Frailty degree and illness trajectories in older people towards the end-of-life:a prospective observational study

Objectives To assess the degree of frailty in older people with different advanced diseases and its relationship with end-of-life illness trajectories and survival.Methods Prospective, observational study, including all patients admitted to the Acute Geriatric Unit of the University Hospital of Vic (Spain) during 12 consecutive months (2014–2015), followed for up to 2 years. Participants were identified as end-of-life people (EOLp) using the NECPAL (NECesidades PALiativas, palliative care needs) tool and were classified according to their dominant illness trajectory. The Frail-VIG index (Valoración Integral Geriátrica, Comprehensive Geriatric Assessment) was used to quantify frailty degree, to calculate the relationship between frailty and mortality (Receiver Operating Characteristic (ROC) curves), and to assess the combined effect of frailty degree and illness trajectories on survival (Cox proportional hazards model). Survival curves were plotted using the Kaplan-Meier estimator with participants classified into four groups (ie, no frailty, mild frailty, moderate frailty and advanced frailty) and were compared using the log-rank test.Results Of the 590 persons with a mean (SD) age of 86.4 (5.6) years recruited, 260 (44.1%) were identified as EOLp, distributed into cancer (n=31, 11.9%), organ failure (n=79, 30.4%), dementia (n=86, 33.1%) and multimorbidity (n=64, 24.6%) trajectories. All 260 EOLp had some degree of frailty, mostly advanced frailty (n=184, 70.8%), regardless of the illness trajectory, and 220 (84.6%) died within 2 years. The area under the ROC curve (95% CI) after 2 years of follow-up for EOLp was 0.87 (0.84 to 0.92) with different patterns of survival decline in the different end-of-life trajectories (p<0.0001). Cox regression analyses showed that each additional deficit of the Frail-VIG index increased the risk of death by 61.5%, 30.1%, 29.6% and 12.9% in people with dementia, organ failure, multimorbidity and cancer, respectively (p<0.01 for all the coefficients).Conclusions All older people towards the end-of-life in this study were frail, mostly with advanced frailty. The degree of frailty is related to survival across the different illness trajectories despite the differing survival patterns among trajectories. Frailty indexes may be useful to assess end-of-life older people, regardless of their trajectory

Structure-based design of a Cortistatin analogue with immunomodulatory activity in models of inflammatory bowel disease

Ulcerative colitis and Crohn's disease are forms of inflammatory bowel disease whose incidence and prevalence are increasing worldwide. These diseases lead to chronic inflammation of the gastrointestinal tract as a result of an abnormal response of the immune system. Recent studies positioned Cortistatin, which shows low stability in plasma, as a candidate for IBD treatment. Here, using NMR structural information, we design five Cortistatin analogs adopting selected native Cortistatin conformations in soln. One of them, A5, preserves the anti-inflammatory and immunomodulatory activities of Cortistatin in vitro and in mouse models of the disease. Addnl., A5 displays an increased half-life in serum and a unique receptor binding profile, thereby overcoming the limitations of the native Cortistatin as a therapeutic agent. This study provides an efficient approach to the rational design of Cortistatin analogs and opens up new possibilities for the treatment of patients that fail to respond to other therapies

Stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc) and ureido-DNJNAc derivatives as new hexosaminidase inhibitors

2-Acetamido-1,2-dideoxyiminosugars are selective and potent inhibitors of hexosaminidases and therefore show high therapeutic potential for the treatment of various diseases, including several lysosomal storage disorders. A stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc), the iminosugar analog of N-acetylglucosamine, with a high overall yield is here described. This novel procedure further allowed accessing ureido-DNJNAc conjugates through derivatization of the endocyclic amine on a key pivotal intermediate. Remarkably, some of the ureido-DNJNAc representatives behaved as potent and selective inhibitors of β-hexosaminidases, including the human enzyme, being the first examples of neutral sp2-iminosugar-type inhibitors reported for these enzymes. Moreover, the amphiphilic character of the new ureido-DNJNAc is expected to confer better drug-like properties

Peptide aromatic interactions modulated by fluorinated residues: Synthesis, structure and biological activity of Somatostatin analogs containing 3-(3',5'difluorophenyl)-alanine

Somatostatin is a 14-residue peptide hormone that regulates the endocrine system by binding to five G-protein-coupled receptors (SSTR1-5). We have designed six new Somatostatin analogs with L-3-(3',5'-difluorophenyl)-alanine (Dfp) as a substitute of Phe and studied the effect of an electron-poor arom. ring in the network of arom. interactions present in Somatostatin. Replacement of each of the Phe residues (positions 6, 7 and 11) by Dfp and use of a D-Trp8 yielded peptides whose main conformations could be characterized in aq. soln. by NMR. Receptor binding studies revealed that the analog with Dfp at position 7 displayed a remarkable affinity to SSTR2 and SSTR3. Analogs with Dfp at positions 6 or 11 displayed a π-π interaction with the Phe present at 11 or 6, resp. Interestingly, these analogs, particularly [D-Trp8,L-Dfp11]-SRIF, showed high selectivity towards SSTR2, with a higher value than that of Octreotide and a similar one to that of native Somatostatin

A trial assessing N-3 as treatment for injury-induced cachexia (ATLANTIC trial): does a moderate dose fish oil intervention improve outcomes in older adults recovering from hip fracture?

