Evaluating the Reach of a Patient Navigation Program for Follow-up Colonoscopy in a Large Federally Qualified Health Center.

Patient navigation (PN) has been shown to improve participation in cancer screening, including colorectal cancer screening, and the Community Preventive Services Task Force now recommends the practice. Despite the effectiveness of PN programs, little is known about the number of contacts needed to successfully reach patients or about the demographic and healthcare utilization factors associated with reach. PRECISE was an individual randomized study of PN vs. usual care conducted as a partnership between two large health systems in the Pacific Northwest. The navigation program was a six topic-area telephonic program designed to support patients with an abnormal fecal test result to obtain a follow-up colonoscopy. We report the number of contact attempts needed to successfully reach navigated patients. We used logistic regression to report the demographic and healthcare utilization characteristics associated with patients allocated to PN who were successfully reached. We identified 1200 patients with an abnormal FIT result, among whom 970 were randomized into the study (45.7% were female, 17.5% were Spanish-speaking, mean age was 60.8). Of the 479 patients allocated to the PN intervention, 382 (79.7%) were reached within 18 call attempts and nearly all (n = 356; 93.2%) were reached within six contact attempts. Patient characteristics associated with reach were race, county of residence, and body mass index. Our findings can guide future efforts to optimize the reach of PN programs.

Engaging with Rural Communities for Colorectal Cancer Screening Outreach Using Modified Boot Camp Translation.

BACKGROUND: Colorectal cancer (CRC) incidence and mortality are disproportionately high among rural residents and Medicaid enrollees. OBJECTIVES: To address disparities, we used a modified community engagement approach, Boot Camp Translation (BCT). Research partners, an advisory board, and the rural community informed messaging about CRC outreach and a mailed fecal immunochemical test program. METHODS: Eligible rural patients (English-speaking and ages 50-74) and clinic staff involved in patient outreach participated in a BCT conducted virtually over two months. We applied qualitative analysis to BCT transcripts and field notes. RESULTS: Key themes included: the importance of directly communicating about the seriousness of cancer, leveraging close clinic-patient relationships, and communicating the test safety, ease, and low cost. CONCLUSIONS: Using a modified version of BCT delivered in a virtual format, we were able to successfully capture community input to adapt a CRC outreach program for use in rural settings. Program materials will be tested during a pragmatic trial to address rural CRC screening disparities.

Herbivore effects increase with latitude across the extent of a foundational seagrass.

Climate change is altering the functioning of foundational ecosystems. While the direct effects of warming are expected to influence individual species, the indirect effects of warming on species interactions remain poorly understood. In marine systems, as tropical herbivores undergo poleward range expansion, they may change food web structure and alter the functioning of key habitats. While this process ('tropicalization') has been documented within declining kelp forests, we have a limited understanding of how this process might unfold across other systems. Here we use a network of sites spanning 23° of latitude to explore the effects of increased herbivory (simulated via leaf clipping) on the structure of a foundational marine plant (turtlegrass). By working across its geographic range, we also show how gradients in light, temperature and nutrients modified plant responses. We found that turtlegrass near its northern boundary was increasingly affected (reduced productivity) by herbivory and that this response was driven by latitudinal gradients in light (low insolation at high latitudes). By contrast, low-latitude meadows tolerated herbivory due to high insolation which enhanced plant carbohydrates. We show that as herbivores undergo range expansion, turtlegrass meadows at their northern limit display reduced resilience and may be under threat of ecological collapse.

The Reach of Calls and Text Messages for Mailed FIT Outreach in the PROMPT Stepped-Wedge Colorectal Cancer Screening Trial.

BACKGROUND: Mailed fecal immunochemical test (FIT) outreach can improve colorectal cancer screening participation. We assessed the reach and effectiveness of adding notifications to mailed FIT programs. METHODS: We conducted secondary analyses of a stepped-wedge evaluation of an enhanced mailed FIT program (n = 15 clinics). Patients were stratified by prior FIT completion. Those with prior FIT were sent a text message (Group 1); those without were randomized 1:1 to receive a text message (Group 2) or live phone call (Group 3). All groups were sent automated phone call reminders. In stratified analysis, we measured reach and effectiveness (FIT completion within 6 months) and assessed patient-level associations using generalized estimating equations. RESULTS: Patients (n = 16,934; 83% Latino; 72% completed prior FIT) were reached most often by text messages (78%), followed by live phone calls (71%), then automated phone calls (56%). FIT completion was higher in patients with prior FIT completion versus without [44% (Group 1) vs. 19% (Group 2 + Group 3); P < 0.01]. For patients without prior FIT, effectiveness was higher in those allocated to a live phone call [20% (Group 3) vs. 18% (Group 2) for text message; P = 0.04] and in those who personally answered the live call (28% vs. 9% no call completed; P < 0.01). CONCLUSIONS: Text messages reached the most patients, yet effectiveness was highest in those who personally answered the live phone call. IMPACT: Despite the broad reach and low cost of text messages, personalized approaches may more successfully boost FIT completion.

