A lay of the land: a description of academic acute care surgery models in Canada.

BACKGROUND: Patients who require emergency general surgery (EGS) are at a substantially higher risk for perioperative morbidity and mortality than patients undergoing elective general surgery. The acute care surgery (ACS) model has been shown to improve EGS patient outcomes and cost-effectiveness. A recent systematic review has shown extensive heterogeneity in the structure of ACS models worldwide. The objective of this study was to describe the current landscape of ACS models in academic centres across Canada. METHODS: We sent an online questionnaire to the 18 academic centres in Canada. The lead ACS physicians from each institution completed the questionnaire, describing the structure of their ACS models. RESULTS: In total, 16 institutions responded, all of which reported having ACS models, with a total of 29 ACS services described. All services had resident coverage. Of the 29, 18 (62%) had dedicated allied health care staff. The staff surgeon was free from elective duties while covering ACS in 17/29 (59%) services. More than half (15/29; 52%) of the services described protected ACS operating room time, but only 7/15 (47%) had a dedicated ACS room all 5 weekdays. Four of 29 services (14%) had no protected ACS operating room time. Only 1/16 (6%) institutions reported a mandate to conduct ACS research, while 12/16 (75%) found ACS research difficult, owing to lack of resources. CONCLUSION: We saw large variations in the structure of ACS models in academic centres in Canada. The components of ACS models that are most important to patient outcomes remain poorly defined. Future research will focus on defining the necessary cornerstones of ACS models.

Breakdown of Boltzmann-type models for the alignment of self-propelled rods.

Studies in the collective motility of organisms use a range of analytical approaches to formulate continuous kinetic models of collective dynamics from rules or equations describing agent interactions. However, the derivation of these kinetic models often relies on Boltzmann's "molecular chaos" hypothesis, which assumes that correlations between individuals are short-lived. While this assumption is often the simplest way to derive tractable models, it is often not valid in practice due to the high levels of cooperation and self-organization present in biological systems. In this work, we illustrated this point by considering a general Boltzmann-type kinetic model for the alignment of self-propelled rods where rod reorientation occurs upon binary collisions. We examine the accuracy of the kinetic model by comparing numerical solutions of the continuous equations to an agent-based model that implements the underlying rules governing microscopic alignment. Even for the simplest case considered, our comparison demonstrates that the kinetic model fails to replicate the discrete dynamics due to the formation of rod clusters that violate statistical independence. Additionally, we show that introducing noise to limit cluster formation helps improve the agreement between the analytical model and agent simulations but does not restore the agreement completely. These results highlight the need to both develop and disseminate improved moment-closure methods for modeling biological and active matter systems.

Endothelial Immunosuppression in Atherosclerosis : Translational Control by Elavl1/HuR.

Atherosclerotic plaques are defined by the accumulation of lipids and immune cells beneath the endothelium of the arterial intima. CD8 T cells are among the most abundant immune cell types in plaque, and conditions linked to their activation correlate with increased levels of cardiovascular disease. As lethal effectors of the immune response, CD8 T cell activation is suppressed at multiple levels. These checkpoints are critical in dampening autoimmune responses, and limiting damage in cardiovascular disease. Endothelial cells are well known for their role in recruiting CD8 T and other hematopoietic cells to low and disturbed flow (LDF) arterial regions that develop plaque, but whether they locally influence CD8 effector functions is unclear. Here, we show that endothelial cells can actively suppress CD8 T cell responses in settings of chronic plaque inflammation, but that this behavior is governed by expression of the RNA-binding protein Embryonic Lethal, Abnormal Vision-Like 1 (Elavl1). In response to immune cell recruitment in plaque, the endothelium dynamically shifts splicing of pre-mRNA and their translation to enhance expression of immune-regulatory proteins including C1q and CD27. This program is immuno-suppressive, and limited by Elavl1. We show this by Cdh5(PAC)-CreERT2-mediated deletion of Elavl1 (ECKO), and analysis of changes in translation by Translating Ribosome Affinity Purification (TRAP). In ECKO mice, the translational shift in chronic inflammation is enhanced, leading to increased ribosomal association of C1q components and other critical regulators of immune response and resulting in a ~70% reduction in plaque CD8 T cells. CITE-seq analysis of the remaining plaque T cells shows that they exhibit lower levels of markers associated with T cell receptor (TCR) signaling, survival, and activation. To understand whether the immunosuppressive mechanism occurred through failed CD8 recruitment or local modulation of T cell responses, we used a novel in vitro co-culture system to show that ECKO endothelial cells suppress CD8 T cell expansion-even in the presence of wild-type myeloid antigen-presenting cells, antigen-specific CD8 T cells, and antigen. Despite the induction of C1q mRNA by T cell co-culture in both wild-type and ECKO endothelial cells, we find C1q protein abundantly expressed only in co-culture with ECKO cells. Together, our data define a novel immune-suppressive transition in the endothelium, reminiscent of the transition of T cells to T-regs, and demonstrate the regulation of this process by Elavl1.

