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Background: Diagnosis-code-based algorithms to identify fall injuries in Medicare data are useful for ascertaining outcomes in interventional and observational studies. However, these algorithms have not been validated against a fully external reference standard, in ICD-10-CM, or in Medicare Advantage (MA) data., Methods: We linked self-reported fall injuries leading to medical attention (FIMA) from the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial (reference standard) to Medicare fee-for-service (FFS) and MA data from 2015-19. We measured the area under the receiver operating characteristic curve (AUC) based on sensitivity and specificity of a diagnosis-code-based algorithm against the reference standard for presence or absence of ≥1 FIMA within a specified window of dates, varying the window size to obtain points on the curve. We stratified results by source (FFS vs MA), trial arm (intervention vs control), and STRIDE's 10 participating health care systems., Results: Both reference standard data and Medicare data were available for 4 941 (of 5 451) participants. The reference standard and algorithm identified 2 054 and 2 067 FIMA, respectively. The algorithm had 45% sensitivity (95% confidence interval [CI]: 43%-47%) and 99% specificity (95% CI: 99%-99%) to identify reference standard FIMA within the same calendar month. The AUC was 0.79 (95% CI: 0.78-0.81) and was similar by FFS or MA data source and by trial arm but showed variation among STRIDE health care systems (AUC range by health care system, 0.71 to 0.84)., Conclusions: An ICD-10-CM algorithm to identify fall injuries demonstrated acceptable performance against an external reference standard, in both MA and FFS data., (Published by Oxford University Press on behalf of The Gerontological Society of America 2024.)

Background: Variable data quality poses a challenge to using electronic health record (EHR) data to ascertain acute clinical outcomes in multi-site clinical trials. Differing EHR platforms and data comprehensiveness across clinical trial sites, especially if patients received care outside of the clinical site's network, can also affect validity of results. Overcoming these challenges requires a structured approach., Methods: We propose a framework and create a checklist to assess the readiness of clinical sites to contribute EHR data to a clinical trial for the purpose of outcome ascertainment, based on our experience with the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) study, which enrolled 5451 participants in 86 primary care practices across 10 healthcare systems (sites)., Results: The site readiness checklist includes assessment of the infrastructure (i.e., size and structure of the site's healthcare system or clinical network), data procurement (i.e., quality of the data), and cost of obtaining study data. The checklist emphasizes the importance of understanding how data are captured and integrated across a site's catchment area and having a protocol in place for data procurement to ensure consistent and uniform extraction across each site., Conclusions: We suggest rigorous, prospective vetting of the data quality and infrastructure of each clinical site before launching a multi-site trial dependent on EHR data. The proposed checklist serves as a guiding tool to help investigators ensure robust and unbiased data capture for their clinical trials., Original Trial Registration Number: NCT02475850., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

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., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Recurrent events are common in clinical studies and are often subject to terminal events. In pragmatic trials, participants are often nested in clinics and can be susceptible or structurally unsusceptible to the recurrent events. We develop a Bayesian shared random effects model to accommodate this complex data structure. To achieve robustness, we consider the Dirichlet processes to model the residual of the accelerated failure time model for the survival process as well as the cluster-specific shared frailty distribution, along with an efficient sampling algorithm for posterior inference. Our method is applied to a recent cluster randomized trial on fall injury prevention., Competing Interests: Conflict of interest: None declared., (© The Royal Statistical Society 2024. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This paper presents novel datasets providing numerical representations of ICD-10-CM codes by generating description embeddings using a large language model followed by a dimension reduction via autoencoder. The embeddings serve as informative input features for machine learning models by capturing relationships among categories and preserving inherent context information. The model generating the data was validated in two ways. First, the dimension reduction was validated using an autoencoder, and secondly, a supervised model was created to estimate the ICD-10-CM hierarchical categories. Results show that the dimension of the data can be reduced to as few as 10 dimensions while maintaining the ability to reproduce the original embeddings, with the fidelity decreasing as the reduced-dimension representation decreases. Multiple compression levels are provided, allowing users to choose as per their requirements, download and use without any other setup. The readily available datasets of ICD-10-CM codes are anticipated to be highly valuable for researchers in biomedical informatics, enabling more advanced analyses in the field. This approach has the potential to significantly improve the utility of ICD-10-CM codes in the biomedical domain., (© 2023. The Author(s).)

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)., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Greater symptom complexity in women than in men could slow acute ST-elevation myocardial infarction (STEMI) recognition and delay door-to-balloon (D2B) times. We sought to determine the sex differences in symptom complexity and their relation to D2B times in 1,677 young and older patients with STEMI using data from the VIRGO and SILVER-AMI studies. Symptom complexity was defined by the number of symptom patterns or phenotypes and average number of symptoms. The numbers of symptom phenotypes were compared in women and men using the Monte Carlo permutation testing. Groups were also compared using the generalized linear regression and logistic regression. The number of symptom phenotypes (244 vs 171, p = 0.02), mean number of symptoms (4.7 vs 4.2, p <0.001), and mean D2B time (114.6 vs 97.8 minutes, p = 0.004) were greater in young women than in young men but were not significantly different in older women compared with older men. The regression analysis did not show a relation between symptom complexity and D2B time overall; although, chest pain was a significant predictor of D2B times, and young women were more likely to report symptoms other than chest pain. Among patients with STEMI, 36% did not receive percutaneous coronary intervention (PCI), which was associated with presentation delay >6 hours. In patients with STEMI with either D2B time ≥90 minutes or no PCI, women had significantly more symptom phenotypes overall and in VIRGO but not in SILVER-AMI. In conclusion, the markers of symptom complexity were not associated with D2B time overall, but more symptom phenotypes in young women were associated with prolonged D2B time or no PCI. In addition, greater frequency of nonchest pain symptoms in young women may have also slowed the recognition of STEMI and D2B times in young women. Further research on symptoms clusters is needed to improve the recognition of STEMIs to improve the D2B times in young women., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Simulation studies play an important role in evaluating the performance of statistical models developed for analyzing complex survival data such as those with competing risks and clustering. This article aims to provide researchers with a basic understanding of competing risks data generation, techniques for inducing cluster-level correlation, and ways to combine them together in simulation studies, in the context of randomized clinical trials with a binary exposure or treatment. We review data generation with competing and semi-competing risks and three approaches of inducing cluster-level correlation for time-to-event data: the frailty model framework, the probability transform, and Moran's algorithm. Using exponentially distributed event times as an example, we discuss how to introduce cluster-level correlation into generating complex survival outcomes, and illustrate multiple ways of combining these methods to simulate clustered, competing and semi-competing risks data with pre-specified correlation values or degree of clustering.

