Fear induced complexity loss in the electrocardiogram of flight phobics: A multiscale entropy analysis

In this study we explored the changes in the variability and complexity of the electrocardiogram (ECG) of flight phobics (N = 61) and a matched non-phobic control group (N = 58) when they performed a paced breathing task and were exposed to flight related stimuli. Lower complexity/entropy values were expected in phobics as compared to controls. The phobic system complexity as well as the heart rate variability (HRV) were expected to be reduced by the exposure to fearful stimuli. The multiscale entropy (MSE) analysis revealed lower entropy values in phobics during paced breathing and exposure, and a complexity loss was observed in phobics during exposure to threatening situations. The expected HRV decreases were not found in this study. The discussion is focused on the distinction between variability and complexity measures of the cardiac output, and on the usefulness of the MSE analysis in the field of anxiety disorders.     

Comparison of real beat-to-beat signals with commercially available 4 Hz sampling on the evaluation of foetal heart rate variability

Evaluation of foetal heart rate (FHR) variability is an essential part of foetal monitoring, but a precise quantification of this parameter depends on the quality of the signal. In this study, we compared real FHR beat-to-beat signals with 4 Hz sampling provided by commercial foetal monitors on linear and nonlinear indices and analysed their clinical implications. Simultaneous acquisition of beat-to-beat signals and their 4 Hz sampling rate counterparts was performed using a scalp electrode, during the last hour of labour in 21 fetuses born with an umbilical artery blood (UAB) pH ≥ 7.20 and 6 born with an UAB pH < 7.20. For each case, the first and last 10 min segments were analysed, using time and frequency domain linear, and nonlinear FHR indices, namely mean FHR, low frequency, high frequency, approximate, sample and multiscale entropy. Significant differences in variability indices were found between beat-to-beat and 4 Hz sampled signals, with a lesser effect seen with 2 Hz sampling. These differences did not affect physiological changes observed during labour progression, such as decreased entropy and linear time domain indices, and increased frequency domain indices. However, significant differences were found in the discrimination between fetuses born with different UAB pHs, with beat-to-beat sampling providing better results in linear indices and 4 Hz sampling better results in entropy indices. In conclusion, different FHR sampling frequencies can significantly affect the quantification of variability indices. This needs to be taken into account in the interpretation of FHR variability and in the development of new equipment.     

多尺度熵在心率变异信号复杂性分析中的应用

介绍了在样本熵基础上提出的多尺度熵的概念、性质与应用,给出了一种计算多尺度熵的算法,并且通过实际算例说明了多尺度熵在表征信号复杂性方面的能力及其在心率变异信号研究中的初步应用.     

Complexity of human postural control in young and older adults during prolonged standing

Aging is known to have a degrading influence on many structures and functions of the human sensorimotor system. The present work assessed aging-related changes in postural sway using fractal and complexity measures of the center of pressure (COP) dynamics with the hypothesis that complexity and fractality decreases in the older individuals. Older subjects (68 ± 4 years) and young adult subjects (28 ± 7 years) performed a quiet stance task (60 s) and a prolonged standing task (30 min) where subjects were allowed to move freely. Long-range correlations (fractality) of the data were estimated by the detrended fluctuation analysis (DFA); changes in entropy were estimated by the multi-scale entropy (MSE) measure. The DFA results showed that the fractal dimension was lower for the older subjects in comparison to the young adults but the fractal dimensions of both groups were not different from a 1/f noise, for time intervals between 10 and 600 s. The MSE analysis performed with the typically applied adjustment to the criterion distance showed a higher degree of complexity in the older subjects, which is inconsistent with the hypothesis that complexity in the human physiological system decreases with aging. The same MSE analysis performed without adjustment showed no differences between the groups. Taken all results together, the decrease in total postural sway and long-range correlations in older individuals are signs of an adaptation process reflecting the diminishing ability to generate adequate responses on a longer time scale.     

