Relationship Between Distressing Symptoms and Changes in Disability After Major Surgery Among Community-living Older Persons.

OBJECTIVES: To evaluate the relationship between distressing symptoms and changes in disability after major surgery and to determine whether this relationship differs according to the timing of surgery (nonelective vs elective), sex, multimorbidity, and socioeconomic disadvantage. BACKGROUND: Major surgery is a common and serious health event that has pronounced deleterious effects on both distressing symptoms and functional outcomes in older persons. METHODS: From a cohort of 754 community-living persons, aged 70 or older, 392 admissions for major surgery were identified from 283 participants who were discharged from the hospital. The occurrence of 15 distressing symptoms and disability in 13 activities were assessed monthly for up to 6 months after major surgery. RESULTS: Over the 6-month follow-up period, each unit increase in the number of distressing symptoms was associated with a 6.4% increase in the number of disabilities [adjusted rate ratio (RR): 1.064; 95% CI: 1.053, 1.074]. The corresponding increases were 4.0% (adjusted RR: 1.040; 95% CI: 1.030, 1.050) and 8.3% (adjusted RR: 1.083; 95% CI: 1.066, 1.101) for nonelective and elective surgeries. Based on exposure to multiple (ie, 2 or more) distressing symptoms, the adjusted RRs (95% CI) were 1.43 (1.35, 1.50), 1.24 (1.17, 1.31), and 1.61 (1.48, 1.75) for all, nonelective, and elective surgeries. Statistically significant associations were observed for each of the other subgroups with the exception of individual-level socioeconomic disadvantage for the number of distressing symptoms. CONCLUSIONS: Distressing symptoms are independently associated with worsening disability, providing a potential target for improving functional outcomes after major surgery.

Association of Childhood Adversity With Frailty and the Mediating Role of Unhealthy Lifestyle: A Lifespan Analysis.

OBJECTIVES: Childhood adversity and lifestyle have been associated with frailty in later life, but not much is known about factors that may explain these associations. Therefore, this study aims to investigate the association of childhood adversity with frailty, and the mediating role of unhealthy lifestyle in the association. METHODS: This lifespan analysis included 152,914 adults aged 40-69 years old from the UK Biobank. We measured childhood adversity with five items: physical neglect, emotional neglect, sexual abuse, physical abuse, and emotional abuse through online mental health survey. Frailty was measured by the frailty index; an unhealthy lifestyle score (range: 0-5) was calculated based on unhealthy body mass index, smoking, alcohol consumption, physical inactivity, and unhealthy diet at the baseline survey. Multiple logistic regression and mediation analysis were performed. RESULTS: A total of 10,078 participants (6.6%) were defined as having frailty. Participants with any childhood adversity had higher odds of frailty. For example, in the fully adjusted model, with a one-point increase in cumulative score of childhood adversity, the odds of frailty increased by 38% (odds ratio: 1.38; 95% Confidence Interval: 1.36, 1.40). Unhealthy lifestyle partially mediated the associations of childhood adversity with frailty (mediation proportion: 4.4%-7.0%). The mediation proportions were largest for physical (8.2%) and sexual (8.1%) abuse. CONCLUSIONS: Childhood adversity was positively associated with frailty, and unhealthy lifestyle partially mediated the association. This newly identified pathway highlights the potential of lifestyle intervention strategies among those who experienced childhood adversity (in particular, physical, and sexual abuse) to promote healthy aging.

Is residential exposure to oil refineries a novel contextual risk factor for coronary heart disease?

