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OBJECTIVE: The Hospital Frailty Risk Score (HFRS) can be applied to medico-administrative datasets to determine the risks of 30-day mortality and long length of stay (LOS) in hospitalized older patients. The objective of this study was to compare the HFRS with Charlson and Elixhauser comorbidity indices, used separately or combined. DESIGN: A retrospective analysis of the French medical information database. The HFRS, Charlson index, and Elixhauser index were calculated for each patient based on the index stay and hospitalizations over the preceding 2 years. Different constructions of the HFRS were considered based on overlapping diagnostic codes with either Charlson or Elixhauser indices. We used mixed logistic regression models to investigate the association between outcomes, different constructions of HFRS, and associations with comorbidity indices. SETTING: 743 hospitals in France. PARTICIPANTS: All patients aged 75 years or older hospitalized as an emergency in 2017 (n=1,042,234).Main outcome measures: 30-day inpatient mortality and LOS >10 days. RESULTS: The HFRS, Charlson, and Elixhauser indices were comparably associated with an increased risk of 30-day inpatient mortality and long LOS. The combined model with the highest c-statistic was obtained when associating the HFRS with standard adjustment and Charlson for 30-day inpatient mortality (adjusted c-statistics: HFRS=0.654; HFRS + Charlson = 0.676) and with Elixhauser for long LOS (adjusted c-statistics: HFRS= 0.672; HFRS + Elixhauser =0.698). CONCLUSIONS: Combining comorbidity indices and HFRS may improve discrimination for predicting long LOS in hospitalized older people, but adds little to Charlson's 30-day inpatient mortality risk.
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Fragilidad , Multimorbilidad , Humanos , Anciano , Estudios Retrospectivos , Comorbilidad , Fragilidad/epidemiología , Mortalidad Hospitalaria , Factores de Riesgo , HospitalesRESUMEN
Host kinases play essential roles in the host cell cycle, innate immune signaling, the stress response to viral infection, and inflammation. Previous work has demonstrated that coronaviruses specifically target kinase cascades to subvert host cell responses to infection and rely upon host kinase activity to phosphorylate viral proteins to enhance replication. Given the number of kinase inhibitors that are already FDA approved to treat cancers, fibrosis, and other human disease, they represent an attractive class of compounds to repurpose for host-targeted therapies against emerging coronavirus infections. To further understand the host kinome response to betacoronavirus infection, we employed multiplex inhibitory bead mass spectrometry (MIB-MS) following MERS-CoV and SARS-CoV-2 infection of human lung epithelial cell lines. Our MIB-MS analyses revealed activation of mTOR and MAPK signaling following MERS-CoV and SARS-CoV-2 infection, respectively. SARS-CoV-2 host kinome responses were further characterized using paired phosphoproteomics, which identified activation of MAPK, PI3K, and mTOR signaling. Through chemogenomic screening, we found that clinically relevant PI3K/mTOR inhibitors were able to inhibit coronavirus replication at nanomolar concentrations similar to direct-acting antivirals. This study lays the groundwork for identifying broad-acting, host-targeted therapies to reduce betacoronavirus replication that can be rapidly repurposed during future outbreaks and epidemics. The proteomics, phosphoproteomics, and MIB-MS datasets generated in this study are available in the Proteomics Identification Database (PRIDE) repository under project identifiers PXD040897 and PXD040901.
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COVID-19 , Hepatitis C Crónica , Coronavirus del Síndrome Respiratorio de Oriente Medio , Humanos , Antivirales/farmacología , Inhibidores mTOR , Fosfatidilinositol 3-Quinasas , SARS-CoV-2 , Replicación Viral , Coronavirus del Síndrome Respiratorio de Oriente Medio/fisiología , Serina-Treonina Quinasas TORRESUMEN
Extended transition state-natural orbitals for chemical valence (ETS-NOCV)] data were used to rank electron acceptor capacities for several potentially synergistic anionic ligands incorporated into linear d10 [(NH3)Pd(A)]-, square planar d8 [(NN2)Ru(A)]-, and octahedral d6 [(AsN4)Tc(A)]- complexes [A = anionic ligand, NN2 = HN(CH2CH2CH2NH2)2, and AsN4 = [As(CH2CH2CH2NH2)4]-]. It was possible to differentiate between the best acceptors, among them BI2- and B(CF3)2-, and the poorest ones. A sizable fraction of the anionic ligands studied exhibit similar acceptor capacities (backbonding), mostly regardless of d electron count. A number of trends were discerned, including the fact that acceptor capacity decreases down families and across rows but increases down families of the peripheral substituents. The latter appears tied to the ability of the peripheral ligands to compete with the metal in donating electrons to the ligand-binding atom.
