Towards a comprehensive methodology for ecotoxicological assessment: Prioritizing plant protection products for mixture testing in edge-of-field surface waterbodies.

Pesticide applications in agriculture result in complex mixtures of Plant Protection Products (PPPs) in the environment. The ecotoxicological effects of these mixtures can occur at concentrations considered safe for individual chemicals, indicating potential risks underestimated by current regulatory assessments focused on individual active ingredients. To address this challenge, our study introduces a methodology for identifying priority PPPs for formulating mixtures, enabling further ecotoxicological testing in water and sediment compartments of edge-of-field surface water bodies, targeting pelagic and benthic organisms. This methodology was primarily based on the actual quantification of PPPs present in these compartments from selected case study sites (CSSs) in Europe and Argentina (11 and 4 for water and sediments, respectively). A conceptual framework was developed that discriminates and selects concerning PPPs based on their individual risk quotient and frequency of occurrence in each CSS, drawing upon two EU regulatory risk assessment approaches, i.e., the general approach under REACH for any environmental contaminant of concern - the European Chemicals Agency (ECHA) approach; and that specifically focusing on PPPs - the European Food Safety Authority (EFSA) approach. Irrespective of whether the focus is on water or sediments, the study revealed disparities in PPP rankings depending on the approach used to identify PPPs of concern, with the ECHA approach being more conservative than the EFSA approach. Despite this, the EFSA approach follows a more standardized assessment factor definition strategy, potentially allowing avoidance of risk overestimation, as well as resulting in a more balanced representation of different PPP classes for subsequent mixtures testing. Overall, the methodological development reported herein, along with the inconsistencies found when comparing different regulatory approaches to assess the risk of environmental contaminants, highlight the need for further discussion on the most appropriate directions towards the standardization of the regulatory risk assessment of PPP mixtures.

Identifying pesticides of high concern for ecosystem, plant, animal, and human health: A comprehensive field study across Europe and Argentina.

The widespread and excessive use of pesticides in modern agricultural practices has caused pesticide contamination of the environment, animals, and humans, with confirmed serious health consequences. This study aimed to identify the 20 most critical substances based on an analysis of detection frequency (DF) and median concentrations (MC) across environmental and biological matrices. A sampling campaign was conducted across 10 case study sites in Europe and 1 in Argentina, each encompassing conventional and organic farming systems. We analysed 209 active substances in a total of 4609 samples. All substances ranked among the 20 most critical were detected in silicon wristbands worn by humans and animals and indoor dust from both farming systems. Five of them were detected in all environmental matrices. Overall, higher values of DF and MC, including in the blood plasma of animals and humans, were recorded in samples of conventional compared to organic farms. The differences between farming systems were greater in the environmental samples and less in animal and human samples. Ten substances were detected in animal blood plasma from conventional farms and eight in animal blood plasma from organic farms. Two of those, detected in both farming systems, are classified as hazardous for mammals (acute). Five substances detected in animal blood plasma from organic farms and seven detected in animal blood plasma from conventional farms are classified as hazardous for mammals (dietary). Three substances detected in human blood plasma are classified as carcinogens. Seven of the substances detected in human blood plasma are classified as endocrine disruptors. Six substances, of which five were detected in human blood plasma, are hazardous for reproduction/development. Efforts are needed to elucidate the unknown effects of mixtures, and it is crucial that such research also considers biocides and banned substances, which constitute a baseline of contamination that adds to the effect of substances used in agriculture.

Occurrence and human risk assessment of pharmaceutically active compounds (PhACs) in indoor dust from homes, schools and offices.

