A randomized trial of behavioral interventions yielding sustained reductions in distracted driving.

Distracted driving is responsible for nearly 1 million crashes each year in the United States alone, and a major source of driver distraction is handheld phone use. We conducted a randomized, controlled trial to compare the effectiveness of interventions designed to create sustained reductions in handheld use while driving (NCT04587609). Participants were 1,653 consenting Progressive® Snapshot® usage-based auto insurance customers ages 18 to 77 who averaged at least 2 min/h of handheld use while driving in the month prior to study invitation. They were randomly assigned to one of five arms for a 10-wk intervention period. Arm 1 (control) got education about the risks of handheld phone use, as did the other arms. Arm 2 got a free phone mount to facilitate hands-free use. Arm 3 got the mount plus a commitment exercise and tips for hands-free use. Arm 4 got the mount, commitment, and tips plus weekly goal gamification and social competition. Arm 5 was the same as Arm 4, plus offered behaviorally designed financial incentives. Postintervention, participants were monitored until the end of their insurance rating period, 25 to 65 d more. Outcome differences were measured using fractional logistic regression. Arm 4 participants, who received gamification and competition, reduced their handheld use by 20.5% relative to control (P < 0.001); Arm 5 participants, who additionally received financial incentives, reduced their use by 27.6% (P < 0.001). Both groups sustained these reductions through the end of their insurance rating period.

Experiment aversion does not appear to generalize.

Over the past decade, governments and organizations around the world have established behavioral insights teams advocating for randomized experiments. However, recent findings by M. N. Meyer et al., Proc. Natl. Acad. Sci. U.S.A. 116, 10723-10728 (2019) and P. R. Heck, C. F. Chabris, D. J. Watts, M. N. Meyer, Proc. Natl. Acad. Sci. U.S.A. 117, 18948-18950 (2020) suggest that people often rate randomized experiments as less appropriate than the policies they contain even when approving the implementation of either policy untested and when none of the individual policies is clearly superior. The authors warn that this could cause policymakers to avoid running large-scale field experiments or being transparent about running them and might contribute to an adverse heterogeneity bias in terms of who is participating in experiments. In one direct and six conceptual preregistered replications (total N = 5,200) of the previously published larger-effect studies, using the same main dependent variable but with variations in scenario wordings, recruitment platforms, and countries, and the addition of further measures to assess people's views, we test the generalizability and robustness of these findings. Together, we find that the original results do not appear to generalize. That is, our triangulation reveals insufficient evidence to conclude that people exhibit a common pattern of behavior that would be consistent with relative experiment aversion, thereby supporting recent findings by R. Mislavsky, B. Dietvorst, U. Simonsohn, Mark. Sci. 39, 1092-1104 (2020). Thus, policymakers may not need to be concerned about employing evidence-based practices more so than about universally implementing policies.

Quantifying the potential persuasive returns to political microtargeting.

Much concern has been raised about the power of political microtargeting to sway voters' opinions, influence elections, and undermine democracy. Yet little research has directly estimated the persuasive advantage of microtargeting over alternative campaign strategies. Here, we do so using two studies focused on U.S. policy issue advertising. To implement a microtargeting strategy, we combined machine learning with message pretesting to determine which advertisements to show to which individuals to maximize persuasive impact. Using survey experiments, we then compared the performance of this microtargeting strategy against two other messaging strategies. Overall, we estimate that our microtargeting strategy outperformed these strategies by an average of 70% or more in a context where all of the messages aimed to influence the same policy attitude (Study 1). Notably, however, we found no evidence that targeting messages by more than one covariate yielded additional persuasive gains, and the performance advantage of microtargeting was primarily visible for one of the two policy issues under study. Moreover, when microtargeting was used instead to identify which policy attitudes to target with messaging (Study 2), its advantage was more limited. Taken together, these results suggest that the use of microtargeting-combining message pretesting with machine learning-can potentially increase campaigns' persuasive influence and may not require the collection of vast amounts of personal data to uncover complex interactions between audience characteristics and political messaging. However, the extent to which this approach confers a persuasive advantage over alternative strategies likely depends heavily on context.

