A Phase 1 study for safety and pharmacokinetics of BIO101 (20-hydroxyecdysone) in healthy young and older adults.

BACKGROUND: Sarcopenia is an age-related skeletal muscle disorder characterized by loss of muscle mass and strength leading to mobility disability. 20-Hydroxyecdysone (20E) is a polyhydroxylated plant steroid that demonstrates pharmacological effects in many disease animal models including ageing/sarcopenia. BIO101 is a 20E purified investigational drug (≥97%) that previously demonstrated good toxicology profiles in rat and dog. BIO101 is evaluated in healthy young and older adults in a Phase 1 study. METHODS: This study is a Single Ascending Dose (SAD) followed by a 14-day Multiple Ascending Dose (MAD). In SAD, BIO101 was administered orally to 16 young adults at doses from 100 to 1400 mg and to 8 older adults (age ≥65 years) at 1400 mg. In MAD, doses of 350 mg once daily (qd), 350 mg twice daily (bid) and 450 mg bid were administered to 10 older adults. The primary objective was to evaluate safety and pharmacokinetics (PK), including dosing of circulating metabolites. Pharmacodynamic effects were investigated with regard to myostatin, procollagen-III-amino-terminal propeptide (PIIINP), myoglobin, creatine-kinase Muscle Brain (CKMB), renin and aldosterone plasma/serum levels. RESULTS: BIO101 showed a good safety profile with only mild to moderate adverse events and a satisfactory pharmacokinetic profile. In SAD, at 100 mg to 1400 mg, mean Cmax and areas under the curve increased less than dose-proportionally. Mean half-life was short (2.4-4.9 h), and mean renal clearance was comparable in all doses (4.05-5.05 L/h). Mean plasma exposure was slightly lower in older adults (22% lower for Cmax and 13%-15% lower for AUCs) compared with young subjects. In MAD, 350 and 450 mg bid led to a slight accumulation over 14 days (mean ratio of accumulation [Rac] of 1.31 in both cohorts). Reduction of biomarkers (myoglobin, CK-MB) mean serum levels (vs. baseline) was observed at 450 mg bid. Two major metabolites of 20E (14-deoxy-20-hydroxyecdysone and 14-deoxypoststerone) were identified and quantified. CONCLUSIONS: BIO101 shows a good safety and pharmacokinetic profile that led to the selection of doses for the subsequent interventional clinical trials of Phase 2 in age-related sarcopenia (SARA-INT) and Phase 3 in Covid-19 (COVA).

Indoor Mobility, Frailty, and Disability in Community-Dwelling Older Adults: A Mediation Model.

The general population, but especially older adults, were forced or encouraged to stay home during the recent COVID-19 pandemic. In this context, indoor mobility (IM, the number of steps performed daily at home) may be informative about the general health status of older adults. The present study aimed at evaluating the relationship between IM, frailty (loss of functional reserve including both physical and psychosocial domains), and disability (loss of autonomy measured as activities of daily life, ADLs) in a sample of community-dwelling Italian older adults. Specifically, the primary objective was to investigate IM and disability differences between robust and frail older adults. The secondary objective was to test if frailty is in the causal sequence between IM and disability, i.e., as a mediator in their relationship. Thirty-two participants (mean age = 70 ± 6 years; 56.2% women) were recruited. Frailty and disability were evaluated using the Tilburg Frailty Indicator and the Groningen Activity Restriction Scale, respectively. IM at home was measured via an Adamo wristwatch (a connected accelerometer). One-way analyses of covariance, controlling for age and gender, showed that robust participants, classified according to a score higher than five points in the Tilburg Frailty Indicator, performed significantly more IM (F1,28 = 4.639; p = 0.04) and presented lower disability grade than frail ones (F1,28 = 4.342; p =0.046). Only physical frailty was a mediator in the relationship between IM and disability (F2,29 = 8.538, p < 0.001), with a fully mediated model (z = -2.073, p < 0.04). Conversely, the total frailty score was not a mediator in the same relationship, but with IM accounted for the variance in disability (F2,29 = 8.538, p < 0.001; R2 = 33.7%). Our results suggested that frail older adults restricted their IM more and presented a higher level of disability compared to robust older adults. Moreover, data suggest that IM reduction may have a negative impact on physical frailty and indirectly increase disability.

