Oral Cannabis consumption and intraperitoneal THC:CBD dosing results in changes in brain and plasma neurochemicals and endocannabinoids in mice.

BACKGROUND: While the use of orally consumed Cannabis, cannabidiol (CBD) and tetrahydrocannabinol (THC) containing products, i.e. "edibles", has expanded, the health consequences are still largely unknown. This study examines the effects of oral consumption of whole Cannabis and a complex Cannabis extract on neurochemicals, endocannabinoids (eCB), and physiological parameters (body temperature, heart rate) in mice. METHODS: In this pilot study, C57BL/6 J mice were treated with one of the following every other day for 2 weeks: a complex Cannabis extract by gavage, whole Cannabis mixed with nutritional gel through free feeding, or purified THC/CBD by intraperitoneal (i.p.) injection. Treatments were conducted at 4 doses ranging from 0-100 mg/kg/day of CBD with THC levels of ≤ 1.2 mg/kg/day for free feeding and gavage and 10 mg/kg/day for i.p. Body temperature and heart rate were monitored using surgically implanted telemetry devices. Levels of neurochemicals, eCB, THC, CBD, and 11-OH-THC were measured using mass spectrometry 48 h after the final treatment. Statistical comparisons were conducted using ANOVA and t-tests. RESULTS: Differences were found between neurochemicals in the brains and plasma of mice treated by i.p. (e.g. dopamine, p < 0.01), gavage (e.g., phenylalanine, p < 0.05) and in mice receiving whole Cannabis (e.g., 3,4-dihydroxyphenylacetic DOPAC p < 0.05). Tryptophan trended downward or was significantly decreased in the brain and/or plasma of all mice receiving Cannabis or purified CBD/THC, regardless of dose, compared to controls. Levels of the eCB, arachidonoyl glycerol (2-AG) were decreased in mice receiving lowest doses of a complex Cannabis extract by gavage, but were higher in mice receiving highest doses compared to controls (p < 0.05). Plasma and brain levels of THC and 11-OH-THC were higher in mice receiving 1:1 THC:CBD by i.p. compared to those receiving 1:5 or 1:10 THC:CBD. Nominal changes in body temperature and heart rate following acute and repeated exposures were seen to some degree in all treatments. CONCLUSIONS: Changes to neurochemicals and eCBs were apparent at all doses regardless of treatment type. Levels of neurochemicals seemed to vary based on the presence of a complex Cannabis extract, suggesting a non-linear response between THC and neurochemicals following repeated oral dosing.

The Revival of US Hospital Care, 2004-2019.

BACKGROUND: Between 2004 and 2019, the US hospital industry reversed the 21-year decline in its share of national health spending. OBJECTIVE: To measure and explain changes in hospital utilization, cost, charges, and inpatient case mix. DATA SOURCES: Principal sources were the American Hospital Association annual survey, the National Inpatient Sample, and the Healthcare Cost Reporting Information System. The study included all US community hospitals (n=5141 in 2019). ANALYTIC APPROACH: We used factor decomposition to separate the impacts of population, utilization, unit cost, and charge markups on the growth in cost and charges for inpatient and outpatient care nationwide and for each state. For unit cost, we separated the impacts of input price inflation and treatment intensity. To measure the inpatient case mix, we applied an all-patient diagnosis-related groups algorithm. RESULTS: Between 2004 and 2019, charges more than tripled to $4.11 trillion. The cost more than doubled to $911 billion. For inpatient care, discharges fell 5%, discharges per person fell 15%, cost per discharge increased 88%, and charge markups rose 43%. For outpatient care, visits rose 36%, visits per person rose 21%, cost per visit rose 119%, and charge markups rose 52%. Treatment intensity increased by 33% per discharge and 55% per visit. Nationwide, the inpatient case mix increased by 34%, reflecting sicker patients and better clinical documentation. CONCLUSIONS: We quantified 3 important trends: rapid growth in outpatient visits, increased treatment intensity, and sustained increases in markups. Increased treatment intensity was the largest factor behind $491 billion in hospital cost growth between 2004 and 2019.

Salmon Food-Specific Compounds and Their Metabolites Increase in Human Plasma and Are Associated with Cardiometabolic Health Indicators Following a Mediterranean-Style Diet Intervention.

