Post-treatment Period Research Articles

N-acetyl-L-tryptophan provides radioprotection to mouse and primate models by antagonizing the TRPV1 receptor and substance P inhibition

Purpose The present study was carried out to evaluate the radioprotective activities of N-acetyl-L-tryptophan (L-NAT) using rodent and non-human primate (NHP) models. Materials and methods The antagonistic effect of L-NAT on the Transient receptor potential vanilloid-1 (TRPV1) receptor and substance P inhibition was determined using molecular docking and Elisa assays. The in vivo radioprotective activity of L-NAT was evaluated using whole-body survival assays in mice and NHPs. Radioprotective activity of L-NAT was also determined at the systemic level using quantitative histological analysis of bone marrow, jejunum, and seminiferous tubules of irradiated mice. Results Molecular docking studies revealed a strong binding of L-NAT with TRPV1 receptor at similar binding pockets to which capsaicin, an agonist of the TRPV1 receptor, binds. Further, capsaicin and gamma radiation were found to induce substance P levels in the intestines and serum of the mice, while L-NAT pretreatment was found to inhibit it. Significant whole-body survival (>80%) was observed in irradiated (9.0 Gy) mice that pretreated with L-NAT (150 mg/kg, b.wt. im) compared to 0% survival in irradiated mice that not pretreated with L-NAT. The quantitative histology of the hematopoietic, gastrointestinal, and male reproductive systems demonstrated significant protection against radiation-induced cellular degeneration. Interestingly, 100% survival was observed with irradiated NHPs (6.5 Gy) that pretreated with L-NAT (37.5 mg/kg, b.wt.im). Significant improvement in the hematology profile was observed after days 10-20 post-treatment periods in irradiated (6.5 Gy) NHPs that were pretreated with L-NAT. Conclusion L-NAT demonstrated excellent radioprotective activity in the mice and NHP models, probably by antagonizing TRPV1 receptor and subsequently inhibiting substance P expression.

Restoration treatments enhance tree growth and alter climatic constraints during extreme drought.

The frequency and severity of drought events are predicted to increase due to anthropogenic climate change, with cascading effects across forested ecosystems. Management activities such as forest thinning and prescribed burning, which are often intended to mitigate fire hazard and restore ecosystem processes, may also help promote tree resistance to drought. However, it is unclear whether these treatments remain effective during the most severe drought conditions or whether their impacts differ across environmental gradients. We used tree-ring data from a system of replicated, long-term (>20 years) experiments in the southwestern United States to evaluate the effects of forest restoration treatments (i.e., evidence-based thinning and burning) on annual growth rates (i.e., basal area increment; BAI) of ponderosa pine (Pinus ponderosa), a broadly distributed and heavily managed species in western North America. The study sites were established at the onset of the most extreme drought event in at least 1200 years and span much of the climatic niche of Rocky Mountain ponderosa pine. Across sites, tree-level BAI increased due to treatment, where trees in treated units grew 133.1% faster than trees in paired, untreated units. Likewise, trees in treated units grew an average of 85.6% faster than their pre-treatment baseline levels (1985 to ca. 2000), despite warm, dry conditions in the post-treatment period (ca. 2000-2018). Variation in the local competitive environment promoted variation in BAI, and larger trees were the fastest-growing individuals, irrespective of treatment. Tree thinning and prescribed fire altered the climatic constraints on growth, decreasing the effects of belowground moisture availability and increasing the effects of atmospheric evaporative demand over multi-year timescales. Our results illustrate that restoration treatments can enhance tree-level growth across sites spanning ponderosa pine's climatic niche, even during recent, extreme drought events. However, shifting climatic constraints, combined with predicted increases in evaporative demand in the southwestern United States, suggest that the beneficial effects of such treatments on tree growth may wane over the upcoming decades.

Return to work and its predictors among nasopharyngeal carcinoma survivors in the early post-treatment period: A prospective, observational study.

This study aims to investigate return to work (RTW) status and identify its predictors in the early post-treatment period among nasopharyngeal carcinoma (NPC) survivors. A prospective observational study was conducted. A convenience sample of 209 NPC survivors were recruited from a tertiary cancer center in Southern China between July 2021 and March 2022. The research instruments comprised the Readiness for Return to Work Scale, M.D. Anderson Symptom Inventory - Head and Neck, Work Motivation Scale, and demographic, disease-related, and work-related questionnaire. Return to work status and current job characteristics were assessed via telephone interview three months after completing treatment. Logistic regression analysis was conducted to determine the predictive factors. Approximately 31.1% of NPC survivors returned to work in the early post-treatment period. Logistic regression analysis showed that NPC survivors who were male, had one child, had higher family monthly income per capita, were in the stages of prepared for action-self-evaluation/prepared for action-behavior, and had stronger work motivation were more likely to return to work in the early post-treatment period. The RTW is low among NPC survivors in the early post-treatment period. Factors predicting RTW are complex under Chinese culture context. Healthcare professionals should prioritize the early identification of survivors with low RTW intention and provide culturally sensitive interventions to enhance their work motivation and readiness. These efforts are crucial to supporting NPC survivors in achieving successful early RTW.

