Regular Dose Research Articles

OR31-01 The Dose-dependent Effect Of Estrogen On Bone Mineral Density In Trans Girls

Abstract Disclosure: L.S. Boogers: None. M.A. van der Loos: None. C.M. Wiepjes: None. A. van Trotsenburg: None. M. den Heijer: None. S.E. Hannema: None. Introduction: Treatment in transgender girls can consist of puberty suppression with Gonadotrophin-releasing hormone agonists (GnRHa) followed by estrogen treatment. A decrease in bone mineral density (BMD) Z-scores is a known effect of GnRHa. After initiation of estradiol BMD Z-scores remain relatively low, even after several years of treatment. It has been hypothesized that the estradiol dosage may be insufficient, explaining the persistently low Z-scores. Some trans girls are treated with a higher dosage of estradiol or ethinylestradiol in order to limit growth. This provides the opportunity to evaluate if a higher estradiol dosage results in a greater increase in BMD Z-scores. Methods: Trans girls diagnosed with gender dysphoria were included if they were treated with GnRHa for a minimum of one year prior to treatment with estradiol. Estradiol was increased to the regular dosage (2 mg), or high growth-reductive dosages of estradiol (6 mg) or ethinyl estradiol (100-200 μg (EE)) before the age of 18 years. BMD was assessed using DXA scans performed regularly during GnRHa and estrogen treatment. Z-scores of the lumbar spine were adjusted for height, and the development over time was compared between the different treatment groups. Results: A total of 100 trans girls were included with a mean duration of GnRHa treatment of 2.3±0.7 years. Mean BMD Z-score of the lumbar spine at start of PS was -0.26±0.84. During PS, Z-scores decreased in all three treatment groups to a mean Z-score of -0.99±0.86. After two years of estrogen treatment, Z-scores increased by 0.15 (95% CI 0.00 to 0.30) in the 2 mg estradiol group (n=65) versus 0.35 (95%CI 0.08 to 0.62) in individuals treated with 6 mg estradiol (n=21), and 0.74 (95%CI 0.27 to 1.21) in the EE group (n=14). Compared with 2 mg estradiol, the increase in trans girls treated with EE was significantly higher (0.59, 95% 0.10 to 1.08). There was no difference in individuals treated with 2 mg or 6 mg estradiol (0.20 , 95%CI -0.11 to 0.51). After three years of estrogen treatment, only in the individuals treated with EE, Z-scores were not significantly different from start of GnRHa (-0.01, 95%CI -0.38 to 0.36). Conclusion: When compared to the regular 2 mg dosage of estradiol, a higher estradiol dose, and especially treatment with EE resulted in a greater increase in BMD Z-scores in the lumbar spine in trans girls. This might indicate that 2 mg estradiol is insufficient as a maintenance dose during adolescence and that a higher adult dose is required to optimise BMD. Presentation: Sunday, June 18, 2023

Losartan alleviates renal fibrosis by inhibiting the biomechanical stress-induced epithelial-mesenchymal transition of renal epithelial cells

Angiotensin receptor blockers (ARBs) have been reported to be beneficial of renal fibrosis, but the molecular and cellular mechanisms are still unclear. In this study, we investigated the effectiveness and relevant mechanism of ARBs in alleviating renal fibrosis, especially by focusing on biomechanical stress-induced epithelial to mesenchymal transition (EMT) of renal epithelial cells. Unilateral ureteral obstruction (UUO) renal fibrosis model was established in mice by ligating the left ureter, and then randomly received losartan at a low dose (1 mg/kg) or a regular dose (3 mg/kg) for 2 weeks. Compared to the control, histological analysis showed that losartan treatment at either a low dose or a regular dose effectively attenuated renal fibrosis in the UUO model. To further understand the mechanism, we ex vivo loaded primary human renal epithelial cells to 50 mmHg hydrostatic pressure. Western blot and immunostaining analyses indicated that the loading to 50 mmHg hydrostatic pressure for 24 h significantly upregulated vimentin, β-catenin and α-SMA, but downregulated E-cadherin in renal epithelial cells, suggesting the EMT. The addition of 10 or 100 nM losartan in medium effectively attenuated the EMT of renal epithelial cells induced by 50 mmHg hydrostatic pressure loading. Our in vivo and ex vivo experimental data suggest that losartan treatment, even at a low dose can effectively alleviate renal fibrosis in mouse UUO model, at least partly by inhibiting the biomechanical stress-induced EMT of renal epithelial cells. A low dose of ARBs may repurpose for renal fibrosis treatment.

