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Aims Little is known about the impact of weight loss on developing comorbidities in patients with obesity in real-world settings. Understanding health benefits and associated comorbidities with weight loss are critical to addressing the global obesity health epidemic. This study aimed to determine health outcomes associated with weight loss in individuals with obesity, and to better understand the relationship between disease burden (i.e., prior comorbidities, healthcare utilization) and weight loss in individuals with obesity. Electronic health records (EHRs) represent an important resource to investigate these impacts. Materials and methods We conducted a case-control study using deidentified EHR-derived information from 204,921 patients seen at the Cleveland Clinic between 2000-2018. Patients were ≥20 years of age with BMI ≥30 kg/m2 and ≥7 weight measurements, over ≥3 years. Thirty outcomes were investigated, including chronic and acute diseases, as well as psychological and metabolic disorders. Weight change was investigated three, five, and ten years prior to an event. Results Weight loss was associated with reduced incidence of many outcomes (e.g., type 2 diabetes, non-alcoholic steatohepatitis/non-alcoholic fatty liver disease, obstructive sleep apnea, hypertension) (P 10% was associated with increased incidence of certain outcomes including stroke and substance abuse. However, many outcomes that increased with weight loss were attenuated by disease burden adjustments. Conclusions This study provides the most comprehensive real-world evaluation of health impacts of weight change to date. After comorbidity burden and healthcare utilization adjustments, weight loss was associated with an overall reduction in risk of many adverse outcomes. This article is protected by copyright. All rights reserved.

Hepatocellular carcinoma (HCC) and secondary liver tumors, such as colorectal cancer liver metastases are significant contributors to the overall burden of cancer‐related morality. Current biomarkers, such as alpha‐fetoprotein (AFP) for HCC, result in too many false negatives, necessitating noninvasive approaches with improved sensitivity. Volatile organic compounds (VOCs) detected in the breath of patients can provide valuable insight into disease processes and can differentiate patients by disease status. Here, we investigate whether 22 VOCs from the breath of 296 patients can distinguish those with no liver disease (n = 54), cirrhosis (n = 30), HCC (n = 112), pulmonary hypertension (n = 49), or colorectal cancer liver metastases (n = 51). This work extends previous studies by evaluating the ability for VOC signatures to differentiate multiple diseases in a large cohort of patients. Pairwise disease comparisons demonstrated that most of the VOCs tested are present in significantly different relative abundances (false discovery rate P, We identified a signature of volatile organic compounds in breath that accurately distinguishes patients with no liver disease, cirrhosis, pulmonary hypertension, hepatocellular carcinoma, or colorectal liver metastasis.

Objective Current type 2 diabetes (T2D) management contraindicates intensive glycemia treatment in patients with high cardiovascular disease (CVD) risk, and is partially motivated by evidence of harms in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Heterogeneity in response to intensive glycemia treatment has been observed, suggesting potential benefit for some individuals. Research Design and Methods ACCORD was a randomized controlled trial that investigated whether intensively treating glycemia in individuals with T2D reduced CVD outcomes. Using a novel approach to cluster HbA1c trajectories, we identified groups in the intensive glycemia arm with modified CVD risk. Genome-wide analysis and polygenic score (PS) were developed to predict group membership. Mendelian randomization was performed to infer causality. Results We identified four clinical groupings in the intensive glycemia arm, and clinical group 4 (C4) displayed fewer CVD outcomes (HR=0.34, P=2.01x10-3) and microvascular outcomes (HR=0.86, P=.015) than standard treatment. A single nucleotide polymorphism, rs220721, in MAS1, reached suggestive significance with C4 (P=4.34x10-7). The PS predicted C4 with high accuracy (AUC=0.98), and predicted C4 displayed reduced CVD risk on intensive versus standard glycemia treatment (HR=0.53, P=4.02x10-6), but not for microvascular outcomes (PP Conclusions We found evidence of a T2D clinical group in ACCORD that benefited from intensive glycemia treatment, and membership of this group can be predicted using genetic variants. This study generates new hypotheses with implications for precision medicine in T2D and represents an important development for this landmark clinical trial warranting further investigation.