Pharmacodynamic effects and exploratory efficacy of afimetoran, a TLR7/8 inhibitor, in patients with cutaneous lupus erythematosus

Background: Cutaneous lupus erythematosus (CLE) is a chronic inflammatory skin condition occurring alone or as a manifestation of systemic lupus erythematosus (SLE). There is an unmet need for safe and effective CLE-focused treatments. Afimetoran is an investigational, first-in-class, potent oral inhibitor of toll-like receptors (TLRs) 7/8. Given the involvement of TLRs 7/8 in SLE, afimetoran may have therapeutic potential for CLE. A phase 1b randomized, double-blind, placebo-controlled study (NCT04493541) demonstrated preliminary safety and efficacy of afimetoran in patients with active CLE. We assessed the pharmacodynamics, safety, and efficacy of afimetoran and its impact on CLE pathobiology. Methods: Patients aged 18–65 years with SLE and cutaneous manifestations by EULAR/ACR 2019 classification criteria or biopsy-proven CLE, and modified CLE Disease Area and Severity Index-Activity (CLASI-A) score ≥6, were randomized 2:1 to once-daily afimetoran (30 mg) or placebo for 16 weeks with a 4-week post-treatment follow-up period. The primary endpoints were safety and tolerability; efficacy was exploratory. Transcriptomics and cytokine analyses were performed using peripheral whole blood and serum, respectively, at baseline (pre-dose) and each study visit (weeks 1, 2, 4, 8, 12, 16, and 20 [post-dose]). Statistical analyses compared data from the 13 randomized patients with thirteen age-, ethnicity-, and gender-matched healthy volunteers. Treatment responses were evaluated longitudinally in each treatment arm. The dataset was analyzed using a linear regression model. Gene set variation analysis (GSVA) was performed for pathway enrichment. Results: 13 patients with CLE were randomized (afimetoran, n=8; placebo, n=5); 12 patients completed 16 weeks of treatment and 1 discontinued after 6 weeks due to COVID-19. Compared with placebo, afimetoran demonstrated a favorable safety profile with no serious adverse events, and showed a greater reduction in CLASI-A scores as early as week 4, which persisted to week 20. Improvement in the molecular disease profile was rapid (week 1), sustained through the 16-week treatment period, and the 4-week post-treatment follow-up period. Expression of interferon (IFN) pathway genes was significantly reduced with afimetoran compared with baseline (ΔGSVA enrichment score [ES]=1.57, P<0.0001) and placebo (ΔGSVA ES=0.56, P<0.01); this effect was maintained through week 16 and ≥4 weeks post-treatment. Expression of TLR7 and TLR8 pathway genes and key cytokines (interleukin [IL]-6, tumor necrosis factor α, IL-18, IFNγ, macrophage inflammatory protein-1 alpha [CCL3/MiP1α] or beta [CCL4/MiP1β]) were greatly reduced with afimetoran treatment. GSVA demonstrated robust pharmacodynamic activity on immune cell populations, including immature and activated dendritic cells, macrophages, and inflammatory pathway signatures. Conclusion: In patients with CLE, afimetoran was safe, well tolerated, and demonstrated durable efficacy beyond the treatment period. Afimetoran’s clinical effects and potent pharmacodynamic impact on the molecular disease profile suggest a substantial therapeutic benefit for patients with CLE.

Half-life-extended Monoclonal Antibody APG777 for Atopic Dermatitis: Design of the Phase 2 APEX Study

Introduction: Current treatments for moderate-to-severe atopic dermatitis (AD) include topical and systemic therapies. The latter includes monoclonal antibodies (mAbs) targeting the IL-13 pathway, which is implicated in AD pathophysiology. While currently available mAbs directed against the IL-13 pathway have demonstrated efficacy for AD, they require ongoing injections every 2 or 4 weeks. APG777 is a humanized, anti-IL-13 mAb that binds IL-13 and blocks downstream signaling mediated by the IL-13Rα1/IL-4Rα complex. APG777 contains amino acid modifications designed to extend plasma half-life through increased FcRn-mediated antibody recycling. Interim results from an ongoing phase 1 study in healthy participants suggest a favorable safety and PK/PD profile for APG777, and a half-life of approximately 75 days. Methods: APEX (NCT06395948) is a 2-part, multicenter, phase 2, randomized, double-blinded, placebo-controlled clinical trial evaluating the efficacy and safety of APG777 in adults with moderate-to-severe AD. Adults (≥18 years of age) are eligible to participate if they have a diagnosis of AD for ≥1 year prior to screening and exhibit moderate-to-severe AD (EASI ≥16, IGA ≥3, BSA ≥10%) at both screening and baseline visits. Part A of the study (proof-of-concept) is evaluating the efficacy and safety of one induction dose regimen of APG777 compared with placebo over 16 weeks; this is followed by a 36-week maintenance period. Part B (dose-regimen finding) will evaluate different dose regimens of APG777 compared with placebo over 16 weeks followed by a 36-week maintenance period. Participants completing the maintenance period of Part A or B of the study will be eligible to enroll in a separate long-term extension study or enter the post-treatment follow-up period (up to 52 weeks). The primary outcome measure for the study is the percentage change from baseline to week 16 in the Eczema Area and Severity Index (EASI). The APEX study is currently enrolling.

