Modest Reduction Research Articles

Impact of shield location on staff and caregiver dose rates for I-131 radiopharmaceutical therapy patients

The goal of this study is to investigate the effect of the location and width of a single lead shield on the dose rate of staff and caregivers in a hospital room with an I-131 patient. The best orientation of the patient and caregiver relative to the shield was determined based on minimizing staff and caregiver radiation dose rates. Shielded and unshielded dose rates were simulated using a Monte Carlo computer simulation and validated using real-world ionisation chamber measurements. Based on a radiation transport analysis using an adult voxel phantom published by the International Commission on Radiological Protection, placing the shield near the caregiver yielded the lowest dose rates. However, this strategy reduced the dose rate in only a tiny area of the room. Furthermore, positioning the shield near the patient in the caudal direction provided a modest dose rate reduction while shielding a large room area. Finally, increased shield width was associated with decreasing dose rates, but only a four-fold dose-rate reduction was observed for standard width shields. The recommendations of this case study may be considered as potential candidate room configurations where radiation dose rates are minimized, however these findings must be weighed against additional clinical, safety, and comfort considerations.

Reconsidering Anode Materials for Fluoride-Ion Batteries - The Unexpected Roles of Carbide Formation.

Carbon is a ubiquitous additive to enhance the electrical conductivity of battery electrodes. Although carbon is generally assumed to be inert, the poor reversibility seen in some fluoride-ion battery electrodes has not been explained or systematically explored. Here, we utilize the Materials Project database to assess electrode deactivation reactions that result in the formation of a metal carbide. Specifically, we compare the theoretical potentials of MFy reduction to either the corresponding metal or metal carbide MCx. We find that the formation of MCx is unlikely to be important in anodes that operate at modest reduction potentials, such as those made from electronegative metals like Zn, Sn, or Pb. However, in anodes that operate at extreme reduction potentials, such as alkaline earths or lanthanides, we find that formation of MCx is relevant and can emerge as a mechanism for capacity loss. Thus, side reactions of metals with carbon additives that form metal carbides offer a possible explanation of the poor reversibility of lanthanide- or alkaline earth metal-based electrode materials. Finally, we highlight that the carbide formation process might be exploited for designing cheap anode systems with improved reversibility.

Acid/Base Balance in Fortified Donor Human Milk: An Experimental Study.

To quantify the pH of human milk fortified with human milk fortifiers (HMFs), powder infant formulas, and protein additives. Commercial liquid HMFs and powder infant formulas were added to pasteurized pooled donor human milk in triplicate and stirred. The pH of unfortified and fortified human milk at 22, 24, 26, 27, 28, and 30 kilocalories/ounce was determined using a pH meter. Phenolphthalein acidity at 24 and 30 kcal/ounce was determined using diluted sodium hydroxide (NaOH). The pH of unfortified human milk increased within the first hour (6.52 ± 0.06 vs. 6.62 ± 0.05, p < 0.0001). Changes in pH largely correlated with caloric density; however, directional changes varied considerably between HMFs and powder infant formulas. Two liquid HMFs demonstrated modest reductions in pH with increasing caloric density while one liquid HMF alkalinized human milk with increasing caloric density (ANOVA p < 0.0001). Phenolphthalein acidity was significantly higher for 5 HMFs and lower for 1 HMF at 30, but not 24 kcal/ounce. Powder infant formulas generally increased pH with increasing caloric density (ANOVA p < 0.0001), but no differences in phenolphthalein acidity were noted. Changes in acid/base balancefor fortified human milk is variable and may be a consideration when selecting a fortifying agent for human milk. This article is protected by copyright. All rights reserved.

