Subsequent Doses Research Articles

Maximum a posteriori Bayesian methods out-perform non-compartmental analysis for busulfan precision dosing

Dose personalization improves patient outcomes for many drugs with a narrow therapeutic index and high inter-individuality variability, including busulfan. Non-compartmental analysis (NCA) and model-based methods like maximum a posteriori Bayesian (MAP) approaches are two methods routinely used for dose optimization. These approaches vary in how they estimate patient-specific pharmacokinetic parameters to inform a dose and the impact of these differences is not well-understood. Using busulfan as an example application and area under the concentration–time curve (AUC) as a target exposure metric, these estimation methods were compared using retrospective patient data (N = 246) and simulated precision dosing treatment courses. NCA was performed with or without peak extension, and MAP Bayesian estimation was performed using either the one-compartment Shukla model or the two-compartment McCune model. All methods showed good agreement on real-world data (correlation coefficients of 0.945–0.998) as assessed by Bland–Altman plots, although agreement between NCA and MAP methods was higher during the first dosing interval (0.982–0.994) compared to subsequent dosing intervals (0.918–0.938). In dose adjustment simulations, both NCA and MAP estimated high target attainment (> 98%) although true simulated target attainment was lower for NCA (63–66%) versus MAP (91–93%). The largest differences in AUC estimation were due to different assumptions for the shape of the concentration curve during the infusion phase, followed by how the methods considered time-dependent clearance and concentration–time points collected in earlier intervals. In conclusion, although AUC estimates between the two methods showed good correlation, in a simulated study, MAP lead to higher target attainment. When changing from one method to another, or changing infusion duration and other factors, optimum estimated exposure targets may require adjusting to maintain a consistent exposure.

Abstract 4057: Beyond IL-2: The promise of anti PD-1-attenuated IL-2 fusion protein in cancer immunotherapy

Abstract PD1+ CD8+ tumor-infiltrating T-cells have been at the forefront of cancer immunotherapies due to their antigen-specificity, cytotoxicity, proliferative capacity, and stem-like/memory properties. IL-2 is essential for T cell growth and proliferation, however, its systemic administration at a high dose was associated with intolerable toxicities, while low-dose treatment contradicted the intended therapeutic effect by activating regulatory T cells.To overcome the limitations of IL-2, we fused modified IL-2 sequences with reduced affinity for the murine IL-2 receptor to a PD1 antibody designed to target the PD1+ T cells found in tumors. The resulting murine PD1 antibody-attenuated-IL-2 (mAnti-PD1-IL2Att) demonstrated similar IL-2 potency on PD1+ cells as native IL-2, but diminished potency by orders of magnitude on PD1- cells. The agent was furthermore designed to bind PD1 non-competitively with known PD1-blocking antibodies, so that it could be used in combination with them to achieve effective anti-tumor response. We demonstrated that mAnti-PD1-IL2Att exhibits potent anti-tumor activity, resulting in complete tumor regression in a syngeneic MC38 colorectal cancer model, and significant anti-tumor activity in other models of different tumor types. The mechanism was evaluated by immunophenotyping and single-cell RNAseq. Shortly after the first administration of mAnti-PD1-IL2Att, CD8+ T cells, rather than Tregs, emerged as the primary responding cells; these CD8+ T cells exhibited increased proliferation and activation with reduced expression of exhaustion markers (PD1+Tim3+). Following subsequent doses, there was a notable increase in the number of effector cells, followed by a prolonged generation of effector and memory cells at a later stage. Myeloid cells exhibited increased transcriptional programs related to chemotaxis, co-stimulation, and co-inhibition, including the upregulation of the PD1-PDL1 pathway. By contrast, blockade of PD1 with a naked PD1 antibody led to distinct cellular responses and less pronounced anti-tumor activity, and a combination of the blocking antibody with PD1-attIL-2 was superior to either agent alone. Together, our findings suggest that mAnti-PD1-IL2Att potent anti-tumor activity was driven by its direct targeting of PD1+ on tumor-infiltrating CD8+ T-cells, shedding light on the specific changes in their dynamic differentiation trajectory and their impact on the tumor microenvironment. Citation Format: Sarah Amar, Yulia Liubomirski, Eilam Yeini, Michael Monsonego, Tomer Weiss, Galia Tiram, Anshika Katyal, Opal Avramoff, Anne Krinsky, Keren Reshef, Shai Dulberg, Ayelet Kaminitz, Dana Bar On, Inbal Ben Eliezer, Ortal Iancu, Tetsuya Taura, David Wilson, Paul Ayton, Ronit Satchi-Fainaro, Asaf Madi. Beyond IL-2: The promise of anti PD-1-attenuated IL-2 fusion protein in cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4057.

The Effect of a Subsequent Dose of Dexmedetomidine or Other Sedatives following an Initial Dose of Dexmedetomidine on Electrolytes, Acid-Base Balance, Creatinine, Glucose, and Cardiac Troponin I in Cats: Part II.

