ABSTRACT
BACKGROUND: Studies that have reported lower risk for cardiovascular outcomes in users of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) are limited by residual cofounding and lack of information on prior cardiovascular disease (CVD). This study compared risk of cardiovascular events in patients within routine care settings in Europe and Asia with type 2 diabetes (T2D) initiating empagliflozin compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) stratified by pre-existing CVD and history of heart failure (HF). METHODS AND RESULTS: Adults initiating empagliflozin and DPP-4i in 2014-2018/19 from 11 countries in Europe and Asia were compared using propensity score matching and Cox proportional hazards regression to assess differences in rates of primary outcomes: hospitalisation for heart failure (HHF), myocardial infarction (MI), stroke; and secondary outcomes: cardiovascular mortality (CVM), coronary revascularisation procedure, composite outcome including HHF or CVM, and 3-point major adverse cardiovascular events (MACE: MI, stroke and CVM). Country-specific results were meta-analysed and pooled hazard ratios (HR) with 95% confidence intervals (CI) from random-effects models are presented. In total, 85,244 empagliflozin/DPP4i PS-matched patient pairs were included with overall mean follow-up of 0.7 years. Among those with pre-existing CVD, lower risk was observed for HHF (HR 0.74; 95% CI 0.64-0.86), CVM (HR 0.55; 95% CI 0.38-0.80), HHF or CVM (HR 0.57; 95% CI 0.48-0.67) and stroke (HR 0.79; 95% CI 0.67-0.94) in patients initiating empagliflozin vs DPP-4i. Similar patterns were observed among patients without pre-existing CVD and those with and without pre-existing HF. CONCLUSION: These results from diverse patient populations in routine care settings across Europe and Asia demonstrate that initiation of empagliflozin compared to DPP-4i results in favourable cardioprotective effects regardless of pre-existing CVD or HF status.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Heart Failure , Myocardial Infarction , Sodium-Glucose Transporter 2 Inhibitors , Stroke , Humans , Adult , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/prevention & control , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/epidemiology , Dipeptidyl-Peptidase IV Inhibitors/adverse effects , Risk Factors , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Stroke/diagnosis , Stroke/epidemiology , Stroke/prevention & control , Asia/epidemiology , Europe/epidemiology , Heart Disease Risk Factors , Dipeptidyl-Peptidases and Tripeptidyl-PeptidasesABSTRACT
The structural characterization of supported molecular catalysts is challenging due to the low density of active sites and the presence of several organic/organometallic surface groups resulting from the often complex surface chemistry associated with support functionalization. Here, we provide a complete atomic-scale description of all surface sites in an N-heterocyclic carbene based on iridium and supported on silica, at all stages of its synthesis. By combining a suitable isotope labeling strategy with the implementation of multinuclear dipolar recoupling DNP-enhanced NMR experiments, the 3D structure of the Ir-NHC sites, as well as that of the synthesis intermediates were determined. As a significant fraction of parent surface fragments does not react during the multistep synthesis, site-selective experiments were implemented to specifically probe proximities between the organometallic groups and the solid support. The NMR-derived structure of the iridium sites points to a well-defined conformation. By interpreting EXAFS spectroscopy and chemical analysis data augmented by computational studies, the presence of two coordination geometries is demonstrated: Ir-NHC fragments coordinated by a 1,5-cyclooctadiene and one Cl ligand, as well as, more surprisingly, a fragment coordinated by two NHC and two Cl ligands. This study demonstrates a unique methodology to disclose individual surface structures in complex, multisite environments, a long-standing challenge in the field of heterogeneous/supported catalysts, while revealing new, unexpected structural features of metallo-NHC-supported substrates. It also highlights the potentially large diversity of surface sites present in functional materials prepared by surface chemistry, an essential knowledge to design materials with improved performances.
Subject(s)
Heterocyclic Compounds , Organometallic Compounds , Catalysis , Heterocyclic Compounds/chemistry , Iridium/chemistry , Ligands , Molecular Structure , Organometallic Compounds/chemistryABSTRACT
To accelerate the discovery of new or improved homogeneous catalysts, research groups in industry and academia have embraced high throughput experimentation (HTE). Such methodologies consist of preparing and testing large numbers of catalysts in parallel. Homogeneous metal catalysts are very well-suited for HTE, since in many cases, they can be prepared by simply mixing a metal precursor and a ligand. However, an HTE program requires a large set of chemically diverse ligands, i.e. a ligand library. In this review, we describe five different approaches for assembling ligand libraries based on an extensive survey of the literature. These approaches are based on commercial ligands, modular ligands, mixtures of ligands, supramolecular ligands or ligands prepared via the tools of biochemistry.
