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Competing Interests: The authors have no conflicts of interest to declare.

Source Citation: Giamarellos-Bourboulis EJ, Siampanos A, Bolanou A, et al. Clarithromycin for early anti-inflammatory responses in community-acquired pneumonia in Greece (ACCESS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2024;12:294-304. 38184008., Competing Interests: Disclosures: The commentator has reported no disclosures of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=J24-0022.

Background: The supraclavicular fossa is the dominant location for human brown adipose tissue (BAT). Activation of BAT promotes non-shivering thermogenesis by utilization of glucose and free fatty acids and has been the focus of pharmacological and non-pharmacological approaches for modulation in order to improve body weight and glucose homeostasis. Sympathetic neural control of supraclavicular BAT has received much attention, but its innervation has not been extensively investigated in humans., Methods: Dissection of the cervical region in human cadavers was performed to find the distribution of sympathetic nerve branches to supraclavicular fat pad. Furthermore, proximal segments of the 4th cervical nerve were evaluated histologically to assess its sympathetic components., Results: Nerve branches terminating in supraclavicular fat pad were identified in all dissections, including those from the 3rd and 4th cervical nerves and from the cervical sympathetic plexus. Histology of the proximal segments of the 4th cervical nerves confirmed tyrosine hydroxylase positive thin nerve fibers in all fascicles with either a scattered or clustered distribution pattern. The scattered pattern was more predominant than the clustered pattern (80% vs. 20%) across cadavers. These sympathetic nerve fibers occupied only 2.48% of the nerve cross sectional area on average., Conclusions: Human sympathetic nerves use multiple pathways to innervate the supraclavicular fat pad. The present finding serves as a framework for future clinical approaches to activate human BAT in the supraclavicular region., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mori et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Source Citation: Paton NI, Cousins C, Suresh C, et al; TRUNCATE-TB Trial Team. Treatment strategy for rifampin-susceptible tuberculosis. N Engl J Med. 2023;388:873-887. 36808186., Competing Interests: Disclosures: The commentator has reported no disclosures of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=J23-0036.

Source Citation: Thornhill MH, Gibson TB, Yoon F, et al. Antibiotic prophylaxis against infective endocarditis before invasive dental procedures. J Am Coll Cardiol. 2022;80:1029-41. 35987887.

Adropin is a peptide largely secreted by the liver and known to regulate energy homeostasis; however, it also exerts cardiovascular effects. Herein, we tested the hypothesis that low circulating levels of adropin in obesity and type 2 diabetes (T2D) contribute to arterial stiffening. In support of this hypothesis, we report that obesity and T2D are associated with reduced levels of adropin (in liver and plasma) and increased arterial stiffness in mice and humans. Establishing causation, we show that mesenteric arteries from adropin knockout mice are also stiffer, relative to arteries from wild-type counterparts, thus recapitulating the stiffening phenotype observed in T2D db/db mice. Given the above, we performed a set of follow-up experiments, in which we found that 1 ) exposure of endothelial cells or isolated mesenteric arteries from db/db mice to adropin reduces filamentous actin (F-actin) stress fibers and stiffness, 2 ) adropin-induced reduction of F-actin and stiffness in endothelial cells and db/db mesenteric arteries is abrogated by inhibition of nitric oxide (NO) synthase, and 3 ) stimulation of smooth muscle cells or db/db mesenteric arteries with a NO mimetic reduces stiffness. Lastly, we demonstrated that in vivo treatment of db/db mice with adropin for 4 wk reduces stiffness in mesenteric arteries. Collectively, these findings indicate that adropin can regulate arterial stiffness, likely via endothelium-derived NO, and thus support the notion that "hypoadropinemia" should be considered as a putative target for the prevention and treatment of arterial stiffening in obesity and T2D. NEW & NOTEWORTHY Arterial stiffening, a characteristic feature of obesity and type 2 diabetes (T2D), contributes to the development and progression of cardiovascular diseases. Herein we establish that adropin is decreased in obese and T2D models and furthermore provide evidence that reduced adropin may directly contribute to arterial stiffening. Collectively, findings from this work support the notion that "hypoadropinemia" should be considered as a putative target for the prevention and treatment of arterial stiffening in obesity and T2D.

Source Citation: Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients. N Engl J Med. 2022;386:509-20. 34914868.