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Oncogenic KRAS drives cancer growth by activating diverse signaling networks, not all of which have been fully delineated. We set out to establish a system-wide profile of the KRAS-regulated kinase signaling network (kinome) in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). We knocked down KRAS expression in a panel of six cell lines and then applied multiplexed inhibitor bead/MS to monitor changes in kinase activity and/or expression. We hypothesized that depletion of KRAS would result in downregulation of kinases required for KRAS-mediated transformation and in upregulation of other kinases that could potentially compensate for the deleterious consequences of the loss of KRAS. We identified 15 upregulated and 13 downregulated kinases in common across the panel of cell lines. In agreement with our hypothesis, all 15 of the upregulated kinases have established roles as cancer drivers (e.g., SRC, TGF-ß1, ILK), and pharmacological inhibition of one of these upregulated kinases, DDR1, suppressed PDAC growth. Interestingly, 11 of the 13 downregulated kinases have established driver roles in cell cycle progression, particularly in mitosis (e.g., WEE1, Aurora A, PLK1). Consistent with a crucial role for the downregulated kinases in promoting KRAS-driven proliferation, we found that pharmacological inhibition of WEE1 also suppressed PDAC growth. The unexpected paradoxical activation of ERK upon WEE1 inhibition led us to inhibit both WEE1 and ERK concurrently, which caused further potent growth suppression and enhanced apoptotic death compared with WEE1 inhibition alone. We conclude that system-wide delineation of the KRAS-regulated kinome can identify potential therapeutic targets for KRAS-mutant pancreatic cancer.
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Carcinoma Ductal Pancreático , Proteínas de Ciclo Celular/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Mutación , Neoplasias Pancreáticas , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas p21(ras) , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/enzimología , Carcinoma Ductal Pancreático/genética , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/enzimología , Neoplasias Pancreáticas/genética , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismoRESUMEN
BACKGROUND: The Hospital Frailty Risk Score (HFRS) has made it possible internationally to identify subgroups of patients with characteristics of frailty from routinely collected hospital data. OBJECTIVE: To externally validate the HFRS in France. DESIGN: A retrospective analysis of the French medical information database. SETTING: 743 hospitals in Metropolitan France. SUBJECTS: All patients aged 75 years or older hospitalised as an emergency in 2017 (n = 1,042,234). METHODS: The HFRS was calculated for each patient based on the index stay and hospitalisations over the preceding 2 years. Main outcome measures were 30-day in-patient mortality, length of stay (LOS) >10 days and 30-day readmissions. Mixed logistic regression models were used to investigate the association between outcomes and HFRS score. RESULTS: Patients with high HFRS risk were associated with increased risk of mortality and prolonged LOS (adjusted odds ratio [aOR] = 1.38 [1.35-1.42] and 3.27 [3.22-3.32], c-statistics = 0.676 and 0.684, respectively), while it appeared less predictive of readmissions (aOR = 1.00 [0.98-1.02], c-statistic = 0.600). Model calibration was excellent. Restricting the score to data prior to index admission reduced discrimination of HFRS substantially. CONCLUSIONS: HFRS can be used in France to determine risks of 30-day in-patient mortality and prolonged LOS, but not 30-day readmissions. Trial registration: Reference ID on clinicaltrials.gov: ID: NCT03905629.