Assessment of autonomic function in the late term fetus: The effects of sex and state

Researchers have reported associations between fetal sex and heart rate (FHR) and heart rate variability (FHRV) but rarely in the context of fetal behavioral sleep state. We examined differences in measures of fetal autonomic function by sex and sleep state. Fetal abdominal ECG monitoring technology was used to measure FHR and two measures of FHRV—standard deviation of FHR (SD) and beat-to-beat variability (RMSSD). FHR and movement patterns were also recorded with standard Doppler ultrasound monitor technology employed to code sleep states. Data were collected from 82 healthy fetuses ranging from 36 to 39 weeks gestation. A one-way MANOVA showed that FHR was significantly lower and SD was significantly higher for males than females. Independent samples t tests found that these sex differences were only in the active sleep state. There were no significant differences in RMSSD by sex. Repeated measures MANOVA for a subset that exhibited more than one state (N = 22) showed that SD was significantly different by state. RMSSD showed a marginally significant sleep state difference. In conclusion, fetal sex differences in HR and HRV may indicate more mature autonomic functioning in near-term males than females and fetal sleep state can influence abdominal fECG derived measures of FHR and FHRV.     

Computerised electronic foetal heart rate monitoring in labour: automated contraction identification

The foetal heart rate (FHR) response to uterine contractions is crucial to detect foetal distress by electronic FHR monitoring during labour. We are developing a new automated system (OxSys) for decision support in labour, using the Oxford database of intrapartum FHR records. We describe here a novel technique for automated detection of uterus contractions. In addition, we present a comparison of the new method with four other computerised approaches. During training, OxSys achieved sensitivity above 95% and positive predictive value (PPV) of up to 90% for traces of good quality. During testing, OxSys achieved sensitivity = 87% and PPV = 75%. For comparison, a second clinical expert obtained sensitivity = 93% and PPV = 80%, and all other computerised approaches achieved lower values. It was concluded that the proposed method can be employed with confidence in our study on foetal health assessment in labour and future OxSys development.     

Haemodynamic changes in IUGR fetus with chronic hypoxia evaluated by fetal heart-rate monitoring and Doppler measurement of blood flow velocity

The measurement of fetal blood flow velocity and 24 h monitoring of fetal heart-rate (FHR) using a computer were performed to clarify the haemodynamics of growth-retarded fetuses with chronic hypoxia. One hundred normal-growth and 18 growth-retarded fetuses were analysed. All the growth-retarded fetuses with chronic hypoxia were characterised by abnormal blood flow velocity waveforms (with the pulsatility index in the descending aorta below the −1·0 SD and in the middle cerebral artery above the +1·0 SD for our reference range, from 100 normal-growth fetuses). In the latter, the incidence of accelerations of defined size and variability in FHR patterns showed a diurnal variation after 30 weeks' gestation. The initial change in FHR patterns during hypoxia in 11 growth-retarded fetuses, resulting in fetal distress, was a derangement of diurnal variations in FHR patterns, followed by a decrease in variability. A rapid increase in blood flow velocity in the middle cerebral artery with the advance of hypoxia was observed before the onset of distress. Maternal low-dose oxygen inhalation elicited a temporary increase in FHR variability in the growth-retarded but not in normal fetuses. Re-inhalation after 1 h elicited a similar change, suggesting that intermittent rather than continuous, oxygen inhalation may be more effective.     

Linear and nonlinear fetal heart rate analysis of normal and acidemic fetuses in the minutes preceding delivery

Linear and nonlinear fetal heart rate (FHR) indices, namely mean FHR, interval index (II), very low, low and high frequencies, approximate (ApEn) and sample entropy (SampEn), were computed, immediately before delivery, in the initial and final FHR tracing segments, from 48 normal, 10 mildly acidemic and 10 moderate-to-severely acidemic fetuses. Progression of labor was associated with a significant increase in linear frequency domain indices whereas nonlinear indices were significantly decreased. Moderate-to-severe fetal acidemia was associated with a significant decrease in nonlinear indices. The best discrimination between moderate-to-severe acidemic fetuses and the remaining cases was obtained combining II and ApEn(2,0.15), with a specificity of 71% and a sensitivity of 80%. These findings support the hypothesis of increased autonomic nervous system activity in the final minutes of labor and of decreased central nervous system activity, both in the final minutes of labor and in moderate-to-severe acidemic fetuses.     