The administered dose of dexmedetomidine may occasionally fail to produce the anticipated sedative effects. Therefore, a subsequent dose or administration of another sedative may enhance sedation; however, patient safety may be affected. The safety of seven different drugs administered at the following time point after an insufficient dose of dexmedetomidine was evaluated in a crossover, blind, experimental study that included six healthy adult cats. All cats received an initial dose of dexmedetomidine and a subsequent dose of either dexmedetomidine (Group DD), NS 0.9% (DC), tramadol (DT), butorphanol (DBT), buprenorphine (DBP), ketamine (DK), or midazolam (DM). Animal safety was assessed using repeated blood gas analysis and measurement of electrolytes, glucose, cardiac troponin I, and creatinine to evaluate cardiac, respiratory, and renal function. The median values of creatinine, cardiac troponin I, pH, partial pressure of carbon dioxide, potassium, and sodium did not change significantly throughout the study. Heart rate was significantly decreased in all groups after administration of the drug combinations, except for in the DK group. Respiratory rate decreased significantly after administration of the initial dose of dexmedetomidine and in the DBP and DM groups. The partial pressure of oxygen, although normal, decreased significantly after the administration of dexmedetomidine, whereas the median concentration of glucose increased significantly following the administration of dexmedetomidine. The results of our study suggest that the drug combinations used did not alter the blood parameters above normal limits, while cardiac and renal function were not compromised. Therefore, a safe level of sedation was achieved. However, the administration of dexmedetomidine reduced the partial pressure of oxygen; thus, oxygen supplementation during sedation may be advantageous. Additionally, the increase in glucose concentration indicates that dexmedetomidine should not be used in cats with hyperglycaemia, whereas the decrease in haematocrit suggests that dexmedetomidine is not recommended in anaemic cats.

Abstract 3732: Peripheral pharmacodynamic activity of epcoritamab as monotherapy and in combination with rituximab + lenalidomide in patients with follicular lymphoma

Abstract Introduction: Epcoritamab (DuoBody®-CD3xCD20) is a subcutaneous IgG1 bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on malignant B cells, inducing activation and cytotoxic activity of T cells to mediate killing of target lymphoma cells. Epcoritamab is approved in the US for the treatment of adults with relapsed/refractory (R/R) diffuse and high-grade large B-cell lymphoma after ≥2 lines of systemic therapy (also approved in Europe, the UK, Japan, and Canada). Here we present the pharmacodynamic effects of epcoritamab as monotherapy (EPCORE NHL-1: NCT03625037) or in combination with rituximab + lenalidomide (R2) (EPCORE NHL-2: NCT04663347) in peripheral blood of patients with follicular lymphoma (FL), a heterogeneous disease for which many patients have an unmet medical need for efficacious, well-tolerated, off-the-shelf therapies. Methods: In EPCORE NHL-1 expansion phase, adults with R/R FL received epcoritamab monotherapy; in EPCORE NHL-2, adults with R/R (arm 2) or newly diagnosed (ND) (arm 6) FL received epcoritamab combined with R2. B-cell markers and T-cell proliferation and activation markers in whole blood were assessed using validated flow cytometry assays. Cytokines in plasma were measured using a validated multiplex immunoassay. Results: Epcoritamab as monotherapy and in combination with R2 induced rapid depletion of circulating peripheral B cells (CD19+) in patients with detectable peripheral B cells at baseline. Additionally, within the first 2 cycles, epcoritamab monotherapy induced a transient elevation of peripheral CD8+ and CD4+ T cells expressing proliferation (Ki67+%) and activation (HLA-DR+% and PD-1+%) markers. R/R and ND patient groups treated with epcoritamab + R2 showed a trend for greater induction of proliferating and activated peripheral T cells. Likewise, elevation in T-cell absolute counts was observed from cycle 2 onward, with a trend of higher levels with epcoritamab + R2 vs epcoritamab monotherapy. In addition, a moderate but transient elevation of circulating cytokines including IFNγ, IL-6, and IL-10 during cycle 1 was observed with epcoritamab monotherapy and epcoritamab + R2. Importantly, IL-6 and IL-10 returned to approximate baseline levels prior to the subsequent dose. Compared with epcoritamab monotherapy, patients treated with epcoritamab + R2 showed a trend for lower median levels of IL-6 peaks 24 hours after the first full dose. Conclusion: The pharmacodynamic activity of epcoritamab combined with R2 in R/R and ND FL was consistent with epcoritamab’s mechanism of action as monotherapy. Epcoritamab + R2 showed a favorable pharmacodynamic profile with a trend toward increased T-cell activation and T-cell elevation, and lower IL-6 levels. These data support the ongoing phase 3 trial of epcoritamab + R2 compared with R2 alone in patients with R/R FL (EPCORE FL-1: NCT05409066). Citation Format: Han Si, Jimin Zhang, Monica Wielgos-Bonvallet, Lorenzo Falchi, Kim Linton, Wojciech Jurczak, David Belada, Işıl Altıntaş, Mariana Sacchi, Elena Favaro, Ali Rana, Daniela Hoehn, David Soong, Christopher W. Chiu, Maria Jure-Kunkel. Peripheral pharmacodynamic activity of epcoritamab as monotherapy and in combination with rituximab + lenalidomide in patients with follicular lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3732.

