Post-treatment Period Research Articles

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.

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.

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.

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.

Psychological Factors Related to Treatment Outcomes in Head and Neck Cancer.

Patients with head and neck cancer (HNC) often demonstrate stress, distress, anxiety, depression, and are at risk forsuicide. These affect their quality of life (QoL) but less attention has been given to psychological variables that may impact response to treatment. This study aims to systematically review publications during 2013-2023 to collate evidence on the effects of psychological variables on HNC treatment outcomes. We searched Ovid Medline, PubMed, Scopus, and Web of Science for articles that examined psychological factors related to treatment outcomes in patients with HNC. There were 29 studies (5 before treatment, 2 during, 17 after, and 5 covering the whole management trajectory) including 362,766 patients. The psychological factors were either behavioral (adjustment and coping strategy, unrealistic ideas, self-blame), cognitive (elevated risk of psychiatric co-comorbidity), or emotional (distress, depression, anxiety, nervousness, and fear of disfigurement and complications). It was found that there was a relationship between depression and decreased survival in patients with HNC. Pretreatment pain was an independent predictor of decreased survival in a large sample of patients. The distress level was approximately 54%, emotional problems ranged between 10 and 44%, while financial difficulties wereidentified in 54% of the patients. Sixty-nine percent of patientswere reported to have used at least one cost-coping strategy within 6months after treatment initiation. During post-treatment period, depression increased from 15% at the baseline to 29%, while the fear of recurrence was found among at least 35% of patients. Several psychological factors predict QoL and survival among HNC survivors. Distress encompasses depression and anxiety, and physical burden from HNC diagnosis and treatment. Routine screening and early interventions that target distress could improve HNC survivors' QoL. A systematic and standardized measurement approach for QoL is warranted to homogenize these findings and to understand the underlying relationships.

A method of moments approach to asymptotically unbiased Synthetic Controls

A common approach to constructing a Synthetic Control unit is to fit on the outcome variable and covariates in pre-treatment time periods, but it has been shown by Ferman and Pinto (2021) that this approach does not provide asymptotic unbiasedness when the fit is imperfect and the number of controls is fixed. Many related panel methods have a similar limitation when the number of units is fixed. I introduce and evaluate a new method in which the Synthetic Control is constructed using a General Method of Moments approach where units not being included in the Synthetic Control are used as instruments. I show that a Synthetic Control Estimator of this form will be asymptotically unbiased as the number of pre-treatment time periods goes to infinity, even when pre-treatment fit is imperfect and the number of units is fixed. Furthermore, if both the number of pre-treatment and post-treatment time periods go to infinity, then averages of treatment effects can be consistently estimated. I provide a model selection procedure for deciding whether a unit should be used as an instrument or as a control. I also conduct simulations and an empirical application to compare the performance of this method with existing approaches in the literature.

마음챙김 기반 교원 웰빙 증진 프로그램 개발 및 효과 분석

In this study, a mindfulness-based intervention program for teachers and empirically validated the effects on teachers’ stress and subjective well-being was developed. More specifically, based on the latest neuroscience and positive psychology research on mindfulness, we developed a mindfulness-based well-being program for teachers that incorporated mindfulness meditation and positive psychological factors such as compassion, loving-kindness, and gratitude. We implemented the program for eight weeks with the teachers in the experimental group. For the program effectiveness analysis, first, we compared between groups using Repeated Measure ANOVA to determine the treatment effect between the experimental and control groups. Second, Repeated Measure ANOVA and paired sample t-tests to examine the treatment effect within the experimental group were compared. In particular, we examined the persistence of the treatment effect, focusing on changes from pre- to 4-week follow up tests. The results showed that the mindfulness-based teacher well-being program was effective in increasing mindfulness and self-kindness, one of the components of compassion, and decreasing stress, such as anger and physical reactions. Furthermore, the effects on stress, which includes not only mindfulness and self-kindness but also depression, anger, and physical reactions as a result of these variables, were sustained up to four weeks after the program ended. On the other hand, self-criticism, life satisfaction, and negative affect showed significant treatment effects in the pre- and post-treatment periods, but the effects did not persist four weeks after the program ended. Based on the results of this study, we suggested ways to improve teachers' mental health and subjective well-being.

