Load Reduction Research Articles

N-acetylcysteine antimicrobial action against endodontic pathogens-systematic review and meta-analysis.

Effective root canal disinfection is crucial for the success of endodontic treatment. N-acetylcysteine (NAC), known for its antimicrobial properties, has recently been investigated as a potential endodontic irrigant or intracanal medication. This systematic review aims to assess the antimicrobial efficacy of NAC in comparison to sodium hypochlorite, chlorhexidine, and calcium hydroxide against endodontic pathogens. A comprehensive search was conducted in PubMed, Scopus, Web of Science, Cochrane Library, and LILACS databases up to April 2024, without language or date restrictions. The PICO strategy for this review were as follows: population-teeth requiring endodontic treatment; intervention-NAC used as an endodontic irrigant or intracanal medication; comparison-sodium hypochlorite, chlorhexidine, and calcium hydroxide; Outcomes: reduction in microbial load, encompassing clinical and in vitro studies. Risks of bias assessment and data extraction were conducted with two reviewers independently selecting studies, extracting data, and assessing risk of bias. A general meta-analysis was performed across all included studies, with additional meta-analyses evaluating different exposure times, NAC concentrations, control groups and evaluation methods. After removing duplicates, 9170 studies were initially identified, and seven in vitro studies were included in the systematic review, of which five were included in the meta-analysis. Data were compared using standardized mean differences within a random-effects model. No clinical studies using NAC as an antimicrobial agent were identified. The overall meta-analysis demonstrated that NAC effectively reduced Enterococcus faecalis. Further meta-analyses revealed that exposure time, NAC concentration and choice of control group significantly influenced NAC's effectiveness. NAC effectively reduced Enterococcus faecalis, showing comparable antimicrobial activity to CHX and NaOCl, especially at concentrations of 25-50 mg/mL over a 7-day exposure. Despite significant heterogeneity across studies, NAC demonstrated satisfactory antimicrobial effects in vitro. This suggests that NAC merits reconsideration as an effective intracanal medication for clinical use.

Clinical Trial to Evaluate Safety and Efficacy of Thinqure20 (A Herbal Composition) in the Treatment and Prophylaxis of Novel Coronavirus and Testing its In vitro- Potential against MS2 Bacteriophagae, Corona Virus, Influenza Virus and Mucor racemosus

Background and Objective: Thinqure20 is a polyherbal, reverse-pharmacology-based formulation that contains Piper longum, Piper nigrum, Zingiber officinale, and rock salt as active ingredients. It is designed to work as an effective antiviral agent and also as a preventive measure against SARS-CoV-2. Clinical and non-clinical studies have established significant safety efficacy and tolerability of Thinqure20 formulation in the treatment of COVID-19 infection. Methods: In vivo human study was conducted on COVID-19 patients for 5 days. A total of 30 Covid-19 patients (n = 30) were enrolled. In vitro, cell line studies were also carried out to evaluate the potential effectiveness of Thinqure20 polyherbal formulation as an antiviral, antifungal, and Angiotensin- Converting Enzyme 2 (ACE2) inhibition. Results: Human studies have demonstrated a mean percentage of reduction in viral load from baseline to end of the study visit which was found to be 75.4%. The minimum and maximum reduction in viral load was found to be 59.3% and 100%, respectively. Viral load testing was carried out by Reverse Transcriptase-quantitative Polymerase Chain Reaction (RT-qPCR) test. In vitro studies of Thinqure, 20 extracts showed potential antiviral activity against MS2 bacteriophage, influenza, and human coronavirus, antifungal activity against Mucor racemosus, and significant ACE2 receptor inhibition. Conclusion: Thinqure20, a polyherbal formulation, is a potentially effective antiviral agent against non-enveloped viruses (MS2 bacteriophage), enveloped viruses (influenza and human coronavirus), and antifungal agent against mucor strains. It is also proven to be effective in the treatment of COVID-19 and can be attributed to an early recovery by the reduction in viral load.

Functional characterization of MMAR_1296 in Mycobacterium marinum and its potential as a vaccine candidate.

