Predicting gastric emptying of drug substances taken under postprandial conditions by combination of biorelevant dissolution and mechanistic in silico modeling.

Physiologically based pharmacokinetic (PBPK) models can help to understand the effects of gastric emptying on pharmacokinetics and in particular also provide a platform for understanding mechanisms of food effects, as well as extrapolation between different postprandial conditions, whether standardized clinical or patient-oriented, non-clinical conditions. By integrating biorelevant dissolution data from the GastroDuo dissolution model into a previously described mechanistic model of fed-state gastric emptying, we simulated the effects of a high-calorie high-fat meal on the pharmacokinetics of sildenafil, febuxostat, acetylsalicylic acid, theobromine and caffeine. The model was able to simulate the variability in Cmax and tmax caused by the presence of the stomach road. The main influences investigated to affect the gastric emptying process were drug solubility (theobromine and caffeine), tablet dissolution rate (acetylsalicylic acid) and sensitivity to gastric motility (sildenafil and febuxostat). Finally, we showed how PBPK models can be used to extrapolate pharmacokinetics between different prandial states using theobromine as an example with results from a clinical study being presented.

Prolongation of the gastric residence time of caffeine after administration in fed state: Comparison of effervescent granules with an extended release tablet.

The aim of the present study was to investigate the gastroretentive capacity of different formulation principles. This was indirectly determined by the absorption behavior of caffeine from the dosage forms. A slow and continuous appearance of caffeine in the saliva of healthy volunteers was used as a parameter for a prolonged gastric retention time. For this purpose, a four-way study was conducted with twelve healthy volunteers using the following test procedures: (1) Effervescent granules with 240 mL of still water administered in fed state, (2) effervescent granules with 20 mL of still water in fed state, (3) extended release (ER) tablet with 240 mL of still water in fed state, and (4) effervescent granules with 240 mL of still water in fasted state. The initial rise of the caffeine concentrations was more pronounced after the intake of the effervescent granules in the fed state compared to that of the ER tablets. However, tmax tended to be shorter in the fed study arms following administration of the ER tablet compared to the granules. Overall, the application of active pharmaceutical ingredients formulated as effervescent granules seems to be a promising approach to increase their gastric residence time after intake in fed state.

Doctor's Orders-Why Radiologists Should Consider Adjusting Commercial Machine Learning Applications in Chest Radiography to Fit Their Specific Needs.

This retrospective study evaluated a commercial deep learning (DL) software for chest radiographs and explored its performance in different scenarios. A total of 477 patients (284 male, 193 female, mean age 61.4 (44.7-78.1) years) were included. For the reference standard, two radiologists performed independent readings on seven diseases, thus reporting 226 findings in 167 patients. An autonomous DL reading was performed separately and evaluated against the gold standard regarding accuracy, sensitivity and specificity using ROC analysis. The overall average AUC was 0.84 (95%-CI 0.76-0.92) with an optimized DL sensitivity of 85% and specificity of 75.4%. The best results were seen in pleural effusion with an AUC of 0.92 (0.885-0.955) and sensitivity and specificity of each 86.4%. The data also showed a significant influence of sex, age, and comorbidity on the level of agreement between gold standard and DL reading. About 40% of cases could be ruled out correctly when screening for only one specific disease with a sensitivity above 95% in the exploratory analysis. For the combined reading of all abnormalities at once, only marginal workload reduction could be achieved due to insufficient specificity. DL applications like this one bear the prospect of autonomous comprehensive reporting on chest radiographs but for now require human supervision. Radiologists need to consider possible bias in certain patient groups, e.g., elderly and women. By adjusting their threshold values, commercial DL applications could already be deployed for a variety of tasks, e.g., ruling out certain conditions in screening scenarios and offering high potential for workload reduction.

Is there a fast track ("Darmstrasse") for fluids in the small intestine? Evidence from magnetic resonance imaging.