Perioperative use of gabapentinoids in pediatric patients

Effective management of pediatric perioperative pain is typically goal-directed and multimodal, requiring various imperfect agents in combination to provide analgesia and support recovery. Gabapentinoids are one such class of agents often used in pediatric analgesic and enhanced recovery pathways. In adults, gabapentinoids have been associated with a modest reduction in pain scores but are often avoided due to undesired side effects. Children may be less susceptible to these unwanted effects, and the reduction in pain, agitation, and post-operative nausea and vomiting seen with these medications may confer significant benefit. While further studies are needed, to date there is no evidence to suggest a significantly increased risk of adverse effects in generally healthy children treated with gabapentinoids in the perioperative period. Although current evidence does not support their indiscriminate use, there appears to be a subset of pediatric surgical patients who stand to benefit from perioperative gabapentinoids. Pediatric use should not be abandoned, but rather further investigated to support thoughtful goal-directed application.Graphical

A Coordinated Voltage Regulation Algorithm of a Power Distribution Grid with Multiple Photovoltaic Distributed Generators Based on Active Power Curtailment and On-Line Tap Changer

The aim of this research is to manage the voltage of an active distribution grid with a low X/R ratio and multiple Photovoltaic Distributed Generators (PVDGs) operating under varying conditions. This is achieved by providing a methodology for coordinating three voltage-based controllers implementing an Adaptive Neuro-Fuzzy Inference System (ANFIS). The first controller is for the On-Line Tap Changer (OLTC), which computes its adequate voltage reference. Whereas the second determines the required Active Power Curtailment (APC) setpoint for PVDG units with the aim of regulating the voltage magnitude and preventing continuous tap operation (the hunting problem) of OLTC. Finally, the last component is an auxiliary controller designed for reactive power adjustment. Its function is to manage voltage at the Common Coupling Point (CCP) within the network. This regulation not only aids in preventing undue stress on the OLTC but also contributes to a modest reduction in active power generated by PVDGs. The algorithm coordinating between these three controllers is simulated in MATLAB/SIMULINK and tested on a modified IEEE 33-bus power distribution grid (PDG). The results revealed the efficacy of the adopted algorithm in regulating voltage magnitudes in all buses compared to the traditional control method.

A phase 2 trial of defibrotide for the prevention of chimeric antigen receptor T-cell–associated neurotoxicity syndrome

AbstractChimeric antigen receptor T-cell (CAR-T) therapy represents a major advance in cancer immunotherapy; however, it can be associated with life-threatening neurotoxicity linked to blood-brain barrier disruption and endothelial activation. Defibrotide was shown to reduce endothelial cell activation in vitro and is approved in the United States for treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients with renal or pulmonary dysfunction after hematopoietic cell transplantation (HCT), and in the European Union for severe VOD/SOS after HCT in patients aged >1 month. Defibrotide may stabilize the endothelium during CAR-T therapy and reduce the rate of CAR-T–associated neurotoxicity. This phase 2 study evaluated the safety and efficacy of defibrotide for prevention of CAR-T–associated neurotoxicity in patients with relapsed/refractory large B-cell lymphoma receiving axicabtagene ciloleucel. Part 1 established the recommended phase 2 dose (RP2D; 6.25 mg/kg); 20 patients (from parts 1 and 2) receiving the RP2D were evaluable for efficacy. Rate of CAR-T–associated neurotoxicity by day 30 (primary end point) was ∼50%, lower than reported in the ZUMA-1 trial (64%). Median event duration of grade ≥3 neurotoxicity was 7 days. No unexpected defibrotide-related safety findings and defibrotide-related treatment-emergent adverse events or deaths were reported. Results showed modest reduction in rate of CAR-T–associated neurotoxicity and high-grade neurotoxicity event duration relative to historical data; however, reduction was unlikely to meet the primary end point, so the study was terminated early. Nevertheless, results contribute valuable data for potential therapeutic insight on the management of CAR-T–associated neurotoxicity. This trial was registered at www.clinicaltrials.gov as #NCT03954106.

