tbuckley/cabot-search huggingface dataset:
Abstract P292: THE LACK OF FASTING INSULIN MEASUREMENT DELAYS THE MANAGEMENT OF PREDIABETES IN OBESE ADOLESCENTS.
Authors: Julie St-pierre, Maude Sirois, Genevieve Paquin, Elisa Jean-Baptiste, Maryline Robert
Journal: Circulation (2020)

Background: Insulin resistance is a medical complication associated with obesity and metabolic syndrome in youth. Data have shown that pediatric obesity can stop or even decrease by an adequate clinical management of the insulin resistance-associated syndrome. Despite those new evidences, measurement of insulin resistance in youth remains quite low. Objective: The objective was to review and evaluate the proportion of pediatric obese patients referred to a 2nd line pediatric multidisciplinary obesity clinic among whom insulin resistance was screened or not. Material &amp; Method: We have looked, retrospectively, at the initial blood tests among 133 obese patients (body mass index above 97th percentile with respect for age and sex) above 10 years of age, between July 2017 and April 2019. Sixty percent (60%) of our urban cohort is represented by 1st and 2nd generation immigrants. Hyperinsulinemia was defined as a value above 100 pmol/L. Pediatric obese patients were referred by general practitionniers or community pediatricians. Results: Among the 133 medical files revised, 91 patients shown hyperinsulinemia (68%). Of those 91 patients, 64 were not initially screened for hyperinsulinemia (70%). Interestingly, in the hyperinsulinemia pediatric group, mean HDL-cholesterol was lower, mean triglycérides were higher, as well as the mean alanine transaminase (ALT) compared to the normal insulin group (p smaller than 0.05). In the hyperinsulinemia group, 71,8% of our pediatric cohort was started on metformin therapy in addition to a multidisciplinary intensive educational family interventions as recommended by WHO. Conclusions: Fasting insulin can be variable among puberty stages and general guidelines for the use of metformin in the pediatric population are still to come. However, measurement of elevated fasting insulin among pre- and post-pubertal patients was previously associated with markers of cardiovascular and hepatic complications in obese young patients. Fasting insulin is a simple, cheap, easily accessible measure in all clinical settings. Multidisciplinary health care for pediatric obesity is still embryonic and difficult to access. Appropriate and complete initial clinical investigations, including fasting insulin measurement, should be performed in order not to delay its medical intensive multidisciplinary management both in 1st and 2nd lines practitioners.
Determining the minimal important change scores of the Vitiligo Impact Scale ( <scp>VIS</scp> )‐22 and Dermatology Life Quality Index ( <scp>DLQI</scp> ) scores in Indian patients with vitiligo using anchor‐ and distribution‐based approaches
Authors: V. Gupta, N. Taneja, H. C. Sati, V. Sreenivas, M. Ramam
Journal: British Journal of Dermatology (2020)
Abstract P124: The Impact of Combined Prediabetes and Prehypertension on Cardiovascular Morbidity
Authors: Annie Sjöli, Bledar Daka, Ulf Lindblad, Margareta Hellgren
Journal: Circulation (2020)

Introduction: Cardiovascular disease (CVD) is often preceded by prediabetes (pre-DM) and/or prehypertension (pre-HT), but few studies have investigated the effect of concurrent pre-DM and pre-HT on cardiovascular risk. Hypothesis: We assessed the hypothesis that concurrent pre-DM and pre-HT increases the risk of CVD. Furthermore, we examined if the estimated cardiovascular risk differs with sex and with the definition of pre-DM. Methods: In 2002-2005, 2816 randomly selected individuals from two Swedish municipalities were enrolled in a health survey. The participants’ cardiometabolic profiles, including blood pressure (BP) and glucose tolerance, were examined. Individuals with diabetes mellitus and/or hypertension were excluded, leaving 2330 persons for analyses. Out of these, 150 had co-existing pre-DM (IFG and/or IGT) and pre-HT (WHO 2013 criteria), while 1250 had simultaneous normal glucose tolerance (NGT) and optimal BP (&lt; 120/80 mmHg). Outcomes were assessed in 2011 using national Swedish registers. Hazard ratios (HR) for CVD were calculated for pre-DM, pre-HT and pre-HT combined with pre-DM, all versus NGT/optimal BP. Analyses were adjusted for age, BMI, sex, smoking and earlier CVD. Results: A total of 80 CVD events occurred during 8.1±0.9 years of follow-up. The unadjusted HR for CVD for combined pre-DM/pre-HT was 22.5. The association was attenuated after adjustments but persisted in the full model, see Figure 1. A test for interaction between combined pre-DM/pre-HT and sex on the outcome of CVD was non-significant (p = 0.6). IFG/pre-HT predicted CVD in all adjustment models (HR 3.2, p = 0.005) while IGT/pre-HT did not. Conclusions: Combined pre-DM and pre-HT substantially increases the risk of CVD. Those with pre-DM defined by IFG might be at particularly high risk, while the risk is likely the same in both sexes. Intensified treatment strategies should be considered in those with concomitant pre-DM and pre-HT.
On the factors that contribute to the risk of asthma exacerbations in children and adolescents: the MAPCAH study
Authors: B Erbas, S Dharmage, M Akram, R Hyndman, E Newbigin, D Vicendese, M O'Sullivan, K Allen, P Taylor, M Tang, P Bardin, M Abramson
Journal: Allergy (2013)
Effect of Statins on the Risk of Extrahepatic Cholangiocarcinoma
Authors: Sravanthi Lavu, Terry M. Therneau, William S. Harmsen, Kristin C. Mara, Nicha Wongjarupong, Mohamed Hassan, Hamdi A. Ali, Samuel Antwi, Nasra H. Giama, Katsuyuki Miyabe, Lewis R. Roberts
Journal: Hepatology (2020)

