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We report a case series of four patients with cystic fibrosis (CF) and previous solid organ transplantation (SOT) receiving elexacaftor/tezacaftor/ivacaftor therapy for 6 months or more. Data was collected retrospectively. The treatment was well tolerated and all patients reported subjective improvements.

BACKGROUND & AIMS: Hyperammonaemia is a key pathological feature of liver disease and the primary driver of hepatic encephalopathy (HE). However, the relative roles of increased ammonia production and reduced clearance are poorly understood as is the action of ammonia-targeting HE drugs. We aimed to quantify whole-body ammonia metabolism in healthy persons and patients with cirrhosis and to validate our method by examining the effects of glycerol phenylbutyrate and lactulose + rifaximin treatment.METHODS: Ten healthy men and ten male patients with cirrhosis were investigated by 90-minute constant ammonia infusion to achieve steady-state plasma ammonia. Whole-body ammonia clearance was calculated as infusion rate divided by steady-state concentration increase and ammonia production as clearance times baseline ammonia concentration. Participants were re-investigated after the ammonia targeting interventions.RESULTS: In healthy persons, ammonia clearance was 3.5 (3.1-3.9) L/min and production 49 (35-63) μmol/min. Phenylbutyrate increased clearance by 11% (4-19%, p=0.009). Patients with cirrhosis had a 20% decreased ammonia clearance of 2.7 (2.1-3.3) L/min (p = 0.02) and a nearly tripled production to 131 (102-159) μmol/min (pCONCLUSIONS: Whole-body ammonia clearance and production may be measured separately by the technique used. The method identified a lower clearance and a higher production in patients with cirrhosis, and showed that phenylbutyrate increases clearance, whereas lactulose + rifaximin reduces production. The method may be used to examine a range of questions related to normo-/pathophysiology and ammonia-targeting treatment mechanisms.IMPACT AND IMPLICATIONS: High blood ammonia plays a key role in liver cirrhosis related brain dysfunction. However, the relative roles of increased ammonia production and reduced ammonia clearance are poorly understood as is the action of ammonia-targeting treatments. This study presents a relatively simple test to measure ammonia metabolism. By use of this test, it was possible to show that patients with liver cirrhosis have decreased ammonia clearance and increased ammonia production compared with healthy persons and to quantify distinctively different ammonia-targeting treatment effects. The test presented holds several perspectives for future studies of normal physiology and pathophysiology, not least in regard to elucidating effects of ammonia-targeting therapies.CLINICAL TRIAL NUMBER: ClinicalTrials.gov (1-16-02-297-20).

BACKGROUND & AIMS: Wilson disease (WD) is a genetic disease with systemic accumulation of copper that leads to symptoms from the liver and brain. However, the underlying defects in copper transport kinetics are only partly understood. We sought to quantify hepatic copper turnover in patients with WD compared with heterozygote and control subjects using positron emission tomography (PET) with copper-64 (64 Cu) as tracer. Furthermore, we assessed the diagnostic potential of the method.METHODS: Nine patients with WD, five healthy heterozygote subjects, and eight healthy controls were injected with an intravenous bolus of 64 Cu followed by a 90-min dynamic PET scan of the liver and static whole-body PET/CT scans after 1.5, 6, and 20 hours. Blood 64 Cu concentrations were measured in parallel. The hepatic copper retention and redistribution were evaluated by standardized uptake values (SUV).RESULTS: At 90 min, the hepatic SUVs were similar in the three groups. In contrast, at 20 hours post injection, the SUV in WD patient (Mean±SEM 31±4) was higher than in heterozygotes (24±3) or controls (21±4), (p < 0.001). An SUV-ratio of the hepatic 64 Cu concentration at 20 and 1.5 hours completely discriminated between the WD patients and control groups (p < 0.0001; ANOVA). By Patlak-analysis of the initial 90 min of the PET scan, the steady-state hepatic clearance of 64 Cu was estimated to be slightly lower in the patients with WD than in controls, (p = 0.04).CONCLUSIONS: 64 Cu PET imaging enables visualisation and quantification of the hepatic copper retention characteristic for WD patients. This method represents a valuable tool for future studies of WD pathophysiology, which may assist the development of novel therapies, and accurate diagnosis.