<p>Abstract</p> <p>Background</p> <p>Proximal femoral fractures are associated with increased morbidity and mortality. Pre-existing malnutrition and weight loss amongst this patient group is of primary concern, with conventional nutrition support being largely ineffective. The inflammatory response post proximal femoral fracture surgery and the subsequent risk of cachexia may explain the inability of conventional high energy high protein management to produce an anabolic response amongst these patients. Omega-3 fatty acids derived from fish oils have been extensively studied for their anti-inflammatory benefits. Due to their anti-inflammatory properties, the benefit of fish oil combined with individualized nutrition support amongst proximal femoral fracture patients post surgery is an attractive potential therapeutic strategy. The aim of the ATLANTIC trial is to assess the potential benefits of an anti-inflammatory dose of fish oil within the context of a 12 week individualised nutrition program, commencing seven days post proximal femoral fracture surgery.</p> <p>Methods/Design</p> <p>This randomized controlled, double blinded trial, will recruit 150 community dwelling elderly patients aged ≥65 years, within seven days of surgery for proximal femoral fracture. Participants will be randomly allocated to receive either a 12 week individualized nutrition support program complemented with 20 ml/day anti-inflammatory dose fish oil (~3.6 g eicosapentaenoic acid, ~2.4 g docosahexanoic acid; intervention), or, a 12 week individualized nutrition support program complemented with 20 ml/day low dose fish oil (~0.36 g eicosapentaenoic acid, ~0.24 g docosahexanoic acid; control).</p> <p>Discussion</p> <p>The ATLANTIC trial is the first of its kind to provide fish oil combined with individualized nutrition therapy as an intervention to address the inflammatory response experienced post proximal femoral fracture surgery amongst elderly patients. The final outcomes of this trial will assist clinicians in the development of effective and alternative treatment methods post proximal femoral fracture surgery which may ultimately result in a reduction in systemic inflammation, loss of weight and lean muscle and improvements in nutritional status, mobility, independence and quality of life among elderly patients.</p> <p>Trial Registration</p> <p>ACTRN12609000241235</p

Short Physical Performance Battery and all-cause mortality: systematic review and meta-analysis

Background: The Short Physical Performance Battery (SPPB) is a well-established tool to assess lower extremity physical performance status. Its predictive ability for all-cause mortality has been sparsely reported, but with conflicting results in different subsets of participants. The aim of this study was to perform a meta-analysis investigating the relationship between SPPB score and all-cause mortality.Methods: Articles were searched in MEDLINE, the Cochrane Library, Google Scholar, and BioMed Central between July and September 2015 and updated in January 2016. Inclusion criteria were observational studies; > 50 participants; stratification of population according to SPPB value; data on all-cause mortality; English language publications. Twenty-four articles were selected from available evidence. Data of interest (i.e., clinical characteristics, information after stratification of the sample into four SPPB groups [0-3, 4-6, 7-9, 10-12]) were retrieved from the articles and/or obtained by the study authors. The odds ratio (OR) and/or hazard ratio (HR) was obtained for all-cause mortality according to SPPB category (with SPPB scores 10-12 considered as reference) with adjustment for age, sex, and body mass index.Results: Standardized data were obtained for 17 studies (n = 16,534, mean age 76 +/- 3 years). As compared to SPPB scores 10-12, values of 0-3 (OR 3.25, 95% CI 2.86-3.79), 4-6 (OR 2.14, 95% CI 1.92-2.39), and 7-9 (OR 1.50, 95% CI 1. 32-1.71) were each associated with an increased risk of all-cause mortality. The association between poor performance on SPPB and all-cause mortality remained highly consistent independent of follow-up length, subsets of participants, geographic area, and age of the population. Random effects meta-regression showed that OR for all-cause mortality with SPPB values 7-9 was higher in the younger population, diabetics, and men.Conclusions: An SPPB score lower than 10 is predictive of all-cause mortality. The systematic implementation of the SPPB in clinical practice settings may provide useful prognostic information about the risk of all-cause mortality. Moreover, the SPPB could be used as a surrogate endpoint of all-cause mortality in trials needing to quantify benefit and health improvements of specific treatments or rehabilitation programs