A ratiometric substrate for rapid evaluation of transfer hydrogenation efficiency in solution.

A cyclometalated iridium(III) complex bearing a self-immolative quinolinium moiety was developed as a ratiometric substrate for transfer hydrogenation studies. This photoluminescent probe allowed the rapid screening of a variety of Ir catalysts using a microplate reader, offering a convenient method to assess activity using a minimum amount of catalyst sample.

Progressive alterations of left atrial and ventricular volume and strain across chronic kidney disease stages: a speckle tracking echocardiography study.

Background: It has been a scarcity of evidence regarding differences in left ventricular (LV) and left atrial (LA) size and strain changes across stages of chronic kidney disease (CKD) and which echocardiographic parameters could be utilized to predict the decline of glomerular filtration rate (GFR). Objectives: This study aimed to evaluate the alterations of LV and LA strain across the reduction of renal function and potential echocardiographic parameters which could be correlated with the GFR decline among patients with CKD. Method: A cross-sectional study was conducted on 169 CKD patients at Bach Mai General Hospital, Hanoi, Vietnam from April to November 2022. Demographic, clinical and laboratory characteristics of patients were collected. Transthoracic echocardiography was performed to measure LV and LA size and strains. Jonckheere-Terpstra test was used to measure the tendency of change. Multivariate linear regression models were performed to find associations between different echocardiographic parameters and renal function reduction. Results: The number of patients with CKD stages 1, 2, 3, 4, and 5 was 21 (12.4%), 28 (16.6%), 27 (16.0%), 22 (13.0%) and 71 (42.0%), respectively. CKD severity was positively associated with LV diastolic and systolic diameters, LV mass, E/e' ratio, and maximal tricuspid regurgitation velocity (TR max), and negatively correlated with the LV global longitudinal strain. Higher severity of CKD stage was associated with higher LA diameter, LA strain, and volume in four and two-chamber views, and lower LA reservoir and conduit function. Left ventricular mass (ß = 0.068), ejection fraction (ß = 0.112) and left atrial reservoir (ß = -0.077) were associated with reduced GFR. Conclusion: Left ventricular mass, ejection fraction, and atrial longitudinal strain by STE should be done at the earlier stages of CKD patients for better follow-up of GFR decline.

Lewis acid-driven self-assembly of diiridium macrocyclic catalysts imparts substrate selectivity and glutathione tolerance.

Molecular inorganic catalysts (MICs) tend to have solvent-exposed metal centers that lack substrate specificity and are easily inhibited by biological nucleophiles. Unfortunately, these limitations exclude many MICs from being considered for in vivo applications. To overcome this challenge, a strategy to spatially confine MICs using Lewis acid-driven self-assembly is presented. It was shown that in the presence of external cations (e.g., Li+, Na+, K+, or Cs+) or phosphate buffered saline, diiridium macrocycles spontaneously formed supramolecular iridium-cation species, which were characterized by X-ray crystallography and dynamic light scattering. These nanoassemblies selectively reduced sterically unhindered C[double bond, length as m-dash]O groups via transfer hydrogenation and tolerated up to 1 mM of glutathione. In contrast, when non-coordinating tetraalkylammonium cations were used, the diiridium catalysts were unable to form higher-ordered structures and discriminate between different aldehyde substrates. This work suggests that in situ coordination self-assembly could be a versatile approach to enable or enhance the integration of MICs with biological hosts.

Variations in Intracellular Organometallic Reaction Frequency Captured by Single-Molecule Fluorescence Microscopy.

Studies of organometallic reactions in living cells commonly rely on ensemble-averaged measurements, which can obscure the detection of reaction dynamics or location-specific behavior. This information is necessary to guide the design of bioorthogonal catalysts with improved biocompatibility, activity, and selectivity. By leveraging the high spatial and temporal resolution of single-molecule fluorescence microscopy, we have successfully captured single-molecule events promoted by Ru complexes inside live A549 human lung cells. By observing individual allylcarbamate cleavage reactions in real-time, our results revealed that they occur with greater frequency inside the mitochondria than in the non-mitochondria regions. The estimated turnover frequency of the Ru complexes was at least 3-fold higher in the former than the latter. These results suggest that organelle specificity is a critical factor to consider in intracellular catalyst design, such as in developing metallodrugs for therapeutic applications.

