Frailty in clinical drug trials: Frailty assessments, subgroup analyses and outcomes.

With population ageing, drug trials are increasingly turning their attention to including older, frailer people. This review aimed to provide an overview of how frailty was assessed in published studies related to clinical pharmacological trials, and on the interaction of frailty on the efficacy of the treatments. We searched MEDLINE, EMBASE and Cochrane for clinical drug trials in older people. A total of 4031 abstracts were screened and 17 relevant studies were included in this review. We summarized the findings of these 17 trials into five main clinical areas: cardiovascular (eight studies), cognition (one study), vaccination (two studies), cancer (four studies) and other (two studies). Frailty was assessed retrospectively in most of the studies. Frailty was treated as an ordinal variable (with different levels of frailty) or binary variable (frail/non-frail) using cut-offs in some studies, and as a continuous in some other studies. The effect of frailty on the treatment efficacy was not consistent among the studies. While several trials, such as the Action in Diabetes and Vascular Disease-Preterax and Diamicron Modified Release Controlled Evaluation trials, the Systolic Blood Pressure Intervention Trial and the Aspirin in Reducing Events in the Elderly trial, showed some reduced effects of the treatment in frail patients, most of the trials showed that the benefits of the treatment are not affected by frailty. Some trials even showed that the benefits of the treatment were more significant in frailer patients (the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure and the Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure trials). The results of this review suggest that routine measurement of frailty in participants in clinical drug trials would improve our knowledge of the effect of treatment in the frail and identify those who have more or least to gain from treatment.

Lower Energy Excitation of Water Soluble Near-Infrared Emitting Mixed-Ligand Metallacrowns.

By combining advantages of two series of lanthanide(III)/zinc(II) metallacrowns (MCs) assembled using pyrazine- (pyzHA2- ) and quinoxaline- (quinoHA2- ) hydroximate building blocks ligands, we created here water-soluble mixed-ligand MCs with extended absorption to the visible range. The YbIII analogue demonstrated improved photophysical properties in the near-infrared (NIR) range in cell culture media, facilitating its application for NIR optical imaging in living HeLa cells.

Catalyst Regeneration via Chemical Oxidation Enables Long-Term Electrochemical Carbon Dioxide Reduction.

Electrochemical CO2 reduction (ECR) with industrially relevant current densities, high product selectivity, and long-term stability has been a long-sought goal. Unfortunately, copper (Cu) catalysts for producing valuable multicarbon (C2+) products undergo structural and morphological changes under ECR conditions, especially at high current densities, resulting in a rapid decrease in product selectivity. Herein, we report a catalyst regeneration strategy, one that employs an electrolysis method comprising alternating "on" and "off" operating regimes, to increase the operating stability of a Cu catalyst. We find that it increases operating lifetime many times, maintaining ethylene selectivity ≥40% for at least 200 h of electrolysis in neutral pH media at a current density of 150 mA cm-2 using a flow cell. We also demonstrate ECR to ethylene at a current density of 1 A cm-2 with ethylene selectivity ≥40% using a three-dimensional Cu gas diffusion electrode, finding that this system under these conditions is rendered stable for greater than 36 h. This work illustrates that Cu-based catalysts, once they have entered into the state conventionally considered to possess degraded catalytic activity, may be recovered to deliver high C2+ selectivity. We present evidence that the combination of short periods of electrolysis, which minimizes the morphological changes during "on" segments, with the progressive chemical oxidation of Cu atoms on the catalyst surface during "off" segments, united with the added effects of washing the accumulated salt and decreasing the catholyte temperature prolong together the catalyst's operating lifetime.

Gas diffusion electrode design for electrochemical carbon dioxide reduction.