Background: Evidence-based multifactorial fall prevention interventions in clinical practice have been less effective than expected. One plausible reason is that older adults' engagement in fall prevention care is suboptimal., Methods: This was a post-hoc analysis of 2403 older adults' engagement in a multifactorial fall prevention intervention in the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) pragmatic trial. Based on the direct clinical care level of the Patient and Family Continuum of Engagement (CE) framework, three indicators of progressively interactive engagement were assessed: (1) Consultation (receiving information), (2) Involvement (prioritizing risks), and (3) Partnership (identifying prevention actions). Drop off at each step was determined as well as predictors of engagement., Results: The participants' engagement waned with increasingly interactive CE domains. Although all participants received information about their positive fall risk factors (consultation) and most (51%-96%) prioritized them (involvement), fewer participants (33%-55%) identified fall prevention actions (partnership) for most of their risk factors, except for strength gait or balance problems (95%). More participants (70%) identified home exercises than other actions. Finally, fall prevention actions were identified more commonly among participants who received two visits compared to one (OR = 2.33 [95% CI, 2.06-2.64]), were ≥80 years old (OR = 1.83 [95% CI, 1.51-2.23]), and had fewer fall risk factors (OR = 0.90 [95% CI, 0.83-0.99])., Conclusions: The drop-off in participants' engagement based on the level of their interaction with clinicians suggests that future multifactorial fall prevention interventions need to be more focused on interactive patient-clinician partnerships that help older adults increase and maintain fall prevention actions. Our analyses suggest that more frequent contact with clinicians and more monitoring of the implementation and outcomes of Fall Prevention Care Plans could potentially improve engagement and help older adults maintain fall prevention actions., (© 2022 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Background: Falls are common in older adults and can lead to severe injuries. The Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial cluster-randomized 86 primary care practices across 10 health systems to a multifactorial intervention to prevent fall injuries, delivered by registered nurses trained as falls care managers, or enhanced usual care. STRIDE enrolled 5451 community-dwelling older adults age ≥70 at increased fall injury risk., Methods: We assessed fall-related outcomes via telephone interviews of participants (or proxies) every 4 months. At baseline, 12 and 24 months, we assessed health-related quality of life (HRQOL) using the EQ-5D-5L and EQ-VAS. We used Poisson models to assess intervention effects on falls, fall-related fractures, fall injuries leading to hospital admission, and fall injuries leading to medical attention. We used hierarchical longitudinal linear models to assess HRQOL., Results: For recurrent event models, intervention versus control incidence rate ratios were 0.97 (95% confidence interval [CI], 0.93-1.00; p = 0.048) for falls, 0.93 (95% CI, 0.80-1.08; p = 0.337) for self-reported fractures, 0.89 (95% CI, 0.73-1.07; p = 0.205) for adjudicated fractures, 0.91 (95% CI, 0.77-1.07; p = 0.263) for falls leading to hospital admission, and 0.97 (95% CI, 0.89-1.06; p = 0.477) for falls leading to medical attention. Similar effect sizes (non-significant) were obtained for dichotomous outcomes (e.g., participants with ≥1 events). The difference in least square mean change over time in EQ-5D-5L (intervention minus control) was 0.009 (95% CI, -0.002 to 0.019; p = 0.106) at 12 months and 0.005 (95% CI, -0.006 to 0.015; p = 0.384) at 24 months., Conclusions: Across a standard set of outcomes typically reported in fall prevention studies, we observed modest improvements, one of which was statistically significant. Future work should focus on patient-, practice-, and organization-level operational strategies to increase the real-world effectiveness of interventions, and improving the ability to detect small but potentially meaningful clinical effects., Clinicaltrials: gov identifier: NCT02475850., (© 2022 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

While statistical methods for analyzing cluster randomized trials with continuous and binary outcomes have been extensively studied and compared, little comparative evidence has been provided for analyzing cluster randomized trials with survival outcomes in the presence of competing risks. Motivated by the Strategies to Reduce Injuries and Develop Confidence in Elders trial, we carried out a simulation study to compare the operating characteristics of several existing population-averaged survival models, including the marginal Cox, marginal Fine and Gray, and marginal multi-state models. For each model, we found that adjusting for the intraclass correlations through the sandwich variance estimator effectively maintained the type I error rate when the number of clusters is large. With no more than 30 clusters, however, the sandwich variance estimator can exhibit notable negative bias, and a permutation test provides better control of type I error inflation. Under the alternative, the power for each model is differentially affected by two types of intraclass correlations-the within-individual and between-individual correlations. Furthermore, the marginal Fine and Gray model occasionally leads to higher power than the marginal Cox model or the marginal multi-state model, especially when the competing event rate is high. Finally, we provide an illustrative analysis of Strategies to Reduce Injuries and Develop Confidence in Elders trial using each analytical strategy considered.

