Initial Dose Research Articles

Brazilian bentonite/MgO composites for adsorption of cationic and anionic dyes.

Industrial effluents, especially those containing dyes, have become the main cause of contamination of water resources. In this context, Brazilian bentonite/MgO composites, with excellent adsorptive properties, were prepared and investigated for their effectiveness in removing cationic and anionic dyes from aqueous solutions. The new adsorbents were obtained using Brazilian bentonites and MgO using the mechanochemical method followed by heat treatment (at 700°C for 4h). Different characterization techniques were used for the chemical, mineralogical, thermal, surface, and morphological analysis of the raw clays and the composites. The experimental adsorption isotherms were quantified under different conditions of initial concentration, contact time, pH, adsorbent dosage, and temperature variation to interpret the adsorption mechanism of the crystal violet (CV) and Congo red (CR) dyes. The modeling results were obtained from the empirical Sips equation and Pseudo Second Order (PSO) kinetics, indicating that the adsorption of molecules is a heterogeneous phenomenon that occurs in a monolayer on the surface (ns > 1), with the adsorption rate determined by chemisorption. The composites showed the best removal efficiency performance compared to the raw bentonites, with an increase of 12% for the CV dye and 46% for the CR dye. In addition, the qmax values obtained were 423.02mg/g and 479.86mg/g (AM01). This research underscores the potential of Brazilian bentonite/MgO composites as a promising solution for the removal of cationic and anionic dyes from water, offering hope for future applications in the field of environmental engineering and materials science.

The dose of remimazolam combined with sufentanil for the induction of general anesthesia in obese patients undergoing bariatric surgery: an up-and-down sequential allocation trial.

Background and purpose: Remimazolam is a newly developed benzodiazepine drug with water-soluble, esterase degradation, and ultra-short-acting properties. The dose for general anesthesia induction in obese patients was not known. This study aimed to determine the optimal dose of remimazolam in combination with sufentanil for the induction of general anesthesia in obese patients. Methods: It was a prospective observational study. We recruited 46 patients scheduled for bariatric surgery from October 2022 to December 2023. One patient refused to provide informed consent, and six patients were receiving psychotropic medication. Thirty-nine patients were enrolled. The Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale was used to assess the patient's response. The dose of sufentanil was 0.5 µg/kg (lean body weight [LBW]). The initial dose of remimazolam was 0.3mg/kg (LBW). The dose of remimazolam was modified using the up-and-down allocation technique. Successful sedation (negative group) was characterized by achieving a MOAA/S score ≤ 1 within 3min of commencing remimazolam infusion. If negative, the next patient received a low-level dose at a ratio of 0.9. Failed sedation (positive group) was defined as a MOAA/S score of >1 within 3min of commencing remimazolam infusion. The patients in the positive group received propofol 0.5mg/kg as a remedial measure, and the next dose was increased to a higher level. The primary outcome was to determine the half-effective dose (ED50) and 95% effective dose (ED95) of remimazolam in combination with sufentanil 0.5 µg/kg for induction in obese patients. The secondary outcome was to determine the occurrence of adverse effects such as hypotension, hypertension, and intraoperative awareness. Results: The ED50 and ED95 values of remimazolam (LBW) combined with sufentanil (0.5 µg/kg) (LBW) were 0.115mg/kg (95% CI: 0.072-0.137) and 0.179mg/kg (95% CI: 0.150-0.434), respectively, and the time of loss of consciousness in the negative group was 120.13 ± 25.03s. The cardiovascular system was stable during the induction period. The incidence of post operative nausea and vomiting (PONV) was 38.5% in 39 patients. Respiratory depression, allergic reaction, intraoperative awareness, and delayed emergence were not observed in any patient. Conclusion: Remimazolam combined with sufentanil (0.5 µg/kg) (LBW) can be effectively used for general anesthesia induction in obese patients. The ED50 and ED95 values of remimazolam (LBW) were 0.115mg/kg and 0.179mg/kg, respectively. Clinical Trial Registration: www.chictr.org.cn, identifier ChiCTR2200065602.

Incidence of buprenorphine-precipitated opioid withdrawal in adults with opioid use disorder: A systematic review.