Organoiridium Complexes Enhance Cellular Defense Against Reactive Aldehydes Species.

Although reactive aldehyde species (RASP) are associated with the pathogenesis of many major diseases, there are currently no clinically approved treatments for RASP overload. Conventional aldehyde detox agents are stoichiometric reactants that get consumed upon reacting with their biological targets, which limits their therapeutic efficiency. To achieve longer-lasting detoxification effects, small-molecule intracellular metal catalysts (SIMCats) were used to protect cells by converting RASP into non-toxic alcohols. It was shown that SIMCats were significantly more effective in lowering cell death from the treatment with 4-hydroxynon-2-enal than aldehyde scavengers over a 72 h period. Studies revealed that SIMCats reduced the aldehyde accumulation in cells exposed to the known RASP inducer arsenic trioxide. This work demonstrates that SIMCats offer unique benefits over stochiometric agents, potentially providing new ways to combat diseases with greater selectivity and efficiency than existing approaches.

Harmonising Individual Patient Level Cardiac Registry Data Across the Asia Pacific Region-A Feasibility Study of In-Hospital Outcomes of STEMI Patients From the Asia Pacific Evaluation of Cardiovascular Therapies (ASPECT) Network.

OBJECTIVE: The Asia-Pacific Evaluation of Cardiovascular Therapies (ASPECT) collaboration was established to inform on percutaneous coronary intervention (PCI) in the Asia-Pacific Region. Our aims were to (i) determine the operational requirements to assemble an international individual patient dataset and validate the processes of governance, data quality and data security, and subsequently (ii) describe the characteristics and outcomes for ST-elevation myocardial infarction (STEMI) patients undergoing PCI in the ASPECT registry. METHODS: Seven (7) ASPECT members were approached to provide a harmonised anonymised dataset from their local registry. Patient characteristics were summarised and associations between the characteristics and in-hospital outcomes for STEMI patients were analysed. RESULTS: Six (6) participating sites (86%) provided governance approvals for the collation of individual anonymised patient data from 2015 to 2017. Five (5) sites (83%) provided >90% of agreed data elements and 68% of the collated elements had <10% missingness. From the registry (n=12,620), 84% were male. The mean age was 59.2±12.3 years. The Malaysian cohort had a high prevalence of previous myocardial infarction (34%), almost twice that of any other sites (p<0.001). Adverse in-hospital outcomes were the lowest in Hong Kong whilst in-hospital mortality varied from 2.7% in Vietnam to 7.9% in Singapore. CONCLUSIONS: Governance approvals for the collation of individual patient anonymised data was achieved with a high level of data alignment. Secure data transfer process and repository were established. Patient characteristics and presentation varied significantly across the Asia-Pacific region with this likely to be a major predictor of variations in the clinical outcomes observed across the region.

Sex differences in quality of life of patients following percutaneous coronary intervention in Vietnam.

PURPOSE: Data regarding the health-related quality of life (HRQoL) in men and women after percutaneous coronary intervention (PCI) in low-and-middle incomes countries remains scarce. To investigate sex difference in the HRQoL at 30 days and 12 months post PCI in Vietnam. METHODS: We used data from a single percutaneous coronary registry established in the Vietnam National Heart Institute. The HRQoL was measured using the EQ-5D-3L instrument via telephone interviews, and information about demographics, clinical presentation and procedures was obtained through face-to-face interviews and medical records. The HRQoL between men and women were compared using independent samples t tests, the Mann-Whitney U test or univariate/multivariate logistic regression. RESULTS: There were 866 patients included in this cohort, with the proportion of women being nearly half of men (32.1 vs 67.9%). Women were 3.5 years older, had lower income and educational levels but greater prevalence of cardiovascular risk factors. At 30 days, women significantly had more problems in mobility, personal care and pain/discomfort compared to men. At 12 months, women had more problem than men in usual activity. The geometric means of HRQoL was lower in women at 30 days, but not in 12 months. From 30 days to 12 months after discharge, women showed better recovery in mobility compared to men, but not in other dimensions. CONCLUSIONS: In this first insight of sex differences in HRQoL following PCI in Vietnam, women appeared to have worse quality of life, especially at 30 days after discharge but they showed better recovery in mobility at 12 months compared to men.