This study investigates the current situation and possible health risks due to pharmaceutically active compounds (PhACs) including analgesics, antibiotics, antifungals, anti-inflammatories, psychiatric and cardiovascular drugs, and metabolites, in indoor environments. To achieve this objective, a total of 85 dust samples were collected in 2022 from three different Spanish indoor environments: homes, classrooms, and offices. The analytical method was validated meeting SANTE/2020/12830 and SANTE/12682/2019 performance criteria. All indoor dust samples except one presented at least one PhAC. Although concentration levels ranged from < LOQ to 18 µg/g, only acetaminophen, thiabendazole, clotrimazole, and anhydroerythromycin showed quantification frequencies (Qf %) above 19% with median concentrations of 166 ng/g, 74 ng/g, 25 ng/g and 14 ng/g, respectively. The PhAC distribution between dust deposited on the floor and settled on elevated (> 0.5 m) surfaces was assessed but no significant differences (p > 0.05, Mann-Whitney U-test) were found. However, concentrations quantified at the three types of locations showed significant differences (p < 0.05, Kruskal-Wallis H-test). Homes turned out to be the indoor environment with higher pharmaceutical concentrations, especially acetaminophen (678 ng/g, median). The use of these medicines and their subsequent removal from the body were identified as the main PhAC sources in indoor dust. Relationships between occupant habits, building characteristics, and/or medicine consumption and PhAC concentrations were studied. Finally, on account of concentration differences, estimated daily intakes (EDIs) for inhalation, ingestion and dermal adsorption exposure pathways were calculated for toddlers, adolescents and adults in homes, classrooms and offices separately. Results proved that dust ingestion is the main route of exposure, contributing more than 99% in all indoor environments. Moreover, PhAC intakes for all studied groups, at occupational locations (classrooms and offices) are much lower than that obtained for homes, where hazard indexes (HIs) obtained for acetaminophen (7%-12%) and clotrimazole (4%-7%) at the worst scenario (P95) highlight the need for continuous monitoring.

Assessing pesticide residues occurrence and risks in water systems: A Pan-European and Argentina perspective.

Freshwater ecosystems face a particularly high risk of biodiversity loss compared to marine and terrestrial systems. The use of pesticides in agricultural fields is recognized as a relevant stressor for freshwater environments, exerting a negative impact worldwide on the overall status and health of the freshwater communities. In the present work, part of the Horizon 2020 funded SPRINT project, the occurrence of 193 pesticide residues was investigated in 64 small water bodies of distinct typology (creeks, streams, channels, ditches, rivers, lakes, ponds and reservoirs), located in regions with high agricultural activity in 10 European countries and in Argentina. Mixtures of pesticide residues were detected in all water bodies (20, median; 8-40 min-max). Total pesticide levels found ranged between 6.89 and 5860 ng/L, highlighting herbicides as the dominant type of pesticides. Glyphosate was the compound with the highest median concentration followed by 2,4-D and MCPA, and in a lower degree by dimethomorph, fluopicolide, prothioconazole and metolachlor(-S). Argentina was the site with the highest total pesticide concentration in water bodies followed by The Netherlands, Portugal and France. One or more pesticides exceeded the threshold values established in the European Water Framework Directive for surface water in 9 out of 11 case study sites (CSS), and the total pesticide concentration surpassed the reference value of 500 ng/L in 8 CSS. Although only 5 % (bifenthrin, dieldrin, fipronil sulfone, permethrin, and terbutryn) of the individual pesticides denoted high risk (RQ > 1), the ratios estimated for pesticide mixtures suggested potential environmental risk in the aquatic compartment studied.

Pesticide residues with hazard classifications relevant to non-target species including humans are omnipresent in the environment and farmer residences.

Intensive and widespread use of pesticides raises serious environmental and human health concerns. The presence and levels of 209 pesticide residues (active substances and transformation products) in 625 environmental samples (201 soil, 193 crop, 20 outdoor air, 115 indoor dust, 58 surface water, and 38 sediment samples) have been studied. The samples were collected during the 2021 growing season, across 10 study sites, covering the main European crops, and conventional and organic farming systems. We profiled the pesticide residues found in the different matrices using existing hazard classifications towards non-target organisms and humans. Combining monitoring data and hazard information, we developed an indicator for the prioritization of pesticides, which can support policy decisions and sustainable pesticide use transitions. Eighty-six percent of the samples had at least one residue above the respective limit of detection. One hundred residues were found in soil, 112 in water, 99 in sediments, 78 in crops, 76 in outdoor air, and 197 in indoor dust. The number, levels, and profile of residues varied between farming systems. Our results show that non-approved compounds still represent a significant part of environmental cocktails and should be accounted for in monitoring programs and risk assessments. The hazard profiles analysis confirms the dominance of compounds of low-moderate hazard and underscores the high hazard of some approved compounds and recurring "no data available" situations. Overall, our results support the idea that risk should be assessed in a mixture context, taking environmentally relevant mixtures into consideration. We have uncovered uncertainties and data gaps that should be addressed, as well as the policy implications at the EU approval status level. Our newly introduced indicator can help identify research priority areas, and act as a reference for targeted scenarios set forth in the Farm to Fork pesticide reduction goals.

