Core sepsis-related competencies for medical students: an international consensus by Delphi technique.

BACKGROUND: Sepsis is a life-threatening condition which may arise from infection in any organ system and requires early recognition and management. Healthcare professionals working in any specialty may need to manage patients with sepsis. Educating medical students about this condition may be an effective way to ensure all future doctors have sufficient ability to diagnose and treat septic patients. However, there is currently no consensus on what competencies medical students should achieve regarding sepsis recognition and treatment. This study aims to outline what sepsis-related competencies medical students should achieve by the end of their medical student training in both high or upper-middle incomes countries/regions and in low or lower-middle income countries/regions. METHODS: Two separate panels from high or upper-middle income and low or lower-middle income countries/regions participated in a Delphi method to suggest and rank sepsis competencies for medical students. Each panel consisted of 13-18 key stakeholders of medical education and doctors in specialties where sepsis is a common problem (both specialists and trainees). Panelists came from all continents, except Antarctica. RESULTS: The panels reached consensus on 38 essential sepsis competencies in low or lower-middle income countries/regions and 33 in high or upper-middle incomes countries/regions. These include competencies such as definition of sepsis and septic shock and urgency of antibiotic treatment. In the low or lower-middle income countries/regions group, consensus was also achieved for competencies ranked as very important, and was achieved in 4/5 competencies rated as moderately important. In the high or upper-middle incomes countries/regions group, consensus was achieved in 41/57 competencies rated as very important but only 6/11 competencies rated as moderately important. CONCLUSION: Medical schools should consider developing curricula to address essential competencies, as a minimum, but also consider addressing competencies rated as very or moderately important.

Population study on diagnosis, treatment and outcomes of critically ill patients with tuberculosis (2008-2018).

BACKGROUND: Tuberculosis (TB) is a preventable and curable disease, but mortality remains high among those who develop sepsis and critical illness from TB. METHODS: This was a population-based, multicentre retrospective cohort study of patients admitted to all 15 publicly funded Hong Kong adult intensive care units (ICUs) between 1 April 2008 and 31 March 2019. 940 adult critically ill patients with at least one positive Mycobacterium tuberculosis (MTB) culture were identified out of 133 858 ICU admissions. Generalised linear modelling was used to determine the impact of delay in TB treatment on hospital mortality. Trend of annual Acute Physiology and Chronic Health Evaluation (APACHE) IV-adjusted standardised mortality ratio (SMR) over the 11-year period was analysed by Mann-Kendall's trend test. RESULTS: ICU and hospital mortality were 24.7% (232/940) and 41.1% (386/940), respectively. Of those who died in the ICU, 22.8% (53/232) never received antituberculosis drugs. SMR for ICU patients with TB remained unchanged over the study period (Kendall's τb=0.37, p=0.876). After adjustment for age, Charlson comorbidity index, APACHE IV, albumin, vasopressors, mechanical ventilation and renal replacement therapy, delayed TB treatment was directly associated with hospital mortality. In 302/940 (32.1%) of patients, TB could only be established from MTB cultures alone as Ziehl-Neelsen staining or PCR was either not performed or negative. Among this group, only 31.1% (94/302) had concurrent MTB PCR performed. CONCLUSIONS: Survival of ICU patients with TB has not improved over the last decade and mortality remains high. Delay in TB treatment was associated with higher hospital mortality. Use of MTB PCR may improve diagnostic yield and facilitate early treatment.

Lysosome activation in peripheral blood mononuclear cells and prognostic significance of circulating LC3B in COVID-19.

Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide, causing significant mortality. There is a mechanistic relationship between intracellular coronavirus replication and deregulated autophagosome-lysosome system. We performed transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients and identified the aberrant upregulation of genes in the lysosome pathway. We further determined the capability of two circulating markers, namely microtubule-associated proteins 1A/1B light chain 3B (LC3B) and (p62/SQSTM1) p62, both of which depend on lysosome for degradation, in predicting the emergence of moderate-to-severe disease in COVID-19 patients requiring hospitalization for supplemental oxygen therapy. Logistic regression analyses showed that LC3B was associated with moderate-to-severe COVID-19, independent of age, sex and clinical risk score. A decrease in LC3B concentration <5.5 ng/ml increased the risk of oxygen and ventilatory requirement (adjusted odds ratio: 4.6; 95% CI: 1.1-22.0; P = 0.04). Serum concentrations of p62 in the moderate-to-severe group were significantly lower in patients aged 50 or below. In conclusion, lysosome function is deregulated in PBMCs isolated from COVID-19 patients, and the related biomarker LC3B may serve as a novel tool for stratifying patients with moderate-to-severe COVID-19 from those with asymptomatic or mild disease. COVID-19 patients with a decrease in LC3B concentration <5.5 ng/ml will require early hospital admission for supplemental oxygen therapy and other respiratory support.