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The use of an equivalent amount of an organic base leads to high enantiomeric excess in the asymmetric hydrogenation of N-benzylated 3-substituted pyridinium salts into the corresponding piperidines. Indeed, in the presence of Et3 N, a Rh-JosiPhos catalyst reduced a range of pyridinium salts with ee values up to 90 %. The role of the base was elucidated with a mechanistic study involving the isolation of the various reaction intermediates and isotopic labeling experiments. Additionally, this study provided some evidence for an enantiodetermining step involving a dihydropyridine intermediate.
ABSTRACT
Renal cell carcinoma (RCC) is a kidney neoplasm that accounts for 85% of cases and has complex genetic pathways that affect its development and progression. RCC metastasis can occur in 20%-50% of patients and usually affects distant organs. Gastric metastases (GM) from RCC are rare and present as polyp-like growths in the submucosal layer, accounting for 0.2%-0.7% of cases. This case report describes an 84-year-old female with Furhman grade II ccRCC who presented with an atherothrombotic ischemic stroke and gastrointestinal bleeding nine years post-radical nephrectomy. Gastroscopy revealed a 12mm pseudopedicled gastric lesion with ulceration and bleeding, diagnosed as metastatic ccRCC. The discussion focuses on the rarity, diagnostic challenges, and prognostic elements of gastric metastasis from RCC. The median survival after detecting digestive metastasis varies widely, and the mechanisms include direct invasion and dissemination through lymphatic, transcelomic, or hematogenous routes. Prognostic markers encompass patient history, symptoms, time since RCC diagnosis, overall health, and genetic factors. Surgical removal of gastric lesions and targeted therapy are treatment options that can improve survival. This case report highlights the need for further research to enhance diagnostic and treatment strategies for this rare aspect of RCC pathophysiology.
ABSTRACT
PURPOSE: This research examined the cost-effectiveness of adding empagliflozin to standard of care (SoC) compared with SoC alone for treatment of heart failure with reduced ejection fraction (HFrEF) from the perspective of healthcare payers in the United Kingdom (UK), Spain and France. METHODS: A lifetime Markov cohort model was developed to simulate patients' progression through health states based on Kansas City Cardiomyopathy Questionnaire Clinical Summary Score. The model predicted risk of death, hospitalisation for worsening heart failure (HHF), treatment-related adverse events, and treatment discontinuation each monthly cycle. Clinical inputs and utilities were derived from EMPEROR-Reduced trial data, supplemented by published literature and national costing databases. Costs (2021 pound sterling/euro) and quality-adjusted life-years (QALYs) were discounted annually for the UK (3.5%), Spain (3.0%) and France (2.5%). RESULTS: In the UK, Spain and France, empagliflozin plus SoC yielded additional QALYs (0.19, 0.23 and 0.21) at higher cost (£1185, 1770 and 1183 per patient) than SoC alone, yielding incremental cost-effectiveness ratios of £6152/QALY, 7736/QALY and 5511/QALY, respectively. Reduced HHF incidence provided most cost offsets for empagliflozin plus SoC. Similar results were obtained for a range of subgroups and sensitivity analyses. Probabilistic sensitivity results indicated empagliflozin plus SoC remained cost-effective vs. SoC at willingness-to-pay thresholds of £20,000/QALY, 20,000/QALY and 30,000/QALY in 79.6%, 75.5% and 97.3% of model runs for the UK, Spain and France, respectively. CONCLUSIONS: Empagliflozin added to SoC leads to health benefits for patients with HFrEF and is a cost-effective treatment option for payers in multiple European countries (UK, Spain, France).
