Derivation of internal dose-based thresholds of toxicological concern for occupational inhalation exposure to systemically acting organic chemicals

This study aimed at deriving occupational thresholds of toxicological concern for inhalation exposure to systemically-acting organic chemicals using predicted internal doses. The latter were also used to evaluate the quantitative relationship between occupational exposure limit and internal dose. Three internal dose measures were identified for investigation: (i) the daily area under the venous blood concentration vs. time curve, (ii) the daily rate of the amount of parent chemical metabolized, and (iii) the maximum venous blood concentration at the end of an 8-hr work shift. A dataset of 276 organic chemicals with 8-hr threshold limit values-time-weighted average was compiled along with their molecular structure and Cramer classes (Class I: low toxicity, Class II: intermediate toxicity, Class III: suggestive of significant toxicity). Using a human physiologically-based pharmacokinetic model, the three identified dose metrics were predicted for an 8-hr occupational inhalation exposure to the threshold limit value for each chemical. Distributional analyses of the predicted dose metrics were performed to identify the percentile values corresponding to the occupational thresholds of toxicological concern. Also, simple linear regression analyses were performed to evaluate the relationship between the 8-hr threshold limit value and each of the predicted dose metrics, respectively. No threshold of toxicological concern could be derived for class II due to few chemicals. Based on the daily rate of the amount of parent chemical metabolized, the proposed internal dose-based occupational thresholds of toxicological concern were 5.61?×?10^?2 and 9?×?10^?4 mmol/d at the 10th percentile level for classes I and III, respectively, while they were 4.55?×?10^?1 and 8.5?×?10^?3 mmol/d at the 25th percentile level. Even though high and significant correlations were observed between the 8-hr threshold limit values and the predicted dose metrics, the one with the rate of the amount of chemical metabolized was remarkable regardless of the Cramer class (r² = 0.81; n = 276). The proposed internal dose-based occupational thresholds of toxicological concern are potentially useful for screening-level assessments as well as prioritization within an integrated occupational risk assessment framework.     

Use of different combination diphtheria-tetanus-acellular pertussis vaccines does not increase risk of 30-day infant mortality. A population-based linkage cohort study using administrative data from the Australian Childhood Immunisation Register and the National Death Index.

Objective

To determine whether differences in combination DTaP vaccine types at 2, 4 and 6?months of age were associated with mortality (all-cause or non-specific), within 30?days of vaccination.

Safety profile of the adjuvanted recombinant zoster vaccine: Pooled analysis of two large randomised phase 3 trials

Background

The ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) phase 3 clinical trials showed that the adjuvanted recombinant zoster vaccine (RZV) was ≥90% efficacious in preventing herpes zoster in adults. Here we present a comprehensive overview of the safety data from these studies.

Tester and testing procedure influence clinically determined gait speed

BackgroundThere is a clinical need to be able to reliably detect meaningful changes (0.1 to 0.2 m/s) in usual gait speed (UGS) considering reduced gait speed is associated with morbidity and mortality.Research questionWhat is the impact of tester on UGS assessment, and the influence of test repetition (trial 1 vs. 2), timing method (manual stopwatch vs. automated timing), and starting condition (stationary vs. dynamic start) on the ability to detect changes in UGS and fast gait speed (FGS)?MethodsUGS and FGS was assessed in 725 participants on a 8-m course with infrared timing gates positioned at 0, 2, 4 and 6 m. Testing was performed by one of 13 testers trained by a single researcher. Time to walk 4-m from a stationary start (i.e. from 0-m to 4-m) was measured manually using a stopwatch and automatically via the timing gates at 0-m and 4-m. Time taken to walk 4-m with a dynamic start was measured during the same trial by recording the time to walk between the timing gates at 2-m and 6-m (i.e. after 2-m acceleration).ResultsTesters differed for UGS measured using manual vs. automated timing (p = 0.02), with five and two testers recording slower and faster UGS using manual timing, respectively. 95% limits of agreement for trial 1 vs. 2, manual vs. automated timing, and dynamic vs. stationary start ranged from ±0.15 m/s to ±0.20 m/s, coinciding with the range for a clinically meaningful change. Limits of agreement for FGS were larger ranging from ±0.26 m/s to ±0.35 m/s.SignificanceRepeat testing of UGS should performed by the same tester or using an automated timing method to control for tester effects. Test protocol should remain constant both between and within participants as protocol deviations may result in detection of an artificial clinically meaningful change.     