Buprenorphine is an evidence-based treatment for opioid use disorder, and the risk of precipitated withdrawal contributes to its underuse. The goal of this systematic review was to determine the incidence of buprenorphine-precipitated withdrawal in adults with opioid use disorder. This systematic review was registered on PROSPERO (CRD42023437634). We searched Medline, Embase Classic + Embase, and Cochrane CENTRAL from inception to 10 November 2023, and included original research that reported the incidence of sublingual buprenorphine-precipitated withdrawal in adults with opioid use disorder. Primary screening was completed by four independent reviewers. Full text review, data extraction and risk of bias assessments using the Newcastle Ottawa Scale and the Cochrane Risk of Bias 2 tool were completed by two independent reviewers. The primary outcome was precipitated withdrawal. Secondary outcomes were baseline opioids used, induction dose, initial Clinical Opiate Withdrawal Scale (COWS) score, location of induction, definition and severity of precipitated withdrawal and adverse events. The range of incidence of precipitated withdrawal across studies was described. Our search yielded 10 197 unique citations. Twenty-one cohort and five randomized trials met inclusion criteria (n = 4497, range 20-1293). The overall incidence of precipitated withdrawal ranged from 0 to 13.2%. Nine studies defined precipitated withdrawal; definitions were inconsistent. Most patients used heroin at baseline. The most common initial dose of buprenorphine was between 2mg and 8mg (range: 0.075 mg-24 mg). Initial minimum COWS score ranged from 5 to 13. Induction locations included home, inpatient, emergency department, pre-hospital, outpatient and residential units. Of the fifteen studies with cases of precipitated withdrawal, nine studies did not report the severity of withdrawal experienced. Other induction-related adverse events varied. The overall quality of included studies was poor. The best available evidence suggests the incidence of buprenorphine-precipitated withdrawal in adults with opioid use disorder is low and should not be a barrier to use.

Spatial spread of Ditylenchus gigas and its interaction with Botrytis fabae on Vicia faba

AbstractDitylenchus gigas Vovlas is the dominant species of Ditylenchus nematode on faba bean in the UK. It is normally reported with Botrytis fabae Sardiña, which causes chocolate spot of faba bean. The aim of the work reported here was to estimate how fast isolated infections of D. gigas may spread spatially and how background infection of the host with B. fabae alters multiplication of D. gigas. Spatial spread in field conditions was measured in plants growing in square grids. After establishment, single plants at the centre of each grid were spray inoculated with D. gigas. In summer 2017, D. gigas spread to a distance of at least 1 m, the edge of each 2 m × 2 m plot. Incidence on shoots decreased very slowly with distance beyond 0.4 m. In a repeat experiment harvested in autumn 2018, D. gigas was detected at distances of up to 160 cm in 4 m × 4 m plots. The yield effect and reproduction rate of D. gigas were measured in glasshouse experiments, alone and following brush inoculation with low (103) or high (106 conidia/mL) doses of B. fabae. At low doses of D. gigas inoculum multiplied by approximately 75‐fold, with lower rates of multiplication as the inoculum dose increased. The reproduction rate of D. gigas was reduced in plants inoculated with B. fabae, especially at high doses of D. gigas. The reduction was approximately proportional to log (B. fabae dose). Seed yield from inoculated plants decreased approximately in proportion to the logarithms of the initial dose of D. gigas and of B. fabae.

Population pharmacokinetic study in children with vascular anomalies: body weight as a key variable in predicting the initial dose and dosing frequency of sirolimus.

The main challenges faced when using sirolimus in children with vascular anomalies (VAs) still include significant pharmacokinetic (PK) variability, uncertainty in the target concentration range, as well as inconsistencies in initial dosing and dosing frequency. The aim of this study is to establish a new population pharmacokinetic (PPK) model for children with VAs to guide the individualized use of sirolimus. A PPK study was performed using data from children with VAs who received sirolimus between July 2017 and April 2022. A nonlinear mixed-effect modeling with a one-compartment model structure was applied. Monte Carlo simulation was employed to propose specific dosing recommendations to achieve the target trough concentrations (C trough) of 5-15ng/mL. In total, 134 blood concentrations from 49 pediatric patients were used to characterize the sirolimus pharmacokinetics. Covariate analysis identified body weight (BW) as a significant factor affecting clearance (CL) in the final PPK model. The typical clearance rate and distribution volume, standardized to a BW of 16kg, were 4.06L/h (4% relative standard error, RSE) and 155L (26% RSE), respectively. Optimal dosing regimens were simulated for different BWs. For a twice-daily regimen, the recommended doses were 0.05, 0.06, 0.07, and 0.08mg/kg/day for BW of <10, 10-20, 20-40, and ≥40kg, respectively; for a once-daily regimen, the recommended doses were 0.06, 0.07, 0.08, and 0.09mg/kg/day for BW of <10, 10-30, 30-50, and ≥50kg, respectively. Notably, sirolimus C trough could be maintained between 5-15ng/mL across various dosing frequencies based on the recommended dosing regimen. We established a PPK model of sirolimus for children with VAs and proposed an initial dosing strategy. Integrating initial dose and medication frequency recommendations into sirolimus' guidelines will broaden its clinical options and simplify the clinical management for childhood VAs.

