Nonlinear Analysis of Stride Interval Time Series in Gait Maturation Using Distribution Entropy

ObjectivesThis study aimed to investigate whether DistEn was capable of identifying complexity or irregularity for gait data and whether having low parameter-dependency sensitivity by comparing with the Approximate Entropy (ApEn) and Sample Entropy (SampEn).Material and methodsThe data were divided into three groups according to gait maturation. Firstly, the mean amplitude histogram, standard deviation (SD), and the power spectrum were calculated for each group. Secondly, ApEn, SampEn, and DistEn algorithms were calculated. Statistical analyses were then performed to compare groups.ResultsFor m=3 with M= 256 and M=512 parameters, DistEn showed a statistically significant difference between in pairwise comparisons between all groups (P_a, P_b, and P_c < 0.05). DistEn consistently decreased from Group1, to Group2, and to Group 3. For m=2 with r=0.30 values, SampEn showed a statistically significant difference only in pairwise comparisons between Group1 and Group3 (P_b < 0.05). For with m=3 and r=0.30 parameters, SampEn also showed a statistically significant difference in pairwise comparisons between Group1 and Group3 (P_c < 0.05) as well as Group2 and Group3 (P_c < 0.05) SampEn increased from Group1 to Group3 and from Group2 to Group3. There was not any statistically significant difference in pairwise comparisons of groups for ApEn. Furthermore, DistEn showed less parameter consistency than ApEn and SampEn.ConclusionDistEn showed the best performance in capture the complexity changes in gain patterns with growth.     

Influence of Sub-Daily Variation on Multi-Fractal Detrended Fluctuation Analysis of Wind Speed Time Series

Using multi-fractal detrended fluctuation analysis (MF-DFA), the scaling features of wind speed time series (WSTS) could be explored. In this paper, we discuss the influence of sub-daily variation, which is a natural feature of wind, in MF-DFA of WSTS. First, the choice of the lower bound of the segment length, a significant parameter of MF-DFA, was studied. The results of expanding the lower bound into sub-daily scope shows that an abrupt declination and discrepancy of scaling exponents is caused by the inability to keep the whole diel process of wind in one single segment. Additionally, the specific value, which is effected by the sub-daily feature of local meteo-climatic, might be different. Second, the intra-day temporal order of wind was shuffled to determine the impact of diel variation on scaling exponents of MF-DFA. The results illustrate that disregarding diel variation leads to errors in scaling. We propose that during the MF-DFA of WSTS, the segment length should be longer than 1 day and the diel variation of wind should be maintained to avoid abnormal phenomena and discrepancy in scaling exponents.     

Unbiased and Mobile Gait Analysis Detects Motor Impairment in Parkinson's Disease

Motor impairments are the prerequisite for the diagnosis in Parkinson''s disease (PD). The cardinal symptoms (bradykinesia, rigor, tremor, and postural instability) are used for disease staging and assessment of progression. They serve as primary outcome measures for clinical studies aiming at symptomatic and disease modifying interventions. One major caveat of clinical scores such as the Unified Parkinson Disease Rating Scale (UPDRS) or Hoehn&Yahr (H&Y) staging is its rater and time-of-assessment dependency. Thus, we aimed to objectively and automatically classify specific stages and motor signs in PD using a mobile, biosensor based Embedded Gait Analysis using Intelligent Technology (eGaIT). eGaIT consist of accelerometers and gyroscopes attached to shoes that record motion signals during standardized gait and leg function. From sensor signals 694 features were calculated and pattern recognition algorithms were applied to classify PD, H&Y stages, and motor signs correlating to the UPDRS-III motor score in a training cohort of 50 PD patients and 42 age matched controls. Classification results were confirmed in a second independent validation cohort (42 patients, 39 controls). eGaIT was able to successfully distinguish PD patients from controls with an overall classification rate of 81%. Classification accuracy increased with higher levels of motor impairment (91% for more severely affected patients) or more advanced stages of PD (91% for H&Y III patients compared to controls), supporting the PD-specific type of analysis by eGaIT. In addition, eGaIT was able to classify different H&Y stages, or different levels of motor impairment (UPDRS-III). In conclusion, eGaIT as an unbiased, mobile, and automated assessment tool is able to identify PD patients and characterize their motor impairment. It may serve as a complementary mean for the daily clinical workup and support therapeutic decisions throughout the course of the disease.     

