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Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin Versus Transarterial Chemoembolization for Large Hepatocellular Carcinoma: A Randomized Phase III Trial.
Li, QJ, He, MK, Chen, HW, Fang, WQ, Zhou, YM, Xu, L, Wei, W, Zhang, YJ, Guo, Y, Guo, RP, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2022;(2):150-160
Abstract
PURPOSE In a previous phase II trial, hepatic arterial infusion chemotherapy (HAIC) with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) yielded higher treatment responses than transarterial chemoembolization (TACE) in large unresectable hepatocellular carcinoma. We aimed to compare the overall survival of patients treated with FOLFOX-HAIC versus TACE as first-line treatment in this population. METHODS In this randomized, multicenter, open-label trial, adults with unresectable hepatocellular carcinoma (largest diameter ≥ 7 cm) without macrovascular invasion or extrahepatic spread were randomly assigned 1:1 to FOLFOX-HAIC (oxaliplatin 130 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2 on day 1, and fluorouracil infusion 2,400 mg/m2 for 24 hours, once every 3 weeks) or TACE (epirubicin 50 mg, lobaplatin 50 mg, and lipiodol and polyvinyl alcohol particles). The primary end point was overall survival by intention-to-treat analysis. Safety was assessed in patients who received ≥ 1 cycle of study treatment. RESULTS Between October 1, 2016, and November 23, 2018, 315 patients were randomly assigned to FOLFOX-HAIC (n = 159) or TACE (n = 156). The median overall survival in the FOLFOX-HAIC group was 23.1 months (95% CI, 18.5 to 27.7) versus 16.1 months (95% CI, 14.3 to 17.9) in the TACE group (hazard ratio, 0.58; 95% CI, 0.45 to 0.75; P < .001). The FOLFOX-HAIC group showed a higher response rate than the TACE group (73 [46%] v 28 [18%]; P < .001) and a longer median progression-free survival (9.6 [95% CI, 7.4 to 11.9] v 5.4 months [95% CI, 3.8 to 7.0], P < .001). The incidence of serious adverse events was higher in the TACE group than in the FOLFOX-HAIC group (30% v 19%, P = .03). Two deaths in the FOLFOX-HAIC group and two in the TACE group were deemed to be treatment-related. CONCLUSION FOLFOX-HAIC significantly improved overall survival over TACE in patients with unresectable large hepatocellular carcinoma.
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Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study.
Ren, Z, Xu, J, Bai, Y, Xu, A, Cang, S, Du, C, Li, Q, Lu, Y, Chen, Y, Guo, Y, et al
The Lancet. Oncology. 2021;(7):977-990
Abstract
BACKGROUND China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2-3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. METHODS This randomised, open-label, phase 2-3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab-bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes. FINDINGS Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab-bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8-46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5-11·7) in the sintilimab-bevacizumab biosimilar group and 10·0 months (8·4-11·7) in the sorafenib group. Patients in the sintilimab-bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1-5·7]) than did patients in the sorafenib group (2·8 months [2·7-3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46-0·70; p<0·0001). In the first interim analysis of overall survival, sintilimab-bevacizumab biosimilar showed a significantly longer overall survival than did sorafenib (median not reached [95% CI not reached-not reached] vs 10·4 months [8·5-not reached]; HR 0·57, 95% CI 0·43-0·75; p<0·0001). The most common grade 3-4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patients in the sintilimab-bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab-bevacizumab biosimilar group and 36 (19%) patients in the sorafenib group had serious adverse events. Treatment-related adverse events that led to death occurred in six (2%) patients in the sintilimab-bevacizumab biosimilar group (one patient with abnormal liver function, one patient with both hepatic failure and gastrointestinal haemorrhage, one patient with interstitial lung disease, one patient with both hepatic faliure and hyperkalemia, one patient with upper gastrointestinal haemorrhage, and one patient with intestinal volvulus) and two (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhage and one patient with death of unknown cause). INTERPRETATION Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. FUNDING Innovent Biologics. TRANSLATION For the Chinese translation of the abstract see Supplementary Materials section.
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COMPARISON OF THE INTERNAL LIMITING MEMBRANE INSERTION TECHNIQUE AND THE INVERTED INTERNAL LIMITING MEMBRANE FLAP TECHNIQUE WITH VITRECTOMY TO TREAT MACULAR HOLE-ASSOCIATED RETINAL DETACHMENT.