Mandibular overdenture retained by four one-piece titanium-zirconium mini implants: A 2-year RCT on patient-reported outcomes

AimThe positive impact of implant interventions on dental patient-reported outcomes is an essential parameter of treatment effectiveness. This study assessed the 2-year changes in patient satisfaction and oral health-related quality of life (OHRQoL) of edentulous patients treated with a four mini implant mandibular overdenture (IOD) MethodsThe study was planned as a 2 × 2 factorial randomized clinical trial that tested two surgical approaches (flapped or flapless) and two loading protocols (immediate and delayed) using a titanium-zirconium mini implant (Straumann Mini Implant System®) and a PEEK retentive system (Straumann® Optiloc® Retentive System). Outcome measures (OHIP-Edent scores and the McGill Denture Satisfaction questionnaire) were assessed before treatment and at the 3-, 6-, 12-, and 24-month follow-ups. The Friedman test and multiple regression using Generalized Estimating Equations (GEE) were used for data analysis, considering the per-protocol (PP) and intention-to-treat (ITT) approaches ResultsSeventy-four patients were randomized to the study groups. No implant failure occurred during the study period. Marked improvement in all post-treatment periods compared to baseline were observed for the two outcomes. No significant effect of patient's gender, age, and surgical protocol on the study outcomes. The effect of treatment provision was significant for the two outcomes in the PP and ITT approaches (p < 0.001). A barely significant positive effect of the immediate loading was observed for OHIP-Edent in the PP approach (p = 0.020) ConclusionIOD treatment significantly improved patient-reported outcomes measures, with sustained benefits over the two years of overdenture use, and can be considered a promising treatment option in for the edentulous mandible.

Cost-effectiveness analysis of a digital diabetes-prevention programme versus an in-person diabetes-prevention programme in people with prediabetes in the United States.

To assess the cost-effectiveness of a digital diabetes prevention programme (d-DPP) compared with a diabetes prevention programme (DPP) for preventing type 2 diabetes (T2D) in individuals with prediabetes in the United States. A Markov cohort model was constructed, simulating a 10-year period starting at the age of 45 years, with a societal and healthcare sector perspective. The effectiveness of the d-DPP intervention was evaluated using a meta-analysis, with that of the DPP as the comparator. The initial cycle represented the treatment period, and transition probabilities for the post-treatment period were derived from a long-term lifestyle intervention meta-analysis. The onset of T2D complications was estimated using microsimulation. Quality-adjusted life years (QALYs) were calculated based on health utility measured by short form (SF)-12 scores, and a willingness-to-pay threshold of $100 000 per QALY gained was applied. The d-DPP intervention resulted in cost savings of $3,672 from a societal perspective and $2,990 from a healthcare sector perspectiveand a gain of 0.08 QALYs compared with the DPP. The dropout rate was identified as a significant factor influencing the results. Probabilistic sensitivity analysis showed that the d-DPP intervention was preferred in 85.8% in the societal perspective and 85.2% in the healthcare sector perspective. The d-DPP is a cost-effective alternative to in-person lifestyle interventions for preventing the development of T2D among individuals with prediabetes in the United States.

Genotoxicity, acute and sub-acute toxicity profiles of methanolic Cordyceps militaris (L.) Fr. extract in Swiss Albino Mice

Ethnopharmacological relevanceCordyceps militaris, a traditional medicinal fungus, parasitizes the intestines of lepidopteron pupae or larvae, predominantly during the winter, and undergoes fruiting in the summer or autumn. Compounds extracted from C. militaris have demonstrated a broad spectrum of pharmacological effects, including antioxidant, anti-tumor, anti-metastatic, anti-inflammatory, antiviral, anti-diabetic, and various others. Aim of the studyHerein, our study aimed at elucidating the acute, sub-acute toxicity, and genotoxicity profiles of C. militaris methanolic extract following oral administration in Swiss albino mice, representing the inaugural comprehensive exploration of the toxicological and safety profiles of C. militaris. Materials and methodsPrior studies have predominantly focused on its biological activities rather than its toxicity. Acute oral toxicity study was conducted at 500, 1000, and 2000 mg/Kg B.W. doses of C. militaris over a 14-day period. For sub-acute toxicity study, three groups of mice were administered 100, 300, and 600 mg/Kg B.W. of C. militaris extract for 28 consecutive days; one group served as a control. Mice were monitored for their body weight and behavioural changes once daily. Hematological, serum biochemical, histopathological, histomorphometric, seminal parameters, and mutagenic investigations were performed post-treatment period. ResultsAcute oral toxicity study at 2000 mg/Kg revealed no signs of toxicity, with an LD50 value surpassing 2000 mg/Kg. No occurrences of mortality observed, and no significant changes were noted in body weight, organ weight, or behaviour. Hematological analysis illustrated a marked upsurge in RBC, Hb, HCT, PLT, MPV, and PCT, alongside minor variations in differential leucocyte count post 28-day treatment. Liver enzyme tests indicated slight elevation in ALP, while renal enzyme tests showed alterations in CRE and BUN levels. Genotoxicity profile and histopathological assessments of the liver, spleen, testis, and ovary manifested no remarkable irregularities, except for mild renal toxicity. Seminal parameters including sperm concentration, motility and testosterone levels demonstrated a noteworthy increase. ConclusionsThe study sheds light on the potential risks and safety considerations associated with C. militaris-based medicinal products. These findings establish a foundation for further investigations and the refinement of dosage optimization in the application of C. militaris, with the aim of mitigating any potential adverse effects.