Background and Aims Statins have been proven to be cytotoxic to human cholangiocarcinoma cells by inhibiting cell division and inducing apoptosis. We aimed to determine the effect of statin use on the risk of cancer development and survival in patients with extrahepatic cholangiocarcinoma (ECC), including perihilar cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (dCCA). Approach and Results A total of 394 patients with ECC and hyperlipidemia who received care at Mayo Clinic Rochester between 2005 and 2015 were matched by age, sex, race, ethnicity, and residency to 788 controls with hyperlipidemia. Clinical and outcome data were abstracted. The odds ratios (ORs) for risk and hazard ratios for outcomes were calculated. The mean age and standard deviation (SD) for cases and controls was 65.6 years (13.8). The number of statin users in cases and controls was 73 (19%) and 403 (51%), respectively. Hepatitis C virus infection (OR, 15.84; 95% confidence interval [CI], 4.06‐61.87; P &lt; 0.001) was the most significant risk factor for pCCA followed by inflammatory bowel disease and cirrhosis, whereas other liver disease, including biliary stone disease (OR, 4.06; CI, 2.24‐7.36; P &lt; 0.001), was the only significant risk factor for dCCA. Statin use was associated with significantly reduced risk for all ECC (OR, 0.22; CI, 0.16‐0.29) as well as for the subtypes pCCA (OR, 0.3; CI, 0.21‐0.41) and dCCA (OR, 0.06; CI, 0.03‐0.14), all P &lt; 0.0001. Moderate‐intensity dosage was found to decrease the risk of ECC (OR, 0.48; CI, 0.34‐0.67; P &lt; 0.001). Comparing statin ever users to nonusers, patients with dCCA who used statins had significantly overall better survival (hazard ratio = 0.53; CI, 0.29‐0.97; P = 0.04). Conclusions This case‐control study suggests that statins decrease the risk of ECC and may improve survival in patients with dCCA. Additional validation studies are warranted.
A pharmaceutical approach to achieve synergy in vivo: A fixed ratio formulation of Irinotecan and Floxuridine for treatment of colorectal cancer
Authors: Lawrence D. Mayer, Troy Harasym, Natashia Harasym, Paul Tardi, Yu Shu, Cecelia Suragh, Eva-Maria Simms, Marcel B. Bally
Journal: Cancer Research (2004)