Taming glutathione potentiates metallodrug action.

Metallodrugs that are redox sensitive or have labile coordination sites are particularly susceptible to inhibition by glutathione (GSH) and other endogenous thiols. Because GSH is an essential antioxidant, strategies to prevent thiol deactivation must consider their potential effects on normal cellular functions. In this short review, we describe general approaches for taming glutathione in metallodrug therapy and discuss their strengths and limitations. We also offer our perspectives on developing practical solutions that are effective and clinically relevant.

Customizing Polymers by Controlling Cation Switching Dynamics in Non-Living Polymerization.

Controlling the chain growth process in non-living polymerization reactions is difficult because chain termination typically occurs faster than the time it takes to apply an external trigger. To overcome this limitation, we have developed a strategy to regulate non-living polymerizations by exploiting the chemical equilibria between a metal catalyst and secondary metal cations. We have prepared two nickel phenoxyphosphine-polyethylene glycol variants, one with 2-methoxyphenyl (Ni1) and another with 2,6-dimethoxyphenyl (Ni2) phosphine substituents. Ethylene polymerization studies using these complexes in the presence of alkali salts revealed that chain growth is strongly dependent on electronic effects, whereas chain termination is dependent on both steric and electronic effects. By adjusting the solvent polarity, we can favor polymerizations via non-switching or dynamic switching modes. For example, in a 100:0.2 mixture of toluene/diethyl ether, reactions of Ni1 and both Li+ and Na+ cations in the presence of ethylene yielded bimodal polymers with different relative fractions depending on the Li+/Na+ ratio used. In a 98:2 mixture of toluene/diethyl ether, reactions of Ni2 and Cs+ in the presence of ethylene generated monomodal polyethylene with dispersity <2.0 and increasing molecular weight as the amount of Cs+ added increased. Solution studies by NMR spectroscopy showed that cation exchange between the nickel complexes and alkali cations in 98:2 toluene/diethyl ether is fast on the NMR time scale, which supports our proposed dynamic switching mechanism.

Fluorescent half-sandwich iridium picolinamidate complexes for in-cell visualization.

In this work, we report on the development of fluorescent half-sandwich iridium complexes using a fluorophore attachment strategy. These constructs consist of pentamethylcyclopentadienyl (Cp*) iridium units ligated by picolinamidate donors conjugated to green-emitting boron-dipyrromethene (bodipy) dyes. Reaction studies in H2O/THF mixtures showed that the fluorescent Ir complexes were active as catalysts for transfer hydrogenation, with activities similar to that of their non-fluorescent counterparts. The iridium complexes were taken up by NIH-3T3 mouse fibroblast cells, with 50% inhibition concentrations ranging from ~20-70 µM after exposure for 3 h. Visualization of the bodipy-functionalized Ir complexes in cells using fluorescence microscopy revealed that they were localized in the mitochondria and lysosome but not the nucleus. These results indicate that our fluorescent iridium complexes could be useful for future biological studies requiring intracellular catalyst tracking.

Rigidifying Cation-Tunable Nickel Catalysts Increases Activity and Polar Monomer Incorporation in Ethylene and Methyl Acrylate Copolymerization.