The Pro-Glu/Pro-Pro-Glu (PE/PPE) family proteins in mycobacteria plays a crucial role in pathogenesis and immune evasion. These proteins characterized by unique structures with conserved sequences. This study elucidated the specific immunological functions of MMAR_1296 from marine mycobacterium. Expressing MMAR_1296 in Mycobacterium smegmatis (M. smegmatis) led to significant alterations in bacterial morphology, as well as reduced survival of M. smegmatis under adverse in vitro conditions and within macrophages. Furthermore, transcriptome analysis of mouse macrophages indicated that natural immunity-related pathways were upregulated in the group infected with M. smegmatis recombinantly expressing MMAR_1296. Moreover, the mycobacterium Growth Inhibition Assays(MGIA)in mice demonstrated that M. smegmatis expressing MMAR_1296 exerted a significant inhibitory effect against Mycobacterium abscessus (M. abscessus) and Mycobacterium marinum (M. marinum) infections. Immunization challenge experiments in mice further confirmed its protective effects, showing a reduction in organ bacterial loads by 1 log10 value compared to the positive control group. These findings indicate that MMAR_1296 is a promising vaccine candidate for M. abscessus and M. marinum. Given that PE/PPE protein family is also a crucial component of Mycobacterium tuberculosis (M. tuberculosis) antigens, further exploration of sequence functions based on MMAR_1296 could reveal broader applications of PE/PPE proteins family for M. tuberculosis treatment. This study supported vaccine development targeting PE/PPE proteins in mycobacteria and paves the way for broader applications.

In-vitro Study of HIV-derived Reverse Transcriptase Inhibition

Introduction: HIV utilizes a reverse transcriptase (RT) enzyme to convert the HIVRNA into DNA. Inhibition of the reverse transcription mechanism of HIV-RT may serve as a potential therapeutic approach to impede the proliferation of HIV in those who are infected. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a type of medication that directly and non-competitively bind to the allosteric site of HIV-RT, inhibiting its polymerase activity. Aim: This study was aimed at the synthesis of hydrazine derivatives and their evaluation for HIV- reverse transcriptase inhibition using RT-qPCR-based assay. Objective: The objective of this study was to determine the HIV- reverse transcriptase inhibition using chemical compounds as non-nucleoside reverse transcriptase inhibitors in RT-qPCR. Methods: This study involved the synthesis of five distinct hydrazine derivatives, which were subsequently tested for their capacity to inhibit HIV-RNA polymerization by targeting HIVderived reverse transcriptase. For the determination of the study assay, commercially available HIV-RT was subjected to treatment with derivatives and utilized in an RT-qPCR experiment to determine the activity or inhibitory effects of HIV-RT for HIV-RNA polymerization. Results: The in-vitro assay results demonstrated a reduction in viral load due to suppression of reverse transcriptase activity when compared to the pre-quantified values obtained from untreated RT. Among the five compounds, 4-N, N-dimethylamino benzaldehyde hydrazine (C18H22N4) had the highest ability to suppress HIV-RT. This molecule reduced HIV-RNA reverse transcription by more than 90% during RT-qPCR, which is a novel and promising strategy. Conclusion: N, N-dimethylamino benzaldehyde hydrazine (C18H22N4) can suppress the activity of HIV-RT, and this effect becomes more pronounced as the concentration of the compound increases.

Evaluation of the Performance of Microalgae and Constructed Wetlands for the Reduction of Toxicity Organic Load and Pharmaceuticals from Wastewaters

The present study aimed to evaluate the performance of a novel integrated system composed of microalgae and constructed wetlands (CW). The microalgae production tank was designed as a raceway type, and microalgae of the genus Chlorella were inoculated, while the CW was established as the first stage of the French model and vegetated with the macrophytes Chrysopogon zizanioides, Typha domingensis, and Dracaena trifaciata. The hydraulic retention time in each unit was 7 days, totaling 14 days of treatment. Good reductions in dissolved organic carbon (67.2%) and Total N (68.6%) were achieved after the treatment. The treatment also completely eliminated acute ecotoxicity against Daphnia magna and genotoxicity in the Allium cepa test assay. Liquid chromatographic analysis revealed the presence of 9 pharmaceuticals in the raw wastewaters, whereas only residual dipyrone was detected after the CW unit. Thus, the novel system investigated in our study, which combines microalgae and CW using 3 different species of macrophytes, proved to be a promising alternative for treating urban wastewaters, as it effectively reduced organic load, nutrient content, toxicity, and removed emerging contaminants such as pharmaceuticals. Future recommendations include investigating the primary removal mechanisms of the pharmaceuticals and enhancing the separation process of the microalgae.

YafN-YafO toxin-antitoxin system contributes to stress resistance and virulence of avian pathogenic Escherichia coli.