A case of vitamin-D dependent type-1A rickets

Abstract Rickets is a disease of growing bones characterized by softening of bones as a result of defective mineralization of cartilage in the epiphyseal growth plate. The predominant cause is a deficiency or impaired metabolism of vitamin D. Some forms of rickets do not respond to regular doses of cholecalciferol, which leads to suspicion of vitamin D-dependent rickets (VDDR). VDDR is of two types: type I is due to defective renal tubular 25-hydroxyvitamin D 1-α hydroxylase, and type II is due to end-organ resistance to the active metabolite of vitamin D. Here, we describe a child with seizures and calcipenic rickets with biochemical profile suggestive of VDDR type 1 worsened by phenytoin which responded completely to calcium and calcitriol supplementation. Whole exome sequencing revealed a heterozygous missense mutation in exon 7 of the TRPV4 gene (chromosome 12,c.1292C>A), whereas no mutations in CYP2R1, CYP27B1, VDR, and CYP3A4 were detected.

3D Dosimetry for Electron Flash Radiotherapy: Assessment of Radiochromic Dosimeter Phantoms with Optical CT Scanning as a 3D Dosimetry System

Many of the dosimeters used in conventional radiation therapy exhibit dose rate dependence which prohibits their use in ultra-high-dose-rate (FLASH) radiation therapy. Radiochromic plastic dosimeter PRESAGE® has been used for 3D dosimetry for many years. We hypothesized that these phantoms would show dose-rate independence throughout both the conventional and FLASH RT regimes, indicating these phantoms exhibit qualities useful for relative 3D dosimetry in FLASH electron beams. FLASH experiments were performed using a commercially available linear accelerator, converted to deliver an ultra-high-dose-rate 10 MeV electron beam. The LINAC delivered approximately 0.7 Gy/pulse for FLASH irradiations. Dose rate was varied from about 40 Gy/s to 240 Gy/s by changing the repetition rate. PRESAGE phantoms were irradiated en face at six FLASH dose rates: 40 Gy/s, 80 Gy/s, 120 Gy/s, 160 Gy/s, 200 Gy/s, and 240 Gy/s. EBT film and scintillator measurements were used to verify dose delivered. The optical response of the PESAGE phantom versus delivered dose was evaluated with various known doses. A novel parallel-beam optical CT scanner, utilizing fiber optic taper for collimated images, was developed for fast, high resolution, and accurate readout of 3D dosimeters. Percent depth dose curves for various FLASH dose rates and conventional dose rate beams were generated and compared based on the optical response versus dose measurements. Percent depth dose curves from Monte Carlo calculation of the presage phantom were also compared. As shown in Table 1, the percent depth dose as a function of depth for six FLASH dose rates (240-40 Gy/s) are nearly identical, indicating that optical response of PRESAGE is dose-rate independent. The optical density of PRESAGE phantom was confirmed to be linear with absorbed dose for all FLASH dose rates, consistent with the observation at regular treatment dose rates. PRESAGE phantoms show dose-rate independence in electron beams for a wide range of dose rates from conventional to ultra-high-dose-rates, indicating these phantoms can be useful for relative 3D dose measurements in FLASH electron beams. Future experiments will be undertaken as part of the commissioning of a commercially available FLASH radiotherapy unit.

40 Analgesia in Sickle Cell Disease: Do We Give the Right Dose? A Systematic Review of Pharmacokinetic Studies

Abstract Background Children with sickle cell disease (SCD) suffer from lifelong episodes of unpredictable acute pain that alter their quality of life. Despite prompt pain treatment, hospitalization is often required for pain management. SCD is a multisystemic disease affecting organ function (e.g., renal hyperfiltration, change in liver blood flow). Altogether, these changes could alter pharmacokinetics (PK). Objectives We hypothesize that SCD leads to changes in PK of analgesics potentially contributing to treatment failure using regular medication doses. Design/Methods A systematic literature review to describe the current evidence on the effect of SCD on analgesic disposition in children was performed by a librarian on 5 databases from inception until February 2021 and independently assessed by two reviewers. All full text articles, including PK data in children with SCD, were included. The reported differences in PK parameters between children with and without SCD were examined. Results Among 5170 retrieved abstracts, 84 full text articles were reviewed, and 7 studies were included on 128 patients. Studied drugs were morphine (IV and PO), lidocaine (IV), methadone (IV) and rofecoxib (PO). In children with SCD, clearance of IV morphine was 42-61% higher compared with non-SCD controls. Hepatic metabolism of lidocaine was decreased in children with SCD compared to healthy controls. No significant PK changes were noted for methadone and rofecoxib compared with non-SCD controls. Conclusion SCD leads to significant changes in PK of analgesics, but data are scarce. Increased clearance of morphine suggests that higher doses may be needed in children with SCD. Data on commonly used analgesics like acetaminophen, ibuprofen and ketamine are critically missing. Dosing of analgesics adapted to SCD are needed and may potentially improve pain control in this population.

