Potential of Mixed Dipnictogen Molybdenum Complexes in the Self-Assembly of Thallium Coordination Compounds.

The coordination chemistry of the homo- and heterodipnictogen tetrahedrane complexes [{CpMo(CO)2}2(µ,η2:2-EE')] (E, E' = P, As, Sb) (A-F) toward Tl[BArF24] ([BArF24]- = [B(3,5-C6H3(CF3)2)4]-) was studied. Controlled by the used tetrahedranes A-F, and thus depending on the respective pnictogen atoms, the monomers [Tl(η2-A)][BArF24] ([A]Tl) and [Tl(η2-B)][BArF24] ([B]Tl), the double substituted [Tl(η1-C)2][BArF24] ([C]2Tl) or the even higher aggregated compounds [Tl2(η2-D)3(µ,η2:1-D)(µ,η1:1-D)][BArF24]2 ([D]5Tl2), [Tl2(η2-E)2(µ,η2:1-E)3] [BArF24]2 ([E]5Tl2) and [Tl2(η2-F)3(µ,η2:1-F)3][BArF24]2 ([F]6Tl2) were obtained. Utilization of [BArF24]- promises additional stabilization of TlI via η6-coordination of two of its aryl rings as found in compounds [A]Tl, [B]Tl and [C]2Tl. Within the series of reactivity of A-F, the heavier congeners D, E and F tend to form larger aggregates in which σ(E-E') bond contributions to the coordination behavior were observed. Interatomic distances suggest the presence of Tl···Tl interactions in [E]5Tl2 and [F]6Tl2. The features of the respective coordination compounds were studied in the solid-state as well as in solution. For the latter at least a partial dissociation of the assemblies in solution was indicated. The isolated solid-state aggregates are the first examples of heterodipnictogen units as ligands in self-assembled TlI-based coordination compounds.

Synthesis and Reactivity of Hetero-Pnictogen Diazonium Analogs Stabilized by Transition Metal Units.

The reactivity of the mixed dipnictogen complexes [{CpMo(CO)2 }2 (µ,η2 : 2 -PE)] (E=P, As, Sb) towards different group 14 electrophiles is reported. The resulting library of cationic compounds [{CpMo(CO)2 }2 (µ,η2 : 2 -EPR)]+ (R=Mes (2,4,6-C6 H2 Me3 ), CH3 , CPh3 , SnMe3 ) represents formally inorganic diazonium homologs which are stabilized by transition metal units. Modifying the steric and electronic properties of the electrophile drastically impacts the respective P-R bond lengths and is accompanied by increasing (SnMe3 >CPh3 >CH3 ) dynamic behavior in solution. In contrast to the well-studied organic analogs, the prepared compounds are stable at room temperature. The subsequent reaction of the model substrate [{CpMo(CO)2 }2 (µ,η2 : 2 -P2 Me)][OTf] ([OTf]- =[CF3 SO3 ]- ) with different N-heterocyclic carbenes (NHCs) leads to an addition at the unsubstituted P atom which is also predicted by computational methods. NMR spectroscopy confirms the formation of two isomers sync/gauche-[{CpMo(CO)2 }(µ,η2 : 1 -P(NHC)PMe){CpMo(CO)2 }][OTf]. X-ray crystallographic characterization and additional DFT calculations shed light on the spatial arrangement as well as on the possible formation pathways of the isomers.

NHC-Stabilised Parent Tripentelyltrielanes.

A missing family of the extremely air sensitive tripentelyltrielanes was discovered. Their stabilisation was achieved by using the bulky NHC IDipp (NHC=N-heterocyclic carbene, IDipp=1,3-bis(2,6-diisopropylphenyl)-imidazolin-2-ylidene). The tripentelylgallanes and tripentelylalanes IDipp ⋅ Ga(PH2 )3 (1 a), IDipp ⋅ Ga(AsH2 )3 (1 b), IDipp ⋅ Al(PH2 )3 (2 a) and IDipp ⋅ Al(AsH2 )3 (2 b) were synthesised by salt metathesis of IDipp ⋅ ECl3 (E=Al, Ga, In) with alkali metal pnictogenides such as NaPH2 /LiPH2 ⋅ DME and KAsH2 , respectively. Moreover, the detection of the first NHC-stabilised tripentelylindiumane IDipp ⋅ In(PH2 )3 (3) was possible by multinuclear NMR spectroscopy. Initial investigations of the coordination ability of these compounds resulted in the successful isolation of the coordination compound [IDipp ⋅ Ga(PH2 )2 (µ3 -PH2 {HgC6 F4 }3 )] (4) by reaction of 1 a with (HgC6 F4 )3 . The compounds were characterised by multinuclear NMR spectroscopy as well as single crystal X-ray diffraction studies. Supporting computational studies highlight the electronic features of the products.