Avian pathogenic Escherichia coli (APEC) is a major threat to the poultry industry, causing bloodstream and extraintestinal infections. Type II toxin-antitoxin (TA) systems are known to aid bacterial pathogens in adapting to stress, promoting persister cell formation, and enhancing virulence. While type II TA systems have been extensively studied in many pathogens, APEC-derived TAs have received limited attention. Our study focused on the YafN-YafO type II TA system in APEC O2 strain E058. Using bacterial two-hybrid and pull-down assays, we confirmed the interaction between YafN and YafO. Electrophoretic mobility shift assays (EMSA) and lacZ fusion reporter assays demonstrated that YafN negatively autoregulates its own operon. The deletion of yafNO resulted in a significant reduction in persister cell formation under antibiotic and environmental stress (P < 0.01). Moreover, the yafNO mutant showed a ∼3-fold reduction in survival within chicken macrophages and attenuated virulence in chicken infection models, with a 44-fold increase in LD50 and ∼80-fold reduction in bacterial loads in blood and tissues (P < 0.01). These results demonstrate that the YafN-YafO is an active type II TA system in APEC E058, contributing to both stress resistance and virulence. Targeting this system could offer a novel strategy for controlling APEC infections.

Cold atmospheric plasma therapy as a novel treatment for Berlin Heart EXCOR pediatric cannula infections.

Cold atmospheric plasma (CAP) therapy has been recognized as effective treatment option for reducing bacterial load in chronic wounds, such as adult ventricular assist device (VAD) driveline exit-site infections. Currently, there have been no reports on the safety and efficacy of CAP therapy for pediatric cannula infections and inflammations in paracorporeal pulsatile VADs. The mechanical strength of Berlin Heart EXCOR cannulas were tested both before and after CAP treatment (SteriPlas, Adtec Healthcare Limited, UK) to prove material safety. A ring tensile test of 20 untreated and 20 CAP-treated (5 min) EXCOR cannulas (Ø12mm), assessed the force at the breaking point of the cannulas (Fmax), at 25% (F25%) and 50% (F50%) of the maximum displacement. Additionally, the scanning electron microscope (SEM) micrographs for both groups examined any surface changes. Finally, the case of a 13-year-old male EXCOR patient with cannula infections, treated with CAP over 100 days, is presented. The invitro measurements revealed no statistically significant differences in mechanical strength between the control and CAP group for F25% (8.18 ± 0.36 N, vs. 8.02 ± 0.43 N, p = 0.21), F50% (16.87 ± 1.07 N vs. 16.38 ± 1.32 N, p = 0.21), and FMAX (44.55 ± 3.24 N vs. 42.83 ± 4.32 N, p = 0.16). No surface structure alterations were identified in the SEM micrographs. The patient's cannula exit-sites showed a visible improvement in DESTINE wound staging, reduction in bacterial load and inflammatory parameters after CAP treatment without any side effects. Overall, CAP therapy proved to be a safe and effective for treating EXCOR cannula exit-site wound healing disorders in one pediatric patient, but further studies should investigate this therapy in more detail.

Midgut immune profiling and functional characterization of Aedes aegypti ABC transporter gene(s) using systemic and local bacterial challenges

BackgroundThe mosquito midgut is crucial for digestion and immune interactions. It produces several immune factors that protect the organ from invading pathogens and can limit their propagation. Studies on mosquito midgut transcriptome following pathogen exposure have revealed the presence of non-canonical immune genes, such as ABC transporters, whose function in insect immunity remains unexplored. Therefore, this study focuses on identifying and characterising the immune role of ABC transporters in the midgut of Aedes aegypti, a primary arboviral vector.MethodsTo identify the midgut-expressed ABC transporters, the mosquitoes were challenged with a mixture of gram-negative (Escherichia coli) and gram-positive (Micrococcus luteus) bacteria, and the expression of all ABC transporters was analysed with PCR using gene-specific primers. Furthermore, the transcriptional alterations of midgut ABC transporters were explored at different time points upon a thoracic nano-injection (systemic challenge) or infectious blood meal (local challenge) of the bacterial mixture through quantitative real-time PCR (qPCR), and one gene was selected for RNAi-mediated gene silencing and its role assessment in midgut immune responses.ResultsThe expression of all 48 microbial-induced midgut-expressing Ae. aegypti ABC transporter genes upon systemic or local bacterial challenges was analyzed. Based on the transcriptomic data and potential immune expression similar to the well-known immune gene defensin, AaeABCG3 was selected for RNAi-mediated gene silencing and characterization. The AaeABCG3 gene silencing exhibited a significant reduction of midgut bacterial load through the induction of nitric oxide synthase (NOS) in sugar-fed and systemic bacterial-challenged mosquitoes. In contrast, midgut bacterial load was significantly regulated by induction of defensin A and cecropin G in the late hours of local bacterial challenges in AaeABCG3-silenced mosquitoes.ConclusionsThe silencing of AaeABCG3 modulated the mosquito midgut immune response and disturbed the midgut microbiota homeostasis. The systemic immune responses of AaeABCG3-silenced mosquitoes were influenced by the JAK-STAT pathway with no induction of Toll and IMD immune pathways. Interestingly, Toll and IMD immune pathways actively participated in the late hours of local bacterial challenges, suggesting that the route of infection influences these immune responses; however, the molecular mechanism behind these phenomena still needs to be explored. Overall, this work provides significant insight into the importance of ABC transporters in mosquito immunity.Graphical

Evaluating best management practices for nutrient load reductions in tile-drained watersheds of the Laurentian Great Lakes Basin: A literature review.

