Kinetics and metabolism of carbamazepine during combined antiepileptic drug therapy.

The kinetics of carbamazepine using 15N-carbamazepine were investigated in epileptic patients during combined anticonvulsant therapy. The 15N-carbamazepine plasma half-lives ranged from 5.0 to 13.6 hr with a mean of 8.2 hr. These half-lives are appreciably shorter than reported during chronic carbamazepine monotherapy. Predicted steady-state plasma levels and observed plasma levels of carbamazepine were in excellent agreement. Between 32% and 61% of the dose administered is excreted in the urine as carbamazepine-trans-diol, 5.2% to 8.8% as 9-hydroxymethyl-10-carbamoyl acridane, 1% to 1.4% as 10,-11-carbamazepine epoxide, and 0.5% as carbamazepine. The data indicate that it is the epoxide-diol pathway which is induced during long-term treatment. Concomitant therapy with primidone, phenytoin, phenobarbital, ethosuximide, or methsuximide further induces carbamazepine metabolism.     

Assessment of individual vaccine status in a vaccinology experts' group

Rationale  Worldwide, experts in vaccinology have promoted the broad annual coverage of health care workers with the influenza vaccine. Furthermore, pertussis vaccination is now recommended for young adults and health care workers working with newborns.
Aim  To analyse the compliance with these guidelines among experts responsible for the development or dissemination of national immunization schedules.
Method  A cross-sectional survey was conducted in a vaccinology workshop group of French experts, using a self-administered questionnaire.
Results  Among 44 experts, the average rate of influenza vaccination was 69.5% (95% confidence interval, 61.6% to 77.3%) between the 2003/04 and 2005/06 flu seasons, whereas the rate of pertussis vaccination during this period was only 30%. The main reasons that the experts gave for not being vaccinated were a lack of time or simply not remembering to do so.
Conclusion  Experts had low coverage rates for influenza and pertussis vaccination. To improve these rates, a multifaceted intervention combining audit and feedback strategy with a vaccine day is planned.     

DURATION-1: Exenatide Once Weekly Produces Sustained Glycemic Control and Weight Loss Over 52 Weeks

OBJECTIVE

In the Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) study, the safety and efficacy of 30 weeks of treatment with the glucagon-like peptide-1 receptor agonist exenatide once weekly (exenatide QW; 2 mg) was compared with exenatide BID in 295 patients with type 2 diabetes. We now report the safety and efficacy of exenatide QW in 1) patients who continued treatment for an additional 22 weeks (52 weeks total) and 2) patients who switched from exenatide BID to exenatide QW after 30 weeks.

RESEARCH DESIGN AND METHODS

In this randomized, multicenter, comparator-controlled, open-label trial, 258 patients entered the 22-week open-ended assessment phase (n = 128 QW-only; n = 130 BID→QW). A1C, fasting plasma glucose (FPG), body weight, blood pressure, fasting lipids, safety, and tolerability were assessed.

RESULTS

Patients continuing exenatide QW maintained A1C improvements through 52 weeks (least squares mean −2.0% [95% CI −2.1 to −1.8%]). Patients switching from exenatide BID to exenatide QW achieved further A1C improvements; both groups exhibited the same A1C reduction and mean A1C (6.6%) at week 52. At week 52, 71 and 54% of all patients achieved A1C <7.0% and ≤6.5%, respectively. In both treatment arms, FPG was reduced by >40 mg/dl, and body weight was reduced by >4 kg after 52 weeks. Nausea occurred less frequently in this assessment period and was predominantly mild. No major hypoglycemia was observed.