Digital public health interventions at scale: The impact of social media advertising on beliefs and outcomes related to COVID vaccines.

Public health organizations increasingly use social media advertising campaigns in pursuit of public health goals. In this paper, we evaluate the impact of about $40 million of social media advertisements that were run and experimentally tested on Facebook and Instagram, aimed at increasing COVID-19 vaccination rates in the first year of the vaccine roll-out. The 819 randomized experiments in our sample were run by 174 different public health organizations and collectively reached 2.1 billion individuals in 15 languages. We find that these campaigns are, on average, effective at influencing self-reported beliefs-shifting opinions close to 1% at baseline with a cost per influenced person of about $3.41. Combining this result with an estimate of the relationship between survey outcomes and vaccination rates derived from observational data yields an estimated cost per additional vaccination of about $5.68. There is further evidence that campaigns are especially effective at influencing users' knowledge of how to get vaccines. Our results represent, to the best of our knowledge, the largest set of online public health interventions analyzed to date.

Unconditional cash transfers reduce homelessness.

Homelessness is an economic and social crisis. In a cluster-randomized controlled trial, we address a core cause of homelessness-lack of money-by providing a one-time unconditional cash transfer of CAD$7,500 to each of 50 individuals experiencing homelessness, with another 65 as controls in Vancouver, BC. Exploratory analyses showed that over 1 y, cash recipients spent fewer days homeless, increased savings and spending with no increase in temptation goods spending, and generated societal net savings of $777 per recipient via reduced time in shelters. Additional experiments revealed public mistrust toward the ability of homeless individuals to manage money and demonstrated interventions to increase public support for a cash transfer policy using counter-stereotypical or utilitarian messaging. Together, this research offers a new approach to address homelessness and provides insights into homelessness reduction policies.

Cognitive Effects of Body Temperature During Hypothermic Circulatory Arrest Trial (GOT ICE): A Randomized Clinical Trial Comparing Outcomes After Aortic Arch Surgery.

BACKGROUND: Deep hypothermia has been the standard for hypothermic circulatory arrest (HCA) during aortic arch surgery. However, centers worldwide have shifted toward lesser hypothermia with antegrade cerebral perfusion. This has been supported by retrospective data, but there has yet to be a multicenter, prospective randomized study comparing deep versus moderate hypothermia during HCA. METHODS: This was a randomized single-blind trial (GOT ICE [Cognitive Effects of Body Temperature During Hypothermic Circulatory Arrest]) of patients undergoing arch surgery with HCA plus antegrade cerebral perfusion at 4 US referral aortic centers (August 2016-December 2021). Patients were randomized to 1 of 3 hypothermia groups: DP, deep (≤20.0 °C); LM, low-moderate (20.1-24.0 °C); and HM, high-moderate (24.1-28.0 °C). The primary outcome was composite global cognitive change score between baseline and 4 weeks postoperatively. Analysis followed the intention-to-treat principle to evaluate if: (1) LM noninferior to DP on global cognitive change score; (2) DP superior to HM. The secondary outcomes were domain-specific cognitive change scores, neuroimaging findings, quality of life, and adverse events. RESULTS: A total of 308 patients consented; 282 met inclusion and were randomized. A total of 273 completed surgery, and 251 completed the 4-week follow-up (DP, 85 [34%]; LM, 80 [34%]; HM, 86 [34%]). Mean global cognitive change score from baseline to 4 weeks in the LM group was noninferior to the DP group; likewise, no significant difference was observed between DP and HM. Noninferiority of LM versus DP, and lack of difference between DP and HM, remained for domain-specific cognitive change scores, except structured verbal memory, with noninferiority of LM versus DP not established and structured verbal memory better preserved in DP versus HM (P = 0.036). There were no significant differences in structural or functional magnetic resonance imaging brain imaging between groups postoperatively. Regardless of temperature, patients who underwent HCA demonstrated significant reductions in cerebral gray matter volume, cortical thickness, and regional brain functional connectivity. Thirty-day in-hospital mortality, major morbidity, and quality of life were not different between groups. CONCLUSIONS: This randomized multicenter study evaluating arch surgery HCA temperature strategies found low-moderate hypothermia noninferior to traditional deep hypothermia on global cognitive change 4 weeks after surgery, although in secondary analysis, structured verbal memory was better preserved in the deep group. The verbal memory differences in the low- and high-moderate groups and structural and functional connectivity reductions from baseline merit further investigation and suggest opportunities to further optimize brain perfusion during HCA. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02834065.