BACKGROUND: The transit and distribution pattern of fluids in the small intestine is a key parameter for the dissolution and absorption of drugs. Although some information is known about the small intestinal water content after administration of fluid volumes and meals, the intestinal transit of orally ingested fluids and solutions has been barely investigated. The aim of this three-arm, cross-over, 9-subject human study was to investigate the transit of orally ingested water in the small intestine under fasting and postprandial conditions using MRI. To identify the ingested water, manganese gluconate, which can be identified with T1-weighted MRI sequences, was added as a marker. Using Horos (DICOM software), quantification of the distribution of Mn2+ ions in the gastrointestinal tract in fasted versus fed state (standard meal by FDA guidance and a light meal) was possible. The distribution and approximate wetted intestinal length was very similar in the fasting and postprandial states, suggesting rapid transport of water ingested after a meal through the chyme-filled small intestine in continuation of the "Magenstrasse" (stomach road). In some subjects, manganese gluconate reached deeper parts of the small intestine even more quickly in the postprandial state than in the fasting arm of the study. A deeper understanding of the behaviour of solutes in the gastrointestinal tract is fundamental to a mechanistic explanation for the kinetic interaction between food and drug intake (food effects).

Cardiac remodelling in non-alcoholic fatty liver disease in the general population.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with increased risk for cardiovascular disease. Our study investigates the contribution of NAFLD to changes in cardiac structure and function in a general population. METHODS: One thousand ninety-six adults (49.3% female) from the Study of Health in Pomerania underwent magnetic resonance imaging including cardiac and liver imaging. The presence of NAFLD by proton density fat fraction was related to left cardiac structure and function. Results were adjusted for clinical confounders using multivariable linear regression model. RESULTS: The prevalence for NAFLD was 35.9%. In adjusted multivariable linear regression models, NAFLD was positively associated with higher left ventricular mass index (ß = 0.95; 95% confidence interval (CI): 0.45; 1.45), left ventricular concentricity (ß = 0.043; 95% CI: 0.031; 0.056), left ventricular end-diastolic wall thickness (ß = 0.29; 95% CI: 0.20; 0.38), left atrial end-diastolic volume index (ß = 0.67; 95% CI: 0.01; 1.32) and inversely associated with left ventricular end-diastolic volume index (ß = -0.78; 95% CI: -1.51; -0.05). When stratified by sex, we only found significant positive associations of NAFLD with left ventricular mass index, left atrial end-diastolic volume index, left ventricular cardiac output and an inverse association with global longitudinal strain in women. In contrast, men had an inverse association with left ventricular end-diastolic volume index and left ventricular stroke volume. Higher liver fat content was stronger associated with higher left ventricular mass index, left ventricular concentricity and left ventricular end-diastolic wall thickness. CONCLUSION: NAFLD is associated with cardiac remodelling in the general population showing sex specific patterns in cardiac structure and function.

In Vivo Evaluation of a Gastro-Resistant Enprotect® Capsule under Postprandial Conditions.

Ready-to-fill enteric hard capsule shells are an evolving field of oral drug and nutraceutical products. Lonza Capsugel® Enprotect® capsules were recently proven to provide reliable release in the small intestine after fasted intake, but robustness against postprandial intake needed to be proven. In this study, the capsules were administered to 16 healthy young subjects after intake of a light meal. The Enprotect® capsules were labelled with 5 mg black iron oxide and 25 mg 13C3-caffeine. Magnetic Resonance Imaging was used to identify the localization and visual dispersion of the capsule filling. The salivary appearance of caffeine was considered a second independent and sensitive marker for the initial release. Whereas the fasted gastric residence time of the capsules amounted to 43 ± 32 min, it was increased to 158 ± 36 min after postprandial intake. Therefore, the mean dispersion time according to MRI and the mean caffeine appearance time were increased to 196 ± 37 min and 189 ± 37 min, respectively. But, similar to fasted administration, no capsule disintegration or leakage was observed in the stomach and 38% of the capsules disintegrated in the jejunum and 62% in the ileum. The mean dispersion time after gastric emptying and the mean caffeine appearance time after gastric emptying amounted to 38 ± 21 min and 31 ± 17 min, respectively. Both did not relevantly change compared to the fasted intake. Only the absolute dispersion time and caffeine appearance were prolonged due to the increased gastric residence and no relevant influence of the light meal was observed on the disintegration or release behavior of Enprotect® capsules after gastric emptying. The capsules also showed robust enteric properties after postprandial administration.