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Fragilidad , Anciano , Fragilidad/diagnóstico , Fragilidad/epidemiología , Hospitales , Humanos , Tiempo de Internación , Estudios Retrospectivos , Factores de RiesgoRESUMEN
The maternal embryonic leucine zipper kinase (MELK) has been implicated in the regulation of cancer cell proliferation. RNAi-mediated MELK depletion impairs growth and causes G2/M arrest in numerous cancers, but the mechanisms underlying these effects are poorly understood. Furthermore, the MELK inhibitor OTSSP167 has recently been shown to have poor selectivity for MELK, complicating the use of this inhibitor as a tool compound to investigate MELK function. Here, using a cell-based proteomics technique called multiplexed kinase inhibitor beads/mass spectrometry (MIB/MS), we profiled the selectivity of two additional MELK inhibitors, NVS-MELK8a (8a) and HTH-01-091. Our results revealed that 8a is a highly selective MELK inhibitor, which we further used for functional studies. Resazurin and crystal violet assays indicated that 8a decreases triple-negative breast cancer cell viability, and immunoblotting revealed that impaired growth is due to perturbation of cell cycle progression rather than induction of apoptosis. Using double-thymidine synchronization and immunoblotting, we observed that MELK inhibition delays mitotic entry, which was associated with delayed activation of Aurora A, Aurora B, and cyclin-dependent kinase 1 (CDK1). Following this delay, cells entered and completed mitosis. Using live-cell microscopy of cells harboring fluorescent proliferating cell nuclear antigen, we confirmed that 8a significantly and dose-dependently lengthens G2 phase. Collectively, our results provide a rationale for using 8a as a tool compound for functional studies of MELK and indicate that MELK inhibition delays mitotic entry, likely via transient G2/M checkpoint activation.
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Espectrometría de Masas , Mitosis , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Histonas/metabolismo , Humanos , Mitosis/efectos de los fármacos , Proteínas de Neoplasias/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Neoplasias de la Mama Triple Negativas/enzimología , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
"MoCl3(dme)" (dme = 1,2-dimethoxyethane) is an important precursor for midvalent molybdenum chemistry, particularly for triply Mo-Mo bonded compounds of the type Mo2X6 (X = bulky anionic ligand). However, its exact structural identity has been obscure for more than 50 years. In search of a convenient, large-scale synthesis, we have found that trans-MoCl4(Et2O)2 dissolved in dme can be cleanly reduced with dimethylphenylsilane, Me2PhSiH, to provide khaki Mo2Cl6(dme)2 in â¼90% yield. If the reduction is performed on a small scale, single crystals suitable for X-ray crystallography can be obtained. Two different crystal morphologies were identified, each belonging to the P21/n space group, but with slightly different unit cell constants. The refined structure of each form is an edge-shared bioctahedron with overall Ci symmetry and metal-metal separations on the order of 2.8 Å. The bulk material is diamagnetic as determined by both the Gouy method and SQUID magnetometry. Density functional theory calculations suggest a σ2π2δ*2 ground state for the dimer with the diamagnetism arising from a singlet diradical "broken symmetry" electronic configuration. In addition to a definitive structural assignment for "MoCl3(dme)", this work highlights the utility of organosilanes as easy to handle, alternative reductants for inorganic synthesis.
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Systematic computational studies of pericyclic Diels-Alder-type reactions between aminoborane (F3C)2B = N(CH3)2, 1, and all permutations of substituted cyclopentadienes c-C5R1R2R3R4R5aR5b (R = H, CH3, CF3, F) allow isolation of substitutional effects on Gibbs free energy barrier heights and reaction Gibbs free energies. The effects appear to be additive in all cases. Substitution at positions 5a and 5b always increases barriers and reaction energies, an effect explained by steric interactions between substituents and the aminoborane moiety. For cases R = CH3, regioselectivities differ from those expected from canonical organic chemistry predictions. Frontier molecular orbital calculations suggest this arises from the extreme polarization of the π interaction in 1. For cases R = CF3, the 2/3-substitution comparison accords with canon, but the 1/4-substitution comparison does not. This appears to arise from a combination of electronic and steric issues. For cases R = F, many of the reactions are exergonic, in contrast to the cases R = CH3, CF3. Additionally, fluorine substitution at positions 2 and 4 has a barrier-lowering effect. Frontier molecular orbital calculations support an orbital-based preference for formation of 2- and 4-substituted "meta" products rather than "ortho/para" products.
