Natural history of infants with non-SCID T cell lymphopenia identified on newborn screen.

Newborn screening (NBS) for severe combined immunodeficiency (SCID) can identify infants with non-SCID T cell lymphopenia (TCL). The purpose of this study was to characterize the natural history and genetic findings of infants with non-SCID TCL identified on NBS. We analyzed data from 80 infants with non-SCID TCL in the mid-Atlantic region between 2012 and 2019. 66 patients underwent genetic testing and 41 (51%) had identified genetic variant(s). The most common genetic variants were thymic defects (33%), defects with unknown mechanisms (12%) and bone marrow production defects (5%). The genetic cohort had significantly lower median initial CD3+, CD4+, CD8+ and CD4/CD45RA+ T cell counts compared to the non-genetic cohort. Thirty-six (45%) had either viral, bacterial, or fungal infection; only one patient had an opportunistic infection (vaccine strain VZV infection). Twenty-six (31%) of patients had resolution of TCL during the study period.

Red Raspberry and Fructo-Oligosaccharide Supplementation, Metabolic Biomarkers, and the Gut Microbiota in Adults with Prediabetes: A Randomized Crossover Clinical Trial.

BACKGROUND: Evidence suggests that the gut microbiota and cardiometabolic status are associated, suggesting dietary interventions that alter the microbiota may affect metabolic health. OBJECTIVES: We investigated whether supplementation with (poly)phenol-dense red raspberries (RRB), alone or with a fructo-oligosaccharide (FOS) prebiotic, would improve biomarkers of cardiometabolic risk in individuals with prediabetes (PreDM) and insulin resistance (IR) and whether the effects are related to modulation of the gut microbiota. METHODS: Adults with PreDM-IR (n = 26; mean ± SEM age, 35 ± 2 years; fasting glucose, 5.7 ± 0.1 mmol/L; HOMA-IR, 3.3 ± 0.3) or who were metabolically healthy (reference group; n = 10; age, 31 ± 3 years; fasting glucose, 5.1 ± 0.2 mmol/L; HOMA-IR, 1.1 ± 0.1) participated in a randomized crossover trial with two 4-week supplementation periods, in which they consumed either RRB (125 g fresh equivalents) daily or RRB + 8g FOS daily, separated by a 4-week washout. The primary outcome variable was the change in the gut microbiota composition, assessed by shotgun sequencing before (baseline) and at the end of each supplementation period. Secondary outcomes were changes in glucoregulation, lipid metabolism, anti-inflammatory status, and anthropometry. The trial is registered at ClinicalTrials.gov, NCT03049631. RESULTS: In PreDM-IR, RRB supplementation reduced hepatic-IR (-30.1% ± 14.6%; P = 0.04) and reduced plasma total and LDL cholesterol [-4.9% ± 1.8% (P = 0.04) and -7.2% ± 2.3% (P = 0.003), respectively] from baseline. Adding FOS (RRB + FOS) improved ß-cell function [insulin secretion rate, +70.2% ± 32.8% (P = 0.02); Disposition Index, +94.4% ± 50.2% (P = 0.04)], but had no significant effect on plasma cholesterol compared to baseline. RRB increased Eubacterium eligens (2-fold) and decreased Ruminococcus gnavus (-60% ± 34%), whereas RRB + FOS increased Bifidobacterium spp. (4-fold) and decreased Blautia wexlerae (-23% ± 12%) from baseline (all P values ≤ 0.05). R. gnavus was positively correlated with hepatic-IR, and E. eligens and Bifidobacterium catenulatum were negatively correlated with cholesterol concentrations (P ≤ 0.05). CONCLUSIONS: Increased Bifidobacterium spp., concurrently with reduced R. gnavus, was associated with metabolic improvements in adults with PreDM-IR, warranting further research on the mechanisms involved in (poly)phenol/FOS-microbial interactions with host metabolism.

The associations of psoas and masseter muscles with sarcopenia and related adverse outcomes in older trauma patients: a retrospective study.

