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.

Standardizing lymphangiography and lymphatic interventions: a preclinical in vivo approach with detailed procedural steps.

PURPOSE: To present a preclinical in vivo approach for standardization and training of lymphangiography and lymphatic interventions using a pictorial review. MATERIALS AND METHODS: Different lipiodol- and gadolinium-based lymphangiography and lymphatic interventions were performed in twelve (12) landrace pigs with a mean bodyweight of 34 ± 2 kg using various imaging and guiding modalities, similar to the procedures used in humans. The techniques used were explicitly introduced and illustrated. The potential applications of each technique in preclinical training were also discussed. RESULTS: By applying visual, ultrasonography, fluoroscopy, CT, cone-beam CT, and/or MRI examination or guidance, a total of eleven techniques were successfully implemented in twelve pigs. The presented techniques include inguinal postoperative lymphatic leakage (PLL) establishment, interstitial dye test, five types of lymphangiography [incl. lipiodol-based translymphatic lymphangiography (TL), lipiodol-based percutaneous intranodal lymphangiography (INL), lipiodol-based laparotomic INL, lipiodol-based interstitial lymphangiography, and interstitial magnetic resonance lymphangiography (MRL)], and four types of percutaneous interventions in the treatment of PLL [incl. thoracic duct embolization (TDE), intranodal embolization (INE), afferent lymphatic vessel sclerotherapy (ALVS), and afferent lymphatic vessel embolization (ALVE)]. CONCLUSION: This study provides a valuable resource for inexperienced interventional radiologists to undergo the preclinical training in lymphangiography and lymphatic interventions using healthy pig models.

On the adsorption and reactivity of element 114, flerovium.

Flerovium (Fl, element 114) is the heaviest element chemically studied so far. To date, its interaction with gold was investigated in two gas-solid chromatography experiments, which reported two different types of interaction, however, each based on the level of a few registered atoms only. Whereas noble-gas-like properties were suggested from the first experiment, the second one pointed at a volatile-metal-like character. Here, we present further experimental data on adsorption studies of Fl on silicon oxide and gold surfaces, accounting for the inhomogeneous nature of the surface, as it was used in the experiment and analyzed as part of the reported studies. We confirm that Fl is highly volatile and the least reactive member of group 14. Our experimental observations suggest that Fl exhibits lower reactivity towards Au than the volatile metal Hg, but higher reactivity than the noble gas Rn.

Proposal of an algorithm for the management of rectally inserted foreign bodies: a surgical single-center experience with review of the literature.

BACKGROUND: Retained rectal foreign bodies (RFBs) are uncommon clinical findings. Although the management of RFBs is rarely reported in the literature, clinicians regularly face this issue. To date, there is no standardized management of RFBs. The aim of the present study was to evaluate our own data and subsequently develop a treatment algorithm. METHODS: All consecutive patients who presented between January 2006 and December 2019 with rectally inserted RFBs at the emergency department of the Klinikum Stuttgart, Germany, were retrospectively identified. Clinicopathologic features, management, complications, and outcomes were assessed. Based on this experience, a treatment algorithm was developed. RESULTS: A total of 69 presentations with rectally inserted RFBs were documented in 57 patients. In 23/69 cases (33.3%), the RFB was removed transanally by the emergency physician either digitally (n = 14) or with the help of a rigid rectoscope (n = 8) or a colonoscope (n = 1). In 46/69 cases (66.7%), the RFB was removed in the operation theater under general anesthesia with muscle relaxation. Among these, 11/46 patients (23.9%) underwent abdominal surgery, either for manual extraction of the RFB (n = 9) or to exclude a bowel perforation (n = 2). Surgical complications occurred in 3/11 patients. One patient with rectal perforation developed pelvic sepsis and underwent abdominoperineal extirpation in the further clinical course. CONCLUSION: The management of RFBs can be challenging and includes a wide range of options from removal without further intervention to abdominoperineal extirpation in cases of pelvic sepsis. Whenever possible, RFBs should obligatorily be managed in specialized colorectal centers following a clear treatment algorithm.

