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1.
Pharmaceutics ; 16(3)2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38543201

RESUMO

The treatment of peri-implantitis is challenging in the clinical practice of implant dentistry. With limited therapeutic options and drug resistance, there is a need for alternative methods, such as photodynamic therapy (PDT), which is a minimally invasive procedure used to treat peri-implantitis. This study evaluated whether the type of photosensitizer used influences the results of inflammatory control, reduction in peri-implant pocket depth, bleeding during probing, and reduction in bone loss in the dental implant region. We registered the study in the PROSPERO (International Prospective Register of Systematic Review) database. We searched three main databases and gray literature in English without date restrictions. In vivo randomized clinical studies involving individuals with peri-implantitis, smokers, patients with diabetes, and healthy controls were included. PDT was used as the primary intervention. Comparators considered mechanical debridement with a reduction in pocket depth as the primary outcome and clinical attachment level, bleeding on probing, gingival index, plaque index, and microbiological analysis as secondary outcomes. After reviewing the eligibility criteria, we included seven articles out of 266. A great variety of photosensitizers were observed, and it was concluded that the selection of the most appropriate type of photosensitizer must consider the patient's characteristics and peri-implantitis conditions. The effectiveness of PDT, its effects on the oral microbiome, and the clinical patterns of peri-implantitis may vary depending on the photosensitizer chosen, which is a crucial factor in personalizing peri-implantitis treatment.

2.
PLoS One ; 18(11): e0294904, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38019810

RESUMO

Profiling the variability related to the estrous cycle is essential for assessing depressive-like behavior and screening drugs. This study compares circulating plasma corticosterone levels [CORT] and behavioral alterations in mice exposed to sucrose preference, forced swimming, and tail suspension tests (SPT, FST, and TST, respectively). While SPT exposure did not significantly alter [CORT], FST and TST showed notable changes. Mice in the TST exhibited increased movement and decreased immobility time compared to FST, suggesting a lower likelihood of depressive-like behavior in male mice. Notably, during the proestrus phase, female mice displayed the highest tendency for depressive-like behavior and elevated [CORT], but similar response to antidepressants (imipramine and fluoxetine). The inherent stress of the FST and TST tasks appears to influence [CORT] as well as depressant and antidepressant effects. These comparisons provide valuable insights for further behavioral phenotyping, model sensitivity assessment, and deepen our neurobiological understanding of depression in the context of drug screening.


Assuntos
Antidepressivos , Fluoxetina , Camundongos , Masculino , Feminino , Animais , Antidepressivos/farmacologia , Fluoxetina/farmacologia , Depressão/tratamento farmacológico , Imipramina/farmacologia , Comportamento Animal , Natação , Modelos Animais de Doenças , Corticosterona , Elevação dos Membros Posteriores
3.
Front Physiol ; 13: 946402, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36160852

RESUMO

Background: Obesity impairs lung function and mechanics and leads to low-grade inflammation, but the effects of combined physical exercise (CPE) on that are unknown. Methods: We investigated the effects of 12 weeks of combined physical exercise (aerobic + resistance training), in non-obese (n = 12), overweight (n = 17), and obese grade I (n = 11) women. Lung function and lung mechanics were evaluated. The systemic immune response was evaluated by whole blood analysis and biomarker measurements, while pulmonary fibrotic biomarkers were evaluated in the breath condensate. Result: CPE improved forced vital capacity (FVC) % (p < 0.001) and peak expiratory flow (PEF) % (p < 0.0003) in the obese group; resistance of the respiratory system (R5Hz) in non-obese (p < 0.0099), overweight (p < 0.0005), and obese (p < 0.0001) groups; resistance of proximal airways (R20Hz) in non-obese (p < 0.01), overweight (p < 0.0009), and obese (p < 0.0001) groups; resistance of distal airways (R5Hz-R20Hz) in non-obese (p < 0.01), overweight (p < 0.0012), and obese (p < 0.0001) groups; reactance of the respiratory system (X5Hz) in non-obese (p < 0.01), overweight (p < 0.0006), and obese (p < 0.0005) groups; impedance of the respiratory system (Z5Hz) in non-obese (p < 0.0099), overweight (p < 0.0005), and obese (p < 0.0001) groups; central resistance (RCentral) in non-obese (p < 0.01), overweight (p < 0.001), and obese (p < 0.0003) groups; and the peripheral resistance (RPeripheral) in non-obese (p < 0.03), overweight (p < 0.001), and obese (p < 0.0002) groups. CPE reduced the pro-fibrotic IGF-1 levels in BC in overweight (p < 0.0094) and obese groups (p < 0.0001) and increased anti-fibrotic Klotho levels in BC in obese (p < 0.0001) groups, and reduced levels of exhaled nitric oxide in overweight (p < 0.03) and obese (p < 0.0001) groups. Conclusion: CPE improves lung function, mechanics, and pulmonary immune response in overweight and obese grade I women by increasing anti-fibrotic protein Klotho and reducing pro-fibrotic IGF-1.