COVID-19 as a Paradigmatic Model of the Heterogeneous Disease Presentation in Older People: Data from the GeroCovid Observational Study.

COVID-19 may have a heterogeneous onset, especially in older age. However, whether and how COVID-19 signs and symptoms may present and aggregate together according to sociodemographic and health factors is unclear, as well as their prognostic value. This study included 981 COVID-19 inpatients who participated in the GeroCovid Observational study. Signs/symptoms at disease onset, sociodemographic, health, cognitive status, and mobility were systematically recorded. Clusters of signs/symptoms were identified through agglomerative hierarchical clustering. The associations of single signs/symptoms and symptom clusters with longer hospitalization (≥16 days) and in-hospital mortality were explored through logistic and Cox regressions. The signs/symptoms most reported in our sample (age 78.3 ± 9.39 years; 49.4% women) were fever (62.5%), cough (45.5%), and dyspnea (62.7%). Atypical symptoms were reported by up to one-third of patients, and delirium by 9.1%. Atypical symptoms were more frequent with advancing age and with lower pre-COVID-19 cognitive and mobility levels. Older men more likely reported respiratory symptoms than women. Dyspnea (hazard ratio [HR] = 1.47, 95% confidence interval [CI]: 1.02-2.12), tachypnea (HR = 1.53, 95% CI: 1.14-2.07), low oxygen saturation (HR = 1.95, 95% CI: 1.32-2.88) and delirium (HR = 1.60, 95% CI: 1.13-2.28) were associated with higher in-hospital mortality. Four symptom clusters were identified. Compared with the mild respiratory symptoms cluster, the severe clinical impairment cluster was associated with higher mortality (HR = 2.57, 95% CI: 1.58-4.18). The severe clinical impairment and aspecific symptoms clusters were associated with longer hospitalization (odds ratio [OR] = 2.38, 95% CI: 1.56-3.63, and OR = 1.75, 95% CI: 1.08-2.83, respectively). Multiple health aspects influence COVID-19 clinical presentation. A symptom clusters approach may help predict adverse health outcomes in older patients. In addition to respiratory symptoms, delirium is independently associated with mortality risk. ClinicalTrials.gov (NCT04379440).

Multicomponent intervention to prevent mobility disability in frail older adults: randomised controlled trial (SPRINTT project).

OBJECTIVE: To determine whether a multicomponent intervention based on physical activity with technological support and nutritional counselling prevents mobility disability in older adults with physical frailty and sarcopenia. DESIGN: Evaluator blinded, randomised controlled trial. SETTING: 16 clinical sites across 11 European countries, January 2016 to 31 October 2019. PARTICIPANTS: 1519 community dwelling men and women aged 70 years or older with physical frailty and sarcopenia, operationalised as the co-occurrence of low functional status, defined as a short physical performance battery (SPPB) score of 3 to 9, low appendicular lean mass, and ability to independently walk 400 m. 760 participants were randomised to a multicomponent intervention and 759 received education on healthy ageing (controls). INTERVENTIONS: The multicomponent intervention comprised moderate intensity physical activity twice weekly at a centre and up to four times weekly at home. Actimetry data were used to tailor the intervention. Participants also received personalised nutritional counselling. Control participants received education on healthy ageing once a month. Interventions and follow-up lasted for up to 36 months. MAIN OUTCOME MEASURES: The primary outcome was mobility disability (inability to independently walk 400 m in <15 minutes). Persistent mobility disability (inability to walk 400 m on two consecutive occasions) and changes from baseline to 24 and 36 months in physical performance, muscle strength, and appendicular lean mass were analysed as pre-planned secondary outcomes. Primary comparisons were conducted in participants with baseline SPPB scores of 3-7 (n=1205). Those with SPPB scores of 8 or 9 (n=314) were analysed separately for exploratory purposes. RESULTS: Mean age of the 1519 participants (1088 women) was 78.9 (standard deviation 5.8) years. The average follow-up was 26.4 (SD 9.5) months. Among participants with SPPB scores of 3-7, mobility disability occurred in 283/605 (46.8%) assigned to the multicomponent intervention and 316/600 (52.7%) controls (hazard ratio 0.78, 95% confidence interval 0.67 to 0.92; P=0.005). Persistent mobility disability occurred in 127/605 (21.0%) participants assigned to the multicomponent intervention and 150/600 (25.0%) controls (0.79, 0.62 to 1.01; P=0.06). The between group difference in SPPB score was 0.8 points (95% confidence interval 0.5 to 1.1 points; P<0.001) and 1.0 point (95% confidence interval 0.5 to 1.6 points; P<0.001) in favour of the multicomponent intervention at 24 and 36 months, respectively. The decline in handgrip strength at 24 months was smaller in women assigned to the multicomponent intervention than to control (0.9 kg, 95% confidence interval 0.1 to 1.6 kg; P=0.028). Women in the multicomponent intervention arm lost 0.24 kg and 0.49 kg less appendicular lean mass than controls at 24 months (95% confidence interval 0.10 to 0.39 kg; P<0.001) and 36 months (0.26 to 0.73 kg; P<0.001), respectively. Serious adverse events occurred in 237/605 (39.2%) participants assigned to the multicomponent intervention and 216/600 (36.0%) controls (risk ratio 1.09, 95% confidence interval 0.94 to 1.26). In participants with SPPB scores of 8 or 9, mobility disability occurred in 46/155 (29.7%) in the multicomponent intervention and 38/159 (23.9%) controls (hazard ratio 1.25, 95% confidence interval 0.79 to 1.95; P=0.34). CONCLUSIONS: A multicomponent intervention was associated with a reduction in the incidence of mobility disability in older adults with physical frailty and sarcopenia and SPPB scores of 3-7. Physical frailty and sarcopenia may be targeted to preserve mobility in vulnerable older people. TRIAL REGISTRATION: ClinicalTrials.gov NCT02582138.

