Impact of Anatomical and Viability-guided Completeness of Revascularization on Clinical Outcomes in Ischemic Cardiomyopathy.

BACKGROUND: Complete revascularization of coronary disease has been linked to improved outcomes in patients with preserved left ventricular (LV) function. OBJECTIVES: To identify the impact of complete revascularization in patients with severe LV dysfunction. METHODS: Patients enrolled in the REVIVED-BCIS2 trial were eligible if baseline/procedural angiograms and viability studies were available for analysis by independent core laboratories. Anatomical and viability-guided completeness of revascularization were measured by the coronary and myocardial revascularization indices (RIcoro and RImyo) respectively, where RIcoro=[change in BCIS Jeopardy Score (BCIS-JS)] / [baseline BCIS-JS] and RImyo=[number of revascularized viable segments] / [ number of viable segments supplied by diseased vessels]. The PCI group was classified as having complete or incomplete revascularization by median RIcoro and RImyo. The primary outcome was death or hospitalization for heart failure. RESULTS: Of 700 randomized patients, 670 were included. The baseline BCIS-JS and SYNTAX scores were 8 (6 to 10) and 22 (15 to 29) respectively. In those assigned to PCI, median RIcoro and RImyo values were 67% and 85%. Compared to the group assigned to optimal medical therapy alone, there was no difference in the likelihood of the primary outcome in those receiving complete anatomical or viability-guided revascularization (HR 0.90, 95% CI 0.62-1.32 and HR 0.95, 95% CI 0.66-1.35 respectively). A sensitivity analysis by residual SYNTAX score showed no association with outcome. CONCLUSIONS: In patients with severe left ventricular dysfunction, neither complete anatomical nor viability-guided revascularization were associated with improved event-free survival compared to incomplete revascularization or treatment with medical therapy alone.

Harnessing ecological theory to enhance ecosystem restoration.

Ecosystem restoration can increase the health and resilience of nature and humanity. As a result, the international community is championing habitat restoration as a primary solution to address the dual climate and biodiversity crises. Yet most ecosystem restoration efforts to date have underperformed, failed, or been burdened by high costs that prevent upscaling. To become a primary, scalable conservation strategy, restoration efficiency and success must increase dramatically. Here, we outline how integrating ten foundational ecological theories that have not previously received much attention - from hierarchical facilitation to macroecology - into ecosystem restoration planning and management can markedly enhance restoration success. We propose a simple, systematic approach to determining which theories best align with restoration goals and are most likely to bolster their success. Armed with a century of advances in ecological theory, restoration practitioners will be better positioned to more cost-efficiently and effectively rebuild the world's ecosystems and support the resilience of our natural resources.

Species eradication for ecosystem restoration.

Many of the world's ecosystems are under unprecedented stress as human pressures have escalated to be a dominant driver of ecosystem composition and condition. Direct impacts such as agriculture, extraction, and development are impacting vast swathes of land and ocean, while the effects of human-caused climate change are felt even in the most remote parts of marine and terrestrial wildernesses. These impacts are resulting in changes ranging from ecosystem collapse or replacement to novel mixes of species due to temperature-driven range shifts. While reducing human pressures is paramount for the future viability of vulnerable ecosystems, much attention is now also focused on whether degraded areas can be restored. Indeed, the UN has declared 2021-2030 the Decade on Ecosystem Restoration, which aims to "prevent, halt and reverse the degradation of ecosystems on every continent and in every ocean".

PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma.

Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma; DIPG), are uniformly fatal brain tumors that lack effective treatment. Analysis of CRISPR/Cas9 loss-of-function gene deletion screens identified PIK3CA and MTOR as targetable molecular dependencies across patient derived models of DIPG, highlighting the therapeutic potential of the blood-brain barrier-penetrant PI3K/Akt/mTOR inhibitor, paxalisib. At the human-equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic glucose feedback and increased insulin levels commensurate with patients using PI3K inhibitors. To exploit genetic dependence and overcome resistance while maintaining compliance and therapeutic benefit, we combined paxalisib with the antihyperglycemic drug metformin. Metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo, a common mechanism of PI3K-inhibitor resistance, extending survival of orthotopic models. DIPG models treated with paxalisib increased calcium-activated PKC signaling. The brain penetrant PKC inhibitor enzastaurin, in combination with paxalisib, synergistically extended the survival of multiple orthotopic patient-derived and immunocompetent syngeneic allograft models; benefits potentiated in combination with metformin and standard-of-care radiotherapy. Therapeutic adaptation was assessed using spatial transcriptomics and ATAC-Seq, identifying changes in myelination and tumor immune microenvironment crosstalk. Collectively, this study has identified what we believe to be a clinically relevant DIPG therapeutic combinational strategy.