Synthesis of magnesium doped manganese oxide (MnMgO) thin films for photovoltaic applications

A straightforward, inexpensive chemical technique of spray pyrolysis was employed to deposit MnO thin films on glass substrates at suitable flow parameters. In this investigation, spray pyrolysis was used to successfully deposit magnesium-doped manganese oxide thin films at various molar concentrations 0, 0.2, and 0.4. Using X-ray powder diffraction, FE-SEM and UV–Visible spectrophotometry methods, the produced thin film was evaluated to investigate its structural, morphological and optical attributes regarding the variation atomic percentage of magnesium, by maintaining a constant thin film's thickness. The MgMnO film's XRD pattern revealed that it is polycrystalline in nature. The growing magnesium doping is responsible for the noticeable (200) plane. The increase in surface roughness of prepared thin films has been studied with increasing in magnesium doping concentration. By using The magnesium doping of the films had an impact on their absorption. The magnesium doping concentration resulted in a modest reduction in the bandgap of the MgMnO thin films, which is advantageous for solar applications.

Aquaculture-driven evolution of the salmon louse mtDNA genome.

Resistance toward the antiparasitic pyrethroid, deltamethrin, is reported in the Atlantic salmon louse (Lepeophtheirus salmonis salmonis), a persistent ectoparasite of farmed and wild salmonids. The resistance mechanism is linked to mitochondrial DNA (mtDNA), where genetic markers for resistance have been identified. Here, we investigated how widespread pyrethroid use in aquaculture may have influenced mtDNA variation in lice, and the dispersion of resistant haplotypes across the North Atlantic, using historical (2000-2002 "pre-resistance") and contemporary (2014-2017 "post-resistance") samples. To study this, we sequenced ATPase 6 and cytochrome b, genotyped two genetic markers for deltamethrin resistance, and genotyped microsatellites as "neutral" controls of potential population bottlenecks. Overall, we observed a modest reduction in mtDNA diversity in the period 2000-2017, but no reduction in microsatellite variation was observed. The reduction in mtDNA variation was especially distinct in two of the contemporary samples, fixed for one and two haplotypes, respectively. By contrast, all historical samples consisted of close to one mtDNA haplotype per individual. No population genetic structure was detected among the historical samples for mtDNA nor microsatellites. By contrast, significant population genetic differentiation was observed for mtDNA among some of the contemporary samples. However, the observed population genetic structure was tightly linked with the pattern of deltamethrin resistance, and we therefore conclude that it primarily reflects the transient mosaic of pyrethroid usage in time and space. Two historically undetected mtDNA haplotypes dominated in the contemporary samples, both of which were linked to deltamethrin resistance, demonstrating primarily two origins of deltamethrin resistance in the North Atlantic. Collectively, these data demonstrate that the widespread use of pyrethroids in commercial aquaculture has substantially altered the patterns of mtDNA diversity in lice across the North Atlantic, and that long-distance dispersion of resistance is rapid due to high level of genetic connectivity that is observed in this species.

Associations between modest reductions in kidney function and adverse outcomes in young adults: retrospective, population based cohort study

ObjectiveTo study age specific associations of modest reductions in estimated glomerular filtration rate (eGFR) with adverse outcomes.DesignRetrospective, population based cohort study.SettingLinked healthcare administrative datasets in Ontario, Canada.ParticipantsAdult residents (18-65 years)...

ARF6 is a host factor for SARS-CoV-2 infection in vitro.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerged beta-coronavirus that enter cells via two routes, direct fusion at the plasma membrane or endocytosis followed by fusion with the late endosome/lysosome. While the viral receptor, ACE2, multiple entry factors and the mechanism of fusion of the virus at the plasma membrane have been investigated extensively, viral entry via the endocytic pathway is less understood. By using a human hepatocarcinoma cell line, Huh-7, which is resistant to the antiviral action of the TMPRSS2 inhibitor camostat, we discovered that SARS-CoV-2 entry is not dependent on dynamin but on cholesterol. ADP-ribosylation factor 6 (ARF6) has been described as a host factor for SARS-CoV-2 replication and is involved in the entry and infection of several pathogenic viruses. Using CRISPR/Cas9 genetic deletion, a modest reduction in SARS-CoV-2 uptake and infection in Huh-7 was observed. In addition, pharmacological inhibition of ARF6 with the small molecule NAV-2729 showed a dose-dependent reduction of viral infection. Importantly, NAV-2729 also reduced SARS-CoV-2 viral loads in more physiological models of infection: Calu-3 cells and kidney organoids. This highlighted a role for ARF6 in multiple cell contexts. Together, these experiments point to ARF6 as a putative target to develop antiviral strategies against SARS-CoV-2.