Systematic evidence on migrating and extractable food contact chemicals: Most chemicals detected in food contact materials are not listed for use.

Food packaging is important for today's globalized food system, but food contact materials (FCMs) can also be a source of hazardous chemicals migrating into foodstuffs. Assessing the impacts of FCMs on human health requires a comprehensive identification of the chemicals they contain, the food contact chemicals (FCCs). We systematically compiled the "database on migrating and extractable food contact chemicals" (FCCmigex) using information from 1210 studies. We found that to date 2881 FCCs have been detected, in a total of six FCM groups (Plastics, Paper & Board, Metal, Multi-materials, Glass & Ceramic, and Other FCMs). 65% of these detected FCCs were previously not known to be used in FCMs. Conversely, of the more than 12'000 FCCs known to be used, only 1013 are included in the FCCmigex database. Plastic is the most studied FCM with 1975 FCCs detected. Our findings expand the universe of known FCCs to 14,153 chemicals. This knowledge contributes to developing non-hazardous FCMs that lead to safer food and support a circular economy.

Adipogenic Activity of Chemicals Used in Plastic Consumer Products.

Bisphenols and phthalates, chemicals frequently used in plastic products, promote obesity in cell and animal models. However, these well-known metabolism-disrupting chemicals (MDCs) represent only a minute fraction of all compounds found in plastics. To gain a comprehensive understanding of plastics as a source of exposure to MDCs, we characterized the chemicals present in 34 everyday products using nontarget high-resolution mass spectrometry and analyzed their joint adipogenic activities by high-content imaging. We detected 55,300 chemical features and tentatively identified 629 unique compounds, including 11 known MDCs. Importantly, the chemicals extracted from one-third of the products caused murine 3T3-L1 preadipocytes to proliferate, and differentiate into adipocytes, which were larger and contained more triglycerides than those treated with the reference compound rosiglitazone. Because the majority of plastic extracts did not activate the peroxisome proliferator-activated receptor γ and the glucocorticoid receptor, the adipogenic effects are mediated via other mechanisms and, thus, likely to be caused by unknown MDCs. Our study demonstrates that daily-use plastics contain potent mixtures of MDCs and can, therefore, be a relevant yet underestimated environmental factor contributing to obesity.

Plastic Products Leach Chemicals That Induce In Vitro Toxicity under Realistic Use Conditions.

Plastic products contain complex mixtures of extractable chemicals that can be toxic. However, humans and wildlife will only be exposed to plastic chemicals that are released under realistic conditions. Thus, we investigated the toxicological and chemical profiles leaching into water from 24 everyday plastic products covering eight polymer types. We performed migration experiments over 10 days at 40 °C and analyzed the migrates using four in vitro bioassays and nontarget high-resolution mass spectrometry (UPLC-QTOF-MSE). All migrates induced baseline toxicity, 22 an oxidative stress response, 13 antiandrogenicity, and one estrogenicity. Overall, between 17 and 8681 relevant chemical features were present in the migrates. In other words, between 1 and 88% of the plastic chemicals associated with one product were migrating. Further, we tentatively identified ∼8% of all detected features implying that most plastic chemicals remain unknown. While low-density polyethylene, polyvinyl chloride, and polyurethane induced most toxicological endpoints, a generalization for other materials is not possible. Our results demonstrate that plastic products readily leach many more chemicals than previously known, some of which are toxic in vitro. This highlights that humans are exposed to many more plastic chemicals than currently considered in public health science and policies.

Iodination of cyclo-E5 -Complexes (E=P, As).

