Projecting Changes in Tanzania Rainfall for the 21st century: Scenarios, Downscaling & Analysis

A Non-Homogeneous hidden Markov Model (NHMM) is developed using a 40-years record (1950-1990) of daily rainfall at eleven stations in Tanzania and re-analysis atmospheric fields of Temperature (T) at 1000 hPa, Geo Potential Height (GPH) at 1000 hPa, Meridional Winds (MW) and Zonal Winds (ZW) at 850 hPa, and Zonal Winds at the Equator(ZWE) from 10 to 1000 hPa. The NHMM is then used to predict future rainfall patterns under a global warming scenario (RCP8.5), using predictors from the CMCC-CMS simulations from 1950-2100. The model directly considers seasonality through changes in the driving variables thus addressing the question of how future changes in seasonality of precipitation can be modeled. The future downscaled simulations from NHMM, with predictors derived from the simulations of the CMCC-CMS CGM, in the worst conditions of global warming as simulated by RCP8.5 scenario, indicate that, Tanzania may be subjected to to a reduction of total annual rainfall; this reduction is concentrated in the wet seasons, OND, mainly as a consequence of decreasing of seasonal number of wet days. . Frequency and Intensity of extreme events don’t show any evident trend during the 21 century

A stacked ensemble learning and non-homogeneous hidden Markov model for daily precipitation downscaling and projection

Global circulation models (GCMs) are routinely used to project future climate conditions worldwide, such as temperature and precipitation. However, inputs with a finer resolution are required to drive impact-related models at local scales. The nonhomogeneous hidden Markov model (NHMM) is a widely used algorithm for the precipitation statistical downscaling for GCMs. To improve the accuracy of the traditional NHMM in reproducing spatiotemporal precipitation features of specific geographic sites, especially extreme precipitation, we developed a new precipitation downscaling framework. This hierarchical model includes two levels: (1) establishing an ensemble learning model to predict the occurrence probabilities for different levels of daily precipitation aggregated at multiple sites and (2) constructing a NHMM downscaling scheme of daily amount at the scale of a single rain gauge using the outputs of ensemble learning model as predictors. As the results obtained for the case study in the central-eastern China (CEC), show that our downscaling model is highly efficient and performs better than the NHMM in simulating precipitation variability and extreme precipitation. Finally, our projections indicate that CEC may experience increased precipitation in the future. Compared with around 26 years (1990–2015), the extreme precipitation frequency and amount would significantly increase by 21.9%– 48.1% and 12.3%–38.3%, respectively, by the late century (2075–2100) under the Shared Socioeconomic Pathway 585 climate scenario

Hazard Assessment from Storm Tides and Rainfall on a Tidal River Estuary

Here, we report on methods and results for a model-based flood hazard assessment we have conducted for the Hudson River from New York City to Troy/Albany at the head of tide. Our recent work showed that neglecting freshwater flows leads to underestimation of peak water levels at up-river sites and neglecting stratification (typical with two-dimensional modeling) leads to underestimation all along the Hudson. As a result, we use a three-dimensional hydrodynamic model and merge streamflows and storm tides from tropical and extratropical cyclones (TCs, ETCs), as well as wet extratropical cyclone (WETC) floods (e.g. freshets, rain-on-snow events). We validate the modeled flood levels and quantify error with comparisons to 76 historical events. A Bayesian statistical method is developed for tropical cyclone streamflows using historical data and consisting in the evaluation of (1) the peak discharge and its pdf as a function of TC characteristics, and (2) the temporal trend of the hydrograph as a function of temporal evolution of the cyclone track, its intensity and the response characteristics of the specific basin. A k-nearest-neighbors method is employed to determine the hydrograph shape. Out of sample validation tests demonstrate the effectiveness of the method. Thus, the combined effects of storm surge and runoff produced by tropical cyclones hitting the New York area can be included in flood hazard assessment. Results for the upper Hudson (Albany) suggest a dominance of WETCs, for the lower Hudson (at New York Harbor) a case where ETCs are dominant for shorter return periods and TCs are more important for longer return periods (over 150 years), and for the middle-Hudson (Poughkeepsie) a mix of all three flood events types is important. However, a possible low-bias for TC flood levels is inferred from a lower importance in the assessment results, versus historical event top-20 lists, and this will be further evaluated as these preliminary methods and results are finalized. Future funded work will quantify the influences of sea level rise and flood adaptation plans (e.g. surge barriers). It would also be valuable to examine how streamflows from tropical cyclones and wet cool-season storms will change, as this factor will dominate at upriver locations

