Return to Sport After Multiligament Knee Injury in Young Athletes.

Background: While return to sport (RTS) in young athletes after anterior cruciate ligament (ACL) reconstruction has been well studied, little is known regarding their rate of RTS after multiligament knee injury (MLKI). Purpose: To assess the level of and factors associated with RTS after MLKI in young athletes. Study Design: Case series; Level of evidence, 4. Methods: We retrospectively identified 116 patients aged ≤23 years who had sustained an injury to ≥2 knee ligaments and undergone operative reconstruction or repair of ≥1 ligament. Our primary outcome was self-reported RTS at the preinjury level or higher. We estimated the likelihood of RTS using binomial logistic regression. Secondary variables included the 2000 International Knee Documentation Committee Subjective Knee Form (IKDC-SF), ACL-Return to Sport after Injury (ACL-RSI), and 12-Item Short Form Health Survey (SF-12) physical and mental health summaries. Results: A total of 30 (25.9%) patients (24 men, 6 women; mean age, 18.1 ± 2.5 years) completed patient-reported outcome surveys at a mean follow-up of 7.8 years (median, 6.6 years [range, 1.1-19.5 years]). A total of 28 patients underwent surgical treatment of ≥2 ligaments. RTS was achieved by 90% of patients, and 43.3% returned to their preinjury level or higher. Patients who had played sports at a higher level before injury were more likely to RTS at their preinjury level or higher (odds ratio [OR], 3.516 [95% CI, 1.034-11.955]; P = .044), while those who played cutting sports were less likely to do so (OR, 0.013 [95% CI, 0.000-0.461; P = .017). Patients who achieved RTS at their preinjury level or higher had significantly higher IKDC-SF and ACL-RSI scores versus patients who did not (P = .001 and P = .002, respectively). The number of ligaments injured, age, mental health diagnosis, and SF-12 scores were not associated with the ability to RTS at the preinjury or higher levels. Conclusion: Most young athletes who sustained MLKI were able to return to play at some level, but a minority returned to their preinjury level. Patients who did return at preinjury or higher levels had higher IKDC-SF and ACL-RSI scores than those who did not. Performance in cutting and/or pivoting sports was negatively associated with RTS.

Consideration for Limb Salvage in Place of Amputation in Complex Tibial Fracture With Neurovascular Injury: A Case Report.

High-energy tibial fractures often present with associated soft tissue injuries, including neuro-vascular damage, complicating the treatment decision. A 33-year-old male presented with Gustilo Anderson type IIIA fracture of the left distal tibia and fibula with associated closed calcaneus fracture and tibial nerve transection. Amputation was discussed, but the decision was made for limb salvage with nerve allograft. The patient displayed satisfactory functional recovery at 29 months postoperatively without need for major revision, grafting, arthrodesis, or amputation. This case report provides an example of successful limb salvage utilizing tibial nerve allograft in a complex high-energy lower extremity injury. Level of Evidence: IV.

NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson's Disease.

Dysfunctional mitochondrial quality control (MQC) is implicated in the pathogenesis of Parkinson's disease (PD). The improper selection of mitochondria for mitophagy increases reactive oxygen species (ROS) levels and lowers ATP levels. The downstream effects include oxidative damage, failure to maintain proteostasis and ion gradients, and decreased NAD+ and NADPH levels, resulting in insufficient energy metabolism and neurotransmitter synthesis. A ketosis-based metabolic therapy that increases the levels of (R)-3-hydroxybutyrate (BHB) may reverse the dysfunctional MQC by partially replacing glucose as an energy source, by stimulating mitophagy, and by decreasing inflammation. Fasting can potentially raise cytoplasmic NADPH levels by increasing the mitochondrial export and cytoplasmic metabolism of ketone body-derived citrate that increases flux through isocitrate dehydrogenase 1 (IDH1). NADPH is an essential cofactor for nitric oxide synthase, and the nitric oxide synthesized can diffuse into the mitochondrial matrix and react with electron transport chain-synthesized superoxide to form peroxynitrite. Excessive superoxide and peroxynitrite production can cause the opening of the mitochondrial permeability transition pore (mPTP) to depolarize the mitochondria and activate PINK1-dependent mitophagy. Both fasting and exercise increase ketogenesis and increase the cellular NAD+/NADH ratio, both of which are beneficial for neuronal metabolism. In addition, both fasting and exercise engage the adaptive cellular stress response signaling pathways that protect neurons against the oxidative and proteotoxic stress implicated in PD. Here, we discuss how intermittent fasting from the evening meal through to the next-day lunch together with morning exercise, when circadian NAD+/NADH is most oxidized, circadian NADP+/NADPH is most reduced, and circadian mitophagy gene expression is high, may slow the progression of PD.