In this study, we synthesized and characterized two nickel complexes featuring conformationally rigid bisphosphine mono-oxide ligands, where one has an o-methoxyphenyl (Ni2) and the other has an o-(2-methoxyethoxy)phenyl (Ni3) substituent on the P═O moiety. We performed metal binding studies using Ni3 and found that its reaction with Li+ and Na+ most likely produced 1:1 and 1:1/2:1 nickel:alkali species in solution, respectively. The nickel complexes were competent catalysts for ethylene homopolymerization and copolymerization, with activities up to 3.8 × 103 and 8.1 × 10 kg mol-1 h-1, respectively. In reactions of ethylene with methyl acrylate (1.0 M), the addition of Li+ to Ni3 led to a 5.4-fold enhancement in catalyst activity and a 1.9-fold increase in polar monomer incorporation in comparison to those by Ni3 alone under optimized conditions. A comparison with other nickel catalysts reported for ethylene and methyl acrylate copolymerization revealed that our nickel-alkali catalysts are competitive with some of the most efficient Ni-based systems developed thus far.

Tools and Methods for Investigating Synthetic Metal-Catalyzed Reactions in Living Cells.

Although abiotic catalysts are capable of promoting numerous new-to-nature reactions, only a small subset has so far been successfully integrated into living systems. Research in intracellular catalysis requires an interdisciplinary approach that takes advantage of both chemical and biological tools as well as state-of-the-art instrumentations. In this perspective, we will focus on the techniques that have made studying metal-catalyzed reactions in cells possible using representative examples from the literature. Although the lack of quantitative data in vitro and in vivo has somewhat limited progress in the catalyst development process, recent advances in characterization methods should help overcome some of these deficiencies. Given its tremendous potential, we believe that intracellular catalysis will play a more prominent role in the development of future biotechnologies and therapeutics.

Access route selection for percutaneous coronary intervention among Vietnamese patients: Implications for in-hospital costs and outcomes.

BACKGROUND: Little is known about rates of access site (transradial (TRI) or transfemoral (TFI)) preference for percutaneous coronary intervention (PCI) and in-hospital costs of patients undergoing these procedures in lower-and middle-countries. Here, we report on access site use, in-hospital costs and outcomes of patients undergoing PCI in Vietnam. METHODS: Information from 868 patients were included in the cohort of 1022 patients recruited into the first PCI registry in Vietnam. The total hospital costs and in-hospital outcomes of patients undergoing TRI and TFI were compared. Hospital costs were obtained from the hospital admission system, and major adverse cardiac events, major bleeding events and length of stay were identified through review of medical records. FINDINGS: TRI was the dominant access site for interventionists (694/868 patients). The TFI group reported more lesions of the left main artery, more previous coronary artery bypass grafts and previous PCI in comparison with the TRI group (all p < 0.05). The TRI group was associated with a lower overall cost of admission (the adjusted difference was -1526.3 USD, 95% confident interval CI (-1996.2; -1056.3), shorter length of hospital stay (-2 days, CI (-2.8; -1.2)) and lower rates of major bleeding post-procedure. Procedural factors such as radial access site, left main disease, PCI ≥2 stents, and PCI ≥ 2 lesions having the most impact on the in-hospital cost of patients undergoing PCI. INTERPRETATIONS: Among patients undergoing PCI, TRI was associated with lower costs and favourable clinical outcomes relative to TFI. FUNDING: This research received partial financial support from Curtin University, Australia.

Outcomes following the percutaneous coronary intervention in contemporary Vietnamese practice: Insight from a single centre prospective cohort.

BACKGROUND: Evidence regarding the outcomes of percutaneous coronary intervention (PCI) in low-and-middle incomes countries remains limited. OBJECTIVES: To report the outcomes post PCI at discharge, 30 days and 12 months in Vietnam and identify the key factors associated with adverse outcomes at 12 months. METHODS: We used data from a single centre prospective cohort in Vietnam. Data regarding demographics, clinical presentation, procedural information, and outcomes of patients were collected and analysed. Primary outcomes were mortality and major adverse cardiac and cerebrovascular events. RESULTS: In total, 926 patients were included. Poor outcomes were relatively low in those undergoing PCI. Predictors of mortality and major adverse cardiac and cerebrovascular events at 12 months post-PCI included being older than 75, being male, having acute myocardial infarction, left ventricular ejection fraction ≤ 40%, prior cerebral vascular disease and having an unsuccessful PCI. CONCLUSIONS: Adverse outcomes of patients undergoing PCI in Vietnam are relatively low in comparison with those reported in other countries across the Asia Pacific region. Identification of factors associated with poor outcomes is beneficial for improving the quality of cardiac care and developing the prediction model of outcomes post-PCI in Vietnam.