Zhu, K, Lei, B, Wong, W, Zhang, J, Guo, Y, Chen, H, Song, F, Chang, Q, Xu, G, Zhang, Y
Retina (Philadelphia, Pa.). 2021;(1):37-44
Abstract
PURPOSE To compare the anatomical and functional outcomes of macular hole (MH)-associated retinal detachment after vitrectomy with the internal limiting membrane (ILM) insertion technique or the inverted ILM flap technique. METHODS In this retrospective observational study, we reviewed the medical records of 49 eyes with MH-associated retinal detachment that underwent vitrectomy with the ILM insertion (26 eyes) or ILM flap (23 eyes) technique. RESULTS The MH closure rate at 12 months was greater in the ILM flap group versus the ILM insertion group (95% vs. 73%, respectively, P = 0.059). The postoperative best-corrected visual acuity (BCVA) at 12 months was significantly better in the ILM flap group (P = 0.014). All eyes (100%) showed an improvement in the BCVA of ≥0.3 logarithm of the minimum angle of resolution (15 Early Treatment Diabetic Retinopathy Study letters) in the ILM flap group versus 20 eyes (77%) in the ILM insertion group (P = 0.026). The preoperative BCVA and the ILM flap technique were significantly correlated with the postoperative BCVA (P = 0.028 and 0.027, respectively) and BCVA improvement (≥0.3 logarithm of the minimum angle of resolution [15 Early Treatment Diabetic Retinopathy Study letters]; P = 0.003 and 0.026, respectively). CONCLUSION The inverted ILM flap technique was more effective in improving the postoperative BCVA in patients with MH-associated retinal detachment when compared with the ILM insertion technique. The preoperative BCVA and the ILM flap technique were independent prognostic factors for visual outcomes in patients with MH-associated retinal detachment.
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Observational and Genetic Associations of Body Mass Index and Hepatobiliary Diseases in a Relatively Lean Chinese Population.
Pang, Y, Kartsonaki, C, Lv, J, Millwood, IY, Yu, C, Guo, Y, Chen, Y, Bian, Z, Yang, L, Chen, J, et al
JAMA network open. 2020;(10):e2018721
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Abstract
IMPORTANCE There is some support for the existence of genetic associations between adiposity and certain hepatobiliary diseases in Western populations. However, there is little evidence of such genetic associations in China, where the causes of these diseases may differ from those in Western populations and the mean body mass index (BMI) is much lower. OBJECTIVES To compare the observational associations of BMI with hepatobiliary diseases and liver biomarkers with the genetic associations between BMI and these factors and to assess whether the genetic associations of BMI with liver diseases differed by hepatitis B virus infection status. DESIGN, SETTING, AND PARTICIPANTS This cohort study used data from the prospective China Kadoorie Biobank, including 473 938 adults aged 30 to 79 years without hepatobiliary diseases at baseline from 10 diverse areas in China from June 25, 2004, to July 15, 2008. A random sample of 75 736 participants with genotyping data was included in the Mendelian randomization analysis. Follow-up was completed January 1, 2017 (median [interquartile range] length of follow-up, 10.2 [9.2-11.1] years). Data were analyzed from January to October 2019. EXPOSURES Measured BMI obtained during the baseline survey and genetically instrumented BMI derived using 92 single-nucleotide variations. MAIN OUTCOMES AND MEASURES Incident cases of hepatobiliary diseases, liver enzymes, fatty liver index, and fibrosis score. RESULTS Among 473 938 individuals (276 041 [58.2%] women), the mean (SD) age was 52 (10.9) years and mean (SD) BMI was 23.8 (3.4). Baseline BMI was associated with higher risks of chronic liver disease (adjusted risk ratio per 1-SD increase, 1.14; 95% CI, 1.11 to 1.17) and gallbladder disease (adjusted risk ratio per 1-SD increase, 1.29; 95% CI, 1.27 to 1.31), with heterogeneity by disease subtype (P < .001). Genetically instrumented BMI was associated with higher risks of chronic liver disease (risk ratio per 1-SD increase, 1.55; 95% CI, 1.08 to 2.24) and gallbladder disease (risk ratio per 1-SD increase, 1.40; 95% CI, 1.11 to 1.76), with no heterogeneity between subtypes. A meta-analysis of the genetic associations in China Kadoorie Biobank and those calculated in UK Biobank gave a risk ratio of 1.55 (95% CI, 1.30 to 1.84) for chronic liver disease and 1.42 (95% CI, 1.22 to 1.64) for gallbladder disease. In the China Kadoorie Biobank study, there were positive genetic associations of BMI with liver enzymes, steatosis, and fibrosis scores, consistent with observational associations. The genetic associations of BMI with liver diseases and biomarkers did not differ by hepatitis B virus infection status. CONCLUSIONS AND RELEVANCE In this cohort study of a relatively lean Chinese population, there were positive genetic associations of BMI with hepatobiliary diseases. These results suggest that maintaining a healthy weight through diet and physical activity may help prevent hepatobiliary diseases.