Despite a multi-decade decrease in cardiovascular disease, geographic disparities have widened, with excess mortality concentrated within the United States (U.S.) South. Petroleum production and refining, a major contributor to climate change, is concentrated within the U.S. South and emits multiple classes of atherogenic pollutants. We investigated whether residential exposure to oil refineries could explain variation in self-reported coronary heart disease (CHD) prevalence among adults in southern states for the year 2018, where the majority of oil refinery activity occurs (Alabama, Mississippi, Louisiana, Arkansas, Texas, New Mexico, and Oklahoma). We examined census tract-level association between oil refineries and CHD prevalence. We used a double matching method to adjust for measured and unmeasured spatial confounders: one-to-n distance matching and one-to-one generalized propensity score matching. Exposure metrics were constructed based on proximity to refineries, activities of refineries, and wind speed/direction. For all census tracts within 10 km of refineries, self-reported CHD prevalence ranged from 1.2% to 17.6%. Compared to census tracts located at ≥5 km and <10 km, one standard deviation increase in the exposure within 5 km of refineries was associated with a 0.33 (95% confidence interval: 0.04, 0.63) percentage point increase in the prevalence. A total of 1119.0 (123.5, 2114.2) prevalent cases or 1.6% (0.2, 3.1) of CHD prevalence in areas within 5 km from refineries were potentially explained by exposure to oil refineries. At the census tract-level, the prevalence of CHD explained by exposure to oil refineries ranged from 0.02% (0.00, 0.05) to 47.4% (5.2, 89.5). Thus, although we cannot rule out potential confounding by other personal risk factors, CHD prevalence was found to be higher in populations living nearer to oil refineries, which may suggest that exposure to oil refineries can increase CHD risk, warranting further investigation.

Changes in Restricting Symptoms after Critical Illness among Community-Living Older Adults.

Rationale: Survivors of critical illness have multiple symptoms, but how restricting symptoms change after critical illness and whether these changes differ among vulnerable subgroups is unknown. Objectives: To evaluate changes in restricting symptoms over the six months after critical illness among older adults and to determine whether these changes differ by sex, multimorbidity, and individual- and neighborhood-level socioeconomic disadvantage. Methods: From a prospective longitudinal study of 754 community-living adults ⩾70 years old interviewed monthly (1998-2018), we identified 233 admissions from 193 participants to the ICU. The occurrence of 15 restricting symptoms, defined as those leading to restricted activity, were ascertained during interviews in the month before ICU admission (baseline) and each of the six months after hospital discharge. Measurements and Main Results: The occurrence and number of restricting symptoms increased more than threefold in the six months after a critical illness hospitalization (adjusted rate ratio [95% confidence interval], 3.1 [2.1-4.6] and 3.3 [2.1-5.3], respectively), relative to baseline. These increases were largest in the first month after hospitalization (adjusted rate ratio [95% confidence interval], 5.3 [3.8-7.3] and 5.4 [3.9-7.5], respectively] before declining and becoming nonsignificant in the third month. Increases in restricting symptoms did not differ significantly by sex, multimorbidity, or individual- or neighborhood-level socioeconomic disadvantage. Conclusions: Restricting symptoms increase substantially after a critical illness before returning to baseline three months after hospital discharge. Our findings highlight the need to incorporate symptom management into post-ICU care and for further investigation into whether addressing restricting symptoms can improve quality of life and functional recovery among older ICU survivors.

The dementia care study (D-CARE): Recruitment strategies and demographic characteristics of participants in a pragmatic randomized trial of dementia care.

INTRODUCTION: Pragmatic research studies that include diverse dyads of persons living with dementia (PLWD) and their family caregivers are rare. METHODS: Community-dwelling dyads were recruited for a pragmatic clinical trial evaluating three approaches to dementia care. Four clinical trial sites used shared and site-specific recruitment strategies to enroll health system patients. RESULTS: Electronic health record (EHR) queries of patients with a diagnosis of dementia and engagement of their clinicians were the main recruitment strategies. A total of 2176 dyads were enrolled, with 80% recruited after the onset of the pandemic. PLWD had a mean age of 80.6 years (SD 8.5), 58.4% were women, and 8.8% were Hispanic/Latino, and 11.9% were Black/African American. Caregivers were mostly children of the PLWD (46.5%) or spouses/partners (45.2%), 75.8% were women, 9.4% were Hispanic/Latino, and 11.6% were Black/African American. DISCUSSION: Health systems can successfully enroll diverse dyads in a pragmatic clinical trial.

Higher Hospital Frailty Risk Score Is Associated With Increased Risk of Stroke: Observational and Genetic Analyses.

