The usability of daytime and night-time heart rate dynamics as digital biomarkers of depression severity.

BACKGROUND: Alterations in heart rate (HR) may provide new information about physiological signatures of depression severity. This 2-year study in individuals with a history of recurrent major depressive disorder (MDD) explored the intra-individual variations in HR parameters and their relationship with depression severity. METHODS: Data from 510 participants (Number of observations of the HR parameters = 6666) were collected from three centres in the Netherlands, Spain, and the UK, as a part of the remote assessment of disease and relapse-MDD study. We analysed the relationship between depression severity, assessed every 2 weeks with the Patient Health Questionnaire-8, with HR parameters in the week before the assessment, such as HR features during all day, resting periods during the day and at night, and activity periods during the day evaluated with a wrist-worn Fitbit device. Linear mixed models were used with random intercepts for participants and countries. Covariates included in the models were age, sex, BMI, smoking and alcohol consumption, antidepressant use and co-morbidities with other medical health conditions. RESULTS: Decreases in HR variation during resting periods during the day were related with an increased severity of depression both in univariate and multivariate analyses. Mean HR during resting at night was higher in participants with more severe depressive symptoms. CONCLUSIONS: Our findings demonstrate that alterations in resting HR during all day and night are associated with depression severity. These findings may provide an early warning of worsening depression symptoms which could allow clinicians to take responsive treatment measures promptly.

Actigraph GT3X: validation and determination of physical activity intensity cut points.

The aims of this study were: to compare energy expenditure (EE) estimated from the existing GT3X accelerometer equations and EE measured with indirect calorimetry; to define new equations for EE estimation with the GT3X in youth, adults and older people; and to define GT3X vector magnitude (VM) cut points allowing to classify PA intensity in the aforementioned age-groups. The study comprised 31 youth, 31 adults and 35 older people. Participants wore the GT3X (setup: 1-s epoch) over their right hip during 6 conditions of 10-min duration each: resting, treadmill walking/running at 3, 5, 7, and 9 km · h⁻¹, and repeated sit-stands (30 times · min⁻¹). The GT3X proved to be a good tool to predict EE in youth and adults (able to discriminate between the aforementioned conditions), but not in the elderly. We defined the following equations: for all age-groups combined, EE (METs)=2.7406+0.00056 · VM activity counts (counts · min⁻¹)-0.008542 · age (years)-0.01380 · body mass (kg); for youth, METs=1.546618+0.000658 · VM activity counts (counts · min⁻¹); for adults, METs=2.8323+0.00054 · VM activity counts (counts · min⁻¹)-0.059123 · body mass (kg)+1.4410 · gender (women=1, men=2); and for the elderly, METs=2.5878+0.00047 · VM activity counts (counts · min⁻¹)-0.6453 · gender (women=1, men=2). Activity counts derived from the VM yielded a more accurate EE estimation than those derived from the Y-axis. The GT3X represents a step forward in triaxial technology estimating EE. However, age-specific equations must be used to ensure the correct use of this device.

Quantifying the lagged Poincaré plot geometry of ultrashort heart rate variability series: automatic recognition of odor hedonic tone.

The application of Poincaré plot analysis to characterize inter-beat interval dynamics has been successfully proposed in the scientific literature for the assessment of humans' physiological states and related aberrations. In this study, we proposed novel descriptors to trace the evolution of Poincaré plot shape over the lags. Their reliability in ultra-short cardiovascular series analysis was validated on synthetic inter-beat series generated through a physiologically plausible integral pulse frequency modulation model. Furthermore, we used the proposed approach for the investigation of the direct relationship between autonomic nervous system (ANS) dynamics and hedonic olfactory elicitation, in a group of 30 healthy subjects. Participants with a similar olfactory threshold were selected, and were asked to score 5-s stimuli in terms of arousal and valence levels according to the Russell's circumflex model of affect. Their ANS response was investigated in 35-s windows after the elicitation. Experimental results showed a gender-specific, high discriminant power of the proposed approach, discerning between pleasant and unpleasant odorants with an accuracy of 83.33% and 73.33% for men and for women, respectively. Graphical Abstract Olfaction plays a crucial role in our life and is strictly related to the Autonomic Nervous System (ANS) activity, which can be monitored studying Heart Rate Variability. We used the Lagged Poincare Plot approach to recognize gender-specific ANS response in 35-second windows after the elicitation through pleasant/unpleasant odorants.