Differences in the Cellular Immune Response during and after Treatment of Sudanese Patients with Post-kala-azar Dermal Leishmaniasis, and Possible Implications for Outcome

BackgroundThe host cellular immune response associated with two treatments for post-kala-azar dermal leishmaniasis (PKDL) - paromomycin plus miltefosine (Arm 1), and liposomal amphotericin B plus miltefosine (Arm 2) - was examined in Sudanese patients before treatment (D0), at the end of treatment (D42), and during the post-treatment period (D180).MethodsWhole blood samples were stimulated with soluble Leishmania antigen for 24 h (whole blood assay [WBA]) and the concentrations of Th1/Th2/Th17-associated cytokines, IP-10, PDL-1 and granzyme B were determined.ResultsThe Arm 1 treatment (98.2% cure rate) induced a Th1/Th2/Th17 response, while the Arm 2 treatment (80% cure rate) induced a Th1/Th2 response. Five Arm 2 patients relapsed and showed lower IFN-γ, TNF and IL-1β concentrations at D0 than non-relapsers in this Arm. In patients with low-IFN-γ-production at D0, Arm 1 treatment led to a better host immune response and clinical outcome than Arm 2 treatment.ConclusionsA Th1/Th2/Th17 response was associated with a higher cure rate. Patients with low IFN-γ, TNF and IL-1β before treatment are more likely to relapse if they undergo Arm 2-type treatment. Determining IFN-γ, TNF and IL-10 levels prior to treatment could help predict patients at higher risk of relapse/recovery from PKDL.Trial RegistrationClinicalTrials.gov NCT03399955, Registered 17 January 2018, https://clinicaltrials.gov/study/ NCT03399955.Graphical

Safety and efficacy of linaclotide in children aged 2-5 years with functional constipation: Phase 2, randomized study.

Linaclotide, a guanylate cyclase-C agonist, was recently approved in the United States for the treatment of children 6-17 years of age with functional constipation (FC). This study evaluated the dose-response, safety, and efficacy of 4 weeks of linaclotide compared with placebo in children 2-5 years of age with FC. In this phase 2, randomized, double-blind, placebo-controlled, multidose study, 35 children with FC (based on Rome III criteria) were randomized 3:1 to receive linaclotide (18, 36, or 72 μg, for groups 1, 2, and 3, respectively) and 5:1 to receive linaclotide 9, 18, 36, or 72 μg (group 4), or matching placebo. Key endpoints were the changes from baseline in overall spontaneous bowel movement (SBM) frequency (SBMs/week), stool consistency, and straining, as well as the proportion of days with fecal incontinence during the study intervention period. Adverse events (AEs) were recorded. Of the randomized patients, 34 (97.1%) completed the treatment period and 33 (94.3%) completed the posttreatment period. Mean change from baseline over the treatment period for three of the four key efficacy endpoints showed greater improvement in the linaclotide 72 μg group versus placebo. A dose-response trend was seen for stool consistency in patients receiving linaclotide. Four patients randomized to linaclotide experienced treatment-emergent AEs, one of which was treatment-related (mild diarrhea). All AEs were mild or moderate and none were severe. Linaclotide was well tolerated in this pediatric population and an efficacy trend was seen with linaclotide 72 μg versus placebo.