BACKGROUND: Nutrimetabolomics allows for the comprehensive analysis of foods and human biospecimens to identify biomarkers of intake and begin to probe their associations with health. Salmon contains hundreds of compounds that may provide cardiometabolic benefits. OBJECTIVES: We used untargeted metabolomics to identify salmon food-specific compounds (FSCs) and their predicted metabolites that were found in plasma after a salmon-containing Mediterranean-style (MED) diet intervention. Associations between changes in salmon FSCs and changes in cardiometabolic health indicators (CHIs) were also explored. METHODS: For this secondary analysis of a randomized, crossover, controlled feeding trial, 41 participants consumed MED diets with 2 servings of salmon per week for 2 5-wk periods. CHIs were assessed, and fasting plasma was collected pre- and postintervention. Plasma, salmon, and 99 MED foods were analyzed using liquid chromatography-mass spectrometry-based metabolomics. Compounds were characterized as salmon FSCs if detected in all salmon replicates but none of the other foods. Metabolites of salmon FSCs were predicted using machine learning. For salmon FSCs and metabolites found in plasma, linear mixed-effect models were used to assess change from pre- to postintervention and associations with changes in CHIs. RESULTS: Relative to the other 99 MED foods, there were 508 salmon FSCs with 237 unique metabolites. A total of 143 salmon FSCs and 106 metabolites were detected in plasma. Forty-eight salmon FSCs and 30 metabolites increased after the intervention (false discovery rate <0.05). Increases in 2 annotated salmon FSCs and 2 metabolites were associated with improvements in CHIs, including total cholesterol, low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B. CONCLUSIONS: A data-driven nutrimetabolomics strategy identified salmon FSCs and their predicted metabolites that were detectable in plasma and changed after consumption of a salmon-containing MED diet. Findings support this approach for the discovery of compounds in foods that may serve, upon further validation, as biomarkers or act as bioactive components influential to health. The trials supporting this work were registered at NCT02573129 (Mediterranean-style diet intervention) and NCT05500976 (ongoing clinical trial).

Altered Bile Acid and Pouch Microbiota Composition in Patients With Chronic Pouchitis.

BACKGROUND: Patients with ulcerative colitis and total abdominal proctocolectomy with ileal pouch-anal anastomosis have a 50% risk of pouchitis and a 5% to 10% risk of chronic pouchitis. AIMS: The goal of the study was to compare pouch microbiota and stool bile acid composition in patients with chronic pouchitis, chronic pouchitis and primary sclerosing cholangitis, and normal pouch. METHODS: Patients with ulcerative colitis and ileal pouch-anal anastomosis were recruited from March 20, 2014, to August 6, 2019, and categorized into normal pouch, chronic pouchitis, and chronic pouchitis/primary sclerosing cholangitis groups. Stool samples were subjected to bile acid quantification and 16S rRNA gene sequencing. Statistical comparisons of absolute bile acid abundance and pouch microbiota α-diversity, ß-diversity, and taxa abundance were performed among the patient groups. RESULTS: A total of 51 samples were analyzed. Both α-diversity (P = .01, species richness) and ß-diversity (P = .001) significantly differed among groups. Lithocholic acid was significantly lower in patients with chronic pouchitis/primary sclerosing cholangitis than in those with chronic pouchitis (P = .01) or normal pouch (P = .03). Decreased α-diversity was associated with an increased primary to secondary bile acid ratio (P = .002), which was also associated with changes in ß-diversity (P = .006). CONCLUSIONS: Pouch microbiota α- and ß-diversity differed among patients with normal pouch, chronic pouchitis, and chronic pouchitis/primary sclerosing cholangitis. Lithocholic acid level and primary to secondary bile acid ratio were highly associated with pouch microbiota richness, structure, and composition. These findings emphasize the associations between pouch microbiota and bile acid composition in dysbiosis and altered metabolism, suggesting that secondary bile acids are decreased in chronic pouchitis.

The α- and ß-diversity of the pouch microbiota significantly differed in chronic pouchitis, chronic pouchitis and primary sclerosing cholangitis, and normal pouch. Microbiota changes were associated with stool bile acid composition. Decreased diversity was associated with decreased secondary bile acids.

