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PurposePremorbid conditions affect prognosis of acutely-ill aged patients. Several lines of evidence suggest geriatric syndromes need to be assessed but little is known on their relative effect on the 30-day survival after ICU admission. The primary aim of this study was to describe the prevalence of frailty, cognition decline and activity of daily life in addition to the presence of comorbidity and polypharmacy and to assess their influence on 30-day survival.MethodsProspective cohort study with 242 ICUs from 22 countries. Patients 80 years or above acutely admitted over a six months period to an ICU between May 2018 and May 2019 were included. In addition to common patients’ characteristics and disease severity, we collected information on specific geriatric syndromes as potential predictive factors for 30-day survival, frailty (Clinical Frailty scale) with a CFS > 4 defining frail patients, cognitive impairment (informant questionnaire on cognitive decline in the elderly (IQCODE) with IQCODE ≥ 3.5 defining cognitive decline, and disability (measured the activity of daily life with the Katz index) with ADL ≤ 4 defining disability. A Principal Component Analysis to identify co-linearity between geriatric syndromes was performed and from this a multivariable model was built with all geriatric information or only one: CFS, IQCODE or ADL. Akaike’s information criterion across imputations was used to evaluate the goodness of fit of our models.ResultsWe included 3920 patients with a median age of 84 years (IQR: 81–87), 53.3% males). 80% received at least one organ support. The median ICU length of stay was 3.88 days (IQR: 1.83–8). The ICU and 30-day survival were 72.5% and 61.2% respectively. The geriatric conditions were median (IQR): CFS: 4 (3–6); IQCODE: 3.19 (3–3.69); ADL: 6 (4–6); Comorbidity and Polypharmacy score (CPS): 10 (7–14). CFS, ADL and IQCODE were closely correlated. The multivariable analysis identified predictors of 1-month mortality (HR; 95% CI): Age (per 1 year increase): 1.02 (1.–1.03, p = 0.01), ICU admission diagnosis, sequential organ failure assessment score (SOFA) (per point): 1.15 (1.14–1.17, p < 0.0001) and CFS (per point): 1.1 (1.05–1.15, p < 0.001). CFS remained an independent factor after inclusion of life-sustaining treatment limitation in the model.ConclusionWe confirm that frailty assessment using the CFS is able to predict short-term mortality in elderly patients admitted to ICU. Other geriatric syndromes do not add improvement to the prediction model. Since CFS is easy to measure, it should be routinely collected for all elderly ICU patients in particular in connection to advance care plans, and should be used in decision making.

Background Atrial fibrillation (AF) is common in older people with frailty and is associated with an increased risk of stroke and systemic embolism. Whilst oral anticoagulation is associated with a reduction in this risk, there is a lack of data on the safety and efficacy of direct oral anticoagulants (DOACs) in people with frailty. This study aims to report clinical outcomes of patients with AF in the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial by frailty status. Methods Post hoc analysis of 20,867 participants in the ENGAGE AF-TIMI 48 trial, representing 98.8% of those randomised. This double-blinded double-dummy trial compared two once-daily regimens of edoxaban (a DOAC) with warfarin. Participants were categorised as fit, living with pre-frailty, mild-moderate, or severe frailty according to a standardised index, based upon the cumulative deficit model. The primary efficacy endpoint was stroke or systemic embolism and the safety endpoint was major bleeding. Results A fifth (19.6%) of the study population had frailty (fit: n  = 4459, pre-frailty: n  = 12,326, mild-moderate frailty: n  = 3722, severe frailty: n  = 360). On average over the follow-up period, the risk of stroke or systemic embolism increased by 37% (adjusted HR 1.37, 95% CI 1.19–1.58) and major bleeding by 42% (adjusted HR 1.42, 1.27–1.59) for each 0.1 increase in the frailty index (four additional health deficits). Edoxaban was associated with similar efficacy to warfarin in every frailty category, and a lower risk of bleeding than warfarin in all but those living with severe frailty. Conclusions Edoxaban was similarly efficacious to warfarin across the frailty spectrum and was associated with lower rates of bleeding except in those with severe frailty. Overall, with increasing frailty, there was an increase in stroke and bleeding risk. There is a need for high-quality, frailty-specific population randomised control trials to guide therapy in this vulnerable population. Trial registration ClinicalTrials.gov NCT00781391 . First registered on 28 October 2008