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Advances in research on treatment of heart failure with nitrosyl hydrogen.
Guo, Y, Xu, J, Wu, L, Deng, Y, Wang, J, An, J
Heart failure reviews. 2019;(6):941-948
Abstract
Heart failure is the end stage of various heart diseases such as ischemic heart disease, dilated cardiomyopathy, valvular heart disease, congenital heart disease, and hypertensive myocardial damage. It is characterized by a decrease in myocardial contractility, but there is currently no ideal treatment. Nitroxyl hydrogen (HNO) is considered to be a protonated form of NO. It has special chemical properties compared to other nitrogen oxides. In the body of organisms, HNO can participate in all aspects of the occurrence and development of heart failure (HF) and react with some proteins closely related to cardiac activity, changing its spatial structure and exerting cardioprotective effects. In recent years, studies have shown that HNO can inhibit cardiomyocyte hypertrophy, reduce inflammation, enhance myocardial contractility, dilate coronary arteries as well as peripheral blood vessels in early heart failure, and protect the heart against heart failure. This paper, combined with the latest research results at home and abroad, clarifies that nitrosyl hydrogen exerts cardioprotective effects through various processes that occur in the development of heart failure.
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Bioavailability and bioactivity of free ellagic acid compared to pomegranate juice.
Long, J, Guo, Y, Yang, J, Henning, SM, Lee, RP, Rasmussen, A, Zhang, L, Lu, QY, Heber, D, Li, Z
Food & function. 2019;(10):6582-6588
Abstract
Pomegranates are an excellent source of ellagic acid (EA), ellagitannins (ETs), anthocyanins and other phytochemicals. The health benefits of pomegranate (Pom) have been mainly related to its EA and ET content. The objective of the present study was to determine EA bioavailability and bioactivity from different sources such as pure/free or natural form (PomJ). This was a cross-over study with healthy volunteers consuming one dose of EA dietary supplement (500 mg free EA) vs. one serving of PomJ (237 mL, ∼120 mg of EA) in a random order. Our data showed that there was no difference in plasma EA concentration between PomJ and EA intake; however, urinary dimethylellagic acid glucuronide (DMEAG), normalized to creatinine, was significantly higher after the consumption of PomJ compared to EA. Plasma insulin at 1 h increased after PomJ consumption compared to the baseline while decreased after EA consumption compared to the baseline. Plasma glucose decreased below the baseline 2 h after the consumption of PomJ but not EA. Plasma leptin was significantly decreased at 1 and 2 h after PomJ and EA consumption. Plasma MCP1 decreased only after PomJ but not after pure EA consumption. To conclude, one serving of PomJ provided the same level of EA in blood, while the increase in phase II metabolism of EA and an acute suppression of plasma MCP1 were only observed after PomJ consumption, suggesting that other constituents present in PomJ, in addition to EA, are bioactive and likely play a role in regulating EA phase II metabolism.
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Spectroscopic and Reactivity Comparisons between Nonheme Oxoiron(IV) and Oxoiron(V) Species Bearing the Same Ancillary Ligand.