A Multiclass Arousal Recognition using HRV Nonlinear Analysis and Affective Images.

This paper reports on a multiclass arousal recognition system based on autonomic nervous system linear and nonlinear dynamics during affective visual elicitation. We propose a new hybrid method based on Lagged Poincaré Plot (LPP) and symbolic analysis, hereinafter called LPPsymb. This tool uses symbolic analysis to evaluate the irregularity of the trends of Lagged Poincaré Plot (LPP) quantifiers over the lags, and is here applied to investigate complex Heart Rate Variability (HRV) changes during emotion stimuli. In the experimental protocol 22 healthy subjects were elicited through a passive visualization of affective images gathered from the international affective picture system. LPPsymb and standard HRV analysis (defined in time and frequency domains) were applied to HRV series of one minute length. Then, an ad-hoc pattern recognition algorithm based on quadratic discriminant classifier was implemented and validated through a leave-onesubject-out procedure. The best performance of the proposed classification algorithm for recognizing the four classes of arousal was obtained using nine features comprising heartbeat complex dynamics, achieving an accuracy of 71.59%.

A novel Heart Rate Variability analysis using Lagged Poincaré plot: A study on hedonic visual elicitation.

This paper reports on a novel method for the analysis of Heart Rate Variability (HRV) through Lagged Poincaré Plot (LPP) theory. Specifically a hybrid method, LPPsymb, including LPP quantifiers and related symbolic dynamics was proposed. LPP has been applied to investigate the autonomic response to pleasant and unpleasant pictures extracted from the International Affective Picture System (IAPS). IAPS pictures are standardized in terms of level of arousal, i.e. the intensity of the evoked emotion, and valence, i.e. the level of pleasantness/unpleasantness, according to the Circumplex model of Affects (CMA). Twenty-two healthy subjects were enrolled in the experiment, which comprised four sessions with increasing arousal level. Within each session valence increased from positive to negative. An ad-hoc pattern recognition algorithm using a Leave-One-Subject-Out (LOSO) procedure based on a Quadratic Discriminant Classifier (QDC) was implemented. Our pattern recognition system was able to classify pleasant and unpleasant sessions with an accuracy of 71.59%. Therefore, we can suggest the use of the LPPsymb for emotion recognition.

Investigation of Lagged Poincaré Plot reliability in ultra-short synthetic and experimental Heart Rate Variability series.

This study reports on the reliability of Lagged Poincaré Plot (LPP) parameters calculated from ultra-short cardiovascular time series (from 30 to 180 seconds). ity (HRV) signals, whereas a few studies have studied nonlinear approaches. Particularly, methods derived from the phase-space theory, especially the ones employing multi-lag analyses, are usually considered to be inaccurate with a low number of samples. Here we propose a comprehensive study about LPP, using both synthetic and real RR series. Specifically, we considered 109 5-minutes HRV series: 60 synthetic series generated through the Integral Pulse Frequency Modulation (IPFM) model and 49 experimental series acquired from healthy subjects during resting-state. Three parameters have been extracted through the ellipse-fitting method, SD1, SD2 and S, using ten values of lag. All LPP parameters were estimated by averaging estimates gathered from segments of 30, 120 and 180 seconds, and compared with the once from 5-minute series. Results showed Spearman's correlation coefficients higher than 0.9 in both synthetic and real series. In conclusion, SD1 gave promising results in terms of percentage absolute error, when it was extracted from series with a duration less than three minutes.

Nitrogenous compounds of interest in clinical nutrition.