Cognitive frailty refers to a clinical syndrome in which physical frailty and mild cognitive impairment coexist. Motor-cognitive training and virtual reality (VR) have been used to launch various therapeutic modalities to promote health in older people. The literature advocates that motor-cognitive training and VR are effective in promoting the cognitive and physical function of older people. However, the effects on older people with cognitive frailty are unclear. This study examined the effects of VR motor-cognitive training (VRMCT) on global cognitive function, physical frailty, walking speed, visual short-term memory, inhibition of cognitive interference, and executive function in older people with cognitive frailty. This study used a multicentered, assessor-blinded, 2-parallel-group randomized controlled trial design. Participants were recruited face-to-face in 8 older adult community centers. Eligible participants were aged ≥60 years, were community dwelling, lived with cognitive frailty, had no dementia, and were not mobility restricted. In the intervention group, participants received VRMCT led by interventionists with 16 one-hour training sessions delivered twice per week for 8 weeks. In the control group, participants received the usual care provided by the older adult community centers that the investigators did not interfere with. The primary outcome was global cognitive function. The secondary outcomes included physical frailty, walking speed, verbal short-term memory, inhibition of cognitive interference, and executive function. Data were collected at baseline (T0) and the week after the intervention (T1). Generalized estimating equations were used to examine the group, time, and interaction (time × group) effects on the outcomes. In total, 293 eligible participants enrolled in the study. The mean age of the participants was 74.5 (SD 6.8) years. Most participants were female (229/293, 78.2%), had completed primary education (152/293, 52.1%), were married (167/293, 57.2%), lived with friends (127/293, 43.3%), and had no VR experience (232/293, 79.5%). In the intervention group, 81.6% (119/146) of participants attended >80% (13/16, 81%) of the total number of sessions. A negligible number of participants experienced VR sickness symptoms (1/146, 0.7% to 5/146, 3%). VRMCT was effective in promoting global cognitive function (interaction effect: P=.03), marginally promoting executive function (interaction effect: P=.07), and reducing frailty (interaction effect: P=.03). The effects were not statistically significant on other outcomes. VRMCT is effective in promoting cognitive functions and reducing physical frailty and is well tolerated and accepted by older people with cognitive frailty, as evidenced by its high attendance rate and negligible VR sickness symptoms. Further studies should examine the efficacy of the intervention components (eg, VR vs non-VR or dual task vs single task) on health outcomes, the effect of using technology on intervention adherence, and the long-term effects of the intervention on older people with cognitive frailty at the level of daily living. ClinicalTrials.gov NCT04730817; https://clinicaltrials.gov/study/NCT04730817.

The “very old intensive care patients” (abbreviated to VOPs; greater than 80 years old) are probably the fastest expanding subgroup of all intensive care unit (ICU) patients. Up until recently most ICU physicians have been reluctant to admit these VOPs. The general consensus was that there was little survival to gain and the incremental life expectancy of ICU admission was considered too small. Several publications have questioned this belief, but others have confirmed the poor long-term mortality rates in VOPs. More appropriate triage (resource limitation enforced decisions), admission decisions based on shared decision-making and improved prediction models are also needed for this particular patient group. Here, an expert panel proposes a research agenda for VOPs for the coming years.

