EnGraft: a multicentre, open-label, randomised, two-arm, superiority study protocol to assess bioavailability and practicability of Envarsus® versus Advagraf™ in liver transplant recipients.

BACKGROUND: Graft rejection and chronic CNI toxicity remain obstacles to organ transplant success. Current formulations of tacrolimus, such as Prograf® and Advagraf™, exhibit limitations in terms of pharmacokinetics and tolerability, related in part to suboptimal bioavailability. As dosing non-compliance can result in graft rejection, the once daily formulation of tacrolimus, Advagraf™, was developed (vs 2x/day Prograf®). Benefits of Advagraf™ are counterbalanced by delayed achievement of therapeutic trough levels and need for up to 50% higher doses to maintain Prograf®-equivalent troughs. Envarsus® is also a prolonged-release once-daily tacrolimus formulation, developed using MeltDose™ drug-delivery technology to increase drug bioavailability; improved bioavailability results in low patient drug absorption variability and less pronounced peak-to-trough fluctuations. In phase III de novo kidney transplant studies, Envarsus® proved non-inferior to twice-daily tacrolimus; however, no phase IV studies show superiority of Envarsus® vs Advagraf™ in de novo liver transplant (LTx) recipients. METHODS: The EnGraft compares bioavailability and tests superiority of Envarsus® (test arm) versus Advagraf™ (comparator arm) in de novo LTx recipients. A total of 268 patients from 15 German transplant centres will be randomised 1:1 within 14 days post-LTx. The primary endpoint is dose-normalised trough level (C/D ratio) measured 12 weeks after randomisation. Secondary endpoints include the number of dose adjustments, time to reach first defined trough level and incidence of graft rejections. Additionally, clinical and laboratory parameters will be assessed over a 3-year period. DISCUSSION: C/D ratio is an estimate for tacrolimus bioavailability. Improving bioavailability and increasing C/D ratio using Envarsus could reduce renal dysfunction and other tacrolimus-related toxicities; previous trials have shown that a higher C/D ratio (i.e. slower tacrolimus metabolism) is not only associated with improved renal function but also linked to reduced neurotoxic side effects. A higher C/D ratio could improve clinical outcomes for LTx recipients; EnGraft has begun, with one third of patients recruited by January 2022. TRIAL REGISTRATION: This trial has been registered (4 May 2020) in the EU Clinical Trials Register, EudraCT-Nummer: 2020-000796-20. Additionally, this trial has been registered (22 January 2021) at ClinicalTrials.gov: NCT04720326. The trial received a favourable opinion from the concerned lead ethics committee at the University of Regensburg, under the reference 20-1842-112.

Surgical reporting for laparoscopic cholecystectomy based on phase annotation by a convolutional neural network (CNN) and the phenomenon of phase flickering: a proof of concept.

PURPOSE: Surgical documentation is an important yet time-consuming necessity in clinical routine. Beside its core function to transmit information about a surgery to other medical professionals, the surgical report has gained even more significance in terms of information extraction for scientific, administrative and judicial application. A possible basis for computer aided reporting is phase detection by convolutional neural networks (CNN). In this article we propose a workflow to generate operative notes based on the output of the TeCNO CNN. METHODS: Video recordings of 15 cholecystectomies were used for inference. The annotation of TeCNO was compared to that of an expert surgeon (HE) and the algorithm based annotation of a scientist (HA). The CNN output then was used to identify aberrance from standard course as basis for the final report. Moreover, we assessed the phenomenon of 'phase flickering' as clusters of incorrectly labeled frames and evaluated its usability. RESULTS: The accordance of the HE and CNN was 79.7% and that of HA and CNN 87.0%. 'Phase flickering' indicated an aberrant course with AUCs of 0.91 and 0.89 in ROC analysis regarding number and extend of concerned frames. Finally, we created operative notes based on a standard text, deviation alerts, and manual completion by the surgeon. CONCLUSION: Computer-aided documentation is a noteworthy use case for phase recognition in standardized surgery. The analysis of phase flickering in a CNN's annotation has the potential of retrieving more information about the course of a particular procedure to complement an automated report.