Determination of Gastric Water Emptying in Fasted and Fed State Conditions Using a Compression-Coated Tablet and Salivary Caffeine Kinetics.

Because of the importance of gastric emptying for pharmacokinetics, numerous methods have been developed for its determination. One of the methods is the salivary tracer technique, which utilizes an ice capsule containing caffeine as a salivary tracer. Despite the ice capsule's advantage in labeling ingested fluids with caffeine for subsequent salivary detection, its risk of premature melting before swallowing, and its complicated storage and preparation, limit its application, particularly in special populations (e.g., older people). For this reason, here, a compression-coated tablet was developed and validated against the ice capsule in a cross-over clinical trial. The two dosage forms were administered simultaneously to 12 volunteers in an upright position under fasted and fed state conditions. To distinguish the caffeine concentrations in saliva from each dosage form, regular type of caffeine (12C) was added to the tablet, while for the ice capsule 13C3 labelled caffeine was used. The salivary caffeine concentrations showed no statistically significant differences for the pharmacokinetic parameters tmax and AUC0→60 (p > 0.05). Thus, the new formulation is a useful tool for determining gastric emptying that can also be used in special populations.

The Effect of Cooling Fluid Composition on Ablation Size in Hepatic Laser Ablation: A Comparative Study in an Ex Vivo Bovine Setting.

PURPOSE: Hyperthermic ablation is a minimally invasive mode of tumour therapy which serves as a viable alternative to surgical intervention. However, one of the major drawbacks, besides the heat sink effect and the risk of damaging adjacent organs, is limited ablation size. The use of a cooling fluid during ablation has been shown to increase the ablation volume and decrease the carbonisation rate. The aim of this study was to investigate whether the composition of the cooling fluid has an effect on ablation size and carbonisation rate during hepatic laser ablation in an ex vivo bovine setting. METHOD: In this study bovine hepatic tissue was ablated in an ex vivo setting using an internally cooled laser applicator. A total of 45 tissue samples were assigned to three groups: 0.9% saline infusion (n = 15), distilled water infusion (n = 15) and a 50%/50% mixture of 0.9% saline and distilled water (n = 15). Ablation was conducted using a 1064 nm Nd:YAG laser at a wattage of 25 W and time interval of 10 min. The ablation volume and carbonisation rate were then measured and recorded through postprocedural MRI. One-way ANOVA and post-hoc testing were performed to assess the effect of the cooling fluid composition on the ablation volumes. RESULTS: We found that using a mixture of saline and distilled water as a cooling fluid during hyperthermic ablation resulted in a larger ablation volume (mean ± SD: 22.64 ± 0.99 cm3) when compared to saline infusion (21.08 ± 1.11 cm3) or distilled water infusion (20.92 ± 0.92 cm3). This difference was highly significant (p < 0.001). There was no significant difference in ablation size between the saline group and the distilled water group. The highest carbonisation rate occurred in the saline group (12/15), followed by the mixed infusion group (3/15) and the distilled water group (1/15). CONCLUSIONS: The results of this study suggest that cooling fluid composition during hepatic laser ablation affects ablation volume in an ex vivo bovine setting. There was no statistically significant difference when comparing ablation volumes during saline infusion and distilled water infusion, but the carbonisation rate was significantly higher when using saline. The combination of saline and distilled water in a 50%/50% mixture as cooling fluid appears to be an auspicious alternative, as ablation volumes created with it are larger when compared to saline and distilled water alone, while carbonisation rate remains low. This might improve patient outcome as well as patient eligibility for hyperthermic ablation.