Detrended Fluctuation Analysis of Heart Rate Dynamics Is an Important Prognostic Factor in Patients with End-Stage Renal Disease Receiving Peritoneal Dialysis

Background and Objectives

Patients with severe kidney function impairment often have autonomic dysfunction, which could be evaluated noninvasively by heart rate variability (HRV) analysis. Nonlinear HRV parameters such as detrended fluctuation analysis (DFA) has been demonstrated to be an important outcome predictor in patients with cardiovascular diseases. Whether cardiac autonomic dysfunction measured by DFA is also a useful prognostic factor in patients with end-stage renal disease (ESRD) receiving peritoneal dialysis (PD) remains unclear. The purpose of the present study was designed to test the hypothesis.

Materials and Methods

Patients with ESRD receiving PD were included for the study. Twenty-four hour Holter monitor was obtained from each patient together with other important traditional prognostic makers such as underlying diseases, left ventricular ejection fraction (LVEF) and serum biochemistry profiles. Short-term (DFAα1) and long-term (DFAα2) DFA as well as other linear HRV parameters were calculated.

Results

A total of 132 patients (62 men, 72 women) with a mean age of 53.7±12.5 years were recruited from July 2007 to March 2009. During a median follow-up period of around 34 months, eight cardiac and six non-cardiac deaths were observed. Competing risk analysis demonstrated that decreased DFAα1 was a strong prognostic predictor for increased cardiac and total mortality. ROC analysis showed that the AUC of DFAα1 (<0.95) to predict mortality was 0.761 (95% confidence interval (CI). = 0.617–0.905). DFAα1≧ 0.95 was associated with lower cardiac mortality (Hazard ratio (HR) 0.062, 95% CI = 0.007–0.571, P = 0.014) and total mortality (HR = 0.109, 95% CI = 0.033–0.362, P = 0.0003).

Conclusion

Cardiac autonomic dysfunction evaluated by DFAα1 is an independent predictor for cardiac and total mortality in patients with ESRD receiving PD.     

Aerobic Exercise for Parkinson's Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background

Although some trials assessed the effectiveness of aerobic exercise for Parkinson''s disease (PD), the role of aerobic exercise in the management of PD remained controversial.

Objective

The purpose of this systematic review is to evaluate the evidence about whether aerobic exercise is effective for PD.

Methods

Seven electronic databases, up to December 2013, were searched to identify relevant studies. Two reviewers independently extracted data and assessed methodological quality based on PEDro scale. Standardised mean difference (SMD) and 95% confidence intervals (CI) of random-effects model were calculated. And heterogeneity was assessed based on the I² statistic.

Results

18 randomized controlled trials (RCTs) with 901 patients were eligible. The aggregated results suggested that aerobic exercise should show superior effects in improving motor actions (SMD, −0.57; 95% CI −0.94 to −0.19; p = 0.003), balance (SMD, 2.02; 95% CI 0.45 to 3.59; p = 0.01), and gait (SMD, 0.33; 95% CI 0.17 to 0.49; p<0.0001) in patients with PD, but not in quality of life (SMD, 0.11; 95% CI −0.23 to 0.46; p = 0.52). And there was no valid evidence on follow-up effects of aerobic exercise for PD.

Conclusion

Aerobic exercise showed immediate beneficial effects in improving motor action, balance, and gait in patients with PD. However, given no evidence on follow-up effects, large-scale RCTs with long follow-up are warrant to confirm the current findings.     