Combined effect of acute altitude exposure and vigorous exercise on platelet activation.

Exposure to high altitudes and exercise alters body's physiology and may cause acute cardiovascular events. Platelet activation is one of the key players in these events. Therefore, we investigated the effect of vigorous exercise at higher altitude (2650 m) on platelet aggregation and serum markers of platelet activation. 14 healthy subjects performed a step incremental ergometer test until exhaustion at the Environmental Research Station (UFS, 2650 m) at Zugspitze. Platelet aggregation and serum levels of endothelin-1, soluble p-selectin, platelet factor 4 and Chromogranin A were measured. Platelet activation was significantly enhanced after exercise at high altitude compared to measures immediately prior exercise. We detected significantly enhanced serum levels of endothelin-1 and soluble p-selectin whereas chromogranin A and platelet factor 4 remained unchanged. This effect might be due to increased endothelin-1 levels causing pulmonary vasoconstriction, rheological changes and direct platelet activation. This might be of clinical relevance, especially in patients with pre-existing diseases.

Role of clinical and CT findings in the identification of adult small-bowel intussusception requiring surgical intervention.

BACKGROUND: In adults, intussusception has been considered traditionally to have an underlying aetiology. The aim of this study was to determine CT and clinical features of small-bowel intussusceptions that required surgical intervention. METHODS: Adult patients were identified in whom small-bowel intussusceptions were noted on CT images. The appearance, number, type (enteroenteric versus enterocolic), length and maximum short-axis diameter of intussusceptions, and presence of bowel obstruction (short-axis diameter of proximal small bowel greater than 3 cm) were analysed. The outcome was defined as surgical (complicated) or self-limiting (uncomplicated). Associations between complicated and uncomplicated intussusceptions and patient characteristics were investigated. RESULTS: Among 75 patients (56 male) with a mean age of 45 years, 103 intussusceptions were identified, of which 98 (95 per cent) were enteroenteric and 5 (5 per cent) enterocolic. Only 12 of 103 intussusceptions (12 per cent) in 12 of 75 (16 per cent) patients required surgical therapy and were considered to be complicated, with half of these having a neoplastic lead point. Length (P < 0.001), diameter (P < 0.001) and type (P = 0.002) of intussusception as well as presence of vessels (P = 0.023) within an intussusception on a CT scan, clinical symptoms (P = 0.007) and signs of bowel obstruction (P < 0.001) were associated with a surgical outcome. CONCLUSION: Clinical symptoms, signs of bowel obstruction, type and length of intussusception, and a visible tumour within an intussusception on CT scan were critical signs of complicated intussusception, requiring surgical intervention.

Stereotactic Percutaneous Electrochemotherapy as Primary Approach for Unresectable Large HCC at the Hepatic Hilum.

Electrochemotherapy (ECT) is a novel non-thermal ablative technique that combines chemotherapy and the application of electric pulses for reversible cell membrane electroporation. This method was recently performed in the treatment of deep-seated liver tumors during open surgery but experience about percutaneous ECT is rare and further developments like combination of percutaneous ECT with stereotactic navigated devices may be very promising. We report on a case of a 4.7 × 4.5 × 3.5 cm unresectable HCC at the hepatic hilum adjacent to the major vessels and the bile duct that was successfully treated using percutaneous ECT in combination with stereotactic navigation. Follow-up imaging 6 weeks and 6 months after ECT showed complete response.

Super selective percutaneous transhepatic coil embolization of intrahepatic pseudoaneurysm after pediatric liver transplantation: a case report.