Monitoring COVID-19 vaccine use in Italian long term care centers: The GeroCovid VAX study.

The COVID-19 pandemic has changed routine care practice for older persons, especially in those with frailty living in long term care (LTC) facilities. Due to the high mortality rates of Nursing home (NH) residents during the first wave of the COVID-19 pandemic, priority for COVID-19 vaccinations was given to this vulnerable population. However, the safety and efficacy of such vaccines in older frail elders remains questionable due to the fact that initial randomized clinical trials (RCTs) for such vaccines did not include this population. This type of discrimination in patient participation in RCTs continues and has been recognized in the literature. Nevertheless, in the context of a worldwide emergency, COVID-19 vaccination in older persons living in LTC facilities may provide a solid basis to protect against negative outcomes, such as COVID-19 infection and death. In this report, we present the protocol of the GeroCovid Vax study, an Italian study that began in February 2021 which is aimed at investigating the safety and efficacy of the anti-SARS-CoV-2 vaccinations in older persons living in LTCs. This protocol specially aims to continuously and closely monitor events related to- and following- the anti-SARS-CoV-2 vaccination in elderly living in LTC facilities. In this report, we will provide information related to the study protocol and describe baseline characteristics of the sample.

Computed tomography findings and prognosis in older COVID-19 patients.

BACKGROUND: In older and multimorbid patients, chronic conditions may affect the prognostic validity of computed tomography (CT) findings in COVID-19. This study aims at assessing to which extent CT findings have prognostic implications in COVID-19 older patients. METHODS: Hospitalized COVID-19 patients aged 60 years or more enrolled in the multicenter, observational and longitudinal GeroCovid study who underwent chest CT were included. Patients were stratified by tertiles of age and pneumonia severity to compare CT findings. Hierarchical clustering based on CT findings was performed to identify CT-related classificatory constructs, if any. The hazard ratio (HR) of mortality was calculated for individual CT findings and for clusters, after adjusting for potential confounders. RESULTS: 380 hospitalized COVID-19 patients, with a mean age of 78 (SD:9) years, underwent chest CT scan. Ground glass opacity (GGO), consolidation, and pleural effusion were the three most common CT findings, with GGO prevalence decreasing from younger to older patients and pleural effusion increasing. More severe the pneumonia more prevalent were GGO, consolidation and pleural effusion. HR of mortality was 1.94 (95%CI 1.24-3.06) for pleural effusion and 13 (95%CI 6.41-27) for cluster with a low prevalence of GGO and a high prevalence of pleural effusion ("LH"), respectively. Out of the three CT based clusters, "LH" was the only independent predictor in the multivariable model. CONCLUSIONS: Pleural effusion qualifies as a distinctive prognostic marker in older COVID-19 patients. Research is needed to verify whether pleural effusion reflects COVID-19 severity or a coexisting chronic condition making the patient at special risk of death. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04379440.