Mammary epithelial cells have lineage-rooted metabolic identities.

Cancer metabolism adapts the metabolic network of its tissue of origin. However, breast cancer is not a disease of a single origin. Multiple epithelial populations serve as the culprit cell of origin for specific breast cancer subtypes, yet our knowledge of the metabolic network of normal mammary epithelial cells is limited. Using a multi-omic approach, here we identify the diverse metabolic programmes operating in normal mammary populations. The proteomes of basal, luminal progenitor and mature luminal cell populations revealed enrichment of glycolysis in basal cells and of oxidative phosphorylation in luminal progenitors. Single-cell transcriptomes corroborated lineage-specific metabolic identities and additional intra-lineage heterogeneity. Mitochondrial form and function differed across lineages, with clonogenicity correlating with mitochondrial activity. Targeting oxidative phosphorylation and glycolysis with inhibitors exposed lineage-rooted metabolic vulnerabilities of mammary progenitors. Bioinformatics indicated breast cancer subtypes retain metabolic features of their putative cell of origin. Thus, lineage-rooted metabolic identities of normal mammary cells may underlie breast cancer metabolic heterogeneity and targeting these vulnerabilities could advance breast cancer therapy.

Distinctive Features of Kawasaki Disease Following SARS-CoV-2 Infection: a Controlled Study in Paris, France.

BACKGROUND: An outbreak of multisystem inflammatory syndrome in children, including Kawasaki disease (KD), emerged during COVID-19 pandemic. We explored whether Kawasaki-like disease (KD), when associated with confirmed SARS-CoV-2 infection, has specific characteristics. METHODS: We included children and adolescents with KD criteria admitted in the department of general pediatrics of a university hospital in Paris, France, between January 1, 2018, and May 26, 2020. The incidence of KD was compared between the outbreak and a pre-outbreak control period (January 1, 2018, to April 25). Characteristics of patients with positive SARS-CoV-2 testing (KD-SARS-CoV-2) were compared to those of the pre-outbreak period (classic KD). RESULTS: A total of 30 and 59 children with KD were admitted during the outbreak and pre-outbreak periods, respectively (incidence ratio 13.2 [8.3-21.0]). During the outbreak, 23/30 (77%) children were diagnosed as KD-SARS-CoV-2. When compared with patients with classic KD, those with KD-SARS-CoV-2 were more frequently of sub-Saharan African ancestry (OR 4.4 [1.6-12.6]) and older (median 8.2 vs. 4.0 years, p < 0.001), had more often initial gastrointestinal (OR 84 [4.9-1456]) and neurological (OR 7.3 [1.9-27.7] manifestations, and shock syndrome (OR 13.7 [4.2-45.1]). They had significantly higher CRP and ferritin levels. Noticeably, they had more frequently myocarditis (OR 387 [38-3933]). CONCLUSIONS: Children and adolescents with KD-SARS-CoV-2 have specific features when compared with those with classic KD. These findings should raise awareness and facilitate the study of their pathogenesis.

A Practical Guide for Navigating the Design, Build, and Clinical Integration of Electronic Patient-Reported Outcomes in the Radiation Oncology Department.

The development and integration of electronic patient-reported outcomes (ePROs) into the radiation oncology clinic workflow provide novel opportunities, accompanied by unique design considerations and implementation challenges. The processes required for implementation of ePROs are entirely distinct from standard paper-based surveys, with the majority of time devoted to conception and design before initiating questionnaire build, detailed workflow process mapping including development of new workflows, comprehensive communication of the vision between providers and the information technology team, and quality assurance. Based on our experience with implementation of ePROs in our radiation oncology department, we developed a stepwise framework for approaching ePRO conceptual design, build, workflow integration, and the electronic health record interface. Here, we provide a guide for the numerous considerations, decision points, and solutions associated with the implementation of ePROs in the radiation oncology department setting. Although various ePRO tools and electronic health record capabilities impose different requirements, opportunities, and limitations, the conceptual processes and many of the electronic build considerations are broadly applicable.

COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm.

Human SARS-CoV-2 infection is characterized by a high mortality rate due to some patients developing a large innate immune response associated with a cytokine storm and acute respiratory distress syndrome (ARDS). This is characterized at the molecular level by decreased energy metabolism, altered redox state, oxidative damage, and cell death. Therapies that increase levels of (R)-beta-hydroxybutyrate (R-BHB), such as the ketogenic diet or consuming exogenous ketones, should restore altered energy metabolism and redox state. R-BHB activates anti-inflammatory GPR109A signaling and inhibits the NLRP3 inflammasome and histone deacetylases, while a ketogenic diet has been shown to protect mice from influenza virus infection through a protective γδ T cell response and by increasing electron transport chain gene expression to restore energy metabolism. During a virus-induced cytokine storm, metabolic flexibility is compromised due to increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that damage, downregulate, or inactivate many enzymes of central metabolism including the pyruvate dehydrogenase complex (PDC). This leads to an energy and redox crisis that decreases B and T cell proliferation and results in increased cytokine production and cell death. It is hypothesized that a moderately high-fat diet together with exogenous ketone supplementation at the first signs of respiratory distress will increase mitochondrial metabolism by bypassing the block at PDC. R-BHB-mediated restoration of nucleotide coenzyme ratios and redox state should decrease ROS and RNS to blunt the innate immune response and the associated cytokine storm, allowing the proliferation of cells responsible for adaptive immunity. Limitations of the proposed therapy include the following: it is unknown if human immune and lung cell functions are enhanced by ketosis, the risk of ketoacidosis must be assessed prior to initiating treatment, and permissive dietary fat and carbohydrate levels for exogenous ketones to boost immune function are not yet established. The third limitation could be addressed by studies with influenza-infected mice. A clinical study is warranted where COVID-19 patients consume a permissive diet combined with ketone ester to raise blood ketone levels to 1 to 2 mM with measured outcomes of symptom severity, length of infection, and case fatality rate.

Relationship between inorganic ion distribution, resting membrane potential, and the ΔG' of ATP hydrolysis: a new paradigm.

Cell membrane potential and inorganic ion distributions are currently viewed from a kinetic electric paradigm, which ignores thermodynamics. The resting membrane potential is viewed as a diffusion potential. The 9 major inorganic ions found in blood plasma (Ca2+, Na+, Mg2+, K+, H+, Cl-, HCO3-, H2PO4-, and HPO42-) are distributed unequally across the plasma membrane. This unequal distribution requires the energy of ATP hydrolysis through the action of the Na+-K+ ATPase. The cell resting membrane potential in each of 3 different tissues with widely different resting membrane potentials has been shown to be equal to the Nernst equilibrium potential of the most permeant inorganic ion. The energy of the measured distribution of the 9 major inorganic ions between extra- and intracellular phases was essentially equal to the independently measured energy of ATP hydrolysis, showing that the distribution of these 9 major ions was in near-equilibrium with the ΔG' of ATP. Therefore, thermodynamics does appear to play an essential role in the determination of the cell resting membrane potential and the inorganic ion distribution across the plasma membrane.-Veech, R. L., King, M. T., Pawlosky, R., Bradshaw, P. C., Curtis, W. Relationship between inorganic ion distribution, resting membrane potential, and the ΔG' of ATP hydrolysis: a new paradigm.

Effect of Preoperative Opioid Usage on Pain After Total Shoulder Arthroplasty.

INTRODUCTION: Preoperative opioid use has recently been associated with increased perioperative pain. This study evaluates the effect of preoperative opioid use on postoperative pain and duration of opioid use after total shoulder arthroplasty (TSA). METHODS: We retrospectively identified 138 TSAs (69.1% reverse and 30.9% anatomic) between January 2013 and April 2017 that met inclusion criteria. Patients were stratified into two groups based on opioid usage within the 4 weeks before surgery. Primary outcome was resting pain at 3 months postoperatively using a 10-point numerical rating scale system. Duration of postoperative opioid consumption was also recorded and compared between cohorts. RESULTS: The opioid cohort (n = 50) reported significantly greater resting pain and pain with activity at 3 months postoperatively, at which time the reported numerical rating scale pain scores were 1.6 and 2.8 points greater in the opioid cohort compared with the non-opioid cohort (P < 0.001). Preoperative opioid use strongly predicted postoperative opioid use at all follow-up time points (P < 0.0001). DISCUSSION: Preoperative opioid consumption is associated with higher pain and increased duration of opioid use after TSA.