Background: Clinicians make a medical diagnosis by recognizing diagnostic possibilities, often using memories of prior examples. These memories, called "exemplars," reflect specific symptom combinations in individual patients, yet most clinical studies report how symptoms aggregate in populations. We studied how symptoms of acute myocardial infarction combine in individuals as symptom phenotypes and how symptom phenotypes are distributed in women and men., Methods: In this analysis of the SILVER-AMI Study, we studied 3041 patients (1346 women and 1645 men) 75 years of age or older with acute myocardial infarction. Each patient had a standardized in-person interview during the acute myocardial infarction admission to document the presenting symptoms, which enabled a thorough examination of symptom combinations in individuals. Specific symptom combinations defined symptom phenotypes and distributions of symptom phenotypes were compared in women and men using Monte Carlo permutation testing and repeated subsampling., Results: There were 1469 unique symptom phenotypes in the entire SILVER-AMI cohort of patients with acute myocardial infarction. There were 831 unique symptom phenotypes in women, as compared with 819 in men, which was highly significant, given the larger number of men than women in the study (P < .0001). Women had significantly more symptom phenotypes than men in almost all acute myocardial infarction subgroups., Conclusions: Older patients with acute myocardial infarction have enormous variation in symptom phenotypes. Women reported more symptoms and had significantly more symptom phenotypes than men. Appreciation of the diversity of symptom phenotypes may help clinicians recognize the less common phenotypes that occur more often in women., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.

While the gold standard for clinical trials is to blind all parties-participants, researchers, and evaluators-to treatment assignment, this is not always a possibility. When some or all of the above individuals know the treatment assignment, this leaves the study open to the introduction of postrandomization biases. In the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial, we were presented with the potential for the unblinded clinicians administering the treatment, as well as the individuals enrolled in the study, to introduce ascertainment bias into some but not all events comprising the primary outcome. In this article, we present ways to estimate the ascertainment bias for a time-to-event outcome, and discuss its impact on the overall power of a trial vs changing of the outcome definition to a more stringent unbiased definition that restricts attention to measurements less subject to potentially differential assessment. We found that for the majority of situations, it is better to revise the definition to a more stringent definition, as was done in STRIDE, even though fewer events may be observed., (© 2020 John Wiley & Sons, Ltd.)

Background/objectives: In the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) study, a multifactorial intervention was associated with a nonsignificant 8% reduction in time to first serious fall injury but a significant 10% reduction in time to first self-reported fall injury relative to enhanced usual care. The effect of the intervention on other outcomes important to patients has not yet been reported. We aimed to evaluate the effect of the intervention on patient well-being including concern about falling, anxiety, depression, physical function, and disability., Design: Pragmatic cluster-randomized trial of 5,451 community-living persons at high risk for serious fall injuries., Setting: A total of 86 primary care practices within 10 U.S. healthcare systems., Participants: A random subsample of 743 persons aged 75 and older., Measurements: The well-being measures, assessed at baseline, 12 months, and 24 months, included a modified version of the Fall Efficacy Scale, Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety and depression scales, and Late-Life Function and Disability Instrument., Results: Participants in the intervention (n = 384) and control groups (n = 359) were comparable in age: mean (standard deviation) of 81.9 (4.7) versus 81.8 (5.0) years. Mean scores were similar between groups at 12 and 24 months for concern about falling, physical function, and disability, whereas the intervention group's mean scores on anxiety and depression were .7 points lower (i.e., better) at 12 months and .6 to .8 points lower at 24 months. For each of these outcomes, differences between the groups' adjusted least square mean changes from baseline to 12 and 24 months, respectively, were quantitatively small. The overall difference in means between groups over 2 years was statistically significant only for depression, favoring the intervention: -1.19 (99% confidence interval, -2.36 to -.02), with 3.5 points representing a minimally important difference., Conclusions: STRIDE's multifactorial intervention to reduce fall injuries was not associated with clinically meaningful improvements in patient well-being., (© 2020 The American Geriatrics Society.)

Background/objectives: Although several approaches have been developed to provide comprehensive care for persons living with dementia (PWD) and their family or friend caregivers, the relative effectiveness and cost effectiveness of community-based dementia care (CBDC) versus health system-based dementia care (CBDC) and the effectiveness of both approaches compared with usual care (UC) are unknown., Design: Pragmatic randomized three-arm superiority trial. The unit of randomization is the PWD/caregiver dyad., Setting: Four clinical trial sites (CTSs) based in academic and clinical health systems., Participants: A total of 2,150 English- or Spanish-speaking PWD who are not receiving hospice or residing in a nursing home and their caregivers., Interventions: Eighteen months of (1) HSDC provided by a nurse practitioner or physician's assistant dementia care specialist who works within the health system, or (2) CBDC provided by a social worker or nurse care consultant who works at a community-based organization, or (3) UC with as needed referral to the Alzheimer's Association Helpline., Measurements: Primary outcomes: PWD behavioral symptoms and caregiver distress as measured by the Neuropsychiatric Inventory Questionnaire (NPI-Q) Severity and Modified Caregiver Strain Index scales., Secondary Outcomes: NPI-Q Distress, caregiver unmet needs and confidence, and caregiver depressive symptoms. Tertiary outcomes: PWD long-term nursing home placement rates, caregiver-reported PWD functional status, cognition, goal attainment, "time spent at home," Dementia Burden Scale-Caregiver, a composite measure of clinical benefit, Quality of Life of persons with dementia, Positive Aspects of Caregiving, and cost effectiveness using intervention costs and Medicare claims., Results: The results will be reported in the spring of 2024., Conclusion: D-CARE will address whether emphasis on clinical support and tighter integration with other medical services has greater benefit than emphasis on social support that is tied more closely to community resources. It will also assess the effectiveness of both interventions compared with UC and will evaluate the cost effectiveness of each intervention., (© 2020 The American Geriatrics Society.)