The term "conditionally essential" (or semi-essential), initially applied to amino acids, has been generalized to other nutrients. A conditionally essential nutrient is a compound usually produced in adequate amounts by endogenous synthesis but that is exogenously required under certain circumstances. Thus, arginine, glutamine, cysteine, glycine, carnitine, choline, and polyamines are conditionally essential compounds. In addition, dietary nucleotides are considered semi-essential since some rapidly growing tissues such as the gut, bone marrow, and lymphocytes, preferentially use preformed purine and pyrimidine bases for nucleic acid synthesis. This review discusses the study of conditionally essential nitrogenous nutrients of interest in clinical nutrition. Among them we highlight arginine, involved in endothelial, immune, gastrointestinal, and renal functions, in reproduction, neonatal development, wound healing, and tumorigenicity; glutamine, necessary for maintaining bowel integrity, and with beneficial effects on catabolic states such as sepsis, infection, trauma, and cancer; and nucleotides, implicated in cell growth and differentiation, and with various effects on lipid metabolism, intestinal microbiota, and immune system.

Towards an objective measurement of emotional stress: Preliminary analysis based on heart rate variability.

This paper presents a study performed in 25 young healthy subjects measuring the evolution of heart rate variability (HRV) indices during emotional stress. Acute emotional stress was generated with a modified version of Trier Social Stress Test (TSST). The TSST comprises several tasks which include a memory test, anticipation of stress, public exposition, and an arithmetic task. Each task has different demanding conditions, carrying subjects' emotional stress to different states. An autogenic relaxation was done before TSST. Significant differences in HRV indices were observed in the arithmetic and memory task with respect to the relaxation stage. In particular during the arithmetic task, mean heart rate increased 22% (p-value <0.00001) the power in the very low frequency band increased 47% (p-value <0.00001 and normalized power in the low frequency (LF) band increased 19% (p-value <0.04). These results support a sympathetic activation during these tasks.

Attenuation of the influence of cardiolocomotor coupling in heart rate variability interpretation during exercise test.

During exercise test, cardiolocomotor coupling related components appear in heart rate variability (HRV), blurring its interpretation as autonomic nervous system (ANS) marker. These cardiolocomotor coupling related components are centered at the pedalling and running stride frequency, as well as at their aliases, and may overlap with the low frequency (LF) and high frequency (HF) components of HRV. In this work cardiolocomotor-related HRV components are studied during maximal exercise test on treadmill and cycle ergometer. Power in the bands related to cardiolocomotor coupling increases with exercise intensity in cycle ergometer but not in treadmill exercise test, where it displays higher values for all exercise intensities. A method is proposed to reduce the effect of this coupling in the interpretation of HRV. Evolution of the power in the low frequency (LF) and high frequency (HF) bands are studied after the proposed reduction of cardiolocomotor coupling, showing more significant changes with exercise intensity than before the method is applied.

Identification of patients prone to hypotension during hemodialysis based on the analysis of cardiovascular signals.

Intradialytic hypotension (IDH) is a major complication during hemodialysis treatment, and therefore it is highly desirable to identify, at an early stage during treatment, whether the patient is prone to IDH. Heart rate variability (HRV), blood pressure variability (BPV) and baroreflex sensitivity (BRS) were analyzed during the first 30 min of treatment to assess information on the autonomic nervous system. Using the sequential floating forward selection method and linear classification, the set of features with the best discriminative power was selected, resulting in an accuracy of 92.1%. Using a classifier based on the HRV features only, thereby avoiding that continuous blood pressure has to be recorded, accuracy decreased to 90.2%. The results suggest that an HRV-based classifier is useful for determining whether a patient is prone to IDH at the beginning of the treatment.

Depot leuprolide acetate dosage for sexual precocity.

