Correction: Paszkiewicz et al. A Peripheral CB1R Antagonist Increases Lipolysis, Oxygen Consumption Rate, and Markers of Beiging in 3T3-L1 Adipocytes Similar to RIM, Suggesting That Central Effects Can Be Avoided. Int. J. Mol. Sci. 2020, 21, 6639.

The authors wish to make the following corrections to this paper [...].

Defining cutoffs to diagnose obesity using the relative fat mass (RFM): Association with mortality in NHANES 1999-2014.

BACKGROUND/OBJECTIVES: We have recently proposed and validated a simple and accurate method to estimate whole-body fat percentage in adults, the relative fat mass (RFM), derived from the ratio of height to waist circumference. We aimed to identify RFM cutoffs to diagnose obesity based on the association between RFM and all-cause mortality. SUBJECTS/METHODS: We used data from adult participants (≥20 years of age, n = 43,793) of the National Health and Nutrition Examination Survey (NHANES) 1999-2014 linked with death certificate records from the National Death Index. Optimal RFM cutoffs were determined using receiver-operating characteristic analysis (the Youden's index and the Euclidean minimum distance to the coordinate (0,1)). RESULTS: Final dataset for analyses comprised 31,008 adults. During a median follow-up of 8.3 years (IQR, 7.6-13.7), 2,517 deaths occurred. Youden and Euclidean optimal cutoffs of baseline RFM for all-cause mortality were 40.8% and 41.6% for women, and 30.9% and 28.9% for men, respectively. Similar cutoffs were obtained using measured whole-body fat percentage by dual energy X-ray absorptiometry. Adjusting for age, BMI category, ethnicity, education level, and smoking status, the hazard ratio for mortality using Cox proportional hazard regression was 1.41 (95% CI, 1.02-1.95) among women who had an RFM of 40.0-44.9% compared with women who had an RFM <35% (P = 0.035). Among men, the hazard ratio was 1.57 (95% CI, 1.07-2.30) among those with an RFM of 30.0-34.9% compared with men who had an RFM <25% (P = 0.020). Similar adjusted hazard ratios for same RFM categories were obtained in our validation population (NHANES III, n = 12,650, median follow-up: 23.3 years): 1.42 (95% CI, 1.01-2.00) among women (P = 0.043) and 1.50 (95% CI, 1.07-2.10) among men (P = 0.021). CONCLUSIONS: We suggest rounded RFM cutoffs of 40% for women and 30% for men to diagnose obesity and identify individuals at higher risk of death.

A Peripheral CB1R Antagonist Increases Lipolysis, Oxygen Consumption Rate, and Markers of Beiging in 3T3-L1 Adipocytes Similar to RIM, Suggesting that Central Effects Can Be Avoided.

With the increased prevalence of obesity and related co-morbidities, such as type 2 diabetes (T2D), worldwide, improvements in pharmacological treatments are necessary. The brain- and peripheral-cannabinoid receptor 1 (CB1R) antagonist rimonabant (RIM) has been shown to induce weight loss and improve glucose homeostasis. We have previously demonstrated that RIM promotes adipose tissue beiging and decreased adipocyte cell size, even during maintenance on a high-fat diet. Given the adverse side-effects of brain-penetrance with RIM, in this study we aimed to determine the site of action for a non-brain-penetrating CB1R antagonist AM6545. By using in vitro assays, we demonstrated the direct effects of this non-brain-penetrating CB1R antagonist on cultured adipocytes. Specifically, we showed, for the first time, that AM6545 significantly increases markers of adipose tissue beiging, mitochondrial biogenesis, and lipolysis in 3T3-L1 adipocytes. In addition, the oxygen consumption rate (OCR), consisting of baseline respiratory rate, proton leak, maximal respiratory capacity, and ATP synthase activity, was greater for cells exposed to AM6545, demonstrating greater mitochondrial uncoupling. Using a lipolysis inhibitor during real-time OCR measurements, we determined that the impact of CB1R antagonism on adipocytes is driven by increased lipolysis. Thus, our data suggest the direct role of CB1R antagonism on adipocytes does not require brain penetrance, supporting the importance of focus on peripheral CB1R antagonism pharmacology for reducing the incidence of obesity and T2D.