Dantignana, V, Serrano-Plana, J, Draksharapu, A, Magallón, C, Banerjee, S, Fan, R, Gamba, I, Guo, Y, Que, L, Costas, M, et al
Journal of the American Chemical Society. 2019;(38):15078-15091
Abstract
This work directly compares the spectroscopic and reactivity properties of an oxoiron(IV) and an oxoiron(V) complex that are supported by the same neutral tetradentate N-based PyNMe3 ligand. A complete spectroscopic characterization of the oxoiron(IV) species (2) reveals that this compound exists as a mixture of two isomers. The reactivity of the thermodynamically more stable oxoiron(IV) isomer (2b) is directly compared to that exhibited by the previously reported 1e--oxidized analogue [FeV(O)(OAc)(PyNMe3)]2+ (3). Our data indicates that 2b is 4 to 5 orders of magnitude slower than 3 in hydrogen atom transfer (HAT) from C-H bonds. The origin of this huge difference lies in the strength of the O-H bond formed after HAT by the oxoiron unit, the O-H bond derived from 3 being about 20 kcal·mol-1 stronger than that from 2b. The estimated bond strength of the FeIVO-H bond of 100 kcal·mol-1 is very close to the reported values for highly active synthetic models of compound I of cytochrome P450. In addition, this comparative study provides direct experimental evidence that the lifetime of the carbon-centered radical that forms after the initial HAT by the high valent oxoiron complex depends on the oxidation state of the nascent Fe-OH complex. Complex 2b generates long-lived carbon-centered radicals that freely diffuse in solution, while 3 generates short-lived caged radicals that rapidly form product C-OH bonds, so only 3 engages in stereoretentive hydroxylation reactions. Thus, the oxidation state of the iron center modulates not only the rate of HAT but also the rate of ligand rebound.
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Anti-Inflammatory Effects of a Vegan Diet Versus the American Heart Association-Recommended Diet in Coronary Artery Disease Trial.
Shah, B, Newman, JD, Woolf, K, Ganguzza, L, Guo, Y, Allen, N, Zhong, J, Fisher, EA, Slater, J
Journal of the American Heart Association. 2018;7(23):e011367
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Plain language summary
Inflammation plays a central role in the progression of atherosclerosis and is associated with adverse cardiovascular events. The aim of this study was to determine the effects of a vegan versus American Heart Association (AHA)-recommended diet on high-sensitivity C-reactive protein (hsCRP) [a type of protein found in blood plasma], as well as other markers of inflammation, glucometabolic markers, and lipid profiles in patients with established coronary artery disease (CAD) on guideline-directed medical therapy. This study is a prospective, randomized, open-label, blinded end point study design. The active study duration was 8 weeks, with an interim visit at 4 weeks and a final visit at 8 weeks. Results show: - a significantly greater reduction in hsCRP with a vegan versus AHA-recommended diet in patients with established CAD on guideline-directed medical therapy. - that the degree of weight loss, as measured by both body mass index and waist circumference, did not significantly differ between the 2 diet groups. - that markers of glycaemic control and lipid profiles, overall, also did not significantly differ in the vegan diet group when compared with the AHA-recommended diet group. Authors conclude that in patients with CAD and an elevated hsCRP, despite guideline-directed medical therapy, a vegan diet may be considered to further lower the parameters of inflammation.
Abstract
Background Dietary interventions may play a role in secondary cardiovascular prevention. hsCRP (High-sensitivity C-reactive protein) is a marker of risk for major adverse cardiovascular outcomes in coronary artery disease. Methods and Results The open-label, blinded end-point, EVADE CAD (Effects of a Vegan Versus the American Heart Association-Recommended Diet in Coronary Artery Disease) trial randomized participants (n=100) with coronary artery disease to 8 weeks of a vegan or American Heart Association-recommended diet with provision of groceries, tools to measure dietary intake, and dietary counseling. The primary end point was high-sensitivity C-reactive protein. A linear regression model compared end points after 8 weeks of a vegan versus American Heart Association diet and adjusted for baseline concentration of the end point. Significance levels for the primary and secondary end points were set at 0.05 and 0.0015, respectively. A vegan diet resulted in a significant 32% lower high-sensitivity C-reactive protein (β, 0.68, 95% confidence interval [0.49-0.94]; P=0.02) when compared with the American Heart Association diet. Results were consistent after adjustment for age, race, baseline waist circumference, diabetes mellitus, and prior myocardial infarction (adjusted β, 0.67 [0.47-0.94], P=0.02). The degree of reduction in body mass index and waist circumference did not significantly differ between the 2 diet groups (adjusted β, 0.99 [0.97-1.00], P=0.10; and adjusted β, 1.00 [0.98-1.01], P=0.66, respectively). There were also no significant differences in markers of glycemic control between the 2 diet groups. There was a nonsignificant 13% reduction in low-density lipoprotein cholesterol with the vegan diet when compared with the American Heart Association diet (adjusted β, 0.87 [0.78-0.97], P=0.01). There were no significant differences in other lipid parameters. Conclusions In patients with coronary artery disease on guideline-directed medical therapy, a vegan diet may be considered to lower high-sensitivity C-reactive protein as a risk marker of adverse outcomes. Clinical Trial Registration URL http://www.clinicaltrials.gov . Unique identifier: NCT 02135939.
