Prediction of adverse health outcomes using an electronic frailty index among nonfrail and prefrail community elders.

BACKGROUND: Early recognition of older people at risk of undesirable clinical outcomes is vital in preventing future disabling conditions. Here, we report the prognostic performance of an electronic frailty index (eFI) in comparison with traditional tools among nonfrail and prefrail community-dwelling older adults. The study is to investigate the predictive utility of a deficit-accumulation eFI in community elders without overt frailty. METHODS: Participants aged 65-80 years with a Clinical Frailty Scale of 1-3 points were recruited and followed for 2 years. The eFI score and Fried's frailty scale were determined by using a semiautomated platform of self-reported questionnaires and objective measurements which yielded cumulative deficits and physical phenotypes from 80 items of risk variables. Kaplan-Meier method and Cox proportional hazards regression were used to analyze the severity of frailty in relation to adverse outcomes of falls, emergency room (ER) visits and hospitalizations during 2 years' follow-up. RESULTS: A total of 427 older adults were evaluated and dichotomized by the median FI score. Two hundred and sixty (60.9%) and 167 (39.1%) elders were stratified into the low- (eFI ≤ 0.075) and the high-risk (eFI > 0.075) groups, respectively. During the follow-up, 77 (47.0%) individuals developed adverse events in the high-risk group, compared with 79 (30.5%) in the low-risk group (x2, p = 0.0006). In multivariable models adjusted for age and sex, the increased risk of all three events combined in the high- vs. low-risk group remained significant (adjusted hazard ratio (aHR) = 3.08, 95% confidence interval (CI): 1.87-5.07). For individual adverse event, the aHRs were 2.20 (CI: 1.44-3.36) for falls; 1.67 (CI: 1.03-2.70) for ER visits; and 2.84 (CI: 1.73-4.67) for hospitalizations. Compared with the traditional tools, the eFI stratification (high- vs. low-risk) showed better predictive performance than either CFS rating (managing well vs. fit to very fit; not discriminative in hospitalizations) or Fried's scale (prefrail to frail vs. nonfrail; not discriminative in ER visits). CONCLUSION: The eFI system is a useful frailty tool which effectively predicts the risk of adverse healthcare outcomes in nonfrail and/or prefrail older adults over a period of 2 years.

Multimorbidity and prior falls correlate with risk of 30-day hospital readmission in aged 80+: A prospective cohort study.

BACKGROUND/PURPOSE: Thirty-day hospital readmission rate significantly raised with advanced age. The performance of existing predictive models for readmission risk remained uncertain in the oldest population. We aimed to examine the effect of geriatric conditions and multimorbidity on readmission risk among older adults aged 80 and over. METHODS: This prospective cohort study enrolled patients aged 80 and older discharged from a geriatric ward at a tertiary hospital, with phone follow-up for 12 months. Demographics, multimorbidity, and geriatric conditions were assessed before hospital discharge. Logistic regression models were conducted to analyse risk factors for 30-day readmission. RESULTS: Patients readmitted had higher Charlson comorbidity index scores, and were more likely to have falls, frailty, and longer hospital stay, compared to those without 30-day readmission. Multivariate analysis revealed that higher Charlson comorbidity index score was associated with readmission risk. Older patients with a fall history within 12 months had a near 4-fold increase in readmission risk. Severe frailty status before index admission was associated with a higher 30-day readmission risk. Functional status at discharge was not associated with readmission risk. CONCLUSION: In addition to multimorbidity, history of falls and frailty were associated with higher hospital readmission risk in the oldest.

Validation of clinical frailty scale in Chinese translation.