Polygenic Risk in Families With Spontaneous Coronary Artery Dissection.

Importance: Spontaneous coronary artery dissection (SCAD) is a poorly understood cause of acute coronary syndrome that predominantly affects women. Evidence to date suggests a complex genetic architecture, while a family history is reported for a minority of cases. Objective: To determine the contribution of rare and common genetic variants to SCAD risk in familial cases, the latter via the comparison of a polygenic risk score (PRS) with those with sporadic SCAD and healthy controls. Design, Setting, and Participants: This genetic association study analyzed families with SCAD, individuals with sporadic SCAD, and healthy controls. Genotyping was undertaken for all participants. Participants were recruited between 2017 and 2021. A PRS for SCAD was calculated for all participants. The presence of rare variants in genes associated with connective tissue disorders (CTD) was also assessed. Individuals with SCAD were recruited via social media or from a single medical center. A previously published control database of older healthy individuals was used. Data were analyzed from January 2022 to October 2023. Exposures: PRS for SCAD comprised of 7 single-nucleotide variants. Main Outcomes and Measures: Disease status (familial SCAD, sporadic SCAD, or healthy control) associated with PRS. Results: A total of 13 families with SCAD (27 affected and 12 unaffected individuals), 173 individuals with sporadic SCAD, and 1127 healthy controls were included. A total of 188 individuals with SCAD (94.0%) were female, including 25 of 27 with familial SCAD and 163 of 173 with sporadic SCAD; of 12 unaffected individuals from families with SCAD, 6 (50%) were female; and of 1127 healthy controls, 672 (59.6%) were female. Compared with healthy controls, the odds of being an affected family member or having sporadic SCAD was significantly associated with a SCAD PRS (where the odds ratio [OR] represents an increase in odds per 1-SD increase in PRS) (affected family member: OR, 2.14; 95% CI, 1.78-2.50; adjusted P = 1.96 × 10-4; sporadic SCAD: OR, 1.63; 95% CI, 1.37-1.89; adjusted P = 5.69 × 10-4). This association was not seen for unaffected family members (OR, 1.03; 95% CI, 0.46-1.61; adjusted P = .91) compared with controls. Further, those with familial SCAD were overrepresented in the top quintile of the control PRS distribution (OR, 3.70; 95% CI, 2.93-4.47; adjusted P = .001); those with sporadic SCAD showed a similar pattern (OR, 2.51; 95% CI, 1.98-3.04; adjusted P = .001). Affected individuals within a family did not share any rare deleterious variants in CTD-associated genes. Conclusions and Relevance: Extreme aggregation of common genetic risk appears to play a significant role in familial clustering of SCAD as well as in sporadic case predisposition, although further study is required.

Effects of cyanoacrylate on leakage pressures of cooled canine cadaveric jejunal enterotomies.

OBJECTIVE: To compare the intraluminal initial and maximal pressures of enterotomies closed using three different techniques (single-layer appositional continuous closure; closure with cyanoacrylate; a single-layer appositional closure augmented with cyanoacrylate) in a cooled canine cadaveric jejunal model and to report the initial leak location in all samples. STUDY DESIGN: Experimental, ex-vivo study. SAMPLE POPULATION: Grossly normal chilled small intestine segments from three canine cadavers. METHODS: A total of 45 chilled jejunal segments (n = 15 segments/group) were assigned to a handsewn group (HSE), a cyanoacrylate only group (CE) and a handsewn and cyanoacrylate group (HS + CE). A 2 cm antimesenteric enterotomy was performed and closure with one of the above techniques. Initial leakage pressures (ILP), maximal intraluminal pressures (MIP) and initial leakage location were recorded by a single observer. RESULTS: Handsewn enterotomies leaked at higher ILP when augmented with cyanoacrylate (83.3 ± 4.6 mmHg, p < .001) compared to both the HSE group (43.8 ± 5.3 mmHg) and the CE group (18.6 ± 3.5 mmHg). Those sealed with cyanoacrylate only leaked at a lower MIP compared with the other groups (p < .001). Maximal intraluminal pressures did not differ between handsewn enterotomies, whether augmented or not (p = .19). CONCLUSION: Reinforcement of a sutured enterotomy closure with cyanoacrylate was easy to perform and resulted in significantly increased initial leak pressures in cadaveric jejunum. CLINICAL SIGNIFICANCE: The increased leakage pressures achieved by reinforcing enterotomies with cyanoacrylate could consequently reduce the incidence of postoperative intestinal leakage following an enterotomy and may result in reduced patient morbidity or mortality.

Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle.

Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta-analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle samples (n = 3176). We show that: (1) individuals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, (2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns toward a younger profile, and (3) muscle disuse "ages" the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted toward a younger state after exercise training interventions, while the transcriptome shifted toward an older state after forced muscle disuse. We demonstrate that exercise training targets many of the age-related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism, and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity.

The recalibration and redevelopment of a model to calculate patients' probability of completing a colonoscopy following an abnormal fecal test.

OBJECTIVES: Fecal immunochemical testing (FIT) is an effective screening tool for colorectal cancer. If an FIT is abnormal, a follow-up colonoscopy is necessary to remove polyps or find cancers. We sought to develop a usable risk prediction model to identify patients unlikely to complete a colonoscopy following an abnormal FIT test. METHODS: We recalibrated and then redeveloped a prediction model in federally qualified health centers (FQHCs), using a retrospective cohort of patients aged 50-75 with an abnormal FIT test and clinical data. Logistic and Cox regressions were used to recalibrate and then redevelop the model. RESULTS: The initial risk model used data from eight FQHCs (26 clinics) including 1723 patients. When we applied the model to a single large FQHC (34 clinics, 884 eligible patients), the model did not recalibrate successfully (c-statistic dropped more than 0.05, from 0.66 to 0.61). The model was redeveloped in the same FQHC in a cohort of 1401 patients with a c-statistic of 0.65. CONCLUSIONS: The original model developed in a group of FQHCs did not adequately recalibrate in the single large FQHC. Health system, patient characteristics or data differences may have led to the inability to recalibrate the model. However, the redeveloped model provides an adequate model for the single FQHC.

Developing Patient-Refined Messaging for Follow-Up Colonoscopy After Abnormal Fecal Testing in Hispanic Communities: Key Learnings from Virtual Boot Camp Translation.

Colorectal cancer (CRC) is a leading cause of cancer death in the US. Screening by fecal immunochemical test (FIT) is a strategy to lower CRC rates. Unfortunately, only half of patients with an abnormal FIT result complete the follow-up colonoscopy, an essential component of screening. We used virtual Boot Camp Translation (BCT), to elicit input from partners to develop messaging/materials to motivate patients to complete a follow-up colonoscopy. Participants were Hispanic, ages 50 to 75 years, and Spanish-speaking. All materials were developed in English and Spanish. The first meeting included expert presentations that addressed colorectal health. The two follow-up sessions obtained feedback on messaging/materials developed based on themes from the first meeting. Ten participants attended the first meeting and eight attended the follow-up sessions. The two key barriers to follow-up colonoscopy after abnormal FIT noted by participants were (a) lack of colonoscopy awareness and (b) fear of the colonoscopy procedure. We learned that participants valued simple messaging to increase knowledge and alleviate concerns, patient-friendly outreach materials, and increased access to health information. Using virtual BCT, we included participant feedback to design culturally relevant health messages to promote follow-up colonoscopy after abnormal fecal testing among Hispanic patients served by community clinics.

No phylogenetic evidence for angiosperm mass extinction at the Cretaceous-Palaeogene (K-Pg) boundary.

The Cretaceous-Palaeogene mass extinction event (K-Pg) witnessed upwards of 75% of animal species going extinct, most notably among these are the non-avian dinosaurs. A major question in macroevolution is whether this extinction event influenced the rise of flowering plants (angiosperms). The fossil record suggests that the K-Pg event had a strong regional impact on angiosperms with up to 75% species extinctions, but only had a minor impact on the extinction rates of major lineages (families and orders). Phylogenetic evidence for angiosperm extinction dynamics through time remains unexplored. By analysing two angiosperm mega-phylogenies containing approximately 32 000-73 000 extant species, here we show relatively constant extinction rates throughout geological time and no evidence for a mass extinction at the K-Pg boundary. Despite high species-level extinction observed in the fossil record, our results support the macroevolutionary resilience of angiosperms to the K-Pg mass extinction event via survival of higher lineages.