Chronic Obstructive Pulmonary Disease and Obstructive Sleep Apnea Overlap Syndrome: An Update on the Epidemiology, Pathophysiology, and Management.

This review provides an up-to-date summary of the prevalence, pathophysiology, diagnosis, and treatment of the chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) overlap syndrome (OVS). The presence of OVS is high in patients with COPD and in patients with OSA and is associated with profound nocturnal oxygen desaturation and systemic inflammation. There is a high prevalence of cardiovascular disease among patients with OVS and this likely contributes to increased mortality. Observational studies suggest that positive airway pressure therapy improves survival and reduces COPD exacerbations; however, randomized controlled trials will be required to confirm these findings.

CUT&Tag applied to zebrafish adult tail fins reveals a return of embryonic H3K4me3 patterns during regeneration.

Regenerative potential is governed by a complex process of transcriptional reprogramming, involving chromatin reorganization and dynamics in transcription factor binding patterns throughout the genome. The degree to which chromatin and epigenetic changes contribute to this process remains only partially understood. Here we provide a modified CUT&Tag protocol suitable for improved characterization and interrogation of changes in chromatin modifications during adult fin regeneration in zebrafish. Our protocol generates data that recapitulates results from previously published ChIP-Seq methods, requires far fewer cells as input, and significantly improves signal to noise ratios. We deliver high-resolution enrichment maps for H3K4me3 of uninjured and regenerating fin tissues. During regeneration, we find that H3K4me3 levels increase over gene promoters which become transcriptionally active and genes which lose H3K4me3 become silenced. Interestingly, these reprogramming events recapitulate the H3K4me3 patterns observed in developing fin folds of 24-h old zebrafish embryos. Our results indicate that changes in genomic H3K4me3 patterns during fin regeneration occur in a manner consistent with reactivation of developmental programs, demonstrating CUT&Tag to be an effective tool for profiling chromatin landscapes in regenerating tissues.

A portable inflatable soft wearable robot to assist the shoulder during industrial work.

Repetitive overhead tasks during factory work can cause shoulder injuries resulting in impaired health and productivity loss. Soft wearable upper extremity robots have the potential to be effective injury prevention tools with minimal restrictions using soft materials and active controls. We present the design and evaluation of a portable inflatable shoulder wearable robot for assisting industrial workers during shoulder-elevated tasks. The robot is worn like a shirt with integrated textile pneumatic actuators, inertial measurement units, and a portable actuation unit. It can provide up to 6.6 newton-meters of torque to support the shoulder and cycle assistance on and off at six times per minute. From human participant evaluations during simulated industrial tasks, the robot reduced agonist muscle activities (anterior, middle, and posterior deltoids and biceps brachii) by up to 40% with slight changes in joint angles of less than 7% range of motion while not increasing antagonistic muscle activity (latissimus dorsi) in current sample size. Comparison of controller parameters further highlighted that higher assistance magnitude and earlier assistance timing resulted in statistically significant muscle activity reductions. During a task circuit with dynamic transitions among the tasks, the kinematics-based controller of the robot showed robustness to misinflations (96% true negative rate and 91% true positive rate), indicating minimal disturbances to the user when assistance was not required. A preliminary evaluation of a pressure modulation profile also highlighted a trade-off between user perception and hardware demands. Finally, five automotive factory workers used the robot in a pilot manufacturing area and provided feedback.

Modeling and design of solar + storage-powered community resilience hubs across California.