Treatment of insomnia in myasthenia gravis-A prospective study on non-benzodiazepine hypnotics in the treatment of myasthenia gravis patients with insomnia.

This study aimed to evaluate the efficacy and safety of non-benzodiazepine hypnotics in the treatment of myasthenia gravis (MG) patients with insomnia. This is a prospective longitudinal study. Outpatients who met the criteria for stable MG and insomnia diagnosis according to the International Classification of Sleep Disorders (third edition) were included in the study. They took a regular dose of non-benzodiazepine hypnotics (zolpidem 10 mg per night or zopiclone 7.5 mg per night) based on their own preferences. Patients received psychotherapy (including sleep health education) and were followed up for 4-5 weeks. Cases with lung diseases, respiratory disorders, or inappropriate use of hypnotic medications were excluded. The primary outcome is the difference in total Pittsburgh Sleep Quality Index (PSQI) score between baseline and the end of follow-up period. Secondary outcomes include the difference in Myasthenia Gravis Activities of Daily Living (MG-ADL) score, 7-item Generalized Anxiety Disorder Questionnaire (GAD-7), and the Patient Health Questionnaire-9 (PHQ-9) between baseline and the end of follow-up period and the safety of medication. A total of 75 MG patients with insomnia were included in this study. After 4-5 weeks of treatment, the total PSQI score and MG-ADL score were lower than baseline (p < 0.01). No patients had an increased MG-ADL score. The incidence rate of adverse events was 16.0% (12 cases), including dizziness (6 cases, 8.0%), drowsiness (3 cases, 4.0%), fatigue (2 cases, 2.7%), and nausea (1 case, 1.3%), all of which were mild. No patients had new onset breathing disorders. Non-benzodiazepine hypnotics are safe and effective for stable MG patients who need insomnia treatment.

Optimizing the Use of Iodinated Contrast Media: Conservation Strategies Used Across Canada During the 2022 Shortage

&#x0D; A shortage of iodinated contrast media (ICM) used in contrast-enhanced CT exams led to the adoption of necessary conservation strategies across Canada.&#x0D; Conservation strategies included multidispensing from single-use and multiuse ICM bottles, diluting or reducing ICM dose volumes, switching to weight-based dosing from fixed-based dosing, lower tube voltage, performing unenhanced CT scans, using alternative imaging modalities, or prioritizing urgent cases. One of the more common alternative conservation strategies was to prioritize urgent cases for contrast-enhanced CT exams.&#x0D; Most medical imaging staff who responded to a national survey on ICM conservation strategies reported they would return to their regular doses used before the shortage despite little to no perceived effect on the contrast conspicuity of images or on patient adverse events with reduced ICM volumes.&#x0D; The ICM shortage represents an opportunity to reconsider ICM usage practices given environmental sustainability concerns with ICM and potential cost savings in reducing its use.&#x0D;

Effectiveness and potential mechanism of Jiawei-Xiaoyao-San for hyperthyroidism: a systematic review.

To evaluate the effectiveness and potential mechanism of traditional Chinese medicine Jiawei-Xiaoyao-San (JWXYS) as an adjunct or mono- therapy for antithyroid drugs (ATDs) in the treatment of hyperthyroidism. Eight databases and three trial registries were searched from inception until May 2023. Randomized controlled trials (RCTs) were included and meta-analysis was conducted using RevMan 5.4 and Stata 14.0. The Cochrane risk of bias (ROB) tool 1.0 and GRADE tool was used for quality appraisal. The findings from case reports using mono-JWXYS and pharmacological studies were summarized in tables. Thirteen RCTs with 979 participants were included. The majority of the included studies were assessed as high risk of bias in one ROB domain. Compared with ATDs, JWXYS plus ATDs resulted in lower free triiodothyronine (FT3) (MD = -1.31 pmol/L, 95% CI [-1.85, -0.76]; low-certainty), lower free thyroxine (MD = -3.24 pmol/L, 95% CI [-5.06, -1.42]; low-certainty), higher thyroid stimulating hormone (MD = 0.42 mIU/L, 95% CI [0.26, 0.59]; low-certainty), higher effectiveness rate of traditional Chinese medicine syndrome (RR = 1.28, 95% CI [1.08, 1.52]; low-certainty), lower goiter score (MD = -0.66, 95% CI [-1.04, -0.29]; very low-certainty), lower thyrotrophin receptor antibody (SMD = -0.44, 95% CI [-0.73, -0.16]; low-certainty) and fewer adverse events (AEs) (RR = 0.34, 95% CI [0.18, 0.67]; moderate-certainty). Compared with regular dosage of ATDs, JWXYS plus half-dose ATDs resulted in fewer AEs (RR = 0.24, 95% CI [0.10, 0.59]; low-certainty). Compared with ATDs in 1 trial, JWXYS resulted in higher FT3, lower goiter score and fewer AEs. Three case reports showed that the reasons patients sought TCM-only treatment include severe AEs and multiple relapses. Three pharmacological studies demonstrated that JWXYS restored Th17/Treg balance, lowered deiodinases activity, regulated thyroid cell proliferation and apoptosis, and alleviated liver oxidative stress in mouse or rat models. JWXYS may enhance the effectiveness of ATDs for hyperthyroidism, particularly in relieving symptoms and reducing AEs. Mono-JWXYS is not recommended except in patients intolerant to ATDs. The findings should be interpreted with caution due to overall high risk of bias. Further pharmacological studies with more reliable models are needed. https://www.crd.york.ac.uk/prospero/, identifier CRD42023394923.