A narrative review on antimicrobial therapy in septic shock: updates and controversies.

PURPOSE OF REVIEW: Antibiotics are an essential treatment for septic shock. This review provides an overview of the key issues in antimicrobial therapy for septic shock. We include a summary of available evidence with an emphasis on data published in the last few years. RECENT FINDINGS: We examine apparently contradictory data supporting the importance of minimizing time to antimicrobial therapy in sepsis, discuss approaches to choosing appropriate antibiotics, and review the importance and challenges presented by antimicrobial dosing. Lastly, we evaluate the evolving concepts of de-escalation, and optimization of the duration of antimicrobials. SUMMARY: The topics discussed in this review provide background to key clinical decisions in antimicrobial therapy for septic shock: timing, antibiotic choice, dosage, de-escalation, and duration. Although acknowledging some controversy, antimicrobial therapy in septic shock should be delivered early, be of the adequate spectrum, appropriately and individually dosed, rationalized when possible, and of minimal effective duration.

Medical students and professionalism - Do the hidden curriculum and current role models fail our future doctors?

PURPOSE: Formal medical curricula aim to promote professionalism through learning from lectures, interactive tutorials and simulations. We report an exploratory voting exercise, conducted within a new integrated professional teaching module, examining the likely influence on students' knowledge and perceptions of truth telling. METHODS: Responses were collected from cohorts of final year students over a six-year period. Students were asked to pick between two responses to a standardized clinical vignette, firstly the response that they personally thought was the more desirable action, and subsequently the response they believed would most likely result in the context of everyday real-life clinical practice. RESULTS: The difference (proportional change) in voting for "avoid full disclosure" from vote 1 (more desirable action) to vote 2 (likely real-life response) was 50% (95% CI: 36-64%, p < 0.001) favoring avoidance of full disclosure. CONCLUSIONS: This finding highlights a substantial inconsistency between the knowledge taught by the formal curriculum, and the perception generated by the hidden curriculum. Medical Schools should develop strategies to manage the hidden curriculum, prepare clinical teachers to be good role models, and prepare students to be discerning about the hidden curriculum and when choosing role models.

The Effect of a Freely Available Flipped Classroom Course on Health Care Worker Patient Safety Culture: A Prospective Controlled Study.

BACKGROUND: Patient safety culture is an integral aspect of good standard of care. A good patient safety culture is believed to be a prerequisite for safe medical care. However, there is little evidence on whether general education can enhance patient safety culture. OBJECTIVE: Our aim was to assess the impact of a standardized patient safety course on health care worker patient safety culture. METHODS: Health care workers from Intensive Care Units (ICU) at two hospitals (A and B) in Hong Kong were recruited to compare the changes in safety culture before and after a patient safety course. The BASIC Patient Safety course was administered only to staff from Hospital A ICU. Safety culture was assessed in both units at two time points, one before and one after the course, by using the Hospital Survey on Patient Safety Culture questionnaire. Responses were coded according to the Survey User's Guide, and positive response percentages for each patient safety domain were compared to the 2012 Agency for Healthcare Research and Quality ICU sample of 36,120 respondents. RESULTS: We distributed 127 questionnaires across the two hospitals with an overall response rate of 74.8% (95 respondents). After the safety course, ICU A significantly improved on teamwork within hospital units (P=.008) and hospital management support for patient safety (P<.001), but decreased in the frequency of reporting mistakes compared to the initial survey (P=.006). Overall, ICU A staff showed significantly greater enhancement in positive responses in five domains than staff from ICU B. Pooled data indicated that patient safety culture was poorer in the two ICUs than the average ICU in the Agency for Healthcare Research and Quality database, both overall and in every individual domain except hospital management support for patient safety and hospital handoffs and transitions. CONCLUSIONS: Our study demonstrates that a structured, reproducible short course on patient safety may be associated with an enhancement in several domains in ICU patient safety culture.