Anthropogenic carbon dioxide (CO2) emissions contribute to the greenhouse effect and global warming, which can lead to undesirable climate change and extinction of species. Besides the ongoing efforts to develop environmentally benign sources of energy and to advance technologies for the capture and sequestration of CO2, the transformation of emitted CO2 into valuable products is a pragmatic solution to curb its accumulation in the atmosphere. In this regard, electrochemical CO2 reduction (ECR) powered by renewable electricity provides an attractive approach because it not only converts CO2 to valuable fuels and chemicals but also offers a solution for the long-term storage of intermittent renewable energies. In ECR, the gas diffusion electrode (GDE) is the most critical component and has been the subject of intensive research in the last few years. This tutorial review provides an insightful guide to developing GDEs with high activity, selectivity, and stability, the three important performance metrics in ECR. First, we introduce critical fundamentals of ECR, including the chemical and physical phenomena at the electrodes as well as the electrochemical cell configurations. Next, we discuss recent advances in GDE design, focusing on their structure-performance correlation and fabrication techniques for each component of GDEs. Finally, we discuss the remaining challenges and propose promising research directions for the design of efficient GDEs. This review aims at promoting the development of industrially relevant ECR systems to bring this technology to practical applications.

CO2 Methanation via Amino Alcohol Relay Molecules Employing a Ruthenium Nanoparticle/Metal Organic Framework Catalyst.

Methanation of carbon dioxide (CO2 ) is attractive within the context of a renewable energy refinery. Herein, we report an indirect methanation method that harnesses amino alcohols as relay molecules in combination with a catalyst comprising ruthenium nanoparticles (NPs) immobilized on a Lewis acidic and robust metal-organic framework (MOF). The Ru NPs are well dispersed on the surface of the MOF crystals and have a narrow size distribution. The catalyst efficiently transforms amino alcohols to oxazolidinones (upon reaction with CO2 ) and then to methane (upon reaction with hydrogen), simultaneously regenerating the amino alcohol relay molecule. This protocol provides a sustainable, indirect way for CO2 methanation as the process can be repeated multiple times.

Selective, Fast-Response, and Regenerable Metal-Organic Framework for Sampling Excess Fluoride Levels in Drinking Water.

Prolonged consumption of water contaminated with fluoride ions (F-) at concentrations exceeding 1.5 ppm can lead to considerable health implications, particularly in children and developing embryos. With irreversible and potentially severe forms of fluoride (F-) toxicity such as skeletal fluorosis being endemic in at least 25 countries, constructing affordable, remote-access, reliable water-sampling methods for F- contamination is an important goal. In this work, we present a novel lanthanide-based luminescent metal-organic framework, named SION-105, with a boron (B) receptor site whose interactions with F- in aqueous solutions are simultaneously electrostatic and specific in nature because of its carefully designed structural environment. This allows the material to be easily regenerated and used over 10 cycles, setting it apart from most existing molecular and polymeric F- sensors. SION-105 has been combined with a portable prototype sampling device that was designed and built in-house to measure F- concentrations in natural groundwater samples taken from three different countries, with the results showing excellent agreement with ion chromatography analysis.

Incarceration of Iodine in a Pyrene-Based Metal-Organic Framework.

A pyrene-based metal-organic framework (MOF) SION-8 captured iodine (I2 ) vapor with a capacity of 460 and 250 mg g-1 MOF at room temperature and 75 °C, respectively. Single-crystal X-ray diffraction analysis and van-der-Waals-corrected density functional theory calculations confirmed the presence of I2 molecules within the pores of SION-8 and their interaction with the pyrene-based ligands. The I2 -pyrene interactions in the I2 -loaded SION-8 led to a 104 -fold increase of its electrical conductivity compared to the bare SION-8. Upon adsorption, ≥95 % of I2 molecules were incarcerated and could not be washed out, signifying the potential of SION-8 towards the permanent capture of radioactive I2 at room temperature.

Multimorbidity, polypharmacy and primary prevention in community-dwelling adults in Quebec: a cross-sectional study.