Tile drainage systems are extensively implemented across the Laurentian Great Lakes Basin (GLB) to enhance agricultural productivity on poorly drained soils. However, these systems substantially contribute to excess nutrient runoff, particularly phosphorus (P) and nitrogen (N), exacerbating eutrophication and harmful algal blooms in the Great Lakes. This literature review synthesized current knowledge on nutrient loadings from tile-drained agricultural watersheds and evaluated the effectiveness of various agricultural best management practices (BMPs) in mitigating nutrient losses in the GLB. Through a meta-synthesis of field and watershed scale monitoring and modeling studies and statistical analysis using Box-Whisker plots and Monte Carlo simulations, we assessed the nutrient reduction potential of representative BMPs, including cover cropping, nutrient management, controlled drainage, and constructed wetlands in tile-drained landscapes. Findings indicated that individual BMPs substantially reduced nutrient loadings, but the effectiveness of these BMPs depended on site-specific factors, including climate conditions, soil type, and drainage system design. Integrated approaches at field, edge-of-field, and watershed scales with a combination of multiple BMPs enhanced nutrient reduction benefits, aligning with regional water quality targets. The review also highlighted the challenges of climate change that may undermine BMP performance by altering precipitation patterns and increasing extreme weather events. To address these complexities, we proposed a framework for developing adaptive BMP scenarios tailored to specific watershed conditions, emphasizing the need for long-term monitoring and hydrologic model enhancements. This framework was designed to help policymakers, stakeholders, and farmers protect water quality and balance agricultural productivity in the GLB and similar agricultural regions globally.

Extremal structures with embedded prefailure indicators

Preemptive identification of potential failure under loading of engineering structures is a critical challenge. Our study presents an innovative approach to design built-in prefailure indicators within multiscale structural designs with optimized load carrying capabilities utilizing the design freedom of topology optimization. The indicators are engineered to visibly signal load conditions approaching the global critical buckling load at predefined locations. By showing noncritical local buckling when activated, the indicators provide early warning without compromising the overall structural integrity of the design. This proactive safety feature enhances structural reliability. The method is particularly beneficial for offshore wind turbines, where many sensors are located below sea level and are inaccessible for maintenance. By allowing the placement of indicators in accessible predetermined locations, our method can reduce the number of required sensors and improve structural health monitoring. Additionally, the potential use of memory overload indicators exploiting plasticity offers a reliable means of detecting overloads during offline periods. Experimental testing of 3D-printed designs confirms a strong correlation between measurements and numerical simulations, demonstrating the feasibility of creating structures that can signal the need for load reduction or maintenance at predetermined locations. This research contributes to the design of safer structures by introducing built-in early-warning failure systems.

P-1099. Correlation Analysis of Cefiderocol In vitro Activity and In vivo Efficacy Against Acinetobacter baumannii Strains with Difficult-to-Read MIC Endpoints