P-642 The effect of oral dydrogesterone (DYD) on the hypothalamic-pituitary-ovarian (HPO) axis (gonadotropin and sex-steroid levels) and ovulation inhibition: a double-blind, phase I, randomized-controlled, parallel-group trial

Abstract Study question What is the effect of oral dydrogesterone (three cycles daily 20mg/30mg) on pituitary, ovarian and adrenal hormones, ovulation inhibition and endometrium in healthy ovulatory women? Summary answer Daily oral dydrogesterone, 20mg or 30mg, suppresses LH and inhibits ovulation in 33% and 73% of subjects, respectively, while not reducing E2 and other hormones. What is known already Dydrogesterone, a stereoisomer of progesterone, has high oral bioavailability and has demonstrated clinical utility in several indications, including endometriosis and assisted reproduction technologies. Progestin primed ovarian stimulation (PPOS) provides a cost effective and convenient alternative to the GnRH antagonist protocol to suppress a premature LH surge during ovarian stimulation in preparation for frozen embryo transfer IVF. In PPOS, studies have shown that dydrogesterone provides a comparable number of mature oocytes as a standard GnRH antagonist. The effects of various formulations and routes of administration of different progestins on sex hormones and the HPO has not been determined across the indications. Study design, size, duration A single-centre, double-blind, randomised, multiple-dose, parallel-group study of two doses of oral dydrogesterone over three 28-day treatment cycles: dydrogesterone 30mg, 10mg in the morning, afternoon and evening; dydrogesterone 20mg, afternoon dose replaced with placebo. The primary efficacy outcome was the number of subjects with “no ovulation at all” (Hoogland and Skouby score [HSS] 1-4) or “ovulation without pregnancy risk” (HSS 5-6 with negative Landgren criterion) recorded in all treatment cycles. Participants/materials, setting, methods The study population was 44 healthy, pre-menopausal women aged 18–35 years, with proven pre-treatment ovulation. The inclusion/exclusion criteria were defined to reflect the intended target population and the general contraindications for hormonal preparations. The primary objective was to compare the effect of the two self-administered doses of dydrogesterone on ovarian follicular growth leading to ovulation and E2 suppression. Secondary objectives included effect on other HPO hormones, the endometrium, PK characteristics and safety. Main results and the role of chance The number of responders to ovulation inhibition was dose-dependent: DYD 30mg, 72.7%, 95% CI: 49.78–89.27%; DYD 20mg, 33.3%, 95% CI: 14.59–56.97%. Based on HSS and Landgren criteria, there was 42.4% and 15.15% ovulation with pregnancy risk with the 20mg and 30mg doses, respectively. Neither dose had any clinically relevant influence on the average E2 concentration or FSH, androstenedione, dehydroepiandrosterone sulphate, testosterone and sex hormone binding globulin levels, while both doses suppressed the pre-ovulatory LH surge. Endometrial proliferation was mildly suppressed to a comparable extent with both daily doses. Hyperechogenic endometrium pattern was observed in 50% and 72% of treatment cycles in ovulating women in the 20mg and 30mg groups, respectively. Treatment with DYD did not significantly delay follicular growth or postpone ovulation in ovulating women. The more pronounced progesterone suppression with the higher 30mg dose may be due to the higher number of subjects without ovulation and thus without a post-ovulatory progesterone rise in that group. Return of ovulation after treatment cessation occurred in 91% women in the 42-day post-treatment period. The most frequently reported TEAE was ‘ovarian cyst’; all cases were of mild intensity and resolved at the end of the trial. No severe TEAE was reported. Limitations, reasons for caution Only two doses were studied in healthy, ovulatory women. DYD is used in various clinical contexts with concomitant other medications, such as gonadotropins for ovarian stimulation, or under luteotropic circumstances with human chorionic gonadotropin activity from exogenous or endogenous sources. Only limited morning PK sampling was performed. Wider implications of the findings Oral dydrogesterone used for endometriosis symptom reduction may be associated with a low risk of long-term adverse events from hypoestrogenism and suppression of androgens. Oral dydrogesterone displays relevant and short-term effects on LH levels, supporting its use in PPOS protocols. At therapeutic doses, dydrogesterone does not completely inhibit ovulation. Trial registration number EudraCT-No.: 2021-004747-24

O-269 Long term efficacy of Linzagolix in women with endometriosis-associated pain