BACKGROUND: Frailty is a prevalent state associated with several aging-related traits and conditions. The relationship between frailty and stroke remains understudied. Here we aim to investigate whether the hospital frailty risk score (HFRS) is associated with the risk of stroke and determine whether a significant association between genetically determined frailty and stroke exists. DESIGN: Observational study using data from All of Us research program and Mendelian Randomization analyses. METHODS: Participants from All of Us with available electronic health records were selected for analysis. All of Us began national enrollment in 2018 and is expected to continue for at least 10 years. All of Us is recruiting members of groups that have traditionally been underrepresented in research. All participants provided informed consent at the time of enrollment, and the date of consent was recorded for each participant. Incident stroke was defined as stroke event happening on or after the date of consent to the All of Us study HFRS was measured with a 3-year look-back period before the date of consent for stroke risk. The HFRS was stratified into 4 categories: no-frailty (HFRS=0), low (HFRS ≥1 and <5), intermediate (≥5 and <15), and high (HFRS ≥15). Last, we implemented Mendelian Randomization analyses to evaluate whether genetically determined frailty is associated with stroke risk. RESULTS: Two hundred fifty-three thousand two hundred twenty-six participants were at risk of stroke. In multivariable analyses, frailty status was significantly associated with risk of any (ischemic or hemorrhagic) stroke following a dose-response way: not-frail versus low HFRS (HR, 4.9 [CI, 3.5-6.8]; P<0.001), not-frail versus intermediate HFRS (HR, 11.4 [CI, 8.3-15.7]; P<0.001) and not-frail versus high HFRS (HR, 42.8 [CI, 31.2-58.6]; P<0.001). We found similar associations when evaluating ischemic and hemorrhagic stroke separately (P value for all comparisons <0.05). Mendelian Randomization confirmed this association by indicating that genetically determined frailty was independently associated with risk of any stroke (OR, 1.45 [95% CI, 1.15-1.84]; P=0.002). CONCLUSIONS: Frailty, based on the HFRS was associated with higher risk of any stroke. Mendelian Randomization analyses confirmed this association providing evidence to support a causal relationship.

The Incidence and Cumulative Risk of Major Surgery in Older Persons in the United States.

OBJECTIVE: The objective of this study was to estimate the incidence and cumulative risk of major surgery in older persons over a 5-year period and evaluate how these estimates differ according to key demographic and geriatric characteristics. BACKGROUND: As the population of the United States ages, there is considerable interest in ensuring safe, high-quality surgical care for older persons. Yet, valid, generalizable data on the occurrence of major surgery in the geriatric population are sparse. METHODS: We evaluated data from a prospective longitudinal study of 5571 community-living fee-for-service Medicare beneficiaries, aged 65 or older, from the National Health and Aging Trends Study from 2011 to 2016. Major surgeries were identified through linkages with Centers for Medicare and Medicaid Services data. Population-based incidence and cumulative risk estimates incorporated National Health and Aging Trends Study analytic sampling weights and cluster and strata variables. RESULTS: The nationally representative incidence of major surgery per 100 person-years was 8.8, with estimates of 5.2 and 3.7 for elective and nonelec-tive surgeries. The adjusted incidence of major surgery peaked at 10.8 in persons 75 to 79 years, increased from 6.6 in the non-frail group to 10.3 in the frail group, and was similar by sex and dementia. The 5-year cumulative risk of major surgery was 13.8%, representing nearly 5 million unique older persons, including 12.1% in persons 85 to 89 years, 9.1% in those ≥90 years, 12.1% in those with frailty, and 12.4% in those with probable dementia. CONCLUSIONS: Major surgery is a common event in the lives of community-living older persons, including high-risk vulnerable subgroups.

Factors Associated With Days Away From Home in the Year After Major Surgery Among Community-living Older Persons.

OBJECTIVE: To identify the factors associated with days away from home in the year after hospital discharge for major surgery. BACKGROUND: Relatively little is known about which older persons are susceptible to spending a disproportionate amount of time in hospitals and other health care facilities after major surgery. METHODS: From a cohort of 754 community-living persons, aged 70+ years, 394 admissions for major surgery were identified from 289 participants who were discharged from the hospital. Candidate risk factors were assessed every 18 months. Days away from home were calculated as the number of days spent in a health care facility. RESULTS: In the year after major surgery, the mean (SD) and median (interquartile range) number of days away from home were 52.0 (92.2) and 15 (0-51). In multivariable analysis, 5 factors were independently associated with the number of days away from home: age 85 years and older, low score on the Short Physical Performance Battery, low peak expiratory flow, low functional self-efficacy, and musculoskeletal surgery. Based on the presence versus absence of these factors, the absolute mean differences in the number of days away from home ranged from 31.2 for age 85 years and older to 53.5 for low functional self-efficacy. CONCLUSIONS: The 5 independent risk factors can be used to identify older persons who are particularly susceptible to spending a disproportionate amount of time away from home after major surgery, and a subset of these factors can also serve as targets for interventions to improve quality of life by reducing time spent in hospitals and other health care facilities.

