Tracking activities and adaptations in a multi-site stepped wedge pragmatic trial of a cancer symptom management intervention.

Background: Pragmatic trials may need to adapt interventions to enhance local fit, and adaptation tracking is critical to evaluation. This study describes the tracking approach for a multisite, stepped-wedge hybrid pragmatic trial testing implementation and effectiveness of a cancer symptom management intervention. Methods: Study activities were documented in a spreadsheet by date and category. Intervention adaptations were tracked across multiple workgroups in a database structured around the Framework for Reporting Adaptations and Modifications-Expanded (FRAME) domains, e.g., reasons for change. Implementation strategies were tracked longitudinally and by cluster in a database using the Longitudinal Implementation Strategy Tracking System (LISTS) method. A logic model was created at the end of the study to describe core intervention components and implementation strategies with dates of adaptations. Results: Between January 2019 and January 2023, 187 study activities were documented. Most intervention activities took place early, but there were important intervention refinements during the course of the trial, including the expansion of interventionist roles to add two new disciplines. Eleven intervention adaptations were documented. Most were unplanned and aimed at improving fit or increasing engagement. Thirty-three implementation strategies were documented, the largest number of which were related to educating stakeholders. Most (but not all) component and strategy additions were consistent with the mechanisms of change as hypothesized at trial launch. Conclusions: A multifaceted approach to adaptation tracking, combined with a logic model, supported identification of meaningful changes for use in evaluation, but further work is needed to minimize burden and ensure robust and practical systems that inform both evaluation and timely decision-making. Trial: Registration: ClinicalTrials.gov, NCT03892967. Registered on March 25, 2019. https://www.clinicaltrials.gov/.

Comparative transcriptomics coupled to developmental grading via transgenic zebrafish reporter strains identifies conserved features in neutrophil maturation.

Neutrophils are evolutionarily conserved innate immune cells playing pivotal roles in host defense. Zebrafish models have contributed substantially to our understanding of neutrophil functions but similarities to human neutrophil maturation have not been systematically characterized, which limits their applicability to studying human disease. Here we show, by generating and analysing transgenic zebrafish strains representing distinct neutrophil differentiation stages, a high-resolution transcriptional profile of neutrophil maturation. We link gene expression at each stage to characteristic transcription factors, including C/ebp-ß, which is important for late neutrophil maturation. Cross-species comparison of zebrafish, mouse, and human samples confirms high molecular similarity of immature stages and discriminates zebrafish-specific from pan-species gene signatures. Applying the pan-species neutrophil maturation signature to RNA-sequencing data from human neuroblastoma patients reveals association between metastatic tumor cell infiltration in the bone marrow and an overall increase in mature neutrophils. Our detailed neutrophil maturation atlas thus provides a valuable resource for studying neutrophil function at different stages across species in health and disease.

Generation of an NCS1 gene knockout human induced pluripotent stem cell line using CRISPR/Cas9.

NCS1 (Neuronal calcium sensor protein 1) encodes a highly conserved calcium binding protein abundantly expressed in neurons. It modulates intracellular calcium homeostasis, calcium-dependent signaling pathways as well as neuronal transmission and plasticity. Here, we generated a NCS1 knockout human induced pluripotent stem cell (hiPSC) line using CRISPR-Cas9 genome editing. It shows regular expression of pluripotent markers, normal iPSC morphology and karyotype as well as no detectable off-target effects on top 6 potentially affected genes. This newly generated cell line constitutes a valuable tool for studying the role of NCS1 in the pathophysiology of various neuropsychiatric disorders and non-neurological disease.

The Interplay Between Group Identity, Suicidality, and Bullying in Midwestern Middle School Youth, 18-42.

Bullying peaks in middle school and is a risk factor for negative mental health outcomes, including suicidality. Suicide rates are higher in nonmetropolitan/rural areas and for American Indian/Alaska Natives compared to other racial/ethnic groups. Stigma-related bullying, a type of interpersonal discrimination, is increasingly considered an important driver of peer victimization. This study centers on the group identity characteristics of race/ethnicity, weight status, and sex to explore how school-based and electronic-bullying victimization mediate suicidality amongst a cohort of middle school students in North Dakota. Bivariate, multivariate, and structural equation modeling were performed using data from the 2015 North Dakota Middle School Youth Risk Behavior Survey. Minoritized race/ethnicity, very overweight, and female students all experienced statistically higher suicidality than comparison groups, mediated in some instances by bullying. Group identity, stigma, and discrimination may influence suicidality in North Dakota middle school youth. More information is needed on stigma and discrimination, including intersections of identity, as drivers of bullying and suicidality in minoritized youth in nonmetropolitan/rural areas.

