized layers available for download with an online data querying platform that allows users to extract data for specific point locations with finer control of summary statistics. In creating these global layers and online platform, we hope to make the data accessible to a wide array of end-users with the goal of advancing marine ecosystem studies.

Tissue Uptake, Distribution, and Elimination of Perfluoroalkyl Substances in Juvenile Perch through Perfluorooctane Sulfonamidoethanol Based Phosphate Diester Dietary Exposure.

Perfluorooctane sulfonamidoethanol based phosphate diester (SAmPAP) is a potential perfluorooctanesulfonate (PFOS) precursor. To examine whether SAmPAP exposure would result in fish contamination by perfluoroalkyl and polyfluoroalkyl substances (PFASs), juvenile Eurasian perch were dietarily exposed to this compound (dosed group) or exposed to the same tank water but fed control feed (control group). SAmPAP and metabolites were monitored in the muscle, liver, and serum during the 45-day exposure phase and 35-day depuration phase. SAmPAP was only detected in the dosed group and the absorption efficiency (0.04-2.25%) was very low, possibly related to its low bioavailability in the gastrointestinal tract, steric constraints in crossing biological membranes, and clearing by enterohepatic circulation. Although SAmPAP was biotransformed and eliminated at a slow rate (t1/2 > 18 days), its biomagnification factor was low. The observed metabolites in fish were N-ethyl perfluorooctane sulfonamidoacetic acid, perfluorooctane sulfonamidoacetic acid, perfluorooctane sulfonamide, and PFOS. Considering that SAmPAP was the only source of PFASs in the tanks, the occurrence of metabolites indicates that SAmPAP could be biotransformed in fish and contribute to PFOS bioaccumulation. However, levels of metabolites were not significantly different in the dosed and control groups, indicating that metabolite excretion followed by re-exposure to these metabolites from water was the main uptake route.

Clinical use of ferric carboxymaltose in patients with solid tumours or haematological malignancies in France.

PURPOSE: This study collected data on the use of ferric carboxymaltose (FCM) in a cancer patient population in France to evaluate the feasibility and the conditions of use of FCM in routine clinical practice beyond the limiting criteria of clinical trials. METHODS: This observational, prospective study of patients with a solid tumour or a haematological malignancy who have received treatment with FCM after 01 July 2011 evaluated data about the circumstances of iron administration, concomitant medication and laboratory tests in the period from 3 months prior to the first FCM administration (baseline) until 3 months post-baseline. RESULTS: Data from 367 FCM-treated patients were analysed. FCM was mainly given as a single dose at baseline (69.2%) and without additional erythropoiesis-stimulating agent (ESA, 64.3%). The median total iron dose was 1000 mg per patient. Median haemoglobin (Hb) levels of FCM-treated patients improved from 10.3 g/dL (interquartile range 9.5, 11.1 g/dL) at baseline to 11.8 g/dL (11.1, 13.0 g/dL) until the end of the 3-month observational period. Patients treated with FCM alone or additional ESA achieved similar median Hb increase (1.3 [0.4, 2.1] g/dL and 1.4 [0.4, 2.5] g/dL, respectively). Patients with baseline Hb up to 11.0 g/dL and serum ferritin up to 500 ng/mL and beyond achieved stable median Hb levels ≥11.0 g/dL without signs of iron overload. No severe or serious adverse reaction and no hypersensitivity reactions were reported. CONCLUSIONS: The results of this observational study confirm the effectiveness and tolerability of FCM when given in clinical routine practice alone or in combination with an ESA.

Determination of bisphenol A and related substitutes/analogues in human breast milk using gas chromatography-tandem mass spectrometry.

Bisphenol A (BPA) is an industrial chemical widely used in the production of polycarbonate and epoxy resins. Identified as an endocrine-disrupting chemical (EDC), BPA is a matter of existing or ongoing restrictive regulations and then is increasingly being replaced by other analogues used as BPA's substitutes. Human biomonitoring studies focusing on both BPA and emerging related analogues consequently appear as a requirement either for documenting the efficiency of regulatory actions toward BPA and for fuelling incoming risk assessment studies toward BPA's substitutes. In particular, the increasing concern about the late effects consecutive to early exposures naturally identify human breast milk as a target biological matrix of interest for priority exposure assessment focused on critical sub-populations such as pregnant women, fetuses, and/or newborns. In this context, an accurate and sensitive analytical method based on gas chromatography coupled to tandem mass spectrometry (GC-MS/MS) was developed for the quantification of 18 "BPA-like" compounds in breast milk samples at trace levels (<0.05 µg kg(-1)). The method includes a preliminary protein precipitation step followed by two successive solid-phase extraction (SPE) stages. Quantification of the targeted compounds was achieved according to the isotopic dilution method using (13)C12-BPA as internal standard. The method was validated according to current EU guidelines and criteria. Linearity (R (2)) was better than 0.99 for each molecule within the concentration range 0-5 µg kg(-1). The detection and quantification limits ranged from 0.001 to 0.030 µg kg(-1) and from 0.002 to 0.050 µg kg(-1), respectively. The analytical method was successfully applied to the first set of human breast milk samples (n = 30) originating from French women in the Region Pays-de-la-Loire. The measured levels of BPA were found in the

