With increasing frequency and intensity under global climate change, storms, particularly typhoons, have become critical drivers reshaping coastal morphology. However, researches capturing the full morphodynamic sequence, especially the pre-landfall phase, remain scarce due to the challenges of field observations under extreme conditions. To address this, continuous observations were conducted throughout the Typhoon Fung-wong on the Yangtze Estuary intertidal flat. Here we found that, the loose and easily erodible surface layer of the intertidal mudflat was primarily eroded prior to typhoon landfall, exposing stiff, well-consolidated subsurface sediments. Subsequently, bed-level change remained minimal during peak hydrodynamics at typhoon landfall, showing that vertical sediment properties modulate morphodynamic responses. The decade-long continuous observations at the Sheshan Station in the Yangtze Estuary confirmed this severe pre-landfall erosion which also appears common across both China and the United States. This highlights the importance of pre-landfall erosion and sediment stratification in storm-driven coastal change prediction and management.

While particulate matter (PM) instruments are widely used for air quality monitoring and policy development, there is limited research on how wind speed (U0) and contact angle (θ) affect the measurement accuracy of submicron PM, or particles with their diameters ≤ one µm (PM1). This study addresses this gap by employing a wind tunnel experiment with a common sampling system featuring a customized thick-walled cylindrical metal inlet. The results reveal that wind-induced aerosol losses can reach up to 9%, and the sampling efficiency has a negative linear relationship with U0 and a third-order polynomial relationship with cos(θ). This model demonstrates a significant discrepancy with classic models in predicting sampling efficiency, which indicates the inapplicability of classic sampling efficiency models to submicron aerosols. The findings of this study can help correct wind-induced errors, improve sampling protocols, and develop new predictive models, which have implications for improving hazardous air quality warning systems and safeguarding public well-being.

In river research, forecasting flow velocity accurately in vegetated channels is a significant challenge. The forecasting performance of various independent and hybrid machine learning (ML) models are thus quantified for the first time in this work. Utilizing flow velocity measurements in both natural and laboratory flume experiments, we assess the efficacy of four distinct standalone machine learning techniques-Kstar, M5P, reduced error pruning tree (REPT) and random forest (RF) models. In addition, we also test for eight types of hybrid ML algorithms trained with an Additive Regression (AR) and Bagging (BA) (AR-Kstar, AR-M5P, AR-REPT, AR-RF, BA-Kstar, BA-M5P, BA-REPT and BA-RF). Findings from a comparison of their predictive capabilities, along with a sensitivity analysis of the influencing factors, indicated: (1) Vegetation height emerged as the most sensitive parameter for determining the flow velocity; (2) all ML models displayed outperforming empirical equations; (3) nearly all ML algorithms worked optimal when the model was built using all of the input parameters. Overall, the findings showed that hybrid ML algorithms outperform regular ML algorithms and empirical equations at forecasting flow velocity. AR-M5P (R-2=0.954, R=0.977, NSE=0.954, MAE=0.042, MSE=0.003, and PBias=1.466) turned out to be the optimal model for forecasting of flow velocity in vegetated-rivers.