A model of weight-based stigma in health care and utilization outcomes: Evidence from the learning health systems network.

Objective: Obesity is stigmatized and people with obesity report experiencing stigmatizing situations when seeking health care. The implications of these experiences are not well understood. This study tests an indirect effects model of negative care experiences as an intermediate variable between obesity and care avoidance/utilization and switching primary care doctors. Methods: A survey was completed by 2380 primary care patients in the Learning Health Systems Network (LHSNet) Clinical Data Research Network with a BMI >25 kg/m2. Measures included scales assessing stigmatizing situations, perceived patient-centered communication, perceived respect, having delayed needed care, and having looked for a new primary doctor in the past 12 months. Sequential and serial indirect effects of care experiences and respect in the association between BMI and care utilization outcomes was modeled. Results: The hypothesized model was supported by findings. The associations between BMI and delaying needed care (OR = 1.06, p < 0.001) and attempting to switch primary doctors (OR = 1.02, p = 0.04) was mediated by both stigmatizing situations experienced in a health care context and lower patient-centered communication. Lower perceived respect mediated the association between care experiences and utilization outcomes. Conclusions: People with higher BMIs may avoid care or switch doctors as a result of stigmatizing experiences and poor communication with doctors. These outcomes may contribute to morbidity in people with obesity if they delay or avoid care for health concerns when symptoms first present.

A hybrid method of healthcare delivery research and human-centered design to develop technology-enabled support for caregivers of hematopoietic stem cell transplant recipients.

Health information technology (HIT) is a widely recognized strategy to encourage cancer patients and caregivers to participate in healthcare delivery in a sustainable and cost-effective way. In the context of autologous hematopoietic cell transplant (HSCT), HIT-enabled tools have the potential to effectively engage, educate, support, and optimize outcomes of patients and caregivers in the outpatient setting. This study sought to leverage human-centered design to develop a high-fidelity prototype of a HIT-enabled psychoeducational tool for HSCT caregivers. Phase 1 focuses on breadth and depth of information gathering through a systematic review and semi-structured interviews to determine optimal tool use. Phase 2 engages in human-centered design synthesis and visualization methods to identify key opportunities for the HIT design. Phase 3 employs human-centered design evaluation, engaging caregivers to respond to low-fidelity concepts and scenarios to help co-design an optimal tool for HSCT. This study outlines a hybrid method of healthcare delivery research and human-centered design to develop technology-enabled support for HSCT caregivers. Herein, we present a design methodology for developing a prototype of HIT-enabled psychoeducational tool which can be leveraged to develop future eHealth innovations to optimize HSCT.

Reusability of autoclaved 3D printed polypropylene compared to a glass filled polypropylene composite.

Health care waste can be a costly expenditure for facilities as specific disposal methods must be used to prevent the spread of pathogens. If more multi-use medical devices were available, it could potentially relieve some of this burden; however, sterilization between uses is important in preventing disease transmission. 3D printing has the ability to easily create custom medical devices at a low cost, but the majority of filaments utilized cannot survive steam sterilization. Polypropylene (PP) can withstand autoclave temperatures, but is difficult to print as it warps and shrinks during printing; however, a composite PP filament reduces these effects. Commercially available PP and glass filled PP (GFPP) filaments were successfully 3D printed into 30 × 30 × 30 mm cubes with no shrinking or warping and were autoclaved. The 134 °C autoclave temperature was too high as several cubes melted after two to three rounds, but both PP and GFPP cubes displayed minimal changes in mass and volume after one, four, seven, and ten rounds of autoclaving at 121 °C. GFPP cubes autoclaved zero, four, seven, and ten times had significantly smaller average compressive stress values compared to all PP groups, but the GFPP cubes autoclaved once were only less than PP cubes autoclaved zero, seven and ten times. GFPP cubes autoclaved zero, one, four, and seven times also deformed less indicating that the embedded glass fibers provided additional strength. While a single method was found that successfully printed PP and GFPP cubes that were able to survive up to ten rounds of autoclaving, future work should include further investigation into the mechanical properties and increasing the number of autoclave rounds.