Treatment of Lenalidomide Exposed or Refractory Multiple Myeloma: Network Meta-Analysis of Lenalidomide-Sparing Regimens

Over the past 10 years, the treatment of multiple myeloma (MM) dramatically changed due to the introduction of a number of new agents and combination regimens both in the frontline and in the relapsed/refractory setting. Currently, at least 11 classes of therapeutic agents, including steroids, alkylators (melphalan and cyclophosphamide), proteasome inhibitors (PI: bortezomib, carfilzomib, ixazomib), immunomodulatory agents (thalidomide, lenalidomide, pomalidomide), monoclonal antibodies (mAbs: elotuzumab, daratumumab), HDAC-inhibitors (panobinostat), BCL2 inhibitors (venetoclax), selective inhibitors of nuclear export (selinexor), drug-conjugated mAbs (belantamab mafodotin), bispecific agents and CAR-T, are approved (or are going to be approved) alone or in different combinations for the treatment of this disease, while few or no data are available to guide the therapeutic strategy to adopt at diagnosis or relapse (1). The choice of the treatment at relapse (2), in particular, poses particular challenges, and is currently dependent on patients (age, comorbidities, fitness, renal impairment, frailty) and disease characteristics (aggressive vs biochemical relapse, cytogenetics, presence of extra-medullary disease), previous treatments (classes of agents, duration of response, progression while on therapy), regional drug access (approval of combinations, reimbursement, costs) and, finally, patient’s choice. Unfortunately, there is a lack of trials specifically designed to help in this choice, and often, pre-planned subgroup analyses, do not include a sufficient number of patients to reach statistical evidence. Recently, since lenalidomide is progressively becoming the preferred one-line option to treat MM patients (and often, it is administered until progression), the choice of the treatment to be offered at relapse should be carefully evaluated. Interestingly, it has been reported that the longest prior lenalidomide treatment duration (>12 months) and IMiD-free interval (>18 months) could positively impact patients’ outcome (3), making the choice of a lenalidomide-sparing regimen of particular interest in this setting. On the bases of these premises, we performed a systematic review and a frequentist network meta-analysis in R [by using the netmeta package (4)] comparing direct and indirect evidence on the efficacy of seven different lenalidomide-sparing regimens (bortezomib-dexamethasone, VD; daratumumab-VD, DVD; carfilzomib-D, KD; daratumumab-KD, KdD; pomalidomide-VD, PVD; isatuximab-KD, IKD; selinexor-VD, SVD) in lenalidomide-exposed and lenalidomide-refractory patients, to provide statistical evidence to support clinical decision makin

ALART: A novel lidar system for vegetation height retrieval from space

We propose a multi-kHz Single-Photon Counting (SPC) space LIDAR, exploiting low energy pulses with high repetition frequency (PRF). The high PRF allows one to overcome the low signal limitations, as many return shots can be collected from nearly the same scattering area. The ALART space instrument exhibits a multi-beam design, providing height retrieval over a wide area and terrain slope measurements. This novel technique, working with low SNRs, allows multiple beam generation with a single laser, limiting mass and power consumption. As the receiver has a certain probability to detect multiple photons from different levels of canopy, a histogram is constructed and used to retrieve the properties of the target tree, by means of a modal decomposition of the reconstructed waveform. A field demonstrator of the ALART space instrument is currently being developed by a European consortium led by cosine | measurement systems and funded by ESA under the TRP program. The demonstrator requirements have been derived to be representative of the target instrument and it will be tested in an equipped tower in woodland areas in the Netherlands. The employed detectors are state-of-the-art CMOS Single-Photon Avalanche Diode (SPAD) matrices with 1024 pixels. Each pixel is independently equipped with an integrated Time-to-Digital Converter (TDC), achieving a timing accuracy that is much lower than the SPAD dead time, resulting in a distance resolution in the centimeter range. The instrument emits nanosecond laser pulses with energy on the order of several J, at a PRF of ~ 10 kHz, and projects on ground a three-beams pattern. An extensive field measurement campaign will validate the employed technologies and algorithms for vegetation height retrieval

