A randomized,double-blind study of SHP465 mixed amphetamine salts extended-release in adults with ADHD using a simulated adult workplace design

Objectives: The objective of this paper was to evaluate the efficacy, duration of effect, and tolerability of SHP465 mixed amphetamine salts (MAS) extended-release versus placebo and immediate-release MAS (MAS IR) in adults with attention-deficit/hyperactivity disorder (ADHD).

Methods: Adults with ADHD Rating Scale, Version IV (ADHD-RS-IV) scores ≥24 were randomized to SHP465 MAS (50 or 75 mg), placebo, or 25 mg MAS IR in a double-blind, three-period, crossover study using a simulated adult workplace environment. On the final day of each 7-day treatment period, efficacy was assessed for 16 h postdose. Primary efficacy analyses for Permanent Product Measure of Performance (PERMP) total score averaged across all postdose assessments and each postdose time point were conducted in the intent-to-treat population using a mixed linear model. Secondary end-points included PERMP problems attempted and answered correctly and ADHD-RS-IV scores based on clinician ratings of counselor observations using the Time Segment Rating System and participant self-report. Tolerability assessments included treatment-emergent adverse events (TEAEs) and vital signs.

Results: Least squares mean (95% CI) treatment differences (combined 50/75 mg SHP465 MAS–placebo) significantly favored SHP465 MAS over placebo for PERMP total score averaged across all postdose assessments (18.38 [11.28, 25.47]; P < .0001) and at each postdose assessment (all P < .02). Nominal superiority of MAS IR over placebo for PERMP total score averaged across all postdose assessments was observed (nominal P = .0001); treatment differences between SHP465 MAS and MAS IR were not significant (nominal P = .2443). The two most frequently reported TEAEs associated with SHP465 MAS were insomnia (36.5%) and anorexia (21.2%). Mean increases in pulse and blood pressure with SHP465 MAS exceeded those of placebo.

Conclusions: SHP465 MAS (combined 50/75 mg) significantly improved PERMP total score versus placebo, with superiority observed from 2 to 16 h postdose. The tolerability profile of SHP465 MAS was similar to previous reports of SHP465 MAS in adults with ADHD.

Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT00928148 identifier is NCT00928148.     

DPOAE level mapping for detecting noise-induced cochlear damage from short-duration music exposures

Distortion product otoacoustic emission (DPOAE) level mapping provides a comprehensive picture of cochlear responses over a range of DP frequencies and f₂/f₁ ratios. We hypothesized that individuals exposed to high-level sound would show changes detectable by DPOAE mapping, but not apparent on a standard DP-gram. Thirteen normal hearing subjects were studied before and after attending music concerts. Pure-tone audiometry (500-8,000 Hz), DP-grams (0.3-10 kHz) at 1.22 ratio, and DPOAE level maps were collected prior to, as soon as possible after, and the day after the concerts. All maps covered the range of 2,000-6,000 Hz in DP frequency and from 1.3 to -1.3 in ratio using equi-level primary tone stimuli. Changes in the pure-tone audiogram were significant (P ≤ 0.01) immediately after the concert at 1,000 Hz, 4,000 Hz, and 6,000 Hz. The DP-gram showed significant differences only at f₂ = 4,066 (P = 0.01) and f₂ = 4,348 (P = 0.04). The postconcert changes were readily apparent both visually and statistically (P ≤ 0.01) on the mean DP level maps, and remained statistically significantly different from baseline the day after noise exposure although no significant changes from baseline were seen on the DP-gram or audiogram the day after exposure. Although both the DP-gram and audiogram showed recovery by the next day, the average DPOAE level maps remained significantly different from baseline. The mapping data showed changes in the cochlea that were not detected from the DP-gram obtained at a single ratio. DPOAE level mapping provides comprehensive information on subtle cochlear responses, which may offer advantages for studying and tracking noise-induced hearing loss (NIHL).     

Calendering as a direct shaping tool for the continuous production of fixed-dose combination products via co-extrusion

In this study calendering is used as a downstream technique to shape monolithic co-extruded fixed-dose combination products in a continuous way. Co-extrudates with a metoprolol tartrate-loaded sustained-release core and a hydrochlorothiazide-loaded immediate-release coat were produced and immediately shaped into a monolithic drug delivery system via calendering, using chilled rolls with tablet-shaped cavities. In vitro metoprolol tartrate release from the ethylcellulose core of the calendered tablets was prolonged in comparison with the sustained release of a multiparticulate dosage form, prepared manually by cutting co-extrudates into mini-matrices. Analysis of the dosage forms using X-ray micro-computed tomography only detected small differences between the pore structure of the core of the calendered tablet and the mini-matrices. Diffusion path length was shown to be the main mechanism behind the release kinetics. Terahertz pulsed imaging visualized that adhesion between the core and coat of the calendered tablet was not complete and a gradient in coat thickness (varying from 200 to 600 μm) was observed. Modulated differential scanning calorimetry and X-ray diffraction indicated that the solid-state properties of both drugs were not affected by the calendering procedure.     

