AKA-TPG: A Program for Kinetic and Epidemiological Analysis of Data from Labeled Glucose Investigations Using the Two-Pool Model and Database Technology

Background: The Two-Pool Glucose (TPG) model has an important role to play in diabetes research since it enables analysis of data obtained from the frequently sampled labeled (hot) glucose tolerance test (FSHGT). TPG modeling allows determination of the separate effects of insulin on the disposal of glucose and on the hepatic production of glucose. It therefore provides a basis for the accurate estimation of glucose effectiveness, insulin sensitivity, and the profile of the rate of endogenous glucose production. Until now, there has been no program available dedicated to the TPG model, and a number of technical reasons have deterred researchers from performing TPG analysis. Methods and Results: In this paper, we describe AKA-TPG, a new program that combines automatic kinetic analysis of the TPG model data with database technologies. AKA-TPG enables researchers who have no expertise in modeling to quickly fit the TPG model to individual FSHGT data sets consisting of plasma concentrations of unlabeled glucose, labeled glucose, and insulin. Most importantly, because the entire process is automated, parameters are almost always identified, and parameter estimates are accurate and reproducible. AKA-TPG enables the demographic data of hundreds of individual subjects, their individual unlabeled and labeled glucose and insulin data, and each subject\u27s parameters and indices derived from AKA-TPG to be securely stored in, and retrieved from, a database. We describe how the stratification and population analysis tools in AKA-TPG are used and present population estimates of TPG model parameters for young, healthy (without diabetes) Nordic men. Conclusion: Researchers now have a practical tool to enable kinetic and epidemiological analysis of TPG data sets

Insulin Action, Glucose Homeostasis and Free Fatty Acid Metabolism: Insights From a Novel Model

Glucose and free fatty acids (FFA) are essential nutrients that are both partly regulated by insulin. Impaired insulin secretion and insulin resistance are hallmarks of aberrant glucose disposal, and type 2 diabetes (T2DM). In the current study, a novel model of FFA kinetics is proposed to estimate the role insulin action on FFA lipolysis and oxidation allowing estimation of adipose tissue insulin sensitivity (SIFFA). Twenty-five normal volunteers were recruited for the current study. To participate, volunteers had to be less than 40 years of age and have a body mass index (BMI) < 30 kg/m2, and be free of medical comorbidity. The proposed model of FFA kinetics was used to analyze the data derived from the insulin-modified FSIGT. Mean fractional standard deviations of the parameter estimates were all less than 20%. Standardized residuals of the fit of the model to the FFA temporal data were randomly distributed, with only one estimated point lying outside the 2-standard deviation range, suggesting an acceptable fit of the model to the FFA data. The current study describes a novel one-compartment non-linear model of FFA kinetics during an FSIGT that provides an FFA metabolism insulin sensitivity parameter (SIFFA). Furthermore, the models suggest a new role of glucose as the modulator of FFA disposal. Estimates of SIFFA confirmed previous findings that FFA metabolism is more sensitive to changes in insulin than glucose metabolism. Novel derived indices of insulin sensitivity of FFA (SIFFA) were correlated with minimal model indices. These associations suggest a cooperative rather than competitive interplay between the two primary nutrients (glucose and FFA) and allude to the FFA acting as the buffer, such that glucose homeostasis is maintained

Dose patterns in commercially insured subjects chronically exposed to opioids: a large cohort study in the United States

<p>Abstract</p> <p>Background</p> <p>Little data exist on how opioid doses vary with the length of exposure among chronic opioid users.</p> <p>Methods</p> <p>To characterize the change in the dosage of opioids over time, a retrospective cohort study using the PharMetrics database for the years 1999 through 2008 was conducted. Individuals exposed to opioids in 2000 who had 2 opioid dispensings at least 6 months apart and were opioid naive (did not receive any opioid 6 month before their exposure in 2000) were included. The date of the first dispensing in 2000 was defined as the index date and the dispensing had to be for a strong and full agonist opioid. All opioid doses were converted to oral morphine equivalent doses. Exposure was classified as continuous or intermittent. Mean, median, interquartile range, and 95^thpercentile of opioid dose over 6-month periods, as well as the percentage of subjects who ever received a high or very high opioid dose, were calculated.</p> <p>Results</p> <p>Among the 48,986 subjects, the mean age was 44.5 years and 54.5% were women. Intermittent exposure was observed in 99% of subjects; continuous exposure was observed in 1% of subjects. The mean duration of exposure for the subjects who were continuously exposed to opioids was 477 days. In subjects with no cancer diagnosis who were continuously exposed to opioids, the mean, 25^th, 50^th, and 75^thpercentile of dose was stable during the first 2 years of use, but the 95^thpercentile increased. Seven percent of them were exposed to doses of 180 mg or more of morphine at some point.</p> <p>Conclusions</p> <p>Dose escalation is uncommon in subjects with intermittent exposure to opioids. For subjects with continuous exposure to opioids who have cancer, doses rise substantially with time. For those without cancer, doses remain relatively stable for the first 2 years of use, but subsequently increase. Seven percent of subjects with no cancer diagnosis will be exposed to daily doses of 180 mg or more of morphine equivalent at some point.</p