Best Practice Alerts: A Poke in the Eye or an Efficient Method for Safer Prescribing?

Best Practice Alerts: A Poke in the Eye or an Efficient Method for Safer Prescribing?

An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activity.

Most drugs used to treat viral disease target a virus-coded product. They inhibit a single virus or virus family, and the pathogen can readily evolve resistance. Host-targeted antivirals can overcome these limitations. The broad-spectrum activity achieved by host targeting can be especially useful in combating emerging viruses and for treatment of diseases caused by multiple viral pathogens, such as opportunistic agents in immunosuppressed patients. We have developed a family of compounds that modulate sirtuin 2, an NAD+-dependent deacylase, and now report the properties of a member of that family, FLS-359. Biochemical and x-ray structural studies show that the drug binds to sirtuin 2 and allosterically inhibits its deacetylase activity. FLS-359 inhibits the growth of RNA and DNA viruses, including members of the coronavirus, orthomyxovirus, flavivirus, hepadnavirus, and herpesvirus families. FLS-359 acts at multiple levels to antagonize cytomegalovirus replication in fibroblasts, causing modest reductions in viral RNAs and DNA, together with a much greater reduction in infectious progeny, and it exhibits antiviral activity in humanized mouse models of infection. Our results highlight the potential of sirtuin 2 inhibitors as broad-spectrum antivirals and set the stage for further understanding of how host epigenetic mechanisms impact the growth and spread of viral pathogens.

Implications of reducing antibiotic treatment duration for antimicrobial resistance in hospital settings: A modelling study and meta-analysis.

Reducing antibiotic treatment duration is a key component of hospital antibiotic stewardship interventions. However, its effectiveness in reducing antimicrobial resistance is uncertain and a clear theoretical rationale for the approach is lacking. In this study, we sought to gain a mechanistic understanding of the relation between antibiotic treatment duration and the prevalence of colonisation with antibiotic-resistant bacteria in hospitalised patients. We constructed 3 stochastic mechanistic models that considered both between- and within-host dynamics of susceptible and resistant gram-negative bacteria, to identify circumstances under which shortening antibiotic duration would lead to reduced resistance carriage. In addition, we performed a meta-analysis of antibiotic treatment duration trials, which monitored resistant gram-negative bacteria carriage as an outcome. We searched MEDLINE and EMBASE for randomised controlled trials published from 1 January 2000 to 4 October 2022, which allocated participants to varying durations of systemic antibiotic treatments. Quality assessment was performed using the Cochrane risk-of-bias tool for randomised trials. The meta-analysis was performed using logistic regression. Duration of antibiotic treatment and time from administration of antibiotics to surveillance culture were included as independent variables. Both the mathematical modelling and meta-analysis suggested modest reductions in resistance carriage could be achieved by reducing antibiotic treatment duration. The models showed that shortening duration is most effective at reducing resistance carriage in high compared to low transmission settings. For treated individuals, shortening duration is most effective when resistant bacteria grow rapidly under antibiotic selection pressure and decline rapidly when stopping treatment. Importantly, under circumstances whereby administered antibiotics can suppress colonising bacteria, shortening antibiotic treatment may increase the carriage of a particular resistance phenotype. We identified 206 randomised trials, which investigated antibiotic duration. Of these, 5 reported resistant gram-negative bacteria carriage as an outcome and were included in the meta-analysis. The meta-analysis determined that a single additional antibiotic treatment day is associated with a 7% absolute increase in risk of resistance carriage (80% credible interval 3% to 11%). Interpretation of these estimates is limited by the low number of antibiotic duration trials that monitored carriage of resistant gram-negative bacteria, as an outcome, contributing to a large credible interval. In this study, we found both theoretical and empirical evidence that reducing antibiotic treatment duration can reduce resistance carriage, though the mechanistic models also highlighted circumstances under which reducing treatment duration can, perversely, increase resistance. Future antibiotic duration trials should monitor antibiotic-resistant bacteria colonisation as an outcome to better inform antibiotic stewardship policies.

