Three‐dimensional forward stratigraphic modelling of the sedimentary architecture of meandering‐river successions in evolving half‐graben rift basins

The spatial organisation of meandering‐river deposits varies greatly within the sedimentary fills of rift basins, depending on how differential rates of fault propagation and subsidence interplay with autogenic processes to drive changes in fluvial channel‐belt position and rate of migration, avulsion frequency and mechanisms of meander‐bend cut off. This set of processes fundamentally influences stacking patterns of the accumulated successions. Quantitative predictions of the spatio‐temporal evolution and internal architecture of meandering fluvial deposits in such tectonically active settings remain limited. A numerical forward stratigraphic model—the Point‐Bar Sedimentary Architecture Numerical Deduction (PB‐SAND)—is applied to examine relationships between differential rates of subsidence and resultant fluvial channel‐belt migration, reach avulsion and channel‐deposit stacking in active, fault‐bounded half‐grabens. The model is used to reconstruct and predict the complex morphodynamics of fluvial meanders, their generated channel belts, and the associated lithofacies distributions that accumulate as heterogeneous fluvial successions in rift settings, constrained by data from seismic images and outcrop successions. The 3D modelling outputs are used to explore sedimentary heterogeneity at various spatio‐temporal scales. Results show how the connectivity of sand‐prone geobodies can be quantified as a function of subsidence rate, which itself decreases both along and away from the basin‐bounding fault. In particular, results highlight the spatial variability in the size and connectedness of sand‐prone geobodies that is seen in directions perpendicular and parallel to the basin axis, and that arises as a function of the interaction between spatial and temporal variations in rates of accommodation generation and fault‐influenced changes in river morphodynamics. The results have applied significance, for example, to both hydrocarbon exploration and assessment of groundwater aquifers. The expected greatest connectivity of fluvial sandbody in a half‐graben is primarily determined by the complex interplay between the frequency and rate of subsidence, the style of basin propagation, the rates of migration of channel belts, the frequency of avulsion and the proportion and spatial distribution of variably sand‐prone channel and bar deposits

Allogeneic hematopoietic cell transplantation for multiple myeloma in Europe: trends and outcomes over 25 years. A study by the EBMT Chronic Malignancies Working Party

We describe the use and outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for multiple myeloma (MM) in Europe between January 1990 and December 2012. We identified 7333 patients, median age at allo-HSCT was 51 years (range: 18-78), of whom 4539 (62%) were males. We distinguished three groups: (1) allo-HSCT upfront (n=1924), (2) tandem auto-allo-HSCT (n=2004) and (3) allo-HSCT as a second line treatment and beyond (n=3405). Overall, there is a steady increase in numbers of allo-HSCT over the years. Upfront allo-HSCT use increased up to year 2000, followed by a decrease thereafter and represented 12% of allo-HSCTs performed in 2012. Tandem auto-allo-HSCT peaked around year 2004 and contributed to 19% of allo-HSCTs in 2012. Allo-HSCT as salvage after one or two or three autografts was steadily increasing over the last years and represented 69% of allo-HSCTs in 2012. Remarkable heterogeneity in using allo-HSCT was observed among the different European countries. The 5-year survival probabilities from time of allo-HSCT for the three groups after year 2004 were 42%, 54% and 32%, respectively. These results show that the use of allo-HSCT is increasing in Europe, especially as second line treatment and beyond. There is an unmet need for well-designed prospective studies investigating allo-HSCT as salvage therapy for MM

COVID-19 patients share common, corticosteroid-independent features of impaired host immunity to pathogenic molds

Patients suffering from coronavirus disease-2019 (COVID-19) are susceptible to deadly secondary fungal infections such as COVID-19-associated pulmonary aspergillosis and COVID-19-associated mucormycosis. Despite this clinical observation, direct experimental evidence for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-driven alterations of antifungal immunity is scarce. Using an ex-vivo whole blood stimulation assay, we challenged blood from twelve COVID-19 patients with Aspergillus fumigatus and Rhizopus arrhizus antigens and studied the expression of activation, maturation, and exhaustion markers, as well as cytokine secretion. Compared to healthy controls, T-helper cells from COVID-19 patients displayed increased expression levels of the exhaustion marker PD-1 and weakened A. fumigatus - and R. arrhizus -induced activation. While baseline secretion of proinflammatory cytokines was massively elevated, whole blood from COVID-19 patients elicited diminished release of T-cellular (e.g., IFN-γ, IL-2) and innate immune cell-derived (e.g., CXCL9, CXCL10) cytokines in response to A. fumigatus and R. arrhizus antigens. Additionally, samples from COVID-19 patients showed deficient granulocyte activation by mold antigens and reduced fungal killing capacity of neutrophils. These features of weakened anti-mold immune responses were largely decoupled from COVID-19 severity, the time elapsed since diagnosis of COVID-19, and recent corticosteroid uptake, suggesting that impaired anti-mold defense is a common denominator of the underlying SARS-CoV-2 infection. Taken together, these results expand our understanding of the immune predisposition to post-viral mold infections and could inform future studies of immunotherapeutic strategies to prevent and treat fungal superinfections in COVID-19 patients

Prognostic Factors Affecting Outcome after Allogeneic Transplantation for Hematological Malignancies from Unrelated Donors: Results from a Randomized Trial