Imipramine Suppresses Tumor Growth and Induces Apoptosis in Oral Squamous Cell Carcinoma: Targeting Multiple Processes and Signaling Pathways.

Oral squamous cell carcinoma (OSCC) has limited treatment options. This study investigated imipramine, a tricyclic antidepressant, as a potential therapy for OSCC using a SAS-bearing xenograft animal model. The SAS-bearing xenograft model evaluated imipramine's impact on tumor growth. The control group received no treatment, while the imipramine-treated group received regular doses. Tumor growth, confirmed by imaging, and histological analysis assessed size and weight. Imipramine's effects on apoptosis, epithelial-to-mesenchymal transition (EMT), and transcription factors (AKT, ERK, STAT3) were analyzed. Imipramine significantly suppressed tumor growth within 6 days of treatment, with sustained activity. Computer tomography (CT) scans and histology confirmed reduced size and weight by imipramine. Imipramine induced apoptosis via caspase-dependent/-independent pathways, inhibited EMT, and down-regulated phosphorylated AKT, ERK, and STAT3. Imipramine shows promise as an effective OSCC therapy, inhibiting tumor growth, inducing apoptosis, and inhibiting EMT. Its impact on transcription factors and modulation of the AKT/ERK/STAT3 pathway suggest a multifaceted approach.

Understanding the Clinical Implications of Individual Patient Characteristics and Treatment Choice on the Risk of Exacerbation in Asthma Patients with Moderate-Severe Symptoms.

The assessment of future risk has become an important feature in the management of patients with asthma. However, the contribution of patient-specific characteristics and treatment choices to the risk of exacerbation is poorly understood. Here we evaluated the effect of interindividual baseline differences on the risk of exacerbation and treatment performance in patients receiving regular maintenance doses of inhaled corticosteroids (ICS) or ICS/long-acting beta-agonists (LABA) combination therapy. Exacerbations and changes to asthma symptoms 5-item Asthma Control Questionnaire (ACQ-5) were simulated over a 12-month period using a time-to-event and a longitudinal model developed from phaseIII/IV studies in patients with moderate-severe asthma (N = 16,282). Simulations were implemented to explore treatment performance across different scenarios, including randomised designs and real-world settings. Treatment options included regular dosing with ICS monotherapy [fluticasone propionate (FP)] and combination therapy [fluticasone propionate/salmeterol (FP/SAL) or budesonide/formoterol (BUD/FOR)]. Exacerbation rate was analysed using the log-rank test. The cumulative incidence of events was summarised stratified by treatment. Being a woman, smoker, having higher baseline ACQ-5 and body mass index (BMI) and lower forced expiratory volume in the first second (FEV1) are associated with increased exacerbation risk (p < 0.01). This risk is bigger in winter because of the seasonal variation effect. Across the different scenarios, the use of FP/SAL resulted in a 10% lower annual incidence of exacerbations relative to FP or regular dosing BUD/FOR, independently of baseline characteristics. Similar differences in the annual incidence of exacerbations were also observed between treatments in obese patients (BMI ≥ 25-35kg/m2) (p < 0.01) and in patients who do not achieve symptom control on FP monotherapy. Individual baseline characteristics and treatment choices affect future risk. Achieving comparable levels of symptom control whilst on treatment does not imply comparable risk reduction, as shown by the lower exacerbation rates in FP/SAL vs. BUD/FOR-treated patients. These factors should be considered as a basis for personalised clinical management of patients with moderate-severe asthma.

Impact of inhaled and intranasal corticosteroids on glucose metabolism and diabetes mellitus: A mini review.

