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Background: Simultaneous pancreas kidney transplantation (SPK), pancreas transplantation alone (PTA) or pancreas transplantation after kidney (PAK) are the only curative treatment options for patients with type 1 (juvenile) diabetes mellitus with or without impaired renal function. Unfortunately, transplant waiting lists for this indication are increasing because the current organ acceptability criteria are restrictive; morbidity and mortality significantly increase with time on the waitlist. Currently, only pancreas organs from donors younger than 50 years of age and with a body mass index (BMI) less than 30 are allocated for transplantation in the Eurotransplant (ET) area. To address this issue we designed a study to increase the available donor pool for these patients.
Methods/Design: This study is a prospective, multicenter (20 German centers), single blinded, non-randomized, two armed trial comparing outcome after SPK, PTA or PAK between organs with the currently allowed donor criteria versus selected organs from donors with extended criteria. Extended donor criteria are defined as organs procured from donors with a BMI of 30 to 34 or a donor age between 50 and 60 years. Immunosuppression is generally standardized using induction therapy with Myfortic, tacrolimus and low dose steroids. In principle, all patients on the waitlist for primary SPK, PTA or PAK are eligible for the clinical trial when they consent to possibly receiving an extended donor criteria organ. Patients receiving an organ meeting the current standard criteria for pancreas allocation (control arm) are compared to those receiving extended criteria organ (study arm); patients are blinded for a follow-up period of one year. The combined primary endpoint is survival of the pancreas allograft and pancreas allograft function after three months, as an early relevant outcome parameter for pancreas transplantation.
Discussion: The EXPAND Study has been initiated to investigate the hypothesis that locally allocated extended criteria organs can be transplanted with similar results compared to the currently allowed standard ET organ allocation. If our study shows a favorable comparison to standard organ allocation criteria, the morbidity and mortality for patients waiting for transplantation could be reduced in the future.
Trial registered at: NCT01384006
Molecular analysis of the ribosome recycling factor ABCE1 bound to the 30S post-splitting complex
(2020)
Ribosome recycling by the twin-ATPase ABCE1 is a key regulatory process in mRNA translation and surveillance and in ribosome-associated protein quality control in Eukarya and Archaea. Here, we captured the archaeal 30S ribosome post-splitting complex at 2.8 Å resolution by cryo-electron microscopy. The structure reveals the dynamic behavior of structural motifs unique to ABCE1, which ultimately leads to ribosome splitting. More specifically, we provide molecular details on how conformational rearrangements of the iron–sulfur cluster domain and hinge regions of ABCE1 are linked to closure of its nucleotide-binding sites. The combination of mutational and functional analyses uncovers an intricate allosteric network between the ribosome, regulatory domains of ABCE1, and its two structurally and functionally asymmetric ATP-binding sites. Based on these data, we propose a refined model of how signals from the ribosome are integrated into the ATPase cycle of ABCE1 to orchestrate ribosome recycling.
Introduction: Prophylaxis with factor VIII (FVIII) concentrates in children with haemophilia A (HA) is current standard of care. The benefit of prophylactic treatment for adult HA patients is not commonly accepted.
Aim: To investigate the benefit of prophylaxis over on‐demand treatment in adult and elderly patients with severe or non‐severe HA in a real‐life setting.
Methods: Data from 163 patients comprising 1202 patient‐years were evaluated for 7.5 (±5.3) years. The effects on the annual bleeding rate (ABR, including spontaneous and traumatic bleeds) of treatment with a plasma‐derived FVIII concentrate, the patient's age and disease severity were investigated. The effect of changing the treatment from on demand to continuous prophylaxis on the patients’ ABRs was further analysed.
Results: Prophylaxis had the greatest effect on the ABRs of patients of any age with severe or non‐severe HA. The difference in ABR of all patients treated on demand (median 31.4; interquartile range (IQR) 27.6; N = 83) compared with those treated prophylactically (median 1.3; IQR 3.6; N = 122) was statistically significant (P < .05), even for patients with non‐severe HA (median 8.4; IQR 15.5; N = 11) vs median 1.5; IQR 4.2 (N = 17), P < .05). Patients, aged up to 88 years, switching from on demand to continuous prophylaxis showed the lowest median ABR (1.1; N = 51) after their regimen change.
Conclusion: Any (even low‐frequency) prophylaxis results in lower ABR than on‐demand treatment. Patients switching to prophylaxis benefitted the most, irrespective of age or HA severity. Prophylactic treatment—even tertiary—is the regimen of choice for patients of any age, including elderly patients, with severe or non‐severe HA.
Background: Available data on the incidence and outcome of invasive fungal diseases (IFD) in children with hematological malignancies or after allogeneic hematopoietic stem cell transplantation (HSCT) are mostly based on monocenter, retrospective studies or on studies performed prior to the availability of newer triazoles or echinocandins.
Procedure: We prospectively collected clinical data on incidence, diagnostic procedures, management and outcome of IFD in children treated for hematological malignancies or undergoing HSCT in three major European pediatric cancer centers.
