Outcome of atypical haemolytic uraemic syndrome relapse after eculizumab withdrawal

Background. The introduction of eculizumab has significantly improved the outcome of patients with atypical haemolytic uraemic syndrome (aHUS). Because of the risk of relapse after discontinuation, eculizumab was proposed as life-long therapy. However, data on the outcome of relapse are limited. In the Netherlands, patients with aHUS are treated with a restrictive eculizumab regime and are included in a national observational study (CUREiHUS, Dutch Trial Register NTR5988/NL5833). Methods. For this interim safety analysis, we evaluated the outcome of all adult patients with a suspected relapse, defined as the need to intensify eculizumab after tapering or withdrawal of therapy. Results. We describe 11 patients who received renewed eculizumab therapy because of suspected relapse. In three patients with aHUS in native kidneys, estimated glomerular filtration rate (eGFR) returned to baseline value and remained stable without overt proteinuria after follow-up. Six out of eight transplanted patients responded to eculizumab therapy with improvement in eGFR. After a median follow-up of 24.6 months, a reduction of eGFR >= 25% was observed in three of these transplanted patients, which was attributed to the aHUS relapse in only one patient. Conclusions. This interim analysis suggests that re-treatment with eculizumab after relapse is safe and feasible. We will continue to use our restrictive treatment strategy

The clonal relation of primary upper urinary tract urothelial carcinoma and paired urothelial carcinoma of the bladder

The risk of developing urothelial carcinoma of the bladder (UCB) in patients treated by radical nephroureterectomy (RNU) for an upper urinary tract urothelial carcinoma (UTUC) is 22% to 47% in the 2 years after surgery. Subject of debate remains whether UTUC and the subsequent UCB are clonally related or represent separate origins. To investigate the clonal relationship between both entities, we performed targeted DNA sequencing of a panel of 41 genes on matched normal and tumor tissue of 15 primary UTUC patients treated by RNU who later developed 19 UCBs. Based on the detected tumor-specific DNA aberrations, the paired UTUC and UCB(s) of 11 patients (73.3%) showed a clonal relation, whereas in four patients the molecular results did not indicate a clear clonal relationship. Our results support the hypothesis that UCBs following a primary surgically resected UTUC are predominantly clonally derived recurrences and not separate entities

SUGAR-DIP trial: Oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial

Introduction In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. Methods The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. Ethics and dissemination The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals

Estimating the global conservation status of more than 15,000 Amazonian tree species

Estimates of extinction risk for Amazonian plant and animal species are rare and not often incorporated into land-use policy and conservation planning. We overlay spatial distribution models with historical and projected deforestation to show that at least 36% and up to 57% of all Amazonian tree species are likely to qualify as globally threatened under International Union for Conservation of Nature (IUCN) Red List criteria. If confirmed, these results would increase the number of threatened plant species on Earth by 22%. We show that the trends observed in Amazonia apply to trees throughout the tropics, and we predict thatmost of the world’s >40,000 tropical tree species now qualify as globally threatened. A gap analysis suggests that existing Amazonian protected areas and indigenous territories will protect viable populations of most threatened species if these areas suffer no further degradation, highlighting the key roles that protected areas, indigenous peoples, and improved governance can play in preventing large-scale extinctions in the tropics in this century

Geographic patterns of tree dispersal modes in Amazonia and their ecological correlates

Aim: To investigate the geographic patterns and ecological correlates in the geographic distribution of the most common tree dispersal modes in Amazonia (endozoochory, synzoochory, anemochory and hydrochory). We examined if the proportional abundance of these dispersal modes could be explained by the availability of dispersal agents (disperser-availability hypothesis) and/or the availability of resources for constructing zoochorous fruits (resource-availability hypothesis). Time period: Tree-inventory plots established between 1934 and 2019. Major taxa studied: Trees with a diameter at breast height (DBH) ≥ 9.55 cm. Location: Amazonia, here defined as the lowland rain forests of the Amazon River basin and the Guiana Shield. Methods: We assigned dispersal modes to a total of 5433 species and morphospecies within 1877 tree-inventory plots across terra-firme, seasonally flooded, and permanently flooded forests. We investigated geographic patterns in the proportional abundance of dispersal modes. We performed an abundance-weighted mean pairwise distance (MPD) test and fit generalized linear models (GLMs) to explain the geographic distribution of dispersal modes. Results: Anemochory was significantly, positively associated with mean annual wind speed, and hydrochory was significantly higher in flooded forests. Dispersal modes did not consistently show significant associations with the availability of resources for constructing zoochorous fruits. A lower dissimilarity in dispersal modes, resulting from a higher dominance of endozoochory, occurred in terra-firme forests (excluding podzols) compared to flooded forests. Main conclusions: The disperser-availability hypothesis was well supported for abiotic dispersal modes (anemochory and hydrochory). The availability of resources for constructing zoochorous fruits seems an unlikely explanation for the distribution of dispersal modes in Amazonia. The association between frugivores and the proportional abundance of zoochory requires further research, as tree recruitment not only depends on dispersal vectors but also on conditions that favour or limit seedling recruitment across forest types

Geography and ecology shape the phylogenetic composition of Amazonian tree communities