Purpose: The optimal age for minimally invasive repair of pectus excavatum (MIRPE) is unclear; this study investigates the differences in complication rates among different age groups undergoing repair., Methods: PubMed and Embase databases were searched from inception to October 2020. To assess age as a risk factor for complications, odds ratios from relevant studies were analyzed using the Mantel-Haenszel method with a random-effects model for younger vs older patients. Specific complication rates were compared between the two cohorts using a chi-squared test., Results: Of the 4448 studies retrieved, 25 studies stratified complication data by age groups. From these studies, ten studies compared groups at ages < 18 and ≥ 18 and four studies compared ages < 20 and ≥ 20, and one study compared ages < 19 and ≥ 19. These fifteen studies reported on 5978 patients, with 1188 complications, for a complication rate of 19.87%. Older patients were more likely to have complications in a pooled analysis of studies comparing older vs younger patients (OR = 1.66, 95% CI = 1.28-2.14, heterogeneity I 2  = 49%). Specifically, older patients were significantly more likely to experience pneumothorax, pleural effusion, wound infection, bar displacement, and reoperations., Conclusion: Increased age is a risk factor for complications of MIRPE. This supports repair of pectus excavatum prior to late adolescence., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The World Trade Center (WTC) general responder cohort (GRC) was exposed to environmental toxins possibly associated with increased risk of developing autoimmune conditions., Objectives: Two study designs were used to assess incidence and risks of autoimmune conditions in the GRC., Methods: Three clinically trained professionals established the status of possible GRC cases of autoimmune disorders adhering to diagnostic criteria, supplemented, as needed, by specialists' review of consenting responders' medical records. Nested case-control analyses using conditional logistic regression estimated the risk associated with high WTC exposure (being in the 9/11/2001 dust cloud or ≥median days' response worked) compared with low WTC exposure (all other GRC members'). Four controls were matched to each case on age at case diagnosis (±2 years), sex, race/ethnicity, and year of program enrollment. Sex-specific and sensitivity analyses were performed. GRC age- and sex-adjusted standardized incidence ratios (SIRs) were compared with the Rochester Epidemiology Project (REP). Complete REP inpatient and outpatient medical records were reviewed by specialists. Conditions meeting standardized criteria on ≥2 visits were classified as REP confirmed cases., Results: Six hundred and twenty-eight responders were diagnosed with autoimmune conditions between 2002 and 2017. In the nested case-control analyses, high WTC exposure was not associated with autoimmune domains and conditions (rheumatologic domain odds ratio [OR] = 1.03, 95% confidence interval [CI] = 0.77, 1.37; rheumatoid arthritis OR = 1.12, 95% CI = 0.70, 1.77). GRC members had lower SIR than REP. Women's risks were generally greater than men's., Conclusions: The study found no statistically significant increased risk of autoimmune conditions with WTC exposures., (© 2021 Wiley Periodicals LLC.)

Source Citation: Heath PT, Galiza EP, Baxter DN, et al. Safety and efficacy of NVX-CoV2373 Covid-19 vaccine. N Engl J Med. 2021;385:1172-83. 34192426.

Beige adipocyte mitochondria contribute to thermogenesis by uncoupling and by ATP-consuming futile cycles. Since uncoupling may inhibit ATP synthesis, it is expected that expenditure through ATP synthesis is segregated to a disparate population of mitochondria. Recent studies in mouse brown adipocytes identified peridroplet mitochondria (PDM) as having greater ATP synthesis and pyruvate oxidation capacities, while cytoplasmic mitochondria have increased fatty acid oxidation and uncoupling capacities. However, the occurrence of PDM in humans and the processes that result in their expansion have not been elucidated. Here, we describe a novel high-throughput assay to quantify PDM that is successfully applied to white adipose tissue from mice and humans. Using this approach, we found that PDM content varies between white and brown fat in both species. We used adipose tissue from pheochromocytoma (Pheo) patients as a model of white adipose tissue browning, which is characterized by an increase in the capacity for energy expenditure. In contrast with control subjects, PDM content was robustly increased in the periadrenal fat of Pheo patients. Remarkably, bioenergetic changes associated with browning were primarily localized to PDM compared to cytoplasmic mitochondria (CM). PDM isolated from periadrenal fat of Pheo patients had increased ATP-linked respiration, Complex IV content and activity, and maximal respiratory capacity. We found similar changes in a mouse model of re-browning where PDM content in whitened brown adipose tissue was increased upon re-browning induced by decreased housing temperature. Taken together, this study demonstrates the existence of PDM as a separate functional entity in humans and that browning in both mice and humans is associated with a robust expansion of peri-droplet mitochondria characterized by increased ATP synthesis linked respiration., (Copyright © 2021. Published by Elsevier B.V.)

Source Citation: Sadoff J, Gray G, Vandebosch A, et al. Safety and efficacy of single-dose Ad26.COV2.S vaccine against Covid-19. N Engl J Med. 2021. [Epub ahead of print.] 33882225.

Source Citation: Riccò M, Ferraro P, Gualerzi G, et al. Point-of-care diagnostic tests for detecting SARS-CoV-2 antibodies: a systematic review and meta-analysis of real-world data. J Clin Med. 2020;9:1515. 32443459.

Background: Following the September 11, 2001, attacks on the World Trade Center (WTC), thousands of workers were exposed to an array of toxins known to cause adverse health effects, including cancer. This study evaluates cancer incidence in the WTC Health Program General Responder Cohort occurring within 12 years post exposure., Methods: The study population consisted of 28 729 members of the General Responder Cohort enrolled from cohort inception, July 2002 to December 31, 2013. Standardized incidence ratios (SIRs) were calculated with cancer case inclusion and follow-up starting post September 11, 2001 (unrestricted) and, alternatively, to account for selection bias, with case inclusion and follow-up starting 6 months after enrollment in the WTC Health Program (restricted). Case ascertainment was based on linkage with six state cancer registries. Under the restricted criterion, hazard ratios were estimated using multivariable Cox proportional hazards models for all cancer sites combined and for prostate cancer., Results: Restricted analyses identified 1072 cancers in 999 responders, with elevations in cancer incidence for all cancer sites combined (SIR = 1.09, 95% confidence interval [CI] = 1.02 to 1.16), prostate cancer (SIR = 1.25, 95% CI = 1.11 to 1.40), thyroid cancer (SIR = 2.19, 95% CI = 1.71 to 2.75), and leukemia (SIR = 1.41, 95% CI = 1.01 to 1.92). Cancer incidence was not associated with any WTC exposure index (composite or individual) for all cancer sites combined or for prostate cancer., Conclusion: Our analyses show statistically significant elevations in cancer incidence for all cancer sites combined and for prostate and thyroid cancers and leukemia. Multivariable analyses show no association with magnitude or type of exposure., (© The Author(s) 2020. Published by Oxford University Press.)