Subject(s)
Heart Failure , Humans , Cost-Effectiveness Analysis , Stroke Volume , Cost-Benefit Analysis , Quality-Adjusted Life YearsABSTRACT
Dynamic Nuclear Polarization (DNP) has recently emerged as a key method to increase the sensitivity of solid-state NMR spectroscopy under Magic Angle Spinning (MAS). While efficient binitroxide polarizing agents such as AMUPol have been developed for MAS DNP NMR at magnetic fields up to 9.4 T, their performance drops rapidly at higher fields due to the unfavorable field dependence of the cross-effect (CE) mechanism and AMUPol-like radicals were so far disregarded in the context of the development of polarizing agents for very high-field DNP. Here, we introduce a new family of water-soluble binitroxides, dubbed TinyPols, which have a three-bond non-conjugated flexible amine linker allowing sizable couplings between the two unpaired electrons. We show that this adjustment of the linker is crucial and leads to unexpectedly high DNP enhancement factors at 18.8 T and 21.1 T: an improvement of about a factor 2 compared to AMUPol is reported for spinning frequencies ranging from 5 to 40 kHz, with ε H of up to 90 at 18.8 T and 38 at 21.1 T for the best radical in this series, which are the highest MAS DNP enhancements measured so far in aqueous solutions at these magnetic fields. This work not only breathes a new momentum into the design of binitroxides tailored towards high magnetic fields, but also is expected to push the application frontiers of high-resolution DNP MAS NMR, as demonstrated here on a hybrid mesostructured silica material.
ABSTRACT
Thiolate-coordinated ruthenium alkylidene complexes can give high Z-selectivity and stereoretentivity in olefin metathesis. To investigate their applicability as heterogeneous catalysts, we have successfully developed a methodology to easily immobilize prototype ruthenium alkylidenes onto hybrid mesostructured silica via a thiolate tether. In contrast, the preparation of the corresponding molecular complexes appeared very challenging in solution. These prototype supported complexes contain small thiolates but still, they are slightly more Z-selective than their molecular analogues. These results open the door to more active and selective heterogeneous catalysts by supporting more advanced thiolate Ru-complexes.
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Estimates of paleodiversity patterns through time have relied on datasets that lump taxonomic occurrences from geographic areas of varying size per interval of time. In essence, such estimates assume that the species-area effect, whereby more species are recorded from larger geographic areas, is negligible for fossil data. We tested this assumption by using the newly developed Miocene Mammal Mapping Project database of western North American fossil mammals and its associated analysis tools to empirically determine the geographic area that contributed to species diversity counts in successive temporal bins. The results indicate that a species-area effect markedly influences counts of fossil species, just as variable spatial sampling influences diversity counts on the modern landscape. Removing this bias suggests some traditionally recognized peaks in paleodiversity are just artifacts of the species-area effect while others stand out as meriting further attention. This discovery means that there is great potential for refining existing time-series estimates of paleodiversity, and for using species-area relationships to more reliably understand the magnitude and timing of such biotically important events as extinction, lineage diversification, and long-term trends in ecological structure.
Subject(s)
Biodiversity , Fossils , Geography , Animals , Geographic Information Systems , Mammals/classification , Paleontology/methods , ProbabilityABSTRACT
Earth has experienced five major extinction events in the past 450 million years. Many scientists suggest we are now witnessing a sixth, driven by human impacts. However, it has been difficult to quantify the real extent of the current extinction episode, either for a given taxonomic group at the continental scale or for the worldwide biota, largely because comparisons of pre-anthropogenic and anthropogenic biodiversity baselines have been unavailable. Here, we compute those baselines for mammals of temperate North America, using a sampling-standardized rich fossil record to reconstruct species-area relationships for a series of time slices ranging from 30 million to 500 years ago. We show that shortly after humans first arrived in North America, mammalian diversity dropped to become at least 15%-42% too low compared to the "normal" diversity baseline that had existed for millions of years. While the Holocene reduction in North American mammal diversity has long been recognized qualitatively, our results provide a quantitative measure that clarifies how significant the diversity reduction actually was. If mass extinctions are defined as loss of at least 75% of species on a global scale, our data suggest that North American mammals had already progressed one-fifth to more than halfway (depending on biogeographic province) towards that benchmark, even before industrialized society began to affect them. Data currently are not available to make similar quantitative estimates for other continents, but qualitative declines in Holocene mammal diversity are also widely recognized in South America, Eurasia, and Australia. Extending our methodology to mammals in these areas, as well as to other taxa where possible, would provide a reasonable way to assess the magnitude of global extinction, the biodiversity impact of extinctions of currently threatened species, and the efficacy of conservation efforts into the future.