Metabolic requirement of septic shock patients before and after liberation from mechanical ventilation

Objectives:Negative energy balance can impair regeneration of the respiratory epithelium and limit the functionality of respiratory muscles, which can prolong mechanical ventilation. The present study sought to quantify and identify the difference in energy expenditure of patients with septic shock during and upon liberation from mechanical ventilation. Methods:Patients admitted into intensive care with initial diagnosis of septic shock and mechanical ventilation-dependent were recruited. Their metabolic requirements before and after liberation from mechanical ventilation were measured by indirect calorimetry. A paired t-test was used to examine the variance between the two modes of breathing and a Spearman rho correlation coefficient to examine relationship of selected indicators.Results: Thirty-five patients, 20 males and 15 females mean age 69 ±10 years, body height of 1.58 ±0.08 meters, and ideal body mass 59.01 ±7.63 kg were recruited. Median APACHEII score was 22, length of stay in the intensive care was 45 ±65 days and duration on mechanical ventilation was 24 ±25 days. Measured energy expenditure during ventilation was 2090 ±489 kcal∙d-1 upon liberation from ventilation was 1910 ±579 kcal∙d-1 and actual caloric intake was 1148 ±495 kcal∙d-1. Measured energy expenditure (p=0.02), actual calories provision and energy expenditure with (p=0.00) and without (p=0.00) ventilator support were all significantly different. Mean carbohydrate oxidation was 0.17 ±0.09 g·min-1 when patients were on mechanical ventilation compared to 0.14 ±0.08 g·min-1 upon liberation, however, this difference was not statistically significant. Furthermore, mean lipid oxidation was 0.08 ±0.05 g·min-1 during mechanical ventilation and 0.09±0.07 g·min-1 upon liberation, which was also not statistically different. Comparison of carbohydrate utilization and lipid oxidation was not different during (0.7±0.36 vs 0.75±0.47 kcal·min-1) and upon liberation from mechanical ventilation (0.55±0.33 vs 0.78±0.59 kcal·min-1).Conclusions: This study examined energy expenditure and substrate oxidation within a single cohort of patients with and without mechanical ventilation. Measured energy expenditure was found to be higher during mechanical ventilation. The possible explanations were positive pressure support from ventilation, the repeated cycle of “rest” and “work” during weaning from ventilators and the asynchronization between self-initiated breathing effort and the ventilatory support. The change energy expenditure with and without ventilatory support should be monitored so that mismatch could be aligned. Future studies are important to examine whether matching energy expenditure with energy intake would promote positive outcomes.<br/

Exogenous Expression of Human apoA-I Enhances Cardiac Differentiation of Pluripotent Stem Cells

The cardioprotective effects of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 (apoA-I) are well documented, but their effects in the direction of the cardiac differentiation of embryonic stem cells are unknown. We evaluated the effects of exogenous apoA-I expression on cardiac differentiation of ESCs and maturation of ESC-derived cardiomyocytes. We stably over-expressed full-length human apoA-I cDNA with lentivirus (LV)-mediated gene transfer in undifferentiated mouse ESCs and human induced pluripotent stem cells. Upon cardiac differentiation, we observed a significantly higher percentage of beating embryoid bodies, an increased number of cardiomyocytes as determined by flow cytometry, and expression of cardiac markers including α-myosin heavy chain, β-myosin heavy chain and myosin light chain 2 ventricular transcripts in LV-apoA-I transduced ESCs compared with control (LV-GFP). In the presence of noggin, a BMP4 antagonist, activation of BMP4-SMAD signaling cascade in apoA-I transduced ESCs completely abolished the apoA-I stimulated cardiac differentiation. Furthermore, co-application of recombinant apoA-I and BMP4 synergistically increased the percentage of beating EBs derived from untransduced D3 ESCs. These together suggests that that pro-cardiogenic apoA-I is mediated via the BMP4-SMAD signaling pathway. Functionally, cardiomyocytes derived from the apoA-I-transduced cells exhibited improved calcium handling properties in both non-caffeine and caffeine-induced calcium transient, suggesting that apoA-I plays a role in enhancing cardiac maturation. This increased cardiac differentiation and maturation has also been observed in human iPSCs, providing further evidence of the beneficial effects of apoA-I in promoting cardiac differentiation. In Conclusion, we present novel experimental evidence that apoA-I enhances cardiac differentiation of ESCs and iPSCs and promotes maturation of the calcium handling property of ESC-derived cardiomyocytes via the BMP4/SMAD signaling pathway