Results: A total of 304 children (median age 6.0 years) who underwent 360 therapies (211 chemotherapy treatments, 138 allogeneic HSCTs and/or 11 investigational chemotherapeutic treatments) were included in the analysis. Nineteen children developed proven/probable IFD, mostly due to Aspergillus (n = 10) and Candida spp. (n = 5), respectively. In patients receiving chemotherapy, 11 IFDs occurred, all during induction or re-induction therapy. None of these patients died due to IFD, whereas IFD was lethal in 3 of the 8 HSCT recipients with IFD. Significant differences among centers were observed with regard to the use of imaging diagnostics and the choice, initiation and duration of antifungal prophylaxis.
Conclusion: This prospective multicenter study provides information on the current incidence and outcome of IFD in the real life setting. Practice variation between the centers may help to ultimately improve antifungal management in children at highest risk for IFDs.
We present the data of the 2nd research expedition of the European Dry Grassland Group (EDGG), which was conducted in 2010 in Central Podolia, Ukraine. The aim was to collect plot data to compare Ukrainian dry grasslands with those of other parts of Europe in terms of syntaxonomy and biodiversity. We sampled 21 nested-plot series (0.0001–100 m2) and 184 normal plots (10 m2) covering the full variety of dry grassland types occurring in the study region. For all plots, we recorded species composi-tion of terrestrial vascular plants, bryophytes and lichens, while for the 226 10-m2 plots we estimated and measured percentage cover of all species, structural, topographic, soil and landuse parameters. The 10-m² plots were used for phytosociological classification based on iteratively refined TWINSPAN classification as well as for DCA ordination. Differences between the derived vegetation types with respect to environmental conditions and species richness were assessed with ANOVAs. We assigned our plots to nine association-level units but refrained from placing them into formal associations with two exceptions. In the study area, dry grasslands of the Festuco-Brometea were far more common than those of the Koelerio-Corynephoretea. Among the Festuco-Brometea, xeric Festucetalia valesiacae grasslands were more frequent and represented by the Festucion valesiacae (2 associations, including the Allio taurici-Dichanthietum ischaemi ass. nova) and the Stipion lessingianae (1) compared to the Brachypodietalia pinnati with the Agrostio vinealis-Avenulion schellianae (3). The Koelerio-Corynephoretea were represented by three associations, each from a different order and alliance: basiphilous outcrops (Alysso alyssoidis-Sedetalia: Alysso alyssoidis-Sedion?), acidophilous outcrops (Sedo-Scleranthetalia: Veronico dillenii-Sedion albi?) and mesoxeric sandy grasslands (Trifolio arvensis-Festucetalia ovinae: Agrostion vinealis). We discuss the issue of the mesoxeric order Galietalia veri placed within the Molinio-Arrhenatheretea by Ukrainian authors and conclude that the content of that order would probably be better placed in the mesoxeric orders of the Koelerio-Corynephoretea and Festuco-Brometea. Other syntaxonomic questions could not be solved with our geographically limited dataset and await a supraregional analysis, e.g. whether the Ukrainian outcrop communities should be assigned to the same alliances as known from Central Europe or rather represent new vicariant units. The analysis of the biodiversity patterns showed that at a grain size of 10 m2, Podolian Koelerio-Corynephoretea communities were overall richer than Festuco-Brometea communities (46.4 vs. 40.6 species). This difference was due to the Koelerio-Corynephoretea containing twice as many bryophytes and nine times more lichens, while vascular plant species richness did not differ significantly between classes. The orders within the classes showed no real differences in species richness. The richness patterns observed in Podolia were almost the opposite of those usually found in dry grasslands, where Brachypodietalia pinnati are richer than Festucetalia valesiacae, and these richer than stands of the Koelerio-Corynpehoretea – and we do not have a good explanation for these idiosyncrasies. In conclusion, Podolian dry grasslands behave quite unexpectedly regarding biodiversity, and their syntaxonomy is still poorly understood. These knowledge gaps can only be addressed with supranational analyses based on comprehensive datasets.
Acute kidney injury is associated with mortality in COVID-19 patients. However, host cell changes underlying infection of renal cells with SARS-CoV-2 remain unknown and prevent understanding of the molecular mechanisms that may contribute to renal pathology. Here, we carried out quantitative translatome and whole-cell proteomics analyses of primary renal proximal and distal tubular epithelial cells derived from human donors infected with SARS-CoV-2 or MERS-CoV to disseminate virus and cell type–specific changes over time. Our findings revealed shared pathways modified upon infection with both viruses, as well as SARS-CoV-2-specific host cell modulation driving key changes in innate immune activation and cellular protein quality control. Notably, MERS-CoV infection–induced specific changes in mitochondrial biology that were not observed in response to SARS-CoV-2 infection. Furthermore, we identified extensive modulation in pathways associated with kidney failure that changed in a virus- and cell type–specific manner. In summary, we provide an overview of the effects of SARS-CoV-2 or MERS-CoV infection on primary renal epithelial cells revealing key pathways that may be essential for viral replication.
