IMPROVE 2022 International Meeting on Pathway-Related Obesity: Vision of Excellence.

Nearly 90 clinicians and researchers from around the world attended the first IMPROVE 2022 International Meeting on Pathway-Related Obesity. Delegates attended in person or online from across Europe, Argentina and Israel to hear the latest scientific and clinical developments in hyperphagia and severe, early-onset obesity, and set out a vision of excellence for the future for improving the diagnosis, treatment, and care of patients with melanocortin-4 receptor (MC4R) pathway-related obesity. The meeting co-chair Peter Kühnen, Charité Universitätsmedizin Berlin, Germany, indicated that change was needed with the rapidly increasing prevalence of obesity and the associated complications to improve the understanding of the underlying mechanisms and acknowledge that monogenic forms of obesity can play an important role, providing insights that can be applied to a wider group of patients with obesity. World-leading experts presented the latest research and led discussions on the underlying science of obesity, diagnosis (including clinical and genetic approaches such as the role of defective MC4R signalling), and emerging clinical data and research with targeted pharmacological approaches. The aim of the meeting was to agree on the questions that needed to be addressed in future research and to ensure that optimised diagnostic work-up was used with new genetic testing tools becoming available. This should aid the planning of new evidence-based treatment strategies for the future, as explained by co-chair Martin Wabitsch, Ulm University Medical Center, Germany.

Transient Radiation-Induced Berkelium(III) and Californium(III) Redox Chemistry in Aqueous Solution.

Despite the significant impact of radiation-induced redox reactions on the accessibility and lifetimes of actinide oxidation states, fundamental knowledge of aqueous actinide metal ion radiation chemistry is limited, especially for the late actinides. A quantitative understanding of these intrinsic radiation-induced processes is essential for investigating the fundamental properties of these actinides. We present here a picosecond electron pulse reaction kinetics study into the radiation-induced redox chemistry of trivalent berkelium (Bk(III)) and californium (Cf(III)) ions in acidic aqueous solutions at ambient temperature. New and first-of-a-kind, second-order rate coefficients are reported for the transient radical-induced reduction of Bk(III) and Cf(III) by the hydrated electron (eaq-) and hydrogen atom (H•), demonstrating a significant reactivity (up to 1011 M-1 s-1) indicative of a preference of these metals to adopt divalent states. Additionally, we report the first-ever second-order rate coefficients for the transient radical-induced oxidation of these elements by a reaction with hydroxyl (•OH) and nitrate (NO3•) radicals, which also exhibited fast reactivity (ca. 108 M-1 s-1). Transient Cf(II), Cf(IV), and Bk(IV) absorption spectra are also reported. Overall, the presented data highlight the existence of rich, complex, intrinsic late actinide radiation-induced redox chemistry that has the potential to influence the findings of other areas of actinide science.

Curium(iii) radiation-induced reaction kinetics in aqueous media.

Insight into the effects of radiolytic processes on the actinides is critical for advancing our understanding of their solution chemistry because the behaviour of these elements cannot be easily separated from the influence of their inherent radiation field. However, minimal information exists on the radiation-induced redox behaviour of curium (Cm), a key trivalent transuranic element present in used nuclear fuel and frequently used as an alpha radiation source. Here we present a kinetic study on the aqueous redox reactions of Cm(iii) with radicals generated through the radiolysis of aqueous media. In particular, we probe reaction kinetics in nitric acid solutions that are used as the aqueous phase component of used nuclear fuel reprocessing solvent systems. Second-order rate coefficients (k) were measured for the reaction of Cm(iii) with the hydrated electron (eaq-, k = (1.25 ± 0.03) × 1010 M-1 s-1), hydrogen atom (H˙, k = (5.16 ± 0.37) × 108 M-1 s-1), hydroxyl radical (˙OH, k = (1.69 ± 0.24) × 109 M-1 s-1), and nitrate radical (NO3˙, k = (4.83 ± 0.09) × 107 M-1 s-1). Furthermore, the first-ever Cm(ii) absorption spectrum (300-700 nm) is also reported. These kinetic data dispel the status quo notion of Cm(iii) possessing little to no redox chemistry in aqueous solution, and suggest that the resulting Cm(ii) and Cm(iv) transients could exist in irradiated aqueous solutions and be available to undergo subsequent redox chemistry with other solutes.