Use of standard musculoskeletal ultrasound to determine the need for fasciotomy in an elevated muscle compartment pressure cadaver leg model.

INTRODUCTION: Acute compartment syndrome (ACS) is a limb-threatening condition often associated with leg injury. The only treatment of ACS is fasciotomy with the purpose of reducing muscle compartment pressures (MCP). Patient discomfort and low reliability of invasive MCP measurements, has led to the search for alternative methods. Our goal was to test the feasibility of using ultrasound to diagnose elevated MCP. METHODS: A cadaver model of elevated MCPs was used in 6 cadaver legs. An ultrasound transducer was combined with a pressure sensing transducer to obtain a B-mode image of the anterior compartment, while controlling the amount of pressure applied to the skin. MCP was increased from 0 to 75 mmHg. The width of the anterior compartment (CW) and the pressure needed to flatten the bulging superficial compartment fascia (CFFP) were measured. RESULTS: Both the CW and CFFP showed high correlations to MCP in the individual cadavers. Average CW and CFFP significantly increased between baseline and the first elevated MCP states. Both Inter-observer and intra-observer agreements for the ultrasound measurements were good to excellent. DISCUSSION: Ultrasound indexes showed excellent correlations in compartment pressures, suggesting that there is a potential for the clinical use of this modality in the future.

The "great" controlling nucleotide coenzymes.

Nucleotide coenzymes dot the map of metabolic pathways providing energy to drive the reactions of the pathway and play an important role in regulating and controlling energy metabolism through their shared potential energy, which is widely unobserved due to the paradox that the energy in the coenzyme pools cannot be determined from the concentration of the coenzyme couples. The potential energy of the nucleotide couples in the mitochondria or the cytoplasm is expressed in the enzyme reactions in which they take part. The energy in these couples, [NAD+]/[NADH], [NADP+]/[NADPH], [acetyl CoA]/[CoA], and [ATP]/[ADP]x[Pi], regulates energy metabolism. The energy contained in the couples can be altered by suppling energy equivalents in the form of ketones, such as, D-ß-hydroxybutyrate to overcome insulin resistance, to restore antioxidants capacity, to form potential treatments for Alzheimer's and Parkinson's diseases, to enhance life span, and to increase physiological performance. © 2019 IUBMB Life, 71(5):565-579, 2019.

Meningococcal serogroup B outbreak response University of Wisconsin-Madison.

A meningococcal serogroup B (MenB) outbreak at a large public university prompted an emergency response to immunize undergraduates. OBJECTIVE: To report on a successful meningococcal serogroup B (MenB) vaccine clinic response at a large public university. METHODS: We assembled the team leaders to write this case report. RESULTS: Activation of the emergency plan and points of dispensing required cooperation of many units on campus under the leadership of university health officials with support from Centers for Disease Control and Prevention, state division of public health and the city-county health department. Significant efforts to provide consistent messages to students and parents regarding the outbreak and the availability of the MenB vaccines were made. Volunteers were recruited to staff the clinics alongside university healthcare providers. Over 22,000 doses of vaccine were administered. CONCLUSION: We report our experience and lessons learned which may be helpful to universities in preventing and responding to disease outbreaks.

Quantitative MRI of Diffuse Liver Disease: Current Applications and Future Directions.

As radiologic technology advances, quantitative imaging is becoming more prevalent in clinical practice. This article reviews quantitative hepatic MRI, specifically involving fat and iron deposition, by demonstrating how they were iteratively improved. These iterative improvements involved incorporating more knowledge about the physiology of liver disease and MRI physics to reduce the adverse effects caused by confounding factors. The relevant foundations of MRI physics and liver pathophysiology are briefly reviewed, followed by the various improvements made by expanding on this foundational knowledge. Results from the literature are then discussed within this context, validating the improvement of these resultant methods into clinically robust and useful techniques. Fibrosis quantification, which has been more difficult to robustly perform in clinical practice, is similarly reviewed in an online appendix, with proposals for future multiparametric directions to improve performance on the basis of the insights gained from fat and iron quantification in the liver.