Tai Chi for Improvement of Motor Function,Balance and Gait in Parkinson's Disease: A Systematic Review and Meta-Analysis

Background

Recently, several studies assessed the effectiveness of Tai Chi for Parkinson''s disease (PD), but the role of Tai Chi in the management of PD remained controversial. Therefore, the purpose of this systematic review is to evaluate the evidence on the efficacy of Tai Chi for PD.

Methods

Six English and Chinese electronic databases, up to April 2014, were searched to identify relevant studies. The risk of bias in eligible studies was assessed by Cochrane Collaboration''s tools. The primary outcomes were motor function, balance and gait in individuals with PD. Standardized mean difference (SMD) and 95% confidence intervals (CI) of random-effect model were calculated. And heterogeneity was assessed based on the I²statistic.

Results

7 randomized controlled trials and 1 non-randomized controlled trial were eligible. The aggregated results suggested that Tai Chi showed beneficial effects in improving motor function (SMD, −0.57; 95% CI −1.11 to −0.04; p = 0.03), balance (SMD, 1.22; 95% CI 0.80 to 1.65; p<0.00001) and functional mobility (SMD, 1.06; 95% CI 0.68 to 1.44; p<0.00001) in patients with PD, but not in improving gait velocity (SMD, −0.02; 95% CI −0.58 to 0.54; p = 0.94), step length (SMD, −0.00; 95% CI −0.57 to 0.56; p = 0.99), or gait endurance (SMD, 0.53; 95% CI −0.07 to 1.12; p = 0.08). Comparing with other active therapies, however, Tai Chi only showed better effects in improving balance (SMD, 0.74; 95% CI 0.38 to 1.10; p<0.0001).

Conclusion

Tai Chi should be a valid complementary and alternative therapy for PD, especially in improving motor function and balance. However, more studies with long follow-up are warrant to confirm the current finding of Tai Chi for PD.     

临床试验进展: 适应性设计及透明性

临床试验中的适应性设计是根据累积信息来修正试验的一种设计方法,旨在使临床试验和临床开发计划效率更高,并为患者提供更加有效的治疗。此外,因信息隐匿造成试验失败和患者死亡,从而导致公众对医药行业的信任度下降,故关于公开临床数据的观点已开始朝着提升透明度方向调整。介绍3 类适应性设计方法的特点和应用,以及国外药政部门和制药企业对提高临床试验透明性的举措。     

Mutational Analysis of Angiogenin Gene in Parkinson's Disease

Mutations in the angiogenic factor, angiogenin (ANG), have been identified in patients with both familial and sporadic amyotrophic lateral sclerosis (ALS) and are thought to have a neuroprotective function. Parkinsonism has been noted in kindreds with ANG mutations and variants in the ANG gene have been found to associate with PD in two Caucasian populations. We therefore hypothesized that mutations in ANG may also contribute to idiopathic Parkinson''s disease (PD). We sequenced ANG gene in a total of 1498 participants comprising 750 PD patients and 748 age/gender matched controls from Taiwan. We identified one novel synonymous substitution, c.C100T (p.L10L), in a single heterozygous state in one PD patient, which was not observed in controls. The clinical phenotypes and [^99mTc]-TORDAT-SPECT images of the p.L10L carrier were similar to that seen in idiopathic PD. In addition, we also identified one common variant, c.T330G (p.G110G, rs11701), which was previously reported to associate with PD risk in Caucasians. However, the frequency of TG/GG genotype was comparable between PD cases and controls (odds ratio: 0.85, 95% confidence interval: 0.29–2.55, P = 0.78). Our results did not support that ANG rs11701 variant is a genetic risk factor for PD in our population. We conclude that mutations in ANG are not a common cause for idiopathic PD.     