Generation of 20 human induced pluripotent stem cell lines from patients with focal segmental glomerulosclerosis (FSGS).

Focal segmental glomerulosclerosis (FSGS) is a major cause of familial nephrotic syndrome. We generated 20 induced pluripotent stem cell lines from patients diagnosed with FSGS. The iPSC lines include 8 female and 12 male lines and cover a donor age range from 31 to 78. The lines were generated from peripheral blood mononuclear cells by integration-free reprogramming using Sendai virus vectors. Cell lines were fully characterized regarding their pluripotency and differentiation potential, and quality controlled for karyotypic integrity, identity and clearance of reprogramming vectors. The generated cell lines represent a valuable tool for disease modelling and drug development for FSGS.

Successful Use of Telemedicine Infectious Diseases Consultation With an Antimicrobial Stewardship-Led Staphylococcus aureus Bacteremia Care Bundle.

BACKGROUND: Telemedicine (TM) programs can be implemented to deliver specialty care through virtual platforms and overcome geographic/resource constraints. Few data exist to describe outcomes associated with TM-based infectious diseases (ID) management. The purpose of this study was to compare outcomes associated with TM and onsite standard-of-care (SOC) ID consultation after implementation of an antimicrobial stewardship (AMS)-led Staphylococcus aureus bacteremia (SAB) bundle. METHODS: A retrospective cohort study was conducted on the effects of a SAB bundle comparing ID consult delivery (SOC or TM) at 10 US hospitals within Atrium Health in adult patients admitted from September 2016 through December 2017. The type of ID consult provided was based on the admitting hospital; no hospital had both modalities. Bundle components included the following: (1) ID consult, (2) appropriate antibiotics, (3) repeat blood cultures until clearance, (4) echocardiogram obtainment, and (5) appropriate antibiotic duration. The AMS facilitated bundle initiation and compliance. The primary outcome was bundle adherence between groups. Differences in clinical outcomes were also assessed. RESULTS: We evaluated 738 patients with SAB (576 with SOC, 162 with TM ID). No differences were observed in overall bundle adherence (SOC 86% vs TM 89%, P = .33). In addition, no significant differences resulted between groups for hospital mortality, 30-day SAB-related readmission, persistent bacteremia, and culture clearance. Groups did not differ in 30-day mortality when controlling for demographics, bacteremia source, and physiological measures with multivariable logistic regression. CONCLUSIONS: Our findings provide evidence to support effective use of TM ID consultation and AMS-led care bundles for SAB management in resource-limited settings.

Generation of human induced pluripotent stem cell lines from 2 patients with MIRAGE syndrome.

MIRAGE syndrome is a multisystem disorder caused by mutations in SAMD9 (sterile α motif domain-containing protein 9) with a high mortality in the first decade of life. We generated 2 human induced pluripotent stem cell lines from male children diagnosed with MIRAGE syndrome. The cell lines were generated from fibroblasts by integration-free reprogramming using the Sendai virus. Both cell lines were fully characterized regarding their pluripotent identity and differentiation potential, and quality controlled for karyotypic integrity, cell line identity and clearance of reprogramming vectors. The generated cell lines represent a valuable tool to study the disease mechanism of MIRAGE syndrome.

National Survey of Patient Factors Associated with Colorectal Cancer Screening Preferences.