Metabolomics Profiling of White Button, Crimini, Portabella, Lion's Mane, Maitake, Oyster, and Shiitake Mushrooms Using Untargeted Metabolomics and Targeted Amino Acid Analysis.

Mushrooms contain multiple essential nutrients and health-promoting bioactive compounds, including the amino acid L-ergothioneine. Knowledge of the chemical composition of different mushroom varieties will aid research on their health-promoting properties. We compared the metabolomes of fresh raw white button, crimini, portabella, lion's mane, maitake, oyster, and shiitake mushrooms using untargeted liquid chromatography mass spectrometry (LC/MS)-based metabolomics. We also quantified amino acid concentrations, including L-ergothioneine, a potential antioxidant which is not synthesized by plants or animals. Among the seven mushroom varieties, more than 10,000 compounds were detected. Principal Component Analysis indicated mushrooms of the same species, Agaricus Bisporus (white button, portabella, crimini), group similarly. The other varieties formed individual, distinct clusters. A total of 1344 (520 annotated) compounds were detected in all seven mushroom varieties. Each variety had tens-to-hundreds of unique-to-mushroom-variety compounds. These ranged from 29 for crimini to 854 for lion's mane. All three Agaricus bisporus varieties had similar amino acid profiles (including detection of all nine essential amino acids), while other varieties had less methionine and tryptophan. Lion's mane and oyster mushrooms had the highest concentrations of L-ergothioneine. The detection of hundreds of unique-to-mushroom-variety compounds emphasizes the differences in chemical composition of these varieties of edible fungi.

The Lasting Impact of the COVID-19 Pandemic on Surgical Key Indicator Cases for Otolaryngology Residency Education.

OBJECTIVES: Early on during the COVID-19 pandemic, the US Centers for Medicare & Medicaid Services (CMS) and other government as well as medical institutions recommended that surgeons postpone nonessential surgeries. The aim of our study is to examine the impact of the COVID-19 pandemic on otolaryngology surgical training by evaluating changes in surgical volumes through various time points relative to the height of the pandemic. METHODS: We performed a retrospective review of all surgical cases performed by the Otolaryngology-Head and Neck Surgery department at a tertiary care academic center from 3 time periods: July 1st, 2018, to June 30th, 2019; July 1st, 2019, to June 30th, 2020; and July 1st, 2020, to June 30th, 2021. RESULTS: From the 2018-19 period to the 2020-21 period, the total number of overall cases decreased by 9.9%, from 2386 to 2148 cases. During this same time duration, the number of key indicator cases decreased by 13.4%, from 1715 to 1486 cases. Relative to other cases, ethmoidectomy, rhinoplasty, and stapes/OCR cases decreased the most during the 2019-20 period by 41.9%, 41.8%, and 29.5%, respectively. From the 2018-19 period to the 2020-21 period, thyroid/parathyroid cases decreased the most by 35.4%. Only ethmoidectomy and oral cavity cases showed increases during this period at 9.7% and 24.4%, respectively. CONCLUSIONS: Although case volumes have stayed relatively constant, key indicator case volumes at the present tertiary care academic center have not yet fully recovered from the COVID-19 pandemic. Efforts must be made to determine how this has impacted residency surgical education.

The Predictive Value of a Modified Frailty Index on Perioperative Morbidity and Mortality Following Otologic Surgery.