Rethinking False Positive Exercise Electrocardiographic Stress Tests by Assessing Coronary Microvascular Function.

BACKGROUND: Exercise electrocardiographic stress testing (EST) has historically been validated against the demonstration of obstructive coronary artery disease. However, myocardial ischemia can occur because of coronary microvascular dysfunction (CMD) in the absence of obstructive coronary artery disease. OBJECTIVES: The aim of this study was to assess the specificity of EST to detect an ischemic substrate against the reference standard of coronary endothelium-independent and endothelium-dependent microvascular function in patients with angina with nonobstructive coronary arteries (ANOCA). METHODS: Patients with ANOCA underwent invasive coronary physiological assessment using adenosine and acetylcholine. CMD was defined as impaired endothelium-independent and/or endothelium-dependent function. EST was performed using a standard Bruce treadmill protocol, with ischemia defined as the appearance of ≥0.1-mV ST-segment depression 80 ms from the J-point on electrocardiography. The study was powered to detect specificity of ≥91%. RESULTS: A total of 102 patients were enrolled (65% women, mean age 60 ± 8 years). Thirty-two patients developed ischemia (ischemic group) during EST, whereas 70 patients did not (nonischemic group); both groups were phenotypically similar. Ischemia during EST was 100% specific for CMD. Acetylcholine flow reserve was the strongest predictor of ischemia during exercise. Using endothelium-independent and endothelium-dependent microvascular dysfunction as the reference standard, the false positive rate of EST dropped to 0%. CONCLUSIONS: In patients with ANOCA, ischemia on EST was highly specific of an underlying ischemic substrate. These findings challenge the traditional belief that EST has a high false positive rate.

Caregivers' and providers' perspectives of social and medical care after pediatric liver transplant: Results from the multicenter SOCIAL-Tx study.

Disparities exist in pediatric liver transplant (LT). We characterized barriers and facilitators to providing transplant and social care within pediatric LT clinics. This was a multicenter qualitative study. We oversampled caregivers reporting household financial strain, material economic hardship, or demonstrating poor health literacy. We also enrolled transplant team members. We conducted semistructured interviews with participants. Caregiver interviews focused on challenges addressing transplant and household needs. Transplant provider interviews focused on barriers and facilitators to providing social care within transplant teams. Interviews were recorded, transcribed, and coded according to the Capability, Opportunity, Motivation-Behavior model. We interviewed 27 caregivers and 27 transplant team members. Fifty-two percent of caregivers reported a household income <$60,000, and 62% reported financial resource strain. Caregivers reported experiencing (1) high financial burdens after LT, (2) added caregiving labor that compounds the financial burden, (3) dependency on their social network's generosity for financial and logistical support, and (4) additional support being limited to the perioperative period. Transplant providers reported (1) relying on the pretransplant psychosocial assessment for identifying social risks, (2) discomfort initiating social risk discussions in the post-transplant period, (3) reliance on social workers to address new social risks, and (4) social workers feeling overburdened by quantity and quality of the social work referrals. We identified barriers to providing effective social care in pediatric LT, primarily a lack of comfort in assessing and addressing new social risks in the post-transplant period. Addressing these barriers should enhance social care delivery and improve outcomes for these children.

Ambient air pollution is associated with graft failure/death in pediatric liver transplant recipients.