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BACKGROUND: The electronic Frailty Index (eFI) has been developed in primary care settings. The Hospital Frailty Risk Score (HFRS) was derived using secondary care data. OBJECTIVE: Compare the two different tools for identifying frailty in older people admitted to hospital. DESIGN AND SETTING: Retrospective cohort study using the Secure Anonymised Information Linkage Databank, comprising 126,600 people aged 65+ who were admitted as an emergency to hospital in Wales from January 2013 up until December 2017. METHODS: Pearson's correlation coefficient and weighted kappa were used to assess the correlation between the tools. Cox and logistic regression were used to estimate hazard ratios (HRs) and odds ratios (ORs). The Concordance statistic and area under the receiver operating curves (AUROC) were estimated to determine discrimination. RESULTS: Pearson's correlation coefficient was 0.26 and the weighted kappa was 0.23. Comparing the highest to the least frail categories in the two scores the HRs for 90-day mortality, 90-day emergency readmission and care home admissions within 1-year using the HFRS were 1.41, 1.69 and 4.15 for the eFI 1.16, 1.63 and 1.47. Similarly, the ORs for inpatient death, length of stay greater than 10 days and readmission within 30-days were 1.44, 2.07 and 1.52 for the HFRS, and 1.21, 1.21 and 1.44 for the eFI. AUROC was determined as having no clinically relevant difference between the tools. CONCLUSIONS: The eFI and HFRS have a low correlation between their scores. The HRs and ORs were higher for the increasing frailty categories for both the HFRS and eFI.
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Fragilidad , Anciano , Anciano Frágil , Fragilidad/diagnóstico , Fragilidad/epidemiología , Hospitalización , Humanos , Estudios Retrospectivos , GalesRESUMEN
Lucca and Moench (2015) document large average excess returns in U.S. equities before scheduled Federal Open Market Committee (FOMC) meetings from September 1994 to March 2011, leading to a puzzle not explained by standard asset pricing theory. We extend the sample to December 2019. We find that after first appearing before FOMC announcements accompanied by the Fed Chair press conferences, the pre-FOMC drift essentially disappeared after 2015 in both announcements accompanied by press conferences and announcements not accompanied by press conferences. We discuss a possible explanation for this change: reduced uncertainty.
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Recurrence rates in the laparoscopic repair of the hiatal hernia range from 12% to 59%. Limitation of reinforcement has been principally the risk of adverse events caused by synthetic materials. Biologic and resorbable synthetic materials are valid alternatives. This study compares the host response to all these materials after hiatal hernia repair. A total of 20 Landrace pigs, underwent laparoscopic primary hiatal hernia repair and reinforced with a polypropylene mesh (PROLENE: polypropylene [PP]), an absorbable synthetic scaffold (GOREBIO-A: polyglycolic acid [PGA]), a urinary bladder matrix scaffold, (Gentrix: urinary bladder matrix [UBM]), or without reinforcement, control group (C). Animals were survived for 3 months. Endpoints included gross morphology, biomechanical testing, and histology. Pigs in PP and PGA groups showed fibrosis at the repair site, with robust adhesions. In UBM and C groups, only mild adhesions were found. Load at failure (gr) and stiffness (gr/mm) of PP were higher than C group (PP:2103 ± 548.3 versus C:951.1 ± 372.7, P = 0.02; PP:643.3 ± 301 versus C:152.6 ± 142.7, P = 0.01). PGA and UBM values for both parameters were in between PP and C samples. However, stiffness in UBM was tended to be lower than PP group, and approached a significant difference (643.3 ± 301 versus 243 ± 122.1, P = 0.0536). In UBM group, the histology resembled native tissue. By contrast, PP and PGA groups showed mononuclear infiltrates, fibroencapsulation, necrosis, remnants of mesh, and disorganized tissue that was validated with a histologic score. In this setting, UBM scaffolds showed the most appropriate features for hiatal hernia repair, recovering the tissue properties that can help reduce the possibility of early failure and prevent complications associated with the implanted material.