Fear induced complexity loss in the electrocardiogram of flight phobics: a multiscale entropy analysis

In this study we explored the changes in the variability and complexity of the electrocardiogram (ECG) of flight phobics (N=61) and a matched non-phobic control group (N=58) when they performed a paced breathing task and were exposed to flight related stimuli. Lower complexity/entropy values were expected in phobics as compared to controls. The phobic system complexity as well as the heart rate variability (HRV) were expected to be reduced by the exposure to fearful stimuli. The multiscale entropy (MSE) analysis revealed lower entropy values in phobics during paced breathing and exposure, and a complexity loss was observed in phobics during exposure to threatening situations. The expected HRV decreases were not found in this study. The discussion is focused on the distinction between variability and complexity measures of the cardiac output, and on the usefulness of the MSE analysis in the field of anxiety disorders.     

Atrial fibrillation organization: quantification of propofol effects

The effect of conventional i.v. anaesthetic agents on atrial fibrillation (AF) dynamics has not been fully addressed. We aim to evaluate whether the most frequently used intravenous anaesthetic agent, propofol, modifies AF organization parameters. Multiple and simultaneous intraatrial bipolar recordings from 27 patients in AF were analyzed before and after infusing a propofol bolus. Signal organization parameters were determined using time and frequency domain analysis. Non-linear analysis was also performed to determine signal entropy. Linear analysis showed that AF becomes more organized in right atrial recordings after infusing propofol, increasing interelectrode correlation (difference of 0.017 ± 0.005), with the contrary effect on the left atrial dipoles (difference of −0.015 ± 0.009, p = 0.008). Entropy analysis showed similar findings, achieving a statistical significance of p = 0.001 with Shannon Entropy.     

Clinicopathologic implications of TNFAIP3/A20 deletions in extranodal NK/T‐cell lymphoma

The A20/Tumor necrosis factor‐alpha‐induced protein 3 (A20/TNFAIP3) is a negative regulator of NF‐κB signaling. We analyzed the clinicopathologic implications of A20 deletions in extranodal NK/T‐cell lymphoma (NKTL). Fluorescence in situ hybridization analysis of the A20 gene was performed using archived formalin‐fixed tissues in 49 cases of NKTL. Among the 49 NKTL patients (median age, 48 y [10‐79]), stage I‐II (75% [36/48]) and upper aerodigestive tract (UAT)‐origin (84% [41/49]) were predominant. All A20 deletions were monoallelic and found in cases with UAT‐origin, accounting for 18% (9/49) of all NKTLs and 22% (9/41) of UAT‐origin. In univariate analysis, overall survival (OS) and progression‐free survival (PFS) were associated with stage, international prognostic index (IPI), B symptoms and number of extranodal sites, and OS with performance status and non‐UAT‐origin, but none with A20 deletion. In multivariate analysis, IPI predicted OS (P = .008 [HR = 23.4]) and PFS (P = .005 [HR = 34.0]). Risk was divided by B symptoms (P = .001 [OS]; P = .034 [PFS]) in low IPI subset (n = 36), and by A20 deletion (P = .029 [PFS]) in high IPI subset (n = 13). These results suggest a clinicopathologic implication of A20 in progression of NKTL.     