Children exposed to disproportionately higher levels of air pollution experience worse health outcomes. In this population-based, observational registry study, we examine the association between air pollution and graft failure/death in children following liver transplantation (LT) in the US. We modeled the associations between air pollution (PM2.5) levels localized to the patient's ZIP code at the time of transplant and graft failure or death using Cox proportional-hazards models in pediatric LT recipients aged <19 years in the US from 2005-2015. In univariable analysis, high neighborhood PM2.5 was associated with a 56% increased hazard of graft failure/death (HR: 1.56; 95% CI: 1.32, 1.83; P < .001). In multivariable analysis, high neighborhood PM2.5 was associated with a 54% increased risk of graft failure/death (HR: 1.54; 95% CI: 1.29, 1.83; P < .001) after adjusting for race as a proxy for racism, insurance status, rurality, and neighborhood socioeconomic deprivation. Children living in high air pollution neighborhoods have an increased risk of graft failure and death posttransplant, even after controlling for sociodemographic variables. Our findings add further evidence that air pollution contributes to adverse health outcomes for children posttransplant and lay the groundwork for future studies to evaluate underlying mechanisms linking PM2.5 to adverse LT outcomes.

Functional consequences of animal community changes in managed grasslands: An application of the CAFE approach.

In the midst of an ongoing biodiversity crisis, much research has focused on species losses and their impacts on ecosystem functioning. The functional consequences (ecosystem response) of shifts in communities are shaped not only by changes in species richness, but also by compositional shifts that result from species losses and gains. Species differ in their contribution to ecosystem functioning, so species identity underlies the consequences of species losses and gains on ecosystem functions. Such research is critical to better predict the impact of disturbances on communities and ecosystems. We used the "Community Assembly and the Functioning of Ecosystems" (CAFE) approach, a modification of the Price equation to understand the functional consequences and relative effects of richness and composition changes in small nonvolant mammal and dung beetle communities as a result of two common disturbances in North American prairie restorations, prescribed fire and the reintroduction of large grazing mammals. Previous research in this system has shown dung beetles are critically important decomposers, while small mammals modulate much energy in prairie food webs. We found that dung beetle communities were more responsive to bison reintroduction and prescribed fires than small nonvolant mammals. Dung beetle richness increased after bison reintroduction, with higher dung beetle community biomass resulting from changes in remaining species (context-dependent component) rather than species turnover (richness components); prescribed fire caused a minor increase in dung beetle biomass for the same reason. For small mammals, bison reintroduction reduced energy transfer through the loss of species, while prescribed fire had little impact on either small mammal richness or energy transfer. The CAFE approach demonstrates how bison reintroduction controls small nonvolant mammal communities by increasing prairie food web complexity, and increases dung beetle populations with possible benefits for soil health through dung mineralization and soil bioturbation. Prescribed fires, however, have little effect on small mammals and dung beetles, suggesting a resilience to fire. These findings illustrate the key role of re-establishing historical disturbance regimes when restoring endangered prairie ecosystems and their ecological function.

Herbivory limits success of vegetation restoration globally.

Restoring vegetation in degraded ecosystems is an increasingly common practice for promoting biodiversity and ecological function, but successful implementation is hampered by an incomplete understanding of the processes that limit restoration success. By synthesizing terrestrial and aquatic studies globally (2594 experimental tests from 610 articles), we reveal substantial herbivore control of vegetation under restoration. Herbivores at restoration sites reduced vegetation abundance more strongly (by 89%, on average) than those at relatively undegraded sites and suppressed, rather than fostered, plant diversity. These effects were particularly pronounced in regions with higher temperatures and lower precipitation. Excluding targeted herbivores temporarily or introducing their predators improved restoration by magnitudes similar to or greater than those achieved by managing plant competition or facilitation. Thus, managing herbivory is a promising strategy for enhancing vegetation restoration efforts.

Avirulent Isolates of Penicillium chrysogenum to Control the Blue Mold of Apple Caused by P. expansum.