The occurrence of mental health symptoms in isotretinoin-treated adolescents.

Isotretinoin treatment for acne can reduce adverse psychiatric outcomes in adults, but there has been little investigation of the incidence of psychiatric outcomes in treated adolescents. This retrospective cohort study using the Rochester Epidemiology Project identified 606 patients aged 12-18 prescribed isotretinoin over a 10-year period between January 1, 2008 and December 31, 2017. Medical records were reviewed to identify psychiatric diagnoses before and during isotretinoin therapy, as well as psychiatric symptoms not captured by formal diagnoses and changes to isotretinoin dosing because of psychiatric diagnoses or symptoms. One hundred seventy-seven (29.2%) had a psychiatric diagnosis prior to isotretinoin initiation, but 98 (16.2%) had a new psychiatric diagnosis or psychiatric symptom while taking isotretinoin. Patients with a psychiatric history were no more likely than those without to receive a new psychiatric diagnosis during treatment (4.5% vs. 3.7%; p = .650), but did experience more psychiatric symptoms, primarily low mood and mood swings (23.7% vs. 7.7%; p < .001). Only 25.5% of the 98 with a new psychiatric diagnosis or psychiatric symptom had a subsequent dose change. A dose change was more likely if patients received a new psychiatric diagnosis (41.7% vs. 20.3%; p = .037) or patients did not have a psychosocial explanation for psychiatric symptoms (34.4% vs. 10.8%; p = .009). A substantial proportion of adolescent patients prescribed isotretinoin had a prior psychiatric diagnosis.This predicts more psychiatric symptoms during isotretinoin treatment. Adolescents with a psychiatric history who have worsening symptoms and those with new-onset psychiatric symptoms would benefit from close monitoring while taking isotretinoin.

Uptake of COVID-19 vaccinations amongst 3,433,483 children and young people: meta-analysis of UK prospective cohorts

SARS-CoV-2 infection in children and young people (CYP) can lead to life-threatening COVID-19, transmission within households and schools, and the development of long COVID. Using linked health and administrative data, we investigated vaccine uptake among 3,433,483 CYP aged 5–17 years across all UK nations between 4th August 2021 and 31st May 2022. We constructed national cohorts and undertook multi-state modelling and meta-analysis to identify associations between demographic variables and vaccine uptake. We found that uptake of the first COVID-19 vaccine among CYP was low across all four nations compared to other age groups and diminished with subsequent doses. Age and vaccination status of adults living in the same household were identified as important risk factors associated with vaccine uptake in CYP. For example, 5–11 year-olds were less likely to receive their first vaccine compared to 16–17 year-olds (adjusted Hazard Ratio [aHR]: 0.10 (95%CI: 0.06–0.19)), and CYP in unvaccinated households were less likely to receive their first vaccine compared to CYP in partially vaccinated households (aHR: 0.19, 95%CI 0.13–0.29).

A Consequence-Informed Licensing Path Selection for the Design of Physical Protection Systems at Commercial Nuclear Power Facilities

The survivability of the domestic nuclear power industry depends on the cost-competitiveness of safe and secure nuclear power generation. Advanced reactor design concepts aim to have increased safety margins over traditional large light water reactors (LWRs). With increased safety margins comes the potential for a corresponding decrease in off-site risk to the general public from a hypothetical release of radioactivity due to sabotage or theft. Without sacrificing safety or security, advanced reactor designers may be able to achieve operational cost improvements over current LWRs in part by designing less burdensome physical protection systems (PPSs) and by replacing on-site response forces with off-site response forces. To accommodate these developments, the U.S. Nuclear Regulatory Commission is drafting new rulemakings for physical security when licensing through the current frameworks in 10 CFR 50 or 10 CFR 52 along with drafting an entirely new licensing framework: 10 CFR 53. A novel technology-inclusive consequence-informed methodology for the selection of the optimal licensing path for the design of PPSs at advanced fixed-site commercial nuclear power facilities is presented herein. This methodology proposes integrating security considerations at the beginning of a reactor facility design effort to streamline the licensing process. Off-site total effective dose equivalents at the exclusion area and low population zone boundaries were identified as the key metrics when determining a design’s most appropriate licensing path that in turn affects the design requirements placed upon the PPS. Given these metrics, source-term generation of potential adversary-induced physics-based sabotage actions utilizing severe accident modeling software and off-site plume dispersal modeling were identified as appropriate for determining siting constraints, potential target sets for hypothetical sabotage events, and their subsequent off-site dose consequences. The methodology proposes using the consequence results from the sabotage modeling, in combination with desired cost-saving PPS characteristics, to help inform the licensing path selection. Once a licensing path is chosen, the methodology utilizes the Design and Evaluation Process Outline to evaluate an effective PPS following the licensing requirements placed on the facility. This paper also presents examples of hypothetical commercial nuclear power facilities with varying consequence levels and demonstrations of how to select the optimal licensing pathways for each.