Background: Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed exclusively in the B-cell lineage, and at a higher level on multiple myeloma (MM) cells than on normal B cells. Cevostamab is a FcRH5xCD3 bispecific antibody that facilitates T cell-mediated killing of MM cells. In an ongoing Phase I dose-escalation and dose-expansion study (GO39775; NCT03275103), cevostamab monotherapy demonstrated target dose (TD)-dependent activity and manageable safety in patients (pts) with heavily pretreated RRMM (Trudel et al. ASH 2021). We report updated efficacy and safety data from pts who received cevostamab once every 3 weeks (Q3W) at the 160mg TD level. Methods: Eligible pts were those with RRMM for which no established therapy was available or appropriate. Cevostamab was initiated with Cycle (C) 1 single-step (SS) dosing, double-step (DS) dosing (Trudel et al. ASH 2021), or triple-step (TS) dosing (step doses on D1, D2 [or D3 or D4 depending on the emergence and resolution of cytokine release syndrome [CRS] with the previous administration], and D8, TD on D9 [or D10 or D11]). Cevostamab was then continued at the TD on D1 of each subsequent 21-day cycle. Cevostamab was continued for 17 cycles, unless disease progression or unacceptable toxicity occurred. Results: As of February 23, 2024, 167 pts (median age: 66 years, range: 40-90; ECOG PS: 0, 35% or 1, 65%; median time from first MM therapy: 6.3 years, range: 0.3-21.8) had received cevostamab at the 160mg TD level (SS: n=10; DS: n=97; TS: n=60); 28% of pts had extramedullary disease and 38% of pts with a conclusive assay result (38/100) had high-risk cytogenetics (t(4;14), t(14;16), or del(17p)). The median number of prior lines of therapy was 6 (range: 2-18). Almost all pts (95.8%) were triple-class refractory and 73.7% were penta-drug refractory; 85.0% were refractory to their last prior therapy. A majority (57%) of pts had received ≥1 prior B-cell maturation antigen (BCMA)-targeted therapy. Twenty four percent of pts had received ≥1 prior bispecific antibody. Median observation time was 11.3 months (range: 0.5-42.8). The overall response rate (ORR) in all pts who received cevostamab at the 160mg TD level was 43.1% (72/167 pts); 6.6% achieved a stringent complete response (CR), 6.6% a CR, 12.6% a very good partial response (VGPR), and 17.4% a partial response (PR). The VGPR or better rate was 25.7%. Median time to first response (PR or better) was 1.4 months (range: 0.6-4.6) and to best response was 2.4 months (range: 0.7-13.4). Median duration of response was 10.4 months (95% CI: 6.8, 10.5). ORR was 30.2% (29/96) in pts with ≥1 prior BCMA-targeted therapy and 60.6% (43/71) in those without. ORR was 30.0% (12/40) in pts with ≥1 prior bispecific antibody, 33.3% (20/60) with ≥1 prior chimeric antigen receptor (CAR) T-cell, and 41.2% (14/34) with ≥1 prior antibody-drug conjugate. Common (≥20%) adverse events (AEs) included CRS (74.3%; Grade [Gr] 1: 52.7%; Gr 2: 19.8%; Gr 3: 1.2%; Gr 4: 0.6%), neutropenia (31.1%; Gr 1-2: 3.0%; Gr 3: 12.0%; Gr 4: 16.2%), cough (30.5%; Gr 1-2: 29.9%; Gr 3: 0.6%), nausea (28.1%; Gr 1-2: 27.5%; Gr 3: 0.6%), diarrhea (24.0%; all Gr 1-2), anemia (23.4%; Gr 1-2: 5.4%; Gr 3: 17.4%; Gr 4: 0.6%), and fatigue (21.0%; Gr 1-2: 19.8%; Gr 3: 1.2%). Possible immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 13.2% of pts (Gr 1: 6.0%; Gr 2: 5.4%; Gr 3: 1.8%). Infections occurred in 53.9% of pts, with serious events and Gr ≥3 events in 22.2% and 19.2%, respectively. Treatment-related AEs leading to cevostamab discontinuation occurred in 11 pts (6.6%) and treatment-related Gr 5 (fatal) AEs in 3 pts (1.8%; hemophagocytic lymphohistiocytosis, n=2; disseminated intravascular coagulation and pseudomonal sepsis, n=1). In the 0.3/1.2/3.6/160mg TS cohort, CRS occurred in 19/30 pts (63.3%) and was all Gr 1 (46.7%) or Gr 2 (16.7%). Pts with CRS were managed with tocilizumab (47.4%), steroids (21.1%), or both agents (10.5%). No pts discontinued cevostamab due to CRS and all events were resolved at cut-off. Conclusions: Cevostamab demonstrates clinically meaningful activity and manageable safety at the 160mg TD level in pts with heavily pretreated RRMM. C1 TS dosing provides effective CRS mitigation. Cevostamab combination studies may use the 0.3/1.2/3.6mg TS regimen and the Q3W 160mg TD (or similar TD exposure).

The potential of advanced tree-based models and optimized deep learning algorithms to predict fluvial bedload transport was explored, identifying the most flexible and accurate algorithm, and the optimum set of readily available and reliable inputs. Using 926 datasets for 20 rivers, the performance of three groups of models was tested: (1) standalone tree-based models Alternating Model Tree (AMT) and Dual Perturb and Combine Tree (DPCT); (2) ensemble tree-based models Iterative Absolute Error Regression (IAER), ensembled with AMT and DPCT; and (3) optimized deep learning models Long Short-Term Memory (LSTM) and Recurrent Neural Network (RNN) ensembled with Grey Wolf Optimizer. Comparison of the predictive performance of the models with that of commonly used empirical equations and sensitivity analysis of the driving variables revealed that: (i) the coarse grain-size percentile D90 was the most effective variable in bedload transport prediction (where Dx is the xth percentile of the bed surface grain size distribution), followed by D84, D50, flow discharge, D16, and channel slope and width; (ii) all tree-based models and optimized deep learning algorithms displayed ‘very good’ or ‘good’ performance, outperforming empirical equations; and (iii) all algorithms performed best when all input parameters were used. Thus, a range of different input variable combinations must be considered in the optimization of these models. Overall, ensemble algorithms provided more accurate predictions of bedload transport than their standalone counterpart. In particular, the ensemble tree-based model IAER-AMT performed most strongly, displaying great potential to produce robust predictions of bedload transport in coarse-grained rivers based on a few readily available flow and channel variables.