Effectiveness and Cost of an Enhanced Mailed Fecal Test Outreach Colorectal Cancer Screening Program: Findings from the PROMPT Stepped-Wedge Trial.

BACKGROUND: Mailed fecal immunochemical test (FIT) outreach can improve colorectal cancer screening rates, yet little is known about how to optimize these programs for effectiveness and cost. METHODS: PROMPT was a pragmatic, stepped-wedge, cluster-randomized effectiveness trial of mailed FIT outreach. Participants in the standard condition were mailed a FIT and received live telephone reminders to return it. Participants in the enhanced condition also received a tailored advance notification (text message or live phone call) and two automated phone call reminders. The primary outcome was 6-month FIT completion; secondary outcomes were any colorectal cancer screening completion at 6 months, implementation, and program costs. RESULTS: The study included 27,585 participants (80% ages 50-64, 82% Hispanic/Latino; 68% preferred Spanish). A higher proportion of enhanced participants completed FIT at 6 months than standard participants, both in intention-to-treat [+2.8%, 95% confidence interval (CI; 0.4-5.2)] and per-protocol [limited to individuals who were reached; +16.9%, 95% CI (12.3-20.3)] analyses. Text messages and automated calls were successfully delivered to 91% to 100% of participants. The per-patient cost for standard mailed FIT was $10.84. The enhanced program's text message plus automated call reminder cost an additional $0.66; live phone calls plus an automated call reminder cost an additional $10.82 per patient. CONCLUSIONS: Adding advance notifications and automated calls to a standard mailed FIT program boosted 6-month FIT completion rates at a small additional per-patient cost. IMPACT: Enhancements to mailed FIT outreach can improve colorectal cancer screening participation. Future research might test the addition of educational video messaging for screening-naïve adults.

Speciation across the Earth driven by global cooling in terrestrial orchids.

Although climate change has been implicated as a major catalyst of diversification, its effects are thought to be inconsistent and much less pervasive than localized climate or the accumulation of species with time. Focused analyses of highly speciose clades are needed in order to disentangle the consequences of climate change, geography, and time. Here, we show that global cooling shapes the biodiversity of terrestrial orchids. Using a phylogeny of 1,475 species of Orchidoideae, the largest terrestrial orchid subfamily, we find that speciation rate is dependent on historic global cooling, not time, tropical distributions, elevation, variation in chromosome number, or other types of historic climate change. Relative to the gradual accumulation of species with time, models specifying speciation driven by historic global cooling are over 700 times more likely. Evidence ratios estimated for 212 other plant and animal groups reveal that terrestrial orchids represent one of the best-supported cases of temperature-spurred speciation yet reported. Employing >2.5 million georeferenced records, we find that global cooling drove contemporaneous diversification in each of the seven major orchid bioregions of the Earth. With current emphasis on understanding and predicting the immediate impacts of global warming, our study provides a clear case study of the long-term impacts of global climate change on biodiversity.

Implementing an enhanced mailed FIT program to improve CRC screening at a federally qualified health center: experiences of patients and staff.

Colorectal cancer (CRC) is a leading cause of cancer death in the USA. Screening programs in federally qualified health centers (FQHCs) are essential to reducing CRC-related mortality and morbidity among underserved populations. Centralized, population-based mailed fecal immunochemical test (FIT) programs can improve CRC screening rates, but barriers to implementation remain. We qualitatively explored barriers and facilitators to implementation of a mailed FIT program at a large, urban FQHC that employed advance notification "primers" (live calls and texts) and automated reminders. We interviewed 25 patients and 45 FQHC staff by telephone about their experience with the program. Interviews were transcribed, coded, and content analyzed using NVivo.12. Patients and staff found advance notifications conveyed through live phone calls or text messages to be acceptable and motivational for FIT completion. Live phone primers were helpful in addressing patients' questions and misconceptions about screening, particularly for patients new to screening. Advance notifications sent by text were considered timely and useful in preparing patients for receipt of the FIT. Barriers to implementation included lack of receipt of primers, reminders, or the mailed FIT itself due to inaccurate patient contact information within the FQHC medical record; lack of systems for documenting mailed FIT outreach to coordinate with clinical care; and lack of local caller identification for primers and reminders. Our findings demonstrate that an enhanced mailed FIT program using primers and reminders was acceptable. Our findings can help other FQHCs implement and optimize their mailed FIT programs.

