Neonatal trials often use binary and composite outcomes that fail to distinguish differential importance of events – death, for instance, being more impactful than a non-fatal event – and obscure the differences that matter most to families. There is a need to integrate multiple endpoints into outcome measures that reflect relative importance.
The Desirability Of Outcome Ranking (DOOR) approach shifts the unit of analysis from outcomes to overall patient improvement. When applied retroactively to trials involving delayed cord clamping and cord milking, it revealed a clinical benefit that was originally masked by traditional composite outcomes.
This “whole-child” approach comes with its own set of challenges. Parents care about long-term outcomes, and long-term follow-up is often not feasible. The study team, seeking to identify short-term neonatal intensive care unit outcomes that predict meaningful long-term outcomes, created a neonatal inpatient outcome called neoDOOR.
Discussion Themes
Trials that utilize DOOR will still require significant power to detect clinical differences.
Dr. Katheria emphasized the importance that neonatology adopts advanced trial methodologies that are already more common in adult medicine, e.g. platform trials.
Charles Scales, MD, MSHS
Associate Dean for Clinical Research Initiatives
Associate Professor, Urology and Population Health Sciences
Duke Clinical Research Institute
10% of Americans will experience urinary stones (US) in their lifetime. Hydration is a mainstay of dietary US prevention, with guidelines recommending sufficient intake to produce 2500 mL of urine per day.
The Prevention of Urinary Stones with Hydration (PUSH) trial team sought to test whether behavioral interventions to increase adherence to higher fluid intake prevented stone recurrence. The US incidence rate in the intervention group was slightly lower than that of the control group, but the difference was not statistically significant.
PUSH was designed as a clinical trial with pragmatic features responsive to participant and coordinator feedback. Dr. Scales shared lessons learned around screening/baseline procedures, recruitment practices, leveraging data, and more. Next steps will include secondary analyses of 24-hour urine data and adolescents with urinary stone disease.
Discussion Themes
The trial’s negative result should not be interpreted as a failure of hydration to prevent kidney stones. It demonstrates, rather, that long-term adherence to hydration is difficult to maintain through behavioral nudges.
Dr. Scales recommended that future behavioral intervention trials consider SMART trial designs and incorporate patient preference assessments. He noted the importance of following patient-important outcomes.
Post-hoc analyses suggested a dose-response effect: Individuals who successfully increased their urine output by at least 0.5 liters had fewer stones.
The field should move toward tailoring hydration goals to an individual’s body habitus or activity level rather than a one-size-fits-all volume target.
Sebastian Tong, MD, MPH
Associate Professor, Department of Family Medicine
University of Washington
Kushang Patel, PhD, MPH
Research Professor, Department of Anesthesiology and Pain Medicine
University of Washington
Keywords
Rural; Chronic Pain; Nurse Care Management; Feasibility
Key Points
Chronic pain affects roughly 20% of U.S. adults. In rural areas, that figure is closer to 30% – a disparity due, in part, to the concentration of older individuals and those with more physically demanding jobs. Rural residents often have less access to pain specialists and non-pharmacologic pain management approaches.
Nurse care management (NCM) has been shown to be effective in treating other diseases that disproportionately affect rural residents. In the feasibility phase, the research team sought to test and adapt a virtual NCM model – including care meetings with nurses, cognitive behavioral therapy (CBT), Tele-Enhance® fitness, and a pain tracker – for chronic pain in rural primary care.
The research team identified several adaptions to implement before scaling up to a 450-person randomized controlled trial. These include establishing a clinic learning collaborative; providing more take-home CBT and exercise options; implementing flexibility around who can serve as care manager; and providing asynchronous administrative support for care managers.
Discussion Themes
The research team focused on 2 systems during the feasibility phase given the research team’s limited bandwidth. In retrospect, Dr. Tong noted, continued engagement with the other health systems over the course of the feasibility phase may have helped maintain interest in the trial.
Different sites faced similar challenges; the learning collaborative will serve to harmonize implementation and provide a centralized space for troubleshooting.
While including non-RNs in care delivery makes the model more practical for rural clinics, the researchers acknowledged this creates a challenge for long-term sustainability, as insurance often only reimburses care managed by registered nurses.