Activation of NPRs and UCP1-independent pathway following CB1R antagonist treatment is associated with adipose tissue beiging in fat-fed male dogs.

CB1 receptor (CB1R) antagonism improves the deleterious effects of a high-fat diet (HFD) by reducing body fat mass and adipocyte cell size. Previous studies demonstrated that the beneficial effects of the CB1R antagonist rimonabant (RIM) in white adipose tissue (WAT) are partially due to an increase of mitochondria numbers and upregulation thermogenesis markers, suggesting an induction of WAT beiging. However, the molecular mechanism by which CB1R antagonism induces weight loss and WAT beiging is unclear. In this study, we probed for genes associated with beiging and explored longitudinal molecular mechanisms by which the beiging process occurs. HFD dogs received either RIM (HFD+RIM) or placebo (PL) (HFD+PL) for 16 wk. Several genes involved in beiging were increased in HFD+RIM compared with pre-fat, HFD, and HFD+PL. We evaluated lipolysis and its regulators including natriuretic peptide (NP) and its receptors (NPRs), ß-1 and ß-3 adrenergic receptor (ß1R, ß3R) genes. These genes were increased in WAT depots, accompanied by an increase in lipolysis in HFD+RIM. In addition, RIM decreased markers of inflammation and increased adiponectin receptors in WAT. We observed a small but significant increase in UCP1; therefore, we evaluated the newly discovered UCP1-independent thermogenesis pathway. We confirmed that SERCA2b and RYR2, the two key genes involved in this pathway, were upregulated in the WAT. Our data suggest that the upregulation of NPRs, ß-1R and ß-3R, lipolysis, and SERCA2b and RYR2 may be one of the mechanisms by which RIM promotes beiging and overall the improvement of metabolic homeostasis induced by RIM.

Assessment of hepatic insulin extraction from in vivo surrogate methods of insulin clearance measurement.

Hyperinsulinemia, accompanied by reduced first-pass hepatic insulin extraction (FPE) and increased secretion, is a primary response to insulin resistance. Different in vivo methods are used to estimate the clearance of insulin, which is assumed to reflect FPE. We compared two methodologically different but commonly used indirect estimates with directly measured FPE in healthy dogs ( n = 9). The indirect methods were 1) metabolic clearance rate of insulin (MCR) during the hyperinsulinemic-euglycemic clamp (EGC), a steady-state method, and 2) fractional clearance rate of insulin (FCR) during the frequently sampled intravenous glucose tolerance test (FSIGT), a dynamic method. MCR was calculated as the ratio of insulin infusion rate to steady-state plasma insulin. FCR was calculated as the exponential decay rate constant of the injected insulin. Directly measured FPE is based on the difference in insulin measurements during intraportal vs. peripheral vein insulin infusions. We found a strong correlation between indirect FCR (min-1) and FPE (%). In contrast, we observed a poor association between MCR (ml·min-1·kg-1) and FPE (%). Our findings in canines suggest that FCR measured during FSIGT can be used to estimate FPE. However, MCR calculated during EGC appears to be a poor surrogate for FPE.

Re-visiting the Endocannabinoid System and Its Therapeutic Potential in Obesity and Associated Diseases.