Developing patient-refined colorectal cancer screening materials: application of a virtual community engagement approach.

INTRODUCTION: In partnership with a federally qualified health center (FQHC), an adapted virtual version of boot camp translation (BCT) was used to elicit input from Spanish-speaking Latino patients and staff to develop messaging and patient education materials for follow-up colonoscopy after abnormal fecal testing. We describe how we adapted an existing in-person BCT process to be delivered virtually and present evaluations from participants on the virtual format. METHODS: Three virtual BCT sessions were facilitated by bilingual staff and conducted via Zoom. These sessions included introductions and discussions on colorectal cancer (CRC), CRC screening, and gathered feedback from participants on draft materials. Ten adults were recruited from the FQHC. A research team member from the FQHC served as the point of contact (POC) for all participants and offered Zoom introductory sessions and/or technology support before and during the sessions. Following the third session, participants were invited to complete an evaluation form about their virtual BCT experience. Using a 5-point Likert Scale (where 5 = strongly agree), questions focused on session utility, group comfort level, session pacing, and overall sense of accomplishment. RESULTS: Average scores ranged from 4.3 to 5.0 indicating strong support towards the virtual BCT sessions. Additionally, our study emphasized the importance of a POC to provide technical support to participants throughout the process. Using this approach, we successfully incorporated feedback from participants to design culturally relevant materials to promote follow-up colonoscopy. CONCLUSION: We recommend ongoing public health emphasis on the use of virtual platforms for community engaged work.

Common Iliac Artery to Below-Knee Popliteal Artery Bypass via Obturator Foramen in a Third-Time Reoperative Groin for Limb Salvage in Chronic Limb-Threatening Ischemia.

This case report presents the management of a 69-year-old man with an extensive history of peripheral vascular disease including 2 previous failed right femoral to distal bypasses and a left above-the-knee amputation who presented with right lower extremity rest pain and non-healing shin ulcers. A redo bypass was performed for limb salvage via the obturator foramen to avoid his extensively scarred femoral region. The postoperative course was uneventful and the bypass remained patent in the early period. This case demonstrates the usefulness of the obturator bypass to provide revascularization and avoid amputation in a patient with chronic limb-threatening ischemia and multiple failed bypasses.

Evaluation of veterinary students' confidence and competence with surgical entrustable professional activities after repeated use of low-fidelity training models.

BACKGROUND: This study aimed to evaluate whether low-fidelity surgical training models increased veterinary students' surgical confidence and competence and decreased procedural stress related to core surgical entrustable professional activities (EPAs). METHODS: Final-year veterinary students repeatedly performed one of three surgical EPAs on a low-fidelity surgical training model (canine castration, subcutaneous lump removal and eyelid laceration repair) and completed a survey at set time points. In addition, a grading rubric was used to assess participants' competence in performing the assigned EPA at two different time points. Survey results and competency gradings were compiled and analysed. RESULTS: Students' self-assessed confidence significantly increased, and stress significantly decreased, between assessment points on all three EPA surgical training models. Graded competence significantly improved between the assessment points on all training models, and most students deemed the models to be realistic and helpful for student practices. LIMITATIONS: Limitations relate to the study involving a single cohort from a single institute and the reliance on student self-assessment. CONCLUSIONS: Repeated exposure to low-fidelity surgical training models increased final-year students' surgical confidence and competence and reduced procedural stress related to three key surgical EPAs. Assessment of competence using a grading rubric was successful and could be incorporated into a competence-based veterinary education assessment framework to allow screening of competence prior to graduation.

Characteristics of patient navigation programs in the Cancer Moonshot ACCSIS colorectal cancer screening initiative.

BACKGROUND: Although patient navigation has shown promise for increasing participation in colorectal cancer screening and follow-up, little evidence is available to guide implementation of patient navigation in clinical practice. We characterize 8 patient navigation programs being implemented as part of multi-component interventions of the National Cancer Institute's Cancer Moonshot Accelerating Colorectal Cancer Screening and Follow-Up Through Implementation Science (ACCSIS) initiative. METHODS: We developed a data collection template organized by ACCSIS framework domains. The template was populated by a representative from each of the 8 ACCSIS research projects. We report standardized descriptions of 1) the socio-ecological context in which the navigation program was being conducted, 2) navigation program characteristics, 3) activities undertaken to facilitate program implementation (eg, training), and 4) outcomes used in program evaluation. RESULTS: ACCSIS patient navigation programs varied broadly in their socio-ecological context and settings, the populations they served, and how they were implemented in practice. Six research projects adapted and implemented evidence-based patient navigation programs; the remaining projects developed new programs. Five projects began navigation when patients were due for initial colorectal cancer screening; 3 projects began navigation later in the screening process, when patients were due for follow-up colonoscopy after an abnormal stool-test result. Seven projects relied on existing clinical staff to deliver the navigation; 1 hired a centralized research navigator. All project researchers plan to evaluate the effectiveness and implementation of their programs. CONCLUSIONS: Our detailed program descriptions may facilitate cross-project comparisons and guide future implementation and evaluation of patient navigation programs in clinical practice.