COVID-19 and Atrial Fibrillation in Older Patients: Does Oral Anticoagulant Therapy Provide a Survival Benefit?-An Insight from the GeroCovid Registry.

INTRODUCTION: Atrial fibrillation (AF), the most frequent arrhythmia of older patients, associates with serious thromboembolic complications and high mortality. Coronavirus disease 2019 (COVID-19) severely affects aged subjects, determining an important prothrombotic status. The aim of this study was to evaluate mortality-related factors in older AF patients with COVID-19. METHODS: Between March and June 2020, we enrolled ≥60 year-old in-hospital COVID-19 patients (n = 806) in GeroCovid, a multicenter observational study promoted by the Italian Society of Gerontology and Geriatric Medicine. RESULTS: The prevalence of AF was 21.8%. In-hospital mortality was higher in the AF group (36.9 vs. 27.5%, p = 0.015). At admission, 51.7, 10.2, and 38.1% of AF cases were taking, respectively, oral anticoagulants (OACs), antiplatelet agents, and no antithrombotic therapy. During hospitalization, 51% patients switched to low-molecular-weight heparins. AF patients who survived were younger (81 ± 8 vs. 84 ± 7 years; p = 0.002) and had a lower CHA2DS2-VASc score (3.9 ± 1.6 vs. 4.4 ± 1.3; p = 0.02) than those who died. OAC use before (63.1 vs. 32.3%; p < 0.001) and during hospitalization (34.0 vs. 12.7%; p = 0.002) was higher among survivors. At multivariable analysis, lower age, higher self-sufficiency, less severe initial COVID-19 presentation, and the use of vitamin K antagonists (odds ratio [OR] = 0.16, 95% confidence interval [CI]: 0.03-0.84) or direct OACs (OR = 0.22, 95% CI: 0.08-0.56) at admission, or the persistence of OAC during hospitalization (OR = 0.05, 95% CI: 0.01-0.24), were associated with a lower chance of in-hospital death. CONCLUSION: AF is a prevalent and severe condition in older COVID-19 patients. Advanced age, dependency, and relevant clinical manifestations of disease characterized a worse prognosis. Preadmission and in-hospital anticoagulant therapies were positively associated with survival.

Atrial fibrillation and COVID-19 in older patients: how disability contributes to shape the risk profile. An analysis of the GeroCovid registry.

BACKGROUND AND AIMS: Atrial fibrillation (AF) is often complicated by disabling conditions in the elderly. COVID-19 has high mortality in older people. This study aimed at evaluating the relationship of pre-infection AF with characteristics and survival of older COVID-19 patients. METHODS: We retrospectively analyzed inpatients aged ≥ 60 years enrolled in GeroCovid Observational, a multicenter registry endorsed by the Italian and the Norwegian Societies of Gerontology and Geriatrics. Pre-COVID-19 sociodemographic, functional, and medical data were systematically collected, as well as in-hospital mortality. RESULTS: Between March and June 2020, 808 COVID-19 subjects were enrolled (age 79 ± 9 years; men 51.7%). The prevalence of AF was 21.8%. AF patients were older (82 ± 8 vs. 77 ± 9 years, p < 0.001), had a higher CHA2DS2-VASc score (4.1 ± 1.5 vs. 3.2 ± 1.5, p < 0.001) and were more likely to present almost all comorbidities. At multivariable analysis, advanced age, white blood cell count, the presence of heart and peripheral artery diseases were significantly associated with the presence of AF. In-hospital mortality was higher in AF patients (36.9 vs. 27.5%; OR = 1.55, 95% CI = 1.09-2.20; p = 0.015). A decision tree analysis showed that, in AF subjects, preserved functional status at admission was the most important factor associated with survival. In patients without AF, baseline COVID-19 severity was the most relevant variable related to clinical prognosis. CONCLUSIONS: AF is frequent in older patients with COVID-19, in whom it associates with clinical complexity and high mortality. Pre-infection disability shapes the prognosis of this extremely vulnerable segment of hospitalized subjects. CLINICAL TRIAL REGISTRATION: GeroCovid Observational was registered at www.clinicaltrials.gov (NCT04379440).