Angiotensin II involvement in the development and persistence of amphetamine-induced sensitization: Striatal dopamine reuptake implications.

Amphetamine (AMPH) exposure induces behavioural and neurochemical sensitization observed in rodents as hyperlocomotion and increased dopamine release in response to a subsequent dose. Brain Angiotensin II modulates dopaminergic neurotransmission through its AT1 receptors (AT1-R), positively regulating striatal dopamine synthesis and release. This work aims to evaluate the AT1-R role in the development and maintenance of AMPH-induced sensitization. Also, the AT1-R involvement in striatal dopamine reuptake was analysed. The sensitization protocol consisted of daily AMPH administration for 5days and tested 21 days after withdrawal. An AT1-R antagonist, candesartan, was administered before or after AMPH exposure to evaluate the participation of AT1-R in the development and maintenance of sensitization, respectively. Sensitization was evaluated by locomotor activity and c-Fos immunostaining. Changes in dopamine reuptake kinetics were evaluated 1day after AT1-R blockade withdrawal treatment, with or without the addition of AMPH in vitro. The social interaction test was performed as another behavioural output. Repeated AMPH exposure induced behavioural and neurochemical sensitization, which was prevented and reversed by candesartan. The AT1-R blockade increased the dopamine reuptake kinetics. Neither the AMPH administration nor the AT1-R blockade altered the performance of social interaction. Our results highlight the AT1-R's crucial role in AMPH sensitization. The enhancement of dopamine reuptake kinetics induced by the AT1-R blockade might attenuate the neuroadaptive changes that lead to AMPH sensitization and its self-perpetuation. Therefore, AT1-R is a prominent candidate as a target for pharmacological treatment of pathologies related to dopamine imbalance, including drug addiction and schizophrenia.

Eptinezumab for the preventive treatment of episodic and chronic migraine: a narrative review.

Eptinezumab, a monoclonal antibody that targets calcitonin gene-related peptide (CGRP), was recently approved in Europe for the prophylactic treatment of migraine in adults who have at least four migraine days a month. Eptinezumab is administered by intravenous infusion every 12 weeks. During recent months, a considerable amount of evidence from eptinezumab trials has been published. The aim of this review is to describe the existing evidence on the tolerability, safety and efficacy of eptinezumab in patients with migraine. Data from randomized (PROMISE-1, PROMISE-2, RELIEF and DELIVER) and open-label (PREVAIL) phase 3 clinical trials have demonstrated the favorable effect of eptinezumab in migraine symptoms from first day of treatment. These studies showed that eptinezumab results in an overall reduction in mean monthly migraine days (MMDs), increases in the ≥50% and ≥ 75% migraine responder rates (MRRs) and improvements in patient-reported outcome measures in both patients with episodic migraine (EM) and with chronic migraine (CM), including patients who failed previous preventive treatments. The RELIEF trial also showed that eptinezumab, within 2 h of administration, reduced headache pain, migraine-associated symptoms and acute medication use when administered during a migraine attack. Eptinezumab benefits manifested as early as day 1 after dosing and with the subsequent doses lasted up to at least 2 years. Treatment-emergent adverse events reported by ≥2% of patients included upper respiratory tract infection and fatigue. Current evidence demonstrates that eptinezumab has a potent, fast-acting, sustained migraine preventive effect in patients with EM and CM. Eptinezumab has also shown to be well tolerated, supporting its use in the treatment of patients with migraine and inclusion in the current migraine therapeutic options.

Multiple resistance to EPSPS and ALS inhibitors in Palmer amaranth (Amaranthus palmeri) identified in Turkey

AbstractAmaranthus palmeri was first reported in Turkey in 2016, and an immediate heavy infestation of the weed was found in fruit orchards and summer crops such as maize, cotton, and sunflower. There have been farmers' complaints about the ineffective control of Palmer amaranth through the use of glyphosate and some sulfonylureas herbicides. Hence, this study aimed to determine the possible herbicide resistance evolution in Palmer amaranth against glyphosate and acetolactate synthase (ALS) herbicides. Seeds of 21 Palmer amaranth populations were collected from five provinces of Turkey where control problems with glyphosate and ALS inhibitors were reported in maize fields. Seeds of certain biotypes categorized as resistant or susceptible were grown to obtain the F2 generation. A single‐dose experiment determined the possible resistance to ALS inhibitors and glyphosate among the 21 populations. Of this, 18 populations were included in the subsequent dose–response experiments due to evident survival. Based on ED50 values from the dose–response experiment, SNU‐04 and ADN‐21 biotypes had the highest resistance index for glyphosate which was more than 7. The biotypes ADN‐21, OSM‐15, and DIR‐09 recorded the highest ED50 value with a resistance index of 9.21–10.35 after nicosulfuron application. Whereas, the biotypes SNU‐04, OSM‐15, and ADN‐21 were with the highest ED50 value and resistance index of 6.41–7.44, after the application of foramsulfuron + iodosulfuron methyl‐sodium. The increase in genomic 5‐enolpyruvylshikimate‐3‐phosphate synthase (EPSPS) copy number has been observed in suspected cases that have been accepted as the molecular basis for the development of resistance against glyphosate. The sequence alignment results for the ALS gene contained Ala122Val and Pro197Arg mutations related to target‐site resistance against ALS herbicides.