BACKGROUND: Polypharmacy carries the risk of adverse events, especially in people with multimorbidity. OBJECTIVE: To investigate the prevalence of polypharmacy in community-dwelling adults, the association of multimorbidity with polypharmacy and the use of medications for primary prevention. METHODS: Cross-sectional analysis of the follow-up data from the Program of Research on the Evolution of a Cohort Investigating Health System Effects (PRECISE) in Quebec, Canada. Multimorbidity was defined as the presence of three or more chronic diseases and polypharmacy as self-reported concurrent use of five or more medications. Primary prevention was conceptualized as the use of statin or low-dose antiplatelets without a reported diagnostic of cardiovascular disease. RESULTS: Mean age 56.7 ± 11.6, 62.5% female, 30.3% had multimorbidity, 31.9% had polypharmacy (n = 971). The most common drugs used were statins, renin-angiotensin system inhibitors and psychotropics. Compared to participants without any chronic disease, the adjusted odds ratios (ORs) for having polypharmacy were 2.78 [95% confidence interval (CI): 1.23-6.28] in those with one chronic disease, 8.88 (95% CI: 4.06-19.20) in those with two chronic diseases and 25.31 (95% CI: 11.77-54.41) in those with three or more chronic diseases, P < 0.001. In participants without history of cardiovascular diseases, 16.2% were using antiplatelets and 28.5% were using statins. Multimorbidity was associated with increased likelihood of using antiplatelets (adjusted OR: 2.98, 95% CI: 1.98-4.48, P < 0.001) and statins (adjusted OR: 3.76, 95% CI: 2.63-5.37, P < 0.001) for primary prevention. CONCLUSION: There was a high prevalence of polypharmacy in community-dwelling adults in Quebec and a strong association with multimorbidity. The use of medications for primary prevention may contribute to polypharmacy and raise questions about safety.

Novel Framework Based on HOSVD for Ski Goggles Defect Detection and Classification.

No matter your experience level or budget, there is a great ski goggle waiting to be found.Goggles are an essential part of skiing or snowboarding gear to protect your eyes from harsh environmental elements and injury. In the ski goggles manufacturing industry, defects, especially on the lens surface, are unavoidable. However, defect detection and classification by visual inspection in the manufacturing process is very difficult. To overcome this problem, a novel framework based on machine vision is presented, named as the ski goggles lens defect detection, with five high-resolution cameras and custom-made lighting field to achieve a high-quality ski goggles lens image. Next, the defects on the lens of ski goggles are detected by using parallel projection in opposite directions based on adaptive energy analysis. Before being put into the classification system, the defect images are enhanced by an adaptive method based on the high-order singular value decomposition (HOSVD). Finally, dust and five types of defect images are classified into six types, i.e., dust, spotlight (type 1, type 2, type 3), string, and watermark, by using the developed classification algorithm. The defect detection and classification results of the ski goggles lens are compared to the standard quality of the manufacturer. Experiments using 120 ski goggles lens samples collected from the largest manufacturer in Taiwan are conducted to validate the performance of the proposed framework. The accurate defect detection rate is 100% and the classification accuracy rate is 99.3%, while the total running time is short. The results demonstrate that the proposed method is sound and useful for ski goggles lens inspection in industries.

In†Situ Formation of Frustrated Lewis Pairs in a Water-Tolerant Metal-Organic Framework for the Transformation of CO2.

Frustrated Lewis pairs (FLPs) consist of sterically hindered Lewis acids and Lewis bases, which provide high catalytic activity towards non-metal-mediated activation of "inert" small molecules, including CO2 among others. One critical issue of homogeneous FLPs, however, is their instability upon recycling, leading to catalytic deactivation. Herein, we provide a solution to this issue by incorporating a bulky Lewis acid-functionalized ligand into a water-tolerant metal-organic framework (MOF), named SION-105, and employing Lewis basic diamine substrates for the in situ formation of FLPs within the MOF. Using CO2 as a C1-feedstock, this combination allows for the efficient transformation of a variety of diamine substrates into benzimidazoles. SION-105 can be easily recycled by washing with MeOH and reused multiple times without losing its identity and catalytic activity, highlighting the advantage of the MOF approach in FLP chemistry.

One-Step Assembly of Visible and Near-Infrared Emitting Metallacrown Dimers Using a Bifunctional Linker.

