Will biomarker-based diagnosis of Alzheimer’s disease maximize scientific progress? Evaluating proposed diagnostic criteria

A recently published framework for the diagnosis of Alzheimer’s disease (AD) in research studies would allow diagnosis on the sole basis of two biomarkers (β-amyloid and pathologic tau), even in people with no objective or subjective memory or cognitive changes. This revision will have substantial implications for future Alzheimer’s research, and the changes should be rigorously evaluated before widespread adoption. We propose three principles for evaluating any revision to diagnostic frameworks for AD: (1) does the revision improve the validity of the diagnosis; (2) does the revision improve the reliability or reduce the expense of the diagnosis; and (3) will the revision foster innovative and rigorous research across populations. The new diagnostic framework is unlikely to achieve any of these goals. Instead, it has the potential to handicap future researchers, and slow progress towards identifying effective strategies to prevent or treat AD.     

Dietary intake of total polyphenol and polyphenol classes and the risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Polyphenols may play a chemopreventive role in colorectal cancer (CRC); however, epidemiological evidence supporting a role for intake of individual polyphenol classes, other than flavonoids is insufficient. We evaluated the association between dietary intakes of total and individual classes and subclasses of polyphenols and CRC risk and its main subsites, colon and rectum, within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The cohort included 476,160 men and women from 10 European countries. During a mean follow-up of 14 years, there were 5991 incident CRC cases, of which 3897 were in the colon and 2094 were in the rectum. Polyphenol intake was estimated using validated centre/country specific dietary questionnaires and the Phenol-Explorer database. In multivariable-adjusted Cox regression models, a doubling in total dietary polyphenol intake was not associated with CRC risk in women (HR_log2?=?1.06, 95% CI 0.99–1.14) or in men (HR_log2?=?0.97, 95% CI 0.90–1.05), respectively. Phenolic acid intake, highly correlated with coffee consumption, was inversely associated with colon cancer in men (HR_log2?=?0.91, 95% CI 0.85–0.97) and positively associated with rectal cancer in women (HR_log2?=?1.10, 95% CI 1.02–1.19); although associations did not exceed the Bonferroni threshold for significance. Intake of other polyphenol classes was not related to colorectal, colon or rectal cancer risks. Our study suggests a possible inverse association between phenolic acid intake and colon cancer risk in men and positive with rectal cancer risk in women.     

The combination of cardiorespiratory fitness and muscle strength,and mortality risk

Little is known about the combined associations of cardiorespiratory fitness (CRF) and hand grip strength (GS) with mortality in general adult populations. The purpose of this study was to compare the relative risk of mortality for CRF, GS, and their combination. In UK Biobank, a prospective cohort of >?0.5 million adults aged 40–69 years, CRF was measured through submaximal bike tests; GS was measured using a hand-dynamometer. This analysis is based on data from 70,913 men and women (832 all-cause, 177 cardiovascular and 503 cancer deaths over 5.7-year follow-up) who provided valid CRF and GS data, and with no history of heart attack/stroke/cancer at baseline. Compared with the lowest CRF category, the hazard ratio (HR) for all-cause mortality was 0.76 [95% confidence interval (CI) 0.64–0.89] and 0.65 (95% CI 0.55–0.78) for the middle and highest CRF categories, respectively, after adjustment for confounders and GS. The highest GS category had an HR of 0.79 (95% CI 0.66–0.95) for all-cause mortality compared with the lowest, after adjustment for confounders and CRF. Similar results were found for cardiovascular and cancer mortality. The HRs for the combination of highest CRF and GS were 0.53 (95% CI 0.39–0.72) for all-cause mortality and 0.31 (95% CI 0.14–0.67) for cardiovascular mortality, compared with the reference category of lowest CRF and GS: no significant association for cancer mortality (HR 0.70; 95% CI 0.48–1.02). CRF and GS are both independent predictors of mortality. Improving both CRF and muscle strength, as opposed to either of the two alone, may be the most effective behavioral strategy to reduce all-cause and cardiovascular mortality risk.     