Objective: Biologics have an important role in the treatment of juvenile idiopathic arthritis (JIA). Long‐term safety data are limited. Direct comparison of different agents regarding occurrence of adverse events (AEs), especially of rare events, requires large quantities of patient years. In this analysis, long‐term safety with regard to AE of special interest (AESI) was compared between different biologics.
Methods: Patients with nonsystemic JIA were selected from the German BIKER registry. Safety assessments were based on AE reports. Number of AEs, serious AEs, and 25 predefined AESIs, including medically important infection, uveitis, inflammatory bowel disease, cytopenia, hepatic events, anaphylaxis, depression, pregnancy, malignancy, and death, were analyzed. Event rates and relative risks were calculated using AEs reported after first dose through 70 days after last dose.
Results: A total of 3873 patients entered the analysis with 7467 years of exposure to biologics. The most common AESIs were uveitis (n = 231) and medically important infections (n = 101). Cytopenia and elevation of transaminases were more frequent with tocilizumab (risk ratio [RR] 8.0, 95% confidence interval [CI] 4.2‐15, and RR 4.7, 95% CI 1.8‐12.2, respectively). Anaphylactic events were associated with intravenous route of administration. In patients ever exposed to biologics, eight malignancies were reported. Six pregnancies have been documented in patients with tumor necrosis factor inhibitors. No death occurred in this patient cohort during observation.
Conclusion: Surveillance of pharmacotherapy as provided by the BIKER registry is an import approach, especially for long‐term treatment of children. Overall, tolerance was acceptable. Differences between biologics were noted and should be considered in daily patient care.
Ribosome recycling orchestrated by the ATP binding cassette (ABC) protein ABCE1 can be considered as the final—or the first—step within the cyclic process of protein synthesis, connecting translation termination and mRNA surveillance with re-initiation. An ATP-dependent tweezer-like motion of the nucleotide-binding domains in ABCE1 transfers mechanical energy to the ribosome and tears the ribosome subunits apart. The post-recycling complex (PRC) then re-initiates mRNA translation. Here, we probed the so far unknown architecture of the 1-MDa PRC (40S/30S·ABCE1) by chemical cross-linking and mass spectrometry (XL-MS). Our study reveals ABCE1 bound to the translational factor-binding (GTPase) site with multiple cross-link contacts of the helix–loop–helix motif to the S24e ribosomal protein. Cross-linking of the FeS cluster domain to the ribosomal protein S12 substantiates an extreme lever-arm movement of the FeS cluster domain during ribosome recycling. We were thus able to reconstitute and structurally analyse a key complex in the translational cycle, resembling the link between translation initiation and ribosome recycling.
Reintroductions of plant species are increasingly popular in conservation practice. Steppe grasslands contain many rare and endangered plant species that are potential objects for such reintroductions. Most reintroduction projects, however, can only target a restricted number of species, which raises the question of how species should be prioritised. Here, we present a method to select priority species for reintroduction based on species' characteristics that are widely used in conservation practice. We first determined the local species pool containing those vascular plant species that occurred both in our target region (Thuringia, Germany) and target habitat (steppe grasslands), yielding 369 species. With the help of an a priori filter that selected currently endangered species with limited distribution, 136 potential target species were determined. These potential target species had experienced stronger decline, had a narrower phytosociological amplitude and were more likely to be species of the Festuco-Brometea class and the Festucetalia valesiacae order than non-target species. Potential target species were then ranked by a points system based on ten conservation-relevant characteristics of the species from the categories "threat and protection status", "distribution and decline", and "habitat affiliation". In the ranking, six steppe grassland plant species (Astragalus exscapus, Bothriochloa ischaemum, Prunella laciniata, Pulsatilla pratensis subsp. nigricans, Scorzonera purpurea, and Seseli hippomarathrum) achieved the highest scores. An additional seven species not specifically characteristic for steppe grasslands also scored highly. A post hoc evaluation of these 13 highest scoring species based on additional conservation criteria left five species (Astragalus exscapus, Linum leonii, Orchis morio, Pulsatilla pratensis subsp. nigricans and Scorzonera purpurea) as species with highest priority for reintroductions and another five species as highly suitable for reintroductions. Associations between the ranking order and different ranking criteria revealed that a species’ threat and rarity in Thuringia and its protection status had the highest representation in the ranking, followed by threat in Germany, regional decline and habitat affiliation. In contrast, international threat and responsibility of Thuringia for its conservation had only low representation in the ranking, probably because these characteristics applied to only a few species. The ranking list gives a selection of species for reintroductions, which combined with additional information based on comprehensive local and floristic knowledge, allows the identification of the species with the highest priority. Our method can be transferred to other regions or habitat types.
Heterogenous subtypes of breast cancer need to be analyzed separately. Pooling of datasets can provide reasonable sample sizes but dataset bias is an important concern. We assembled a combined dataset of 579 Affymetrix microarrays from triple negative breast cancer (TNBC) in Gene Expression Omnibus (GEO) series GSE31519. We developed a method for selecting comparable datasets and to control for the amount of dataset bias of individual probesets.