Calcium channel blockers and beta blockers in pediatric supraventricular tachycardia.

Supraventricular tachycardia (SVT) is a common pediatric arrhythmia. Beta blockers (BBs) and calcium channel blockers (CCBs) are used for treatment despite little data examining their use. We describe the prescriptive tendencies, efficacy, and tolerability of BBs and CCBs used in the treatment of pediatric SVT. This is a multicenter retrospective cohort study from three academic children's hospitals. Individuals aged 1-21 years at time of SVT diagnosis initiated on a BB or a CCB between 01/01/2010 and 12/31/2020 were included. Exclusion criteria were pre-excitation, ectopic atrial tachycardia, and hemodynamically significant heart disease. Demographic, comorbidity, symptomatology, and medication data were collected. Treatment success was defined using a composite data abstraction tool. Of 164 patients, 151 received a BB and 13 received a CCB. The success rate on the initial dosage was 46% for both BB and CCB; the success rate following dosage adjustments was also comparable for BBs (98/151, 65%) and CCBs (9/13, 69%). While 27 (18%) BB patients experienced intolerable side effects, no CCB patient did. Treatment with a BB or CCB was successful in half of patients. BBs were prescribed more frequently than CCBs but were associated with more side effects.

UV-radiation manufacturing of natural macromolecular products salecan and tannic acid-based functional gel material as superadsorbent for toluidine blue remediation

Adsorbent materials constructed from natural macromolecular products are favored because of their wide range of sources, biodegradability, and environmental friendliness. Salecan is a novel extracellular polysaccharide with ideal physicochemical and biological activities. Here, we have designed a polymer gel through UV-initiated polymerization of [2-(Methacryloyloxy) ethyl] dimethyl-(3-sulfopropyl) ammonium hydroxide (SBMA) in the mixture of salecan and tannic acid. Photopatterned polymerization process allowed in situ formation of gel adsorbent in a mild reaction condition with energy-efficient manner. Batch experiments for toluidine blue (TB) adsorption were carried out as a function of initial dye concentration, solution pH, contact time, and gel dosage to examine the adsorption capacity, potential mechanism, and removal efficiency. Adsorption behavior exhibited a pH-dependence pattern, which was closely related to their swelling and morphological properties. Adsorption process was in conformity to pseudo-second-order kinetic and Langmuir isotherm models, unlocking a chemical adsorption behavior and monolayer-type removal. The maximum adsorption was 490.2 mg/g, which could be considered a superiorly competing value. Additionally, the UV-gel still showed desirable recyclability and maintained the adsorption effectiveness over 95 % after five regeneration cycles. This study opened up new prospects in preparing high performance adsorbent for TB decontamination and laid the foundation for polysaccharide-based adsorption material research.

Optimizing tacrolimus dosing in Hispanic renal transplant patients: insights from real-world data.

Tacrolimus, an immunosuppressant used to prevent organ rejection in renal transplant patients, exhibits high inter-patient variability, necessitating therapeutic drug monitoring. Early post-transplant tacrolimus exposure in Hispanics is understudied. Although genotypic information is linked to pharmacokinetic differences, its clinical application remains limited. This study aimed to use a real-world data-driven, pharmacokinetic model-based approach for tacrolimus in Hispanics to determine a suitable initial dose and design an optimal dose titration strategy by simulations to achieve plasma trough concentration target levels of 10-12ng/mL at the earliest. Sparse concentration-time data of tacrolimus were obtained from electronic medical records for self-identified Hispanic subjects following renal transplant. Rich pharmacokinetic literature data was leveraged to estimate structural pharmacokinetic model parameters, which were then fixed in the current analysis. Only apparent clearance was estimated with the sparse tacrolimus data and potential covariates were identified. Simulations of various starting doses and different dose titration strategies were then evaluated. The analysis included 121 renal transplant patients with 2,215 trough tacrolimus concentrations. A two-compartment transit absorption model with allometrically scaled body weight and time-varying hematocrit on apparent clearance adequately described the data. The estimated apparent clearance was 13.7L/h for a typical patient weighing 70kg and at 30% hematocrit, demonstrating a 40% decrease in clearance compared to other patient populations. Model based simulations indicated the best initial dose for the Hispanic population is 0.1mg/kg/day. The proposed titration strategy, with three dose adjustments based on trough levels of tacrolimus, increased the proportion of patients within the target range (10-12ng/mL) more than 2.5-fold and decreased the proportion of patients outside the therapeutic window by 50% after the first week of treatment. Hispanic renal transplant population showed an estimated 40% decrease of apparent clearance in the typical patient compared to other populations with similar characteristics. The proposed dose adjustment attained the target range rapidly and safely. This study advocates for tailored tacrolimus dosing regimens based on population pharmacokinetics to optimize therapy in Hispanic renal transplant recipients.