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Exponential Sum Modeling of Reswick and Rogers Pressure- Duration Curve: A New Analysis and Model

Reswick and Rogers model is not valid for predicting the effects of short- and long-time tissue exposures to contact pressures because it lacks intercepts. A different model, without those asymptotic properties, that could fit the shape of the curve well, could potentially provide useful information. We used modeling to test the hypotheses that an exponential model could fit Reswick and Rogers pressure-duration curve, and, if so, to determine the order of the best fit exponential model. Up to four exponential sum models were fit. Three exponentials provided the best fit [Weighted sum-of-squared residuals 72, Akaike Information Criterion 89, r=0.997]. Thereby identifying three homogeneously distinct anatomical pressure-load containing tissue compartments: skin, fat, and muscle. A fourth compartment, bone, could not be identified because of limited resolution of the data. Our results suggest that the fat pressure-load containing compartment may play an adaptive compensatory preventive role in response to pressure loads—“a cushion effect.” Exponential sum modeling of pressure-duration curves provides a new approach for studying the dynamics of compression in normal and disease states in humans, and it may be useful for practical application at the point-of-care to assist with prevention and treatment of pressure ulcers

Exponential Sum Modeling of Reswick and Rogers Pressure-Duration Curve: A New Analysis and Model

Reswick and Rogers model is not valid for predicting the effects of short- and long-time tissue exposures to contact pressures because it lacks intercepts. A different model, without those asymptotic properties, that could fit the shape of the curve well, could potentially provide useful information. We used modeling to test the hypotheses that an exponential model could fit Reswick and Rogers pressure-duration curve, and, if so, to determine the order of the best fit exponential model. Up to four exponential sum models were fit. Three exponentials provided the best fit [Weighted sum-of-squared residuals 72, Akaike Information Criterion 89, r=0.997]. Thereby identifying three homogeneously distinct anatomical pressure-load containing tissue compartments: skin, fat, and muscle. A fourth compartment, bone, could not be identified because of limited resolution of the data. Our results suggest that the fat pressure-load containing compartment may play an adaptive compensatory preventive role in response to pressure loads—“a cushion effect.” Exponential sum modeling of pressure-duration curves provides a new approach for studying the dynamics of compression in normal and disease states in humans, and it may be useful for practical application at the point-of-care to assist with prevention and treatment of pressure ulcers

Enostosis-like lesions in equids: 79 cases (1997-2009)

Objective—To evaluate equids with enostosis-like lesions (ELLs) and document the clinical and epidemiological features of this disease.Design—Retrospective case series.Animals—79 equids with a scintigraphic diagnosis of at least 1 ELL on _1 occasion. Procedures—Medical records of 4,992 equids that underwent bone scintigraphy between March 1997 and March 2009 were reviewed; 78 horses and 1 pony had a scintigraphic diagnosis of an ELL. For those equids, signalment; physical, scintigraphic, radiographic, and lameness examination results; and outcome were reviewed.Results—Of the 79 equids, 4 (5.1%) had anatomically distinct ELLs on 2 (n = 3) or 4 (1) separate occasions that caused lameness in different limbs. Thus, there were 85 ELL-related admissions to the hospital. Overall, 157 ELLs were detected. Among all equids undergoing scintigraphic examination, Thoroughbreds were more commonly and Standardbreds were less commonly affected. Older animals were more likely to have ELLs. Lameness was directly attributed to scintigraphically evident ELLs in 42 of the 85 (49.4%) admissions. The tibia (62/157 [39.5%]) and the radius (46/157 [29.3%]) were most commonly affected. The ELLs located in the humerus caused more severe lameness than did ELLs in other anatomic locations. Lameness severity was associated with radiopharmaceutical uptake intensity. Among racehorses, those with 1 ELL were more likely to return to racing than were those with multiple ELLs detected in 1 scintigraphic examination; mean interval from diagnosis to first start was 184 days.Conclusions and Clinical Relevance—Results of this retrospective evaluation of a large group of equids with ELLs have provided a better understanding of this disease process. (J Am Vet Med Assoc 2014;245:1042–1047)