The prevailing dogma is that thermogenic brown adipose tissue (BAT) contributes to improvements in glucose homeostasis in obesogenic animal models, though much of the evidence supporting this premise is from thermostressed rodents. Determination of whether modulation of the BAT morphology/function drives changes in glucoregulation at thermoneutrality requires further investigation. We used loss- and gain-of-function approaches including genetic manipulation of the lipolytic enzyme Pnpla2 , change in environmental temperature, and lifestyle interventions to comprehensively test the premise that a thermogenic-like BAT phenotype is coupled with enhanced glucose tolerance in female mice. In contrast to this hypothesis, we found that 1 ) compared to mice living at thermoneutrality, enhanced activation of BAT and its thermogenic phenotype via chronic mild cold stress does not improve glucose tolerance in obese mice, 2 ) silencing of the Pnpla2 in interscapular BAT causes a brown-to-white phenotypic shift accompanied with inflammation but does not disrupt glucose tolerance in lean mice, and 3 ) exercise and low-fat diet improve glucose tolerance in obese mice but these effects do not track with a thermogenic BAT phenotype. Collectively, these findings indicate that a thermogenic-like BAT phenotype is not linked to heightened glucose tolerance in female mice., (© 2019 by the American Diabetes Association.)

Premenopausal females are protected against adipose tissue inflammation and insulin resistance, until loss of ovarian hormone production (e.g., menopause). There is some evidence that females have greater brown adipose tissue (BAT) thermogenic capacity. Because BAT mass correlates inversely with insulin resistance, we hypothesized that increased uncoupling protein 1 (UCP1) expression contributes to the superior metabolic health of females. Given that UCP1 transiently increases in BAT following ovariectomy (OVX), we hypothesized that UCP1 may 'buffer' OVX-mediated metabolic dysfunction. Accordingly, female UCP1-knockout (KO) and WT mice received OVX or sham (SHM) surgeries at 12 weeks of age creating four groups (n = 10/group), which were followed for 14 weeks and compared for body weight and adiposity, food intake, energy expenditure and spontaneous physical activity (metabolic chambers), insulin resistance (HOMA-IR, ADIPO-IR and glucose tolerance testing) and adipose tissue phenotype (histology, gene and protein expression). Two-way ANOVA was used to assess the main effects of genotype (G), OVX treatment (O) and genotype by treatment (GxO) interactions, which were considered significant when P ≤ 0.05. UCP1KO mice experienced a more adverse metabolic response to OVX than WT. Whereas OVX-induced weight gain was not synergistically greater for KO compared to WT (GxO, NS), OVX-induced insulin resistance was significantly exacerbated in KO compared to WT (GxO for HOMA-IR, P < 0.05). These results suggest UCP1 is protective against metabolic dysfunction associated with loss of ovarian hormones and support the need for more research into therapeutics to selectively target UCP1 for prevention and treatment of metabolic dysfunction following ovarian hormone loss.

Brown adipose tissue (BAT) is considered protective against obesity and related cardiometabolic dysfunction. Indeed, activation of BAT improves glucose homeostasis and attenuates cardiovascular disease development. However, whether a reduction in BAT mass perturbs metabolic function and increases risk for cardiovascular disease remains largely unknown. To address this question, C57BL/6J male mice underwent a sham procedure or surgical bilateral excision of interscapular BAT (iBATx) and were fed a normal chow or a Western diet for 18 wk, creating four groups ( n = 10/group). Mice were housed at 25°C. As expected, the Western diet increased final body weight and adiposity; however, contrary to our hypothesis, iBATx did not potentiate adiposity independent of diet. Furthermore, iBATx did not affect indexes of glycemic control (HbA 1c , fasting glucose and insulin, and glucose area under the curve during a glucose tolerance test) and produced minimal-to-no effects on lipid homeostasis. The absence of metabolic disturbances with iBATx was not attributed to regrowth of iBAT or a "browning" or proliferative compensatory response of other BAT depots. Notably, iBATx caused an increase in aortic stiffness in normal chow-fed mice only, which was associated with an increase in aortic uncoupling protein-1. Collectively, we demonstrated that, at 25°C (i.e., limited thermal stress conditions), a substantial reduction in BAT mass via iBATx does not disrupt systemic glucose metabolism, challenging the current dogma that preservation of BAT is obligatory for optimal metabolic function. However, iBATx caused aortic stiffening in lean mice, hence supporting the existence of an interplay between iBAT and aortic stiffness, independent of alterations in glucose homeostasis.