Abstract Background Cefiderocol (FDC) is a siderophore-conjugated cephalosporin with broad activity against Gram-negative bacteria, including Acinetobacter baumannii. For some isolates, determining the minimum inhibitory concentration (MIC) endpoints for FDC can be difficult due to the trailing growth phenomenon. Recently guidance on how to determine the MIC when trailing occurs has been updated in the CLSI M100 document, to enhance MIC reproducibility. In this study, we determined MICs of A. baumannii strains that show difficult to determine MIC endpoint due to trailing according to the updated CLSI guidance and analyzed correlations between MICs and in vivo efficacy. In vivo bacterial growth or reduction from start of treatment with cefiderocol against Acinetobacter baumannii in the neutropenic murine thigh infection model using humanized pharmacokinetic exposure of cefiderocol. In vivo (S): mean of reduction in bacterial cell number at 24 hours after initial treatment with cefiderocol (mean of change &amp;lt;0 log10 colony forming unit (CFU) /thigh) CFU/thigh), in vivo (R): mean of increase in bacterial cell number at 24 hours after initial treatment with cefiderocol (mean of change ≥0 log10 CFU/thigh). MIC values shown blue, orange, and red indicate susceptible, intermediate, and resistant, respectively, according to CLSI guideline 2024. Methods MICs were determined according to the 2024 CLSI guidance using iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) from BD-BBL for 43 A. baumannii isolates, including 13 strains that show severe trailing. All strains had been evaluated in vivo in the murine thigh infection model using humanized pharmacokinetic exposure of FDC (1). Categorical agreements between MICs and in vivo efficacy in murine thigh infection model Susceptible (S), Non-susceptible (NS), breakpoints as published by CLSI (2024), In vivo (S): mean of reduction in bacterial cell number at 24 hours after initial treatment with cefiderocol (mean of change &amp;lt;0 log10 colony forming unit (CFU)/thigh, in vivo (R): mean of increase in bacterial cell number at 24 hours after initial treatment with cefiderocol (mean of change ≥0 log10 CFU/thigh). Results FDC MIC range of tested A. baumannii strains was 0.12 to &amp;gt;32 μg/mL. Among 19 strains that showed a reduction in bacterial load after treatment with FDC in the murine thigh infection model, 94.7% (18/19 strains) were categorized as FDC susceptible (Figure and Table 1). Among 24 strains that showed increase in bacterial load after treatment with FDC in vivo, 87.5% (21/24 strains) were categorized as FDC non-susceptible. The categorical agreement of MICs and in vivo efficacy was 90.7% (39/43). As for the 13 strains that showed severe trailing, the categorical agreement of MICs and in vivo efficacy was 84.6% (11/13, Table 2). The updated CLSI guidance did not impact the overall agreement that was obtained earlier using the previous CLSI guidance (Table 1, 2). Categorical agreements between MICs and in vivo efficacy in murine thigh infection model for 13 strains that showed severe trailing Susceptible (S), Non-susceptible (NS), breakpoints as published by CLSI (2024), In vivo (S): mean of reduction in bacterial cell number at 24 hours after initial treatment with cefiderocol (mean of change &amp;lt;0 log10 colony forming unit (CFU)/thigh, in vivo (R): mean of increase in bacterial cell number at 24 hours after initial treatment with cefiderocol (mean of change ≥0 log10 CFU/thigh). Conclusion Our correlation analysis between MICs and in vivo efficacy in thigh infection model confirms the validity of MIC endpoint determinations described in CLSI M100 document, including strains that show severe trailing. Reference: 1. Monogue L, et al. Antimicrob Agents Chemother. 2017;61(11):e01022-17. Disclosures Hidenori Yamashiro, Shionogi &amp; Co., Ltd.: Employee Motoyasu Onishi, PhD, Shionogi &amp; Co., Ltd.: Employee Naomi Anan, MSc, Shionogi &amp; Co., Ltd.: Employee Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Christopher M. Longshaw, PhD, Shionogi BV: Employee Miki Takemura, n/a, Shionogi &amp; Co., Ltd.: Employee Yoshinori Yamano, PhD, Shionogi &amp; Co., Ltd.: Employee

Regional modeling of surface solar radiation, aerosol, and cloud cover spatial variability and projections over northern France and Benelux

Abstract. Investigating the current and future evolution of surface solar radiation (SSR) is essential in the context of climate change and associated environmental issues. We focus on the influence of atmospheric aerosols, along with cloud cover and water vapor content, on northern France and Benelux in spring and summer. Our analysis relies on the National Centre for Meteorological Research–Limited Area Adaptation Dynamic International Development v6.4 (CNRM-ALADIN64) regional climate model at 12.5 km resolution, which includes an interactive aerosol scheme. A regional evaluation of 2010–2020 ALADIN hindcast simulations of clear-sky and all-sky SSR, clear-sky frequency, and aerosols, through comparison to coincident multi-site ground-based measurements, shows reasonable agreement. In addition, these hindcast simulations emphasize how elevated aerosol loads over Benelux and high cloud cover over southwestern England reduce the SSR. Additional ALADIN climate simulations for 2050 and 2100 under Coupled Model Intercomparison Project phase 6 (CMIP6) Shared Socioeconomic Pathway (SSP) 1-1.9 predict a significant reduction in aerosol loads compared to 2005–2014, especially over Benelux, associated with future increases in clear-sky SSR but geographically limited all-sky SSR evolution. In contrast, under SSP3-7.0, clear-sky and all-sky SSR is projected to decline significantly over the domain. This decline is greatest in spring over Benelux due to combined increases in cloud cover and nitrate aerosols projected from 2050 onwards. In summer, projected decreases in cloud cover largely attenuate the reduction in SSR due to aerosols in 2050, while by 2100 rising water vapor contents counteract this attenuation. Thus, our results highlight seasonally and spatially variable impacts of future anthropogenic aerosol emissions on SSR evolution due to cloud cover and water vapor modifications that will likely largely contribute to the modulation of forthcoming aerosol influences.