Quality of Life in Patients With Chronic Limb-Threatening Ischemia Treated With Revascularization.

BACKGROUND: In the BEST-CLI trial (Best Endovascular Versus Best Surgical Therapy for Patients With Chronic Limb-Threatening Ischemia), a prespecified secondary objective was to assess the effects of revascularization strategy on health-related quality of life (HRQoL). METHODS: Patients with chronic limb-threatening ischemia were randomized to surgical bypass (Bypass) or endovascular intervention (Endo) in 2 parallel trials. Cohort 1 included patients with single-segment great saphenous vein; cohort 2 included those lacking suitable single-segment great saphenous vein. HRQoL was assessed over the trial duration using Vascular Quality-of-Life (VascuQoL), European Quality-of-Life-5D (EQ-5D), the Short Form-12 (SF-12) Physical Component Summary (SF-12 PCS), SF-12 Mental Component Summary (SF-12 MCS), Utility Index Score (SF-6D R2), and numeric rating scales of pain. HRQoL was summarized by cohort and compared within and between groups using mixed-model linear regression. RESULTS: A total of 1193 and 335 patients in cohorts 1 and 2 with a mean follow-up of 2.9 and 2.0 years, respectively, were analyzed. In cohort 1, HRQoL significantly improved from baseline to follow-up for both groups across all measures. For example, mean (SD) VascuQoL scores were 3.0 (1.3) and 3.0 (1.2) for Bypass and Endo at baseline and 4.7 (1.4) and 4.8 (1.5) over follow-up. There were significant group differences favoring Endo when assessed with VascuQoL (difference, -0.14 [95% CI, -0.25 to -0.02]; P=0.02), SF-12 MCS (difference, -1.03 [95% CI, -1.89 to -0.18]; P=0.02), SF-6D R2 (difference, -0.01 [95% CI, -0.02 to -0.001]; P=0.03), numeric rating scale pain at present (difference, 0.26 [95% CI, 0.03 to 0.49]; P=0.03), usual level during previous week (difference, 0.26 [95% CI, 0.04 to 0.48]; P=0.02), and worst level during previous week (difference, 0.29 [95% CI, 0.02 to 0.56]; P=0.04). There was no difference between treatment arms on the basis of EQ-5D (difference, -0.01 [95% CI, -0.03 to 0.004]; P=0.12) or SF-12 PCS (difference, -0.41 [95% CI, -1.2 to 0.37]; P=0.31). In cohort 2, HRQoL also significantly improved from baseline to the end of follow-up for both groups based on all measures, but there were no differences between Bypass and Endo on any measure. CONCLUSIONS: Among patients with chronic limb-threatening ischemia deemed eligible for either Bypass or Endo, revascularization resulted in significant and clinically meaningful improvements in HRQoL. In patients with an available single-segment great saphenous vein for bypass, but not among those without one, Endo was statistically superior on some HRQoL measures; however, these differences were below the threshold of clinically meaningful difference.

Practical causal mediation analysis: extending nonparametric estimators to accommodate multiple mediators and multiple intermediate confounders.