CONCLUSION

Exenatide QW elicited sustained improvements in glycemic control and body weight through 52 weeks of treatment. Patients switching to exenatide QW experienced further improvements in A1C and FPG, with sustained weight loss.Type 2 diabetes is a complex and increasingly prevalent disease associated with interrelated comorbidities, including obesity, dyslipidemia, and hypertension. The importance of treating not only hyperglycemia, but also the associated comorbidities, is recognized as necessary to reduce the risk of complications, particularly cardiovascular disease (1). Lifestyle modification can improve glycemic control as well as body weight, blood pressure, and lipid profiles; however, behavioral modifications are inherently difficult, and most patients eventually require multiple medications (2–6). Although several classes of antihyperglycemic medications are currently indicated for the treatment of type 2 diabetes, most of them do not improve the comorbidities and several are associated with weight gain.Exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, improves glycemic control in patients with type 2 diabetes through multiple mechanisms of action: increased glucose-dependent insulin secretion, attenuated postprandial glucagon secretion, slowed gastric emptying, and increased satiety (7,8). The twice-daily formulation of exenatide (exenatide BID) improves both fasting and postprandial glucose control, resulting in A1C reductions of roughly 0.8–1.0% in placebo-controlled trials (9–12) and 1.0–1.4% in open-label trials (13–15). These improvements in glucose control were maintained in patients completing 3 years of treatment (−1.0%) (16). Exenatide therapy is also associated with weight loss and improvement in cardiovascular risk factors, including blood pressure and serum lipid profiles (16). Furthermore, the glucose-dependent mechanisms of action of exenatide minimize the risk of hypoglycemia. GLP-1R agonists have recently been added to the American Diabetes Association and European Association for the Study of Diabetes consensus algorithm for the treatment of type 2 diabetes as an option after the addition of metformin in patients in whom body weight and hypoglycemia risk are concerns (1).Exenatide BID is administered within the 60-min period before the morning and evening meals and primarily exerts its pharmacodynamic effects on glucose concentrations during the postprandial period. A long-acting once-weekly formulation of exenatide (exenatide QW) has been developed. Weekly administration of 2 mg exenatide QW results in therapeutic plasma exenatide concentrations within 2 weeks and steady-state plasma exenatide concentrations within the therapeutic target range 6–7 weeks after initiation of therapy (17,18).The Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) trial was designed as a two-stage protocol. We previously reported the first stage, a randomized open-label comparison of exenatide QW to exenatide BID in patients with type 2 diabetes over 30 weeks (17). Both therapies improved glycemic control, and the improvement in A1C observed with exenatide QW treatment was significantly greater than that observed with exenatide BID (−1.9 vs. −1.5%, respectively). Similar improvements in body weight, blood pressure, and fasting lipids were demonstrated with both forms of exenatide therapy. We now describe 52-week results from the second phase of the DURATION-1 trial which examined the safety and efficacy of 1) switching from exenatide BID to exenatide QW after 30 weeks of treatment and 2) continuing exenatide QW treatment for an additional 22 weeks (52 weeks total).     

Reperfused myocardial infarction in mice: 3D mapping of late gadolinium enhancement and strain.

We developed mathematical modeling tools for mapping 3D infarct geometry from multislice late gadolinium enhancement data, allowing fusion with multislice MR tagging data, in mice with myocardial infarction. Five C57BL/6 mice were imaged at baseline, 1, 7 and 28 days after 60 min occlusion of the left anterior descending coronary artery. The 3D infarct geometry was mapped in material coordinates, and registered with 3D strain, showing permanent dysfunction in infarcted segments, intermediate function in the adjacent zone, and maintained function in the remote zone. 3D mapping of late enhancement and strain allows registration of multiple studies in a consistent framework.     

Turkish Transplant Registry: a comparative analysis of national activity with the EBMT European Activity Survey

SCT is a curative approach using chemo-, radio- and immunotherapy for malignant and non-malignant hematological disorders. The European Group for Blood and Marrow Transplantation (EBMT) has been collecting yearly data on a survey basis since 1990. The variables within the survey are limited to detailed indications, number of patients, transplant type, stem cell source, type of conditioning regimen and donor type. The transplant rates in certain indications, patterns of stem cell source selection and donor availability and alternative donor use were analyzed in detail. The Turkish transplant registry data within EBMT-European Activity Survey (EBMT-EAS) were delivered by the EBMT Activity Survey Office. We compared the national data with the international EBMT-EAS data pool.     

The impact of visual dysfunctions in recent-onset psychosis and clinical high-risk state for psychosis

Subtle subjective visual dysfunctions (VisDys) are reported by about 50% of patients with schizophrenia and are suggested to predict psychosis states. Deeper insight into VisDys, particularly in early psychosis states, could foster the understanding of basic disease mechanisms mediating susceptibility to psychosis, and thereby inform preventive interventions. We systematically investigated the relationship between VisDys and core clinical measures across three early phase psychiatric conditions. Second, we used a novel multivariate pattern analysis approach to predict VisDys by resting-state functional connectivity within relevant brain systems. VisDys assessed with the Schizophrenia Proneness Instrument (SPI-A), clinical measures, and resting-state fMRI data were examined in recent-onset psychosis (ROP, n = 147), clinical high-risk states of psychosis (CHR, n = 143), recent-onset depression (ROD, n = 151), and healthy controls (HC, n = 280). Our multivariate pattern analysis approach used pairwise functional connectivity within occipital (ON) and frontoparietal (FPN) networks implicated in visual information processing to predict VisDys. VisDys were reported more often in ROP (50.34%), and CHR (55.94%) than in ROD (16.56%), and HC (4.28%). Higher severity of VisDys was associated with less functional remission in both CHR and ROP, and, in CHR specifically, lower quality of life (Qol), higher depressiveness, and more severe impairment of visuospatial constructability. ON functional connectivity predicted presence of VisDys in ROP (balanced accuracy 60.17%, p = 0.0001) and CHR (67.38%, p = 0.029), while in the combined ROP + CHR sample VisDys were predicted by FPN (61.11%, p = 0.006). These large-sample study findings suggest that VisDys are clinically highly relevant not only in ROP but especially in CHR, being closely related to aspects of functional outcome, depressiveness, and Qol. Findings from multivariate pattern analysis support a model of functional integrity within ON and FPN driving the VisDys phenomenon and being implicated in core disease mechanisms of early psychosis states.Subject terms: Predictive markers, Psychosis     