Throughfall exclusion and fertilization effects on tropical dry forest tree plantations, a large-scale experiment

Abstract. Across tropical ecosystems, global environmental change is causing drier climatic conditions and increased nutrient deposition. Such changes represent large uncertainties due to unknown interactions between drought and nutrient availability in controlling ecosystem net primary productivity (NPP). Using a large-scale manipulative experiment, we studied for 4 years whether nutrient availability affects the individual and integrated responses of aboveground and belowground ecosystem processes to throughfall exclusion in 30-year-old mixed plantations of tropical dry forest tree species in Guanacaste, Costa Rica. We used a factorial design with four treatments: control, fertilization (F), drought (D), and drought + fertilization (D + F). While we found that a 13 %–15 % reduction in soil moisture only led to weak effects in the studied ecosystem processes, NPP increased as a function of F and D + F. The relative contribution of each biomass flux to NPP varied depending on the treatment, with woody biomass being more important for F and root biomass for D + F and D. Moreover, the F treatment showed modest increases in maximum canopy cover. Plant functional type (i.e., N fixation or deciduousness) and not the experimental manipulations was the main source of variation in tree growth. Belowground processes also responded to experimental treatments, as we found a decrease in nodulation for F plots and an increase in microbial carbon use efficiency for F and D plots. Our results emphasize that nutrient availability, more so than modest reductions in soil moisture, limits ecosystem processes in tropical dry forests and that soil fertility interactions with other aspects of drought intensity (e.g., vapor pressure deficit) are yet to be explored.

#3000 EFFICACY AND SAFETY OF COTADUTIDE, A DUAL GLP1-GLUCAGON RECEPTOR AGONIST, IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND T2DM