Jennifer Kawi, PhD, MSN, FNP-BC, CNE, FAAN
Maria C. and Christopher J. Pappas Family Distinguished Chair in Nursing
Lee and Joseph Jamail Distinguished Professor
Department of Research
Cizik School of Nursing at UTHealth Houston
Hulin Wu, PhD, MS
The Betty Wheless Trotter Professor & Chair
Department of Biostatistics & Data Science
School of Public Health at UTHealth Houston
Jane Bolin, PhD, JD, RN
Senior Research Professor
College of Nursing, UNT Health Science Center at Fort Worth
Regents Professor Emeritus
Texas A&M School of Nursing
Keywords
Auricular Point Acupressure, Chronic pain, Pain management, Rural communities.
Key Points
Auricular Point Acupressure (APA) uses small seeds embedded into tape and placed on areas of the ear that correspond to areas of the body that are in pain. Placement decisions come from the literature on (APA) locations. APA has been shown to stimulate the central nervous system in fMRI studies, decreased pro-inflammatory substances (IL-ꞵ, TNFα), and increased anti-inflammatory substances (IL-4, IL-10).
To scale APA care, our self-managed approach for the Personalized Auricular Point Acupressure for Chronic Pain Self-management in Rural Populations UG3 study used an electronic application that was created to provide participants with tutorial videos, answers to frequently asked questions, and a pain tracking system. A previous study using this self-managed approach in urban areas showed improved physical function and lessoned pain intensity.
The current study focused on APA in rural communities that experience challenges with access to pain care, transportation, staff shortages, and technology and internet access. Building trust with rural communities was very important.
After the APA intervention, participants felt a regained control over pain and were satisfied with improved comfort. Challenges presented with difficulty reaching points on the back of the ear and discomfort while sleeping.
A full UH3 Pragmatic Randomized Clinical Trial is now being organized to expand the reach of the study. This 3-arm trial will randomize 693 participants to a control, APA in-person, or APA remote group. This study aims to determine the effectiveness of APA in chronic musculoskeletal pain, assess the cost-effectiveness, and identify predictive factors for APA treatment response.
Discussion Themes
Supporting rural communities in research requires leveraging existing partners while building new relationships, listening to the needs of the community and adjusting study procedures to meet these needs, and working with community advisory boards to disseminate findings.
The control group for this study was a pain education intervention group. Creating a sham control group for this type of study is difficult because there are many APA points in the ear. Attempting to create a sham control group that targets other points in the ear may inadvertently be influencing other APA points.
Roy Perlis, MD, MSc
Editor in Chief, JAMA+ AI
Director, MGH Center for Quantitative Health
Vice Chair for Research, Mass General-Brigham Psychiatry
Professor of Psychiatry, Harvard Medical School
Keywords
Artificial Intelligence; Publishing; Medical Publishing; Peer Review; Trust
Key Points
Though medical publishing was in flux before artificial intelligence (AI) became ubiquitous, the contemporary state of the industry is defined by AI-driven trends: an increased volume of submissions, an increased volume of low-quality submissions, and increased complexity of submissions. Academics are concurrently less willing to participate in the peer-review process – paradoxically making peer review into an area ripe for AI intervention.
Scientific communities are divided about the appropriate role of AI in manuscript preparation and review. In mid-2023, JAMA Network journals began requiring authors and peer reviewers to answer questions about their use of AI to create or assist with creation or editing of submitted manuscripts, or with preparation of reviews. While author disclosure of AI use is low, those figures likely represent an underestimate.
That peer review improves manuscript quality is a fringe benefit; its real value is instilling trust in the contents. The age of AI poses twin dangers: the simulation and politicization of expertise. AI may be capable of handling rote tasks like checking protocols, human subjects approval, and reporting checklists, but it comes with a potential cost in terms of the public’s already-eroded faith in scientific expertise.
Discussion Themes
The most commonly disclosed use of AI in manuscripts is for language and grammar cleanup, particularly by non-native English speakers. On the whole, AI has improved the clarity of international submissions.
Perlis predicted that administrative editorial tasks will be automated but human editors will remain essential for scientific taste: the ability to curate impactful stories and select which of hundreds of AI-generated hypotheses are worth pursuing.
Researchers were encouraged to master the use of AI agents as local analytic partners or writing assistants to automate aspects of their workflow without losing human oversight.
Older adults are often overprescribed medications or prescribed potentially inappropriate medications like benzodiazepines, non-benzodiazepine sedative hypnotics, or strongly anticholinergic medications with long-term use associated with a 30% increased risk of hospitalizations and falls.