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.)., (Copyright © 2020 Massachusetts Medical Society.)

Objectives: The Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) study is testing the effectiveness of a multifactorial intervention to prevent serious fall injuries. Our aim was to describe procedures that were implemented to optimize participant retention; report retention yields by age, sex, clinical site, and follow-up time; provide reasons for study withdrawals; and highlight the successes and lessons learned from the STRIDE retention efforts., Design: Pragmatic cluster randomized trial., Setting: A total of 86 primary care practices within 10 US healthcare systems., Participants: A total of 5451 community-living persons, 70 years of age or older, at high risk for serious fall injuries., Measurements: Study outcomes were collected every 4 months by a central call center. Reconsent was required to extend follow-up beyond the originally planned 36 months., Results: Over a median follow-up of 3.2 years (interquartile range = 2.8-3.7 y), 439 (8.1%) participants died and 600 (11.0%) withdrew their consent or did not reconsent to extend follow-up beyond 36 months, yielding rates (per 100 person-years) of deaths and withdrawals of 2.6 and 3.6, respectively. The withdrawal rate increased with advancing age, was comparable for men and women, and did not differ much by clinical site. The most common reasons for withdrawal were illness and unable to contact for reconsent at 36 months. Completion of the follow-up interviews was greater than 93% at each time point. Most participants completed all (71.8%) or all but one (9.2%) of the follow-up interviews. The most common reason for not completing a follow-up interview was unable to contact, with rates ranging from 2.8% at 40 months to 4.6% at 20 months., Conclusion: Completion of the thrice-yearly follow-up interviews in STRIDE was high, and retention of participants over 44 months exceeded the original projections. The procedures used in STRIDE, together with lessons learned, should assist other investigators who are planning or conducting large pragmatic trials of vulnerable older persons. J Am Geriatr Soc 68:1242-1249, 2020., (© 2020 The American Geriatrics Society.)

Background: The diagnosis of acute myocardial infarction (AMI) is missed more frequently in young women than men, which may be related to the cognitive psychology of the diagnostic process. Physicians start the diagnostic process by intuitively recognizing familiar symptom phenotypes, but little is known about how symptoms combine in individuals as unique symptom phenotypes. We examined how symptoms of AMI combine as unique symptom phenotypes in individual patients to compare the distribution of symptom phenotypes in women versus men., Methods and Results: The VIRGO study (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients) was a multicenter, observational cohort study of 3501 young adults hospitalized with AMI. Data were collected on presenting symptoms with standardized interviews and from medical record abstraction. The number and distribution of unique symptom phenotypes were compared between women and men. Because of the 2:1 female-to-male enrollment ratio, women and men were compared with permutation testing and repeated subsampling. There were 426 interview-symptom phenotypes in women and 280 in men. The observed difference between women and men of 146 phenotypes was significant, even allowing for the greater enrollment of women (permutation P =0.004, median difference 110 under the null hypothesis of no association between sex and phenotype). The repeated subsample analysis also showed significantly more interview-symptom phenotypes in women than men (206.8±7.3 versus 188.6±6.0, P <0.001). Women were more broadly distributed among symptom phenotype subgroups than men ( P <0.001). Similar findings were observed in the analysis of symptoms abstracted from the medical record., Conclusions: Women exhibited substantially more variation in unique symptom phenotypes than men, regardless of whether the symptoms were derived from structured interviews or abstracted from the medical record. These findings may provide an explanation for the higher missed diagnosis rate in young women with AMI and may have important implications for teaching and improving clinicians' ability to recognize the diagnosis of AMI in women.