Background: Wilson disease is an inherited disorder of copper transport. Whereas penicillamine is used therapeutically to re-establish copper balance, trientine is indicated for patients with penicillamine intolerance. We aimed to compare penicillamine with trientine tetrahydrochloride (TETA4) for maintenance therapy in patients with Wilson disease. Methods: We conducted a randomised, open-label, non-inferiority, phase 3 trial at 15 health-care centres across nine countries (patients were recruited from 13 of these health-care centres across Brazil, Europe, and the USA). We enrolled patients aged 18–75 years with stable Wilson disease who were treated for at least 1 year with penicillamine. Patients entered a 12-week period to determine stability through clinical assessment by site investigators and predefined thresholds for serum non-caeruloplasmin-bound copper (NCC; by an exchangeable copper assay; 25–150 μg/L), 24 h urinary copper excretion (100–900 μg/24 h), and alanine aminotransferase (ALT

Zinc inhibits intestinal copper uptake, an effect utilized for treating Wilson’s disease (WD). We used copper-64 (64Cu) PET/CT to examine how much four weeks of treatment with different zinc regimens reduced the hepatic 64Cu content after oral 64Cu administration and test if alternative regimens were noninferior to the standard regimen of zinc acetate 50 mg × 3 daily. Forty healthy persons were randomized to four different zinc protocols. The WD standard treatment zinc acetate 50 mg × 3 reduced the hepatic 64Cu content from 26.9 ± 7.5% to 13.3 ± 5.6% of the administered 64Cu. Zinc gluconate 50 mg × 3 was noninferior (P = 0.02) (35.8 ± 9.0% to 17.4 ± 7.5%). Zinc acetate 150 mg × 1 (33.1 ± 9.9% to 17.4 ± 7.5%) and zinc gluconate 150 mg × 1 (28.1 ± 6.7% to 22.0 ± 6.7%) were less effective. These effects were intra- and inter-individually highly variable, and 14% had no effect of any zinc regimen, which may explain disparities in zinc treatment efficacy in WD patients.

This paper proposes a multi-modal cross learning approach to augment the neural network training phase by additional sensor data. The approach is multi-modal during training (i.e., radar Range-Doppler maps, thermal camera images, and RGB camera images are used for training). In inference, the approach is single-modal (i.e., only radar Range-Doppler maps are needed for classification). The proposed approach uses a multi-modal autoencoder training which creates a compressed data representation containing correlated features across modalities. The encoder part is then used as a pretrained network for the classification task. The benefits are that expensive sensors like high resolution thermal cameras are not needed in the application but a higher classification accuracy is achieved because of the multi-modal cross learning during training. The autoencoders can also be used to generate hallucinated data of the absent sensors. The hallucinated data can be used for user interfaces, a further classification, or other tasks. The proposed approach is verified within a simultaneous cooking process classification, $2\times 2$ cooktop occupancy detection, and gesture recognition task. The main functionality is an overboil protection and gesture control of a $2\times 2$ cooktop. The multi-modal cross learning approach considerably outperforms single-modal approaches on that challenging classification task.

Smart-Kameras sind ein elementarer Bestandteil in der industriellen Fertigung. Jedoch veraltet deren Datenverarbeitungshardware schnell, während die Optik langlebig ist. Um Bildanalysealgorithmen mit erhöhtem Ressourcenbedarf trotz Limitierung der Smart-Kamera in Fertigungsanlagen flexibel integrieren zu können, werden in diesem Beitrag die Möglichkeiten diskutiert, wie solche Systeme mit Ressourcen in der Cloud erweiterbar sind. Es wird eine Systemarchitektur und deren Umsetzung vorgestellt, die konstante, wie auch schwankende Bildverarbeitungskapazitäten in der Cloud skalierbar erschließen.

Background: The prognosis of Wilson’s disease (WD) has changed radically since the introduction of medical therapy with chelators and zinc. However, there is an unmet need for methods to evaluate the long-term treatment response and the liver disease progression in order to identify treatment failures. The galactose elimination capacity test (GEC) is a physiological measure of the total metabolic capacity of the liver, and a strong predictor of long- and short-term mortality in patients with liver cirrhosis. Our aim was to investigate if the GEC test is useful for evaluation of treatment response and prediction of treatment failures in WD patients. Methods: We included all patients with WD in Denmark from 1992 through 2017 and retrieved data on GEC along with data on transplantation and death. Results: In total, 37 patients had completed one or more GEC tests. Of these, 31 were alive (three transplanted) and six were dead (two transplanted). A total of 24 patients had completed more than one GEC test. All 18 alive, nontransplanted patients showed improvement in GEC values following onset of treatment, except one patient, who was clinically confirmed with treatment failure. All six patients who underwent liver transplantation or died had a prior decline in their GEC. The difference in GEC development between patients alive and not transplanted and patients dead or transplanted was significant (p