Longitudinal associations of lifetime adiposity with leukocyte telomere length and mitochondrial DNA copy number

Adiposity may cause adverse health outcomes by increasing oxidative stress and systemic inflammation, which can be reflected by altered telomere length (TL) and mitochondrial DNA copy number (mtCN) in peripheral blood leukocytes. However, little is known about the influence of lifetime adiposity on TL and mtCN in later life. This study was performed to investigate the associations of lifetime adiposity with leukocyte TL and mtCN in 9613 participants from the Nurses’ Health Study. A group-based trajectory modelling approach was used to create trajectories of body shape from age 5 through 60 years, and a genetic risk score (GRS) was created based on 97 known adiposity susceptibility variants. Associations of body shape trajectories and GRS with dichotomized TL and mtCN were assessed by logistic regression models. After adjustment for lifestyle and dietary factors, compared with the lean-stable group, the lean-marked increase group had higher odds of having below-median TL (OR?=?1.18, 95% CI 1.04, 1.35; P?=?0.01), and the medium-marked increase group had higher odds of having below-median mtCN (OR?=?1.28, 95% CI 1.00, 1.64; P?=?0.047). There was a suggestive trend toward lower mtCN across the GRS quartiles (P for trend?=?0.07). In conclusion, telomere attrition may be accelerated by marked weight gain in middle life, whereas mtCN is likely to be reduced persistently by adiposity over the life course. The findings indicate the importance of lifetime weight management to preserve functional telomeres and mitochondria.     

Associations of serum 25-hydroxyvitamin D level with incidence of lung cancer and histologic types in Norwegian adults: a case-cohort analysis of the HUNT study

Previous prospective studies have shown inconsistent associations between serum 25-hydroxyvitamin D [25(OH)D] level and lung cancer incidence. The aim of the present study was to explore the associations of serum 25(OH)D levels with incidence of lung cancer overall and different histologic types. We performed a population-based prospective case-cohort study including 696 incident lung cancer cases and 5804 individuals in a subcohort who participated in the second survey of the Nord-Trøndelag Health Study in Norway. Cox proportional hazards regression models counting for the case-cohort design were used to estimate hazard ratios (HRs) with 95% confidence interval (CIs) for lung cancer overall or histologic types in relation to serum 25(OH)D levels. Compared with the fourth season-specific quartile of 25(OH)D (median 68.0 nmol/L), lower 25(OH)D levels were not associated with the incidence of overall, small or squamous cell lung cancer. However, the risk of adenocarcinoma was lower in the second and third quartiles (median 39.9 and 51.5 nmol/L) compared with the fourth quartile, with HRs of 0.63 (95% CI 0.41–0.98) and 0.58 (0.38–0.88), respectively. The associations of lower levels of 25(OH)D with a reduced risk of adenocarcinoma were only observed in the overweight/obese subjects [HRs for second and third quartiles: 0.40 (0.22–0.72) and 0.50 (0.27–0.92)] but not in the normal weight subjects [HRs: 0.95 (0.52–1.75) and 0.60 (0.32–1.10)]. Serum 25(OH)D levels were not associated with the risk of lung cancer in general. The observation that lower 25(OH)D levels were associated with a lower risk of adenocarcinoma should be interpreted with caution.     

New cancer cases in France in 2015 attributable to infectious agents: a systematic review and meta-analysis

To provide an assessment of the burden of cancer in France in 2015 attributable to infectious agents. A systematic literature review in French representative cancer cases series was undertaken of the prevalence of infectious agents with the major associated cancer types. PubMed was searched for original studies published up to September 2016; random-effects meta-analyses were performed. Cancer incidence data were obtained from the French Cancer Registries Network, thereby allowing the calculation of national incidence estimates. The number of new cancer cases attributable to infectious agents was calculated using population-attributable fractions according to published methods. Of the 352,000 new cancer cases in France in 2015, 14,336 (4.1% of all new cancer cases) were attributable to infectious agents. The largest contributors were human papillomavirus (HPV) and Helicobacter pylori, responsible for 6333 and 4406 new cancer cases (1.8 and 1.3% of all new cancer cases) respectively. Infectious agents caused a non-negligible number of new cancer cases in France in 2015. Most of these cancers were preventable. The expansion of vaccination (i.e., for hepatitis B virus and HPV) and screen-and-treat programs (for HPV and hepatitis C virus, and possibly for H. pylori) could greatly reduce this cancer burden.     