[Endovascular aortic repair: the hostile aneurysm neck : Morphologic definition, impact on long-term outcome, and treatment options]. / Endovaskuläre Versorgung: der komplizierte Aneurysmahals : Morphologische Definition, Auswirkungen auf das Langzeitergebnis und Therapieoptionen.

DEFINITION: A hostile neck is defined by various anatomical conditions that describe a morphology of the proximal aneurysmal neck of infrarenal aortic aneurysms that is unfavorable for endovascular treatment (endovascular aortic repair, EVAR): proximal landing zone length ≤ 15 mm, angulation of the aortic neck > 60°, conical aortic neck, diameter of the aortic neck > 32 mm, and circumferential calcification/thrombus. EFFECTS ON OUTCOME: These morphological parameters are not only associated with a higher perioperative technical failure rate (primary type 1 endoleak) but also with poorer long-term results (secondary type 1 endoleak) and thus a higher reintervention rate in standard EVAR, so that standard EVAR should be reserved for a few exceptions in these cases. TREATMENT OPTIONS: Due to the rapid development of endovascular techniques in the last decade, we now have a variety of endovascular options for aneurysms with hostile necks, for both elective treatment and emergency care, in addition to conventional open surgery, which is still the standard method in many cases and is currently undergoing a renaissance: fenestrated endovascular aortic repair (FEVAR) as the method of first choice in the elective setting, EVAR with chimneys (ChEVAR), endosuture aneurysm repair (ESAR). An important option is the conservative approach, which can be a reasonable choice if the patient's preference is taken into account and a careful risk-benefit assessment is performed.

First Study on Nihonium (Nh, Element 113) Chemistry at TASCA.

Nihonium (Nh, element 113) and flerovium (Fl, element 114) are the first superheavy elements in which the 7p shell is occupied. High volatility and inertness were predicted for Fl due to the strong relativistic stabilization of the closed 7p 1/2 sub-shell, which originates from a large spin-orbit splitting between the 7p 1/2 and 7p 3/2 orbitals. One unpaired electron in the outermost 7p 1/2 sub-shell in Nh is expected to give rise to a higher chemical reactivity. Theoretical predictions of Nh reactivity are discussed, along with results of the first experimental attempts to study Nh chemistry in the gas phase. The experimental observations verify a higher chemical reactivity of Nh atoms compared to its neighbor Fl and call for the development of advanced setups. First tests of a newly developed detection device miniCOMPACT with highly reactive Fr isotopes assure that effective chemical studies of Nh are within reach.

Heterogeneity of neurons reprogrammed from spinal cord astrocytes by the proneural factors Ascl1 and Neurogenin2.

Astrocytes are a viable source for generating new neurons via direct conversion. However, little is known about the neurogenic cascades triggered in astrocytes from different regions of the CNS. Here, we examine the transcriptome induced by the proneural factors Ascl1 and Neurog2 in spinal cord-derived astrocytes in vitro. Each factor initially elicits different neurogenic programs that later converge to a V2 interneuron-like state. Intriguingly, patch sequencing (patch-seq) shows no overall correlation between functional properties and the transcriptome of the heterogenous induced neurons, except for K-channels. For example, some neurons with fully mature electrophysiological properties still express astrocyte genes, thus calling for careful molecular and functional analysis. Comparing the transcriptomes of spinal cord- and cerebral-cortex-derived astrocytes reveals profound differences, including developmental patterning cues maintained in vitro. These relate to the distinct neuronal identity elicited by Ascl1 and Neurog2 reflecting their developmental functions in subtype specification of the respective CNS region.

Taxonomy and phylogeny of the Erysiphe lonicerae complex (Helotiales, Erysiphaceae) on Lonicera spp.