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Materiales Biocompatibles , Hernia Hiatal/cirugía , Herniorrafia/instrumentación , Prevención Secundaria/instrumentación , Andamios del Tejido , Implantes Absorbibles , Animales , Modelos Animales de Enfermedad , Femenino , Herniorrafia/métodos , Humanos , Ensayo de Materiales , Prevención Secundaria/métodos , Estrés Mecánico , Mallas Quirúrgicas , Sus scrofaRESUMEN
Pericardium closure after cardiac surgery is recommended to prevent postoperative adhesions to the sternum. Synthetic materials have been used as substitutes, with limited results because of impaired remodeling and fibrotic tissue formation. Urinary bladder matrix (UBM) scaffolds promote constructive remodeling that more closely resemble the native tissue. The aim of the study is to evaluate the host response to UBM scaffolds in a porcine model of partial pericardial resection. Twelve Landrace pigs were subjected to a median sternotomy. A 5 × 7 cm pericardial defect was created and then closed with a 5 × 7 cm multilayer UBM patch (UBM group) or left as an open defect (control group). Animals were survived for 8 wk. End points included gross morphology, biomechanical testing, histology with semiquantitative score, and cardiac function. The UBM group showed mild adhesions, whereas the control group showed fibrosis at the repair site, with robust adhesions and injury to the coronary bed. Load at failure (gr) and stiffness (gr/mm) were lower in the UBM group compared with the native pericardium (199.9 ± 59.2 versus 405.3 ± 99.89 g, P = 0.0536 and 44.23 ± 15.01 versus 146.5 ± 24.38 g/mm, P = 0.0025, respectively). In the UBM group, the histology resembled native pericardial tissue, with neovascularization, neofibroblasts, and little inflammatory signs. In contrast, control group showed fibrotic tissue with mononuclear infiltrates and a lack of organized collagen fibers validated with a histologic score. Both groups had normal ultrasonography results without cardiac motility disorders. In this setting, UBM scaffolds showed appropriate features for pericardial repair, restoring tissue properties that could help reduce postsurgical adhesions and prevent its associated complications.
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Procedimientos Quirúrgicos Cardíacos/efectos adversos , Pericardio/cirugía , Complicaciones Posoperatorias/prevención & control , Adherencias Tisulares/prevención & control , Andamios del Tejido , Animales , Procedimientos Quirúrgicos Cardíacos/métodos , Modelos Animales de Enfermedad , Matriz Extracelular , Femenino , Humanos , Pericardio/patología , Complicaciones Posoperatorias/etiología , Mallas Quirúrgicas , Sus scrofa , Adherencias Tisulares/etiología , Adherencias Tisulares/patología , Vejiga Urinaria/citologíaRESUMEN
Cerebral amyloid angiopathy (CAA) is a common cerebrovascular disease involved in ischemic and hemorrhagic strokes, and its progression is correlated to cognitive decline. In vivo diagnosis of CAA is guided by the modified Boston criteria, with the presence of multiple intracerebral hemorrhage or cerebral microbleeds (CMB), or single hemorrhage and cortical superficial siderosis. The diagnosis of CAA is highly dependent on the quality of imaging and the advent of susceptibility-weighted imaging (SWI) sequences has improved sensitivity of MRI to detect hemosiderin deposition and CMB, hallmarks of CAA. We report here 3 clinical cases of patients with Alzheimer's disease and a focal form (i.e., not disseminated) of probable CAA, diagnosed with SWI sequences. Focal CAA may require closer attention and could offer keys in the understanding of both Alzheimer's disease and CAA pathogenesis.