Diagnostic test accuracy of preoperative nutritional screening tools in adults for malnutrition: a systematic review and network meta-analysis.

BACKGROUND: Good nutritional screening tests can triage malnourished patients for further assessment and management by dietitians before surgery to reduce the risk of postoperative complications. The authors assessed the diagnostic test accuracy of common nutritional screening tools for preoperative malnutrition in adults undergoing surgery and determined which test had the highest accuracy. METHODS: MEDLINE, EMBASE, CINAHL, and Web of Science were searched for relevant titles with no language restriction from inception till 1 January 2023. Studies reporting on the diagnostic test accuracy of preoperative malnutrition in adults using one or more of the following index nutritional screening tools were included: Malnutrition Screening Tool (MST), Malnutrition Universal Screening Tool (MUST), Mini Nutritional Assessment (MNA), short-form Mini Nutritional Assessment (MNA-SF), Nutritional Risk Index (NRI), Nutrition Risk Screening Tool 2002 (NRS-2002), and Preoperative Nutrition Screening (PONS). The reference standard was the Subjective Global Assessment (SGA) before surgery. Random-effects bivariate binomial model meta-analyses, meta-regressions, and a network meta-analysis were used to estimate the pooled and relative sensitivities and specificities. RESULTS: Of the 16 included studies (5695 participants with an 11 957 index and 11 957 SGA tests), all were conducted after hospital admission before surgery. Eleven studies ( n =3896) were at high risk of bias using the Quality Assessment of Diagnostic Accuracy Studies tool due to a lack of blinded assessments. MUST had the highest overall test accuracy performance (sensitivity 86%, 95% CI: 75-93%; specificity 89%, 95% CI: 83-93%). Network meta-analysis showed NRI had similar relative sensitivity (0.93, 95% CI: 0.77-1.13) but lower relative specificity (0.75, 95% CI: 0.61-0.92) than MUST. CONCLUSIONS: Of all easy-to-use tests applicable at the bedside, MUST had the highest test accuracy performance for screening preoperative malnutrition. However, its predictive accuracy is likely insufficient to justify the application of nutritional optimization interventions without additional assessments.

Preoperative rectus femoris muscle ultrasound, its relationship with frailty scores, and the ability to predict recovery after cardiac surgery: a prospective cohort study.

BACKGROUND: Frailty is common in patients undergoing cardiac surgery and is associated with poorer postoperative outcomes. Ultrasound examination of skeletal muscle morphology may serve as an objective assessment tool as lean muscle mass reduction is a key feature of frailty. METHODS: This study investigated the association of ultrasound-derived muscle thickness, cross-sectional area, and echogenicity of the rectus femoris muscle (RFM) with preoperative frailty and predicted subsequent poor recovery after surgery. Eighty-five patients received preoperative RFM ultrasound examination and frailty-related assessments: Clinical Frailty Scale (CFS) and 5-m gait speed test (GST5m). Association of each ultrasound measurement with frailty assessments was examined. Area under receiver-operating characteristic curve (AUROC) was used to assess the discriminative ability of each ultrasound measurement to predict days at home within 30 days of surgery (DAH30). RESULTS: By CFS and GST5m criteria, 13% and 34% respectively of participants were frail. RFM cross-sectional area alone demonstrated moderate predictive association for frailty by CFS criterion (AUROC: 0.76, 95% CI: 0.66-0.85). Specificity improved to 98.7% (95% CI: 93.6%-100.0%) by utilising RFM cross-sectional area as an 'add-on' test to a positive gait speed test, and thus a combined muscle size and function test demonstrated higher predictive performance (positive likelihood ratio: 40.4, 95% CI: 5.3-304.3) for frailty by CFS criterion than either test alone (p < 0.001). The combined 'add-on' test predictive performance for DAH30 (AUROC: 0.90, 95% CI: 0.81-0.95) may also be superior to either CFS or gait speed test alone. CONCLUSIONS: Preoperative RFM ultrasound examination, especially when integrated with the gait speed test, may be useful to identify patients at high risk of frailty and those with poor outcomes after cardiac surgery. TRIAL REGISTRATION: The study was registered on the Chinese Clinical Trials Registry (ChiCTR2000031098) on 22 March 2020.

Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism.

OBJECTIVE: Glucagon-like peptide 1 (GLP-1) receptor agonists reduce food intake, producing remarkable weight loss in overweight and obese individuals. While much of this weight loss is fat mass, there is also a loss of lean mass, similar to other approaches that induce calorie deficit. Targeting signaling pathways that regulate skeletal muscle hypertrophy is a promising avenue to preserve lean mass and modulate body composition. Myostatin and Activin A are TGFß-like ligands that signal via the activin type II receptors (ActRII) to antagonize muscle growth. Pre-clinical and clinical studies demonstrate that ActRII blockade induces skeletal muscle hypertrophy and reduces fat mass. In this manuscript, we test the hypothesis that combined ActRII blockade and GLP-1 receptor agonism will preserve muscle mass, leading to improvements in skeletomuscular and metabolic function and enhanced fat loss. METHODS: In this study, we explore the therapeutic potential of bimagrumab, a monoclonal antibody against ActRII, to modify body composition alone and during weight loss induced by GLP-1 receptor agonist semaglutide in diet-induced obese mice. Mechanistically, we define the specific role of the anabolic kinase Akt in mediating the hypertrophic muscle effects of ActRII inhibition in vivo. RESULTS: Treatment of obese mice with bimagrumab induced a ∼10 % increase in lean mass while simultaneously decreasing fat mass. Daily treatment of obese mice with semaglutide potently decreased body weight; this included a significant decrease in both muscle and fat mass. Combination treatment with bimagrumab and semaglutide led to superior fat mass loss while simultaneously preserving lean mass despite reduced food intake. Treatment with both drugs was associated with improved metabolic outcomes, and increased lean mass was associated with improved exercise performance. Deletion of both Akt isoforms in skeletal muscle modestly reduced, but did not prevent, muscle hypertrophy driven by ActRII inhibition. CONCLUSIONS: Collectively, these data demonstrate that blockade of ActRII signaling improves body composition and metabolic parameters during calorie deficit driven by GLP-1 receptor agonism and demonstrate the existence of Akt-independent pathways supporting muscle hypertrophy in the absence of ActRII signaling.

Therapeutic drug monitoring of carbapenem antibiotics in critically ill patients: an overview of principles, recommended dosing regimens, and clinical outcomes.

INTRODUCTION: The importance of antibiotic treatment for sepsis in critically ill septic patients is well established. Consistently achieving the dose of antibiotics required to optimally kill bacteria, minimize the development of resistance, and avoid toxicity is challenging. The increasing understanding of the pharmacokinetic and pharmacodynamic (PK/PD) characteristics of antibiotics, and the effects of critical illness on key PK/PD parameters, is gradually re-shaping how antibiotics are dosed in critically ill patients. AREAS COVERED: The PK/PD characteristics of commonly used carbapenem antibiotics, the principles of the application of therapeutic drug monitoring (TDM), and current as well as future methods of utilizing TDM to optimally devise dosing regimens will be reviewed. The limitations and evidence-base supporting the use of carbapenem TDM to improve outcomes in critically ill patients will be examined. EXPERT OPINION: It is important to understand the principles of TDM in order to correctly inform dosing regimens. Although the concept of TDM is attractive, and the ability to utilize PK software to optimize dosing in the near future is expected to rapidly increase clinicians' ability to meet pre-defined PK/PD targets more accurately, current evidence provides only limited support for the use of TDM to guide carbapenem dosing in critically ill patients.

Comparison of COVID-19 with influenza A in the ICU: a territory-wide, retrospective, propensity matched cohort on mortality and length of stay.