A Randomized Trial of a Multifactorial Strategy to Prevent Serious Fall Injuries.

BACKGROUND: Injuries from falls are major contributors to complications and death in older adults. Despite evidence from efficacy trials that many falls can be prevented, rates of falls resulting in injury have not declined. METHODS: We conducted a pragmatic, cluster-randomized trial to evaluate the effectiveness of a multifactorial intervention that included risk assessment and individualized plans, administered by specially trained nurses, to prevent fall injuries. A total of 86 primary care practices across 10 health care systems were randomly assigned to the intervention or to enhanced usual care (the control) (43 practices each). The participants were community-dwelling adults, 70 years of age or older, who were at increased risk for fall injuries. The primary outcome, assessed in a time-to-event analysis, was the first serious fall injury, adjudicated with the use of participant report, electronic health records, and claims data. We hypothesized that the event rate would be lower by 20% in the intervention group than in the control group. RESULTS: The demographic and baseline characteristics of the participants were similar in the intervention group (2802 participants) and the control group (2649 participants); the mean age was 80 years, and 62.0% of the participants were women. The rate of a first adjudicated serious fall injury did not differ significantly between the groups, as assessed in a time-to-first-event analysis (events per 100 person-years of follow-up, 4.9 in the intervention group and 5.3 in the control group; hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P = 0.25). The rate of a first participant-reported fall injury was 25.6 events per 100 person-years of follow-up in the intervention group and 28.6 events per 100 person-years of follow-up in the control group (hazard ratio, 0.90; 95% CI, 0.83 to 0.99; P = 0.004). The rates of hospitalization or death were similar in the two groups. CONCLUSIONS: A multifactorial intervention, administered by nurses, did not result in a significantly lower rate of a first adjudicated serious fall injury than enhanced usual care. (Funded by the Patient-Centered Outcomes Research Institute and others; STRIDE ClinicalTrials.gov number, NCT02475850.).

Association of frailty with the incidence risk of cardiovascular disease and type 2 diabetes mellitus in long-term cancer survivors: a prospective cohort study.

BACKGROUND: Comorbidities among cancer survivors remain a serious healthcare burden and require appropriate management. Using two widely used frailty indicators, this study aimed to evaluate whether frailty was associated with the incidence risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) among long-term cancer survivors. METHODS: We included 13,388 long-term cancer survivors (diagnosed with cancer over 5 years before enrolment) free of CVD and 6101 long-term cancer survivors free of T2DM, at the time of recruitment (aged 40-69 years), from the UK Biobank. Frailty was assessed by the frailty phenotype (FP_Frailty, range: 0-5) and the frailty index (FI_Frailty, range: 0-1) at baseline. The incident CVD and T2DM were ascertained through linked hospital data and primary care data, respectively. The associations were examined using Cox proportional hazards regression models. RESULTS: Compared with non-frail participants, those with pre-frailty (FP_Frailty [met 1-2 of the components]: hazard ratio [HR]=1.18, 95% confidence interval [CI]: 1.05, 1.32; FI_Frailty [0.10< FI ≤0.21]: HR=1.51, 95% CI: 1.32, 1.74) and frailty (FP_Frailty [met ≥3 of the components]: HR=2.12, 95% CI: 1.73, 2.60; FI_Frailty [FI >0.21]: HR=2.19, 95% CI: 1.85, 2.59) had a significantly higher risk of CVD in the multivariable-adjusted model. A similar association of FI_Frailty with the risk of incident T2DM was observed. We failed to find such an association for FP_Frailty. Notably, the very early stage of frailty (1 for FP_Frailty and 0.1-0.2 for FI_Frailty) was also positively associated with the risk of CVD and T2DM (FI_Frailty only). A series of sensitivity analyses confirmed the robustness of the findings. CONCLUSIONS: Frailty, even in the very early stage, was positively associated with the incidence risk of CVD and T2DM among long-term cancer survivors, although discrepancies existed between frailty indicators. While the validation of these findings is required, they suggest that routine monitoring, prevention, and interventive programs of frailty among cancer survivors may help to prevent late comorbidities and, eventually, improve their quality of life. Especially, interventions are recommended to target those at an early stage of frailty when healthcare resources are limited.