Management of Older Outpatients during the COVID-19 Pandemic: The GeroCovid Ambulatory Study.

OBJECTIVES: The GeroCovid Study is a multi-setting, multinational, and multi-scope registry that includes the GeroCovid home and outpatients' care cohort. The present study aims to evaluate whether outpatient and home care services with remote monitoring and consultation could mitigate the impact of the COVID-19 pandemic on mental and affective status, perceived well-being, and personal capabilities of outpatients and home care patients with cognitive disorders. METHODS: Prospectively recorded patients in an electronic web registry provided by BlueCompanion Ltd. Up to October 31, 2020, the sample included 90 patients receiving regular care from the Center for Cognitive Disorders and Dementia in Catanzaro Lido, Italy. It was made of 52 ambulatory outpatients and 38 home care patients, mean age 83.3 ± 7.54 years. Participants underwent a multidimensional assessment at baseline (T0) and after 90 days (T1). For each patient, we administered the Mini-Mental State Examination (MMSE) for cognitive functions, the Activities of Daily Living (ADL) and Instrumental ADL (IADL) scales for functional capabilities, the Cumulative Illness Rating Scale (CIRS) for comorbidities and their impact on patients' health, the 5-items Geriatric Depression Scale (GDS) for mood, and the Euro Quality of Life (EuroQoL) for perceived quality of life. Contacts with both ambulatory and home care patients were managed in person or via telephone, preferably through video calls (WhatsApp or FaceTime). RESULTS: Contacts with patients were kept at T0 through telephone. At T1, visits were made in person for over 95% out of the cases. The ADL, IADL, CIRS, GDS, MMSE, and EuroQoL changed slightly between T0 and T1. Most of the patients were clinically stable over time on the majority of the scales explored, but behavioral changes were found in 24.4% of patients and anxiety and insomnia in 17.7% of patients. CONCLUSION: Our study suggests that contacts through telephone and video consultations are likely associated with a health status preservation of the patients.

Assessing the impact of COVID-19 on the health of geriatric patients: The European GeroCovid Observational Study.

BACKGROUND: Despite the growing evidence on COVID-19, there are still many gaps in the understanding of this disease, especially in individuals in advanced age. We describe the study protocol of GeroCovid Observational, a multi-purpose, multi-setting and multicenter initiative that aims at investigating: risk factors, clinical presentation and outcomes of individuals affected by COVID-19 in acute and residential care settings; best strategies to prevent infection in long-term care facilities; and, impact of the pandemic on neuropsychologic, functional and physical health, and on medical management in outpatients and home care patients at risk of COVID-19, with a special focus on individuals with dementia. METHODS: GeroCovid involves individuals aged ≥60 years, at risk of or affected by COVID-19, prospectively or retrospectively observed since March 1st, 2020. Data are collected in multiple investigational sites across Italy, Spain and Norway, and recorded in a de-identified clinical e-Registry. A common framework was adapted to different care settings: acute wards, long-term care facilities, geriatric outpatient and home care, and outpatient memory clinics. RESULTS: At September 16th, 2020, 66 investigational sites obtained their Ethical Committee approval and 1618 cases (mean age 80.6 [SD=9.0] years; 45% men) have been recorded in the e-Registry. The average inclusion rate since the study start on April 25th, 2020, is 11.2 patients/day. New cases enrollment will ended on December 31st , 2020, and the clinical follow-up will end on June 30th, 2021. CONCLUSION: GeroCovid will explore relevant aspects of COVID-19 in adults aged ≥60 years with high-quality and comprehensive data, which will help to optimize COVID-19 prevention and management, with practical implications for ongoing and possible future pandemics. TRIAL REGISTRATION: NCT04379440 (clinicaltrial.gov).

A comparison between an ICT tool and a traditional physical measure for frailty evaluation in older adults.