Impact of Immunomodulatory Therapy on COVID-19 Vaccine Response in Patients with Autoimmune Inflammatory Rheumatic Diseases.

Coronavirus disease 2019 (COVID-19) vaccination is essential for patients with autoimmune inflammatory rheumatic diseases (AIIRD) to reduce the risk of morbidity and mortality associated with serious COVID-19 infection. With endemicity, waning of vaccine- and infection-acquired immunity, and development of SARS-CoV-2 variants, the need for additional doses of vaccines against serious illness in high-risk immunocompromised persons remains imperative. This review examines how immunomodulatory therapies affect vaccine-induced immune response in patients with AIIRD. Glucocorticoids, methotrexate, azathioprine, calcineurin inhibitors, mycophenolate mofetil, tumor necrosis factor inhibitors, and abatacept have been shown to variably attenuate both humoral and cellular immune responses to vaccination. Janus kinase inhibitors reduce humoral immune response. In contrast, sulfasalazine, leflunomide, belimumab, interleukin (IL)-17, IL-12/23, IL-6, and IL-1 inhibitors appear favorable, with mild or no impact on vaccine response. Although rituximab is known to profoundly diminish humoral immune response, cellular immunity is relatively preserved. Administering a third and subsequent vaccine dose or temporally coordinating the dosing of immunomodulatory drugs may improve vaccine effectiveness. Further research is needed to personalise vaccination strategies for AIIRD patients, considering their specific immunomodulatory treatments.

Egg white hydrolysate protects white adipose tissue against metabolic insult in deoxycorticosterone acetate-salt rats.

The purpose of this study was to investigate the effect of an egg white hydrolysate (EWH) to protect white adipose tissue damage from cardiometabolic changes induced by severe hypertension. Male Wistar rats were uninephrectomised and divided: SHAM (weekly subcutaneous vehicle (mineral oil + propylene glycol, 1:1)), SHAM + EWH (subcutaneous vehicle plus EWH via gavage, 1 g/kg per day), DOCA (deoxycorticosterone acetate diluted in vehicle subcutaneously weekly in subsequent doses of 20 mg/kg -1st week, 12 mg/kg - 2–3th week, and 6 mg/kg -4–8th week, respectively, plus 1 % NaCl and 0·2 % KCl in drinking water), and DOCA + EWH. Body weight gain, food and water intake, glucose and lipid metabolism were evaluated. Oxidative stress was assessed by biochemical assay and immunofluorescence for NOX-1, nuclear factor kappa B (NFκB), and caspase-3 in retroperitoneal white adipose tissue (rtWAT). Proinflammatory cytokines (IL-6 and 1β), CD163+ macrophage infiltration, and immunohistochemistry for TNFα and uncoupling protein-1 were evaluated, as well as histological analysis on rtWAT. Glutathione peroxidase and reductase were also determined in plasma. EWH showed hypocholesterolemic, antioxidant, anti-inflammatory, and anti-apoptotic properties in the arterial hypertension DOCA-salt model. The results demonstrated the presence of functional changes in adipose tissue function by a decrease in macrophage infiltration and in the fluorescence intensity of NFκB, NOX-1, and caspase-3. A reduction of proinflammatory cytokines and restoration of antioxidant enzymatic activity and mitochondrial oxidative damage by reducing uncoupling protein-1 fluorescence intensity were also observed. EWH could be used as a potential alternative therapeutic strategy in the treatment of cardiometabolic complications associated with malignant secondary arterial hypertension.

CPU-GPU-coupled acceleration method for point flux calculation in Monte Carlo particle transport.

In Monte Carlo particle transport simulations, point flux tallying is a variance reduction technique that performs well with small detectors and finds broad application in source-detector problems and local point dose calculations. However, its use in large-scale point flux tallying computation adds substantial computational time. To address this issue, we propose a CPU-GPU-coupled acceleration method, which separates the complex logic and computationally intensive parts of particle transport calculation and assigns them to the CPU and GPU, respectively. This proposed method greatly enhances the efficiency of large-scale point flux tallies, providing significant convenience for subsequent dose calculations and other related steps. We validated our method by comparing the performance of a pure CPU program with our CPU-GPU accelerated program using the NUREG/CR-6115 PWR benchmark problem. The results indicate identical outcomes for photon point flux estimation, with the accelerated program being ~50 times faster.