Effects of body mass index on the immune response within the first days after major stroke in humans.

INTRODUCTION: Immunological alterations associated with increased susceptibility to infection are an essential aspect of stroke pathophysiology. Several immunological functions of adipose tissue are altered by obesity and are accompanied by chronic immune activation. The purpose of this study was to examine immune function (monocytes, granulocytes, cytokines) as a function of body mass index (BMI: 1st group: 25; 2nd group: 25 BMI 30; 3rd group: 30) and changes in body weight post stroke. METHOD: Fat status was assessed using standardized weight measurements on days 1, 2, 3, 4, 5, and 7 after ischemic stroke in a cohort of 40 stroke patients and 16 control patients. Liver fat and visceral fat were assessed by MRI on day 1 or 2 [I] and on day 5 or 7 [II]. Leukocyte subpopulations in peripheral blood, cytokines, chemokines, and adipokine concentrations in sera were quantified. In a second cohort (stroke and control group, n = 17), multiple regression analysis was used to identify correlations between BMI and monocyte and granulocyte subpopulations. RESULTS: Weight and fat loss occurred from the day of admission to day 1 after stroke without further reduction in the postischemic course. No significant changes in liver or visceral fat were observed between MRI I and MRI II. BMI was inversely associated with IL-6 levels, while proinflammatory cytokines such as eotaxin, IFN-ß, IFN -γ and TNF-α were upregulated when BMI increased. The numbers of anti-inflammatory CD14+CD16+ monocytes and CD16+CD62L- granulocytes were reduced in patients with higher BMI values, while that of proinflammatory CD16dimCD62L+ granulocytes was increased. CONCLUSION: A small weight loss in stroke patients was detectable. The data demonstrate a positive correlation between BMI and a proinflammatory poststroke immune response. This provides a potential link to how obesity may affect the clinical outcome of stroke patients.

The relationship between homoarginine and liver biomarkers: a combination of epidemiological and clinical studies.

Homoarginine (hArg) is a non-essential cationic amino acid which inhibits hepatic alkaline phosphatases to exert inhibitory effects on bile secretion by targeting intrahepatic biliary epithelium. We analyzed (1) the relationship between hArg and liver biomarkers in two large population-based studies and (2) the impact of hArg supplementation on liver biomarkers. We assessed the relationship between alanine transaminase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), alkaline phosphatases (AP), albumin, total bilirubin, cholinesterase, Quick's value, liver fat, and Model for End-stage Liver Disease (MELD) and hArg in appropriately adjusted linear regression models. We analyzed the effect of L-hArg supplemention (125 mg L-hArg daily for 4 weeks) on these liver biomarkers. We included 7638 individuals (men: 3705; premenopausal women: 1866, postmenopausal women: 2067). We found positive associations for hArg and ALT (ß 0.38 µkatal/L 95% confidence interval (CI): 0.29; 0.48), AST (ß 0.29 µkatal/L 95% CI 0.17; 0.41), GGT (ß 0.033 µkatal/L 95% CI 0.014; 0.053), Fib-4 score (ß 0.08 95% CI 0.03; 0.13), liver fat content (ß 0.016% 95% CI 0.006; 0.026), albumin (ß 0.030 g/L 95% CI 0.019; 0.040), and cholinesterase (ß 0.003 µkatal/L 95% CI 0.002; 0.004) in males. In premenopausal women hArg was positively related with liver fat content (ß 0.047% 95%CI 0.013; 0.080) and inversely with albumin (ß - 0.057 g/L 95% CI - 0.073; - 0.041). In postmenopausal women hARG was positively associated with AST (ß 0.26 µkatal/L 95% CI 0.11; 0.42). hArg supplementation did not affect liver biomarkers. We summarize that hArg may be a marker of liver dysfunction and should be explored further.