BACKGROUND: There is an emerging role for radiological evaluation of psoas muscle as a marker of sarcopenia in trauma patients. Older trauma patients are more likely to undergo cranial than abdomino-pelvic imaging. Identifying sarcopenia using masseter cross-sectional area (M-CSA) has shown correlation with mortality. We sought to determine the correlation between psoas: lumbar vertebral index (PLVI) and the M-CSA, and their association with health outcomes. METHODS: Patients aged 65 or above, who presented as a trauma call over a 1-year period were included if they underwent cranial or abdominal CT imaging. Images were retrospectively analysed to obtain PLVI and mean M-CSA measurements. Electronic records were abstracted for outcomes. Logistic regression methods, log scale analyses, Cox regression model and Kaplan-Meier plots were used to determine association of sarcopenia with outcomes. RESULTS: There were 155 eligible patients in the M-CSA group and 204 patients in the PLVI group. Sarcopenia was defined as the lowest quartile in each group. Pearson's correlation indicated a weakly positive linear relationship (r = 0.35, p < 0.001) between these. There was no statistical association between M-CSA sarcopenia status and any measured outcomes. Those with PLVI sarcopenia were more likely to die in hospital (adjusted OR 3.38, 95% CI 1.47-9.73, p = 0.006) and at 2 years (adjusted HR 1.90, 95% CI 1.11-3.25, p = 0.02). Only 29% patients with PLVI sarcopenia were discharged home, compared with 58% without sarcopenia (p = 0.001). CONCLUSION: Sarcopenia, defined by PLVI, is predictive of increased in-patient and 2-year mortality. Our study did not support prognostic relevance of M-CSA.

Strawberry Consumption, Cardiometabolic Risk Factors, and Vascular Function: A Randomized Controlled Trial in Adults with Moderate Hypercholesterolemia.

BACKGROUND: Certain fruits, such as strawberries, may impart cardiometabolic benefits due to their phytochemical content. OBJECTIVES: Study aims were to assess the effects of strawberry intake on cardiometabolic risk factors and vascular endothelial function in adults with moderate hypercholesterolemia. METHODS: This study was a randomized, controlled, double-blinded, 2-arm, 2-period (4-wk/period) crossover trial. Adults (n = 34; male/female 1:1; mean ± SEM age, 53 ± 1 y; BMI, 31 ± 1 kg/m2;  LDL cholesterol, 133 ± 3 mg/dL) were randomly allocated to 1 of 2 study sequences in a 1:1 ratio. Participants drank study beverages twice daily containing freeze-dried strawberry powder (2 × 25 g) or energy-, volume-matched control powder for 4 wk separated by a 4-wk washout. The primary outcome variable was the difference in fasting LDL cholesterol after 4-wk interventions. Secondary outcomes were metabolic markers, inflammation, quantitative (poly)phenolic metabolomics, flow-mediated dilation (FMD), and blood pressure (BP), with the latter (FMD, BP) also assessed acutely at 1 h and 2 h after a 50-g bolus strawberry or control beverage. Mixed-model analysis of repeated measures via PROC MIXED, PC-SAS was performed on primary and secondary outcome variables. RESULTS: LDL cholesterol did not differ after the 4-wk interventions (P > 0.05), nor did fasting total cholesterol, triglycerides, glucose, insulin, high-sensitivity C-reactive protein, FMD, or BP (all P > 0.05). Significant intervention-by-hour interaction for FMD (P = 0.03) and BP (P = 0.05) revealed increased FMD at 1 h after strawberry compared with control by 1.5 ± 0.38% (P = 0.0008) and attenuated systolic BP at 2 h by 3.1 ± 0.99 mmHg (P = 0.02). Select phenolic metabolites increased significantly (P < 0.05) in blood following strawberry consumption while others decreased, including 3-(4-methoxyphenyl)propanoic acid-3-O-glucuronide, which was significantly correlated with increased FMD (P < 0.05). CONCLUSION: Strawberries may improve vascular health, independent of other metabolic changes. The effect may be related to changes in microbial-derived phenolic metabolites after strawberry consumption influencing endothelial function. Data support inclusion of strawberries in a heart-healthy diet in adults with moderate hypercholesterolemia.This trial was registered at clinicaltrials.gov as NCT02612090.

Watermelon and L-Citrulline in Cardio-Metabolic Health: Review of the Evidence 2000-2020.

