Understanding the Influence of Nanocarrier-Mediated Brain Delivery on Therapeutic Performance Through Pharmacokinetic-Pharmacodynamic Modeling

This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation.     

Opportunities and barriers to effective operation and maintenance of public toilets in informal settlements: perspectives from toilet operators in Kampala

Although classified by the Joint Monitoring Programme (JMP) as unimproved sanitation facilities, public toilets still play a critical role in eliminating open defecation in informal settlements. We explored perspectives of toilet operators on opportunities and barriers to operation and maintenance (O&M) of public toilets in informal settlements. A cross-sectional study design was used. Up to 20 in-depth interviews were used to obtain data on the experiences of public toilet operators. Thematic content analysis was used.

Ressults show that opportunities for improving O&M include; operation of public toilets is a source of livelihood; operators are knowledgeable on occupational risks, and the community is involvedin sanitation activities. Barriers to effective O&M include; high operation costs, failure to break even and a lack of investments in occupational health Therefore, there is need to recognise the significance of public toilets as a viable alternative to open defecation in areas where ownership of private sanitation facilities is difficult. Failure to observe the health and safety of toilet operators may further compromise O&M.     

肌少症对老年肝癌术后恢复及预后的影响

目的:肌少症对老年肝癌术后恢复及预后的影响。方法:选取2015年1月至2017年12月收治的114例老年肝癌，根据有无合并肌少症，分为肌少症组（n=35）和非肌少症组（n=79）。比较两组患者的术后恢复及生存情况。结果:肌少症组总并发症发生率、住院时间和30 d再入院率均高于对照组，差异均有统计学意义（P＜0.05）。肌少症组中位生存时间为25.9个月，1年、2年、3年累积总生存率为74.3%、51.1%、24.5%，而非肌少症组中位生存时间为35.7个月，1年、2年、3年累积总生存率为87.3%、75.6%、49.4%，差异有统计学意义（P=0.004）。单因素分析结果显示，老年肝癌术后预后与Charlson合并症指数（CCI）、肌少症、巴塞罗那分期（BCLC）、甲胎蛋白、肿瘤大小、肿瘤个数、肿瘤分化程度、微血管侵犯（MVI）相关（P＜0.05）。Cox多因素分析结果显示，CCI、肌少症、BCLC分期、肿瘤个数、MVI是老年肝癌术后预后的独立危险因素（P＜0.05）。结论:肌少症会增加老年肝癌患者术后并发症发生率，延长住院时间，影响术后恢复，同时也会降低总生存率。     

Family history of cancer and subsequent risk of cancer: A large-scale population-based prospective study in Japan

Family history (FH) of cancer is an important factor of increased risk of several cancers. Although the association between FH of cancer and concordant cancer risk has been reported in many previous epidemiological studies, no comprehensive prospective study with adjustment for lifestyle habits has evaluated the association of FH of cancer and concordant cancer risk. We investigated the association between FH of cancer and concordant cancer risk in a Japanese population-based prospective study, initiated in 1990 for cohort I and in 1993 for cohort II. We analyzed data on 103,707 eligible subjects without a history of cancer who responded to a self-administered questionnaire including FH of cancer at baseline. Study subjects were followed through 2012 and analyzed using multivariable-adjusted Cox proportional hazards regression models. During 1,802,581 person-years of follow-up, a total of 16,336 newly diagnosed cancers were identified. Any site (Hazard ratios = 1.11 (95% confidence interval = 1.07–1.15]), esophagus (2.11 [1.00–4.45]), stomach (1.36 [1.19–1.55]), liver (1.69 [1.10–2.61]), pancreas (2.63 [1.45–4.79]), lung (1.51 [1.14–2.00]), uterus (1.93 [1.06–3.51]) and bladder cancers (6.06 [2.49–14.74]) with FH of the concordant cancer were associated with an increased risk compared to those without FH. Our findings suggest that having FH of cancer is associated with an increased risk of several concordant cancer incidences in an Asian population. Enquiring about FH of several types of cancer may be important in identifying groups at high-risk of those cancers.     

Sex and gender differences in Alzheimer’s disease: current challenges and implications for clinical practice

Alzheimer’s disease (AD) is characterized by high heterogeneity in disease manifestation, progression and risk factors. High phenotypic variability is currently regarded as one of the largest hurdles in early diagnosis and in the design of clinical trials; there is therefore great interest in identifying factors driving variability that can be used for patient stratification. In addition to genetic and lifestyle factors, the individual’s sex and gender are emerging as crucial drivers of phenotypic variability. Evidence exists on sex and gender differences in the rate of cognitive deterioration and brain atrophy, and in the effect of risk factors as well as in the patterns of diagnostic biomarkers. Such evidence might be of high relevance and requires attention in clinical practice and clinical trials. However, sex and gender differences are currently seldom appreciated; importantly, consideration of sex and gender differences is not currently a focus in the design and analysis of clinical trials for AD. The objective of this position paper is (i) to provide an overview of known sex and gender differences that might have implications for clinical practice, (ii) to identify the most important knowledge gaps in the field (with a special regard to clinical trials) and (iii) to provide conclusions for future studies. This scientific statement is endorsed by the European Academy of Neurology.