High-density neutrophils in MGUS and multiple myeloma are dysfunctional and immune-suppressive due to increased STAT3 downstream signaling

To understand neutrophil impairment in the progression from MGUS through active MM, we investigated the function of mature, high-density neutrophils (HDNs), isolated from peripheral blood. In 7 MM, 3 MGUS and 3 healthy subjects by gene expression profile, we identified a total of 551 upregulated and 343 downregulated genes in MM-HDN, involved in chemokine signaling pathway and FC-gamma receptor mediated phagocytosis conveying in the activation of STAT proteins. In a series of 60 newly diagnosed MM and 30 MGUS patients, by flow-cytometry we found that HDN from MM, and to a lesser extend MGUS, had an up-regulation of the inducible FcγRI (also known as CD64) and a down-regulation of the constitutive FcγRIIIa (also known as CD16) together with a reduced phagocytic activity and oxidative burst, associated to increased immune-suppression that could be reverted by arginase inhibitors in co-culture with lymphocytes. In 43 consecutive newly-diagnosed MM patients, who received first-line treatment based on bortezomib, thalidomide and dexamethasone, high CD64 could identify at diagnosis patients with inferior median overall survival (39.5 versus 86.7 months, p = 0.04). Thus, HDNs are significantly different among healthy, MGUS and MM subjects. In both MGUS and MM neutrophils may play a role in supporting both the increased susceptibility to infection and the immunological dysfunction that leads to tumor progression

Flagellin outer domain dimerization modulates motility in pathogenic and soil bacteria from viscous environments.

Flagellar filaments function as the propellers of the bacterial flagellum and their supercoiling is key to motility. The outer domains on the surface of the filament are non-critical for motility in many bacteria and their structures and functions are not conserved. Here, we show the atomic cryo-electron microscopy structures for flagellar filaments from enterohemorrhagic Escherichia coli O157:H7, enteropathogenic E. coli O127:H6, Achromobacter, and Sinorhizobium meliloti, where the outer domains dimerize or tetramerize to form either a sheath or a screw-like surface. These dimers are formed by 180° rotations of half of the outer domains. The outer domain sheath (ODS) plays a role in bacterial motility by stabilizing an intermediate waveform and prolonging the tumbling of E. coli cells. Bacteria with these ODS and screw-like flagellar filaments are commonly found in soil and human intestinal environments of relatively high viscosity suggesting a role for the dimerization in these environments

DEDALO: PHASE II STUDY OF DARATUMUMAB PLUS POMALIDOMIDE AND DEXAMETHASONE (DPD) IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA AND 17P DELETION

N

Belantamab mafodotin in triple-refractory multiple myeloma patients: A retro-prospective observational study in Italy

Belantamab mafodotin is the first-in-class antibody-drug conjugates targeting B-cell maturation antigen to have demonstrated effectiveness in triple-class refractory multiple myeloma (TCR-MM) patients. We performed a retrospective study including 78 TCR patients, with at least four prior lines of therapy (LOTs), who received belantamab mafodotin within named patient program and expanded access program in Italy between 2020 and 2022. Median age was 65 years (range 42-86 years), ECOG performance status was >= 1 in 45% of patients. Overall, a clinical benefit was obtained in 36 out of 74 evaluable patients (49%), with 43%, 28%, and 13.5% achieving at least partial response, very good partial response, and complete response, respectively. After a median follow-up of 12 months (range 6-21 months), median duration of response, progression-free survival (PFS), and overall survival (OS) were 14, 5.5, and 12 months, respectively. Age >70 years, good performance status and response were associated with longer PFS and OS. Keratopathy occurred in 58% of patients (G3 2.5%), corneal symptoms in 32% (G3 1.2%) and a reduction in visual acuity in 14%. Grade 3 thrombocytopenia occurred in 9% of patients. Only 3% of patients discontinued belantamab mafodotin because of side effects. This real-life study demonstrated significant and durable responses of belantamab in TCR-MM patients with four prior LOTs, otherwise ineligible for novel immunotherapies