Recommended colorectal cancer screening modalities vary with respect to safety, efficacy, and cost. Better understanding of the factors that influence patient preference is, therefore, critical for improving population adherence to colorectal cancer screening. To address this knowledge gap, we conducted a panel survey focused on three commonly utilized colorectal cancer screening options [fecal immunochemical test or guaiac-based fecal occult blood test (FIT/gFOBT), multi-target stool DNA (mt-sDNA) test, and colonoscopy] with a national sample of U.S. adults, ages 40-75 years and at average risk of colorectal cancer, in November 2019. Of 5,097 panelists invited to participate, 1,595 completed the survey (completion rate, 31.3%). Our results showed that when presented a choice between two colorectal cancer screening modalities, more respondents preferred mt-sDNA (65.4%) over colonoscopy, FIT/gFOBT (61%) over colonoscopy, and mt-sDNA (66.9%) over FIT/gFOBT. Certain demographic characteristics and awareness of and/or experience with various screening modalities influenced preferences. For example, uninsured people were more likely to prefer stool-based tests over colonoscopy [OR, 2.53; 95% confidence interval (CI), 1.22-5.65 and OR, 2.73; 95% CI, 1.13-7.47]. People who had heard of stool-based screening were more likely to prefer mt-sDNA over FIT/gFOBT (OR, 2.07; 95% CI, 1.26-3.40). People who previously had a stool-based test were more likely to prefer FIT/gFOBT over colonoscopy (OR, 2.75; 95% CI, 1.74-4.41), while people who previously had a colonoscopy were less likely to prefer mt-sDNA or FIT/gFOBT over colonoscopy (OR, 0.39; 95% CI, 0.24-0.63 and OR, 0.40; 95% CI, 0.26-0.62). Our survey demonstrated broad patient preference for stool-based tests over colonoscopy, contrasting the heavy reliance on colonoscopy for colorectal cancer screening in clinical practice and highlighting the importance of considering patient preference in colorectal cancer screening recommendations. PREVENTION RELEVANCE: Our national survey demonstrated broad patient preference for stool-based tests over colonoscopy, contrasting the heavy reliance on colonoscopy for colorectal cancer screening in clinical practice and highlighting the importance of considering patient preference in colorectal screening recommendations.

Using Critical Analysis of Scientific Literature to Maintain an Interactive Learning Environment for In-Person and Online Course Modalities.

Every instructor has concerns about effectively balancing the amount of course content with experiences to enhance a student's skills for professional success. The COVID-19 pandemic made this process even more challenging by requiring many instructors to shift rapidly from in-person to online instruction while maintaining academic integrity. The objective of this course on tissue engineering, a multidisciplinary field that aims to repair and/or replace body damage, was to increase undergraduate students' ability to read primary scientific literature and use critical analysis to creatively solve problems. Every week, a lecture covered the necessary background information to identify the current research questions and prepare students for reading the assigned research article. Students completed an analysis worksheet prior to the subsequent class, and a summary presentation followed by a student-led critical analysis discussion occurred in class. Small student groups completed an in-class thought exercise that designed several experiments that built on the article's data. The modular course design enabled a quick and successful transition to an online asynchronous modality in less than two weeks due to the COVID-19 pandemic. A recorded weekly lecture was posted online by the instructor, and students completed the analysis worksheet, watched a student-recorded summary presentation, and posted to a discussion board. The experimental design worksheet became an individual assignment to provide more flexibility. Pretransition and posttransition assessment showed no significant differences and provided positive proof of concept evidence. This process can be adapted to a number of topic-themed scientific courses that use in-person, online, or hybrid modalities.

ActivinA Induced SMAD1/5 Signaling in an iPSC Derived EC Model of Fibrodysplasia Ossificans Progressiva (FOP) Can Be Rescued by the Drug Candidate Saracatinib.

Balanced signal transduction is crucial in tissue patterning, particularly in the vasculature. Heterotopic ossification (HO) is tightly linked to vascularization with increased vessel number in hereditary forms of HO, such as Fibrodysplasia ossificans progressiva (FOP). FOP is caused by mutations in the BMP type I receptor ACVR1 leading to aberrant SMAD1/5 signaling in response to ActivinA. Whether observed vascular phenotype in human FOP lesions is connected to aberrant ActivinA signaling is unknown. Blocking of ActivinA prevents HO in FOP mice indicating a central role of the ligand in FOP. Here, we established a new FOP endothelial cell model generated from induced pluripotent stem cells (iECs) to study ActivinA signaling. FOP iECs recapitulate pathogenic ActivinA/SMAD1/5 signaling. Whole transcriptome analysis identified ActivinA mediated activation of the BMP/NOTCH pathway exclusively in FOP iECs, which was rescued to WT transcriptional levels by the drug candidate Saracatinib. We propose that ActivinA causes transcriptional pre-patterning of the FOP endothelium, which might contribute to differential vascularity in FOP lesions compared to non-hereditary HO.

The role of weight bias and role-modeling in medical students' patient-centered communication with higher weight standardized patients.

