Frail patients having vascular surgery during the early COVID-19 pandemic experienced high rates of adverse perioperative events and amputation.

BACKGROUND: Frailty predicts adverse perioperative outcomes and increased mortality in patients having vascular surgery. Frailty assessment is a potential tool to inform resource allocation, and shared decision-making about vascular surgery in the resource constrained COVID-19 pandemic environment. This cohort study describes the prevalence of frailty in patients having vascular surgery and the association between frailty, mortality and perioperative outcomes. METHODS: The COVID-19 Vascular Service in Australia (COVER-AU) prospective cohort study evaluates 30-day and six-month outcomes for consecutive patients having vascular surgery in 11 Australian vascular units, March-July 2020. The primary outcome was mortality, with secondary outcomes procedure-related outcomes and hospital utilization. Frailty was assessed using the nine-point visual Clinical Frailty Score, scores of 5 or more considered frail. RESULTS: Of the 917 patients enrolled, 203 were frail (22.1%). The 30 day and 6 month mortality was 2.0% (n = 20) and 5.9% (n = 35) respectively with no significant difference between frail and non-frail patients (OR 1.68, 95%CI 0.79-3.54). However, frail patients stayed longer in hospital, had more perioperative complications, and were more likely to be readmitted or have a reoperation when compared to non-frail patients. At 6 months, frail patients had twice the odds of major amputation compared to non-frail patients, after adjustment (OR 2.01; 95% CI 1.17-3.78), driven by a high rate of amputation during the period of reduced surgical activity. CONCLUSION: Our findings highlight that older, frail patients, experience potentially preventable adverse outcomes and there is a need for targeted interventions to optimize care, especially in times of healthcare stress.

Biglycan reduces body weight by regulating food intake in mice and improves glucose metabolism through AMPK/AKT dual pathways in skeletal muscle.

While biglycan (BGN) is suggested to direct diverse signaling cascades, the effects of soluble BGN as a ligand on metabolic traits have not been studied. Herein, we tested the effects of BGN on obesity in high-fat diet (HFD)-induced obese animals and glucose metabolism, with the underlying mechanism responsible for observed effects in vitro. Our results showed that BGN administration (1 mg/kg body weight, intraperitoneally) significantly prevented HFD-induced obesity, and this was mainly attributed to reduced food intake. Also, intracerebroventricular injection of BGN reduced food intake and body weight. The underlying mechanism includes modulation of neuropeptides gene expression involved in appetite in the hypothalamus in vitro and in vivo. In addition, BGN regulates glucose metabolism as shown by improved glucose tolerance in mice as well as AMPK/AKT dual pathway-driven enhanced glucose uptake and GLUT4 translocation in L6 myoblast cells. In conclusion, our results suggest BGN as a potential therapeutic target to treat risk factors for metabolic diseases.

Ethanol abolishes vigilance-dependent astroglia network activation in mice by inhibiting norepinephrine release.

Norepinephrine adjusts sensory processing in cortical networks and gates plasticity enabling adaptive behavior. The actions of norepinephrine are profoundly altered by recreational drugs like ethanol, but the consequences of these changes on distinct targets such as astrocytes, which exhibit norepinephrine-dependent Ca2+ elevations during vigilance, are not well understood. Using in vivo two-photon imaging, we show that locomotion-induced Ca2+ elevations in mouse astroglia are profoundly inhibited by ethanol, an effect that can be reversed by enhancing norepinephrine release. Vigilance-dependent astroglial activation is abolished by deletion of α1A-adrenergic receptor from astroglia, indicating that norepinephrine acts directly on these ubiquitous glial cells. Ethanol reduces vigilance-dependent Ca2+ transients in noradrenergic terminals, but has little effect on astroglial responsiveness to norepinephrine, suggesting that ethanol suppresses their activation by inhibiting norepinephrine release. Since abolition of astroglia Ca2+ activation does not affect motor coordination, global suppression of astroglial networks may contribute to the cognitive effects of alcohol intoxication.

Effect of chitinase-3-like protein 1 on glucose metabolism: In vitro skeletal muscle and human genetic association study.

We investigated the effect of chitinase-3-like protein 1 (CHI3L1) on glucose metabolism and its underlying mechanisms in skeletal muscle cells, and evaluated whether the observed effects are relevant in humans. CHI3L1 was associated with increased glucose uptake in skeletal muscles in an AMP-activated protein kinase (AMPK)-dependent manner, and with increased intracellular calcium levels via PAR2. The improvement in glucose metabolism observed in an intraperitoneal glucose tolerance test on male C57BL/6J mice supported this association. Inhibition of the CaMKK was associated with suppression of CHI3L1-mediated glucose uptake. Additionally, CHI3L1 was found to influence glucose uptake through the PI3K/AKT pathway. Results suggested that CHI3L1 stimulated the phosphorylation of AS160 and p38 MAPK downstream of AMPK and AKT, and the resultant GLUT4 translocation. In primary myoblast cells, stimulation of AMPK and AKT was observed in response to CHI3L1, underscoring the biological relevance of CHI3L1. CHI3L1 levels were elevated in cells under conditions that mimic exercise in vitro and in exercised mice in vivo, indicating that CHI3L1 is secreted during muscle contraction. Finally, similar associations between CHI3L1 and metabolic parameters were observed in humans alongside genotype associations between CHI3L1 and diabetes at the population level. CHI3L1 may be a potential therapeutic target for the treatment of diabetes.