Curcumin-laden hydrogel coating medical device for periprosthetic joint infection prevention and control.

The Periprosthetic Joint Infection (PJI) is one of the most important complications of the joint arthroplasty. This surgical procedure is rising worldwide and is further affecting the public health because of the widespread resistance to antibiotics. New therapeutic strategies and innovative antimicrobial biomaterials development are needed to eradicate pathogens without inducing resistance and accelerating recovery. In this direction, herein Curcumin I- (Cur-) loaded DAC® (Defensive Antibacterial Coating, a hydrogel based on hyaluronic acid conjugate to polylactic acid, hereafter named DAC) has been built on. To incorporate Cur in the DAC, so obtaining Cur-DAC (Cur ≅ 0.93 mg/g), the generally recognized as safe (GRAS) propylene glycol (PG) was used as cosolvent. The drugs combinations of Cur (≅0.93 mg/g) and Vancomycin (Van) (at low dose that is ≅ 0.033 mg/g) within the hydrogel (Cur/Van-DAC) was experienced too. Hydrogels were prepared and characterized by rheological investigations and their erosion together with the drug release profile over the time evaluated in physiological conditions. The nanohydrogels produced upon water dilution were characterized by AFM, DLS, and UV/Vis absorption and emission spectroscopies. Superior Cur stability over pH-, solvent- and photo-induced degradations resulted in the DAC matrix. The photoinduced antimicrobial activity of Cur-DAC against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium was evaluated by spreading loaded DAC-based hydrogel onto titanium disk mimicking prosthesis, thus detecting a good reduction of bacterial load after 30 min of exposure to light and a subsequent decrease of cells number at 24 h. The drug association in Cur/Van-DAC demonstrated the best activity against MRSA, even in the presence of nutrients, respect to established DAC loaded with high amounts of Van (ranging from 18.7 mg/g to 45.8 mg/g) used during the surgery, due to the photo-antibacterial activity of Cur, becoming promising to prevent and control joint infections.

P-1225. The population Pharmacodynamics study of Ganciclovir in Thai kidney transplant recipients with cytomegalovirus infection

Abstract Background The aim of this study was to describe the population pharmacodynamic (PPD) of intravenous Ganciclovir for preemptive and treatment in Thai kidney transplant recipients (KT) with cytomegalovirus (CMV) infection who were not during hemodialysis or KT-related systemic lupus erythematous. Simulations of CMV viral load overtime according to recommended dose Methods A retrospective study was conducted by collecting data from medical records, from 1 January 2020-31 December 2022. The estimated pharmacokinetic (PK) parameters derived from published model were applied to link with PPD, subsequently simulate the changes of blood CMV viral load overtime according to recommended dosage, stratified by glomerular filtration rate (GFR). PK/PPD modelling, and simulation were performed with parametric methodology using Phoenix® software, version 8.4, Certara. Visual Predictive Check Results Twelve patients were included. The PPD model was developed by mechanistic indirect response equation, applying Emax model to stimulate the rate of CMV clearance. There were not any significant clinical and laboratory covariates affecting CMV dynamic. Goodness-of-fit plots were acceptable. A visual predictive check showed good consistency with observed data, whereas 1000 times-bootstrapping analysis was completed with 100% success rate. Ten thousand times-simulation indicated the time required for achieving 1-log10 and 2-log10 reduction of CMV viral load by recommended dose were 7-8 days and 15.8-18.5 days respectively. Viral decline was delayed in patients with lowered GFR. Goodness-of-fit plot Conclusion The developed model described Ganciclovir-CMV viral load relationship and simulation result indicating the longer time for CMV viral load reduction in patients who had lower GFR. Our analysis demonstrated that the current recommended dose is required to be reconsidered and further systematic PD study is needed. Disclosures All Authors: No reported disclosures

P-2026. Obeldesivir for the Treatment of COVID-19 in People with Risk Factors for Progression to Severe Disease: the BIRCH Study