Perfluoroalkyl substances in the meat of Polish farm animals and game - Occurrence, profiles and dietary intake.

Meat from farm animals (pigs, cattle and poultry) and game (wild boar and deer) was analysed in terms of thirteen perfluoroalkyl substances (PFASs). Wild boar muscle tissue was statistically significantly more contaminated than muscle tissue from other animals, and the species order of the lower-bound (LB) sum of four (∑4) PFAS (perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid, perfluorononanoic acid and perfluorohexanesulfonic acid) concentrations was wild boar > cattle > deer > pigs > poultry. None of the samples exceeded the maximum levels set by Commission Regulation (EU) 2023/915. Linear PFOS was the most frequently detected compound (in 21 % of all samples analysed and 100 % of wild boar samples), reaching its highest concentration of 1.87 µg/kg wet weight in wild boar. Dietary intake was estimated on the basis of the average per-serving consumption of pork, beef and poultry, and in the absence of such data for game, a 100 g portion was used for the calculation. Mean LB∑4 PFAS concentrations led to intakes between 0.000 and 1.75 ng/kg body weight (BW) for children and 0.000 and 0.91 ng/kg BW for adults. The potential risk to consumers was assessed in relation to the tolerable weekly intake (TWI) of 4.4 ng/kg BW established by the European Food Safety Authority in 2020. Exposure associated with the consumption of poultry, pork, beef and venison was negligible, being only <1 % of the TWI for children and adults; higher exposure was found to associate with the consumption of wild boar, being 63 % and 21 % of the TWI for children and adults, respectively. The findings of this research suggest that the intake of PFASs through the consumption of meat from Polish livestock and deer is unlikely to be a health concern. However, frequent consumption of wild boar meat could be a significant source of PFASs.

Short-term functional outcomes of robotic-assisted TKA are better with functional alignment compared to adjusted mechanical alignment.

INTRODUCTION: Ligament balancing is essential to the functional outcome of total knee arthroplasty (TKA). The optimal method of alignment remains a controversial issue. The primary objective was to compare the clinical outcomes of TKA between functional and adjusted mechanical alignment techniques. The secondary objectives were to compare bone resection, robotic alignment, and radiological assessment. MATERIALS AND METHODS: This was a retrospective case-control series comparing TKA performed with functional alignment (FA) and adjusted mechanical alignment (aMA). Sixty-four FA subjects were matched with 64 aMA controls. These two groups were matched for age, gender, body mass index (BMI), surgeon, and type of frontal deformity. Both surgical procedures were performed using the MAKO® haptic robotic system. Functional scores (Forgotten Joint Score (FJS), Knee Society Score (KSS), and Oxford Knee Score (OKS)) were measured at the final postoperative follow-up. A radiographic evaluation was performed at the same time. RESULTS: Mean FJS were respectively 63.4 ± 25.1 [0-100] and 51.2 ± 31.8 [0-100] in FA versus aMA group (p = 0.034). Mean OKS were respectively 40.8 ± 6.3 [21-48] and 34.9 ± 11.8 [3-48] in FA versus aMA group (p = 0.027). Mean KSS were respectively 184.9 ± 17.0 [126-200] and 175.6 ± 23.1 [102-200] in FA versus aMA group (p = 0.02). The main residual symptom was "none" for 73.0% versus 57.8%, "instability" for 6.4% versus 21.9%, "Pain" for 19.1% versus 12.5%, and "effusion" for 1.6% and 7.8% respectively for FA and aMA group (p = 0.016). There were 4 complications in the FA group versus 5 in the aMA group (p > 0.999). Mean postoperative hip-knee-ankle (HKA) robotic assessment were respectively 177.3° ± 2.0 [172-180] and 178.2° ± 2.0 [173-180] for FA and aMA group (p = 0.018). The median difference between HKA robotic and HKA radiological was -3.0° (IQR = 3.0; p < 0.001). CONCLUSION: With greater residual deformity and without release, functional alignment showed a statistically significantly better short-term clinical outcome than adjusted mechanical alignment. This difference may not be clinically significant.