Our coasts are facing a growing threat from rising sea levels and detrimental storm events. Nature-based solutions are gaining interest for their potential to provide multiple ecosystem services, including coastal protection. Seagrass can influence coastal sediment transport and wave propagation, however, whether seagrass can be used as an effective intervention for coastal protection is unclear. Using the Delft3D model, this study looks at how seagrass affects coastal hydrodynamics in a macrotidal bay, under idealised scenarios that simulate a rise in sea level and storm wave heights, emulating projected sea conditions under climate change. Through the use of a habitat suitability model, a seagrass patch in Morecambe Bay was simulated, based on a location within the bay that is most suitable for seagrass species Zostera marina. Hydrodynamic simulations were run for a number of scenarios for a domain with and without a seagrass patch. Scenarios included variable boundary wave heights, sea levels and vegetation parameters, to test the influence of seagrass in future climates. Results show that there is a reduction in mean and maximum wave height inside and behind the seagrass patch, with the largest changes in wave dissipation observed during higher boundary wave conditions. In these conditions the maximum wave height reduced by over a half within the patch. Simulations examining the influence of seagrass density and canopy height found that a lower density seagrass patch reduced maximum wave height more substantially than higher density patches. Although alternative hard engineered solutions are able to attenuate wave energy more effectively than seagrass, these results demonstrate seagrass could play an important role in conjunction with salt marsh restoration or existing hard engineering solutions, helping to mitigate the risk of flooding and erosion, whilst providing additional ecosystem services such as carbon sequestration and habitat provision.

Background: Immunoparesis (IP), the suppression of one or more uninvolved immunoglobulins (Ig) below the lower limit of normal (LLN), is frequently observed in patients with multiple myeloma (MM). IP is associated with a negative impact on survival in patients with relapsed MM (Chakraborty et al. Br J Haematol 2019) and may increase the risk of infection in patients with MM (Pratt et al. Br J Haematol 2007). Cevostamab is a FcRH5xCD3 T-cell engaging bispecific antibody that facilitates T-cell directed killing of myeloma cells. Cevostamab has demonstrated clinically meaningful activity and a favorable toxicity profile when given once every 3 weeks for up to 17 cycles (approximately 1 year) in an ongoing Phase I trial (GO39775; NCT03275103) involving patients with heavily pre-treated RRMM (Trudel et al. ASH 2021). Hypogammaglobulinemia is a potential side effect due to the targeting of FcRH5 on normal plasma cells (Hammons et al. JAMA Netw Open 2022). The purpose of the current study was to evaluate whether reducing monoclonal Ig burden while on therapy allows for polyclonal Ig recovery, despite the mechanism of action of cevostamab. Specifically, we evaluated whether responders in the GO39775 study demonstrated evidence of immune reconstitution (IR) while on cevostamab therapy. Methods: All patients were aged ≥18 years and had RRMM for which no established therapies were available. Cevostamab was administered via intravenous infusion every 21 days for 17 cycles unless disease progression or unacceptable toxicity occurred. Patients who received concomitant IVIg therapy were excluded from the analysis. Patients were included if they were enrolled for ≥100 days, demonstrated a partial response or better, and had IP at baseline, defined as ≥1 Ig below the LLN. IR was defined as recovery of ≥1 polyclonal Ig within the normal range. Results: At data cut-off (March 1, 2023), a total of 310 patients were enrolled in GO39775. 76 patients met the inclusion criteria and were eligible for analysis. Median age was 65 years (range: 43-82), with a median of 6 previous lines of therapy (range: 2-12). 46 patients (60.5%) had IgG isotype, 10 (13.2%) had IgA isotype, and 20 (26.3%) had light chain disease. Of the 76 patients who met the inclusion criteria, 10 (13.2%) experienced IR (see Table); 5 patients had IgG isotype, 3 had IgA isotype, and 2 had light chain disease. The 10 patients with IR were treated for a median of 323 days (range: 64-364). Of these, 6 patients had IR at a median time of Day 156 (range: 123-260) while on cevostamab, while 4 patients had IR at a median time of Day 242 (range: 133-309) after stopping cevostamab. Of the 6 patients who reconstituted on cevostamab, 1 had IgG isotype, 3 had IgA isotype, and 2 had light chain disease. All 4 patients who reconstituted after stopping cevostamab had IgG isotype. Apart from disease isotype, no other baseline characteristic demonstrated a trend with IR. Discussion: The majority of patients with a response to cevostamab in the GO39775 study had baseline IP, consistent with previous findings in RRMM. Among eligible responders, 10 patients (13.2%) reconstituted ≥1 polyclonal Ig, highlighting that disease control may allow some patients to reverse IP. Of the patients who had IR, 6 had immune recovery while on cevostamab therapy, which indicates that IR is possible on cevostamab once disease control is achieved. Our findings demonstrate that despite normal plasma cell targeting, IR can occur while receiving a FcRH5xCD3 bispecific antibody. Further analysis on a larger patient pool may provide more insight into the characteristics of patients with RRMM who experience IR on cevostamab therapy.