Assessment of the effectiveness of weight-adjusted antibiotic administration, for reduced duration, in surgical prophylaxis of primary hip and knee arthroplasty.

Prophylactic antibiotics have significantly led to a reduction in the risk of post-operative surgical site infections (SSI) in orthopaedic surgery. The aim of using antibiotics for this purpose is to achieve serum and tissue drug levels that exceed, for the duration of the operation, the minimum inhibitory concentration of the likely organisms that are encountered. Prophylactic antibiotics reduce the rate of SSIs in lower limb arthroplasty from between 4% and 8% to between 1% and 3%. Controversy, however, still surrounds the optimal frequency and dosing of antibiotic administration. To evaluate the impact of introduction of a weight-adjusted antibiotic prophylaxis regime, combined with a reduction in the duration of administration of post-operative antibiotics on SSI incidence during the 2 years following primary elective total hip and knee arthroplasty. Following ethical approval, patients undergoing primary total hip arthroplasty (THA)/total knee arthroplasty (TKA) with the old regime (OR) of a preoperative dose [cefazolin 2 g intravenously (IV)], and two subsequent doses (2 h and 8 h), were compared to those after a change to a new regime (NR) of a weight-adjusted preoperative dose (cefazolin 2 g IV for patients < 120 kg; cefazolin 3g IV for patients > 120 kg) and a post-operative dose at 2 h. The primary outcome in both groups was SSI rates during the 2 years post-operatively. A total of n = 1273 operations (THA n = 534, TKA n = 739) were performed in n = 1264 patients. There was no statistically significant difference in the rate of deep (OR 0.74% (5/675) vs NR 0.50% (3/598); fishers exact test P = 0.72), nor superficial SSIs (OR 2.07% (14/675) vs NR 1.50% (9/598); chi-squared test P = 0.44) at 2 years post-operatively. With propensity score weighting and an interrupted time series analysis, there was also no difference in SSI rates between both groups [RR 0.88 (95%CI 0.61 to 1.30) P = 0.46]. A weight-adjusted regime, with a reduction in number of post-operative doses had no adverse impact on SSI incidence in this population.

Change in intention and hesitancy regarding COVID-19 vaccines in a cohort of adults in Quebec during the pandemic

ABSTRACT Although COVID-19 vaccine uptake was high in Quebec for the primary series, vaccine acceptance decreased for the subsequent booster doses. This article presents the evolution of vaccine intention, self-reported vaccination behaviors, and vaccine hesitancy over 2 years. A series of cross-sectional surveys were conducted in Quebec between March 2020 and March 2023, with a representative sample of 3,330 adults recruited biweekly via a Web panel. Panelists could have answered multiple times over the course of the project. A cohort of respondents was created to assess how attitudes and behaviors about COVID-19 vaccines evolved. Descriptive statistics and multivariate logistic regressions were performed. Among the 1,914 individuals with no or low intention of getting vaccinated in Fall 2021 (Period 1), 1,476 (77%) reported having received at least two doses in the Winter 2023 (Period 2). Not believing in conspiracy theory (OR = 2.08, 95% CI: 1.65–2.64), being worried about catching COVID-19 (OR = 2.12, 95% CI: 1.65–2.73) and not living in a rural area (ORs of other areas are 2.27, 95% CI: 1.58–3.28; 1.66, 95% CI: 1.23–2.26; 1.82 95% CI: 1.23–2.73) were the three main factors associated with being vaccinated at Period 2. Among the 11,117 individuals not hesitant at Period 1, 1,335 (12%) became hesitant at Period 2. The three main factors significantly associated with becoming vaccine hesitant were the adherence to conspiracy theories (OR = 2.28, 95% CI: 1.95–2.66), being a female (OR = 1.67, 95% CI: 1.48–1.90) and being younger than 65 years old (the ORs for 18–34, 35–49, and 50–64 compared with 65 and over are 2.82, 95% CI: 2.32–3.44; 2.39, 95% CI: 2.00–2.86 and 1.82, 95% CI: 1.55–2.15 respectively). As the pandemic is over, monitoring the evolution of vaccine attitudes and uptake will be important.

Disease activity-guided dose optimisation including discontinuation of TNF-inhibitors in rheumatoid arthritis is effective for up to 10 years: an observational follow-up of the DRESS study.