Distributed clean, reliable energy resources like solar plus battery storage (solar + storage) can reduce harmful emissions while supporting resilience. Solar + storage-powered resilience hubs provide energy for critical services during disasters while increasing human adaptive capacity year round. We studied where utility rates, local climate, and historical injustice make solar + storage resilience hubs more valuable and more challenging. We modeled the economic and climate impacts of outfitting candidate hub sites across California with solar + storage for everyday operations and identified designs and costs required to withstand a range of outages considering weather impacts on energy needs and availability. We integrated sociodemographic data to prioritize the siting of resilience hubs, to focus potential policy and funding priorities on regions where solar + storage for resilience hubs is hard or expensive, and where populations are most in need. We identified almost 20,000 candidate buildings with more than 8 GW of total rooftop solar potential capable of reducing CO2 emissions by 5 million tons per year while providing energy for community resilience. Hub capacity for one of the most challenging missions-providing emergency shelter during a power outage and smoke event-could have a statewide average lifetime cost of less than $2000 per seat. We identified regional challenges including insufficient rooftop solar capacity in cities, low sunlight in northern coastal California, and high costs driven by utility rate structures in Sacramento and the Imperial Valley. Results show that rates and net metering rules that incentivize solar + storage during everyday operations decrease resilience costs.

Annihilation dynamics during spiral defect chaos revealed by particle models.

Pair-annihilation events are ubiquitous in a variety of spatially extended systems and are often studied using computationally expensive simulations. Here, we develop an approach in which we simulate the pair-annihilation of spiral wave tips in cardiac models using a computationally efficient particle model. Spiral wave tips are represented as particles with dynamics governed by diffusive behavior and short-ranged attraction. The parameters for diffusion and attraction are obtained by comparing particle motion to the trajectories of spiral wave tips in cardiac models during spiral defect chaos. The particle model reproduces the annihilation rates of the cardiac models and can determine the statistics of spiral wave dynamics, including its mean termination time. We show that increasing the attraction coefficient sharply decreases the mean termination time, making it a possible target for pharmaceutical intervention.

Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility.

Immune checkpoint inhibition has shown success in treating metastatic cutaneous melanoma but has limited efficacy against metastatic uveal melanoma, a rare variant arising from the immune privileged eye. To better understand this resistance, we comprehensively profile 100 human uveal melanoma metastases using clinicogenomics, transcriptomics, and tumor infiltrating lymphocyte potency assessment. We find that over half of these metastases harbor tumor infiltrating lymphocytes with potent autologous tumor specificity, despite low mutational burden and resistance to prior immunotherapies. However, we observe strikingly low intratumoral T cell receptor clonality within the tumor microenvironment even after prior immunotherapies. To harness these quiescent tumor infiltrating lymphocytes, we develop a transcriptomic biomarker to enable in vivo identification and ex vivo liberation to counter their growth suppression. Finally, we demonstrate that adoptive transfer of these transcriptomically selected tumor infiltrating lymphocytes can promote tumor immunity in patients with metastatic uveal melanoma when other immunotherapies are incapable.

Thromboprophylaxis in hospitalized trauma patients: a systematic review and meta-analysis of implementation strategies.

Introduction: Venous thromboembolism (VTE) prophylaxis implementation strategies are well-studied in some hospitalized medical and surgical patients. Although VTE is associated with substantial mortality and morbidity in trauma patients, implementation strategies for the prevention of VTE in trauma appear to be based on limited evidence. Therefore, we conducted a systematic review and meta-analysis of published literature on active implementation strategies for VTE prophylaxis administration in hospitalized trauma patients and the impact on VTE events. Methods: A systematic review and meta-analysis was performed in adult hospitalized trauma patients to assess if active VTE prevention implementation strategies change the proportion of patients who received VTE prophylaxis, VTE events, and adverse effects such as bleeding or heparin-induced thrombocytopenia as well as hospital length of stay and the cost of care. An academic medical librarian searched Medline, Scopus, and Web of Science until December 2022. Results: Four studies with a total of 1723 patients in the active implementation strategy group (strategies included education, reminders, human and computer alerts, audit and feedback, preprinted orders, and/or root cause analysis) and 1324 in the no active implementation strategy group (guideline creation and dissemination) were included in the analysis. A higher proportion of patients received VTE prophylaxis with an active implementation strategy (OR=2.94, 95% CI (1.68 to 5.15), p<0.01). No significant difference was found in VTE events. Quality was deemed to be low due to bias and inconsistency of studies. Conclusions: Active implementation strategies appeared to improve the proportion of major trauma patients who received VTE prophylaxis. Further implementation studies are needed in trauma to determine effective, sustainable strategies for VTE prevention and to assess secondary outcomes such as bleeding and costs. Level of evidence: Systematic review/meta-analysis, level III. PROSPERO registration number: CRD42023390538.