Individually-matched etiologic studies: classical estimators made new again

With greater access to regression-based methods for confounder control, the etiologic study with individual matching, analyzed by classical (calculator) methods, lost favor in recent decades. This design was costly, and the data sometimes mis-analyzed. Now, with Big Data, individual matching becomes an economical option. To many, however, conditional logistic regression, commonly used to estimate the incidence density ratio parameter, is somewhat of a black box whose output is not easily checked. An epidemiologist-statistician pair recently proposed a new estimator that is easily applied to data from individually-matched series with a 2:1 ratio (and no other confounding variables) using just a hand calculator or spreadsheet. Surprisingly—or possibly not—they overlooked classical estimators developed in earlier decades. This prompts me to re-introduce some of these, to highlight their considerable flexibility and ease of use, and to update them. Nowadays, for any matching ratio (M:1), the Maximum Likelihood result can be easily computed from data gathered under the matched design in two different ways, each using just the summary data. One is via any binomial regression program that allows offsets, applied to just M ‘rows’ of data. The other is by hand! The aim of this note is not to save on computation; instead, it is to make connections between classical and regression-based methods, to promote terminology that reflects the concepts and structure of the etiologic study, and to focus attention on what parameter is being estimated.     

《儿科阿奇霉素注射使用的快速建议指南》临床问题与结局指标的调查分析

目的:通过总结《儿科阿奇霉素注射使用的快速建议指南》临床问题与结局指标的前期调查结果,与指南专家评估结果进行对比,探讨开展该工作的意义。方法:通过电子问卷,对临床一线医务人员进行调查,调查内容主要包括参与者的基本信息、对指南拟纳入的临床问题(5分制)和结局指标(9分制)进行重要程度评分以及补充。计算各题平均分,采用变异系数表示一致性,采用Wilcoxon秩和检验,对比参与者和专家评估结果,对补充的内容进行描述性分析。结果:共纳入155位参与者的调查结果,各年龄段、文化程度和职称等均有分布。结果显示,注射用阿奇霉素的用法用量(4.56分)和有效性指标(7.28分)最受关注,特殊人群用药(42.71%)和安全性(34.52%)的一致性较差;与专家评估对比分析显示,对于大部分问题和指标,前期调研和专家评估的评分差异无显著性,专家评估的变异系数更低;共收集有效补充15条,最终将新生儿的使用问题纳入。结论:在指南制订前期,有必要对临床问题和结局指标进行广泛调查,收集并分析评估和补充意见,这对指南专家组的评估具有一定的参考意义。     

HPLC-MS/MS法定量研究氧化白藜芦醇对沙奎那韦在大鼠体内药动学的影响

目的:应用高效液相色谱-串联质谱(HPLC-MS/MS)技术建立大鼠血浆中沙奎那韦的定量测定方法,并用于氧化白藜芦醇对沙奎那韦在大鼠体内药动学研究。方法:液相色谱分离采用C₁₈反相色谱柱(150mm×2.1mm,5.0μm),流动相为乙腈/水(含0.2mmol·L^-1甲酸铵),流速为300μL·min^-1;质谱检测采用电喷雾正离子(ESI^+)模式,多反应监测。血浆样品采用液-液萃取方式提取,检测反应为m/z671.4→570.4(沙奎那韦),m/z721.4→296.2(利托那韦,内标)。将10只SD大鼠分为2组,对照组与实验组分别灌胃给予沙奎那韦(30mg·kg^-1)、沙奎那韦(30mg·kg^-1)+氧化白藜芦醇(40mg·kg^-1),于不同时间取血,测定血药浓度。结果:沙奎那韦在1.0~100.0ng·mL^-1范围内呈良好的线性关系(r=0.998 5),日内和日间精密度均小于12.16%,偏差为0.89%~6.24%,回收率为67.85%~82.38%,血浆样品稳定性好。同时服用氧化白藜芦醇时,大鼠体内沙奎那韦达峰浓度C_max、C_max1显著降低,而C_max、T_max、t_1/2、CL/F均无显著差异。结论:HPLC-MS/MS测定方法准确度高、专属性强、灵敏度高、快速高效。沙奎那韦的药时曲线存在双峰现象;氧化白藜芦醇可以显著降低沙奎那韦的达峰浓度,但对口服生物利用度等其他药动学参数没有显著性影响。     

国外药师与医师协作实践及其对我国的启示

目的：研究国外药师与医师协作实践现状,为提升我国药师与医师的协作提供借鉴。方法：查阅文献,梳理国外药师与医师协作实践经验,总结出对我国的启示。结果：美国、英国、加拿大等国家在药师与医师协作方面取得较大进展,采取有效的激励措施,形成了较为完善的协作模式,建立了较为健全的法律规章,对我国有重要的参考意义。结论：我国应从优化药学课程设置、设置协作药物治疗管理项目、拓展药师工作职能、运用财务激励、健全相关法律法规等方面着手促进我国药师与医师协作。