Background: The objective of this study was to assess differences in hepatitis C virus (HCV) incidence by sex in people who inject drugs (PWID), using a large international multicohort set of pooled biological and behavioral data from prospective observational studies of incident human immunodeficiency virus (HIV) and HCV infections in high-risk cohorts (the InC3 Collaborative)., Methods: HCV infection date was estimated based on a hierarchy of successive serological (anti-HCV), virological (HCV RNA), and clinical (symptoms and/or liver function tests) data. We used a Cox proportional hazards model to calculate the crude and adjusted female to male (F:M) hazard ratio (HR) for HCV incidence using biological sex as the main exposure., Results: A total of 1868 PWID were observed over 3994 person-years of observation (PYO). Unadjusted F:M HR was 1.38 (95% confidence interval [CI], 1.15-1.65) and remained significant after adjusting for behavioral and demographic risk factors (1.39 [95% CI, 1.12-1.72]). Although syringe and equipment sharing were associated with the highest HCV incidence rate in women (41.62 and 36.83 PYO, respectively), we found no sex differences attributed to these risk factors., Conclusions: Our findings indicate that women who inject drugs may be at greater risk of HCV acquisition than men, independent of demographic characteristics and risk behaviors. Multiple factors, including biological (hormonal), social network, and differential access to prevention services, may contribute to increased HCV susceptibility in women who inject drugs., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Females are typically more insulin sensitive than males, which may be partly attributed to greater brown adipose tissue (BAT) activity and uncoupling protein 1 (UCP1) content. Accordingly, we tested the hypothesis that UCP1 deletion would abolish sex differences in insulin sensitivity and that whitening of thoracic periaortic BAT caused by UCP1 loss would be accompanied with impaired thoracic aortic function. Furthermore, because UCP1 exerts antioxidant effects, we examined whether UCP1 deficiency-induced metabolic dysfunction was mediated by oxidative stress. Compared with males, female mice had lower HOMA- and AT-insulin resistance (IR) despite no significant differences in BAT UCP1 content. UCP1 ablation increased HOMA-IR, AT-IR, and whitening of BAT in both sexes. Expression of UCP1 in thoracic aorta was greater in wild-type females compared with males. Importantly, deletion of UCP1 enhanced aortic vasomotor function in females only. UCP1 ablation did not promote oxidative stress in interscapular BAT. Furthermore, daily administration of the free radical scavenger tempol for 8 wk did not abrogate UCP1 deficiency-induced increases in adiposity, hyperinsulinemia, or liver steatosis. Collectively, we report that 1 ) in normal chow-fed mice housed at 25°C, aortic UCP1 content was greater in females than males and its deletion improved ex vivo aortic vasomotor function in females only; 2 ) constitutive UCP1 content in BAT was similar between females and males and loss of UCP1 did not abolish sex differences in insulin sensitivity; and 3 ) the metabolic disruptions caused by UCP1 ablation did not appear to be contingent upon increased oxidative stress in mice under normal dietary conditions.

Background: Pericoronary epicardial adipose tissue (cEAT) serves as a metabolic and paracrine organ that contributes to inflammation and is associated with macrovascular coronary artery disease (CAD) development. Although there is a strong correlation in humans between cEAT volume and CAD severity, there remains a paucity of experimental data demonstrating a causal link of cEAT to CAD. The current study tested the hypothesis that surgical resection of cEAT attenuates inflammation and CAD progression., Methods: Female Ossabaw miniature swine (n = 12) were fed an atherogenic diet for 8 months and randomly allocated into sham (n = 5) or adipectomy (n = 7) groups. Both groups underwent a thoracotomy, opening of the pericardial sac, and placement of radioopaque clips to mark the proximal left anterior descending artery. Adipectomy swine underwent removal of 1 to 1.5 cm 2 of cEAT from the proximal artery. After sham or adipectomy, CAD severity was assessed with intravascular ultrasonography. Swine recovered for an additional 3 months on an atherogenic diet, and CAD was assessed immediately before euthanasia. Artery sections were processed for histologic and immunohistochemical analysis., Results: Severity of CAD as assessed by percent stenosis was reduced in the adipectomy cohort compared with shams; however, plaque size remained unaltered, whereas larger plaque sizes developed in sham-operated swine. Adipectomy resulted in an expanded arterial diameter, similar to the Glagov phenomenon of positive outward remodeling. No differences in inflammatory marker expression were observed., Conclusions: These data indicate that cEAT resection did not alter inflammatory marker expression, but arrested CAD progression through increased positive outward remodeling and arrest of atherogenesis., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Excess visceral adiposity, in particular that located adjacent to the heart and coronary arteries is associated with increased cardiovascular risk. In the pathophysiological state, dysfunctional adipose tissue secretes an array of factors modulating vascular function and driving atherogenesis. Conversely, brown and beige adipose tissues utilise glucose and lipids to generate heat and are associated with improved cardiometabolic health. The cardiac and thoracic perivascular adipose tissues are now understood to be composed of brown adipose tissue in the healthy state and undergo a brown-to-white transition i.e. during obesity which may be a driving factor of cardiovascular disease. In this review we discuss the risks of excess cardiac and vascular adiposity and potential mechanisms by which restoring the brown phenotype i.e. "re-browning" could potentially be achieved in clinically relevant populations., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Women who inject drugs have been shown to have higher incidence of HIV and risk behaviours than men, but there are conflicting reports about hepatitis C virus (HCV) incidence. We systematically reviewed the literature to examine the female-to-male (F:M) HCV incidence in female and male persons who inject drugs (PWID), and also to explore the heterogeneity (i.e. methodological diversity) in these differences. We searched PubMed and EMBASE for studies published between 1989 and March 2015 for research that reported incidence of HCV infection by sex or HCV incidence F:M rate ratio. A total of 28 studies, which enrolled 9325 PWID, were included. The overall pooled HCV incidence rate (per 100 person-years observation) was 20.36 (95% CI: 13.86, 29.90) and 15.20 (95% CI: 10.52, 21.97) in females and males, respectively. F:M ratio was 1.36:1 (95% CI: 1.13, 1.64) with substantial heterogeneity (I-squared=71.6%). The F:M ratio varied by geographic location from 4.0 (95% CI: 1.80, 8.89) in China to 1.17 (95% CI: 0.95, 1.43) in the U.S. In studies which recruited participants from community settings, the F:M ratio was 1.24 (95% CI: 1.03, 1.48), which was lower than that reported in the clinical settings (1.72, 95% CI: 0.86, 3.45). The number of studies included provided sufficient statistical power to detect sex differences in this analysis. Our findings raise questions and concerns regarding sex differences with respect to the risk of HCV. Both behavioural and biological studies are needed to investigate causes and potential mechanisms as well as sex-specific prevention approaches to HCV infection., Competing Interests: Authors have no commercial or other association that might pose a conflict of interest., (© 2016 John Wiley & Sons Ltd.)