Evaluation of Pharmacobezoar Formation from Suspensions of Spray-Dried Amorphous Solid Dispersions: An MRI Study in Rats.

Spray-dried amorphous solid dispersions of new chemical entities and pH-dependent soluble polymer hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were found to form solid agglomerates in the gastrointestinal tract of rodents after oral administration. These agglomerates, referring to descriptions of intra-gastrointestinal aggregated oral dosage forms termed pharmacobezoars, represent a potential risk for animal welfare. Previously, we introduced an in vitro model to assess the agglomeration potential of amorphous solid dispersions from suspensions and how it can be reduced. In this work, we investigated if the in vitro effective approach of viscosity enhancement of the vehicle used to prepare suspensions of amorphous solid dispersions could reduce the pharmacobezoar formation potential following repeated daily oral dosing to rats as well. The dose level of 2400 mg/kg/day used in the main study was determined in a dose finding study carried out in advance. In the dose finding study, MRI investigations were carried out at short time intervals to gain insights into the process of pharmacobezoar formation. Whereas MRI investigations underlined the importance of the forestomach for the formation of pharmacobezoars, viscosity enhancement of the vehicle reduced the incidence of pharmacobezoars, delayed the onset of pharmacobezoar formation and reduced the overall mass of pharmacobezoars found at necropsy.

Intragastric Carbon Dioxide Release Prolongs the Gastric Residence Time of Postprandially Administered Caffeine.

Sparkling water is said to increase gastric motility by the release of carbon dioxide, thereby potentially affecting the pharmacokinetics of orally administered drugs. The hypothesis of the present work was that the induction of gastric motility by intragastric release of carbon dioxide from effervescent granules could promote the mixing of drugs into the chyme under postprandial conditions, resulting in a prolonged drug absorption. For this purpose, an effervescent and a non-effervescent granule formulation of caffeine as a marker for gastric emptying were developed. In a three-way crossover study with twelve healthy volunteers, the salivary caffeine pharmacokinetics, after administration of the effervescent granules with still water and the administration of the non-effervescent granules with still and sparkling water, were investigated after intake of a standard meal. While the administration of the effervescent granules with 240 mL of still water led to a significantly prolonged gastric residence of the substance compared to the administration of the non-effervescent granules with 240 mL still water, the application of the non-effervescent granules with 240 mL sparkling water did not prolong gastric residence via mixing into caloric chyme. Overall, the mixing of caffeine into the chyme following the administration of the effervescent granules did not seem to be a motility mediated process.

In Vitro and In Vivo Evaluation of Carbopol 71G NF-Based Mucoadhesive Minitablets as a Gastroretentive Dosage Form.

Gastroretentive dosage forms are intended to stay inside the stomach for a long period of time while releasing an active pharmaceutical ingredient. Such systems may offer significant benefits for numerous drugs compared to other sustained release systems, such as improved pharmacokinetics/bioavailability and reduced intake frequency and thereby improved adherence to the medical therapy. However, there is no gastroretentive product on the market with proven reliable gastroretentive properties in humans. A major obstacle is the motility pattern of the stomach in the fasting state in humans, which reliably ensures gastric emptying of even large indigestible objects into the small intestine. One promising approach to avoid gastric emptying is adhesion of the drug delivery system to the gastric mucosa. In order to achieve mucoadhesive properties, minitablets containing Carbopol 71G NF were developed and compared to minitablets without adhesive properties. In a specialized mucoadhesive test system, the adhesion time was prolonged for adhesive minitablets (240 min) compared to non-adhesive minitablets (30 min). The in vivo transit behavior was investigated using magnetic resonance imaging in 11 healthy volunteers in fasted state in a crossover setup. It was found that the gastric residence time (GRT) of the adhesive minitablets (median of 37.5 min with IQR = 22.5-52.5) was statistically significantly prolonged compared to the non-adhesive minitablets (median of 7.5 with IQR = 7.5-22.5), indicating a delay in gastric emptying by adhesion to the gastric mucosa. However, the system needs further improvement to create a clinical benefit. Furthermore, it was observed that for 9 of 22 administrations (three minitablets were given simultaneously with every administration), the minitablets were not emptied together but showed different GRTs.