PURPOSE OF REVIEW: The purpose of the review was to revisit the possibility of the endocannabinoid system being a therapeutic target for the treatment of obesity by focusing on the peripheral roles in regulating appetite and energy metabolism. RECENT FINDINGS: Previous studies with the global cannabinoid receptor blocker rimonabant, which has both central and peripheral properties, showed that this drug has beneficial effects on cardiometabolic function but severe adverse psychiatric side effects. Consequently, focus has shifted to peripherally restricted cannabinoid 1 (CB1) receptor blockers as possible therapeutic agents that mitigate or eliminate the untoward effects in the central nervous system. Targeting the endocannabinoid system using novel peripheral CB1 receptor blockers with negligible penetrance across the blood-brain barrier may prove to be effective therapy for obesity and its co-morbidities. Perhaps the future of blockers targeting CB1 receptors will be tissue-specific neutral antagonists (e.g., skeletal muscle specific to treat peripheral insulin resistance, adipocyte-specific to treat fat excess, liver-specific to treat fatty liver and hepatic insulin resistance).

Effective endothelial cell and human pluripotent stem cell interactions generate functional insulin-producing beta cells.

AIMS/HYPOTHESIS: Endothelial cells (ECs) play an essential role in pancreatic organogenesis. We hypothesise that effective in vitro interactions between human microvascular endothelial cells (HMECs) and human pluripotent stem cells (hPSCs) results in the generation of functional pancreatic beta cells. METHODS: Embryoid bodies (EBs) derived from hPSCs were cultured alone (controls) or with ECs in collagen gels. Subsequently, cells were analysed for pancreatic beta cell markers, and then isolated and expanded. Insulin secretion in response to glucose was evaluated in vitro by static and dynamic (perifusion) assays, and in vivo by EB transplantation into immunodeficient mice. RESULTS: Co-cultured EBs had a higher expression of mature beta cells markers and enhanced insulin secretion in vitro, compared with controls. In mice, transplanted EBs had higher levels of human C-peptide secretion with a significant reduction in hyperglycaemia after the selective destruction of native pancreatic beta cells. In addition, there was significant in vitro upregulation of bone morphogenetic proteins 2 and 4 (BMP-2, 4) in co-cultured cells, compared with controls. CONCLUSIONS/INTERPRETATION: ECs provide essential signalling in vitro, such as activation of the BMP pathway, for derivation of functional insulin-producing beta cells from hPSCs.

CB1R antagonist increases hepatic insulin clearance in fat-fed dogs likely via upregulation of liver adiponectin receptors.

The improvement of hepatic insulin sensitivity by the cannabinoid receptor 1 (CB1R) antagonist rimonabant (RIM) has been recently been reported to be due to upregulation of adiponectin. Several studies demonstrated that improvement in insulin clearance accompanies the enhancement of hepatic insulin sensitivity. However, the effects of RIM on hepatic insulin clearance (HIC) have not been fully explored. The aim of this study was to explore the molecular mechanism(s) by which RIM affects HIC, specifically to determine whether upregulation of liver adiponectin receptors (ADRs) and other key genes regulated by adiponectin mediate the effects. To induce insulin resistance in skeletal muscle and liver, dogs were fed a hypercaloric high-fat diet (HFD) for 6 wk. Thereafter, while still maintained on a HFD, animals received RIM (HFD+RIM; n = 11) or placebo (HFD+PL; n = 9) for an additional 16 wk. HIC, calculated as the metabolic clearance rate (MCR), was estimated from the euglycemic-hyperinsulinemic clamp. The HFD+PL group showed a decrease in MCR; in contrast, the HFD+RIM group increased MCR. Consistently, the expression of genes involved in HIC, CEACAM-1 and IDE, as well as gene expression of liver ADRs, were increased in the HFD+RIM group, but not in the HFD+PL group. We also found a positive correlation between CEACAM-1 and the insulin-degrading enzyme IDE with ADRs. Interestingly, expression of liver genes regulated by adiponectin and involved in lipid oxidation were increased in the HFD+RIM group. We conclude that in fat-fed dogs RIM enhances HIC, which appears to be linked to an upregulation of the adiponectin pathway.

Hepatic portal vein denervation impairs oral glucose tolerance but not exenatide's effect on glycemia.

