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.

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).

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.

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.

mTOR inhibition improves fibroblast growth factor receptor targeting in hepatocellular carcinoma.

BACKGROUND: Systemic therapy has proven only marginal effects in hepatocellular carcinoma (HCC) so far. The aim of this study was to evaluate the effect of targeting fibroblast growth factor receptor (FGFR) on tumour and stromal cells in HCC models. METHODS: Human and murine HCC cells, endothelial cells (ECs), vascular smooth muscle cells (VSMCs), hepatic stellate cells (HSCs), human HCC samples, FGFR inhibitor BGJ398 and mammalian target of rapamycin (mTOR) inhibitor rapamycin were used. Effects on growth, motility, signalling and angiogenic markers were determined. In vivo subcutaneous and syngeneic orthotopic tumour models were used. RESULTS: In tumour cells and ECs, targeting FGFR showed significant inhibitory effects on signalling and motility. Minor effects of FGFR inhibition were observed on VSMCs and HSCs, which were significantly enhanced by combining FGFR and mTOR blockade. In vivo daily (5 mg kg(-1)) treatment with BGJ398 led to a significant growth inhibition in subcutaneous tumour models, but only a combination of FGFR and mTOR blockade impaired tumour growth in the orthotopic model. This was paralleled by reduced tumour cell proliferation, vascularisation, pericytes and increased apoptosis. CONCLUSIONS: Targeting FGFR with BGJ398 affects tumour cells and ECs, whereas only a combination with mTOR inhibition impairs recruitment of VSMCs and HSCs. Therefore, this study provides evidence for combined FGFR/mTOR inhibition in HCC.

Mobilisation of haemopoietic stem cells in teriparatide-treated patients.

Parathyroid hormone (PTH) is the predominant regulator of calcium/phosphate homeostasis in the human body. Beside this classical function, preclinical and clinical studies indicated a relevant role for PTH in mobilisation of bone marrow-derived cells into peripheral blood. In addition, recombinant PTH (teriparatide) was recently approved for the treatment of severe osteoporosis. Therefore, it was the aim of the present study to investigate the dynamics of haemopoietic stem cells and corresponding in peripheral blood of 13 patients with osteoporosis during treatment with teriparatide. We were able to show that administration of teriparatide is sufficient to mobilise haemopoietic stem cells into the bloodstream accompanied by an alteration of mobilising cytokines. In conclusion, teriparatide might be a useful tool in the context of stem cell mobilisation.

Prognosis according to histochemical analysis of liver metastases removed at liver resection.

BACKGROUND: Liver metastases occur in 40-50 per cent of patients with colorectal cancer and determine long-term survival. The aim of this study was to examine the immunological architecture of colorectal liver metastases and its impact on patient survival. METHODS: Specimens from patients with colorectal liver metastases were stained with haematoxylin and eosin and Masson trichrome, immunostained for α-smooth muscle actin, CD4, CD45RO and CD8, and analysed by flow cytometry. In addition to histomorphological evaluation, immunohistochemically stained sections were analysed for cell numbers in the tumour area, infiltrative margin and distant liver stroma separately. These findings were correlated with clinical data and patient outcome. RESULTS: Tumour containment by a fibrotic capsule around liver metastases was observed in 37·8 per cent of 201 patients and was prognostic for improved survival (median (s.e.) survival 64 (6) and 31 (4) months for patients with capsule and no capsule respectively; P < 0·001) and independently led to higher R0 resection rates (P = 0·040). In multivariable analysis, CD45RO(+) cell infiltration at the peritumoral margin with low CD45RO(+) cell infiltration in the distant liver stroma (P = 0·001) and fibrotic capsule formation (P = 0·008) both independently prolonged patient survival. Using these two factors, a cellular immune score was designed and shown to stratify patient survival in test and validation samples (both P < 0·001). CONCLUSION: Fibrotic capsule formation and localized cell infiltration of colorectal liver metastases by CD45RO(+) cells were related to prolonged patient survival. Based on these immunological criteria a cellular immune score was developed to stratify patients according to prognosis.

Inhibition of innate co-receptor TREM-1 signaling reduces CD4(+) T cell activation and prolongs cardiac allograft survival.