Regular monitoring is essential for vulnerable coastal locations such as areas of landward retreat. However, for coastal practitioners, surveying is limited by budget, specialist personnel/equipment and weather. In combination structure-from-motion and multi-view stereo (SfM-MVS) has helped to improve accessibility to topographic data acquisition. Pole-mounted cameras with SfM-MVS have gained traction but to guarantee coverage and reconstruction quality, greater understanding of camera position and interaction is required. This study uses a multi-camera array for image acquisition and reviews processing procedures in Agisoft Photoscan (Metashape). The camera rig was deployed at three sites and results were verified against a terrestrial laser scanner (TLS) and independent precision estimates. The multi-camera approach provided effective image acquisition ~11 times faster than the TLS. Reconstruction quality equalled (>92% similarity) the TLS, subject to processing parameters. A change in the image alignment parameter demonstrated a significant influence on deformation, reducing reprojection error by~94%. A lower densification parameter (‘High’) offered results ~4.39% dissimilar from the TLS at 1/8th of the processing time of other parameters. Independent precision estimates were <8.2 mm for x, y and z dimensions. These findings illustrate the potential of multi-camera systems and the influence of processing on point cloud quality and computation time.

Varying thermal atmospheric stability conditions and their effects on shearing flows has long been a subject of interest for researchers working in atmospheric science. The development of new instrument technologies now offers an opportunity to study flows with high spatial and temporal resolutions in wind tunnel atmospheric boundary layers. In the presented study, we use a laser Doppler anemometer within the Trent Environmental Wind Tunnel Laboratory to investigate the influence of thermal stratification on the constant stress layer. An-alyses of the thermal stratification represented by the gradient Richardson number and the apparent von K ' arm ' an parameter, shear velocity, and the slope of the streamwise velocity profiles reveal strong linear relationships. An exponential relationship between thermal stability and the apparent roughness length is also revealed. Profiles of the streamwise and vertical velocity and turbulence intensity, as well as the dimensionless Reynolds stress, are influenced by the gradient Richardson number. These findings have implications for producing accurate models of sediment entrainment and transport by wind in non-neutral conditions.

Accurate assessment of soil water erosion (SWE) susceptibility is critical for reducing land degradation and soil loss, and for mitigating the negative impacts of erosion on ecosystem services, water quality, flooding and infrastructure. Deep learning algorithms have been gaining attention in geoscience due to their high performance and flexibility. However, an understanding of the potential for these algorithms to provide fast, cheap, and accurate predictions of soil erosion susceptibility is lacking. This study provides the first quantification of this potential. Spatial predictions of susceptibility are made using three deep learning algorithms - Convolutional Neural Network (CNN), Recurrent Neural Network (RNN) and Long-Short Term Memory (LSTM) - for an Iranian catchment that has historically experienced severe water erosion. Through a comparison of their predictive performance and an analysis of the driving geo-environmental factors, the results reveal: (1) elevation was the most effective variable on SWE susceptibility; (2) all three developed models had good prediction performance, with RNN being marginally the most superior; (3) maps of SWE susceptibility revealed that almost 40 % of the catchment was highly or very highly susceptible to SWE and 20 % moderately susceptible, indicating the critical need for soil erosion control in this catchment. Through these algorithms, the soil erosion susceptibility of catchments can potentially be predicted accurately and with ease using readily available data. Thus, the results reveal that these models have great potential for use in data poor catchments, such as the one studied here, especially in developing nations where technical modeling skills and understanding of the erosion processes occurring in the catchment may be lacking.

