In Vitro-In Vivo Extrapolation and Hepatic Clearance-Dependent Underprediction

Accurately predicting the hepatic clearance of compounds using in vitro to in vivo extrapolation (IVIVE) is crucial within the pharmaceutical industry. However, several groups have recently highlighted the serious error in the process. Although empirical or regression-based scaling factors may be used to mitigate the common underprediction, they provide unsatisfying solutions because the reasoning behind the underlying error has yet to be determined. One previously noted trend was intrinsic clearance-dependent underprediction, highlighting the limitations of current in vitro systems. When applying these generated in vitro intrinsic clearance values during drug development and making first-in-human dose predictions for new chemical entities though, hepatic clearance is the parameter that must be estimated using a model of hepatic disposition, such as the well-stirred model. Here, we examine error across hepatic clearance ranges and find a similar hepatic clearance-dependent trend, with high clearance compounds not predicted to be so, demonstrating another gap in the field.     

不同规格怀牛膝不同极性部位HPLC指纹图谱

目的研究并比较不同规格怀牛膝不同极性部位的HPLC指纹图谱,探索其内部质量差异,为该药材的规格标准完善及临床用药提供参考。方法将怀牛膝用体积分数75%乙醇水浴回流提取,得体积分数75%乙醇回流提取物,用40 mL水溶解后,依次用石油醚、三氯甲烷、乙酸乙酯、正丁醇进行萃取,得到各萃取相及萃取后的水相,浓缩至浸膏,采集各部位HPLC指纹图谱;运用相似度、综合聚类法进行数据分析,同时对其不同部位的指纹图谱进行比对分析。结果石油醚、氯仿部位均标定了11个共有峰,乙酸乙酯部位标定了10个共有峰,正丁醇部位标定了19个共有峰,水部位标定8个共有峰;氯仿部位指纹图谱相似度差异较大,其他部位指纹图谱相似度差异较小,均在0.9以上;石油醚部位指纹图谱差异主要体现在峰高,乙酸乙酯部位、氯仿部位、水部位的化学成分种类及峰高均存在差异;综合聚类分析能将不同规格怀牛膝区分开。结论不同规格怀牛膝内部质量存在差异;实验中所建立的HPLC指纹图谱可以全面反映不同规格怀牛膝的化学成分分布,为不同规格怀牛膝的整体质量评价提供参考。     

Sequential Therapy Based on Evolvement of Patterns: A New Model for Treatment of Alzheimer’s Disease

In order to solve the problem of long-term (>9 months) efficacy in the treatment of Alzheimer''s disease (AD) by conventional therapy (CT), a staged and multiply-targeted sequential therapy based on the evolvement of patterns (STEP) was developed. Its main innovations include: (1) the time order of evolution of patterns defined by Chinese medicine (CM) in AD was found, that is, "the orderly pattern evolution starting from Shen (Kidney) deficiency, progressing to phlegm, stasis and fire, and worsening to severe toxin as well as functional collapse"; (2) the cascade hypothesis of Shen deficiency in AD and its sequential therapy based on Shen-reinforcing was proposed, that is, "reinforcing Shen in the early stage and throughout the whole process, resolving phlegm, activating blood and purging fire in the middle stage, detoxifying and replenishing vitality to stop the collapse in the advanced stage", and through meta-analysis, clinical drug use was optimized, thus the leap from "inferential selection" to "evidence-based selection" was realized; (3) the STEP regimen combined with CT maintained cognitive and behavioral stability in AD patients for at least 12 months, with cognitive enhancement and behavioral synergy after 9 months, and cognitive benefit was superior to CT at 9, 12, 15, 18, 21, and 24 months, respectively. The 2-year cognitive improvement rate was increased by 25.64% (P=0.020) and the cognitive deterioration rate was decreased by 48.71% (P=0.000). Among them, the cognitive and functional benefits of Shen-reinforcing therapy for very early AD (350 cases) for 1 year were better than the placebo (P<0.001), and the dementia conversion rate was reduced by 8.85% (P=0.002). The behavioral symptomatic relief of patients with vascular dementia received fire-purging therapy (540 cases) was superior to those received CT (P=0.016). These data suggested that the STEP regimen has synergistic effects on CTs at least in terms of cognitive benefit, and the earlier the use, the greater the benefit will have. Therefore, the STEP regimen should be considered as one of the clinical options, particularly for the dearth of effective pharmaceutical or immunological interventions that are currently available for AD.     