BACKGROUND: Intrahepatic arterial pseudoaneurysms are a rare, life-threatening complication after pediatric liver transplantation. Treatment of choice represents interventional radiological management with endovascular embolization of the segmental artery proximal and distal to the aneurysm. However, this technique results in loss of arterial perfusion distal to the aneurysm with subsegment arterial ischemia. CASE PRESENTATION: We report a case of a 1-year-old girl with a pseudoaneurysm in the split-liver graft. Direct percutaneous, transhepatic access to the pseudoaneurysm was performed followed by super selective coil application into the aneurysm. CONCLUSION: Super selective percutaneous, transhepatic coil application is feasible even in pediatric patients after liver transplantation and results in preservation of the entire course of the liver artery.

[Esophagotracheal and esophagobronchial fistulas]. / Ösophagotracheobronchiale Fisteln.

Esophagobronchial and esophagotracheal fistulas are rare but complex diseases with a heterogeneous spectrum of underlying etiologies. Common causes are locally advanced tumors of the esophagus and larynx, traumatic perforation from the esophageal or tracheal side as well as postoperative fistulas. The management of esophagotracheal and esophagobronchial fistulas always involves different health care providers and in most cases patients require a multidisciplinary treatment on the intensive care unit. The therapeutic concept primarily depends on the underlying cause, localization and size of the fistula but decision making is also influenced by the severity of the course of sepsis and the extent of the respiratory dysfunction. Endoscopic management with esophageal and/or tracheobronchial stenting is the most common treatment. Surgical reconstructive procedures are predominantly reserved for patients with a treatment refractory fistula or a septic multiple organ failure. The prognosis is particularly influenced by the underlying disease.

MIEO: a micro-invasive endoscopic operation port system for transluminal interventions-an acute and survival porcine study.

BACKGROUND: A reliable and sterile access through the intestinal wall to ease flexible endoscopic transluminal interventions is still appealing but lacks a suitable port system. METHODS: In a granted industry cooperation, we developed the MIEO-Port, a flexible three components overtube system that provides a temporary hermetic sealing of the intestinal wall to allow endoscopic disinfection and manipulation to gain access to the abdominal cavity. The port features an innovative head part which allows for coupling the port to the intestinal wall by vacuum suction and for controlled jetting the isolated intestinal surface with a disinfectant. The device was tested in vivo in 6 pigs for acute and long-term usability. All animal tests were approved by the local ethics committee. RESULTS: In the acute experiment, the port system supported sealed endoscopic mucosa resection and transluminal cholecystectomy. In the survival study on 5 animals, the MIEO-Port proved its reliability after transcolonic peritoneoscopy. In one animal, a port dislocation occurred after extensive retroperitoneal preparation, one animal revealed bacterial contamination at necropsy; however, all animals showed a favourable course over ten days and offered no signs of peritonitis or abscedation during post-mortem examination. DISCUSSION: To the best of our knowledge, the MIEO-Port system is the first device to provide a reliable and sterile flexible access to the peritoneal cavity that can be used throughout the entire gastrointestinal tract regardless of the access route and which combines hermetic sealing with local sterilization. Further studies are warranted.

A 6-month randomized, double-blind, placebo-controlled trial of weekly exenatide in adolescents with obesity.