Metabolic requirement of septic shock patients before and after liberation from mechanical ventilation

Objectives:Negative energy balance can impair regeneration of the respiratory epithelium and limit the functionality of respiratory muscles, which can prolong mechanical ventilation. The present study sought to quantify and identify the difference in energy expenditure of patients with septic shock during and upon liberation from mechanical ventilation. Methods:Patients admitted into intensive care with initial diagnosis of septic shock and mechanical ventilation-dependent were recruited. Their metabolic requirements before and after liberation from mechanical ventilation were measured by indirect calorimetry. A paired t-test was used to examine the variance between the two modes of breathing and a Spearman rho correlation coefficient to examine relationship of selected indicators.Results: Thirty-five patients, 20 males and 15 females mean age 69 ±10 years, body height of 1.58 ±0.08 meters, and ideal body mass 59.01 ±7.63 kg were recruited. Median APACHEII score was 22, length of stay in the intensive care was 45 ±65 days and duration on mechanical ventilation was 24 ±25 days. Measured energy expenditure during ventilation was 2090 ±489 kcal∙d-1 upon liberation from ventilation was 1910 ±579 kcal∙d-1 and actual caloric intake was 1148 ±495 kcal∙d-1. Measured energy expenditure (p=0.02), actual calories provision and energy expenditure with (p=0.00) and without (p=0.00) ventilator support were all significantly different. Mean carbohydrate oxidation was 0.17 ±0.09 g·min-1 when patients were on mechanical ventilation compared to 0.14 ±0.08 g·min-1 upon liberation, however, this difference was not statistically significant. Furthermore, mean lipid oxidation was 0.08 ±0.05 g·min-1 during mechanical ventilation and 0.09±0.07 g·min-1 upon liberation, which was also not statistically different. Comparison of carbohydrate utilization and lipid oxidation was not different during (0.7±0.36 vs 0.75±0.47 kcal·min-1) and upon liberation from mechanical ventilation (0.55±0.33 vs 0.78±0.59 kcal·min-1).Conclusions: This study examined energy expenditure and substrate oxidation within a single cohort of patients with and without mechanical ventilation. Measured energy expenditure was found to be higher during mechanical ventilation. The possible explanations were positive pressure support from ventilation, the repeated cycle of “rest” and “work” during weaning from ventilators and the asynchronization between self-initiated breathing effort and the ventilatory support. The change energy expenditure with and without ventilatory support should be monitored so that mismatch could be aligned. Future studies are important to examine whether matching energy expenditure with energy intake would promote positive outcomes.<br/

Sequential algorithm to stratify liver fibrosis risk in overweight/obese metabolic dysfunction-associated fatty liver disease

BackgroundNon-diabetic overweight/obese metabolic dysfunction-associated fatty liver disease (MAFLD) represents the largest subgroup with heterogeneous liver fibrosis risk. Metabolic dysfunction promotes liver fibrosis. Here, we investigated whether incorporating additional metabolic risk factors into clinical evaluation improved liver fibrosis risk stratification among individuals with non-diabetic overweight/obese MAFLD.Materials and methodsComprehensive metabolic evaluation including 75-gram oral glucose tolerance test was performed in over 1000 participants from the New Hong Kong Cardiovascular Risk Factor Prevalence Study (HK-NCRISPS), a contemporary population-based study of HK Chinese. Hepatic steatosis and fibrosis were evaluated based on controlled attenuation parameter and liver stiffness (LS) measured using vibration-controlled transient elastography, respectively. Clinically significant liver fibrosis was defined as LS ≥8.0 kPa. Our findings were validated in an independent pooled cohort comprising individuals with obesity and/or polycystic ovarian syndrome.ResultsOf the 1020 recruited community-dwelling individuals, 312 (30.6%) had non-diabetic overweight/obese MAFLD. Among them, 6.4% had LS ≥8.0 kPa. In multivariable stepwise logistic regression analysis, abnormal serum aspartate aminotransferase (AST) (OR 7.95, p&lt;0.001) and homeostasis model assessment of insulin resistance (HOMA-IR) ≥2.5 (OR 5.01, p=0.008) were independently associated with LS ≥8.0 kPa, in a model also consisting of other metabolic risk factors including central adiposity, hypertension, dyslipidaemia and prediabetes. A sequential screening algorithm using abnormal AST, followed by elevated HOMA-IR, was developed to identify individuals with LS ≥8.0 kPa, and externally validated with satisfactory sensitivity (&gt;80%) and negative predictive value (&gt;90%).ConclusionA sequential algorithm incorporating AST and HOMA-IR levels improves fibrosis risk stratification among non-diabetic overweight/obese MAFLD individuals