To investigate safety and effectiveness of disease activity-guided dose optimisation of TNF-inhibitors in rheumatoid arthritis over 10 years. Observational long-term extension of a randomised study of participants who completed the 3-year extension of the DRESS-study. After the randomised phase (month 0-18), disease activity-guided dose optimisation was allowed for all. Main outcomes were mean time-weighted DAS28-CRP; biological and targeted synthetic anti-rheumatic drug (b/tsDMARD) use per year as proportion of daily defined dose; proportion of patients reaching discontinuation; durability, effectiveness of subsequent dose reduction attempts; and radiographic progression between 3 and 10 years using the Sharp-van der Heijde score. 170 patients were included of whom 127 completed 10-year follow-up. The mean disease activity remained low (DAS28-CRP 2.13, 95% confidence interval 2.10-2.16), whilst the b/tsDMARD dose reduced from 97% at baseline (95%CI 96% to 99%, n = 170)% to56% at year 10 (49% to 63%, n = 127). 119 of 161 participants (74%) with an optimisation attempt reached discontinuation, with a median duration of 7 months (interquartile range 3-33 months), and 25 participants never had to restart their b/tsDMARD (21%, 14% to 29%). The mean dose reduction after dose optimisation was 48% (n = 159) for the first optimisation attempt and 33% for subsequent attempt (n = 86). 48% (41/86) of participants had radiographic progression exceeding the smallest detectable change (5.7 units), and progression was associated with disease activity, not b/tsDMARD use. Long-term disease activity-guided dose optimisation of TNF-inhibitors in rheumatoid arthritis, including discontinuation and multiple tapering attempts, remains safe and effective.

Validation of an automated dispensing system for subsequent dose dispensing of different radionuclides

BackgroundAutomated dispensing systems (ADSs) for radiopharmaceuticals have been developed to reduce the radiation exposure of personnel, to improve the accuracy of the dispensed dose and to limit the microbiological contamination. However, before implementing such systems, validation according to various applicable guidelines is necessary to ensure safety and quality. Here we present the selection, validation and implementation of the PT459R2 from manufacturer Lynax s.r.o. as a guidance protocol for validation according to GMP and GRPP guidelines. Validation included linearity accuracy and precision of the internal scintillation detector for different isotopes and microbiological validation for aseptic procedures.ResultsThe ADS can dispense accurate doses in the following linear range: 1000–10,000 MBq for lutetium-177, 20–74 MBq for zirconium-89, 100–1000 MBq for gallium-68 and 100–2000 MBq for fluorine-18. The maximum bias is 2.35% and the maximum coefficient of variation is 3.03% which meets the acceptance criteria of < 5%. Furthermore, the ADS does not affects the GMP class A environment in a laminar airflow cabinet and can dispense aseptically. In addition, radiation exposure is acceptable and data integrity is preserved.ConclusionThe PT459R2 ADS met all the requirements from our performance qualification and is therefore suitable for daily routine use in our center. Our approach can be used as a guidance for PQ of an ADS in a Radiopharmacy according to GMP and GRPP guidelines.

549 - Laboratory parameters in adolescent patients aged 12–17 with moderate-to-severe atopic dermatitis treated with tralokinumab up to week 52: results from the phase 3 ECZTRA 6 trial

Abstract Introduction/Background Tralokinumab, a high-affinity, monoclonal antibody that targets IL-13, is approved in the EU and Canada for adolescents (aged ≥12 years) with inadequately controlled moderate-to-severe atopic dermatitis (AD), and it does not require laboratory monitoring. The phase 3 ECZTRA 6 (NCT03526861) clinical trial demonstrated efficacy and safety up to 52 weeks in that population. Objectives To further characterize the safety profile of tralokinumab by evaluating laboratory parameters of adolescents in the ECZTRA 6 trial. Methods ECZTRA 6 subjects received tralokinumab 150mg (n=98), 300mg (n=97) or placebo (n=94) every 2 weeks (Q2W) from week 0–16 after a loading dose at week 0 (twice the subsequent dose), and then randomized to maintenance [original tralokinumab dose either Q2W or every 4 weeks (Q4W) or placebo Q2W] or open-label (tralokinumab 300mg Q2W) until week 52. Laboratory parameters included hematology, serum biochemistry, and urinalysis throughout the trial (weeks 0, 8, 16, 28, and 52). Results Overall (n= 289 subjects), laboratory baseline parameters were similar across treatment groups. Mean and median changes of most hematology parameters showed minor fluctuations within the normal ranges through week 52, except for eosinophils. At baseline, elevated mean eosinophil counts (&amp;gt;0.5 109/L) were observed for 40.8% (tralokinumab 150mg), 48.5% (tralokinumab 300mg), and 43.6% (placebo) of subjects in each respective treatment group. Some tralokinumab-treated patients had small transient increases in eosinophils (maximum mean change from baseline 0.2×109/L) before week 16. Continued treatment with tralokinumab or placebo did not correspond with further increase in eosinophil levels over time, and no adverse events of eosinophilia were reported. Mean levels of most biochemistry parameters, including electrolytes, renal and liver function parameters, and lipid panel, were within normal range at baseline, and mean and median changes showed minor fluctuations within normal ranges in all treatment arms. Mean lactate dehydrogenase levels were around or above the upper limit of normal at baseline and decreased to within the normal ranges during the trial across all groups. Overall, no clinically meaningful differences were observed in hematology, biochemistry, or urinalysis parameters between active treatment groups or placebo. Conclusions Similar to findings in adult trials, no meaningful changes in laboratory parameters were observed in adolescents through week 52 with tralokinumab treatment. No routine laboratory monitoring is needed for adult or adolescent AD patients treated with tralokinumab.