In a high-yield one-pot synthesis, the reactions of [Cp*M(η5 -P5 )] (M=Fe (1), Ru (2)) with I2 resulted in the selective formation of [Cp*MP6 I6 ]+ salts (3, 4). The products comprise unprecedented all-cis tripodal triphosphino-cyclotriphosphine ligands. The iodination of [Cp*Fe(η5 -As5 )] (6) gave, in addition to [Fe(CH3 CN)6 ]2+ salts of the rare [As6 I8 ]2- (in 7) and [As4 I14 ]2- (in 8) anions, the first di-cationic Fe-As triple decker complex [(Cp*Fe)2 (µ,η5:5 -As5 )][As6 I8 ] (9). In contrast, the iodination of [Cp*Ru(η5 -As5 )] (10) did not result in the full cleavage of the M-As bonds. Instead, a number of dinuclear complexes were obtained: [(Cp*Ru)2 (µ,η5:5 -As5 )][As6 I8 ]0.5 (11) represents the first Ru-As5 triple decker complex, thus completing the series of monocationic complexes [(CpR M)2 (µ,η5:5 -E5 )]+ (M=Fe, Ru; E=P, As). [(Cp*Ru)2 As8 I6 ] (12) crystallizes as a racemic mixture of both enantiomers, while [(Cp*Ru)2 As4 I4 ] (13) crystallizes as a symmetric and an asymmetric isomer and features a unique tetramer of {AsI} arsinidene units as a middle deck.

Benchmarking the in Vitro Toxicity and Chemical Composition of Plastic Consumer Products.

Plastics are known sources of chemical exposure and few, prominent plastic-associated chemicals, such as bisphenol A and phthalates, have been thoroughly studied. However, a comprehensive characterization of the complex chemical mixtures present in plastics is missing. In this study, we benchmark plastic consumer products, covering eight major polymer types, according to their toxicological and chemical signatures using in vitro bioassays and nontarget high-resolution mass spectrometry. Most (74%) of the 34 plastic extracts contained chemicals triggering at least one end point, including baseline toxicity (62%), oxidative stress (41%), cytotoxicity (32%), estrogenicity (12%), and antiandrogenicity (27%). In total, we detected 1411 features, tentatively identified 260, including monomers, additives, and nonintentionally added substances, and prioritized 27 chemicals. Extracts of polyvinyl chloride (PVC) and polyurethane (PUR) induced the highest toxicity, whereas polyethylene terephthalate (PET) and high-density polyethylene (HDPE) caused no or low toxicity. High baseline toxicity was detected in all "bioplastics" made of polylactic acid (PLA). The toxicities of low-density polyethylene (LDPE), polystyrene (PS), and polypropylene (PP) varied. Our study demonstrates that consumer plastics contain compounds that are toxic in vitro but remain largely unidentified. Since the risk of unknown compounds cannot be assessed, this poses a challenge to manufacturers, public health authorities, and researchers alike. However, we also demonstrate that products not inducing toxicity are already on the market.

Zebrafish Oatp-mediated transport of microcystin congeners.

Microcystins (MC), representing >100 congeners being produced by cyanobacteria, are a hazard for aquatic species. As MC congeners vary in their toxicity, the congener composition of a bloom primarily dictates the severity of adverse effects and appears primarily to be governed by toxicokinetics, i.e., whether transport of MCs occurs via organic anion-transporting polypeptides (Oatps). Differences in observed MC toxicity in various fish species suggest differential expression of Oatp subtypes leading to varying tissue distribution of the very same MC congener within different species. The objectives of this study were the functional characterization and analysis of the tissue distribution of Oatp subtypes in zebrafish (Danio rerio) as a surrogate model for cyprinid fish. Zebrafish Oatps (zfOatps) were cloned, and the organ distribution was determined at the mRNA level. zfOatps were transiently expressed in HEK293 cells for functional characterization using the Oatp substrates estrone-3-sulfate, taurocholate and methotrexate and specific MC congeners (MC-LR, MC-RR, MC-LF and MC-LW). Novel zfOatp isoforms were isolated. Among these isoforms, the organ-specific expression of zfOatp1d1 and of members of the zfOatp1f subfamily was identified. At the functional level, zfOatp1d1, zfOatp1f2, zfOatp1f3 and zfOatp1f4 transported at least one of the Oatp substrates, and zfOatp1d1, zfOatp1f2 and zfOatp1f4 were shown to transport MC congeners. MC-LF and MC-LW were generally transported faster than MC-LR and MC-RR. The subtype-specific expression of zfOatp1d1 and of members of the zfOatp1f subfamily as well as differences in the transport of MC congeners could explain the MC congener-dependent differences in toxicity in cyprinids.