Impact on Ant Communities by Chemical Pesticides Applied in Controlling the Red Imported Fire Ant (Solenopsis invicta Buren) in the Field.

The red imported fire ant (RIFA, Solenopsis invicta Buren) represents a significant invasive pest in China, exerting extensive negative impacts on ecosystems. The invasion of RIFA not only poses a severe threat to biodiversity within the environment; inappropriate controlling measures can also adversely affect community dynamics. Therefore, while implementing effective management strategies to control the proliferation of RIFA populations, it is imperative to evaluate the potential effects of these measures on the structure of local biological communities to safeguard native biodiversity. This study employs a "two-step method" using dust and bait formulations, respectively, to control RIFA while conducting ecological monitoring to further assess the impact of RIFA population decline on ant communities. The results of RIFA management showed that after post-treatment periods of 28 days, 35 days, and 60 days, the worker ant reduction rates for the three insecticides-0.5% beta-cypermethrin dust, 1.0% hydramethylnon bait, and 0.1% indoxacarb bait-reached approximately 72%, with their efficacy ranked as follows: 1.0% hydramethylnon bait > 0.1% indoxacarb bait > 0.5% beta-cypermethrin dust. By the 60th day of the experiment, the ant nest reduction rates reached their highest values-66.84% for 0.5% beta-cypermethrin dust, 77.89% for 1.0% hydramethylnon bait, and 87.52% for 0.1% indoxacarb bait-with the latter performing the best. Meanwhile, the occurrence level of RIFAs in all three pesticide treatment areas decreased from level III to level I 60 days post-treatment. Following the application of these three insecticides, the RIFA population significantly decreased, leading to an increase in species richness within the ant community. The reduction in RIFA numbers had a positive impact on the restoration of ant community diversity, as evidenced by significant improvements in both diversity and evenness indices. Notably, 0.1% indoxacarb bait was particularly effective in enhancing the ant community diversity and species richness, while 1.0% hydramethylnon bait was more effective in improving community evenness. These findings indicate that the controlling strategy used in this study not only effectively manages RIFA populations but also promotes recovery and contributes to the ecological balance of local ant communities, providing an important reference for future biodiversity conservation efforts.

Long-term effect of postoperative radioactive iodine therapy on parathyroid function in patients with differentiated thyroid cancer.

The study aimed to assess the impact of postoperative radioactive iodine (RAI) therapy on parathyroid function in patients who underwent total or subtotal thyroidectomy for differentiated thyroid cancer (DTC). Data from 150 patients treated with RAI for DTC and 76 patients with low-risk DTC not receiving RAI were retrospectively analyzed. Clinical characteristics, preoperative and 1-month postoperative biochemical parameters, and adjusted calcium, phosphorus, parathyroid hormone (PTH), and 25-hydroxyvitamin D3 (25-OH-D) levels at 3months, 1year, 3years, and 5years post-RAI (or in the low-risk group) were recorded. A total of 226 DTC patients were included in the study (80.5% female, mean age 42.7 ± 13.2years). Total thyroidectomy was performed in 97.3% (n = 220) of patients, with central lymph node dissection (CLND) in 41.6% (n = 94). No significant preoperative differences in PTH, aCa, P, Mg, or 25-hydroxyvitamin D3 levels were observed. However, patients receiving ≥ 3.7GBq (or 100mCi) RAI (n = 70) had lower calcium and PTH levels at the end of the first year following RAI treatment (p = 0.048, p = 0.032). The non-RAI group showed significantly higher calcium levels at one month postoperatively (p = 0.031) and lower rates of CLND and neck dissection. No significant differences in biochemical parameters were found at the five-year follow-up, except for one patient who developed normocalcemic hyperparathyroidism after RAI. High-dose RAI therapy may lead to transient decreases in calcium and PTH levels in the early post-treatment period. However, long-term parathyroid function appears to remain unaffected in DTC patients, regardless of the RAI dose administered. Nonetheless, close monitoring of calcium and PTH levels is recommended, particularly in the early post-treatment period, to promptly manage any potential transient hypoparathyroidism.

Resilience in Chinese Spouses of Patients with Advanced Cancer: A Longitudinal Exploration.