A family of dimeric LnIII [12-MCGa(III)N(shi) -4] metallacrowns (MCs) (LnIII =Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, and Yb) was synthesized using the isophthalate group (ip2- ) as a linker. The [LnGa4 ]2 complexes exhibit remarkable photophysical properties, with large molar absorptivities of ≈4×104 m-1 cm-1 , high quantum yields and long luminescence lifetimes with values of (i) 31.2(2)% and 1.410(1) ms, respectively for the visible-emitting [TbGa4 ]2 complex and (ii) 2.43(6)% and 30.5(1) µs for the near-infrared (NIR) emitting [YbGa4 ]2 in the solid state. The NIR emission was obtained not only from Yb, Nd, and Er complexes but also from the less frequently observed emitters such as Pr and Ho. In addition, emission in both visible and NIR domains could be detected for Dy and Sm MCs. ESI-MS and UV/Vis data revealed that the complexes are highly stable in dimethylsulfoxide (DMSO) solution with the 1 H- and COSY-NMR spectra of the diamagnetic [YGa4 ]2 analogue providing evidence for long-term solution stability. This new approach allows one to construct a basis for highly luminescent MCs that may be further modified to be adapted for applications such as optical imaging.

Shedding Light on the Protonation States and Location of Protonated N Atoms of Adenine in Metal-Organic Frameworks.

We report the syntheses and structures of five metal-organic frameworks (MOFs) based on transition metals (NiII, CuII, and ZnII), adenine, and di-, tri-, and tetra-carboxylate ligands. Adenine, with multiple N donor sites, was found to coordinate to the metal centers in different binding modes including bidentate (through N7 and N9, or N3 and N9) and tridentate (through N3, N7, and N9). Systematic investigations of the protonation states of adenine in each MOF structure via X-ray photoelectron spectroscopy revealed that adenine can be selectively protonated through N1, N3, or N7. The positions of H atoms connected to the N atoms were found from the electron density maps, and further supported by the study of C-N-C bond angles compared to the literature reports. DFT calculations were performed to geometrically optimize and energetically assess the structures simulated with different protonation modes. The present study highlights the rich coordination chemistry of adenine and provides a method for the determination of its protonation states and the location of protonated N atoms of adenine within MOFs, a task that would be challenging in complicated adenine-based MOF structures.

Near-Infrared Optical Imaging of Necrotic Cells by Photostable Lanthanide-Based Metallacrowns.

Sensitive detection of cell necrosis is crucial for the determination of cell viability. Because of its high resolution at the cellular level and sensitivity, optical imaging is highly attractive for identifying cell necrosis. However, challenges associated with this technique remain present such as the rapid photobleaching of several types of organic fluorophores and/or the interference generated by biological autofluorescence. Herein, we synthesized novel biologically compatible Zn2+/Ln3+ metallacrowns (MCs) that possess attractive near-infrared (NIR) emission and are highly photostable. In addition, these MCs have the ability to label differentially necrotic HeLa cells from living cells. This work is also the first demonstration of (i) the use of the NIR emission arising from a single lanthanide(III) cation for optical biological imaging of cells under single photon excitation, (ii) the first example of a lanthanide(III)-based NIR-emitting probe that can be targeted to a specific type of cell.

A Recyclable Metal-Organic Framework as a Dual Detector and Adsorbent for Ammonia.

Recyclable materials for simultaneous detection and uptake of ammonia (NH3 ) are of great interest due to the hazardous nature of NH3 . The structural versatility and porous nature of metal-organic frameworks (MOFs) make them ideal candidates for NH3 capture. Herein, the synthesis of a water-stable and porous 3-dimensional CuII -based MOF (SION-10) displaying a ship-in-a-bottle structure is reported; the pores of the host SION-10 framework accommodate mononuclear CuII -complexes. SION-10 spontaneously uptakes NH3 as a result of two concurrent mechanisms: chemisorption due to the presence of active CuII sites and physisorption (bulk permanent porosity). The color of the material changes from green to blue upon NH3 capture, with the shifts of the UV/Vis absorption bands clearly seen at NH3 concentrations as low as 300 ppm. SION-10 can be recovered upon immersion of SION-10⊃NH3 in water and can be further reused for NH3 capture for at least three cycles.

Prevalence of frailty and its associated factors in older hospitalised patients in Vietnam.