Organoiridium-quinone conjugates for facile hydrogen peroxide generation.

An organoiridium complex bearing a quinone moiety was shown to significantly accelerate the rate of H2O2 formation in the presence of air and sodium formate at low catalyst concentrations. This reaction is proposed to operate through a synergistic mechanism involving transfer hydrogenation catalysis and radical chemistry. Our bifunctional iridium complex could potentially be used in anti-cancer chemotherapy or other applications requiring rapid generation of reactive oxygen species.

Novel insights into clinical characteristics and in-hospital outcomes of patients undergoing percutaneous coronary intervention in Vietnam.

BACKGROUND: Little is known about percutaneous coronary intervention (PCI) practices and outcomes in low-and middle-income nations, despite its rapid uptake across Asia. For the first time, we report on clinical characteristics and in-hospital outcomes for patients undergoing PCI at a leading cardiac centre in Vietnam. METHODS: Information on characteristics, treatments, and outcomes of patients undergoing PCI was collected into the first PCI registry through direct interviews using a standardised form, medical record abstraction, and reading PCI imaging data on secured disks. Subgroup analysis was also conducted to explore gender differences. RESULTS: Between September 2017 and May 2018, 1022 patients undergoing PCI were recruited from a total of 1041 procedures. The mean age was 68.3 years and two thirds were male. While 54.4% of patients presented with acute coronary syndromes, the rate of ST-elevation myocardial infarction was 14.5%. The majority of lesions were classified as type B2 and C and the radial artery was the most common access location for PCI (79.2%). The use of drug-eluting stents was universal and the angiographic success rate was 99.4%. Cardiac complications following PCI were rare with the exception of major bleeding (2.0%). Female patients were older with relatively more comorbidities and a higher incidence of major bleeding than males (p < 0.05). CONCLUSIONS: Findings of this study provide an opportunity to benchmark current PCI practices in Vietnam, identify possible care gaps and potentially inform the adoption of treatment guidelines as well as use of prevention strategies.

Scope and Limitations of Reductive Amination Catalyzed by Half-Sandwich Iridium Complexes Under Mild Reaction Conditions.

The conversion of aldehydes and ketones to 1° amines could be promoted by half-sandwich iridium complexes using ammonium formate as both the nitrogen and hydride source. To optimize this method for green chemical synthesis, we tested various carbonyl substrates in common polar solvents at physiological temperature (37 °C) and ambient pressure. We found that in methanol, excellent selectivity for the amine over alcohol/amide products could be achieved for a broad assortment of carbonyl-containing compounds. In aqueous media, selective reduction of carbonyls to 1° amines was achieved in the absence of acids. Unfortunately, at Ir catalyst concentrations of <1 mM in water, reductive amination efficiency dropped significantly, which suggest that this catalytic methodology might be not suitable for aqueous applications where very low catalyst concentration is required (e.g., inside living cells).

Establishment of a Percutaneous Coronary Intervention Registry in Vietnam: Rationale and Methodology.

Background: In lower- and middle-income countries across Asia there has been a rapid expansion and uptake of percutaneous coronary intervention (PCI). However, there has been limited routine collection of related data, particularly around quality, safety and cost. The aim of this study was to assess the viability of implementing routine collection of PCI data in a registry at a leading hospital in Hanoi, Vietnam. Method: A Vietnamese data collection form and collection strategy were developed in collaboration with the Vietnam National Heart Institute. Information on patient characteristics, treatments, and outcomes was collected through direct interviews using a standardised form and medical record abstraction, while PCI data was read and coded into paper forms by interventional cardiologists. Viability of the registry was determined by four main factors: 1) being able to collect a representative sample; 2) quality of data obtained; 3) costs and time taken for data collection by hospital staff; and 4) level of support from key stakeholders in the institute. Results: Between September 2017 and May 2018, 1,022 patients undergoing PCI were recruited from a total of 1,041 procedures conducted during that time frame. The estimated mean time to collect information from patients before discharge was 60 minutes. Of the collected data fields, 98% were successfully completed. Most hospital staff surveyed indicated support for the continuation of the activity following the implementation of the pilot study. Conclusions: The proposed methodology for establishing a PCI registry in a large hospital in Vietnam produced high quality data and was considered worthwhile by hospital staff. The model has the potential opportunity for replication in other cardiac catheterisation sites, leading to a national PCI registry in Vietnam.

