Use of High-Frequency In-Home Monitoring Data May Reduce Sample Sizes Needed in Clinical Trials

Background

Trials in Alzheimer’s disease are increasingly focusing on prevention in asymptomatic individuals. This poses a challenge in examining treatment effects since currently available approaches are often unable to detect cognitive and functional changes among asymptomatic individuals. Resultant small effect sizes require large sample sizes using biomarkers or secondary measures for randomized controlled trials (RCTs). Better assessment approaches and outcomes capable of capturing subtle changes during asymptomatic disease stages are needed.

Objective

We aimed to develop a new approach to track changes in functional outcomes by using individual-specific distributions (as opposed to group-norms) of unobtrusive continuously monitored in-home data. Our objective was to compare sample sizes required to achieve sufficient power to detect prevention trial effects in trajectories of outcomes in two scenarios: (1) annually assessed neuropsychological test scores (a conventional approach), and (2) the likelihood of having subject-specific low performance thresholds, both modeled as a function of time.

Methods

One hundred nineteen cognitively intact subjects were enrolled and followed over 3 years in the Intelligent Systems for Assessing Aging Change (ISAAC) study. Using the difference in empirically identified time slopes between those who remained cognitively intact during follow-up (normal control, NC) and those who transitioned to mild cognitive impairment (MCI), we estimated comparative sample sizes required to achieve up to 80% statistical power over a range of effect sizes for detecting reductions in the difference in time slopes between NC and MCI incidence before transition.

Results

Sample size estimates indicated approximately 2000 subjects with a follow-up duration of 4 years would be needed to achieve a 30% effect size when the outcome is an annually assessed memory test score. When the outcome is likelihood of low walking speed defined using the individual-specific distributions of walking speed collected at baseline, 262 subjects are required. Similarly for computer use, 26 subjects are required.

Conclusions

Individual-specific thresholds of low functional performance based on high-frequency in-home monitoring data distinguish trajectories of MCI from NC and could substantially reduce sample sizes needed in dementia prevention RCTs.     

Optic Disc - Fovea Angle: The Beijing Eye Study 2011

Purpose

To determine the optic disc-fovea angle (defined as angle between the horizontal and the line between the optic disc center and the fovea) and to assess its relationships with ocular and systemic parameters.

Methods

The population-based cross-sectional Beijing Eye Study 2011 included 3468 individuals. A detailed ophthalmic examination was carried out. Using fundus photographs, we measured the disc-fovea angle.

Results

Readable fundus photographs were available for 6043 eyes of 3052 (88.0%) individuals with a mean age of 63.6±9.3 years (range: 50–91 years) and a mean axial length of 23.2±1.0 mm (range: 18.96–28.87 mm). Mean disc-fovea angle was 7.76 ± 3.63° (median: 7.65°; range: -6.3° to 28.9°). The mean inter-eye difference was 4.01 ± 2.94° (median: 3.49°; range: 0.00–22.3°). In multivariate analysis, larger disc-fovea angle was associated (regression coefficient r²: 0.08) with older age (P = 0.009; standardized regression coefficient beta: 0.05), thinner RNFL in the nasal superior sector (P<0.001; beta: -0.17), superior sector (P<0.001; beta: -0.10) and temporal superior sector (P<0.001; beta: -0.11) and thicker RNFL in the inferior sector (P<001; beta: 0.13), nasal inferior sector (P<001; beta: 0.13) and nasal sector (P = 0.007; beta: 0.06), higher prevalence of retinal vein occlusion (P = 0.02; beta: 0.04), and with larger cylindrical refractive error (P = 0.04; beta: 0.04).

Conclusions

The optic disc-fovea angle markedly influences the regional distribution of the RNFL thickness pattern. The disc-fovea angle may routinely be taken into account in the morphological glaucoma diagnosis and in the assessment of structure-function relationship in optic nerve diseases. Future studies may address potential associations between a larger disc-fovea angle and retinal vein occlusions and between the disc-fovea angle and the neuroretinal rim shape.     

Intra- and Intersession Repeatability of an Optical Quality and Intraocular Scattering Measurement System in Children

Purpose

To evaluate intra- and intersession repeatability of objective optical quality and intraocular scattering measurements with a double-pass system in children.