BackgroundFrailty is an independent risk factor for cardiovascular events. It is uncertain whether frailty modifies the efficacy of intensive blood pressure (BP) control among participants with type 2 diabetes mellitus(T2DM).MethodsThe Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD BP) trial, a two-by-two factorial trial, examined the effects of systolic BP (<120 vs <140 mm Hg) and glycaemic control on cardiovascular events in T2DM. We constructed a frailty index using the Rockwood cumulative deficit approach. Cox proportional hazard models were used to estimate the effectiveness of intensive BP treatment according to frailty status. The primary composite outcome was non-fatal myocardial infarction, non-fatal stroke or death from cardiovascular causes.ResultsThere were 4733 participants (mean age: 62.7 years; 39.9% frailty). The mean average number of antihypertensive medications was higher in frail patients compared with non-frail patients in both the standard (2.2 vs 1.7) and intensive (3.1 vs 2.7) treatment groups. In the standard glycaemic arm, intensive BP treatment reduced the risk of the primary outcome (HR 0.75, 95% CI 0.58 to 0.97) regardless of frailty status (p value for interaction=0.86). The benefits of intensive BP intervention were consistent across the spectrum of the frailty index (p value for interaction=0.96) in the standard glycaemic arm. However, no benefits of intensive BP treatment (HR 1.08, 95% CI 0.82 to 1.43) were observed in the intensive glycaemic arm.ConclusionsIn the ACCORD BP study, the benefit of intensive BP treatment was consistent regardless of frailty in the setting of standard glycaemic control. Frailty should not be a barrier to intensive BP control in patients with T2DM treated with guideline-recommended standard glycaemic control.

BackgroundClinical trials and meta-analyses indicate a reduced reinfarction risk with invasive management in older patients with non-ST-segment elevation myocardial infarction (NSTEMI). This study investigated whether similar benefits might be observed in frail patients.MethodsThe coMOrbilidades Síndrome Coronario Agudo - FRAIL (MOSCA-FRAIL) trial included 167 adults aged ≥70 years with frailty (Clinical Frailty Scale ≥4 points) and NSTEMI, who were randomised to invasive (n=84) or conservative (n=83) strategy during the index hospitalisation. The primary end point of this subanalysis was reinfarction, considering all-cause mortality as a competing event, at a 3-year median follow-up. The time to first reinfarction and all reinfarctions (first and recurrent) were considered. The substudy was not prespecified.ResultsThe total number of deaths (93, 56%) exceeded that of first reinfarctions (32, 19%). Invasive treatment did not influence the reinfarction risk when accounting for death as a competing risk (subdistribution HR=0.87, 95% CI 0.54 to 1.40, p=0.56). An initially increased mortality risk with invasive management (significant between days 131 and 175) shifted to a lower mortality risk over time. A total of 45 reinfarctions (first and recurrent) were observed. The longitudinal trajectories corroborated that the invasive strategy did not reduce the risk of reinfarction over time (p=0.72). However, mortality followed a biphasic pattern, with higher mortality in the invasive group during the first 6 months and a reduction between 9 months and 3 years (p=0.05 for the entire time-dependent trajectory). The win ratio for the invasive strategy versus the conservative strategy was 1.08 (95% CI 0.72 to 1.63, p=0.70).ConclusionsIn older adults with frailty and NSTEMI, routine invasive management did not reduce the reinfarction risk at a 3-year follow-up. The high all-cause mortality associated with frailty may limit the impact of invasive management. Due to the limited sample size and risk for type II error, these findings should be considered hypothesis-generating.Trial registration number NCT03208153.