In China, spouses of patients with advanced cancer have reported experiencing psychological distress. However, little attention has been paid to the positive psychological health trajectories of these caregivers, particularly regarding their resilience and the factors influencing its development over time. To examine the trajectories of resilience in Chinese spousal caregivers over a nine-month post-treatment period and to identify the basic characteristics associated with these trajectory patterns. This was a longitudinal, observational study conducted in mainland Chinese between January 2022 and May 2024. A total of 306 spouses of patients receiving cancer treatment were recruited from five local hospitals. Data was collected in four waves: within one month of initial treatment, and then at three-, six-, and nine-month intervals post-treatment. Socio-demographic questionnaires, the Connor-Davidson Resilience Scale, and the Beliefs in Chinese Familism Scale were used to collect data. Growth mixture modeling was employed to determine the various trajectories of resilience, followed by logistic regression analysis to examine the associated factors to predict types of trajectories. Growth mixture modeling showed two distinct trajectories of resilience were identified: an increased group (N = 78, 25.5%) and a stable group (N = 228, 74.5%). The increased group began with a low baseline level (intercept = 46.713) and showed a slight increase over time (slope = 7.505, p < 0.001), while the stable group had a moderate baseline level (intercept = 56.565) and remained stable over time (slope = 0.068, p > 0.05). Those in the stable group were more likely to be female, and to have achieved a middle school level of education, a lower family income, and greater Chinese familism at baseline than those in the increased group. Our findings underscore the importance of tracking the trajectories of resilience and predictors of trajectory patterns among spouses caring for patients with advanced cancer within a specific cultural context. Healthcare providers should provide tailored interventions to enhance resilience in spousal caregivers, considering the trajectory patterns of mental health change.

Thinning Impacts on Carbon and Water Budgets in a Temperate Deciduous Forest Ecosystem

Among various forest management activities, thinning is a prevalent treatment that affects tree growth and living biomass. Increased moisture and light availability may also enhance the mineralization of litter and dead wood organic matter, impacting soil carbon stocks. Thinning may also affect the services forests provide, including water production and nutrient cycling. The impacts of thinning on water yield and carbon stocks have been well documented around the globe while targeting mainly one of these ecosystem services. Our experimental paired catchment study covers both and puts forward long term results. We assessed the carbon stock changes caused by two slight thinning treatments together with the impacts on water yield in experimental paired catchments of 71.9 (W–I) and 77.5 hectares (W–IV) in Istanbul, Türkiye. The null hypothesis was that the slight thinnings did not affect the water yield and carbon stocks significantly. On the carbon stock part, we calibrated and parametrized the CBM–CF3 model with field measurements to simulate changes in carbon stocks of mixed deciduous forest stands. The intensities of the treatments (thinnings) were 11% and 18% of the basal area, performed in 1986 and 2011, respectively. We found that, while C stocks decreased by around 30 tons per hectare during the 1986–2020 period, the water yield was enhanced by approximately 25 mm/yr in the treatment catchment compared to the control watershed during the four-year post-treatment period. This amount of streamflow increase was around 10 percent of the average water yield of the catchments. It was concluded that there was a detectable increase in water yield during the following four years of the slight thinning treatments, while the reduction in abovegound carbon stocks continued for more than three decades.

Role of Steroid Therapy in Preventing Recurrence of Atrial Fibrillation After Ablation: A Systematic Review and Meta-Analysis.

Atrial fibrillation (AF) is the most common cardiac arrhythmia with challenging management due to its potential complications and high recurrence rates. Catheter ablation is a standard treatment option for symptomatic patients, particularly those unresponsive to medical management but has variable success rates. Inflammation plays a critical role in the pathogenesis and persistence of AF.This systematic review aims to study the potential benefits of corticosteroid use in the prevention of AF recurrence after procedures such as catheter ablation, providing a more comprehensive understanding of their role in improving outcomes.Four randomized controlled trials (RCTs) with 824 total participants and four cohort studies with 1128 participants were included for qualitative and quantitative analysis. All RCTs and cohort studies suggestno significant benefit of corticosteroids with ablation in preventing short-term (lessthan three months) AF recurrence. However, RCTsindicate that corticosteroid use with ablationsignificantly reduces the recurrence of AFover three months, but such a statistically significant effect is not seen in cohort studies for AF recurrenceup to one year. This suggests that there might be some beneficial role of using steroids with ablation proceduresin preventing recurrences of AF, but further large-scale studies are warranted for better evidence to support the use of steroids with ablation. Future research should focus on understanding the optimal duration and dosing of corticosteroid treatment to maximize benefits and minimize risks, especially in the immediate post-treatment period where the data currently showless clarity and higher variability. Additionally, further studies should explore the mechanisms through which corticosteroids exert their effects over different durations to better tailor treatment protocols.