The hepatoportal area is an important glucohomeostatic metabolic sensor, sensing hypoglycemia, hyperglycemia, and hormones such as glucagon-like peptide-1 (GLP-1). We have reported previously that activation of hepatoportal sensors by intraportal infusion of glucose and GLP-1 or by subcutaneous administration of GLP-1 receptor activator exenatide and of intraportal glucose improved glycemia independent of corresponding changes in pancreatic hormones. It is not clear whether this effect is mediated via the portal vein (PV) or by direct action on the liver itself. To test whether receptors in the PV mediate exenatide's beneficial effect on glucose tolerance, we performed 1) paired oral glucose tolerance tests (OGTT) with and without exenatide and 2) intravenous glucose tolerance tests before and after PV denervation in canines. Denervation of the portal vein affected oral glucose tolerance; post-denervation (POST-DEN) OGTT glucose and insulin AUC were 50% higher than before denervation (P = 0.01). However, portal denervation did not impair exenatide's effect to improve oral glucose tolerance (exenatide effect: 48 ± 12 mmol·l⁻¹·min before vs. 64 ± 26 mmol·l⁻¹·min after, P = 0.67). There were no changes in insulin sensitivity or secretion during IVGTTs. Portal vein sensing might play a role in controlling oral glucose tolerance during physiological conditions but not in pharmacological activation of GLP-1 receptors by exenatide.

On the paper by E. R. Muslikhov, I. F. Sukhanova, and P. V. Avdonin entitled "arachidonic acid activates release of calcium ions from reticulum via ryanodine receptor channels in C2C12 skeletal myotubes" published in Biochemistry (Moscow), Vol. 79, No. 5, pp. 435-439 (2014).

A recent study published by Muslikhov et al. (Biochemistry (Moscow), 79, 435439 (2014)) showed that arachi donic acid increases cytosolic Ca2+ concentrations in C2C12 skeletal myotubes mainly via activation of the ryanodine (RY) receptor 1. These results are consistent with the data from another study demonstrating that arachidonic acid targets RY receptor 2 in clonal and primary pancreatic ßcells (Woolcott et al., 2006). A novel and intriguing finding by Muslikhov's group is that arachidonic acid also appears to activate the twopore ion channel (TPC), suggesting that arachidonic acid could be a mediator in the interaction between TPCs and RY receptors.

Temporal trends in obesity defined by the relative fat mass (RFM) index among adults in the United States from 1999 to 2020: a population-based study.

OBJECTIVES: The body mass index (BMI) largely underestimates excess body fat, suggesting that the prevalence of obesity could be underestimated. Biologically, women are known to have higher body fat than men. This study aimed to compare the temporal trends in general obesity by sex, ethnicity and age among adults in the USA using the relative fat mass (RFM), a validated surrogate for whole-body fat percentage and BMI. DESIGN: Population-based study. SETTING: US National Health and Nutrition Examination Survey, from 1999-2000 to 2017-March 2020. PARTICIPANTS: A representative sample of adults 20-79 years in the USA. MAIN OUTCOME MEASURES: Age-adjusted prevalence of general obesity. RFM-defined obesity was diagnosed using validated cut-offs to predict all-cause mortality: RFM≥40% for women and ≥30% for men. BMI-defined obesity was diagnosed using a cut-off of 30 kg/m2. RESULTS: Analysis included data from 47 667 adults. Among women, RFM-defined obesity prevalence was 64.7% (95% CI 62.1% to 67.3%) in 2017-2020, a linear increase of 13.9 percentage points (95% CI 9.0% to 18.9%; p<0.001) relative to 1999-2000. In contrast, the prevalence of BMI-defined obesity was 42.2% (95% CI 39.4% to 45.0%) in 2017-2020. Among men, the corresponding RFM-defined obesity prevalence was 45.8% (95% CI 42.0% to 49.7%), a linear increase of 12.0 percentage points (95% CI 6.6% to 17.3%; p<0.001). In contrast, the prevalence of BMI-defined obesity was 42.0 (95% CI 37.8% to 46.3%). The highest prevalence of RFM-defined obesity across years was observed in older adults (60-79 years) and Mexican Americans, in women and men. Conversely, the highest prevalence of BMI-defined obesity across years was observed in middle-age (40-59 years) and older adults, and in African American women. CONCLUSIONS: The use of a surrogate for whole-body fat percentage revealed a much higher prevalence of general obesity in the USA from 1999 to 2020, particularly among women, than that estimated using BMI, and detected a disproportionate higher prevalence of general obesity in older adults and Mexican Americans.