Radiation-induced effects on the extraction properties of hexa-n-octylnitrilo-triacetamide (HONTA) complexes of americium and europium.

The candidate An(iii)/Ln(iii) separation ligand hexa-n-octylnitrilo-triacetamide (HONTA) was irradiated under envisioned SELECT (Solvent Extraction from Liquid waste using Extractants of CHON-type for Transmutation) process conditions (n-dodecane/0.1 M HNO3) using a solvent test loop in conjunction with cobalt-60 gamma irradiation. The extent of HONTA radiolysis and complementary degradation product formation was quantified by HPLC-ESI-MS/MS. Further, the impact of HONTA radiolysis on process performance was evaluated by measuring the change in 243Am and 154Eu distribution ratios as a function of absorbed gamma dose. HONTA was found to decay exponentially with increasing dose, affording a dose coefficient of d = (4.48 ± 0.19) × 10-3 kGy-1. Multiple degradation products were detected by HPLC-ESI-MS/MS with dioctylamine being the dominant quantifiable species. Both 243Am and 154Eu distribution ratios exhibited an induction period of ∼70 kGy for extraction (0.1 M HNO3) and back-extraction (4.0 M HNO3) conditions, after which both values decreased with absorbed dose. The decrease in distribution ratios was attributed to a combination of the destruction of HONTA and ingrowth of dioctylamine, which is capable of interfering in metal ion complexation. The loss of HONTA with absorbed gamma dose was predominantly attributed to its reaction with the n-dodecane radical cation (R˙+). These R˙+ reaction kinetics were measured for HONTA and its 241Am and 154Eu complexes using picosecond pulsed electron radiolysis techniques. All three second-order rate coefficients (k) were essentially diffusion limited in n-dodecane indicating a significant reaction pathway: k(HONTA + R˙+) = (7.6 ± 0.8) × 109 M-1 s-1, k(Am(HONTA)2 + R˙+) = (7.1 ± 0.7) × 1010 M-1 s-1, and k(Eu(HONTA)2 + R˙+) = (9.5 ± 0.5) × 1010 M-1 s-1. HONTA-metal ion complexation afforded an order-of-magnitude increase in rate coefficient. Nanosecond time-resolved measurements showed that both direct and indirect HONTA radiolysis yielded the short-lived (<100 ns) HONTA radical cation and a second long-lived (µs) species identified as the HONTA triplet excited state. The latter was confirmed by a series of oxygen quenching picosecond pulsed electron measurements, affording a quenching rate coefficient of k(3[HONTA]* + O2) = 2.2 × 108 M-1 s-1. Overall, both the HONTA radical cation and triplet excited state are important precursors to the suite of measured HONTA degradation products.

The Canadian 2014 porcine epidemic diarrhoea virus outbreak: Important risk factors that were not considered in the epidemiological investigation could change the conclusions.

The introduction and spread of porcine epidemic diarrhoea virus (PEDV) in North America resulted in significant death loss in the swine industry. As the industry learned how to manage this disease, many new risks were identified, including the potential for feed and feed ingredients to become contaminated and spread PEDV. In addition, biosecurity practices were reevaluated and strengthened throughout the industry. At the time of the outbreak epidemiologists did not understand, as well as they are understood today, all the risk factors that contribute to the spread of PEDV. As a result, the epidemiological investigations into the 2014 PEDV outbreak in eastern Canada may not have investigated all risk factors as thoroughly as they would be investigated today. In retrospect, many of the Bradford Hill criteria used to determine causation were not fulfilled. This review identifies risk factors that were not included in the 2014 epidemiology. If these risk factors were included in the epidemiology, the conclusions and determination of causation may have been different.

