The My Active and Healthy Aging (My-AHA) ICT platform to detect and prevent frailty in older adults: Randomized control trial design and protocol

[EN] Introduction Frailty increases the risk of poor health outcomes, disability, hospitalization, and death in older adults and affects 7%¿12% of the aging population. Secondary impacts of frailty on psychological health and socialization are significant negative contributors to poor outcomes for frail older adults. Method The My Active and Healthy Aging (My-AHA) consortium has developed an information and communications technology¿based platform to support active and healthy aging through early detection of prefrailty and provision of individually tailored interventions, targeting multidomain risks for frailty across physical activity, cognitive activity, diet and nutrition, sleep, and psychosocial activities. Six hundred adults aged 60 years and older will be recruited to participate in a multinational, multisite 18-month randomized controlled trial to test the efficacy of the My-AHA platform to detect prefrailty and the efficacy of individually tailored interventions to prevent development of clinical frailty in this cohort. A total of 10 centers from Italy, Germany, Austria, Spain, United Kingdom, Belgium, Sweden, Japan, South Korea, and Australia will participate in the randomized controlled trial. Results Pilot testing (Alpha Wave) of the My-AHA platform and all ancillary systems has been completed with a small group of older adults in Europe with the full randomized controlled trial scheduled to commence in 2018. Discussion The My-AHA study will expand the understanding of antecedent risk factors for clinical frailty so as to deliver targeted interventions to adults with prefrailty. Through the use of an information and communications technology platform that can connect with multiple devices within the older adult's own home, the My-AHA platform is designed to measure an individual's risk factors for frailty across multiple domains and then deliver personalized domain-specific interventions to the individual. The My-AHA platform is technology-agnostic, enabling the integration of new devices and sensor platforms as they emerge.This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 689582 and the Australian National Health and Medical Research Council (NHRMC) European Union grant scheme (1115818). M.J.S. reports personal fees from Eli Lilly (Australia) Pty Ltd and grants from Novotech Pty Ltd, outside the submitted work. All other authors report nothing to disclose.Summers, MJ.; Rainero, I.; Vercelli, AE.; Aumayr, GA.; De Rosario Martínez, H.; Mönter, M.; Kawashima, R. (2018). The My Active and Healthy Aging (My-AHA) ICT platform to detect and prevent frailty in older adults: Randomized control trial design and protocol. Alzheimer's and Dementia: Translational Research and Clinical Interventions. 4:252-262. https://doi.org/10.1016/j.trci.2018.06.004S2522624Blair, S. N. (1995). Changes in Physical Fitness and All-Cause Mortality. JAMA, 273(14), 1093. doi:10.1001/jama.1995.03520380029031Fried, L. P., Ferrucci, L., Darer, J., Williamson, J. D., & Anderson, G. (2004). Untangling the Concepts of Disability, Frailty, and Comorbidity: Implications for Improved Targeting and Care. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 59(3), M255-M263. doi:10.1093/gerona/59.3.m255Gillick, M. (2001). Guest Editorial: Pinning Down Frailty. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 56(3), M134-M135. doi:10.1093/gerona/56.3.m134Hamerman, D. (1999). Toward an Understanding of Frailty. Annals of Internal Medicine, 130(11), 945. doi:10.7326/0003-4819-130-11-199906010-00022Fried, L. P., Tangen, C. M., Walston, J., Newman, A. B., Hirsch, C., Gottdiener, J., … McBurnie, M. A. (2001). Frailty in Older Adults: Evidence for a Phenotype. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 56(3), M146-M157. doi:10.1093/gerona/56.3.m146Panza, F., Solfrizzi, V., Barulli, M. R., Santamato, A., Seripa, D., Pilotto, A., & Logroscino, G. (2015). Cognitive Frailty: A Systematic Review of Epidemiological and Neurobiological Evidence of an Age-Related Clinical Condition. Rejuvenation Research, 18(5), 389-412. doi:10.1089/rej.2014.1637Soong, J., Poots, A., Scott, S., Donald, K., Woodcock, T., Lovett, D., & Bell, D. (2015). Quantifying the prevalence of frailty in English hospitals. BMJ Open, 5(10), e008456. doi:10.1136/bmjopen-2015-008456Varadhan, R., Walston, J., Cappola, A. R., Carlson, M. C., Wand, G. S., & Fried, L. P. (2008). Higher Levels and Blunted Diurnal Variation of Cortisol in Frail Older Women. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 63(2), 190-195. doi:10.1093/gerona/63.2.190BROWN, I., RENWICK, R., & RAPHAEL, D. (1995). Frailty. International Journal of Rehabilitation Research, 18(2), 93-102. doi:10.1097/00004356-199506000-00001Buchner, D. M., & Wagner, E. H. (1992). Preventing Frail Health. Clinics in Geriatric Medicine, 8(1), 1-18. doi:10.1016/s0749-0690(18)30494-4Kojima, G., Iliffe, S., Jivraj, S., & Walters, K. (2016). Association between frailty and quality of life among community-dwelling older people: a systematic review and meta-analysis. Journal of Epidemiology and Community Health, 70(7), 716-721. doi:10.1136/jech-2015-206717Ory, M. G., Schechtman, K. B., Miller, J. P., Hadley, E. C., Fiatarone, M. A., … Province, M. A. (1993). Frailty and Injuries in Later Life: The FICSIT Trials. Journal of the American Geriatrics Society, 41(3), 283-296. doi:10.1111/j.1532-5415.1993.tb06707.xShamliyan, T., Talley, K. M. C., Ramakrishnan, R., & Kane, R. L. (2013). Association