Background: This paper describes a protocol for determining the incidence of serious fall injuries for Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE), a large, multicenter pragmatic clinical trial with limited resources for event adjudication. We describe how administrative data (from participating health systems and Medicare claims) can be used to confirm participant-reported events, with more time- and resource-intensive full-text medical record data used only on an "as-needed" basis., Methods: STRIDE is a pragmatic cluster-randomized controlled trial involving 5451 participants age ≥ 70 and at increased risk for falls, served by 86 primary care practices in 10 US health systems. The STRIDE intervention involves a nurse falls care manager who assesses a participant's underlying risks for falls, suggests interventions using motivational interviewing, and then creates, implements and longitudinally follows up on an individualized care plan with the participant (and caregiver when appropriate), in partnership with the participant's primary care provider. STRIDE's primary outcome is serious fall injuries, defined as a fall resulting in: (1) medical attention billable according to Medicare guidelines with a) fracture (excluding isolated thoracic vertebral and/or lumbar vertebral fracture), b) joint dislocation, or c) cut requiring closure; OR (2) overnight hospitalization with a) head injury, b) sprain or strain, c) bruising or swelling, or d) other injury determined to be "serious" (i.e., burn, rhabdomyolysis, or internal injury). Two sources of data are required to confirm a serious fall injury. The primary data source is the participant's self-report of a fall leading to medical attention, identified during telephone interview every 4 months, with the confirmatory source being (1) administrative data capturing encounters at the participating health systems or Medicare claims and/or (2) the full text of medical records requested only as needed., Discussion: Adjudication is ongoing, with over 1000 potentially qualifying events adjudicated to date. Administrative data can be successfully used for adjudication, as part of a hybrid approach that retrieves full-text medical records only when needed. With the continued refinement and availability of administrative data sources, future studies may be able to use administrative data completely in lieu of medical record review to maximize the quality of adjudication with finite resources., Trial Registration: ClinicalTrials.gov (NCT02475850)., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Background: We describe the recruitment of participants for Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE), a large pragmatic cluster randomized trial that is testing the effectiveness of a multifactorial intervention to prevent serious fall injuries. Eligible persons were 70 years or older, community-living, and at increased risk for serious fall injuries. The modified goal was to recruit 5,322 participants over 20 months from 86 primary care practices within 10 diverse health care systems across the United States., Methods: The at-risk population was identified using two distinct but complementary screening strategies that included three questions administered centrally via the mail (nine sites) or in the clinic (one site), while recruitment was completed centrally by staff at Yale., Results: For central screening, 226,603 letters mailed to 135,118 patients yielded 28,719 positive screens (12.7% of those mailed and 46.5% of the 61,729 returned). In the clinic, 22,537 screens were completed, leading to 5,732 positive screens (25.4%). Of the 34,451 patients who screened positive for high risk of serious fall injuries, 31,872 were sent a recruitment packet and, of these, 5,451 (17.1%) were enrolled over 20 months (mean age: 80 years; 62% female). The participation rate was 34.0% among eligible patients. The enrollment yields were 3.6% (vs 5% projected) for each patient screened centrally, despite multiple screens, and 10.5% (vs 33.9% projected) for each positive clinic screen., Conclusions: Despite lower-than-expected yields, the STRIDE Study exceeded its modified recruitment goal. If the STRIDE intervention is found to be effective, the two distinct strategies for identifying a high-risk population of older persons could be implemented by most health care systems.

Background: Physicians "purchase" many health care services on behalf of patients yet remain largely unaware of the costs of these services. Electronic health record (EHR) cost displays may facilitate cost-conscious ordering of health services., Objective: To determine whether displaying hospital lab and imaging order costs is associated with changes in the number and costs of orders placed., Design: Quasi-experimental study., Participants: All patients with inpatient or observation encounters across a multi-site health system from April 2013 to October 2015., Intervention: Display of order costs, based on Medicare fee schedules, in the EHR for 1032 lab tests and 1329 imaging tests., Main Measures: Outcomes for both lab and imaging orders were (1) whether an order was placed during a hospital encounter, (2) whether an order was placed on a given patient-day, (3) number of orders placed per patient-day, and (4) cost of orders placed per patient-day., Key Results: During the lab and imaging study periods, there were 248,214 and 258,267 encounters, respectively. Cost display implementation was associated with a decreased odds of any lab or imaging being ordered during the encounter (lab adjusted odds ratio [AOR] = 0.97, p = .01; imaging AOR = 0.97, p < .001), a decreased odds of any lab or imaging being ordered on a given patient-day (lab AOR = 0.95, p < .001; imaging AOR = 0.97, p < .001), a decreased number of lab or imaging orders on patient-days with orders (lab adjusted count ratio = 0.93, p < .001; imaging adjusted count ratio = 0.98, p < .001), and a decreased cost of lab orders and increased cost of imaging orders on patient-days with orders (lab adjusted cost ratio = 0.93, p < .001; imaging adjusted cost ratio = 1.02, p = .003). Overall, the intervention was associated with an 8.5 and 1.7% reduction in lab and imaging costs per patient-day, respectively., Conclusions: Displaying costs within EHR ordering screens was associated with decreases in the number and costs of lab and imaging orders.

Background: Fall injuries are a major cause of morbidity and mortality among older adults. We describe the design of a pragmatic trial to compare the effectiveness of an evidence-based, patient-centered multifactorial fall injury prevention strategy to an enhanced usual care., Methods: Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) is a 40-month cluster-randomized, parallel-group, superiority, pragmatic trial being conducted at 86 primary care practices in 10 health care systems across United States. The 86 practices were randomized to intervention or control group using covariate-based constrained randomization, stratified by health care system. Participants are community-living persons, ≥70 years, at increased risk for serious fall injuries. The intervention is a comanagement model in which a nurse Falls Care Manager performs multifactorial risk assessments, develops individualized care plans, which include surveillance, follow-up evaluation, and intervention strategies. Control group receives enhanced usual care, with clinicians and patients receiving evidence-based information on falls prevention. Primary outcome is serious fall injuries, operationalized as those leading to medical attention (nonvertebral fractures, joint dislocation, head injury, lacerations, and other major sequelae). Secondary outcomes include all fall injuries, all falls, and well-being (concern for falling; anxiety and depressive symptoms; physical function and disability). Target sample size was 5,322 participants to provide 90% power to detect 20% reduction in primary outcome rate relative to control., Results: Trial enrolled 5,451 subjects in 20 months. Intervention and follow-up are ongoing., Conclusions: The findings of the STRIDE study will have important clinical and policy implications for the prevention of fall injuries in older adults.

Ivers et al. (2012) have recently stressed the importance to both statistical power and face validity of balancing allocations to study arms on relevant covariates. While several techniques exist (e.g., minimization, pair-matching, stratification), the covariate-constrained randomization (CCR) approach proposed by Moulton (2004) is favored when clusters can be recruited prior to randomization. CCRA V1.0, a macro published by Chaudhary and Moulton (2006), provides a SAS implementation of CCR for a particular subset of possible designs (those with two arms, small numbers of strata and clusters, an equal number of clusters within each stratum, and constraints that can be expressed as absolute mean differences between arms). This paper presents a more comprehensive macro, CCR , that is applicable across a wider variety of designs and provides statistics describing the range of possible allocations meeting the constraints in addition to performing the actual random assignment.