Electrochemical Studies of Selected Lanthanide and Californium Cryptates.

Efforts to quantitatively reduce CfIII → CfII in solution as well as studies of its cyclic voltammetry have been hindered by its scarcity, significant challenges associated with manipulating an unusually intense γ emitter, small reaction scales, the need for nonaqueous solvents, and its radiolytic effects on ligands and solvents. In an effort to overcome these impediments, we report on the stabilization of CfII by encapsulation in 2.2.2-cryptand and comparisons with the readily reducible lanthanides, Sm3+, Eu3+, and Yb3+. Cyclic voltammetry measurements suggest that CfIII/II displays electrochemical behavior with characteristics of both SmIII/II and YbIII/II. The °E1/2 values of -1.525 and -1.660 V (vs Fc/Fc+ in tetrahydrofuran (THF)) for [Cf(2.2.2-crypt)]3+/2+ and [Sm(2.2.2-crypt)]3+/2+, respectively, are similar. However, the ΔE values upon complexation by 2.2.2-cryptand for CfIII/II more closely parallels YbIII/II with postencapsulation shifts of 705 and 715 mV, respectively, whereas the shift of SmIII/II (520 mV) mirrors that of EuIII/II (524 mV). This suggests more structural similarities between CfII and YbII in solution than with SmII that likely originates from more similar ionic radii and local coordination environments, a supposition that is corroborated by crystallographic and extended X-ray absorption fine structure measurements from other systems. Competitive-ion binding experiments between EuIII/II, SmIII/II, and YbIII/II were also performed and show less favorable binding by YbIII/II. Connectivity structures of [Ln(2.2.2-cryptand)(THF)][BPh4]2 (Ln = EuII, SmII) are reported to show the important role that THF plays in these redox reactions.

Experimental and Theoretical Comparison of Transition-Metal and Actinide Tetravalent Schiff Base Coordination Complexes.

A series of homoleptic tetravalent transition-metal and actinide Schiff-base coordination complexes, ML2 {M = Zr, Hf, Th, U; L = N, N'-bis[(4,4'-diethylamino)salicylidene]-1,2-phenylenediamine}, have been synthesized that feature a rigid phenyl backbone. These complexes create the opportunity for comparing a series of complexes containing metal cations in the formal IV+ oxidation state by structural, spectroscopic, and theoretical analysis that also incorporate the previously reported Ce(IV) and Pu(IV) analogues. X-ray crystallographic analysis reveals that all complexes are isomorphous and feature a co-facial ligand geometry. TD-DFT and other quantum mechanical methods were used to explore bonding differences across between the complexes, and resulting calculated absorbance spectra for ML2 are in good agreement with the experimental data. The computational results also suggest that U(IV) and Pu(IV) analogs have more covalent character in their bonding than found with the other metal cations reported here.

Examination of Structure and Bonding in 10-Coordinate Europium and Americium Terpyridyl Complexes.

M(TpyNO2)(NO3)3(H2O)·THF (M = La, Nd, Sm, Eu, Tb, Am; TpyNO2 = 4'-nitrophenyl terpyridyl) have been prepared from the reaction of M(NO3)3· nH2O with TpyNO2 in THF. Structural analysis shows that the metal centers are 10-coordinate, providing the first example of AmIII with this coordination number. Further spectroscopic and theoretical evaluation of these complexes reveals utilization of the 5f orbitals in bonding in the AmIII complex. Comparison of Nd-L, Eu-L, and Am-L bond distances demonstrates that some caution should be taken in comparing EuIII versus AmIII in extraction experiments.

Schiff-base coordination complexes with plutonium(iv) and cerium(iv).

PuL2 and CeL2 (L = N,N'-bis[(4,4'-diethylamino)salicylidene]-1,2-phenylenediamine) have been synthesized, and characterized by single crystal X-ray diffraction, UV/vis/NIR spectroscopy, and cyclic voltammetry. These studies reveal the enhanced stabilization of Pu(iv) versus Ce(iv) with this Schiff base, and quasi-reversible redox behaviour only with the plutonium complex.