BACKGROUND: Identification of frailty is crucial to guide patient care for the elderly. The Clinical Frailty Scale (CFS) is a reliable, synthesis and clinical judgment-based tool. However, a validated Chinese version of CFS (CFS-C) is lacking. The aim of this study is to describe the translation process of CFS into traditional Chinese and to evaluate its reliability and validity in a geriatric study population in Taiwan. METHODS: This cross-sectional study recruited 221 geriatric outpatients aged 65 years or older at a medical center in Taipei, Taiwan. The Chinese version of CFS was produced following Brislin's translation model. Weighted kappa for agreement and Kendall's tau for correlation were used to assess inter-rater reliability (a subgroup of 52 outpatients) between geriatricians and one research assistant, and validity tests (221 outpatients) by comparing CFS-C with Fried frailty phenotype and Frailty Index based on Comprehensive Geriatric Assessment (FI-CGA). Correlation between CFS-C and other geriatric conditions were also assessed. RESULTS: The inter-rater reliability revealed moderate agreement (weighted kappa = 0.60) and strong correlation (Kendall's tau = 0.67). For criterion validity, CFS-C categorisation showed fair agreement (weighted kappa = 0.37) and significant correlation (Kendall's tau = 0.46) with Fried frailty phenotype, and higher agreement (weighted kappa = 0.51) and correlation (Kendall's tau = 0.63) with FI-CGA categorisation. CFS-C was significantly correlated with various geriatric assessments, including functional disability, physical performance, hand grip, comorbidity, cognition, depression, and nutrition status. No significant correlation was found between CFS-C and appendicular muscle mass. CONCLUSIONS: The CFS-C demonstrated acceptable validity and reliability in Chinese older adults in Taiwan. Development of CFS-C enhanced consistency and accuracy of frailty assessment, both in research and clinical practice.

A DNA-encoded library for the identification of natural product binders that modulate poly (ADP-ribose) polymerase 1, a validated anti-cancer target.

Natural products have been an invaluable source of drug discovery, but their targets remain largely unknown. Natural products enriched DNA-encoded chemical libraries (nDELs) empower the researchers to rapidly and economically screen numerous natural products against various protein targets, and therefore promote the elucidation of the molecular mechanisms. In this work, we used poly (ADP-ribose) polymerase 1 (PARP1), as an example to explore the usage of nDEL for the functional natural products selection. We used late-stage modification approach to label three positive binders with unique DNA barcodes, whose dissociation constants range from sub-micromolar to micromolar. The selection criterion was set up according to the enrichment of these controls. Five natural products selected by this criterion directly bind to PARP1 in SPR, among which luteolin exhibits the highest inhibitory activity against PARP1. Moreover, luteolin selectively induces accumulation of DNA double-strand breaks and G2/M phase arrest in BRCA-deficient cells. All the findings from these investigations on luteolin support that PARP1 inhibition is one of the mechanisms for its anti-cancer activity.

A Chemistry for Incorporation of Selenium into DNA-Encoded Libraries.

Conventional direct C-H selenylation suffers from simple selenation with limited atom economy and complicated reaction system. In this work, we designed benzoselenazolone as a novel bifunctional selenide reagent for both off- and on-DNA C-H selenylation under rhodium(III) catalysis. We show that using benzoselenazolone allowed production of a series of selenylation products containing an adjacent aminoacyl group in a fast and efficient way, with high atom economy. The synthetic application of this method was demonstrated by taking advantage of the amide functionality as a nucleophile, directing group, and amide coupling partner. This work shows great potential in facilitating rapid construction of selenium-containing DNA-encoded chemical libraries (SeDELs), and lays the foundation for the development of selenium-containing drugs.

Synthesis of N-Acyl Sulfamates from Fluorosulfonates and Potassium Trimethylsilyloxyl Imidates.

An efficient and operationally simple method for the synthesis of N-acyl sulfamates from fluorosulfonates and potassium trimethylsilyloxyl imidates as amide precursor is reported. This approach showed broad substrate scope, mild and base-free reaction conditions, short reaction time, and high to excellent yields. Notably, we demonstrated the power of this reaction in the rapid late-stage functionalization of three complex phenol-containing bioactive molecules. Given the prevalence of phenol-containing drugs and building blocks, this method is applicable toward a diversity-oriented drug discovery.

The impact of early comprehensive geriatric screening on the readmission rate in an acute geriatric ward: a quasi-experimental study.