Evaluating denoising strategies in resting‐state functional magnetic resonance in traumatic brain injury (EpiBioS4Rx)

Resting‐state functional MRI is increasingly used in the clinical setting and is now included in some diagnostic guidelines for severe brain injury patients. However, to ensure high‐quality data, one should mitigate fMRI‐related noise typical of this population. Therefore, we aimed to evaluate the ability of different preprocessing strategies to mitigate noise‐related signal (i.e., in‐scanner movement and physiological noise) in functional connectivity (FC) of traumatic brain injury (TBI) patients. We applied nine commonly used denoising strategies, combined into 17 pipelines, to 88 TBI patients from the Epilepsy Bioinformatics Study for Anti‐epileptogenic Therapy clinical trial. Pipelines were evaluated by three quality control (QC) metrics across three exclusion regimes based on the participant''s head movement profile. While no pipeline eliminated noise effects on FC, some pipelines exhibited relatively high effectiveness depending on the exclusion regime. Once high‐motion participants were excluded, the choice of denoising pipeline becomes secondary ‐ although this strategy leads to substantial data loss. Pipelines combining spike regression with physiological regressors were the best performers, whereas pipelines that used automated data‐driven methods performed comparatively worse. In this study, we report the first large‐scale evaluation of denoising pipelines aimed at reducing noise‐related FC in a clinical population known to be highly susceptible to in‐scanner motion and significant anatomical abnormalities. If resting‐state functional magnetic resonance is to be a successful clinical technique, it is crucial that procedures mitigating the effect of noise be systematically evaluated in the most challenging populations, such as TBI datasets.     

Identifying the regional substrates predictive of Alzheimer's disease progression through a convolutional neural network model and occlusion

Progressive brain atrophy is a key neuropathological hallmark of Alzheimer''s disease (AD) dementia. However, atrophy patterns along the progression of AD dementia are diffuse and variable and are often missed by univariate methods. Consequently, identifying the major regional atrophy patterns underlying AD dementia progression is challenging. In the current study, we propose a method that evaluates the degree to which specific regional atrophy patterns are predictive of AD dementia progression, while holding all other atrophy changes constant using a total sample of 334 subjects. We first trained a dense convolutional neural network model to differentiate individuals with mild cognitive impairment (MCI) who progress to AD dementia versus those with a stable MCI diagnosis. Then, we retested the model multiple times, each time occluding different regions of interest (ROIs) from the model''s testing set''s input. We also validated this approach by occluding ROIs based on Braak''s staging scheme. We found that the hippocampus, fusiform, and inferior temporal gyri were the strongest predictors of AD dementia progression, in agreement with established staging models. We also found that occlusion of limbic ROIs defined according to Braak stage III had the largest impact on the performance of the model. Our predictive model reveals the major regional patterns of atrophy predictive of AD dementia progression. These results highlight the potential for early diagnosis and stratification of individuals with prodromal AD dementia based on patterns of cortical atrophy, prior to interventional clinical trials.     

Endoscopist-Driven Sedation Practices in South Korea: Re-evaluation Considering the Nationwide Survey in 2019

Background/AimsThis study aimed to determine changes in endoscopist-driven sedation practices 5 years after the first nationwide survey in 2014 by the Korean Society of Gastrointestinal Endoscopy (KSGE).MethodsA 59-item survey covering current practices was electronically mailed to all members of the KSGE in 2019.ResultsIn total, 955 (12.8%) out of 7,486 questionnaires were returned. A total of 738 (77.7%) out of 955 respondents attended dedicated sedation education programs. The American Society of Anesthesiologists class was recorded by 464 (51.2%) out of 907 respondents. The recording rate was higher in respondents who completed sedation education (p=0.014) and worked in general or tertiary hospitals (p<0.001). Compared to that reported in the previous survey, the reported use of propofol was higher in 2019. The respondents had higher satisfaction scores for propofol-based sedation compared with midazolam monotherapy (p<0.001). The rates of oxygen supplementation (p<0.001) and oxygen saturation level monitoring (p<0.001) during sedative endoscopy were higher in 2019 than in the previous survey. A total of 876 (98.4%) out of 890 respondents reported a separate recovery bay, and 615 (70.5%) out of 872 respondents reported that personnel were assigned solely to the recovery bay.ConclusionsEndoscopist-driven sedation and monitoring practices in 2019 were significantly different than those in 2014. The respondents favored propofol-based sedation and utilized oxygen supplementation and monitoring of O₂ saturation more frequently in 2019 than in 2014. (Gut Liver, Published online August 1, 2022)