Tolerability and Safety of a Novel Ketogenic Ester,Bis-Hexanoyl (R)-1,3-Butanediol: A Randomized Controlled Trial in Healthy Adults

Nutritional ketosis is a state of mildly elevated blood ketone concentrations resulting from dietary changes (e.g., fasting or reduced carbohydrate intake) or exogenous ketone consumption. In this study, we determined the tolerability and safety of a novel exogenous ketone diester, bis-hexanoyl-(R)-1,3-butanediol (BH-BD), in a 28-day, randomized, double-blind, placebo-controlled, parallel trial ({"type":"clinical-trial","attrs":{"text":"NCT04707989","term_id":"NCT04707989"}}NCT04707989). Healthy adults (n = 59, mean (SD), age: 42.8 (13.4) y, body mass index: 27.8 (3.9) kg/m²) were randomized to consume a beverage containing 12.5 g (Days 0–7) and 25 g (Days 7–28) of BH-BD or a taste-matched placebo daily with breakfast. Tolerability, stimulation, and sedation were assessed daily by standardized questionnaires, and blood and urine samples were collected at Days 0, 7, 14, and 28 for safety assessment. There were no differences in at-home composite systemic and gastrointestinal tolerability scores between BH-BD and placebo at any time in the study, or in acute tolerability measured 1-h post-consumption in-clinic. Weekly at-home composite tolerability scores did not change when BH-BD servings were doubled. At-home scores for stimulation and sedation did not differ between groups. BH-BD significantly increased blood ketone concentrations 1-h post-consumption. No clinically meaningful changes in safety measures including vital signs and clinical laboratory measurements were detected within or between groups. These results support the overall tolerability and safety of consumption of up to 25 g/day BH-BD.     

Instrumental variables estimation and inference in the presence of many exogenous regressors

Summary We consider a standard instrumental variables model contaminated by the presence of a large number of exogenous regressors. In an asymptotic framework where this number is proportional to the sample size, we study the impact of their ratio on the validity of existing estimators and tests. When the instruments are few, the inference using the conventional 2SLS estimator and associated t and J statistics, as well as the Anderson–Rubin and Kleibergen tests, is still valid. When the instruments are many, the LIML estimator remains consistent, but the presence of many exogenous regressors changes its asymptotic variance. Moreover, the conventional bias correction of the 2SLS estimator is no longer appropriate. We provide asymptotically correct versions of bias correction for the 2SLS estimator, derive its asymptotically correct variance estimator, extend the Hansen–Hausman–Newey LIML variance estimator to the case of many exogenous regressors, and propose asymptotically valid modifications of the J overidentification tests based on the LIML and bias‐corrected 2SLS estimators.     

Ezetimibe

Ezetimibe is a cholesterol absorption inhibitor that significantly lowers low- density lipoprotein cholesterol (LDL-C), and favourably affects triglyceride and high-density lipoprotein cholesterol blood levels in monotherapy and in combination with statins. Hepatic and extrahepatic (peripheral) cholesterol synthesis are well-known sources of cholesterol found in LDL-C. However, the emergence of ezetimibe has highlighted intestinal cholesterol absorption as an additional, important source of cholesterol in LDL-C, and has better illuminated how genetic factors, dietary content, pharmaceutical agents, and nuclear receptor activation (such as liver X receptors) all influence the relative contribution of these important cholesterol sources to LDL-C. In fact, investigations into ezetimibe have sometimes challenged existing scientific dogma, has prompted reconsideration of older data, and has helped create ‘new’ paradigms in cholesterol metabolism. Thus, ezetimibe's efficacy, excellent tolerability, and safety has not only expanded potential treatment options for dyslipidaemic patients, but also has promoted exploration of new frontiers of lipid research towards a better understanding of cholesterol metabolism.     

Drinking patterns within households: the estimation and interpretation of individual and group variables

Levels of alcohol consumption tend to be similar for individuals living in the same household. This may be because: (a) individuals with similar characteristics collect in households (correlated effects); (b) individuals in the same household are influenced by common factors (exogenous effects); and/or (c) the consumption levels of an individual directly influences the consumption levels of other individuals in the same household (endogenous effects). Whichever of these three possibilities is the principal reason underlying household clustering of consumption levels has important policy implications. In this paper we propose a testing strategy to distinguish between the three types of effect in a cross-sectional data-set. Allowing for exogenous or endogenous effects shows that the significant socio-economic gradient in a model containing only individual variables arises because of misspecification. However, because we find significant evidence of correlated effects, we cannot identify whether it is endogenous or exogenous effects which give rise to statistically significant group level variables. The results indicate the possible pitfalls of omitting group level influences.Copyright © 1998 John Wiley & Sons, Ltd.     

双氢青蒿素诱导肿瘤细胞铁死亡及其机制研究

目的阐明双氢青蒿素(DHA)诱导肿瘤细胞铁死亡的作用及其机制。方法利用3,3′,5,5′-四甲基联苯胺(TMB)检测DHA与FeSO_4体外芬顿样(Fenton)反应生成氧自由基(·OH)的能力;MTT法检测DHA对人肝癌HepG2细胞的毒性(包括FeSO_4与去铁胺预处理组)。MTT法考察谷胱甘肽(GSH)与铁死亡抑制剂(Fer-1)对DHA细胞毒性的影响;采用DCFH-DA染料考察DHA(包括FeSO_4预处理组)诱导的细胞内活性氧的生成能力;采用C11-BODIPY581/591与DiO分别考察DHA(包括FeSO_4预处理组)对细胞内脂质过氧化物生成能力以及细胞膜结构的影响;利用谷胱甘肽过氧化物酶4(GPX-4)试剂盒测定DHA(包括FeSO_4预处理组)对HepG2细胞内GPX-4活性的影响。结果 Fe~(2+)能够催化DHA发生芬顿样反应并生成·OH;DHA的半数抑制浓度(IC_(50))为(39.96±8.78)μmol/L,FeSO_4与去铁胺分别能够增加或者降低DHA的细胞毒性;DHA处理后细胞内活性氧含量与脂质过氧化物含量升高,细胞形态变大,细胞膜呈散点状分布并呈现解离状态。FeSO_4预处理组与DHA组相比较进一步增加细胞内活性氧含量与脂质过氧化物含量,并且细胞膜形态完全破坏。FeSO_4能够增强DHA对GPX-4活性的抑制作用。结论 DHA通过芬顿样反应升高细胞内活性氧而最终诱导肿瘤细胞铁死亡。另外,外源性铁可以加速DHA发生芬顿样反应进而加速肿瘤细胞铁死亡的发生与发展。     