Intussusception in a premature neonate: A rare and often misdiagnosed clinical entity

Intussusception is a very rare cause of intestinal obstruction in neonates. It is of extremely rare occurrence among premature neonates. We present a case of 11-day-old premature neonate who presented with abdominal distension, intolerance to feeds, vomiting, significant bilious aspirate and bleeding per rectum. The initial diagnosis of necrotizing enterocolitis (NEC) led to a delay in the diagnosis. On exploratory laparotomy, it turned out to be a case of ileo-colic intussusception with Meckel''s diverticulum as a lead point. This site of intussusception (ileo-colic) and presence of a lead point among premature neonate is of exceedingly rare occurrence and very few such cases have been reported.In this article, the published work about clinical features and management on intussusceptions in premature neonates has been reviewed. The authors intend to highlight the difficulty in distinguishing the NEC and intussusception. Subtle clinical and radiological features which can help in differentiating the two conditions have been emphasized. This can avoid the delay in diagnosis and management which can prove critical. High index of suspicion with timely intervention is the key for optimizing outcome. A diagnosis of intussusception should always be considered in any preterm infant with suspected NEC.     

Risk communication in a patient decision aid for radiotherapy in breast cancer: How to deal with uncertainty?

Background and aimPatient decision aids for oncological treatment options, provide information on the effect on recurrence rates and/or survival benefit, and on side-effects and/or burden of different treatment options. However, often uncertainty exists around the probability estimates for recurrence/survival and side-effects which is too relevant to be ignored. Evidence is lacking on the best way to communicate these uncertainties. The aim of this study is to develop a method to incorporate uncertainties in a patient decision aid for breast cancer patients to support their decision on radiotherapy.MethodsFirstly, qualitative interviews were held with patients and health care professionals. Secondly, in the development phase, thinking aloud sessions were organized with four patients and 12 health care professionals, individual and group-wise.ResultsConsensus was reached on a pictograph illustrating the whole range of uncertainty for local recurrence risks, in combination with textual explanation that a more exact personalized risk would be given by their own physician. The pictograph consisted of 100 female icons in a 10 x 10 array. Icons with a stepwise gradient color indicated the uncertainty margin. The prevalence and severity of possible side-effects were explained using verbal labels.ConclusionsWe developed a novel way of visualizing uncertainties in recurrence rates in a patient decision aid. The effect of this way of communicating risk uncertainty is currently being tested in the BRASA study (NCT03375801).     

妊娠早期糖化血红蛋白联合PAPP-A对妊娠期糖尿病的预测意义

目的:探讨妊娠早期血清学指标糖化血红蛋白(glycohemoglobin,HbA1c)联合妊娠相关血浆蛋白A(pregnancy-associated plasma protein A,PAPP-A)对妊娠期糖尿病(gestational diabetes mellitus,GDM)的预测意义。方法:随机选取2018年12月1日-2019年7月30日孕11~13+6周于我院门诊产检的妊娠妇女,进行临床资料采集并记录妊娠早期(11~13+6周)空腹血糖(fasting plasma glucose,FPG)、HbA1c、PAPP-A中位数倍数(multiple of the median,MoM)水平,根据孕24~28周进行的75 g口服葡萄糖耐量试验(oral glucose tolerance test,OGTT)结果将研究对象分为研究组和对照组,统计分析妊娠早期血清学指标预测GDM的最佳截断值并得出最适宜的联合预测方案。结果:多因素Logistic回归分析显示,高水平FPG和HbA1c、低水平PAPP-A、受孕方式采用辅助生殖技术、有家族糖尿病史以及妊娠早期体质量指数(BMI)为超重或肥胖均是GDM发生的独立危险因素。有糖尿病家族史和使用辅助生殖技术受孕发生GDM的风险显著增高(OR分别为7.206和47.512,均P<0.001)。分析不同预测指标的受试者工作特征(receiver operating characteristic,ROC)曲线及曲线下面积(area under the curve,AUC)显示,PAPP-A MoM联合HbA1c及FPG诊断时AUC最大(0.728),其后依次为PAPPA MoM联合HbA1c(0.721)、HbA1c联合FPG(0.717),均大于HbA1c(0.707)和FPG(0.647),而PAPP-A MoM的AUC为0.380,对GDM没有诊断意义。结论:具有高风险因素的孕妇,推荐在妊娠早期联合检测HbA1c与PAPPA MoM,以早期预测GDM。     

