Longitudinal validity of PET‐based staging of regional amyloid deposition

Positron emission tomography (PET)‐based staging of regional amyloid deposition has recently emerged as a promising tool for sensitive detection and stratification of pathology progression in Alzheimer's Disease (AD). Here we present an updated methodological framework for PET‐based amyloid staging using region–specific amyloid‐positivity thresholds and assess its longitudinal validity using serial PET acquisitions. We defined region‐specific thresholds of amyloid‐positivity based on Florbetapir‐PET data of 13 young healthy individuals (age ≤ 45y), applied these thresholds to Florbetapir‐PET data of 179 cognitively normal older individuals to estimate a regional amyloid staging model, and tested this model in a larger sample of patients with mild cognitive impairment (N = 403) and AD dementia (N = 85). 2‐year follow‐up Florbetapir‐PET scans from a subset of this sample (N = 436) were used to assess the longitudinal validity of the cross‐sectional model based on individual stage transitions and data‐driven longitudinal trajectory modeling. Results show a remarkable congruence between cross‐sectionally estimated and longitudinally modeled trajectories of amyloid accumulation, beginning in anterior temporal areas, followed by frontal and medial parietal areas, the remaining associative neocortex, and finally primary sensory‐motor areas and subcortical regions. Over 98% of individual amyloid deposition profiles and longitudinal stage transitions adhered to this staging scheme of regional pathology progression, which was further supported by corresponding changes in cerebrospinal fluid biomarkers. In conclusion, we provide a methodological refinement and longitudinal validation of PET‐based staging of regional amyloid accumulation, which may help improving early detection and in‐vivo stratification of pathologic disease progression in AD.     

The secrets of human stem cell-derived transfusable RBC for targeted large-scale production and clinical applications: A fresh look into what we need most and lessons to be learned

Blood transfusion, using the safest conventional blood bioproducts, is an irreplaceable part of substitution therapy. It is considered the most essential supportive clinical intervention aimed to restore the health of patients in need. Nevertheless, numerous unresolved problems are still associated with current blood substitution therapy. To alleviate our dependency on blood donors, many investigators have been focusing on the quest for stem cell-derived blood cells in line with major developments in the field of regenerative medicine. The main objective is to provide a safe and highly standardized universal cultured red cell concentrate [CRBC] for all clinical applications, regardless of blood groups. Currently, we are close to overcoming some of the main obstacles in culturing cells. This concise report is a prelude to the immortalized cell lines that are ready for in vivo clinical trials. It is only through the sharing of experimental ideas and knowledge-based strategies that we will be able to achieve such an enormous task and better understand ‘’the one for all concept’’ of CRBCs and their universal usage in all clinical settings.     

黄连解毒汤治疗新型冠状病毒肺炎(COVID-19)重型气营两燔证的中医方证关系及药理研究进展

自新型冠状病毒肺炎(COVID-19)疫情暴发以来,国家卫生健康委员会及各地相关单位陆续发布多个诊疗方案,其中重症期治疗推荐方剂中黄连解毒汤的中医证侯与《新型冠状病毒肺炎诊疗方案(试运行第七版)》中重型气营两燔证相应,可用于治疗气营两燔证。气营两燔证津液营阴耗损、正不敌邪,气营热毒炽盛,黄连解毒汤清热解毒,可通过祛邪达到扶正护阴的治疗目的。现代药理研究表明黄连解毒汤在治疗COVID-19重型气营两燔证中具有潜在的抗炎解热、抗病毒、抗氧化、调节机体免疫力、保护脏器组织等作用。通过对COVID-19重型气营两燔证的病机演变、黄连解毒汤的方证关系及现代药理作用进行梳理,分析黄连解毒汤治疗重型气营两燔证的中医方证关系及现代药理学基础,以期为黄连解毒汤用于COVID-19重型气营两燔证的有效治疗提供依据。     

How is safety of dermatology drugs assessed: trials,registries, and spontaneous reporting

ABSTRACT

Introduction: Skin conditions are common and highly varied in their etiology; therefore, a diverse array of therapeutics are utilized. Drug safety studies in dermatology can be challenging as there are over 3000 diagnoses to consider. As a result, dermatologists rely on data from multiple sources including clinical trials and real-world evidence.