In Vivo Evaluation of a Gastro-Resistant HPMC-Based "Next Generation Enteric" Capsule.

Many orally dosed APIs are bioavailable only when formulated as an enteric dosage form to protect them from the harsh environment of the stomach. However, an enteric formulation is often accompanied with a higher development effort in the first place and the potential degradation of fragile APIs during the coating process. Ready-to-use enteric hard capsules would be an easily available alternative to test and develop APIs in enteric formulations, while decreasing the time and cost of process development. In this regard, Lonza Capsugel® Next Generation Enteric capsules offer a promising approach as functional capsules. The in vivo performance of these capsules was observed with two independent techniques (MRI and caffeine in saliva) in eight human volunteers. No disintegration or content release in the stomach was observed, even after highly variable individual gastric residence times (range 7.5 to 82.5 min), indicating the reliable enteric properties of these capsules. Seven capsules disintegrated in the distal part of the small intestine; one capsule showed an uncommonly fast intestinal transit (15 min) and disintegrated in the colon. The results for this latter capsule by MRI and caffeine appearance differed dramatically, whereas for all other capsules disintegrating in the small intestine, the results were very comparable, which highlights the necessity for reliable and complementary measurement methods. No correlation could be found between the gastric residence time and disintegration after gastric emptying, which confirms the robust enteric formulation of those capsules.

Identification of early predictors for infected necrosis in acute pancreatitis.

BACKGROUND: In acute pancreatitis, secondary infection of pancreatic necrosis is a complication that mostly necessitates interventional therapy. A reliable prediction of infected necrotizing pancreatitis would enable an early identification of patients at risk, which however, is not possible yet. METHODS: This study aims to identify parameters that are useful for the prediction of infected necrosis and to develop a prediction model for early detection. We conducted a retrospective analysis from the hospital information and reimbursement data system and screened 705 patients hospitalized with diagnosis of acute pancreatitis who underwent contrast-enhanced computed tomography and additional diagnostic puncture or drainage of necrotic collections. Both clinical and laboratory parameters were analyzed for an association with a microbiologically confirmed infected pancreatic necrosis. A prediction model was developed using a logistic regression analysis with stepwise inclusion of significant variables. The model quality was tested by receiver operating characteristics analysis and compared to single parameters and APACHE II score. RESULTS: We identified a total of 89 patients with necrotizing pancreatitis, diagnosed by computed tomography, who additionally received biopsy or drainage. Out of these, 59 individuals had an infected necrosis. Eleven parameters showed a significant association with an infection including C-reactive protein, albumin, creatinine, and alcoholic etiology, which were independent variables in a predictive model. This model showed an area under the curve of 0.819, a sensitivity of 0.692 (95%-CI [0.547-0.809]), and a specificity of 0.840 (95%-CI [0.631-0.947]), outperforming single laboratory markers and APACHE II score. Even in cases of missing values predictability was reliable. CONCLUSION: A model consisting of a few single blood parameters and etiology of pancreatitis might help for differentiation between infected and non-infected pancreatic necrosis and assist medical therapy in acute necrotizing pancreatitis.

Epidemiological Factors Associated With Intraductal Papillary Mucinous Neoplasm of the Pancreas: A Dual Center Case-Control Study.