Abstract Background and Aims Cotadutide is a dual GLP1-glucagon receptor agonist under development for NASH and CKD with T2DM. Incretin-based therapies have been shown to promote improvements in albuminuria while the addition of glucagon has been suggested to provide hepatic benefits; the renal benefits of dual GLP1-glucagon receptor agonism are unknown but kidney and liver are the organs with highest expression of glucagon receptor. We sought to evaluate the efficacy and safety of cotadutide in patients with CKD and T2DM. Method In this randomised, double-blind, phase 2b study, patients with T2DM and CKD on insulin and/or oral therapy including ≥ 40% treated with SGLT-2i (HbA1c ≥ 6.5 and ≤ 10.5%), eGFR ≥ 20 and &amp;lt; 90 ml/min/1.73m2 and BMI ≥ 25 (23 in Japan) kg/m2 were treated for 26 weeks. Participants were randomised (n = 45 per arm) to receive once-daily SC cotadutide titrated up to 100, 300 or 600 µg, or placebo. The primary endpoint was percentage change in UACR (log-transformed) at 14 weeks. Secondary endpoints evaluated urinary albumin creatinine ratio (UACR) at 26 weeks, safety and tolerability. Changes in renal function was evaluated as an exploratory endpoint. Results A total of 248 Participants were randomised. Approximately 47% were on SGLT-2i and 97% were on ACE inhibitors or ARBs at baseline. The primary endpoint was met. Dose dependent reductions in UACR from baseline were observed after 26 weeks treatment with 300 and 600 µg of cotadutide, -39.9% (95% CI -52,5, -23.9) and -46.0% (95% CI -57.1, -32.1) vs placebo (P &amp;lt;0.001). In patients on background SGLT2i therapy, similar reductions in UACR from baseline were observed after 26 weeks treatment with 300 and 600 µg of cotadutide, - 31.2% (95% CI – 51.9, -1.5) and - 48.7% (95% CI -64.1, - 26.6) vs placebo (P = 0.01 and &amp;lt;0.001 respectively). There was no observed change in eGFR early in dosing. At 26 weeks, an increase in eGFR (+5.5 ml/min/1.73m2) was observed with 600 µg of cotadutide (p = 0.028). A statistically significant, modest reduction in serum uric acid was observed as an exploratory endpoint at 26 weeks in the 100 and 600 µg arms (- 0.54 mg/dL, p = 0.03 and 0.76 mg/dL, p = 0.001 respectively) but not the 300 µg arm (- 0.32 mg/dL, p = 0.17). No significant changes in urine KIM-1 were observed. A significant increase in pulse rate was observed (+4.8 bpm), alongside a numerical reduction in systolic BP (-8.3 mmHg) at 600 µg on office-based measures. SAEs were balanced across all arms and there were fewer AE-related discontinuations at 100 and 300 ug versus placebo, but more discontinuations at 600 µg. Conclusion In patients with CKD with T2DM, cotadutide promoted clinically important effects on UACR on top of standard of care with an acceptable tolerability profile. The results suggest cotadutide has potential to provide benefit to patients with CKD and T2DM. Larger studies will be required to evaluate this.

Delivery of a Prevention Program in Large College Classes: Effectiveness of the Expectancy Challenge Alcohol Literacy Curriculum

Background: Despite modest reductions in alcohol use among college students, drinking-related harms continue to be prevalent. Group-delivered programs have had little impact on drinking except for experiential expectancy challenge interventions that are impractical because they rely on alcohol administration. Expectancy Challenge Alcohol Literacy Curriculum (ECALC), however, offers a non-experiential alternative suitable for widespread implementation for universal, selective, or indicated prevention. Objectives: ECALC has been effective with mandated students, fraternity members, and small classes of 30 or fewer first-year college students. Larger universities, however, typically have classes with 100 students or more, and ECALC has not yet been tested with groups of this size. To fill this gap, we conducted a group randomized trial in which five class sections with over 100 college students received either ECALC or an attention-matched control presentation and completed follow-up at four weeks. Results: ECALC was associated with significant changes on six subscales of the Comprehensive Effects of Alcohol Scale (CEOA), post-intervention expectancies predicted drinking at four-week follow-up, and there were significant expectancy differences between groups. Compared to the control group, students who received ECALC demonstrated significant expectancy changes and reported less alcohol use at follow-up. Conclusions: Findings suggest ECALC is an effective, single session group-delivered intervention program that can be successfully implemented in large classes.

Use of Quantile Treatment Effects Analysis to Describe Antidepressant Response in Randomized Clinical Trials Submitted to the US Food and Drug Administration