Loss to follow-up of patients after antiviral treatment as an additional barrier to HCV elimination

BackgroundEliminating hepatitis C virus (HCV) infections is a goal set by the World Health Organization. This has become possible with the introduction of highly effective and safe direct-acting antivirals (DAA) but limitations remain due to undiagnosed HCV infections and loss of patients from the cascade of care at various stages, including those lost to follow-up (LTFU) before the assessment of the effectiveness of the therapy. The aim of our study was to determine the extent of this loss and to establish the characteristics of patients experiencing it.MethodsPatients with chronic HCV infection from the Polish retrospective multicenter EpiTer-2 database who were treated with DAA therapies between 2015 and 2023 were included in the study.ResultsIn the study population of 18,968 patients, 106 had died by the end of the 12-week post-treatment follow-up period, and 509 patients did not report for evaluation of therapy effectiveness while alive and were considered LTFU. Among patients with available assessment of sustained virological response (SVR), the effectiveness of therapy was 97.5%. A significantly higher percentage of men (p<0.0001) and a lower median age (p=0.0001) were documented in LTFU compared to the group with available SVR assessment. In LTFU patients, comorbidities such as alcohol (p<0.0001) and drug addiction (p=0.0005), depression (p=0.0449) or other mental disorders (p<0.0001), and co-infection with human immunodeficiency virus (HIV) (p<0.0001) were significantly more common as compared to those with SVR assessment. They were also significantly more often infected with genotype (GT) 3, less likely to be treatment-experienced and more likely to discontinue DAA therapy.ConclusionsIn a real-world population of nearly 19,000 HCV-infected patients, we documented a 2.7% loss to follow-up rate. Independent predictors of this phenomenon were male gender, GT3 infection, HIV co-infection, alcohol addiction, mental illnesses, lack of prior antiviral treatment and discontinuation of DAA therapy.

Total body irradiation is associated with long-term deficits in femoral bone structure but not mechanical properties in male rhesus macaques.

Exposure to ionizing radiation for oncological therapy increases the risk for late-onset fractures in survivors. However, the effects of total body irradiation (TBI) on adult bone are not well-characterized. The primary aim of this study was to quantify the long-term effects of TBI on bone microstructure, material composition, and mechanical behavior in skeletally mature rhesus macaque (Macaca mulatta) non-human primates. Femora were obtained post-mortem from animals exposed to an acute dose of TBI (6.0-6.75Gy) nearly a decade earlier, age-matched non-irradiated controls, and non-irradiated young animals. The microstructure of femoral trabecular and cortical bone was assessed via micro-computed tomography. Material composition was evaluated by measuring total fluorescent advanced glycation end products (fAGEs). Cortical bone mechanical behavior was quantified via four-point bending and cyclic reference point indentation (cRPI). Animals exposed to TBI had slightly worse cortical microstructure, including lower cortical thickness (-11%, p = 0.037) and cortical area (-24%, p = 0.049), but similar fAGE content and mechanical properties as age-matched controls. Aging did not influence cortical microstructure, fAGE content, or cRPI measures but diminished femoral cortical post-yield properties, including toughness to fracture (-32%, p = 0.032). Because TBI was administered after the acquisition of peak bone mass, these results suggest that the skeletons of long-term survivors of adulthood TBI may be resilient, retaining or recovering their mechanical integrity during the post-treatment period, despite radiation-induced architectural deficits. Further investigation is necessary to better understand radiation-induced skeletal fragility in mature and immature bone to improve care for radiation patients of all ages.

7269 Interim Analysis of Gonadotropin-Releasing Hormone Agonist (GnRHa) Treatment in Children with Central Precocious Puberty: Focus on FMV Urinary LH Levels and Clinical Outcomes

Abstract Disclosure: X. Luo: Advisory Board Member; Self; Takeda. L. Hou: Advisory Board Member; Self; Takeda. Y. Li: Advisory Board Member; Self; Takeda. Y. Sun: Advisory Board Member; Self; Takeda. X.K. Jin: Employee; Self; Takeda. Background: Central precocious puberty (CPP) refers to early activation of the hypothalamic–pituitary–gonadal (HPG) axis in children. There is an urgent need to understand the treatment pattern and clinical outcomes among children suffering from CPP. Studies have reported that first morning voided (FMV) urinary Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) have substantial association with CPP tested in GnRH stimulation test and can be useful in diagnosis and management of CPP in children. Gonadotropin-releasing hormone agonists (GnRHa) such as Leuprolide acetate (LA) are the recommended treatment for children suffering from CPP. The current study aimed to provide the information on level of LH and FSH in FMV urine when CPP diagnosis at baseline and the present results may also revealed trend of FMV-LH and FMV-FSH change during LA intervention in children with CPP. Here we present interim results from this study. Methods: This is an open-label, multicentre, single arm, prospective study that enrolled 31 subjects with CPP. Individuals were administered LA depot 11.25 mg, subcutaneously every 12 weeks. The study comprises a screening period; a 6-month treatment period: 24 weeks; and a post-treatment follow-up period: 12 weeks. The FMV urinary LH and FSH were diagnosed by Clopper-Pearson method with a 95% confidence interval. Results: Due to the data collection time point for the interim analysis, only 8 female subjects reached the 12-week visit time point and had a 12-week visit for FMV urinary Gn testing. Therefore, for this interim analysis, only FMV Gn decline at week 12 of the 8 subjects who had a 12-week visit will be presented. At baseline, the mean value of FMV urinary LH and FSH is 0.58 IU/L and 2.27 IU/L respectively. The FMV Gn urinary LH was demonstrated a decrease in 87.5% (95% CI: 47.35,99.68) of the children after LA intervention. Additionally, urinary FSH value of FMV urinary Gn was found to decrease in 75.00% of the children (95% CI: 34.91,96.81) compared to baseline FSH value. Conclusion: The present study reveals a decreasing trend in FMV Gn urinary LH and FSH levels in CPP children treated with LA during interim analysis. LA was shown to be safe and effective in ameliorating the level of LH and FSH in children suffering from CPP. From the study, it can be concluded that urinary LH and FSH may act as a potential biomarker for diagnosis and management of CPP. Presentation: 6/3/2024