Blue mold is an economically significant postharvest disease of pome fruit that is primarily caused by Penicillium expansum. To manage this disease and sustain product quality, novel decay intervention strategies are needed that also maintain long-term efficacy. Biocontrol organisms and natural products are promising tools for managing postharvest diseases. Here, two Penicillium chrysogenum isolates, 404 and 413, were investigated as potential biocontrol agents against P. expansum in apple. Notably, 404 and 413 were non-pathogenic in apple, yet they grew vigorously in vitro when compared to the highly aggressive P. expansum R19 and Pe21 isolates. Whole-genome sequencing and species-specific barcoding identified both strains as P. chrysogenum. Each P. chrysogenum strain was inoculated in apple with the subsequent co-inoculation of R19 or Pe21 simultaneously, 3, or 7 days after prior inoculation with 404 or 413. The co-inoculation of these isolates showed reduced decay incidence and severity, with the most significant reduction from the longer establishment of P. chrysogenum. In vitro growth showed no antagonism between species, further suggesting competitive niche colonization as the mode of action for decay reduction. Both P. chrysogenum isolates had incomplete patulin gene clusters but tolerated patulin treatment. Finally, hygromycin resistance was observed for both P. chrysogenum isolates, yet they are not multiresistant to apple postharvest fungicides. Overall, we demonstrate the translative potential of P. chrysogenum to serve as an effective biocontrol agent against blue mold decay in apples, pending practical optimization and formulation.

Viability and Outcomes With Revascularization or Medical Therapy in Ischemic Ventricular Dysfunction: A Prespecified Secondary Analysis of the REVIVED-BCIS2 Trial.

Importance: In the Revascularization for Ischemic Ventricular Dysfunction (REVIVED-BCIS2) trial, percutaneous coronary intervention (PCI) did not improve outcomes for patients with ischemic left ventricular dysfunction. Whether myocardial viability testing had prognostic utility for these patients or identified a subpopulation who may benefit from PCI remained unclear. Objective: To determine the effect of the extent of viable and nonviable myocardium on the effectiveness of PCI, prognosis, and improvement in left ventricular function. Design, Setting, and Participants: Prospective open-label randomized clinical trial recruiting between August 28, 2013, and March 19, 2020, with a median follow-up of 3.4 years (IQR, 2.3-5.0 years). A total of 40 secondary and tertiary care centers in the United Kingdom were included. Of 700 randomly assigned patients, 610 with left ventricular ejection fraction less than or equal to 35%, extensive coronary artery disease, and evidence of viability in at least 4 myocardial segments that were dysfunctional at rest and who underwent blinded core laboratory viability characterization were included. Data analysis was conducted from March 31, 2022, to May 1, 2023. Intervention: Percutaneous coronary intervention in addition to optimal medical therapy. Main Outcomes and Measures: Blinded core laboratory analysis was performed of cardiac magnetic resonance imaging scans and dobutamine stress echocardiograms to quantify the extent of viable and nonviable myocardium, expressed as an absolute percentage of left ventricular mass. The primary outcome of this subgroup analysis was the composite of all-cause death or hospitalization for heart failure. Secondary outcomes were all-cause death, cardiovascular death, hospitalization for heart failure, and improved left ventricular function at 6 months. Results: The mean (SD) age of the participants was 69.3 (9.0) years. In the PCI group, 258 (87%) were male, and in the optimal medical therapy group, 277 (88%) were male. The primary outcome occurred in 107 of 295 participants assigned to PCI and 114 of 315 participants assigned to optimal medical therapy alone. There was no interaction between the extent of viable or nonviable myocardium and the effect of PCI on the primary or any secondary outcome. Across the study population, the extent of viable myocardium was not associated with the primary outcome (hazard ratio per 10% increase, 0.98; 95% CI, 0.93-1.04) or any secondary outcome. The extent of nonviable myocardium was associated with the primary outcome (hazard ratio, 1.07; 95% CI, 1.00-1.15), all-cause death, cardiovascular death, and improvement in left ventricular function. Conclusions and Relevance: This study found that viability testing does not identify patients with ischemic cardiomyopathy who benefit from PCI. The extent of nonviable myocardium, but not the extent of viable myocardium, is associated with event-free survival and likelihood of improvement of left ventricular function. Trial Registration: ClinicalTrials.gov Identifier: NCT01920048.

An invasive appetite: Combining molecular and stable isotope analyses to reveal the diet of introduced house mice (Mus musculus) on a small, subtropical island.