Biochemical imaging of cervical intervertebral discs with glycosaminoglycan chemical exchange saturation transfer magnetic resonance imaging: feasibility and initial results.

OBJECTIVE: To evaluate glycosaminoglycan chemical exchange saturation transfer (gagCEST) imaging at 3T in the assessment of the GAG content of cervical IVDs in healthy volunteers. MATERIALS AND METHODS: Forty-two cervical intervertebral discs of seven healthy volunteers (four females, three males; mean age: 21.4 ± 1.4 years; range: 19-24 years) were examined at a 3T MRI scanner in this prospective study. The MRI protocol comprised standard morphological, sagittal T2 weighted (T2w) images to assess the magnetic resonance imaging (MRI) based grading system for cervical intervertebral disc degeneration (IVD) and biochemical imaging with gagCEST to calculate a region-of-interest analysis of nucleus pulposus (NP) and annulus fibrosus (AF). RESULTS: GagCEST of cervical IVDs was technically successful at 3T with significant higher gagCEST values in NP compared to AF (1.17% ± 1.03% vs. 0.79% ± 1.75%; p = 0.005). We found topological differences of gagCEST values of the cervical spine with significant higher gagCEST effects in lower IVDs (r = 1; p = 0). We could demonstrate a significant, negative correlation between gagCEST values and cervical disc degeneration of NP (r = -0.360; p = 0.019). Non-degenerated IVDs had significantly higher gagCEST effects compared to degenerated IVDs in NP (1.76% ± 0.92% vs. 0.52% ± 1.17%; p < 0.001). CONCLUSION: Biochemical imaging of cervical IVDs is feasible at 3T. GagCEST analysis demonstrated a topological GAG distribution of the cervical spine. The depletion of GAG in the NP with increasing level of morphological degeneration can be assessed using gagCEST imaging.

Supramolecular compounds assembled from the heteroleptic tetrahedral complex [{CpMo(CO)2}2(µ,η2-AsSb)] and metal salts.

The reaction of the tetrahedral complex [{CpMo(CO)2}2(µ,η2-AsSb)] with CuI and AgI salts is presented which gives unprecedented neutral and cationic supramolecular aggregates featuring mixed As/Sb-donor molecules as ligands/linkers between metal ions.

Validation and Application of Thresholds to Define Meaningful Change in Vasomotor Symptoms Frequency: Analysis of Pooled SKYLIGHT 1 and 2 Data.

INTRODUCTION: Vasomotor symptoms (VMS), the characteristic symptoms of menopausal transition, are often the primary reason women seek treatment. Current treatment options for VMS include fezolinetant, a nonhormonal, selective neurokinin 3 receptor antagonist. This study aimed to define a clinically meaningful threshold for reduction of moderate-to-severe VMS in postmenopausal women treated with fezolinetant and then apply it in a responder analysis of the pooled trial data. METHODS: This analysis pooled data from two identical phase 3, double-blind, placebo-controlled studies that randomized women with moderate-to-severe VMS to once-daily fezolinetant 30 mg, 45 mg, or placebo (SKYLIGHT 1 and 2). The frequency of VMS was collected daily using an electronic diary. Patients completed the Patient Global Impression of Change in VMS (PGI-C VMS) instrument, which assessed changes in hot flushes/night sweats at weeks 4 and 12 compared with baseline using a seven-point Likert scale. VMS frequency data were anchored to PGI-C VMS data; the anchor level for meaningful within-patient change in PGI-C VMS was "moderately better." RESULTS: In the pooled population (N = 1022), the mean (standard deviation) estimated thresholds for a meaningful within-patient change in moderate-to-severe VMS frequency were - 5.73 (3.47) at week 4 and - 6.20 (5.18) at week 12. Applying the thresholds for meaningful within-patient change to responder analyses ("missing as non-responder" imputation method) indicated a favorable clinical benefit: greater proportions of responders were observed in the fezolinetant 30-mg and 45-mg groups compared with placebo at week 4 (odds ratio range 2.48-2.91; P < 0.001) and week 12 (odds ratio range 1.908-2.68; P < 0.001). CONCLUSION: PGI-C VMS is sensitive to change and correlates with VMS frequency: a reduction of approximately six VMS episodes per day from baseline to week 12 was meaningful at the individual patient level. Fezolinetant provides a meaningful clinical benefit for women with moderate-to-severe VMS associated with menopause and represents an important nonhormonal treatment option. TRIAL REGISTRATION NUMBER: NCT04003155 and NCT04003142.