Messaging to Reduce Booster Hesitancy among the Fully Vaccinated.

Vaccine hesitancy was a serious problem in the United States throughout the COVID-19 pandemic, due in part to the reduction in public trust in science that accompanied the pandemic. Now we are facing a new, similar but more extensive problem: booster hesitancy. Even fewer Americans are current on the mRNA booster. We present the results of an experiment with residents of the US who received all initial doses of the mRNA vaccine but who were not up to date on the booster. Participants read a scientific explanation describing either the safety or the effectiveness of the boosters or nothing in the control group. The explanations significantly increased (compared to the control) participants' perceptions of the safety and effectiveness of the mRNA booster, as well as their willingness to get boosted. Explanations also improved emotions and attitudes toward the booster. Furthermore, although liberals were significantly more willing to get boosted than were conservatives, improvement due to the explanations was similar across political ideology groups. However, when interactions were observed, conservatives increased to a greater degree. Importantly, the explanations increased participants' perception of scientists' expertise and knowledge, as well as participants' trust in scientists and the vaccine technology.

Vancomycin in Pediatric Patients with Cystic Fibrosis: Dose Optimization Using Population Pharmacokinetic Approach.

An increase in Staphylococcus aureus infections has been reported in pediatric patients with cystic fibrosis (CF) over the last few years. This pathogen is commonly treated with vancomycin, an antibiotic for which therapeutic drug monitoring (TDM) is recommended. Updated guidelines were recently published regarding new targets of exposure for the TDM of vancomycin through a Bayesian approach, using population pharmacokinetic (popPK) models. This study aims to assess the predictive performance of vancomycin popPK models in pediatric patients with CF and to recommend optimal initial dosing regimens based on simulations. Patient data were collected from two centers in Canada, and a literature review was conducted to identify all published vancomycin popPK models for pediatric CF patients. External evaluation and simulations were performed according to patient and occasion of treatment. A total of 53 vancomycin concentrations were collected from six pediatric CF patients. Only two popPK models of vancomycin for pediatric CF patients were identified through the literature review. The external evaluation results for both centers combined revealed a population bias of 28.1% and an imprecision of 33.7%. A re-estimation of parameters was performed to improve predictive performance. The optimal initial dosing regimen was 15 mg/kg/dose administered every 6 hours according to the per occasion remodel. The predictive performance and identified optimal initial dosing regimens associated with the model were different depending on the data used, showing external evaluation's importance before implementing a model in clinical practice.

Impact of implementation of 2019 European respiratory distress syndrome guidelines on bronchopulmonary dysplasia in very preterm infants

BackgroundTo evaluate the impact of implementation of 2019 European respiratory distress syndrome (RDS) guidelines on the incidence of bronchopulmonary dysplasia (BPD).MethodWe retrospectively collected the clinical data of very preterm infants (VPIs) born before 32 gestational weeks from January 1st 2018 to December 31st 2021. VPIs were divided into group A and group B according to their birth date which was before or at/after January 1st 2020, when the 2019 European RDS guidelines were introduced. BPD is considered as primary outcome. We statistically analyzed all the data, and we compared the general characteristics, ventilation support, medication, nutrition and the outcomes between the two groups.ResultsA total of 593 VPIs were enrolled, including 380 cases in group A and 213 cases in group B. There were no statistic differences regarding to gender ratio, gestational age, birth weight and delivery mode between the two groups. Compared with group A, group B showed higher rate of antenatal corticosteroid therapy (75.1% vs. 65.5%). The improvement of ventilation management in these latter patients included lower rate of invasive ventilation (40.4% vs. 50.0%), higher rate of volume guarantee (69.8% vs. 15.3%), higher positive end expiratory pressure (PEEP) [6 (5, 6) vs. 5 (5, 5) cmH2O] and higher rate of synchronized nasal intermittent positive pressure ventilation (sNIPPV) (36.2% vs. 5.6%). Compared with group A, group B received higher initial dose of pulmonary surfactant [200 (160, 200) vs. 170 (130, 200) mg/Kg], shorter antibiotic exposure time [13 (7, 23) vs. 17 (9, 33) days], more breast milk (86.4% vs. 70.3%) and earlier medication for hemodynamically significant patent ductus arteriosus (hsPDA) treatment [3 (3, 4) vs. 8 (4, 11) days] (p < 0.05). As the primary outcome, the incidence of BPD was significantly decreased (16.9% vs. 24.2%) (p < 0.05), along with lower extrauterine growth retardation (EUGR) rate (39.0% vs. 59.7%), while there were no statistic differences regarding to other secondary outcomes, including mortality, intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), retinopathy of preterm (ROP) and necrotizing enterocolitis (NEC). However, in the subgroups of infants less than 28 gestational weeks or infants less than 1,000 g, the incidence of BPD was not significantly decreased (p > 0.05).ConclusionsAfter implementation of 2019 European RDS guidelines, the overall incidence of BPD was significantly decreased in VPIs. Continuous quality improvement is still needed in order to decrease the incidence of BPD in smaller infants who are less than 28 gestational weeks or less than 1,000 g.