House mice (Mus musculus) pose a conservation threat on islands, where they adversely affect native species' distributions, densities, and persistence. On Sand Island of Kuaihelani, mice recently began to depredate nesting adult moli (Laysan Albatross, Phoebastria immutabilis). Efforts are underway to eradicate mice from Sand Island, but knowledge of mouse diet is needed to predict ecosystem response and recovery following mouse removal. We used next-generation sequencing to identify what mice eat on Sand Island, followed by stable isotope analysis to estimate the proportions contributed by taxa to mouse diet. We collected paired fecal and hair samples from 318 mice between April 2018 to May 2019; mice were trapped approximately every eight weeks among four distinct habitat types to provide insight into temporal and spatial variation. Sand Island's mice mainly consume arthropods, with nearly equal (but substantially smaller) contributions of C3 plants, C4 plants, and moli. Although seabird tissue is a small portion of mouse diet, mice consume many detrital-feeding arthropods in and around seabird carcasses, such as isopods, flesh flies, ants, and cockroaches. Additionally, most arthropods and plants eaten by mice are non-native. Mouse diet composition differs among habitat types but changes minimally throughout the year, indicating that mice are not necessarily limited by food source availability or accessibility. Eradication of house mice may benefit seabirds on Sand Island (by removing a terrestrial, non-native predator), but it is unclear how arthropod and plant communities may respond and change. Non-native and invasive arthropods and plants previously consumed (and possibly suppressed) by mice may be released post-eradication, which could prevent recovery of native taxa. Comprehensive knowledge of target species' diet is a critical component of eradication planning. Dietary information should be used both to identify and to monitor which taxa may respond most strongly to invasive species removal and to assess if proactive, pre-eradication management activities are warranted.

Hold big business to task on ecosystem restoration.

Corporate reporting must embrace holistic, scientific principles.

Arrhythmia and Death Following Percutaneous Revascularization in Ischemic Left Ventricular Dysfunction: Prespecified Analyses From the REVIVED-BCIS2 Trial.

BACKGROUND: Ventricular arrhythmia is an important cause of mortality in patients with ischemic left ventricular dysfunction. Revascularization with coronary artery bypass graft or percutaneous coronary intervention is often recommended for these patients before implantation of a cardiac defibrillator because it is assumed that this may reduce the incidence of fatal and potentially fatal ventricular arrhythmias, although this premise has not been evaluated in a randomized trial to date. METHODS: Patients with severe left ventricular dysfunction, extensive coronary disease, and viable myocardium were randomly assigned to receive either percutaneous coronary intervention (PCI) plus optimal medical and device therapy (OMT) or OMT alone. The composite primary outcome was all-cause death or aborted sudden death (defined as an appropriate implantable cardioverter defibrillator therapy or a resuscitated cardiac arrest) at a minimum of 24 months, analyzed as time to first event on an intention-to-treat basis. Secondary outcomes included cardiovascular death or aborted sudden death, appropriate implantable cardioverter defibrillator (ICD) therapy or sustained ventricular arrhythmia, and number of appropriate ICD therapies. RESULTS: Between August 28, 2013, and March 19, 2020, 700 patients were enrolled across 40 centers in the United Kingdom. A total of 347 patients were assigned to the PCI+OMT group and 353 to the OMT alone group. The mean age of participants was 69 years; 88% were male; 56% had hypertension; 41% had diabetes; and 53% had a clinical history of myocardial infarction. The median left ventricular ejection fraction was 28%; 53.1% had an implantable defibrillator inserted before randomization or during follow-up. All-cause death or aborted sudden death occurred in 144 patients (41.6%) in the PCI group and 142 patients (40.2%) in the OMT group (hazard ratio, 1.03 [95% CI, 0.82-1.30]; P=0.80). There was no between-group difference in the occurrence of any of the secondary outcomes. CONCLUSIONS: PCI was not associated with a reduction in all-cause mortality or aborted sudden death. In patients with ischemic cardiomyopathy, PCI is not beneficial solely for the purpose of reducing potentially fatal ventricular arrhythmias. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01920048.

Midwifery care during labor and birth in the United States.