Methods

Forty-two eyes of 42 children were included in the study. An optical quality analysis system (OQAS) was used to measure optical quality parameters, including modulation transfer function cutoff frequency (MTF_cutoff), Strehl ratio (SR), OQAS values (OV) at 3 different contrasts and objective scatter index (OSI). Three measurement sessions with 10-min intervals were operated by the same technician, and in each session four consecutive measurements were obtained.

Results

Mean values for MTF_cutoff, SR and OSI were 46.85 ± 7.45cpd, 0.27 ± 0.06 and 0.34 ± 0.22 respectively. 1) The intraclass correlation coefficients were ranged from 0.89 to 0.97 and coefficients of variation from 0.06 to 0.16 for all the parameters in the first session; the relative repeatability were 11.1% (MTF_cutoff), 22.5% (SR), 10.9% (OV100%), 16.6% (OV2%), 22.4% (OV9%) and 56.3% (OSI). Similar results were found in the second and third sessions. 2) Bland-Altman analysis showed that narrow 95% confidence intervals (compared between the first and second sessions) ranged from -5.42 to 5.28 (MTF_cutoff), -0.05 to 0.07 (SR), -0.18 to 0.18 (OV100%), -0.26 to 0.29 (OV20%), -0.33 to 0.39 (OV9%) and -0.11 to 0.09 (OSI); the comparison between any two of the three sessions showed similar results.

Conclusion

Measurements of optical quality and intraocular scattering in children by the double-pass system showed good intra- and intersession repeatability. Retinal image quality is high and intraocular scattering is low in children.     

Evidence in Obese Children: Contribution of Hyperlipidemia,Obesity-Inflammation,and Insulin Sensitivity

Background

Evidence shows a high incidence of insulin resistance, inflammation and dyslipidemia in adult obesity. The aim of this study was to assess the relevance of inflammatory markers, circulating lipids, and insulin sensitivity in overweight/obese children.

Methods

We enrolled 45 male children (aged 6 to 13 years, lean control = 16, obese = 19, overweight = 10) in this study. The plasma total cholesterol, HDL cholesterol, triglyceride, glucose and insulin levels, the circulating levels of inflammatory factors, such as TNF-α, IL-6, and MCP-1, and the high-sensitive CRP level were determined using quantitative colorimetric sandwich ELISA kits.

Results

Compared with the lean control subjects, the obese subjects had obvious insulin resistance, abnormal lipid profiles, and low-grade inflammation. The overweight subjects only exhibited significant insulin resistance and low-grade inflammation. Both TNF-α and leptin levels were higher in the overweight/obese subjects. A concurrent correlation analysis showed that body mass index (BMI) percentile and fasting insulin were positively correlated with insulin resistance, lipid profiles, and inflammatory markers but negatively correlated with adiponectin. A factor analysis identified three domains that explained 74.08% of the total variance among the obese children (factor 1: lipid, 46.05%; factor 2: obesity-inflammation, 15.38%; factor 3: insulin sensitivity domains, 12.65%).

Conclusions

Our findings suggest that lipid, obesity-inflammation, and insulin sensitivity domains predominantly exist among obese children. These factors might be applied to predict the outcomes of cardiovascular diseases in the future.     

Author Credit for Transdisciplinary Collaboration

Transdisciplinary collaboration is the key for innovation. An evaluation mechanism is necessary to ensure that academic credit for this costly process can be allocated fairly among coauthors. This paper proposes a set of quantitative measures (e.g., t_credit and t_index) to reflect authors’ transdisciplinary contributions to publications. These measures are based on paper-topic probability distributions and author-topic probability distributions. We conduct an empirical analysis of the information retrieval domain which demonstrates that these measures effectively improve the results of harmonic_credit and h_index measures by taking into account the transdisciplinary contributions of authors. The definitions of t_credit and t_index provide a fair and effective way for research organizations to assign credit to authors of transdisciplinary publications.     