Using functional MRI, we investigated reality monitoring for auditory information. During scanning, healthy young adults heard words in another person's voice and imagined hearing other words in that same voice. Later, outside the scanner, participants judged words as "heard," "imagined," or "new." An area of left middle frontal gyrus (Brodmann's area, or BA, 6) was more active at encoding for imagined items subsequently correctly called "imagined" than for items incorrectly called "heard." An area of left inferior frontal gyrus (BA 45, 44) was more active at encoding for items subsequently called "heard" than "imagined," regardless of the actual source of the item. Scores on an Auditory Hallucination Experience Scale were positively related to activity in superior temporal gyrus (BA 22) for imagined words incorrectly called "heard." We suggest that activity in these areas reflects cognitive operations information (middle frontal gyrus) and semantic and perceptual detail (inferior frontal gyrus and superior temporal gyrus, respectively) used to make reality-monitoring attributions.

Age-related source memory deficits may arise, in part, from changes in the agenda-driven processes that control what features of events are relevant during remembering. Using fMRI, we compared young and older adults on tests assessing source memory for format (picture, word) or encoding task (self-, other-referential), as well as on old-new recognition. Behaviorally, relative to old-new recognition, older adults showed disproportionate and equivalent deficits on both source tests compared to young adults. At encoding, both age groups showed expected activation associated with format in posterior visual processing areas, and with task in medial prefrontal cortex. At test, the groups showed similar selective, agenda-related activity in these representational areas. There were, however, marked age differences in the activity of control regions in lateral and medial prefrontal cortex and lateral parietal cortex. Results of correlation analyses were consistent with the idea that young adults had greater trial-by-trial agenda-driven modulation of activity (i.e., greater selectivity) than did older adults in representational regions. Thus, under selective remembering conditions where older adults showed clear differential regional activity in representational areas depending on type of test, they also showed evidence of disrupted frontal and parietal function and reduced item-by-item modulation of test-appropriate features. This pattern of results is consistent with an age-related deficit in the engagement of selective reflective attention., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A short-term source monitoring procedure with functional magnetic resonance imaging assessed neural activity when participants made judgments about the format of 1 of 4 studied items (picture, word), the encoding task performed (cost, place), or whether an item was old or new. The results support findings from long-term memory studies showing that left anterior ventrolateral prefrontal cortex (PFC) is engaged when people make source attributions about reflectively generated information (cognitive operations, conceptual features). The findings also point to a role for right lateral PFC in attention to perceptual features and/or familiarity in making source decisions. Activity in posterior regions also differed depending on what was evaluated. These results provide neuroimaging evidence for theoretical approaches emphasizing that agendas influence which features are monitored during remembering (e.g., M. K. Johnson, S. Hashtroudi, & D. S. Lindsay, 1993). They also support the hypothesis that some of the activity in left lateral PFC and posterior regions associated with remembering specific information is not unique to long-term memory but rather is associated with agenda-driven source monitoring processes common to working memory and long-term memory., ((c) 2008 APA)

We explored age-related differences in executive function during selection of a target from among active representations. Refreshing (thinking briefly of a just-activated representation) is an executive process that foregrounds a target relative to other active representations. In a behavioral study, participants saw one or three words, then saw a cue to refresh one of the words, saw one word again and read it, or read a new word. Increasing the number of active representations increased response times (RTs) only in the refresh condition for young adults but increased RTs equally in all conditions for older adults, suggesting that they experienced interference from activated irrelevant information during perception and reflection. Consistent with this interpretation, in a functional magnetic resonance imaging study, young adults showed two areas of the left dorsolateral frontal cortex and a medial area of frontal cortex, including anterior cingulate, that were relatively more sensitive to number of active representations during refresh than read trials; for older adults these areas were equally sensitive to number of active items for refresh and read trials. Young and older adults showed activity associated with refreshing on trials requiring selection in left mid-ventral frontal cortex (an area associated with selection from active representations); older adults also showed activity in left anterior ventral frontal cortex (an area associated with controlled semantic activation). Our results support the hypothesis of an age-related decrease in ability to gate out activated but currently irrelevant information, and are consistent with a dissociation of function between left mid-ventral and left anterior ventral frontal cortex.

Executive functions include processes by which important information (e.g., words, objects, task goals, contextual information) generated via perception or thought can be foregrounded and thereby influence current and subsequent processing. One simple executive process that has the effect of foregrounding information is refreshing--thinking briefly of a just-activated representation. Previous studies (e.g., Johnson et al., 2005) identified refresh-related activity in several areas of left prefrontal cortex (PFC). To further specify the respective functions of these PFC areas in refreshing, in Experiment 1, healthy young adult participants were randomly cued to think of a just previously seen word (refresh) or cued to press a button (act). Compared to simply reading a word, refresh and act conditions resulted in similar levels of activity in left lateral anterior PFC but only refreshing resulted in greater activity in left dorsolateral PFC. In Experiment 2, refreshing was contrasted with a minimal phonological rehearsal condition. Refreshing was associated with activity in left dorsolateral PFC and rehearsing with activity in left ventrolateral PFC. In both experiments, correlations of activity among brain areas suggest different functional connectivity for these processes. Together, these findings provide evidence that (1) left lateral anterior PFC is associated with initiating a non-automatic process, (2) left dorsolateral PFC is associated with foregrounding a specific mental representation, and (3) refreshing and rehearsing are neurally distinguishable processes.