Objectives: Recently, determinants of frailty have become an increasingly recognized perioperative risk stratification tool. This study examines the predictive value of a 5-factor modified frailty index (mFI-5) on perioperative morbidity and mortality in patients undergoing otologic surgery, with a subgroup analysis based on surgery site. Study Design: Cross-sectional analysis. Setting: National surgical quality improvement program dataset 2005-2019. Patients: Current procedural terminology (CPT) codes were used to identify patients undergoing all otologic surgeries. Interventions: Otologic surgeries as indicated by CPT codes, including external ear, middle ear/mastoid, implants, and inner ear/facial nerve subgroups. Main Outcome Measures: Primary outcomes examined in this study included rates of overall complications and life-threatening complications within 30 days after surgery. Overall complications included superficial surgical site infections (SSI), deep incisional SSI, readmission, deep vein thrombosis, life-threatening complications, and mortality. Life-threatening complications included those classified as Clavien-Dindo grade IV: cerebrovascular accident, mechanical ventilation for more than 48 hours, reintubation, pulmonary embolism, acute renal failure, cardiac arrest, and myocardial infarction. Results: A total of 16,859 patients who underwent otologic surgery were identified, resulting in a cohort that was 47.5% male with an average age of 47.6 years (17.1 SD). Multivariable regression analysis of the entire cohort demonstrated a score of 3 or more on the mFI-5 was independently predictive of all postoperative complications (odds ratio (OR): 2.02, P < 0.0001). However, subgroup analysis showed that only "external ear" surgery correlated with mFi-5 (OR 8.03, P = 0.013). Conclusions: Higher frailty scores as measured by the mFI-5 correlate with postoperative morbidity and mortality after otologic surgery, though subgroup analysis reveals an association only with cases performed on the external ear. These findings suggest that for most otologic surgery, the mFI-5 frailty score is not predictive of postoperative complications.

The Effect of Dietary Carbohydrate and Fat Manipulation on the Metabolome and Markers of Glucose and Insulin Metabolism: A Randomised Parallel Trial.

High carbohydrate, lower fat (HCLF) diets are recommended to reduce cardiometabolic disease (CMD) but low carbohydrate high fat (LCHF) diets can be just as effective. The effect of LCHF on novel insulin resistance biomarkers and the metabolome has not been fully explored. The aim of this study was to investigate the impact of an ad libitum 8-week LCHF diet compared with a HCLF diet on CMD markers, the metabolome, and insulin resistance markers. n = 16 adults were randomly assigned to either LCHF (n = 8, <50 g CHO p/day) or HCLF diet (n = 8) for 8 weeks. At weeks 0, 4 and 8, participants provided fasted blood samples, measures of body composition, blood pressure and dietary intake. Samples were analysed for markers of cardiometabolic disease and underwent non-targeted metabolomic profiling. Both a LCHF and HCLF diet significantly (p < 0.01) improved fasting insulin, HOMA IR, rQUICKI and leptin/adiponectin ratio (p < 0.05) levels. Metabolomic profiling detected 3489 metabolites with 78 metabolites being differentially regulated, for example, an upregulation in lipid metabolites following the LCHF diet may indicate an increase in lipid transport and oxidation, improving insulin sensitivity. In conclusion, both diets may reduce type 2 diabetes risk albeit, a LCHF diet may enhance insulin sensitivity by increasing lipid oxidation.

A multidimensional pairwise comparison model for heterogeneous perceptions with an application to modelling the perceived truthfulness of public statements on COVID-19.

Pairwise comparison models are an important type of latent attribute measurement model with broad applications in the social and behavioural sciences. Current pairwise comparison models are typically unidimensional. The existing multidimensional pairwise comparison models tend to be difficult to interpret and they are unable to identify groups of raters that share the same rater-specific parameters. To fill this gap, we propose a new multidimensional pairwise comparison model with enhanced interpretability which explicitly models how object attributes on different dimensions are differentially perceived by raters. Moreover, we add a Dirichlet process prior on rater-specific parameters which allows us to flexibly cluster raters into groups with similar perceptual orientations. We conduct simulation studies to show that the new model is able to recover the true latent variable values from the observed binary choice data. We use the new model to analyse original survey data regarding the perceived truthfulness of statements on COVID-19 collected in the summer of 2020. By leveraging the strengths of the new model, we find that the partisanship of the speaker and the partisanship of the respondent account for the majority of the variation in perceived truthfulness, with statements made by co-partisans being viewed as more truthful.

Defining normal pouch function in patients with ileal pouch-anal anastomosis: a pilot study.