Areas covered: In this review, we cover the main sources of safety data available, their strengths and weaknesses and how dermatologists should utilize such data. We use real-world examples of the different types of adverse events reported and how they are best captured by either randomized controlled trials or post-marketing pharmacovigilance methods. With multiple new therapies in dermatology, such as dupilumab for atopic dermatitis and janus-kinase inhibitors for alopecia areata the specialty is awash with evolving high-level evidence for their use. It is important to understand the optimal way to assess safety from trials but also appreciate the need for ongoing capture of safety data in clinical practice.

Expert opinion: In dermatology, there is a plethora of conditions to treat and clinical trials, post-marketing surveillance, such as drug registries and spontaneous reporting, all enable dermatologists to gain a more comprehensive understanding of the safety profiles of drugs being used.     

补肺逐瘀汤联合常规治疗对稳定期慢性阻塞性肺疾病患者的临床疗效

目的探讨补肺逐瘀汤联合常规治疗对稳定期慢性阻塞性肺疾病患者的临床疗效。方法144例患者随机分为对照组和观察组,每组72例,对照组给予常规治疗(沙美特罗替卡松、常规康复训练),观察组在对照组基础上加用补肺逐瘀汤,疗程12周。检测临床疗效、肺功能指标[每分钟最大通气量占预计值百分比(MVV%pred)、第1秒用力呼气容积(FEV1)与用力肺活量(FVC)比值(FEV1/FVC)、一氧化碳弥散量(DLCO)与肺泡通气量(VA)比值(DLCO/VA)、FEV1占预计值百分比(FEV1%pred)]、活动耐力指标[6 min步行距离(6MWD)]、中医证候评分、气道黏液分泌相关指标[咳嗽、咳痰评分及诱导痰中基质金属蛋白酶⁃9(MMP⁃9)、中性粒细胞弹性蛋白酶(NE)]、不良反应发生率变化。结果观察组总有效率高于对照组(P<0.05)。治疗后,2组肺功能指标升高(P<0.05),中医证候评分、气道黏液分泌相关指标降低(P<0.05),以观察组更明显(P<0.05)。2组不良反应发生率比较差异无统计学意义(P>0.05)。结论补肺逐瘀汤联合常规治疗能有效缓解稳定期慢性阻塞性肺疾病患者肺气虚兼血瘀证相关症状,改善肺功能,增强活动耐力,抑制气道黏液高分泌,安全性较高。     

含功能性油的水飞蓟宾超饱和自纳米乳的制备与体外评价

目的制备含功能性油的水飞蓟宾超饱和自纳米乳(SLB-S-SNEDDS),并对其进行表征及体外评价研究,以提高难溶性药物水飞蓟宾的生物利用度。方法铁氢化钾还原力与1,1-二苯基-2-苦肼基(DPPH)自由基清除实验筛选功能性油脂;伪三元相图考察乳化剂乳化能力;测定粒径、多分散指数(PDI)、Zeta电位等考察混合油相比例与载药量;相容性与溶出度实验筛选促过饱和物质并考察其质量浓度;从外观、粒径分布、自乳化效率、形态学等方面表征SLB-S-SNEDDS,并进行溶出度、抗氧化能力、细胞毒性等体外评价。结果所得SLB-S-SNEDDS处方为(1)小麦胚芽油/Capryol 90-Cremophor ELP-Transcutol HP与(2)沙棘籽油/Capryol 90-Cremophor ELP-Transcutol HP,1 g基质(包含0.043 g小麦胚芽油或沙棘籽油、0.387 g Capryol 90、0.380 g Cremophor ELP、0.190 g Transcutol HP),水飞蓟宾的添加量为各组分平衡溶解度之和的20%,Soluplus的添加量为上述总质量的0.1%。小麦胚芽油、沙棘籽油体系分别为淡黄色、亮黄色透明状均一液体,2种体系自乳化分散后均呈近球形白色扁平乳滴,粒径约为50 nm,乳化时间均为65 s。与药物原料及SLB-SNEDDS相比,SLB-S-SNEDDS中水飞蓟宾的累积溶出率8h内均维持在85%～110%,表明该体系能够显著提高药物的溶出度。SLB-S-SNEDDS与铁氰化钾反应后的吸光度(A值0.452～0.782,0.488～0.765)以及DPPH自由基清除率(39.09%～96.02%,30.54%～89.20%)均高于相应质量浓度下水飞蓟宾原料的A值与清除率(0.411～0.760,22.89%～63.21%),表明2种处方体系均能提高水飞蓟宾的抗氧化能力。细胞毒性实验结果显示,在5、10μmol/L药物浓度下,水飞蓟宾原料组、水飞蓟宾S-SNEDDS组及其相应的空白S-SNEDDS组细胞生存率均90%,说明SLB-S-SNEDDS及其所用辅料对人克隆结肠腺癌细胞(Caco-2)毒性较小、安全性较好。结论制备的含功能性油SLB-S-SNEDDS在提高水飞蓟宾累积溶出率的同时,增强了其抗氧化能力,为将超饱和自纳米乳(S-SNEDDS)用于改善难溶性药物水溶性及其生物活性提供有益参考。     