Major depressive disorder (MDD) is a leading cause of global distress and disability. Earlier studies have indicated that antidepressant therapy confers a modest reduction in depressive symptoms on average, but the distribution of this reduction requires more research. To estimate the distribution of antidepressant response by depression severity. In this secondary analysis of pooled trial data, quantile treatment effect (QTE) analysis was conducted from the US Food and Drug Administration (FDA) database of antidepressant monotherapy for patients with MDD, encompassing 232 positive and negative trials submitted to the FDA between 1979 and 2016. Analysis was restricted to participants with severe MDD (17-item Hamilton Rating Scale for Depression [HAMD-17] score ≥20). Data analysis was conducted from August 16, 2022, to April 16, 2023. Antidepressant monotherapy compared with placebo. The distribution of percentage depression response was compared between the pooled treatment arm and pooled placebo arm. Percentage depression response was defined as 1 minus the ratio of final depression severity to baseline depression severity, expressed as a percentage. Depression severity was reported in HAMD-17-equivalent units. A total of 57 313 participants with severe depression were included in the analysis. There was no significant imbalance in baseline depression severity between the pooled treatment arm and pooled placebo arm, with a mean HAMD-17 difference of 0.037 points (P = .11 by Wilcoxon rank sum test). An interaction term test for rank similarity did not reject the rank similarity governing percentage depression response (P > .99). The entire distribution of depression response was more favorable in the pooled treatment arm than in the pooled placebo arm. The maximum separation between treatment and placebo occurred at the 55th quantile and corresponded to an absolute improvement in depression due to active drug of 13.5% (95% CI, 12.4%-14.4%). The separation between treatment and placebo diminished near the tails of the distribution. In this QTE analysis of pooled clinical trial data from the FDA, antidepressants were found to confer a small reduction in depression severity that was broadly distributed across participants with severe depression. Alternatively, if the assumptions behind the QTE analysis are not met, then the data are also compatible with antidepressants eliciting more complete response in a smaller subset of participants than is suggested by this QTE analysis.

An experimental investigation of the effect of ride control systems on the motions response of high-speed catamarans in irregular waves

To ensure high-quality passenger comfort and enhance the operability and performance of high-speed catamarans, reducing the severity of motions and structural loads using Ride Control Systems (RCS) is beneficial. To optimize ride control algorithms, it is essential to have a thorough understanding of the RCS in actual ship sailing conditions. In this paper, a set of towing tank tests was undertaken to study the effectiveness of different control algorithms, including linear and nonlinear versions of the heave control, pitch control, and local control, on motion responses of a 2.5 m scaled model of a 112 m INCAT Tasmania high-speed catamaran in irregular waves. The RCS included a centre bow-fitted T- Foil and two transom-mounted stern tabs. Obtained results were also compared with the scale model responses with passive RCS and with no RCS fitted. Heave and pitch motion responses as well as vertical accelerations of the catamaran were calculated in head seas at a model speed of 2.89 m/s (37 knot full scale), a modal period of 1.5 s (10 s full scale) and two significant wave heights of 60 mm and 90 mm, simulating full scale wave heights of 2.7 m and 4 m, respectively. It was demonstrated that deploying a passive RCS led to modest reductions in the peak motion responses. The most significant reductions in ship motions took place in the nonlinear modes of the heave and pitch control algorithms at a significant wave height of 60 mm (full-scale 2.7 m). In this condition, the nonlinear pitch control mode was demonstrated to be the most effective algorithm since this control mode mitigated the peak pitch RAO by 41% and vertical accelerations by 46%. This was a substantial reduction in ship motions with the RCS at an equivalent full-scale speed of 37 knot at 2.7 m wave height in the random sea condition.