PURPOSE OF REVIEW: Watermelon (Citrullus lanatus) distinctively contains L-citrulline and L-arginine, precursors of nitric oxide (NO), along with polyphenols and carotenoids suggesting a role in cardio-metabolic health. The goal of this paper is to review the preclinical and clinical trial evidence published from 2000 to 2020 to assess watermelon intake and L-citrulline, as a signature compound of watermelon, on cardiovascular and metabolic outcomes, and to identify future directions important for establishing dietary guidance and therapeutic recommendations actionable by health care professionals, patients, and the general public. RECENT FINDINGS: Watermelon and L-citrulline supplementation reduced blood pressure in human trials. Evidence for benefits in lipids/lipoprotein metabolism is emerging based on human literature and consistently reported in animal models. A role for watermelon intake in body weight control, possibly through satiety mechanisms, warrants further research. Likewise, improved glucose homeostasis in chemically and diet-induced animal models of diabetes is apparent, though limited data are available in humans. Emerging areas include brain and gut health indicated by NO bioavailability in all tissues, and evidence suggesting improvements in gut barrier function and altered microbial composition after watermelon intake that may influence metabolite pools and physiological function. Watermelon fruit contains unique vaso- and metabolically-active compounds. Accumulating evidence supports regular intake for cardio-metabolic health. Future research to determine the amount and frequency of watermelon/citrulline intake for desired outcomes in different populations requires attention to advance preventative and therapeutic strategies for optimal health and disease risk reduction.

Plasma and Urinary (Poly)phenolic Profiles after 4-Week Red Raspberry (Rubus idaeus L.) Intake with or without Fructo-Oligosaccharide Supplementation.

Red raspberries (RRB) are high in anthocyanin- and ellagitannin- type (poly)phenols. This study aimed to investigate the effect of 4-week RRB supplementation on (poly)phenolic metabolism in adults with prediabetes and insulin-resistance (PreDM-IR); and whether adding fructo-oligosaccharides (FOS), prebiotics, would augment the microbial metabolites of RRB (poly)phenols. In a randomized crossover clinical trial, subjects (n = 35: PreDM-IR, n = 25; healthy Reference group, n = 10) consumed 1 cup RRB (fresh weight equivalence) per day and RRB with 8 g FOS per day each for 4 weeks in random order separated by 4-week washout. Plasma and urinary (poly)phenolic metabolites were characterized after (0-24h) consuming a RRB-based test drink (2 cups RRB) at baseline/week 0 and again after 4-week supplementations. A total of 123 (poly)phenolic metabolites were quantified. After 4-week RRB supplementation, several metabolite groups were significantly increased (p < 0.05), including urolithins, phenyl-γ-valerolactones, and phenolic acids. Supplementing FOS with RRB for 4 weeks enhanced benzoic acid derivatives compared to the baseline (p < 0.05). Specific effects of supplementation by metabolic status indicated 4-week RRB supplementation significantly increased microbial metabolites that were lower in PreDM-IR group. Our results suggest alterations in the capacity of PreDM-IR group to metabolize and render bioavailable raspberry-derived (poly)phenols when consumed regularly.

Pharmacokinetic Characterization of (Poly)phenolic Metabolites in Human Plasma and Urine after Acute and Short-Term Daily Consumption of Mango Pulp.

Pharmacokinetic (PK) evaluation of polyphenolic metabolites over 24 h was conducted in human subjects (n = 13, BMI = 22.7 ± 0.4 kg/m2) after acute mango pulp (MP), vitamin C (VC) or MP + VC test beverage intake and after 14 days of MP beverage intake. Plasma and urine samples were collected at different time intervals and analyzed using targeted and non-targeted mass spectrometry. The maximum concentrations (Cmax) of gallotannin metabolites were significantly increased (p < 0.05) after acute MP beverage intake compared to VC beverage alone. MP + VC beverage non-significantly enhanced the Cmax of gallic acid metabolites compared to MP beverage alone. Pyrogallol (microbial-derived metabolite) derivatives increased (3.6%) after the 14 days of MP beverage intake compared to 24 h acute MP beverage intake (p < 0.05). These results indicate extensive absorption and breakdown of gallotannins to galloyl and other (poly)phenolic metabolites after MP consumption, suggesting modulation and/or acclimation of gut microbiota to daily MP intake.