Peri-Operative Anaesthetic Documentation: A Report of Three Sequential Audits on the Quality of Outcomes, with an Insight Into Surrounding Legal Issues.

OBJECTIVE: The aim of the audits was to assess contemporary performance, with comparison of the same against previous outcomes, to gauge trends in clinical practice. This allowed for completion of the audit cycle, as well as the ability to analyse and consistently improve the quality of care delivered to our patients. METHODS: We undertook three prospective audits on the quality of peri-operative anaesthetic documentation in the years 2009, 2011 and 2014, respectively. Anaesthetic records for patients undergoing elective as well as emergency surgical procedures were assessed for 'adequacy of peri-operative documentation' based on a combination of select criteria outlined by the Royal College of Anaesthetists and the Australian and New Zealand College of Anaesthetists. RESULTS: A total of 1000 anaesthetic records were analysed in 2009, followed by a review of 412 records and 376 documents in 2011 and 2014 respectively. In the year 2014, 43.8% of pre-operative anaesthetic records were 'appropriately' documented. This was in stark comparison to 16.3% and 25.9% in the years 2009 and 2011, respectively. The quantity of 'adequately' documented intra-operative records increased to 35.1% in 2014, in comparison to 25.5% and 22.7% in 2009 and 2011, respectively. There was an overall improvement in the standards of peri-operative documentation in consecutive audits. CONCLUSION: We propose that regular audits on 'anaesthetic record keeping' can lead to an improvement in the standards of this often overlooked, but essential scope of our practice.

Resection Arthroplasty Compared With Total Hip Arthroplasty in Treating Chronic Hip Pain of Patients With a History of Substance Abuse.

BACKGROUND: Retrospective comparison of surgical management of severe hip pain in patients with a history of substance abuse treated by modified Girdlestone resection arthroplasty (RA) vs delayed total hip arthroplasty (THA) following yearlong sobriety pathway. METHODS: Patients were identified using charts, current procedural terminology (CPT) code query, and THA sobriety pathway registry. The primary outcome was adequate pain control following surgery, defined as visual analog scale ≤ 5 or verbal description of "moderate" or lower pain. RA patients with infectious arthritis were analyzed separately. The secondary outcome was the level of mobility after surgery. RESULTS: In the THA pathway, 15 of 28 (53.6%) proved sobriety, 11 (39.3%) underwent THA, and 9 (32.1%) achieved adequate pain control (median 77 days). After RA, 19 (76%) achieved adequate pain control (median 119.5 days). Preoperative infection did not significantly affect time to pain control after RA (P = .94). Time to adequate pain control was not significantly different between RA and THA patients (P = .19). Three patients (30%) experienced improved level of mobility after THA and 7 (70%) experienced no change. After RA, 7 patients (29.1%) experienced improved level of mobility, 3 (13.6%) lost mobility, and 14 (63.6%) experienced no change. Three RA patients were later converted to THA without complication. CONCLUSION: Yearlong sobriety pathway leading to THA leads to successful pain control in less than one-third of enrolled patients. Compared to delayed THA, RA enables more patients with substance abuse to be treated sooner and results in successful reduction of pain in a similar proportion of patients. RA may be an effective pain-reducing procedure for these patients.

Acute non-traumatic disease of the abdominal aorta.

Acute pathology in the abdominal aorta is associated with significant morbidity and mortality. The most feared complication of abdominal aortic disease is acute rupture in the setting of atherosclerotic abdominal aortic aneurysm. Although frank rupture often is easily diagnosed on CT, other findings such as a hyperattenuating crescent, discontinuous intimal calcium, and draping of the aorta are subtle signs of aneurysm instability. A true aneurysm should be distinguished from a rapidly growing, saccular pseudoaneurysm in the setting of infectious aortitis, as treatment strategy differs. Acute aortic syndrome involving the abdominal aorta, such as dissection and intramural hematoma, often is an extension of thoracic aortic disease, whereas penetrating atherosclerotic ulcers occasionally involve only the abdominal aorta. The goal of treating acute aortic pathology is to repair and prevent rupture, as well as restore and maintain perfusion of the lower extremities, kidneys, and mesentery. However, both open and endovascular repair of the abdominal aorta may become acutely complicated, resulting in compromise of these goals. Examples include aortoenteric fistula, endoleak, anastomotic pseudoaneurysm, graft infection, and thrombosis or kinking of a stent graft resulting in ischemia of the limbs and mesentery.