The innate receptor "triggering-receptor-expressed-on-myeloid-cells-1" (TREM-1) enhances downstream signaling of "pattern recognition receptor" (PRR) molecules implicated in inflammatory responses. However the mechanistic role of TREM-1 in chronic heart rejection has yet to be elucidated. We examined the effect of TREM-1(+) antigen-presenting cells (APC) on alloreactive CD4(+) lymphocytes. Bm12 donor hearts were transplanted into wild-type MHC-class-II-mismatched C57BL/6J recipient mice. Progressive allograft rejection of bm12-donor hearts with decreased organ function, severe vasculopathy and allograft fibrosis was evident within 4 weeks. TREM-1(+) CD11b(+) MHC-II(+) F4/80(+) CCR2(+) APC and IFNγ-producing CD4(+) cells were detected during chronic rejection. Peptide inhibition of TREM-1 attenuated graft vasculopathy, reduced graft-infiltrating leukocytes and prolonged allograft survival, while being accompanied by sustained low levels of CD4(+) and CD8(+) cell infiltration. Remarkably, temporary inhibition of TREM-1 during early immune activation was sufficient for long-term allograft survival. Mechanistically, TREM-1 inhibition leads to reduced differentiation and proliferation of IFNγ-producing Th1 cells. In conclusion, TREM-1 influences chronic heart rejection by regulating the infiltration and differentiation of CD4(+) lymphocytes.

Kinetic theory and Vlasov simulation of nonlinear ion-acoustic waves in multi-ion species plasmas.

The theory of damping and nonlinear frequency shifts from particles resonant with ion-acoustic waves (IAWs) is presented for multi-ion species plasma and compared to driven wave Vlasov simulations. Two distinct IAW modes may be supported in multi-ion species plasmas, broadly classified as fast and slow by their phase velocity relative to the constituent ion thermal velocities. In current fusion-relevant long pulse experiments, the ion to electron temperature ratio, T(i)/T(e), is expected to reach a level such that the least damped and thus more readily driven mode is the slow mode, with both linear and nonlinear properties that are shown to differ significantly from the fast mode. The lighter ion species of the slow mode is found to make no significant contribution to the IAW frequency shift despite typically being the dominant contributor to the Landau damping.

Kinetic simulations of the self-focusing and dissipation of finite-width electron plasma waves.

Two-dimensional simulations, both Vlasov and particle-in-cell, are presented that show the evolution of the field and electron distribution of finite-width, nonlinear electron plasma waves. The intrinsically intertwined effects of self-focusing and dissipation of field energy caused by electron trapping are studied in simulated systems that are hundreds of wavelengths long in the transverse direction but only one wavelength long and periodic in the propagation direction. From various initial wave states, both the width at focus Δm relative to the initial width Δ0 and the maximum field amplitude at focus are shown to be a function of the growth rate of the transverse modulational instability γTPMI divided by the loss rate of field energy νE to electrons escaping the trapping region. With dissipation included, an amplitude threshold for self-focusing γTPMI/νE∼1 is found that supports the analysis of Rose [Phys. Plasmas 12, 012318 (2005)].

Maternal insulin resistance, triglycerides and cord blood insulin in relation to post-natal weight trajectories and body composition in the offspring up to 2 years.

AIMS: The intrauterine metabolic environment might have a programming effect on offspring body composition. We aimed to explore associations of maternal variables of glucose and lipid metabolism during pregnancy, as well as cord blood insulin, with infant growth and body composition up to 2 years post-partum. METHODS: Data of pregnant women and their infants came from a randomized controlled trial designed to investigate the impact of nutritional fatty acids on adipose tissue development in the offspring. Of the 208 pregnant women enrolled, 118 infants were examined at 2 years. In the present analysis, maternal fasting plasma insulin, homeostasis model assessment of insulin resistance and serum triglycerides measured during pregnancy, as well as insulin in umbilical cord plasma, were related to infant growth and body composition assessed by skinfold thickness measurements and abdominal ultrasonography up to 2 years of age. RESULTS: Maternal homeostasis model assessment of insulin resistance at the 32nd week of gestation was significantly inversely associated with infant lean body mass at birth, whereas the change in serum triglycerides during pregnancy was positively associated with ponderal index at 4 months, but not at later time points. Cord plasma insulin correlated positively with birthweight and neonatal fat mass and was inversely associated with body weight gain up to 2 years after multiple adjustments. Subsequent stratification by gender revealed that this relationship with weight gain was stronger, and significant only in girls. CONCLUSIONS: Cord blood insulin is inversely associated with subsequent infant weight gain up to 2 years and this seems to be more pronounced in girls.

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.

[Superficial venous thrombosis. A review]. / Oberflächliche Venenthrombose. Eine Übersicht.

This review summarizes the epidemiology, clinical aspects, diagnosis and new therapeutic options of the superficial venous thrombosis. An important new finding is, that the thrombophlebitis is actually a thrombosis, which occurs in an intra- or epifascial vein. It can be associated with deep venous thrombosis or pulmonary embolism, thus carrying considerable risk. Other underlying diseases such as underlying tumors or infections as well as acquired or inherited disorders of coagulation must be considered. New placebo-controlled studies show a clear benefit for low molecular weight heparin or the pentasaccharide fondaparinux. In addition to the medical treatment, compression is recommended for superficial venous thrombosis in varicose veins, but not in normal veins.

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.

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.

[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.

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.

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.

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.