Clinical management, pathogen spectrum and outcomes in patients with pyogenic liver abscess in a German tertiary-care hospital.

Pyogenic liver abscesses (PLA) are life-threatening disorders and require immediate treatment, but structured evidence is sparse and treatment guidelines are not established. In a retrospective observational study of 221 adult PLA patients (mean age 63 years, 63% men) treated between 2013 and 2019 at the Leipzig University Medical Center, we characterized pathogen spectrum, clinical management and outcomes. Biliary malignancies (33%), cholelithiasis (23%) and ischemic biliary tract disease (16%) were most common causes of PLA. Comorbidities included malignancies (40%) and diabetes mellitus (35%). Abdominal ultrasound was the preferred initial imaging modality (58%). Enterobacterales (58%), enterococci (42%) and streptococci (18%) were identified as most frequent pathogens. 97% of patients were treated with antibiotics and 75% of patients underwent an invasive treatment procedure. The 30-day mortality was almost identical in patients with and without underlying malignancy (14.6% vs. 14.4%, p = 0.96), while the one-year outcome differed significantly (58.4% vs. 29.6%, p < 0.001). Positive blood cultures (OR 4.78, 95% CI 1.39 to 22.5, p = 0.023) and detection of Enterobacterales (OR 3.55, 95% CI 1.40 to 9.97, p = 0.010) were associated with increased 30-day-mortality. We conclude that ultrasound, extensive microbiologic diagnosis, adequate anti-infective therapy and early intervention are crucial for the management of PLA.

Lower incidence of grade II-IV acute Graft-versus-Host-Disease in pediatric patients recovering with high Vδ2+ T cells after allogeneic stem cell transplantation with unmanipulated bone marrow grafts: a prospective single-center cohort study.

Gamma delta (γδ) T cells represent a minor fraction of human T cell repertoire but play an important role in mediating anti-infectious and anti-tumorous effects in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We performed a prospective study to analyze the effect of different transplant modalities on immune reconstitution of γδ T cells and subsets. CD3, CD4 and CD8 T cells were analyzed in parallel. Secondly, we examined the impact of γδ T cell reconstitution on clinical outcomes including acute Graft-versus-Host-Disease (aGvHD) and viral infections. Our cohort includes 49 pediatric patients who received unmanipulated bone marrow grafts from matched unrelated (MUD) or matched related (MRD) donors. The cohort includes patients with malignant as well as non-malignant diseases. Cell counts were measured using flow cytometry at 15, 30, 60, 100, 180 and 240 days after transplantation. Cells were stained for CD3, CD4, CD8, CD45, TCRαß, TCRγδ, TCRVδ1, TCRVδ2, HLA-DR and combinations. Patients with a MRD showed significantly higher Vδ2+ T cells than those with MUD at timepoints +30, +60, +100 (p<0.001, respectively) and +180 (p<0.01) in univariate analysis. These results remained significant in multivariate analysis. Patients recovering with a high relative abundance of total γδ T cells and Vδ2+ T cells had a significantly lower cumulative incidence of grade II-IV aGvHD after transplantation (p=0.03 and p=0.04, respectively). A high relative abundance of Vδ2+ T cells was also associated with a lower incidence of EBV infection (p=0.02). Patients with EBV infection on the other hand showed higher absolute Vδ1+ T cell counts at days +100 and +180 after transplantation (p=0.046 and 0.038, respectively) than those without EBV infection. This result remained significant in a multivariate time-averaged analysis (q<0.1). Our results suggest a protective role of γδ T cells and especially Vδ2+ T cell subset against the development of aGvHD and EBV infection after pediatric HSCT. Vδ1+ T cells might be involved in the immune response after EBV infection. Our results encourage further research on γδ T cells as prognostic markers after HSCT and as possible targets of adoptive T cell transfer strategies.