BACKGROUND: Unplanned readmission is an important healthcare quality issue. We studied the effect of a comprehensive geriatric screen (CGS) in the early admission course followed by a comprehensive geriatric assessment on readmission rates in elderly patients. METHODS: This quasi-experimental study with a historical comparison group was conducted in the geriatric ward of a referral centre in northern Taiwan. Older adults (aged > = 65 y/o) admitted from June 2013 to December 2013 were recruited for the geriatric screen group (N = 377). Patients admitted to the same ward from July 2011 to June 2012 were selected for the historical group (N = 380). The CGS was administered within the first 48 h after admission and was followed by a comprehensive geriatric assessment (CGA). Confounding risk factors included age, gender, Charlson comorbidity index, Barthel index score and medical utilization (length of stay and number of admissions), which were controlled using logistic regression models. We also developed a scoring system to identify the group that would potentially benefit the most from the early CGS. RESULTS: The 30-day readmission rate was significantly lower in the early CGS group than in the historical comparison group (11.4% vs 16.9%, p = 0.03). After adjusting for confounding variables, the hazard ratio of the early CGS group was 0.64 (95% CI 0.43-0.95). After scoring the potential benefit to the patients in the early CGS group, the log rank test showed a significant difference (p = 0.001 in the high-potential group and p = 0.98 in the low-potential group). CONCLUSION: An early CGS followed by a CGA may significantly reduce the 30-day readmission rate of elderly patients.

Effects of depression, dementia and delirium on activities of daily living in elderly patients after discharge.

BACKGROUND: The three geriatric conditions, depression, dementia and delirium (3D's), are common among hospitalized older patients and often lead to impairments of activities of daily living. The aim of this study is to explore the impact of depression, dementia and delirium on activities of daily living (ADLs) during and after hospitalization. METHODS: A prospective cohort study was conducted between 2012 and 2013 in a tertiary medical center in Taiwan. Patients who aged over 65 years and admitted to the geriatric ward were invited to this study. Geriatric Depression Scale Short Form, Mini-Mental State and Confusion Assessment Method were used to identify patients with depression, dementia and delirium on admission, respectively. Barthel Index (BI) was used to evaluate patients' functional status on admission, at discharge, 30-day, 90-day and 180-day after discharge. Generalized Estimating Equation (GEE) was used to calculate the associations between 3 D's and BI. RESULTS: One-hundred-and-forty-nine patients were included in this study. Twenty-seven patients (18.1%) had depression, 37 (24.8%) had dementia, and 85 (57.0%) had delirium. The study demonstrated that all the geriatric patients with functional decline presented gradual improvements of physical function up to 180 days after discharge. Whether depression exists did not substantially affect functional recovery after discharge, whilst either dementia or delirium could impede elder people functional status. The recovery of functional improvement in delirium or dementia was relatively irreversible when comparing with depression. Once delirium or dementia was diagnosed, poorer functional restore was expected. In brief, intensive work and strategies on modifying delirium or dementia should be put more effort as early as possible. CONCLUSIONS: Old hospitalized patients with depression can recover well after adequate intervention. We emphasize that early detection of dementia and delirium is imperative in subsequent functional outcome, even if at or before admission. Comprehensive plan must be implemented timely.

Functionality-Independent DNA Encoding of Complex Natural Products.

DNA encoded chemical libraries (DELs) link the powers of genetics and chemical synthesis via combinatorial optimization. Through combinatorial chemistry, DELs can grow to the unprecedented size of billions to trillions. To take full advantage of the DEL approach, linking the power of genetics directly to chemical structures would offer even greater diversity in a finite chemical world. Natural products have evolved an incredible structural diversity along with their biological evolution. Herein, we used traditional Chinese medicines (TCMs) as examples in a late-stage modification toolbox approach to annotate these complex organic compounds with amplifiable DNA barcodes, which could be easily incorporated into a DEL. The method of end-products labeling also generates a cluster of isomers with a single DNA tag at different sites. These isomers provide an additional spatial diversity for multiple accessible pockets of targeted proteins. Notably, a novel PARP1 inhibitor from TCM has been identified from the natural products enriched DEL (nDEL).

BAY 60-6583 Enhances the Antitumor Function of Chimeric Antigen Receptor-Modified T Cells Independent of the Adenosine A2b Receptor.