Mediation analysis is appealing for its ability to improve understanding of the mechanistic drivers of causal effects, but real-world data complexities challenge its successful implementation, including (i) the existence of post-exposure variables that also affect mediators and outcomes (thus, confounding the mediator-outcome relationship), that may also be (ii) multivariate, and (iii) the existence of multivariate mediators. All three challenges are present in the mediation analysis we consider here, where our goal is to estimate the indirect effects of receiving a Section 8 housing voucher as a young child on the risk of developing a psychiatric mood disorder in adolescence that operate through mediators related to neighborhood poverty, the school environment, and instability of the neighborhood and school environments, considered together and separately. Interventional direct and indirect effects (IDE/IIE) accommodate post-exposure variables that confound the mediator-outcome relationship, but currently, no readily implementable nonparametric estimator for IDE/IIE exists that allows for both multivariate mediators and multivariate post-exposure intermediate confounders. The absence of such an IDE/IIE estimator that can easily accommodate both multivariate mediators and post-exposure confounders represents a significant limitation for real-world analyses, because when considering each mediator subgroup separately, the remaining mediator subgroups (or a subset of them) become post-exposure intermediate confounders. We address this gap by extending a recently developed nonparametric estimator for the IDE/IIE to allow for easy incorporation of multivariate mediators and multivariate post-exposure confounders simultaneously. We apply the proposed estimation approach to our analysis, including walking through a strategy to account for other, possibly co-occurring intermediate variables when considering each mediator subgroup separately.

Estimating causal effects for binary outcomes using per-decision inverse probability weighting.

Micro-randomized trials are commonly conducted for optimizing mobile health interventions such as push notifications for behavior change. In analyzing such trials, causal excursion effects are often of primary interest, and their estimation typically involves inverse probability weighting (IPW). However, in a micro-randomized trial, additional treatments can often occur during the time window over which an outcome is defined, and this can greatly inflate the variance of the causal effect estimator because IPW would involve a product of numerous weights. To reduce variance and improve estimation efficiency, we propose two new estimators using a modified version of IPW, which we call "per-decision IPW." The second estimator further improves efficiency using the projection idea from the semiparametric efficiency theory. These estimators are applicable when the outcome is binary and can be expressed as the maximum of a series of sub-outcomes defined over sub-intervals of time. We establish the estimators' consistency and asymptotic normality. Through simulation studies and real data applications, we demonstrate substantial efficiency improvement of the proposed estimator over existing estimators. The new estimators can be used to improve the precision of primary and secondary analyses for micro-randomized trials with binary outcomes.

Transient brain structure changes after high phenylalanine exposure in adults with phenylketonuria.

Phenylketonuria is a rare metabolic disease resulting from a deficiency of the enzyme phenylalanine hydroxylase. Recent cross-sectional evidence suggests that early-treated adults with phenylketonuria exhibit alterations in cortical grey matter compared to healthy peers. However, the effects of high phenylalanine exposure on brain structure in adulthood need to be further elucidated. In this double-blind, randomised, placebo-controlled crossover trial, we investigated the impact of a four-week high phenylalanine exposure on the brain structure and its relationship to cognitive performance and metabolic parameters in early-treated adults with phenylketonuria. Twenty-eight adult patients with early-treated classical phenylketonuria (19-48 years) underwent magnetic resonance imaging before and after the four-week phenylalanine and placebo interventions (four timepoints). Structural T1-weighted images were preprocessed and evaluated using DL+DiReCT, a deep-learning-based tool for brain morphometric analysis. Cortical thickness, white matter volume, and ventricular volume were compared between the phenylalanine and placebo periods. Brain phenylalanine levels were measured using 1H spectroscopy. Blood levels of phenylalanine, tyrosine, and tryptophan were assessed at each of the four timepoints, along with performance in executive functions and attention. Blood phenylalanine levels were significantly higher after the phenylalanine period (1441µmol/L) than after the placebo period (873µmol/L, P<0.001). Morphometric analyses revealed a statistically significant decrease in cortical thickness in 17 out of 60 brain regions after the phenylalanine period compared to placebo. The largest decreases were observed in the right pars orbitalis (point estimate=-0.095mm, P<0.001) and the left lingual gyrus (point estimate=-0.070mm, P<0.001). Bilateral white matter and ventricular volumes were significantly increased after the phenylalanine period. However, the structural alterations in the Phe-placebo group returned to baseline measures following the washout and placebo period. Additionally, elevated blood and brain phenylalanine levels were related to increased bilateral white matter volume (rs=0.43 to 0.51, P≤0.036) and decreased cortical thickness (rs=-0.62 to -0.39, not surviving FDR correction) after the phenylalanine and placebo periods. Moreover, decreased cortical thickness was correlated with worse cognitive performance after both periods (rs=-0.54 to -0.40, not surviving FDR correction). These findings provide evidence that a four-week high phenylalanine exposure in adults with phenylketonuria results in transient reductions of the cortical grey matter and increases in white matter volume. Further research is needed to determine the potential long-term impact of high phenylalanine levels on brain structure and function in adults with phenylketonuria.