Inhaled corticosteroids (ICS) and intranasal corticosteroids (INS) are the mainstays of treatment for chronic respiratory diseases like asthma, chronic obstructive pulmonary disease, and allergic rhinosinusitis. In addition, these localized forms of steroid therapy are generally considered to have fewer systemic side effects compared to long-term oral corticosteroids. However, concern and controversy remain over the impact of ICS and INS on the incidence and control of diabetes mellitus (DM). Given the widespread use of ICS and INS, even small individual effects on DM could lead to large consequences for the global popu-lation. Multiple large observational studies suggest that high dose ICS is associated with increased incident DM and worsened DM control, though the contribution of other risk factors is less certain. In addition, only two studies were done to investigate the association of INS and DM, with both studies demon-strating a short-term association of INS use with hyperglycemia. While more research evaluating the risk of ICS/INS for DM-related adverse events is needed, high doses of ICS/INS should be avoided when possible. The following strategies for ICS/INS dose minimization can be considered: Use of non-pharmacological measures (trigger avoidance, smoking cessation, vaccination to avoid infection), control of comorbid conditions, use of non-ICS-containing medications, inter-mittent rather than regular ICS dosing, and appropriate de-escalation of high ICS doses.

Clinical Outcomes in Elderly Atrial Fibrillation Patients at Increased Bleeding Risk Treated with Very-Low-Dose versus Regular-Dose Non-Vitamin K Antagonist Oral Anticoagulants: a Nationwide Cohort Study.

The ELDERCARE-AF trial showed that edoxaban at a very-low-dosage (VLD) of 15mg/day was more effective than a placebo at preventing stroke/systemic embolism without significantly increasing the risk of serious bleeding. We aimed to compare the effectiveness and safety for VLD non-vitamin K antagonist oral anticoagulants (NOACs) (edoxaban 15mg once daily, dabigatran 110 or 150 once daily, apixaban 2.5mg once daily, or rivaroxaban 10mg (without the diagnosis of chronic kidney disease) or less than 10mg once daily) versus regular-dosage (RD) NOACs (edoxaban 60/30mg once daily or other labeling-dosage NOACs) among a real-world cohort of elderly AF population similar to the ELDERCARE-AF cohort. In this nationwide retrospective cohort study from Taiwan National Health Insurance Research Database (NHIRD), we identified a total of 7294 and 4151 consecutive AF patients aged 80 years or older with a CHADS2 score≥2 who met the enrollment criteria (generally similar to ELDERCARE-AF) taking VLD and RD NOACs from June 1, 2012, to December 31, 2019, respectively. Propensity-score stabilized weighting (PSSW) was used to balance covariates across study groups. Patients were followed up from the first date of prescription for NOACs until the first occurrence of any study outcome, death, or until the end date of the study period (December 31, 2020). After PSSW, VLD NOAC was associated with a comparable risk of ischemic stroke/systemic embolism and major bleeding but a higher risk of major adverse limb events (MALEs) requiring lower limb revascularization or amputation (Hazard ratio [HR]:1.54, 95% confidential interval [CI]:1.09-2.18; p=0.014), venous thrombosis (HR:3.75,95%CI:1.56-8.97; p=0.003), and all-cause mortality (HR:1.21,95%CI:1.15-1.29; p<0.001) compared to RD NOACs. VLD NOACs showed worse outcomes in most net clinical benefits (NCOs). The main result was consistent based on on-treatment analysis or accounting for death as a competing risk. In general, the advantage of NCOs for the RD NOACs over VLD NOACs persisted in most high-risk subgroups, consistent with the main analysis (P for interaction>0.05). Use of VLD NOACs was associated with a greater risk of arterial and venous thrombosis, death as well as the composite outcomes, when compared to that of RD NOAC in high-risk elderly AF patients at increased bleeding risk. Thromboprophylaxis with RD NOAC is still preferable over VLD NOAC for the majority of elderly AF patients at increased bleeding risk.

The dose-dependent effect of estrogen on bone mineral density in trans girls.