Medication management or optimization in older adults is often difficult due to a tendency to maintain the status quo, time constraints, patient preference, or diffusion of responsibility, and existing interventions for medication management are highly resource intensive.
Behavioral science techniques employed in the NUDGE-EHR and NUDGE-HER-2 trials may enhance the effectiveness of electronic health record (EHR) tools to alert clinicians to inappropriate medications during patient visits.
NUDGE-EHR was a 16 arm two-stage adaptive pragmatic trial among 216 primary care providers and older adult patients conducted from October 2020 to August 2022 examining 14 promising EHR tools using 9 different behavioral principles with deprescribing as a primary outcome.
The 2 most promising tools were included in the second 3 parallel arm pragmatic trial, NUDGE-EHR-2, in a different health system from November 2022 to March 2024. EHR tools used pop-up windows to suggest deprescribing. The study provided a set of helpful options to providers including a tapering algorithm, instructions for patients, orders for alternative medications, and referrals to behavioral health providers to make this process faster and easier.
Deprescribing increased by 6.5% to 10.4% over usual care. Active discontinuation by primary care providers appeared to drive the results.
Discussion Themes
The adaptive trial design of the first NUDGE-EHR study helped inform the more traditional confirmation trial NUDGE-EHR-2.
The way EHR tools are used varies widely from provider to provider. Tools may be adapted over time so the tool works best for the individual provider.
Of the nearly 100 million U.S. adults with prediabetes, approximately 70% will progress to type 2 diabetes in their lifetime. The Diabetes Prevention Program (DPP), a gold-standard program focused on lifestyle interventions, has demonstrated a 58% reduction in diabetes incidence. However, an effort to implement the program nationally fails to reach 99% of eligible individuals.
The research team sought to investigate whether a fully automated, AI-based DPP could effectively replicate the outcomes of the human coach-based DPP and potentially bridge this access gap. This was the first trial comparing a fully automated versus human DPP. It adds to a limited evidence base evaluating AI interventions against established standards in medicine.
The research team found that the AI-driven DPP delivered without human intervention was non-inferior to the traditional human coach-based DPP. Participants in the AI-driven DPP arm had comparable health outcomes and adequate engagement – though they were less likely to express a preference for their intervention than those in the human coach-based arm. The study team concluded that diabetes prevention remains an implementation challenge, not an efficacy problem.
Discussion Themes
While absolute weight loss was modest when compared to the effect of new medications like GLP-1s, Dr. Dakis argued that lifestyle interventions remain more cost-effective and that future automation efforts may bridge the effectiveness gap.
In the future, large language models could bolster the trust and human connection lacking in fully automated digital interventions.
Sarah L. Cutrona, MD, MPH
Acting Director, Center for Health Optimization and Implementation Research (CHOIR)
VA Bedford Healthcare System
Professor, Division of Health Informatics and Implementation Science
Department of Population and Quantitative Health Sciences
UMass Chan Medical School
Keywords
Blood Pressure; Hypertension; Self-Management; Video; Texting; Black Americans; Veterans
Key Points
Black Americans experience disproportionate morbidity and mortality due to hypertension (HTN). Simultaneously, self-management is made more difficult by differential rates of diagnosis and treatment titration; decreased access to, trust in, and engagement with the healthcare system; and cost, access, and environmental barriers. This study sought to improve HTN control and self-management among about 600 Black Veterans by supplementing a preexisting video story intervention with longitudinal texting support.
Those in the intervention arm watched 5 video stories featuring other Black Veterans, chose their preferred storyteller, and received educational and interactive messages aligned with that storyteller. Those in the control arm received only interactive messages. The researchers hypothesized that peer stories would promote participants’ emotional engagement with the messages via a parasocial relationship with the storyteller, enhancing self-efficacy, influencing health behaviors and ultimately improving HTN control.
While participants in both arms saw marginal improvements in systolic and diastolic blood pressure (BP), there was no significant difference in the BP change between the arms. The intervention saw high treatment fidelity (92%) and sustained engagement, with over 55% of participants responding to texts through the end of the 6-month period. The researchers concluded that the interactive text messages, which were present in both arms, were an effective way to maintain engagement in a multi-month study and may serve as a useful strategy for future longitudinal interventions supporting Black Veterans.
