Two randomized controlled trials of nudges to encourage referrals to centralized pharmacy services for evidence-based statin initiation in high-risk patients: Rationale and design of the SUPER LIPID program.

BACKGROUND: In patients with or at risk for atherosclerotic vascular disease, statins reduce the incidence of major adverse cardiovascular events, but the majority of US adults with an indication for statin therapy are not prescribed statins at guideline-recommended intensity. Clinicians' limited time to address preventative care issues is cited as one factor contributing to gaps in statin prescribing. Centralized pharmacy services can fulfill a strategic role for population health management through outreach, education, and statin prescribing for patients at elevated ASCVD risk, but best practices for optimizing referrals of appropriate patients are unknown. STUDY DESIGN AND OBJECTIVES: SUPER LIPID (NCT05537064) is a program consisting of two pragmatic clinical trials testing the effect of nudges in increasing referrals of appropriate patients to a centralized pharmacy service for lipid management, conducted within 11 primary care practices in a large community health system. In both trials, patients were eligible for inclusion if they had an assigned primary care provider (PCP) in a participating practice and were not prescribed a high- or moderate-intensity statin despite an indication, identified via an electronic health record (EHR) algorithm. Trial #1 was a stepped wedge trial, conducted at a single practice with randomization at the PCP level, of an interruptive EHR message that appeared during eligible patients' visits and facilitated referral to the pharmacy service. For the first 3 months, no PCPs received the message; for the second 3 months, half were randomly selected to receive the message; and for the last 3 months, all PCPs received the message. Trial #2 was a cluster-randomized trial conducted at 10 practices, with randomization at the practice level. Practices were randomized to usual care or to have eligible patients automatically referred to centralized pharmacy services via a referral order placed in PCPs EHR inboxes for co-signature. In both trials, when a patient was referred to centralized pharmacy services, a pharmacist reviewed the patient's chart, contacted the patient, and initiated statin therapy if the patient agreed. The primary endpoint of both trials was the proportion of patients prescribed a statin; secondary endpoints include the proportion of patients prescribed a statin at guideline-recommended intensity, the proportion of patients filling a statin prescription, and serum low-density lipoprotein level. CONCLUSIONS: SUPER LIPID is a pair of pragmatic clinical trials assessing the effectiveness of two strategies to encourage referral of appropriate patients to a centralized pharmacy service for lipid management. The trial results will develop the evidence base for simple, scalable, EHR-based strategies to integrate clinical pharmacists into population health management and increase appropriate statin prescribing. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov; NCT05537064.

Evaluating the implementation of a community health worker-delivered intervention integrating asthma care in West Philadelphia public schools.

OBJECTIVE: Schools are an important setting because students spend much of their time in school and engage in physical activity during the school day that could exacerbate asthma symptoms. Our objective is to understand the barriers and facilitators to implementing an experimental community health worker-delivered care coordination program for students with asthma within the context of the West Philadelphia Controls Asthma study. METHODS: Surveys (n = 256) and semi-structured interviews (n = 41) were completed with principals, teachers, nurses, and community health workers from 21 public and charter schools in West Philadelphia between January 2019 and September 2021. Survey participants completed the Evidence Based Practice Attitudes Scale, the Implementation Leadership Scale, and Organizational Climate Index. Semi-structured qualitative interview guides were developed, informed by the Consolidated Framework for Implementation Research. RESULTS: Participant responses indicate that they perceived benefits for schools and students related to the community health worker-based care coordination program. Several barriers and facilitators to implementing the program were noted, including challenges associated with incorporating the program into school nurse workflow, environmental triggers in the school environment, and challenges communicating with family members. An important facilitator that was identified was having supportive school administrators and staff who were engaged and saw the benefits of the program. CONCLUSIONS: This work can inform implementation planning for other locales interested in implementing community-based pediatric asthma control programs delivered by community health workers in schools.

Reappraisal-related downregulation of amygdala BOLD activation occurs only during the late trial window.

During cognitive reappraisal, an individual reinterprets the meaning of an emotional stimulus to regulate the intensity of their emotional response. Prefrontal cortex activity has been found to support reappraisal and is putatively thought to downregulate the amygdala response to these stimuli. The timing of these regulation-related responses during the course of a trial, however, remains poorly understood. In the current fMRI study, participants were instructed to view or reappraise negative images and then rate how negative they felt following each image. The hemodynamic response function was estimated in 11 regions of interest for the entire time course of the trial including image viewing and rating. Notably, within the amygdala there was no evidence of downregulation in the early (picture viewing) window of the trial, only in the late (rating) window, which also correlated with a behavioral measure of reappraisal success. With respect to the prefrontal regions, some (e.g., inferior frontal gyrus) showed reappraisal-related activation in the early window, whereas others (e.g., middle frontal gyrus) showed increased activation primarily in the late window. These results highlight the temporal dynamics of different brain regions during emotion regulation and suggest that the amygdala response to negative images need not be immediately dampened to achieve successful cognitive reappraisal.