550  Purpose: To define a fixed ratio formulation of irinotecan and floxuridine (CPX-1) for use in the treatment of colorectal cancer. Methods: The cytotoxic effects of irinotecan and floxuridine were examined alone and combined at various fixed ratios in a number of tumor cell lines. These in vitro data were analyzed utilizing the median effect principle (Chou and Talalay, Adv Enzyme Regul, 22: 27-55, 1984). Liposomal formulations were developed for the drug combination with the goal of identifying a single lipid composition capable of encapsulating both drugs in a manner where the rate of drug release from the liposomes following intravenous administration was matched for both agents. The resulting co-encapsulated fixed ratio CPX-1 formulation was then assessed in a number of in vivo tumor models. Results: In vitro results demonstrate that synergistic interactions for irinotecan and floxuridine combinations were dependent on drug-to-drug ratio. In the human colorectal cell lines HCT-116 and HT-29, mole ratios of irinotecan and floxuridine of 1:1, 1:5 and 1:10 produced the largest synergistic effects over the broadest range of effective doses. Exposure of cancer cells to a mole ratio of 10:1 typically resulted in additive or antagonistic interactions. A mole ratio of 1:1 was defined as optimal for a range of tumor cell lines and a liposomal formulation was developed with co-encapsulated irinotecan and floxuridine at this ratio. Evaluations of the co-encapsulated drugs indicated that following i.v. administration the concentrations of each drug in the plasma were comparable over time, thus the drug-to-drug ratio in the plasma was maintained at the optimal 1:1 mole ratio. For HT-29 efficacy studies, delays in tumor growth achieved following treatment with the maximum tolerated dose of the free drug cocktail were significantly less than those achieved with the fixed ratio formulation administered at an 8-fold lower dose. Control tumors grew to 500 mg 28 days after cell inoculation. Using identical drug doses (25 mg/kg of irinotecan and 9.25 mg/kg floxuridine) and treatment schedule (Q7D x 3), HT29 tumors grew to 500 mg by day 30 and 60 following treatment with free irinotecan:floxuridine and CPX-1, respectively. Similar results were seen when evaluating therapy in the HCT-116 xenograft tumor model. Conclusion: Irinotecan and floxuridine acted synergistically in vitro when combined at a molar ratio of 1:1. When evaluated in preclinical models of human solid tumors, a fixed ratio formulation exhibited dramatic improvements in antitumor activity.
Use of Disposable Perioperative Jackets and Surgical Site Infections
Authors: Andrew M. Thomas
Journal: JAMA Surgery (2020)

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Abstract P542: Association of Psychosocial Factors With Heart Rate Variability: The Atherosclerosis Risk in Communities Study
Authors: Anish Shah, Alvaro Alonso, Eric A Whitsel, Elsayed Z SOLIMAN, Viola Vaccarino, Amit J Shah
Journal: Circulation (2020)

Introduction: Psychosocial factors are associated with cardiovascular morbidity and mortality, but our understanding of causal mechanisms is limited. Understanding such mechanisms may help formulate prevention strategies. We therefore sought to evaluate potential physiologic effects of psychosocial factors by studying their associations with heart rate variability (HRV), a measure of autonomic function, in the Atherosclerosis Risk in Communities (ARIC) study. Hypothesis: Higher psychosocial stress levels are associated with lower HRV cross-sectionally in a diverse community sample. Methods: We included ARIC cohort participants with information on psychosocial factors in 1990-1992 into our analysis. Psychosocial factors were assessed using validated instruments, including: 1) vital exhaustion, a somatic manifestation of chronic stress and depression, 2) anger proneness, a personality trait, and 3) perceived social support, a potential buffering factor for stress. Short-term time and frequency domain HRV were measured from a two-minute electrocardiographic recording in 1987-1989. Linear regression models adjusted for sociodemographic and cardiovascular risk factors. Results: We included 9,332 participants (mean age 54.4 ± 5.7 years, 55% women, and 25% black) in the analysis. Only vital exhaustion was consistently associated with HRV, as per the table, which shows the change in ln(HRV) per point increase in score. Compared to the lowest quartile, the highest quartile of vital exhaustion was associated with a 13.3% (95% CI, 3.9% - 21.3%) decrease in low frequency HRV in adjusted models. By comparison, each year of added age was associated with a 3.7% (95% CI, 3.1% to 4.2%) decrease in LF HRV. Conclusion: A high level of vital exhaustion was associated with low HRV, while anger proneness and social support were not. The inverse vital exhaustion-HRV association raises concern regarding the somatic manifestations of stress, a potential target for preventive interventions.
Abstract MP74: Association of Albuminuria With Incident Atrial Fibrillation: The Multi-ethnic Study of Atherosclerosis (MESA)
Authors: Yoshihiro Tanaka, Ravi B Patel, Erin D Michos, Moyses Szklo, Philip Greenland
Journal: Circulation (2020)