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Coupling individual kernel-filling processes with source-sink interactions into GREENLAB-Maize.
Ma, Y, Chen, Y, Zhu, J, Meng, L, Guo, Y, Li, B, Hoogenboom, G
Annals of botany. 2018;(5):961-973
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Abstract
BACKGROUND AND AIMS Failure to account for the variation of kernel growth in a cereal crop simulation model may cause serious deviations in the estimates of crop yield. The goal of this research was to revise the GREENLAB-Maize model to incorporate source- and sink-limited allocation approaches to simulate the dry matter accumulation of individual kernels of an ear (GREENLAB-Maize-Kernel). METHODS The model used potential individual kernel growth rates to characterize the individual potential sink demand. The remobilization of non-structural carbohydrates from reserve organs to kernels was also incorporated. Two years of field experiments were conducted to determine the model parameter values and to evaluate the model using two maize hybrids with different plant densities and pollination treatments. Detailed observations were made on the dimensions and dry weights of individual kernels and other above-ground plant organs throughout the seasons. KEY RESULTS Three basic traits characterizing an individual kernel were compared on simulated and measured individual kernels: (1) final kernel size; (2) kernel growth rate; and (3) duration of kernel filling. Simulations of individual kernel growth closely corresponded to experimental data. The model was able to reproduce the observed dry weight of plant organs well. Then, the source-sink dynamics and the remobilization of carbohydrates for kernel growth were quantified to show that remobilization processes accompanied source-sink dynamics during the kernel-filling process. CONCLUSIONS We conclude that the model may be used to explore options for optimizing plant kernel yield by matching maize management to the environment, taking into account responses at the level of individual kernels.
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Comparing the measured basal metabolic rates in patients with chronic disorders of consciousness to the estimated basal metabolic rate calculated from common predictive equations.
Xiao, G, Xie, Q, He, Y, Wang, Z, Chen, Y, Jiang, M, Ni, X, Wang, Q, Murong, M, Guo, Y, et al
Clinical nutrition (Edinburgh, Scotland). 2017;(5):1397-1402
Abstract
BACKGROUND Accurately predicting the basal metabolic rate (BMR) of patients in a vegetative state (VS) or minimally conscious state (MCS) is critical to proper nutritional therapy, but commonly used equations have not been shown to be accurate. Therefore, we compared the BMR measured by indirect calorimetry (IC) to BMR values estimated using common predictive equations in VS and MCS patients. METHODS Body composition variables were measured using the bioelectric impedance analysis (BIA) technique. BMR was measured by IC in 82 patients (64 men and 18 women) with VS or MCS. Patients were classified by body mass index as underweight (<18.5 kg/m2, n = 34) or normal-weight (18.5 ≤ BMI < 25 kg/m2, n = 48). BMR was estimated for each group using the Harris-Benedict (H-B), Schofield, or Cunningham equations and compared to the measured BMR using Bland-Altman analyses. RESULTS For the underweight group, there was a significant difference between the measured BMR values and the estimated BMR values calculated using the H-B, Schofield, and Cunningham equations (p < 0.05). For the normal-weight group, the BMR values estimated using the H-B and Cunningham equations were different significantly from the measured BMR (p < 0.05 and p < 0.01 respectively). Of the predictive equations, only Schofield was not significantly different from the measured BMR in the normal-weight group. The Schofield equation showed the best concordance (only 41.5%) with the BMR values measured by IC. CONCLUSIONS None of the commonly used equations to estimate BMR were suitable for the VS or MCS populations. Indirect calorimetry is the preferred way to avoid either over or underestimate of BMR values.