Abstract Background COVID-19 remains a serious condition, as the risk of severe outcomes increases with age and comorbid conditions. Early antiviral therapy has been shown to prevent disease progression. Obeldesivir (ODV) is an oral, broad spectrum, nucleoside analog prodrug inhibitor of SARS-CoV-2 RNA-dependent RNA polymerase. Methods BIRCH was a Phase 3, double-blind, placebo-controlled study in adults with risk factors for developing severe COVID-19 who were randomized 1:1 to ODV 350 mg or placebo twice daily for 5 days. The primary endpoint was COVID-19-related hospitalization or all-cause death through Day 29. Other endpoints included time to symptom alleviation and change in viral load and infectious titer. Safety assessments included adverse events (AEs) and laboratory abnormalities. Results Study enrollment was stopped early, reflecting the evolving COVID-19 landscape with low rates of clinical events. Overall, 465 participants were randomized and received ≥1 dose. 56% were female, 4% were Black, 9% were American Indian or Alaska native, and 12% were Asian. Median age was 56 years; 29% were ≥65 years of age. 76% were randomized within 3 days of symptom onset, 42% had never been vaccinated, and 92% were SARS-CoV-2 seropositive. 90% were SARS-CoV-2 positive by nucleic acid amplification test at baseline for efficacy analyses. COVID-19-related hospitalization or all-cause death through Day 29 was reported in 0% for ODV (0/211 participants) and 0.5% for placebo (1/207 participants; P = 0.3161). Among the 162 participants who completed a symptom questionnaire, ODV showed a 2-day improvement in median time to symptom alleviation by Day 15 (ODV: 7.3 days; placebo: 9.3 days; P = 0.0859). ODV demonstrated greater reductions in viral load from baseline to Day 5 (–0.58 log10 copies/mL; P &amp;lt; 0.0001), and a greater proportion with negative infectious titer at Day 5 (ODV: 68/68 [100%]; placebo: 56/69 [81%]; P = 0.0001). The safety profiles of ODV and placebo were comparable, with similar rates of AEs, serious AEs, and AEs leading to discontinuation of study drug. Conclusion ODV treatment resulted in greater decreases in viral load and infectious titer, and a trend in faster time to symptom alleviation. In this population of participants with risk factors for severe COVID-19, ODV was generally safe and well tolerated. Disclosures Anca Streinu-Cercel, MD PhD Prof. Infectious Diseases, Gilead Sciences, Inc.: Grant/Research Support|Gilead Sciences, Inc.: Honoraria Antonella Castagna, MD, Bristol-Myers Squibb: Advisor/Consultant|Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Grant/Research Support|Gilead Sciences, Inc.: Honoraria|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Janssen: Honoraria|Merck Sharp &amp; Dohme: Advisor/Consultant|Merck Sharp &amp; Dohme: Grant/Research Support|Merck Sharp &amp; Dohme: Honoraria|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support|ViiV Healthcare: Honoraria Yiannis Koullias, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Afsaneh Mozaffarian, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Robert H. Hyland, DPhil, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Rita Humeniuk, PhD, Gilead Sciences, Inc.: Former Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Luzelena Caro, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Santosh Davies, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Charlotte Hedskog, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Shuguang Chen, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Kim Etchevers, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Nicole Behenna-Renton, BSc Hons, Gilead Science Europe Ltd: Employee|Gilead Science Europe Ltd: Stocks/Bonds (Public Company) Joe Llewellyn, PharmD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Anu Osinusi, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Frank Duff, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Jesus Abraham Simón Campos, MD, AstraZeneca: Advisor/Consultant|AstraZeneca: Honoraria|Lilly: Advisor/Consultant|Lilly: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Roche: Advisor/Consultant|Roche: Honoraria

Impact and optimization of vehicle charging scheduling on regional clean energy power supply network management

Driven by the global energy transition, the widespread use of electric vehicles has profoundly reshaped the transportation landscape and thrown many problems to the power system, and coordinating their charging needs with renewable energy generation has become a key part of ensuring the stable operation of regional clean energy power supply networks. This study focuses on the problem of vehicle charging dispatch to make a breakthrough, deeply analyzes the effect and efficiency of the clean energy grid, and then proposes a series of targeted measures to effectively improve the operational efficiency and reliability of the energy system. The comprehensive model integrates electric vehicle charging stations, distributed photovoltaic power generation systems, wind farms, and battery energy storage devices and enables the charging process to be accurately controlled with real-time monitoring and intelligent algorithms. In particular, the demand forecasting model based on machine learning effectively solves the dilemma of matching the charging load with a clean energy supply. Experimental data strongly confirms that the optimization strategy has led to a 15% reduction in peak load on the grid, a 23% increase in the proportion of clean energy consumption, and a 10% reduction in total electricity consumption. For policymakers, these achievements can be used as a guide to help formulate energy policies and build a framework for adapting to the development of new energy. For practitioners, they serve as a guide to energy planning, grid dispatch, and technology research and development to improve effectiveness. The research promotes the growth of green energy, optimizes the energy structure, lays the foundation for a low-carbon and environmentally friendly society, affects the economy, environment, culture, and other fields, and becomes a key force driving sustainable development.

