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This Viewpoint discusses how patient blood management can help curb the demand for blood products and reduce harm by determining who would most benefit from a blood transfusion.

Abstract Background Early diagnosis and appropriate management of concussion/mild traumatic brain injury (mTBI) is critical for preventing poor outcomes and minimizing health care burden. Current clinical guidelines for concussion management focus mostly on diagnosis and return to cognitive and physical activity but provide limited guidance on the use of specific therapeutic interventions. Objective To systematically review the available evidence on therapeutic interventions for concussion/mTBI and develop an evidence‐based consensus statement on the use of these interventions in clinical practice. Literature Survey A systematic literature search was performed first in 2018 and 2019, and again in 2022, to identify relevant original research on these interventions. A total of 6303 articles were retrieved through the systematic literature search and screened for inclusion. Eighty articles met inclusion criteria and were included in this review and consensus process. Methodology A multispecialty panel was convened to explore management of concussion/mTBI. Interventions evaluated included rest, exercise, rehabilitation, and return to activity (RTA) protocols. Studies were assessed for relevance and methodologic quality and were voted upon to develop an evidence‐based consensus statement on the therapeutic appropriateness of these interventions for concussion/mTBI. A meta‐analysis was not performed. Synthesis There was sufficient evidence to recommend exercise as an appropriate therapy for adolescents with acute concussion/mTBI. In other age groups and for other therapeutic modalities, although some studies demonstrated benefits for some of the interventions, mixed results and study limitations prevented the panel from drawing firm conclusions on the efficacy of those interventions. The panel found evidence of detrimental effects from strict rest and high‐intensity physical activity. Conclusions The panel recommended exercise as an appropriate therapy for acute concussion in adolescents. The evidence on other therapeutic interventions for concussion/mTBI remains limited to small randomized controlled trials and observational studies of moderate to low quality. The panel found no strong evidence to support or recommend against the other evaluated interventions but found most interventions to be safe when used judiciously and in consideration of individual patient needs. High‐quality randomized studies with sufficient power are needed to evaluate the effects of rest, rehabilitation, and RTA protocols for the management of concussion/mTBI.

Background: Plaque fibrosis and re-differentiation of vascular smooth muscle cells (VSMCs) from a contractile to a “synthetic” phenotype are hallmarks of advanced atherosclerosis. While in vitro studies demonstrated a clear role of oxidative stress in the loss of VSMC contractile phenotypes, the roles of specific antioxidant mechanisms and their therapeutic utility remain unclear. Here we test the hypothesis that overexpression of catalase protects against excess plaque fibrosis and losses in contractile phenotypes in vivo . Methods: We used littermate-matched, hypercholesteremic (ldlr -/- /ApoB 100/100 ; LA) mice lacking a transgenic construct (LA-CAT 0/0 ) or harboring a single copy of the human catalase gene (LA-CAT Tg/0 ), which were fed a Western Diet for 3 or 12 months. Isolated organ bath chambers, histopathological analyses, and quantitative RT-PCR were used to assess vasomotor function, structure, and molecular changes in aorta. Results: Oxidative stress increased with disease progression in aortic tissue from LA-CAT 0/0 mice and was modestly reduced in LA-CAT Tg/0 mice. Collagen deposition and fiber thickness increased with disease progression in LA-CAT 0/0 mice, and these increases in fiber thickness were attenuated in LA-CAT Tg/0 mice at 12 months and more pronounced in male mice. In parallel, we observed favorable rightward shifts in the vascular stress-strain relationship in LA-CAT Tg/0 mice that were more pronounced in aged male mice. Interestingly, these structural changes were associated with improved contractile responses to either PGF 2α or serotonin in male LA-CAT Tg/0 mice at 12 months. Consistent with these changes, the contractile marker calponin-1 was profoundly reduced with increasing age in LA-CAT 0/0 mice, with these changes being partially attenuated in aging, male LA-CAT Tg/0 mice. In vitro, treatment of VSMCs with PEG-catalase attenuated BMP2-dependent contractile protein expression. Conclusion: These results demonstrate that moderate overexpression of catalase can attenuate deleterious fibrotic and contractile changes associated with prolonged progression of atherosclerosis. Future mechanistic investigation exploring the context-dependence of these changes (e.g., sex dependence) is warranted.