An Improved Spectrophotometric Method for Toluene-4-Monooxygenase Activity.

Monooxygenases, an important class of enzymes, have been the subject of enzyme engineering due to their high activity and versatile substrate scope. Reactions performed by these biocatalysts have long been monitored by a colorimetric method involving the coupling of a dye precursor to naphthalene hydroxylation products generated by the enzyme. Despite the popularity of this method, we found the dye product to be unstable, preventing quantitative readout. By incorporating an extraction step to solubilize the dye produced, we have improved this assay to the point where quantitation of enzyme activity is possible. Further, by incorporating spectral deconvolution, we have, for the first time, enabled independent quantification of the two possible regioisomeric products: 1-naphthol and 2-naphthol. Previously, such analysis was only possible with chromatographic separation, increasing the cost and complexity of analysis. The efficacy of our improved workflow was evaluated by monitoring the activity of a toluene-4-monooxygenase enzyme from Pseudomonas mendocina KR-1. Our colorimetric regioisomer quantification was found to be consistent with chromatographic analysis by HPLC. The development and validation of a quantitative colorimetric assay for monooxygenase activity that enables regioisomeric distinction and quantification represents a significant advance in analytical methods to monitor enzyme activity. By maintaining facile, low-cost, high-throughput readout while incorporating quantification, this assay represents an important alternative to more expensive chromatographic quantification techniques.

Costs of fall injuries in the STRIDE study: an economic evaluation of healthcare system heterogeneity and heterogeneity of treatment effect.

OBJECTIVES: The Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) Study cluster-randomized 86 primary care practices in 10 healthcare systems to a patient-centered multifactorial fall injury prevention intervention or enhanced usual care, enrolling 5451 participants. We estimated total healthcare costs from participant-reported fall injuries receiving medical attention (FIMA) that were averted by the STRIDE intervention and tested for healthcare-system-level heterogeneity and heterogeneity of treatment effect (HTE). METHODS: Participants were community-dwelling adults age ≥ 70 at increased fall injury risk. We estimated practice-level total costs per person-year of follow-up (PYF), assigning unit costs to FIMA with and without an overnight hospital stay. Using independent variables for treatment arm, healthcare system, and their interaction, we fit a generalized linear model with log link, log follow-up time offset, and Tweedie error distribution. RESULTS: Unadjusted total costs per PYF were $2,034 (intervention) and $2,289 (control). The adjusted (intervention minus control) cost difference per PYF was -$167 (95% confidence interval (CI), -$491, $216). Cost heterogeneity by healthcare system was present (p = 0.035), as well as HTE (p = 0.090). Adjusted total costs per PYF in control practices varied from $1,529 to $3,684 for individual healthcare systems; one system with mean intervention minus control costs of -$2092 (95% CI, -$3,686 to -$944) per PYF accounted for HTE, but not healthcare system cost heterogeneity. CONCLUSIONS: We observed substantial heterogeneity of healthcare system costs in the STRIDE study, with small reductions in healthcare costs for FIMA in the STRIDE intervention accounted for by a single healthcare system. TRIAL REGISTRATION: Clinicaltrials.gov (NCT02475850).

Geographic Variation in the Utilization of and Mortality After Emergency General Surgery Operations in the Northeastern and Southeastern United States.