Occurrence of pesticide residues in indoor dust of farmworker households across Europe and Argentina.

Pesticides are widely used as plant protection products (PPPs) in farming systems to preserve crops against pests, weeds, and fungal diseases. Indoor dust can act as a chemical repository revealing occurrence of pesticides in the indoor environment at the time of sampling and the (recent) past. This in turn provides information on the exposure of humans to pesticides in their homes. In the present study, part of the Horizon 2020 funded SPRINT project, the presence of 198 pesticide residues was assessed in 128 indoor dust samples from both conventional and organic farmworker households across Europe, and in Argentina. Mixtures of pesticide residues were found in all dust samples (25-121, min-max; 75, median). Concentrations varied in a wide range (<0.01 ng/g-206 µg/g), with glyphosate and its degradation product AMPA, permethrin, cypermethrin and piperonyl butoxide found in highest levels. Regarding the type of pesticides, insecticides showed significantly higher levels than herbicides and fungicides. Indoor dust samples related to organic farms showed a significantly lower number of residues, total and individual concentrations than those related to conventional farms. Some pesticides found in indoor dust were no longer approved ones (29 %), with acute/chronic hazards to human health (32 %) and with environmental toxicity (21 %).

Shockwave Treatment vs Surgery for Proximal Fifth Metatarsal Stress Fractures in Soccer Players: A Pilot Study.

BACKGROUND: To compare the clinical, radiologic, and functional outcomes between shockwave and operative treatments for proximal fifth metatarsal stress fractures in soccer players in a pilot study. METHODS: Between 2017 and 2019, 18 soccer players with fifth metatarsal stress fractures attended at Mutualidad de Futbolistas Españoles-Delegación Catalana were included. Patients were randomly assigned into 2 groups receiving either surgery with an intramedullary screw (group 1) or high-energy focused extracorporeal shockwave treatment (group 2 performed once a week for 3 weeks using 2000 impulses at an energy flux density of 0.21 mJ/mm2 and 4 Hz frequency). Clinical (pain), radiologic (bone healing), and functional (Tegner Activity Scale and American Orthopaedic Foot & Ankle Society [AOFAS] ankle-hindfoot scales) outcomes before and after receiving the treatment were compared between both groups. In addition, ability and time to return to play was also compared between groups. RESULTS: No patients were lost to follow-up. There were no statistically significant differences at last follow-up between surgery and extracorporeal shockwave treatment for bone healing, pain relief, AOFAS ankle-hindfoot score, Tegner score, and time return to play. No complications were reported in either of the 2 groups. CONCLUSION: In this pilot study, extracorporeal shockwave treatment and operative treatment were found to be equally effective at reducing pain, achieving bone healing, and allowing the soccer players to return to play after proximal fifth metatarsal stress fractures. This study suggests that ESWT may be a good option for the management of proximal fifth metatarsal stress fractures in soccer players. If this approach proves successful in larger trials, the shockwave approach might help avoid known complications of the surgical treatment like wound problems, nerve injury, and hardware intolerance. Further investigations with larger sample size should be conducted in order to confirm the present conclusions. LEVEL OF EVIDENCE: Level II, therapeutic, pilot randomized controlled trial.

Pharmaceutically active compounds (PhACs) in surface water: Occurrence, trends and risk assessment in the Tagus River Basin (Spain).