4.
Int J Clin Pract ; 75(8): e14347, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33977587

RESUMO

AIMS: To test the hypothesis of a semi-supervised home physical exercise programme that is likely to improve the functional mobility and quality of life (QOL) of elderly in the community. METHODS: This trial included elderly adults (88% female) aged 60 years or older and who were sedentary and without cognitive decline. The participants were randomly assigned to an intervention group (IG, home physical exercise and sleep hygiene) and a control group (CG, sleep hygiene). The International Questionnaire on Physical Activity, mental state mini-exam, World Health Organization Quality of Life Instrument-Older Adults Module (WHOQOL-OLD) and the Timed Up and Go (TUG) tests were conducted before and after the 12-week intervention period. RESULTS: The study was concluded with 125 elderly participants. Anthropometric data were indicative of pre-obesity, with a mean body mass index of 27.3 ± 4, a low-income socio-economic profile (78% ≤ 2 SM) and low schooling rates (76% ≤ 3 years of study). Most of the elderly (87%) were considered physically active with IPAQ > 150 min/week. The group of elderly people who performed the home physical exercise programme showed a significant improvement in functional mobility according to the time of execution of the TUG test before (9.1 ± 2) and after (7.1 ± 1) with an average reduction of 2 ± 1 s (P < .01). The difference in the QOL of the elderly who participated in the exercise protocol was also observed, verified through the WHOQOL-OLD global score, which presented an initial score of 85 ± 10, changing to 90.4 ± 9 after the intervention. CONCLUSION: Semi-supervised physical home exercise is safe and effective in improving the functional mobility and QOL of sedentary elderly people in the community.


Assuntos
Exercício Físico , Qualidade de Vida , Idoso , Terapia por Exercício , Feminino , Humanos , Masculino , Estudos Prospectivos , Inquéritos e Questionários
5.
J Aging Phys Act ; 29(6): 952-958, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33863853

RESUMO

This study investigated the acute blood pressure (BP) effects of different exercise modalities in older adults with hypertension. Sixty volunteers were randomly assigned (n = 15/group) into different exercise protocols: resistance, bike, water-based exercise (WE), and a control session-all for ∼45 min. Clinic BP measurements were taken before, immediately after, and 15 and 30 min after protocols. The data were analyzed by one-way analysis of variance; generalized estimating equations, following Bonferroni post hoc (p < .05). Immediately after exercise, the systolic BP (SBP) increased in all exercise protocols (resistance exercise = Δ10.3, bike exercise = Δ5.8, WE = Δ9.5 mmHg; p < .001), while the diastolic BP was not altered. Afterward, the SBP reached the value observed before exercise. In Minute 30, only WE presented a significant reduction for SBP (WE = Δ-4.6 mmHg; p < .05). This study has important clinical implications in hemodynamic safety for acute BP increases immediately after exercises, as well as, in the SBP, reduction benefits for older adults with hypertension.