Measurement of the average radiation dose to the local skin and thyroid gland during intracranial aneurysm coil embolization

IntroductionIntracranial aneurysm coil embolisation is a fluoroscopically guided procedure associated with high radiation dose. The increase in the number of coil embolisation procedures raises concern for the amount of radiation and the associated radiation risks to the patients. This research study was conducted to determine the average radiation dose to patients’ thyroid glands and local skin during intracranial aneurysm coil embolisation and to establish preliminary local diagnostic reference levels for this procedure. In this paper, local skin dose refers to the absorbed radiation dose on the areas of the skin exposed to radiation during intracranial aneurysm coil embolisation, namely neck, face and scalp.MethodsThis study employed air-kerma area product meters to determine the local skin dose and diagnostic reference levels during intracranial aneurysm coil embolisation. In addition, thyroid radiation doses were measured using thermo-luminescent dosimeters on a phantom during simulation of embolisation procedures.ResultsThe local skin doses as determined by air-kerma area product ranged between 33 and 125 Gy.cm2. The mean thyroid dose was 9.87 mGy. The established local diagnostic reference level was 52.1 Gy cm², 17.8 min’ fluoroscopy time and 503 image frames.ConclusionThe average air-kerma area product values and the proposed diagnostic reference levels were lower than most published values for intracranial aneurysm coil embolisation.Implications for practiceThe established local diagnostic reference levels are recommended for use as radiation dose optimisation tool at the research site. The findings of this study cannot be generalised or applied to other hospitals. The complexity of the embolisation procedures was not classified for this study. Further research on diagnostic reference levels for intracranial aneurysm coil embolisation, taking into account the complexity of the procedures, is recommended.     

Multi-institution assessment of the use and risk of cardiovascular computed tomography in pediatric patients with congenital heart disease

BackgroundCardiac computed tomography (CT) is increasingly used in pediatric patients with congenital heart disease (CHD). Variability of practice and of comprehensive diagnostic risk across institutions is not known.MethodsFour centers prospectively enrolled consecutive pediatric CHD patients <18 years of age undergoing cardiac CT from January 6, 2017 to 1/30/2020. Patient characteristics, cardiac CT data and comprehensive diagnostic risk were compared by age and institutions. Risk categories included sedation and anesthesia use, vascular access, contrast exposure, cardiovascular medication, adverse events (AEs), and estimated radiation dose.ResultsCardiac CT was performed in 1045 pediatric patients at a median (interquartile range, IQR) age of 1.7 years (0.3, 11.0). The most common indications were arterial abnormalities, suspected coronary artery anomalies, functionally single ventricle heart disease, and tetralogy of Fallot/pulmonary atresia. Sedation was used in 8% and anesthesia in 11% of patients. Peripheral vascular access was utilized for 93%. Median contrast volume was 2 ​ml/kg. Beta blockers were administered in 11% of cases and nitroglycerin in 2% of cases. The median (IQR) total procedural dose length product (DLP) was 20 ​mGy1cm (10, 50). Sedation, vascular access, contrast exposure, use of cardiovascular medications and radiation dose estimates varied significantly by institution and age (p ​< ​0.001). Seven minor adverse events (0.7%) and no major adverse events were reported.ConclusionCardiac CT for CHD is safe in pediatric patients when appropriate CT technology and expertise are available. Scans can be acquired at relatively low radiation exposure with few minor adverse events.     