Generation, Characterization and Reactivity of a High-Valent Mononuclear Cobalt(IV)-Diazide Complex.

High-valent Fe(IV)=O intermediates of metalloenzymes have inspired numerous efforts to generate synthetic analogs to mimic and understand their substrate oxidation reactivities. However, high-valent M(IV) complexes of late transition metals are rare. We have recently reported a novel Co(IV)-dinitrate complex (1-NO3) that activates sp3 C-H bonds up to 87 kcal/mol. In this work, we have shown that the nitrate ligands in 1-NO3 can be replaced by azide, a more basic coordinating base, resulting in the formation of a more potent Co(IV)-diazide species (1-N3) that reacts with substrates (hydrocarbons and phenols) at faster rate constants and activates stronger C-H bonds than the parent complex 1-NO3. We have characterized 1-N3 employing a combination of spectroscopic and computational approaches. Our results clearly show that the coordination of azide leads to the modulation of the Co(IV) electronic structure and the Co(IV/III) redox potential. Together with the higher basicity of azide, these thermodynamic parameters contribute to the higher driving forces of 1-N3 than 1-NO3 for C-H bond activation. Our discoveries are thus insightful for designing more reactive bio-inspired high-valent late transition metal complexes for activating inert aliphatic hydrocarbons.

CUT&Tag Applied to Zebrafish Adult Tail Fins Reveals a Return of Embryonic H3K4me3 Patterns During Regeneration.

Regenerative potential is governed by a complex process of transcriptional reprogramming, involving chromatin reorganization and dynamics in transcription factor binding patterns throughout the genome. The degree to which chromatin and epigenetic changes contribute to this process remains partially understood. Here we provide a modified CUT&Tag protocol suitable for improved characterization and interrogation of epigenetic changes during adult fin regeneration in zebrafish. Our protocol generates data that recapitulates results from previously published ChIP-Seq methods, requires far fewer cells as input, and significantly improves signal to noise ratios. We deliver high-resolution enrichment maps for H3K4me3 of uninjured and regenerating fin tissues. During regeneration, we find that H3K4me3 levels increase over gene promoters which become transcriptionally active and genes which lose H3K4me3 become silenced. Interestingly, these epigenetic reprogramming events recapitulate the H3K4me3 patterns observed in developing fin folds of 24-hour old zebrafish embryos. Our results indicate that changes in genomic H3K4me3 patterns during fin regeneration occur in a manner consistent with reactivation of developmental programs, demonstrating CUT&Tag to be an effective tool for profiling chromatin landscapes in regenerating tissues.

Pack the chest: Damage control strategy for management in thoracic trauma.

BACKGROUND: Damage control surgery aims to control hemorrhage and contamination in the operating room (OR) with definitive management of injuries delayed until normal physiology is restored in the intensive care unit (ICU). There are limited studies evaluating the use of damage control thoracotomy (DCT) in trauma, and the best method of temporary closure is unclear. METHODS: A retrospective review of trauma patients at two level I trauma centers who underwent a thoracotomy operation was performed. Subjects who underwent a thoracotomy after 24 h, age less than 16, expired in the trauma bay, or in the OR prior to ICU admission were excluded. One-way ANOVA and Kruskal-Wallis test were used to compare continuous and categorical variables between DCT and definitive thoracotomy (DT) patients. RESULTS: 207 trauma patients underwent thoracotomy, 76 met our inclusion criteria. DCT was performed in 30 patients (39%), 46 (61 %) underwent DT operation. Techniques for temporizing the chest varied from skin closure with suture (8), adhesive dressing (5), towel clamps (2), or negative pressure devices (12). Compared to definitive closure, DCT had more derangements in HR, pH, (110 vs. 95, p = 0.04; 7.05 vs 7.24, p < 0.001), and injury severity score (41 vs 25, p < 0.001), and required more blood transfusions (40 vs 6, p < 0.001). Eleven (36.7 %) DCT patients survived to discharge compared to 38 patients (95.0 %) in the DT group. DCT showed significantly higher differences in cardiac arrest and unplanned returns to the OR rates. No differences were observed in ventilator days, or ICU length of stay. CONCLUSIONS: DCT is a viable option for management of patients in extremis following thoracic trauma. DCT was associated with higher mortality rates, likely due to differences in injury and physiologic derangement. Despite this, DCT was associated with similar rates of complications, ICU stay, and ventilator days.