BACKGROUND: Frailty is an emerging issue in geriatrics and gerontology. The prevalence of frailty is increasing as the population ages. Like many developing countries, Vietnam has a rapidly ageing population. However, there have been no studies about frailty in older people in Vietnam. This study aims to investigate the prevalence of frailty and its associated factors in older hospitalised patients at the National Geriatric Hospital in Hanoi, Vietnam. METHODS: Prospective observational study in inpatients aged ≥60 years at the National Geriatric Hospital in Hanoi, Vietnam from 4/2015 to 10/2015. Frailty was assessed using the Reported Edmonton Frail Scale (REFS) and Fried frailty phenotype. RESULTS: A total of 461 patients were recruited (56.8% female, mean age 76.2 ± 8.9 years). The prevalence of frailty was 31.9% according to the REFS. Using the Fried frailty criteria, the percentages of non-frail, pre-frail and frail participants were 24.5, 40.1 and 35.4%, respectively. Factors associated with frailty defined by REFS were age (OR 1.05 per year, 95% CI 1.03-1.08), poor reported nutritional status (OR 4.51, 95% CI 2.15-9.44), and not finishing high school (OR 2.18, 95% CI 1.37-3.46). Factors associated with frailty defined by the Fried frailty criteria included age (OR 1.07 per year, 95% CI 1.05-1.10), poor reported nutritional status (OR 2.96, 95%CI 1.43-6.11), not finishing high school (OR 1.58, 95% CI 1.01-2.46) and cardiovascular disease (OR 1.76, 95% CI 1.16-2.67). CONCLUSIONS: While further studies are needed to examine the impact of frailty on outcomes in Vietnam, the observed high prevalence of frailty in older inpatients is likely to have implications for health policy and planning for the ageing population in Vietnam.

Ga(3+)/Ln(3+) Metallacrowns: A Promising Family of Highly Luminescent Lanthanide Complexes That Covers Visible and Near-Infrared Domains.

Luminescent lanthanide(III)-based molecular scaffolds hold great promises for materials science and for biological applications. Their fascinating photophysical properties enable spectral discrimination of emission bands that range from the visible to the near-infrared (NIR) regions. In addition, their strong resistance to photobleaching makes them suitable for long duration or repeated biological experiments using a broad range of sources of excitation including intense and focalized systems such as lasers (e.g., confocal microscopy). A main challenge in the creation of luminescent lanthanide(III) complexes lies in the design of a ligand framework that combines two main features: (i) it must include a chromophoric moiety that possesses a large molar absorptivity and is able to sensitize several different lanthanide(III) ions emitting in the visible and/or in the near-infrared, and (ii) it must protect the Ln(3+) cation by minimizing nonradiative deactivation pathways due to the presence of -OH, -NH and -CH vibrations. Herein, a new family of luminescent Ga(3+)/Ln(3+) metallacrown (MC) complexes is reported. The MCs with the general composition [LnGa4(shi)4(C6H5CO2)4(C5H5N) (CH3OH)] (Ln-1, Ln = Sm(3+)-Yb(3+)) were synthesized in a one pot reaction using salicylhydroxamic acid (H3shi) with Ga(3+) and Ln(3+) nitrates as reagents. The molecular structure of [DyGa4(shi)4(C6H5CO2)4(C5H5N) (CH3OH)] was obtained by X-ray analysis of single crystals and shows that the complex is formed as a [12-MCGa(III)shi-4] core with four benzoate molecules bridging the central Dy(3+) ion to the Ga(3+) ring metals. The powder X-ray diffraction analysis demonstrates that all other isolated complexes are isostructural. The extended analysis of the luminescence properties of these complexes, excited by the electronic states of the chromophoric ligands, showed the presence of characteristic, sharp f-f transitions that can be generated not only in the NIR (Sm, Dy, Ho, Er, Yb) but also in the visible (Sm, Eu, Tb, Dy, Tm). All Ln-1 complexes possess very high quantum yield values with respect to other literature compounds, indicating a good sensitization efficiency of the [12-MCGa(III)shi-4] scaffold. Especially, as of today, the Yb-1 complex exhibits the highest NIR quantum yield reported for a lanthanide(III) complex containing C-H bonds with a value of 5.88(2)% in the solid state. This work is a significant step forward toward versatile, easily prepared luminescent lanthanide(III) complexes suitable for a variety of applications including highly in demand biological imaging, especially in the NIR domain.