Knowledge of the Brain Death Concept in Dominican Immigration Residents in Spain and Florida

The Latin American population has a double way of immigration, one toward the United States by proximity and another toward Spain by sociocultural affinity. This population increase is affecting organ donation and transplantation in receiving countries.

Lung Ultrasound for the Emergency Diagnosis of Pneumonia,Acute Heart Failure,and Exacerbations of Chronic Obstructive Pulmonary Disease/Asthma in Adults: A Systematic Review and Meta-analysis

Background

Lung ultrasound can accelerate the diagnosis of life-threatening diseases in adults with respiratory symptoms.

Acute total hip arthroplasty for older patients with acetabular fractures: A meta-analysis

ObjectiveMultiple treatment options for acetabular fractures in geriatric patients exist. However, no large-scale studies have reported the outcomes of acute total hip arthroplasty (THA) in this patient population. We systematically evaluated all available evidence to characterize clinical outcomes, complications, and revisions of acute THA for acetabular fractures in geriatric patients.MethodsMeta-analysis of 21 studies of 430 acetabular fractures with mean follow-up of 44 months (range, 17−97 months). Two independent researchers searched and evaluated the databases of Ovid, Embase, and United States National Library of Medicine using a Boolean search string up to December 2019. Population demographics and complications, including presence of heterotopic ossification (HO), dislocation, infection, revision rate, neurological deficits, and venous thromboembolic event (VTE), were recorded and analyzed.ResultsWeighted mean Harris Hip Score was 83.3 points, and 20% of the patients had reported complications. The most common complication was HO, with a rate of 19.5%. Brooker grade III and IV HO rates were lower at 6.8%. Hip dislocation occurred at a rate of 6.1%, 4.1% of patients developed VTE, deep infection occurred in 3.8%, and neurological complications occurred in 1.9%. Although the revision rate was described in most studies, we were unable to perform a survival analysis because the time to each revision was described in only a few studies. The revision rate was 4.3%.ConclusionsAcute THA is a viable option for treatment of acetabular fracture and can result in acceptable clinical outcomes and survivorship rates in older patients but with an associated complication rate of approximately 20%. Considering the limited treatment options, THA might be a viable alternative for appropriately selected patients.     

Pediatric asthma quality of life questionnaire (PAQLQ): Validation among asthmatic children in Thailand

Quality of life (QoL) is an important consideration among asthma sufferers. The Pediatric Asthma Quality of Life Questionnaire (PAQLQ) is one of the most widely used instruments for measuring health-related QoL in children with asthma. The standardized version of PAQLQ contains 23 questions in three domains, i.e., activity limitation, symptoms and emotional function. The objective of this study was to validate the Thai-translated version of the PAQLQ. The study design consisted of a five-week single cohort study. Patients recorded symptoms, and peak expiratory flow rate (PEFR) each morning and evening during the first and fifth week of the study in asthma diary. At each clinic visit, a trained-interviewer administered the PAQLQ and performed spirometric measurements. Fifty-one children, ages between 7 and 17 yr participated in the study. Scores from the asthma diary were used to classify patients into stable vs. unstable groups. The construct validity of the questionnaire was confirmed in both cross-sectional and longitudinal studies by demonstrating correlations between various PAQLQ domains with clinical asthma parameters (asthma diary, beta-agonist use and PEFR). There was high internal consistency for scores of the three domains (Cronbach's alpha-coefficient = 0.83-0.95). For those with stable asthma, the reliability of PAQLQ was good for the rating scale (intra-class correlation coefficient--ICC = 0.84) and for total score (alpha = 0.97) indicating high reproducibility of the PAQLQ. The significant difference of changes QoL scores between stable and unstable groups was observed in all domains. We conclude that the Thai version of PAQLQ is valid and reliable for implementing in Thai children with asthma.