Effect of Nudges to Clinicians, Patients, or Both to Increase Statin Prescribing: A Cluster Randomized Clinical Trial.

Importance: Statins reduce the risk of major adverse cardiovascular events, but less than one-half of individuals in America who meet guideline criteria for a statin are actively prescribed this medication. Objective: To evaluate whether nudges to clinicians, patients, or both increase initiation of statin prescribing during primary care visits. Design, Setting, and Participants: This cluster randomized clinical trial evaluated statin prescribing of 158 clinicians from 28 primary care practices including 4131 patients. The design included a 12-month preintervention period and a 6-month intervention period between October 19, 2019, and April 18, 2021. Interventions: The usual care group received no interventions. The clinician nudge combined an active choice prompt in the electronic health record during the patient visit and monthly feedback on prescribing patterns compared with peers. The patient nudge was an interactive text message delivered 4 days before the visit. The combined nudge included the clinician and patient nudges. Main Outcomes and Measures: The primary outcome was initiation of a statin prescription during the visit. Results: The sample comprised 4131 patients with a mean (SD) age of 65.5 (10.5) years; 2120 (51.3%) were male; 1210 (29.3%) were Black, 106 (2.6%) were Hispanic, 2732 (66.1%) were White, and 83 (2.0%) were of other race or ethnicity, and 933 (22.6%) had atherosclerotic cardiovascular disease. In unadjusted analyses during the preintervention period, statins were prescribed to 5.6% of patients (105 of 1876) in the usual care group, 4.8% (97 of 2022) in the patient nudge group, 6.0% (104 of 1723) in the clinician nudge group, and 4.7% (82 of 1752) in the combined group. During the intervention, statins were prescribed to 7.3% of patients (75 of 1032) in the usual care group, 8.5% (100 of 1181) in the patient nudge group, 13.0% (128 of 981) in the clinician nudge arm, and 15.5% (145 of 937) in the combined group. In the main adjusted analyses relative to usual care, the clinician nudge significantly increased statin prescribing alone (5.5 percentage points; 95% CI, 3.4 to 7.8 percentage points; P = .01) and when combined with the patient nudge (7.2 percentage points; 95% CI, 5.1 to 9.1 percentage points; P = .001). The patient nudge alone did not change statin prescribing relative to usual care (0.9 percentage points; 95% CI, -0.8 to 2.5 percentage points; P = .32). Conclusions and Relevance: Nudges to clinicians with and without a patient nudge significantly increased initiation of a statin prescription during primary care visits. The patient nudge alone was not effective. Trial Registration: ClinicalTrials.gov Identifier: NCT04307472.

Home-delivered meals for people with dementia: Which model delays nursing home placement? - Protocol for a feasibility pilot.

BACKGROUND: Home-delivered meals promote food security, socialization, and independence among homebound older adults. However, it is unclear which of the two predominant modes of meal delivery, daily-delivered vs. drop-shipped, frozen meals, promotes community living for homebound older adults with dementia. Our objective is to present the protocol for a pilot multisite, two-arm, pragmatic feasibility trial comparing the effect of two modes of meal delivery on nursing home placement among people with dementia. We include justifications for individual randomization with different consent processes and waivers for specific elements of the trial. METHODS: 236 individuals with dementia on waiting lists at three Meals on Wheels programs' in Florida and Texas will be randomized to receive either: 1) meals delivered multiple times per week by a Meals on Wheels volunteer or paid driver who may socialize with and provide an informal wellness check or 2) frozen meals that are mailed to participants' homes every two weeks. We will evaluate and refine processes for recruitment and randomization; assess adherence to the intervention; identify common themes in participant experience; and test processes for linking participant data with Medicare records and nursing home assessment data. We will conduct exploratory analyses examining time to nursing home placement, the primary outcome for the larger trial. CONCLUSION: This pilot will inform the follow-on large-scale, definitive pragmatic trial. In addition, the justifications for individual randomization with differing consent procedures for elements of a pragmatic trial provide a model for future trialists looking to develop ethical and feasible pragmatic studies enrolling people with dementia.

CLIC-01: Manufacture and distribution of non-cryopreserved CAR-T cells for patients with CD19 positive hematologic malignancies.