We tested the hypothesis that female mice null for uncoupling protein 1 (UCP1) would have increased susceptibility to Western diet-induced "whitening" of brown adipose tissue (AT) and glucose intolerance. Six-week-old C57BL/6J wild-type (WT) and UCP1 knockout (UCP1 -/- ) mice, housed at 25°C, were randomized to either a control diet (10% kcal from fat) or Western diet (45% kcal from fat and 1% cholesterol) for 28 wk. Loss of UCP1 had no effect on energy intake, energy expenditure, spontaneous physical activity, weight gain, or visceral white AT mass. Despite similar susceptibility to weight gain compared with WT, UCP1 -/- exhibited whitening of brown AT evidenced by a striking ~500% increase in mass and appearance of large unilocular adipocytes, increased expression of genes related to inflammation, immune cell infiltration, and endoplasmic reticulum/oxidative stress (P < 0.05), and decreased mitochondrial subunit protein (COX I, II, III, and IV, P < 0.05), all of which were exacerbated by Western diet (P < 0.05). UCP1 -/- mice also developed liver steatosis and glucose intolerance, which was worsened by Western diet. Collectively, these findings demonstrate that loss of UCP1 exacerbates Western diet-induced whitening of brown AT, glucose intolerance, and induces liver steatosis. Notably, the adverse metabolic manifestations of UCP1 -/- were independent of changes in body weight, visceral adiposity, and energy expenditure. These novel findings uncover a previously unrecognized metabolic protective role of UCP1 that is independent of its already established role in energy homeostasis., (Copyright © 2017 the American Physiological Society.)

Context: Patients with pheochromocytoma (pheo) show presence of multilocular adipocytes that express uncoupling protein 1 within periadrenal (pADR) and omental (OME) fat depots. It has been hypothesized that this is due to adrenergic stimulation by catecholamines produced by the pheo tumors., Objective: To characterize the prevalence and respiratory activity of brown-like adipocytes within pADR, OME, and SC fat depots in human adult pheo patients., Design: This was an observational cohort study., Setting: The study took place in a university hospital., Patients: We studied 46 patients who underwent surgery for benign adrenal tumors (21 pheos and 25 controls with adrenocortical adenomas)., Main Outcome Measure: We characterized adipocyte browning in pADR, SC, and OME fat depots for histological and immunohistological features, mitochondrial respiration rate, and gene expression. We also determined circulating levels of catecholamines and other browning-related hormones., Results: Eleven of 21 pheo pADR adipose samples, but only one of 25 pADR samples from control patients exhibited multilocular adipocytes. The pADR browning phenotype was associated with higher plasma catecholamines and raised uncoupling protein 1. Mitochondria from multilocular pADR fat of pheo patients exhibited increased rates of coupled and uncoupled respiration. Global gene expression analysis in pADR fat revealed enrichment in β-oxidation genes in pheo patients with multilocular adipocytes. No SC or OME fat depots exhibited aspects of browning., Conclusion: Browning of the pADR depot occurred in half of pheo patients and was associated with increased catecholamines and mitochondrial activity. No browning was detected in other fat depots, suggesting that other factors are required to promote browning in these depots.

People living with human immunodeficiency virus frequently use dietary supplements, including probiotics, but concern exists about ingesting live organisms. We performed a systematic review of the benefits of probiotics and a meta-analysis of sepsis risk. We undertook a protocol-driven, comprehensive review to identify all relevant studies, assess their quality, and summarize the evidence. Of 2068 references, 27 were analyzed. The data suggest possible benefits for CD4 count, recurrence or management of bacterial vaginosis, and diarrhea management. We examined randomized, controlled studies explicitly assessing sepsis in any patient population, and we found zero cases of supplement-associated bacteremia or fungemia in 39 randomized controlled trials comprising 9402 subjects. The estimated number needed to harm is 7369 in Bayesian approach (95% credible interval: 1689, ∞), which should reassure clinicians. No or mild adverse effects were reported. Longer duration studies investigating different individual and mixed strains for plausible indications are needed to establish best practices.