The phylogeny and taxonomy of powdery mildews, belonging to the genus Erysiphe, on Lonicera species throughout the world are examined and discussed. Phylogenetic analyses revealed that sequences retrieved from Erysiphe lonicerae, a widespread powdery mildew species distributed in the Northern Hemisphere on a wide range of Lonicera spp., constitutes a complex of two separate species, viz., E. lonicerae (s. str.) and Erysiphe ehrenbergii comb. nov. Erysiphe lonicerae occurs on Lonicera spp. belonging to Lonicera subgen. Lonicera (= subgen. Caprifolium and subgen. Periclymenum), as well as L. japonica. Erysiphe ehrenbergii comb. nov. occurs on Lonicera spp. of Lonicera subgen. Chamaecerasus. Phylogenetic and morphological analyses have also revealed that Microsphaera caprifoliacearum (≡ Erysiphe caprifoliacearum) should be reduced to synonymy with E. lonicerae (s. str.). Additionally, Erysiphe lonicerina sp. nov. on Lonicera japonica in Japan is described and the new name Erysiphe flexibilis, based on Microsphaera lonicerae var. flexuosa, is introduced. The phylogeny of Erysiphe ehrenbergii and E. lonicerae as well as other Erysiphe species on honeysuckle is discussed, and a survey of all species, including a key to the species concerned, is provided. Citation: Bradshaw M, Braun U, Götz M, Takamatsu S (2020). Taxonomy and phylogeny of the Erysiphe lonicerae complex (Helotiales, Erysiphaceae) on Lonicera spp. Fungal Systematics and Evolution 7: 49-65. doi: 10.3114/fuse.2021.07.03.

Percutaneous Irreversible Electroporation for Treatment of Small Hepatocellular Carcinoma Invisible on Unenhanced CT: A Novel Combined Strategy with Prior Transarterial Tumor Marking.

INTRODUCTION: To explore the feasibility, safety, and efficiency of ethiodized oil tumor marking combined with irreversible electroporation (IRE) for small hepatocellular carcinomas (HCCs) that were invisible on unenhanced computed tomography (CT). METHODS: A retrospective analysis of the institutional database was performed from January 2018 to September 2018. Patients undergoing ethiodized oil tumor marking to improve target-HCC visualization in subsequent CT-guided IRE were retrieved. Target-HCC visualization after marking was assessed, and the signal-to-noise ratios (SNRs) and contrast-to-noise ratios (CNR) were compared between pre-marking and post-marking CT images using the paired t-test. Standard IRE reports, adverse events, therapeutic endpoints, and survival were summarized and assessed. RESULTS: Nine patients with 11 target-HCCs (11.1-18.8 mm) were included. After marking, all target-HCCs demonstrated complete visualization in post-marking CT, which were invisible in pre-marking CT. Quantitatively, the SNR of the target-HCCs significantly increased after marking (11.07 ± 4.23 vs. 3.36 ± 1.79, p = 0.006), as did the CNR (4.32 ± 3.31 vs. 0.43 ± 0.28, p = 0.023). In sequential IRE procedures, the average current was 30.1 ± 5.3 A, and both the delta ampere and percentage were positive with the mean values of 5.8 ± 2.1 A and 23.8 ± 6.3%, respectively. All procedures were technically successful without any adverse events. In the follow-up, no residual unablated tumor (endpoint-1) was observed. The half-year, one-year, and two-year local tumor progression (endpoint-2) rate was 0%, 9.1%, and 27.3%. The two-year overall survival rate was 100%. CONCLUSIONS: Ethiodized oil tumor marking enables to demarcate small HCCs that were invisible on unenhanced CT. It potentially allows a safe and complete ablation in subsequent CT-guided IRE.