Impact of Anti-PEG IgM Induced via the Topical Application of a Cosmetic Product Containing PEG Derivatives on the Antitumor Effects of PEGylated Liposomal Antitumor Drug Formulations in Mice.

Poly(ethylene glycol) (PEG) is used in many common products, such as cosmetics. PEG, however, is also used to covalently conjugate drug molecules, proteins, or nanocarriers, which is termed PEGylation, to serve as a shield against the natural immune system of the human body. Repeated administration of some PEGylated products, however, is known to induce anti-PEG antibodies. In addition, preexisting anti-PEG antibodies are now being detected in healthy individuals who have never received PEGylated therapeutics. Both treatment-induced and preexisting anti-PEG antibodies alter the pharmacokinetic properties, which can result in a subsequent reduction in the therapeutic efficacy of administered PEGylated therapeutics through the so-called accelerated blood clearance (ABC) phenomenon. Moreover, these anti-PEG antibodies are widely reported to be related to severe hypersensitivity reactions following the administration of PEGylated therapeutics, including COVID-19 vaccines. We recently reported that the topical application of a cosmetic product containing PEG derivatives induced anti-PEG immunoglobulin M (IgM) in a mouse model. Our finding indicates that the PEG derivatives in cosmetic products could be a major cause of the preexistence of anti-PEG antibodies in healthy individuals. In this study, therefore, the pharmacokinetics and therapeutic effects of Doxil (doxorubicin hydrochloride-loaded PEGylated liposomes) and oxaliplatin-loaded PEGylated liposomes (Liposomal l-OHP) were studied in mice. The anti-PEG IgM antibodies induced by the topical application of cosmetic products obviously accelerated the blood clearance of both PEGylated liposomal formulations. Moreover, in C26 tumor-bearing mice, the tumor growth suppressive effects of both Doxil and Liposomal l-OHP were significantly attenuated in the presence of anti-PEG IgM antibodies induced by the topical application of cosmetic products. These results confirm that the topical application of a cosmetic product containing PEG derivatives could produce preexisting anti-PEG antibodies that then affect the therapeutic efficacy of subsequent doses of PEGylated therapeutics.

Antipsychotics and the QTc Interval During Delirium in the Intensive Care Unit

Antipsychotic medications, often prescribed for delirium in intensive care units (ICUs), may contribute to QTc interval prolongation. To determine whether antipsychotics increase the QTc interval in patients with delirium in the ICU. An a priori analysis of a randomized clinical trial in medical/surgical ICUs within 16 centers across the US was conducted. Participants included adults with delirium in the ICU with baseline QTc interval less than 550 ms. The study was conducted from December 2011 to August 2017. Data analysis was performed from April 25 to August 18, 2021. Patients were randomized 1:1:1 to intravenous haloperidol, ziprasidone, or saline placebo administered twice daily until resolution of delirium, ICU discharge, or 14 days. Twelve-lead electrocardiograms were used to measure baseline QTc before study drug initiation and telemetry was used to measure QTc before each subsequent dose of study drug. Unadjusted day-to-day changes in QTc were calculated and multivariable proportional odds regression was used to estimate the effects of antipsychotics vs placebo on next-day maximum QTc interval, adjusting for prespecified baseline covariates and potential interactions with sex. Safety end points, including the occurrence of torsade de pointes, were evaluated. All analyses were conducted based on the intention to treat principle. A total of 566 patients were randomized to haloperidol (n = 192), ziprasidone (n = 190), or placebo (n = 184). Median age was 60.1 (IQR, 51.4-68.7) years; 323 were men (57%). Baseline median QTc intervals across the groups were similar: haloperidol, 458.0 (IQR, 432.0-479.0) ms; ziprasidone, 451.0 (IQR, 424.0-472.0) ms; and placebo, 452.0 (IQR, 432.0-472.0) ms. From day 1 to day 2, median QTc changed minimally: haloperidol, -1.0 (IQR, -28.0 to 15.0) ms; ziprasidone, 0 (IQR, -23.0 to 20.0) ms; and placebo, -3.5 (IQR, -24.8 to 17.0) ms. Compared with placebo, neither haloperidol (odds ratio [OR], 0.95; 95% CI, 0.66-1.37; P = .78) nor ziprasidone (OR, 1.09; 95% CI, 0.75-1.57; P = .78) was associated with next-day QTc intervals. Effects were not significantly modified by sex (P = .41 for interaction). There were 2 occurrences of nonfatal torsade de pointes, both in the haloperidol group. Neither was associated with study drug administration. The findings of this trial suggest that daily QTc interval monitoring during antipsychotic use may have limited value in patients in the ICU with normal baseline QTc and few risk factors for QTc prolongation. ClinicalTrials.gov Identifier: NCT01211522.