Background: The economic value of robotic-assisted laparoscopic prostatectomy (RALP) in the United States is still not well understood because of limited view analyses., Objectives: The objective of this study was to examine the costs and benefits of RALP versus retropubic radical prostatectomy from an expanded view, including hospital, payer, and societal perspectives., Methods: We performed a model-based cost comparison using clinical outcomes obtained from a systematic review of the published literature. Equipment costs were obtained from the manufacturer of the robotic system; other economic model parameters were obtained from government agencies, online resources, commercially available databases, an advisory expert panel, and the literature. Clinical point estimates and care pathways based on National Comprehensive Cancer Network guidelines were used to model costs out to 3 years. Hospital costs and costs incurred for the patients' postdischarge complications, adjuvant and salvage radiation treatment, incontinence and potency treatment, and lost wages during recovery were considered. Robotic system costs were modeled in two ways: as hospital overhead (hospital overhead calculation: RALP-H) and as a function of robotic case volume (robotic amortization calculation: RALP-R). All costs were adjusted to year 2014 US dollars., Results: Because of more favorable clinical outcomes over 3 years, RALP provided hospital ($1094 savings with RALP-H, $341 deficit with RALP-R), payer ($1451), and societal ($1202) economic benefits relative to retropubic radical prostatectomy., Conclusions: Monte-Carlo probabilistic sensitivity analysis demonstrated a 38% to 99% probability that RALP provides cost savings (depending on the perspective). Higher surgical consumable costs are offset by a decreased hospital stay, lower complication rate, and faster return to work., (Copyright © 2016 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Objective: Antibiotic use, particularly type and duration, is a crucial modifiable risk factor for Clostridium difficile. Cardiac surgery is of particular interest because prophylactic antibiotics are recommended for 48 hours or less (vs ≤24 hours for noncardiac surgery), with increasing vancomycin use. We aimed to study associations between antibiotic prophylaxis (duration/vancomycin use) and C difficile among patients undergoing coronary artery bypass grafting., Methods: We extracted data on coronary artery bypass grafting procedures from the national Premier Perspective claims database (2006-2013, n = 154,200, 233 hospitals). Multilevel multivariable logistic regressions measured associations between (1) duration (<2 days, "standard" vs ≥2 days, "extended") and (2) type of antibiotic used ("cephalosporin," "cephalosporin + vancomycin," "vancomycin") and C difficile as outcome., Results: Overall C difficile prevalence was 0.21% (n = 329). Most patients (59.7%) received a cephalosporin only; in 33.1% vancomycin was added, whereas 7.2% received vancomycin only. Extended prophylaxis was used in 20.9%. In adjusted analyses, extended prophylaxis (vs standard) was associated with significantly increased C difficile risk (odds ratio, 1.43; confidence interval, 1.07-1.92), whereas no significant associations existed for vancomycin use as adjuvant or primary prophylactic compared with the use of cephalosporins (odds ratio, 1.21; confidence interval, 0.92-1.60, and odds ratio, 1.39; confidence interval, 0.94-2.05, respectively). Substantial inter-hospital variation exists in the percentage of extended antibiotic prophylaxis (interquartile range, 2.5-35.7), use of adjuvant vancomycin (interquartile range, 4.2-61.1), and vancomycin alone (interquartile range, 2.3-10.4)., Conclusions: Although extended use of antibiotic prophylaxis was associated with increased C difficile risk after coronary artery bypass grafting, vancomycin use was not. The observed hospital variation in antibiotic prophylaxis practices suggests great potential for efforts aimed at standardizing practices that subsequently could reduce C difficile risk., Competing Interests: Statement Authors have nothing to disclose with regard to commercial support., (Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Chronic neuropathic pain, the most frequent condition affecting the peripheral nervous system, remains underdiagnosed and difficult to treat. Inhaled cannabis may alleviate chronic neuropathic pain. Our objective was to synthesize the evidence on the use of inhaled cannabis for chronic neuropathic pain. We performed a systematic review and a meta-analysis of individual patient data. We registered our protocol with PROSPERO CRD42011001182. We searched in Cochrane Central, PubMed, EMBASE, and AMED. We considered all randomized controlled trials investigating chronic painful neuropathy and comparing inhaled cannabis with placebo. We pooled treatment effects following a hierarchical random-effects Bayesian responder model for the population-averaged subject-specific effect. Our evidence synthesis of individual patient data from 178 participants with 405 observed responses in 5 randomized controlled trials following patients for days to weeks provides evidence that inhaled cannabis results in short-term reductions in chronic neuropathic pain for 1 in every 5 to 6 patients treated (number needed to treat = 5.6 with a Bayesian 95% credible interval ranging between 3.4 and 14). Our inferences were insensitive to model assumptions, priors, and parameter choices. We caution that the small number of studies and participants, the short follow-up, shortcomings in allocation concealment, and considerable attrition limit the conclusions that can be drawn from the review. The Bayes factor is 332, corresponding to a posterior probability of effect of 99.7%., Perspective: This novel Bayesian meta-analysis of individual patient data from 5 randomized trials suggests that inhaled cannabis may provide short-term relief for 1 in 5 to 6 patients with neuropathic pain. Pragmatic trials are needed to evaluate the long-term benefits and risks of this treatment., (Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Background: Approximately 28.5 million people living with HIV are eligible for treatment (CD4<500), but currently have no access to antiretroviral therapy. Reduced serum level of micronutrients is common in HIV disease. Micronutrient supplementation (MNS) may mitigate disease progression and mortality., Objectives: We synthesized evidence on the effect of micronutrient supplementation on mortality and rate of disease progression in HIV disease., Methods: We searched MEDLINE, EMBASE, the Cochrane Central, AMED and CINAHL databases through December 2014, without language restriction, for studies of greater than 3 micronutrients versus any or no comparator. We built a hierarchical Bayesian random effects model to synthesize results. Inferences are based on the posterior distribution of the population effects; posterior distributions were approximated by Markov chain Monte Carlo in OpenBugs., Principal Findings: From 2166 initial references, we selected 49 studies for full review and identified eight reporting on disease progression and/or mortality. Bayesian synthesis of data from 2,249 adults in three studies estimated the relative risk of disease progression in subjects on MNS vs. control as 0.62 (95% credible interval, 0.37, 0.96). Median number needed to treat is 8.4 (4.8, 29.9) and the Bayes Factor 53.4. Based on data reporting on 4,095 adults reporting mortality in 7 randomized controlled studies, the RR was 0.84 (0.38, 1.85), NNT is 25 (4.3, ∞)., Conclusions: MNS significantly and substantially slows disease progression in HIV+ adults not on ARV, and possibly reduces mortality. Micronutrient supplements are effective in reducing progression with a posterior probability of 97.9%. Considering MNS low cost and lack of adverse effects, MNS should be standard of care for HIV+ adults not yet on ARV.