Chimeric antigen receptor (CAR) T cells are powerful in eradicating hematological malignancies, but their efficacy is limited in treating solid tumors. One of the barriers is the immunosuppressive response induced by immunomodulatory signaling pathways. Pharmacological targeting of these immunosuppressive pathways may be a simple way to improve the efficacy of CAR T cells. In this study, anti-CD133 and anti-HER2 CAR T cells were generated from healthy donors, and combination therapy using CAR T cells and small molecules targeting adenosine receptors was performed in vitro and in vivo with the goal of probing for potential synergistic antitumor activities. The adenosine A2b receptor agonist, BAY 60-6583, was found to significantly increase cytokine secretion of CD133-or HER2-specific CAR T cells when co-cultured with the respective target tumor cells. The in vitro cytotoxicity and proliferation of CAR T cells were also enhanced when supplied with BAY 60-6583. Furthermore, the combination with this small molecule facilitated the anti-HER2 CAR T cell-mediated elimination of tumor cells in a xenograft mouse model. However, the enhanced antitumor activities could not be suppressed by knockout of the adenosine A2b receptor in CAR T cells. Furthermore, mass spectrometry and computational methods were used to predict several potential alternative targets. Four potential targets (pyruvate kinase M (PKM), Talin-1, Plastin-2, and lamina-associated polypeptide 2) were captured by a photo-affinity probe, of which PKM and Talin-1 were predicted to interact with BAY 60-6583. Overall, our data suggest that BAY 60-6583 upregulates T cell functions through a mechanism independent of the adenosine A2b receptor.

Restoration of dysnatremia and acute kidney injury benefits outcomes of acute geriatric inpatients.

Dysnatremia and dyskalemia are common problems in acutely hospitalized elderly patients. These disorders are associated with an increased risk of mortality and functional complications that often occur concomitantly with acute kidney injury in addition to multiple comorbidities. In a single-center prospective observational study, we recruited 401 acute geriatric inpatients. In-hospital outcomes included all-cause mortality, length of stay, and changes in functional status as determined by the Activities of Daily Living (ADL) scale, Eastern Cooperative Oncology Group (ECOG) performance, and Clinical Frailty Scale (CFS). The prevalence of dysnatremia alone, dyskalemia alone, and dysnatremia plus dyskalemia during initial hospitalization were 28.4%, 14.7% and 32.4%, respectively. Patients with electrolyte imbalance exhibited higher mortality rates and longer hospital stays than those without electrolyte imbalance. Those with initial dysnatremia, or dysnatremia plus dyskalemia were associated with worse ADL scores, ECOG performance and CFS scores at discharge. Subgroup analyses showed that resolution of dysnatremia was related to reduced mortality risk and improved CFS score, whereas recovery of renal function was associated with decreased mortality and better ECOG and CFS ratings. Our data suggest that restoration of initial dysnatremia and acute kidney injury during acute geriatric care may benefit in-hospital survival and functional status at discharge.

Twelve-month specific IgG response to SARS-CoV-2 receptor-binding domain among COVID-19 convalescent plasma donors in Wuhan.

To investigate the duration of humoral immune response in convalescent coronavirus disease 2019 (COVID-19) patients, we conduct a 12-month longitudinal study through collecting a total of 1,782 plasma samples from 869 convalescent plasma donors in Wuhan, China and test specific antibody responses. The results show that positive rate of IgG antibody against receptor-binding domain of spike protein (RBD-IgG) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the COVID-19 convalescent plasma donors exceeded 70% for 12 months post diagnosis. The level of RBD-IgG decreases with time, with the titer stabilizing at 64.3% of the initial level by the 9th month. Moreover, male plasma donors produce more RBD-IgG than female, and age of the patients positively correlates with the RBD-IgG titer. A strong positive correlation between RBD-IgG and neutralizing antibody titers is also identified. These results facilitate our understanding of SARS-CoV-2-induced immune memory to promote vaccine and therapy development.

Correction: Iridium-catalyzed C-H amidation of s-tetrazines.

Correction for 'Iridium-catalyzed C-H amidation of s-tetrazines' by Huan Xiong et al., Chem. Commun., 2020, DOI: 10.1039/d0cc01647k.

Iridium-catalyzed C-H amidation of s-tetrazines.

An efficient, selective and scalable C-H amidation of s-tetrazines under iridium(III) catalysis is reported. This reaction features a broad substrate scope, high functional group tolerance, and air and water tolerance. This reaction also shows great potential for the rapid preparation of tri- and tetra-functional building blocks, which can be applied either in bioconjugation or synthesis of DNA-encoded library.

Selection of Small Molecules that Bind to and Activate the Insulin Receptor from a DNA-Encoded Library of Natural Products.