Randomized CRISPR-Cas Transcriptional Perturbation Screening Reveals Protective Genes against Alpha-Synuclein Toxicity.

The genome-wide perturbation of transcriptional networks with CRISPR-Cas technology has primarily involved systematic and targeted gene modulation. Here, we developed PRISM (Perturbing Regulatory Interactions by Synthetic Modulators), a screening platform that uses randomized CRISPR-Cas transcription factors (crisprTFs) to globally perturb transcriptional networks. By applying PRISM to a yeast model of Parkinson's disease (PD), we identified guide RNAs (gRNAs) that modulate transcriptional networks and protect cells from alpha-synuclein (αSyn) toxicity. One gRNA identified in this screen outperformed the most protective suppressors of αSyn toxicity reported previously, highlighting PRISM's ability to identify modulators of important phenotypes. Gene expression profiling revealed genes differentially modulated by this strong protective gRNA that rescued yeast from αSyn toxicity when overexpressed. Human homologs of top-ranked hits protected against αSyn-induced cell death in a human neuronal PD model. Thus, high-throughput and unbiased perturbation of transcriptional networks via randomized crisprTFs can reveal complex biological phenotypes and effective disease modulators.

Household Air Pollution Interventions to Improve Health in Low- and Middle-Income Countries: An Official American Thoracic Society Research Statement.

Background: An estimated 3 billion people, largely in low- and middle-income countries, rely on unclean fuels for cooking, heating, and lighting to meet household energy needs. The resulting exposure to household air pollution (HAP) is a leading cause of pneumonia, chronic lung disease, and other adverse health effects. In the last decade, randomized controlled trials of clean cooking interventions to reduce HAP have been conducted. We aim to provide guidance on how to interpret the findings of these trials and how they should inform policy makers and practitioners.Methods: We assembled a multidisciplinary working group of international researchers, public health practitioners, and policymakers with expertise in household air pollution from within academia, the American Thoracic Society, funders, nongovernmental organizations, and global organizations, including the World Bank and the World Health Organization. We performed a literature search, convened four sessions via web conference, and developed consensus conclusions and recommendations via the Delphi method.Results: The committee reached consensus on 14 conclusions and recommendations. Although some trials using cleaner-burning biomass stoves or cleaner-cooking fuels have reduced HAP exposure, the committee was divided (with 55% saying no and 45% saying yes) on whether the studied interventions improved measured health outcomes.Conclusions: HAP is associated with adverse health effects in observational studies. However, it remains unclear which household energy interventions reduce exposure, improve health, can be scaled, and are sustainable. Researchers should engage with policy makers and practitioners working to scale cleaner energy solutions to understand and address their information needs.