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Angiopatía Amiloide Cerebral/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Anciano , Anciano de 80 o más Años , Biomarcadores/análisis , Diagnóstico Diferencial , Humanos , MasculinoRESUMEN
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, and at least one-third of its patients relapse after treatment with the current chemotherapy regimen, R-CHOP. By gene-expression profiling, patients with DLBCL can be categorized into two clinically relevant subtypes: activated B-cell (ABC) and germinal center B-cell (GCB) DLBCL. Patients with the ABC subtype have a worse prognosis than those with GCB, and the subtype is defined by chronic, over-active signaling through the B-cell receptor and NF-κB pathways. We examined the effects of the Src family kinase (SFK) inhibitor dasatinib in a panel of ABC and GCB DLBCL cell lines and found that the former are much more sensitive to dasatinib than the latter. However, using multiplexed inhibitor bead coupled to mass spectrometry (MIB/MS) kinome profiling and Western blot analysis, we found that both subtypes display inhibition of the SFKs in response to dasatinib after both short- and long-term treatment. The MIB/MS analyses revealed that several cell-cycle kinases, including CDK4, CDK6, and the Aurora kinases, are down-regulated by dasatinib treatment in the ABC, but not in the GCB, subtype. The present findings have potential implications for the clinical use of dasatinib for the treatment of ABC DLBCL, either alone or in combination with other agents.
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Dasatinib/farmacología , Centro Germinal/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Linfocitos B/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Dasatinib/uso terapéutico , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Centro Germinal/patología , Humanos , Linfoma de Células B Grandes Difuso/clasificaciónRESUMEN
Controlling which particular members of a large protein family are targeted by a drug is key to achieving a desired therapeutic response. In this study, we report a rational data-driven strategy for achieving restricted polypharmacology in the design of antitumor agents selectively targeting the TYRO3, AXL, and MERTK (TAM) family tyrosine kinases. Our computational approach, based on the concept of fragments in structural environments (FRASE), distills relevant chemical information from structural and chemogenomic databases to assemble a three-dimensional inhibitor structure directly in the protein pocket. Target engagement by the inhibitors designed led to disruption of oncogenic phenotypes as demonstrated in enzymatic assays and in a panel of cancer cell lines, including acute lymphoblastic and myeloid leukemia (ALL/AML) and nonsmall cell lung cancer (NSCLC). Structural rationale underlying the approach was corroborated by X-ray crystallography. The lead compound demonstrated potent target inhibition in a pharmacodynamic study in leukemic mice.
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Antineoplásicos/química , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Estructura Molecular , Neoplasias ExperimentalesRESUMEN
BACKGROUND: Older people are increasing users of health care globally. We aimed to establish whether older people with characteristics of frailty and who are at risk of adverse health-care outcomes could be identified using routinely collected data. METHODS: A three-step approach was used to develop and validate a Hospital Frailty Risk Score from International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes. First, we carried out a cluster analysis to identify a group of older people (≥75 years) admitted to hospital who had high resource use and diagnoses associated with frailty. Second, we created a Hospital Frailty Risk Score based on ICD-10 codes that characterised this group. Third, in separate cohorts, we tested how well the score predicted adverse outcomes and whether it identified similar groups as other frailty tools. FINDINGS: In the development cohort (n=22â139), older people with frailty diagnoses formed a distinct group and had higher non-elective hospital use (33·6 bed-days over 2 years compared with 23·0 bed-days for the group with the next highest number of bed-days). In the national validation cohort (n=1â013â590), compared with the 429â762 (42·4%) patients with the lowest risk scores, the 202â718 (20·0%) patients with the highest Hospital Frailty Risk Scores had increased odds of 30-day mortality (odds ratio 1·71, 95% CI 1·68-1·75), long hospital stay (6·03, 5·92-6·10), and 30-day readmission (1·48, 1·46-1·50). The c statistics (ie, model discrimination) between individuals for these three outcomes were 0·60, 0·68, and 0·56, respectively. The Hospital Frailty Risk Score showed fair overlap with dichotomised Fried and Rockwood scales (kappa scores 0·22, 95% CI 0·15-0·30 and 0·30, 0·22-0·38, respectively) and moderate agreement with the Rockwood Frailty Index (Pearson's correlation coefficient 0·41, 95% CI 0·38-0·47). INTERPRETATION: The Hospital Frailty Risk Score provides hospitals and health systems with a low-cost, systematic way to screen for frailty and identify a group of patients who are at greater risk of adverse outcomes and for whom a frailty-attuned approach might be useful. FUNDING: National Institute for Health Research.