Oncological outcome after free jejunal flap reconstruction for carcinoma of the hypopharynx

It has been a common practice among the oncologist to reduce the dosage of adjuvant radiotherapy for patients after free jejunal flap reconstruction. The current aims to study potential risk of radiation to the visceral flap and the subsequent oncological outcome. Between 1996 and 2010, consecutive patients with carcinoma of the hypopharynx requiring laryngectomy, circumferential pharyngectomy and post-operative irradiation were recruited. Ninety-six patients were recruited. TNM tumor staging at presentation was: stage II (40.6%), stage III (34.4%) and stage IV (25.0%). Median follow-up period after surgery was 68 months. After tumor ablation, reconstruction was performed using free jejunal flap (60.4%), pectoralis major myocutaneous (PM) flap (31.3%) and free anterolateral thigh (ALT) flap (8.3%). All patients underwent adjuvant radiotherapy within 6.4 weeks after surgery. The mean total dose of radiation given to those receiving cutaneous and jejunal flap reconstruction was 62.2 Gy and 54.8 Gy, respectively. There was no secondary ischaemia or necrosis of the flaps after radiotherapy. The 5-year actuarial loco-regional tumor control for the cutaneous flap and jejunal flap group was: stage II (61 vs. 69%, p = 0.9), stage III (36 vs. 46%, p = 0.2) and stage IV (32 vs. 14%, p = 0.04), respectively. Reduction of radiation dosage in free jejunal group adversely affects the oncological control in stage IV hypopharyngeal carcinoma. In such circumstances, tubed cutaneous flaps are the preferred reconstructive option, so that full-dose radiotherapy can be given

Genome-Wide Association Study in Asian Populations Identifies Variants in ETS1 and WDFY4 Associated with Systemic Lupus Erythematosus

Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33×10−11, OR = 1.29; WDFY4: rs7097397, P = 8.15×10−12, OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3′-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved

Targeted gene sanger sequencing should remain the first-tier genetic test for children suspected to have the five common X-linked inborn errors of immunity

DATA AVAILABILITY STATEMENT : The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.To address inborn errors of immunity (IEI) which were underdiagnosed in resource-limited regions, our centre developed and offered free genetic testing for the most common IEI by Sanger sequencing (SS) since 2001. With the establishment of The Asian Primary Immunodeficiency (APID) Network in 2009, the awareness and definitive diagnosis of IEI were further improved with collaboration among centres caring for IEI patients from East and Southeast Asia. We also started to use whole exome sequencing (WES) for undiagnosed cases and further extended our collaboration with centres from South Asia and Africa. With the increased use of Next Generation Sequencing (NGS), we have shifted our diagnostic practice from SS to WES. However, SS was still one of the key diagnostic tools for IEI for the past two decades. Our centre has performed 2,024 IEI SS genetic tests, with in-house protocol designed specifically for 84 genes, in 1,376 patients with 744 identified to have disease-causing mutations (54.1%). The high diagnostic rate after just one round of targeted gene SS for each of the 5 common IEI (X-linked agammaglobulinemia (XLA) 77.4%, Wiskott–Aldrich syndrome (WAS) 69.2%, X-linked chronic granulomatous disease (XCGD) 59.5%, X-linked severe combined immunodeficiency (XSCID) 51.1%, and X-linked hyper-IgM syndrome (HIGM1) 58.1%) demonstrated targeted gene SS should remain the first-tier genetic test for the 5 common X-linked IEI.The Hong Kong Society for Relief of Disabled Children and Jeffrey Modell Foundation.http://www.frontiersin.org/Immunologyam2023Paediatrics and Child Healt

Hierarchical operational control of automated manufacturing systems

published_or_final_versionIndustrial and Manufacturing Systems EngineeringDoctoralDoctor of Philosoph