Epidemiology of Hepatic Steatosis at a Tertiary Care Center: An MRI-based Analysis.

RATIONALE AND OBJECTIVES: Little is known about the frequency and risk factors of hepatic steatosis in the tertiary care setting. Such knowledge is essential to clinicians making decisions about testing for this condition. Thus, our aim was to describe the epidemiology of hepatic steatosis, as captured by magnetic resonance imaging (MRI), at a tertiary care center. MATERIALS AND METHODS: A near-consecutive cohort of 1006 adult patients underwent standard-of-care liver MRIs. Images were retrospectively processed to derive proton density fat fraction (PDFF) maps. Data from three spatially distinct regions of interest (ROIs) were aggregated to derive overall hepatic PDFF values. Demographic, anthropometric, clinical, and laboratory variables were included in a multivariate analysis to determine predictors of hepatic steatosis grades (based on established PDFF cutoffs). Hepatic steatosis grades derived from single vs aggregated ROIs were compared. RESULTS: Hepatic steatosis was observed in 25% of patients (19% grade 1; 3% grade 2; 3% grade 3). Controlling for all other variables, the odds of hepatic steatosis increased by 7%-9% (P <.001) for each whole point increase in body mass index (BMI), whereas elevated serum bilirubin was associated with lower odds of hepatic steatosis (P = .002). Race, diabetes mellitus, dyslipidemia, and metabolic syndrome were not independently predictive of hepatic steatosis when controlling for other variables (eg, BMI). Employing single ROIs (rather than three aggregated ROIs) resulted in incorrect steatosis grading in up to 8.0% of patients. CONCLUSION: Many adult patients undergoing liver MRI at a tertiary care center have hepatic steatosis, with larger BMIs as the only independent predictor of higher grades. This information can be used by clinicians at such centers to make evidence-based decisions about when to test for hepatic steatosis in their patients.

Ketone bodies mimic the life span extending properties of caloric restriction.

The extension of life span by caloric restriction has been studied across species from yeast and Caenorhabditis elegans to primates. No generally accepted theory has been proposed to explain these observations. Here, we propose that the life span extension produced by caloric restriction can be duplicated by the metabolic changes induced by ketosis. From nematodes to mice, extension of life span results from decreased signaling through the insulin/insulin-like growth factor receptor signaling (IIS) pathway. Decreased IIS diminishes phosphatidylinositol (3,4,5) triphosphate (PIP3 ) production, leading to reduced PI3K and AKT kinase activity and decreased forkhead box O transcription factor (FOXO) phosphorylation, allowing FOXO proteins to remain in the nucleus. In the nucleus, FOXO proteins increase the transcription of genes encoding antioxidant enzymes, including superoxide dismutase 2, catalase, glutathione peroxidase, and hundreds of other genes. An effective method for combating free radical damage occurs through the metabolism of ketone bodies, ketosis being the characteristic physiological change brought about by caloric restriction from fruit flies to primates. A dietary ketone ester also decreases circulating glucose and insulin leading to decreased IIS. The ketone body, d-ß-hydroxybutyrate (d-ßHB), is a natural inhibitor of class I and IIa histone deacetylases that repress transcription of the FOXO3a gene. Therefore, ketosis results in transcription of the enzymes of the antioxidant pathways. In addition, the metabolism of ketone bodies results in a more negative redox potential of the NADP antioxidant system, which is a terminal destructor of oxygen free radicals. Addition of d-ßHB to cultures of C. elegans extends life span. We hypothesize that increasing the levels of ketone bodies will also extend the life span of humans and that calorie restriction extends life span at least in part through increasing the levels of ketone bodies. An exogenous ketone ester provides a new tool for mimicking the effects of caloric restriction that can be used in future research. The ability to power mitochondria in aged individuals that have limited ability to oxidize glucose metabolites due to pyruvate dehydrogenase inhibition suggests new lines of research for preventative measures and treatments for aging and aging-related disorders. © 2017 The Authors IUBMB Life published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology, 69(5):305-314, 2017.