of frailty with survival: A systematic literature review. Ageing Research Reviews, 12(2), 719-736. doi:10.1016/j.arr.2012.03.001Woodhouse, K. W., & O’Mahony, M. S. (1997). Frailty and ageing. Age and Ageing, 26(4), 245-246. doi:10.1093/ageing/26.4.245CAMPBELL, A. J., & BUCHNER, D. M. (1997). Unstable disability and the fluctuations of frailty. Age and Ageing, 26(4), 315-318. doi:10.1093/ageing/26.4.315Drey, M., Pfeifer, K., Sieber, C. C., & Bauer, J. M. (2011). The Fried Frailty Criteria as Inclusion Criteria for a Randomized Controlled Trial: Personal Experience and Literature Review. Gerontology, 57(1), 11-18. doi:10.1159/000313433Albert, M. S., DeKosky, S. T., Dickson, D., Dubois, B., Feldman, H. H., Fox, N. C., … Phelps, C. H. (2011). The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia, 7(3), 270-279. doi:10.1016/j.jalz.2011.03.008Petersen, R. C., Smith, G. E., Waring, S. C., Ivnik, R. J., Tangalos, E. G., & Kokmen, E. (1999). Mild Cognitive Impairment. Archives of Neurology, 56(3), 303. doi:10.1001/archneur.56.3.303Winblad, B., Palmer, K., Kivipelto, M., Jelic, V., Fratiglioni, L., Wahlund, L.-O., … Petersen, R. C. (2004). Mild cognitive impairment - beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. Journal of Internal Medicine, 256(3), 240-246. doi:10.1111/j.1365-2796.2004.01380.xDubois, B., Hampel, H., Feldman, H. H., Scheltens, P., Aisen, P., … Andrieu, S. (2016). Preclinical Alzheimer’s disease: Definition, natural history, and diagnostic criteria. Alzheimer’s & Dementia, 12(3), 292-323. doi:10.1016/j.jalz.2016.02.002Moher, D., Hopewell, S., Schulz, K. F., Montori, V., Gotzsche, P. C., Devereaux, P. J., … Altman, D. G. (2010). CONSORT 2010 Explanation and Elaboration: updated guidelines for reporting parallel group randomised trials. BMJ, 340(mar23 1), c869-c869. doi:10.1136/bmj.c869Gray, L. C., Bernabei, R., Berg, K., Finne-Soveri, H., Fries, B. E., Hirdes, J. P., … Ariño-Blasco, S. (2008). Standardizing Assessment of Elderly People in Acute Care: The interRAI Acute Care Instrument. Journal of the American Geriatrics Society, 56(3), 536-541. doi:10.1111/j.1532-5415.2007.01590.xRadloff, L. S. (1977). The CES-D Scale. Applied Psychological Measurement, 1(3), 385-401. doi:10.1177/014662167700100306Guralnik, J. M., Simonsick, E. M., Ferrucci, L., Glynn, R. J., Berkman, L. F., Blazer, D. G., … Wallace, R. B. (1994). A Short Physical Performance Battery Assessing Lower Extremity Function: Association With Self-Reported Disability and Prediction of Mortality and Nursing Home Admission. Journal of Gerontology, 49(2), M85-M94. doi:10.1093/geronj/49.2.m85Powell, L. E., & Myers, A. M. (1995). The Activities-specific Balance Confidence (ABC) Scale. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 50A(1), M28-M34. doi:10.1093/gerona/50a.1.m28Kendzierski, D., & DeCarlo, K. J. (1991). Physical Activity Enjoyment Scale: Two Validation Studies. Journal of Sport and Exercise Psychology, 13(1), 50-64. doi:10.1123/jsep.13.1.50Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). «Mini-mental state». Journal of Psychiatric Research, 12(3), 189-198. doi:10.1016/0022-3956(75)90026-6Brandt, J. (1991). The hopkins verbal learning test: Development of a new memory test with six equivalent forms. Clinical Neuropsychologist, 5(2), 125-142. doi:10.1080/13854049108403297Lubben, J. E. (1988). Assessing social networks among elderly populations. Family & Community Health, 11(3), 42-52. doi:10.1097/00003727-198811000-00008Russell, D., Peplau, L. A., & Cutrona, C. E. (1980). The revised UCLA Loneliness Scale: Concurrent and discriminant validity evidence. Journal of Personality and Social Psychology, 39(3), 472-480. doi:10.1037/0022-3514.39.3.472De Vries, O. J., Peeters, G. M. E. E., Lips, P., & Deeg, D. J. H. (2013). Does frailty predict increased risk of falls and fractures? A prospective population-based study. Osteoporosis International, 24(9), 2397-2403. doi:10.1007/s00198-013-2303-zTheou, O., Stathokostas, L., Roland, K. P., Jakobi, J. M., Patterson, C., Vandervoort, A. A., & Jones, G. R. (2011). The Effectiveness of Exercise Interventions for the Management of Frailty: A Systematic Review. Journal of Aging Research, 2011, 1-19. doi:10.4061/2011/569194Cadore, E. (2014). Strength and Endurance Training Prescription in Healthy and Frail Elderly. Aging and Disease, 5(3), 183. doi:10.14336/ad.2014.0500183Cadore, E. L., Rodríguez-Mañas, L., Sinclair, A., & Izquierdo, M. (2013). Effects of Different Exercise Interventions on Risk of Falls, Gait Ability, and Balance in Physically Frail Older Adults: A Systematic Review. Rejuvenation Research, 16(2), 105-114. doi:10.1089/rej.2012.1397Gardner, M. M. (2001). Practical implementation of an exercise-based falls prevention programme. Age and Ageing, 30(1), 77-83. doi:10.1093/ageing/30.1.77Eng, J. J. (2010). Fitness and Mobility Exercise Program for Stroke. Topics in Geriatric Rehabilitation, 26(4), 310-323. doi:10.1097/tgr.0b013e3181fee736Wadlinger, H. A., & Isaacowitz, D. M. (2008). Looking happy: The experimental manipulation of a positive visual attention bias. Emotion, 8(1), 121-126. doi:10.1037/1528-3542.8.1.121MacLeod, C. (2012). Cognitive bias modification procedures in the management of mental disorders. Current Opinion in Psychiatry, 25(2), 114-120. doi:10.1097/yco.0b013e32834fda4aMensink, R. P., & Katan, M. B. (1989). Effect of a Diet Enriched with Monounsaturated or Polyunsaturated Fatty Acids on Levels of Low-Density and High-Density Lipoprotein Cholesterol in Healthy Women and Men. New England Journal of Medicine, 321(7), 436-441. doi:10.1056/nejm19890817321070