Background: In humans there is a positive association between epicardial adipose tissue (EAT) volume and coronary atherosclerosis (CAD) burden. We tested the hypothesis that EAT contributes locally to CAD in a pig model., Methods: Ossabaw miniature swine (n=9) were fed an atherogenic diet for 6 months to produce CAD. A 15 mm length by 3-5 mm width coronary EAT (cEAT) resection was performed over the middle segment of the left anterior descending artery (LAD) 15 mm distal to the left main bifurcation. Pigs recovered for 3 months on atherogenic diet. Intravascular ultrasound (IVUS) was performed in the LAD to quantify atheroma immediately after adipectomy and was repeated after recovery before sacrifice. Coronary wall biopsies were stained immunohistochemically for atherosclerosis markers and cytokines and cEAT was assayed for atherosclerosis-related genes by RT-PCR. Total EAT volume was measured by non-contrast CT before each IVUS., Results: Circumferential plaque length increased (p<0.05) in the proximal and distal LAD segments from baseline until sacrifice whereas plaque length in the middle LAD segment underneath the adipectomy site did not increase. T-cadherin, scavenger receptor A and adiponectin were reduced in the intramural middle LAD. Relative to control pigs without CAD, 11β-hydroxysteroid dehydrogenase (11βHSD-1), CCL19, CCL21, prostaglandin D2 synthase, gp91phox [NADPH oxidase], VEGF, VEGFGR1, and angiotensinogen mRNAs were up-regulated in cEAT. EAT volume increased over 3 months., Conclusion: In pigs used as their own controls, resection of cEAT decreased the progression of CAD, suggesting that cEAT may exacerbate coronary atherosclerosis.

Background: Exercise training elevates circulating irisin and induces the expression of the FNDC5 gene in skeletal muscles of mice. Our objective was to determine whether exercise training also increases FNDC5 protein or mRNA expression in the skeletal muscles of pigs as well as plasma irisin., Methods: Castrated male pigs of the Rapacz familial hypercholesterolemic (FHM) strain and normal (Yucatan miniature) pigs were sacrificed after 16-20 weeks of exercise training. Samples of cardiac muscle, deltoid and triceps brachii muscle, subcutaneous and epicardial fat were obtained and FNDC5 mRNA, along with that of 6 other genes, was measured in all tissues of FHM pigs by reverse transcription polymerase chain reaction. FNDC protein in deltoid and triceps brachii was determined by Western blotting in both FHM and normal pigs. Citrate synthase activity was measured in the muscle samples of all pigs as an index of exercise training. Irisin was measured by an ELISA assay., Results: There was no statistically significant effect of exercise training on FNDC5 gene expression in epicardial or subcutaneous fat, deltoid muscle, triceps brachii muscle or heart muscle. Exercise-training elevated circulating levels of irisin in the FHM pigs and citrate synthase activity in deltoid and triceps brachii muscle. A similar increase in citrate synthase activity was seen in muscle extracts of exercise-trained normal pigs but there was no alteration in circulating irisin., Conclusion: Exercise training in pigs does not increase FNDC5 mRNA or protein in the deltoid or triceps brachii of FHM or normal pigs while increasing circulating irisin only in the FHM pigs. These data indicate that the response to exercise training in normal pigs is not comparable to that seen in mice., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Context: Human epicardial fat has been designated previously as brown-like fat. The supraclavicular fat depot in man has been defined as beige coexistent with classical brown based on its gene expression profile., Objective: The aim of the study was to establish the gene expression profile and morphology of human epicardial and visceral paracardial fat compared with sc fat., Setting: The study was conducted at a tertiary care hospital cardiac center., Patients: Epicardial, visceral paracardial, and sc fat samples had been taken from middle-aged patients with severe coronary atherosclerosis or valvular heart disease., Interventions: Gene expression was determined by reverse transcription-quantitative PCR and relative abundance of the mitochondrial uncoupling protein-1 (UCP-1) by Western blotting. Epicardial tissue sections from patients were examined by light microscopy, UCP-1 immunohistochemistry, and cell morphometry., Main Outcome Measures: We hypothesized that epicardial fat has a mixed phenotype with a gene expression profile similar to that described for beige cell lineage., Results: Immunoreactive UCP-1 was clearly measurable in each epicardial sample analyzed but was undetectable in each of the 4 other visceral and sc depots. Epicardial fat exhibited high expression of genes for UCP-1, PRDM16, PGC-1α, PPARγ, and the beige adipocyte-specific marker CD137, which were also expressed in visceral paracardial fat but only weakly in sternal, upper abdominal, and lower extremity sc fat. Histology of epicardial fat showed small unilocular adipocytes without UCP-1 immunostaining., Conclusion: UCP-1 is relatively abundant in epicardial fat, and this depot possesses molecular features characteristic of those found in vitro in beige lineage adipocytes.