Cyclo-E5-bridged trinuclear triple-decker complexes (E = P, As) containing a triply-bonded Mo2 unit and their isomerisation.

The reaction of the low-coordinate quadruply-bonded dimolybdenum complex Mo2[µ,κ2-PhB(N-2,6-iPr2C6H3)2]2 (1) with Cp*Fe(η5-E5) (E = P, As) gives two trinuclear species Cp*Fe(µ3,η5:2:2-E5)Mo2[µ,κ2-PhB(N-2,6-iPr2C6H3)2]2 (E = P (4) and As (5)). 4 undergoes facile isomerisation upon heating to give Cp*FeMo2[κ2-PhB(N-2,6-iPr2C6H3)2](µ3,κ:κ:η2-P2)[µ3,κ:κ:η3κ-P3PhB(N-2,6-iPr2C6H3)2] (6), where the FeMo2P5 core motif displays a cubane-like structure.

Snapshots of sequential polyphosphide rearrangement upon metallatetrylene addition.

Insertion and functionalization of gallasilylenes [LPhSi-Ga(Cl)LBDI] (LPh = PhC(NtBu)2; LBDI = [{2,6-iPr2C6H3NCMe}2CH]) into the cyclo-E5 rings of [Cp*Fe(η5-E5)] (Cp* = η5-C5Me5; E = P, As) are reported. Reactions of [Cp*Fe(η5-E5)] with gallasilylene result in E-E/Si-Ga bond cleavage and the insertion of the silylene in the cyclo-E5 rings. [(LPhSi-Ga(Cl)LBDI){(η4-P5)FeCp*}], in which the Si atom binds to the bent cyclo-P5 ring, was identified as a reaction intermediate. The ring-expansion products are stable at room temperature, while isomerization occurred at higher temperature, and the silylene moiety further migrates to the Fe atom, forming the corresponding ring-construction isomers. Furthermore, reaction of [Cp*Fe(η5-As5)] with the heavier gallagermylene [LPhGe-Ga(Cl)LBDI] was also investigated. All the isolated complexes represent rare examples of mixed group 13/14 iron polypnictogenides, which could only be synthesized by taking advantage of the cooperativity of the gallatetrylenes featuring low-valent Si(ii) or Ge(ii) and Lewis acidic Ga(iii) units/entities.

Novel synthetic route towards heteroleptic pnictogen-rich organometallic-inorganic coordination compounds.

The reaction of the Ag(I) dimer [Ag2(η2-A)2(µ,η1:η1-A)2][TEF]2 (A = [{CpMo(CO)2}2(µ,η2-P2)]) possessing labile η2-coordinated P2 ligands with the organometallic dipnictogen compounds [{CpMo(CO)2}2(µ,η2-EE')] (E = E' = As, Sb; E = P, E' = As, Sb) represents a facile synthetic route towards unprecedented heteroleptic pnictogen-rich supramolecular complexes. This method can also be extended to the analogous Cu(I) dimer and is studied by DFT computations.

Anticoagulant Treatment Adherence and Persistence in German Patients with Atrial Fibrillation.

INTRODUCTION: Treatment adherence and persistence impact the effectiveness of edoxaban for the prevention of thromboembolism in patients with atrial fibrillation (AF). The objective of this analysis was to assess adherence and persistence of edoxaban vs. other non-vitamin K antagonist oral anticoagulants (NOACs) and vitamin K antagonists (VKAs). METHODS: Utilizing a German claims database, adults with AF with the first pharmacy claim identified for edoxaban, apixaban, dabigatran, rivaroxaban, or VKAs from January 2013 to December 2017 were included in a propensity score-matched analysis. The first pharmacy claim was the index claim. Adherence (i.e., proportion of days covered [PDC]) and persistence (proportion of patients who continued therapy) were compared between edoxaban and other therapies. Patients receiving once-daily (QD) vs. twice-daily (BID) NOAC were also analyzed. RESULTS: Overall, 21,038 patients were included (1236 edoxaban, 6053 apixaban, 1306 dabigatran, 7013 rivaroxaban, and 5430 VKA). After matching, baseline characteristics were well balanced across cohorts. Adherence was significantly higher for edoxaban vs. apixaban, dabigatran, and VKAs (all P < 0.0001). Significantly more edoxaban patients continued therapy vs. rivaroxaban (P = 0.0153), dabigatran (P < 0.0001), and VKAs (P < 0.0001). Time to discontinuation was significantly longer for edoxaban vs. dabigatran, rivaroxaban, and VKAs (all P < 0.0001). More patients receiving NOACs QD had a PDC ≥ 0.8 compared with those receiving NOACs BID (65.3 vs. 49.6%, respectively; P < 0.05); persistence rates were comparable between QD and BID groups. CONCLUSIONS: Patients with AF receiving edoxaban had significantly higher adherence and persistence compared with those receiving VKAs. This trend was also seen in NOAC QD regimens vs. NOAC BID regimens for adherence. These results provide insight into how adherence and persistence may contribute to the effectiveness of edoxaban for stroke prevention in patients with AF in Germany.