Huperzine A suppresses absence seizures in the genetic absence epilepsy rat from Strasbourg (GAERS) model of genetic generalized epilepsy with absence seizures.

We evaluated huperzine A treatment in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) model of genetic generalized epilepsy (GGE) with absence seizures. Adult male GAERS (N = 15) were implanted with EEG recording electrodes 10 days before receiving study drug. Each animal received the following six treatments as a single, intraperitoneal dose, 7 days apart (in random order): huperzine A (0.3, 1.0, or 3.0 mg/kg), two periods of vehicle (0.9% NaCl), or ethosuximide (100 mg/kg) as a positive control. Electroencephalograms (EEGs) were acquired for 24 h before and after each treatment and analyzed for seizure activity during the 90-min period immediately post-treatment, including 30-min intervals at 30, 60, and 90 min. Additional analyses evaluated seizure activity over the 24-h post-treatment period using 60-min intervals at 6, 12, and 24 h. The cumulative 24-h periods before and after each administered treatment were also compared. Two-way ANOVA showed a treatment difference [F(91,182) = 3.592, p < 0.0001] on the number of seizures over the first 90-min post-treatment (primary outcome); Tukey's post hoc analyses showed that, compared to vehicle, huperzine A (3.0 mg/kg) significantly reduced seizures in the 30-min (p = 0.02) and 60-min (p = 0.001) intervals, and ethosuximide significantly reduced seizures at all measured time intervals except the 1-h blocks at 12 and 24 h. Huperzine A 3.0 mg/kg and ethosuximide significantly reduced seizures during the cumulative 24-h post-treatment period relative to pretreatment baseline. While huperzine A 3.0 mg/kg did not differ significantly from ethosuximide at any time point, the study was not designed to evaluate non-inferiority. The only adverse event after huperzine A or ethosuximide was mild, dose-dependent sedation. Huperzine A potently suppressed absence-like seizures in GAERS, albeit with a shorter duration of action relative to ethosuximide, showing promise for clinical efficacy in GGE. This study looked at how huperzine A affects seizures in rats with similar abnormal brain activity as seen in humans with absence epilepsy. Rats received different treatments, placebo (i.e., saline solution), huperzine A, and ethosuximide. Ethosuximide is considered a gold standard treatment for absence epilepsy. We recorded brain activity to measure seizures before and after each treatment. We found that huperzine A (3.0 mg/kg) reduced seizures soon after treatment, like ethosuximide. Both treatments appeared safe, causing only mild sleepiness. The study shows that huperzine A could be a good new treatment for a type of absence epilepsy.

Coadministration of Cariprazine with a Moderate CYP3A4 Inhibitor in Patients with Schizophrenia: Implications for Dose Adjustment and Safety Monitoring.

Cariprazine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. This study aimed to evaluate the effects of erythromycin, a moderate cytochrome P450 (CYP)3A4 inhibitor, on the pharmacokinetics of cariprazine in male patients with schizophrenia, and to assess the influence of CYP2D6 phenotypes on cariprazine metabolism. Forty-two patients received oral doses of 1.5 mg cariprazine alone for 28 days (to reach steady state), followed by a co-administration of cariprazine 1.5 mg daily with erythromycin 500 mg twice daily (BID) and Enterol 250 mg BID for 21 days, followed by a 14-day post-treatment period. Blood samples were collected at predefined time points and analysed for cariprazine, its two active metabolites: desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), and erythromycin using validated high performance liquid chromatography-tandem mass spectrometry methods. CYP2D6 phenotypes were determined by genotyping. The pharmacokinetic parameters were calculated using non-compartmental analysis. Erythromycin increased the area under the curve (AUCτ) and peak concentration (Cmax) of Total cariprazine (cariprazine + DCAR + DDCAR) by about 40-50% but did not affect the time to peak concentration (Tmax). The CYP2D6 phenotypes had no substantial effect on the pharmacokinetics of cariprazine and its metabolites, either alone or in combination with erythromycin. Cariprazine was well tolerated and safe. The findings suggest that co-administration of cariprazine with moderate CYP3A4 inhibitors may require dose adjustment or monitoring; however, pharmacogenetic testing for CYP2D6 is not necessary for optimising cariprazine therapy. Trial registration number (EudraCT Number): 2018-003721-28. Date of registration: 21-SEP-2018.