Evidence in support of chromosomal sex influencing plasma based metabolome vs APOE genotype influencing brain metabolome profile in humanized APOE male and female mice.

Late onset Alzheimer's disease (LOAD) is a progressive neurodegenerative disease with four well-established risk factors: age, APOE4 genotype, female chromosomal sex, and maternal history of AD. Each risk factor impacts multiple systems, making LOAD a complex systems biology challenge. To investigate interactions between LOAD risk factors, we performed multiple scale analyses, including metabolomics, transcriptomics, brain magnetic resonance imaging (MRI), and beta-amyloid assessment, in 16 months old male and female mice with humanized human APOE3 (hAPOE3) or APOE4 (hAPOE4) genes. Metabolomic analyses indicated a sex difference in plasma profile whereas APOE genotype determined brain metabolic profile. Consistent with the brain metabolome, gene and pathway-based RNA-Seq analyses of the hippocampus indicated increased expression of fatty acid/lipid metabolism related genes and pathways in both hAPOE4 males and females. Further, female transcription of fatty acid and amino acids pathways were significantly different from males. MRI based imaging analyses indicated that in multiple white matter tracts, hAPOE4 males and females exhibited lower fractional anisotropy than their hAPOE3 counterparts, suggesting a lower level of white matter integrity in hAPOE4 mice. Consistent with the brain metabolomic and transcriptomic profile of hAPOE4 carriers, beta-amyloid generation was detectable in 16-month-old male and female brains. These data provide therapeutic targets based on chromosomal sex and APOE genotype. Collectively, these data provide a framework for developing precision medicine interventions during the prodromal phase of LOAD, when the potential to reverse, prevent and delay LOAD progression is greatest.

Accelerating ethylene polymerization using secondary metal ions in tetrahydrofuran.

We have prepared a new series of nickel phosphine phosphonate ester complexes that feature two metal-chelating polyethylene glycol (PEG) side arms. Metal binding and reactivity studies in polar solvents showed that they readily coordinate external cations, including alkali (Li+, Na+, K+), alkaline (Mg2+, Ca2+), transition (Sc3+, Co2+, Zn2+), post-transition (Ga3+), and lanthanide (La3+) metals. Although olefin polymerization reactions are typically performed in non-polar solvents, which cannot solubilize +2 and +3 metal cations, we discovered that our nickel catalysts could promote ethylene polymerization in neat tetrahydrofuran. This advance allowed us, for the first time, to systematically investigate the effects of a wide range of M+, M2+, and M3+ ions on the reactivity of nickel olefin polymerization catalysts. In ethylene homopolymerization, the addition of Co(OTf)2 to our nickel-PEG complexes provided the largest boost in activity (up to 11-fold, 2.7 × 106 g mol-1 h-1) compared to that in the absence of external salts. The catalyst enhancing effects of secondary metals were also observed in studies of ethylene and polar olefin (e.g., propyl vinyl ether, allyl butyl ether, methyl-10-undecenoate, and 5-acetoxy-1-pentene) copolymerization. Notably, combining either Co2+ or Zn2+ with our nickel complexes increased the rates of polymerization in the presence of propyl vinyl ether by about 5.0- and 2.4-fold, respectively. Although further studies are needed to elucidate the structural and mechanistic roles of the secondary metals, this work is an important advance toward the development of cation-switchable polymerization catalysts.