Introduction: While increased hydrogen peroxide (H 2 O 2 ) accelerates atherosclerotic vascular disease, the role of catalase---which selectively metabolizes H 2 O 2 in lysosomes—is unclear. Given the established role of H 2 O 2 in accelerating osteogenic vascular calcification and vascular smooth muscle cell de-differentiation, we sought to determine the effects of reducing catalase in vivo on functional and molecular changes in aorta in early and late-stage atherosclerosis. Hypothesis: Haploinsufficiency of catalase will worsen vascular contractile function and promote ectopic osteogenesis in early and late-stage atherosclerosis. Methods: We used ldlr -/- /ApoB 100/100 (LA) mice, which were wild-type or heterozygous for catalase (LA-Cat +/+ or LA-Cat +/- , respectively) and fed a western diet for 3 or 12 months. Vasomotor function was assessed using an isolated organ chamber system. Gene expression of VSMC contractile proteins and osteogenic markers was quantified using qRT-PCR. Results: Endothelial function worsened over time in both strains of mice and was modestly worsened in LA-Cat +/- mice. Vascular contraction to PGF 2α was reduced with aging in LA-Cat +/+ mice, and unaffected by catalase deficiency at 3 months. Surprisingly, contractile tension in response to PGF 2α was increased in LA-Cat +/- at 12 months, with this effect being most pronounced in female mice. Consistent with previous literature, expression of VSMC contractile genes (smooth muscle α-actin and calponin-1) was decreased in all groups following 12 months of diet (p<0.0001), and expression of osteogenic genes (BMP2, Runx2, and osterix) increased with aging (p<0.05). Surprisingly, and in contrast to our contractile function data, these time-dependent changes in gene expression tended to be augmented in LA-Cat +/- mice compared to LA-Cat +/+ littermates. Conclusions: Our data suggest that systemic inactivation of one copy of catalase increases contractile function in aorta from aged, hypercholesterolemic mice while paradoxically increasing osteogenic signaling. Future investigation into the role of specific antioxidant enzymes in driving functional and structural changes in advanced vascular disease will be critical to informing therapeutic strategies in this domain.

Introduction: Senescent cell accumulation and senescence-associated secretory phenotype (SASP) are putative major mechanisms of tissue aging, and growing evidence suggests that pharmacological clearance of senescent cells slows progression of multiple age-related diseases. Here, we hypothesized that treating with a known senolytic, Fisetin (FIS), would reduce molecular drivers of fibrosis and calcification and ultimately slow disease progression of fibrocalcific aortic valve stenosis (FCAVS) in mice when initiated in mild/moderate stages of disease. Methods: Male and female Ldlr -/- / ApoB 100/100 mice were fed a western diet for 9 months and assigned to one of two treatment groups: FIS or vehicle, with treatment beginning at 6 months of diet. Results: Treatment with FIS reduced CDKN2A (p < 0.01) and SASP marker TNFα (p < 0.002) in both sexes, and consistent with our hypothesis was associated with reduced expression of the osteogenic markers RUNX2 (p < 0.021) and SPP1 (p < 0.006) in valve tissue from female mice. In contrast, expression of WNT5A was reduced in valves only from male mice (p < 0.004). In line with these molecular changes, valvular calcium burden (alizarin red staining) also tended to decrease in both sexes. Interestingly, TGFβ1 expression was significantly reduced (p < 0.018) in both sexes and was associated with reductions in collagen 3A1. These molecular changes in fibrogenic signaling manifested as a shift towards thinner collagen fibers only in male animals (p < 0.05). Functionally, slower progression of valvular dysfunction (declines in aortic valve cusp separation distance assessed with high-resolution echocardiography) was observed predominantly in females (p < 0.002). Conclusions: In conclusion, these data suggest that long-term, intermittent clearance of senescent cells robustly attenuates osteogenic and fibrogenic signaling in mild/moderate FCAVS, although the molecular, histopathological, and functional consequences of senolytic therapy may occur in a sex-specific manner. Future studies evaluating preclinical efficacy of senolytics should account for tissue and sex specificity and warrant longer-term treatment to assess the functional consequences of the biological and histopathological changes observed here.

People with disabilities (PWDs) experience worse health outcomes than people who do not have disabilities. Making meaningful progress on disability equity requires new ways of thinking about disability, new tools and processes, and new ways of working within the existing health care system. Immediate actions to increase disability equity include expanded data collection including patient-reported outcomes measures, more transparent, person-centered data governance and management, integration of public health and clinic-based health data, and renewed efforts to communicate with and treat PWDs with respect. Prevention of threats to realization of disability equity including a resurgence in the practice of eugenics, misuse of emerging technologies such as CRISPR, and surveillance-promoting technologies also are critical.

Abstract Dynamic measures of resilience—the ability to resist and recover from a challenge—may be informative of the rate of aging before overt manifestations such as chronic disease, disability, and frailty. From this perspective mid-life resilience may predict longevity and late-life health. To test this hypothesis, we developed simple, reproducible, clinically relevant challenges, and outcome measures of physical resilience that revealed differences between and within age groups of genetically heterogeneous mice, and then examined associations between mid-life resilience and both lifespan and late-life measures of physiological function. We demonstrate that time to recovery from isoflurane anesthesia and weight change following a regimen of chemotherapy significantly differed among young, middle-aged, and older mice, and were more variable in older mice. Females that recovered faster than the median time from anesthesia (more resilient) at 12 months of age lived 8% longer than their counterparts, while more resilient males in mid-life exhibited better cardiac (fractional shortening and left ventricular volumes) and metabolic (glucose tolerance) function at 24 months of age. Moreover, female mice with less than the median weight loss at Day 3 of the cisplatin challenge lived 8% longer than those that lost more weight. In contrast, females who had more weight loss between Days 15 and 20 were relatively protected against early death. These data suggest that measures of physical resilience in mid-life may provide information about individual differences in aging, lifespan, and key parameters of late-life health.