A Pooled Analysis of Eight Clinical Studies Suggests a Link Between Influenza-Like Symptoms and Pharmacodynamics of the Toll-Like Receptor-7 Agonist Vesatolimod.

Vesatolimod is a Toll-like receptor-7 (TLR7) agonist in clinical development as part of a combination regimen for human immunodeficiency virus (HIV) cure. Influenza-like symptoms associated with TLR7-mediated immune activation have been reported in clinical trials of vesatolimod. Therefore, a broader understanding of the safety profile of vesatolimod and association with dose and mechanism of action will help inform future clinical studies. In this analysis, data on flu-like adverse events of interest (AEIs) were pooled from eight clinical studies in which 606 participants either received single or multiple doses of vesatolimod (0.3-12mg; n = 505) or placebo (n = 101). Vesatolimod pharmacokinetics, inflammatory responses, and pharmacodynamics were assessed. The incidence of flu-like AEIs was higher with vesatolimod versus placebo (19% [96/505] vs. 8% [8/101]) and increased with vesatolimod dose and exposure. Most flu-like AEIs with vesatolimod were grade 1 or 2 severity (55% [53 of 96] grade 1; 35% [34 of 96] grade 2) with onset primarily after the first and second dose. Occurrence of flu-like AEIs after doses 1-3 was predictive of reoccurrence after later doses. Dose-dependent elevations of pharmacodynamic biomarkers (interferon-stimulated gene 15, 2'-5'-oligoadenylate synthetase 1, myxovirus resistance-1, interferon-α, interleukin-1 receptor antagonist, interferon-γ-induced protein 10, interferon-inducible T-cell-α chemoattractant) observed in participants with flu-like AEIs suggest a link with vesatolimod mechanism of action. Flu-like AEIs associated with vesatolimod administration were typically mild but increased with exposure, which may be predicted by the response to initial doses. The data suggest that adaptive clinical monitoring could help maximize pharmacodynamic responses and balance adverse events in future clinical trials of vesatolimod.

HN-SIB-BPI: A single click, sub-site specific, dosimetric scorecard tuned RapidPlan model created from a foundation model for treating head and neck with bilateral neck

To develop a Knowledge Based Planning (KBP) model for creating quantifiably high quality VMAT treatment plans in a single click for head and neck cases treated Simultaneous Integrated Boost (SIB) with bilateral parotid involvement (BPI) where both parotids are near, abutting or partially overlapping target volume. Eclipse RapidPlan and the publicly available PlanScorecard tool were used to assess existing Head and Neck RapidPlan models on two representative cases. The best performer was used as a foundation model to assist in creating new initial training set doses from previously treated cases. Those initial 27 cases were first replanned using only the selected foundation model, then further improved based on manual replanning, informed by dosimetric scorecard assessment. A new, initial model was trained from those 27 foundation model created cases that had been manually improved. Then, that initial model was used to replan those cases again, resulting in higher scores. Additional cases were also replanned using the initial model along with some manual changes to the optimization objectives to increase the score. This resulted in a total of 66 cases from which the final, released, HN-SIB-BPI was trained. A 27 case subset of the full training set was replanned and rescored at each phase of the process with a 260 total point 3-target scorecard. The average score increased: 210.5 foundation model; 226.96 manually improved plans; 230.1 initial model; 231.7 HN-SIB-BPI. On the same 27 case subset, mean ipsilateral and contralateral parotid dose decreased by 1.05Gy and 1.58Gy respectively from the foundation model to HN-SIB-BP. Eight external cases were created from HN-SIB-BPI with dosimetric scorecard validation on Halcyon (3-PTV:221.38/260; 2-PTV:196.1/228.5) and TrueBeam (3-PTV:222.01/260; 2-PTV:202.24/228.5). A specific clinical intent (ie: max parotid sparing) can be articulated in a comprehensive and precise manner by creating a dosimetric scorecard with individual metrics points assigned to each OAR and target metric reflecting their relative importance. This process improved the KBP model (HN-SIB-BPI) in several quantifiable ways including further sparing of parotid dose. All results and tools in this work are shared publicly.