The impact of a poverty reduction intervention on infant brain activity.

Early childhood poverty is a risk factor for lower school achievement, reduced earnings, and poorer health, and has been associated with differences in brain structure and function. Whether poverty causes differences in neurodevelopment, or is merely associated with factors that cause such differences, remains unclear. Here, we report estimates of the causal impact of a poverty reduction intervention on brain activity in the first year of life. We draw data from a subsample of the Baby's First Years study, which recruited 1,000 diverse low-income mother-infant dyads. Shortly after giving birth, mothers were randomized to receive either a large or nominal monthly unconditional cash gift. Infant brain activity was assessed at approximately 1 y of age in the child's home, using resting electroencephalography (EEG; n = 435). We hypothesized that infants in the high-cash gift group would have greater EEG power in the mid- to high-frequency bands and reduced power in a low-frequency band compared with infants in the low-cash gift group. Indeed, infants in the high-cash gift group showed more power in high-frequency bands. Effect sizes were similar in magnitude to many scalable education interventions, although the significance of estimates varied with the analytic specification. In sum, using a rigorous randomized design, we provide evidence that giving monthly unconditional cash transfers to mothers experiencing poverty in the first year of their children's lives may change infant brain activity. Such changes reflect neuroplasticity and environmental adaptation and display a pattern that has been associated with the development of subsequent cognitive skills.

Prevention of antimicrobial prescribing among infants following maternal vaccination against respiratory syncytial virus.

SignificanceStrategies to reduce consumption of antimicrobial drugs are needed to contain the growing burden of antimicrobial resistance. Respiratory syncytial virus (RSV) is a prominent cause of upper and lower respiratory tract infections, as a single agent and in conjunction with bacterial pathogens, and may thus contribute to the burden of both inappropriately treated viral infections and appropriately treated polymicrobial infections involving bacteria. In a double-blind, randomized, placebo-controlled trial, administering an RSV vaccine to pregnant mothers reduced antimicrobial prescribing among their infants by 12.9% over the first 3 mo of life. Our findings implicate RSV as an important contributor to antimicrobial exposure among infants and demonstrate that this exposure is preventable by use of effective maternal vaccines against RSV.

The causal effect of a family planning intervention on women's contraceptive use and birth spacing.

Studies have suggested that improving access to family planning (FP) may improve contraceptive use and reduce fertility. However, high-quality evidence, particularly from randomized implementation trials, of the effect of FP programs and interventions on longer-term fertility and birth spacing is lacking. We conduct a nonblinded, randomized, controlled trial to assess the causal impact of improved access to FP on contraceptive use and pregnancy spacing in Lilongwe, Malawi. A total of 2,143 married women aged 18 to 35 who were either pregnant or had recently given birth were recruited through home visits between September 2016 and January 2017 and were randomly assigned to an intervention arm or a control arm. The intervention arm received four services over a 2-y period: 1) up to six FP counseling sessions; 2) free transportation to an FP clinic; 3) free FP services at the clinic or financial reimbursement for FP services obtained elsewhere; and 4) treatment for contraceptive-related side effects. Contraceptive use after 2 y of intervention exposure increased by 5.9 percentage points, mainly through an increased use of contraceptive implants. The intervention group's hazard of pregnancy was 43.5% lower 24 mo after the index birth. Our results highlight the positive impact of increased access to FP on a woman's contraceptive use. In addition, we show that exposure to the FP intervention led to a prolongation of birth intervals among intervention women relative to control women and increased her control over birth spacing and postpartum fertility, which, in turn, may contribute to her longer-term health and well-being.

Reforming the police through procedural justice training: A multicity randomized trial at crime hot spots.