Lower Prevalence of Body Fat-Defined Obesity at Higher Altitudes in Peruvian Adults.

Woolcott, Orison O., Till Seuring, and Oscar A. Castillo. Lower prevalence of body fat-defined obesity at higher altitudes in Peruvian adults. High Alt Med Biol. 24:214-222, 2023. Background: Previous studies have reported a lower prevalence of obesity (defined as a body mass index [BMI] ≥30 kg/m2) in populations from higher altitudes. Since BMI does not distinguish fat mass and fat-free mass, it is unclear whether there is an inverse association between altitude and body fat-defined obesity. Methods: We performed an analysis of cross-sectional data to examine the association between altitude and body fat-defined obesity (as opposed to BMI-defined obesity) using individual-level data from a nationally representative sample of the Peruvian adult population living between 0 and 5,400 m altitude. Body fat-defined obesity was diagnosed using the relative fat mass (RFM), an anthropometric index validated to estimate whole-body fat percentage. RFM cutoffs for obesity diagnosis were ≥40% for women and ≥30% for men. We utilized Poisson regression to estimate the prevalence ratio and confidence intervals (CIs) as the measure of the association, adjusting for age, cigarette use, and diabetes. Results: Analysis comprised 36,727 individuals (median age, 39 years; 50.1% women). In rural areas, for a one-km increase in altitude, the prevalence of body fat-defined obesity decreased by 12% among women (adjusted prevalence ratio: 0.88; 95% CI, 0.86 - 0.90; p < 0.001) and 19% among men (adjusted prevalence ratio: 0.81; 95% CI, 0.77 - 0.86; p < 0.001), on average, when all the other variables were held constant. The inverse association between altitude and obesity was less strong in urban areas than in rural areas but remained significant among women (p = 0.001) and men (p < 0.001). However, the relationship between altitude and obesity in women who live in urban areas appears to be nonlinear. Conclusions: In Peruvian adults, the prevalence of body fat-defined obesity was inversely associated with altitude. Whether this inverse association is explained by altitude per se or confounded by socioeconomic or other environmental factors, or differences in race/ethnicity or lifestyle, warrants further investigation.

Dapagliflozin prevents abdominal visceral and subcutaneous adipose tissue dysfunction in the insulin-resistant canine model.

OBJECTIVE: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) promote urinary glucose excretion, induce weight loss, and reduce fat accumulation. The effects of the SGLT2i dapagliflozin (DAPA) on subcutaneous (SC) and visceral (VIS) adipose tissue function remain unclear. The objective of this study is to evaluate SC and VIS adipose tissue function in an insulin-resistant canine model. METHODS: A total of 12 dogs were fed a high-fat diet (HFD) for 6 weeks and then were given a single low dose of streptozotocin (18.5 mg/kg) to induce insulin resistance. Animals were then randomized and exposed to DAPA (n = 6, 1.25 mg/kg) or placebo (n = 6) once per day for 6 weeks while remaining on the HFD. RESULTS: DAPA prevented further weight gain induced by the HFD and normalized fat mass. DAPA reduced fasting glucose and increased free fatty acids, adiponectin, and ß-hydroxybutyrate. DAPA reduced adipocyte diameter and cell distribution. Furthermore, DAPA increased genes associated with beiging, lipolysis, and adiponectin secretion and the expression of the adiponectin receptor ADR2, in SC and VIS adipose tissue. DAPA increased AMP-activated protein kinase activity and maximal mitochondrial respiratory function, especially in the SC depot. Furthermore, DAPA reduced cytokines and ceramide synthesis enzymes in SC and VIS depots. CONCLUSIONS: For the first time, to our knowledge, we identify mechanisms by which DAPA enhances adipose tissue function in regulating energy homeostasis in an insulin-resistant canine model.