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Interleukin (IL)-6 receptor blockade with the monoclonal antibody tocilizumab (TCZ) is an established strategy for the management of cytokine release syndrome (CRS) induced by chimeric antigen receptor (CAR) T-cells and bispecific antibodies. TCZ pre-treatment could prevent or limit the emergence and/or severity of CRS. Aims: To assess whether a single dose of TCZ given prior to the initiation of cevostamab, a FcRH5xCD3 bispecific antibody, reduces the incidence of CRS in patients (pts) with RRMM. Methods: A dedicated TCZ pre-treatment arm was included in the ongoing GO39775 Phase I study (NCT03275103) of cevostamab. Pts with RRMM for which no established therapy was available, appropriate, or tolerable were enrolled. A single 8mg/kg intravenous (IV) dose of TCZ was given 2 hours before the initiation of IV cevostamab at the 3.6mg step-dose level on Day (D) 1 of Cycle (C) 1; cevostamab was continued at the 90mg target-dose level on C1D8 and D1 of each subsequent 21-day cycle. Data from the corresponding 3.6/90mg non-TCZ group were used as a retrospective comparator. Corticosteroid, antihistamine, and acetaminophen pre-medication was given to all pts prior to cevostamab. ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019) were used to report CRS. All pts provided written informed consent. Results: At cut-off (August 22, 2022), 75 pts had enrolled (TCZ group: 31 pts; non-TCZ: 44; median age: 63 years in both groups). Median prior lines of therapy was 4 in the TCZ group and 6 in the non-TCZ (range: 2–11 in both groups). Most pts were triple-class refractory (TCZ group: 80.6%; non-TCZ: 86.4%) and many were penta-drug refractory (TCZ group: 45.2%; non-TCZ: 72.7%). Median follow-up was 8.5 months in the TCZ group (range: 1.1–16.8) and 12.8 months in the non-TCZ (range: 0.2–36.3). The overall rate of CRS was significantly lower in the TCZ group than in the non-TCZ (38.7% vs 90.9%, respectively; p<0.001; Figure). Grade (Gr) 3 CRS occurred in 2 pts (one in each group). No Gr 4–5 CRS occurred. In C2+, no CRS events were observed in the TCZ group vs 5 events in the non-TCZ group. Overall rates of non-CRS adverse events were generally comparable, with the exception of neutropenia (TCZ: 71.0%; Gr 3–4: 67.7%; non-TCZ: 38.6%, all Gr 3–4). Notably, neutropenia was reversible, manageable with growth factor where indicated, and did not lead to discontinuation. No negative impact on the anti-myeloma activity of cevostamab was observed in the TCZ group. Overall response rates were 54.8% (95% CI: 35.7–74.0) and 37.2% (95% CI: 21.6–52.8) in the TCZ and non-TCZ groups, respectively. Very good partial response or better rates were 32.3% and 25.6%, respectively. At cut-off, median duration of response was 11.3 months (range: 1–12) in the TCZ group and 10.9 months (range: 1–34) in the non-TCZ group. Peak IL-6 levels after the 3.6mg step dose were significantly higher in the TCZ group (median: 2311pg/mL) than in the non-TCZ group (median: 245pg/mL), likely due to TCZ-mediated reduction in IL-6 clearance. However, the peak level of C-reactive protein, a downstream marker of inflammation, was significantly lower in the TCZ group (median: 4mg/L) relative to the non-TCZ group (median: 123mg/L), suggesting near complete suppression of the IL-6-mediated signalling pathway. Summary/Conclusion: TCZ pre-treatment significantly reduces the incidence of CRS in pts with RRMM who receive cevostamab. Importantly, TCZ pre-treatment has no negative impact on the anti-myeloma activity of cevostamab.Keywords: Cytokine release syndrome, Antibody, Bispecific, Multiple myeloma

We compiled 447 datasets from different sources and lab- and field-based measurements. These datasets included Einstein and Banks (1950), Fenzl (1962), Kouwen et al. (1969), Ree and Crow (1977), Murota (1984), Tsujimoto and Kitamura (1990), Tsujimoto (1991), Tsujimoto (1993), Shimizu (1994), Dunn et al. (1996), Ikeda and Kanazawa (1996), Meijer (1998), Jarvela (2002), Rowinski and Kubrak (2002), Stone and Shen (2002), Poggi et al. (2004), Carollo et al. (2005), and Murphy et al. (2007).