Clinical characteristics, treatment, and outcomes of nivolumab induced immune thrombocytopenia.

Immune thrombocytopenia (ITP) represents an uncommon hematological side effect associated with nivolumab, and its distinct clinical attributes remain poorly defined. This research aimed to explore the clinical manifestations and outcomes of ITP induced by nivolumab. Reports on nivolumab induced ITP up to April 30, 2024, were collected for retrospective analysis. The study involved 34 patients with a median age of 67 years (range 32, 82). The onset of ITP varied from 10 to 100 days post initial dosage, with a median onset at 70 days. The majority of patients exhibited no symptoms, with only 23.5% experiencing clinically significant bleeding and 11.8% facing non-clinically significant bleeding. The median platelet count was 12 × 109/L (range 0, 115), with 67.6% of patients having platelet levels below 25 × 109/L. Bone marrow biopsy revealed mainly elevated megakaryocytes. Platelet-associated IgG levels were elevated with a median of 210 ng/107 cells (range 73, 1130). Subsequent interventions, which included cessation of nivolumab, administration of systemic corticosteroids, intravenous immunoglobulin therapy, a thrombopoietin receptor agonist, platelet transfusion, and rituximab treatment, resulted in 82.4% of subjects achieving normalized platelet counts, whereas 5.9% passed away due to ITP. ITP is a rare life-threatening immune-related adverse event and necessitates close monitoring. Systemic steroids are the primary treatment for ITP, while intravenous immunoglobulin, thrombopoietin receptor agonist and rituximab are other options.

Clinical Characteristics and Treatment Outcomes of Patients With Newly Diagnosed Takayasu Arteritis in Japan During the First 2 Years of Treatment - A Nationwide Retrospective Cohort Study.

This study aimed to clarify recent clinical features and treatment outcomes in Japanese patients with newly diagnosed Takayasu arteritis (TAK) during the first 2 years of treatment. A nationwide multicenter retrospective cohort study for TAK was implemented to collect data between 2007 and 2014. The primary outcome of the study was clinical remission at Week 24. Of the 184 participants registered, 129 patients with newly diagnosed TAK were analyzed: 84% were female and the mean age at onset was 35 years. Clinical symptoms at diagnosis were mostly associated with large-vessel lesions. Frequent sites of vascular involvement included the carotid artery, subclavian artery, aortic arch, and descending aorta. The mean initial dose of prednisolone administered was 0.68 mg/kg/day, and 59% and 17% of patients received immunosuppressive drugs and biologics, respectively, by Week 104. Clinical remission at Week 24 and sustained clinical remission with daily prednisolone at ≤10 mg at Week 52 were achieved in 107 (82.9%) and 51 (39.5%) patients, respectively. The presence of signs and symptoms linked to large-vessel lesions was associated with failure to achieve sustained clinical remission at Week 52. We elucidated the clinical characteristics, treatment outcomes, and factors associated with failure to achieve sustained clinical remission in patients with newly diagnosed TAK in Japan during the first 2 years of treatment.

Meropenem Usage Assessment amid the Antibiotic Resistance Crisis: A Comprehensive Analysis in a Tertiary Care Hospital in Pakistan

BACKGROUND: With antibiotic resistance posing a growing threat to global health, the prudent use of antibiotics like meropenem is imperative. However, empirical prescribing practices and inadequate adherence to guidelines contribute to challenges in meropenem utilization. This study aims to comprehensively assess prescribing patterns, adherence to guidelines, and patient education practices in a tertiary care hospital in Pakistan. METHODS: A cross-sectional study was conducted over six months, enrolling 100 patients. Data collection included variables such as age, gender, hospital stay duration, indication for meropenem prescription, dosage regimen, basis of prescription, treatment duration, and patient education. Statistical analysis was performed using IBM SPSS version 26. RESULTS: Empirical prescribing was common, with an initial diagnosis accuracy rate of 64%. Disparities were noted in aligning culture sensitivity with meropenem use, with only 36% of cases following culture results. Regarding treatment duration, an alarming 86% of cases had incorrect durations. Comparative analyses highlighted areas for prescription protocol and clinical outcome improvement. For instance, 96% of cases had the correct initial meropenem dosage. Despite meticulous monitoring, deficiencies persisted in patient education and antibiotic stewardship. CONCLUSION: The study underscores the urgent need for standardized guidelines, enhanced diagnostics, and educational initiatives to mitigate antibiotic resistance emergence. Addressing these challenges is crucial for safeguarding antibiotic efficacy and public health.

Corticosteroid Prescribing Patterns in the Emergency Department for Acute COPD Exacerbations: A Retrospective Analysis Following an Educational Intervention.