Assuntos
Hipertensão , Hipotensão Pós-Exercício , Idoso , Pressão Sanguínea/fisiologia , Exercício Físico/fisiologia , Terapia por Exercício/métodos , Humanos , Hipertensão/terapia
6.
Naunyn Schmiedebergs Arch Pharmacol ; 392(9): 1071-1083, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31049606

RESUMO

The search for new drugs remains an important focus for the safe and effective treatment of cardiovascular diseases. Previous evidence has shown that choline analogs can offer therapeutic benefit for cardiovascular complications. The current study investigates the effects of 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol (LQFM032) on cardiovascular function and cholinergic-nitric oxide signaling. Synthesized LQFM032 (0.3, 0.6, or 1.2 mg/kg) was administered by intravenous and intracerebroventricular routes to evaluate the potential alteration of mean arterial pressure, heart rate, and renal sympathetic nerve activity of normotensive and hypertensive rats. Vascular function was further evaluated in isolated vessels, while pharmacological antagonists and computational studies of nitric oxide synthase and muscarinic receptors were performed to assess possible mechanisms of LQFM032 activity. The intravenous and intracerebroventricular administration of LQFM032 elicited a temporal reduction in mean arterial pressure, heart rate, and renal sympathetic nerve activity of rats. The cumulative addition of LQFM032 to isolated endothelium-intact aortic rings reduced vascular tension and elicited a concentration-dependent relaxation. Intravenous pretreatment with L-NAME (nitric oxide synthase inhibitor), atropine (nonselective muscarinic receptor antagonist), pirenzepine, and 4-DAMP (muscarinic M1 and M3 subtype receptor antagonist, respectively) attenuated the cardiovascular effects of LQFM032. These changes may be due to a direct regulation of muscarinic signaling as docking data shows an interaction of choline analog with M1 and M3 but not nitric oxide synthase. Together, these findings demonstrate sympathoinhibitory, hypotensive, and antihypertensive effects of LQFM032 and suggest the involvement of muscarinic receptors.


Assuntos
Anti-Hipertensivos/farmacologia , Hipotensão/fisiopatologia , Piperazinas/farmacologia , Pirazóis/farmacologia , Receptor Muscarínico M1/fisiologia , Receptor Muscarínico M3/fisiologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Atropina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/induzido quimicamente , Masculino , Antagonistas Muscarínicos/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Piperidinas/farmacologia , Pirenzepina/farmacologia , Ratos Endogâmicos SHR , Ratos Wistar
7.
Front Psychiatry ; 10: 192, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31031652

RESUMO

Background: Depression is associated with a decreased cardiorespiratory fitness, and physical activity [PA] levels, higher rates of obesity, and dysfunction in autonomic control of heart rate [HR]. However, these parameters were mostly recorded with indirect methods. Thus, the aim of the current study was to investigate the relationships between depression scores and objective measures of body fatness, autonomic indices (i.e. HRV and HRR), cardiorespiratory fitness and PA levels; and subsequently to present the best predictive models of depression scores for this population, based on these variables. Methods: Thirty-five non-exercising women (26-43 years; maximal oxygen consumption [VO2max] ~ 17.4-38.3 mL/kg/min) volunteered for participation in this study. All participants responded to the Beck Depression Inventory [DBI] and were evaluated for body mass index [BMI], percentage of body fat, sum of skinfolds, and VO2max. Subsequently, over four consecutive days, an orthostatic test and a submaximal exercise on a cycle ergometer were performed to record HRV and HRR, respectively. In addition, incidental PA was recorded during 5 consecutive days using accelerometers. Results: depression scores were related to VO2max (r = -0.446, p = 0.007) and the sum of skinfolds (r = 0.434, p = 0.009). Several stepwise multiple linear regression models were performed and only VO2max was revealed as an independent predictor of the Beck scores (ß = -0.446, R 2 = 0.199, p = 0.007). Conclusion: The present study revealed that VO2max and the sum of skinfolds were moderately related to depression scores, while VO2max was the only independent predictor of depression scores in female workers.