Mathematical modeling of the adsorption/desorption characteristics of anthocyanins from muscadine (Vitis rotundifolia cv. Noble) juice pomace on Amberlite FPX66 resin in a fixed bed column.

BACKGROUND: Muscadine grape pomace, a by-product of juicing and wine-making, contains significant amounts of anthocyanin 3,5-diglucosides, known to be beneficial to human health. RESULTS: The objective of this research was to use mathematical modeling to investigate the adsorption/desorption characteristics of these anthocyanins from muscadine grape pomace on Amberlite FPX66 resin in a fixed bed column. Anthocyanins were extracted using hot water and ultrasound, and the extracts were loaded onto a resin column at five bed depths (5, 6, 8, 10 and 12 cm) using three flow rates (4, 6 and 8 mL min-1 ). It was found that adsorption on the column fitted the bed depth service time (BDST) model and the empty bed residence time (EBRT) model. Desorption was achieved by eluting the column using ethanol at four concentrations (25, 40, 55 and 70% v/v) and could be described with an empirical sigmoid model. The breakthrough curves of anthocyanins fitted the BDST model for all three flow rates with R2 values of 0.983, 0.992 and 0.984 respectively. The EBRT model was successfully employed to find the operating lines, which allow for column scale-up while still achieving similar results to those found in a laboratory operation. Desorption with 40% (v/v) ethanol achieved the highest recovery rate of anthocyanins at 79.6%. CONCLUSION: The mathematical models established in this study can be used in designing a pilot/industrial- scale column for the separation and concentration of anthocyanins from muscadine juice pomace. © 2018 Society of Chemical Industry.

Huanglongbing modifies quality components and flavonoid content of 'Valencia' oranges.

BACKGROUND: In order to evaluate the effect of citrus greening disease, or Huanglongbing (HLB), on quality components and flavonoid contents of 'Valencia' oranges, fruit from non-infected trees (control), from infected trees but symptom-less (asymptomatic) and from infected trees and showing clear HLB symptoms (symptomatic) were harvested in March and in May, 2013. Fruit peel, pulp and juice were separated, the main quality components were determined, and hesperidin, nobiletin, tangeretin, narirutin and didymin were quantified using liquid chromatography. RESULTS: Peel colour, total soluble solids and citric acid were similar in control and asymptomatic fruits. Symptomatic fruits were smaller, yielded less juice, had higher acidity and lower sugar and peel colour than control fruits. In the peel, hesperidin, nobiletin, tangeretin, narirutin and didymin were higher in symptomatic than in asymptomatic and control fruits. Peel flavonoids decreased with fruit maturation. Also, in pulp and juice, flavonoid content was higher in symptomatic than in asymptomatic and control fruits. CONCLUSIONS: These results show that asymptomatic fruits are similar to control fruits more than to symptomatic fruits, suggesting that secondary metabolism and physical properties of fruits are only affected at a later and more advanced stage of HLB infection. Despite the significant loss of quality, fruit with clear HLB symptoms accumulate high quantities of flavonoids in peel and pulp.

Clinical hypothermia temperatures increase complement activation and cell destruction via the classical pathway.