BACKGROUND: Pharmacological treatment options for adolescents with obesity are very limited. Glucagon-like-peptide-1 (GLP-1) receptor agonist could be a treatment option for adolescent obesity. OBJECTIVE: To investigate the effect of exenatide extended release on body mass index (BMI)-SDS as primary outcome, and glucose metabolism, cardiometabolic risk factors, liver steatosis, and other BMI metrics as secondary outcomes, and its safety and tolerability in adolescents with obesity. METHODS: Six-month, randomized, double-blinded, parallel, placebo-controlled clinical trial in patients (n = 44, 10-18 years, females n = 22) with BMI-SDS > 2.0 or age-adapted-BMI > 30 kg/m2 according to WHO were included. Patients received lifestyle intervention and were randomized to exenatide extended release 2 mg (n = 22) or placebo (n = 22) subcutaneous injections given once weekly. Oral glucose tolerance tests (OGTT) were conducted at the beginning and end of the intervention. RESULTS: Exenatide reduced (P < .05) BMI-SDS (-0.09; -0.18, 0.00), % BMI 95th percentile (-2.9%; -5.4, -0.3), weight (-3 kg; -5.8, -0.1), waist circumference (-3.2 cm; -5.8, -0.7), subcutaneous adipose tissue (-552 cm3 ; -989, -114), 2-hour-glucose during OGTT (-15.3 mg/dL; -27.5, -3.1), total cholesterol (11.6 mg/dL; -21.7, -1.5), and BMI (-0.83 kg/m2 ; -1.68, 0.01) without significant change in liver fat content (-1.36; -3.12, 0.4; P = .06) in comparison to placebo. Safety and tolerability profiles were comparable to placebo with the exception of mild adverse events being more frequent in exenatide-treated patients. CONCLUSIONS: Treatment of adolescents with severe obesity with extended-release exenatide is generally well tolerated and leads to a modest reduction in BMI metrics and improvement in glucose tolerance and cholesterol. The study indicates that the treatment provides additional beneficial effects beyond BMI reduction for the patient group.

Misleading symptoms and successful noninvasive rewarming of a patient with severe hypothermia (23.1 °C).

Accidental severe hypothermia is a medical emergency in which symptoms may include coma, apnea, pulmonary edema, ventricular dysrhythmia or asystole. Despite optimal treatment, mortality remains high. This article reports a case of severe hypothermia in a geriatric hypothyroid patient, where despite a body core temperature of 23.1 °C the patient presented conscious and with stable vital signs, pronounced motor response, and a Glasgow Coma Scale score of 9. Blood gas analysis (alpha stat at 37 °C) indicated sufficient pulmonary function. A noninvasive rewarming approach proved successful and resulted in discharge without sequelae. This case highlights that symptoms considered pathognomonic for specific stages of hypothermia should be interpreted with great care in clinical practice. Hypothyroidism may have contributed to this uncommon clinical presentation. Body temperature needs to be taken into account when interpreting blood gas analyses. Even at the stage of severe hypothermia, noninvasive forced-air warming enabled rewarming without complications.

Maternal insulin resistance, triglycerides and cord blood insulin are not determinants of offspring growth and adiposity up to 5 years: a follow-up study.

AIMS: Metabolic dysregulation in utero may influence fetal metabolism and early growth. We previously investigated relationships between maternal indices of glucose homeostasis and triglycerides as well as cord blood insulin with offspring anthropometry up to 2 years. The aim of this analysis was to follow these relationships up to the age of 5 years. METHODS: Associations between maternal metabolic variables of glucose and lipid metabolism measured at 32 weeks' gestation and cord blood insulin with growth and body composition of 162 offspring aged 3-5 years were explored. Both indirect (i.e. body weight, BMI percentiles, sum of four skinfold thicknesses) and direct (i.e. ultrasonography, magnetic resonance imaging in a subgroup) measurement techniques were employed. RESULTS: Maternal metabolic indices were largely unrelated to child body composition. Cord blood insulin was negatively associated with fat mass and lean body mass at 3 years in unadjusted analyses, and the sum of four skinfold thicknesses and body fat percentage in adjusted analyses, whereas the association with lean body mass was no longer observed. An inverse relationship between cord blood insulin and weight gain up to 5 years was observed in girls only with small effect sizes. CONCLUSIONS: Results from this follow-up do not provide convincing evidence that these markers are independently related to offspring growth and adiposity in early childhood. Although cord blood insulin was weakly inversely related to weight gain in girls at 5 years, we cannot conclude that the observed changes in outcomes are clinically meaningful. (Clinical Trials Registry No: NCT00362089).