Twenty-one children with early puberty have been evaluated to determine adequate dosage of depot leuprolide acetate. The minimal dosage of depot leuprolide acetate required, using intervals of 1.5 mg or less when given every 28 days, was determined. This dosage, as determined by suppression of gonadotropin responses to GnRH stimulation, was 4.14 +/- 1.33 mg (mean +/- SD) and 0.15 +/- 0.07 mg/kg.28 days. The dosage correlates with bone age and pubertal stage and is larger among patients with more advanced puberty. Five patients required a larger dosage from 5-10 months after initial suppression. Therefore, to monitor suppression, GnRH testing should be repeated at least at 6-month intervals. Samples 20 and 40 min after GnRH stimulation are sufficient to indicate adequacy of treatment, so an abbreviated test could be used.

Treatment of central precocious puberty: comparison of urinary gonadotropin excretion and gonadotropin-releasing hormone (GnRH) stimulation tests in monitoring GnRH analog therapy.

GnRH analogs (GnRH-a) have proven to be efficacious and have become the standard treatment for central precocious puberty (CPP). To confirm the diagnosis of CPP and to monitor the adequacy of hvpothalamic-pituitary-gonadal (HPG) axis suppression, GnRH stimulation testing has been essential. To determine whether 24-h urinary gonadotropin excretion could adequately assess HPG axis suppression, we compared the results of simultaneous GnRH stimulation tests and 24-h urinary gonadotropin determinations in 18 girls with CPP who were receiving GnRH-a therapy (leuprolide acetate, Depot-Lupron, TAP Pharmaceuticals). HPG axis suppression was defined as the absence of significant LH and FSH responses to GnRH stimulation. Simultaneous GnRH stimulation tests and urinary gonadotropin determinations had a concordance rate of 68% (42 of 62). The sensitivity and specificity of urinary LH determinations to detect inadequate HPG suppression were 75% and 64%, respectively. For urinary FSH determinations, the sensitivity and specificity were 90% and 28%, respectively. Hence, single timed urine collections lacked the sensitivity and specificity to assess HPG axis suppression and, thus, cannot replace GnRH stimulation tests for monitoring the adequacy of the GnRH-a dose.

Recovery of ovarian function after childbirth, lactation and sexual activity with relation to age of women.

The time for recovery of ovulation, lactation and initiation of sexual intercourse after childbirth was studied in 90 women, who were divided into three groups: 1) adolescents less than 19 years old (n = 30); 2) younger mothers 19 to 32 years old (n = 30); and 3) older women more than 32 years old (n = 30). No differences were found in the duration of breast-feeding or in the initiation of sexual intercourse among the three groups. The postpartum amenorrhea in lactating women was significantly longer than in nonlactating mothers. The amenorrhea was significantly less in younger women than in older mothers and tended to be lower than in adolescents. The time between delivery and detection of ovulation was significantly longer in women who breast-fed than in those who did not. Furthermore, this time was significantly shorter in younger women than in older mothers. The present work suggests that younger women had a quicker recovery of ovarian function than adolescents and older women.

Mesigyna once-a-month combined injectable contraceptive: experience in Latin America.

A phase III clinical study was carried out among 534 fertile Latin American women to evaluate cycle control, side effects, and contraceptive efficacy of a once-a-month combined injectable, Mesigyna, consisting of 50 mg norethisterone enanthate and 5 mg estradiol valerate. The pregnancy rate at 1 year was 0 per 100 woman-years for a total experience of 4688 woman-months. The overall discontinuation rate at one year was 17.9%. Discontinuation rate for bleeding problems was 5.1%. The Colombian women had a significant increase (p <0.001) in bleeding problems compared to other countries. The discontinuation rate for amenorrhea was 1.1%. There were no significant differences between the groups regarding discontinuation for other medical or non-medical reasons. Mean weight gain after one year of use was 1.02 kg. Mesigyna is an appropiate once-a-month injectable contraceptive for Latin American women since it is highly effective and its perception of normal menstrual bleeding is of importance in the Latin American population.

Time course of ECG depolarization and repolarization changes during ischemia in PTCA recordings.