BACKGROUND: Therapeutic hypothermia is a treatment modality that is increasingly used to improve clinical neurological outcomes for ischemia-reperfusion injury-mediated diseases. Antibody-initiated classical complement pathway activation has been shown to contribute to ischemia-reperfusion injury in multiple disease processes. However, how therapeutic hypothermia affects complement activation is unknown. Our goal was to measure the independent effect of temperature on complement activation, and more specifically, examine the relationship between clinical hypothermia temperatures (31-33°C), and complement activation. METHODS: Antibody-sensitized erythrocytes were used to assay complement activation at temperatures ranging from 0-41°C. Individual complement pathway components were assayed by ELISA, Western blot, and quantitative dot blot. Peptide Inhibitor of complement C1 (PIC1) was used to specifically inhibit activation of C1. RESULTS: Antibody-initiated complement activation resulting in eukaryotic cell lysis was increased by 2-fold at 31°C compared with 37°C. Antibody-initiated complement activation in human serum increased as temperature decreased from 37°C until dramatically decreasing at 13°C. Quantitation of individual complement components showed significantly increased activation of C4, C3, and C5 at clinical hypothermia temperatures. In contrast, C1s activation by heat-aggregated IgG decreased at therapeutic hypothermia temperatures consistent with decreased enzymatic activity at lower temperatures. However, C1q binding to antibody-coated erythrocytes increased at lower temperatures, suggesting that increased classical complement pathway activation is mediated by increased C1 binding at therapeutic hypothermia temperatures. PIC1 inhibited hypothermia-enhanced complement-mediated cell lysis at 31°C by up to 60% (P = 0.001) in a dose dependent manner. CONCLUSIONS: In summary, therapeutic hypothermia temperatures increased antibody-initiated complement activation and eukaryotic cell destruction suggesting that the benefits of therapeutic hypothermia may be mediated via other mechanisms. Antibody-initiated complement activation has been shown to contribute to ischemia-reperfusion injury in several animal models, suggesting that for diseases with this mechanism hypothermia-enhanced complement activation may partially attenuate the benefits of therapeutic hypothermia.

Phytochemical Composition and Health Benefits of Figs (Fresh and Dried): A Review of Literature from 2000 to 2022.

With their rich history dating back 6000 years, figs are one of the oldest known plants to mankind and are a classical fruit in the Mediterranean diet. They possess a diverse array of bioactive components, including flavonoids, phenolic acids, carotenoids, and tocopherols, which have been used for centuries in traditional medicine for their health-promoting effects addressing gastrointestinal, respiratory, inflammatory, metabolic, and cardiovascular issues. This review summarizes the updated information on the phenolic composition, antioxidant capacity and other functional properties of fresh and dried figs cultivated in various parts of the world, highlighting variation in phenolic composition based on cultivar, harvesting time, maturity stage, processing, and fig parts. Additionally, the review delves into the bio-accessibility and bio-availability of bioactive components from figs and their potential influence on cardiovascular health, diabetes, obesity, and gut/digestive health. Data suggest that the intake of figs regularly in the diet, alone or with other dried fruits, increases select micronutrient intake and is associated with higher diet quality, respectively. Research in animal and human models of health and disease risk provide preliminary health benefits data on figs and their extracts from fig parts; however, additional well-controlled human studies, particularly using fig fruit, will be required to uncover and verify the potential impact of dietary intake of figs on modern day health issues.

Characterization and Pharmacokinetic Profile of Herbs and Spices' Phytochemicals over 24 h after Consumption in Overweight/Obese Adults.

SCOPE: This study aims to characterize the phytochemicals in commonly consumed herbs/spices (H/S) in the United States and their pharmacokinetic profile (PK) over 24 h in humans after consumption. METHOD AND RESULTS: The clinical trial is a randomized, single-blinded, four-arm, 24 h, multi-sampling, single-center crossover design (Clincaltrials.gov NCT03926442) conducted in obese/overweight adults (n = 24, aged 37 ± 3 years, BMI = 28.4 ± 0.6 kg m-2 ). Study subjects consume a high-fat high-carbohydrate meal with salt and pepper (control) or the control meal with 6 g of three different H/S mixtures (Italian herb: rosemary, basil, thyme, oregano, and parsley in the same ratio; cinnamon; and pumpkin pie spice containing cinnamon, ginger, nutmeg, and allspice, the ratio is unknown). Three H/S mixtures are analyzed and 79 phytochemicals are tentatively identified and quantified. Following H/S consumption, 47 metabolites are tentatively identified and quantified in plasma samples. The PK data suggest that some metabolites appear in blood as early as 0.5 h while others can extend up to 24 h. CONCLUSION: Phytochemicals from H/S include in a meal are absorbed and undergo phase I and phase II metabolism and/or catabolized to phenolic acids peaking at different times.

Analysis of Eight Types of Plant-based Milk Alternatives from the United States Market for Target Minerals and Trace Elements.