Treatment in transgender girls can consist of puberty suppression (PS) with a gonadotropin-releasing hormone agonist (GnRHa) followed by gender-affirming hormonal treatment (GAHT) with estrogen. Bone mineral density (BMD) Z-scores decrease during PS and remain relatively low during GAHT, possibly due to insufficient estradiol dosage. Some adolescents receive high-dose estradiol or ethinyl estradiol (EE) to limit growth allowing comparison of BMD outcomes with different dosages. Retrospective study. Adolescents treated with GnRHa for ≥1 year prior to GAHT followed by treatment with a regular estradiol dose (gradually increased to 2 mg), 6 mg estradiol or 100-200 µg EE were included to evaluate height-adjusted BMD Z-scores (HAZ scores) on DXA. Eighty-seven adolescents were included. During 2.3 ± 0.7 years PS, lumbar spine HAZ scores decreased by 0.69 [95% confidence interval (CI) -0.82 to -0.56)]. During 2 years HT, lumbar spine HAZ scores hardly increased in the regular group (0.14, 95% CI -0.01 to 0.28, n = 59) vs 0.42 (95% CI 0.13 to 0.72) in the 6 mg group (n = 13), and 0.68 (95% CI 0.20 to 1.15) in the EE group (n = 15). Compared with the regular group, the increase with EE treatment was higher (0.54, 95% CI 0.05 to 1.04). After 2 years HT, HAZ scores approached baseline levels at start of PS in individuals treated with 6 mg or EE (difference in 6 mg group -0.20, 95% CI -0.50 to 0.09; in EE 0.17, 95% CI -0.16 to 0.50) but not in the regular group (-0.64, 95% CI -0.79 to -0.49). Higher estrogen dosage is associated with a greater increase in lumbar spine BMD Z-scores. Increasing dosage up to 2 mg estradiol is insufficient to optimize BMD and approximately 4 mg may be required for adequate serum concentrations.

Investigation of the influencing factors with the uptake of the COVID-19 vaccine booster dose among the general population of Ardabil, Iran: A cross-sectional study.

Vaccination is one of the most efficient approaches to combating COVID-19 if it is adequately embraced by the general population. Numerous factors influence the uptake or refusal of the booster dose. The goal of this study was to look at the different factors that affect how the general population in Ardabil feels about getting vaccine boosters (annual boosters) for COVID-19 and to evaluate those feelings. In the city of Ardabil, general population, perceptions towards the COVID-19 vaccine booster (annual boosters) dose were evaluated using a cross-sectional survey design between January 2 and March 25, 2022. A questionnaire was developed and filled out by 662 subjects via phone calls from healthcare providers. Descriptive statistics, the Chi-square test, the correlation coefficient, and regression analysis were run for the analysis of quantitative data. The findings of the research revealed that 238 participants, or 35.9%, had previously gotten the booster dose of the COVID-19 vaccination, while 198 participants, or 29.2%, expressed a desire to do so as soon as feasible. A total of 187 (28.2%) respondents reported not wanting to get a booster dose, and 39 (5.7%) could not decide. In the factors found to affect decisions not to accept regular doses, adverse effects (45.4%) and the presence of misinformation (30%) were the most important. Regression in educational achievement, and following the COVID-19 news showed to be the major predictors of the subjects' attitudes toward the regular COVID-19 vaccine. The present findings revealed that low confidence in the efficiency of the booster shot and misinformation are two critical factors to consider in educational planning and interventions.

A network meta-analysis of the association between patient traits and response to regular dosing with ICS/long-acting β2-agonist plus short-acting β2 agonist reliever or maintenance and reliever therapy for asthma

IntroductionCurrent treatment for moderate–severe asthma with inhaled corticosteroid (ICS)-based therapy can follow two strategies: a single inhaler maintenance and reliever therapy (MART) regimen, or regular dosing with ICS/long-acting β2-agonist used as maintenance therapy plus a separate short acting β2-agonist reliever inhaler. It would be clinically useful to understand the potential of patient traits to influence regular dosing or MART treatment outcomes. ObjectivesA systematic literature review (SLR) and meta-analysis was conducted to identify specific patient traits that may predict improved clinical outcomes with regular dosing or MART. ResultsThe SLR identified 28 studies in patients with moderate–severe asthma assessing regular dosing or MART treatments and reporting the traits and outcomes of interest. Network meta-regressions found no significant difference in the relative efficacy of regular dosing as compared with MART on any of the clinical outcomes (exacerbation rate, time to first exacerbation, FEV1, reliever use and adherence) for any of the patient traits (baseline lung function, baseline ACQ, age, BMI, and smoking history) evaluated. However, some trends towards traits influencing treatment efficacy were identified. Inconsistent reporting of traits and outcomes was observed between trials. ConclusionsThe analysed patient traits evaluated in this study were associated with similar efficacy for the analysed outcomes to either regular dosing or MART; however, trends from the data observed encourage future analyses for possible identification of additional traits, or a combination of traits, that may be of interest. More comparable reporting of clinically important traits and outcomes would improve future analyses.

An Overview of Chemistry, Kinetics, Toxicity and Therapeutic Potential of Boldine in Neurological Disorders.