Analysis of Clonal Type-Specific Antibody Reactions in Toxoplasma gondii Seropositive Humans from Germany by Peptide-Microarray

BACKGROUND: Different clonal types of Toxoplasma gondii are thought to be associated with distinct clinical manifestations of infections. Serotyping is a novel technique which may allow to determine the clonal type of T. gondii humans are infected with and to extend typing studies to larger populations which include infected but non-diseased individuals. METHODOLOGY: A peptide-microarray test for T. gondii serotyping was established with 54 previously published synthetic peptides, which mimic clonal type-specific epitopes. The test was applied to human sera (n = 174) collected from individuals with an acute T. gondii infection (n = 21), a latent T. gondii infection (n = 53) and from T. gondii-seropositive forest workers (n = 100). FINDINGS: The majority (n = 124; 71%) of all T. gondii seropositive human sera showed reactions against synthetic peptides with sequences specific for clonal type II (type II peptides). Type I and type III peptides were recognized by 42% (n = 73) or 16% (n = 28) of the human sera, respectively, while type II-III, type I-III or type I-II peptides were recognized by 49% (n = 85), 36% (n = 62) or 14% (n = 25) of the sera, respectively. Highest reaction intensities were observed with synthetic peptides mimicking type II-specific epitopes. A proportion of the sera (n = 22; 13%) showed no reaction with type-specific peptides. Individuals with acute toxoplasmosis reacted with a statistically significantly higher number of peptides as compared to individuals with latent T. gondii infection or seropositive forest workers. CONCLUSIONS: Type II-specific reactions were overrepresented and higher in intensity in the study population, which was in accord with genotyping studies on T. gondii oocysts previously conducted in the same area. There were also individuals with type I- or type III-specific reactions. Well-characterized reference sera and further specific peptide markers are needed to establish and to perform future serotyping approaches with higher resolution

Microcavity enhanced single photon emission from an electrically driven site-controlled quantum dot