We investigated the hypothesis that arousal recruits attention to item information, thereby disrupting working memory processes that help bind items to context. Using functional magnetic resonance imaging, we compared brain activity when participants remembered negative or neutral picture-location conjunctions (source memory) versus pictures only. Behaviorally, negative trials showed disruption of short-term source, but not picture, memory; long-term picture recognition memory was better for negative than for neutral pictures. Activity in areas involved in working memory and feature integration (precentral gyrus and its intersect with superior temporal gyrus) was attenuated on negative compared with neutral source trials relative to picture-only trials. Visual processing areas (middle occipital and lingual gyri) showed greater activity for negative than for neutral trials, especially on picture-only trials.

Motivationally significant agendas guide perception, thought and behaviour, helping one to define a 'self' and to regulate interactions with the environment. To investigate neural correlates of thinking about such agendas, we asked participants to think about their hopes and aspirations (promotion focus) or their duties and obligations (prevention focus) during functional magnetic resonance imaging and compared these self-reflection conditions with a distraction condition in which participants thought about non-self-relevant items. Self-reflection resulted in greater activity than distraction in dorsomedial frontal/anterior cingulate cortex and posterior cingulate cortex/precuneus, consistent with previous findings of activity in these areas during self-relevant thought. For additional medial areas, we report new evidence of a double dissociation of function between medial prefrontal/anterior cingulate cortex, which showed relatively greater activity to thinking about hopes and aspirations, and posterior cingulate cortex/precuneus, which showed relatively greater activity to thinking about duties and obligations. One possibility is that activity in medial prefrontal cortex is associated with instrumental or agentic self-reflection, whereas posterior medial cortex is associated with experiential self-reflection. Another, not necessarily mutually exclusive, possibility is that medial prefrontal cortex is associated with a more inward-directed focus, while posterior cingulate is associated with a more outward-directed, social or contextual focus.

To investigate whether emotional arousal affects memorial feature binding, we had participants complete a short-term source-monitoring task-remembering the locations of four different pictures over a brief delay. On each trial, the four pictures were all either high arousal, medium arousal, or low arousal. Memory for picture-location conjunctions decreased as arousal increased. In addition, source memory for the location of negative pictures was worse among participants with higher depression scores. Two subsequent functional magnetic resonance imaging experiments showed that relative to low-arousal trials, high- and medium-arousal trials resulted in greater activity in areas associated with visual processing (fusiform gyrus, middle temporal gyrus/middle occipital gyrus, lingual gyrus) and less activity in superior precentral gyrus and the precentral-superior temporal intersect. These findings suggest that arousal (and perhaps negative valence for depressed people) recruits attention to items thereby disrupting working memory processes that help bind features together.

Using functional magnetic resonance imaging (fMRI) and a working memory procedure, we compared source memory judgments (format and location) with old-new judgments in young and older adults. Consistent with previous fMRI findings, for young adults, an area of left dorsolateral prefrontal cortex showed greater activity during format than old-new judgments made immediately, as well as those made after a brief, filled delay. In contrast, for older adults, activity in this area was not greater during format than old-new judgments at either retention interval. These data provide additional evidence that left lateral prefrontal cortex is important in monitoring specific source information and new evidence that older adults' source memory deficits may be related, in part, to reduced function of this brain area.

Using fMRI, we investigated the functional organization of prefrontal cortex (PFC) as participants briefly thought of a single just-experienced item (i.e., refreshed an active representation). The results of six studies, and a meta-analysis including previous studies, identified regions in left dorsolateral, anterior, and ventrolateral PFC associated in varying degrees with refreshing different types of information (visual and auditory words, drawings, patterns, people, places, or locations). In addition, activity increased in anterior cingulate with selection demands and in orbitofrontal cortex when a nonselected item was emotionally salient, consistent with a role for these areas in cognitive control (e.g., overcoming "mental rubbernecking"). We also found evidence that presenting emotional information disrupted an anterior component of the refresh circuit. We suggest that refreshing accounts for some neural activity observed in more complex tasks, such as working memory, long-term memory, and problem solving, and that its disruption (e.g., from aging or emotion) could have a broad impact.

Using functional magnetic resonance imaging (fMRI), we investigated prefrontal cortex (PFC) activity during remembering specific source information (format, location judgments) versus remembering that could be based on undifferentiated information, such as familiarity (old/new recognition [ON], recency judgments). A working memory (WM) paradigm with an immediate test yielded greater activation in the lateral PFC for format and location source memory (SM) tasks than ON recognition; this SM-related activity was left lateralized. The same regions of PFC were recruited in Experiment 2 when information was tested immediately and after a filled delay. Substituting recency for location judgments (Experiment 3) resulted in an overall shift in task context that produced greater right PFC activity associated with ON and recency tasks compared to the format task, in addition to left SM-related activity. These data extend to WM previous findings from long-term memory (LTM) indicating that the left and right PFC may be differentially involved in memory attributions depending on the specificity of information evaluated. The findings also provide evidence for the continuity of evaluative processes recruited in WM and LTM.

Older adults are slower than young adults to think of an item they just saw, that is, to engage or execute (or both) the simple reflective operation of refreshing just-activated information. In addition, they derive less long-term memory benefit from refreshing information. Using functional magnetic resonance imaging (fMRI), we found that relative to young adults, older adults showed reduced refresh-related activity in an area of dorsolateral prefrontal cortex (left middle frontal gyrus, Brodmann's Area 9), but not in other refresh-related areas. This provides strong evidence that a frontal component of the circuit that subserves this basic cognitive process is especially vulnerable to aging. Such a refresh deficit could contribute to poorer performance of older than young adults on a wide range of cognitive tasks.