Discussion Themes
The control group was intentionally kept active – i.e., received educational texts – to isolate the specific impact of storytelling rather than just the impact of receiving text messages.
The intervention was shaped by direct feedback from veteran consultants, who provided guidance on tone, word choice, and structure to ensure the messages felt authentic.
Attendees noted that negative studies are vital for informing future research and that the intervention provided valuable moments of outreach to a population facing socioeconomic vulnerabilities and isolation.
Lauralyn McIntyre, MD, FRCPC, MSc
Senior Scientist, Acute Care Research Program
Ottawa Hospital Research Institute
Professor, University of Ottawa
Monica Taljaard, PhD
Senior Scientist
Methodological and Implementation Research
Ottawa Hospital Research Institute
Full Professor, School of Epidemiology and Public Health
University of Ottawa
Crystalloid fluids are among the most common interventions administered to patients; they touch nearly every person admitted to the hospital. However, the evidence base to inform their use is limited. Few trials were done until this past decade, and recent trials tend to focus on the critically ill. Though those studies found very small clinical outcome differences between fluids, even a 0.5% reduction in death and hospital readmission translates to 2,500 lives and $5 million saved in Ottawa alone.
The study team sought to address this study question at the hospital/health system level by comparing the effects of two usual care fluids, normal saline and Ringer’s Lactate, on the death or readmission of all hospitalized patients. After a pilot trial indicated feasibility, they launched FLUID: a cluster-randomized, cross-over trial across four Ontario hospitals.
The FLUID trial found a 0.5% reduction in death in the patients that received Ringer’s Lactate. This is a small but clinically meaningful reduction, with major implications for mortality at the hospital and health care system level. The findings are limited by the study’s early termination due to the COVID-19 pandemic.
Discussion Themes
While there are theoretical benefits to multiple crossovers, including the mitigation of period effects, the logistical burden of restocking an entire hospital’s fluid supply more than once was insurmountable.
The study team used a composite endpoint that gave hospital readmission the same weight as death. McIntyre attributed this decision to the significance of readmission for their patient partners and to its status as an indicator of resource use and subsequent mortality risk.
Trials disrupted by crises such as a pandemic or supply chain issues may be salvaged by Bayesian sequential testing, which allows researchers to assess data continuously without alpha penalties.
FLUID exemplifies the importance of asking simple, high-impact research questions. It was also incredibly cost-effective, costing less than $400,000 (in Canadian dollars) to conduct.
John A. Dodson, MD, MPH
Associate Professor of Medicine and Population Health
Director, Geriatric Cardiology Program
Director, Cardiovascular Digital Health Laboratory
NYU Langone Health
NYU Grossman School of Medicine
Roughly half of patients with cardiovascular disease (CVD) are nonadherent with their medications. This occurs across conditions and for multiple reasons, including cost, side effects, lack of symptoms, and inconvenience. BETTER-BP, a phase 2, multisite trial, sought to test the effect of a lottery on antihypertensive adherence. The lottery intervention was based in behavioral economics, a field that represents a novel and potentially scalable approach to improving medication adherence.
In a safety-net population, the lottery doubled adequate antihypertensive medication adherence from baseline to 6 months. This did not translate to a significant reduction in office-measured systolic blood pressure (BP) and increased adherence was not sustained after the lottery was removed. Other strategies will likely be required for long-term behavior change.
BETTER-BP had pragmatic components and non-pragmatic components. It was pragmatic in that it utilized minimal exclusion criteria; took place in a real-world setting; used existing medications; paired study visits with regular ambulatory visits; and used the electronic health record to ascertain some measures. It was not pragmatic in that it utilized traditional informed consent; the intervention and monitoring strategies were not usual practice; and the primary outcome was measured via an in-person BP assessment.
Discussion Themes
Dr. Dodson noted that many trials of behavioral economics in CVD medication adherence have not had durable effects on either adherence or clinical outcomes. Even with trials that are positive, no intervention has been a “home run.”
The lottery payouts (ranging from $5 to $50) were based on an estimated daily value intended to influence behavior without being coercive or exceeding study budgets.
Recruitment for the trial was a challenge; the team made approximately 9,000 phone calls to reach their final sample of 400 participants.
Behavioral incentives might be better suited for time-limited interventions, such as smoking cessation, rather than the lifelong management required for conditions like hypertension.