COPD is a progressive lung disease with marked airflow limitation. It has a large global prevalence and is managed with antibiotics, bronchodilators, and corticosteroids. Despite the prevalence, corticosteroid prescribing regimens differ widely amongst providers. This study aims to evaluate baseline corticosteroid prescribing patterns, the ability to change corticosteroid prescribing patterns with the utilization of an educational initiative, and to evaluate the effect of corticosteroid dose on length of stay, 30-day hospital readmission, mortality, and total hospital insulin dosing. This study was conducted via a retrospective observational study. Providers at a single institution answered a baseline questionnaire on COPD corticosteroid prescribing patterns and subsequently received an educational presentation regarding evidence-based corticosteroid recommendations. Data were then retrospectively obtained and analyzed evaluating corticosteroid prescribing patterns both pre- and post-educational intervention. Data were analyzed using IBM SPSS Version 25. The provider survey revealed that most (95.3%) administered 125 mg of methylprednisolone to patients treated for AECOPD. The most common reason a particular dose of corticosteroid was administered was due to previous teaching or practice patterns. The mean initial steroid dose of methylprednisolone decreased following the educational initiative from 114.24 mg to 72.8 mg (p < 0.01). This corresponded to a 69% (n=41) decrease of providers using 125 mg methylprednisolone (p < 0.01), and increased prescribing of 62.5 mg methylprednisolone by 42.6% (n=66). The mean LOS following hospital admission for AECOPD in the pre-intervention group was 5.80 days, while the mean LOS following the targeted educational intervention decreased to 4.82 days (p = 0.01). The implementation of an educational intervention may change provider corticosteroid prescribing patterns. Additionally, lower corticosteroid dose in the Emergency Department may decrease patient length of stay. Keywords: Corticosteroid, COPD, LOS, recommendations, steroid.

Impact of Previous Alopecia Areata Treatment on Efficacy Responses up to Week 48 Following Ritlecitinib Treatment: A Post Hoc Analysis.

Patients with alopecia areata (AA) may have received several therapies for management of AA during their lives. In the ALLEGRO phase 2b/3 (NCT03732807) study, the oral JAK3/TEC family kinase inhibitor ritlecitinib demonstrated efficacy and an acceptable safety profile in patients aged ≥ 12years with AA and ≥ 50% scalp hair loss. This post hoc analysis investigated associations between prior use of AA therapies and Severity of Alopecia Tool (SALT) responses in patients receiving ritlecitinib for AA. Patients receiving ritlecitinib 30mg or 50mg once daily with or without an initial 4-week 200-mg daily loading dose were grouped by previous exposure to AA treatments, including topicals, intralesional corticosteroids (ILCS), topical immunotherapy, and systemic immunosuppressants or any prior AA treatment. Multivariable logistic regression analyses evaluated the association between response based on a SALT score of ≤ 20 and any prior treatment for AA at weeks 24 and 48. Of 522 patients, 360 (69.0%) had previous exposure to any AA treatment. At Week 24, SALT ≤ 20 response was positively associated with prior use of ILCS (odds ratio [OR], 2.12; 95% confidence interval [CI], 1.23-3.65; P < 0.05) and negatively associated with prior use of systemic immunosuppressants (OR 0.50; 95% CI 0.28-0.88; P < 0.05). Prior use of topicals or topical immunotherapy was not associated with SALT ≤ 20 response at Week 24. By Week 48, no association was identified between SALT ≤ 20 response and prior use of topicals, ILCS, topical immunosuppressants, or systemic immunosuppressants (all P > 0.05). Previous exposure to any AA therapy was not associated with SALT ≤ 20 response at weeks 24 or 48 (all P > 0.05). Prior AA treatment history had no effect on longer-term treatment response to ritlecitinib. NCT03732807.

Evaluating the effectiveness and adverse effects of oral versus transdermal estradiol for endometrial preparation in frozen-thawed embryo transfer: a randomized controlled trial