Background: Relapsed/refractory multiple myeloma (RRMM) remains an incurable disease, with most treatment regimens continued until disease progression (PD). New treatments that are efficacious when given for a fixed duration and offer the potential for an extended treatment-free period may also decrease cumulative toxicities and reduce the burden of treatment on both patients and healthcare systems. Cevostamab is an FcRH5xCD3 T-cell engaging bispecific monoclonal antibody that facilitates T-cell directed killing of myeloma cells and has demonstrated clinically meaningful activity and a favorable toxicity profile when given Q3W for up to 17 cycles (approximately 1 year) in an ongoing Phase I trial (GO39775; NCT03275103) in patients with heavily pre-treated RRMM (Trudel et al. ASH 2021). Here, we report early duration of response data for patients in GO39775 who completed 17 cycles of cevostamab and stopped treatment. Methods: All patients were aged ≥18 years and had RRMM for which no established therapy was available, appropriate, or tolerable, and an ECOG performance status of 0-1. Cevostamab was administered by intravenous infusion in 21-day cycles with step-up dosing in Cycle (C) 1 for cytokine release syndrome mitigation. Treatment was continued for 17 cycles (approximately 1 year) unless PD or unacceptable toxicity occurred. Patients who achieved a partial response (PR) or better by C17 and maintained a response through C17 were included in the analysis. Results: At data cut-off (March 8, 2022), a total of 16 patients (median age: 66.5 years; range: 45-80) completed C17 of cevostamab treatment and were eligible for analysis. Patients had received a median of 6 prior lines of therapy (range: 2-11), with 12 patients having received ≥5 prior therapies. Thirteen patients were triple-class refractory and 11 were penta-refractory. Fifteen patients were refractory to their last prior therapy. Five patients had received prior anti-B-cell maturation antigen (BCMA) targeted therapies, 4 of whom were refractory to anti-BCMA treatment. Patients received cevostamab target doses ranging from 40-160mg and received a median of 17 cycles of treatment (range: 16-17). Among the 16 patients analyzed, the best overall response (BOR) achieved was: stringent complete response (sCR) in 7 patients, CR in 3 patients, very good partial response (VGPR) in 5 patients, and PR in 1 patient. At data cut-off, 13 of the 16 patients remained in remission, with 8 patients (BOR: 5 sCR, 1 CR, 2 VGPR) maintaining a response ≥6 months after completion of therapy and 3 patients (BOR: 2 sCR, 1 CR) maintaining a response ≥12 months after completion of therapy. Eight patients had <6 months of follow-up. None of the patients (0/10) who completed C17 and attained a sCR or CR had relapsed. Only 3 of the 16 patients (BOR: 2 VGPR, 1 PR) had PD after the completion of C17 of cevostamab. Time to progression following completion of therapy for the 2 patients who achieved a VGPR was 7.8 months and 12.9 months. For the patient who achieved a PR, time to progression was 1.3 months. Due to its mechanism of action, treatment with cevostamab may be associated with an increased risk of infection. Infections occurred in 2 patients after the completion of C17 of cevostamab therapy. Pneumonia was reported in both patients, with onset after the last dose of 1.3 months and 3.8 months. Both events resolved and both patients have remained on study. Conclusions: Early data from this Phase I study suggest that patients can maintain durable responses (≥6 months) after completion of 17 cycles of cevostamab treatment, highlighting the potential for an extended treatment-free period following fixed-duration therapy. Further data are needed to confirm the duration of response and associated correlates following completion of treatment. Additional data on responding patients with premature discontinuation of treatment (i.e. prior to completion of C17) and patients retreated with cevostamab will be presented.