BACKGROUND: Most patients experience good functional outcomes following ileal pouch-anal anastomosis (IPAA) for ulcerative colitis. AIM: We aimed to determine if asymptomatic patients with an IPAA had findings consistent with normal defecation on standard objective anorectal tests. METHODS: Patients 18-65 years old with IPAA and self-reported healthy pouch function were recruited. Patients with chronic pouchitis, Crohn's disease, anastomotic stricture, or indication for IPAA other than ulcerative or indeterminate colitis were excluded. Patients underwent an interview with an abbreviated Rome Questionnaire followed by high-resolution ano-pouch manometry, balloon expulsion test, pouch barostat, and magnetic resonance (MR) defecography. RESULTS: Twenty patients completed all testing. Six patients were excluded from the final analysis due to symptoms suggestive of pouch evacuation disorder on the abbreviated Rome Questionnaire (n = 2), structural abnormality on MR imaging (n = 3), or both (n = 1). Of the remaining 14 patients, mean anal resting pressure during high-resolution manometry was 72 ± 16 mmHg, mean anal squeeze pressure was 247 ± 69 mmHg, and mean pouch-anal gradient during the simulated evacuation was -27 ± 37 mmHg. The meantime to balloon expulsion was 54 seconds. During dynamic MR defecography, the mean descent of ano-pouch junction was 2.6 cm, and mean pouch evacuation was 44.5% and 74.2% pre- and posttoilet phase, respectively. CONCLUSIONS: A substantial proportion of patients with IPAA and self-reported healthy pouch function have anatomic and/or functional abnormalities of the pouch. In asymptomatic IPAA patients with an anatomically normal pouch, we have proposed normal parameters for high-resolution ano-pouch manometry, time to balloon expulsion, pouch barostat, and MR defecography.

Discovering metabolite quantitative trait loci in asthma using an isolated population.

BACKGROUND: Integration of metabolomics with genetics may advance understanding of disease pathogenesis but has been underused in asthma genetic studies. OBJECTIVE: We sought to discover new genetic effects in asthma and to characterize the molecular consequences of asthma genetic risk through integration with the metabolome in a homogeneous population. METHODS: From fasting serum samples collected on 348 Tangier Island residents, we quantified 2612 compounds using untargeted metabolomics. Genotyping was performed using Illumina's MEGA array imputed to the TOPMed reference panel. To prioritize metabolites for genome-wide association analysis, we performed a metabolome-wide association study with asthma, selecting asthma-associated metabolites with heritability q value less than 0.01 for genome-wide association analysis. We also tested the association between all metabolites and 8451 candidate asthma single nucleotide polymorphisms previously associated with asthma in the UK Biobank. We followed up significant associations by characterizing shared genetic signal for metabolites and asthma using colocalization analysis. For detailed Methods, please see this article's Online Repository at www.jacionline.org. RESULTS: A total of 60 metabolites were associated with asthma (P < .01), including 40 heritable metabolites tested in genome-wide association analysis. We observed a strong association peak for the endocannabinoid linoleoyl ethanolamide on chromosome 6 in VNN1 (P < 2.7 × 10-9). We found strong evidence (colocalization posterior probability >75%) for a shared causal variant between 3 metabolites and asthma, including the polyamine acisoga and variants in LPP, and derivative leukotriene B4 and intergenic variants in chr10p14. CONCLUSIONS: We identified novel metabolite quantitative trait loci with asthma associations. Identification and characterization of these genetically driven metabolites may provide insight into the functional consequences of genetic risk factors for asthma.

Primary Sclerosing Cholangitis-Associated Pouchitis: A Distinct Clinical Phenotype.

BACKGROUND & AIMS: Patients with primary sclerosing cholangitis (PSC) commonly undergo ileal pouch-anal anastomosis (IPAA) for medically-refractory ulcerative colitis (UC) or colorectal dysplasia. Pouchitis develops more frequently in patients with PSC, potentially leading to increased morbidity. We aimed to assess clinical characteristics and treatment outcomes for pouchitis in patients with PSC compared to a matched, non-PSC cohort. METHODS: All patients with PSC who underwent IPAA and were diagnosed with pouchitis (PSC-pouchitis) were identified. A matched cohort composed of non-PSC patients who underwent IPAA for UC and subsequently developed pouchitis (UC-pouchitis) was developed. Relevant demographic, clinical, endoscopic, histologic, and treatment data were collected and compared between groups. RESULTS: Of those with PSC-pouchitis (n=182), 53.9% and 46.1% underwent IPAA for medically-refractory disease and dysplasia, respectively, compared to 88.7% and 11.3% in the UC-pouchitis group (P < .001). Patients with PSC-pouchitis were more likely to develop chronic pouchitis (68.1% vs 34.1%; P < .001), have moderate-to-severe pouch inflammation (54.9% vs 32.4%; P < .001), and prepouch ileitis (34.1% vs 11.5%; P < .001) compared to UC-pouchitis. Of those with PSC-pouchitis, 50.6% and 17.6% developed chronic antibiotic-dependent or antibiotic-refractory pouchitis, respectively, compared to 25.8% and 7.7% with UC-pouchitis. There was no difference in treatment response between the two groups with use of thiopurines, anti-tumor necrosis factor agents, and newer biologics. CONCLUSIONS: PSC-associated pouchitis presents with a unique clinical phenotype, characterized by increased risk of chronic pouchitis, moderate-to-severe pouch inflammation, prepouch ileitis, and less response to conventional antimicrobial therapy.