Financial toxicity part II: A practical guide to measuring and tracking long-term financial outcomes among acute care surgery patients.

ABSTRACT: Acute care surgery (ACS) patients are frequently faced with significant long-term recovery and financial implications that extend far beyond their hospitalization. While major injury and emergency general surgery (EGS) emergencies are often viewed solely as acute moments of crisis, the impact on patients can be lifelong. Financial outcomes after major injury or emergency surgery have only begun to be understood. The Healthcare Economics Committee from the American Association for the Surgery of Trauma previously published a conceptual overview of financial toxicity in ACS, highlighting the association between financial outcomes and long-term physical recovery. The aims of second-phase financial toxicity review by the Healthcare Economics Committee of the American Association for the Surgery of Trauma are to (1) understand the unique impact of financial toxicity on ACS patients; (2) delineate the current limitations surrounding measurement domains of financial toxicity in ACS; (3) explore the "when, what and how" of optimally capturing financial outcomes in ACS; and (4) delineate next steps for integration of these financial metrics in our long-term patient outcomes. As acute care surgeons, our patients' recovery is often contingent on equal parts physical, emotional, and financial recovery. The ACS community has an opportunity to impact long-term patient outcomes and well-being far beyond clinical recovery.

A collaborative multidisciplinary trauma program improvement team improves VTE chemoprophylaxis guideline compliance in non-operative stable TBI.

BACKGROUND: Delays in initiating venous thromboembolism (VTE) prophylaxis in patients suffering from traumatic brain injury (TBI) persist despite guidelines recommending early initiation. We hypothesized that the expansion of a Trauma Program Performance Improvement (PI) team will improve compliance of early (24-48 hours) initiation of VTE prophylaxis and will decrease VTE events in TBI patients. METHODS: We performed a single-center retrospective review of all TBI patients admitted to a Level I trauma center before (2015-2016,) and after (2019-2020,) the expansion of the Trauma Performance Improvement and Patient Safety (PIPS) team and the creation of trauma process and outcome dashboards. Exclusion criteria included discharge or death within 48 hours of admission, expanding intracranial hemorrhage on CT scan, and a neurosurgical intervention (craniotomy, pressure monitor, or drains) prior to chemoprophylaxis initiation. RESULTS: A total of 1,112 patients met the inclusion criteria, of which 54% (n = 604) were admitted after Trauma PIPS expansion. Following the addition of a dedicated PIPS nurse in the trauma program and creation of process dashboards, the time from stable CT to VTE prophylaxis initiation decreased (52 hours to 35 hours; p < 0.001) and more patients received chemoprophylaxis at 24 hours to 48 hours (59% from 36%, p < 0.001) after stable head CT. There was no significant difference in time from first head CT to stable CT (9 vs. 9 hours; p = 0.15). The Contemporary group had a lower rate of VTE events (1% vs. 4%; p < 0.001) with no increase in bleeding events (2% vs. 2%; p = 0.97). On multivariable analysis, being in the Early cohort was an independent predictor of VTE events (adjusted odds ratio, 3.74; 95% confidence interval, 1.45-6.16). CONCLUSION: A collaborative multidisciplinary Trauma PIPS team improves guideline compliance. Initiation of VTE chemoprophylaxis within 24 hours to 48 hours of stable head CT is safe and effective. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Thoracic cavity irrigation prevents retained hemothorax and decreases surgical intervention in trauma patients.