In this study, the presence of 23 pharmaceutically active compounds (PhACs) including antibiotics, analgesics, anti-inflammatories, psychiatric and cardiovascular drugs, antifungals and metabolites was investigated in surface waters. A total of 89 samples were collected during 3 years (2020, 2021 and 2022) from a European representative river basin (Tagus, Spain). To elucidate PhAC potential sources, sampling points located in areas with low, median and high anthropogenic influence were selected. The analytical method based on solid phase extraction (SPE) followed by UHPLC-MS/MS analysis was validated meeting SANTE/2020/12830 and SANTE/12682/2019 performance criteria. PhACs were quantified above limits of quantification (LOQs) in 96 % of water samples, being the antihypertensives valsartan (648 ng/L, 87 % quantification frequency) and irbesartan (390 ng/L, 75 %) and the antidepressant o-desmethylvenlafaxine (495 ng/L, 76 %) the predominant pollutants. The rest of the target PhACs showed median concentrations between 4 and 172 ng/L with quantification frequencies ranging from 35 to 75 %. ∑PhAC concentrations did not show temporal or seasonal trends. However, valsartan and naproxen presented lower levels in drier (spring and summer) compared to the wetter. Source identification revealed a clear anthropogenic origin since concentrations obtained in highly populated areas were statistically higher (p < 0.01) than those quantified in sparsely populated ones. This finding was also confirmed by calculating PhACs mass flow rates, which ranged between 1.4 and 235 kg/y. Finally, data generated were used to estimate the potential risk to the aquatic ecosystem for three trophic levels (phototrophic, invertebrate and vertebrate organisms). Risk quotient ratios (RQs) were calculated for all PhACs at the median (P50) and worst-case (max) scenarios. Up to 7 PhACs (acetaminophen, carbamazepine, gemfibrozil, ibuprofen, irbesartan, ketoprofen and venlafaxine) showed high risk for the highest trophic level (fish) in >45 % of investigated locations.

Comorbidity clusters associated with newly treated type 2 diabetes mellitus: a Bayesian nonparametric analysis.

Type 2 diabetes mellitus (T2DM) is associated with the development of chronic comorbidities, which can lead to high drug utilization and adverse events. We aimed to identify common comorbidity clusters and explore the progression over time in newly treated T2DM patients. The IQVIA Medical Research Data incorporating data from THIN, a Cegedim database of anonymized electronic health records, was used to identify all patients with a first-ever prescription for a non-insulin antidiabetic drug (NIAD) between January 2006 and December 2019. We selected 58 chronic comorbidities of interest and used Bayesian nonparametric models to identify disease clusters and model their progression over time. Among the 175,383 eligible T2DM patients, we identified the 20 most frequent comorbidity clusters, which were comprised of 14 latent features (LFs). Each LF was associated with a primary disease (e.g., 98% of patients in cluster 2, characterized by LF2, had congestive heart failure [CHF]). The presence of certain LFs increased the probability of having another LF active. For example, LF2 (CHF) frequently appeared with LFs related to chronic kidney disease (CKD). Over time, the clusters associated with cardiovascular diseases, such as CHF, progressed rapidly. Moreover, the onset of certain diseases led to further complications. Our models identified established T2DM complications and previously unknown connections, thus, highlighting the potential for Bayesian nonparametric models to characterize complex comorbidity patterns.

Opioid sales and opioid-related poisonings in Switzerland: A descriptive population-based time-series analysis.

Background: To examine time trends and characteristics of calls related to opioid poisonings reported to the National Poison Centre and opioid sales in Switzerland. Methods: We used population-level data from the Swiss National Poisons Information Centre on reported opioid-related poisonings and data provided by the Swiss Pharmacists' Association (pharmaSuisse) based on IQVIA data to identify sold opioid packages. The rate of opioid-related poisoning calls and dispensed opioid packages per 100,000 Swiss inhabitants between 2000 and 2019 were plotted by year and annual trends were assessed. All analyses were stratified by individual opioid and potency (strong vs weak). Findings: There was a significant 177% increase in the rate of calls for opioid-related poisonings (1·4 to 3·9 per 100,000 inhabitants, p<0·001) and a 91·3% increase in opioid sales (from 14,364·0 to 27,477·6 per 100,000 inhabitants, p<0.001). The increase associated with strong opioids was higher when compared to weak opioids, in both poison centre calls and sales. In 2019, tramadol was the most frequently reported opioid in the poison centre data (35·7%, n=133) and sales (37·5%, n=8,863,377), followed by oxycodone calls (24·4%, n=91) and sales 23·4%, n= 552,751). Poisoning calls and sales related to oxycodone increased substantially between 2009 and 2016, as did the rate of poison centre calls requiring medical care. Interpretation: Calls to the Swiss National poison centre and sales for opioid have increased substantially in Switzerland in the last two-decades. Increases were primarily driven by oxycodone and tramadol; however, sales have attenuated since 2016. Our findings mirror other European countries and stress the importance of surveillance and monitoring. Funding: The research did not receive external funding. Translation of the abstract in German, French and Italian are available in the Supplementary section.