The Curious Rise and Incomplete Fall of "Paracusis Willisii".

In 1672, Dr. Thomas Willis, a founder of the Royal Society and accomplished anatomist, described a peculiar phenomenon he had heard about "from a Credible Person" wherein two people with hearing loss appreciated some recovery of hearing when in the presence of increased background noise. Over time, this clinical entity came to bear his name, and Paracusis of Willis (or Paracusis Willisii) became a subject of both clinical interest as well as contention. In the early 1900s, a burgeoning appreciation for the diseases of the middle and inner ear heralded a boom in the study of paracuses, with many incorporating it as one of the diagnostic criteria of otosclerosis. At its peak interest, several potential etiologies were hypothesized in an effort to explain this puzzling entity-some plausible by today's understanding, many not. In the 1950s, however, its prominence in medical literature began to decline, though over the subsequent six decades it has yet to completely disappear. References to this peculiar phenomenon can still be found in prominent textbooks, review articles, and teaching resources. The fascinating story arc of paracusis of Willis serves as an illustration of how and why other questionable eponymic clinical descriptions can persist in conventional wisdom.

SPM pathway marker analysis of the brains of obese mice in the absence and presence of eicosapentaenoic acid ethyl esters.

Obesity drives an imbalanced signature of specialized pro-resolving mediators (SPM). Herein, we investigated if high fat diet-induced obesity dysregulates the concentration of SPM intermediates in the brains of C57BL/6 J mice. Furthermore, given the benefits of EPA for cardiometabolic diseases, major depression, and cognition, we probed the effect of an EPA supplemented high fat diet on brain SPM intermediates. Mass spectrometry revealed no effect of the high fat diet on PUFA-derived brain metabolites. EPA also did not have an effect on most brain PUFA-derived metabolites except an increase of 12-hydroxyeicosapentaenoic acid (12-HEPE). In contrast, EPA dramatically increased serum HEPEs and lowered several PUFA-derived metabolites. Finally, untargeted mass spectrometry showed no effects of the high fat diet, with or without EPA, on the brain metabolome. Collectively, these results show the murine brain resists a deficiency in SPM pathway markers in response to a high fat diet and that EPA supplementation increases 12-HEPE levels.

Systems Analysis of Gut Microbiome Influence on Metabolic Disease in HIV-Positive and High-Risk Populations.

Poor metabolic health, characterized by insulin resistance and dyslipidemia, is higher in people living with HIV and has been linked with inflammation, antiretroviral therapy (ART) drugs, and ART-associated lipodystrophy (LD). Metabolic disease is associated with gut microbiome composition outside the context of HIV but has not been deeply explored in HIV infection or in high-risk men who have sex with men (HR-MSM), who have a highly altered gut microbiome composition. Furthermore, the contribution of increased bacterial translocation and associated systemic inflammation that has been described in HIV-positive and HR-MSM individuals has not been explored. We used a multiomic approach to explore relationships between impaired metabolic health, defined using fasting blood markers, gut microbes, immune phenotypes, and diet. Our cohort included ART-treated HIV-positive MSM with or without LD, untreated HIV-positive MSM, and HR-MSM. For HIV-positive MSM on ART, we further explored associations with the plasma metabolome. We found that elevated plasma lipopolysaccharide binding protein (LBP) was the most important predictor of impaired metabolic health and network analysis showed that LBP formed a hub joining correlated microbial and immune predictors of metabolic disease. Taken together, our results suggest the role of inflammatory processes linked with bacterial translocation and interaction with the gut microbiome in metabolic disease among HIV-positive and -negative MSM.IMPORTANCE The gut microbiome in people living with HIV (PLWH) is of interest since chronic infection often results in long-term comorbidities. Metabolic disease is prevalent in PLWH even in well-controlled infection and has been linked with the gut microbiome in previous studies, but little attention has been given to PLWH. Furthermore, integrated analyses that consider gut microbiome, together with diet, systemic immune activation, metabolites, and demographics, have been lacking. In a systems-level analysis of predictors of metabolic disease in PLWH and men who are at high risk of acquiring HIV, we found that increased lipopolysaccharide-binding protein, an inflammatory marker indicative of compromised intestinal barrier function, was associated with worse metabolic health. We also found impaired metabolic health associated with specific dietary components, gut microbes, and host and microbial metabolites. This study lays the framework for mechanistic studies aimed at targeting the microbiome to prevent or treat metabolic endotoxemia in HIV-infected individuals.