OBJECTIVE: The present study aimed to identify epidemiological factors associated with the development of intraductal papillary mucinous neoplasms (IPMN) of the pancreas comparing patients after IPMN resection with population-based controls. METHODS: Preoperative data of 811 patients undergoing pancreatic resection for IPMN were matched in a 1:1 ratio with a random sample of volunteers from the Study of Health in Pomerania, which showed no pancreatic cyst greater than 2 mm in magnetic resonance cholangiopancreaticography. RESULTS: A total of 811 controls with a mean age of 61.9 years (standard deviation, 8.4 years) were matched to cases with a mean age of 66.1 years (standard deviation, 9.3 years). A previous history of pancreatitis, endocrine pancreatic insufficiency was significantly more frequent in IPMN patients compared with controls (P = 0.001). Moreover, adjusted data revealed that urogenital cancer (P = 0.034), colorectal cancer (P = 0.021), as well as first-degree family history of colorectal cancer (P = 0.001) were significantly more frequent in IPMN patients. CONCLUSIONS: A history of urogenital and colorectal cancer often coincides with IPMN, which have an indication for surgery and are associated with preoperative episodes of pancreatitis and with endocrine insufficiency. Prospective studies are needed to investigate the role of these factors in IPMN development.

Association between thyroid function and assessment of hepatic fat and iron contents by magnetic resonance imaging.

The associations of thyroid function parameters with non-alcoholic fatty liver disease (NAFLD) and hepatic iron overload are not entirely clear. We have cross-sectionally investigated these associations among 2734 participants of two population-based cross-sectional studies of the Study of Health in Pomerania. Serum levels of thyroid-stimulating hormone (TSH), free tri-iodothyronine (fT3), and free thyroxine (fT4) levels were measured. Liver fat content (by proton-density fat fraction) as well as hepatic iron content (by transverse relaxation rate; R2*) were assessed by quantitative MRI. Thyroid function parameters were associated with hepatic fat and iron contents by median and logistic regression models adjusted for confounding. There were no associations between serum TSH levels and liver fat content, NAFLD, or hepatic iron overload. Serum fT4 levels were inversely associated with liver fat content, NAFLD, hepatic iron contents, and hepatic iron overload. Serum fT3 levels as well as the fT3 to fT4 ratio were positively associated with hepatic fat, NAFLD, hepatic iron contents, but not with hepatic iron overload. Associations between fT3 levels and liver fat content were strongest in obese individuals, in which we also observed an inverse association between TSH levels and NAFLD. These findings might be the result of a higher conversion of fT4 to the biologically active form fT3. Our results suggest that a subclinical hyperthyroid state may be associated with NAFLD, particularly in obese individuals. Furthermore, thyroid hormone levels seem to be more strongly associated with increased liver fat content compared to hepatic iron content.

Associations of liver volume and other markers of hepatic steatosis with all-cause mortality in the general population.

AIMS: We examined the associations between liver volume and other quantitative and qualitative markers of hepatic steatosis with all-cause mortality in the general population. METHODS: We included 2769 German middle-aged individuals with a median follow-up of 8.9 years (23,898 person-years). Quantitative markers used were serum liver enzymes and FIB-4 score, while qualitative markers of hepatic steatosis included magnetic resonance imaging (MRI) measurements of liver fat content and total liver volume. Cox proportional hazards models, adjusted for confounding factors, were undertaken to investigate the associations of liver volume and other markers of hepatic steatosis with all-cause mortality. RESULTS: A larger MRI-assessed liver volume was associated with a nearly three-fold increased risk of all-cause mortality (Hazard Ratio = 3.16; 95% confidence interval 1.88; 5.30), independent of age, sex, body mass index, food frequency score, alcohol consumption and education level. This association was consistent in all subgroups considered (men vs. women; presence or absence of overweight/obesity, metabolic syndrome or diabetes). Higher serum liver enzyme levels and FIB-4 score were also significantly associated with higher all-cause mortality in the total population and in all subgroups. No independent associations were found between other quantitative and qualitative markers of hepatic steatosis and the risk of all-cause mortality. CONCLUSIONS: We showed for the first time that larger liver volume was associated with a three-fold increase in long-term risk of all-cause mortality. This association remained significant after adjustment for age, sex, alcohol consumption, obesity and other coexisting metabolic disorders.