Drug Triggers and Clinic of Acute Generalized Exanthematous Pustulosis (AGEP): A Literature Case Series of 297 Patients.

Acute generalized exanthematous pustulosis (AGEP) is a rare skin reaction, commonly caused by drugs. Available evidence mostly relies on small studies or case reports. We collected published AGEP case reports and, subsequently, described the patient characteristics, suspect and concomitant drugs, time to onset, disease management, and clinical prognosis. This study included 297 AGEP patients (64.3% women) obtained from 250 published case reports or case series with individual patient data. AGEP affected patients of all ages, but the majority of patients (88.2%) were ≥25 years old. The most frequently reported suspect drugs were anti-infectives for systemic use (36.5%), particularly antibacterials for systemic use (31.0%), and especially beta-lactam antibacterials (18.3%) and macrolides (4.3%). Other frequent suspect drugs were antineoplastics (12.2%), and anti-inflammatory/anti-rheumatic products (5.2%) plus hydroxychloroquine (12.8%). Mean time to onset was 9.1 days (standard deviation SD 13.94). Some patients developed fever (64.3%) and systemic involvement (18.9%), and most patients (76.4%) received pharmacological treatment for AGEP. Seven patients died, although five of them were already critically ill prior to AGEP. In conclusion, antibiotics remain the most common suspected cause of AGEP. While case mortality rate may be up to 2.5%, disentangling the role of AGEP on the fatal outcome from the role of the preexisting health conditions remains challenging.

Environmental risk assessment of neonicotinoids in surface water.

Neonicotinoids (NNIs) are active substances used as insecticides mainly in plant protection products (PPPs) but also in veterinary applications. The increasing evidence of affecting non-targeted organisms led the European Commission to severely restrict or even ban outdoor uses. To evaluate their current use and their influence in the ecological status of freshwater ecosystem, a total of 19 river water samples were collected to determine the presence of 5 NNIs (acetamiprid, clothianidin, imidacloprid, thiamethoxam and thiacloprid) in the Tagus basin. At least one target analyte was quantified by HPLC-MS/MS analysis in 17 of the 19 water samples, with ∑NNIs ranging from 1) and for the mix of NNIs (RCRmix (PEC/PNEC) > 1). RCRmix(PEC/PNEC) and the sum of toxic units (STU) showed a risky situation for some locations with different organisms related to agriculture practices. This data arouses concern about NNis (legal or forbidden) use in Tagus basin, and manifest the need of monitoring their presence and effect on the aquatic ecosystem.

A Fermented Milk Product Containing B. lactis CNCM I-2494 Improves the Tolerance of a Plant-Based Diet in Patients with Disorders of Gut-Brain Interactions.

Healthy, plant-based diets, rich in fermentable residues, may induce gas-related symptoms. The aim of this exploratory study was to assess the effects of a fermented milk product, containing probiotics, on the tolerance of a healthy diet in patients with disorders of gut-brain interactions (DGBI), complaining of excessive flatulence. In an open design, a 3-day healthy, mostly plant-based diet was administered to patients with DGBI (52 included, 43 completed) before and at the end of 28 days of consumption of a fermented milk product (FMP) containing Bifidobacterium animalis subsp. lactis CNCM I-2494 and lactic acid bacteria. As compared to a habitual diet, the flatulogenic diet increased the perception of digestive symptoms (flatulence score 7.1 ± 1.6 vs. 5.8 ± 1.9; p < 0.05) and the daily number of anal gas evacuations (22.4 ± 12.5 vs. 16.5 ± 10.2; p < 0.0001). FMP consumption reduced the flatulence sensation score (by -1.6 ± 2.2; p < 0.05) and the daily number of anal gas evacuations (by -5.3 ± 8.2; p < 0.0001). FMP consumption did not significantly alter the overall gut microbiota composition, but some changes in the microbiota correlated with the observed clinical improvement. The consumption of a product containing B. lactis CNCM I-2494 improved the tolerance of a healthy diet in patients with DGBI, and this effect may be mediated, in part, by the metabolic activity of the microbiota.