In this work we report on the integration of single site-controlled quantum dots (SCQDs) into electrically driven micropillar cavities. The electroluminescence of these devices features emission of single SCQDs with inhomogeneous broadenings down to 170 mu eV. The enhancement of electroluminescence by quantum dot-cavity coupling is demonstrated by temperature dependent investigations. Single photon emission from a spatially and spectrally coupled SCQD-resonator system is confirmed by photon autocorrelation measurements under electrical excitation yielding a g((2))(0) value of 0.42. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.3689782]</p

Multidisciplinary Design Optimization of Reusable Launch Vehicles

Reusable launch vehicles have once again become an attractive proposition, due to recent advancements in technology, and the opportunity to massively expand our accessibility to space. This paper discusses the optimization software under ongoing development at the University of Glasgow, that can be applied to such vehicles. Considering the diversity of previous and existing concepts, this work seeks to rapidly produce novel configurations using low-fidelity analysis methods. At present, surface inclination methods for high-speed aerodynamic computation are coupled with a simple six degree-of-freedom finite element beam model. The resulting aerostructural system is then utilized in a population based design optimization framework. Discussions of these methodologies are provided, along with an overall outline of their combination in a typical large design space optimization. Descriptions of the design variables employed are presented, along with an analysis of the methods utilized to constrain geometric properties and performance metrics, in order to avoid undesirable characteristics or infeasible configurations. Finally, a multi-objective aerostructural trim optimization is carried out, with comparison to a prior reusable launch vehicle concept

Dedicated launch of small satellites using scramjets

Reduced scale and improved responsiveness will be the technical and economic drivers of future satellite systems. Based on decades of practical experience with rocket-only expendable launch vehicles, current technology is operated close to theoretical limits. Scramjets have an advantage over rocket propulsion in terms of a significantly higher specific impulse. Other benefits of airbreathing propulsion for access-to-space are increased launch flexibility and the possibility of reusable aircraft-like operations. This article describes the use of a three-stage rocket-scramjet-rocket system for transporting payloads of the order of 100 kg to a Sun Synchronous Orbit. The reusable second stage is based on a winged-cone vehicle and is powered by hydrogen fueled scramjets. Analysis of the complete three-stage system was performed based around a fully trimmed trajectory simulation of the second stage. The scramjet powered second stage accelerated from Mach 6.0 to Mach 9.3 with an average net specific impulse of 923 seconds. As a result, the overall system showed a payload mass fraction of 1.26% to Sun Synchronous orbit, which is significantly higher than expendable rocket based systems of this scale

Fast-killing tyrosine amide ((S)-SW228703) with blood- and liver-stage antimalarial activity associated with the cyclic amine resistance locus (PfCARL)

Current malaria treatments are threatened by drug resistance, and new drugs are urgently needed. In a phenotypic screen for new antimalarials, we identified (S)-SW228703 ((S)-SW703), a tyrosine amide with asexual blood and liver stage activity and a fast-killing profile. Resistance to (S)-SW703 is associated with mutations in the Plasmodium falciparum cyclic amine resistance locus (PfCARL) and P. falciparum acetyl CoA transporter (PfACT), similarly to several other compounds that share features such as fast activity and liver-stage activity. Compounds with these resistance mechanisms are thought to act in the ER, though their targets are unknown. The tyramine of (S)-SW703 is shared with some reported PfCARL-associated compounds; however, we observed that strict S-stereochemistry was required for the activity of (S)-SW703, suggesting differences in the mechanism of action or binding mode. (S)-SW703 provides a new chemical series with broad activity for multiple life-cycle stages and a fast-killing mechanism of action, available for lead optimization to generate new treatments for malaria

Distinct Roles for CARMIL Isoforms in Cell Migration

Molecular mechanisms for cell migration, especially how signaling and cytoskeletal systems are integrated, are not understood well. Here, we examined the role of CARMIL (capping protein, Arp2/3, and Myosin-I linker) family proteins in migrating cells. Vertebrates express three conserved genes for CARMIL, and we examined the functions of the two CARMIL genes expressed in migrating human cultured cells. Both isoforms, CARMIL1 and 2, were necessary for cell migration, but for different reasons. CARMIL1 localized to lamellipodia and macropinosomes, and loss of its function caused loss of lamellipodial actin, along with defects in protrusion, ruffling, and macropinocytosis. CARMIL1-knockdown cells showed loss of activation of Rac1, and CARMIL1 was biochemically associated with the GEF Trio. CARMIL2, in contrast, colocalized with vimentin intermediate filaments, and loss of its function caused a distinctive multipolar phenotype. Loss of CARMIL2 also caused decreased levels of myosin-IIB, which may contribute to the polarity phenotype. Expression of one CARMIL isoform was not able to rescue the knockdown phenotypes of the other. Thus, the two isoforms are both important for cell migration, but they have distinct functions