SignificanceOur study is a randomized trial in policing confirming that intensive training in procedural justice (PJ) can lead to more procedurally just behavior and less disrespectful treatment of people at high-crime places. The fact that the PJ intervention reduced arrests by police officers, positively influenced residents' perceptions of police harassment and violence, and also reduced crime provides important guidance for police reform in a period of strong criticism of policing. This randomized trial points to the potential for PJ training not simply to encourage fair and respectful policing but also to improve evaluations of the police and crime prevention effectiveness.

Colchicine in acutely decompensated heart failure: the COLICA trial.

BACKGROUND AND AIMS: Acute heart failure (AHF) promotes inflammatory activation, which is associated with worse outcomes. Colchicine has proven effective in other cardiovascular conditions characterized by inflammatory activation, but has never been evaluated in the setting of AHF. METHODS: This multicenter, randomized, double-blind and placebo-controlled trial included patients with AHF, requiring ≥40 mg of intravenous furosemide, regardless of their left ventricular ejection fraction (LVEF) and inpatient or outpatient setting. Patients were randomized within the first 24 hours of presentation to receive either colchicine or placebo, with loading dose of 2 mg followed by 0.5 mg every 12 hours for 8 weeks. RESULTS: A total of 278 patients (median age 75 years, LVEF 40%, baseline N-terminal pro-B-type natriuretic peptide [NT-proBNP] 4390 pg/mL) were randomized to colchicine (n=141) or placebo (n=137). The primary endpoint, the time-averaged reduction in NT-proBNP levels at 8 weeks, did not differ between the colchicine group (-62.2%, 95% confidence interval [CI] -68.9% to -54.2%) and the placebo group (-62.1%, 95% CI -68.6% to -54.3%) (ratio of change 1.0). The reduction in inflammatory markers was significantly greater with colchicine: ratio of change 0.60 (p<0.001) for C-reactive protein and 0.72 (p=0.019) for interleukin-6. No differences were found in new worsening heart failure episodes (14.9% with colchicine vs. 16.8% with placebo, p=0.698); however, the need for intravenous furosemide during follow-up was lower with colchicine (p=0.043). Diarrhea was slightly more common with colchicine, but it did not result in differences in medication withdrawal (8.5% vs. 8.8%). CONCLUSIONS: Colchicine was safe and effective in reducing inflammation in patients with AHF, however colchicine and placebo exhibited comparable effects on reducing NT-proBNP and preventing new worsening heart failure events.

Pulmonary artery pressure monitoring in chronic heart failure: effects across clinically relevant subgroups in the MONITOR-HF trial.

BACKGROUND AND AIMS: In patients with chronic heart failure (HF), the MONITOR-HF trial demonstrated the efficacy of pulmonary artery (PA)-guided HF therapy over standard of care in improving quality of life and reducing HF hospitalizations and mean PA pressure. This study aimed to evaluate the consistency of these benefits in relation to clinically relevant subgroups. METHODS: The effect of PA-guided HF therapy was evaluated in the MONITOR-HF trial among predefined subgroups based on age, sex, atrial fibrillation, diabetes mellitus, left ventricular ejection fraction, HF aetiology, cardiac resynchronization therapy, and implantable cardioverter defibrillator. Outcome measures were based upon significance in the main trial and included quality of life-, clinical-, and PA pressure endpoints, and were assessed for each subgroup. Differential effects in relation to the subgroups were assessed with interaction terms. Both unadjusted and multiple testing adjusted interaction terms were presented. RESULTS: The effects of PA monitoring on quality of life, clinical events, and PA pressure were consistent in the predefined subgroups, without any clinically relevant heterogeneity within or across all endpoint categories (all adjusted interaction P-values were non-significant). In the unadjusted analysis of the primary endpoint quality-of-life change, weak trends towards a less pronounced effect in older patients (Pinteraction = .03; adjusted Pinteraction = .33) and diabetics (Pinteraction = .01; adjusted Pinteraction = .06) were observed. However, these interaction effects did not persist after adjusting for multiple testing. CONCLUSIONS: This subgroup analysis confirmed the consistent benefits of PA-guided HF therapy observed in the MONITOR-HF trial across clinically relevant subgroups, highlighting its efficacy in improving quality of life, clinical, and PA pressure endpoints in chronic HF patients.