Background: Pro- and antiinflammatory genes are expressed in epicardial adipose tissue (EAT). Our objectives were to characterize genes in EAT that may contribute specifically to coronary atherogenesis and to measure circulating adipokines matched to their messenger RNAs (mRNAs) in EAT. We hypothesized that severe coronary atherosclerosis (CAD) would preferentially affect gene expression in EAT as compared to substernal fat or subcutaneous thoracic adipose tissue (SAT), as well as circulating levels of adipokines., Methods: Fat mRNA was quantified using reverse transcription polymerase chain reaction (RT-PCR), and circulating adipokines were measured by enzyme-linked immunosorbent assays (ELISAs) in patients with severe stable CAD and controls without severe CAD undergoing open heart surgery., Results: A total of 39 of 70 mRNAs in EAT were significantly increased in CAD. Only 4 and 3 of these mRNAs were increased in substernal fat and SAT, respectively. Of the mRNAs increased in EAT, 17 were either inflammatory adipokines or proteins known to be involved in inflammatory processes, 7 were involved in oxidative stress and or oxygen species regulation, whereas 15 were proteins involved in metabolism and regulation of gene transcription or proteins unique to fat cells. The largest increases, over three-fold, were seen in GPX3, gp91 phox, p47phox, heme oxygenase, and interleukin-8 (IL-8). Tpl2 mRNA was uniquely elevated in all three fat depots from CAD patients, and its expression in SAT, but not in EAT or substernal fat, was directly correlated with homeostasis model assessment of insulin resistance (HOMA-IR) values. Compared to controls, there were no associations between circulating levels of IL-8, lipocalin-2, nerve growth factor (NGF), RANTES, CD-163, GPX-3, monocyte chemotactic protein-1 (MCP-1)/CCL2, leptin, soluble vascular endothelial growth factor receptor-1 (sFLT1), fatty acid binding protein-4 (FABP-4), and plasminogen activator inhibitor-1 (PAI-1) and increases in their gene expression in EAT adjacent to CAD., Conclusions: Expression of proinflammatory, redox, endothelial cell, and angiogenic genes in EAT is depot specific and supports the hypothesis that pathophysiologically EAT contributes locally to CAD. CAD links with these fat depots might involve Tpl2 as a primary response indicator.

1. Putative physiological functions of human epicardial adipose tissue (EAT) include: (i) lipid storage for the energy needs of the myocardium; (ii) thermoregulation, whereby brown fat components of EAT generate heat by non-shivering thermogenesis in response to core cooling; (iii) neuroprotection of the cardiac autonomic ganglia and nerves; and (iv) regulation of vasomotion and luminal size of the coronary arteries. Under pathophysiological circumstances, EAT may play an adverse paracrine role in cardiac arrhythmias and in lipotoxic cardiomyopathy, but of major current interest is its hypothetical role as an immunological organ contributing to inflammation around coronary artery disease (CAD). 2. The amount of EAT measured either by echocardiographic thickness over the free wall of the right ventricle or as volume by computed tomography expands in patients with obesity both without and with CAD. The mechanisms other than obesity governing the increase in EAT volume in CAD are unknown, but EAT around CAD is infiltrated by chronic inflammatory cells and overexpresses genes for adipokines that have pro- or anti-inflammatory actions and regulate oxidative stress plus angiogenesis. 3. Many cross-sectional studies have shown positive associations between increased EAT mass and stable CAD burden. One prospective population-based epidemiological study suggested that EAT volume at baseline is a predictor of acute myocardial infarction, but was without significant incremental predictive value after adjustment for established cardiovascular risk factors. However, strategies are needed to obtain robust epidemiological, interventional and experimental evidence to prove or disprove the hypothesis that EAT is a cardiovascular risk factor locally contributing to CAD., (© 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.)