Wilson's disease (WD) is a genetic disease with systemic accumulation of copper that leads to symptoms from the liver and brain. However, the underlying defects in copper transport kinetics are only partly understood. We sought to quantify hepatic copper turnover in patients with WD compared with heterozygote and control subjects using PET with copper-64 (Nine patients with WD, 5 healthy heterozygote subjects, and 8 healthy controls were injected with an i.v. bolus of

Hepatic encephalopathy (HE) is a frequent and devastating but generally reversible neuropsychiatric complication secondary to chronic and acute liver failure. During HE, brain energy metabolism is markedly reduced and it remains unclear whether this is due to external or internal energy supply limitations, or secondary to depressed neuronal cellular functions - and if so, which mechanisms that are in play. The extent of deteriorated cerebral function correlates to blood ammonia levels but the metabolic link to ammonia is not clear. Early studies suggested that high levels of ammonia inhibited key tricarboxylic acid (TCA) cycle enzymes thus limiting mitochondrial energy production and oxygen consumption; however, later studies by us and others showed that this is not the case in vivo. Here, based on a series of translational studies from our group, we advocate the view that the low cerebral energy metabolism of HE is likely to be caused by neuronal metabolic depression due to an elevated GABAergic tone rather than by restricted energy availability. The increased GABAergic tone seems to be secondary to synthesis of large amounts of glutamine in astrocytes for detoxification of ammonia with the glutamine acting as a precursor for elevated neuronal synthesis of vesicular GABA.

Impaired liver function may lead to hyperammonemia and risk for hepatic encephalopathy. In brain, detoxification of ammonia is mediated mainly by glutamine synthetase (GS) in astrocytes. This requires a continuous de novo synthesis of glutamate, likely involving the action of both pyruvate carboxylase (PC) and glutamate dehydrogenase (GDH). An increased PC activity upon ammonia exposure and the importance of PC activity for glutamine synthesis has previously been demonstrated while the importance of GDH for generation of glutamate as precursor for glutamine synthesis has received little attention. We therefore investigated the functional importance of GDH for brain metabolism during hyperammonemia. To this end, brain slices were acutely isolated from transgenic CNS-specific GDH null or litter mate control mice and incubated in aCSF containing [U-13C]glucose in the absence or presence of 1 or 5 mM ammonia. In another set of experiments, brain slices were incubated in aCSF containing 1 or 5 mM 15N-labeled NH4Cl and 5 mM unlabeled glucose. Tissue extracts were analyzed for isotopic labeling in metabolites and for total amounts of amino acids. As a novel finding, we reveal a central importance of GDH function for cerebral ammonia fixation and as a prerequisite for de novo synthesis of glutamate and glutamine during hyperammonemia. Moreover, we demonstrated an important role of the concerted action of GDH and alanine aminotransferase in hyperammonemia; the products alanine and α-ketoglutarate serve as an ammonia sink and as a substrate for ammonia fixation via GDH, respectively. The role of this mechanism in human hyperammonemic states remains to be studied.

Background: In Wilson disease (WD), mutations in the gene encoding the ATP7B copper transport protein causes accumulation of copper especially in liver and brain. WD typically presents with hepatic and/or neuropsychiatric symptoms. Impaired cognition is a well-described feature in patients neurological WD, while the reports on cognition in hepatic WD patients are fewer and less conclusive. We examined cognition in a cohort of WD patients with both phenotypes. Methods: In this cross-sectional pilot study, we investigated cognition in 28 stable Danish WD patients by portosystemic encephalopathy (PSE) and continuous reaction time (CRT) tests. Half of the patients were female and median age was 35.5 years (IQR 24.5). The phenotype was hepatic in 14 (50%), neurologic in 10 (36%) and mixed in 4 4 (14%). The duration of treatment was >2 year in all patients, and the condition stable as judged by urinary copper excretion, liver enzymes, and clinical assessment.Results: In total, 16 (57%) patients performed worse than normal in the PSE and/or CRT tests. The two tests correlated (rho=0.60, p=0.0007) with each other, but neither correlated with phenotype, MELD-, Child-Pugh score, 24h-U-Cu, or treatment type.Conclusion: Measurable cognitive impairment was present in more than half of the stable WD patients independent of phenotype. Thus, our data questions the existence of a purely hepatic phenotype.