Pulmonary hypertension in type 1 Gaucher's disease: genetic and epigenetic determinants of phenotype and response to therapy.

Type 1 Gaucher's disease (GD) is recognized for striking but unexplained phenotypic diversity. Rarely, severe pulmonary hypertension (PH) may occur in GD but its clinical spectrum, determinants or its response to enzyme replacement therapy (ERT)+/-vasodilators is not known. One hundred and thirty-four consecutive patients with Type 1 GD were screened to estimate right ventricular systolic pressure (RVSP) by Doppler echocardiography. Ninety-four patients were on ERT and 40 were untreated. Eight additional GD patients were studied that represented consecutive tertiary referrals with severe PH. Angiotensin converting enzyme (ACE) gene polymorphisms and acid beta-glucosidase gene (GBA) mutations were determined by DNA analysis. Mild, asymptomatic PH (RVSP>35<50 mmHg) was prevalent in Type 1 GD: 30% in untreated patients and 7.4% among patients receiving ERT (P<0.001). Splenectomy was strongly associated with severe, life-threatening PH: all patients with severe PH (RVSP 50-130 mmHg) were asplenic compared to only 31% of patients with RVSP<50 mmHg (Odds ratio [OR] 28.8, 95% CI 1.6-531.6, P<0.001). Other characteristics of patients presenting with severe PH were poor compliance to ERT (4/9 patients) or no ERT (5/9 patients), a family history of a sib with GD and PH (2/2 patients), an excess of ACE I allele (OR 2.3, 95% CI 1.1-4.9, P=0.034) and an excess of non-N370S GBA mutation (OR 6.0, 95% CI 1.1-33, P=0.003). Severe PH was ameliorated by ERT+/-vasodilators during 4.6+/-4.0 yr (range 1-12 yr) follow-up; three patients were initially considered for lung transplantation but improved such that they are no longer active transplant candidates. Our study reveals a remarkable predisposition for PH in type 1 GD. Progression to severe, life-threatening PH occurs in the presence of additional genetic factors (non-N370S GBA mutation, positive family history, and ACE I gene polymorphism) and epigenetic modifiers (i.e., asplenia and female sex). Splenectomy should be avoided and in high-risk patients, ERT+/-vasodilators/coumadin should be initiated.

Recombinant human transgenic antithrombin in cardiac surgery: a dose-finding study.

BACKGROUND: Acquired antithrombin III (AT) deficiency may render heparin less effective during cardiac surgery and cardiopulmonary bypass (CPB). The authors examined the pharmacodynamics and optimal dose of recombinant human AT (rh-AT) needed to maintain normal AT activity during CPB, optimize the anticoagulant response to heparin, and attenuate excessive activation of the hemostatic system in patients undergoing coronary artery bypass grafting. METHODS: Thirty-six patients scheduled to undergo elective primary coronary artery bypass grafting and who had received heparin for 12 h or more before surgery were enrolled in the study. Ten cohorts of three patients each received rh-AT in doses of 10, 25, 50, 75, 100, 125, 175, or 200 U/kg, a cohort of six patients received 150 U/kg of rh-AT, and a control group of six patients received placebo. RESULTS: Antithrombin III activity exceeded 600 U/dl before CPB at the highest dose (200 U/kg). Doses of 75 U/kg rh-AT normalized AT activity to 100 U/dl during CPB. Activated clotting times during CPB were significantly (P < 0.0001) greater in patients who received rh-AT (844 +/- 191 s) compared with placebo patients (531 +/- 180 s). Significant (P = 0.001) inverse relations were observed between rh-AT dose and both fibrin monomer (r = -0.51) and D-dimer (r = -0.51) concentrations. No appreciable adverse events were observed with any rh-AT doses used in the study. CONCLUSIONS: Supplementation of native AT with transgenically produced protein (rh-AT) in cardiac surgical patients was well tolerated and resulted in higher activated clotting times during CPB and decreased levels of fibrin monomer and D-dimer.