OBJECTIVE: Patients with obesity may experience less patient-centered care. We assessed whether medical students' implicit/explicit weight-related attitudes and perceptions of normative attitudes are associated with patient-centered care for patients with obesity. METHODS: Third and fourth year medical students (N = 111) at one medical school completed a survey and participated in a patient care scenario with a standardized patient with obesity. Encounters were coded for patient-centered behavior. Predictors of patient-centered behaviors were assessed. RESULTS: Student perceptions that negative attitudes about patients with obesity are normative in medical school were significantly associated with poorer patient-centered behaviors, including lower attentiveness (b=-0.19, p = 0.01), friendliness (b=-0.28, p < 0.001), responsiveness (b=-0.21, p = 0.002), respectfulness (b=-0.17, p = 0.003), interactivity (b=-0.22, p = 0.003), likelihood of being recommended by observers (b=-0.34, p < 0.001), and patient-centeredness index scores (b=-0.16, p = 0.002). Student reported faculty role-modeling of discrimination against patients with obesity predicted lower friendliness (b=-0.16, p = 0.03), recommendation likelihood (b=-0.22, p = 0.04), and patient-centeredness index score (b=-0.12, p = 0.03). CONCLUSIONS: Negative normative attitudes and behaviors regarding obesity in the medical school environment may adversely influence the quality of patient-centered behaviors provided to patients with obesity. PRACTICE IMPLICATIONS: Efforts to improve patient-centered communication quality among medical trainees may benefit from intervention to improve group normative attitudes about patients with obesity.

Relationship of Clinician Care Team Composition and Diabetes Quality Outcomes.

The objective was to determine if a greater proportion of physician full-time equivalent (FTE%) relative to nurse practitioners/physician assistants (NPs/PAs) on care teams was associated with improved individual clinician diabetes quality outcomes. The authors conducted a retrospective cross-sectional study of 420 family medicine clinicians in 110 care teams in a Midwest health system, using administrative data from January 1, 2017 to December 31, 2017. Poisson regression was used to examine the relationship between physician FTE% and the number of patients meeting 5 criteria included in a composite metric for diabetes management (D5). Covariates included panel size, clinician type, sex, years in practice, region, patient satisfaction, care team size, rural location, and panel complexity. Of the 420 clinicians, 167 (40%) were NP/PA staff and 253 (60%) were physicians. D5 criteria were achieved in 37.9% of NP/PA panels compared with 44.5% of physician panels (P < .001). In adjusted analysis, rate of patients achieving D5 was unrelated to physician FTE% on the care team (P = .78). Physicians had a 1.082 (95% confidence interval 1.007-1.164) times greater rate of patients with diabetes achieving D5 than NPs/PAs. Clinicians at rural locations had a .904 (.852-.959) times lower rate of achieving D5 than those at urban locations. Physicians had a greater rate of patients achieving D5 compared with NPs/PAs, but physician FTE% on the care team was unrelated to D5 outcomes. This suggests that clinician team composition matters less than team roles and the dynamics of collaborative care between members.

The Association of Direct Observation of Medical Students With Patient-Centered Care for Obesity.

BACKGROUND AND OBJECTIVES: Teaching medical students patient-centered approaches to weight loss counseling occurs in myriad ways. We examined lectures and direct faculty observation to see which was associated with better patient-centered care in medical students, measured by both self-perception and independent observer evaluation. METHODS: Third- and fourth-year students attending one medical school were surveyed regarding their education in (1) weight loss and health behavior counseling, (2) obesity stigma, and (3) whether they had experienced direct faculty observation of their weight loss counseling. Several weeks later, the students were observed during a standardized patient encounter for obesity and an obesity-relevant comorbidity. A postencounter survey assessed overall student satisfaction with the encounter and with the care they provided. Independent coders rated their patient-centered communication using a validated measure. RESULTS: There was no consistent association between any dependent variable and student ratings of adequacy of instruction, nor with instructional content. Direct faculty observation was not associated with overall encounter satisfaction or their overall patient-centeredness. However, experiences with direct faculty observation were significantly and positively associated with students' perceptions of patient engagement (b=0.1, P=.05), and with independent coders' ratings of student friendliness (b=0.13, P=.01), responsiveness (b=0.113, P=.03), and lower student anxiety (b=-0.1, P=.01). CONCLUSIONS: Independent observation and self-report of instruction adequacy and content had no consistent association with care quality. However, direct faculty observation predicted improvement in both student self-reports and independent observer ratings of students' interpersonal quality of care. Further work is needed to define optimal methods of imparting patient-centered care.