An investigational tetravalent meningococcal serogroups A, C, W-135 and Y-tetanus toxoid conjugate vaccine co-administered with Infanrix™ hexa is immunogenic, with an acceptable safety profile in 12-23-month-old children

Tetravalent meningococcal serogroups ACWY conjugate vaccines will provide an advantage to those at most risk of invasive meningococcal disease; namely young children. Co-administration of ACWY-TT with DTaP-HBV-IPV/Hib was assessed in a randomized trial in 793 children aged 12-23 months. Pre-specified criteria for non-inferiority of immunogenicity following co-administration versus separate ACWY-TT and DTaP-HBV-IPV/Hib administration were reached. One month post-vaccination, ≥97.3% of ACWY-TT vaccinees had rSBA titres ≥1:8 (all serogroups). Seroprotection/seropositivity rates against DTaP-HBV-IPV/Hib antigens were ≥98.2%. The safety profile of co-administration was similar to that of DTaP-HBV-IPV/Hib alone. ACWY-TT and DTaP-HBV-IPV/Hib co-administration during the second year would facilitate introduction of ACWY-TT into routine toddler vaccination schedules.     

从湿论治过敏性鼻炎探賾

过敏性鼻炎属于临床常见的过敏性疾病之一,其病因病机复杂难辨.湿邪伤人多从口鼻而入,不仅影响鼻的生理功能,又内伤五脏六腑,易致过敏性鼻炎发作.文章从湿邪与过敏性鼻炎的相关性进行探讨,认为无论外湿或内湿皆可引发过敏性鼻炎.其旨在充实中医湿邪致病理论的同时,亦为临床防治过敏性鼻炎提供一定的研究方向.     

中药退热煎剂足浴法辅助治疗小儿外感发热的疗效观察

目的：观察中药退热煎剂足浴法对小儿外感发热的临床疗效。方法：采用随机、对照法,将外感发热患儿120例随机分为治疗组和对照组各60例,在常规抗炎抗病毒等治疗基础上,分别进行中药退热煎剂足浴法和冰力降温贴的辅助治疗,采用卡方检验和t检验比较2组的总有效率、治疗后0．5、1、1．5小时体温变化及降温幅度,并观察2组用药后24、48、72小时的退热疗效。结果：2组治疗总有效率分别为治疗组71．67％,对照组46．67％,两者之间差异显著（P〈0．01）;用药1．5小时后治疗组退热效果优于对照组,差异显著（P〈0．01）;2组体温下降幅度比较,治疗组显著高于对照组,差异有统计学意义（P〈0．05）．结论：中药退热煎剂足浴法治疗小儿外感发热,退热快,体温不宜复升,经济、方便且副作用小。     

清营解表法与温病传统辨治体系关系研究

从卫气营血和三焦辨证论治角度探讨清营解表法与温病传统辨治体系的关系。认为运用复杂性辨证思维,结合当今环境、体质的时代特征,动态把握外感病之传变规律而提出的"营热体质外感"及"清营解表法"理论,是对温病传统理论、治法和药物运用原则的突破和创新,丰富了当今外感病的辨证论治内容。     

Definition and classification of eczemas--a pertinent challenge to dermatologists

Since, in dermatological literature, the term ‘dermatitis’ is frequently confused with ‘eczema’, is has to be unequivocally stated that ‘dermatitis’ is a generic term covering very different patterns of dermal inflammation, whereas ‘eczema’ (or ‘eczematous dermatitis’, resp.) represents a distinct pattern of superficial dermatitis histologically characterized by spongiotic dermo-epidermitis. Eczemas can be defined as inflammatory, non-infectious intolerance reactions of the epidermo-papillary skin compartment with reversible epidermotropic exudation caused by an immense variety of external and/or internal agents combined with increased individual susceptibility to respond. As current classifications only partially reflect the complex causative conditions involved in the etiology and pathodynamics of eczematous disease, the author proposes to classify eczemas according to the following major categories: 1) Mainly exogenous eczemas including those of contact-induced non-allergic, allergic and photo-allergic origin, 2) mainly endogenous (or atopic, resp.) eczemas, and 3) eczemas of combined dysregulatory-microbial origin. The latter group comprises eczemas caused by various functional and/or structural derangements of epidermal protective properties (summarized by the term ‘dysregulation’) which in turn permit the resident and/or transient microflora of the damaged horny layer to induce eczematous inflammatory responses. Since topical and morphological attributes may change during the course of the very same eczema, they are inappropriate for basic classification and should be used only as minor criteria for characterizing the sites and predominant lesional type of the respective eczema. The possible combination of eczemas representing two or even three major categories in one patient leads to intermediate forms entirely in keeping with the division into three principal groups. The proposed classification is aimed at eliminating the terminological confusion of eczemas as well as enabling reliable documentation for statistics which can be used in computer-aided comparisons of multicenter studies on etiology or epidemiology of eczemas.