Background Physical frailty is related with morbidity and mortality in patients with cirrhosis. Currently, there is no approved treatment of frailty in these patients. Here, we evaluated the efficacy of 16 weeks branched-chain amino acids (BCAA) supplementation on frailty in frail compensated cirrhotic patients. Methods After a 4-week run-in period consisted of dietary and exercise counseling, compensated cirrhotic patients with frailty, defined by liver frailty index (LFI)≥4.5, were randomly assigned (1:1) to BCAA or control group. The BCAA group received twice daily BCAAs supplementation (210 kcal, protein 13.5 g, BCAA 2.03 g) for 16 weeks. The primary outcome was frailty reversion. The secondary outcomes were changes in biochemistries, body composition evaluated by bioelectrical impedance analysis, and quality of life (QoL). Results 54 patients were prospectively enrolled (age 65.5 ± 9.9 years, 51.9% female, Child-Pugh A/B 68.5%/31.5%, MELD 10.3 ± 3.1). Baseline characteristics were similar between both groups. At week 16, BCAA group had a significant improvement in LFI (-0.36 ± 0.3 vs. -0.15 ± 0.28, P = 0.01), BMI (+ 0.51 ± 1.19 vs. -0.49 ± 1.89 kg/m 2 , P = 0.03), and serum albumin (+ 0.26 ± 0.27 vs. +0.06 ± 0.3 g/dl, P = 0.01). The proportion of frailty reversion at week 16 was significantly higher in BCAA group (36% vs. 0%, P < 0.001). Compared with baseline, BCAA group had a significant increase in skeletal muscle index (7.5 ± 1.6 to 7.8 ± 1.5 kg/m 2 , P = 0.03). Regarding the QoL, only the BCAA group had a significant improvement in all 4 domains of physical component score of the SF-36 questionnaire. Conclusions A 16-week BCAA supplementation improved frailty in frail compensated cirrhotic patients. In addition, this intervention resulted in an improvement of muscle mass and physical domain of QoL in these patients. Trial registration This study was registered with Thai Clinical Trial Registry (TCTR20210928001; https://www.thaiclinicaltrials.org/# ).

SummaryBackgroundPatients with frailty and newly diagnosed multiple myeloma have worse outcomes due to higher rates of adverse events (AEs) and treatment discontinuation. This study evaluated a dexamethasone-sparing regimen of daratumumab plus lenalidomide versus lenalidomide plus dexamethasone in frail patients with newly diagnosed multiple myeloma. MethodsIn this prospective, randomised, open-label trial, conducted at 61 active Intergroup Francophone of Myeloma centres, patients aged 65 years or older with newly diagnosed multiple myeloma and an Eastern Cooperative Oncology Group proxy frailty score of 2 or more were randomly assigned 2:1 to receive daratumumab (1800 mg subcutaneously) plus oral lenalidomide (25 mg daily for 21 days of a 28 day cycle) and dexamethasone (20mg weekly) for two cycles (dexamethasone-sparing group) or lenalidomide (25 mg daily) and oral dexamethasone (20 mg weekly; control group), with stratification by International Staging System, age, and centre. The primary endpoint was progression-free survival. Efficacy was assessed in the intention-to-treat population and safety was assessed in all patients exposed to at least one dose of randomised intervention. This trial is registered with ClinicalTrials.gov, NCT03993912, and is complete. FindingsFrom Oct 18, 2019 to July 20, 2021, 335 patients were screened, of whom 295 patients were randomly assigned (200 to lenalidomide plus daratumumab, 95 to lenalidomide plus dexamethasone). The median age was 81 years (IQR 77–84), with 180 (61%) aged older than 80 years, and 151 (51%) patients were female and 144 (49%) were male. Median follow-up was 46·3 months (IQR 46·0–52·7). Median progression-free survival was 53·4 months (95% CI 35·3–not reached) in the dexamethasone-sparing group versus 22·5 months (16·5–39·0) in the control group (hazard ratio [HR] 0·51, 95% CI 0·37–0·70, p<0·0001). The most common grade 3–5 AEs were neutropenia (110 [55%] of 200 patients in the dexamethasone-sparing group vs 23 [24%] of 95 patients in the control group), and infection (38 [19%] vs 20 [21%]). Serious adverse events occurred in 126 patients (63%) in the dexamethasone-sparing group and 66 patients (69%) in the control group. AEs leading to death occurred in 23 patients (12%) in the dexamethasone-sparing group and 12 patients (13%) in the control group, with 4 (2%) and 2 (2%) grade 5 treatment-emergent adverse events, respectively. InterpretationIn the IFM2017-03 trial, use of lenalidomide plus daratumumab, with dexamethasone limited to the first 2 treatment cycles, reduced the risk of progression or death compared with lenalidomide plus dexamethasone, with no additional safety concerns. Lenalidomide plus daratumumab could therefore be considered as a treatment option for older patients with frailty and newly diagnosed multiple myeloma. FundingThe study was funded by Johnson & Johnson.