Steps to Take to Enhance Gait Stability: The Effect of Stride Frequency,Stride Length,and Walking Speed on Local Dynamic Stability and Margins of Stability

The purpose of the current study was to investigate whether adaptations of stride length, stride frequency, and walking speed, independently influence local dynamic stability and the size of the medio-lateral and backward margins of stability during walking. Nine healthy subjects walked 25 trials on a treadmill at different combinations of stride frequency, stride length, and consequently at different walking speeds. Visual feedback about the required and the actual combination of stride frequency and stride length was given during the trials. Generalized Estimating Equations were used to investigate the independent contribution of stride length, stride frequency, and walking speed on the measures of gait stability. Increasing stride frequency was found to enhance medio-lateral margins of stability. Backward margins of stability became larger as stride length decreased or walking speed increased. For local dynamic stability no significant effects of stride frequency, stride length or walking speed were found. We conclude that adaptations in stride frequency, stride length and/or walking speed can result in an increase of the medio-lateral and backward margins of stability, while these adaptations do not seem to affect local dynamic stability. Gait training focusing on the observed stepping strategies to enhance margins of stability might be a useful contribution to programs aimed at fall prevention.     

临床试验进展：大数据方法在临床试验中的应用

药物研发的复杂性与日俱增,而大数据时代的到来使得临床试验的进展大大加快。本期“临床试验进展”讨论了皮肤病学新创试验中面向数据的亮点,探讨了现实采用的大数据方法,剖析了对风险导向监察的新兴方法学。此外还汇总了银屑病和特应性皮炎新疗法的临床研究报告,揭示了这些疾病的影响以及Ⅱ期和Ⅲ期研究中已经取得成功的候选药。     

Analysis of Variety Trials in the Presence of Non-Random Time Effect

The assumption of random year effect in the analysis of variety trials data over locations and years clearly contradicts the practice of conducting the trials over only a few consecutive years. A method of analysis of such trials which assumes that the year-dependent effects are serially correlated is proposed in this paper to cater for the non-randomness in the selection of years of the experiments. A simple autoregressive model was assumed for the serial relationship. A reduction in the variance estimate of the difference between two variety means was obtained using this method.     

Differential Neural Activation Patterns in Patients with Parkinson's Disease and Freezing of Gait in Response to Concurrent Cognitive and Motor Load

Freezing of gait is a devastating symptom of Parkinson''s disease (PD) that is exacerbated by the processing of cognitive information whilst walking. To date, no studies have explored the neural correlates associated with increases in cognitive load whilst performing a motor task in patients with freezing. In this experiment, 14 PD patients with and 15 PD patients without freezing of gait underwent 3T fMRI while performing a virtual reality gait task. Directions to walk and stop were presented on the viewing screen as either direct cues or as more cognitively indirect pre-learned cues. Both groups showed a consistent pattern of BOLD response within the Cognitive Control Network during performance of the paradigm. However, a between group comparison revealed that those PD patients with freezing of gait were less able to recruit the bilateral anterior insula, ventral striatum and the pre-supplementary motor area, as well as the left subthalamic nucleus when responding to indirect cognitive cues whilst maintaining a motor output. These results suggest that PD patients with freezing of gait are unable to properly recruit specific cortical and subcortical regions within the Cognitive Control Network during the performance of simultaneous motor and cognitive functions.     

Association between Respiratory Syncytial Virus Activity and Pneumococcal Disease in Infants: A Time Series Analysis of US Hospitalization Data

BackgroundThe importance of bacterial infections following respiratory syncytial virus (RSV) remains unclear. We evaluated whether variations in RSV epidemic timing and magnitude are associated with variations in pneumococcal disease epidemics and whether changes in pneumococcal disease following the introduction of seven-valent pneumococcal conjugate vaccine (PCV7) were associated with changes in the rate of hospitalizations coded as RSV.ConclusionsThese analyses provide evidence for an interaction between RSV and pneumococcal pneumonia. Future work should evaluate whether treatment for secondary bacterial infections could be considered for pneumonia cases even if a child tests positive for RSV.Please see later in the article for the Editors'' Summary     