OBJECTIVES: Direct comparisons between COVID-19 and influenza A in the critical care setting are limited. The objective of this study was to compare their outcomes and identify risk factors for hospital mortality. DESIGN AND SETTING: This was a territory-wide, retrospective study on all adult (≥18 years old) patients admitted to public hospital intensive care units in Hong Kong. We compared COVID-19 patients admitted between 27 January 2020 and 26 January 2021 with a propensity-matched historical cohort of influenza A patients admitted between 27 January 2015 and 26 January 2020. We reported outcomes of hospital mortality and time to death or discharge. Multivariate analysis using Poisson regression and relative risk (RR) was used to identify risk factors for hospital mortality. RESULTS: After propensity matching, 373 COVID-19 and 373 influenza A patients were evenly matched for baseline characteristics. COVID-19 patients had higher unadjusted hospital mortality than influenza A patients (17.5% vs 7.5%, p<0.001). The Acute Physiology and Chronic Health Evaluation IV (APACHE IV) adjusted standardised mortality ratio was also higher for COVID-19 than influenza A patients ((0.79 (95% CI 0.61 to 1.00) vs 0.42 (95% CI 0.28 to 0.60)), p<0.001). Adjusting for age, PaO2/FiO2, Charlson Comorbidity Index and APACHE IV, COVID-19 (adjusted RR 2.26 (95% CI 1.52 to 3.36)) and early bacterial-viral coinfection (adjusted RR 1.66 (95% CI 1.17 to 2.37)) were directly associated with hospital mortality. CONCLUSIONS: Critically ill patients with COVID-19 had substantially higher hospital mortality when compared with propensity-matched patients with influenza A.

Acute Deletion of the FOXO1-dependent Hepatokine FGF21 Does not Alter Basal Glucose Homeostasis or Lipolysis in Mice.

The hepatic transcription factor forkhead box O1 (FOXO1) is a critical regulator of hepatic and systemic insulin sensitivity. Previous work by our group and others demonstrated that genetic inhibition of FOXO1 improves insulin sensitivity both in genetic and dietary mouse models of metabolic disease. Mechanistically, this is due in part to cell nonautonomous control of adipose tissue insulin sensitivity. However, the mechanisms mediating this liver-adipose tissue crosstalk remain ill defined. One candidate hepatokine controlled by hepatic FOXO1 is fibroblast growth factor 21 (FGF21). Preclinical and clinical studies have explored the potential of pharmacological FGF21 as an antiobesity and antidiabetic therapy. In this manuscript, we performed acute loss-of-function experiments to determine the role of hepatocyte-derived FGF21 in glucose homeostasis and insulin tolerance both in control and mice lacking hepatic insulin signaling. Surprisingly, acute deletion of FGF21 did not alter glucose tolerance, insulin tolerance, or adipocyte lipolysis in either liver-specific FGF21KO mice or mice lacking hepatic AKT-FOXO1-FGF21, suggesting a permissive role for endogenous FGF21 in the regulation of systemic glucose homeostasis and insulin tolerance in mice. In addition, these data indicate that liver FOXO1 controls glucose homeostasis independently of liver-derived FGF21.

Activation of Liver mTORC1 Protects Against NASH via Dual Regulation of VLDL-TAG Secretion and De Novo Lipogenesis.

BACKGROUND & AIMS: Dysregulation of liver lipid metabolism is associated with the development and progression of nonalcoholic fatty liver disease, a spectrum of liver diseases including nonalcoholic steatohepatitis (NASH). In the liver, insulin controls lipid homeostasis by increasing triglyceride (TAG) synthesis, suppressing fatty acid oxidation, and enhancing TAG export via very low-density lipoproteins. Downstream of insulin signaling, the mechanistic target of rapamycin complex 1 (mTORC1), is a key regulator of lipid metabolism. Here, we define the role of hepatic mTORC1 activity in mouse models of NASH and investigate the mTORC1-dependent mechanisms responsible for protection against liver damage in NASH. METHODS: Utilizing 2 rodent NASH-promoting diets, we demonstrate that hepatic mTORC1 activity was reduced in mice with NASH, whereas under conditions of insulin resistance and benign fatty liver, mTORC1 activity was elevated. To test the beneficial effects of hepatic mTORC1 activation in mouse models of NASH, we employed an acute, liver-specific knockout model of TSC1 (L-TSC-KO), a negative regulator of mTORC1. RESULTS: L-TSC-KO mice are protected from and have improved markers of NASH including reduced steatosis, decreased circulating transaminases, and reduced expression of inflammation and fibrosis genes. Mechanistically, protection from hepatic inflammation and fibrosis by constitutive mTORC1 activity occurred via promotion of the phosphatidylcholine synthesizing enzyme, CCTα, and enhanced very low-density lipoprotein-triglyceride export. Additionally, activation of mTORC1 protected from hepatic steatosis via negative feedback of the mTORC2-AKT-FOXO-SREBP1c lipogenesis axis. CONCLUSIONS: Collectively, this study identifies a protective role for liver mTORC1 signaling in the initiation and progression of NASH in mice via dual control of lipid export and synthesis.