Boldine is an alkaloid obtained from the medicinal herb Peumus boldus (Mol.) (Chilean boldo tree; boldo) and belongs to the family Monimiaceae. It exhibits a wide range of pharmacological effects such as antioxidant, anticancer, hepatoprotective, neuroprotective, and anti-diabetic properties. There is a dearth of information regarding its pharmacokinetics and toxicity in addition to its potential pharmacological activity. Boldine belongs to the aporphine alkaloid class and possesses lipophilic properties which enable its efficient absorption and distribution throughout the body, including the central nervous system. It exhibits potent free radical scavenging activity, thereby reducing oxidative stress and preventing neuronal damage. Through a variety of neuroprotective mechanisms, including suppression of AChE and BuChE activity, blocking of connexin-43 hemichannels, pannexin 1 channel, reduction of NF-κβ mediated interleukin release, and glutamate excitotoxicity which successfully reduces neuronal damage. These results point to its probable application in reducing neuroinflammation and oxidative stress in epilepsy, Alzheimer's disease (AD), and Parkinson's disease (PD). Moreover, its effects on serotonergic, dopaminergic, opioid, and cholinergic receptors were further investigated in order to determine its applicability for neurobehavioral dysfunctions. The article investigates the pharmacokinetics of boldine and reveals that it has a low oral bioavailability and a short half-life, requiring regular dosage to maintain therapeutic levels. The review studies boldine's potential therapeutic uses and mode of action while summarizing its neuroprotective benefits. Given the favorable results for boldine as a potential neurotherapeutic drug in laboratory animals, more research is required. However, in order to optimise its therapeutic potential, it must be more bioavailable with fewer detrimental side effects.

Epinephrine Dosing Use During Extracorporeal Cardiopulmonary Resuscitation: Single-Center Retrospective Cohort.

During pediatric cardiac arrest, contemporary guidelines recommend dosing epinephrine at regular intervals, including in patients requiring extracorporeal membrane oxygenation (ECMO). The impact of epinephrine-induced vasoconstriction on systemic afterload and venoarterial ECMO support is not well-defined. Nested retrospective observational study within a single center. The primary exposure was time from last dose of epinephrine to initiation of ECMO flow; secondary exposures included cumulative epinephrine dose and arrest time. Systemic afterload was assessed by mean arterial pressure and use of systemic vasodilator therapy; ECMO pump flow and Vasoactive-Inotrope Score (VIS) were used as measures of ECMO support. Clearance of lactate was followed post-cannulation as a marker of systemic perfusion. PICU and cardiac ICU in a quaternary-care center. Patients 0-18 years old who required ECMO cannulation during resuscitation over the 6 years, 2014-2020. Patients were excluded if ECMO was initiated before cardiac arrest or if the resuscitation record was incomplete. None. A total of 92 events in 87 patients, with 69 events having complete data for analysis. The median (interquartile range) of total epinephrine dosing was 65 mcg/kg (37-101 mcg/kg), with the last dose given 6 minutes (2-16 min) before the initiation of ECMO flows. Shorter interval between last epinephrine dose and ECMO initiation was associated with increased use of vasodilators within 6 hours of ECMO (p = 0.05), but not with mean arterial pressure after 1 hour of support (estimate, -0.34; p = 0.06). No other associations were identified between epinephrine delivery and mean arterial blood pressure, vasodilator use, pump speed, VIS, or lactate clearance. There is limited evidence to support the idea that regular dosing of epinephrine during cardiac arrest is associated with increased in afterload after ECMO cannulation. Additional studies are needed to validate findings against ECMO flows and clinically relevant outcomes.

Assessing the Effects of Changing Patterns of Inhaled Corticosteroid Dosing and Adherence with Fluticasone Furoate and Budesonide on Asthma Management.

Pharmacological asthma management focuses on the use of inhaled corticosteroid (ICS)-containing therapies, which reduce airway inflammation and provide bronchoprotection, improving symptom control and reducing exacerbation risk. ICS underuse due to poor adherence is common, leading to poor clinical outcomes including increased risk of mortality. This article reviews efficacy versus systemic activity profiles for various adherence patterns and dosing regimens of fluticasone furoate (FF)-containing and budesonide (BUD)-containing asthma therapies in clinical trials and real-world studies. We performed a structured literature review (1January 2000-3March 2022) and mathematical modelling analysis of FF-containing and BUD-containing regular daily dosing in patients with mild-to-severe asthma, as-needed BUD/formoterol (FOR) in mild asthma, and BUD/FOR maintenance and reliever therapy (MART) dosing in moderate-to-severe asthma, to assess efficacy (bronchoprotection) and systemic activity (cortisol suppression) profiles of dosing patterns of ICS use in multiple adherence scenarios. A total of 22 manuscripts were included in full-text review and 18 in the model simulations. Focusing on FF-containing or BUD-containing treatments at comparable adherence rates, regular daily FF or FF/vilanterol (VI) dosing provided more prolonged bronchoprotection and fewer systemic effects than daily BUD, daily BUD/FOR, or BUD/FOR MART dosing, especially in low adherence scenarios. In model simulations and the real-world setting, FF/VI generally provided longer bronchoprotection, lower systemic activity, and greater clinical benefits over BUD/FOR as well as consistently higher adherence. In this literature review and modelling analysis, FF/VI was found to show clinical advantages on asthma control over BUD/FOR. These findings have implications for helping clinicians select the most suitable inhaled therapy for their patients with asthma.