Background: Atrial fibrillation (AF) shares risk factors with atherosclerotic cardiovascular disease (CVD). Albuminuria (AU) is an established risk factor for renal failure and CVD. Endothelial dysfunction, inflammation and hemostasis underlie the pathogenesis of AU. However, the association of AU with incident AF and its effect modifiers are not fully understood. Purpose: To assess the association of AU with incident AF and to identify its effect modifiers. Methods: We studied MESA participants, free of clinical CVD and AF at baseline, with urine samples at exam 1. Participants were followed for incident AF ascertained by follow up visit ECGs, hospital discharge diagnoses or Medicare claims data. Participants were compared by the presence or absence of AU (albumin-creatine ratio of ≥30). Kaplan-Meier curves were used to estimate the cumulative rate of incident AF and log-rank test to evaluate statistical significance. Hazard ratio (HR) and 95% confidence interval (CI) were computed by Cox proportional hazard models. Final adjusted model included CHARGE-AF risk score covariates with socioeconomic variables, current alcohol use, renal function, and lipid lowering medication use. Results: A total of 6376 participants were analyzed (median age 62 years, male 47.4%, White race 38.8%, mean BMI 28.3 ± 5.5). During median follow-up of 13.9 years, there were a total of 924 AF events. Participants with AU had a higher incidence of AF than those without AU at 10 years (23.9% vs 10.4%, p &lt; 0.05, Figure 1A ). In fully adjusted model, AU was significantly associated with incident AF [HR 1.53 (95% CI 1.27 - 1.85, p &lt; 0.01). Low high-density lipoprotein cholesterol (&lt; 40 mg/dL) and high triglyceride (≥ 150 mg/dL) augmented the association between AU and incident AF (p-interaction &lt; 0.05 for all, Figure 1B ). Conclusion: AU was significantly associated with incident AF after adjusting for conventional risk factors in a multi-racial prospective cohort. Lipid markers were identified as effect modifiers in the association of AU with AF.
Abstract MP73: Years of Potential Life Lost Due to Premature Cardiometabolic Mortality in The United States, 1999-2017
Authors: Nilay S Shah, Donald M Lloyd-jones, Kiarri N Kershaw, Mercedes R Carnethon, Sadiya S Khan
Journal: Circulation (2020)

Introduction: Age of onset for heart disease (HD), cerebrovascular disease (CBD), and diabetes (DM) has shifted earlier, with increases in avoidable cardiometabolic deaths. We quantified total and trends in years of potential life lost (YPLL) before the age of 65 from HD, CBD, and DM, to describe population burden of premature preventable cardiometabolic mortality. Hypothesis: YPLL from premature cardiometabolic deaths in the U.S. have increased and are highest in black adults. Methods: Death certificates from the CDC’s Wide-Ranging Online Database for Epidemiologic Research (WONDER) were used to quantify mean age at death and proportion of deaths that were premature (&lt;65 years) from HD, CBD, and DM as underlying cause of death. We then calculated age standardized premature YPLL (before age 65) per 100,000 people and mean annual percent change (APC) in YPLL, overall and in black and white women and men, before and after the previously published inflection in cardiometabolic death rates in 2011. Results: Between 1999-2017, 19% of HD deaths, 14% of CBD deaths, and 27% of DM deaths were premature. Overall, premature YPLL from HD decreased between 1999-2011 from 512 to 416 per 100,000 (APC -1.7%/year, 95% CI [-2.0, -1.5]), then remained unchanged from 2011-2017. For CBD, premature YPLL decreased 1.8%/year (-2.2, -1.5) to 70 per 100,000 in 2011, but remained unchanged through 2017. Premature YPLL from DM remained unchanged at 71 per 100,000 from 1999-2011, then increased 2.5%/year (1.8, 3.1) to 81 per 100,000 in 2017. Premature YPLL were higher in black men and women compared with white men and women, respectively (FIGURE). Conclusions: Premature YPLL from cardiometabolic causes plateaued or increased after 2011. Disparities in YPLL have persisted in the past decade with nearly half of cardiometabolic deaths in black men occurring before age 65. Equitable promotion of cardiometabolic health early in the lifespan may reduce population, health system, and financial burden of premature cardiometabolic mortality.
Transitioning from Basic toward Systems Pharmacodynamic Models: Lessons from Corticosteroids
Authors: Vivaswath S. Ayyar, William J. Jusko
Journal: Pharmacological Reviews (2020)