Although insulin is a life-saving medicine, administration by daily injection remains problematic. Our goal was to exploit the power of DNA-encoded libraries to identify molecules with insulin-like activity but with the potential to be developed as oral drugs. Our strategy involved using a 104-member DNA-encoded library containing 160 Traditional Chinese Medicines (nDEL) to identify molecules that bind to and activate the insulin receptor. Importantly, we used the natural ligand, insulin, to liberate bound molecules. Using this selection method on our relatively small, but highly diverse, nDEL yielded a molecule capable of both binding to and activating the insulin receptor. Chemical analysis showed this molecule to be a polycyclic analog of the guanidine metformin, a known drug used to treat diabetes. By using our protocol with other, even larger, DELs we can expect to identify additional organic molecules capable of binding to and activating the insulin receptor.

DNA-Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On-DNA Suzuki, Sonogashira, and Buchwald Reactions.

Using (hetero)aryl fluorosulfonates as versatile electrophiles, facile on-DNA cross-coupling reactions of Suzuki, Sonogashira, and Buchwald are reported here. Notably, all of these reactions show excellent functional group tolerance, mild reaction conditions (relative low temperature and open to air), rich heterocyclic coupling partners, and more importantly, DNA-compatibility. Thus, these new reactions based on efficient formation of C(sp2)-C(sp2), C(sp2)-C(sp), and C(sp2)-N bonds are highly amenable to synthesis of DNA-encoded libraries with great molecular diversity.

Geriatric conditions, rather than multimorbidity, as predictors of disability and mortality among octogenarians: A population-based cohort study.

AIM: To examine the impact of geriatric conditions and multimorbidity on the risk of incident disability and mortality among young-old and old-old adults. METHODS: The present study used nationally-representative data from the "Survey of Health and Living Status of the Elderly in Taiwan" for the years 2003 and 2007. Non-disabled older adults were divided into two age groups (65-79 years and ≥80 years). Chronic morbidities and geriatric conditions were assessed in 2003. Incident disability was defined as dependency in one or more activities of daily living in 2007. Vital statistics of the participants was linked to death registration data through 31 December 2007. Multivariable logistic regression and Cox regression were used to determine the effect of multimorbidity and geriatric conditions on health outcomes. RESULTS: Among those aged 65-79 years (n = 1874), the presentation of multimorbidity or two or more geriatric conditions was related to incident disability. Among octogenarians, the presentation of one or more geriatric conditions, but not multimorbidity, was shown to be independently associated with the risk of disability. Multimorbidity was related to a higher adjusted risk of mortality in the young-old group (hazard ratio 1.54; 95% confidence interval 1.1-2.2) but not in the old-old group. Among octogenarians, those with two or more geriatric conditions had a higher adjusted risk of mortality (hazard ratio 1.7; 95% confidence interval 1.2-2.5), compared with those with 0-1 geriatric conditions. CONCLUSIONS: The risk of incident disability and mortality increased in octogenarians with geriatric conditions, but not in cases with multimorbidity.

Multidimensional health-transition patterns among a middle-aged and older population.

AIM: Previous studies on health transition have focused on single-dimension outcomes and minimally evaluated heterogeneity. This study aimed to explore heterogeneous and multidimensional health-transition patterns on comorbidity, frailty and disability while examining the factors predicting different patterns of health transition. METHODS: This study drew on data from a nationwide and longitudinally-followed sample of 5131 Taiwanese aged 50 years and older who were interviewed in 1996, 1999, 2003 and 2007. Latent class analysis (LCA) and multinomial logistic regression were applied to identify health-transition patterns and their predictors. RESULTS: We identified six health-transition classes by applying LCA, including "persistently healthy", "well-managed comorbidity", "originally comorbid and gradually deteriorating to disability", "deteriorating gradually and died in late stage of the follow-up period", "deteriorating and died in middle stage of the follow-up period", and "originally comorbid and died in early stage of the follow-up period". Using the "well-managed comorbidity" class as the reference group, men had higher probabilities of being in the categories of dying in the follow-up period, but a lower risk of deteriorating to disability. Younger baseline age, higher education, having social engagement and non-smoking were predictors of "persistently healthy" and were associated with a lower risk of deteriorating to disability and death. Having a spouse and health examinations were associated with a lower risk of death, and also a lower probability of "persistently healthy". CONCLUSIONS: Heterogeneous and multidimensional health-transition patterns exist in middle-aged and older populations. Several factors might have an effect on health-transition patterns.