A wide variety of commercial plant-based foods that are marketed and sold as alternatives for milk (plant-based milk alternatives or PBMAs) are available to consumers. In this study, PBMAs from the United States (n=85) were subjected to analysis for target minerals (magnesium, phosphorus, selenium, and zinc) to compare their variability across PBMA types, brands, and production lots. Samples were also screened for the environmental contaminant elements arsenic, cadmium, and lead. The eight PBMA types sampled were produced from almond, cashew, coconut, hemp, oat, pea, rice, and soy. Elemental analysis was conducted using microwave-assisted acid digestion followed by inductively coupled plasma-mass spectrometry. The results showed that pea PBMAs contained the highest mean amounts of phosphorus, selenium, and zinc, while soy PBMAs were highest in magnesium. Mean amounts of minerals were lower than those found in milk for the majority of PBMA types. There was significant variation (P<0.05) in amounts of minerals across the majority of product brands. The amounts of phosphorus and magnesium varied across production lots (P<0.05), but the absolute value of these differences was low. Total arsenic was highest in rice PBMAs; amounts of cadmium and lead across PBMAs were generally found at low or non-quantifiable amounts. These results underscore the importance of generating analytical data on the elemental composition of products within the rapidly growing category of PBMA.

An Improved Validated Method for the Determination of Short-Chain Fatty Acids in Human Fecal Samples by Gas Chromatography with Flame Ionization Detection (GC-FID).

Short-chain fatty acids (SCFAs) are metabolites produced by the gut microbiota through the fermentation of non-digestible carbohydrates. Recent studies suggest that the gut microbiota composition, diet and metabolic status play an important role in the production of SCFAs. The primary objective of this study was to develop a simplified method for SCFA analysis in human fecal samples by gas chromatography with flame ionization detection (GC-FID). The secondary objective was to apply the method to fecal samples collected from a clinical trial. The developed GC-FID method showed excellent linearity (R2 > 0.99994), with a limit of detection (LOD) ranging from 0.02 to 0.23 µg/mL and a limit of quantification (LOQ) ranging from 0.08 to 0.78 µg/mL. Recovery for the method ranged between 54.24 ± 1.17% and 140.94 ± 2.10%. Intra- and inter-day repeatability ranged from 0.56 to 1.03 and from 0.10 to 4.76% RSD, respectively. Nine SCFAs were identified and quantified (acetic, propionic, iso-butyric, butyric, iso-valeric, valeric, 4-methyl valeric, hexanoic and heptanoic acids) in freeze-dried fecal samples. The clinical trial compared participants with prediabetes mellitus and insulin resistance (IR-group, n = 20) to metabolically healthy participants (reference group, R-group, n = 9) following a 4-week intervention of a daily red raspberry smoothie (RRB, 1 cup fresh-weight equivalent) with or without fructo-oligosaccharide (RRB + FOS, 1 cup RRB + 8 g FOS). The statistical analysis (Student's t-test, ANCOVA) was performed on PC-SAS 9.4 (SAS Institute). Acetic acid was higher in the R-group compared to the IR-group at baseline/week 0 (p = 0.14). No significant changes in fecal SCFA content were observed after 4 weeks of either RRB or RRB + FOS.

Market Basket Survey of the Micronutrients Vitamin A, Vitamin D, Calcium, and Potassium in Eight Types of Commercial Plant-Based Milk Alternatives from United States Markets.

We performed a market basket survey of plant-based milk alternatives (PBMAs) from the US market for vitamin A, vitamin D, calcium, and potassium to identify the amount and variability of these micronutrients across various PBMAs. The PBMA types included in this analysis were almond, cashew, coconut, hemp, oat, pea, rice, and soy (n=90 total product units). Analyses for vitamin A (as retinyl palmitate), vitamin D2/D3, and minerals were performed using high-performance liquid chromatography, liquid chromatography-tandem mass spectrometry, and inductively coupled plasma-mass spectrometry, respectively. A majority of PBMA types had significant differences (P<0.05) in the amounts of target micronutrients across brands. The coefficient of variation (%CV) for micronutrient concentrations within one lot of a single brand ranged from 4.1-42.2% for vitamin A, 1.5-44.1% for vitamin D, 1.7%-37.6% for calcium, and 0.7%-39.0% for potassium. The variability of these micronutrients should be taken into account when considering the nutritional value of PBMAs.

Development and Evaluation of Machine Learning in Whole-Body Magnetic Resonance Imaging for Detecting Metastases in Patients With Lung or Colon Cancer: A Diagnostic Test Accuracy Study.