8.
PLoS One ; 13(12): e0209834, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30589905

RESUMO

Cycling is a sport which requires great physical effort from athletes. The stress and anxiety of competition might interfere greatly with performance, by impacting the autonomic system. Physiological alterations, such as situations that irritate, frighten or excite the individual can cause a stress response, defined as a response of the organism to reestablish the homeostasis, regardless of its relationship to a sports situation. The aim of this study was to present data on the autonomic changes induced by precompetitive stress in cyclists and their relation with physical fitness and anxiety. Twelve healthy cyclists aged between 18 and 40 years, with previous experience in competition at the regional level, participated in the study. Heart rate variability (HRV) and physical fitness (body mass index, body fat and aerobic capacity) were measured 5 days before the Mountain Bike championship and remeasured 45 minutes before the start of the race (HRV and Anciety). Paired T test, effect size and correlational test were used. Cycling competition is a stressful situation capable of altering autonomic and hemodynamic parameters. We observed the increase in SDNN, reflecting an increase in sympathetic autonomic control. There were correlations between physical fitness with some autonomic parameters, while anxiety correlated with the years of experience in competition.


Assuntos
Sistema Nervoso Autônomo/fisiologia , Sistema Nervoso Autônomo/fisiopatologia , Aptidão Física/fisiologia , Aptidão Física/psicologia , Adolescente , Adulto , Ansiedade/fisiopatologia , Atletas/psicologia , Atletas/estatística & dados numéricos , Frequência Cardíaca/fisiologia , Hemodinâmica/fisiologia , Humanos , Esportes/fisiologia , Esportes/psicologia , Adulto Jovem
9.
PeerJ ; 6: e5804, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30356977

RESUMO

BACKGROUND: The ability to jump has been related to muscle strength and power, speed and amplitude of the lower limbs movements, and specifically for the elderly, the vertical jump has been shown to be a good predictor of functional capacity and risk of falling. The use of a mobile application (App) which can measure the vertical jump (i.e., iPhone App My Jump) has recently emerged as a simple, cheap and very practical tool for evaluation of jump ability. However, the validity of this tool for the elderly population has not been tested yet. The elderly usually perform very low jumps and therefore the signal-to-noise ratio may compromise the validity and reliability of this method. Thus, the aim of the current study was to verify the validity and reliability of the iPhone App "My Jump" for the evaluation of countermovement jump (CMJ) height within an elderly population. METHODS: After familiarization, 41 participants performed three CMJs assessed via a contact mat and the My Jump App. The intraclass correlation coefficient (ICC) was used to verify the relative reliability, while the coefficient of variation (CV%) and the typical error of measurement (TEM) were used to verify the absolute reliability. Pearson's correlation coefficient was used to verify the strength of the relationship between methods (i.e., concurrent validity), a Bland-Altman plot to show their agreement, and the Student's t-test to identify systematic bias between them. For reliability analyses, all jumps were considered (i.e., 123). All jumps (i.e., 123), the average height of each attempt (i.e., 41), and the highest jump, were considered for validity analyses. RESULTS: The CMJ height of the highest jump was 10.78 ± 5.23 cm with contact mat, and 10.87 ± 5.32 with My Jump App, with an identified systematic bias of 0.096 cm (P = 0.007). There was a nearly perfect correlation between methods (r = 0.999; P = 0.000, in all cases) with a very good agreement observed (0.3255 to -0.5177 cm, 0.2797 to -0.5594 cm, and 0.3466 to -0.6264 cm, for highest jump height, average jump height, and all jump heights, respectively). The ICC of the My Jump App was 0.948, the TEM was 1.150 cm, and the CV was 10.10%. CONCLUSION: Our results suggest that the My Jump App is a valid and reliable tool compared to the contact mat for evaluating vertical jump performance in the elderly. Therefore, it allows a simple and practical assessment of lower limbs' power in this population. For the elderly, as well as for other populations with low jumping heights, the highest jump height and the average jump height could be used indistinctly.