Several prognostic factors for the outcome after allogeneic hematopoietic stem-cell transplant (HSCT) from matched unrelated donors have been postulated from registry data; however, data from randomized trials are lacking. We present analyses on the effects of patient-related, donor-related, and treatment-related prognostic factors on acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS) in a randomized, multicenter, open-label, phase III trial comparing standard graft-versus-host-disease (GVHD) prophylaxis with and without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before HSCT from HLA-A, HLA-B antigen, HLA-DRB1, HLA-DQB1 allele matched unrelated donors. High-resolution testing (allele) of HLA-A, HLA-B, and HLA-C were obtained after study closure, and the impact of an HLA 10/10 4-digit mismatch on outcome and on the treatment effect of ATG-F versus control investigated. Advanced disease was a negative factor for relapse, DFS, and OS. Donor age ≥40 adversely affected the risk of aGVHD III-IV, extensive cGVHD, and OS. Younger donors are to be preferred in unrelated donor transplantation. Advanced disease patients need special precautions to improve outcome. The degree of mismatch had no major influence on the positive effect of ATG-F on the reduction of aGVHD and cGVHD

Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomib-containing regimens

The past decade has witnessed a paradigm shift in the initial treatment of multiple myeloma with the introduction of novel agents such as thalidomide, lenalidomide, and bortezomib, leading to improved outcomes. High-dose therapy and autologous stem cell transplantation remains an important therapeutic option for patients with multiple myeloma eligible for the procedure. Before the advent of the novel agents, patients underwent stem cell collection prior to significant alkylating agent exposure, given its potential deleterious effect on stem cell collection. With increasing use of the novel agents in the upfront setting, several reports have emerged raising concerns about their impact on the ability to collect stem cells. An expert panel of the International Myeloma Working Group (IMWG) was convened to examine the implications of these therapies on stem collection in patients with myeloma and to develop recommendations for addressing these issues. Here we summarize the currently available data and present our perspective on the problem and potential options to overcome this problem. Specifically, we recommend early mobilization of stem cells, preferably within the first 4 cycles of initial therapy, in patients treated with novel agents and encourage participation in clinical trials evaluating novel approaches to stem cell mobilization. (Blood. 2009;114:1729-1735

Monoclonal gammopathy of renal significance (MGRS): Real-world data on outcomes and prognostic factors

Monoclonal gammopathy of renal significance (MGRS) is a recognized clinical entity. Literature regarding treatment and its outcomes in MGRS is sparse due to the rarity and misdiagnosis of MGRS. We retrospectively analyzed 280 adults with an MGRS diagnosis from 2003 to 2020 across 19 clinical centers from 12 countries. All cases required renal biopsy for the pathological diagnosis of MGRS. Amyloidosis-related to MGRS (MGRS-A) was present in 180 patients; nonamyloidosis MGRS (MGRS-NA), including a broad spectrum of renal pathologies, was diagnosed in 100 patients. The median overall survival in the studied cohort was 121.0 months (95% CI: 105.0–121.0). Patients with MGRS-A had a shorter overall survival than patients with MGRS-NA (HR = 0.41, 95%CI: 0.25–0.69; p = 0.0007). Both hematologic and renal responses were associated with longer survival. Achievement of ≥VGPR was generally predictive of a renal response (OR = 8.03 95%CI: 4.04–115.96; p < 0.0001), one-fourth of patients with ≥VGPR were renal nonresponders. In MGRS-A, factors associated with poor prognosis included elevated levels of creatinine, beta-2-microglobulin, and hemodialysis at diagnosis. In MGRS-NA, only age >65 years was associated with increased risk of death. Treatments provided similar hematologic response rates in both types of MGRS. Autologous stem cell transplantation led to better response than other treatments. This multicenter and international effort is currently the largest report on MGRS

Petrology of Indus River sands : a key to interpret erosion history of the Western Himalayan Syntaxis

Author Posting. © The Authors, 2004. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Earth and Planetary Science Letters 229 (2005): 287-302, doi:10.1016/j.epsl.2004.11.008.The Indus River has been progressively transformed in the last decades into a tightly-regulated system of dams and channels, to produce food and energy for the rapidly growing population of Pakistan. Nevertheless, Indus River sands as far as the delta largely retain their distinct feldspar- and amphibole-rich composition, which is unique with respect to all other major rivers draining the Alpine-Himalayan belt except for the Brahmaputra. Both the Indus and Brahmaputra Rivers flow for half of their course along the India-Asia suture zone, and receive major contributions from both Asian active-margin batholiths and upper-amphibolite-facies domes rapidly exhumed at the Western and Eastern Himalayan syntaxes. Composition of Indus sands changes repeatedly and markedly in Ladakh and Baltistan, indicating overwhelming sediment flux from each successive tributary as the syntaxis is approached. Provenance estimates based on our integrated petrographic-mineralogical dataset indicate that active-margin units (Karakorum and Transhimalayan arcs) provide ~81% of the 250±50 106 t of sediments reaching the Tarbela reservoir each year. Partitioning of such flux among tributaries and among source units allows us to tentatively assess sediment yields from major sub-catchments. Extreme yields and erosion rates are calculated for both the Karakorum Belt (up to 12,500±4700 t/km2 yr and 4.5±1.7 mm/yr for the Braldu catchment) and Nanga Parbat Massif (8100±3500 t/km2 yr and 3.0±1.3 mm/yr). These values approach denudation rates currently estimated for South Karakorum and Nanga Parbat crustal-scale antiforms, and highlight the major influence that rapid tectonic uplift and focused glacial and fluvial erosion of young metamorphic massifs around the Western Himalayan Syntaxis have on sediment budgets of the Indus system. Detailed information on bulk petrography and heavy minerals of modern Indus sands not only represents an effective independent method to constrain denudation rates obtained from temperature-time histories of exposed bedrock, but also provides an actualistic reference for collision-orogen provenance, and gives us a key to interpreting provenance and paleodrainage changes recorded by clastic wedges deposited in the Himalayan foreland basin and Arabian Sea during the Cenozoic.Financial support by FIRB 2002 and PRIN 2003 to E.Garzanti