OBJECTIVES: Whole-body magnetic resonance imaging (WB-MRI) has been demonstrated to be efficient and cost-effective for cancer staging. The study aim was to develop a machine learning (ML) algorithm to improve radiologists' sensitivity and specificity for metastasis detection and reduce reading times. MATERIALS AND METHODS: A retrospective analysis of 438 prospectively collected WB-MRI scans from multicenter Streamline studies (February 2013-September 2016) was undertaken. Disease sites were manually labeled using Streamline reference standard. Whole-body MRI scans were randomly allocated to training and testing sets. A model for malignant lesion detection was developed based on convolutional neural networks and a 2-stage training strategy. The final algorithm generated lesion probability heat maps. Using a concurrent reader paradigm, 25 radiologists (18 experienced, 7 inexperienced in WB-/MRI) were randomly allocated WB-MRI scans with or without ML support to detect malignant lesions over 2 or 3 reading rounds. Reads were undertaken in the setting of a diagnostic radiology reading room between November 2019 and March 2020. Reading times were recorded by a scribe. Prespecified analysis included sensitivity, specificity, interobserver agreement, and reading time of radiology readers to detect metastases with or without ML support. Reader performance for detection of the primary tumor was also evaluated. RESULTS: Four hundred thirty-three evaluable WB-MRI scans were allocated to algorithm training (245) or radiology testing (50 patients with metastases, from primary 117 colon [n = 117] or lung [n = 71] cancer). Among a total 562 reads by experienced radiologists over 2 reading rounds, per-patient specificity was 86.2% (ML) and 87.7% (non-ML) (-1.5% difference; 95% confidence interval [CI], -6.4%, 3.5%; P = 0.39). Sensitivity was 66.0% (ML) and 70.0% (non-ML) (-4.0% difference; 95% CI, -13.5%, 5.5%; P = 0.344). Among 161 reads by inexperienced readers, per-patient specificity in both groups was 76.3% (0% difference; 95% CI, -15.0%, 15.0%; P = 0.613), with sensitivity of 73.3% (ML) and 60.0% (non-ML) (13.3% difference; 95% CI, -7.9%, 34.5%; P = 0.313). Per-site specificity was high (>90%) for all metastatic sites and experience levels. There was high sensitivity for the detection of primary tumors (lung cancer detection rate of 98.6% with and without ML [0.0% difference; 95% CI, -2.0%, 2.0%; P = 1.00], colon cancer detection rate of 89.0% with and 90.6% without ML [-1.7% difference; 95% CI, -5.6%, 2.2%; P = 0.65]). When combining all reads from rounds 1 and 2, reading times fell by 6.2% (95% CI, -22.8%, 10.0%) when using ML. Round 2 read-times fell by 32% (95% CI, 20.8%, 42.8%) compared with round 1. Within round 2, there was a significant decrease in read-time when using ML support, estimated as 286 seconds (or 11%) quicker ( P = 0.0281), using regression analysis to account for reader experience, read round, and tumor type. Interobserver variance suggests moderate agreement, Cohen κ = 0.64; 95% CI, 0.47, 0.81 (with ML), and Cohen κ = 0.66; 95% CI, 0.47, 0.81 (without ML). CONCLUSIONS: There was no evidence of a significant difference in per-patient sensitivity and specificity for detecting metastases or the primary tumor using concurrent ML compared with standard WB-MRI. Radiology read-times with or without ML support fell for round 2 reads compared with round 1, suggesting that readers familiarized themselves with the study reading method. During the second reading round, there was a significant reduction in reading time when using ML support.

Endothelial Function and Postprandial Glucose Control in Response to Test-Meals Containing Herbs and Spices in Adults With Overweight/Obesity.