CB(1) antagonism restores hepatic insulin sensitivity without normalization of adiposity in diet-induced obese dogs.

The endocannabinoid system is highly implicated in the development of insulin resistance associated with obesity. It has been shown that antagonism of the CB(1) receptor improves insulin sensitivity (S(I)). However, it is unknown whether this improvement is due to the direct effect of CB(1) blockade on peripheral tissues or secondary to decreased fat mass. Here, we examine in the canine dog model the longitudinal changes in S(I) and fat deposition when obesity was induced with a high-fat diet (HFD) and animals were treated with the CB(1) antagonist rimonabant. S(I) was assessed (n = 20) in animals fed a HFD for 6 wk to establish obesity. Thereafter, while HFD was continued for 16 additional weeks, animals were divided into two groups: rimonabant (1.25 mg·kg(-1)·day(-1) RIM; n = 11) and placebo (n = 9). Euglycemic hyperinsulinemic clamps were performed to evaluate changes in insulin resistance and glucose turnover before HFD (week -6) after HFD but before treatment (week 0) and at weeks 2, 6, 12, and 16 of treatment (or placebo) + HFD. Magnetic resonance imaging was performed to determine adiposity- related changes in S(I). Animals developed significant insulin resistance and increased visceral and subcutaneous adiposity after 6 wk of HFD. Treatment with RIM resulted in a modest decrease in total trunk fat with relatively little change in peripheral glucose uptake. However, there was significant improvement in hepatic insulin resistance after only 2 wk of RIM treatment with a concomitant increase in plasma adiponectin levels; both were maintained for the duration of the RIM treatment. CB(1) receptor antagonism appears to have a direct effect on hepatic insulin sensitivity that may be mediated by adiponectin and independent of pronounced reductions in body fat. However, the relatively modest effect on peripheral insulin sensitivity suggests that significant improvements may be secondary to reduced fat mass.

The effect of age on the association between diabetes and mortality in adult patients with COVID-19 in Mexico.

Diabetes is associated with severe COVID-19 and mortality. The aim of the present study was to determine the effect of age on the association between diabetes and mortality in patients with laboratory-confirmed COVID-19 in Mexico. This retrospective cohort study involved patients aged 20 years or older with symptoms of viral respiratory disease who were screened for SARS-CoV-2 infection across the System of Epidemiological Surveillance of Viral Respiratory Disease in Mexico from January 1 through November 4, 2020. Cox proportional-hazard regression was used to calculate the hazard ratio for 28-day mortality and its 95% confidence interval (CI). Among 757,210 patients with COVID-19 (outpatients and inpatients), 120,476 (16%) had diabetes and 80,616 died. Among 878,840 patients without COVID-19 (those who tested negative for SARS-CoV-2 infection), 88,235 (10.0%) had diabetes and 20,134 died. Among patients with COVID-19, diabetes was associated with a hazard ratio for death of 1.49 (95% CI 1.47-1.52), adjusting for age, sex, smoking habit, obesity, hypertension, immunodeficiency, and cardiovascular, pulmonary, and chronic renal disease. The strength of the association decreased with age (trend test: P = 0.004). For example, the adjusted hazard ratio for death was 3.12 (95% CI 2.86-3.40) for patients 20-39 years of age; in contrast, the adjusted hazard ratio of death for patients 80 years of age or older was 1.11 (95% CI 1.06-1.16). The adjusted hazard ratios were 1.66 (95% CI 1.58-1.74) in outpatients and 1.14 (95% CI 1.12-1.16) in inpatients. In hospitalized patients 80 years of age or older, no association was observed between diabetes and COVID-19-related mortality (adjusted hazard ratio: 1.03; 95% CI 0.98-1.08). Among patients without COVID-19, the adjusted hazard ratio for death was 1.78 (95% CI 1.73-1.84). In conclusion, in adult patients with COVID-19 in Mexico, the risk of death associated with diabetes decreased with age. No association between diabetes and mortality was observed among inpatients 80 years of age or older. Our findings should be verified in other populations.