The intrapartum period is a crucial time in the continuum of pregnancy and parenting. Events during this time are shaped by individuals' unique sociocultural and health characteristics and by their healthcare providers, practice protocols, and the physical environment in which care is delivered. Childbearing people in the United States have less opportunity for midwifery care than in other high-income countries. In the United States, there are 4 midwives for every 1000 live births, whereas, in most other high-income countries, there are between 30 and 70 midwives. Furthermore, these countries have lower maternal and neonatal mortality rates and have consistently lower costs of care. National and international evidences consistently report that births attended by midwives have fewer interventions, cesarean deliveries, preterm births, inductions of labor, and more vaginal births after cesarean delivery. In addition, midwifery care is consistently associated with respectful care and high patient satisfaction. Midwife-physician collaboration exists along a continuum, including births attended independently by midwives, births managed in consultation with a physician, and births attended primarily by a physician with a midwife acting as consultant on the normal aspects of care. This expert review defined midwifery care and provided an overview of midwifery in the United States with an emphasis on the intrapartum setting. Health outcomes associated with midwifery care, specific models of intrapartum care, and workforce issues have been presented within national and international contexts. Recommendations that align with the integration of midwifery have been suggested to improve national outcomes and reduce pregnancy-related disparities.

ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma.

Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA mutations showed increased sensitivity to ONC201, whereas those harboring TP53 mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992. SIGNIFICANCE: PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib.

ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma.

Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9-11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA-mutations showed increased sensitivity to ONC201, while those harboring TP53-mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992.

Tracking the global application of conservation translocation and social attraction to reverse seabird declines.

The global loss of biodiversity has inspired actions to restore nature across the planet. Translocation and social attraction actions deliberately move or lure a target species to a restoration site to reintroduce or augment populations and enhance biodiversity and ecosystem resilience. Given limited conservation funding and rapidly accelerating extinction trajectories, tracking progress of these interventions can inform best practices and advance management outcomes. Seabirds are globally threatened and commonly targeted for translocation and social attraction ("active seabird restoration"), yet no framework exists for tracking these efforts nor informing best practices. This study addresses this gap for conservation decision makers responsible for seabirds and coastal management. We systematically reviewed active seabird restoration projects worldwide and collated results into a publicly accessible Seabird Restoration Database. We describe global restoration trends, apply a systematic process to measure success rates and response times since implementation, and examine global factors influencing outcomes. The database contains 851 active restoration events in 551 locations targeting 138 seabird species; 16% of events targeted globally threatened taxa. Visitation occurred in 80% of events and breeding occurred in 76%, on average 2 y after implementation began (SD = 3.2 y). Outcomes varied by taxonomy, with the highest and quickest breeding response rates for Charadriiformes (terns, gulls, and auks), primarily with social attraction. Given delayed and variable response times to active restoration, 5 y is appropriate before evaluating outcomes. The database and results serve as a model for tracking and evaluating restoration outcomes, and is applicable to measuring conservation interventions for additional threatened taxa.

Blockade of ROS production inhibits oncogenic signaling in acute myeloid leukemia and amplifies response to precision therapies.

Mutations in the type III receptor tyrosine kinase FLT3 are frequent in patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. AML is characterized by the overproduction of reactive oxygen species (ROS), which can induce cysteine oxidation in redox-sensitive signaling proteins. Here, we sought to characterize the specific pathways affected by ROS in AML by assessing oncogenic signaling in primary AML samples. The oxidation or phosphorylation of signaling proteins that mediate growth and proliferation was increased in samples from patient subtypes with FLT3 mutations. These samples also showed increases in the oxidation of proteins in the ROS-producing Rac/NADPH oxidase-2 (NOX2) complex. Inhibition of NOX2 increased the apoptosis of FLT3-mutant AML cells in response to FLT3 inhibitors. NOX2 inhibition also reduced the phosphorylation and cysteine oxidation of FLT3 in patient-derived xenograft mouse models, suggesting that decreased oxidative stress reduces the oncogenic signaling of FLT3. In mice grafted with FLT3 mutant AML cells, treatment with a NOX2 inhibitor reduced the number of circulating cancer cells, and combining FLT3 and NOX2 inhibitors increased survival to a greater extent than either treatment alone. Together, these data raise the possibility that combining NOX2 and FLT3 inhibitors could improve the treatment of FLT3 mutant AML.