Community Pharmacist-Administered COVID-19 Vaccinations: A Pilot Customer Survey on Satisfaction and Motivation to Get Vaccinated.

In response to the coronavirus disease 2019 (COVID-19) pandemic, Swiss health authorities approved and ordered two mRNA vaccines in 2021. The canton of Zurich was the second in Switzerland to allow community pharmacists to administer the COVID-19 mRNA Vaccine Moderna to the adult population. We aimed to pilot a customer satisfaction questionnaire regarding COVID-19 vaccinations in Zurich pharmacies. Questions focused on satisfaction with different aspects of the service, motivation for getting the vaccination, and reasons for being vaccinated in a pharmacy. Zurich pharmacies administered 68,169 COVID-19 doses until June 2021, and 421 questionnaires were filled. Respondents' mean age was 43.5 (±13.2) years, with 42.3% reporting being women and 46.1% being men. Of the 372 complete questionnaires, 98.7% of the respondents would have recommended the service to others. High levels of satisfaction were reported concerning pre-vaccination discussion (98.9%), pharmacies' information level on COVID-19 vaccines (98.9%), general comfort with receiving the vaccination in a pharmacy (99.5%), injection technique (99.2%), and premises used (98.1%). Most respondents (57.3%) would have had the option of another vaccination provider, but the pharmacies were chosen for their opening hours, ease of access, and perceived trust. The availability of pharmacist-administered services may be an important contributor to a successful vaccination programme in Switzerland.

A Network Analysis of Drug Combinations Associated with Acute Generalized Exanthematous Pustulosis (AGEP).

Acute generalized exanthematous pustulosis (AGEP) is a rare skin adverse drug reaction. The pathophysiology and causative drugs associated with AGEP are poorly understood, with the majority of studies in AGEP focusing on a single-drug-outcome association. We therefore aimed to explore and characterize frequently reported drug combinations associated with AGEP using the WHO pharmacovigilance database VigiBase. In this explorative cross-sectional study of a pharmacovigilance database using a data-driven approach, we assessed individual case safety reports (ICSR) with two or more drugs reported to VigiBase. A total of 2649 ICSRs reported two or more drugs. Cardiovascular drugs, including antithrombotics and beta-blockers, were frequently reported in combination with other drugs, particularly antibiotics. The drug pair of amoxicillin and furosemide was reported in 57 ICSRs (2.2%), with an O/E ratio of 1.3, and the combination of bisoprolol and furosemide was recorded 44 times (1.7%), with an O/E ratio of 5.5. The network analysis identified 10 different communities of varying sizes. The largest cluster primarily consisted of cardiovascular drugs. This data-driven and exploratory study provides the largest real-world assessment of drugs associated with AGEP to date. The results identify a high frequency of cardiovascular drugs, particularly used in combination with antibiotics.

National Poison Center Calls Before vs After Availability of High-Dose Acetaminophen (Paracetamol) Tablets in Switzerland.