Rapidly developing Compressed Sensing theory looks promising for many practical applications, since it allows us to reconstruct K-sparce signals and to reduce some hardware requirements. In this work, we consider the problem of changing noise properties after recovering and its influence on the radar false alarm rate. Due to nonlinearity of the recovering algorithm there is no analytical solution allowing finding a noise distribution after the reconstruction. Therefore, by an empirical approach we come to a solution, where the well-known cell averaging constant false alarm rate detector can be used for a compressed sensing radar. We analyze its performance by simulation and test it with real radar data.

This paper proposes a cognitive radar setup to learn the minimal sequence of Range-Doppler measurements for accurate multi-target detection with adaptive parameters. This minimal measurement sequence is achieved by a novel reward definition in a Reinforcement Learning approach. Thus, the cognitive radar learns to optimize its measurement time and energy savings. Based on Range-Doppler maps, the Reinforcement Learning agent adapts the FMCW parameters like bandwidth, sweep time, chirp repetition time and number of chirps to optimize the recognition in a three-target scenario. The agent is trained using Proximal Policy Optimization (PPO) in a simulated radar environment.

Sequentially stacked impingement channels allow for a more effective use of the cooling fluid and can limit the heat transfer reduction due to the crossflow when the number of jets increases. In this paper, sequential impingement channels are experimentally investigated using the transient liquid crystal technique. Twelve configurations are tested: the baseline consists in a double rectangular channel with 5 jets per channel; other configurations feature different number of jets, variations of the jet-to-jet spacing and of the transition zone length, reduction of the cross-section in the transition zone and addition of a bypass between the channels. Results show that heat transfer coefficients (HTC) in the 2nd channel are similar to the 1st, and that the cross-section reduction in the transition zone allows for an increase of the HTC in this critical zone with only a moderate increase of pressure losses.

In this paper two Kalman filter models are presented to filter a signal of a FMCW radar sensor. The measurement object is a rhythmic hand movement of a conductor. From the radar signal we get the distance and velocity. The models are intended to correct the noisy signal for later analysis of frequency and phase so that the tempo and beat of the conductor can be estimated. We evaluate and compare the models with simulated and real data from a chirp-sequence radar sensor.

In our pilot study, we exposed third-trimester fetuses, from week 34 of gestation onwards, twice daily to a maternal spoken nursery rhyme. Two and five weeks after birth, 34 newborns, who were either familiarized with rhyme stimulation in utero or stimulation naïve, were (re-)exposed to the familiar, as well as to a novel and unfamiliar, rhyme, both spoken with the maternal and an unfamiliar female voice. For the stimulation-naïve group, both rhymes were unfamiliar. During stimulus presentation, heart rate activity and high-density electroencephalography were collected and newborns’ responses during familiar and unfamiliar stimulation were analyzed. All newborns demonstrated stronger speech–brain coupling at 1 Hz during the presentation of the maternal voice vs. the unfamiliar female voice. Rhyme familiarity originating from prenatal exposure had no effect on speech–brain coupling in experimentally stimulated newborns. Furthermore, only stimulation-naïve newborns demonstrated an increase in heart rate during the presentation of the unfamiliar female voice. The results indicate prenatal familiarization to auditory speech and point to the specific significance of the maternal voice already in two- to five-week-old newborns.

The global outbreak of severe acute respiratory syndrome coronavirus 2 has had an enormous impact on the world. It remains unclear to what extent liver transplant recipients should be considered at a higher risk of severe disease due to the limited data available. We describe a moderate course of COVID-19 in a patient who underwent a liver transplant two years earlier due to Budd-Chiari syndrome. The patient presented with malaise, headache, dry cough and fever for four days. Immunosuppressive therapy with tacrolimus and mycophenolate mofetil was continued throughout the course of infection, oxygen therapy was given for a single night and the patient gradually recovered with supportive care only. With this case report, we demonstrate that liver transplantation and immunosuppression is not necessarily associated with severe COVID-19 disease and emphasize that more information on this matter is urgently required. Withdrawal of immunosuppressive therapy could be associated with a higher mortality., Highlights • There is sparse evidence about the impact of SARS-CoV2 on liver transplant recipients. • Limited data suggest a high early mortality in these patients. • Withdrawal of immunosuppressive therapy could be associated with poorer outcomes. • Each case must be evaluated and managed carefully by experts.