OBJECTIVE Current type 2 diabetes (T2D) management contraindicates intensive glycemia treatment in patients with high cardiovascular disease (CVD) risk and is partially motivated by evidence of harms in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Heterogeneity in response to intensive glycemia treatment has been observed, suggesting potential benefit for some individuals. RESEARCH DESIGN AND METHODS ACCORD was a randomized controlled trial that investigated whether intensively treating glycemia in individuals with T2D would reduce CVD outcomes. Using a novel approach to cluster HbA1c trajectories, we identified groups in the intensive glycemia arm with modified CVD risk. Genome-wide analysis and polygenic score (PS) were developed to predict group membership. Mendelian randomization was performed to infer causality. RESULTS We identified four clinical groupings in the intensive glycemia arm, and clinical group 4 (C4) displayed fewer CVD (hazard ratio [HR] 0.34; P = 2.01 × 10−3) and microvascular outcomes (HR 0.86; P = 0.015) than those receiving standard treatment. A single-nucleotide polymorphism, rs220721, in MAS1 reached suggestive significance in C4 (P = 4.34 × 10−7). PS predicted C4 with high accuracy (area under the receiver operating characteristic curve 0.98), and this predicted C4 displayed reduced CVD risk with intensive versus standard glycemia treatment (HR 0.53; P = 4.02 × 10−6), but not reduced risk of microvascular outcomes (P < 0.05). Mendelian randomization indicated causality between PS, on-trial HbA1c, and reduction in CVD outcomes (P < 0.05). CONCLUSIONS We found evidence of a T2D clinical group in ACCORD that benefited from intensive glycemia treatment, and membership in this group could be predicted using genetic variants. This study generates new hypotheses with implications for precision medicine in T2D and represents an important development in this landmark clinical trial warranting further investigation.

High liver uptake presents a problem for 3’-deoxy-3’-[(18)F]fluorothymidine ([(18)F]FLT) as a radiotracer for imaging cellular proliferation in the liver with positron emission tomography (PET). This investigation re-visited some issues related to the high liver background uptake of [(18)F]FLT with an animal model of woodchucks. Several enzymes involved in the hepatic catabolism of FLT, thymidine phosphorylase (TP, TYMP), uridine 5’-diphospho-glucuronosyl-transferases (UDP-GTs, short for UGTs), and β-glucuronidase (GUSB), their homology as well as hepatic expression between the human and the woodchuck was examined. Inhibitors of these enzymes, TP inhibitor (TPI) tipiracil hydrochloride, UGT inhibitor probenecid, β-glucuronidase inhibitor L-aspartate, were administered to the animals at human equivalent doses either intravenously (i.v.) and orally before the injection of tracer-dose [(18)F]FLT for PET imaging to examine any changes in liver uptake. Liver tissue samples were harvested from the animals after PET imaging and used to perform polymerase chain reaction (PCR) for TP expression or assays for enzymatic activities of TP and β-glucuronidase. Non-radiolabeled (cold) FLT was also applied for enzyme saturation. Animals administered with TPI displayed lower radioactivity in the liver in comparison with the baseline scan. The application of probenecid did not change [(18)F]FLT liver uptake even though it reduced renal uptake. L-aspartate reduced the liver background uptake of [(18)F]FLT slightly. The application of cold FLT reduced overall uptake of [(18)F]FLT including the liver background. Therefore, the combined application of cold FLT and [(18)F]FLT merits further clinical investigation for reducing liver background uptake of [(18)F]FLT.

Breath analysis is the study of volatile organic compounds (VOC's) in exhaled breath. This analysis provides information on the body's condition. In this study we investigated the relationship between 22 VOC's detected in exhaled breath and plasma headspace using a selected ion flow tube mass spectrometer (SYFT-MS). We compared pairs of exhaled breath and plasma samples from patients with pulmonary hypertension inflammatory bowel disease (IBD), and IBD patients after J-pouch surgery (pouch group). Half of the measured VOC's from exhaled breath were significantly associated with the VOC's from plasma headspace. Interestingly, six breath VOC's (trimethyl amine (FDR p = 0.02), hydrogen sulfide (FDR p = 7.64 × 10-30), ethanol (FDR p = 1.56 × 10-4), dimethyl sulfide (FDR p = 5.70 × 10-19), benzene (FDR p = 8.40 × 10-27), and acetaldehyde (FDR p = 4.27 × 10-17)) and two plasma headspace VOC's (1-Octene (FDR p = 0.02) and 2-propanol (FDR p = 2.47 × 10-9)) were able to differentiate between the three groups. Breath and plasma headspace share a similar signature with significant association in half of the measured VOCs. The disease discriminatory capacity of breath and plasma headspace appear to be different. Therefore, using the VOC's print from both breath and plasma headspace may better help diagnose patients.