Importance: Acetaminophen (paracetamol) is among the most widely used pain medications worldwide; while safe within the therapeutic range, intake exceeding 4000 mg/d can lead to hepatotoxicity. Prior evidence suggests that limiting the availability of large quantities of acetaminophen is associated with decreased acetaminophen-related poisonings and mortality; in Switzerland, 500-mg tablets are available over-the-counter (OTC) and, as of October 2003, 1000-mg tablets are available with prescription. Objective: To evaluate the association of adding 1000-mg acetaminophen tablets to the Swiss market with utilization and poisonings. Design, Setting, and Participants: This cross-sectional study used a quasi-experimental interrupted time series analysis to evaluate 15 790 acetaminophen poison records from January 1, 2000, to December 31, 2018. All calls for acetaminophen-related poisonings identified from the National Swiss Poisons Centre and all sales for oral acetaminophen tablets (prescription and OTC) dispensed between January 2000 and December 2018 were included. Exposure: October 3, 2003 (Q4 2003), was defined as the intervention date, corresponding to the date of market entry for 1000-mg acetaminophen tablets in Switzerland. Main Outcomes and Measures: The primary outcome was the number of quarterly acetaminophen-related poison calls to the National Poison Centre. Additional outcomes included quarterly sales for acetaminophen and change in poisoning circumstances, stratified by preintervention and postintervention periods and by formulation (ie, 500-mg and 1000-mg tablets). Results: Between 2000 and 2018, 15 790 acetaminophen-related poisoning calls were identified, of which 10 628 (67.3%) were regarding women, and the mean (SD) age of patients was 25.2 (18.2) years. The interrupted time series analysis identified a significant increase in the slope for the number of reported poisonings following the intervention point, particularly for accidental circumstances (z score, -3.62; P < .001). In the preintervention period, 120 of 961 poisonings (15.3%) involved a dose greater than 10 000 mg, while for the postintervention period, 1140 of 5696 (30.6%) had a dose larger than 10 000 mg (P < .001). There was a rapid uptake in 1000-mg acetaminophen sales, while sales of the 500-mg tablet decreased slightly. Since 2012, a mean (SD) of 20.7 million (1.4 million) 1000-mg tablets were dispensed quarterly compared with 2.7 million (0.5 million) 500-mg tablets. Conclusions and Relevance: This study found a significant increase in acetaminophen dispensing and acetaminophen-related poisonings in Switzerland following the approval of 1000-mg tablets in 2003. The availability of 1000-mg acetaminophen should be re-evaluated to minimize the potential for accidental poisonings.

Investigating the presence of emerging and legacy POPs in European domestic air.

Presence of organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and dechlorane plus (DP) were evaluated in indoor domestic air from four European countries (Belgium, Italy, Spain and Portugal). The main pollutants were hexachlorohexanes (sum of α-, ß- and γ-HCH; ΣHCHs) and ΣPCBs (sum of PCB-28, 52, 101, 118, 138, 153 and 180), with median concentrations of 366 and 306 pg/m3, respectively. By decreasing order came hexachlorobenzene (HCB; 130 pg/m3), ΣDDXs (sum of DDTs, DDEs and DDDs; 94.4 pg/m3), ΣPBDEs (sum of BDE-17, 28, 47, 66, 99, 100, 153, 154, 183, 206, 207 and 209; 6.08 pg/m3) and DP (0.30 pg/m3). Lower ΣPCBs and ΣDDXs levels were found at Portuguese homes compared to Belgian, Italian and Spanish households. Italian samples presented also lower ΣHCHs concentrations while Spanish homes revealed higher HCB and BDE-209 indoor air concentrations than those obtained in the other countries. ΣHCHs, ΣDDXs and ΣPBDE levels mirrored lindane, dicofol and Penta-, DecaBDE use, respectively. The influence of building characteristics, surroundings and inhabitants habits on pollutant air concentrations was investigated. Data generated were used to conduct a human exposure assessment for toddlers and adults with median (P50) and upper (P95) concentrations. Results indicated that health risk posed by inhalation of ΣPCBs, ΣHCHs, ΣDDXs, HCB, ΣPBDEs and DP were 2 to 5 orders of magnitude lower than oral Reference Dose (RfD) values, and 90 (PCB-28) and 12 (γ-HCH) times lower than Minimal Risk Levels (MRLs) for toddlers at the worst case scenario.

Early Postoperative Endoscopic Recurrence in Crohn's Disease Is Characterised by Distinct Microbiota Recolonisation.