Neuroimaging evidence is conflicting regarding whether human prefrontal cortex (PFC) shows functional organization by type of processes engaged or type of information processed. Most studies use complex working or long-term memory tasks requiring multiple processes and the combinations of processes recruited for different materials may vary. Using functional magnetic resonance imaging (fMRI) and simple tasks suggested by a component process approach, we found activity in left PFC when participants thought about (refreshed) a just-seen item and in right PFC when participants noted whether an item had been presented previously. Furthermore, the distribution of activation in left or right PFC varied with type of information. Thus, at the component process level, PFC shows functional organization by both process and type of information.

Neuroimaging studies of human working memory (WM) show conflicting results regarding whether dorsolateral prefrontal cortex (PFC) contributes to maintaining information in consciousness or is recruited primarily when information must be manipulated. Using functional magnetic resonance imaging (fMRI), we looked at a minimal maintenance process--thinking back to a single, just-seen stimulus (refreshing). We found greater activity in left dorsolateral PFC (BA9) when participants refreshed a word compared to reading a word once or a second time. Furthermore, recognition memory was subsequently more accurate and faster for items that had been refreshed, demonstrating that a single thought that maintains activation can have consequences for long-term memory. Our fMRI results call into question any class of models of the functional organization of PFC and WM that associates simple and/or maintenance processes only with ventrolateral PFC or that associates dorsolateral PFC only with more complex processes such as manipulation.

In vivo administration to rats of the mixed-function oxidase modifiers 3-methylcholanthrene (MC), pregnenolone-16 alpha-carbonitrile (PCN) or beta-naphthoflavnoe (beta-f) inhibits the hepatic microsome-catalyzed in vitro binding of dimethylnitrosamine (DMN) to DNA. This parallels their effect on DMN-demethylase I, regarded to be the sole activating step in DMN carcinogenesis and fails to account for the previously observed anomaly that MC and PCN inhibit, while beta-NF enhances, the hepatocarcinogenic activity of DMN. The in vitro binding of DMN is clearly dependent on microsomes and NADPH, and is strongly enhanced by soluble cytoplasmic proteins; the presence of the latter has no effect. however, on the relative response to pretreatment by the modifiers. In mice beta-NF enhances and PCN inhibits DMN-demethylase I; beta-NF has no effect on either the cytochrome P-450 level or on the LD50, while PCN strongly increases the cytochrome P-450 level but without influencing the LD50. Neither of the two modifiers has any effect in mice on the host-mediated mutagenicity of DMN in a dose-response study, except for the highest dose of DMN (200 mg/kg) where PCN pretreatment significantly enhanced mutagenicity. To account for the anomalous observations, other potential pathways of DMN metabolism have been explored. Whole rat liver nuclei or isolated nuclear membrane fractions contain no DMN-demethylase or diethylnitrosamine-deethylase activity. In a microsomal mixed-function amine-oxidase assay system neither purified enzyme preparations nor whole microsomes catalyze NADPH oxidation in the presence of DMN as substrate. In addition, the purified enzyme does not catalyze formaldehyde production in the DMN-demethylase assay system. Benzylamine, a typical inhibitor of mitochondrial monoamine oxidase (MAO), is a potent inhibitor of DMN-demethylase activity, but microsomes are devoid of MAO activity. Furthermore, purified MAO has no DMN-demethylase activity. The differential effect of modifiers on the carcinogenicity of DMN probably involves pathways other than DMN metabolism.

Phenylglycidyl ether (1,2-epoxy-3-phenoxy propane) (PGE) was tested for genetic activity in bacterial and mammalian tests. It was active in the Salmonella/microsome mutagenicity test. Concentration-dependent mutagenicity was demonstrated in S. typhimurium strains TA1535 and TA100 with and without rat S9, but not in strains TA98, TA1537, or TA1538. These results suggest PGE, is a direct-acting mutagen causing base substitutions. Phenylglycidyl ether did not induce 6-thioguanine-resistant mutants of Chinese hamster ovary cells, with or without rat S9, and with or without serum in the medium. Dose-dependent enhancement of SA7 virus transformation of primary hamster embryo cells was observed at concentrations of 1.6 microgram/ml and higher. In addition, this compound was able to chemically transform secondary hamster embryo cells at concentrations of 6.2 micrograms/ml and higher. At a dose of 2500 mg/kg p.o., PGE was active in the host-mediated assay using C57B1/6 X C3H mice and S. typhimurium strain TA1535. This activity represented a positive response in 2 of 5 animals tested. Murine testicular DNA synthesis was not inhibited by oral administration of PGE at 500 mg/kg.

Sarcoidosis involves the spleen in a significant percentage of patients afflicted with this disease. The most commonly applied modality for studying such patients is the (99m)Tc-sulfur colloid scan. Different patterns have been recognized: "normal" spleen and nonspecific splenic enlargement, with or without focal areas of photon deficiency, which was thought to represent an infarction in a previous report. We have encountered two patients showing splenomegaly and multifocal photon deficiencies secondary to sarcoid granulomata. These cases are presented to inform clinicians of a new pattern. Our patients were managed with systemic corticosteroids and palliation of pain. If symptoms persist or worsen, splenectomy may be necessary to avoid spontaneous rupture. An abbreviated differential diagnosis of the enlarged spleen with multiple focal defects is discussed.