Technology in bioanalysis, -omics, and computation have evolved over the past half century to allow for comprehensive assessments of the molecular to whole body pharmacology of diverse corticosteroids. Such studies have advanced pharmacokinetic and pharmacodynamic (PK/PD) concepts and models that often generalize across various classes of drugs. These models encompass the "pillars" of pharmacology, namely PK and target drug exposure, the mass-law interactions of drugs with receptors/targets, and the consequent turnover and homeostatic control of genes, biomarkers, physiologic responses, and disease symptoms. Pharmacokinetic methodology utilizes noncompartmental, compartmental, reversible, physiologic [full physiologically based pharmacokinetic (PBPK) and minimal PBPK], and target-mediated drug disposition models using a growing array of pharmacometric considerations and software. Basic PK/PD models have emerged (simple direct, biophase, slow receptor binding, indirect response, irreversible, turnover with inactivation, and transduction models) that place emphasis on parsimony, are mechanistic in nature, and serve as highly useful "top-down" methods of quantitating the actions of diverse drugs. These are often components of more complex quantitative systems pharmacology (QSP) models that explain the array of responses to various drugs, including corticosteroids. Progressively deeper mechanistic appreciation of PBPK, drug-target interactions, and systems physiology from the molecular (genomic, proteomic, metabolomic) to cellular to whole body levels provides the foundation for enhanced PK/PD to comprehensive QSP models. Our research based on cell, animal, clinical, and theoretical studies with corticosteroids have provided ideas and quantitative methods that have broadly advanced the fields of PK/PD and QSP modeling and illustrates the transition toward a global, systems understanding of actions of diverse drugs. SIGNIFICANCE STATEMENT: Over the past half century, pharmacokinetics (PK) and pharmacokinetics/pharmacodynamics (PK/PD) have evolved to provide an array of mechanism-based models that help quantitate the disposition and actions of most drugs. We describe how many basic PK and PK/PD model components were identified and often applied to the diverse properties of corticosteroids (CS). The CS have complications in disposition and a wide array of simple receptor-to complex gene-mediated actions in multiple organs. Continued assessments of such complexities have offered opportunities to develop models ranging from simple PK to enhanced PK/PD to quantitative systems pharmacology (QSP) that help explain therapeutic and adverse CS effects. Concurrent development of state-of-the-art PK, PK/PD, and QSP models are described alongside experimental studies that revealed diverse CS actions.
Cetuximab plus weekly oxaliplatin/5FU/FA (FUFOX) in 1<sup>st</sup> line metastatic gastric cancer. Final results from a multicenter phase II study of the AIO upper GI study group
Authors: F. Lordick, S. Lorenzen, S. Hegewisch-Becker, G. Folprecht, E. Wöll, T. Decker, E. Endlicher, N. Röthling, F. Fend, C. Peschel
Journal: Journal of Clinical Oncology (2007)

4526 Background: Cetuximab and oxaliplatin-5FU/FA are active in first-line metastatic colorectal cancer. Here we report on the final results from a trial assessing the efficacy of this combination in advanced gastric cancer. Methods: Pts received cetuximab 400mg/m 2 at first infusion followed by weekly 250mg/m 2 combined with the FUFOX regimen (oxaliplatin 50mg/m 2 plus 5FU 2,000mg/m 2 plus DL-folinic acid 200mg/m 2 d1,8,15,22 qd36). The primary endpoint was response according to RECIST. Toxicity was reported according to NCI.CTC v3.0. Results: From 4/05 until 03/06 we included 52 pts at 7 study centers: 13 women and 39 men; median age 63 years (38–80). ECOG-PS 0/1/2 in 19/25/8 patients. Median number of involved organ sites 3 (1–5), 46% liver and 31% peritoneal involvement. EGFR was detectable by immunohistochemistry (IHC) in 59.5%. 5 pts (9.6%) died within 60 days after study inclusion, two deaths were treatment-related (1 hypersensitivity reaction, 1 septic diarrhea). One patient withdrew consent during the first infusion cycle and is therefore excluded from the following analyses. Reported grade 3/4 adverse events in 51 evaluable pts were: leukopenia 2.0%, febrile neutropenia 5.9%, thrombocytopenia 2.0%, nausea 5.9%, diarrhea 33.3%, fatigue 9.8%, sensory neuropathy 3.9%, hand-foot-syndrome 5.9%, skin-reactions 23.5%. Response is evaluable in 46 patients showing an overall response rate of 65.2% [CI 95%: 49.8; 78.6] including 4 complete and 26 partial responses. Eighteen (39.1%) responses have been confirmed. The reponse rate according to the EGFR-status is 76.5% in undetectable and 54.2% in detectable tumors. Intention-to-treat analysis reveals a time to progression (TTP) of 7.6 months [CI 95% 5.0; 10.1] and an overall survival (OS) of 9.5 months [CI 95%: 7.9; 11.1]. Conclusions: Cetuximab plus FUFOX is highly active in metastatic gastric cancer, irrespective of the EGFR detection by IHC. No significant financial relationships to disclose.