BACKGROUND AND AIMS: Intestinal microbiota dysbiosis is implicated in Crohn's disease [CD] and may play an important role in triggering postoperative disease recurrence [POR]. We prospectively studied faecal and mucosal microbial recolonisation following ileocaecal resection to identify the predictive value of recurrence-related microbiota. METHODS: Mucosal and/or faecal samples from 121 CD patients undergoing ileocaecal resection were collected at predefined time points before and after surgery. Ileal biopsies were collected from 39 healthy controls. POR was defined by a Rutgeerts score ≥i2b. The microbiota was evaluated by 16S rRNA sequencing. Prediction analysis was performed using C5.0 and Random Forest algorithms. RESULTS: The mucosa-associated microbiota in CD patients was characterised by a depletion of butyrate-producing species (false discovery rate [FDR] <0.01) and enrichment of Proteobacteria [FDR = 0.009] and Akkermansia spp. [FDR = 0.02]. Following resection, a mucosal enrichment of Lachnospiraceae [FDR <0.001] was seen in all patients but in POR patients, also Fusobacteriaceae [FDR <0.001] increased compared with baseline. Patients without POR showed a decrease of Streptococcaceae [FDR = 0.003] and Actinomycineae [FDR = 0.06]. The mucosa-associated microbiota profile had good discriminative power to predict POR, and was superior to clinical risk factors. At Month 6, patients experiencing POR had a higher abundance of taxa belonging to Negativicutes [FDR = 0.04] and Fusobacteria [FDR = 0.04] compared with patients without POR. CONCLUSIONS: Microbiota recolonisation after ileocaecal resection is different between recurrence and non-recurrence patients, with Fusobacteria as the most prominent player driving early POR. These bacteria involved in the early recolonisation and POR represent a promising therapeutic strategy in the prevention of disease recurrence.

A Fermented Milk Product with B. Lactis CNCM I-2494 and Lactic Acid Bacteria Improves Gastrointestinal Comfort in Response to a Challenge Diet Rich in Fermentable Residues in Healthy Subjects.

BACKGROUND: Healthy plant-based diets rich in fermentable residues may induce gas-related symptoms. Our aim was to determine the potential of a fermented milk product with probiotics in improving digestive comfort with such diets. METHODS: In an open design, a 3-day high-residue diet was administered to healthy subjects (n = 74 included, n = 63 completed) before and following 28 days consumption of a fermented milk product (FMP) containing Bifidobacterium animalis subsp. lactis CNCM I-2494 and lactic acid bacteria. MAIN OUTCOMES: digestive sensations, number of daytime anal gas evacuations, and gas volume evacuated during 4 h after a probe meal. RESULTS: As compared to the habitual diet, the high-residue diet induced gas-related symptoms (flatulence score 4.9 vs. 1.2; p ≤ 0.0001), increased the daily number of anal gas evacuations (20.7 vs. 8.7; p < 0.0001), and impaired digestive well-being (1.0 vs. 3.4; p < 0.05). FMP consumption reduced flatulence sensation (by -1.7 [-1.9; -1.6]; p < 0.0001), reduced the number of daily evacuations (by -5.8 [-6.5; -5.1]; p < 0.0001), and improved digestive well-being (by +0.6 [+0.4; +0.7]; p < 0.05). FMP consumption did not affect the gas volume evacuated after a probe meal. CONCLUSION: In healthy subjects, consumption of a FMP containing B. lactis CNCM I-2494 and lactic acid bacteria improves the tolerance of a flatulogenic diet by subjective and objective criteria (sensations and number of anal gas evacuations, respectively).

Organophosphate compounds, polybrominated diphenyl ethers and novel brominated flame retardants in European indoor house dust: Use, evidence for replacements and assessment of human exposure.

52 pollutants including organophosphate flame retardants and plasticizers (OPs), polybrominated diphenyl ethers (PBDEs) and novel brominated flame retardants (NBFRs) were evaluated in household dust from Belgium, Italy and Spain. Pollutant pattern was dominated by ∑OPs (12.8 µg/g; median) followed in decreasing order by ∑PBDEs (229 ng/g), decabromodiphenyl ethane (DBDPE, 130 ng/g), 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE, 1.35 ng/g), hexabromobenzene (HBB, 0.28 ng/g) and finally pentabromoethylbenzene (PBEB, 0.03 ng/g). Country differences and substitution of regulated chemicals by unregulated ones were explored. Results clearly reflected a decrease in c-penta and c-octaBDE commercial mixtures, which are mainly substituted by OPs, BTBPE and PBEB. On the other hand, c-decaBDE concentrations increased in Spanish case. However, positive correlations with its proposed substitute (DBDPE) and recent restricted policies make it possible to assume that this trend will change in the coming years. On the basis of the relationship between pollutants, house characteristics and inhabitant habits, potential sources were studied. Finally, data obtained were used to determine estimated daily intakes (EDI) via house dust ingestion and dermal absorption for toddlers and adults at central and upper percentiles. Calculated EDI levels even at worst case scenario were below available reference dose (RfD) values in all cases.