INTRODUCTION: Retained hemothorax (HTX) is a common complication following thoracic trauma. Small studies demonstrate the benefit of thoracic cavity irrigation at the time of tube thoracostomy (TT) for the prevention of retained HTX. We sought to assess the effectiveness of chest irrigation in preventing retained HTX leading to a secondary surgical intervention. METHODS: We performed a single-center retrospective study from 2017 to 2021 at a Level I trauma center, comparing bedside thoracic cavity irrigation via TT versus no irrigation. Using the trauma registry, patients with traumatic HTX were identified. Exclusion criteria were TT placement at an outside hospital, no TT within 24 hours of admission, thoracotomy or video-assisted thoracoscopic surgery (VATS) prior to or within 6 hours after TT placement, VATS as part of rib fixation or diaphragmatic repair, and death within 96 hours of admission. Bivariate and multivariable analyses were conducted. RESULTS: A total of 370 patients met the inclusion criteria, of whom 225 (61%) were irrigated. Patients who were irrigated were more likely to suffer a penetrating injury (41% vs. 30%, p = 0.03) and less likely to have a flail chest (10% vs. 21%, p = 0.01). On bivariate analysis, irrigation was associated with lower rates of VATS (6% vs. 19%, p < 0.001) and retained HTX (10% vs. 21%, p < 0.001). The irrigated cohort had a shorter TT duration (4 vs. 6 days, p < 0.001) and hospital length of stay (7 vs. 9 days, p = 0.04). On multivariable analysis, thoracic cavity irrigation had lower odds of VATS (adjusted odds ratio, 0.37; 95% confidence interval [CI], 0.30-0.54), retained HTX (adjusted odds ratio, 0.42; 95% CI, 0.25-0.74), and a shorter TT duration ( ß = -1.58; 95% CI, -2.52 to -0.75). CONCLUSION: Our 5-year experience with thoracic irrigation confirms findings from smaller studies that irrigation prevents retained HTX and decreases the need for surgical intervention. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Home noninvasive ventilation in severe COPD: in whom does it work and how?

Background: Not all hypercapnic COPD patients benefit from home noninvasive ventilation (NIV), and mechanisms through which NIV improves clinical outcomes remain uncertain. We aimed to identify "responders" to home NIV, denoted by a beneficial effect of NIV on arterial partial pressure of carbon dioxide (PaCO2), health-related quality of life (HRQoL) and survival, and investigated whether NIV achieves its beneficial effect through an improved PaCO2. Methods: We used individual patient data from previous published trials collated for a systematic review. Linear mixed-effect models were conducted to compare the effect of NIV on PaCO2, HRQoL and survival, within subgroups defined by patient and treatment characteristics. Secondly, we conducted a causal mediation analysis to investigate whether the effect of NIV is mediated by a change in PaCO2. Findings: Data of 1142 participants from 16 studies were used. Participants treated with lower pressure support (<14 versus ≥14 cmH2O) and with lower adherence (<5 versus ≥5 h·day-1) had less improvement in PaCO2 (mean difference (MD) -0.30 kPa, p<0.001 and -0.29 kPa, p<0.001, respectively) and HRQoL (standardised MD 0.10, p=0.002 and 0.11, p=0.02, respectively), but this effect did not persist to survival. PaCO2 improved more in patients with severe dyspnoea (MD -0.30, p=0.02), and HRQoL improved only in participants with fewer than three exacerbations (standardised MD 0.52, p=0.03). The results of the mediation analysis showed that the effect on HRQoL is mediated partially (23%) by a change in PaCO2. Interpretation: With greater pressure support and better daily NIV usage, a larger improvement in PaCO2 and HRQoL is achieved. Importantly, we demonstrated that the beneficial effect of home NIV on HRQoL is only partially mediated through a reduction in diurnal PaCO2.

Epigenetic erosion of H4K20me1 induced by inflammation drives aged stem cell ferroptosis.

Aging is associated with a decline in stem cell functionality and number across the organism. In this study, we aimed to further unravel Muscle Stem Cells (MuSCs) aging by assessing how systemic factors influence MuSC fate decisions through long-term epigenetic landscape remodelling. As aging is intricately linked to a pro-inflammatory shift, we studied the epigenetic effects of inflammatory signals in MuSCs and measured decreased H4K20me1 levels. This loss disrupts MuSC quiescence, largely through epigenetic silencing of Notch target genes. In the setting of inflammatory signals or aging, the lack of Kmt5a and the subsequent absence of de novoH4K20me1 culminate in cell death by ferroptosis. Aged MuSCs manifest abnormal iron metabolism and reduced Gpx4 levels, resulting in the accumulation of intracellular iron, increased reactive oxygen species, genomic instability, and lipid peroxidation. We showed that ferroptosis is the predominant mode of cell death in aged MuSCs, with remarkably high levels of lipid peroxidation; a phenomenon we also observed in aged hematopoietic stem cells. Implementing preventative strategies to inhibit systemic inflammation prevented aged MuSC ferroptosis, preserving their numbers and regenerative capabilities. This intervention significantly enhanced aged muscle regeneration and strength recovery and extended both lifespan and healthspan in mice. This study delineates a previously underappreciated fate trajectory for stem cell aging, and offers meaningful insights into the treatment of age-related disorders.