临床试验进展：临床数据与实验室质量管理规范

将临床研究数据用于临床日常规范及健康相关决策的制定对于改善全球医疗保健至关重要。汤森路透Cortellis 临床试验情报对临床试验数据的应用价值及各国临床实验室质量管理规范的实施情况进行了介绍,提供描绘临床图景关键元素和当前趋势的专家分析,从而指导临床开发决策。     

Integrative Network Analysis Unveils Convergent Molecular Pathways in Parkinson's Disease and Diabetes

Background

Shared dysregulated pathways may contribute to Parkinson''s disease and type 2 diabetes, chronic diseases that afflict millions of people worldwide. Despite the evidence provided by epidemiological and gene profiling studies, the molecular and functional networks implicated in both diseases, have not been fully explored. In this study, we used an integrated network approach to investigate the extent to which Parkinson''s disease and type 2 diabetes are linked at the molecular level.

Methods and Findings

Using a random walk algorithm within the human functional linkage network we identified a molecular cluster of 478 neighboring genes closely associated with confirmed Parkinson''s disease and type 2 diabetes genes. Biological and functional analysis identified the protein serine-threonine kinase activity, MAPK cascade, activation of the immune response, and insulin receptor and lipid signaling as convergent pathways. Integration of results from microarrays studies identified a blood signature comprising seven genes whose expression is dysregulated in Parkinson''s disease and type 2 diabetes. Among this group of genes, is the amyloid precursor protein (APP), previously associated with neurodegeneration and insulin regulation. Quantification of RNA from whole blood of 192 samples from two independent clinical trials, the Harvard Biomarker Study (HBS) and the Prognostic Biomarker Study (PROBE), revealed that expression of APP is significantly upregulated in Parkinson''s disease patients compared to healthy controls. Assessment of biomarker performance revealed that expression of APP could distinguish Parkinson''s disease from healthy individuals with a diagnostic accuracy of 80% in both cohorts of patients.

Conclusions

These results provide the first evidence that Parkinson''s disease and diabetes are strongly linked at the molecular level and that shared molecular networks provide an additional source for identifying highly sensitive biomarkers. Further, these results suggest for the first time that increased expression of APP in blood may modulate the neurodegenerative phenotype in type 2 diabetes patients.     

Outcomes in Clinical Trials of Inhaled Corticosteroids for Children with Asthma Are Narrowly Focussed on Short Term Disease Activity

Background

Little work has been done to determine which outcomes should be measured in randomised controlled trials (RCTs) in children with asthma. Drug regulatory authorities require that short term disease activity is measured, but other outcome domains are not mandatory for licensing and marketing purposes. We aimed to identify whether any domains were underrepresented in RCTs of regular therapies for children with asthma over a 20 year period, and to examine what consistency there was between RCTs in the outcomes used to assess the domains.

Methodology/Principal Findings

By searching the Cochrane Central Register of Controlled Trials in January 2008, we identified all parallel-group RCTs, published between January 1988 and December 2007, which assessed inhaled corticosteroids (ICS) as regular therapy for children with asthma. We evaluated how frequently RCTs measured the following pre-defined domains: disease activity; disease damage; functional status; quality of life; health resource utilisation; and adverse effects of therapy. Our initial search identified 1668 abstracts, of which 412 were retrieved in full. 159 RCTs, of which 115 involved only children and 44 involved children and adults, were included in the review. Disease activity was measured in 157 RCTs, adverse effects of ICS in 135, functional status in 25, quality of life in 21, and health resource utilisation in 17. No RCT measured long term disease damage, although two used FEV1 as a measure of ‘lung growth’. RCTs were inconsistent in the outcomes used to measure the domains.

Conclusions

Short term disease activity is the most frequently measured outcome domain in RCTs in children with asthma. Effects of regular therapies on functional status, quality of life, and long term consequences of asthma are infrequently assessed. A core set of outcomes, developed using consensus techniques, would standardise the measurement of appropriate outcomes in these RCTs. Involving patients would identify outcomes which are most relevant from their perspective.