Reconstituting human somitogenesis in vitro.

The segmented body plan of vertebrates is established during somitogenesis, a well-studied process in model organisms; however, the details of this process in humans remain largely unknown owing to ethical and technical limitations. Despite recent advances with pluripotent stem cell-based approaches1-5, models that robustly recapitulate human somitogenesis in both space and time remain scarce. Here we introduce a pluripotent stem cell-derived mesoderm-based 3D model of human segmentation and somitogenesis-which we termed 'axioloid'-that captures accurately the oscillatory dynamics of the segmentation clock and the morphological and molecular characteristics of sequential somite formation in vitro. Axioloids show proper rostrocaudal patterning of forming segments and robust anterior-posterior FGF-WNT signalling gradients and retinoic acid signalling components. We identify an unexpected critical role of retinoic acid signalling in the stabilization of forming segments, indicating distinct, but also synergistic effects of retinoic acid and extracellular matrix on the formation and epithelialization of somites. Comparative analysis demonstrates marked similarities of axioloids to the human embryo, further validated by the presence of a Hox code in axioloids. Finally, we demonstrate the utility of axioloids for studying the pathogenesis of human congenital spine diseases using induced pluripotent stem cells with mutations in HES7 and MESP2. Our results indicate that axioloids represent a promising platform for the study of axial development and disease in humans.

Early cardiac aging linked to impaired stress-resistance and transcriptional control of stress response, quality control and mitochondrial pathways.

Phenotypic and transcriptomic evidence of early cardiac aging, and associated mechanisms, were investigated in young to middle-aged male mice (C57Bl/6; ages 8, 16, 32, 48 wks). Left ventricular gene expression (profiled via Illumina MouseWG-6 BeadChips), contractile and coronary function, and stress-resistance were assessed in Langendorff perfused hearts under normoxic conditions and following ischemic insult (20 min global ischemia-45 min reperfusion; I-R). Baseline or normoxic contractile function was unaltered by age, while cardiac and coronary 'reserves' (during ß-adrenoceptor stimulation; 1 µM isoproterenol) declined by 48 wks. Resistance to I-R injury fell from 16 to 32 wks. Age-dependent transcriptional changes In un-stressed hearts were limited to 104 genes (>1.3-fold; 0.05 FDR), supporting: up-regulated innate defenses (glutathione and xenobiotic metabolism, chemotaxis, interleukins) and catecholamine secretion; and down-regulated extracellular matrix (ECM), growth factor and survival (PI3K/Akt) signaling. In stressed (post-ischemic) myocardium, ∼15-times as many genes (1528) were age-dependent, grouped into 6 clusters (>1.3-fold change; 0.05 FDR): most changing from 16 wks (45 % up/44 % down), a further 5 % declining from 32 wks. Major age-dependent Biological Processes in I-R hearts reveal: declining ATP metabolism, oxidative phosphorylation, cardiac contraction and morphogenesis, phospholipid metabolism and calcineurin signaling; increasing proteolysis and negative control of MAPK; and mixed changes in nuclear transport and angiogenic genes. Pathway analysis supports reductions in: autophagy, stress response, ER protein processing, mRNA surveillance and ribosome/translation genes; with later falls in mitochondrial biogenesis, oxidative phosphorylation and proteasome genes in I-R hearts. Summarizing, early cardiac aging is evident from 16 to 32 wks in male mice, characterized by: declining cardiovascular reserve and stress-resistance, transcriptomic evidence of constitutive stress and altered catecholamine and survival/growth signaling in healthy hearts; and declining stress response, quality control, mitochondrial energy metabolism and cardiac modeling processes in stressed hearts. These very early changes, potentially key substrate for advanced aging, may inform approaches to healthy aging and cardioprotection in the adult heart.