Bugs and Drugs: Collaboration Between Infection Prevention and Antibiotic Stewardship.

Overall goals of antibiotic stewardship and infection prevention programs are to improve patient safety as it pertains to risk of infection or multidrug-resistant organism (MDRO) acquisition. Although the focus of day-to-day activities may differ, the themes of surveillance, education, clinician engagement, and multidisciplinary interactions are prevalent in both programs. Synergistic work between programs has yielded benefits in prevention of MDROs, surgical site infections, Clostridioides difficile infection, and reducing inappropriate testing and treatment for asymptomatic bacteriuria. Collaboration between programs can help maximize resources and minimize redundant work to keep issues related to bugs and drugs at bay.

Multi-Material Tissue Engineering Scaffold with Hierarchical Pore Architecture.

Multi-material polymer scaffolds with multiscale pore architectures were characterized and tested with vascular and heart cells as part of a platform for replacing damaged heart muscle. Vascular and muscle scaffolds were constructed from a new material, poly(limonene thioether) (PLT32i), which met the design criteria of slow biodegradability, elastomeric mechanical properties, and facile processing. The vascular-parenchymal interface was a poly(glycerol sebacate) (PGS) porous membrane that met different criteria of rapid biodegradability, high oxygen permeance, and high porosity. A hierarchical architecture of primary (macroscale) and secondary (microscale) pores was created by casting the PLT32i prepolymer onto sintered spheres of poly(methyl methacrylate) (PMMA) within precisely patterned molds followed by photocuring, de-molding, and leaching out the PMMA. Pre-fabricated polymer templates were cellularized, assembled, and perfused in order to engineer spatially organized, contractile heart tissue. Structural and functional analyses showed that the primary pores guided heart cell alignment and enabled robust perfusion while the secondary pores increased heart cell retention and reduced polymer volume fraction.

Poly(Limonene Thioether) Scaffold for Tissue Engineering.

A photocurable thiol-ene network polymer, poly(limonene thioether) (PLT32o), is synthesized, characterized, fabricated into tissue engineering scaffolds, and demonstrated in vitro and in vivo. Micromolded PLT32o grids exhibit compliant, elastomeric mechanical behavior similar to grids made of poly(glycerol sebacate) (PGS), an established biomaterial. Multilayered PL32o scaffolds with regular, geometrically defined pore architectures support heart cell seeding and culture in a manner similar to multilayered PGS scaffolds. Subcutaneous implantation of multilayered PLT32o scaffolds with cultured heart cells provides long-term 3D structural support and retains the exogenous cells, whereas PGS scaffolds lose both their structural integrity and the exogenous cells over 31 d in vivo. PLT32o membrane implants retain their dry mass, whereas PGS implants lose 70 percent of their dry mass by day 31. Macrophages are initially recruited to PLT32o and PGS membrane implants but are no longer present by day 31. Facile synthesis and processing in combination with the capability to support heart cells in vitro and in vivo suggest that PLT32o can offer advantages for tissue engineering applications where prolonged in vivo maintenance of 3D structural integrity and elastomeric mechanical behavior are required.

Spatially Resolved Genome-wide Transcriptional Profiling Identifies BMP Signaling as Essential Regulator of Zebrafish Cardiomyocyte Regeneration.

In contrast to mammals, zebrafish regenerate heart injuries via proliferation of cardiomyocytes located near the wound border. To identify regulators of cardiomyocyte proliferation, we used spatially resolved RNA sequencing (tomo-seq) and generated a high-resolution genome-wide atlas of gene expression in the regenerating zebrafish heart. Interestingly, we identified two wound border zones with distinct expression profiles, including the re-expression of embryonic cardiac genes and targets of bone morphogenetic protein (BMP) signaling. Endogenous BMP signaling has been reported to be detrimental to mammalian cardiac repair. In contrast, we find that genetic or chemical inhibition of BMP signaling in zebrafish reduces cardiomyocyte dedifferentiation and proliferation, ultimately compromising myocardial regeneration, while bmp2b overexpression is sufficient to enhance it. Our results provide a resource for further studies on the molecular regulation of cardiac regeneration and reveal intriguing differential cellular responses of cardiomyocytes to a conserved signaling pathway in regenerative versus non-regenerative hearts.