Objectives: Herbs and Spices (H/S) contain bioactive compounds with purported health benefits. This study investigated the effect of H/S intake on indicators of vascular and metabolic health over 24 h using a test-meal challenge paradigm in adults with overweight or obesity. Methods: In a randomized, single-blinded, 4-arm, 24 h, multi-sampling, crossover clinical trial, adults (n = 25) aged 36.6 ± 3.1 years with BMI 28.5 ± 0.6 kg/m2 (mean ± SEM) consumed a high-fat, high-carbohydrate challenge meal (~810 kcal) with salt/pepper only (control) or control with one of three different H/S combinations: Italian herb (rosemary, basil, thyme, oregano, and parsley), cinnamon, or pumpkin pie spice mix (cinnamon, ginger, nutmeg, and allspice) on four separate visits at least 3 days apart. Meals provided 35% of subjects' energy to maintain weight and ~1 g H/S per 135 kcal of the meal. Flow-mediated dilation (FMD) and blood samples were collected at 0, 1, 2, 4, 5.5, 7, and 24 h for endpoint analysis (additional blood draw at 0.5 h for insulin/glucose). Mixed-model analysis of repeated measures via PROC MIXED PC-SAS 9.4 was performed on the primary outcome (FMD) and secondary outcome variables. This study was registered at ClinicalTrials.gov (NCT03926442). Results: Italian herb and pumpkin spice meals significantly increased %FMD at 24 h compared to the control meal (P = 0.048 and P = 0.027, respectively). The cinnamon meal reduced postprandial glycemia (Δ) compared to control (P = 0.01), and pumpkin pie spice mix and cinnamon meals reduced postprandial insulin at 0.5 h compared to the control meal (P = 0.01 and P = 0.04, respectively). IL-6 and triglycerides increased in response to all meals (Time, P < 0.0001) but were not significantly different between meals. Conclusions: The test-meal challenge study design coupled with multiple sampling over 24 h provides insights into time-course bioactivity of H/S on vascular function and metabolic indices in overweight/obese adults. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT03926442.

Pharmacokinetic Evaluation of Red Raspberry (Poly)phenols from Two Doses and Association with Metabolic Indices in Adults with Prediabetes and Insulin Resistance.

This study aimed to investigate pharmacokinetic variables of two doses of red raspberry (RR) (poly)phenols and their association with metabolic indices in adults with prediabetes and insulin resistance (preDM-IR) compared to metabolically healthy adults (reference). Thirty-two adults (preDM-IR, n = 21; reference, n = 11) consumed three meals containing 0 g (control), 125 g, or 250 g of frozen RR on three separate days in random order. Plasma (poly)phenolic metabolites and metabolic indices were characterized over a 0-8 h period and again at 24 h. Twenty-four metabolites were significantly increased by RR interventions in all subjects (p < 0.05). Individuals with preDM-IR compared to reference had a lower capacity to generate several metabolites, including 4'-hydroxy-3'-methoxycinnamic acid and hydroxymethoxycinnamic acid isomer, both negatively correlated with postprandial insulin concentrations (p < 0.05). The results suggest that RR (poly)phenols are metabolized in a dose-related manner, and further research is required to understand their role in insulin management.

Comprehensive Characterization of Bile Acids in Human Biological Samples and Effect of 4-Week Strawberry Intake on Bile Acid Composition in Human Plasma.

Primary bile acids (BAs) and their gut microbial metabolites have a role in regulating human health. Comprehensive characterization of BAs species in human biological samples will aid in understanding the interaction between diet, gut microbiota, and bile acid metabolism. Therefore, we developed a qualitative method using ultra-high performance liquid chromatography (UHPLC) coupled with a quadrupole time-of-flight (Q-TOF) to identify BAs in human plasma, feces, and urine samples. A quantitative method was developed using UHPLC coupled with triple quadrupole (QQQ) and applied to a previous clinical trial conducted by our group to understand the bile acid metabolism in overweight/obese middle-aged adults (n = 34) after four weeks strawberry vs. control intervention. The qualitative study tentatively identified a total of 81 BAs in human biological samples. Several BA glucuronide-conjugates were characterized for the first time in human plasma and/or urine samples. The four-week strawberry intervention significantly reduced plasma concentrations of individual secondary BAs, deoxycholic acid, lithocholic acid and their glycine conjugates, as well as glycoursodeoxycholic acid compared to control (p < 0.05); total glucuronide-, total oxidized-, total dehydroxyl-, total secondary, and total plasma BAs were also lowered compared to control (p < 0.05). The reduced secondary BAs concentrations suggest that regular strawberry intake modulates the microbial metabolism of BAs.