10.
Open Access J Sports Med ; 8: 155-160, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28721108

RESUMO

PURPOSE: The aim of this study was to investigate the effect of self-paced active recovery (AR) and passive recovery (PR) on blood lactate removal following a 200 m freestyle swimming trial. PATIENTS AND METHODS: Fourteen young swimmers (with a training frequency of 6-8 sessions per week) performed two maximal 200 m freestyle trials followed by 15 minutes of different recovery methods, on separate days. Recovery was performed with 15 minutes of passive rest or 5 minutes of passive rest and 10 minutes of self-paced AR. Performance variables (trial velocity and time), recovery variables (distance covered and AR velocity), and physiological variables (blood lactate production, blood lactate removal, and removal velocity) were assessed and compared. RESULTS: There was no difference between trial times in both conditions (PR: 125.86±7.92 s; AR: 125.71±8.21 s; p=0.752). AR velocity was 69.10±3.02% of 200 m freestyle trial velocity in AR. Blood lactate production was not different between conditions (PR: 8.82±2.47 mmol L-1; AR: 7.85±2.05 mmol L-1; p=0.069). However, blood lactate removal was higher in AR (PR: 1.76±1.70 mmol L-1; AR: 4.30±1.74 mmol L-1; p<0.001). The velocity of blood lactate removal was significantly higher in AR (PR: 0.18±0.17 mmol L-1 min-1; AR: 0.43±0.17 mmol L-1 min-1; p<0.001). CONCLUSION: Self-paced AR shows a higher velocity of blood lactate removal than PR. These data suggest that athletes may be able to choose the best recovery intensity themselves.

11.
PLoS One ; 11(3): e0150679, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26934357

RESUMO

PURPOSE: Given the co-existence of post-activation potentiation (PAP) and fatigue within muscle, it is not known whether PAP could influence performance and pacing during distance running by moderating fatigue. The aim of this study was to assess the influence of PAP on pacing, jumping and other physiological measures during a self-paced 30 km trial. METHODS: Eleven male endurance-trained runners (half-marathon runners) volunteered to participate in this study. Runners participated in a multi-stage 30 km trial. Before the trial started, determination of baseline blood lactate (bLa) and countermovement jump (CMJ) height was performed. The self-paced 30 km trial consisted of 6 × 5 km splits. At the end of each 5 km split (60 s break), data on time to complete the split, CMJ height, Rating of Perceived Exertion (RPE) and blood lactate were collected while heart rate was continuously monitored. RESULTS: There was a significant decrease in speed (e.g. positive pacing strategy after the 4th split, p<0.05) with a progressive increase in RPE throughout the trial. Compared with baseline, CMJ height was significantly (p<0.05) greater than baseline and was maintained until the end of the trial with an increase after the 5th split, concomitant with a significant reduction in speed and an increase in RPE. Significant correlations were found between ΔCMJ and ΔSPEED (r = 0.77 to 0.87, p<0.05) at different time points as well as between RPE and speed (r = -0.61 to -0.82, p<0.05). CONCLUSION: Our results indicates that fatigue and potentiation co-exist during long lasting endurance events, and that the observed increase in jump performance towards the end of the trial could be reflecting a greater potentiation potentially perhaps counteracting the effects of fatigue and preventing further reductions in speed.


Assuntos
Desempenho Atlético , Fadiga Muscular , Resistência Física , Corrida , Adulto , Frequência Cardíaca , Humanos , Ácido Láctico/sangue , Masculino , Percepção , Adulto Jovem
12.
Front Physiol ; 7: 648, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28082914

RESUMO

The aim of this study was to examine the influence of physical fitness on cardiac autonomic control in passengers prior to, during and following commercial flights. Twenty-two, physically active men (36.4 ± 6.4 years) undertook assessments of physical fitness followed by recordings of 24-h heart rate (HR), heart rate variability (HRV), and blood pressure (BP) on a Control (no flight) and Experimental (flight) day. Recordings were analyzed using a two-way analysis of variance for repeated measures with relationships between variables examined via Pearson product-moment correlation coefficients. Compared to the Control day, 24-h HR was significantly greater (>7%) and HRV measures (5-39%) significantly lower on the Experimental day. During the 1-h flight, HR (24%), and BP (6%) were increased while measures of HRV (26-45%) were reduced. Absolute values of HRV during the Experimental day and relative changes in HRV measures (Control-Experimental) were significantly correlated with measures of aerobic fitness (r = 0.43 to 0.51; -0.53 to -0.52) and body composition (r = -0.63 to -0.43; 0.48-0.61). The current results demonstrated that short-term commercial flying significantly altered cardiovascular function including the reduction of parasympathetic modulations. Further, greater physical fitness and lower body fat composition were associated with greater cardiac autonomic control for passengers during flights. Enhanced physical fitness and leaner body composition may enable passengers to cope better with the cardiovascular stress and high allostatic load associated with air travel for enhanced passenger well-being.