Lipidomics-Based Comparison of Molecular Compositions of Green, Yellow, and Red Bell Peppers.

Identifying and annotating the molecular composition of individual foods will improve scientific understanding of how foods impact human health and how much variation exists in the molecular composition of foods of the same species. The complexity of this task includes distinct varieties and variations in natural occurring pigments of foods. Lipidomics, a sub-field of metabolomics, has emerged as an effective tool to help decipher the molecular composition of foods. For this proof-of-principle research, we determined the lipidomic profiles of green, yellow and red bell peppers (Capsicum annuum) using liquid chromatography mass spectrometry and a novel tool for automated annotation of compounds following database searches. Among 23 samples analyzed from 6 peppers (2 green, 1 yellow, and 3 red), over 8000 lipid compounds were detected with 315 compounds (106 annotated) found in all three colors. Assessments of relationships between these compounds and pepper color, using linear mixed effects regression and false discovery rate (<0.05) statistical adjustment, revealed 11 compounds differing by color. The compound most strongly associated with color was the carotenoid, ß-cryptoxanthin (p-value = 7.4 × 10-5; FDR adjusted p-value = 0.0080). These results support lipidomics as a viable analytical technique to identify molecular compounds that can be used for unique characterization of foods.

Comparing the effects of an exposure to a polycyclic aromatic hydrocarbon mixture versus individual polycyclic aromatic hydrocarbons during monocyte to macrophage differentiation: Mixture exposure results in altered immune metrics.

Polycyclic aromatic hydrocarbons (PAHs) are generated by the incomplete combustion of carbon. Exposures correlate with systemic immune dysfunction and overall immune suppression. Real-world exposures to PAHs are almost always encountered as mixtures; however, research overwhelmingly centers on isolated exposures to a single PAH, benzo[a]pyrene (B[a]P). Here, a human monocyte line (U937) was exposed to B[a]P, benz[a]anthracene (B[a]A), or a mixture of six PAHs (6-MIX) to assess the differential toxicity on monocytes. Further, monocytes were exposed to PAHs with and without CYP1A1 inhibitors during macrophage differentiation to delineate PAH exposure and PAH metabolism-driven alterations to the immune response. U937 monocytes exposed to B[a]P, B[a]A, or 6-MIX had higher levels of cellular health and growth not observed following equimolar exposures to other individual PAHs. PAH exposures during differentiation did not alter monocyte-derived macrophage (MDM) numbers; however, B[a]A and 6-MIX exposures significantly altered M1/M2 polarization in a CYP1A1-dependent manner. U937-MDM adherence was differentially suppressed by all three PAH treatments with 6-MIX exposed U937-MDM having significantly more adhesion than U937-MDM exposed to either individual PAH. Finally, 6-MIX exposures during differentiation reduced U937-MDM endocytic function significantly less than B[a]A exposed cells. Exposure to a unique PAH mixture during U937-MDM differentiation resulted in mixture-specific alterations of pro-inflammatory markers compared to individual PAH exposures. While subtle, these differences highlight the probability that using a model PAH, B[a]P, may not accurately reflect the effects of PAH mixture exposures. Therefore, future studies should include various PAH mixtures that encompass probable real-world PAH exposures for the endpoints under investigation.