A Narrative Review on the Approach to Antimicrobial Use in Ventilated Patients with Multidrug Resistant Organisms in Respiratory Samples-To Treat or Not to Treat? That Is the Question.

Multidrug resistant organisms (MDRO) are commonly isolated in respiratory specimens taken from mechanically ventilated patients. The purpose of this narrative review is to discuss the approach to antimicrobial prescription in ventilated patients who have grown a new MDRO isolate in their respiratory specimen. A MEDLINE and PubMed literature search using keywords "multidrug resistant organisms", "ventilator-associated pneumonia" and "decision making", "treatment" or "strategy" was used to identify 329 references as background for this review. Lack of universally accepted diagnostic criteria for ventilator-associated pneumonia, or ventilator-associated tracheobronchitis complicates treatment decisions. Consideration of the clinical context including signs of respiratory infection or deterioration in respiratory or other organ function is essential. The higher the quality of respiratory specimens or the presence of bacteremia would suggest the MDRO is a true pathogen, rather than colonization, and warrants antimicrobial therapy. A patient with higher severity of illness has lower safety margins and may require initiation of antimicrobial therapy until an alternative diagnosis is established. A structured approach to the decision to treat with antimicrobial therapy is proposed.

Global-run on sequencing identifies Gm11967 as an Akt-dependent long noncoding RNA involved in insulin sensitivity.

The insulin responsive Akt and FoxO1 signaling axis is a key regulator of the hepatic transcriptional response to nutrient intake. Here, we used global run-on sequencing (GRO-seq) to measure the nascent transcriptional response to fasting and refeeding as well as define the specific role of hepatic Akt and FoxO1 signaling in mediating this response. We identified 599 feeding-regulated transcripts, as well as over 6,000 eRNAs, and mapped their dependency on Akt and FoxO1 signaling. Further, we identified several feeding-regulated lncRNAs, including the lncRNA Gm11967, whose expression was dependent upon the liver Akt-FoxO1 axis. Restoring Gm11967 expression in mice lacking liver Akt improved insulin sensitivity and induced glucokinase protein expression, indicating that Akt-dependent control of Gm11967 contributes to the translational control of glucokinase. More broadly, we have generated a unique genome-wide dataset that defines the feeding and Akt/FoxO1-dependent transcriptional changes in response to nutrient availability.

AKT controls protein synthesis and oxidative metabolism via combined mTORC1 and FOXO1 signalling to govern muscle physiology.