Mortality Attributed to COVID-19 in High-Altitude Populations.

Woolcott, Orison O., and Richard N. Bergman. Mortality attributed to COVID-19 in high-altitude populations. High Alt Med Biol. 21:409-416, 2020. Background: Since partial oxygen pressure decreases as altitude increases, environmental hypoxia could worsen Coronavirus Disease 2019 (COVID-19) patient's hypoxemia. We compared COVID-19 mortality at different altitudes. Methods: Retrospective analysis of population-level data on COVID-19 deaths was conducted in the United States (1,016 counties) and Mexico (567 municipalities). Mixed-model Poisson regression analysis of the association between altitude and COVID-19 mortality was conducted using individual-level data from 40,168 Mexican subjects with COVID-19, adjusting for multiple covariates. Results: Between January 20 and April 13, 2020, mortality rates were higher in U.S. counties located at ≥2,000 m elevation versus those located <1,500 m (12.3 vs. 3.2 per 100,000; p < 0.001). In Mexico, between March 13 and May 13, 2020, mortality rates were higher in municipalities located at ≥2,000 m versus those located <1,500 m (5.3 vs. 3.9 per 100,000; p < 0.001). Among Mexican subjects younger than 65 years, the risk of death was 36% higher in those living at ≥2,000 m versus those living at <1,500 m (adjusted incidence rate ratio [IRR]: 1.36; confidence interval [95% CI], 1.05-1.78; p = 0.022). Among Mexican men, the risk of death was 31% higher at ≥2,000 m versus that at <1,500 m (adjusted IRR: 1.31; 95% CI, 1.03-1.66; p = 0.025). No association between altitude and COVID-19 mortality was found among Mexican women or among Mexican subjects 65 years of age and older. Conclusions: Altitude is associated with COVID-19 mortality in men younger than 65 years.

Sudden cardiac arrest with shockable rhythm in patients with heart failure.

BACKGROUND: Patients with shockable sudden cardiac arrest (SCA; ventricular fibrillation/tachycardia) have significantly better resuscitation outcomes than do those with nonshockable rhythm (pulseless electrical activity/asystole). Heart failure (HF) increases the risk of SCA, but presenting rhythms have not been previously evaluated. OBJECTIVE: We hypothesized that based on unique characteristics, HFpEF (HF with preserved ejection fraction; left ventricular ejection fraction [LVEF] ≥50%), bHFpEF (HF with borderline preserved ejection fraction; LVEF >40% and <50%), and HFrEF (HF with reduced ejection fraction; LVEF ≤40%) manifest differences in presenting rhythm during SCA. METHODS: Consecutive cases of SCA with HF (age ≥18 years) were ascertained in the Oregon Sudden Unexpected Death Study (2002-2019). LVEF was obtained from echocardiograms performed before and unrelated to the SCA event. Presenting rhythms were identified from first responder reports. Logistic regression was used to evaluate the independent association of presenting rhythm with HF subtype. RESULTS: Of 648 subjects with HF and SCA (median age 72 years; interquartile range 62-81 years), 274 had HFrEF (23.4% female), 92 had bHFpEF (35.9% female), and 282 had HFpEF (42.5% female). The rates of shockable rhythms were 44.5% (n = 122), 48.9% (n = 45), and 27.0% (n = 76) for HFrEF, bHFpEF, and HFpEF, respectively (P < .001). Compared with HFpEF, the adjusted odds ratios for shockable rhythm were 1.86 (95% confidence interval 1.27-2.74; P = .002) in HFrEF and 2.26 (95% CI 1.35-3.77; P = .002) in bHFpEF. The rates of survival to hospital discharge were 10.6% (n = 29) in HFrEF, 22.8% (n = 21) in bHFpEF, and 9.9% (n = 28) in HFpEF (P = .003). CONCLUSION: The rates of shockable rhythm during SCA depend on the HF clinical subtype. Patients with bHFpEF had the highest likelihood of shockable rhythm, correlating with the highest rates of survival.