Background Frailty is associated with poor outcomes among older adults with hypertension and complicates its pharmacological management. Here, we assessed whether 12-weeks of instructor-guided, group Tai Chi (TC) practice improved frailty relative to Healthy Aging Practice-centered Education (HAP-E) classes in older adults with hypertension. Methods Secondary analysis of a randomized controlled trial in San Diego County, USA, of 167 community-dwelling individuals aged ≥ 60 yrs (70% female; 72.1 ± 7.5 yrs), defined as non-frail (66%) or frail (34%) based on 53-item deficit accumulation frailty index (FI). Linear mixed-effects models were used to assess pre-to-post intervention differences in FI and logistic regression to explore differential odds of clinically meaningful FI change. Results One hundred thirty-one participants completed post-intervention assessments. Frailty decreased pre-to-post intervention in the TC (ΔFI = − 0.016, d  = − 0.39, − 0.75 to − 0.03), but not the HAP-E arm (ΔFI = − 0.009, d  = − 0.13, − 0.52–0.27), despite no significant group differences between the TC and HAP-E arms ( d  = − 0.11, − 0.46–0.23). Furthermore, greater odds of improved FI were observed for frail participants in the TC (OR = 3.84, 1.14–14.9), but not the HAP-E (OR = 1.34, 0.39–4.56) arm. Subgroup analysis indicated treatment effects in TC were attributed to frail participants (frail: ΔFI = − 0.035, d  = − 0.68, -1.26 to − 0.08; non-frail: ΔFI = − 0.005, d  = − 0.19, − 0.59–0.22), which was not the case in the HAP-E arm (frail: ΔFI = − 0.017, d  = − 0.23, − 0.81–0.35; non-frail: ΔFI = − 0.003, d  = − 0.07, − 0.47–0.33). Frail participants were no more likely to drop-out of the study than non-frail (71% vs. 69% retained). Conclusions Twelve weeks of twice-weekly guided TC practice was well-tolerated, associated with decreases in frailty, and increased odds of clinically meaningful FI improvement at post-intervention.

This study aimed to assess the factors associated with pain and evaluate the impact of dual-task exercise on pain improvement, quality of life (QOL), cognition and function in older adults. This study is a secondary data analysis of the HAPPY (Healthy Ageing Promotion Program for You) study. At risk older adults ≥ 60 years old were enrolled in a community dual-task exercise program. Assessments for frailty, sarcopenia, falls, quality of life (QOL) and perceived health, depression, cognition and physical function were performed at baseline and 3 months. Pain intensity was derived from EQ-5D and stratified into no pain, slight pain and moderate to extreme pain. Out of 296 participants, 37.2% had slight pain and 11.1% had moderate to severe pain. Both slight and moderate to extreme pain compared with no pain group were significantly associated with lower perceived health (68.2,63.6 vs 76.0) and QOL index (0.70,0.59 vs 0.93); moderate to extreme pain was also significantly associated with depression, low mental vitality, frailty, sarcopenia and poorer physical performance. After 3 months of dual-task exercise, pain improved in 70.8% of the moderate to extreme pain group and 50.8% of slight pain group. Significant improvement in perceived health, QOL, physical function and cognition were also observed. Proactive efforts are required to screen for pain and manage frailty, sarcopenia and depression. Dual-task exercise proved safe and possibly effective in reducing pain and improving QOL, physical and cognitive function in older adults. Prospective randomized studies are needed to validate the effectiveness of dual-task vs single-task exercise, including impact of reversal of frailty and sarcopenia in pain management.