Generation of Multicellular Tumor Spheroids with Microwell-Based Agarose Scaffolds for Drug Testing

Three dimensional multicellular aggregate, also referred to as cell spheroid or microtissue, is an indispensable tool for in vitro evaluating antitumor activity and drug efficacy. Compared with classical cellular monolayer, multicellular tumor spheroid (MCTS) offers a more rational platform to predict in vivo drug efficacy and toxicity. Nevertheless, traditional processing methods such as plastic dish culture with nonadhesive surfaces are regularly time-consuming, laborious and difficult to provide uniform-sized spheroids, thus causing poor reproducibility of experimental data and impeding high-throughput drug screening. In order to provide a robust and effective platform for in vitro drug evaluation, we present an agarose scaffold prepared with the template containing uniform-sized micro-wells in commercially available cell culture plates. The agarose scaffold allows for good adjustment of MCTS size and large-scale production of MCTS. Transparent agarose scaffold also allows for monitoring of spheroid formation under an optical microscopy. The formation of MCTS from MCF-7 cells was prepared using different-size-well templates and systematically investigated in terms of spheroid growth curve, circularity, and cell viability. The doxorubicin cytotoxicity against MCF-7 spheroid and MCF-7 monolayer cells was compared. The drug penetration behavior, cell cycle distribution, cell apoptosis, and gene expression were also evaluated in MCF-7 spheroid. The findings of this study indicate that, compared with cellular monolayer, MCTS provides a valuable platform for the assessment of therapeutic candidates in an in vivo-mimic microenvironment, and thus has great potential for use in drug discovery and tumor biology research.     

METTL3/N6‐methyladenosine/ miR‐21‐5p promotes obstructive renal fibrosis by regulating inflammation through SPRY1/ERK/NF‐κB pathway activation

Renal fibrosis induced by urinary tract obstruction is a common clinical occurrence; however, effective treatment is lacking, and a deeper understanding of the mechanism of renal fibrosis is needed. Previous studies have revealed that miR‐21 impacts liver and lung fibrosis progression by activating the SPRY1/ERK/NF‐kB signalling pathway. However, whether miR‐21 mediates obstructive renal fibrosis through the same signalling pathway has not been determined. Additionally, studies have shown that N6‐methyladenosine (m⁶A) modification‐dependent primary microRNA (pri‐microRNA) processing is essential for maturation of microRNAs, but its role in the maturation of miR‐21 in obstructive renal fibrosis has not yet been investigated in detail. To address these issues, we employed a mouse model of unilateral ureteral obstruction (UUO) in which the left ureters were ligated for 3, 7 and 14 days to simulate the fibrotic process. In vitro, human renal proximal tubular epithelial (HK‐2) cells were transfected with plasmids containing the corresponding sequence of METTL3, miR‐21‐5p mimic or miR‐21‐5p inhibitor. We found that the levels of miR‐21‐5p and m⁶A modification in the UUO model groups increased significantly, and as predicted, the SPRY1/ERK/NF‐kB pathway was activated by miR‐21‐5p, confirming that miR‐21‐5p plays an important role in obstructive renal fibrosis by enhancing inflammation. METTL3 was found to play a major catalytic role in m⁶A modification in UUO mice and drove obstructive renal fibrosis development by promoting miR‐21‐5p maturation. Our research is the first to demonstrate the role of the METTL3‐m⁶A‐miR‐21‐5p‐SPRY1/ERK/NF‐kB axis in obstructive renal fibrosis and provides a deeper understanding of renal fibrosis.     

布氏田鼠母体青春期捕食风险应激对后代反捕食行为和HPA轴基础活动水平的影响

本研究以28日龄的青春期雌性布氏田鼠作为亲代实验动物,每天分别暴露于蒸馏水、兔尿和猫尿60min,连续18d,成年后与正常雄鼠交配.随后检测其子代在28日龄(青春期)和90日龄(成年期)时暴露于这3种气味源的行为反应,以及下丘脑促肾上腺皮质激素释放激素、血浆促肾上腺皮质激素和皮质酮的基础水平.结果显示:与母体青春期暴露...     

热激蛋白对细胞凋亡的调节作用

细胞凋亡是生物发育过程中或在正常生理状态下清除衰老及受损细胞的一种普遍现象。细胞凋亡的发生受胞外或胞内的多种刺激源所诱导,其中热激蛋白是细胞凋亡的调控因子之一。本文着重讨论了热激蛋白在细胞凋亡调节中所发挥的作用。     

线粒体呼吸链复合物Ⅰ的结构与装配路径

线粒体是起源于最后真核生物共同祖先(last eukaryotic common ancestor,LECA)半自主性双层膜细胞器.线粒体氧化磷酸化(oxidative phosphorylation,OXPHOS)系统由细胞核和线粒体基因组协同编码5个蛋白质复合物组成,在内膜建立电子传递链并利用质子梯度产生三磷酸腺苷...