[Surgical innovations in treatment of metastatic colorectal cancer : Complexity of metastatic surgery as example for personalized medicine]. / Chirurgische Innovationen in der Therapie des metastasierten kolorektalen Karzinoms : Die Komplexität der Metastasenchirurgie als Beispiel für personalisierte Medizin.

BACKGROUND: Extensive, bilobular and multifocal colorectal liver metastases (CLM) or metastases that are critically situated require an experienced surgeon and advanced surgical techniques to enable curative resection. OBJECTIVE: This article describes the toolbox of hepato-oncologic surgery including functional augmentation of liver segments by portal vein embolization/ligation, combinations of ablation and resection, two-stage resections and in situ split liver resection, also known as associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). Furthermore, the curative resection of extrahepatic, oligometastatic disease are briefly discussed. MATERIAL AND METHODS: Review of current literature as well as discussion of the ALPPS procedure, which was developed at our institute. RESULTS: In recent years, oncologic resections for CLM have been significantly refined, leading to a constant increase of curative resection rates. CONCLUSION: In a multimodality treatment setting, surgical resection of CLM remains the gold standard curative approach and even in the event of presumed hopeless cases with extensive metastasis, experienced hepatobiliary surgeons must evaluate the resectability of colorectal metastases.

High resolution vs conventional esophageal manometry in the assessment of esophageal motor disorders in patients with non-cardiac chest pain.

BACKGROUND: High-resolution esophageal manometry (HREM) has become a leading tool in the assessment of esophageal motor disorders, replacing conventional manometry. However, there is limited data about the contribution of HREM as compared with conventional manometry to the assessment of esophageal motor disorders in patients with non-cardiac chest pain (NCCP). The aim of the study was to compare the distribution of esophageal motor disorders in patients with NCCP using HREM as compared with conventional manometry and to determine if HREM improved diagnosis of these disorders. METHODS: In this study, we included 300 consecutive patients with NCCP who underwent either HREM or conventional manometry over a period of 10 years. A total of 150 patients had conventional manometry and the other 150 patients HREM. The Chicago 3.0 classification and the Castell and Spechler classification were used to determine the esophageal motor disorder of NCCP patients undergoing HREM and conventional manometry, respectively. KEY RESULTS: In both HREM and the conventional manometry groups, normal esophageal motility was the most frequent finding (47% and 36%; respectively, P = .054). Hypotensive lower esophageal sphincter was the most common motility disorder identified by conventional manometry (27.3%), while ineffective esophageal motility was the most common esophageal motor disorder identified by HREM (25.3%). CONCLUSIONS & INFERENCES: There is a discrepancy in the type of esophageal motor disorders identified by HREM as compared with conventional manometry in NCCP patients. Hypotensive motility disorders are the most commonly diagnosed by both manometric techniques.

Longitudinal and Transverse Instability of Ion Acoustic Waves.

Ion acoustic waves are found to be susceptible to at least two distinct decay processes. Which process dominates depends on the parameters. In the cases examined, the decay channel where daughter modes propagate parallel to the mother mode is found to dominate at larger amplitudes, while the decay channel where the daughter modes propagate at angles to the mother mode dominates at smaller amplitudes. Both decay processes may occur simultaneously and with onset thresholds below those suggested by fluid theory, resulting in the eventual multidimensional collapse of the mother mode to a turbulent state.

Impact of the n-6:n-3 long-chain PUFA ratio during pregnancy and lactation on offspring neurodevelopment: 5-year follow-up of a randomized controlled trial.