OBJECTIVE: To define geographic variations in emergency general surgery (EGS) care, we sought to determine how much variability exists in the rates of EGS operations and subsequent mortality in the Northeastern and Southeastern United States (US). SUMMARY BACKGROUND DATA: While some geographic variations in healthcare are normal, unwarranted variations raise questions about the quality, appropriateness, and cost-effectiveness of care in different areas. METHODS: Patients ≥18 years who underwent 1 of 10 common EGS operations were identified using the State Inpatient Databases (2011-2012) for 6 states, representing Northeastern (New York) and Southeastern (Florida, Georgia, Kentucky, North Carolina, Mississippi) US. Geographic unit of analysis was the hospital service area (HSA). Age-standardized rates of operations and in-hospital mortality were calculated and mapped. Differences in rates across geographic areas were compared using the Kruskal-Wallis test, and variance quantified using linear random-effects models. Variation profiles were tabulated via standardized rates of utilization and mortality to compare geographically heterogenous areas. RESULTS: 227,109 EGS operations were geospatially analyzed across the 6 states. Age-standardized EGS operation rates varied significantly by region (Northeast rate of 22.7 EGS operations per 10,000 in population versus Southeast 21.9; P < 0.001), state (ranging from 9.9 to 29.1; P < 0.001), and HSA (1.9-56.7; P < 0.001). The geographic variability in age-standardized EGS mortality rates was also significant at the region level (Northeast mortality rate 7.2 per 1000 operations vs Southeast 7.4; P < 0.001), state-level (ranging from 5.9 to 9.0 deaths per 1000 EGS operations; P < 0.001), and HSA-level (0.0-77.3; P < 0.001). Maps and variation profiles visually exhibited widespread and substantial differences in EGS use and morality. CONCLUSIONS: Wide geographic variations exist across 6 Northeastern and Southeastern US states in the rates of EGS operations and subsequent mortality. More detailed geographic analyses are needed to determine the basis of these variations and how they can be minimized.

Neighborhood Socioeconomic Disadvantage and Disability After Critical Illness.

OBJECTIVES: Factors common to socioeconomically disadvantaged neighborhoods, such as low availability of transportation, may limit access to restorative care services for critical illness survivors. Our primary objective was to evaluate whether neighborhood socioeconomic disadvantage was associated with an increased disability burden after critical illness. Our secondary objective was to determine if the effect differed for those discharged to the community compared with those discharged to a facility. DESIGN: Longitudinal cohort study with linked Medicare claims data. SETTING: United States. PATIENTS: One hundred ninety-nine older adults, contributing to 239 ICU admissions, who underwent monthly assessments of disability for 12 months following hospital discharge in 13 different functional tasks from 1998 to 2017. MEASUREMENTS AND MAIN RESULTS: Neighborhood disadvantage was assessed using the area deprivation index, a 1-100 ranking evaluating poverty, housing, and employment metrics. Those living in disadvantaged neighborhoods (top quartile of scores) were less likely to self-identify as non-Hispanic White compared with those in more advantaged neighborhoods. In adjusted models, older adults living in disadvantaged neighborhoods had a 9% higher disability burden over the 12 months following ICU discharge compared with those in more advantaged areas (rate ratio, 1.09; 95% Bayesian credible interval, 1.02-1.16). In the secondary analysis adjusting for discharge destination, neighborhood disadvantage was associated with a 14% increase in disability burden over 12 months of follow-up (rate ratio, 1.14; 95% credible interval, 1.07-1.21). Disability burden was 10% higher for those living in disadvantaged neighborhoods and discharged home as compared with those discharged to a facility, but this difference was not statistically significant (interaction rate ratio, 1.10; 95% credible interval, 0.98-1.25). CONCLUSIONS: Neighborhood socioeconomic disadvantage is associated with a higher disability burden in the 12 months after a critical illness. Future studies should evaluate barriers to functional recovery for ICU survivors living in disadvantaged neighborhoods.

New horizons in evidence-based care for older people: individual participant data meta-analysis.

Evidence-based decisions on clinical and cost-effectiveness of interventions are ideally informed by meta-analyses of intervention trial data. However, when undertaken, such meta-analyses in ageing research have typically been conducted using standard methods whereby summary (aggregate) data are extracted from published trial reports. Although meta-analysis of aggregate data can provide useful insights into the average effect of interventions within a selected trial population, it has limitations regarding robust conclusions on which subgroups of people stand to gain the greatest benefit from an intervention or are at risk of experiencing harm. Future evidence synthesis using individual participant data from ageing research trials for meta-analysis could transform understanding of the effectiveness of interventions for older people, supporting evidence-based and sustainable commissioning. A major advantage of individual participant data meta-analysis (IPDMA) is that it enables examination of characteristics that predict treatment effects, such as frailty, disability, cognitive impairment, ethnicity, gender and other wider determinants of health. Key challenges of IPDMA relate to the complexity and resources needed for obtaining, managing and preparing datasets, requiring a meticulous approach involving experienced researchers, frequently with expertise in designing and analysing clinical trials. In anticipation of future IPDMA work in ageing research, we are establishing an international Ageing Research Trialists collective, to bring together trialists with a common focus on transforming care for older people as a shared ambition across nations.