BACKGROUND: Skeletomuscular diseases result in significant muscle loss and decreased performance, paralleled by a loss in mitochondrial and oxidative capacity. Insulin and insulin-like growth factor-1 (IGF-1) are two potent anabolic hormones that activate a host of signalling intermediates including the serine/threonine kinase AKT to influence skeletal muscle physiology. Defective AKT signalling is associated with muscle pathology, including cachexia, sarcopenia, and disuse; however, the mechanistic underpinnings remain unresolved. METHODS: To elucidate the role of AKT signalling in muscle mass and physiology, we generated both congenital and inducible mouse models of skeletal muscle-specific AKT deficiency. To understand the downstream mechanisms mediating AKT's effects on muscle biology, we generated mice lacking AKT1/2 and FOXO1 (M-AKTFOXO1TKO and M-indAKTFOXO1TKO) to inhibit downstream FOXO1 signalling, AKT1/2 and TSC1 (M-AKTTSCTKO and M-indAKTTSCTKO) to activate mTORC1, and AKT1/2, FOXO1, and TSC1 (M-QKO and M-indQKO) to simultaneously activate mTORC1 and inhibit FOXO1 in AKT-deficient skeletal muscle. Muscle proteostasis and physiology were assessed using multiple assays including metabolic labelling, mitochondrial function, fibre typing, ex vivo physiology, and exercise performance. RESULTS: Here, we show that genetic ablation of skeletal muscle AKT signalling resulted in decreased muscle mass and a loss of oxidative metabolism and muscle performance. Specifically, deletion of muscle AKT activity during development or in adult mice resulted in a significant reduction in muscle growth by 30-40% (P  < 0.0001; n = 12-20) and 15% (P < 0.01 and P < 0.0001; n = 20-30), respectively. Interestingly, this reduction in muscle mass was primarily due to an ~40% reduction in protein synthesis in both M-AKTDKO and M-indAKTDKO muscles (P < 0.05 and P < 0.01; n = 12-20) without significant changes in proteolysis or autophagy. Moreover, a significant reduction in oxidative capacity was observed in both M-AKTDKO (P < 0.05, P < 0.01 and P < 0.001; n = 5-12) and M-indAKTDKO (P < 0.05 and P < 0.01; n = 4). Mechanistically, activation and inhibition of mTORC1/FOXO1, respectively, but neither alone, were sufficient to restore protein synthesis, muscle oxidative capacity, and muscle function in the absence of AKT in vivo. In a mouse model of disuse-induced muscle loss, simultaneous activation of mTORC1 and inhibition of FOXO1 preserved muscle mass following immobilization (~5-10% reduction in casted M-indFOXO1TSCDKO muscles vs. ~30-40% casted M-indControl muscles, P < 0.05 and P < 0.0001; n = 8-16). CONCLUSIONS: Collectively, this study provides novel insights into the AKT-dependent mechanisms that underlie muscle protein homeostasis, function, and metabolism in both normal physiology and disuse-induced muscle wasting.

SARS-CoV-2 non-structural protein 6 triggers NLRP3-dependent pyroptosis by targeting ATP6AP1.

A recent mutation analysis suggested that Non-Structural Protein 6 (NSP6) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a key determinant of the viral pathogenicity. Here, by transcriptome analysis, we demonstrated that the inflammasome-related NOD-like receptor signaling was activated in SARS-CoV-2-infected lung epithelial cells and Coronavirus Disease 2019 (COVID-19) patients' lung tissues. The induction of inflammasomes/pyroptosis in patients with severe COVID-19 was confirmed by serological markers. Overexpression of NSP6 triggered NLRP3/ASC-dependent caspase-1 activation, interleukin-1ß/18 maturation, and pyroptosis of lung epithelial cells. Upstream, NSP6 impaired lysosome acidification to inhibit autophagic flux, whose restoration by 1α,25-dihydroxyvitamin D3, metformin or polydatin abrogated NSP6-induced pyroptosis. NSP6 directly interacted with ATP6AP1, a vacuolar ATPase proton pump component, and inhibited its cleavage-mediated activation. L37F NSP6 variant, which was associated with asymptomatic COVID-19, exhibited reduced binding to ATP6AP1 and weakened ability to impair lysosome acidification to induce pyroptosis. Consistently, infection of cultured lung epithelial cells with live SARS-CoV-2 resulted in autophagic flux stagnation, inflammasome activation, and pyroptosis. Overall, this work supports that NSP6 of SARS-CoV-2 could induce inflammatory cell death in lung epithelial cells, through which pharmacological rectification of autophagic flux might be therapeutically exploited.

Loss of FOXO transcription factors in the liver mitigates stress-induced hyperglycemia.