BACKGROUND: Frailty is a clinical condition among older adults defined as the loss of resources in one or more domains (i.e., physical, psychological and social domains) of individual functioning. In frail subjects emergency situations and mobility levels need to be carefully monitored. This study aimed to: i) evaluate differences in the mobility index (MI) provided by ADAMO system, an innovative remote monitoring device for older adults; ii) compare the association of the MI and a traditional physical measure with frailty. METHODS: Twenty-five community-dwelling older adults (71 ± 6 years; 60% women) wore ADAMO continuously for a week. The time percentage spent in Low, Moderate and Vigorous Activities was assessed using ADAMO system. Walking ability and frailty were measured using the 400 m walk test and the Tilburg Frailty Indicator, respectively. RESULTS: Controlling for age and gender, the ANCOVA showed that frail and robust participants were different for Low (frail = 58.8%, robust = 42.0%, p < 0.001), Moderate (frail = 25.5%, robust = 33.8%, p = 0.008), and Vigorous Activity (frail = 15.7%, robust = 24.2%, p = 0.035). Using cluster analysis, participants were divided into two groups, one with higher and one with lower mobility. Controlling for age and gender, linear regression showed that the MI clusters were associated with total (ß = 0.571, p = 0.002), physical (ß = 0.381, p = 0.031) and social (ß = 0.652, p < 0.001) frailty; and the 400 m walk test was just associated with total (ß = 0.404, p = 0.043) and physical frailty (ß = 0.668, p = 0.002). CONCLUSION: ADAMO system seems to be a suitable time tracking that allows to measure mobility levels in a non-intrusive way providing wider information on individual health status and specifically on frailty. For the frail individuals with an important loss of resources in physical domain, this innovative device may represent a considerable help in preventing physical consequences and in monitoring functional status.

The "Sarcopenia and Physical fRailty IN older people: multi-componenT Treatment strategies" (SPRINTT) randomized controlled trial: Case finding, screening and characteristics of eligible participants.

BACKGROUND: The ongoing "Sarcopenia and Physical fRailty IN older people: multi-componenT Treatment strategies (SPRINTT)" randomized controlled trial (RCT) is testing the efficacy of a multicomponent intervention in the prevention of mobility disability in older adults with physical frailty & sarcopenia (PF&S). Here, we describe the procedures followed for PF&S case finding and screening of candidate participants for the SPRINTT RCT. We also illustrate the main demographic and clinical characteristics of eligible screenees. METHODS: The identification of PF&S was based on the co-occurrence of three defining elements: (1) reduced physical performance (defined as a score on the Short Physical Performance Battery between 3 and 9); (2) low muscle mass according to the criteria released by the Foundation for the National Institutes of Health; and (3) absence of mobility disability (defined as ability to complete the 400-m walk test in 15 min). SPRINTT was advertised through a variety of means. Site-specific case finding strategies were developed to accommodate the variability across centers in catchment area characteristics and access to the target population. A quick "participant profiling" questionnaire was devised to facilitate PF&S case finding. RESULTS: During approximately 22 months, 12,358 prescreening interviews were completed in 17 SPRINTT sites resulting in 6710 clinic screening visits. Eventually, 1566 candidates were found to be eligible for participating in the SPRINTT RCT. Eligible screenees showed substantial physical function impairment and comorbidity burden. In most centers, project advertisement through mass media was the most rewarding case finding strategy. CONCLUSION: PF&S case finding in the community is a challenging, but feasible task. Although largely autonomous in daily life activities, older adults with PF&S suffer from significant functional impairment and comorbidity. This subset of the older population is therefore at high risk for disability and other negative health-related events. Key strategies to consider for successfully intercepting at-risk older adults should focus on mass communication methods.

The Reliability of Using Tablet Technology for Screening the Health of Older Adults.

In this study, we assessed the reliability of using a tablet application for collecting health data among older adults, in comparison to using paper surveys for this goal. Test-retest reliability between the two modalities, usability, user experience factors, and older adults' preference were determined. The results show perfect agreement between tablet and paper for the SARC-F and high agreement for the SF-36 physical scale and EQ-5D. Usability and user experience factors were perceived the same for both modalities. The majority of the participants preferred the tablet for health screening purposes, mainly because of its ease of use. This study shows that using tablets for health screenings among older adults does not affect test reliability, and that older adults prefer the tablet to paper for completing these tests.

Physical frailty and sarcopenia (PF&S): a point of view from the industry.