The Effect of Capsule-in-Capsule Combinations on In Vivo Disintegration in Human Volunteers: A Combined Imaging and Salivary Tracer Study.

Controlling the time point and site of the release of active ingredients within the gastrointestinal tract after administration of oral delivery systems is still a challenge. In this study, the effect of the combination of small capsules (size 3) and large capsules (size 00) on the disintegration site and time was investigated using magnetic resonance imaging (MRI) in combination with a salivary tracer technique. As capsule shells, Vcaps® HPMC capsules, Vcaps® Plus HPMC capsules, gelatin and DRcaps® designed release capsules were used. The three HPMC-based capsules (Vcaps®, Vcaps® Plus and DRcaps® capsules) were tested as single capsules; furthermore, seven DUOCAP® capsule-in-capsule combinations were tested in a 10-way crossover open-label study in six healthy volunteers. The capsules contained iron oxide and hibiscus tea powder as tracers for visualization in MRI, and two different caffeine species (natural caffeine and 13C3) to follow caffeine release and absorption as measured by salivary levels. Results showed that the timing and location of disintegration in the gastrointestinal tract can be measured and differed when using different combinations of capsule shells. Increased variability among the six subjects was observed in most of the capsule combinations. The lowest variability in gastrointestinal localization of disintegration was observed for the DUOCAP® capsule-in-capsule configuration using a DRcaps® designed release capsule within a DRcaps® designed release outer capsule. In this combination, the inner DRcaps® designed release capsule always opened reliably after reaching the ileum. Thus, this combination enables targeted delivery to the distal small intestine. Among the single capsules tested, Vcaps® Plus HPMC capsules showed the fastest and most consistent disintegration.

Diagnostic performance and image quality of low-tube voltage and low-contrast medium dose protocol with hybrid iterative reconstruction for hepatic dynamic CT.

OBJECTIVE: To evaluate the diagnostic performance and image quality of the low-tube voltage and low-contrast medium dose protocol for hepatic dynamic CT. METHODS: This retrospective study was conducted between January and May 2018. All patients underwent hepatic dynamic CT using one of the two protocols: tube voltage, 80 kVp and contrast dose, 370   mgI/kg with hybrid iterative reconstruction or tube voltage, 120 kVp and contrast dose, 600  mgI/kg with filtered back projection. Two radiologists independently scored lesion conspicuity and image quality. Another radiologist measured the CT numbers of abdominal organs, muscles, and hepatocellular carcinoma (HCC) in each phase. Lesion detectability, HCC diagnostic ability, and image quality of the arterial phase were compared between the two protocols using the non-inferiority test. CT numbers and HCC-to-liver contrast were compared between the protocols using the Mann-Whitney U test. RESULTS: 424 patients (70.5 ± 10.1 years) were evaluated. The 80-kVp protocol showed non-inferiority in lesion detectability and diagnostic ability for HCC (sensitivity, 85.7-89.3%; specificity, 96.3-98.6%) compared with the 120-kVp protocol (sensitivity, 91.0-93.3%; specificity, 93.6-97.3%) (p < 0.001-0.038). The ratio of fair image quality in the 80-kVp protocol also showed non-inferiority compared with that in the 120-kVp protocol in assessments by both readers (p < 0.001). HCC-to-liver contrast showed no significant differences for all phases (p = 0.309-0.705) between the two protocols. CONCLUSION: The 80-kVp protocol with hybrid iterative reconstruction for hepatic dynamic CT can decrease iodine doses while maintaining diagnostic performance and image quality compared with the 120-kVp protocol. ADVANCES IN KNOWLEDGE: The 80- and 120-kVp protocols showed equivalent hepatic lesion detectability, diagnostic ability for HCC, image quality, and HCC-to-liver contrast.The 80-kVp protocol showed a 38.3% reduction in iodine dose compared with the 120-kVp protocol.