国际辅助技术服务的政策架构、核心内容和发展研究

目的 研究联合国和世界卫生组织(WHO)辅助技术服务的政策架构与核心内容,比较不同经济发展水平国家辅助技术发展现状,探讨未来辅助技术政策与服务发展。方法 基于联合国和WHO辅助技术的相关政策与理论架构,运用WHO健康服务体系构成要素的理论,分析国际辅助技术服务的政策架构与主要内容,比较全球不同经济发展水平国家辅助技术服务政策、辅助产品和服务发展,探讨国际辅助技术的政策与创新技术发展热点。结果 辅助技术服务是康复服务的重要组成部分,发展辅助技术服务是实现联合国可持续发展目标三“确保健康的生活方式,促进各年龄段人群的福祉”的关键步骤。联合国和WHO发布的辅助技术服务相关指南提供了辅助技术服务政策,其核心架构是基于联合国《残疾人权利公约》有关辅助技术内容,并具体表现在WHO《世界残疾报告》《全球残疾行动计划》《健康服务体系中的康复》和《健康服务体系中的康复：行动指南》以及WHA 71.8号有关辅助技术的决议《改善获得辅助技术的机会》等核心文件中。国际辅助技术政策核心内容旨在构建以人为本的综合保健服务,强调将辅助技术纳入公共卫生医疗体系和康复服务范畴,根据WHO健康服务的六大核心构成要素建立和发展辅助技术服务,从而提高获取优质辅助技术机会,以实现全民健康覆盖,并且在辅助产品和辅助技术服务领域,倡导技术和服务创新,形成5P辅助技术模式。高收入国家和中低收入国家在辅助技术服务政策、辅助技术产品提供以及服务覆盖率方面都面临诸多困难,存在着较大差异。未来各国辅助技术发展热点主要是采用WHO提出的5P模式进行政策和服务提供以及技术变革,辅助技术产品开发、辅助技术服务模式的创新将是未来发展的热点。结论 国际社会有关辅助技术的政策是以联合国《残疾人权利公约》为核心,并以联合国及WHO发表的辅助技术服务的相关政策文件为基础形成的,其主旨在于发展辅助技术服务,为残疾人、老年人和其他功能障碍者提供及时、适当和可负担的辅助技术服务,改善他们的健康并提升生活质量和福祉。要将辅助技术纳入全民健康覆盖,并通过初级卫生保健加强服务提供,以实现联合国可持续发展目标三全民健康覆盖的目标,实现辅助技术服务全覆盖。发展辅助技术,要将辅助技术纳入康复服务的范畴,在WHO健康服务体系的六大构成要素架构下,完善辅助技术服务的治理,通过多种机制为辅助技术服务进行筹资,培训康复人才从事辅助技术工作,改善辅助技术的服务提供,提升服务的质量,将辅助技术纳入基本医药技术,建立适应辅助技术发展的健康信息系统并对辅助技术服务提供监测。在世界不同地区,由于经济和社会发展水平的差异,辅助产品和技术服务的发展水平存在着很大差异,在获得辅助技术服务时遇到很大挑战。需要制定相关的政策、规划,并进行技术和服务创新。未来辅助技术发展将围绕辅助技术的5P模式进行产品和服务提供领域的改革以及技术创新,以提升辅助技术服务的覆盖率、有效性、可及性和可负担性,在全民健康覆盖架构下,将辅助技术服务融入健康服务体系,实现全民辅助技术服务全覆盖,提升辅助技术服务的质量和辅助技术消费者的福祉。     

Dairy consumption is associated with lower plasma dihydroceramides in women from the D.E.S.I.R. cohort

AimIn the D.E.S.I.R. cohort, higher consumption of dairy products was associated with lower incidence of hyperglycaemia, and dihydroceramide concentrations were higher in those who progressed to diabetes. Our aim here was to study the relationships between dairy consumption and concentrations of dihydroceramides and ceramides.MethodsIn the D.E.S.I.R. cohort, men and women aged 30–65 years, volunteers from West-Central France, were included in a 9-year follow-up with examinations every 3 years, including food-frequency questionnaires. Two items concerned dairy products (cheese, other dairy products except cheese). At each examination, dihydroceramides and ceramides were determined by mass spectrometry in a cohort subset; in the present study, the 105 people who did not progress to type 2 diabetes were analyzed, as the disorder per se might be a confounding factor.ResultsHigher consumption of dairy products (except cheese) was associated with total plasma dihydroceramides during the follow-up, but only in women (P = 0.01 for gender interaction). In fact, dihydroceramide levels were lower in women with high vs low consumption (P = 0.03), and were significantly increased during follow-up (P = 0.01) in low consumers only. There was also a trend for lower ceramides in women with high dairy (except cheese) intakes (P = 0.08). Cheese was associated with dihydroceramide and ceramide changes during follow-up (P = 0.04 for both), but no clear trend was evident in either low or high consumers.ConclusionThese results show that, in women, there is an inverse association between fresh dairy product consumption and predictive markers (dihydroceramides) of type 2 diabetes.