This editorial comments on the findings from the study by Jindal et al. recently published in The American Journal of Gastroenterology. Weaknesses and strengths of the study are presented, and potential therapeutic strategies for compensated cirrhotic patients with an HVPG ≥20 mm Hg are proposed.

The use of radar systems is limited in some applications by spatial constraints or special thermal and environmental conditions. The spatial separation of the sensitive electronics and the more robust antenna by a ���exible connection therefore opens up new applications. A 160-GHz radar system with a mechanically ���exible front end ful���lling these requirements is proposed in this paper. The ���exible front end is an extremely low loss dielectric waveguide feeding a dielectric elliptical lens antenna (28 dBi gain). The dielectric waveguide has dielectric losses of 4.5 dB/m at 160 GHz and is very ���exible, allowing bending radii of down to 1.5 cm with negligible losses. The dielectric waveguide is fed by a 160-GHz radar monolithic microwave integrated circuit (MMIC), which allows bandwidths of up to 20 GHz for a high range resolution. The transition between MMIC and dielectric waveguide is realized with a rectangular-waveguide interface. The radar back end consists of a phased-locked loop (PLL) with standard components, an intermediate frequency (IF) signal conditioning part, and a Xilinx Zynq 7030 System-On-Module (SOM) with an FPGA and an ARM-based processor. The sampled signal is processed directly on the FPGA with a 2D Fourier transform and is available as a UDP stream with an update rate of up to 15 Hz. In addition, a camera image is taken for each radar measurement. The presented system is used to detect and measure the ���ight behavior of honey bees. The electronics are housed in a building whereas the ���exible dielectric waveguide allows the antenna to be placed anywhere around the beehive, where it is exposed to environmental conditions., publishedVersion

Purpose Copper is essential for enzymatic processes throughout the body. [64Cu]copper (64Cu) positron emission tomography (PET) has been investigated as a diagnostic tool for certain malignancies, but has not yet been used to study copper homeostasis in humans. In this study, we determined the hepatic removal kinetics, biodistribution and radiation dosimetry of 64Cu in healthy humans by both intravenous and oral administration. Methods Six healthy participants underwent PET/CT studies with intravenous or oral administration of 64Cu. A 90 min dynamic PET/CT scan of the liver was followed by three whole-body PET/CT scans at 1.5, 6, and 20 h after tracer administration. PET data were used for estimation of hepatic kinetics, biodistribution, effective doses, and absorbed doses for critical organs. Results After intravenous administration, 64Cu uptake was highest in the liver, intestinal walls and pancreas; the gender-averaged effective dose was 62 ± 5 μSv/MBq (mean ± SD). After oral administration, 64Cu was almost exclusively taken up by the liver while leaving a significant amount of radiotracer in the gastrointestinal lumen, resulting in an effective dose of 113 ± 1 μSv/MBq. Excretion of 64Cu in urine and faeces after intravenous administration was negligible. Hepatic removal kinetics showed that the clearance of 64Cu from blood was 0.10 ± 0.02 mL blood/min/mL liver tissue, and the rate constant for excretion into bile or blood was 0.003 ± 0.002 min− 1. Conclusion 64Cu biodistribution and radiation dosimetry are influenced by the manner of tracer administration with high uptake by the liver, intestinal walls, and pancreas after intravenous administration, while after oral administration, 64Cu is rapidly absorbed from the gastrointestinal tract and deposited primarily in the liver. Administration of 50 MBq 64Cu yielded images of high quality for both administration forms with radiation doses of approximately 3.1 and 5.7 mSv, respectively, allowing for sequential studies in humans. Trial registration number EudraCT no. 2016–001975-59. Registration date: 19/09/2016.

A proper use of the advances of compressed sensing (CS) theory in radar systems may lead to data rate reduction, energy saving and measuring improvement. Using, e.g., randomly placed chirps and CS reconstruction algorithms, the velocity unambiguously measured by FMCW-Radars can be increased. In this paper, we propose to use the Soft Iterative Method with Adaptive Thresholding (soft-IMAT) for the reconstruction of the radar scene. Its performance is analyzed in different scenarios and compared with the original IMAT with respect to detection probability and computational complexity. A modified soft-IMAT is proposed in order to reduce the computational overhead caused by the soft-based decision.