We propose neighbourhood message passing (NMP), an abstract framework for loopy belief propagation (BP), as used in stereo matching (SM). We focus here on generic inter-processing-element messaging over a two-dimensional square grid, but our results apply to lattices of any shape through minimal modification. Specifically, this paper investigates three cP Systems (a type of P systems) models for loopy BP: One based on the classical globally synchronous BP, and two novel variants, (totally) asynchronous and locally synchronous. To model the classic globally synchronous NMP, we extend cP systems messaging rules with antiport features, similar to those used in other P systems. Next, we propose a novel version of NMP by extending it to the asynchronous case. We then derive a locally synchronous NMP variant, which arises naturally as a middle ground between our asynchronous and the classical globally synchronous variants. To clarify the operation of the asynchronous NMP system, we supply a short worked example. Following this, we analyse the proposed asynchronous system and prove that it uses precisely the same number of messages as the globally synchronous variant. We further put forward some runtime and correctness conjectures. Furthermore, we experimentally investigate the asynchronous system’s run-time characteristics. Messages spread from a given location on the lattice similarly in both the asynchronous and synchronous versions, even in the face of slow channels. We also conduct computer experiments and find that, in practice, the locally synchronous system is usually faster than the traditional globally synchronous approach (about 5–13%), and the asynchronous system is typically quicker still (often by approximately another 10%). We thus believe that it is a promising novel approach for faithful implementations of NMP and should be preferred.

Background: Blockade of the cytokine IL-6 receptor by monoclonal antibodies, such as tocilizumab (TCZ), is a key strategy for the management of both CAR-T and T-cell dependent bispecific monoclonal antibody (TDB) induced cytokine release syndrome (CRS). Preclinical data indicate that inhibition of IL-6, IL-1, or TNF-α signaling prior to TDB administration can prevent development of CRS without any impact on anti-tumor activity (Li et al. Sci Transl Med 2019). To test this hypothesis in the clinic, a dedicated TCZ pretreatment arm was added to the ongoing GO39775 Phase I study (NCT03275103) of cevostamab, an FcRH5xCD3 TDB, to determine whether a single dose of TCZ administered prior to the first dose of cevostamab can reduce the incidence of CRS. Methods: Patients (pts) who have RRMM for which no established therapy is available, appropriate or tolerable were enrolled in a dedicated TCZ pretreatment arm. Cevostamab was administered intravenously (IV) in a 21-day Cycle (C). A single 3.6mg priming dose was given on Day (D) 1 of C1 followed by a target dose of 90mg on C1D8 and then C2D1 and beyond. A single IV 8mg/kg dose of TCZ was administered as a pretreatment on C1D1 two hours prior to the administration of cevostamab. Patient data from the previously enrolled non-TCZ 3.6/90mg dosing arm served as a retrospective comparator. Pts in both arms received corticosteroid, antihistamine and acetaminophen premedication prior to cevostamab. CRS is reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: At data cut-off (March 8, 2022), 28 pts had enrolled in the TCZ pretreatment arm (median age: 64.5 years) and 44 pts in the non-TCZ comparator (median age: 63.0 years). Median prior lines of therapy were 4 (2.0-7.0) and 6 (2.0-11.0) in the TCZ pretreatment and non-TCZ arms, respectively. Twenty-two pts (78.6%) were triple-class refractory and 12 pts (42.9%) were penta-refractory in the TCZ pretreatment arm, vs. 38 (86.4%) triple-class refractory and 32 (72.7%) penta-refractory pts in the non-TCZ arm. Pts in the TCZ arm had a median time on study of 4.7 months (range: 0.3-11.3) vs. 13.1 months (range: 0.2-30.8) in the non-TCZ arm. All patients in the TCZ arm experienced at least one adverse event (AE). Overall, 35.7% of pts in the TCZ arm experienced CRS as compared to 90.9% in the non-TCZ 3.6/90mg group (see figure). One patient in each group experienced G3 CRS and no G4/G5 events were observed. Fewer pts required TCZ to treat CRS (5/28) in the TCZ arm than the non-TCZ arm (16/44). Only two pts on the TCZ arm had more than one CRS event (vs. 12/44 non-TCZ) and no CRS events were observed at C2 and beyond (vs. 5/44 non-TCZ). Rates of non-CRS AEs (notably thrombocytopenia, infections, and liver enzyme elevations) in the TCZ arm were similar to the non-TCZ arm with the exception of neutropenia (Trudel et al. ASH 2021). In the TCZ arm 64.3% of pts experienced G3/G4 neutropenia as compared to 38.6% in the comparator arm. In both arms, neutropenia events were reversible, manageable with growth factor as indicated, and none led to the discontinuation of cevostamab. Consistent with preclinical data, no apparent negative impact on anti-tumor activity was observed. The overall response rate in the TCZ arm with 90mg target dose was 50% (13/26) [95% CI: 28.9-71.2] compared to 37.2% (16/43) [95% CI: 21.6-52.8] in pts receiving 90mg without TCZ pretreatment. Very good partial response or better (VGPR+) rates were 26.9% vs. 25.6%, respectively. Available pharmacodynamic data did not demonstrate any apparent change in measures of T-cell activation and proliferation in pts receiving TCZ pretreatment. Consistent with the known mechanism of action of TCZ, levels of C-reactive protein, a downstream product of hepatic IL-6 activation, were heavily suppressed in the vast majority of pts in TCZ arm suggestive of near-complete inhibition of the IL-6 signaling pathway. Conclusions: Clinical data from the GO39775 study shows for the first time that TCZ pretreatment can significantly reduce the risk of developing TDB-induced CRS without an apparent impact on anti-myeloma activity. The data support additional investigation of the use of anti-cytokine pretreatment with the goal of substantially reducing the frequency and potentially the severity of CRS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P systems have been known to provide efficient polynomial (often linear) deterministic solutions to hard problems. In particular, cP systems have been shown to provide very crisp and efficient solutions to such problems, which are typically linear with small coefficients. Building on a recent result by Henderson et al., which solves SAT in square-root-sublinear time, this paper proposes an orders-of-magnitude-faster solution, running in logarithmic time, and using a small fixed-sized alphabet and ruleset (25 rules). To the best of our knowledge, this is the fastest deterministic solution across all extant P system variants. Like all other cP solutions, it is a complete solution that is not a member of a uniform family (and thus does not require any preprocessing). Consequently, according to another reduction result by Henderson et al., cP systems can also solve k-colouring and several other NP-complete problems in logarithmic time.