Modelling ASthma TrEatment Responses (MASTER): Effect of individual patient characteristics on the risk of exacerbation in moderate or severe asthma: A time-to-event analysis of randomized clinical trials.

There is limited understanding of how clinical and demographic characteristics are associated with exacerbation risk in patients with moderate-to-severe asthma, and how these factors correlate with symptom control and treatment response. Here we assess the relationship between baseline characteristics and exacerbation risk during regular dosing with inhaled corticosteroids (ICS) monotherapy or in combination with long-acting beta2-agonists (ICS/LABA) in clinical trial patients with varying levels of symptom control, as assessed by the asthma control questionnaire (ACQ-5). A time-to-event model was developed using pooled patient data (N = 16 282) from nine clinical studies [Correction added on 26 July 2023, after first online publication: The N value in the preceding sentence has been corrected in this version.]. A parametric hazard function was used to describe the time-to-first exacerbation. Covariate analysis included the assessment of the effect of seasonal variation, clinical and demographic baseline characteristics on baseline hazard. Predictive performance was evaluated by standard graphical and statistical methods. An exponential hazard model best described the time-to-first exacerbation in moderate-to-severe asthma patients. Body mass index, smoking status, sex, ACQ-5, % predicted forced expiratory volume over 1 s (FEV1 p) and season were identified as statistically significant covariates affecting baseline hazard irrespective of ICS or ICS/LABA use. Fluticasone propionate/salmeterol (FP/SAL) combination therapy resulted in a significant reduction in the baseline hazard (30.8%) relative to FP monotherapy. Interindividual differences at baseline and seasonal variation affect the exacerbation risk independently from drug treatment. Moreover, it appears that even when a comparable level of symptom control is achieved in a group of patients, each individual may have a different exacerbation risk, depending on their baseline characteristics and time of the year. These findings highlight the importance of personalized interventions in moderate-to-severe asthma patients.

Efficacy of switching from basal-bolus insulin therapy to twice-daily insulin degludec/insulin aspart co-formulation plus insulin aspart in patients with poorly controlled type 2 diabetes.

The aim of this study was to evaluate the efficacy of twice-daily (BID) insulin degludec/insulin aspart (IDegAsp) co-formulation + once-daily (OD) bolus insulin aspart (IAsp) injection (IDegAsp BID-Plus) as simplified intensive insulin therapy in patients with poorly controlled type 2 diabetes mellitus (T2DM) with basal-bolus insulin therapy (BBIT). The retrospective study included 155 patients who switched from BBIT to IDegAsp BID-Plus. After the initiation of the treatment, 73 patients continued regular follow-up and insulin doses, number of injections, hemoglobin A1c (HbA1c) levels, and other parameters were recorded from their files at baseline, 24, and 52 weeks. The mean age of the study population was 54.3±10.2 years, the duration of T2DM was 9.7±5.7 years, fasting plasma glucose (FPG) was 252.7±66.7 mg/dl, and HbA1c levels were 10.5±1.5%. Among the included patients, 15 patients received five injections, 51 patients received four injections, and 7 patients received three injections per day. There was a significant decrease in HbA1c (respectively; 10.46±1.54%, 7.97±1.24%, 7.98±1.23%, baseline and 6th-month p<0.001, baseline and 12th-month p<0.001), FPG (respectively; 251.6±66.5 mg/dl, 136.1±34.7 mg/dl, 125.4±67.0 mg/dl, baseline and 6th-month p<0.001, baseline and 12th-month p<0.001) and daily dose of insulin (respectively; 102.9±29.0 Unit, 73.2±18.2 U, 63.7±20.3 Unit, baseline and 6th-month p<0.001, baseline and 12th-month p<0.001) at the end of week 24 and 52. Based on real-world data, this study demonstrated that IDegAsp BID-Plus treatment provides rapid and sustainable blood glucose control with lower insulin doses and fewer injections than previous intensive insulin therapy.