Best Practices for Counseling Adolescents about the Etonogestrel Implant

Among young persons, ease of use, high efficacy, and high acceptability makes the etonogestrel contraceptive implant an important choice for this age group. Adolescent-friendly, patient-centered counseling considers the patient's cognitive development, the influence of friends and family, as well as their own preferences and values. Age-appropriate language, graphics, and models are useful to explain contraceptive options and relevant side effects. Effectiveness, reversibility, safety, noncontraceptive benefits, and side effects are important attributes and should be discussed when teens are choosing a contraceptive method. In this review we describe suggested best practices for counseling adolescents about the etonogestrel implant so they can make informed, prudent decisions about using this contraceptive method.     

Droit à mourir et suicide assisté : état des lieux et analyse critique

ObjectivesIn the context of the present re-examination of the French bioethical laws by the National Advisory Ethics Committee (“Comité consultatif national d’éthique”: CCNE), a recent survey indicated a request of the public opinion to obtain a medical aid in end of life and a so-called “assisted suicide”. This led psychiatrists to re-consider their role and deontological position which usually led them to consider a request for an assistance in suicide as – a priori – a pathological demand, occurring within a suicidal crisis. The present article intends to: 1) describe the laws and practices of countries which allow medically assisted end of life help procedures; 2) clarify the definitions of “assisted suicide”, “assistance to suicide” and “euthanasia”; 3) consider available epidemiological data and the roles given to doctors and, more specifically psychiatrists, in these procedures; 4) analyse the rationale behind these demands. These considerations should enable French psychiatrists to clarify their position when facing requests for a medical aid in dying.MethodsFour European countries (Switzerland, the Netherlands, Belgium, Luxemburg) and Oregon (the first US state to introduce legislation) were considered, since they accumulated and published a large amount of experiences and data about “assisted suicide” and medical help in dying. In total, 127 articles were selected, mainly from PubMed and Cairn databases, published between 1997 and 2020. These articles deal with legal considerations, epidemiological data, ethical and sociological considerations.ResultsLaws and practices differ notably according to the state/country. In Belgium, the Netherlands and Luxemburg, as in Oregon, the medical help in dying has been de-criminalized, as long as certain legal criteria are met. In Switzerland, where no specific law exists in the penal code, non-governmental associations have benefited from the legal vacuum and organized the practice of “assisted suicide” for “altruistic motives”. In the scientific and legal literature, the terms used to describe and define the medical help in dying upon request differ greatly. In France, the National Advisory Ethics Committee defines euthanasia (“euthanasie”), assisted suicide (“suicide assisté”) and suicide assistance (“assistance au suicide”). Available epidemiological data, whatever the country considered, indicate that requests for a medical aid in dying are expressed mainly by patients aged over 60 years and suffering from cancer. Psychiatric diseases account for only 1% to 3%. Most often, systematic assessment by a psychiatrist is neither requested nor made, when the demand does not occur during a primary psychiatric illness. In the case of an existing primary psychiatric pathology, a psychiatrist assesses the case against formal legal predefined criteria. This latter practice was only recently introduced, after some feedback and after legal actions had been brought to Court. When the underlying motivations of the request are considered, it appears that, even in the absence of an evolving psychiatric condition, several psychological or psychopathological reasons prevail such as spirituality, attachment style, social isolation, despair, depression… which should greatly benefit psychiatric exploration, investigation and expertise.ConclusionIn some countries, the request for medically assisted help in dying has become a legal and social reality. In France, where the public debate is still open, it should be emphasized that a psychiatric assessment and interview should be systematically provided to any person requesting medical assistance to die or commit suicide. It is the commitment of psychiatrists to understand the implicit demands and unexpressed motives underlying this request which have strong links with the unique life-events and emotional experiences of the person. The psychiatrist has a unique role in the contextualization of such a request.