A vision for safer food contact materials: Public health concerns as drivers for improved testing.

Food contact materials (FCMs) and food contact articles are ubiquitous in today's globalized food system. Chemicals migrate from FCMs into foodstuffs, so called food contact chemicals (FCCs), but current regulatory requirements do not sufficiently protect public health from hazardous FCCs because only individual substances used to make FCMs are tested and mostly only for genotoxicity while endocrine disruption and other hazard properties are disregarded. Indeed, FCMs are a known source of a wide range of hazardous chemicals, and they likely contribute to highly prevalent non-communicable diseases. FCMs can also include non-intentionally added substances (NIAS), which often are unknown and therefore not subject to risk assessment. To address these important shortcomings, we outline how the safety of FCMs may be improved by (1) testing the overall migrate, including (unknown) NIAS, of finished food contact articles, and (2) expanding toxicological testing beyond genotoxicity to multiple endpoints associated with non-communicable diseases relevant to human health. To identify mechanistic endpoints for testing, we group chronic health outcomes associated with chemical exposure into Six Clusters of Disease (SCOD) and we propose that finished food contact articles should be tested for their impacts on these SCOD. Research should focus on developing robust, relevant, and sensitive in-vitro assays based on mechanistic information linked to the SCOD, e.g., through Adverse Outcome Pathways (AOPs) or Key Characteristics of Toxicants. Implementing this vision will improve prevention of chronic diseases that are associated with hazardous chemical exposures, including from FCMs.

Determination of Gliadin as a Measure of Gluten in Food by R5 Sandwich ELISA RIDASCREEN® Gliadin Matrix Extension: Collaborative Study 2012.01.

BACKGROUND: According to Codex Alimentarius, food products containing less than 20 mg/kg gluten can be labeled as "gluten-free." Since 2002, the R5 antibody method allowed determination of gluten levels and led to a huge improvement of products available to celiac disease (CD) patients. METHOD: The R5-containing test kit RIDASCREEN® Gliadin in combination with the cocktail solution was endorsed as Codex Type 1 Method in 2006 based on a collaborative study with corn-based bread, rice-based dough, wheat starches, rice, and corn flour. In 2012, the method was approved as First Action Official MethodSM2012.01 with an "in foods" claim. For Final Action in 2016, the matrix claim was reduced to rice- and corn-based matrixes. OBJECTIVE: Therefore, R-Biopharm decided to start a collaborative study to demonstrate the wide applicability of Official Method 2012.01 for the quantitative analysis of gliadin in soy, starches, pseudo cereals, legumes, spices, juice, nut nougat crème, cream cheese, pesto, meat, vegetarian meat alternative, cookies, dessert, cake, fish, bread, candies, and potatoes. Materials for incurring were the MoniQA wheat flour and the PWG gliadin preparation. RESULTS: Gliadin levels ranged from 3.4 up to 27.4 mg gliadin per kg. The results of the collaborative study with 14 participating laboratories showed recoveries ranging from 80 to 130%. Relative reproducibility standard deviations for contaminated samples were between 9.8 and 27.7%. CONCLUSIONS: The collaborative study results confirmed that the method is accurate and suitable to measure gliadin in important gluten-free food matrixes. HIGHLIGHTS: The title and applicability statement of Official Method 2012.01 were changed as proposed.