OBJECTIVES: In this work we studied the temporal evolution of changes in the electrocardiogram (ECG) as a consequence of the induced ischemia during prolonged coronary angioplasty, comparing the time course of indexes reflecting depolarization and those reflecting repolarization. METHODS: We considered both local (measured at specific points of the ECG) and global (obtained from the Karhunen-Loève transform) indexes. In particular, the evolution of Q, R and S wave amplitudes during ischemia was analyzed with respect to classical indexes such as ST level. As a measurement of sensitivity we used an Ischemic Changes Sensor (ICS), which reflects the capacity of an index to detect changes in the ECG. RESULTS: The results showed that, in leads with low-amplitude ST-T complexes, the S wave amplitude was more sensitive in detecting ischemia than was the commonly used index ST60. It was found that in such leads the S wave amplitude initially exhibited a delayed response to ischemia when compared to ST60, but its performance was better from the second minute of occlusion. The global indexes describing the ST-T complex were, in terms of the ICS, superior to the S wave amplitude for ischemia detection. CONCLUSIONS: Ischemic ECG changes occur both at repolarization and depolarization, with alterations in the depolarization period appearing later in time. Local indexes are less sensitive to ischemia than global ones.

Coronary artery disease diagnosis based on exercise electrocardiogram indexes from repolarisation, depolarisation and heart rate variability.

Several indexes have been reported to improve the accuracy of exercise test electrocardiogram (ECG) analysis in the diagnosis of coronary artery disease (CAD), compared with the classical ST depression criterion. Some of them combine repolarisation measurements with heart rate (HR) information (such as the so-called ST/HR hysteresis); others are obtained from the depolarisation period (such as the Athens QRS score); finally, there are heart rate variability (HRV) indexes that account for the nervous system activity. The aim of this study was to identify the best exercise ECG indexes for CAD diagnosis. First, a method to automatically estimate repolarisation and depolarisation indexes in the presence of noise during a stress test was developed. The method is divided into three stages: first, a preprocessing step, where QRS detection, filtering and baseline beat rejection are applied to the raw ECG, prior to a weighted averaging; secondly, a post-processing step in which potentially noisy averaged beats are identified and discarded based on their noise variance; finally, the measurement step, in which ECG indexes are computed from the averaged beats. Then, a multivariate discriminant analysis was applied to classify patients referred for the exercise test into two groups: ischaemic (positive coronary angiography) and low-risk (Framingham risk index < 5%). HR-corrected repolarisation indexes improved the sensitivity (SE) and specificity (SP) of the classical exercise test (SE = 90%, SP = 79% against SE = 65%, SP = 66%). Depolarisation indexes also achieved an improvement over ST depression measurements (SE = 78%, SP = 81%). HRV indexes obtained the best classification results in our study population (SE = 94%, SP = 92%) by means of the very high-frequency power (VHF) (0.4-1 Hz) at stress peak.

[Intranasal administration of GnRH in the treatment of uterine myomatosis]. / Uso de análogos de GnRH por vía nasal en el tratamiento de miomatosis uterina.

Nine patients in which an intranasal GnRH agonist analog (napharelin acetate) was administered with the purpose of decreasing the size of the myomas, were studied. In all a decrement in uterine and myoma size was observed. The FSH levels decreased since the first treated cycle, whereas LH and E2 levels initially increase, but finally decreased. The patients had menstrual bleeding between four and eight weeks after napharelin withdrawal. The mentioned results elicit the effectivity of GnRH agonist analog for leomyomata treatment.

Cross time-frequency analysis for combining information of several sources: application to estimation of spontaneous respiratory rate from photoplethysmography.