Recent High Missouri River Basin Runoff Was Unlikely Caused by Climate Change

Abstract October–September runoff increased 6% and 17% in the upper (UMRB) and lower (LMRB) Missouri River basins, respectively, in a recent (1990–2019) climate in comparison with a past (1960–89) climate. The runoff increases were unanticipated, given various projections for semipermanent drought and/or aridification in the North American Great Plains. Here, five transient coupled climate model ensembles are used to diagnose the effects of natural internal variability and anthropogenic climate change on the observed runoff increases and to project UMRB and LMRB runoff to the mid-twenty-first century. The runoff increases observed in the recent climate in comparison with the past climate were not due to anthropogenic climate change but rather resulted mostly from an extreme occurrence of internal multidecadal variability. High runoff resulted from large, mostly internally generated, precipitation increases (6% in the UMRB and 5% in the LMRB) that exceeded simulated increases attributable to climate change forcing alone (0%–2% intermodel range). The precipitation elasticity of runoff, which relates runoff sensitivity to precipitation differences in the recent climate in comparison with the past climate, led to one–threefold and two–fourfold amplifications of runoff versus precipitation in the UMRB and LMRB, respectively. Without the observed precipitation increases in the recent climate in comparison with the past climate, effects of human-induced warming of about 1°C would alone have most likely induced runoff declines of 7% and 13% in the UMRB and LMRB, respectively. Ensemble model simulations overwhelmingly project lower UMRB and LRMB runoff by 2050 when compared with 1990–2019, a change found to be insensitive to whether individual realizations experienced high flows in the recent climate. Significance Statement Declines in Missouri River basin runoff under climate change pose serious threats to communities that depend on riverine transport, irrigated agriculture, and aquatic recreation. Concerns arising from reports and projections of semipermanent drought in the basin have yet to be realized; observed runoff was greater in a recent climate (1990–2019) than in a past climate (1960–89). We found that the observed runoff increase from past to recent climates was due not to anthropogenic influences but rather to internal multidecadal variability that led to unlikely precipitation increases (&lt;10% probability) that overwhelmed the drying effect of warming temperatures. Model simulations indicate that a modest reduction in runoff of ∼7%–15% was most likely from the past climate to the recent climate.

A preclinical study to evaluate the combination of azeliragon, an inhibitor of the receptor for advanced glycation endproducts (RAGE), with radiation therapy as a potential treatment of glioblastoma.

e14056 Background: Systemic lymphopenia, which is independently associated with poor overall survival, is observed in approximately 30-50% of patients with glioblastoma (GBM) after chemoradiotherapy. We recently found that cranial irradiation of GBM tumors increases circulating myeloid-derived suppressor cells (MDSC) contributing to systemic lymphopenia. Additionally, we found that cranial radiation increases circulating levels of the RAGE ligands S100A8/9 and HMGB1, which have been reported to increase MDSC and their immunosuppressive effects through binding RAGE. We, therefore, hypothesized that targeting RAGE receptors on MDSC could prevent immunosuppression and improve survival in preclinical GBM models. Methods: We orthotopically implanted GBM cells (GL261 and CT2A) into immunocompetent C57BL6 mice. The GBM tumor-bearing mice were treated with five doses of fractionated radiation therapy (RT, 2 Gy/day for 5 consecutive days) to the whole head in combination with RAGE inhibitor azeliragon (0.1mg/mice/day i.p starting one day before RT for up to 10 days). We evaluated the immune cells in the tumor microenvironment (TME) and spleen at 14 days post-tumor implantation. We also evaluated the circulating immune cells and RAGE ligands (HMGB1 and S100A8/A9) in the plasma at 7, 14, and 21 days post-tumor implantation and monitored the mice for survival up to 60 days. Results: GBM tumor-bearing mice (GL261 &amp; CT2A) treated with RT plus azeliragon had significantly improved survival when compared to RT alone or azeliragon alone. RT plus azeliragon significantly reduced the accumulation of granulocytic-MDSC (G-MDSC), monocytic-MDSC (M-MDSC), tumor-associated macrophages (TAM), and regulatory T cells (Treg), while increasing infiltrating CD8 T cells in the TME as compared to RT alone. RT alone significantly increased the accumulation of G-MDSC and M-MDSC in the spleen, which was significantly reduced with concurrent azeliragon. Concurrent administration of azeliragon with RT did not significantly affect the radiation-induced increase of circulating M-MDSC as well as plasma HMGB1 and S100A8/A9 concentration, though there was a modest reduction of circulating G-MDSC. Conclusions: Our study indicates that azeliragon, by blocking RAGE interaction with its ligands, helps to overcome the MDSC-mediated immunosuppression that occurs after RT. The combination of azeliragon with RT enhances survival in preclinical models. Clinical trials evaluating the safety and efficacy of azeliragon in combination with RT for newly diagnosed GBM are currently under development.