Relative Fat Mass as an estimator of whole-body fat percentage among children and adolescents: A cross-sectional study using NHANES.

We evaluated the ability of the Relative Fat Mass (RFM) to estimate whole-body fat percentage among children and adolescents who participated in the National Health and Nutrition Examination Survey from 1999 through 2006 (n = 10,390). The RFM equation for adults (64 - (20 × height/waist circumference) + (12 × sex)) may be used for adolescents 15 to 19 years of age. For children and adolescents 8 to 14 years of age, we suggest a modified RFM equation, named as the RFMp (RFM pediatric): 74 - (22 × height/waist circumference) + (5 × sex). In both equations, sex equals 0 for boys and 1 for girls. RFMp was more accurate than BMI to estimate whole-body fat percentage (measured by dual energy X-ray absorptiometry, DXA) among girls (percentage of estimates that were <20% of measured body fat percentage, 88.2% vs. 85.7%; P = 0.027) and boys 8 to 14 years of age (83.4% vs. 71.0%; P < 0.001). RFM was more accurate than BMI among boys 15 to 19 years of age (82.3% vs. 73.9%; P < 0.001) but slightly less accurate among girls (89.0% vs. 92.6%; P = 0.002). Compared with BMI-for-age percentiles, RFMp had lower misclassification error of overweight or obesity (defined as a DXA-measured body fat percentage at the 85th percentile or higher) among boys 8 to 14 years of age (6.5% vs. 7.9%; P = 0.018) but not girls (RFMp: 8.2%; BMI-for-age: 7.9%; P = 0.681). Misclassification error of overweight or obesity was similar for RFM and BMI-for-age percentiles among girls (RFM: 8.0%; BMI-for-age: 6.6%; P = 0.076) and boys 15 to 19 years of age (RFM: 6.9%; BMI-for-age: 7.8%; P = 0.11). RFMp for children and adolescents 8 to 14 years of age and RFM for adolescents 15 to 19 years of age were useful to estimate whole-body fat percentage and diagnose body fat-defined overweight or obesity.

Relative fat mass (RFM) as a new estimator of whole-body fat percentage ─ A cross-sectional study in American adult individuals.

High whole-body fat percentage is independently associated with increased mortality. We aimed to identify a simple anthropometric linear equation that is more accurate than the body mass index (BMI) to estimate whole-body fat percentage among adult individuals. National Health and Nutrition Examination Survey (NHANES) 1999-2004 data (n = 12,581) were used for model development and NHANES 2005-2006 data (n = 3,456) were used for model validation. From the 365 anthropometric indices generated, the final selected equation was as follows: 64 - (20 × height/waist circumference) + (12 × sex), named as the relative fat mass (RFM); sex = 0 for men and 1 for women. In the validation dataset, compared with BMI, RFM better predicted whole-body fat percentage, measured by dual energy X-ray absorptiometry (DXA), among women and men. RFM showed better accuracy than the BMI and had fewer false negative cases of body fat-defined obesity among women and men. RFM reduced total obesity misclassification among all women and all men and, overall, among Mexican-Americans, European-Americans and African-Americans. In the population studied, the suggested RFM was more accurate than BMI to estimate whole-body fat percentage among women and men and improved body fat-defined obesity misclassification among American adult individuals of Mexican, European or African ethnicity.