OBJECTIVE: Stress-induced hyperglycemia is associated with poor outcomes in nearly all critical illnesses. This acute elevation in glucose after injury or illness is associated with increased morbidity and mortality, including multiple organ failure. Stress-induced hyperglycemia is often attributed to insulin resistance as controlling glucose levels via exogenous insulin improves outcomes, but the mechanisms are unclear. Forkhead box O (FOXO) transcription factors are direct targets of insulin signaling in the liver that regulate glucose homeostasis via direct and indirect pathways. Loss of hepatic FOXO transcription factors reduces hyperglycemia in chronic insulin resistance; however, the role of FOXOs in stress-induced hyperglycemia is unknown. METHODS: We subjected mice lacking FOXO transcription factors in the liver to a model of injury known to cause stress-induced hyperglycemia. Glucose, insulin, glycerol, fatty acids, cytokines, and adipokines were assessed before and after injury. Liver and adipose tissue were analyzed for changes in glycogen, FOXO target gene expression, and insulin signaling. RESULTS: Stress-induced hyperglycemia was associated with reduced hepatic insulin signaling and increased hepatic FOXO target gene expression while loss of FOXO1, 3, and 4 in the liver attenuated hyperglycemia and prevented hyperinsulinemia. Mechanistically, the loss of FOXO transcription factors mitigated the stress-induced hyperglycemia response by directly altering gene expression and glycogenolysis in the liver and indirectly suppressing lipolysis in adipose tissue. Reductions were associated with decreased IL-6, TNF-α, and follistatin and increased FGF21, suggesting that cytokines and FOXO-regulated hepatokines contribute to the stress-induced hyperglycemia response. CONCLUSIONS: This study implicates FOXO transcription factors as a predominant driver of stress-induced hyperglycemia through means that include cross-talk between the liver and adipose, highlighting a novel mechanism underlying acute hyperglycemia and insulin resistance in stress.

Hepatic AKT orchestrates adipose tissue thermogenesis via FGF21-dependent and -independent mechanisms.

Organismal stressors such as cold exposure require a systemic response to maintain body temperature. Brown adipose tissue (BAT) is a key thermogenic tissue in mammals that protects against hypothermia in response to cold exposure. Defining the complex interplay of multiple organ systems in this response is fundamental to our understanding of adipose tissue thermogenesis. In this study, we identify a role for hepatic insulin signaling via AKT in the adaptive response to cold stress and show that liver AKT is an essential cell-nonautonomous regulator of adipocyte lipolysis and BAT function. Mechanistically, inhibition of forkhead box O1 (FOXO1) by AKT controls BAT thermogenesis by enhancing catecholamine-induced lipolysis in the white adipose tissue (WAT) and increasing circulating fibroblast growth factor 21 (FGF21). Our data identify a role for hepatic insulin signaling via the AKT-FOXO1 axis in regulating WAT lipolysis, promoting BAT thermogenic capacity, and ensuring a proper thermogenic response to acute cold exposure.

Effect of preparative rehabilitation on recovery after cardiac surgery: A systematic review.

BACKGROUND: Physical prehabilitation (preparative rehabilitation) programs may have beneficial effects on enhancing physical strength and functional status before surgery, but their effects on postoperative recovery are unclear. OBJECTIVES: This systematic review investigated the effectiveness of physical prehabilitation programs before cardiac surgery on postoperative recovery and other perioperative outcomes. METHODS: We searched for reports of randomised controlled trials of any prehabilitation programs that included physical activity or an exercise training component in adults undergoing elective cardiac surgery, published in any language, from six bibliographic databases (last search on June 20, 2019). We assessed trials for risk of bias, overall certainty of evidence and quality of intervention reporting using the Cochrane Risk of Bias Assessment Tool, GRADE system and the Template for Intervention Description and Replication checklist and guide, respectively. RESULTS: All 7 studies (726 participants) were at high risk of bias because of lack of blinding. The quality of prehabilitation reporting was moderate because program adherence was rarely assessed. The timing of prehabilitation ranged from 5 days to 16 weeks before surgery and from face-to-face exercise prescription to telephone counselling and monitoring. We found uncertain effects of prehabilitation on postoperative clinical outcomes (among the many outcomes assessed): perioperative mortality (Peto odds ratio 1.30, 95% confidence interval [CI] 0.28 to 5.95; I2=0%; low-certainty evidence) and postoperative atrial fibrillation (relative risk 0.75, 95% CI 0.38 to 1.46; I2=50%; very low-certainty evidence). However, prehabilitation may improve postoperative functional capacity and slightly shorten the hospital stay (mean difference -0.66 days, 95% CI -1.29 to -0.03; I2=45%; low-certainty evidence). CONCLUSION: Despite the high heterogeneity among physical prehabilitation trials and the uncertainty regarding robust clinical outcomes, physical prehabilitation before cardiac surgery seems to enhance selected postoperative functional performance measures and slightly reduce the hospital length of stay after cardiac surgery.