Intravenous iron for heart failure, iron deficiency definitions, and clinical response: the IRONMAN trial.

BACKGROUND AND AIMS: What is the relationship between blood tests for iron deficiency, including anaemia, and the response to intravenous iron in patients with heart failure? METHODS: In the IRONMAN trial, 1137 patients with heart failure, ejection fraction ≤ 45%, and either serum ferritin < 100 µg/L or transferrin saturation (TSAT) < 20% were randomized to intravenous ferric derisomaltose (FDI) or usual care. Relationships were investigated between baseline anaemia severity, ferritin and TSAT, to changes in haemoglobin from baseline to 4 months, Minnesota Living with Heart Failure (MLwHF) score and 6-minute walk distance achieved at 4 months, and clinical events, including heart failure hospitalization (recurrent) or cardiovascular death. RESULTS: The rise in haemoglobin after administering FDI, adjusted for usual care, was greater for lower baseline TSAT (Pinteraction < .0001) and ferritin (Pinteraction = .028) and more severe anaemia (Pinteraction = .014). MLwHF scores at 4 months were somewhat lower (better) with FDI for more anaemic patients (overall Pinteraction = .14; physical Pinteraction = .085; emotional Pinteraction = .043) but were not related to baseline TSAT or ferritin. Blood tests did not predict difference in achieved walking distance for those randomized to FDI compared to control. The absence of anaemia or a TSAT ≥ 20% was associated with lower event rates and little evidence of benefit from FDI. More severe anaemia or TSAT < 20%, especially when ferritin was ≥100 µg/L, was associated with higher event rates and greater absolute reductions in events with FDI, albeit not statistically significant. CONCLUSIONS: This hypothesis-generating analysis suggests that anaemia or TSAT < 20% with ferritin > 100 µg/L might identify patients with heart failure who obtain greater benefit from intravenous iron. This interpretation requires confirmation.

Thromboxane biosynthesis and future events in diabetes: the ASCEND trial.

BACKGROUND AND AIMS: Thromboxane (TX) A2, released by activated platelets, plays an important role in atherothrombosis. Urinary 11-dehydro-TXB2 (U-TXM), a stable metabolite reflecting the whole-body TXA2 biosynthesis, is reduced by ∼70% by daily low-dose aspirin. The U-TXM represents a non-invasive biomarker of in vivo platelet activation and is enhanced in patients with diabetes. This study assessed whether U-TXM is associated with the risk of future serious vascular events or revascularizations (SVE-R), major bleeding, or cancer in patients with diabetes. METHODS: The U-TXM was measured pre-randomization to aspirin or placebo in 5948 people with type 1 or 2 diabetes and no cardiovascular disease, in the ASCEND trial. Associations between log U-TXM and SVE-R (n = 618), major bleed (n = 206), and cancer (n = 700) during 6.6 years of follow-up were investigated by Cox regression; comparisons of these associations with the effects of randomization to aspirin were made. RESULTS: Higher U-TXM was associated with older age, female sex, current smoking, type 2 diabetes, higher body size, urinary albumin/creatinine ratio of ≥3 mg/mmol, and higher estimated glomerular filtration rate. After adjustment for these, U-TXM was marginally statistically significantly associated with SVE-R and major bleed but not cancer [hazard ratios per 1 SD higher log U-TXM (95% confidence interval): 1.09 (1.00-1.18), 1.16 (1.01-1.34), and 1.06 (0.98-1.14)]. The hazard ratio was similar to that implied by the clinical effects of randomization to aspirin for SVE-R but not for major bleed. CONCLUSIONS: The U-TXM was log-linearly independently associated with SVE-R in diabetes. This is consistent with the involvement of platelet TXA2 in diabetic atherothrombosis.