13.
Aerosp Med Hum Perform ; 86(10): 875-80, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26564674

RESUMO

BACKGROUND: Physical fitness and dehydration are factors that may influence cardiac autonomic control. We aimed to verify the influence of these factors on cardiac autonomic control before, during, and after a flight. METHODS: At the same time of day, 11 healthy fighter pilots recorded several 1-h bouts of heart rate (HR) activity during a non- (control) and a training flight day. Autonomic control of HR was examined via time domain and non-linear heart rate variability (HRV) analyses. The level of dehydration during the flight was evaluated by changes in hematocrit, while aerobic capacity, muscular strength, and body fatness were the physical fitness components evaluated. RESULTS: The flight induced a significant reduction in most parameters of HRV during flight time when compared to the control day. However, no differences were found between the days before the flight, while the root mean square of successive differences (RMSSD) of HR was the only parameter significantly reduced (11.05 ± 7.7%) after the flight. Significant correlations were observed between the sample entropy of HR during flight and aerobic capacity (r = 0.777) and body fatness (r = -0.617). Correlations between dehydration and changes in HRV (RMSSD and SD1) were also identified (r = -0.61 to -0.81). CONCLUSION: The current results demonstrated significant relationships between aerobic capacity, body fatness, and hydration status on autonomic control of HR during and after flights. No relationship to muscular strength was observed. Future studies may further elucidate the impact of these factors on pilot training in order to accommodate flight's stressors and enhance performance.


Assuntos
Aeronaves , Desidratação/fisiopatologia , Frequência Cardíaca/fisiologia , Militares/estatística & dados numéricos , Aptidão Física/fisiologia , Adulto , Medicina Aeroespacial , Brasil , Tolerância ao Exercício , Humanos , Masculino , Medicina Militar
14.
Front Physiol ; 6: 405, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26779034

RESUMO

Previous studies have suggested that physical activity (PA) levels and cardiorespiratory fitness (CRF) impact on the autonomic control of heart rate (HR). However, previous studies evaluating PA levels did not discriminate between incidental PA and regular exercise. We hypothesized that incidental PA "per se" would influence cardiac autonomic indices as assessed via HR variability (HRV) and HR recovery (HRR) in non-exercisers. Thus, the objective of this study was to investigate the relationships between objective PA levels, CRF, and cardiac autonomic indices in adult, regular non-exercising female workers. After familiarization with procedures and evaluation of body composition, 21 women completed a submaximal cycling test and evaluation of HRR on four different days. Resting (2-min seated and standing) and ambulatory (4-h) HRV were also recorded. Levels of PA were assessed by accelerometry over five consecutive days (i.e., Wednesday to Sunday). Maximum oxygen consumption (VO2max) was measured as an index of CRF. As reliability was low to moderate for most HR measures, relationships between these and PA and CRF were examined using the 4-day average measures. Significant correlations were identified between post-exercise HRR in the first min with various PA indices (daily moderate PA, daily vigorous PA, and the sum of vigorous and very vigorous daily PA). Additionally, VO2max was significantly correlated to HRV but not to HRR. The current results indicated that CRF was influential in enhancing HRV while incidental or non-exercise based PA was associated with greater autonomic reactivation in adult overweight women. Therefore, both CRF and non-exercise based PA contribute significant but diverse effects on cardiac health. The use of 4-day averages instead of single measures for evaluation of autonomic control of HR may provide a better indication of regular cardiac autonomic function that remains to be refined.

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