Genetically Determined Smoking Behavior and Risk of Nontraumatic Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: Animal and observational studies indicate that smoking is a risk factor for aneurysm formation and rupture, leading to nontraumatic subarachnoid hemorrhage (SAH). However, a definitive causal relationship between smoking and the risk of SAH has not been established. Using Mendelian randomization (MR) analyses, we tested the hypothesis that smoking is causally linked to the risk of SAH. METHODS: We conducted a 1-sample MR study using data from the UK Biobank, a large cohort study that enrolled over 500 000 Britons aged 40 to 69 from 2006 to 2010. Participants of European descent were included. SAH cases were ascertained using a combination of self-reported, electronic medical record, and death registry data. As the instrument, we built a polygenic risk score using independent genetic variants known to associate (P<5×10-8) with smoking behavior. This polygenic risk score represents the genetic susceptibility to smoking initiation. The primary MR analysis utilized the ratio method. Secondary MR analyses included the inverse variance weighted and weighted median methods. RESULTS: A total of 408 609 study participants were evaluated (mean age, 57 [SD 8], female sex, 220 937 [54%]). Among these, 132 566 (32%) ever smoked regularly, and 904 (0.22%) had a SAH. Each additional SD of the smoking polygenic risk score was associated with 21% increased risk of smoking (odds ratio [OR], 1.21 [95% CI, 1.20-1.21]; P<0.001) and a 10% increased risk of SAH (OR, 1.10 [95% CI, 1.03-1.17]; P=0.006). In the primary MR analysis, genetic susceptibility to smoking was associated with a 63% increase in the risk of SAH (OR, 1.63 [95% CI, 1.15-2.31]; P=0.006). Secondary analyses using the inverse variance weighted method (OR, 1.57 [95% CI, 1.13-2.17]; P=0.007) and the weighted median method (OR, 1.74 [95% CI, 1.06-2.86]; P=0.03) yielded similar results. There was no significant pleiotropy (MR-Egger intercept P=0.39; MR Pleiotropy Residual Sum and Outlier global test P=0.69). CONCLUSIONS: These findings provide evidence for a causal link between smoking and the risk of SAH.

Functional Effects of Intervening Illnesses and Injuries After Hospitalization for Major Surgery in Community-living Older Persons.

OBJECTIVE: To evaluate the functional effects of intervening illnesses and injuries, that is, events, in the year after major surgery. BACKGROUND: Intervening events have pronounced deleterious effects on functional status in older persons, but have not been carefully evaluated after major surgery. METHODS: From a cohort of 754 community-living persons, aged 70+ years, 317 admissions for major surgery were identified from 244 participants who were discharged from the hospital. Functional status (13 activities) and exposure to intervening hospitalizations, emergency department (ED) visits, and restricted activity were assessed each month. Comprehensive assessments (for covariates) were completed every 18 months. RESULTS: In the year after major surgery, exposure rates (95% CI) per 100-person months to hospitalizations, ED visits, and restricted activity were 10.0 (8.0-12.5), 3.9 (2.8-5.4), and 12.3 (10.2-14.8) for functional recovery and 7.2 (6.1-8.5), 2.5 (1.9-3.2), 11.2 (9.8-12.9) for functional decline. Each of the 3 intervening events were independently associated with reduced recovery, with adjusted hazard ratios (95% CI) of 0.20 (0.09-0.47), 0.35 (0.15-0.81), and 0.57 (0.36-0.90) for hospitalizations, ED visits, and restricted activity. For functional decline, the corresponding odds ratios (95% CI) were 5.68 (3.87-8.33), 1.90 (1.13-3.20), and 1.30 (0.96-1.75). The effect sizes for hospitalizations and ED visits were larger than those for the covariates. CONCLUSIONS: Intervening illnesses/injuries are common in the year after major surgery, and those leading to hospitalization and ED visit are strongly associated with adverse functional outcomes, with effect sizes larger than those of traditional risk factors.

Functional Effects of Intervening Illnesses and Injuries After Critical Illness in Older Persons.