Access to commercial CD19 CAR-T cells remains limited even in wealthy countries like Canada due to clinical, logistical, and financial barriers related to centrally manufactured products. We created a non-commercial academic platform for end-to-end manufacturing of CAR-T cells within Canada's publicly funded healthcare system. We report initial results from a single-arm, open-label study to determine the safety and efficacy of in-house manufactured CD19 CAR-T cells (entitled CLIC-1901) in participants with relapsed/refractory CD19 positive hematologic malignancies. Using a GMP compliant semi-automated, closed process on the Miltenyi Prodigy, T cells were transduced with lentiviral vector bearing a 4-1BB anti-CD19 CAR transgene and expanded. Participants underwent lymphodepletion with fludarabine and cyclophosphamide, followed by infusion of non-cryopreserved CAR-T cells. Thirty participants with non-Hodgkin's lymphoma (n=25) or acute lymphoblastic leukemia (n=5) were infused with CLIC-1901: 21 males (70%), median age 66 (range 18-75). Time from enrollment to CLIC-1901 infusion was a median of 20 days (range 15-48). The median CLIC-1901 dose infused was 2.3 × 106 CAR-T cells/kg (range 0.13-3.6 × 106/kg). Toxicity included ≥ grade 3 cytokine release syndrome (n=2) and neurotoxicity (n=1). Median follow-up was 6.5 months. Overall response rate at day 28 was 76.7%. Median progression-free and overall survival was 6 months (95%CI 3-not estimable) and 11 months (95% 6.6-not estimable), respectively. This is the first trial of in-house manufactured CAR-T cells in Canada and demonstrates that administering fresh CLIC-1901 product is fast, safe, and efficacious. Our experience may provide helpful guidance for other jurisdictions seeking to create feasible and sustainable CAR-T cell programs in research-oriented yet resource-constrained settings. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT03765177, identifier NCT03765177.

Rescuing medical education in times of COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has caused widespread disruptions in various sectors of medicine, including medical education. Although the necessary focus has been on patient care and public safety and the long-lasting impact of COVID-19 remains to be determined, the impact on medical education warrants further attention and action. While it seems minuscule compared with the toll the global pandemic has caused worldwide, the impact on medical education, including graduate medical education, carries the potential to alter career progression and outcomes. We have assessed the effects of COVID-19 on dermatology clinics, residency education, and medical education, exploring recommendations and actions taken by governing bodies and offering additional suggestions of our own.

Leveraging insights from behavioral economics to improve mobility for adults with stroke: Design and rationale of the BE Mobile clinical trial.

Physical inactivity post-stroke can negatively impact long-term health outcomes and contribute to cardiovascular deconditioning, muscle loss, and increased risk for recurrent stroke. The limited number of interventions designed to improve daily physical activity post-stroke have lacked precision in step goals, are resource intensive, and difficult to scale. The purpose of the Leveraging Insights from Behavioral Economics to Improve Mobility for Adults with Stroke (BE Mobile) trial is to examine the preliminary effectiveness of a novel gamification with social incentives intervention for improving physical activity post-stroke. This trial includes adults who have experienced an ischemic or hemorrhagic stroke ≥3 months prior to the time of recruitment who are randomized to a control or gamification arm. All participants receive a Fitbit Inspire 2 wearable device to quantify daily steps and complete a 2-week baseline run-in period followed by an 8-week intervention period. All participants select a daily step goal and the gamification arm is enrolled in a game with loss-framed points and levels to help participants achieve their daily step goal. Participants in the gamification arm also select a support partner who receives weekly updates on their progress in the game. The primary outcome is change in daily steps from baseline during the intervention period. The secondary outcome is difference in the proportion of days participants achieved their daily step goal. Results from this trial will inform future, larger studies that leverage insights from behavioral economics to help improve daily physical activity post-stroke. Trial registration: NCT #04607811.

Ancestral Absence of Electron Transport Chains in Patescibacteria and DPANN.

Recent discoveries suggest that the candidate superphyla Patescibacteria and DPANN constitute a large fraction of the phylogenetic diversity of Bacteria and Archaea. Their small genomes and limited coding potential have been hypothesized to be ancestral adaptations to obligate symbiotic lifestyles. To test this hypothesis, we performed cell-cell association, genomic, and phylogenetic analyses on 4,829 individual cells of Bacteria and Archaea from 46 globally distributed surface and subsurface field samples. This confirmed the ubiquity and abundance of Patescibacteria and DPANN in subsurface environments, the small size of their genomes and cells, and the divergence of their gene content from other Bacteria and Archaea. Our analyses suggest that most Patescibacteria and DPANN in the studied subsurface environments do not form specific physical associations with other microorganisms. These data also suggest that their unusual genomic features and prevalent auxotrophies may be a result of ancestral, minimal cellular energy transduction mechanisms that lack respiration, thus relying solely on fermentation for energy conservation.