AimAmazonia hosts more tree species from numerous evolutionary lineages, both young and ancient, than any other biogeographic region. Previous studies have shown that tree lineages colonized multiple edaphic environments and dispersed widely across Amazonia, leading to a hypothesis, which we test, that lineages should not be strongly associated with either geographic regions or edaphic forest types.LocationAmazonia.TaxonAngiosperms (Magnoliids; Monocots; Eudicots).MethodsData for the abundance of 5082 tree species in 1989 plots were combined with a mega-phylogeny. We applied evolutionary ordination to assess how phylogenetic composition varies across Amazonia. We used variation partitioning and Moran's eigenvector maps (MEM) to test and quantify the separate and joint contributions of spatial and environmental variables to explain the phylogenetic composition of plots. We tested the indicator value of lineages for geographic regions and edaphic forest types and mapped associations onto the phylogeny.ResultsIn the terra firme and várzea forest types, the phylogenetic composition varies by geographic region, but the igapó and white-sand forest types retain a unique evolutionary signature regardless of region. Overall, we find that soil chemistry, climate and topography explain 24% of the variation in phylogenetic composition, with 79% of that variation being spatially structured (R2 = 19% overall for combined spatial/environmental effects). The phylogenetic composition also shows substantial spatial patterns not related to the environmental variables we quantified (R2 = 28%). A greater number of lineages were significant indicators of geographic regions than forest types.Main ConclusionNumerous tree lineages, including some ancient ones (>66 Ma), show strong associations with geographic regions and edaphic forest types of Amazonia. This shows that specialization in specific edaphic environments has played a long-standing role in the evolutionary assembly of Amazonian forests. Furthermore, many lineages, even those that have dispersed across Amazonia, dominate within a specific region, likely because of phylogenetically conserved niches for environmental conditions that are prevalent within regions

Geography and ecology shape the phylogenetic composition of Amazonian tree communities

Aim: Amazonia hosts more tree species from numerous evolutionary lineages, both young and ancient, than any other biogeographic region. Previous studies have shown that tree lineages colonized multiple edaphic environments and dispersed widely across Amazonia, leading to a hypothesis, which we test, that lineages should not be strongly associated with either geographic regions or edaphic forest types. Location: Amazonia. Taxon: Angiosperms (Magnoliids; Monocots; Eudicots). Methods: Data for the abundance of 5082 tree species in 1989 plots were combined with a mega-phylogeny. We applied evolutionary ordination to assess how phylogenetic composition varies across Amazonia. We used variation partitioning and Moran\u27s eigenvector maps (MEM) to test and quantify the separate and joint contributions of spatial and environmental variables to explain the phylogenetic composition of plots. We tested the indicator value of lineages for geographic regions and edaphic forest types and mapped associations onto the phylogeny. Results: In the terra firme and várzea forest types, the phylogenetic composition varies by geographic region, but the igapó and white-sand forest types retain a unique evolutionary signature regardless of region. Overall, we find that soil chemistry, climate and topography explain 24% of the variation in phylogenetic composition, with 79% of that variation being spatially structured (R$^{2}$ = 19% overall for combined spatial/environmental effects). The phylogenetic composition also shows substantial spatial patterns not related to the environmental variables we quantified (R$^{2}$ = 28%). A greater number of lineages were significant indicators of geographic regions than forest types. Main Conclusion: Numerous tree lineages, including some ancient ones (>66 Ma), show strong associations with geographic regions and edaphic forest types of Amazonia. This shows that specialization in specific edaphic environments has played a long-standing role in the evolutionary assembly of Amazonian forests. Furthermore, many lineages, even those that have dispersed across Amazonia, dominate within a specific region, likely because of phylogenetically conserved niches for environmental conditions that are prevalent within regions

Consistent patterns of common species across tropical tree communities

Trees structure the Earth’s most biodiverse ecosystem, tropical forests. The vast number of tree species presents a formidable challenge to understanding these forests, including their response to environmental change, as very little is known about most tropical tree species. A focus on the common species may circumvent this challenge. Here we investigate abundance patterns of common tree species using inventory data on 1,003,805 trees with trunk diameters of at least 10 cm across 1,568 locations1,2,3,4,5,6 in closed-canopy, structurally intact old-growth tropical forests in Africa, Amazonia and Southeast Asia. We estimate that 2.2%, 2.2% and 2.3% of species comprise 50% of the tropical trees in these regions, respectively. Extrapolating across all closed-canopy tropical forests, we estimate that just 1,053 species comprise half of Earth’s 800 billion tropical trees with trunk diameters of at least 10 cm. Despite differing biogeographic, climatic and anthropogenic histories7, we find notably consistent patterns of common species and species abundance distributions across the continents. This suggests that fundamental mechanisms of tree community assembly may apply to all tropical forests. Resampling analyses show that the most common species are likely to belong to a manageable list of known species, enabling targeted efforts to understand their ecology. Although they do not detract from the importance of rare species, our results open new opportunities to understand the world’s most diverse forests, including modelling their response to environmental change, by focusing on the common species that constitute the majority of their trees.Publisher PDFPeer reviewe

Mapping density, diversity and species-richness of the Amazon tree flora

Using 2.046 botanically-inventoried tree plots across the largest tropical forest on Earth, we mapped tree species-diversity and tree species-richness at 0.1-degree resolution, and investigated drivers for diversity and richness. Using only location, stratified by forest type, as predictor, our spatial model, to the best of our knowledge, provides the most accurate map of tree diversity in Amazonia to date, explaining approximately 70% of the tree diversity and species-richness. Large soil-forest combinations determine a significant percentage of the variation in tree species-richness and tree alpha-diversity in Amazonian forest-plots. We suggest that the size and fragmentation of these systems drive their large-scale diversity patterns and hence local diversity. A model not using location but cumulative water deficit, tree density, and temperature seasonality explains 47% of the tree species-richness in the terra-firme forest in Amazonia. Over large areas across Amazonia, residuals of this relationship are small and poorly spatially structured, suggesting that much of the residual variation may be local. The Guyana Shield area has consistently negative residuals, showing that this area has lower tree species-richness than expected by our models. We provide extensive plot meta-data, including tree density, tree alpha-diversity and tree species-richness results and gridded maps at 0.1-degree resolution