We have observed over the last 15 years a wide debate both in the medical scientific community and in the public health arena on the definition and operationalization of frailty, typically a geriatric condition, and in particular of physical frailty linked to sarcopenia. Because physical frailty in its initial phase can still be reversed, fighting sarcopenia in elderly persons has the potential to slow or halt progressive decline towards disability and dependency. Quite recently, regulators focused attention on frailty as an indicator of biological age to be measured to characterize elderly patients before their inclusion in clinical trials. A European guidance regarding most adapted evaluation instruments of frailty is currently under public consultation. Does the regulatory initiative imply we should now consider frailty, and particularly physical frailty, primarily as an important risk factor for adverse events and poor response, or mainly as a clinical tool helping the physician to opt for one therapeutic pathway or another? Or is physical frailty above all a specific geriatric condition deserving an effective and innovative therapeutic approach with the objective to curb the incidence of its most common result, e.g., mobility disability? Pharmaceutical industry developers consider both faces of the coin very relevant. We agree with regulators that better characterization of subpopulations, not only in elderly patients, can improve the benefit risk ratio of medicines. At the same time, we believe it is in the public health interest to develop novel drugs indicated for specific geriatric conditions, like osteoporosis in the 1990s and sarcopenia today. We consider it an important therapeutic goal to effectively delay mobility disability and to extend the active, independent, and healthy life years of aging people. The "Sarcopenia and Physical fRailty IN older people: multi-componenT Treatment strategies" (SPRINTT) collaborative project under IMI is paving the way for adapted methodologies to study the change of physical frailty and sarcopenia in at-risk older persons and to adequately characterize the population that needs to be treated.

Rationale for a preliminary operational definition of physical frailty and sarcopenia in the SPRINTT trial.

In the present article, the rationale that guided the operationalization of the theoretical concept of physical frailty and sarcopenia (PF&S), the condition of interest for the "Sarcopenia and Physical Frailty in Older People: Multicomponent Treatment Strategies" (SPRINTT) trial, is presented. In particular, the decisions lead to the choice of the adopted instruments, and the reasons for setting the relevant thresholds are explained. In SPRINTT, the concept of physical frailty is translated with a Short Physical Performance Battery score of ≥3 and ≤9. Concurrently, sarcopenia is defined according to the recent definitions of low muscle mass proposed by the Foundation for the National Institutes of Health-Sarcopenia Project. Given the preventive purpose of SPRINTT, older persons with mobility disability (operationalized as incapacity to complete a 400-m walk test within 15 min; primary outcome of the trial) at the baseline are not included within the diagnostic spectrum of PF&S.

Making sense of big data in health research: Towards an EU action plan.

Medicine and healthcare are undergoing profound changes. Whole-genome sequencing and high-resolution imaging technologies are key drivers of this rapid and crucial transformation. Technological innovation combined with automation and miniaturization has triggered an explosion in data production that will soon reach exabyte proportions. How are we going to deal with this exponential increase in data production? The potential of "big data" for improving health is enormous but, at the same time, we face a wide range of challenges to overcome urgently. Europe is very proud of its cultural diversity; however, exploitation of the data made available through advances in genomic medicine, imaging, and a wide range of mobile health applications or connected devices is hampered by numerous historical, technical, legal, and political barriers. European health systems and databases are diverse and fragmented. There is a lack of harmonization of data formats, processing, analysis, and data transfer, which leads to incompatibilities and lost opportunities. Legal frameworks for data sharing are evolving. Clinicians, researchers, and citizens need improved methods, tools, and training to generate, analyze, and query data effectively. Addressing these barriers will contribute to creating the European Single Market for health, which will improve health and healthcare for all Europeans.

Fighting against age discrimination in clinical trials.

At the American Geriatrics Society 2008 Annual Meeting, representatives of two geriatric societies, the European Union Geriatric Medicine Societies and the American Geriatrics Society, and two regulatory agencies, the U.S. Food and Drug Administration and the European Medicine Agency, conducted a roundtable discussion aimed at reviewing the participation of older people in clinical trials. This article summarizes the important issues discussed at the meeting. Historically, regulatory agencies started to promote the inclusion of older participants in clinical trials in the late 1980s. The identification of the causes of delay in including older participants in clinical trials, as well as of the ongoing bias against including older participants with multiple comorbidities, is important to help geriatricians fight against age discrimination in clinical trials. To overcome this problem, geriatrics societies and regulatory agencies must work together to propose new definitions, study designs, and technologies aimed at improving the evaluation of drugs in older people with multiple comorbidities and polypharmacy.