Three-Dimensional Printed Auxetic Insole Orthotics for Flat Foot Patients with Quality Function Development/Theory of Inventive Problem Solving/Analytical Hierarchy Process Methods

Foot disorders affect approximately 10% of adults, with plantar heel pain significantly impacting foot-related quality of life and altering walking patterns. Flat feet, characterized by a lack of longitudinal arches, can lead to fatigue during walking. This study aims to develop 3D-printed shoe insoles tailored to the needs of patients. The design process incorporates Quality Function Deployment (QFD), Theory of Inventive Problem Solving (TRIZ), and Analytic Hierarchy Process (AHP) methods to create insoles that alleviate concentrated loads while meeting patient requirements. The AHP analysis indicated that patients prioritize insoles that effectively manage pressure distribution to achieve optimal functionality. QFD and TRIZ facilitated the identification of four product alternatives and production specifications. The analysis indicated that 3D-printed insoles made from TPU filament with 20% auxetic infill best align with patient preferences. This auxetic TPU option emerged as the top choice, achieving a priority value of 0.2506 due to its superior functionality and comfort. Load distribution measurements confirmed that TPU with auxetic infill resulted in the lowest load distribution, with a standard deviation of 0.1434 and a 25.4% reduction in maximum load compared to conditions without the insole.

Suppressing Tymovirus replication in plants using a variant of ubiquitin.

RNA viruses have evolved numerous strategies to overcome host resistance and immunity, including the use of multifunctional proteases that not only cleave viral polyproteins during virus replication but also deubiquitinate cellular proteins to suppress ubiquitin (Ub)-mediated antiviral mechanisms. Here, we report an approach to attenuate the infection of Arabidopsis thaliana by Turnip Yellow Mosaic Virus (TYMV) by suppressing the polyprotein cleavage and deubiquitination activities of the TYMV protease (PRO). Performing selections using a library of phage-displayed Ub variants (UbVs) for binding to recombinant PRO yielded several UbVs that bound the viral protease with nanomolar affinities and blocked its function. The strongest binding UbV (UbV3) candidate had a EC50 of 0.3 nM and inhibited both polyprotein cleavage and DUB activity of PRO in vitro. X-ray crystal structures of UbV3 alone and in complex with PRO reveal that the inhibitor exists as a dimer that binds two copies of PRO. Consistent with our biochemical and structural findings, transgenic expression of UbV3 in the cytosol of A. thaliana suppressed TYMV replication in planta, with the reduction in viral load being correlated to UbV3 expression level. Our results demonstrate the potential of using UbVs to protect plants from tymovirus infection, a family of viruses that contain numerous members of significant agricultural concern, as well as other plant viruses that express functionally related proteases with deubiquitinating activity.

Effect of Axial Modification on the Meshing Performance of Involute Beveloid Gear Pair

In order to enhance the load-bearing capacity of the involute beveloid gear pair, this study proposes research on improving the contact stress through axial modification. Under the condition of segmented parabolic axial modification, the mathematical equation for the tooth flank of the beveloid gear is derived. A simulation meshing model for the beveloid gear pair is constructed to investigate the effects of different amounts and lengths of axial modification on the meshing performance, changes in flank and root stress, and transmission error before and after modification. The results indicate that as the modification amount increases, the maximum equivalent stress initially decreases and then exhibits a tendency towards stability. Moreover, an increase in modification length concentrates the contact zone towards the middle of the tooth flank while expanding the range of tooth root stress distribution, and it also leads to a decrease in maximum equivalent stress. The implementation of the modification has been observed to result in a reduction in cumulative transmission error and an effective reduction in edge load on the beveloid gear pair, which has been demonstrated to enhance the bearing capacity and transmission stability extension while also impacting the dynamic meshing performance.

Characteristics and Optimization of Transient Process of Pump-Turbine Units in Power Generation Mode

Pumped storage power is considered an ideal regulated power source for new energy. However, the traditional one-dimensional characteristic line method cannot predict the pulsating pressure caused by the reverse “S” characteristic of a pump–turbine. In this paper, a variable-step Euler algorithm is presented to calculate the hydraulic transient process of pumped storage units, the interval times of start-up and load regulation between two pump–turbine units are investigated by using the method of peak staggering and valley filling, and the closure law of guide vanes in the transient process of load rejection is optimized. The results show that the presented method is valid, and that pulsating pressure is accurately captured during the transient process of load rejection. The water level fluctuation amplitude in the surge chamber is greatly reduced by the sequential start-up mode. The rotational speed fluctuation amplitude of the sequential load reduction is also reduced. After the load of two pump–turbine units is rejected at the same time, the duration of pulsating pressure in the spiral case is shortened by 45% by using the quick-then-slow closure law compared with the straight-line closure law. Moreover, the pulsating pressure amplitude and the second peak value of rotational speed are also reduced accordingly, and the transient characteristics of the pump–turbine units are greatly improved.