Pharmacokinetics-Based Safety Evaluation in Half-Dose Verteporfin Photodynamic Therapy

Introduction: This study was conducted to assess the systemic pharmacokinetic profiles of half-dose verteporfin photodynamic therapy (PDT) using concentration data from a previous clinical trial and to subsequently suggest safety precaution guidelines. Methods: Coefficients for the bi-exponential model were obtained from published data on post-infusion plasma verteporfin concentrations within a period of 0.17–4 h. Using the extrapolative forecasting method, we plotted the 48-h post-verteporfin plasma concentration model. The time required to achieve a comparable level of verteporfin 48 h after a conventional dose (6 mg/m2 body surface area, BSA) infusion was calculated for a half-dose infusion (3 mg/m2 BSA). Results: At 24 and 48 h post-verteporfin infusion, the plasma concentration following the conventional dose was 1.28 × 10−4 µg/mL and 5.06 × 10−8 µg/mL, compared to 3.57 × 10−5 µg/mL and 7.54 × 10−9 µg/mL for the half-dose PDT, representing concentrations that were 3.6 times and 6.7 times higher, respectively. The estimated time required to attain the same level of verteporfin 48 h after a conventional dose was calculated as 42-h post-half-dose PDT. Conclusions: The results of this study indicate that precautionary measures should be taken to avoid sunlight following both half and conventional doses of PDT during the similar post-treatment periods of two days. Nevertheless, given the substantially higher plasma concentration levels associated with conventional-dose PDT compared with the half-dose, systemic safety should be carefully considered when administering conventional-dose PDT.

Abstract C170: Unveiling sex differences in hospitalization rates for immune-related adverse events in older lung cancer patients treated with ICIs: A SEER-Medicare analysis

Abstract Introduction Immune checkpoint inhibitors (ICIs) offer substantial benefits for older adults with lung cancer (LCa) but they also pose risks of immune-related adverse events (irAEs), necessitating investigation into the demographic influences on hospitalization rates. Sex differences among older adults within this cohort are understudied. Our study aims to explore the gender differences in irAE-related hospitalizations among older adults. Methods We utilized Surveillance, Epidemiology, and End Results (SEER)-linked Medicare data to identify older adults diagnosed with primary LCa from 1999 to 2017 and treated with ICIs between 2011 and 2019. Patients were steroid-naïve and chemo-naïve for 3 and 12 months, respectively, prior to ICI initiation. ICD-9/10 diagnosis codes were used to identify irAEs post-ICI initiation and these diagnosis were flagged during the pre-ICI period for comparison. An adjusted negative binomial model compared irAE-hospitalization rates in the post-ICI period (0-6, 7-12, and 13-24 months) to those in the pre-ICI period (6 months prior), accounting for confounders. An interaction term between gender and treatment period was included to compare differences in rates between males and females. Results Of the 1,089 patients, 54% were female, 79.6% had Charlson Comorbidity Index (CCI) ≥1. Females had 59% higher rates of irAE-hospitalizations at baseline (95% CI: 1.18 – 2.14, p&amp;lt;0.001). Patients with CCI≥3 had a 141% higher rate for irAE- hospitalization compared to those with CCI=0. Specifically for males, compared to 6-months pre-ICI, the irAE-hospitalization rates were 187% higher 0-6 months post-ICI (IRR = 2.87, 95% CI: 1.20-3.74), 134% higher 7-12 months post-ICI (IRR = 2.34, 95% CI: 1.66-3.31), and 122% higher 13-24 months post-ICI (IRR = 2.22, 95% CI: 1.53-3.28). Similarly for females, compared to 6-months pre-ICI, the irAE-hospitalization rates were 123% higher 0-6 months post-ICI (IRR = 2.23, 95% CI: 1.27-3.75), 69% higher 7-12 months post-ICI (IRR = 1.69, 95% CI: 1.27-3.37), and 11% higher 13-24 months post-ICI (IRR = 1.11, 95% CI: 1.03-2.37). Age and race did not impact irAE-hospitalization rates among LCa patients. Conclusions The incidence of irAEs following ICI treatment is notably higher in the first six months post-ICI for both males and females, with males experiencing a higher rate of events across all post-treatment periods. Key factors influencing the rate of irAE-hospitalizations include the CCI and pre-treatment gender differences. These findings underscore the need for tailored post-ICI monitoring strategies to mitigate adverse events in vulnerable populations. Citation Format: Fnu Nikita, Swapnil Sharma, Amy Shaver, Krupa Gandhi, Scott W. Keith, Christina Steinbock- Malfer, Jennifer M. Johnson, Sarah Gordon, Grace Lu-Yao. Unveiling sex differences in hospitalization rates for immune-related adverse events in older lung cancer patients treated with ICIs: A SEER-Medicare analysis [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C170.