A methodology that combines information from several nonstationary biological signals is presented. This methodology is based on time-frequency coherence, that quantifies the similarity of two signals in the time-frequency domain. A cross time-frequency analysis method, based on quadratic time-frequency distribution, has been used for combining information of several nonstationary biomedical signals. In order to evaluate this methodology, the respiratory rate from the photoplethysmographic (PPG) signal is estimated. The respiration provokes simultaneous changes in the pulse interval, amplitude, and width of the PPG signal. This suggests that the combination of information from these sources will improve the accuracy of the estimation of the respiratory rate. Another target of this paper is to implement an algorithm which provides a robust estimation. Therefore, respiratory rate was estimated only in those intervals where the features extracted from the PPG signals are linearly coupled. In 38 spontaneous breathing subjects, among which 7 were characterized by a respiratory rate lower than 0.15 Hz, this methodology provided accurate estimates, with the median error {0.00; 0.98} mHz ({0.00; 0.31}%) and the interquartile range error {4.88; 6.59} mHz ({1.60; 1.92}%). The estimation error of the presented methodology was largely lower than the estimation error obtained without combining different PPG features related to respiration.

Assessment of the dynamic interactions between heart rate and arterial pressure by the cross time-frequency analysis.

In this study, a framework for the characterization of the dynamic interactions between RR variability (RRV) and systolic arterial pressure variability (SAPV) is proposed. The methodology accounts for the intrinsic non-stationarity of the cardiovascular system and includes the assessment of both the strength and the prevalent direction of local coupling. The smoothed pseudo-Wigner-Ville distribution (SPWVD) is used to estimate the time-frequency (TF) power, coherence, and phase-difference spectra with fine TF resolution. The interactions between the signals are quantified by time-varying indices, including the local coupling, phase differences, time delay, and baroreflex sensitivity (BRS). Every index is extracted from a specific TF region, localized by combining information from the different spectra. In 14 healthy subjects, a head-up tilt provoked an abrupt decrease in the cardiovascular coupling; a rapid change in the phase difference (from 0.37 ± 0.23 to -0.27 ± 0.22 rad) and time delay (from 0.26 ± 0.14 to -0.16 ± 0.16 s) in the high-frequency band; and a decrease in the BRS (from 23.72 ± 7.66 to 6.92 ± 2.51 ms mmHg(-1)). In the low-frequency range, during a head-up tilt, restoration of the baseline level of cardiovascular coupling took about 2 min and SAPV preceded RRV by about 0.85 s during the whole test. The analysis of the Eurobavar data set, which includes subjects with intact as well as impaired baroreflex, showed that the presented methodology represents an improved TF generalization of traditional time-invariant methodologies and can reveal dysfunctions in subjects with baroreflex impairment. Additionally, the results also suggest the use of non-stationary signal-processing techniques to analyze signals recorded under conditions that are usually supposed to be stationary.

Photoplethysmography pulse rate variability as a surrogate measurement of heart rate variability during non-stationary conditions.

In this paper we assessed the possibility of using the pulse rate variability (PRV) extracted from the photoplethysmography signal as an alternative measurement of the HRV signal in non-stationary conditions. The study is based on analysis of the changes observed during a tilt table test in the heart rate modulation of 17 young subjects. First, the classical indices of HRV analysis were compared to the indices from PRV in intervals where stationarity was assumed. Second, the time-varying spectral properties of both signals were compared by time-frequency (TF) and TF coherence analysis. Third, the effect of replacing PRV with HRV in the assessment of the changes of the autonomic modulation of the heart rate was considered. Time-invariant HRV and PRV indices showed no statistically significant differences (p > 0.05) and high correlation (>0.97). Time-frequency analysis revealed that the TF spectra of both signals were highly correlated (0.99 +/- 0.01); the difference between the instantaneous power, in the LF and HF bands, obtained from HRV and PRV was small (<10(-3) s(-2)) and their temporal patterns were highly correlated (0.98 +/- 0.04 and 0.95 +/- 0.06 in the LF and HF bands, respectively) and TF coherence in the LF and HF bands was high (0.97 +/- 0.04 and 0.89 +/- 0.08, respectively). Finally, the instantaneous power in the LF band was observed to significantly increase during head-up tilt by both HRV and PRV analysis. These results suggest that although some differences in the time-varying spectral indices extracted from HRV and PRV exist, mainly in the HF band associated with respiration, PRV could be used as a surrogate of HRV during non-stationary conditions, at least during the tilt table test.