Spectroscopy along Flerovium Decay Chains: Discovery of

A nuclear spectroscopy experiment was conducted to study α-decay chains stemming from isotopes of flerovium (element Z=114). An upgraded TASISpec decay station was placed behind the gas-filled separator TASCA at the GSI Helmholtzzentrum für Schwerionenforschung in Darmstadt, Germany. The fusion-evaporation reactions ^{48}Ca+^{242}Pu and ^{48}Ca+^{244}Pu provided a total of 32 flerovium-candidate decay chains, of which two and eleven were firmly assigned to ^{286}Fl and ^{288}Fl, respectively. A prompt coincidence between a 9.60(1)-MeV α particle event and a 0.36(1)-MeV conversion electron marked the first observation of an excited state in an even-even isotope of the heaviest man-made elements, namely ^{282}Cn. Spectroscopy of ^{288}Fl decay chains fixed Q_{α}=10.06(1) MeV. In one case, a Q_{α}=9.46(1)-MeV decay from ^{284}Cn into ^{280}Ds was observed, with ^{280}Ds fissioning after only 518 µs. The impact of these findings, aggregated with existing data on decay chains of ^{286,288}Fl, on the size of an anticipated shell gap at proton number Z=114 is discussed in light of predictions from two beyond-mean-field calculations, which take into account triaxial deformation.

Combined experimental drought and nitrogen loading: the role of species-dependent leaf level control of carbon and water exchange in a temperate grassland.

Nitrogen (N) loading and extreme drought strongly alter biomass production, species composition and carbon and water fluxes of temperate grasslands. Such changes at the community level are often attributed to species- and functional group-specific responses in phenology and/or physiology. In a multifactorial field experiment, we studied the responses of three abundant grassland species (forb Centaurea jacea, grasses Arrhenatherum elatius and Dactylis glomerata) to N loading and extreme drought, focusing on responses of carbon and water relations at the leaf level. We analysed (1) changes in bulk leaf N (uptake efficiency of additional N), (2) adaptation of plant water status (leaf water potential) and (3) impact on leaf carbon and water fluxes. We observed more efficient N utilization in the two grasses compared to C. jacea. Naturally occurring summer drought significantly impacted the plant water status of all species, while extreme drought treatment only further affected water status during and after summer drought. C. jacea was able to maintain much lower leaf water potentials compared to the grasses during drought. Despite these clear species-specific responses to N loading and drought, the species were able to maintain homeostasis of leaf carbon and water fluxes. Thus, strong declines in the (community) carbon sequestration observed at this site during the (natural) summer drought were not related to leaf physiological responses in assimilation, but were driven by phenological adaptions of the species community: the drought-sensitive grasses, even though exhibiting higher N uptake efficiency, responded with a shortened life cycle to severe summer drought.

Preoperative versus pathological staging of rectal cancer-challenging the indication of neoadjuvant chemoradiotherapy.

BACKGROUND: Neoadjuvant chemoradiotherapy (CRT) followed by surgery is recommended for patients with diagnosed rectal cancer UICC stage II/III. The present study aimed to evaluate the accuracy of preoperative staging with focus on tumor infiltration depth and lymph node status challenging the indication of neoadjuvant CRT. METHOD: All consecutive rectal cancer patients who underwent surgical resection without neoadjuvant CRT at the Klinikum Stuttgart, Germany, between January 2015 and December 2018, were included into the study. Clinicopathologic features focusing on preoperative tumor staging and histological outcome were assessed. RESULTS: A total of 100/162 patients (61.7%) underwent primary surgical rectal resection with curative intent. Among these patients, 54/100 had a correct preoperative T-staging, while 34 were overstaged and 12 understaged. With regard to the nodal status, 68 were accurately staged, while 28 were overstaged and 4 understaged. Only 4/40 perirectal lymph nodes of more than 5 mm in diameter in preoperative MRI histologically revealed to be metastasis. CONCLUSION: For patients without neoadjuvant CRT, a tendency to preoperative overstaging was observed. Lymph node size alone did not reliably predict metastasis. According to current guidelines, 21/62 (33.9%) of these patients would have been overtreated by using CRT. On the background of relevant side effects, complications, and the limited benefit of CRT on overall survival, we suggest that primary surgical resection should be recommended more liberally for stages II and III rectal cancer.