BACKGROUND/OBJECTIVES: Evidence regarding the effect of n-3 long-chain polyunsaturated fatty acid (LCPUFA) supplementation during pregnancy on offspring's neurodevelopment is not conclusive. SUBJECTS/METHODS: In this analysis, the effect of a reduced n-6:n-3 LCPUFA ratio in the diet of pregnant/lactating women (1.2 g n-3 LCPUFA together with an arachidonic acid (AA)-balanced diet between 15th wk of gestation-4 months postpartum vs control diet) on child neurodevelopment at 4 and 5 years of age was assessed. A child development inventory (CDI) questionnaire and a hand movement test measuring mirror movements (MMs) were applied and the association with cord blood LCPUFA concentrations examined. RESULTS: CDI questionnaire data, which categorizes children as 'normal', 'borderline' or 'delayed' in different areas of development, showed no significant evidence between study groups at 4 (n=119) and 5 years (n=130) except for the area 'letters' at 5 years of age (P=0.043). Similarly, the results did not strongly support the hypothesis that the intervention has a beneficial effect on MMs (for example, at 5 years: dominant hand, fast: adjusted mean difference, -0.08 (-0.43, 0.26); P=0.631). Children exposed to higher cord blood concentrations of docosahexaenoic acid, eicosapentaenoic acid and AA, as well as a lower ratio of n-6:n-3 fatty acids appeared to show beneficial effects on MMs, but these results were largely not statistically significant. CONCLUSIONS: Our results do not show clear benefits or harms of a change in the n-6:n-3 LCPUFA ratio during pregnancy on offspring's neurodevelopment at preschool age. Findings on cord blood LCPUFAs point to a potential influence on offspring development.

BGO as a hybrid scintillator / Cherenkov radiator for cost-effective time-of-flight PET.

Due to detector developments in the last decade, the time-of-flight (TOF) method is now commonly used to improve the quality of positron emission tomography (PET) images. Clinical TOF-PET systems based on L(Y)SO:Ce crystals and silicon photomultipliers (SiPMs) with coincidence resolving times (CRT) between 325 ps and 400 ps FWHM have recently been developed. Before the introduction of L(Y)SO:Ce, BGO was used in many PET systems. In addition to a lower price, BGO offers a superior attenuation coefficient and a higher photoelectric fraction than L(Y)SO:Ce. However, BGO is generally considered an inferior TOF-PET scintillator. In recent years, TOF-PET detectors based on the Cherenkov effect have been proposed. However, the low Cherenkov photon yield in the order of ∼10 photons per event complicates energy discrimination-a severe disadvantage in clinical PET. The optical characteristics of BGO, in particular its high transparency down to 310 nm and its high refractive index of ∼2.15, are expected to make it a good Cherenkov radiator. Here, we study the feasibility of combining event timing based on Cherenkov emission with energy discrimination based on scintillation in BGO, as a potential approach towards a cost-effective TOF-PET detector. Rise time measurements were performed using a time-correlated single photon counting (TCSPC) setup implemented on a digital photon counter (DPC) array, revealing a prompt luminescent component likely to be due to Cherenkov emission. Coincidence timing measurements were performed using BGO crystals with a cross-section of 3 mm × 3 mm and five different lengths between 3 mm and 20 mm, coupled to DPC arrays. Non-Gaussian coincidence spectra with a FWHM of 200 ps were obtained with the 27 mm3 BGO cubes, while FWHM values as good as 330 ps were achieved with the 20 mm long crystals. The FWHM value was found to improve with decreasing temperature, while the FWTM value showed the opposite trend.

Collisional damping rates for electron plasma waves reassessed.

Collisional damping of electron plasma waves, the primary damping for high phase velocity waves, is proportional to the electron-ion collision rate, ν_{ei,th}. Here, it is shown that the damping rate normalized to ν_{ei,th} depends on the charge state, Z, on the magnitude of ν_{ei,th} and the wave number k in contrast with the commonly used damping rate in plasma wave research. Only for weak collision rates in low-Z plasmas for which the electron self-collision rate is comparable to the electron-ion collision rate is the damping rate given by the commonly accepted value. The result presented here corrects the result presented in textbooks at least as early as 1973. The complete linear theory requires the inclusion of both electron-ion pitch-angle and electron-electron scattering, which itself contains contributions to both pitch-angle scattering and thermalization.