Immediate effects and associations between interoceptive accuracy and range of motion after a HVLA thrust on the thoracolumbar junction: A randomised controlled trial

BackgroundThere is paucity in the literature regarding the role of interoceptive accuracy (IAc) at predicting the effectiveness of osteopathic techniques which increase spinal mobility when directed specifically at the thoracolumbar junction (TLJ).AimsThe study aimed to explore whether a high velocity, low amplitude (HVLA) thrust of the TLJ would increase spinal mobility (measured through Range of Motion; ROM) and change IAc. Also, whether baseline IAc correlated with the post-ROM measures and change in ROM.Method21 asymptomatic participants were allocated into three conditions in a randomised order. These were; (1) a high velocity low amplitude manipulation of the TLJ; (2) sham (basic touch); and (3) a control (laying supine on a plinth). Before and following each intervention, the participants’ spinal ROM was measured using an Acumar digital inclinometer. In addition to this an ECG was used to measure their pre and post condition IAc.ResultsThere were significant increases in ROM for all condition, however, the HVLA thrust led to a significantly greater increase in ROM (p < 0.001) when compared to the control and sham. Baseline IAc was inversely associated with post-ROM but there was no association with change in ROM. The HVLA thrust did not significantly change IAc scores from pre to post intervention. Conclusions. HVLA thrust over the TLJ is a useful intervention for increasing spinal ROM. IAc maybe a useful predictor for intervention effectiveness of this technique and spinal area which could in the future be utilised by osteopaths as part of their diagnostics.     

基于家庭的心理治疗对强迫障碍治疗的研究进展

强迫障碍(obsessive-compulsive disorder,OCD)是常见的难治性精神疾病,经过心理治疗和药物治疗仅有40%~60%患者获得缓解,患者残留各种症状和功能障碍。心理治疗是OCD治疗的重要组成部分,家庭因素在疾病的发生、维持和预后中起重要作用,以家庭为基础的心理治疗越来越受到重视。文章就对OCD采用基于家庭的心理治疗的必要性和进展进行综述,研究显示患者家属的精神心理状态和家庭顺应性等因素与OCD治疗效果密切相关,而家庭成员高度参与,针对家庭因素干预的基于家庭的心理治疗策略可以增强治疗效果,改善患者家庭功能。文章为强迫障碍的临床优化治疗提供了实践依据。     

Trade-offs between acquired and innate immune defenses in humans

Immune defenses provide resistance against infectious disease that is critical to survival. But immune defenses are costly, and limited resources allocated to immunity are not available for other physiological or developmental processes. We propose a framework for explaining variation in patterns of investment in two important subsystems of anti-pathogen defense: innate (non-specific) and acquired (specific) immunity. The developmental costs of acquired immunity are high, but the costs of maintenance and activation are relatively low. Innate immunity imposes lower upfront developmental costs, but higher operating costs. Innate defenses are mobilized quickly and are effective against novel pathogens. Acquired responses are less effective against novel exposures, but more effective against secondary exposures due to immunological memory. Based on their distinct profiles of costs and effectiveness, we propose that the balance of investment in innate versus acquired immunity is variable, and that this balance is optimized in response to local ecological conditions early in development. Nutritional abundance, high pathogen exposure and low signals of extrinsic mortality risk during sensitive periods of immune development should all favor relatively higher levels of investment in acquired immunity. Undernutrition, low pathogen exposure, and high mortality risk should favor innate immune defenses. The hypothesis provides a framework for organizing prior empirical research on the impact of developmental environments on innate and acquired immunity, and suggests promising directions for future research in human ecological immunology.     

探究培美曲塞与多西他赛在晚期非小细胞肺癌靶向治疗失败后挽救化疗中的临床疗效

目的 研究培美曲塞与多西他赛在晚期非小细胞肺癌靶向治疗失败后挽救化疗中的应用效果。方法 筛选2018 年1 月～2020 年1 月本院的60 例晚期非小细胞肺癌靶向治疗失败后挽救化疗的患者作为研究对象，依据患者选择的药物种类分为观察组和对照组，每组各30 例，对照组采用多西他赛治疗，观察组予以培美曲塞治疗，对比分析两组的近期治疗效果、生存质量评分和毒副反应发生情况。结果 观察组病症控制率为66.67%，对照组病症控制率为36.67%，观察组病症控制效果更好；观察组生存质量评分为（65.2±3.4）分，对照组生存质量评分为（51.7±4.6）分，两组比较差异有统计学意义（t=12.926，P=0.000）；观察组各项毒副反应发生率均低于对照组，差异有统计学意义（P＜0.05）。结论 在晚期非小细胞肺癌靶向治疗失败后进行挽救化疗中选用培美曲塞有更好的治疗效果，可以较好的进行临床治疗，改善患者的生活质量，且产生的毒副反应较少，在实际临床中的应用价值较高。