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Registros Electrónicos de Salud/estadística & datos numéricos , Anciano Frágil/estadística & datos numéricos , Evaluación Geriátrica/métodos , Evaluación de Resultado en la Atención de Salud , Anciano , Anciano de 80 o más Años , Bases de Datos Factuales , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Factores de RiesgoRESUMEN
A series of zinc-based catalysts was evaluated for their efficiency in decomposing formic acid into molecular hydrogen and carbon dioxide in the gas phase using quadrupole ion trap mass spectrometry experiments. The effectiveness of the catalysts in the series [(L)Zn(H)]+ , where L=2,2':6',2''-terpyridine (tpy), 1,10-phenanthroline (phen) or 2,2'-bipyrydine (bpy), was found to depend on the ligand used, which turned out to be fundamental in tuning the catalytic properties of the zinc complex. Specifically, [(tpy)Zn(H)]+ displayed the fastest reaction with formic acid proceeding by dehydrogenation to produce the zinc formate complex [(tpy)Zn(O2 CH)]+ and H2 . The catalysts [(L)Zn(H)]+ are reformed by decarboxylating the zinc formate complexes [(L)Zn(O2 CH)]+ by collision-induced dissociation, which is the only reaction channel for each of the ligands used. The decarboxylation reaction was found to be reversible, since the zinc hydride complexes [(L)Zn(H)]+ react with carbon dioxide yielding the zinc formate complex. This reaction was again substantially faster for L=tpy than L=phen or bpy. The energetics and mechanisms of these processes were modelled using several levels of density functional theory (DFT) calculations. Experimental results are fully supported by the computational predictions.
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The asymmetric direct reductive amination of prochiral ketones with aryl amines using 1-hydrosilatrane with a chiral Brønsted acid catalyst is reported. This is the first known example of chiral Brønsted acid-catalyzed asymmetric reductive amination using a silane as the hydride source. The reaction features a highly practical reducing reagent and proceeds efficiently at room temperature without a specialized reaction setup or equipment to exclude air or moisture. This method provides high conversion and enantiomeric excess up to 84% of the desired chiral secondary amines with minimal side products.
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The reaction between (F3C)2BâNMe2, 1, and acetonitrile at low temperature in pentane yields a bora-acetonitrile rather than the expected coordination complex. This appears to arise from the two undergoing an ene reaction followed by a rearrangement analogous to a ketenimine-nitrile rearrangement. Computational studies indicate that mechanistic steps suggested for the latter require energies too large for the reaction to take place under the experimental conditions. Instead, a mechanism in which the ene reaction product is attacked by a second molecule of 1, followed by hydrogen transfer and decomposition, exhibits barriers lower than that for the ene reaction. The mechanism implies that the fragment of 1 in the observed product is not the one that underwent the ene reaction. The ene reaction barrier is rate-determining, and it is low enough to conform to the experimental conditions.
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Computational studies of low spin d6 cis- and trans-[M(en)2X2]+ complexes (M = Co, Rh, Ir) employing multiple model chemistries find that isomer preferences fall into three categories. Complexes where X is largely a σ-donor (H-, CH3-, CF3-) prefer cis geometries, in keeping with predictions associated with the trans influence series. Complexes where this donor characteristic is augmented by π acceptor behavior (B(CF3)2-, BCl2-, SiCl3-) evince even greater preference for cis geometries. QTAIM charge data suggest this is marked by lower positive charge on the metal in cis complexes. In contrast, complexes where X is a π donor and low in the trans influence series (X = OH-, F-, Cl-, I-) prefer trans geometries to varying degrees. QTAIM calculations indicate that this arises because the cis complexes are destabilized by distortions of the electron density in the M-X bonds. This can be viewed conceptually as resulting from repulsions between lone pair electrons on the ligands. Complexes where the X ligands are moderately trans-influencing and can interact conjugatively (CN-, NC-, NO2-, C≡CH-) prefer trans geometries because they combine destabilization of cis geometries with enhanced stabilization of trans geometries resulting from conjugation.