Phylogenetic analysis of small ruminant lentivirus (SRLV) in Italian flocks reveals the existence of novel genetic subtypes

In order to investigate the genetic heterogeneity of small ruminant lentivirus (SRLV) isolates in Italy, 55 clinical samples collected between 1998 and 2010 were analysed. The phylogenetic study was based on analysis of gag–pol sequences. Our findings revealed that the SRLVs belonged to the subtype A9 (n = 3, sheep), B1 (n = 5, goat), B2 (n = 3, sheep) and E2 (n = 5, goat). Interestingly, 39 isolates from both sheep and goat, significantly differed from all the other SRLVs previously described and formed two separate clusters within genotypes A and B tentatively named A11 (n = 27, goat and sheep) and B3 (n = 12, goat and sheep), which have never been shown before. These results revealed a marked diversity among Italian field SRLV strains which might reflect the absence of any systematic control measures.     

Multivariate short-term heart rate variability: a pre-diagnostic tool for screening heart disease

This study has aimed to develop a novel pre-diagnostic tool for primary care screening of heart disease based on multivariate short-term heart rate variability (HRV) analyzed by linear (time and frequency domain) and nonlinear methods (compression entropy (CE), detrended fluctuation analysis (DFA), Poincaré plot analysis, symbolic dynamics) applied to 5-min ECG segments. Firstly, we applied HRV analysis to separate healthy subjects (REF) from heart disease patients (PAT). Then to optimize the results, we subdivided both groups according to gender: REF (♂ = 78, ♀ = 53) versus PAT (♂ = 378, ♀ = 115). Finally, we divided REF and PAT into two age subgroups (30–50 years vs. 51-70 years of age) to consider the influence of age on HRV. Heart disease patients were classified using a scoring system based on cut-off values calculated from all HRV indices obtained from the REF. After combining the optimum indices from all different analyzing methods, sensitivities of more than 72% and a specificity of 100% in all subgroups were revealed. Nonlinear indices proved to be better for discriminating heart disease patients from healthy subjects. Multivariate short-term HRV, analyzed by both linear and nonlinear methods appears to be a suitable pre-diagnostic tool for screening heart disease in primary care settings.     

Targeted copy number screening highlights an intragenic deletion of WDR63 as the likely cause of human occipital encephalocele and abnormal CNS development in zebrafish

Congenital malformations affecting the neural tube can present as isolated malformations or occur in association with other developmental abnormalities and syndromes. Using high‐resolution copy number screening in 66 fetuses with neural tube defects, we identified six fetuses with likely pathogenic mutations, three aneuploidies (one trisomy 13 and two trisomy 18) and three deletions previously reported in NTDs (one 22q11.2 deletion and two 1p36 deletions) corresponding to 9% of the cohort. In addition, we identified five rare deletions and two duplications of uncertain significance including a rare intragenic heterozygous in‐frame WDR63 deletion in a fetus with occipital encephalocele. Whole genome sequencing verified the deletion and excluded known pathogenic variants. The deletion spans exons 14–17 resulting in the expression of a protein missing the third and fourth WD‐repeat domains. These findings were supported by CRISPR/Cas9‐mediated somatic deletions in zebrafish. Injection of two different sgRNA‐pairs targeting relevant intronic regions resulted in a deletion mimicking the human deletion and a concomitant increase of abnormal embryos with body and brain malformations (41%, n = 161 and 62%, n = 224, respectively), including a sac‐like brain protrusion (7% and 9%, P < 0.01). Similar results were seen with overexpression of RNA encoding the deleted variant in zebrafish (total abnormal; 46%, n = 255, P < 0.001) compared with the overexpression of an equivalent amount of wild‐type RNA (total abnormal; 3%, n = 177). We predict the in‐frame WDR63 deletion to result in a dominant negative or gain‐of‐function form of WDR63. These are the first findings supporting a role for WDR63 in encephalocele formation.     

Biology and grading of pleomorphic xanthoastrocytoma—what have we learned about it?

Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytoma predominantly affecting children and young adults. We performed comprehensive genomic characterization on a cohort of 67 patients with histologically defined PXA (n = 53, 79%) or anaplastic PXA (A‐PXA, n = 14, 21%), including copy number analysis (ThermoFisher Oncoscan, n = 67), methylation profiling (Illumina EPIC array, n = 43) and targeted next generation sequencing (n = 32). The most frequent alterations were CDKN2A/B deletion (n = 63; 94%) and BRAF p.V600E (n = 51, 76.1%). In 7 BRAF p.V600 wild‐type cases, alternative driver alterations were identified involving BRAF, RAF1 and NF1. Downstream phosphorylation of ERK kinase was uniformly present. Additional pathogenic alterations were rare, with TERT, ATRX and TP53 mutations identified in a small number of tumors, predominantly A‐PXA. Methylation‐based classification of 46 cases utilizing a comprehensive reference tumor allowed assignment to the PXA methylation class in 40 cases. A minority grouped with the methylation classes of ganglioglioma or pilocytic astrocytoma (n = 2), anaplastic pilocytic astrocytoma (n = 2) or control tissues (n = 2). In 9 cases, tissue was available from matched primary and recurrent tumors, including 8 with anaplastic transformation. At recurrence, two tumors acquired TERT promoter mutations and the majority demonstrated additional non‐recurrent copy number alterations. Methylation class was preserved at recurrence. For 62 patients (92.5%), clinical follow‐up data were available (median follow‐up, 5.4 years). Overall survival was significantly different between PXA and A‐PXA (5‐year OS 80.8% vs. 47.6%; P = 0.0009) but not progression‐free survival (5‐year PFS 59.9% vs. 39.8%; P = 0.05). WHO grade remained a strong predictor of overall survival when limited to 38 cases defined as PXA by methylation‐based classification. Our data confirm the importance of WHO grading in histologically and epigenetically defined PXA. Methylation‐based classification may be helpful in cases with ambiguous morphology, but is largely confirmatory in PXA with well‐defined morphology.     

Association of interferon‐alpha gene polymorphisms with chronic hepatitis B virus infection

In this study, the association between the risk of chronic hepatitis B virus infection and the polymorphisms within promoter regions of IFN‐α1 and five genes was explored. This association study was performed on 180 Thai patients with chronic HBV infection [hepatocellular carcinoma (HCC) = 65 and non‐HCC = 115], 173 individuals with self‐limited HBV infection and 140 healthy controls. Our results showed that the A allele of ‐1823G/A SNP within IFNA1 gene was significantly associated with an increased risk of chronic HBV infection as compared to healthy individuals and self‐limited HBV group [OR (95% CI) = 2.20 (1.51–3.19), P = 0.000014 and OR (95% CI) = 1.61 (1.12–2.33), P = 0.0073, respectively]. The effect of A allele was similar to autosomal recessive in which the presence of AA genotype when compared to GG and GA conferred the OR of 2.79 (95% CI = 1.72–4.52, P = 0.0000085). By multifactor dimensionality reduction analysis, we found the interaction between IFNA5 (‐2529) and IFNA1 (‐1823) genes that gave the risk to chronic HBV infection, with the OR (95% CI) of the high‐risk to low‐risk group was 2.79 (1.77–4.40), P < 0.0001. However, further study in functional significance is required.     

The association of CTLA‐4 A49G polymorphism with colorectal cancer risk in a Chinese Han population

Cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) is expressed in T cells and plays an important role in the regulation of T cell. CTLA‐4 has long been considered to be associated with various kinds of diseases. With the attempt to examine the association between CTLA‐4 A49G polymorphism and colorectal cancer risk in a Chinese Han population, we employed TaqMan assay to genotype the CTLA‐4 A49G polymorphism in 311 colorectal cancer cases and 389 cancer‐free controls. We found evidence of the association between CTLA‐4 A49G polymorphism and colorectal cancer risk (GG vs. AA: OR = 2.01, 95% CI = 1.29–3.07, P = 0.002; GA vs. AA: OR = 2.32, 95% CI = 1.53–3.57, P = 0.001; GA + GG vs. AA: OR = 2.16, 95% CI = 1.46–3.21, P = 0.001). Next, we performed a meta‐analysis to comprehensively examine the association between CTLA‐4 A49G polymorphism and colorectal cancer risk. We found a significant association between CTLA‐4 A49G polymorphism and colorectal cancer risk among Asians, which is consistent with our result. However, we found no evidence for the association between CTLA‐4 A49G polymorphism and colorectal cancer risk among Caucasians. In conclusion, we demonstrated that the CTLA‐4 A49G polymorphism increased the susceptibility of colorectal cancer in Asian population.     

Weakened long-range correlation of renal sympathetic nerve activity in Wistar rats after anaesthesia

In this study we employed multiscale entropy (MSE) measurement to assess the long-range temporal correlation (LRTC) of multifibre renal sympathetic nerve activity (RSNA) signals in conscious and anaesthetized Wistar rats. It was found that both groups presented more complex MSE profiles than an uncorrelated process. Moreover, the results of MSE analysis of RSNA demonstrated that the entropy values, derived from the conscious group, increased on small time scales and then stabilized to a relatively constant value, however, the entropy measure, derived from animals with anaesthesia, almost monotonically decreased. The present study shows that while LRTC in the temporal dynamics of energy fluctuations of RSNA does not implicate a unique mechanism, the data for the first time provide evidence of much less temporal correlation in anaesthetized condition. This suggests the fractal properties of underlying dynamical system have been effectively eliminated by anaesthesia. These results demonstrate that apparently random fluctuations in multifibre RSNA are dictated by a complex deterministic process that imparts "long-term" memory to the dynamic system. However, this memory is significantly weakened by anaesthesia.     

Multiscale entropy and detrended fluctuation analysis of QT interval and heart rate variability during normal pregnancy

Pregnancy leads to physiological changes in various parameters of the cardiovascular system. The aim of this study was to investigate longitudinal changes in the structure and complexity of heart rate variability (HRV) and QT interval variability during the second half of normal gestation. We analysed 30-min high-resolution ECGs recorded monthly in 32 pregnant women, starting from the 20th week of gestation. Heart rate and QT variability were quantified using multiscale entropy (MSE) and detrended fluctuation analyses (DFA). DFA of HRV showed significantly higher scaling exponents towards the end of gestation (p<0.0001). MSE analysis showed a significant decrease in sample entropy of HRV with progressing gestation on scales 1-4 (p<0.05). MSE analysis and DFA of QT interval time series revealed structures significantly different from those of HRV with no significant alteration during the second half of gestation. In conclusion, pregnancy is associated with increases in long-term correlations and regularity of HRV, but it does not affect QT variability. The structure of QT time series is significantly different from that of RR time series, despite its close physiological dependence.     

Utility of a standardized protocol for submitting clinically suspected endometrial polyps to the pathology laboratory

The purpose of the study is to assess whether a protocol for submitting clinically suspected endometrial polyps will improve the detection rate of polyps and evaluation of the background endometrium. A retrospective review from 1999 to 2015 was performed. Cases were divided into (1) polyps and curettings placed in 2 containers (separate, n = 61) and (2) polyps and curettings placed in 1 container (combined, n = 80). Polyps were identified in 100% of cases in the separate compared with 95% in the combined group (P = .62). The background endometrium was evaluable in 79% of cases in the combined compared to 90% in the separate group (P = .07). The frequency of hyperplasia without atypia, atypical hyperplasia, and carcinoma was 4.4%, 3.6%, and 1.5%, respectively. In conclusion, the enhanced rate of polyp detection and evaluation of the background endometrium in the separate group is minimal. This supports the recommendation of submitting endometrial polyps and curettings combined in 1 container.