BackgroundEndometrial preparation significantly influences the success of embryo transfer procedures. Although both oral and transdermal estradiol are common methods for endometrial priming, their efficacy and potential side effects remain uncertain. This randomized controlled trial aims to compare the effectiveness of oral and transdermal estradiol in endometrial preparation, while also evaluating their respective side effects in patients undergoing assisted reproduction treatments.MethodThis randomized clinical trial (ISRCTN15301227) was conducted at Hung Vuong Hospital between July 2020 and March 2022. Among 550 eligible patients undergoing frozen embryo transfer cycles, we included 380 patients for the study. The study protocol and all materials received approval from the Ethics Committee of Hung Vuong Hospital (1315/CN-HĐĐĐ). Participants were randomly assigned to one of two groups: Group A (n =190) received oral estradiol at an initial dose of 4 mg per day for 7 days, with the dose increased according to clinical response. Group B (n =190) received transdermal estradiol at an initial dose of 2 measures of 2.5 g estradiol gel per day for 7 days, with the dose similarly increased according to clinical response. Treatment in both groups began on days 2–3 of the menstrual cycle, with the maximum duration of estradiol administration being 27 days. We compared estradiol levels on the day of progesterone administration, duration of treatment, total estradiol dose, endometrial thickness, pregnancy outcomes, and any observed side effects between the two groups.ResultsGroup A exhibited significantly higher estradiol levels on the day of progesterone administration compared to Group B (270.5 pg/ml versus 186.5 pg/ml, p < 0.001). However, the comparison revealed no significant difference in endometrial thickness between the two groups (10.5 mm versus 10.6 mm, p = 0.85). Furthermore, pregnancy rates including positive human chorionic gonadotropin, clinical pregnancy, ongoing pregnancy, live birth, and pregnancy failure were also found to be similar between the two groups. Notably, a greater proportion of patients in Group A experienced mild side effects compared to those in Group B (20.3% versus 10.1%, respectively; n =37 versus n =18), and this discrepancy was found to be statistically significant (p = 0.007).ConclusionTransdermal estradiol offers comparable endometrial thickness and pregnancy outcomes, along with improved patient compliance and fewer side effects compared to oral estradiol.

Mirtazapine to alleviate severe breathlessness in patients with COPD or interstitial lung diseases (BETTER-B): an international, multicentre, double-blind, randomised, placebo-controlled, phase 3 mixed-method trial

Breathlessness frequently becomes severe among people with respiratory disease. Mirtazapine, a widely used antidepressant, has shown promise in the modulation of respiratory sensation and the response to it, as well as reducing feelings of panic, which often accompanies breathlessness. We aimed to determine the effectiveness of mirtazapine to alleviate severe persisting breathlessness. This international, multicentre, phase 3, parallel-group, double-blind, randomised, placebo-controlled trial across 16 centres in seven countries (Australia, Germany, Ireland, Italy, New Zealand, Poland, and the UK), recruited adults with chronic obstructive pulmonary disease (COPD), interstitial lung diseases, or both, and grade 3 or 4 of the modified Medical Research Council breathlessness scale. Consenting participants were randomly assigned (1:1) to receive oral mirtazapine or matching placebo for 56 days. Randomisation was by minimisation. The initial mirtazapine dose was 15 mg, escalating to a maximum of 45 mg per day, tapered at treatment end. Participants, caregivers, assessors, and investigators were masked to group assignment. The primary outcome was worst breathlessness in the preceding 24 h measured on a 0-10 numerical rating scale (NRS), at 56 days post-treatment start, with follow-up to 180 days. The primary analysis was performed in the modified intention-to-treat population using multivariable multi-level repeated measures model. This trial was registered with ISRCTN (ISRCTN10487976 and ISRCTN15751764 [Australia and New Zealand]) and EudraCT (2019-002001-21) and is complete. Between Feb 4, 2021 and March 28, 2023, we enrolled 225 eligible participants (148 men and 77 women, 113 to the mirtazapine group and 112 to the placebo group). The median age was 74 years (IQR 67-78). No evidence of a difference was found in worst breathlessness at day 56 between mirtazapine and placebo (difference in adjusted mean NRS score was 0·105 [95% CI -0·407 to 0·618]; p=0·69). Although the study was underpowered, the primary endpoint effect did not reach the pre-specified treatment effect of 0·55 for worst breathlessness score reduction that the study was powered to detect for the primary analysis. There were 215 adverse reactions in 72 (64%) of 113 participants in the mirtazapine group versus 116 in 44 (40%) of 110 participants in the placebo group; 11 serious adverse events in six (5%) participants in the mirtazapine group versus eight in seven (6%) participants in the placebo group; and one (1%) suspected unexpected serious adverse reaction in the mirtazapine group. At day 56, there were three deaths in the mirtazapine group and two deaths in the placebo group. At day 180, there were seven deaths in the mirtazapine group and 11 deaths in the placebo group. Our findings suggested that mirtazapine of doses 15 to 45 mg daily over 56 days does not improve severe breathlessness among patients with COPD or interstitial lung diseases and might cause adverse reactions. Based on these findings, we do not recommend mirtazapine as a treatment to alleviate severe breathlessness. EU Horizon 2020 (grant agreement No. 825319); Cicely Saunders International Breathlessness Programme; National Institute for Health and Care Research Applied Research Collaboration South London; Australian National Health and Medical Research Council-EU (application ID: APP1170731).