Quantification of chlorinated paraffins by chromatography coupled to high-resolution mass spectrometry - Part A: Influence of gas chromatography and ionisation source parameters.

The analysis of chlorinated paraffins (CPs) has become a major analytical challenge. GC-ECNI-HRMS coupling is often used to analyse and quantify them. However, the influence of certain GC and ECNI parameters on the responses of polychlorinated n-alkanes (PCAs), the dominant components of CPs, has hardly been studied. In this paper, we investigated not only the influence of GC column characteristics, but also oven, GC inlet and source temperatures for simultaneous analysis of PCAs with chain-length ranging from 10 up to 20 carbon atoms (PCAs-C10-20). Particular attention was paid to the absolute response and PCA homologue group pattern obtained for a CP technical mixture. The optimum conditions for a wide homologue group determination were GC inlet, final gradient and ion source temperatures set at 220-240 °C, 340 °C and 200 °C. At the same time, a higher response was obtained with the Optima 5HT column compared to Optima 1 column, and with a length and film thickness of 12.5 m and 0.25 µm, respectively. The homologue group pattern of the technical mixture studied was significantly modified as a function of the source and GC inlet temperatures, film thickness and composition of the stationary phase. Here we recommend conditions that will improve the overall PCA pattern, in order to better characterise their occurrence in future environmental monitoring and exposure assessment.

Quantification of chlorinated paraffins by chromatography coupled to high-resolution mass spectrometry - Part B: Influence of liquid chromatography separation.

The analysis of chlorinated paraffins (CPs) is today an analytical challenge. Indeed, it is still impractical to describe their real composition in terms of polychlorinated alkanes (PCAs) homologue groups, which dominate technical mixtures. The co-elution of PCA congeners generates interferences due to the competition phenomena which occur during the ionisation process as well as to the dependence of the ionisation sources on the PCA chemistry. Therefore, the aim of this study was to investigate the influence of chromatographic separation, by LC-ESI-HRMS coupling, on the PCA homologue group pattern and, eventually, on their determination in food samples from interlaboratory studies. For this, three different mobile phases and six LC chromatographic columns were studied in order to optimise the analysis of CP mixtures. The first results showed that the use of a MeOH/H2O mobile phase reveals more appropriately the higher chlorinated PCAs. However, using ACN/H2O led to less ion species, with almost exclusively [M + Cl]- adducts, formed using post-column dichloromethane addition. Regarding the choice of the stationary phases, Hypercarb column provided a completely different homologue group pattern from the other chromatographic columns, in relation with the stronger retention of PCAs. Among the other columns, the C30 column better highlighted the short-chain PCAs compared to the C18 column conventionally used. Because the regulations now concern short-chain CPs, the quantification of food samples was then carried out on the C30 column. The optimised LC-ESI-HRMS conditions using C30 column and MeOH/H2O solvent mixture led to a quantification of PCAs in samples from interlaboratory studies with satisfactory accuracy (|Z-score| ≤ 2) and precision (<15%).

Analytical challenges related to the measurement of chlorothalonil in serum in the perspective of human biomonitoring studies.

Chlorothalonil (CTN) is a popular fungicide widely used in the world. However, its determination in serum samples is highly challenging, preventing a reliable investigation of human CTN internal exposure. We first investigated CTN's behaviour all along this analytical process on spiked serum samples. We used a radiolabelled 14C-CTN standard to monitor CTN in spiked serum samples and observed (1) a complete degradation of CTN in deproteinised serum samples after 4 h of contact; (2) a strong interaction between serum proteins and CTN by-products, with only 20 % of the radioactivity found to be extractable after 24 h of contact and (3) a slightly improved stability of CTN in serum following a first step of acidification or EDTA addition to samples. Using liquid chromatography coupled to high resolution mass spectrometry, 4-hydroxy-2,5,6-trichloroisophthalonitrile (HCTN) was identified as the major serum by-product of CTN. A protocol was developed to monitor both extractable CTN and HCTN from serum. This method was implemented on 36 human adult serum samples from the French "Esteban" Cohort. No free CTN was identified in these serum samples. Conversely, HCTN was detected in all samples at concentrations around 15 ± 2 ng mL-1, corresponding to the extractable fraction of CTN. Thus, HCTN may constitute a relevant biomarker of human internal exposure. Of note, the potential CTN contamination during blood collection could also be a source of HCTN detection in serum samples. Finally, blood sampling in EDTA tubes would seem more appropriate than in dry tubes for any future internal exposure studies on CTN.