Neuropsychological outcomes of patients with haematological malignancies undergoing chimeric antigen receptor T-cell therapy: protocol for a prospective study

IntroductionImmune effector cell-associated neurotoxicity syndrome (ICANS) is a common side-effect of chimeric antigen receptor T-cell (CAR-T) therapy, with symptoms ranging from mild to occasionally life-threatening. The neurological, cognitive, psychiatric and...

Effectiveness of mass trapping interventions using autocidal gravid ovitraps (AGO) for the control of the dengue vector, Aedes (Stegomyia) aegypti, in Northern Mexico

BackgroundMosquito-borne diseases, such as malaria, dengue, Zika and chikungunya, pose significant public health threats in tropical and subtropical regions worldwide. To mitigate the impact of these diseases on human health, effective vector surveillance and control strategies are necessary. Traditional vector control methods, which rely on chemical agents such as insecticides and larvicides, face challenges such as resistance and environmental concerns. Consequently, there has been a push to explore novel surveillance and control tools. Mass trapping interventions have emerged as a promising and environmentally friendly approach to reducing the burden of mosquito-borne diseases. This study assessed mass-trapping interventions using autocidal gravid ovitraps (AGOs) on Aedes aegypti populations in Reynosa, Tamaulipas, Mexico.MethodsFour neighborhoods were selected to evaluate the effects of three treatments: AGO mass-trapping, integrated vector control (IVC), which included source reduction and the application of chemical larvicide and adulticide, and AGO + IVC on Ae. aegypti populations. A control area with no interventions was also included.The effectiveness of the interventions was evaluated by comparing Ae. aegypti abundance between the pre-treatment period (9 weeks) and the post-treatment period (11 weeks) for each treatment.ResultsOnly treatment using AGO mass trapping with an 84% coverage significantly reduced Ae. aegypti female populations by 47%, from 3.75 ± 0.32 to 1.96 ± 0.15 females/trap/week. As expected, the abundance of Ae. aegypti in the control area did not differ from the pre- and post-treatment period (range of 4.97 ± 0.59 to 5.78 ± 0.53); Ae. aegypti abundance in the IVC treatment was 3.47 ± 0.30 before and 4.13 ± 0.35 after, which was not significantly different. However, Ae. aegypti abundance in the AGO + IVC treatment increased from 1.43 ± 0.21 before to 2.11 ± 0.20 after interventions; this increase may be explained in part by the low AGO (56%) coverage.ConclusionsThis is the first report to our knowledge on the effectiveness of mass-trapping interventions with AGOs in Mexico, establishing AGOs as a potential tool for controlling Ae. aegypti in Northeastern Mexico when deployed with sufficient coverage.Graphical

Multichannel tDCS with advanced targeting for major depressive disorder: a tele-supervised at-home pilot study.

Proof-of-principle human studies suggest that transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) may improve depression severity. This open-label multicenter study tested remotely supervised multichannel tDCS delivered at home in patients (N=35) with major depressive disorder (MDD). The primary aim was to assess the feasibility and safety of our protocol. As an exploratory aim, we evaluated therapeutic efficacy: the primary efficacy measure was the median percent change from baseline to the end of the 4-week post-treatment follow-up period in the observer-rated Montgomery-Asberg Depression Mood Rating Scale (MADRS). Participants received 37 at-home stimulation sessions (30 minutes each) of specifically designed multichannel tDCS targeting the left DLPFC administered over eight weeks (4 weeks of daily treatments plus 4 weeks of taper), with a follow-up period of 4 weeks following the final stimulation session. The stimulation montage (electrode positions and currents) was optimized by employing computational models of the electric field generated by multichannel tDCS using available structural data from a similar population (group optimization). Conducted entirely remotely, the study employed the MADRS for assessment at baseline, at weeks 4 and 8 during treatment, and at 4-week follow-up visits. 34 patients (85.3% women) with a mean age of 59 years, a diagnosis of MDD according to DSM-5 criteria, and a MADRS score ≥20 at the time of study enrolment completed all study visits. At baseline, the mean time since MDD diagnosis was 24.0 (SD 19.1) months. Concerning compliance, 85% of the participants (n=29) completed the complete course of 37 stimulation sessions at home, while 97% completed at least 36 sessions. No detrimental effects were observed, including suicidal ideation and/or behavior. The study observed a median MADRS score reduction of 64.5% (48.6, 72.4) 4 weeks post-treatment (Hedge's g = -3.1). We observed a response rate (≥ 50% improvement in MADRS scores) of 72.7% (n=24) from baseline to the last visit 4 weeks post-treatment. Secondary measures reflected similar improvements. These results suggest that remotely supervised and supported multichannel home-based tDCS is safe and feasible, and antidepressant efficacy motivates further appropriately controlled clinical studies. https://clinicaltrials.gov/study/NCT05205915?tab=results, identifier NCT05205915.