Abstract Study question Does once-daily linzagolix taken up to 12 months maintain pain reduction observed at 6 months in women with endometriosis? Summary answer Linzagolix alone or in combination with combined add-back therapy (ABT) for 12 months maintains improvements of endometriosis-associated pain (EAP) observed at 6 months. What is known already Linzagolix is an oral GnRH antagonist under development for EAP. In the EDELWEISS 3 study, the 200mg+ABT dose met its co-primary endpoints at 3 months by reducing dysmenorrhea (DYS) and non-menstrual pelvic pain (NMPP) and secondary endpoints such as DYS, NMPP, overall pelvic pain and dyschezia as well as interference of pain with daily activities at 6 months. Linzagolix 75mg significantly reduced dysmenorrhea but not NMPP at 3 months. Both doses of linzagolix were well tolerated over 6 months of treatment. Study design, size, duration EDELWEISS 6 was the extension study of EDELWEISS 3, a placebo-controlled Phase 3 study, investigating linzagolix 75mg and 200mg+ABT for up to 6 months in women with moderate to severe EAP. Subjects who completed EDELWEISS3 were invited to enter the extension study for an additional 6-month treatment on the same linzagolix dose; placebo subjects were randomized to either active dose. After end of treatment, subjects entered a drug-free post-treatment period of 6 months. Participants/materials, setting, methods Women participating to EDELWEISS 6 received linzagolix for up to 12 months consecutively. Key efficacy assessments included dysmenorrhea and non-menstrual pelvic pain (NMPP), dyspareunia (assessed with a 4-point VRS), overall pelvic pain and dyschezia (assessed with an 11-point NRS), and interference of pain with daily activities (assessed with the EHP-30 pain domain) at Month 12. We report the results for dysmenorrhea and NMPP. Main results and the role of chance Of 484 participants in EDELWEISS 3, 353 (72.9%) entered EDELWEISS 6 and were evaluated for efficacy. Demographics were similar to EDELWEISS 3 with a mean age of 35 years, a BMI of 24kg/m2 and 99% of subjects being White. Mean (SD) monthly baseline dysmenorrhea and NMPP pain scores on the VRS were 2.28 (0.41) and 1.76 (0.45), respectively. The threshold for a meaningful pain reduction was established at Month 3, being -1.10 and -0.80 for dysmenorrhea and NMPP, respectively. At Month 3, the proportion of subjects with a reduction of dysmenorrhea of 1.10 or greater, and stable or decreased use of analgesics was 45.2% for the 75mg group and 75.4% for the 200mg+ABT group, which increased to 49.6% and 84.7%, respectively, at Month 6, the end of EDELWEISS 3. At Month 12, the end of EDELWEISS 6 treatment, the proportion of subjects was further increased to 55.9% and 91.0%, respectively. For NMPP, the proportion of subjects with a reduction of 0.80 or greater and stable or decreased use of analgesics at Month 3 was 36.5% for 75 mg and 51.7% for 200mg+ABT, increased to 54% and 61% at Month 6, and increased to 59.5% and 67.6%, respectively, until Month 12. Limitations, reasons for caution Edelweiss 6 is the extension of the previously reported double blind, placebo controlled Edelweiss 3 study. The results confirm efficacy of 200mg + ABT at 12 months. Longer term data is required to further understand efficacy of GnRH antagonists in women with endometriosis associated pain. Wider implications of the findings The linzagolix 200mg+ABT group provided substantial and sustained improvement in EAP symptoms. The 75mg which did not meet the primary endpoint in EDELWEISS 3 still demonstrated marked improvements. There exists a substantial need for different treatment regimens in women suffering from endometriosis. Trial registration number NCT04335591

Combination of a Topical Anti-Inflammatory Drug and a Moisturizer, Both with a Lamellar Structure Containing Synthetic Pseudo-Ceramides, for the Treatment of Patients with Mild-to-Moderate Atopic Dermatitis.

Atopic dermatitis is characterized by chronic inflammation and dryness accompanied by severe itching. The combined use of moisturizers and topical anti-inflammatory drugs is essential for alleviating atopic dermatitis. We have developed a topical anti-inflammatory drug with a steroid and a moisturizer with heparinoid, both in lamellar structure-based formulations containing synthetic pseudo-ceramides. Here, assessed the efficacy of this combination in the treatment of atopic dermatitis. We included 22 patients with mild to moderate atopic dermatitis and subjected them to a seven-week treatment with the test formulations, followed by a four-week post-treatment period. Clinical findings and the quality of life of participants remarkably improved after one week of treatment. Furthermore, skin hydration and transepidermal water loss considerably improved at weeks one and three, respectively. The Cer [NP]/[NS] ratio, an indicator of epidermal turnover, substantially increased during the treatment period and remained elevated even thereafter. The improvement in stratum corneum function was distinctive in participants with lower barrier function. These findings indicated that the combined use of the anti-inflammatory drug and moisturizer, both in lamellar structure-based formulations, is effective in treating atopic dermatitis in patients with fragile barrier function.