Promoter occupancy of the basal class I transcription factor A differs strongly between active and silent VSG expression sites in Trypanosoma brucei.

Monoallelic expression within a gene family is found in pathogens exhibiting antigenic variation and in mammalian olfactory neurons. Trypanosoma brucei, a lethal parasite living in the human bloodstream, expresses variant surface glycoprotein (VSG) from 1 of 15 bloodstream expression sites (BESs) by virtue of a multifunctional RNA polymerase I. The active BES is transcribed in an extranucleolar compartment termed the expression site body (ESB), whereas silent BESs, located elsewhere within the nucleus, are repressed epigenetically. The regulatory mechanisms, however, are poorly understood. Here we show that two essential subunits of the basal class I transcription factor A (CITFA) predominantly occupied the promoter of the active BES relative to that of a silent BES, a phenotype that was maintained after switching BESs in situ. In these experiments, high promoter occupancy of CITFA was coupled to high levels of both promoter-proximal RNA abundance and RNA polymerase I occupancy. Accordingly, fluorescently tagged CITFA-7 was concentrated in the nucleolus and the ESB. Because a ChIP-seq analysis found that along the entire BES, CITFA-7 is specifically enriched only at the promoter, our data strongly indicate that monoallelic BES transcription is activated by a mechanism that functions at the level of transcription initiation.

The Impact of Frailty on Mortality, Length of Stay and Re-hospitalisation in Older Patients with Atrial Fibrillation.

BACKGROUND: Frailty has been found to be associated with increased adverse outcomes in older patients, especially in patients with cardiovascular diseases. There has been no study focussing on the prognostic value of frailty amongst older hospitalised patients with atrial fibrillation. This study aims to investigate the impact of frailty on mortality, length of stay and re-hospitalisation in older hospitalised patients with atrial fibrillation. METHODS: Prospective observational study in patients aged ≥65 years with atrial fibrillation admitted to a teaching hospital in Sydney, Australia. Frailty was assessed using the Reported Edmonton Frail Scale. Participants were followed up for six months for adverse outcomes. RESULTS: We recruited 302 patients (mean age 84.7±7.1, 53.3% frail, 50% female). Frailty was associated with prolonged length of stay and increased mortality but not re-admission during six months after discharge. The coexistence of frailty and delirium significantly increased the risk of mortality. CONCLUSIONS: Frailty is a common geriatric syndrome in older inpatients with atrial fibrillation and is associated with poor outcomes. Screening for frailty along with other clinically important factors like delirium should be considered in older patients with atrial fibrillation to optimise individualised treatment plans.

Covalently Linked Dimer of Mn3 Single-Molecule Magnets and Retention of Its Structure and Quantum Properties in Solution.

[Mn3O(O2CMe)3(dpd)3/2)]2(I3)2 has been obtained from the reaction of 1,3-di(pyridin-2-yl)propane-1,3-dione dioxime (dpdH2) with triangular [Mn(III)3O(O2CMe)(py)3](ClO4). It comprises two [Mn(III)3O](7+) triangular units linked covalently by three dioximate ligands into a [Mn3]2 dimer. Solid state dc and ac magnetic susceptibility measurements reveal that each Mn3 subunit of the dimer is a separate single-molecule magnet (SMM) with an S = 6 ground state and that the two SMM units are very weakly ferromagnetically exchange coupled. High-frequency EPR spectroscopy on a single crystal displays signal splittings indicative of quantum superposition/entanglement of the two SMMs, and parallel studies on MeCN/toluene (1:1) frozen solutions reveal the same spectral features. The dimer thus retains its structure and inter-Mn3 coupling upon dissolution. This work establishes that covalently linked molecular oligomers of exchange-coupled SMMs can be prepared that retain their oligomeric nature and attendant inter-SMM quantum mechanical coupling in solution, providing a second phase for their study and demonstrating the feasibility of using solution methods for their deposition on surfaces and related substrates for study.