Search for Electron-Capture Delayed Fission in the New Isotope

The electron-capture decay followed by a prompt fission process was searched for in the hitherto unknown most neutron-deficient Md isotope with mass number 244. Alpha decay with α-particle energies of 8.73-8.86 MeV and with a half-life of 0.30_{-0.09}^{+0.19} s was assigned to ^{244}Md. No fission event with a similar half-life potentially originating from spontaneous fissioning of the short-lived electron-capture decay daughter ^{244}Fm was observed, which results in an upper limit of 0.14 for the electron-capture branching of ^{244}Md. Two groups of fission events with half-lives of 0.9_{-0.3}^{+0.6} ms and 5_{-2}^{+3} ms were observed. The 0.9_{-0.3}^{+0.6} ms activity was assigned to originate from the decay of ^{245}Md. The origin of eight fission events resulting in a half-life of 5_{-2}^{+3} ms could not be unambiguously identified within the present data while the possible explanation has to invoke previously unseen physics cases.

State-of-the-Art Imaging of the Aorta with Respect to Endoluminal Intervention.

Acute aortic syndrome, aortic aneurysm and stenotic aortic disease are significant challenges for state-of-the art imaging of the aorta. Over the last decade, advanced imaging methods such as multidetector computed tomography, high-resolution ultrasound including color-coded Doppler and contrast-enhanced B-mode imaging and magnetic resonance imaging have assumed an important role in identifying and describing many of the complex aortic pathologies. They play a fundamental role in decision making for treatment such as endovascular, or open surgical or conservative treatment. In this overview, a systematic description of all present imaging modalities is presented and their respective roles for the entire spectrum of aortic diseases are illustrated and defined in their relevance. Furthermore, future aspects such as virtual reality methods are presented.

In Vitro Characterization of a Novel Type of Radiopaque Doxorubicin-Loaded Microsphere.

PURPOSE: To evaluate and compare the material characteristics of a novel type of radiopaque doxorubicin-loaded microsphere (V-100) with radiopaque and non-radiopaque doxorubicin-loaded microspheres. MATERIALS AND METHODS: The prototype V-100 featuring inherent radiopacity and three available commercial controls (DC-Bead-LUMI™-70-150, Embozene-Tandem™-100 and DC-Bead™-M1) were analyzed before and after doxorubicin loading (37.5 mg doxorubicin/1 ml microspheres) in suspension with aqua and/or aqua/iodixanol-320. Study goals included inherent radiopacity [e.g., using conventional computed tomography (CT)], doxorubicin loading efficacy, morphology using light and fluorescence microscopy, size distribution using laser diffraction/light scattering, time-in-suspension, rheological properties using rheometer analysis, and microsphere stability observed over a period of 5 days after doxorubicin loading. RESULTS: V-100 showed good inherent radiopacity without adverse imaging artifacts. Under conventional CT, the quantitative radiopacity was as follows: 480.4 ± 2.9HU for V-100, 2432.7 ± 3.2HU for DC-Bead-LUMI™-70-150, 118.1 ± 3.0HU for Embozene-Tandem™-100, and 19.8 ± 1.5HU for DC-Bead™-M1. All of the types of microspheres showed a similar loading efficiency (> 98%) after 24 h; however, there were slower doxorubicin loading velocities for the radiopaque microspheres. The doxorubicin-loaded V-100 and Embozene-Tandem™-100 showed typical narrow-sized distributions. In aqua/iodixanol-320 suspension, doxorubicin-loaded V-100 showed the best suspension features and ideal deformability and elasticity characteristics. Similar to other microspheres, doxorubicin-loaded V-100 was very stable and storable for at least 5 days. CONCLUSION: V-100 is a promising novel type of radiopaque doxorubicin-loaded microsphere. Compared with the controls, V-100 shows good inherent radiopacity without adverse imaging artifacts and with comparable doxorubicin loading efficacy. Further advantages of V-100 include narrow-sized distribution and excellent suspension, rheology, and stability features.