Background: Cevostamab is an FcRH5xCD3 bispecific antibody that facilitates T-cell directed killing of myeloma cells, and has shown promising activity and manageable safety in a Phase I study in patients (pts) with RRMM (NCT03275103; Trudel et al. ASH 2021). B-cell maturation antigen (BCMA) is a membrane-bound protein that is expressed preferentially by malignant plasma cells and has become an important therapeutic target in MM. Shedding of membrane-bound BCMA, mediated by γ-secretase, gives rise to the soluble form of BCMA (sBCMA) which is often present at elevated levels in pts with MM. Normalization of sBCMA may be a predictor of response to therapy, which may be independent of treatment and target. Aims: To evaluate sBCMA as a biomarker of early response in pts enrolled in the single step-up dosing cohorts of the cevostamab Phase I study. Methods: Plasma samples were collected at baseline and at Cycle (C) 1 Day (D) 1 (pre-infusion and end of infusion [EOI]), C1D2, C1D4, C1D8 (pre-infusion and EOI), C1D9, C1D11, and C2D1 (pre-infusion and EOI). sBCMA levels were quantified using hybrid immunoaffinity capture with LC-MS/MS. Pts were stratified by refractory status, prior therapy, prior transplant, cytogenetic risk and response (responder [≥PR] or non-responder [

Flooding and erosion will pose increasing challenges to urban settlements and critical infrastructure, such as roads and power grids in the future. Improved projections on the impact of climate change to critical infrastructure are essential to assist future planning. This paper uses hydro-sedimentary modelling to predict river erosion threats to electricity transmission infrastructure in an urbanised river valley under multiple increasing flow magnitude scenarios. We use a coupled hydrodynamic and landscape evolution model, CAESAR-Lisflood, to simulate river channel changes along a reach of the River Mersey, UK from the present day to 2050. A range of synthetic flow scenarios, based on recent hydrological records, was used in the model ranging from ‘no change’ up to a flow with 50% higher magnitude. The results revealed: (1) riverbank erosion will pose significant threats to several transmission towers located along the river, requiring intervention to avoid destabilisation by the moving channel; (2) the total area of floodplain erosion and deposition ≥ 0.5 m deep was positively related to increasing projected flow magnitudes. However, through running a ‘low’ and ‘high’ erosion version of the model, the simulations revealed these threats were most sensitive to the calibration of the erosion component of the model, illustrating the challenges and uncertainty in forecasting long-term river channel change; and (3) how long-term simulations can assist in adaptation planning for electricity transmission towers. Further reach- and catchment-scale modelling will be necessary to determine the timings of large floods more accurately, which produce the most significant erosion and deposition events, and to evaluate the efficacy of protections to transmission towers.

Supplementary Figure from Anti-CD79B Antibody–Drug Conjugate DCDS0780A in Patients with B-Cell Non-Hodgkin Lymphoma: Phase 1 Dose-Escalation Study