Resolvin D1 supports skeletal myofiber regeneration via actions on myeloid and muscle stem cells.

Specialized proresolving mediators (SPMs) actively limit inflammation and expedite its resolution by modulating leukocyte recruitment and function. Here we profiled intramuscular lipid mediators via liquid chromatography-tandem mass spectrometry-based metabolipidomics following myofiber injury and investigated the potential role of SPMs in skeletal muscle inflammation and repair. Both proinflammatory eicosanoids and SPMs increased following myofiber damage induced by either intramuscular injection of barium chloride or synergist ablation-induced functional muscle overload. Daily systemic administration of the SPM resolvin D1 (RvD1) as an immunoresolvent limited the degree and duration of inflammation, enhanced regenerating myofiber growth, and improved recovery of muscle strength. RvD1 suppressed inflammatory cytokine expression, enhanced polymorphonuclear cell clearance, modulated the local muscle stem cell response, and polarized intramuscular macrophages to a more proregenerative subset. RvD1 had minimal direct impact on in vitro myogenesis but directly suppressed myokine production and stimulated macrophage phagocytosis, showing that SPMs can modulate both infiltrating myeloid and resident muscle cell populations. These data reveal the efficacy of immunoresolvents as a novel alternative to classical antiinflammatory interventions in the management of muscle injuries to modulate inflammation while stimulating tissue repair.

Single Muscle Fibre Contractility Testing in Rats to Quantify Ischaemic Muscle Damage During Reperfusion Injury.

OBJECTIVES: In this study, the aim was to investigate the potential for single muscle fibre contractility (SMFC) testing to detect the extent of reperfusion injury following various reperfusion periods. The hypothesis was that force generated by muscle fibres will correlate inversely with the extent of reperfusion injury. METHODS: Twenty-four Lewis rats were distributed among five groups. Group 1 served as normal muscle control. In all other groups, femoral artery flow was occluded for four hours. Muscle biopsies were obtained at 0 hour, six hours, day two, and day seven after reperfusion in Groups 2, 3, 4, and 5, respectively. Samples then underwent ultrastructural analysis (H&E stain) and SMFC testing. RESULTS: The maximum isometric force (mN) generated on Days two and seven after reperfusion decreased from baseline by 21% (p < 0.05), and 53% (p < .001), respectively. The specific force (kPa) followed a similar pattern with a 13% decrease at Day two (p > 0.05) and 31% decrease at Day 7 (p < .001). These results correlated inversely with the extent of quantitative injury on histology. CONCLUSIONS: The study demonstrated an inverse relationship between single muscle fibre contractility testing and neutrophil infiltration during the reperfusion phase. Further clinical studies are needed to evaluate its potential in providing prognostic information for patient outcomes.

Symptom burden and medication use in adult sarcoma patients.

PURPOSE: Limited data are available on how symptom burden affects health-related quality of life (HRQoL) in patients with sarcoma. This study aims to describe the symptom burden, HRQoL, and medication use in adult sarcoma patients. METHODS: A single-center, cross-sectional study was conducted, and 79 patients were evaluated using three tools: the Rotterdam Symptom Checklist (RSCL), the Beck Anxiety Inventory (BAI), and the Functional Assessment of Cancer Therapy scale-General (FACT-G). Patients' demographic and clinical information, medication history, and use of concomitant medications were recorded. The proportion of patients with clinically significant RSCL score for a particular symptom was compared with the percentage of patients receiving medication for that symptom. RESULTS: The mean age was 57.3 ± 15.2 years, with majority of the patients diagnosed with stromal tumor (46.8 %), leiomyosarcoma (15.2 %), and liposarcoma (10.1 %). The most prevalent physical symptoms experienced were tiredness (2.38 ± 1.00), lack of energy (2.04 ± 1.02), and difficulty sleeping (2.00 ± 1.15). The most common psychological symptoms experienced were irritability (1.92 ± 1.01), worrying (1.86 ± 0.90), and anxiety (1.68 ± 0.74). Few (6.3 %) patients received hypnotics while 33.0 % of patients reported difficulty sleeping. A proportion of patients (27.9 %) reported experiencing lack of appetite with only 1.3 % received appetite stimulants. CONCLUSION: Adult sarcoma patients experience significant physiological and psychological symptom burden, which has a strong negative impact on HRQoL, with a number of physiological symptoms undertreated with pharmacotherapy.