OBJECTIVES: Intervening illnesses and injuries have pronounced deleterious effects on functional status in older persons, but have not been carefully evaluated after critical illness. We set out to evaluate the functional effects of intervening illnesses and injuries in the year after critical illness. DESIGN: Prospective longitudinal study of 754 nondisabled community-living persons, 70 years old or older. SETTING: Greater New Haven, CT, from March 1998 to December 2018. PATIENTS: The analytic sample included 250 ICU admissions from 209 community-living participants who were discharged from the hospital. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Functional status (13 activities) and exposure to intervening illnesses and injuries leading to hospitalization, emergency department visit, or restricted activity were assessed each month. Comprehensive assessments (for covariates) were completed every 18 months. In the year after critical illness, recovery of premorbid function was observed for 169 of the ICU admissions (67.6%), and the mean (sd) number of episodes of functional decline (from 1 mo to the next) was 2.2 (1.6). The adjusted hazard ratios (95% CI) for recovery were 0.18 (0.09-0.39), 0.46 (0.17-1.26), and 0.75 (0.48-1.18) for intervening hospitalizations, emergency department visits, and restricted activity, respectively. For functional decline, the corresponding odds ratios (95% CI) were 2.06 (1.56-2.73), 1.78 (1.12-2.83), and 1.25 (0.92-1.69). The effect sizes for hospitalization and emergency department visit were larger than those for any of the covariates. CONCLUSIONS: In the year after critical illness, intervening illnesses and injuries leading to hospitalization and emergency department visit are strongly associated with adverse functional outcomes, with effect sizes larger than those of traditional risk factors. To improve functional outcomes, more aggressive efforts will be needed to prevent and manage intervening illnesses and injuries after critical illness.

Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage.

OBJECTIVE: Observational studies point to an inverse correlation between low-density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH. METHODS: We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high-density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses. RESULTS: We identified 410, 339, 393, and 317 lipid-related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10-100 ). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85-0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81-0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65-0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42-0.82; p = 0.002), respectively. INTERPRETATION: Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020 ANN NEUROL 2020;88:56-66.

A case study of ascertainment bias for the primary outcome in the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial.

BACKGROUND/AIM: In clinical trials, there is potential for bias from unblinded observers that may influence ascertainment of outcomes. This issue arose in the Strategies to Reduce Injuries and Develop Confidence in Elders trial, a cluster randomized trial to test a multicomponent intervention versus enhanced usual care (control) to prevent serious fall injuries, originally defined as a fall injury leading to medical attention. An unblinded nurse falls care manager administered the intervention, while the usual care arm did not involve contact with a falls care manager. Thus, there was an opportunity for falls care managers to refer participants reporting falls to seek medical attention. Since this type of observer bias could not occur in the usual care arm, there was potential for additional falls to be reported in the intervention arm, leading to dilution of the intervention effect and a reduction in study power. We describe the clinical basis for ascertainment bias, the statistical approach used to assess it, and its effect on study power. METHODS: The prespecified interim monitoring plan included a decision algorithm for assessing ascertainment bias and adapting (revising) the primary outcome definition, if necessary. The original definition categorized serious fall injuries requiring medical attention into Type 1 (fracture other than thoracic/lumbar vertebral, joint dislocation, cut requiring closure) and Type 2 (head injury, sprain or strain, bruising or swelling, other). The revised definition, proposed by the monitoring plan, excluded Type 2 injuries that did not necessarily require an overnight hospitalization since these would be most subject to bias. These injuries were categorized into those with (Type 2b) and without (Type 2c) medical attention. The remaining Type 2a injuries required medical attention and an overnight hospitalization. We used the ratio of 2b/(2b + 2c) in intervention versus control as a measure of ascertainment bias; ratios > 1 indicated the likelihood of falls care manager bias. We determined the effect of ascertainment bias on study power for the revised (Types 1 and 2a) versus original definition (Types 1, 2a, and 2b). RESULTS: The estimate of ascertainment bias was 1.14 (95% confidence interval: 0.98, 1.30), providing evidence of the likelihood of falls care manager bias. We estimated that this bias diluted the hazard ratio from the hypothesized 0.80 to 0.86 and reduced power to under 80% for the original primary outcome definition. In contrast, adapting the revised definition maintained study power at nearly 90%. CONCLUSION: There was evidence of ascertainment bias in the Strategies to Reduce Injuries and Develop Confidence in Elders trial. The decision to adapt the primary outcome definition reduced the likelihood of this bias while preserving the intervention effect and study power.